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Red Book ®

ATLAS
of pediatric infectious diseases

3rd Edition
Editor: Carol J. Baker, MD, FAAP

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Contents
Preface.......................................................................................................................................................... VII
1/Actinomycosis...............................................................................................................................................1
2/Adenovirus Infections.................................................................................................................................4
3/Amebiasis.......................................................................................................................................................7
4/Amebic Meningoence­phalitis and Keratitis (Naegleria fowleri, Acanthamoeba
species, and Balamuthia mandrillaris)................................................................................................. 13
5/Anthrax........................................................................................................................................................18
6/Arboviruses (Including California serogroup, chikungunya, Colorado tick fever,
eastern equine encephalitis, Japanese encephalitis, Powassan, St. Louis encephalitis,
tick-borne encephalitis, Venezuelan equine encephalitis, western equine
encephalitis, and yellow fever viruses) ................................................................................................24
7/Arcanobacterium ­haemolyticum Infections...........................................................................................33
8/Ascaris lumbricoides Infections............................................................................................................... 35
9/Aspergillosis................................................................................................................................................38
10/Astrovirus Infections...............................................................................................................................43
11/Babesiosis...................................................................................................................................................45
12/Bacillus cereus Infections........................................................................................................................49
13/Bacterial Vaginosis...................................................................................................................................51
14/Bacteroides and ­Prevotella Infections...................................................................................................53
15/Balantidium coli ­Infections (Balantidiasis)..........................................................................................56
16/Baylisascaris Infections...........................................................................................................................58
17/Infections With ­Blastocystis hominis and Other Subtypes...............................................................62
18/Blastomycosis............................................................................................................................................64
19/Bocavirus...................................................................................................................................................66
20/Borrelia Infections (Relapsing Fever)...................................................................................................67
21/Brucellosis.................................................................................................................................................70
22/Burkholderia Infections..........................................................................................................................73
23/Campylobacter Infections.......................................................................................................................76
24/Candidiasis................................................................................................................................................79
25/Cat-scratch Disease (Bartonella henselae)............................................................................................88
26/Chancroid..................................................................................................................................................93
27/Chlamydophila (formerly Chlamydia) ­pneumoniae...........................................................................95
28/Chlamydophila (formerly Chlamydia) psittaci (Psittacosis, Ornithosis, Parrot Fever)................97
29/Chlamydia trachomatis...........................................................................................................................99
30/Botulism and Infant ­Botulism (Clostridium botulinum).................................................................104
31/Clostridial Myonecrosis (Gas Gangrene)...........................................................................................109
32/Clostridium difficile................................................................................................................................111
33/Clostridium perfringens Food Poisoning............................................................................................114
34/Coccidioidomycosis...............................................................................................................................116
35/Coronaviruses, Including SARS and MERS......................................................................................122
36/Cryptococcus neoformans and Cryptococcus gattii Infections (Cryptococcosis).........................126

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IV CONTENTS

37/Cryptosporidiosis...................................................................................................................................129
38/Cutaneous Larva Migrans....................................................................................................................134
39/Cyclosporiasis......................................................................................................................................... 136
40/Cytomegalovirus Infection.................................................................................................................. 138
41/Dengue ....................................................................................................................................................145
42/Diphtheria...............................................................................................................................................149
43/Ehrlichia, Anaplasma, and Related Infections (Human Ehrlichiosis,
Anaplasmosis, and Related Infections).............................................................................................. 154
44/Enterovirus (­Nonpoliovirus) (Group A and B Coxsackieviruses, ­
Echoviruses, Numbered Enteroviruses)............................................................................................160
45/Epstein-Barr Virus ­Infections (Infectious Mononucleosis)............................................................165
46/Escherichia coli and Other Gram-Negative Bacilli (Septicemia and
Meningitis in Neonates).......................................................................................................................169
47/Escherichia coli Diarrhea (Including Hemolytic Uremic Syndrome)............................................ 174
48/Fungal Diseases .....................................................................................................................................179
49/Fusobacterium Infections (Including Lemierre Disease)................................................................183
50/Giardia intestinalis (­formerly Giardia lamblia and Giardia duodenalis)
Infections (Giardiasis)...........................................................................................................................186
51/Gonococcal Infections...........................................................................................................................190
52/Granuloma Inguinale (Donovanosis).................................................................................................198
53/Haemophilus influenzae Infections.....................................................................................................200
54/Hantavirus Pulmonary Syndrome......................................................................................................207
55/Helicobacter pylori ­Infections............................................................................................................... 213
56/Hemorrhagic Fevers Caused by Arenaviruses.................................................................................. 215
57/Hemorrhagic Fevers Caused by Bunyaviruses..................................................................................218
58/Hemorrhagic Fevers Caused by Filoviruses: Ebola and Marburg.................................................221
59/Hepatitis A..............................................................................................................................................226
60/Hepatitis B...............................................................................................................................................230
61/Hepatitis C...............................................................................................................................................238
62/Hepatitis D..............................................................................................................................................242
63/Hepatitis E.............................................................................................................................................. 244
64/Herpes Simplex......................................................................................................................................246
65/Histoplasmosis .......................................................................................................................................258
66/Hookworm Infections (Ancylostoma duodenale and Necator ­americanus)................................264
67/Human Herpesvirus 6 (Including Roseola) and 7............................................................................268
68/Human Herpesvirus 8...........................................................................................................................271
69/Human Immunodeficiency Virus Infection.....................................................................................273
70/Influenza..................................................................................................................................................294
71/Isosporiasis (now ­designated as ­Cystoisosporiasis)..........................................................................306
72/Kawasaki Disease ..................................................................................................................................309
73/Kingella kingae Infections..................................................................................................................... 317
74/Legionella pneumophila Infections...................................................................................................... 319
75/Leishmaniasis.........................................................................................................................................323

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CONTENTS V

76/Leprosy.....................................................................................................................................................330
77/Leptospirosis........................................................................................................................................... 335
78/Listeria monocytogenes Infections (Listeriosis).................................................................................339
79/Lyme Disease (Lyme Borreliosis, Borrelia burgdorferi I­ nfection).................................................343
80/Lymphatic Filariasis (Bancroftian, Malayan, and Timorian)......................................................... 355
81/Lymphocytic ­Choriomeningitis.......................................................................................................... 359
82/Malaria.....................................................................................................................................................361
83/Measles.....................................................................................................................................................372
84/Meningococcal Infections....................................................................................................................378
85/Human Metapneumovirus...................................................................................................................385
86/Microsporidia Infections (Microsporidiosis)....................................................................................386
87/Molluscum Contagiosum.....................................................................................................................389
88/Mumps.....................................................................................................................................................392
89/Mycoplasma pneumoniae and Other Mycoplasma Species Infections..........................................396
90/Nocardiosis.............................................................................................................................................401
91/Norovirus and Other Human Calicivirus ­Infections .....................................................................404
92/Onchocerciasis (River Blindness, Filariasis).....................................................................................405
93/Human Papillomaviruses.....................................................................................................................407
94/Paracoccidioidomycosis (South American Blastomycosis)............................................................411
95/Paragonimiasis....................................................................................................................................... 413
96/Parainfluenza Viral ­Infections............................................................................................................416
97/Parasitic Diseases...................................................................................................................................420
98/Parvovirus B19 (Erythema Infectiosum, Fifth Disease)..................................................................430
99/Pasteurella Infections............................................................................................................................ 435
100/Pediculosis Capitis (Head Lice).........................................................................................................437
101/Pediculosis Corporis (Body Lice)......................................................................................................441
102/Pediculosis Pubis (Pubic Lice, Crab Lice)........................................................................................443
103/Pertussis (­W hooping Cough)............................................................................................................445
104/Pinworm Infection (Enterobius vermicularis)................................................................................452
105/Pityriasis Versicolor (Tinea Versicolor)............................................................................................ 455
106/Plague.....................................................................................................................................................457
107/Pneumococcal Infections...................................................................................................................464
108/Pneumocystis jiroveci Infections........................................................................................................472
109/Poliovirus Infections...........................................................................................................................476
110/Prion Diseases: T ­ ransmissible Spongiform Encephalopathies.....................................................481
111/Q Fever (Coxiella burnetii Infection)................................................................................................485
112/Rabies.....................................................................................................................................................488
113/Rat-bite Fever........................................................................................................................................492
114/Respiratory Syncytial Virus ..............................................................................................................494
115/Rickettsial Diseases..............................................................................................................................498
116/Rickettsialpox.......................................................................................................................................500
117/Rocky Mountain ­Spotted Fever.........................................................................................................502

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VI CONTENTS

118/Rotavirus Infections............................................................................................................................508
119/Rubella...................................................................................................................................................510
120/Salmonella Infections..........................................................................................................................516
121/Scabies....................................................................................................................................................524
122/Schistosomiasis.....................................................................................................................................529
123/Shigella Infections................................................................................................................................ 535
124/Smallpox (Variola)...............................................................................................................................539
125/Sporotrichosis ......................................................................................................................................545
126/Staphylococcal Infections...................................................................................................................548
127/Group A Streptococcal Infections.....................................................................................................568
128/Group B Streptococcal Infections.....................................................................................................582
129/Non–Group A or B ­Streptococcal and ­Enterococcal Infections..................................................586
130/Strongyloidiasis (Strongyloides stercoralis)......................................................................................591
131/Syphilis...................................................................................................................................................594
132/Tapeworm Diseases (Taeniasis and Cysticercosis).........................................................................611
133/Other Tapeworm ­Infections (Including Hydatid Disease)............................................................616
134/Tetanus (Lockjaw)................................................................................................................................ 619
135/Tinea Capitis (Ringworm of the Scalp)............................................................................................622
136/Tinea Corporis (Ringworm of the Body).........................................................................................626
137/Tinea Cruris (Jock Itch).......................................................................................................................629
138/Tinea Pedis and Tinea Unguium (Athlete’s Foot, Ringworm of the Feet).................................631
139/Toxocariasis (Visceral Toxocariasis [previously Visceral Larva Migrans];
Ocular Toxocariasis [­previously Ocular Larva Migrans])..............................................................634
140/Toxoplasma gondii ­Infections (Toxoplasmosis)..............................................................................637
141/Trichinellosis (Trichinella spiralis and Other Species)..................................................................647
142/Trichomonas vaginalis Infections (Trichomoniasis)......................................................................651
143/Trichuriasis (Whipworm Infection).................................................................................................655
144/African Trypanosomiasis (African Sleeping Sickness).................................................................657
145/American Trypanosomiasis (Chagas Disease)................................................................................660
146/Tuberculosis..........................................................................................................................................664
147/Diseases Caused by Nontuberculous Mycobacteria (Environmental
Mycobacteria, Mycobacteria Other Than Mycobacterium tuberculosis)......................................686
148/Tularemia..............................................................................................................................................693
149/Endemic Typhus (Murine Typhus)...................................................................................................698
150/Epidemic Typhus (Louseborne or Sylvatic Typhus).......................................................................700
151/Varicella-Zoster Virus Infections......................................................................................................703
152/Cholera (Vibrio cholerae)....................................................................................................................712
153/Other Vibrio Infections.......................................................................................................................716
154/West Nile Virus....................................................................................................................................718
155/Yersinia enterocolitica and Yersinia pseudo­tuberculosis Infections
(Enteritis and Other Illnesses).............................................................................................................723
Index............................................................................................................................................................. 727

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VII

Preface
The American Academy of Pediatrics (AAP) Red Book® Atlas of Pediatric Infectious Diseases,
3rd Edition, is a summary of key disease information from the AAP Red Book®: 2015 Report of
the Committee on Infectious Diseases. It is intended to be a study guide for students, residents,
and practitioners.
The visual representations of common and atypical clinical manifestations of infectious diseases
provide diagnostic information not found in the print version of the Red Book. The juxtaposition
of these visuals with a summary of the clinical features, epidemiology, diagnostic methods, and
treatment information hopefully will serve as a training tool and a quick reference. The Red Book
Atlas is not intended to provide detailed treatment and management information but rather a
big-picture approach that can be refined by consulting reference texts or infectious disease
­specialists. Complete disease and treatment information from the AAP can be found at http://
redbook.solutions.aap.org, the electronic version of the Red Book.
This Red Book Atlas could not have been completed without the superb assistance of Peter Lynch,
Barrett Winston, Jason Crase, Theresa Wiener, and Peg Mulcahy at the AAP and of those physi-
cians who photographed disease manifestations in their patients and shared these with the AAP.
Some diseases are rarely seen today because of improved preventive strategies, especially immuni-
zation programs. While photographs can’t replace hands-on experience, they have helped me to
consider the likelihood of a correct diagnosis, and I hope this will be so for the reader. I also want
to thank those individuals at the Centers for Disease Control and Prevention who have generously
provided many photographs of the etiologic agents, vectors, and life cycles of parasites and proto-
zoa relevant to these largely domestic infections.
The study of pediatric infectious diseases has been a challenging and ever-changing professional
life that has brought me great joy. To gather information with my ears, eyes, and hands (the his-
tory and physical examination), to place this into the context of relevant epidemiology and incu-
bation period, and then to select a few appropriate diagnostic studies is still exciting for me.
Putting these many pieces together and arriving at the correct diagnosis is akin to solving a crime.
On many occasions, just seeing the clue (a characteristic rash, an asymmetry, a swelling) will solve
the medical puzzle, lead to recovery with the proper management, and bring the satisfaction
almost nothing can replace. It is my hope that the readers of the third edition of the Red Book
Atlas might find a similar enthusiasm for the field.
Carol J. Baker, MD, FAAP
Editor

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Actinomycosis 1

1 Etiology

Actinomycosis The most common species causing human


­disease is Actinomyces israelii.
Clinical Manifestations
A israelii and at least 5 other Actinomyces
Actinomycosis results from pathogen intro- ­species cause human disease. All are slow-
duction following a breakdown in mucocuta- growing, microaerophilic or facultative
neous protective barriers. Spread within the ­anaerobic, gram-positive, filamentous branch-
host is by direct invasion of adjacent tissues, ing bacilli. They can be part of normal oral,
typically forming sinus tracts that cross tis- gastrointestinal tract, or vaginal flora. Actino­
sue planes. myces species frequently are copathogens in
There are 3 common anatomic sites of infec- tissues harboring multiple other anaerobic or
tion. Cervicofacial is most common, often aerobic species. Isolation of Aggregatibacter
occurring after tooth extraction, oral surgery, (Actinobacillus) actinomycetemcomitans, fre-
or other oral/facial trauma, or even from cari- quently detected with Actinomyces species,
ous teeth. Localized pain and induration may may predict the presence of actinomycosis.
progress to cervical abscess and “woody hard” Epidemiology
nodular lesions (“lumpy jaw”), which can
develop draining sinus tracts, usually at the Actinomyces species occur worldwide, being
angle of the jaw or in the submandibular components of endogenous oral and gastroin-
region. Infection may contribute to chronic testinal tract flora. Actinomyces species are
tonsillar airway obstruction. Thoracic disease opportunistic pathogens (reported in patients
most commonly is secondary to aspiration of with HIV and chronic granulomatous disease),
oropharyngeal secretions but may be an exten- with disease usually following penetrating
sion of cervicofacial infection. It occurs rarely (including human bite wounds) and nonpen-
after esophageal disruption secondary to sur- etrating trauma. Infection is uncommon in
gery or nonpenetrating trauma. Thoracic infants and children, with 80% of cases occur-
­presentation includes pneumonia, which can ring in adults. The male to female ratio in
be complicated by abscesses, empyema, and, ­children is 1.5 to 1. Overt, microbiologically
rarely, pleurodermal sinuses. Focal or multi­ confirmed, monomicrobial disease caused by
focal mediastinal and pulmonary masses may Actinomyces species has become rare in the
be mistaken for tumors. Abdominal actino­ era of antimicrobial agents.
mycosis is usually attributable to penetrating Incubation Period
trauma or intestinal perforation. The appendix
Several days to several years.
and cecum are the most common sites; symp-
toms are similar to appendicitis. Slowly devel- Diagnostic Tests
oping masses may simulate abdominal or
Only specimens from normally sterile sites
retroperitoneal neoplasms. Intra-abdominal
should be submitted for culture. Microscopic
abscesses and peritoneal-dermal draining
demonstration of beaded, branched, gram-­
sinuses occur eventually. Chronic localized
positive bacilli in purulent material or tissue
disease often forms draining sinus tracts with
specimens suggests the diagnosis. Acid-fast
purulent discharge. Other sites of infection
staining can distinguish Actinomyces species,
include the liver, pelvis (which, in some cases,
which are acid-fast negative, from Nocardia
has been linked to use of intrauterine devices),
species, which are variably acid-fast positive.
heart, testicles, and brain (which is usually
Yellow “sulfur granules” visualized microscop-
associated with a primary pulmonary focus).
ically or macroscopically in drainage or locula-
Noninvasive primary cutaneous actinomycosis
tions of purulent material also suggest the
has occurred.
diagnosis. A Gram stain of “sulfur granules”
discloses a dense aggregate of bacterial fila-
ments mixed with inflammatory debris.
Immunofluorescent stains for Actinomyces

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2 Actinomycosis

species are available, as well as polymerase effective as intravenous therapy for cases of
chain reaction assay and 16s rRNA sequencing cervicofacial disease. Amoxicillin, erythromy-
for tissue specimens. cin, clindamycin, doxycycline, and tetracycline
are alternative antimicrobial choices. All Acti­
Treatment
nomyces appear resistant to ciprofloxacin and
Initial therapy should include intravenous pen- metronidazole. Surgical drainage or debride-
icillin G or ampicillin for 4 to 6 weeks followed ment is often a necessary adjunct to medical
by high doses of oral penicillin (up to 2 g/d for management and may allow for a shorter
adults), usually for a total of 6 to 12 months. ­duration of antimicrobial treatment.
Exclusively oral therapy has been reported as

Image 1.2
Tissue showing filamentous branching rods of
Actinomyces israelii (Brown and Brenn stain).
Image 1.1
Actinomyces species have fastidious growth
A sulfur granule from an actinomycotic abscess requirements. Staining of a crushed sulfur
(hematoxylin-eosin stain). While pathognomonic granule reveals branching bacilli.
of actinomycosis, granules are not always
present. A Gram stain of sulfur granules shows a
dense reticulum of filaments.

Image 1.4
A 10-year-old boy with chronic pulmonary,
Image 1.3 abdominal, and lower extremity abscesses
A brain heart infusion agar plate culture of with chronic draining sinus tracts from which
Actinomyces species, magnification x573, at Actinomyces israelii was isolated. Prolonged
10 days of incubation. Courtesy of Centers for antimicrobial treatment and surgical drainage
Disease Control and Prevention. were required for resolution of this
infectious process.

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Actinomycosis 3

Image 1.5 Image 1.6


Actinomycotic abscesses of the thigh of the boy An 8-month-old boy with pulmonary actino­
in Image 1.4. Actinomyces infections are often mycosis, an uncommon infection in infancy
polymicrobial. Aggregatibacter (Actinobacillus) that may follow aspiration. As in this infant,
actinomycetemcomitans, one of the HACEK most cases of actinomycosis are caused by
group of organisms, may accompany Actinomyces Actinomyces israelii.
israelii and may cause endocarditis.

Image 1.7 Image 1.8


Periosteal reaction along the left humeral shaft Clubbing of the thumb and fingers of the
(diaphysis) in the 8-month-old boy in Image 1.6, 8-month-old boy in images 1.6 and 1.7 with
with pulmonary actinomycosis. The presence of chronic pulmonary actinomycosis. Blood
clubbing with this chronic suppurative pulmonary cultures were repeatedly negative without
infection and absence of heart disease suggests clinical signs of endocarditis. Courtesy of
pulmonary fibrosis contributed to this infant’s Edgar O. Ledbetter, MD, FAAP.
pulmonary hypertrophic osteoarthropathy.
Courtesy of Edgar O. Ledbetter, MD, FAAP.

Image 1.10
The resected right lower lobe, diaphragm, and
portion of the liver in a 3-year-old previously
healthy girl with an unknown source for her
Image 1.9 pulmonary actinomycosis. Courtesy of Carol J.
Actinomyces cervical abscess in a 6-month-old Baker, MD, FAAP.
girl. Courtesy of Benjamin Estrada, MD.

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4 Adenovirus Infections

2 pharyngoconjunctival fever have been attrib-


uted to water exposure from contaminated
Adenovirus Infections swimming pools and fomites, such as shared
Clinical Manifestations towels. Health care–associated transmission of
adenoviral respiratory tract, conjunctival, and
Adenovirus infections of the upper respiratory gastrointestinal tract infections can occur in
tract are common and, although often subclin- hospitals, residential institutions, and nursing
ical, can result in symptoms of the common homes from exposures to infected health care
cold, pharyngitis, tonsillitis, otitis media, and personnel, patients, or contaminated equip-
pharyngoconjunctival fever. Life-threatening ment. Adenovirus infections in transplant
disseminated infection, severe pneumonitis, recipients can occur from donor tissues. Epi-
hepatitis, meningitis, and encephalitis occur demic keratoconjunctivitis commonly occurs
occasionally, especially among young infants by direct contact, has been associated with
and people who are immunocompromised. equipment used during eye examinations, and
Adenoviruses occasionally cause a pertussis- is caused principally by serotypes 8, 19, and 37.
like syndrome, croup, bronchiolitis, exudative Enteric strains of adenoviruses are transmitted
tonsillitis, pneumonia, and hemorrhagic cysti- by the fecal-oral route. Adenoviruses do not
tis. Ocular adenovirus infections may present demonstrate the marked seasonality of other
as follicular conjunctivitis or epidemic kerato- respiratory tract viruses and circulate through-
conjunctivitis. Ophthalmologic illness fre- out the year. Enteric disease occurs year-round
quently presents with unilateral inflammation and primarily affects children younger than
that becomes bilateral; symptoms include pho- 4 years. Adenovirus infections are most com-
tophobia and, sometimes, vision loss. Enteric municable during the first few days of an acute
adenoviruses are an important cause of child- illness, but persistent and intermittent shed-
hood gastroenteritis. ding for longer periods, even months, is com-
Etiology mon. Asymptomatic infections are common.
Reinfection can occur.
Adenoviruses are double-stranded, nonenvel-
oped DNA viruses; at least 51 distinct serotypes Incubation Period
and multiple genetic variants divided into 7 Respiratory tract infection, 2 to 14 days; gastro-
species (A–G) infect humans. Some adenovirus enteritis, 3 to 10 days.
types are associated primarily with respiratory
tract disease (types 1–5, 7, 14, and 21), and Diagnostic Tests
­others are associated primarily with gastro­ Methods for diagnosis of adenovirus infection
enteritis (types 40 and 41). During 2007, include isolation in cell culture, antigen detec-
­adenovirus type 14 emerged in the United tion, and molecular detection. Adenoviruses
States, where it caused severe and sometimes associated with respiratory tract disease can be
fatal respiratory tract illness in mostly adults, isolated from pharyngeal and eye secretions
­civilian and military, and has now spread to and from feces by inoculation of specimens
Europe and Asia. into susceptible cell cultures. A pharyngeal
Epidemiology or ocular isolate is more suggestive of recent
infection than is a fecal isolate, which may
Infection in infants and children can occur at indicate recent infection or prolonged carriage.
any age. Adenoviruses causing respiratory tract Rapid detection of adenovirus antigens is pos-
infections are usually transmitted by respira- sible in a variety of body fluids by commercial
tory tract secretions through person-to-person immunoassay, including direct fluorescent
contact, airborne droplets, and fomites. Adeno- assay. These rapid assays can be useful for the
viruses are hardy viruses, can survive on envi- diagnosis of respiratory tract infections, ocular
ronmental surfaces for long periods, and are disease, and diarrheal disease. Enteric adeno­
not inactivated by many disinfectants. Con- virus types 40 and 41 usually cannot be iso-
junctiva can provide a portal of entry. Com­ lated in standard cell cultures. Adenoviruses
munity outbreaks of adenovirus-associated can also be identified by electron microscopic

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Adenovirus Infections 5

examination of respiratory and stool speci- Treatment


mens, but this modality lacks sensitivity. Poly- Treatment of adenovirus infection is support-
merase chain reaction assays for adenovirus ive. Randomized clinical trials evaluating
DNA are replacing other detection methods ­specific antiviral therapy have not been
because of improved sensitivity and increasing ­performed. However, case reports of the
commercial availability; however, the persis- ­successful use of cidofovir in immunocom­
tent and intermittent shedding that commonly promised patients with severe adenoviral
follows an acute adenoviral infection can com- ­disease have been published, albeit without
plicate the clinical interpretation of a positive a uniform dose or dosing strategy. An oral
molecular diagnostic test result. Adenovirus lipid conjugate of cidofovir, brincidofovir
typing is available from some reference and (CMX001), is being evaluated for use in
research laboratories. patients who are ­immunocompromised.

Image 2.1
Transmission electron micrograph of adenovirus.
Adenoviruses have a characteristic icosahedral Image 2.2
structure. Courtesy of Centers for Disease Acute follicular adenovirus conjunctivitis. ­
Control and Prevention/Dr William Gary Jr. Adeno­viruses are resistant to alcohol, detergents,
and chlorhexidine and may contaminate
ophthalmologic solutions and equipment.
Instruments can be disinfected by steam
autoclaving or immersion in 1% sodium
hypochlorite for 10 minutes.

Image 2.3
Adenoviral pneumonia in an 8-year-old girl with
diffuse pulmonary infiltrate bilaterally. Most
adenoviral infections in the normal host are self-
limited and require no specific treatment. Lobar
consolidation is unusual.

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6 Adenovirus Infections

Image 2.4
Histopathology of the lung with bronchiolar occlusion in an immunocompromised child who died
with adenoviral pneumonia. Note interstitial mononuclear cell infiltration and hyaline membranes.
Adenoviruses types 3 and 7 can cause necrotizing bronchitis and bronchiolitis. Courtesy of Edgar
O. Ledbetter, MD, FAAP.

Image 2.5
Pulmonary histopathology of the immuno­com­
promised child in Image 2.4 showing multiple Image 2.6
adenovirus intranuclear inclusion cells. Courtesy This previously healthy 3-year-old boy
of Edgar O. Ledbetter, MD, FAAP. presented with respiratory failure requiring
intensive care for adenovirus type 7 pneumonia.
He eventually recovered with some mild
impairment in ­pulmonary function studies.
Note the pneumo­media­stinum. Courtesy of
Carol J. Baker, MD, FAAP.

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Amebiasis 7

3 tenderness, and hepatomegaly, or chronic, with


weight loss, vague abdominal symptoms, and
Amebiasis irritability. Rupture of abscesses into the abdo-
Clinical Manifestations men or chest may be fatal. Evidence of recent
intestinal tract infection usually is absent in
Most individuals with Entamoeba histolytica extraintestinal disease. Infection can also
have asymptomatic, noninvasive intestinal spread from the colon to the genitourinary
tract infection. When symptomatic, clinical tract and skin. The organism rarely spreads
syndromes associated with E histolytica infec- hematogenously to the brain and other areas
tion include cramps, watery or bloody diar- of the body.
rhea, and weight loss. Occasionally, the parasite
may spread to other organs, most commonly Etiology
the liver (liver abscess), and cause fever and The genus Entamoeba includes 6 species that
right upper quadrant pain. Disease is more live in the human intestine. Three of these
severe in people who are very young, elderly, or ­species are identical morphologically: E histo­
malnourished and pregnant women. People lytica, Entamoeba dispar, and Entamoeba
with symptomatic intestinal amebiasis gener- moshkovskii. E dispar and E moshkovskii,
ally have a gradual onset of symptoms over 1 to ­generally believed to be nonpathogenic, have
3 weeks. The mildest form of intestinal tract recently been associated with intestinal and
disease is nondysenteric colitis. However, ame- extraintestinal pathology. Entamoeba species
bic dysentery is the most common clinical are excreted as cysts or trophozoites in stool
manifestation of amebiasis and usually of infected people.
includes diarrhea with gross or microscopic
blood in the stool, lower abdominal pain, and Epidemiology
tenesmus. Weight loss is common, but fever E histolytica can be found worldwide but is
occurs only in a minority of patients (8%–38%). more prevalent in people of lower socioeco-
Symptoms can be chronic, with periods of nomic status who live in resource-limited
diarrhea and intestinal spasms alternating with countries, where the prevalence of amebic
periods of constipation, and can mimic inflam- infection can be as high as 50% in some com-
matory bowel disease. Progressive involvement munities. Groups at increased risk of infection
of the colon can produce toxic megacolon, ful- in resource-rich countries include immigrants
minant colitis, ulceration of the colon and peri- from or long-term visitors to areas with
anal area, and, rarely, perforation. Colonic endemic infection, institutionalized people,
progression can occur at multiples sites and and men who have sex with men. E histolytica
carries a high fatality rate. Progression can is transmitted via amebic cysts by the fecal-oral
occur in patients inappropriately treated with route. Ingested cysts, which are unaffected by
corticosteroids or antimotility drugs. An ame- gastric acid, produce trophozoites that infect
boma may occur as an annular lesion of the the colon. Cysts that develop subsequently are
colon and may present as a palpable mass on the source of transmission, especially from
physical examination. Amebomas can occur in asymptomatic cyst excreters. Infected patients
any area of the colon but are more common in excrete cysts intermittently, sometimes for
the cecum and may be mistaken for colonic years if untreated. Transmission has been asso-
carcinoma. Amebomas usually resolve with ciated with contaminated food or water. Fecal-
antiamebic therapy and do not require surgery. oral transmission can also occur in the setting
In a small proportion of patients, extraintesti- of anal sexual practices or direct rectal inocu-
nal disease may occur. The liver is the most lation through colonic irrigation devices.
common extraintestinal site, and infection can Incubation Period
spread from there to the pleural space, lungs,
Variable; commonly 2 to 4 weeks, ranging from
and pericardium. Liver abscess can be acute,
a few days to months or years.
with fever, abdominal pain, tachypnea, liver

ERRNVPHGLFRVRUJ
8 Amebiasis

Diagnostic Tests Treatment


Definitive diagnosis of intestinal tract infection Treatment involves elimination of the tissue-
depends on identifying trophozoites or cysts invading trophozoites as well as organisms in
in stool specimens. Examination of serial spec- the intestinal lumen. E dispar and E moshkovskii
imens may be necessary. Specimens of stool infections often are considered to be nonpatho-
can be examined microscopically by wet genic and do not always require treatment.
mount within 30 minutes of collection or may Corticosteroids and antimotility drugs admin-
be fixed in formalin or polyvinyl alcohol istered to people with amebiasis can worsen
(­available in kits) for concentration, permanent symptoms and the disease process. The follow-
staining, and subsequent microscopic exami- ing regimens are recommended:
nation. Antigen test kits are available for rou-
• Asymptomatic cyst excreters (intraluminal
tine laboratory testing of E histolytica directly
infections): Treat with a luminal amebicide,
from stool specimens. Biopsy specimens and
such as iodoquinol or paromomycin. Metro-
endoscopy scrapings (not swabs) can be exam-
nidazole is not effective.
ined using similar methods. Polymerase chain
reaction assay and isoenzyme analysis can • Patients with mild to moderate or severe
­differentiate E histolytica from E dispar, intestinal tract symptoms or extraintesti-
E moshkovskii, and other Entamoeba species; nal disease (including liver abscess): Treat
some monoclonal antibody-based antigen with metronidazole or tinidazole, followed
detection assays can also differentiate by a therapeutic course of a luminal amebi-
E ­histolytica from E ­dispar. cide (iodoquinol or, in absence of intestinal
obstruction, paromomycin). Nitazoxanide
Indirect hemagglutination has been replaced
may also be effective for mild to moderate
by commercially available enzyme immuno­
intestinal amebiasis, although it is not US
assay kits for routine serodiagnosis of amebia-
Food and Drug Administration approved
sis. Enzyme immunoassay detects antibody
for this indication. An alternate treatment
specific for E histolytica in approximately 95%
for liver abscess is chloroquine phosphate
or more of patients with extraintestinal amebi-
administered concomitantly with metroni-
asis, 70% of patients with active intestinal tract
dazole or tinidazole, followed by a therapeu-
infection, and 10% of asymptomatic people
tic course of a luminal amebicide.
who are passing cysts of E histolytica. Positive
serologic test results can persist even after Percutaneous or surgical aspiration of large
­adequate therapy. Diagnosis of an E histolytica liver abscesses occasionally is required when
liver abscess and other extraintestinal infec- response of the abscess to medical therapy is
tions is aided by serologic testing because stool unsatisfactory or there is risk of abscess rup-
tests and abscess aspirates frequently are ture. In most patients, drainage is not required
not revealing. and does not speed recovery.
Ultrasonography, computed tomography, and Follow-up stool examination is recommended
magnetic resonance imaging can identify liver after completion of therapy. Household mem-
abscesses and other extraintestinal sites of bers and other suspected contacts should have
infection. Aspirates from a liver abscess usually stool examinations performed and be treated
show neither trophozoites nor leukocytes. if results are positive for E histolytica.

ERRNVPHGLFRVRUJ
Amebiasis 9

Image 3.1
Cysts are passed in feces (1). Infection by Entamoeba histolytica occurs by ingestion of mature cysts
(2) in fecally contaminated food, water, or hands. Excystation (3) occurs in the small intestine and
trophozoites (4) are released, which migrate to the large intestine. The trophozoites multiply by binary
fission and produce cysts (5), which are passed in feces (1). Because of the protection conferred by
their walls, the cysts can survive days to weeks in the external environment and are responsible for
transmission. (Trophozoites can also be passed in diarrheal stools but are rapidly destroyed once
outside the body and, if ingested, would not survive exposure to the gastric environment.) In many
cases, trophozoites remain confined to the intestinal lumen (A, noninvasive infection) of individuals
who are asymptomatic carriers, passing cysts in their stool. In some patients, trophozoites invade
the intestinal mucosa (B, intestinal disease) or, through the bloodstream, extraintestinal sites, such
as the liver, brain, and lungs (C, extraintestinal disease), with resultant pathologic manifestations. It
has been established that invasive and noninvasive forms represent 2 separate species, E histolytica
and Entamoeba dispar, respectively; however, not all persons infected with E histolytica will have
invasive disease. These 2 species are morphologically indistinguishable. Transmission can also occur
through fecal exposure during sexual contact (in which case not only cysts, but also trophozoites,
could prove infective). Courtesy of Centers for Disease Control and Prevention.

Image 3.2
Trophozoites of Entamoeba histolytica with ingested erythrocytes (trichrome stain). The ingested
erythrocytes appear as dark inclusions. Erythrophagocytosis is the only characteristic that can be
used to differentiate morphologically E histolytica from the nonpathogenic Entamoeba dispar. In these
specimens, the parasite nuclei have the typical small, centrally located karyosome and thin, uniform
peripheral chromatin. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
10 Amebiasis

Image 3.3
Cysts of Entamoeba histolytica and Entamoeba dispar. Line drawing (A), wet mounts (B; iodine, C),
and permanent preparations stained with trichrome (D, E). The cysts are usually spherical and often
have a halo (B, C). Mature cysts have 4 nuclei. The cyst in B appears uninucleate, while in C, D, and
E, 2 to 3 nuclei are visible in the focal plane (the fourth nucleus is coming into focus in D). The nuclei
have characteristically centrally located karyosomes and fine, uniformly distributed peripheral
chromatin. The cysts in C, D, and E contain chromatoid bodies, with the one in D being particularly
well demonstrated, with typically blunted ends. E histolytica cysts usually measure 12 to 15 µm.
Courtesy of Centers for Disease Control and Prevention.

Image 3.4
This patient with amebiasis presented with tissue destruction and granulation of the anoperineal
region caused by an Entamoeba histolytica infection. Courtesy of Centers for Disease Control and
Prevention/Kerrison Juniper, MD; George Healy, PhD, DPDx.

ERRNVPHGLFRVRUJ
Amebiasis 11

Image 3.5
Computed tomography scan of the abdomen showing a peripherally enhancing low-density lesion in
the posterior aspect of the right hepatic lobe. Amebic liver abscess amebiasis, caused by the intestinal
protozoal parasite Entamoeba histolytica, remains a global health problem, infecting about 50 million
people and resulting in 40,000 to 100,000 deaths per year. Prevalence may be as high as 50% in
tropical and sub­tropical countries where overcrowding and poor sanitation are common. In the United
States, E histolytica infection is seen most commonly in immigrants from developing countries, long-
term travelers to endemic areas (most frequently Mexico or Southeast Asia), institutionalized individ­uals,
and men who have sex with men. In 1993, the previously known species E histolytica was reclassified
into 2 genetically and bio­chemi­cally distinct but morphologically identical species: the pathogenic
E histolytica and the nonpathogenic commensal Entamoeba dispar. Courtesy of Pediatrics in Review.

Image 3.6
Abdominal ultrasound showing a liver abscess
Image 3.7
caused by Entamoeba histolytica.
Gross pathology of intestinal ulcers due to
amebiasis. Courtesy of Centers for Disease
Control and Prevention/Dr Mae Melvin;
Dr E. West.

ERRNVPHGLFRVRUJ
12 Amebiasis

Image 3.8
Gross pathology of amebic (Entamoeba histolytica) abscess of liver; tube of “chocolate-like” pus
from abscess. Amebic liver abscesses are usually singular and large and in the right lobe of the liver.
Bacterial hepatic abscesses are more likely to be multiple. Courtesy of Centers for Disease Control
and Prevention/Dr Mae Melvin; Dr E. West.

Image 3.9
This patient presented with a case of invasive extraintestinal amebiasis affecting the cutaneous region
of the right flank. Courtesy of Centers for Disease Control and Prevention Prevention/Kerrison Juniper,
MD, and George Healy, PhD, DPDx.

Image 3.10
This patient, also shown in Image 3.9, presented with a case of invasive extraintestinal amebiasis
affecting the cutaneous region of the right flank causing severe tissue necrosis. Here we see the site of
tissue destruction, predebridement. Courtesy of Centers for Disease Control and Prevention/Kerrison
Juniper, MD, and George Healy, PhD, DPDx.

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Amebic Meningoenceph­alitis and Keratitis 13

4 Etiology

Amebic Meningoenceph­ N fowleri, Acanthamoeba species, and


B ­mandrillaris are free-living amebae that
alitis and Keratitis exist as motile, infectious trophozoites and
(Naegleria fowleri, Acanthamoeba species, environmentally hardy cysts.
and Balamuthia mandrillaris)
Epidemiology
Clinical Manifestations
N fowleri is found in warm fresh water and
Naegleria fowleri causes a rapidly progressive, moist soil. Most infections with N fowleri have
almost always fatal, primary amebic meningo- been associated with swimming in natural
encephalitis (PAM). Early symptoms include bodies of warm fresh water, such as ponds,
fever, headache, vomiting, and, sometimes, lakes, and hot springs, but other sources have
disturbances of smell and taste. This illness included tap water from geothermal sources
progresses rapidly to signs of meningoenceph- and contaminated and poorly chlorinated
alitis, including nuchal rigidity, lethargy, con- swimming pools. Disease has been reported
fusion, personality changes, and altered level worldwide but is uncommon. In the United
of consciousness. Seizures are common, and States, infection occurs primarily in the sum-
death generally occurs within a week of onset mer and usually affects children and young
of symptoms. No distinct clinical features dif- adults. Disease has followed inappropriate use
ferentiate this disease from fulminant bacterial of tap water for sinus rinses. The trophozoites
meningitis or meningoencephalitis. of the parasite invade the brain directly from
Granulomatous amebic encephalitis (GAE) the nose along the olfactory nerves via the
caused by Acanthamoeba species and Balamu­ ­cribriform plate. In infections with N fowleri,
thia mandrillaris has a more insidious onset trophozoites, but not cysts, can be visualized
and develops as a subacute or chronic disease. in sections of brain or in cerebrospinal fluid
In general, GAE progresses more slowly than (CSF).
PAM, leading to death several weeks to months Acanthamoeba species are distributed world-
after onset of symptoms. Signs and symptoms wide and are found in soil; dust; cooling towers
include personality changes, seizures, head- of electric and nuclear power plants; heating,
aches, ataxia, cranial nerve palsies, hemipare- ventilating, and air-conditioning units; fresh
sis, and other focal neurologic deficits. Fever and brackish water; whirlpool baths; and
is often low grade and intermittent. Chronic ­physiotherapy pools. The environmental niche
granulomatous skin lesions (pustules, nodules, of B mandrillaris is not delineated clearly,
ulcers) may be present without central nervous although it has been isolated from soil. Central
system (CNS) involvement, particularly in nervous system infection attributable to Acan­
patients with AIDS, and lesions may be present thamoeba occurs primarily in people who are
for months before brain involvement in immu- debilitated or immunocompromised. However,
nocompetent hosts. some patients infected with B mandrillaris
The most common symptoms of amebic have had no demonstrable underlying disease
­keratitis, a vision-threatening infection usually or defect. Central nervous system infection by
caused by Acanthamoeba species, are pain both amebae probably occurs most commonly
(often out of proportion to clinical signs), pho- by inhalation or direct contact with contami-
tophobia, tearing, and foreign body sensation. nated soil or water. The primary foci of these
Characteristic clinical findings include radial infections are, most likely, skin or respiratory
keratoneuritis and stromal ring infiltrate. tract, followed by hematogenous spread to the
Acanthamoeba keratitis generally follows an brain. Fatal encephalitis caused by Balamuthia
indolent course and initially can resemble her- and transmitted by the organ donor has been
pes simplex or bacterial keratitis; delay in diag- reported in recipients of organ transplants.
nosis is associated with worse outcomes. Acanthamoeba keratitis occurs primarily in
people who wear contact lenses, although it

ERRNVPHGLFRVRUJ
14 Amebic Meningoenceph­alitis and Keratitis

also has been associated with corneal trauma. reveal single or multiple space-occupying,
Poor contact lens hygiene or disinfection ring-enhancing lesions that can mimic brain
­practices as well as swimming with contact abscesses, tumors, cerebrovascular accidents,
lenses are risk factors. or other diseases. Acanthamoeba species, but
not Balamuthia species, can be cultured by the
Incubation Period
same method used for N fowleri. B mandrillaris
N fowleri, 3 to 7 days; Acanthamoeba and can be grown using mammalian cell culture.
­Balamuthia GAE, unknown but thought to be Like N fowleri, immunofluorescence and poly-
several weeks or months; Acanthamoeba kera- merase chain reaction assays can be performed
titis, unknown but thought to be several days on clinical specimens to identify Acantha­
to weeks. moeba species and Balamuthia species; these
tests are available through the CDC.
Diagnostic Tests
In N fowleri infection, computed tomography Treatment
scans of the head without contrast are unre- If meningoencephalitis caused by N fowleri is
markable or show only cerebral edema but, suspected because of the presence of amebic
with contrast, might show meningeal enhance- organisms in CSF, therapy should be initiated
ment of the basilar cisterns and sulci. However, promptly while awaiting results of confirma-
these changes are not specific for amebic infec- tory diagnostic tests. Although an effective
tion. Cerebrospinal fluid pressure usually is treatment regimen for PAM has not been
elevated (300 to >600 mm water), and CSF ­identified, amphotericin B is the drug of
indices can show a polymorphonuclear pleo­ choice. However, treatment is usually unsuc-
cytosis, an increased protein concentration, cessful, with only a few cases of complete
and a normal to very low glucose concentra- recovery having been documented. Two sur­
tion. N fowleri infection can be documented by vivors recovered after treatment with ampho-
microscopic demonstration of the motile tro- tericin B in combination with an azole drug
phozoites on a wet mount of centrifuged CSF. (miconazole or fluconazole) plus rifampin.
Smears of CSF should be stained with Giemsa, The most up-to-date guidance for treatment
trichrome, or Wright stain to identify the of PAM can be found on the CDC Web site
­trophozoites, if present. Trophozoites can be (www.cdc.gov/naegleria).
visualized in sections of the brain. Immuno­
fluorescence and polymerase chain reaction Effective treatment for infections caused by
assays performed on CSF and biopsy material Acanthamoeba species and B mandrillaris has
to identify the organism are available through not been established. Several patients with
the Centers for Disease Control and Prevention Acanthamoeba GAE and Acanthamoeba
(CDC). ­cutaneous infections without CNS involve­
ment have been treated successfully with a
In infection with Acanthamoeba species and multidrug regimen consisting of various
B mandrillaris, trophozoites and cysts can be ­combinations of pentamidine, sulfadiazine,
visualized in sections of brain, lungs, and skin; flucytosine, either fluconazole or itraconazole,
in cases of Acanthamoeba keratitis, they can trimethoprim-sulfamethoxazole, and topical
also be visualized in corneal scrapings and by application of chlorhexidine gluconate and
confocal microscopy in vivo in the cornea. In ketoconazole for skin lesions.
GAE infections, CSF indices typically reveal
a lymphocytic pleocytosis and an increased Patients with Acanthamoeba keratitis should
protein concentration, with normal or low be evaluated by an ophthalmologist. Early
­glucose concentration. Computed tomography diagnosis and therapy are important for a
and magnetic resonance imaging of the head good outcome.

ERRNVPHGLFRVRUJ
Amebic Meningoenceph­alitis and Keratitis 15

Image 4.1
Free-living amebae belonging to the genera Acanthamoeba, Balamuthia, and Naegleria are important
causes of disease in humans and animals. Fowleri produces an acute, and usually lethal, central
nervous system disease called primary amebic meningoencephalitis. Naegleria fowleri has 3 stages,
cysts (1), trophozoites (2), and flagellated forms (3), in its life cycle. The trophozoites replicate by
promitosis (nuclear membrane remains intact) (4). N fowleri is found in fresh water, soil, thermal
discharges of power plants, heated swimming pools, hydrotherapy and medicinal pools, aquariums,
and sewage. Trophozoites can turn into temporary flagellated forms, which usually revert back to the
tropho­zoite stage. Trophozoites infect humans or animals by entering the olfactory neuroepithelium
(5) and reaching the brain. N fowleri trophozoites are found in cerebrospinal fluid and tissue,
while flagellated forms are found in cerebrospinal fluid. Acanthamoeba species and Balamuthia
mandrillaris are opportunistic free-living amebae capable of causing granulomatous amebic
encephalitis in individuals with compromised immune systems. Acanthamoeba species have been
found in soil; fresh water, brackish water, and seawater; sewage; swimming pools; contact lens
equipment; medicinal pools; dental treat­ment units; dialysis machines; heating, ventilating, and air-
conditioning systems; mammalian cell cultures; vegetables; human nostrils and throats; and human
and animal brain, skin, and lung tissues. B mandrillaris has not been isolated from the environment
but has been isolated from autopsy specimens of infected humans and animals. Unlike N fowleri,
Acanthamoeba and Balamuthia have only 2 stages, cysts (1) and trophozoites (2), in their life cycle.
No flagellated stage exists as part of the life cycle. The tropho­zoites replicate by mitosis (nuclear
membrane does not remain intact) (3). The trophozoites are the infective forms and are believed to
gain entry into the body through the lower respiratory tract or ulcerated or broken skin and invade
the central nervous system by hematogenous dissemination (4). Acanthamoeba species and
B mandrillaris cysts and trophozoites are found in tissue. Courtesy of Centers for Disease Control
and Prevention.

ERRNVPHGLFRVRUJ
16 Amebic Meningoenceph­alitis and Keratitis

Image 4.2
Naegleria fowleri trophozoite in spinal fluid (trichrome stain). Note the typically large karyosome and
monopodial locomotion. Courtesy of Centers for Disease Control and Prevention.

Image 4.3
Naegleria fowleri trophozoites cultured from
cerebrospinal fluid. These cells have character­
istically large nuclei, with a large, dark-staining
karyosome. The amebae are very active and
extend and retract pseudopods (trichrome stain).
This sample was taken from a patient who died
of primary amebic meningoencephalitis in
Virginia. Courtesy of Centers for Disease
Control and Prevention.
Image 4.4
A, Computed tomographic scan; note the right
frontobasal collection (arrow) with a midline shift
right to left. B, Brain histology; 3 large clusters of
amebic vegetative forms are seen (hematoxylin-
eosin stain, magnification x250). Inset: positive
indirect immunofluorescent analysis on tissue
section with anti–Naegleria fowleri serum.
Courtesy of Emerging Infectious Diseases.

ERRNVPHGLFRVRUJ
Amebic Meningoenceph­alitis and Keratitis 17

Image 4.5
This photomicrograph depicts a magnified view of brain tissue within which is a centrally located
Acanthamoeba species cyst. Acanthamoeba species are opportunistic free-living amebae, capable
of causing granulomatous amebic encephalitis in individuals with compromised immune systems.
Acanthamoeba species have only 2 stages, cysts and trophozoites, in their life cycle. No flagellated
stage exists as part of the life cycle. The trophozoites replicate by mitosis (nuclear membrane does not
remain intact). The trophozoites are the infective forms and are believed to gain entry into the body
through the lower respiratory tract or ulcerated or broken skin and invade the central nervous system
by hematogenous dissemination. Acanthamoeba species can also cause severe keratitis in otherwise
healthy individuals, parti­cularly contact lens users. These amebae have been found in soil; fresh
water, brackish water, and seawater; sewage; swimming pools; contact lens equipment; medicinal
pools; dental treat­ment units; dialysis machines; heating, ventilating, and air-conditioning systems;
mammalian cell cultures; vegetables; human nostrils and throats; and human and animal brain, skin,
and lung tissues. Courtesy of Centers for Disease Control and Prevention/George Healy, PhD, DPDx.

Image 4.6
Balamuthia mandrillaris trophozoites in brain Image 4.7
tissue. Courtesy of Centers for Disease Control Acanthamoeba keratitis. Courtesy of Susan
and Prevention. Lehman, MD, FAAP.

ERRNVPHGLFRVRUJ
18 Anthrax

5 Injection anthrax has not been reported to


date in children. Its primary occurrence has
Anthrax been reported among injecting heroin users;
Clinical Manifestations however, smoking and snorting of heroin also
have been identified as exposure routes. Sys-
Anthrax can occur in 4 forms, depending on temic illness can result from hematogenous
the route of infection: cutaneous, inhalational, and lymphatic dissemination and can occur
gastrointestinal, and injection. with any form of anthrax. Most patients with
Cutaneous anthrax begins as a pruritic papule inhalational, gastrointestinal, and injection
or vesicle and progresses over 2 to 6 days to an anthrax have systemic illness. Anthrax menin-
ulcerated lesion with subsequent formation of gitis can occur in any patient with systemic
a central black eschar. The lesion itself is char- illness regardless of origin; it can also occur in
acteristically painless, with surrounding edema, patients lacking any other apparent clinical
hyperemia, and painful regional lymphade- presentation. The case-fatality rate for patients
nopathy. Patients may have associated fever, with appropriately treated cutaneous anthrax
lymphangitis, and extensive edema. is usually less than 1%. Even with antimicrobial
treatment and supportive care, the mortality
Inhalational anthrax is a frequently lethal rate for inhalational or gastrointestinal tract
form of the disease and constitutes a medical disease is between 40% and 45% and
emergency. The initial presentation is nonspe- approaches 100% for meningitis.
cific with fever, sweats, nonproductive cough,
chest pain, headache, myalgia, malaise, nausea, Etiology
and vomiting, but illness progresses to the ful- Bacillus anthracis is an aerobic, gram-positive,
minant phase 2 to 5 days later. In some cases, encapsulated, spore-forming, nonhemolytic,
the illness is biphasic with a period of improve- nonmotile rod. B anthracis has 3 major viru-
ment between prodromal symptoms and lence factors: an antiphagocytic capsule and
­overwhelming illness. Fulminant manifesta- 2 exotoxins, called lethal and edema toxins.
tions include hypotension, dyspnea, hypoxia, The toxins are responsible for the substantial
cyanosis, and shock occurring as a result of morbidity and clinical manifestations of hem-
hemorrhagic mediastinal lymphadenitis, hem- orrhage, edema, and necrosis.
orrhagic pneumonia, hemorrhagic pleural effu-
sions, and toxemia. A widened mediastinum Epidemiology
is the classic finding on imaging of the chest. Anthrax is a zoonotic disease most commonly
Chest radiography may also show pleural effu- affecting domestic and wild herbivores that
sions or infiltrates, both of which may be hem- occurs in many rural regions of the world.
orrhagic in nature. B anthracis spores can remain viable in the soil
for decades, representing a potential source
Gastrointestinal tract disease can present as
of infection for livestock or wildlife through
one of 2 distinct clinical syndromes—intestinal
ingestion of spore-contaminated vegetation or
or oropharyngeal. Patients with the intestinal
water. In susceptible hosts, the spores germi-
form have nausea, anorexia, vomiting, and
nate to become viable bacteria. Natural infec-
fever progressing to severe abdominal pain,
tion of humans occurs through contact with
massive ascites, hematemesis, and bloody
infected animals or contaminated animal
­diarrhea, related to development of edema
products, including carcasses, hides, hair,
and ulceration of the bowel, primarily the
wool, meat, and bone meal. Outbreaks of gas-
ileum and cecum. Patients with oropharyngeal
trointestinal tract anthrax have occurred after
anthrax may also have dysphagia with poste-
ingestion of undercooked or raw meat from
rior oropharyngeal necrotic ulcers, which can
infected animals. Historically, the vast major-
be associated with marked, often unilateral
ity (more than 95%) of cases of anthrax in the
neck swelling, regional adenopathy, fever,
United States were cutaneous infections among
and sepsis.
animal handlers or mill workers. The incidence

ERRNVPHGLFRVRUJ
Anthrax 19

of naturally occurring human anthrax blue with the capsule visualized in red are
decreased in the United States from an esti- ­considered a presumptive identification of
mated 130 cases annually in the early 1900s to B anthracis. Traditional microbiologic methods
0 to 2 cases per year from 1979 through 2013. can presumptively identify B anthracis from
Recent cases of inhalational, cutaneous, and cultures. Definitive identification of suspect
gastrointestinal tract anthrax have occurred B anthracis isolates can be performed through
in drum makers working with contaminated the Laboratory Response Network in each
animal hides and in people participating in state. Additional diagnostic tests for anthrax
events where spore-contaminated drums were can be accessed through state health depart-
played. Severe soft tissue infections among her- ments, including bacterial DNA detection in
oin users, including cases with disseminated blood, CSF, or exudates by polymerase chain
systemic infection, have been reported, reaction assay, tissue immunohistochemistry,
although, to date, such cases have only been an enzyme immunoassay that measures immu-
reported in Northern Europe. noglobulin G antibodies against B anthracis
protective antigen in paired sera, or a matrix-
B anthracis is one of the most likely agents to
assisted laser desorption/ionization mass spec-
be used as a biological weapon, because its
trometry assay measuring lethal factor activity
spores are highly stable, spores can infect via
in serum samples. The commercially available
the respiratory route, and the resulting inhala-
QuickELISA Anthrax-PA Kit can be used as a
tional anthrax has a high mortality rate. In
screening test.
1979, an accidental release of B anthracis spores
from a military microbiology facility in the Treatment
former Soviet Union resulted in at least 68 A high index of suspicion and rapid adminis-
deaths. In 2001, 22 cases of anthrax (11 inhala- tration of appropriate antimicrobial therapy to
tional, 11 cutaneous) were identified in the people suspected of being infected, along with
United States after intentional contamination access to critical care support, are essential for
of the mail; 5 (45%) of the inhalational anthrax effective treatment of anthrax. No controlled
cases were fatal. In addition to aerosolization, trials in humans have been performed to
there is a theoretical health risk associated ­validate current treatment recommendations
with B anthracis spores being introduced into for anthrax, and there is limited clinical expe-
food products or water supplies. rience. Case reports suggest that naturally
Incubation Period occurring localized or uncomplicated cutane-
ous disease can be treated effectively with oral
For cutaneous or gastrointestinal tract disease,
ciprofloxacin or an equivalent fluoroquinolone;
typically 1 week or less; range 2 to 43 days in
doxycycline and clindamycin are alternatives,
inhalational.
as are penicillins if the isolate is known to be
Diagnostic Tests penicillin-susceptible. For bioterrorism-­
associated cutaneous disease in adults or
Depending on clinical presentation, Gram
­children, ciprofloxacin or doxycycline are
stain, culture, and polymerase chain reaction
­recommended for initial treatment until
testing for anthrax should be performed on
­antimicrobial susceptibility data are available.
specimens of blood, pleural fluid, cerebrospinal
Because of the risk of concomitant inhalational
fluid (CSF), and tissue biopsy specimens and
exposure and subsequent spore dormancy in
on swabs of vesicular fluid or eschar material
the lungs, the antimicrobial regimen in cases
from cutaneous or oropharyngeal lesions,
of bioterrorism-associated cutaneous anthrax
­rectal swabs, or stool. Whenever possible,
or that were exposed to other sources of aero-
­specimens should be obtained before initiating
solized spores should be continued for a total
antimicrobial therapy. Gram-positive bacilli
of 60 days.
seen on unspun peripheral blood smears or in
vesicular fluid or CSF can be an important Ciprofloxacin is recommended as the primary
­initial finding, and polychrome methylene antimicrobial component of an initial multi-
blue-stained smears showing bacilli stained drug regimen for treatment of all forms of

ERRNVPHGLFRVRUJ
20 Anthrax

s­ ystemic anthrax until results of antimicrobial Treatment should continue for at least 14 days
susceptibility testing are known. Meningitis or longer, depending on patient condition.
should be suspected in all cases of inhalational Intravenous therapy can be changed to oral
anthrax and other systemic anthrax infections; therapy when progression of symptoms cease
thus, treatment includes at least 2 other agents and it is clinically appropriate. For anthrax
with known central nervous system penetration. with evidence of systemic illness, including
Meropenem is recommended as the second fever, shock, and dissemination to other
bactericidal antimicrobial. Linezolid is recom- organs, anthrax immune globulin or Raxi-
mended as the preferred protein synthesis bacumab (GlaxoSmithKline, Research Triangle
inhibitor if meningeal involvement is ­suspected. Park, NC), a humanized monoclonal antibody,
should be considered in consultation with the
Centers for Disease Control and Prevention.

Image 5.2
Image 5.1
Sporulation of Bacillus anthracis, a gram-positive,
A photomicrograph of Bacillus anthracis bacteria nonmotile, encapsulated bacillus.
using Gram stain technique. Courtesy of Centers
for Disease Control and Prevention.

Image 5.4
Bacillus anthracis tenacity positive on sheep
Image 5.3 blood agar. B anthracis colony characteristics:
A 24-hour blood agar plate culture of Bacillus consistency sticky (tenacious). When teased with
anthracis. Courtesy of Robert Jerris, MD. loop, colony will stand up like beaten egg white.
Courtesy of Centers for Disease Control and
Prevention/Larry Stauffer, Oregon State Public
Health Laboratory.

ERRNVPHGLFRVRUJ
Anthrax 21

Image 5.5
Anthrax lesion on volar surface of right forearm.
Note the rolled-up margin of the lesion with a
central area of necrosis (eschar). Courtesy of
Centers for Disease Control and Prevention.

Image 5.6
Cutaneous anthrax. Notice edema and typical
lesions. Courtesy of Centers for Disease Control
and Prevention.

Image 5.7
Generalized cutaneous anthrax infection
acquired from an ill cow. The infection began as
a papule and was thought to be simple furuncle.
Following an attempt at drainage, the infection
aggressively spread. Antibiotic therapy was
started and the patient survived. Courtesy of Image 5.8
Mariam Svanidze, MD. Anthrax ulcers on hand and wrist of an adult.
The cutaneous eschar of anthrax had been
misdiagnosed as a brown recluse spider bite.
Edema is common and suppuration is absent.
Courtesy of Gary Overturf, MD.

Image 5.9
Cutaneous anthrax. Vesicle development occurs
from day 2 through day 10 of progression.
Courtesy of Centers for Disease Control and
Prevention.

ERRNVPHGLFRVRUJ
22 Anthrax

Image 5.10
Cutaneous anthrax lesion on the skin of the
forearm caused by the bacterium Bacillus
anthracis. Here, the disease has manifested itself
as a cutaneous ulceration, which has begun to
turn black (hence, the origin of the name anthrax,
after the Greek name for coal). Courtesy of
Centers for Disease Control and Prevention. Image 5.11
Posteroanterior chest radiograph taken on the
fourth day of illness, which shows a large pleural
effusion and marked widening of the mediastinal
shadow. Courtesy of Centers for Disease Control
and Prevention.

Image 5.12
Photomicrograph of lung tissue demonstrating
hemorrhagic pneumonia in a case of fatal human
inhalational anthrax (magnification x50). Courtesy
of Centers for Disease Control and Prevention/Dr
LaForce. Image 5.13
This micrograph reveals submucosal hemorrhage
in the small intestine in a case of fatal human
anthrax (hematoxylin-eosin stain, magnification
x240). The first symptoms of gastrointestinal tract
anthrax are nausea, loss of appetite, bloody
diarrhea, and fever, followed by severe stomach
pain. One-fourth to more than half of gastro­
intestinal tract anthrax cases lead to death. Note
the associated arteriolar degeneration. Courtesy
of Centers for Disease Control and Prevention/Dr
Marshal Fox.

Image 5.14
Gross pathology of fixed, cut brain showing
hemorrhagic meningitis secondary to inhalational
anthrax. Courtesy of Centers for Disease Control
and Prevention.

ERRNVPHGLFRVRUJ
Anthrax 23

Image 5.15
This is a brain section through the ventricles revealing an interventricular hemorrhage. The 3 virulence
factors of Bacillus anthracis are edema toxin, lethal toxin, and an antiphagocytic capsular antigen.
The toxins are responsible for the primary clinical manifestations of hemorrhage, edema, and necrosis.
Courtesy of Centers for Disease Control and Prevention.

Image 5.16
Photomicrograph of meninges demonstrating hemorrhagic meningitis due to fatal inhalational anthrax
(magnification x125). Courtesy of Centers for Disease Control and Prevention/Dr Laforce.

ERRNVPHGLFRVRUJ
24 Arboviruses

6 Most people infected with chikungunya


virus become symptomatic. The incubation
Arboviruses period is typically 3 to 7 days (range,
(Including California serogroup, chikungunya, 1–12 days). The disease is most often charac-
Colorado tick fever, eastern equine encepha- terized by acute onset of fever (typically
litis, Japanese encephalitis, Powassan, St. >39°C [102°F]) and polyarthralgia. Joint
Louis encephalitis, tick-borne encephalitis, symptoms usually are bilateral and sym­
Venezuelan equine encephalitis, western metric and can be severe and debilitating.
equine encephalitis, and yellow fever viruses) Other symptoms may include headache,
Clinical Manifestations myalgia, arthritis, conjunctivitis, nausea/
vomiting, or maculopapular rash. Clinical
More than 100 arthropod-borne viruses (arbo- laboratory findings can include lymphope-
viruses) are known to cause human disease. nia, thrombocytopenia, elevated creatinine,
Although most infections are subclinical, and elevated hepatic transaminases. Acute
symptomatic illness usually manifests as 1 of symptoms typically resolve within 7 to
3 primary clinical syndromes: generalized sys- 10 days. Rare complications include uveitis,
temic febrile illness, neuroinvasive disease, or retinitis, myocarditis, hepatitis, nephritis,
hemorrhagic fever (Table 6.1). bullous skin lesions, hemorrhage, meningo-
• Systemic febrile illness. Most arboviruses encephalitis, myelitis, Guillain-Barré syn-
are capable of causing a systemic febrile ill- drome, and cranial nerve palsies. People at
ness that often includes headache, ­arthralgia, risk for severe disease include neonates
myalgia, and rash. Some viruses can also exposed intrapartum, older adults (eg,
cause more characteristic clinical manifesta- >65 years), and people with underlying
tions, such as severe joint pain (eg, chikun- ­medical conditions (eg, hypertension,
gunya virus) or jaundice (eg, yellow fever ­diabetes, cardiovascular disease). Some
virus). With some arboviruses, fatigue, patients might have relapse of rheumatologic
­malaise, and weakness can linger for weeks symptoms (polyarthralgia, polyarthritis,
following initial infection. tenosynovitis) in the months following acute

Table 6.1
Clinical Manifestations for Select Domestic and
International Arboviral Diseases
Systemic Neuroinvasive Hemorrhagic
Virus Febrile Illness Diseasea Fever
Domestic
Chikungunya Yesb Rare No
Colorado tick fever Yes Rare No
Dengue Yes Rare Yes
Eastern equine encephalitis Yes Yes No
La Crosse Yes Yes No
Powassan Yes Yes No
St. Louis encephalitis Yes Yes No
Western equine encephalitis Yes Yes No
West Nile Yes Yes No
International
Japanese encephalitis Yes Yes No
Tick-borne encephalitis Yes Yes No
Venezuelan equine encephalitis Yes Yes No
Yellow fever Yes No Yes
a Aseptic meningitis, encephalitis, or acute flaccid paralysis.
b Most often characterized by sudden onset of high fever and severe joint pain.

ERRNVPHGLFRVRUJ
Arboviruses 25

illness. Studies report variable proportions responsible for a smaller number of human
of patients with persistent joint pains for arboviral infections (eg, Colorado tick fever)
months to years. Mortality is rare. (Table 6.2).
• Neuroinvasive disease. Many arboviruses Epidemiology
cause neuroinvasive diseases, including Most arboviruses maintain cycles of transmis-
aseptic meningitis, encephalitis, or acute sion between birds or small mammals and
flaccid paralysis. Illness usually presents arthropod vectors. Humans and domestic
with a prodrome similar to the systemic ­animals usually are infected incidentally as
febrile illness followed by neurologic “dead-end” hosts. Important exceptions are
­symptoms. The specific symptoms vary by dengue, yellow fever, and chikungunya viruses,
virus and clinical syndrome but can include which can be spread from person to arthropod
vomiting, stiff neck, mental status changes, to person (anthroponotic transmission). For
seizures, or focal neurologic deficits. The other arboviruses, humans usually do not
severity and long-term outcome of the ill- develop a sustained or high enough level of
ness vary by etiologic agent and the under­ viremia to infect biting arthropod vectors.
lying characteristics of the host, such as Direct person-to-person spread of arboviruses
age, immune status, and preexisting medi- can occur through blood transfusion, organ
cal condition. transplantation, intrauterine transmission,
• Hemorrhagic fever. Hemorrhagic fevers and, possibly, human milk. Transmission
can be caused by dengue or yellow fever through percutaneous, mucosal, or aerosol
viruses. After several days of nonspecific exposure to some arboviruses has occurred
febrile illness, the patient may develop overt rarely in laboratory and occupational settings.
signs of hemorrhage (eg, petechiae, ecchy- In the United States, arboviral infections
moses, bleeding from the nose and gums, ­primarily occur from late spring through early
hematemesis, melena) and septic shock autumn, when mosquitoes and ticks are most
(eg, decreased peripheral circulation, azote- active. The number of domestic or imported
mia, tachycardia, hypotension). Hemor- arboviral disease cases reported in the United
rhagic fever caused by dengue and yellow States varies greatly by specific etiology and
fever viruses can be confused with hemor- year (see Table 6.2). Overall, the risk of severe
rhagic fevers transmitted by rodents (eg, ­clinical disease for most arboviral infections
Argentine hemorrhagic fever, Bolivian hem- in the United States is higher among adults
orrhagic fever, Lassa fever) or those caused than among children. One notable exception is
by Ebola or Marburg viruses. For informa- La Crosse virus infection, for which children
tion on other potential infections causing are at highest risk of severe neurologic disease
hemorrhagic manifestations, see Hemor- and long-term sequelae. Eastern equine
rhagic Fevers Caused by Arenaviruses, encephalitis virus causes a low incidence of
­Hemorrhagic Fevers Caused by Bunyavi- disease but high case-fatality rate (40%) across
ruses, and Hemorrhagic Fevers Caused by all age groups.
Filoviruses: Ebola and Marburg.
Outbreaks of chikungunya have occurred in
Etiology countries in Africa, Asia, Europe, and the
Arboviruses are RNA viruses that are trans- Indian and Pacific oceans. In late 2013, chikun-
mitted to humans primarily through bites of gunya virus was found for the first time in the
infected arthropods (mosquitoes, ticks, sand Americas on islands in the Caribbean, with
flies, and biting midges). The viral families attack rates of up to 80% on some islands. It
responsible for most arboviral infections in has spread rapidly throughout the Caribbean,
humans are Flaviviridae (genus Flavivirus), and local transmission has occurred recently
Togaviridae (genus Alphavirus), and Bunya- in Florida and South America. As of 2014,
viridae (genus Orthobunyavirus and Phlebo­ more than 1 million cases of suspected chikun-
virus). Reoviridae (genus Coltivirus) also are gunya have been reported in the Americas.

ERRNVPHGLFRVRUJ
Table 6.2

26 Arboviruses
Genus, Geographic Location, Vectors, and Average Number of Annual Cases Reported in
the United States for Selected Domestic and International Arboviral Diseases
Predominant Geographic Locations

Number of US Cases/
Virus Genus United States Non–United States Vectors Year (Range)a
Domestic
Chikungunya Alphavirus Imported, and local trans- Asia, Africa, Indian Ocean, Mosquitoes 2006–2013: 28 (5–65)
mission in Floridab Western Pacific, Caribbean,
2014: >1,500c
South America, North Americac
Colorado tick fever Coltivirus Rocky Mountain states Western Canada Ticks 7 (4–14)
Dengue Flavivirus Puerto Rico, Florida, Worldwide in tropical areas Mosquitoes 273 (2–720)d
Texas, and Hawaii
Eastern equine encephalitis Alphavirus Eastern and gulf states Canada, Central and South Mosquitoes 9 (4–22)
America
La Crosse Orthobunyavirus Midwest and Appalachia Canada Mosquitoes 82 (50–130)
Powassan Flavivirus Northeast and Midwest Canada, Russia Ticks 5 (0–16)
St. Louis encephalitis Flavivirus Widespread Canada, Caribbean, Mexico, Mosquitoes 14 (1–49)
Central and South America
Western equine encephalitis Alphavirus Central and West Central and South America Mosquitoes <1
West Nile Flavivirus Widespread Canada, Europe, Africa, Asia Mosquitoes 3,278 (712–9,862)
International
Japanese encephalitis Flavivirus Imported only Asia Mosquitoes <1
Tick-borne encephalitis Flavivirus Imported only Europe, northern Asia Ticks <1
Venezuelan equine encephalitis Alphavirus Imported only Mexico, Central and South Mosquitoes <1
America
Yellow fever Flavivirus Imported only South America, Africa Mosquitoes <1
a Average annual number of domestic or imported cases from 2003 through 2012.
b As of December 2, 2014, 11 cases of local transmission documented in Florida.
c From 2006 through 2013, studies identified an average of 28 people per year in the United States with positive test results for recent chikungunya virus infection (range, 5—65 per year). All were travelers visiting or returning
to the United States from affected areas, mostly Asia. As of December 2, a total of 1,911 chikungunya virus disease cases have been reported during 2014 to ArboNET from US states. Eleven locally transmitted cases have
been reported from Florida. All other cases occurred in travelers returning from affected areas in the Americas (n=1,880), the Pacific Islands (n=9), or Asia (n=11). Updated information on chikungunya in the Americas can be
found at www.cdc.gov/chikungunya/geo/united-states.html and www.paho.org/hq/index.php?Itemid=40931.
d Domestic and imported cases reported to ArboNET excluding indigenous transmission in Puerto Rico; dengue became nationally notifiable in 2010.
Arboviruses 27

­ hikungunya virus primarily is transmitted to


C bodies between acute- and convalescent-phase
humans through the bites of infected mosqui- serum specimens collected 2 to 3 weeks apart
toes, predominantly Aedes aegypti and Aedes may be used to confirm recent infection. In
albopictus. Humans are the primary host of patients who have been immunized against or
chikungunya virus during epidemic periods. infected with another arbovirus from the same
Blood-borne transmission is possible; cases virus family in the past, cross-reactive anti­
have been documented among laboratory per- bodies in the IgM and neutralizing antibody
sonnel handling infected blood and a health assays may make it difficult to identify which
care worker drawing blood from an infected arbovirus is causing the patient’s illness. For
patient. Rare in utero transmission has been some arboviral infections (eg, Colorado tick
documented, mostly during the second trimes- fever), the immune response may be delayed,
ter. Intrapartum transmission has also been with IgM antibodies not appearing until 2 to
documented when the mother was viremic 3 weeks after onset of illness and neutralizing
around the time of delivery. Studies have not antibodies taking up to a month to develop.
found chikungunya virus in human milk. Immunization history, date of symptom onset,
and information on other arboviruses known
Incubation Period
to circulate in the geographic area that may
Typical range, 2 to 15 days. Longer incubation cross-react in serologic assays should be con-
periods can occur in immunocompromised sidered when interpreting results.
people and for tick-borne viruses, such as tick-
borne encephalitis viruses. Viral culture and nucleic acid amplification
tests (NAATs) for RNA can be performed on
Diagnostic Tests acute-phase serum, cerebrospinal fluid, or
Arboviral infections are confirmed most fre- ­tissue specimens. Arboviruses that are more
quently by measurement of virus-specific anti- likely to be detected using culture or NAATs
body in serum or cerebrospinal fluid, usually early in the illness include chikungunya,
using an enzyme immunoassay. Acute-phase ­Colorado tick fever, dengue, and yellow fever
serum specimens should be tested for virus- viruses. For other arboviruses, results of
specific immunoglobulin (Ig) M antibody. these tests often are negative even early in the
With clinical and epidemiologic correlation, ­clinical course because of the relatively short
a positive IgM test result has good diagnostic duration of viremia. Immunohistochemical
predictive value, but cross-reaction with staining can detect specific viral antigen in
related arboviruses from the same viral family fixed tissue.
can occur. For most arboviral infections, IgM Antibody testing for common domestic arbo­
is detectable 3 to 8 days after onset of illness viral diseases is performed in most state public
and persists for 30 to 90 days, but longer per­ health laboratories and many commercial
sistence has been documented. Therefore, a ­laboratories. Confirmatory plaque-reduction
positive IgM test result occasionally reflects a neutralization tests, viral culture, NAATs,
past infection. Serum collected within 10 days immunohistochemical staining, and testing
of illness onset may not have detectable IgM, for less common domestic and international
and the test should be repeated on a convales- arboviruses are performed at the Centers for
cent sample. IgG antibody is generally detect- Disease Control and Prevention.
able in serum shortly after IgM and persists for
years. A plaque-reduction neutralization test Treatment
can be performed to measure virus-specific The primary treatment for all arboviral disease
neutralizing antibodies and to discriminate is supportive. Although various therapies have
between cross-reacting antibodies in primary been evaluated for several arboviral diseases,
arboviral infections. A 4-fold or greater none have shown specific benefit.
increase in virus-specific neutralizing anti­

ERRNVPHGLFRVRUJ
28 Arboviruses

Image 6.1
Digital gangrene in an 8-month-old girl during week 3 of hospitalization. She was admitted to the
hospital with fever, multiple seizures, and a widespread rash; chikungunya virus was detected in her
plasma. A, Little finger of the left hand; B, index finger of the right hand; C, 4 toes on the right foot.
Courtesy of Centers for Disease Control and Prevention/Emerging Infectious Diseases.

Image 6.2
Cutaneous eruption of chikungunya infection, a generalized exanthema comprising noncoales­cent
lesions, occurs during the first week of the disease, as seen in this patient with erythematous
maculopapular lesions with islands of normal skin. Courtesy of Centers for Disease Control and
Prevention/Emerging Infectious Diseases and Patrick Hochedez.

ERRNVPHGLFRVRUJ
Arboviruses 29

Image 6.3
This image of an autopsy specimen shows characteristic changes in liver tissue from yellow fever
infection. Yellow fever is transmitted by the bites of infected mosquitoes. The word “yellow” in the
name refers to the jaundice that affects some patients. The virus is endemic in tropical areas of Africa
and Latin America. There is no cure for yellow fever. Fortunately, most infected patients improve and
their symptoms disappear after 3 to 4 days. However, 15% of patients enter a second, more toxic,
phase of the disease. About half of the patients who enter the second phase die within 10 to 14 days;
the rest recover. Courtesy of Centers for Disease Control and Prevention.

Image 6.4
An electron micrograph of yellow fever virus
virions. Virions are spheroidal, uniform in shape,
and 40 to 60 nm in diameter. The name “yellow
fever” is due to the ensuing jaundice that affects
some patients. The vector is the Aedes aegypti or
Haemagogus species mosquito.
Image 6.5
This colorized transmission electron micrograph
depicts a salivary gland that had been extracted
from a mosquito, which was infected by the
eastern equine encephalitis virus, which has
been colorized red (magnification x83,900).
Courtesy of Centers for Disease Control and
Prevention/Fred Murphy, MD, and Sylvia Whitfield.

ERRNVPHGLFRVRUJ
30 Arboviruses

Image 6.6
Global spread of chikungunya virus during 2005 through 2009. Courtesy of Morbidity and Mortality
Weekly Report.

Image 6.7
Yellow fever vaccine recommendations in Africa, 2010. Courtesy of Centers for Disease Control
and Prevention.

ERRNVPHGLFRVRUJ
Arboviruses 31

Image 6.8
Yellow fever vaccine recommendations in the Americas, 2010. Courtesy of Centers for Disease Control
and Prevention.

Image 6.9
A close-up anterior view of a Culex tarsalis mosquito as it was about to begin feeding. The
epidemiologic importance of C tarsalis lies in its ability to spread western equine encephalo­myelitis,
St. Louis encephalitis, and California encephalitis and is currently the main vector of West Nile virus in
the western United States. Courtesy of Centers for Disease Control and Prevention/James Gathany.

ERRNVPHGLFRVRUJ
32 Arboviruses

Image 6.10
Geographic distribution of Japanese encephalitis. Courtesy of Centers for Disease Control
and Prevention.

Image 6.11
The virus is transmitted by the bites of infected mosquitoes. This is an image of a Culex mosquito
laying eggs. Japanese encephalitis is the most common vaccine-preventable cause of encephalitis
in Asia. Most infections are mild (eg, fever, headache) or without apparent symptoms. However, about
1 in 200 infections results in severe disease characterized by rapid onset of high fever, headache,
neck stiffness, disorientation, coma, seizures, spastic paralysis, and death. Vaccines are available to
prevent Japanese encephalitis. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
ARCANOBACTERIUM ­HAEMOLYTICUM INFECTIONS 33

7 tract secretions. Severe disease occurs almost


exclusively among people who are immuno-
Arcanobacterium compromised. Pharyngitis occurs primarily
­haemolyticum Infections in adolescents and young adults and is very
unusual in young children. Although long-
Clinical Manifestations term pharyngeal carriage with A haemolyticum
Acute pharyngitis attributable to Arcanobac­ has been described after an episode of acute
terium haemolyticum is often indistinguishable pharyngitis, isolation of the bacterium from
from that caused by group A streptococci. the nasopharynx of asymptomatic people
Fever, pharyngeal exudate, lymphadenopathy, is rare.
rash, and pruritus are common, but palatal
Incubation Period
petechiae and strawberry tongue are absent.
In almost half of all reported cases, a maculo- Unknown.
papular or scarlatiniform exanthem is present,
Diagnostic Tests
beginning on the extensor surfaces of the distal
extremities, spreading centripetally to the chest A haemolyticum grows on blood-enriched agar,
and back, and sparing the face, palms, and but colonies are small, have narrow bands of
soles. Rash is associated primarily with cases hemolysis, and may not be visible for 48 to
presenting with pharyngitis and typically 72 hours. Detection is enhanced by culture on
develops 1 to 4 days after onset of sore throat, rabbit or human blood agar rather than sheep
although cases have been reported with rash blood agar because of larger colony size and
preceding pharyngitis. Respiratory tract infec- wider zones of hemolysis. Presence of 5% car-
tions that mimic diphtheria, including mem- bon dioxide also enhances growth. Pits charac-
branous pharyngitis, sinusitis, and pneumonia, teristically form under the colonies on blood
and skin and soft tissue infections, including agar plates. Two biotypes of A haemolyticum
chronic ulceration, cellulitis, paronychia, and have been identified: a rough biotype predomi-
wound infection, have been attributed to A nates in respiratory tract infections, and a
haemolyticum. Invasive infections, including smooth biotype is most commonly associated
septicemia, peritonsillar abscess, Lemierre with skin and soft-tissue infections.
­syndrome, brain abscess, orbital cellulitis, Treatment
meningitis, endocarditis, pyogenic arthritis,
osteomyelitis, urinary tract infection, pneu­ Erythromycin is the drug of choice for treating
monia, spontaneous bacterial peritonitis, and tonsillopharyngitis attributable to A haemoly­
pyothorax, have been reported. No nonsuppu- ticum. A haemolyticum generally is susceptible
rative sequelae have been reported. to azithromycin, clindamycin, cefuroxime,
vancomycin, and tetracycline. Failures in
Etiology ­treatment of pharyngitis with penicillin have
A haemolyticum is a catalase-negative, weakly been reported. Resistance to trimethoprim-­
acid-fast, facultative, hemolytic, anaerobic, sulfamethoxazole is common. In rare cases
gram-positive, slender, sometimes club-shaped of disseminated infection, susceptibility tests
bacillus formerly classified as Corynebacterium should be performed. In disseminated infec-
haemolyticum. tion, parenteral penicillin plus an aminoglyco-
side may be used initially as empiric treatment.
Epidemiology
Humans are the primary reservoir of
A ­haemolyticum, and spread is person to
­person, presumably via droplet respiratory

ERRNVPHGLFRVRUJ
34 ARCANOBACTERIUM ­HAEMOLYTICUM INFECTIONS

Image 7.2
Arcanobacterium haemolyticum–associated
rash on dorsal surface of hand in the 12-year-old
boy in images 7.1, 7.3, and 7.4. Copyright
Williams/Karofsky.

Image 7.1
Arcanobacterium haemolyticum was isolated on
pharyngeal culture from this 12-year-old boy with
an erythematous rash that was followed by mild
desquamation. Copyright Williams/Karofsky.

Image 7.4
Although not present in this patient with facial
skin lesions associated with Arcanobacterium
haemolyticum pharyngitis, a pharyngeal mem­
brane similar to that of diphtheria may occur with
A haemolyticum pharyngeal infection. Copyright
Williams/Karofsky.
Image 7.3
Note that the palms are affected in this patient,
though they are often spared. Copyright Williams/
Karofsky.

Image 7.6
Arcanobacterium haemolyticum on blood agar.
Colonies are small and produce b-hemolysis on
Image 7.5 blood agar. Courtesy of Julia Rosebush, DO;
Arcanobacterium haemolyticum (Gram stain). A Robert Jerris, PhD; and Theresa Stanley,
haemolyticum appears strongly gram-positive in M(ASCP).
young cultures but becomes more gram-variable
after 24 hours of incubation. Copyright Noni
MacDonald, MD, FAAP.

ERRNVPHGLFRVRUJ
ASCARIS LUMBRICOIDES INFECTIONS 35

8 ing rural and urban communities character-


ized by poor sanitation. Adult worms can live
Ascaris lumbricoides for 12 to 18 months, resulting in daily fecal
Infections excretion of large numbers of ova. Female
worms are longer than male worms and can
Clinical Manifestations measure 40 cm in length and 6 mm in diam-
Most infections with Ascaris lumbricoides are eter. Direct person-to-person transmission
asymptomatic, although moderate to heavy does not occur.
infections can lead to malnutrition and non-
Incubation Period
specific gastrointestinal tract symptoms.
­During the larval migratory phase, an acute Approximately 8 weeks (from ingestion to egg-
transient pneumonitis (Löffler syndrome) laying adults).
­associated with fever and marked eosinophilia
Diagnostic Tests
may occur. Acute intestinal obstruction has
been associated with heavy infections. Chil- Ova are routinely detected by examination of
dren are prone to this complication because of a fresh stool specimen using light microscopy.
the small diameter of the intestinal lumen and Infected people may also pass adult worms
their propensity to acquire large worm bur- from the rectum, from the nose after migration
dens. Worm migration can cause peritonitis through the nares, and from the mouth, usu-
secondary to intestinal wall perforation and ally in vomitus. Adult worms may be detected
common bile duct obstruction, resulting in by computed tomographic scan of the abdo-
biliary colic, cholangitis, or pancreatitis. Adult men or by ultrasonographic examination of
worms can be stimulated to migrate by stress- the biliary tree.
ful conditions (eg, fever, illness, anesthesia) Treatment
and by some anthelmintic drugs. A lumbricoi­
des has been found in the appendiceal lumen Albendazole (taken with food in a single dose),
in patients with acute appendicitis. mebendazole for 3 days, or ivermectin (taken
on an empty stomach in a single dose) is rec-
Etiology ommended for treatment of ascariasis. Nita­
A lumbricoides is the most prevalent of all zoxanide taken twice a day for 3 days is also
human intestinal nematodes (roundworms), effective against A lumbricoides. Reexamina-
with more than 1 billion people infected tion of stool specimens can be performed
­worldwide. 2 weeks after therapy to determine whether
the worms have been eliminated.
Epidemiology
Conservative management of small bowel
Adult worms live in the lumen of the small
obstruction, including nasogastric suction and
intestine. Female worms produce approxi-
intravenous fluids, may result in resolution of
mately 200,000 eggs per day, which are
major symptoms before administration of
excreted in stool and must incubate in soil for
anthelmintic therapy. Use of mineral oil or
2 to 3 weeks for an embryo to become infec-
diatrizoate meglumine and diatrizoate sodium
tious. Following ingestion of embryonated
solution (Gastrografin), orally or by nasogas-
eggs, usually from contaminated soil, larvae
tric tube, may cause relaxation of the bolus of
hatch in the small intestine, penetrate the
worms. Surgical intervention occasionally is
mucosa, and are transported passively by por-
necessary to relieve intestinal or biliary tract
tal blood to the liver and lungs. After migrating
obstruction or for volvulus or peritonitis sec-
into the airways, larvae ascend through the
ondary to perforation. Endoscopic retrograde
­tracheobronchial tree to the pharynx, are
cholangiopancreatography has been used
­swallowed, and mature into adults in the small
­successfully for extraction of worms from
intestine. Infection with A lumbricoides is most
the biliary tree.
common in resource-limited countries, includ-

ERRNVPHGLFRVRUJ
36 ASCARIS LUMBRICOIDES INFECTIONS

Image 8.1
This micrograph reveals a fertilized egg of the
roundworm Ascaris lumbricoides (magnification
x400). Fertilized eggs are rounded and have a
thick shell, while unfertilized eggs are elongated
and larger, thinner shelled, and covered by a Image 8.2
more visible mammillated layer, which is some­ A fertilized ascaris egg, still at the unicellular
times covered by protuberances. Courtesy of stage, which is the usual stage when the eggs
Centers for Disease Control and Prevention/ are passed in the stool (complete development
Mae Melvin, MD. of the larva requires 18 days under favorable
conditions). Courtesy of Centers for Disease
Control and Prevention.

Image 8.3
Adult ascaris.

Image 8.4
An adult ascaris. Diagnostic characteristics:
tapered ends; length, 15 to 35 cm (females tend
to be larger). This worm is a female, as evidenced
Image 8.5 by the size and genital girdle (the dark circular
A mass of large roundworms (Ascaris groove at left side of image). Courtesy of Centers
lumbricoides) from a human infestation. for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
ASCARIS LUMBRICOIDES INFECTIONS 37

Image 8.6
Adult worms (1) live in the lumen of the small intestine. A female may produce approximately 200,000
eggs per day, which are passed with the feces (2). Unfertilized eggs may be ingested but are not infec­
tive. Fertile eggs embryonate and become infective after 18 days to several weeks (3), depending on
the environmental conditions (optimum: moist, warm, shaded soil). After infective eggs are swallowed
(4), the larvae hatch (5), invade the intestinal mucosa, and are carried via the portal, and then systemic
circulation to the lungs (6). The larvae mature further in the lungs (10–14 days), penetrate the alveolar
walls, ascend the bronchial tree to the throat, and are swallowed (7). On reaching the small intestine,
they develop into adult worms. Between 2 and 3 months are required from ingestion of the infective
eggs to oviposition by the adult female. Adult worms can live 1 to 2 years. Courtesy of Centers for
Disease Control and Prevention/Courtesy of DPDx.

ERRNVPHGLFRVRUJ
38 Aspergillosis

9 philia, and transient pulmonary infiltrates.


This form of aspergillosis occurs most com-
Aspergillosis monly in immunocompetent children with
Clinical Manifestations asthma or cystic fibrosis and can be a trigger
for asthmatic flares.
Aspergillosis manifests as 3 principal clinical
entities: invasive aspergillosis, pulmonary • Allergic sinusitis is a far less common aller-
aspergilloma, and allergic disease. Coloniza- gic response to colonization by Aspergillus
tion of the respiratory tract is common. The species than allergic bronchopulmonary
clinical manifestations and severity depend aspergillosis. Allergic sinusitis occurs in
on the immune status of the host. children with nasal polyps or previous epi-
sodes of sinusitis or who have undergone
• Invasive aspergillosis occurs almost exclu- sinus surgery. Allergic sinusitis is character-
sively in immunocompromised patients with ized by symptoms of chronic sinusitis with
prolonged neutropenia (eg, cytotoxic chemo- dark plugs of nasal discharge.
therapy), graft-versus-host disease, impaired
phagocyte function (eg, chronic granuloma- Etiology
tous disease), or receipt of T lymphocyte Aspergillus species are ubiquitous molds that
immunosuppressive therapy. Children at grow on decaying vegetation and in soil.
highest risk include those with new-onset ­Aspergillus fumigatus is the most common
acute myelogenous leukemia, with relapse of cause of invasive aspergillosis, with Aspergillus
hematologic malignancy, and recipients of flavus being the next most common. Several
allogeneic hematopoietic stem cell and solid other species, including Aspergillus terreus,
organ transplantation. Invasive infection Aspergillus nidulans, and Aspergillus niger,
usually involves pulmonary, sinus, cerebral, also cause invasive human infections.
or cutaneous sites. Rarely, endocarditis,
osteomyelitis, meningitis, infection of the Epidemiology
eye or orbit, and esophagitis occur. The The principal route of transmission is inhala-
­hallmark of invasive aspergillosis is tion of conidia (spores) originating from
­angio­invasion with resulting thrombosis, ­multiple environmental sources (eg, plants,
dis­semination to other organs, and, vegetables, dust from construction or demoli-
occasion­a lly, erosion of the blood vessel tion), soil, and water supplies (eg, shower-
wall with catastrophic hemorrhage. Asper- heads). Incidence of disease in hematopoietic
gillosis in patients with chronic granuloma- stem cell transplant recipients is highest during
tous disease rarely displays angioinvasion. periods of neutropenia or treatment for graft-
• Pulmonary aspergillomas and otomycosis versus-host disease. In solid organ transplant
are 2 syndromes of nonallergic colonization recipients, the risk is highest 1 to 6 months after
by Aspergillus species in immunocompetent transplantation or during periods of increased
children. Aspergillomas (“fungal balls”) immunosuppression. Health care–associated
grow in preexisting pulmonary cavities or outbreaks of invasive pulmonary aspergillosis
bronchogenic cysts without invading pulmo- in susceptible hosts have occurred in which the
nary tissue; almost all patients have under­ probable source of the fungus was a nearby
lying lung disease, such as cystic fibrosis or construction site or faulty ventilation system.
tuberculosis. Patients with otomycosis have Cutaneous aspergillosis occurs less frequently
chronic otitis media with colonization of the and usually involves sites of skin injury, such
external auditory canal by a fungal mat that as intravenous catheter sites, sites of traumatic
produces a dark discharge. inoculation, and sites associated with occlusive
dressings, burns, or surgery. Transmission by
• Allergic bronchopulmonary aspergillosis direct inoculation of skin abrasions or wounds
is a hypersensitivity lung disease that mani- is less likely. Person-to-person spread does
fests as episodic wheezing, expectoration of not occur.
brown mucus plugs, low-grade fever, eosino-

ERRNVPHGLFRVRUJ
Aspergillosis 39

Incubation Period (Ig) E (≥1,000 ng/mL) and Aspergillus-specific


Unknown. serum IgE, eosinophilia, and a positive result
from a skin test for Aspergillus antigens. In
Diagnostic Tests people with cystic fibrosis, diagnosis is more
Dichotomously branched and septate hyphae, difficult because wheezing, eosinophilia, and
identified by microscopic examination of 10% a positive skin test result not associated with
potassium hydroxide wet preparations or of allergic bronchopulmonary aspergillosis are
Grocott-Gomori methenamine–silver nitrate often ­present.
stain of tissue or bronchoalveolar lavage speci- Treatment
mens, are suggestive of the diagnosis. Isolation
of Aspergillus species or molecular testing with Voriconazole is the drug of choice for invasive
specific reagents is required for definitive diag- aspergillosis, except in neonates, for whom
nosis. The organism is usually not recoverable amphotericin B deoxycholate in high doses is
from blood (except A terreus) but is isolated recommended. Voriconazole has been shown
readily from lung, sinus, and skin biopsy speci- to be superior to amphotericin B in a large,
mens when cultured on fungal media. Asper­ randomized trial in adults. Therapy is contin-
gillus species can be a laboratory contaminant, ued for at least 12 weeks, but treatment dura-
but when evaluating results from ill, immuno- tion should be individualized. Monitoring of
compromised patients, recovery of this organ- serum galactomannan concentrations in those
ism frequently indicates infection. Biopsy of a with significant elevation at onset may be use-
lesion is usually required to confirm the diag- ful to assess response to therapy concomitant
nosis, and care should be taken to distinguish with clinical and radiologic evaluation. Vori-
aspergillosis from mucormycosis, which conazole is metabolized in a linear fashion in
appears similar by diagnostic imaging studies. children, so the recommended adult dosing is
An enzyme immunosorbent assay serologic too low for children. Children 12 years and
test for detection of galactomannan, a molecule older who weigh 50 kg or more should receive
found in the cell wall of Aspergillus species, the adult dose. Close monitoring of voricon-
from the serum or bronchoalveolar lavage fluid azole serum trough concentrations when oral
is available commercially and has been found voriconazole is used is critical for efficacy and
to be useful in children and adults. Monitoring safety and because there is high interpatient
of serum antigen concentrations twice weekly variability in metabolism.
in periods of highest risk (eg, neutropenia, Lipid formulations of amphotericin B can be
active graft-versus-host disease) may be useful considered as alternative primary therapy
for early detection of invasive aspergillosis in in some patients, but A terreus is resistant to
at-risk patients. False-positive test results have all amphotericin B products. In refractory dis-
been reported and can be related to consump- ease, treatment could include posaconazole,
tion of food products containing galactoman- caspofungin, or micafungin. Caspofungin has
nan (eg, rice, pasta) or cross-reactivity with been studied in pediatric patients older than
antimicrobial agents derived from fungi (eg, 3 months as salvage therapy for invasive asper-
penicillins, especially piperacillin-tazobactam). gillosis. Limited data from a predominantly
A negative galactomannan test result does not adult population are available but suggest that
exclude diagnosis. A negative galactomannan micafungin and caspofungin have similar effi-
test result consistently occurs in patients with cacy in treatment of refractory aspergillosis.
chronic granulomatous disease. Children fre- The pharmacokinetics and safety of posacon-
quently do not manifest cavitation or the air azole have not been evaluated in
crescent or halo signs on chest radiography, younger ­children.
and lack of these characteristic signs does not
exclude the diagnosis of invasive aspergillosis. The efficacy and safety of combination anti­
fungal therapy for invasive aspergillosis is
In allergic aspergillosis, diagnosis is suggested uncertain, but the most promising combina-
by a typical clinical syndrome with elevated tion is a broad-spectrum azole combined with
total concentrations of immunoglobulin an echinocandin. Immune reconstitution can

ERRNVPHGLFRVRUJ
40 Aspergillosis

occur during treatment in some patients. surgery is indicated only when a mass is
Decreasing immunosuppression, if possible impinging on a great vessel. Allergic broncho-
(specifically decreasing corticosteroid dose), pulmonary aspergillosis is treated with corti-
is critical to disease control. costeroids, and adjunctive antifungal therapy
is recommended. Allergic sinus aspergillosis is
Surgical excision of a localized invasive lesion
also treated with corticosteroids, and surgery
(eg, cutaneous eschars, a single pulmonary
has been reported to be beneficial in many
lesion, sinus debris, accessible cerebral lesions)
cases. Antifungal therapy has not been found
is usually warranted. In pulmonary disease,
to be useful.

Image 9.2
Image 9.1
Aspergilloma at intravenous line site in a 9-year-
Aspergilloma of the hand in a 7-year-old boy with
old boy with acute lymphoblastic leukemia.
chronic granulomatous disease.

Image 9.3
Aspergillus pneumonia, bilateral, in a 16-year-old
boy with acute myelogenous leukemia. Note
pulmonary cavitation in the right lung field and Image 9.4
perihilar and retrocardiac densities in the left lung Pulmonary aspergillosis in a patient with acute
field. Copyright Michael Rajnik, MD, FAAP. lymphatic leukemia. Courtesy of Dimitris P.
Agamanolis, MD.

ERRNVPHGLFRVRUJ
Aspergillosis 41

Image 9.5
Aspergillomas in a 10-year-old with Hodgkin-type Image 9.6
lymphoma. Courtesy of Benjamin Estrada, MD. Cutaneous aspergillosis in a 23-weeks’ gestation
preterm neonate. Courtesy of David Kaufman, MD.

Image 9.7
A, Computed tomographic chest scan of a patient
with neutropenia who has invasive aspergillosis in
the left upper lung (arrow). A positive serum gala­c­
tomannan test result established the diagnosis
of probable invasive aspergillosis, which averted
the need for an invasive diagnostic procedure.
B, Cavitation of the lesion after a successful
response to therapy and neutrophil recovery
(arrow). C, Vascular invasive aspergillosis, which
is classically associated with neutropenia but can
occur in patients with other conditions, such as in
this case of fatal aspergillosis in a recipient of an
allogeneic hematopoietic stem-cell transplant
who did not have neutropenia but did have severe
graft-versus-host disease. A low-power micro­
graph shows vascular thrombosis (with an arterial
vessel outlined by arrows) that is surrounded by
extensive coagulative necrosis and hemorrhage
(hematoxylin-eosin). D, A high-power micrograph
shows hyphae (arrowheads) transverse to the
blood vessel wall (outlined by arrows) and intra­
vas­cular invasion (Grocott-Gomori methenamine–
silver nitrate stain, with hyphal walls staining dark).
The septated hyphae, some branched at acute
angles, are morphologically consistent with Aspergillus species. However, other molds can have a
similar appearance, so culture or molecular-based analysis at a reference laboratory is required for a
definitive diagnosis. E, Experimental aspergillosis in a knockout mouse model of chronic granulo­ma­
tous disease, an inherited disorder of NADPH oxidase. Densely inflammatory pyogranulomatous
pneumonia without vascular invasion or tissue infarction is visible (hematoxylin-eosin), with invasive
hyphae in the lung as seen with silver staining (inset). These histologic features are similar to those
observed in patients with chronic granulomatous disease and aspergillosis and suggest that NADPH
oxidase-independent pathways are able to defend against hyphal invasion of blood vessel walls.
From The New England Journal of Medicine, Allergic Bronchopulmonary Aspergillosis, 359, e7.
Copyright © 2008. Massachusetts Medical Society. Reprinted with permission from Massachusetts
Medical Society.

ERRNVPHGLFRVRUJ
42 Aspergillosis

Image 9.8
Conidia and phialospore of Aspergillus fumigatus. Courtesy of Centers for Disease Control
and Prevention.

Image 9.9
Aspergillus fumigatus. Courtesy of H. Cody Meissner, MD, FAAP.

ERRNVPHGLFRVRUJ
Astrovirus Infections 43

10 Transmission is via the fecal-oral route


through contaminated food or water, person-
Astrovirus Infections to-person contact, or contaminated surfaces.
Clinical Manifestations Outbreaks tend to occur in closed populations
of the young and elderly, particularly hospital-
Illness is characterized by diarrhea accompa- ized children and children in child care cen-
nied by low-grade fever, malaise, and nausea ters. Excretion lasts a median of 5 days after
and, less commonly, vomiting and mild dehy- onset of symptoms, but asymptomatic excre-
dration. Illness in an immunocompetent host tion after illness can last for several weeks in
is self-limited, lasting a median of 5 to 6 days. healthy children.
Asymptomatic infections are common.
Incubation Period
Etiology
3 to 4 days.
Astroviruses are nonenveloped, single-
stranded RNA viruses with a characteristic Diagnostic Tests
starlike appearance when visualized by elec- Commercial tests for diagnosis are not avail-
tron microscopy. Eight human antigenic types able in the United States, although enzyme
originally were described, and several novel immunoassays are available in many other
species have been identified in recent years. countries. The following tests are available
Epidemiology in some research and reference laboratories:
­electron microscopy for detection of viral par-
Human astroviruses have a worldwide distri- ticles in stool, enzyme immunoassay for detec-
bution. Multiple antigenic types cocirculate tion of viral antigen in stool or antibody in
in the same region. Astroviruses have been serum, latex agglutination in stool, and reverse
detected in as many as 5% to 17% of sporadic ­transcriptase-polymerase chain reaction assay
cases of nonbacterial gastroenteritis among for detection of viral RNA in stool. Of these
young children in the community but appear tests, reverse transcriptase-polymerase chain
to cause a lower proportion of cases of more reaction assay is the most sensitive.
severe childhood gastroenteritis requiring
­hospitalization (~3%–9%). Astrovirus infec- Treatment
tions occur predominantly in children younger No specific antiviral therapy is available. Oral
than 4 years and have a seasonal peak during or parenteral fluids and electrolytes are given
the late winter and spring in the United States. to prevent and correct dehydration.

ERRNVPHGLFRVRUJ
44 Astrovirus Infections

Image 10.1
Electron micrograph of astrovirus obtained from stool of a child with gastroenteritis. Note the
characteristic starlike appearance. Courtesy of Centers for Disease Control and Prevention.

Image 10.2
Astrovirus encephalitis in a boy with X-linked agammaglobulinemia. Panel A: special staining identifies
astrovirus in the brain of the patient; Panel B: histopathological changes in brain tissue. Encephalitis is
a major cause of death worldwide. Although more than 100 pathogens have been identified as
causative agents, the pathogen is not determined for up to 75% of cases. This diagnostic failure
impedes effective treatment and underscores the need for better tools and new approaches for
detecting novel pathogens or determining new manifestations of known pathogens. Although
astroviruses are commonly associated with gastroenteritis, they have not been associated with central
nervous system disease. Using unbiased pyrosequencing, astrovirus was determined to be the
causative agent for encephalitis in a 15-year-old boy with agammaglobulinemia. Quan PL, Wagner TA,
Briese T, et al. Astrovirus encephalitis in boy with X-linked agammaglobulinemia. Emerg Infect Dis.
2010;16(6):918–925.

ERRNVPHGLFRVRUJ
Babesiosis 45

11 r­ eservoir host for B microti is the white-footed


mouse (Peromyscus leucopus), and the primary
Babesiosis vector is the tick Ixodes scapularis, which also
Clinical Manifestations can transmit Borrelia burgdorferi, the causative
agent of Lyme disease, and Anaplasma phago­
Babesia infection is often asymptomatic or cytophilum, the causative agent of human
associated with mild, nonspecific symptoms. ­granulocytic anaplasmosis. Humans become
The infection also can be severe and life threat- infected through tick bites, which typically are
ening, particularly in people who are asplenic, not noticed. The white-tailed deer (Odocoileus
immunocompromised, or elderly. Babesiosis, virginianus) is an important host for blood
like malaria, is characterized by the presence meals for the tick but is not a reservoir host of
of fever and hemolytic anemia; however, some B microti. An increase in the deer population
infected people who are immunocompromised in some geographic areas, including some sub-
or at the extremes of age (eg, preterm new- urban areas, during the past few decades is
borns) are afebrile. There can be a prodromal thought to be a major factor in the spread of
illness, with gradual onset of symptoms, such I scapularis and the increase in numbers of
as malaise, anorexia, and fatigue, followed by reported cases of babesiosis. The reported
development of fever and other influenzalike ­vector-borne cases of B microti infection have
symptoms (eg, chills, sweats, myalgia, arthral- been acquired in the Northeast (particularly,
gia, headache, anorexia, nausea). Less common but not exclusively, in Connecticut, Massachu-
features include sore throat, nonproductive setts, New Jersey, New York, and Rhode Island)
cough, abdominal pain, vomiting, weight loss, and in the upper Midwest (Wisconsin and
conjunctival injection, photophobia, emotional Minnesota). Occasional human cases of babe-
lability, and hyperesthesia. Congenital infec- siosis caused by other species have been
tion with manifestation as severe sepsis syn- described in various regions of the United
drome has been reported. States; tick vectors and reservoir hosts for these
Clinical signs generally are minimal, often agents typically have not yet been identified.
consisting only of fever and tachycardia, Whereas most US vector-borne cases of babe-
although hypotension, respiratory distress, siosis occur during late spring, summer, or
mild hepatosplenomegaly, jaundice, and dark autumn, transfusion-associated cases can
urine may be noted. Thrombocytopenia is occur year-round.
common; disseminated intravascular coagula- Incubation Period
tion can be a complication of severe babesiosis.
If untreated, illness can last for several weeks 1 to 5 weeks after a tick bite; 1 week after a con-
or months; even asymptomatic people can have taminated blood transfusion but occasionally
persistent low-level parasitemia, sometimes for is longer (eg, latent infection might become
longer than 1 year. symptomatic after splenectomy).

Etiology Diagnostic Tests


Babesia species are intraerythrocytic protozoa. Acute, symptomatic cases of babesiosis are typ-
The etiologic agents of babesiosis in the United ically diagnosed by microscopic identification
States include Babesia microti, which is the of the organism on Giemsa- or Wright-stained
cause of most reported cases, and several other blood smears. If the diagnosis of babesiosis is
genetically and antigenically distinct organ- being considered, manual (nonautomated)
isms, such as Babesia duncani (formerly the review of blood smears for parasites should be
WA1-type parasite). requested explicitly. If seen, the tetrad (Maltese
cross) form is pathognomonic. B microti and
Epidemiology other Babesia species can be difficult to distin-
Babesiosis predominantly is a tick-borne guish from Plasmodium falciparum; examina-
­zoonosis. Babesia parasites can also be trans- tion of blood smears by a reference laboratory
mitted by blood transfusion and through peri- should be considered for confirmation of the
natal routes. In the United States, the primary diagnosis. Adjunctive molecular and serologic

ERRNVPHGLFRVRUJ
46 Babesiosis

testing is performed at the Centers for Disease moderate illness. Therapy with atovaquone
Control and Prevention. If indicated, the plus azithromycin is associated with fewer
­possibility of concurrent B burgdorferi or adverse effects. However, clindamycin and
­Anaplasma infection should be considered. ­quinine is preferred for severely ill patients.
Exchange blood transfusions should be con­
Treatment
sidered for patients who are critically ill
Clindamycin plus oral quinine for 7 to 10 days, (eg, hemodynamically unstable), especially,
or atovaquone plus azithromycin for 7 to but not exclusively, for patients with parasit-
10 days, have comparable efficacy for mild to emia levels of 10% or more.

Image 11.1
Infection with Babesia in a 6-year-old girl after a splenectomy performed because of hereditary
spherocytosis (Giemsa-stained thin smears). A, The tetrad (left side of the image), a dividing form,
is pathognomonic for Babesia. Note also the variation in size and shape of the ring stage parasites
(compare A and B) and absence of pigment. Courtesy of Centers for Disease Control and Prevention.

Image 11.2
Image 11.3
Babesia microti in a peripheral blood smear.
Note the typical intraerythrocytic location of the A Giemsa stain of a blood film from an infected
organisms. Babesiosis is often asymptomatic or human used to identify the parasite Babesia
associated with mild symptoms. The infection microti. Babesiosis is caused by hemo-protozoan
can be life-threatening in people who are asplenic parasites of the genus Babesia. While more than
or immunocompromised. 100 species have been reported, B microti and
Babesia divergens have been identified in most
human cases. Courtesy of Centers for Disease
Control and Prevention/Dr George Healy.

ERRNVPHGLFRVRUJ
Babesiosis 47

Image 11.4
The Babesia microti life cycle involves 2 hosts, which include a rodent, primarily the white-footed
mouse (Peromyscus leucopus). During a blood meal, a Babesia-infected tick introduces sporozoites
into the mouse host (1). Sporozoites enter erythrocytes and undergo asexual reproduction (budding)
(2). In the blood, some parasites differentiate into male and female gametes, although these cannot be
distinguished at the light microscope level (3). The definitive host is a tick, in this case the deer tick
(Ixodes scapularis). Once ingested by an appropriate tick (4), gametes unite and undergo a sporogonic
cycle, resulting in sporozoites (5). Transovarial transmission (also known as vertical, or hereditary,
transmission) has been documented for “large” Babesia species but not for the “small” Babesia
species, such as B microti (A). Humans enter the cycle when bitten by infected ticks. During a blood
meal, a Babesia-infected tick introduces sporozoites into the human host (6). Sporozoites enter
erythrocytes (B) and undergo asexual replication (budding) (7). Multiplication of the blood stage
parasites is responsible for clinical manifestations of the disease. Humans are, for all practical
purposes, dead-end hosts, and there is probably little, if any, subsequent transmission that occurs
from ticks feeding on infected persons. However, human-to-human transmission is well recognized to
occur through blood transfusions (8). Note: Deer are the hosts on which the adult ticks feed and are
indirectly part of the Babesia cycle, as they influence the tick population. When deer populations
increase, tick population also increases, thus heightening the potential for transmission. Courtesy of
Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
48 Babesiosis

Image 11.5
Babesiosis is caused by parasites that infect red blood cells and are spread by certain ticks. In
the United States, tick-borne transmission is most common in parts of the Northeast and upper
Midwest, and it usually peaks during the warm months. Although many people who are infected
with Babesia do not have symptoms, effective treatment is available if symptoms develop.
Babesiosis is preventable if simple steps are taken to reduce exposure to ticks. Courtesy of
Centers for Disease Control and Prevention.

Image 11.6
Number of reported cases, by county—United States, 2012. Courtesy of Morbidity and Mortality
Weekly Report.

ERRNVPHGLFRVRUJ
BACILLUS CEREUS INFECTIONS 49

12 enterotoxins over a wide range of temperatures


in foods and in the gastrointestinal tract; the
Bacillus cereus Infections latter results in diarrheal syndrome. The emetic
Clinical Manifestations syndrome occurs after eating contaminated
food containing preformed emetic toxin. The
Bacillus cereus is primarily associated with best known association of the emetic syndrome
2 toxin-mediated foodborne illnesses, emetic is with ingestion of fried rice made from boiled
and diarrheal, but it can also cause invasive rice stored at room temperature overnight, but
extraintestinal infection. The emetic syndrome illness has been associated with a wide variety
develops after a short incubation period, simi- of foods. Foodborne illness caused by B cereus
lar to staphylococcal foodborne illness. It is not transmissible from person to person
is characterized by nausea, vomiting, and
abdominal cramps, and diarrhea can follow Risk factors for invasive disease attributable to
in 30% of patients. The diarrheal syndrome B cereus include history of injection drug use,
has a longer incubation period, is more severe, presence of indwelling intravascular catheters
and resembles Clostridium perfringens food- or implanted devices, neutropenia or immuno-
borne illness. It is characterized by moderate to suppression, and preterm birth. B cereus
severe abdominal cramps and watery diarrhea, endoph­t halmitis has occurred after penetrat-
vomiting in approximately 25% of patients, ing ocular trauma and injection drug use.
and, occasionally, low-grade fever. Both ill-
Incubation Period
nesses are usually short-lived, but the emetic
toxin has been associated with fulminant Emetic syndrome, 0.5 to 6 hours; diarrheal
liver failure. ­syndrome, 6 to 24 hours.

Invasive extraintestinal infection can be severe Diagnostic Tests


and can include a wide range of diseases, For foodborne outbreaks, isolation of B cereus
including wound and soft tissue infections; from the stool or vomitus of 2 or more ill peo-
bacteremia, including central line–associated ple and not from control patients, or isolation
bloodstream infection; endocarditis; osteo­ of 105 colony-forming units/g or greater from
myelitis; purulent meningitis and ventricular epidemiologically implicated food, suggests
shunt infection; pneumonia; and ocular infec- that B cereus is the cause of the outbreak.
tions. Along with staphylococci, B cereus is a Because the organism can be recovered from
significant cause of bacterial endophthalmitis. stool specimens from some well people, the
Ocular involvement includes panophthalmitis, presence of B cereus in feces or vomitus of ill
endophthalmitis, and keratitis. people is not definitive evidence of infection.
Etiology Food samples must be tested for both entero-
toxins because either alone can cause illness.
B cereus is an aerobic and facultatively anaero-
bic, spore-forming, gram-positive bacillus. In patients with risk factors for invasive dis-
ease, isolation of B cereus from wounds, blood,
Epidemiology or other usually sterile body fluids is signifi-
B cereus is ubiquitous in the environment and cant. The common perception of Bacillus spe-
is commonly present in small numbers in raw, cies as “contaminants” may delay recognition
dried, and processed foods. The organism is a and treatment of serious B cereus infections.
common cause of foodborne illness in the
Treatment
United States but may be under-recognized
because physicians and clinical laboratories B cereus foodborne illness usually requires
do not routinely test for B cereus. only supportive treatment. Antimicrobial
­t herapy is indicated for patients with invasive
Spores of B cereus are heat resistant and can disease. Prompt removal of any potentially
survive pasteurization, brief cooking, or boil- infected foreign bodies, such as central lines
ing. Vegetative forms can grow and produce or implants, is essential. For intraocular

ERRNVPHGLFRVRUJ
50 BACILLUS CEREUS INFECTIONS

i­ nfections, an ophthalmologist should be con- B cereus usually is resistant to β-lactam anti­


sulted about use of intravitreal vancomycin biotics and clindamycin but is susceptible to
therapy in addition to systemic therapy. vancomycin, which is the drug of choice.

Image 12.1
Bacillus cereus subsp mycoides (Gram stain). Image 12.2
B cereus is a known cause of toxin-induced Leifson flagella stain. Bacillus cereus food
food poisoning. These organisms may appear poisoning is often associated with contaminated
gram-variable, as shown here. Courtesy of rice containing heat-resistant B cereus spores.
Centers for Disease Control and Prevention/ Courtesy of Centers for Disease Control
Dr William A. Clark. and Prevention/Dr William A. Clark.

Image 12.4
Bacillus cereus on sheep blood agar. Large,
circular, β-hemolytic colonies are noted. The
greenish color and ground-glass appearance
Image 12.3
are typical characteristics of this organism on
Blood agar and bicarbonate agar plate cultures culture media. Courtesy of Julia Rosebush, DO;
of Bacillus cereus (negative encapsulation test). Robert Jerris, PhD; and Theresa Stanley,
Rough colonies of B cereus on blood and bicar­ M(ASCP).
bonate agars. Courtesy of Centers for Disease
Control and Prevention/Dr James Feeley.

ERRNVPHGLFRVRUJ
Bacterial Vaginosis 51

13 transmitted infections. Bacterial vaginosis


occurs more frequently in females with a new
Bacterial Vaginosis sexual partner or a higher number of sexual
Clinical Manifestations partners and in those who engage in douching.
Although evidence of sexual transmission of
Bacterial vaginosis (BV) is a polymicrobial BV is inconclusive, the correct and consistent
clinical syndrome characterized by changes use of condoms reduces the risk of acquisition.
in vaginal flora, with replacement of normally Bacterial vaginosis increases the risk of infec-
abundant Lactobacillus species by high con­ tious complications following gynecologic sur-
centrations of anaerobic bacteria. Bacterial gery as well as pregnancy complications and
vaginosis is diagnosed primarily in sexually the acquisition of HIV, human herpesvirus 2,
active postpubertal females, but women who N gonorrhoeae, and C trachomatis.
have never been sexually active also can be
affected. Bacterial vaginosis is asymptomatic Incubation Period
in 50% to 75% of females. Symptoms include Unknown.
a thin white or gray, homogenous, adherent
vaginal discharge with a fishy odor vaginal Diagnostic Tests
discharge. Symptoms of vulvovaginal irrita- Bacterial vaginosis is most commonly diag-
tion, pruritus, dysuria, or abdominal pain are nosed clinically using the Amsel criteria,
not associated with BV. In pregnant women, requiring that 3 or more of the following
BV has been associated with adverse outcomes, ­symptoms or signs are present:
including chorioamnionitis, premature rup-
ture of membranes, preterm delivery, and • Homogenous, thin gray or white vaginal
­postpartum endometritis. discharge that smoothly coats the vaginal
walls
Vaginitis and vulvitis in prepubertal girls
rarely, if ever, are manifestations of BV. • Vaginal fluid pH greater than 4.5
­Vaginitis in prepubertal girls is frequently • A fishy (amine) odor of vaginal discharge
­nonspecific, but possible causes include foreign before or after addition of 10% potassium
bodies and infections attributable to group A hydroxide (ie, the “whiff test”)
streptococci, Escherichia coli, human herpes­
virus, Neisseria gonorrhoeae, Chlamydia • Presence of clue cells (squamous vaginal
­trachomatis, Trichomonas vaginalis, or enteric epithelial cells covered with bacteria, which
bacteria, including Shigella species. cause a stippled or granular appearance and
ragged “moth-eaten” borders) representing
Etiology at least 20% of the total vaginal epithelial
The microbiologic cause of BV has not been cells seen on microscopic evaluation of
delineated fully. In females with BV, Lactobac­ ­vaginal fluid
illus species largely are replaced by commensal
An alternative method for diagnosing BV is
anaerobes. Typical microbiologic findings in
the Nugent score, which is used widely as the
vaginal specimens show increased concentra-
gold standard for making the diagnosis in the
tions of Gardnerella vaginalis, Mycoplasma
research setting. Douching, recent intercourse,
hominis, Prevotella species, Mobiluncus spe-
menstruation, and coexisting infection can
cies, and Ureaplasma species.
alter findings on Gram stain. The BD Affirm
Epidemiology VPIII test (BD Diagnostic Systems, Sparks,
MD) is a DNA probe test that detects
Bacterial vaginosis is the most common cause
G ­vaginalis and can be used when symptoms
of vaginal discharge in sexually active adoles-
and signs are suggestive of BV but microscopy
cent and adult women. Bacterial vaginosis can
is unavailable. Clinical Laboratory Improve-
be the sole cause of symptoms or accompany
ment Amendments–waived rapid tests for
other conditions associated with vaginal dis-
BV that measure the activity of sialidase, an
charge, such as trichomoniasis or mucopuru-
enzyme generated by several BV-associated
lent cervicitis secondary to other sexually

ERRNVPHGLFRVRUJ
52 Bacterial Vaginosis

bacteria, such as Diagnosit BVBlue (Gryphus decrease the risk of infectious complications.
Diagnostics, Knoxville, TN) and OSOM Treatment considerations should include
BVBlue Test (Sekisui Diagnostics, Lexington, patient preference for oral versus intravaginal
MA), have strong clinical performance com- treatment, possible adverse effects, and pres-
pared with the Nugent criteria. The FemExam ence of coinfections. Nonpregnant patients
G vaginalis PIP Activity TestCard (Litmus may be treated orally with metronidazole or
Concepts Inc, Santa Clara, CA) detects proline topically with metronidazole gel or clinda­
iminopeptidase activity of anaerobes and can mycin cream. Alternative regimens include
be performed as a point-of-care test in less oral tinidazole, oral clindamycin, or clinda­
than 2 minutes. mycin intravaginally.
Sexually active females with BV should be eval- Approximately 30% of appropriately treated
uated for coinfection with syphilis, gonorrhea, females have a recurrence within 3 months.
chlamydia, trichomoniasis, and HIV. Comple- Retreatment with the same regimen or an
tion of the hepatitis B and human papillomavi- alternative regimen are both reasonable options.
rus immunization series should be confirmed.
Pregnant or breastfeeding women with symp-
Treatment toms of BV should be treated with oral metro-
Symptomatic patients should be treated. nidazole or clindamycin. Oral therapies are
The goals of treatment are to relieve the symp- preferred in pregnancy to treat possible upper
toms and signs of infection and to potentially genital tract infection.

Image 13.1
Clue cells are squamous epithelial cells covered
with bacteria found in bacterial vaginosis.
Copyright Noni MacDonald, MD. Image 13.2
This photomicrograph reveals bacteria adhering
to vaginal epithelial cells known as clue cells.
Clue cells are epithelial cells that have had
bacteria adhere to their surface, obscuring their
borders, and imparting a stippled appearance.
The presence of such clue cells is a sign the
patient has bacterial vaginosis. Courtesy of
Centers for Disease Control and Prevention/
M. Rein.

Image 13.3
Gardnerella vaginalis on chocolate agar. Colonies
are small, circular, gray, and convex. Courtesy of
Julia Rosebush, DO; Robert Jerris, PhD; and
Theresa Stanley, M(ASCP).

ERRNVPHGLFRVRUJ
BACTEROIDES AND ­PREVOTELLA INFECTIONS 53

14 Endogenous infection results from aspiration,


bowel perforation, or damage to mucosal sur-
Bacteroides and faces from trauma, surgery, or chemotherapy.
­Prevotella Infections Mucosal injury or granulocytopenia predis-
pose to infection. Enterotoxigenic B fragilis
Clinical Manifestations may be a cause of diarrhea. Except in infections
Bacteroides and Prevotella organisms from the resulting from human bites, no evidence of
oral cavity can cause chronic sinusitis, chronic person-to-person transmission exists.
otitis media, dental infection, peritonsillar
Incubation Period
abscess, cervical adenitis, retropharyngeal
space infection, aspiration pneumonia, lung Usually 1 to 5 days (depending on inoculum
abscess, pleural empyema, or necrotizing and body site).
­pneumonia. Species from the gastrointestinal
Diagnostic Tests
tract are recovered in patients with peritonitis,
intra-abdominal abscess, pelvic inflammatory Anaerobic culture media are necessary for
disease, postoperative wound infection, or vul- recovery of Bacteroides or Prevotella species.
vovaginal and perianal infections. Invasion of Because infections usually are polymicrobial,
the bloodstream from the oral cavity or intesti- aerobic cultures should also be obtained. A
nal tract can lead to brain abscess, meningitis, putrid odor suggests anaerobic infection. Use
endocarditis, arthritis, or osteomyelitis. Skin of an anaerobic transport tube or a sealed
and soft tissue infections include synergistic syringe is recommended for collection of clini-
bacterial gangrene and necrotizing fasciitis; cal specimens.
omphalitis in newborns; cellulitis at the site of Treatment
fetal monitors, human bite wounds, or burns;
infections adjacent to the mouth or rectum; Abscesses should be drained when feasible;
and infected decubitus ulcers. Neonatal infec- abscesses involving the brain, liver, and lungs
tions, including conjunctivitis, pneumonia, may resolve with effective antimicrobial ther-
bacteremia, or meningitis, are rare. In most apy. Necrotizing soft tissue lesions should be
settings where Bacteroides and Prevotella are debrided surgically and can require repeated
implicated, the infections are ­polymicrobial. surgeries.

Etiology The choice of antimicrobial agent(s) is based on


anticipated or known in vitro susceptibility
Most Bacteroides and Prevotella organisms testing. Bacteroides infections of the mouth
associated with human disease are pleomor- and respiratory tract generally are susceptible
phic, nonspore-forming, facultatively anaero- to penicillin G, ampicillin, and extended-­
bic, gram-negative bacilli. spectrum penicillins, such as ticarcillin or
Epidemiology piperacillin. Clindamycin is active against
­v irtually all mouth and respiratory tract
Bacteroides and Prevotella species are part of
­Bacteroides and Prevotella isolates and is
the normal flora of the mouth, gastrointestinal
­recommended by some experts as the drug
tract, and female genital tract. Members of the
of choice for anaerobic infections of the oral
Bacteroides fragilis group predominate in the
cavity and lungs but is not recommended for
gastrointestinal tract flora; members of the Pre­
central nervous system infections. Some spe-
votella melaninogenica (formerly Bacteroides
cies of Bacteroides and almost 50% of Prevotella
melaninogenicus) and Prevotella oralis (for-
species produce β-lactamase. A β-lactam
merly Bacteroides oralis) groups are more com-
­penicillin active against Bacteroides species
mon in the oral cavity. These species cause
combined with a β-lactamase inhibitor
infection as opportunists, usually after an
(­ampicillin-sulbactam, amoxicillin-clavulanate,
alteration in skin or mucosal membranes in
ticarcillin-clavulanate, or piperacillin-­
conjunction with other endogenous species.
tazobactam) can be useful to treat these infec-

ERRNVPHGLFRVRUJ
54 BACTEROIDES AND ­PREVOTELLA INFECTIONS

tions. Bacteroides species of the gastrointestinal phenicol, and, sometimes, clindamycin. More
tract usually are resistant to penicillin G but than 80% of isolates are susceptible to cefoxitin
are predictably susceptible to metronidazole, and meropenem. Cefuroxime, cefotaxime, and
β-lactam plus β-lactamase inhibitors, chloram- ceftriaxone are not reliably effective.

Image 14.1 Image 14.2


Bacteroides fragilis pneumonia in a newborn Prevotella melaninogenica (previously Bacteroides
(B fragilis isolated from the placenta and blood melaninogenicus) and group A α-hemolytic strep­
culture from the newborn). Anaerobic cultures tococcus cultured from a submandibular subcu­
were obtained because of a fecal odor in the taneous abscess aspirate from a 12-year-old boy.
amniotic fluid. There was no apparent dental, pharyngeal, or
middle ear infection.

Image 14.3 Image 14.4


Bacteroides fragilis abdominal abscess in a This photomicrograph shows Bacteroides fragilis
9-year-old boy. Courtesy of Benjamin Estrada, MD. after being cultured in a thioglycollate medium
for 48 hours. B fragilis is a gram-negative rod
that constitutes 1% to 2% of the normal colonic
bacterial microflora in humans. It is associated
with extraintestinal infections such as abscesses
and soft tissue infections, as well as diarrheal
diseases. Courtesy of Centers for Disease
Control and Prevention/Dr V. R. Dowell Jr.

ERRNVPHGLFRVRUJ
BACTEROIDES AND ­PREVOTELLA INFECTIONS 55

Image 14.5
Prevotella melaninogenica pigmented colonies. Courtesy of Centers for Disease Control
and Prevention.

Image 14.6
Bacteroides fragilis on kanamycin-vancomycin–laked blood agar. The organism is not inhibited by
kanamycin and vancomycin and, thus, demonstrates good growth on this agar. Courtesy of Julia
Rosebush, DO; Robert Jerris, PhD; and Theresa Stanley, M(ASCP).

ERRNVPHGLFRVRUJ
56 BALANTIDIUM COLI ­INFECTIONS

15 most areas of the world but are rare in indus­


trialized countries. Cysts excreted in feces can
Balantidium coli ­Infections be transmitted directly from hand to mouth
(Balantidiasis) or indirectly through fecally contaminated
Clinical Manifestations water or food. Excysted trophozoites infect the
colon. A person is infectious as long as cysts
Most human infections are asymptomatic. are excreted in stool. Cysts may remain viable
Acute symptomatic infection is characterized in the environment for months.
by rapid onset of nausea, vomiting, abdominal
discomfort or pain, and bloody or watery Incubation Period
mucoid diarrhea. In some patients, the course Unknown but may be several days.
is chronic with intermittent episodes of diar-
rhea, anorexia, and weight loss. Rarely, organ- Diagnostic Tests
isms spread to mesenteric nodes, pleura, lung, Diagnosis of infection is established by
liver, or genitourinary sites. Inflammation of ­scraping lesions via sigmoidoscopy, histologic
the gastrointestinal tract and local lymphatic examination of intestinal biopsy specimens, or
vessels can result in bowel dilation, ulceration, ova and parasite examination of stool. Diag­
perforation, and secondary bacterial invasion. nosis is usually established by demonstrating
Colitis produced by Balantidium coli often is trophozoites (or, less frequently, cysts) in stool
indistinguishable from colitis produced by or tissue specimens. Stool examination is less
Entamoeba histolytica. Fulminant disease sensitive, and repeated stool examination is
can occur in patients who are malnourished or necessary to diagnose infection because shed-
otherwise debilitated or i­ mmunocompromised. ding of organisms can be intermittent. Micro-
scopic examination of fresh diarrheal stools
Etiology
must be performed promptly because tropho-
B coli, a ciliated protozoan, is the largest patho- zoites degenerate rapidly.
genic protozoan known to infect humans.
Treatment
Epidemiology
The drug of choice is a tetracycline. Alterna-
Pigs are the primary host reservoir of B coli, tive drugs are metronidazole and iodoquinol.
but other sources of infection have been ­Successful use of nitazoxanide has also
reported. Infections have been reported in been reported.

Image 15.1
Balantidium coli trophozoites are characterized
by their large size (40–>70 µm); the presence of
cilia on the cell surface, which are particularly
visible (B); a cytostome (arrows); a bean-shaped Image 15.2
macronucleus that is often visible (A); and a Balantidium coli cyst in stool preparation.
smaller, less conspicuous micronucleus. Courtesy of Centers for Disease Control and
Courtesy of Centers for Disease Control Prevention/Dr L.L.A. Moore Jr.
and Prevention.

ERRNVPHGLFRVRUJ
BALANTIDIUM COLI ­INFECTIONS 57

Image 15.3
Cysts are the parasite stage responsible for transmission of balantidiasis (1). The host most often
acquires the cyst through ingestion of contaminated food or water (2). Following ingestion, excystation
occurs in the small intestine, and the trophozoites colonize the large intestine (3). The trophozoites
reside in the lumen of the large intestine of humans and animals, where they replicate by binary fission,
during which conjugation may occur (4). Trophozoites undergo encystation to produce infective cysts
(5). Some trophozoites invade the wall of the colon and multiply. Some return to the lumen and
disintegrate. Mature cysts are passed with feces (1). Courtesy of Centers for Disease Control and
Prevention/Alexander J. da Silva, PhD/Melanie Moser.

ERRNVPHGLFRVRUJ
58 BAYLISASCARIS INFECTIONS

16 Risk factors for Baylisascaris infection include


contact with raccoon latrines (bases of trees,
Baylisascaris Infections unsealed attics, or flat surfaces such as logs,
Clinical Manifestations tree stumps, rocks, decks, and rooftops) and
uncovered sandboxes, geophagia/pica, age
Baylisascaris procyonis, a raccoon roundworm, younger than 4 years, and, in older children,
is a rare cause of acute eosinophilic meningo- developmental delay. Nearly all reported cases
encephalitis. In a young child, acute central have been in males.
nervous system (CNS) disease (eg, altered men-
tal status, seizures) accompanied by peripheral Incubation Period
or cerebrospinal fluid (CSF) eosinophilia Unknown.
occurs 2 to 4 weeks after infection. Severe neu-
rologic sequelae or death are usual outcomes. Diagnostic Tests
B procyonis is also a rare cause of extraneural Baylisascaris infection is confirmed by identifi-
disease in older children and adults. Ocular cation of larvae in biopsy specimens. Serologic
larva migrans can result in diffuse unilateral testing (serum, CSF) is available at the Centers
subacute neuroretinitis; direct visualization for Disease Control and Prevention. A pre-
of worms in the retina is sometimes possible. sumptive diagnosis can be made on the basis
Visceral larval migrans can present with non- of clinical (meningoencephalitis, diffuse uni-
specific signs, such as macular rash, pneumo- lateral subacute neuroretinitis, pseudotumor),
nitis, and hepatomegaly. Similar to visceral epidemiologic (raccoon exposure), and labora-
larva migrans caused by Toxocara, subclinical tory (blood and CSF eosinophilia) findings.
or asymptomatic infection is thought to be the Neuroimaging results can be normal initially,
most common outcome of infection. but as larvae grow and migrate through CNS
Etiology tissue, focal abnormalities are found in peri-
ventricular white matter and elsewhere. In
B procyonis is a 10- to 25-cm long roundworm ocular disease, ophthalmologic examination
(nematode) with a direct life cycle usually can reveal characteristic chorioretinal lesions
­limited to its definitive host, the raccoon. or, rarely, larvae. Because eggs are not shed in
Domestic dogs and some exotic pets, such as human feces, stool examination is not helpful.
kinkajous and ringtails, can serve as definitive
hosts and a potential source of human disease. Treatment

Epidemiology On the basis of CNS and CSF penetration and


in vitro activity, albendazole, in conjunction
B procyonis is distributed focally throughout with high-dose corticosteroids, has been advo-
the United States; in areas where disease is cated most widely but may not affect clinical
endemic, an estimated 22% to 80% of raccoons outcome in severe CNS infections. If suspected,
can harbor the parasite in their intestine. treatment should be started while the diagnos-
Reports of infections in dogs raise concern tic evaluation is being completed. Some experts
that infected dogs may be able to spread the advocate use of additional anthelmintic agents.
disease. Embryonated eggs containing infec- Limited data are available on safety and effi-
tive larvae are ingested from the soil by rac- cacy of these therapies in children. Preventive
coons, rodents, and birds. When infective eggs therapy with albendazole should be considered
or an infected host is eaten by a raccoon, the for children with a history of ingestion of soil
larvae grow to maturity in the small intestine, potentially contaminated with raccoon feces.
where adult female worms shed millions of Worms localized to the retina may be killed by
eggs per day. Eggs become infective after 2 to direct photocoagulation.
4 weeks in the environment and may persist
long-term in the soil. Fewer than 25 cases of
Baylisascaris disease have been document in
the United States, although cases may be undi-
agnosed or ­underreported.

ERRNVPHGLFRVRUJ
BAYLISASCARIS INFECTIONS 59

Image 16.2
Biopsy-proven Baylisascaris procyonis
encephalitis in a 13-month-old boy. Axial
T2-weighted magnetic resonance images
obtained 12 days after symptom onset show
abnormal high signal throughout most of the
Image 16.1
central white matter (arrows) compared with the
Neuroimaging of human Baylisascaris procyonis dark signal expected at this age (broken arrows).
neural larval migrans. Axial T2-weighted magnetic Sorvillo F, Ash LR, Berlin OGW, Yatabe J,
resonance image (at the level of the lateral Degiorgio C, Morse SA. Baylisascaris procyonis:
ventricles) demonstrates abnormal patchy an emerging helminthic zoonosis. Emerg Infect
hyperintense signal of periventricular white Dis. 2002;8(4):355–359.
matter and basal ganglia. Courtesy of Gavin.

Image 16.4
Unembryonated egg of Baylisascaris procyonis.
B procyonis eggs are 80 to 85 µm by 65 to 70 µm
in size, thick-shelled, and usually slightly oval in
shape. They have a similar morphology to fertile
Image 16.3 eggs of Ascaris lumbricoides, although eggs of A
Coronal T2-weighted magnetic resonance lumbricoides are smaller (55–75 µm x 35–50 µm).
imaging of the brain in a 4-year-old with The definitive host for B procyonis is the raccoon,
Baylisascaris procyonis eosinophilic meningitis. although dogs may also serve as definitive hosts.
Arrow shows diffuse edema of the superior As humans do not serve as definitive hosts for
cerebellar hemispheres (scale bar increments in B procyonis, eggs are not considered a diagnos­
centimeters). Courtesy of Centers for Disease tic finding and are not excreted in human feces.
Control and Prevention/Emerging Infectious Courtesy of Cheryl Davis, MD, Western Kentucky
Diseases and Poulomi J. Pai. University.

ERRNVPHGLFRVRUJ
60 BAYLISASCARIS INFECTIONS

Image 16.5
Baylisascaris procyonis larva in cross-section (at midbody level) (diameter, 60 µm) recovered from
the cerebrum of a rabbit with neural larval migrans. Characteristic features include a centrally located
(slightly compressed) intestine, flanked on either side by large triangular-shaped excretory columns.
Prominent lateral cuticular alae are visible on opposite sides of the body (hematoxylin-eosin stain).
Courtesy of Gavin.

Image 16.6
This illustration depicts the life cycle of Baylisascaris procyonis, the causal agent of Baylisascaris
disease. Courtesy of Centers for Disease Control and Prevention/Alexander J. da Silva, PhD/
Melanie Moser.

ERRNVPHGLFRVRUJ
BAYLISASCARIS INFECTIONS 61

Image 16.7
Baylisascaris is raccoon roundworm, which may cause ocular and neural larval migrans and
encephalitis in humans. Photo used with permission of Michigan DNR Wildlife Disease Lab.

ERRNVPHGLFRVRUJ
62 INFECTIONS WITH ­BLASTOCYSTIS HOMINIS AND OTHER SUBTYPES

17 be fecal-oral, presence of the organism may


be a marker for presence of other pathogens
Infections With spread by fecal contamination. Transmission
­Blastocystis hominis and from animals occurs.
Other Subtypes Incubation Period
Clinical Manifestations Unknown.
The importance of Blastocystis species as a Diagnostic Tests
cause of gastrointestinal tract disease is contro-
Stool specimens should be preserved in poly­
versial. The asymptomatic carrier state is well
vinyl alcohol and stained with trichrome or
documented. Clinical symptoms reported
iron-hematoxylin before microscopic examina-
include bloating, flatulence, mild to moderate
tion. The parasite may be present in varying
diarrhea without fecal leukocytes or blood,
numbers, and infections may be reported as
abdominal pain, nausea, and poor growth.
light to heavy. The presence of 5 or more organ-
When Blastocystis hominis is identified in stool
isms per high-power (magnification x400) field
from symptomatic patients, other causes of this
can indicate heavy infection with many organ-
symptom complex, particularly Giardia intesti­
isms, which, to some experts, suggests causa-
nalis and Cryptosporidium parvum, should be
tion when other enteropathogens are absent.
investigated before assuming B hominis is the
Other experts consider the presence of 10 or
cause of the signs and symptoms.
more organisms per 10 oil immersion fields
Etiology (magnification x1,000) to represent many
organisms.
B hominis has previously been classified as a
protozoan, but molecular studies have charac- Treatment
terized it as a stramenopile (a eukaryote).
Indications for treatment are not established.
­Multiple forms have been described: vacuolar,
Some experts recommend that treatment
which is observed most commonly in clinical
should be reserved for patients who have
specimens; granular, which is seen rarely in
­persistent symptoms and in whom no other
fresh stools; ameboid; and cystic.
pathogen or process is found to explain the
Epidemiology gastrointestinal tract symptoms. Nitazoxanide
and metronidazole have demonstrated benefit
Blastocystis species are recovered from 1% to
in symptomatic patients.
20% of stool specimens examined for ova and
parasites. Because transmission is believed to
Image 17.1
A–D, Blastocystis hominis cystlike forms
(trichrome stain). The sizes vary from 4 to 10 µm.
The vacuoles stain variably from red to blue.
The nuclei in the peripheral cytoplasmic rim
are clearly visible, staining purple (B) (4 nuclei).
Specimens in figures A through C contributed
by Ray Kaplan, MD, SmithKline Beecham
Diagnostic Laboratories, Atlanta, GA. D,
Courtesy of Centers for Disease Control
and Prevention.

ERRNVPHGLFRVRUJ
INFECTIONS WITH ­BLASTOCYSTIS HOMINIS AND OTHER SUBTYPES 63

Image 17.2
Knowledge of the life cycle and transmission are still under investigation; therefore, this is a proposed
life cycle for Blastocystis hominis. The classic form found in human stools is the cyst, which varies
tremendously in size from 6 to 40 µm (1). The thick-walled cyst present in the stools (1) is believed
to be responsible for external transmission, possibly by the fecal-oral route through ingestion of
contaminated water or food (2). The cysts infect epithelial cells of the digestive tract and multiply
asexually (3, 4). Vacuolar forms of the parasite give origin to multivacuolar (5a) and ameboid (5b) forms.
The multivacuolar form develops into a precyst (6a) that gives origin to a thin-walled cyst (7a) thought
to be responsible for autoinfection. The ameboid form gives origin to a precyst (6b), which develops
into thick-walled cyst by schizogony (7b). B hominis stages were reproduced from Singh M, Suresh K,
Ho LC, Ng GC, Yap EH. Elucidation of the life cycle of the intestinal protozoan Blastocystis hominis.
Parasitol Res.1995;81(5):449. Life cycle image and information courtesy of DPDx.

ERRNVPHGLFRVRUJ
64 Blastomycosis

18 Incubation Period

Blastomycosis 2 weeks to 3 months.

Clinical Manifestations Diagnostic Tests

Infections can be acute, chronic, or fulminant Definitive diagnosis of blastomycosis is based


but are asymptomatic in up to 50% of infected on identification of characteristic thick-walled,
people. The most common clinical manifesta- broad-based, single budding yeast cells by
tion of blastomycosis in children is prolonged ­culture or in histopathologic specimens. The
pulmonary disease, with fever, chest pain, and organism can be seen in sputum, tracheal
nonspecific symptoms such as fatigue and ­aspirates, cerebrospinal fluid, urine, or histo-
myalgia. Rarely, patients may develop acute pathologic specimens from lesions processed
respiratory distress syndrome. Typical radio- with 10% potassium hydroxide or a silver stain.
graphic patterns include patchy pneumonitis, a Children with pneumonia who are unable to
masslike infiltrate, or nodules. Blastomycosis produce sputum may require bronchoalveolar
can be misdiagnosed as bacterial pneumonia, lavage or open biopsy to establish the diagno-
tuberculosis, sarcoidosis, or malignant neo- sis. Bronchoalveolar lavage is high yield, even
plasm. Disseminated blastomycosis, which can in patients with bone or skin manifestations.
occur in up to 25% of cases, most commonly Organisms can be isolated by culture. Chemi-
involves the skin, osteoarticular structures, luminescent DNA probes are available for
and genitourinary tract. Cutaneous manifesta- identification of B dermatitidis. Because sero-
tions can be verrucous, nodular, ulcerative, or logic tests (immunodiffusion and complement
pustular. Abscesses are usually subcutaneous fixation) lack adequate sensitivity, effort should
but can involve any organ. Central nervous be made to obtain appropriate specimens for
system infection is uncommon, and intrauter- culture. An assay that detects Blastomyces
ine or congenital infection is rare. ­a ntigen in urine is available commercially, but
significant cross-reactivity occurs in patients
Etiology with other endemic mycoses.
Blastomycosis is caused by Blastomyces derma­ Treatment
titidis, a thermally dimorphic fungus existing
in yeast form at 37°C (98°F) in infected tissues Amphotericin B is recommended for initial
and in a mycelial form at room temperature therapy of severe disease. Oral itraconazole is
and in soil. Conidia, produced from hyphae recommended for step-down therapy and mild
of the mycelial form, are infectious. to moderate infection. Liposomal amphoteri-
cin B is recommended for central nervous
Epidemiology ­system infection and may be followed by a
Infection is acquired through inhalation of ­prolonged course of azole therapy with flu­
conidia from soil and can occur in immuno- conazole, voriconazole, or itraconazole.
competent and immunocompromised hosts. ­Itraconazole is indicated for treatment of
Increased mortality rates for patients with pul- ­nonlife-threatening infection outside of the
monary blastomycosis have been associated central nervous system.
with advanced age, chronic obstructive pulmo- Therapy for severe or central nervous system
nary disease, cancer, and African American infections usually is continued for at least
ethnicity. Person-to-person transmission does 12 months. For mild to moderate pulmonary
not occur. Blastomycosis is endemic in areas and extrapulmonary disease, treatment is
of the central United States, with most cases ­continued for 6 to 12 months.
occurring in the Ohio and Mississippi river
valleys, the southeastern states, and states that
border the Great Lakes. Sporadic cases also
have been reported in Hawaii, Israel, India,
Africa, and Central and South America.

ERRNVPHGLFRVRUJ
Blastomycosis 65

Image 18.1
Nodular skin lesions of blastomycosis, one of
which is a bullous lesion on top of a nodule.
Aspiration of the bulla revealed yeast forms of Image 18.2
Blastomyces dermatitidis. Courtesy of Centers Cutaneous blastomycosis (face). Cutaneous
for Disease Control and Prevention/Libero Ajello, lesions are nodular, verrucous, or ulcerative, as
MD. in this man. Most cutaneous lesions are due
to hematogenous spread from a pulmonary
infection. Courtesy of Edgar O. Ledbetter,
MD, FAAP.

Image 18.3
Histopathology of blastomycosis. Yeast cell of
Blastomyces dermatitidis undergoing broad-base
budding (methenamine silver stain). Courtesy of Image 18.4

Centers for Disease Control and Prevention/ This photomicrograph depicts the fungal agent
Libero Ajello, MD. Blastomyces dermatitidis (hematoxylin-eosin
stain). Courtesy of Centers for Disease Control
and Prevention/Libero Ajello, MD.

Image 18.5
This micrograph shows histopathologic changes
that reveal the presence of the fungal agent
Blastomyces dermatitidis. Courtesy of Centers for
Disease Control and Prevention/Libero Ajello, MD.

ERRNVPHGLFRVRUJ
66 Bocavirus

19 Epidemiology

Bocavirus Detection of HBoV has been described only in


humans. Transmission is presumed to be from
Clinical Manifestations respiratory tract secretions, although fecal-oral
Human bocavirus (HBoV) was first identified transmission may be possible. The frequent
in 2005 from a cohort of children with acute codetection of other viral pathogens of the
respiratory tract symptoms including fever, respiratory tract in association with HBoV
rhinorrhea, cough, and wheezing. Human has led to speculations that it may be a true
bocavirus has been identified in 5% to 33% of copathogen, it may be shed for long periods
children with acute respiratory tract infections. after primary infection (up to 75 days), or it
High rates of HBoV subclinical infection also may reactivate during subsequent viral infec-
occur. The role of HBoV as a human pathogen tions. Human bocavirus circulates worldwide
is confounded by simultaneous detection of and throughout the year. In temperate cli-
other viral pathogens in children with HBoV, mates, seasonal clustering in the spring has
with coinfection rates as high as 80%. Human been reported.
bocavirus has been detected in stool samples Diagnostic Tests
from children with acute gastroenteritis, but its
role in symptoms is uncertain. Nearly all chil- Commercial molecular diagnostic assays for
dren develop serologic evidence of infection HBoV are available. Human bocavirus poly-
by 5 years of age. merase chain reaction and detection of HBoV-
specific antibody also are available in research
Etiology laboratories.
Human bocavirus is a nonenveloped, single- Treatment
stranded DNA virus in the family Parvo­
viridae, genus Bocavirus. Human bocavirus No specific therapy is available.
replicates in the respiratory and gastrointesti-
nal tracts.

ERRNVPHGLFRVRUJ
BORRELIA INFECTIONS 67

20 Epidemiology

Borrelia Infections Endemic tick-borne relapsing fever is distrib-


uted worldwide, is transmitted by soft-bodied
(Relapsing Fever)
ticks (Ornithodoros species), and occurs spo-
Clinical Manifestations radically and in small clusters, often within
Two types of relapsing fever occur in humans: families or cohabiting groups. In the United
tick-borne and louse-borne. Both are charac- States, tick-borne relapsing fever can be
terized by sudden onset of high fever, shaking acquired only in western states but has been
chills, sweats, headache, muscle and joint pain, diagnosed in other states in travelers returning
altered sensorium, nausea, and diarrhea. A from these areas. Ticks become infected by
fleeting macular rash of the trunk and pete- feeding on rodents or other small mammals
chiae of the skin and mucous membranes and transmit infection via their saliva and
sometimes occur. Findings and complications other fluids when they take subsequent blood
can differ between types of relapsing fever and meals. Ticks can serve as reservoirs of infec-
include hepatosplenomegaly, jaundice, throm- tion. Soft-bodied ticks inflict painless bites
bocytopenia, iridocyclitis, cough with pleuritic and feed briefly (15–90 minutes), usually at
pain, pneumonitis, meningitis, and myocardi- night, so people are often unaware of bites.
tis. Mortality rates are 10% to 70% in untreated Most tick-borne relapsing fever in the United
louse-borne relapsing fever (possibly related to States is caused by B hermsii. Infection typi-
comorbidities in refugee-type settings where cally results from tick exposures in rodent-
this disease is typically found) and 4% to 10% infested cabins in western mountainous areas,
in untreated tick-borne relapsing fever. Death including state and national parks. However,
occurs predominantly in people with under­ infection has also occurred in primary resi-
lying illnesses and extremes of age. Early dences and luxurious rental properties.
­treatment reduces mortality to less than 5%. B ­turicatae infections occur less frequently;
Untreated, an initial febrile period of 2 to most cases have been reported from Texas
7 days terminates spontaneously by crisis. and are often associated with tick exposures
The initial febrile episode is followed by an in rodent-infested caves. A single human
afebrile period of several days to weeks, and ­infection with B parkeri has been reported;
then by one relapse or more (0–13 for tick- the tick infected with this Borrelia species is
borne; 1–5 for louse-born). Relapses typically associated with arid areas or grasslands in the
become shorter and progressively milder, as western United States.
afebrile periods lengthen. Relapse is associated
with expression of new borrelial antigens, and Louse-borne epidemic relapsing fever has been
resolution of symptoms is associated with reported in Ethiopia, Eritrea, Somalia, and the
­production of antibody specific to those new Sudan, especially in refugee and displaced pop-
antigenic determinants. Infection during ulations. Epidemic transmission occurs when
­pregnancy is often severe and can result in body lice (Pediculus humanus) become infected
spontaneous abortion, preterm birth, stillbirth, by feeding on humans with spirochetemia;
or neonatal infection. infection is transmitted when infected lice are
crushed and their body fluids contaminate a
Etiology bite wound or skin abraded by scratching.
Relapsing fever is caused by certain spirochetes Infected body lice and ticks may remain alive
of the genus Borrelia. Worldwide, at least and infectious for several years without feed-
14 Borrelia species cause tick-borne (endemic) ing. Relapsing fever is not transmitted person
relapsing fever, including Borrelia hermsii, to person, but perinatal transmission from an
­Borrelia turicatae, and Borrelia parkeri in infected mother to her newborn can occur
North America. Borrelia recurrentis is the only and result in preterm birth, stillbirth, and
species that causes louse-borne (epidemic) ­neonatal death.
relapsing fever, and this organism has no
­a nimal reservoir.

ERRNVPHGLFRVRUJ
68 BORRELIA INFECTIONS

Incubation Period Treatment


2 to 18 days (mean, 7 days). Treatment of tick-borne relapsing fever with a
5- to 10-day course of a tetracycline, usually
Diagnostic Tests
doxycycline, produces prompt clearance of
Spirochetes can be observed by darkfield spirochetes and remission of symptoms. For
microscopy and in Wright-, Giemsa-, or acri- children younger than 8 years and pregnant
dine orange–stained preparations of thin or women, penicillin or erythromycin are the
dehemoglobinized thick smears of peripheral preferred drugs. Penicillin G procaine or intra-
blood or in stained buffy-coat preparations. venous penicillin G is recommended as initial
Organisms can often be visualized in blood therapy for people who are unable to take oral
obtained while the person is febrile, particu- therapy, although low-dose penicillin G has
larly during initial febrile episodes; organisms been associated with a higher frequency of
are less likely to be recovered from subsequent relapse. A Jarisch-Herxheimer reaction (an
relapses. Spirochetes can be cultured from acute febrile reaction accompanied by head-
blood, although these methods are not widely ache, myalgia, respiratory distress in some
available. Serum antibodies to Borrelia species cases, and an aggravated clinical picture last-
can be detected by enzyme immunoassay and ing less than 24 hours) is commonly observed
Western immunoblot analysis at some refer- during the first few hours after initiating
ence and commercial specialty laboratories; ­a ntimicrobial therapy. However, the Jarisch-­
a 4-fold increase in titer is considered confir- Herxheimer reaction in children is typically
matory. These antibody tests are not standard- mild and can usually be managed with anti-
ized and are affected by antigenic variations pyretic agents alone.
among and within Borrelia species and strains.
Serologic cross-reactions occur with other Single-dose treatment using a tetracycline,
­spirochetes, including Borrelia burgdorferi, penicillin, erythromycin, or chlorampheni-
Treponema pallidum, and Leptospira species. col is effective for curing louse-borne relaps-
ing fever.

Image 20.1
Borrelia in peripheral blood smear. The
spirochetes can be seen with darkfield
microscopy and in Wright-, Giemsa-, or
acridine orange–stained smears.
Image 20.2
Borrelia hermsii in the blood of a patient (case 3)
stained with rabbit hyperimmune serum and
antirabbit fluorescein isothiocyanate (scale
bar, 20 mm). Courtesy of Emerging
Infectious Diseases.

ERRNVPHGLFRVRUJ
BORRELIA INFECTIONS 69

Image 20.4
This image depicts an adult female body louse,
Pediculus humanus, and 2 larval young.
Image 20.3 P humanus has been shown to serve as a vector
Borrelia hermsii in a thin smear of mouse blood for diseases such as typhus, due to Rickettsia
stained with Wright-Giemsa and visualized with prowazekii, trench fever caused by Bartonella
oil immersion bright-field microscopy (formerly Rochalimaea) quintana, and relapsing
(magnification x600) for the confirmation of fever due to Borrelia recurrentis. Courtesy of
infection with relapsing fever spirochetes in World Health Organization.
humans and other animals (scale bar, 20 mm).
Courtesy of Emerging Infectious Diseases.

Image 20.6
Ornithodoros moubata ticks frequent traditional
homes in sub-Saharan Africa and mainly feed
nocturnally. Courtesy of Centers for Disease
Control and Prevention/Emerging Infectious
Diseases and Sally J. Cutler.

Image 20.5
An Ornithodoros hermsii nymph. The length of
the soft-bodied tick is 3.0 µm, excluding the legs.
It is responsible for transmitting endemic
relapsing fever. Schwan TG, Policastro PF, Miller
Z, Thompson RL, Damrow T, Keirans JE. Tick-
borne relapsing fever caused by Borrelia hermsii,
Montana. Emerg Infect Dis. 2003;9(9):1151–1154.

ERRNVPHGLFRVRUJ
70 Brucellosis

21 teurized dairy products. People in occupations


such as farming, ranching, and veterinary
Brucellosis medicine, as well as abattoir workers, meat
Clinical Manifestations inspectors, and laboratory personnel, are at
increased risk. Clinicians should alert the labo-
Onset of brucellosis in children can be acute ratory if they anticipate Brucella might grow
or insidious. Manifestations are nonspecific from microbiologic specimens so that appro-
and include fever, night sweats, weakness, priate laboratory precautions can be taken. In
­malaise, anorexia, weight loss, arthralgia, the United States, approximately 100 to 200
myalgia, abdominal pain, and headache. cases of brucellosis are reported annually, and
­Physical findings can include lymphade­ 3% to 10% of cases occur in people younger
nopathy, hepatosplenomegaly, and arthritis. than 19 years. Most pediatric cases reported
Abdominal pain and peripheral arthritis are in the United States result from ingestion of
reported more frequently in children than in unpasteurized dairy products. Although
adults. Neurologic deficits, ocular involvement, human-to-human transmission is rare, in
epididymo-­orchitis, and liver or spleen utero transmission has been reported, and
abscesses are reported. Anemia, leukopenia, infected mothers can transmit Brucella to
thrombocytopenia, or, less frequently, pan­ their newborns through breastfeeding.
cytopenia are hematologic findings that might
suggest the diagnosis. Serious complications Incubation Period
include meningitis, endocarditis, osteomyelitis, Variable (<1 week to several months); most peo-
and, less frequently, pneumonitis and aortic ple become ill within 3 to 4 weeks of exposure.
involvement. A detailed history, including
travel, exposure to animals, and food habits, Diagnostic Tests
including ingestion of raw milk, should be A definitive diagnosis is established by recov-
obtained if brucellosis is considered. Chronic ery of Brucella species from blood, bone mar-
disease is less common among children than row, or other tissue specimens. A variety of
among adults, although the rate of relapse has media will support growth of Brucella species,
been found to be similar. Brucellosis in preg- but the physician should contact laboratory
nancy is associated with risk of spontaneous personnel and ask them to incubate cultures
abortion, preterm delivery, miscarriage, and for a minimum of 4 weeks. Bactec systems
intrauterine infection with fetal death. (BD Diagnostic Systems, Sparks, MD) are reli-
Etiology able and can detect Brucella species within 5 to
7 days. In patients with a clinically compatible
Brucella bacteria are aerobic small, nonmotile, illness, serologic testing using the serum agglu-
gram-negative coccobacilli. The species that tination test can confirm the diagnosis with
are known to infect humans are Brucella a 4-fold or greater increase in antibody titers
­abortus, Brucella melitensis, Brucella suis, between acute and convalescent serum speci-
and, rarely, Brucella canis. Three recently mens collected at least 2 weeks apart. The
­identified species, Brucella ceti, Brucella serum agglutination test, the gold standard
­pinnipedialis, and Brucella inopinata, are for serologic diagnosis, will detect antibodies
potential human pathogens. against B abortus, B suis, and B melitensis but
Epidemiology not B canis, which requires use of B canis–­
specific antigen. Although a single titer is not
Brucellosis is a zoonotic disease of wild and diagnostic, most patients with active infection
domestic animals. It is transmissible to humans in an area without endemic infection will have
by direct or indirect exposure to aborted a titer of 1:160 or greater within 2 to 4 weeks
fetuses or tissues or fluids of infected animals. of clinical disease onset. Lower titers can be
Transmission occurs by inoculation through found early in the course of infection. Immu-
mucous membranes or cuts and abrasions in noglobulin (Ig) M antibodies are produced
the skin, inhalation of contaminated aerosols, within the first week, followed by a gradual
or ingestion of undercooked meat or unpas- increase in IgG synthesis. Low IgM titers may

ERRNVPHGLFRVRUJ
Brucellosis 71

persist for months or years after initial infection. resistance but rather with premature discon­
Increased concentrations of IgG ­agglutinins tinuation of therapy. Because monotherapy is
are found in acute infection, chronic infection, associated with a high rate of relapse, com­
and relapse. When interpreting serum agglu­ bination therapy is recommended as standard
tination test results, the possibility of cross-­ treat­ment. Most combination regimens
reactions of Brucella antibodies with antibodies include oral doxycycline or trimethoprim-­
against other gram-negative bacteria, such as sulfamethoxazole plus rifampin.
Yersinia enterocolitica serotype 09, Francisella
For treatment of serious infections or compli-
tularensis, and Vibrio cholerae, should be con-
cations, including endocarditis, meningitis,
sidered. Enzyme immunoassay is a sensitive
spondylitis, and osteomyelitis, a 3-drug regi-
method for determining IgG, IgA, and IgM
men should be used with gentamicin included
anti-Brucella antibody titers. Until better stan-
for the first 7 to 14 days, in addition to tetra­
dardization is established, enzyme immuno­
cycline (or trimethoprim-sulfamethoxazole,
assay should only be used for suspected cases
if tetracyclines are not used) and rifampin for
with negative serum agglutination test results
a minimum of 6 weeks. For life-threatening
or for evaluation of patients with suspected
complications of brucellosis, such as menin­
chronic brucellosis, reinfection, or complicated
gitis or endocarditis, the duration of therapy
cases. Polymerase chain reaction tests have
is often extended for 4 to 6 months. Surgical
been developed but are not available in most
intervention should be considered in patients
clinical laboratories.
with complications, such as deep tissue
Treatment abscesses, endocarditis, mycotic aneurysm,
Prolonged antimicrobial therapy is imperative and foreign body infections.
for achieving a cure. Relapses generally are The benefit of corticosteroids for people with
not associated with development of Brucella neurobrucellosis is unproven.

Image 21.2
Brucella melitensis colonies. Brucella species
colony characteristics: Fastidious organism and
colonies usually are not visible at 24 hours.
Brucella grows slowly on most standard
laboratory media (eg, sheep blood, chocolate,
and trypticase soy agars). Pinpoint, smooth,
Image 21.1 translucent, nonhemolytic colonies are shown
A calcified Brucella granuloma in the spleen at 48 hours of incubation. Courtesy of Centers
of a man with fever of several years’ duration. for Disease Control and Prevention/Courtesy
Brucella organisms that survive the action of of Larry Stauffer, Oregon State Public
polymorphonuclear leukocytes are ingested Health Laboratory.
by macrophages and become localized in the
organs of the reticuloendothelial system.

ERRNVPHGLFRVRUJ
72 Brucellosis

Image 21.3
Brucellosis. Number of reported cases, by year—United States, 1982–2012. Courtesy of Morbidity and
Mortality Weekly Report.

Image 21.4
Brucellosis. Number of reported cases—United States and US territories, 2012. Courtesy of Morbidity
and Mortality Weekly Report.

ERRNVPHGLFRVRUJ
BURKHOLDERIA INFECTIONS 73

22 f­ requently in children in Thailand and Cambo-


dia but occurs less often in children in other
Burkholderia Infections endemic areas. Localized infection is usually
Clinical Manifestations nonfatal. In severe cutaneous infection, necro-
tizing fasciitis has been reported. In dissemi-
Burkholderia cepacia complex has been associ- nated infection, hepatic and splenic abscesses
ated with infections in individuals with cystic can occur, and relapses are common without
fibrosis, chronic granulomatous disease, hemo- prolonged therapy.
globinopathies, or malignant neoplasms and
in very preterm neonates. Airway infections in Etiology
people with cystic fibrosis usually occur later The Burkholderia genus comprises more than
in the course of disease, after bronchiectasis 40 species that are nutritionally diverse,
has occurred. Patients with cystic fibrosis can ­oxidase- and catalase-producing, nonlactose-­
become chronically infected with no change fermenting, gram-negative bacilli. B cepacia
in the rate of pulmonary decompensation and complex comprises at least 17 species. Addi-
can experience an accelerated decline or have tional members of the complex continue to
an unexpectedly rapid deterioration in clinical be identified but are rare human pathogens.
status that results in death. In patients with Other clinically important species of
chronic granulomatous disease, pneumonia is ­Burkholderia include B pseudomallei,
the most common manifestation of B cepacia ­Burkholderia gladioli, and Burkholderia
complex infection; lymphadenitis also occurs. ­mallei (the agent responsible for glanders).
Disease onset is insidious, with low-grade fever ­Burkholderia thailandensis and Burkholderia
early in the course and systemic effects occur- oklahomensis are rare human pathogens.
ring 3 to 4 weeks later. Pleural effusions are
common, and lung abscesses can occur. Health Epidemiology
care–associated infections, including wound Burkholderia species are environmentally
and urinary tract infections and pneumonia, derived water- and soilborne organisms that
also have been reported, and clusters of disease can survive for prolonged periods in a moist
have been associated with contaminated nasal environment. Depending on the species,
sprays, mouthwash, and sublingual probes. ­transmission can occur from other people
Burkholderia pseudomallei is the cause of (person to person), contact with contaminated
­melioidosis. Its geographic range is expanding, fomites, and exposure to environmental
and disease is now known to be endemic in sources. Epidemiologic studies of recreational
Southeast Asia, northern Australia, areas of the camps and social events attended by people
Indian Subcontinent, southern China, Hong with cystic fibrosis from different geographic
Kong, Taiwan, several Pacific and Indian areas have documented person-to-person
Ocean islands, and some areas of South and spread of B cepacia complex. The source of
Central America. Melioidosis can occur in the acquisition of B cepacia complex by patients
United States, usually among travelers return- with chronic granulomatous disease has not
ing from areas with endemic disease. Melioi­ been identified. Health care–associated spread
dosis can be asymptomatic and can manifest of B cepacia complex is most often associated
as a localized infection or present as fulminant with contamination of disinfectant solutions
septicemia. More than half of individuals with used to clean reusable patient equipment, such
melioidosis are bacteremic at presentation. as bronchoscopes and pressure transducers,
Pneumonia is the most commonly reported or to disinfect skin. Contaminated medical
clinical manifestation of melioidosis. Genito- products, including mouthwash and inhaled
urinary infections, including prostatic medications, have been identified as a cause of
abscesses, skin infections, septic arthritis, multistate outbreaks of colonization and infec-
and osteomyelitis, and central nervous system tion. B gladioli has been isolated from sputum
involvement, including brain abscesses, are of people with cystic fibrosis and may be mis-
also frequently identified. Acute suppurative taken for B ­cepacia. The clinical significance
parotitis is a manifestation that occurs of B gladioli in cystic fibrosis is not known.

ERRNVPHGLFRVRUJ
74 BURKHOLDERIA INFECTIONS

In areas with highly endemic infection, recommended. Definitive diagnosis of melioi-


B ­pseudomallei is acquired early in life, with dosis is made by isolation of B pseudomallei
the highest seroconversion rates between 6 from blood or other infected sites. The likeli-
and 42 months of age. Melioidosis is seasonal, hood of successfully isolating the organism is
with more than 75% of cases occurring during increased by culture of sputum, throat, and
the rainy season. Disease can be acquired by rectum and ulcer or skin lesion specimens. A
direct inhalation of aerosolized organisms direct polymerase chain reaction assay may
or dust particles containing organisms, per­ provide a more rapid result than culture but is
cutaneous or wound inoculation with con­ less sensitive, especially when performed on
taminated soil or water, or ingestion of blood; it is not recommended for routine use.
contami­nated soil, water, or food. People can Serologic testing is not adequate for diagnosis
also become infected as a result of laboratory in endemic areas because of high background
exposures when proper techniques or proper seropositivity. However, a positive result by the
personal protective equipment guidelines are indirect hemagglutination assay for a traveler
not followed. Symptomatic infection can occur who has returned from an area with endemic
in infants 1 year or younger, with pneumonia infection may support the diagnosis of melioi-
and parotitis reported in infants as young as dosis; definitive diagnosis still requires isola-
8 months. Risk factors for melioidosis include tion of B pseudomallei from an infected site.
frequent contact with soil and water as well as
Treatment
under­lying chronic disease, such as diabetes
mellitus, renal insufficiency, chronic pulmonary Meropenem is the agent most active against
disease, thalassemia, and immunosuppression most B cepacia complex isolates, although
not related to HIV infection. B pseudomallei other drugs that may be effective include
has also been reported to cause pulmonary ­imipenem, trimethoprim-sulfamethoxazole,
infection in people with cystic fibrosis and ceftazidime, doxycycline, and chlorampheni-
­septicemia in children with chronic granulo- col. Some experts recommend combinations of
matous disease. antimicrobial agents that provide synergistic
activity against B cepacia complex. The drugs
Incubation Period of choice for initial treatment of melioidosis
Melioidosis, 1 to 21 days (median, 9 days), but depend on the type of clinical infection, sus-
can be prolonged (years). ceptibility testing, and presence of comor­
bidities in the patient (eg, diabetes, liver or
Diagnostic Tests
renal disease, cancer, hemoglobinopathies,
Isolation of B cepacia complex infection from cystic fibrosis). Treatment of severe invasive
appropriate specimens is diagnostic. In cystic infection should include meropenem, imipenem,
fibrosis airway infection, culture of sputum on or ceftazidime (rare resistance) for a ­minimum
selective agar is recommended to decrease the of 10 to 14 days. After acute therapy is completed,
potential for overgrowth by mucoid Pseudomo­ oral eradication therapy with ­trimethoprim-
nas aeruginosa. Confirmation of identification sulfamethoxazole for 3 to 6 months is recom-
of B cepacia complex species by polymerase mended to reduce ­recurrence.
chain reaction assay or mass spectroscopy is
Image 22.1
Scanning electron micrograph of Burkholderia
cepacia. Burkholderia infections often have an
insidious onset, and B cepacia is a nosocomial
pathogen. Courtesy of Centers for Disease
Control and Prevention/Janice Haney Carr.

ERRNVPHGLFRVRUJ
BURKHOLDERIA INFECTIONS 75

Image 22.2
This photograph depicts the colonial morphology displayed by gram-negative Burkholderia
pseudomallei bacteria, which was grown on a medium of chocolate agar, for a 72-hour period,
at a temperature of 37°C (98.6°F). Courtesy of Centers for Disease Control and Prevention/
Dr Todd Parker, Audra Marsh.

Image 22.3
Endemicity of melioidosis infection. Centers for Disease Control and Prevention National Center for
Emerging and Zoonotic Infectious Diseases (NCEZID) Division of Global Migration and Quarantine
(DGMQ).

Image 22.4
Burkholderia cepacia on Burkholderia selective agar. With vancomycin, gentamicin, and poly­myxin B,
this agar is used for the isolation of B cepacia complex from respiratory secretions of patients with
cystic fibrosis. Growth of the organism turns the medium from orange to yellow, and colonies are
surrounded by a pink-yellow zone in the medium. Growth may require up to 72 hours of incubation.
Courtesy of Julia Rosebush, DO; Robert Jerris, PhD; and Theresa Stanley, M(ASCP).

ERRNVPHGLFRVRUJ
76 CAMPYLOBACTER INFECTIONS

23 Epidemiology

Campylobacter Infections Data from the Foodborne Diseases Active


­Surveillance Network (www.cdc.gov/foodnet)
Clinical Manifestations indicate that, although incidence decreased in
Predominant symptoms of Campylobacter the early 2000s, the 2012 incidence represented
infections include diarrhea, abdominal pain, a 14% increase over 2006–2008 baseline. Dis-
malaise, and fever. Stools can contain visible ease incidence has remained stable since 2010–
or occult blood. In neonates and young infants, 2012, with 13.8 cases per 100,000 population
bloody diarrhea without fever can be the only in 2013. The highest rates of infection occur in
manifestation of infection. Pronounced fevers children younger than 5 years. Most Campylo­
in children can result in febrile seizures that bacter infections are acquired domestically, but
can occur before gastrointestinal tract symp- it is also the most common cause of diarrhea in
toms. Abdominal pain can mimic that pro- returning international travelers. In susceptible
duced by appendicitis or intussusception. people, as few as 500 Campylobacter organisms
Mild infection lasts 1 or 2 days and resembles can cause infection.
viral gastroenteritis. Most patients recover in The gastrointestinal tracts of domestic and
less than 1 week, but 10% to 20% have a relapse wild birds and animals are reservoirs of the
or a prolonged or severe illness. Severe or per- bacteria. C jejuni and C coli have been isolated
sistent infection can mimic acute inflamma- from feces of 30% to 100% of healthy chickens,
tory bowel disease. Bacteremia is uncommon turkeys, and water fowl. Poultry carcasses
but can occur in neonates and children. commonly are contaminated. Many farm ani-
­Immunocompromised hosts can have pro- mals and meat sources can harbor the organ-
longed, relapsing, or extraintestinal infections, ism and are potential sources of infection.
especially with Campylobacter fetus and other Transmission of C jejuni and C coli occurs by
Campylobacter species. Immunoreactive ingestion of contaminated food or water or by
­complications, such as acute idiopathic poly- direct contact with fecal material from infected
neuritis (Guillain-Barré syndrome) (occurring animals or people. Improperly cooked poultry,
in an estimated 1 per 1,000 persons), Miller untreated water, and unpasteurized milk have
Fisher variant of Guillain-Barré syndrome been the main vehicles of transmission. Cam­
(ophthalmoplegia, areflexia, ataxia), reactive pylobacter infections usually are sporadic;
arthritis, Reiter syndrome (arthritis, urethritis, ­outbreaks are rare but have occurred among
and bilateral conjunctivitis), myocarditis, peri- schoolchildren who drank unpasteurized milk,
carditis, and erythema nodosum, can occur including children who participated in field
during ­convalescence. trips to dairy farms. Person-to-person spread
Etiology occurs occasionally, particularly among very
young children. Uncommonly, outbreaks of
Campylobacter species are motile, comma- diarrhea in child care centers have been
shaped, gram-negative bacilli. There are reported. Person-to-person transmission has
25 ­species within the genus Campylobacter, also occurred in neonates of infected mothers
but Campylobacter jejuni and Campylobacter and has resulted in health care–associated out-
coli are the species isolated most commonly breaks in nurseries. In neonates, C jejuni and
from patients with diarrhea. C fetus predomi- C coli usually cause gastroenteritis, whereas
nantly causes systemic illness in neonates and C fetus often causes septicemia or meningitis.
debilitated hosts. Other Campylobacter species, Enteritis occurs in people of all ages. Excretion
including Campylobacter upsaliensis, Campylo­ of Campylobacter organisms typically lasts 2
bacter lari, and Campylobacter hyointestinalis, to 3 weeks without treatment but can be as long
can cause similar diarrheal or systemic ill- as 7 weeks.
nesses in children.

ERRNVPHGLFRVRUJ
CAMPYLOBACTER INFECTIONS 77

Incubation Period Salmonella, Shigella, Campylobacter, and Shiga


2 to 5 days but can be longer. toxin-producing Escherichia coli, recently
became available commercially, but data on
Diagnostic Tests their performance characteristics are limited.
C jejuni and C coli can be cultured from feces, Treatment
and Campylobacter species, including C fetus,
can be cultured from blood. Isolation of Rehydration is the mainstay of treatment for
C jejuni and C coli from stool specimens all children with diarrhea. Azithromycin and
requires selective media, microaerobic condi- erythromycin shorten the duration of illness
tions, and an incubation temperature of 42°C and excretion of susceptible organisms and
(107.6°F). Although other Campylobacter spe- prevent relapse when given early in gastrointes-
cies are occasionally isolated using routine tinal tract infection. Treatment with azithro-
­culture methods, additional methods that use mycin or erythromycin usually eradicates the
nonselective isolation techniques and increased organism from stool within 2 or 3 days. A
hydrogen microaerobic conditions are usually ­fluoroquinolone, such as ciprofloxacin, may
required for isolation of species other than be effective, but resistance to ciprofloxacin is
C jejuni and C coli. The presence of motile common (31% of C coli isolates and 22% of
curved, spiral, or S-shaped rods resembling C jejuni isolates in the United States in 2010
Vibrio cholerae by stool phase contrast or [www.cdc.gov/NARMS]) If antimicrobial
­darkfield microscopy can provide rapid, pre- ­t herapy is given for treatment of gastroenteri-
sumptive evidence for Campylobacter species tis, the recommended duration is 3 to 5 days.
infection directly from fresh stool samples. Antimicrobial agents for bacteremia should
This is less sensitive than culture. C jejuni and be selected on the basis of antimicrobial sus-
C coli can be detected directly (but not differ- ceptibility tests. C fetus generally is susceptible
entiated) by commercially available enzyme to aminoglycosides, extended-spectrum cepha-
immunoassays. False-positive results from losporins, meropenem, imipenem, and ampi-
these nonculture-based techniques have been cillin. Antimotility agents should not be used
reported. Two multiplex nucleic acid amplifi­ because they have been shown to prolong
cation tests that detect Campylobacter species symptoms and may be associated with an
and other gastrointestinal pathogens, including increased risk of death.

Image 23.1
This photomicrograph depicts findings observed in a 48-hour culture of Campylobacter jejuni
bacteria revealing characteristic thin-, comma-, or gull winged–shaped forms displayed by this
bacterium. C jejuni is a slender, curved, motile rod that is microaerophilic (ie, it has a reduced
requirement for oxygen). It is a relatively fragile organism, being sensitive to environmental stresses
such as drying, heating, disinfectants, and acidic conditions. Courtesy of Centers for Disease
Control and Prevention/Robert Weaver, PhD.

ERRNVPHGLFRVRUJ
78 CAMPYLOBACTER INFECTIONS

Image 23.2
Image 23.3
This image of a Gram-stained specimen shows
Campylobacter fetus. Leifson flagella stain
the spiral rods of Campylobacter fetus subsp
(digitally colorized) showing comma-shaped,
fetus taken from an 18-hour brain-heart infusion
gram-negative bacilli. Courtesy of Centers for
with a 7% addition of rabbit blood agar plate
Disease Control and Prevention.
culture. Courtesy of Centers for Disease Control
and Prevention.

Image 23.4
Monthly distribution of the number of sporadic cases of Campylobacter infections in humans from July
2000 to October 2001 (columns) and of the prevalence of Campylobacter in whole retail chickens from
November 2000 to October 2001 (line graph), Quebec. Courtesy of Michaud S, Ménard S, Arbeit RD.
Campylobacteriosis, Eastern Townships, Québec. Emerg Infect Dis. 2004;10(10):1844–1847.

ERRNVPHGLFRVRUJ
Candidiasis 79

24 Epidemiology

Candidiasis Like other Candida species, C albicans is pres-


ent on skin and in the mouth, intestinal tract,
Clinical Manifestations and vagina of immunocompetent people. Vul-
Mucocutaneous infection results in oropha- vovaginal candidiasis is associated with preg-
ryngeal (thrush) or vaginal or cervical candi- nancy, and newborns can acquire the organism
diasis; intertriginous lesions of the gluteal in utero, during passage through the vagina,
folds, buttocks, neck, groin, and axilla; paro- or postnatally. Mild mucocutaneous infection
nychia; and onychia. Dysfunction of T lympho- is common in healthy neonates. Person-to-­
cytes, other immunologic disorders, and person transmission occurs rarely. Invasive
endocrinologic diseases are associated with disease typically occurs in people with
chronic mucocutaneous candidiasis. Chronic impaired immunity, with infection usually
or recurrent oral candidiasis can be the pre- arising endogenously from colonized sites.
senting sign of HIV infection or primary ­Factors such as extreme prematurity, neutro­
immunodeficiency. Esophageal and laryngeal penia, or treatment with corticosteroids or
candidiasis can occur in patients who are cytotoxic chemotherapy increase the risk of
immunocompromised. Disseminated or inva- invasive infection. People with diabetes melli-
sive candidiasis occurs in very low birth weight tus generally have localized mucocutaneous
neonates and, in immunocompromised or lesions. In clinical studies, 5% to 20% of new-
debilitated hosts, can involve virtually any borns weighing less than 1,000 g at birth
organ or anatomic site and be rapidly fatal. develop invasive candidiasis. Patients with
Candidemia can occur with or without sys- neutrophil defects, such as chronic granulo­
temic disease in patients with indwelling matous disease or myeloperoxidase deficiency,
­central vascular catheters, especially patients are also at increased risk. Patients undergoing
receiving prolonged intravenous infusions with intravenous alimentation or receiving broad-
parenteral alimentation or lipids. Peritonitis spectrum antimicrobial agents, especially
can occur in patients undergoing peritoneal extended-spectrum cephalosporins, carba­
dialysis, especially in patients receiving pro- penems, and vancomycin, or requiring long-
longed broad-spectrum antimicrobial therapy. term indwelling central venous or peritoneal
Candiduria can occur in patients with indwell- dialysis catheters have increased susceptibility
ing urinary catheters, focal renal infection, or to infection. Postsurgical patients can be at
disseminated disease. risk, particularly after cardiothoracic or
abdominal procedures.
Etiology
Incubation Period
Candida species are yeasts that reproduce by
budding. Candida albicans and several other Unknown.
species form long chains of elongated yeast Diagnostic Tests
forms called pseudohyphae. C albicans causes
most infections, but in some regions and The presumptive diagnosis of mucocutaneous
patient populations, non-albicans Candida candidiasis or thrush can usually be made clin-
­species now account for more than half of ically, but other organisms or trauma can also
­invasive infections. Other species, including cause clinically similar lesions. Yeast cells and
Candida tropicalis, Candida parapsilosis, pseudohyphae can be found in C albicans–
­Candida glabrata (also called Torulopsis gla­ infected tissue and are identifiable by micro-
brata), Candida krusei, Candida guilliermondii, scopic examination of scrapings prepared with
Candida lusitaniae, and Candida dubliniensis, Gram, calcofluor white, or fluorescent antibody
can also cause serious infections, especially in stains or in a 10% to 20% potassium hydroxide
immunocompromised and debilitated hosts. suspension. Endoscopy is useful for diagnosis
C parapsilosis is second only to C albicans as a of esophagitis. Ophthalmologic examination
cause of systemic candidiasis in very low birth can reveal typical retinal lesions attributable to
weight neonates. hematogenous dissemination. Lesions in the

ERRNVPHGLFRVRUJ
80 Candidiasis

brain, kidney, liver, or spleen can be detected t­ reatment depends on severity of illness and
by ultrasonography, computed tomography, or patient factors, such as age and degree of
magnetic resonance imaging; however, these immunocompromise.
lesions typically are not detected by imaging
Skin infections are treated with topical
until late in the course of disease or after neu-
nystatin, miconazole, clotrimazole, naftifine,
tropenia has resolved.
ketoconazole, econazole, or ciclopirox.
A definitive diagnosis of invasive candidiasis Nystatin is usually effective and the least
requires isolation of the organism from a nor- expensive of these drugs.
mally sterile body site (eg, blood, cerebrospinal
Vulvovaginal candidiasis is treated effec-
fluid, bone marrow) or demonstration of
tively with many topical formulations,
organisms in a tissue biopsy specimen. Nega-
including clotrimazole, miconazole, buto-
tive results of culture for Candida species do
conazole, terconazole, and tioconazole.
not exclude invasive infection in immunocom-
Such topically applied azole drugs are more
promised hosts; in some settings, blood culture
effective than nystatin. Oral azole agents
is only 50% sensitive. Recovery of the organism
(fluconazole, itraconazole, and ketoconazole)
is expedited using automated blood culture
are also effective and should be considered
systems or a lysis-centrifugation method. Spe-
for recurrent or refractory cases.
cial fungal culture media are not needed to
grow Candida species. A presumptive species For chronic mucocutaneous candidiasis,
identification of C albicans can be made by fluconazole, itraconazole, and voriconazole
demonstrating germ tube formation, and are effective drugs. Low-dose amphotericin
molecular fluorescence in situ hybridization B administered intravenously is effective in
testing can rapidly distinguish C albicans from severe cases. Relapses are common with any
non-albicans Candida species. Patient serum of these agents once therapy is terminated,
can be tested using the assay for (1,3)-b-D-­ and treatment should be viewed as a lifelong
glucan from fungal cell walls, but this does not process, hopefully using only intermittent
distinguish Candida species from other fungi. pulses of antifungal agents. Invasive infec-
tions in patients with this condition are rare.
Treatment
• Mucous membrane and skin infections. Keratomycosis is treated with corneal baths
Oral candidiasis in immunocompetent of voriconazole (1%) in conjunction with
hosts is treated with oral nystatin suspension systemic therapy. Patients with cystitis
or clotrimazole troches applied to lesions. caused by Candida, especially patients with
Troches should not be used in infants. Flu- neutropenia, with renal allographs, and
conazole may be more effective than oral undergoing urologic manipulation, should
nystatin or clotrimazole troches and may be treated with fluconazole for 7 days
be considered if other treatments fail. Flu­ because of the concentrating effect of flu­
conazole or itraconazole can be beneficial conazole in the urinary tract. An alternative
for immunocompromised patients with is a short course (7 days) of low-dose ampho-
­oropharyngeal candidiasis. Voriconazole tericin B intravenously. A urinary catheter
or posaconazole are alternative drugs. in a patient with candidiasis should be
Although cure rates with fluconazole are removed or replaced promptly.
greater than with nystatin, relapse rates • Invasive infections. Most Candida species
are comparable. are susceptible to amphotericin B, although
Esophagitis caused by Candida species is C lusitaniae and some strains of C glabrata
treated with oral fluconazole or itraconazole and C krusei exhibit decreased susceptibility
solution. For patients who cannot tolerate or resistance. Among patients with persis-
oral therapy, intravenous fluconazole, an tent candidemia despite appropriate therapy,
echinocandin, or amphotericin B is recom- investigation for a deep focus of infection
mended. The recommended duration of should be conducted. Lipid-associated or
therapy is 14 to 21 days, but duration of liposomal preparations of amphotericin B

ERRNVPHGLFRVRUJ
Candidiasis 81

can be used as an alternative to amphoteri- abnormalities have resolved. Echinocandins


cin B deoxycholate in patients who experi- are not recommended for treatment of
ence significant toxicity during therapy. ­central nervous system candidal infections
in neonates. The duration of therapy for
Fluconazole is not an appropriate choice
uncomplicated candidemia is 2 weeks. Lipid
for therapy before the infecting Candida
formulations of amphotericin B should be
species has been identified because C krusei
used with caution in neonates, particularly
is resistant to fluconazole and more than
in patients with urinary tract involvement.
50% of C glabrata isolates can also be resis-
Recent evidence suggests that treatment of
tant. Although voriconazole is effective
neonates with lipid formulations of ampho-
against C krusei, it is often ineffective against
tericin may be associated with worse out-
C ­glabrata. The echinocandins (caspofungin,
comes when compared with amphotericin
micafungin, and anidulafungin) all are
B deoxycholate or fluconazole.
active in vitro against most Candida species
and are appropriate first-line drugs for • Older children and adolescents. In non­
­Candida infections in patients who are neutropenic and clinically stable children
severely ill or neutropenic. The echinocan- and adults, fluconazole or an echinocandin
dins should be used with caution against (eg, caspofungin, micafungin, anidulafun-
C parapsilosis infection because some gin) is the recommended treatment; ampho-
decreased in vitro susceptibility has been tericin B deoxycholate or lipid formulations
reported. If an echinocandin is initiated are alternative. In nonneutropenic patients
empirically and C parapsilosis is isolated in with candidemia and no metastatic com­
a recovering patient, the echinocandin can plications, treatment should continue for
be continued. 14 days after documented clearance of
­Candida from the bloodstream and resolu-
• Neonates. Neonates are more likely than
tion of clinical manifestations associated
older children and adults to have meningitis
with candidemia.
as a manifestation of candidiasis. Although
meningitis can be seen in association with In critically ill neutropenic patients, an
candidemia, approximately half of neonates ­echinocandin or a lipid formulation of
with candida meningitis do not have a posi- amphotericin B is recommended because
tive blood culture result. Central nervous of the fungicidal nature of these agents
system disease in the neonate typically when compared with fluconazole, which is
­manifests as meningoencephalitis and fungistatic. In less seriously ill neutropenic
should be assumed to be present in the patients, fluconazole is the alternative treat-
­neonate with candidemia and signs of ment for patients who have not had recent
meningoencephalitis because of the high azole exposure. Avoidance or reduction of
incidence of this complication. A lumbar systemic immunosuppression is also advised
puncture is recommended for all neonates when feasible.
with ­candidemia.
• Management of indwelling catheters.
Amphotericin B deoxycholate is the drug of In neonates and nonneutropenic children,
choice for treating neonates with systemic prompt removal of any infected vascular
candidiasis, including meningitis. For or peritoneal catheters is strongly recom-
­susceptible Candida species, step-down mended. For neutropenic children, catheter
treatment with fluconazole (12 mg/kg/d removal should be considered. The recom-
administered once daily) may be considered mendation in this population is weaker
after the patient with Candida meningitis because the source of candidemia in the
has responded to initial treatment. Therapy ­neutropenic child is more likely to be gas­
for central nervous system infection is at trointestinal, and it is difficult to determine
least 3 weeks and should continue until all the relative contribution of the catheter. In
signs and cerebrospinal fluid and radiologic the situation in which prompt removal of an

ERRNVPHGLFRVRUJ
82 Candidiasis

infected catheter and rapid clearance is and antimicrobial stewardship, can dimin-
established, treatment could be limited for ish infection rates and should be optimized
a shorter course. before implementation of chemoprophylaxis
as standard practice in a neonatal intensive
• Additional assessments. Ophthalmologic
care unit. Fluconazole prophylaxis is recom-
evaluation is recommended for all patients
mended for extremely low birth weight neo-
with candidemia, although the yield is noted
nates cared for in neonatal intensive care
to be low. Evaluation should occur once can-
units with moderate (5%–10%) or high
didemia is controlled, and, in patients with
(≥10%) rates of invasive candidiasis. The rec-
neutropenia, evaluation should be deferred
ommended regimen for extremely low birth
until recovery of the neutrophil count.
weight neonates is to initiate fluconazole
• Chemoprophylaxis. Invasive candidiasis in treatment intravenously during the first 48
neonates is associated with prolonged hospi- to 72 hours after birth and administer it
talization and neurodevelopmental impair- twice a week for 4 to 6 weeks or until intra-
ment or death in almost 75% of affected venous access is no longer required for care.
neonates with extremely low birth weight
Fluconazole prophylaxis can also decrease
(<1,000 g). Four prospective randomized
the risk of mucosal (eg, oropharyngeal,
controlled trials and 10 retrospective cohort
esophageal) candidiasis in patients with
studies of fungal prophylaxis in neonates
advanced HIV disease. However, an
with birth weight less than 1,000 g or less
increased incidence of infections attributable
than 1,500 g have demonstrated significant
to C krusei (which is intrinsically resistant
reduction of Candida colonization, rates of
to fluconazole) has been reported in non–
invasive candidiasis, and Candida-related
HIV-infected patients receiving prophylactic
mortality in nurseries with a moderate or
fluconazole. Prophylaxis should be consid-
high incidence of invasive candidiasis.
ered for children undergoing allogenic
Besides birth weight, other risk factors for
hematopoietic stem cell transplantation
invasive candidiasis in neonates include
and other highly myelosuppressive chemo-
inadequate infection-prevention practices
therapy during the period of neutropenia.
and prolonged use of antimicrobial agents.
Prophylaxis is not routinely recommended
Adherence to optimal infection-control
for other immunocompromised children,
practices, including “bundles” for intravas-
including children with HIV infection.
cular catheter insertion and maintenance

Image 24.1
This is an image of a Sabhi agar plate culture of the fungus Candida albicans grown at 20°C (68°F).
Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Candidiasis 83

Image 24.2 Image 24.3


Candida albicans on chrome agar. Colonies Candida tropicalis on chrome agar. Colonies
appear light to medium green in color and are appear dark to metallic blue in color with or
smooth and raised. Courtesy of Julia Rosebush, without a halo and are raised and smooth.
DO; Robert Jerris, PhD; and Theresa Stanley, Courtesy of Julia Rosebush, DO; Robert Jerris,
M(ASCP). PhD; and Theresa Stanley, M(ASCP).

Image 24.5
Image 24.4 Candida albicans (thrush) infection of the tonsils
Histopathologic features of Candida albicans and uvula of an otherwise healthy 6-month-old.
infection. Pseudohyphae and true hyphae The white exudate may resemble curds of milk.
(methenamine silver stain) found in a tissue Copyright Edgar O. Ledbetter, MD, FAAP.
biopsy. Copyright American Society for
Clinical Pathology.

Image 24.6
Photograph of a very low birth weight neonate who developed invasive fungal dermatitis of the
back caused by Candida albicans. This is an uncommon presentation that is often accom­panied by
disseminated infection. The diagnosis is established by skin biopsy that reveals invasion of the yeast
into the dermis and culture that grows the yeast on routine culture media within 2 to 4 days. Courtesy
of Carol J. Baker, MD, FAAP.

ERRNVPHGLFRVRUJ
84 Candidiasis

Image 24.7
Flaky skin in an extremely low birth weight neonate (<1,000 g) with congenital cutaneous candidiasis of
varying presentations (all skin cultures positive for Candida albicans). Courtesy of David Kaufman, MD.

Image 24.8
Extremely low birth weight neonate (<1,000 g) with congenital cutaneous candidiasis of varying
presentations (all skin cultures positive for Candida albicans). Courtesy of David Kaufman, MD.

ERRNVPHGLFRVRUJ
Candidiasis 85

Image 24.9
Extremely low birth weight neonate (<1,000 g) with congenital cutaneous candidiasis (all skin cultures
positive for Candida albicans). Courtesy of David Kaufman, MD.

Image 24.11
Image 24.10 Congenital candidiasis is characterized by
Disseminated neonatal candidiasis. Candida widespread erythematous papules or pustules.
microabscess in the brain. Courtesy of Dimitris P. Courtesy of Anthony Mancini, MD, FAAP.
Agamanolis, MD.

Image 24.13
Image 24.12
Oral thrush covering the soft palate and uvula. Candida rash with typical satellite lesions in an
Courtesy of Centers for Disease Control and infant boy.
Prevention.

ERRNVPHGLFRVRUJ
86 Candidiasis

Image 24.15
This patient with HIV/AIDS presented with a
secondary oral pseudomembranous candidiasis
infection. Courtesy of Centers for Disease Control
and Prevention/Sol Silverman Jr, DDS.

Image 24.14
Severe Candida diaper dermatitis with satellite
lesions. Courtesy of George Nankervis, MD.

Image 24.16
Candidiasis of the fingernail bed. Courtesy of Image 24.17
Centers for Disease Control and Prevention/ A 7-month-old white boy with mucocutaneous
Sherry Brinkman. candidiasis, generalized. Courtesy of Larry
Frenkel, MD.

Image 24.18
An immunocompromised 5-year-old boy with multiple Candida granulomatous lesions, a rare
response to an invasive cutaneous infection. These crusted, verrucous plaques and hornlike
projections require systemic candicidal agents for eradication or palliation. Courtesy of George
Nankervis, MD.

ERRNVPHGLFRVRUJ
Candidiasis 87

Image 24.19
Candida albicans esophagitis in a 4-year-old girl. Courtesy of Benjamin Estrada, MD.

Image 24.20
Candida esophagitis with abscesses and ulceration of the mucosa. Courtesy of Dimitris P.
Agamanolis, MD.

Image 24.21
Candida albicans in a 9-year-old boy with chronic mucocutaneous candidiasis. Courtesy of Benjamin
Estrada, MD.

ERRNVPHGLFRVRUJ
88 Cat-scratch Disease

25 involvement has been reported but is less com-


mon. Other rare manifestations include retino-
Cat-scratch Disease choroiditis, anterior uveitis, vitritis, pars
(Bartonella henselae) planitis, retinal vasculitis, retinitis, branch
retinal arteriolar or venular occlusions, and
Clinical Manifestations
macular hole.
Infections with Bartonella henselae can be
asymptomatic, but the predominant clinical Etiology
manifestation of cat-scratch disease (CSD) in B henselae, the causative organism of CSD, is
an immunocompetent person is regional a fastidious, slow-growing, gram-negative
lymphadenopathy or lymphadenitis. Most bacillus that is also the causative agent of
­people with CSD are afebrile or have low-grade ­bacillary angiomatosis (vascular proliferative
fever with mild systemic symptoms, such as lesions of skin and subcutaneous tissue) and
malaise, anorexia, fatigue, and headache. Fever bacillary peliosis (reticuloendothelial lesions
and mild systemic symptoms occur in appro­x­ in visceral organs, primarily the liver). The
imately 30% of patients. A skin papule or latter 2 manifestations of infection are reported
­pustule is often found at the presumed site of among patients who are immunocompromised.
inoculation and usually precedes development B henselae is related closely to Bartonella quin­
of lymphadenopathy by approximately 1 to tana, the agent of louse-borne trench fever and
2 weeks (range, 7–60 days). Lymphadenopathy the causative agent of bacillary ­angiomatosis.
involves nodes that drain the site of inocula-
tion, typically axillary, but cervical, submental, Epidemiology
epitrochlear, or inguinal nodes can be Cat-scratch disease is a common infection,
involved. The skin overlying affected lymph although its true incidence is unknown.
nodes is often tender, warm, erythematous, B henselae is a common causes of regional
and indurated. Most Bartonella-infected lymph lymphadenopathy or lymphadenitis in
nodes will resolve spontaneously within 4 to ­children. Cats are the natural reservoir for
6 weeks, but approximately 10% to 25% of B henselae, with a seroprevalence of 13% to 90%
affected nodes suppurate spontaneously. in domestic and stray cats in the United States.
­Inoculation of the periocular tissue can result Other animals, including dogs, can be infected
in Parinaud oculoglandular syndrome, which and occasionally are associated with human
consists of follicular conjunctivitis and ipsi­ infection. Cat-to-cat transmission occurs via
lateral preauricular lymphadenopathy. Cat- the cat flea (Ctenocephalides felis), with feline
scratch disease can also present with fevers for infection resulting in bacteremia that is usually
1 to 3 weeks (ie, fever of unknown origin) and asymptomatic and lasts weeks to months. Fleas
be associated with nonspecific symptoms, such acquire the organism when feeding on a bacte-
as malaise, abdominal pain, headache, and remic cat and then shed infectious organisms
myalgias. Less common manifestations of in their feces. The bacteria are transmitted to
B henselae infection likely reflect blood-borne humans by inoculation through a scratch or
disseminated disease and include encephalopa- bite from a bacteremic cat or by hands contam-
thy, osteolytic lesions, granulomata in the liver inated by flea feces touching an open wound
and spleen, glomerulonephritis, pneumonia, or the eye. Kittens (more often than cats) and
thrombocytopenic purpura, and erythema animals from shelters or adopted as strays are
nodosum. Ocular manifestations occur in 5% more likely to be bacteremic. Most reported
to 10% of patients. The most frequent presen­ cases occur in people younger than 20 years,
tation of ocular Bartonella infection is neuro- with most patients having a history of recent
retinitis, characterized by unilateral painless contact with apparently healthy cats, typically
vision impairment, granulomatous optic disc kittens. No evidence of person-to-person
swelling, and macular edema, with lipid exu- transmission exists.
dates (macular star); simultaneous bilateral

ERRNVPHGLFRVRUJ
Cat-scratch Disease 89

Incubation Period Treatment


From scratch to primary cutaneous lesion, 7 Management of localized, uncomplicated
to 12 days; from the appearance of the primary CSD is primarily aimed at relief of symptoms
lesion to the appearance of lymphadenopathy, because the disease is usually self-limited,
5 to 50 days (median, 12 days). resolving spontaneously in 2 to 4 months.
Painful suppurative nodes can be treated with
Diagnostic Tests
needle aspiration for relief of symptoms; inci-
B henselae is a fastidious organism; recovery by sion and drainage should be avoided because
routine culture is rarely successful. Specialized this may facilitate fistula formation.
laboratories experienced in isolating Bartonella
organisms are recommended for processing of Azithromycin has been shown to have a mod-
cultures. The indirect immunofluorescent anti- est benefit in treating localized CSD, with a
body assay for detection of serum antibodies significantly greater decrease in lymph node
to antigens of Bartonella species is useful for volume after 1 month of therapy compared
diagnosis of CSD. The indirect immunofluo­ with placebo. Many experts recommend anti-
rescent antibody test is available at many microbial therapy in acutely or severely ill
­commercial laboratories, but because of cross- immunocompetent patients with systemic
reactivity with other infections and a high symptoms, particularly people with retinitis,
seroprevalence in the general population, clini- hepatic or splenic involvement, or painful ade-
cal correlation is essential. Enzyme immuno­ nitis. Antimicrobial therapy is recommended
assays for detection of antibodies to B henselae for all immunocompromised people. Reports
have been developed. Polymerase chain reac- suggest that several oral antimicrobial agents
tion assays are available in some commercial (azithromycin, clarithromycin, ciprofloxacin,
and research laboratories and at the Centers doxycycline, trimethoprim-sulfamethoxazole,
for Disease Control and Prevention for testing and rifampin) and parenteral gentamicin are
of tissue or body fluids. If tissue (eg, lymph effective. The optimal duration of therapy is
node) specimens are available, bacilli occasion- not known but may be several weeks for sys-
ally may be visualized using a silver stain (eg, temic disease.
­Warthin-Starry, Steiner); however, this test is Antimicrobial therapy for patients with bacil-
not specific for B henselae. Early histologic lary angiomatosis and bacillary peliosis has
changes in lymph node specimens consist of been shown to be beneficial and is recom-
lymphocytic infiltration with epithelioid gran- mended. Azithromycin or doxycycline is
uloma formation. Later changes consist of ­effective for treatment of these condition;
polymorphonuclear leukocyte infiltration with ­t herapy should be administered for several
granulomas that become necrotic and resemble months to prevent relapse in people who
granulomas from patients with tularemia, bru- are immunocompromised.
cellosis, and mycobacterial infections.

Image 25.1
Clinical manifestations of cat-scratch disease include Parinaud oculoglandular syndrome, which results
when inoculation of the eye conjunctiva results in conjunctivitis.

ERRNVPHGLFRVRUJ
90 Cat-scratch Disease

Image 25.2
Boy with signs of Parinaud oculoglandular syndrome, with painless, nonpurulent conjunctivitis and
ipsilateral preauricular lymphadenopathy. These findings, combined with the cervical lymphadenopathy
and his exposure to a kitten, make cat-scratch disease, or Bartonella henselae infection, the most
likely possibility. Although most patients who have cat-scratch disease report some contact with
kittens or cats, many do not recall being scratched. Cats younger than 1 year are most likely to
transmit the organism to humans; human-to-human transmission does not occur.

Image 25.4
Cat-scratch granuloma of the finger of a 6-year-
Image 25.3 old white boy. This is a typical inoculation site
Submental lymphadenitis due to cat-scratch lesion, which was noted about 10 days before
disease. the development of regional lymphadenopathy.

Image 25.5
Papules at inoculation sites on the face of a
patient with cat-scratch disease. Image 25.6
A papule at each of 2 inoculation sites on the arm
of a patient with cat-scratch disease.

ERRNVPHGLFRVRUJ
Cat-scratch Disease 91

Image 25.7 Image 25.8


Sanguinopurulent exudate aspirated from the Cat-scratch disease granuloma of the finger in
axillary node of a patient with cat-scratch a 12-year-old white boy with epitrochlear node
disease. Copyright Michael Rajnik, MD, FAAP. involvement (see Image 25.10). Copyright
Michael Rajnik, MD, FAAP.

Image 25.9
Epitrochlear suppurative adenitis of cat-scratch
Image 25.10
disease in the boy in Image 25.9 with a cat-
Stellate microabscess in the lymph node of a
scratch granuloma of the finger. Copyright
patient with cat-scratch disease (Warthin-Starry
Michael Rajnik, MD, FAAP.
silver stain; original magnification x158). Courtesy
of Christopher Paddock, MD.

Image 25.11
A granulomatous lesion of cat-scratch disease Image 25.12
at the base of the right thumb in a 4-year-old A 4-year-old Asian boy with right axillary
white boy. Courtesy of Centers for Disease lymphadenopathy due to cat-scratch disease.
Control and Prevention/Dr Thomas F. Sellers; Courtesy of Ed Fajardo, MD.
Emory University.

ERRNVPHGLFRVRUJ
92 Cat-scratch Disease

Image 25.13
Inguinal lymphadenitis due to cat-scratch disease in a 3-year-old white girl. Courtesy of Ed Fajardo,
MD.

Image 25.14
This 3-year-old was previously scratched on the left side of her neck by a kitten. She developed raised
red bumps around the scratch on day 5. This area ulcerated slightly and was slow to heal. No fever
was noted, although she was less active for the next several days and complained that her arms and
legs were sore. She developed swollen posterior cervical lymph nodes about a week later. Physical
examination indicated two 8-mm ulcerations with raised borders and a papule near an enlarged
minimally tender pos­terior cervical node. Serology result was positive for Bartonella henselae. She
improved with time following a course of azithromycin. Courtesy of Will Sorey, MD.

ERRNVPHGLFRVRUJ
Chancroid 93

26 Incubation Period

Chancroid 1 to 10 days.

Clinical Manifestations Diagnostic Tests

Chancroid is an acute ulcerative disease of the Chancroid is usually diagnosed by clinical


genitalia. An ulcer begins as an erythematous findings (1 or more painful genital ulcers
papule that becomes pustular and erodes over with tender suppurative inguinal adenopathy)
several days, forming a sharply demarcated, and by excluding other genital ulcerative
somewhat superficial lesion with a serpiginous ­diseases, such as syphilis, herpes simplex
border. The base of the ulcer is friable and can ­infection, or lymphogranuloma venereum.
be covered with a gray or yellow, purulent exu- Confirmation is made by isolation of H ducreyi
date. Single or multiple ulcers can be present. from a genital ulcer or lymph node aspirate,
Unlike a syphilitic chancre, which is painless but in less than 80% of patients is this possible.
and indurated, the chancroid ulcer is often Because special culture media and conditions
painful and nonindurated and can be associ- are required for isolation, laboratory personnel
ated with a painful, unilateral inguinal suppu- should be informed of the suspicion of chan-
rative adenitis (bubo). Without treatment, croid. Buboes are almost always sterile. Poly-
ulcer(s) can spontaneously resolve, cause merase chain reaction assays can provide a
extensive erosion of the genitalia, or lead to specific diagnosis but are not available in most
scarring and phimosis, a painful inability to clinical ­laboratories.
retract the foreskin. Treatment
In most males, chancroid manifests as a geni- H ducreyi has been uniformly susceptible to
tal ulcer with or without inguinal tenderness; third-generation cephalosporins, macrolides,
edema of the prepuce is common. In females, and quinolones. Recommended regimens
most lesions are at the vaginal introitus and include azithromycin or ceftriaxone. Alterna-
symptoms include dysuria, dyspareunia, tives include erythromycin or ciprofloxacin.
­vaginal discharge, pain on defecation, or Patients with HIV infection may need pro-
anal bleeding. Constitutional symptoms longed therapy. Syndromic management usu-
are unusual. ally includes treatment for syphilis. Clinical
improvement occurs 3 to 7 days after initiation
Etiology
of therapy, and healing is complete in approxi-
Chancroid is caused by Haemophilus ducreyi, mately 2 weeks. Adenitis is often slow to resolve
which is a gram-negative coccobacillus. and can require needle aspiration or surgical
incision. Patients should be reexamined 3 to
Epidemiology
7 days after initiating therapy to verify healing.
Chancroid is a sexually transmitted infection Slow clinical improvement and relapses can
associated with poverty, prostitution, and occur after therapy, especially in people with
illicit drug use. Chancroid is endemic in Africa HIV infection. Close clinical follow-up is
and the tropics but is rare in the United States; ­recommended; retreatment with the original
when it does occur, it is usually associated with ­regimen is usually effective in patients who
sporadic outbreaks. Coinfection with syphilis experience a relapse.
or human herpesvirus occurs in as many as
17% of patients. Chancroid is a well-established Patients should be evaluated for other sexually
cofactor for transmission of HIV. H ducreyi transmitted infections, including syphilis,
also causes a chronic limb ulceration syn- human herpesvirus, chlamydia, gonorrhea,
drome that is spread by nonsexual contact and HIV, at the time of diagnosis.
in older children and adults in the Western
Pacific islands. Because sexual contact is the
major route of transmission, a diagnosis of
chancroid in young children is strong evidence
of ­sexual abuse.

ERRNVPHGLFRVRUJ
94 Chancroid

Image 26.2
Ulcerative chancroid lesions with inflammation
Image 26.1 of the shaft and glans penis caused by
Haemophilus ducreyi is a gram-negative Haemophilus ducreyi. Chancroid lesions are
coccobacillus, as shown in this preparation. irregular in shape, painful, and soft (nonindurated)
Courtesy of Centers for Disease Control and to touch. Courtesy of Hugh Moffet, MD.
Prevention.

Image 26.4
This adolescent black male presented with a
chancroid lesion of the groin and penis affecting
Image 26.3 the ipsilateral inguinal lymph nodes. First signs
Chancroid ulcer on the glans penis. Coinfection of infection typically appear 3 to 5 days after
with syphilis or human herpesvirus occurs in as exposure, although symptoms can take up to
many as 10% of patients. Courtesy of Hugh 2 weeks to appear. Courtesy of Centers for
Moffet, MD. Disease Control and Prevention/J. Pledger.

Image 26.5
The penile ulcers on the penis of this adolescent white male proved to be due to chancroid, caused
by Haemophilus ducreyi, and not syphilis as initially suspected. Chancroid can cause genital ulcers or
inguinal buboes in the groin area. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
CHLAMYDOPHILA (FORMERLY CHLAMYDIA) ­PNEUMONIAE 95

27 is common, especially in adults. Clusters of


­infection have been reported in groups of chil-
Chlamydial Infections dren and young adults. There is no evidence
of ­seasonality.
Chlamydophila (formerly
Incubation Period
Chlamydia) ­pneumoniae
21 days.
Clinical Manifestations
Diagnostic Tests
Patients can be asymptomatic or mildly to
moderately ill with a variety of respiratory Serologic testing has been the primary means
tract diseases, including pneumonia, acute of diagnosing C pneumoniae infection but is
bronchitis, prolonged cough, and, less com- problematic. The microimmunofluorescent
monly, pharyngitis, laryngitis, otitis media, antibody test is the most sensitive and specific
and sinusitis. In some patients, a sore throat serologic test for acute infection. A 4-fold
precedes the onset of cough by a week or more. increase in immunoglobulin (Ig) G titer
The clinical course can be biphasic, culminat- between acute and convalescent sera is pre-
ing in atypical pneumonia. Chlamydophila ferred to diagnose acute infection, but an IgM
pneumoniae can present as severe community- titer of 1:16 or greater is also useful. Use of a
acquired pneumonia in immunocompromised single IgG titer in diagnosis of acute infection
hosts and has been associated with acute exac- is not recommended because, during primary
erbations in patients with cystic fibrosis and infection, IgG antibody may not appear until
acute chest syndrome in children with sickle 6 to 8 weeks after onset of illness and increases
cell disease. within 1 to 2 weeks with reinfection. In pri-
mary infection, IgM antibody appears approxi-
Physical examination may reveal nonexudative mately 2 to 3 weeks after onset of illness but can
pharyngitis, pulmonary rales, and broncho- be falsely positive because of cross-reactivity
spasm. Chest radiography may reveal a variety with other Chlamydia species or falsely nega-
of findings ranging from bilateral infiltrates to tive in cases of reinfection. Early antimicrobial
a single patchy subsegmental infiltrate. Illness therapy also may suppress antibody response.
can be prolonged, and cough can persist for 2
to 6 weeks or longer. C pneumoniae can be isolated from swab
­specimens obtained from the nasopharynx or
Etiology oropharynx or from sputum, bronchoalveolar
C pneumoniae is an obligate intracellular bac- lavage, or tissue biopsy specimens. Specimens
terium that is distinct antigenically, genetically, should be placed into appropriate transport
and morphologically from Chlamydia species, media and stored at 4°C (39.2°F) until inocula-
so it is grouped in the genus Chlamydophila. tion into cell culture; specimens that cannot
be processed within 24 hours should be fro-
Epidemiology
zen and stored at –70°C (–94°F). Culturing
C pneumoniae infection is presumed to be C ­pneumoniae is difficult and often fails to
transmitted from person to person via infected detect the organism. Nasopharyngeal shedding
respiratory tract secretions. It is unknown can occur for months after acute disease, even
whether there is an animal reservoir. The with treatment. Because of the difficulty of
­disease occurs worldwide, but in tropical and accurately detecting C pneumoniae via culture,
low-income countries, disease occurs earlier serologic testing, or immunohistochemistry
in life than in industrialized countries in tem- testing, several types of polymerase chain
perate climates. The timing of initial infection ­reaction (PCR) assays have been developed.
peaks between 5 and 15 years of age. In the Sensitivity and specificity of these different
United States, approximately 50% of adults PCR techniques remain largely unknown.
have C pneumoniae–serologic evidence of prior A multiplex PCR assay has been cleared by
infection by age 20 years. Recurrent infection

ERRNVPHGLFRVRUJ
96 CHLAMYDOPHILA (FORMERLY CHLAMYDIA) ­PNEUMONIAE

the US Food and Drug Administration for azithromycin, erythromycin, clarithromycin)


­diagnosis of C pneumoniae using nasopharyn- is recommended. Tetracycline or doxycycline
geal samples. The test appears to have high sen- can be used in children older than 7 years.
sitivity and specificity. Newer fluoroquinolones (levofloxacin and
moxifloxacin) are alternative drugs for patients
Treatment
who are unable to tolerate macrolide antibiot-
Most respiratory tract infections thought to ics but should not be used as first-line treat-
be caused by by C pneumoniae are treated ment. Therapy is continued to 10 to 14 days,
empirically. For suspected C pneumoniae except for azithromycin, when 5 days is typi-
infections, treatment with macrolides (eg, cally ­adequate.

ERRNVPHGLFRVRUJ
CHLAMYDOPHILA (FORMERLY CHLAMYDIA) PSITTACI 97

28 e­ xposure described most frequently, although


transmission has been reported through expo-
Chlamydophila (formerly sure to aviaries, bird exhibits, and lawn mow-
Chlamydia) psittaci ing. Excretion of C psittaci from birds can be
(Psittacosis, Ornithosis, Parrot Fever) intermittent or continuous for weeks or
months. Pet owners and workers at poultry
Clinical Manifestations slaughter plants, poultry farms, and pet shops
Psittacosis (ornithosis) is an acute respiratory are at increased risk of infection. Laboratory
tract infection with systemic symptoms and personnel working with C psittaci are also at
signs including fever, nonproductive cough, risk. Psittacosis is worldwide in distribution
headache, and malaise. Less common symp- and tends to occur sporadically in any season.
toms are pharyngitis, diarrhea, and altered Although rare, severe illness and abortion have
mental status. Extensive interstitial pneumonia been reported in pregnant women.
can occur, with radiographic changes charac-
Incubation Period
teristically more severe than would be expected
from chest examination findings. Endocarditis, 5 to 14 days (may be longer).
myocarditis, pericarditis, thrombophlebitis, Diagnostic Tests
nephritis, hepatitis, and encephalitis are rare
complications. Recent studies have suggested A confirmed diagnosis of psittacosis requires a
an association with ocular adnexal marginal clinically compatible illness with fever, chills,
zone lymphomas involving orbital soft tissue, headache, cough, and myalgias, plus laboratory
lacrimal glands, and conjunctiva. confirmation by one of the following: isolation
of C psittaci from respiratory tract specimens
Etiology or blood, or 4-fold or greater increase in immu-
Chlamydophila psittaci is an obligate intra­ noglobulin (Ig) G by complement fixation (CF)
cellular bacterium that is distinct antigenically, or a titer of 1:32 with microimmunofluores-
genetically, and morphologically from Chla­ cence (MIF) against C psittaci between paired
mydia species and, following reclassification, acute- and convalescent-phase serum speci-
is grouped in the genus Chlamydophila. mens obtained at least 2 to 4 weeks apart. A
probable case of psittacosis requires a clinically
Epidemiology compatible illness and either supportive sero-
Birds are the major reservoir of C psittaci. The logic test results (eg, C psittaci IgM ≥1:16) or
term psittacosis commonly is used, although detection of C psittaci DNA in a respiratory
the term ornithosis more accurately describes tract specimen by polymerase chain reaction
the potential for nearly all domestic and wild assay. For serologic testing, MIF is more sensi-
birds to spread this infection, not just psitta- tive and specific than CF, but CF and MIF can
cine birds (eg, parakeets, parrots, macaws). In cross-react with other chlamydial species and
the United States, psittacine birds, pigeons, should be interpreted cautiously. Additionally,
and turkeys are important sources of human nucleic acid amplification tests have been
disease. Importation and illegal trafficking of developed that can distinguish C psittaci from
exotic birds is associated with an increased other chlamydial species and are under investi-
incidence of human disease because shipping, gation for detection of C psittaci from human
crowding, and other stress factors may increase clinical samples. Treatment with antimicrobial
shedding of the organism among birds with agents may suppress the antibody response.
latent infection. Infected birds, whether Culturing the organism is recommended; how-
healthy appearing or obviously ill, can trans- ever, it is difficult and should be attempted only
mit the organism. Infection is usually acquired by experienced personnel in laboratories where
by inhaling aerosolized excrement or respira- strict containment measures to prevent spread
tory secretions from the eyes or beaks of of the organism are used during collection and
infected birds. Handling of plumage and handling of all specimens because of occupa-
mouth-to-beak contact are the modes of tional and laboratory safety concerns.

ERRNVPHGLFRVRUJ
98 CHLAMYDOPHILA (FORMERLY CHLAMYDIA) PSITTACI

Treatment women. Therapy should be for a minimum of


Tetracycline or doxycycline is the drug of 10 days and for 10 to 14 days after fever abates.
choice. Erythromycin and azithromycin are In patients with severe infection, intravenous
alternative agents and are recommended for doxycycline can be considered.
children younger than 8 years and pregnant

Image 28.1
This direct fluorescent antibody stained mouse
brain impression smear reveals the presence of
the bacterium Chlamydophila psittaci. Psittacosis
is acquired by inhaling dried secretions from birds
infected with C psittaci. Although all birds are
susceptible, pet birds and poultry are most Image 28.2
frequently involved in transmission to humans. Chlamydophila psittaci pneumonia in a 16-year-
Courtesy of Courtesy of Centers for Disease old girl with a cough of 3 weeks’ duration. The
Control and Prevention/Vester Lewis, MD. family had several parrots in the home that were
purchased from a roadside stand near the Texas-
Mexico border. Interstitial pneumonia, most
prominent in the lower lobe of the left lung, is
shown. Complement fixation titer for C psittaci
is 1:128. Copyright David Waagner.

Image 28.3
Lateral chest radiograph of the patient in
Image 28.2. Most domestic and wild birds can
transmit Chlamydophila psittaci. Copyright
David Waagner.

ERRNVPHGLFRVRUJ
CHLAMYDIA TRACHOMATIS 99

29 resolved by the time the patient seeks care.


Proctocolitis may occur in women or men
Chlamydia trachomatis who engage in anal intercourse. Symptoms
Clinical Manifestations can resemble those of inflammatory bowel
disease, including mucoid or hemorrhagic
Chlamydia trachomatis is associated with a rectal discharge, constipation, tenesmus,
range of clinical manifestations, including or anorectal pain. Stricture or fistula for­
­neonatal conjunctivitis, nasopharyngitis, mation can follow severe or inadequately
and pneumonia in young infants; genital treated infection.
tract infection; lymphogranuloma venereum
(LGV); and trachoma. • Trachoma is a chronic follicular kerato­
conjunctivitis with neovascularization of
• Neonatal chlamydial conjunctivitis is char- the cornea that results from repeated and
acterized by ocular congestion, edema, and chronic infection. Blindness secondary to
discharge developing a few days to several extensive local scarring and inflammation
weeks after birth and lasting for 1 to 2 weeks occurs in 1% to 15% of people with trachoma.
and sometimes longer. In contrast to tra-
choma, scars and pannus formation are rare. Etiology
• Pneumonia in young infants is usually an C trachomatis is an obligate intracellular
afebrile illness of insidious onset occurring ­bacterium with at least 18 serologic variants
between 2 and 19 weeks after birth. A (serovars) divided between the following bio-
­repe­titive staccato cough, tachypnea, and logic variants (biovars): oculogenital (serovars
rales in an afebrile 1-month-old are charac- A–K) and LGV (serovars L1, L2, and L3). Tra-
teristic but not always present. Wheezing choma usually is caused by serovars A through
is uncommon. Hyperinflation usually C, and genital and perinatal infections are
accompanies infiltrates seen on chest radio- caused by B and D through K.
graphs. Nasal stuffiness and otitis media Epidemiology
may occur. Untreated disease can linger or
recur. Severe chlamydial pneumonia has C trachomatis is the most common reportable
occurred in infants and some immuno­ sexually transmitted infection in the United
compromised adults. States, with high rates among sexually active
adolescents and young adult women. A signifi-
• Genitourinary tract manifestations, such cant proportion of patients are asymptomatic,
as vaginitis in prepubertal girls; urethritis, providing an ongoing reservoir for infection.
cervicitis, endometritis, salpingitis, proctitis, Prevalence of the organism is consistently
and perihepatitis (Fitz-Hugh–Curtis syn- highest among adolescent and young adult
drome) in postpubertal females; urethritis, women. Among all 14- to 25-year-olds partici-
epididymitis, and proctitis in males; and pating in the 2008 National Health and Nutri-
Reiter syndrome (arthritis, urethritis, and tion Examination Survey, prevalence was 3.3%
bilateral conjunctivitis), can occur. Infection among females and 1.7% among males. Racial
can persist for months to years. Reinfection disparities are significant. The estimated preva-
is common. In postpubertal females, chla- lence among non-Hispanic black people (6.7%)
mydial infection can progress to pelvic was higher than the estimated prevalence
inflammatory disease and can result in among non-Hispanic white people (0.3%) and
­ectopic pregnancy, infertility, or chronic Mexican American people (2.4%). Among
pelvic pain. males who have sex with males screened for
rectal chlamydial infection, positivity ranges
• Lymphogranuloma venereum is classically
from 3% to 10%. Oculogenital serovars of
an invasive lymphatic infection with an ini-
C ­trachomatis can be transmitted from the
tial ulcerative lesion on the genitalia accom-
genital tract of infected mothers to their new-
panied by tender, suppurative inguinal or
borns during birth. Acquisition occurs in
femoral lymphadenopathy that is typically
approximately 50% of neonates born vaginally
unilateral. The ulcerative lesion often has

ERRNVPHGLFRVRUJ
100 CHLAMYDIA TRACHOMATIS

to infected mothers and in some neonates born Incubation Period


by cesarean delivery with membranes intact. Variable, depending on infection type; usually
The risk of conjunctivitis is 25% to 50% and the at least 1 week.
risk of pneumonia is 5% to 30% in infants who
contract C trachomatis. The nasopharynx is Diagnostic Tests
the anatomic site most commonly infected. C trachomatis urogenital infection in females
Genital tract infection in adolescents and can be diagnosed by testing first catch urine
adults is transmitted sexually. The possibility or swab specimens from the endocervix or
of sexual abuse should always be considered vagina. Diagnosis of C trachomatis urethral
in prepubertal children beyond infancy who infection in males can be made by testing a
have vaginal, urethral, or rectal chlamydial urethral swab or first catch urine specimen.
infection. Sexual abuse is not limited to prepu- Nucleic acid amplification tests (NAATs)
bertal children, and chlamydial infections can are the most sensitive tests for these speci-
result from sexual abuse or assault in postpu- mens and are the recommended tests for
bertal adolescents as well. C ­trachomatis detection.

Asymptomatic infection of the nasopharynx, For detecting C trachomatis infections of the


conjunctivae, vagina, and rectum can be genital tract among postpubescent individu-
acquired at birth. Nasopharyngeal cultures als, older nonculture tests and non-NAATs,
have been observed to remain positive for as such as DNA probe, direct fluorescent antibody
long as 28 months and vaginal and rectal tests, or enzyme immunoassay tests, have
­cultures for more than 1 year in infants and ­inferior sensitivity and specificity charac­
children with infection acquired at birth. teristics and are no longer recommended for
Infection is not known to be communicable C trachomatis testing. In the evaluation of
among infants and children. The degree of prepubescent children for possible sexual
­contagiousness of pulmonary disease is assault, the Centers for Disease Control and
unknown but seems to be low. Prevention recommends culture for C tracho­
matis of a specimen collected from the rectum
Lymphogranuloma venereum biovars are in boys and girls and from the vagina in girls.
worldwide in distribution but are particularly A meatal specimen should be obtained from
prevalent in tropical and subtropical areas. boys for chlamydia testing if urethral discharge
Although disease rarely occurs in the United is ­present.
States, outbreaks of LGV have been reported
among men who have sex with men. Infection Serum anti–C trachomatis antibody concen-
is often asymptomatic in females. Perinatal trations are difficult to determine, and only a
transmission is rare. Lymphogranuloma vene- few clinical laboratories perform this test. In
reum is infectious during active disease. Little children with pneumonia, an acute microim-
is known about the prevalence or duration of munofluorescent serum titer of C trachomatis–
asymptomatic carriage. specific immunoglobulin M of 1:32 or greater is
diagnostic. Diagnosis of LGV can be supported
Although rarely observed in the United States but not confirmed by a positive result (ie, titer
since the 1950s, trachoma is the leading infec- >1:64) on a complement-fixation test for chla-
tious cause of blindness worldwide, causing mydia or a high titer (typically >1:256, but this
up to 3% of the world’s blindness. It generally can vary by laboratory) on a microimmuno­
is confined to poor populations in resource- fluorescent serologic test for C trachomatis.
limited nations of Africa, the Middle East, However, most available serologic tests in the
Asia, Latin America, the Pacific Islands, and United States are based on enzyme immuno­
remote aboriginal communities in Australia. assay tests and might not provide a quantitative
Trachoma is transmitted by transfer of ocular titer-based result.
discharge. Predictors of scarring and blindness
for trachoma include increasing age and con- Diagnosis of genitourinary tract chlamydial
stant, severe trachoma. disease in a child should prompt examination
for other sexually transmitted infections,

ERRNVPHGLFRVRUJ
CHLAMYDIA TRACHOMATIS 101

including syphilis, gonorrhea, and HIV, and • For uncomplicated C trachomatis anogeni-
investigation of sexual abuse or assault. In the tal tract infection in adolescents or adults,
case of a neonate or an infant, because cultures oral doxycycline for 7 days or single-dose
can be positive for at least 12 months after azithromycin is recommended. Alternatives
infection acquired at birth, evaluation of the include oral erythromycin base, erythromy-
mother is also advisable. cin ethylsuccinate, ofloxacin, levofloxacin, or
doxycycline delayed-release daily for 7 days.
Diagnosis of ocular trachoma is usually made
For children who weigh less than 45 kg, the
clinically in countries with endemic infection.
recommended regimen is oral erythromycin
Treatment base or ethylsuccinate for 14 days. For chil-
dren who weigh 45 kg or more but who are
• Newborns and infants with chlamydial con-
younger than 8 years, the recommended
junctivitis or pneumonia are treated with
regimen is azithromycin, in a single oral
oral erythromycin base or ethylsuccinate for
dose. For children 8 years and older, the
14 days or with azithromycin for 3 days.
recommended regimen is azithromycin as a
Because the efficacy of erythromycin therapy
single oral dose or doxycycline for 7 days.
is approximately 80% for both of these con-
For pregnant women, the recommended
ditions, a second course may be required,
treatment is azithromycin as a single oral
and follow-up of infants is recommended.
dose. Amoxicillin or erythromycin base for
A diagnosis of C trachomatis infection in
7 days are alternative regimens. Doxycycline,
an infant should prompt treatment of the
ofloxacin, and levofloxacin are contraindi-
mother and her sexual partner(s). The need
cated during pregnancy.
for treatment of infants can be avoided by
screening pregnant women to detect and • Follow-up testing. Test of cure is not
treat C trachomatis infection before delivery. ­recommended for nonpregnant adult or
­adolescent patients treated for uncompli-
An association between orally administered
cated chlamydial infection unless compli-
erythromycin and infantile hypertrophic
ance is in question, symptoms persist, or
pyloric stenosis (IHPS) has been reported in
reinfection is suspected. Test of cure (prefer-
newborns and infants younger than 6 weeks.
ably by NAAT) is recommended 3 to 4 weeks
The risk of IHPS after treatment with other
after treatment of pregnant women. Because
macrolides (eg, azithromycin, clarithromy-
some of these regimens for pregnant women
cin) is unknown, although IHPS has been
may not be highly efficacious, a second
reported after use of azithromycin. Because
course of therapy may be required. Reinfec-
confirmation of erythromycin as a contribu-
tion is common after initial infection and
tor to cases of IHPS will require additional
treatment, and all infected adolescents and
investigation and alternative therapies are
adults should be tested for C trachomatis
not as well studied, erythromycin remains
3 months following initial treatment. If
the drug of choice. Physicians who prescribe
retesting at 3 months is not possible, retest
erythromycin to newborns should inform
whenever patients next present for health
parents about the signs and potential risks
care in the 12 months after initial treatment.
of developing IHPS.
• For LGV, doxycycline for 21 days is the
Neonates born to mothers known to have
­preferred treatment for children 8 years
untreated chlamydial infection are at high
and older, and erythromycin for 21 days is
risk of infection; however, prophylactic
an alternative regimen; azithromycin for
­antimicrobial treatment is not recom-
3 weeks is probably effective but has not
mended. Neonates should be monitored
been as well studied.
clinically to ensure appropriate treatment if
infection develops. If adequate follow-up • Treatment of trachoma is azithromycin as
cannot be ensured, preemptive therapy a single oral dose as recommended by the
should be ­considered. World Health Organization and includes
all household contacts of patients.

ERRNVPHGLFRVRUJ
102 CHLAMYDIA TRACHOMATIS

Image 29.1 Image 29.2


Infected HeLa cells (fluorescent antibody stain). Photomicrograph of Chlamydia trachomatis
Chlamydia trachomatis is the most common taken from a urethral scrape (iodine-stained
reportable sexually transmitted infection in the inclusions in McCoy cell line; magnification x200).
United States, with high rates of infection among Untreated, chlamydia can cause severe, costly
sexually active adolescents and young adults. reproductive and other health problems,
Copyright Noni MacDonald, MD. including short- and long-term consequences
(eg, pelvic inflammatory disease, infertility,
potentially fatal tubal pregnancy).

Image 29.3
Chlamydia. Incidence among women—United States and US territories, 2012. Courtesy of Morbidity
and Mortality Weekly Report.

ERRNVPHGLFRVRUJ
CHLAMYDIA TRACHOMATIS 103

Image 29.4
Conjunctivitis due to Chlamydia trachomatis, the most common cause of ophthalmia neonatorum. This
is the same infant as in Image 29.6.

Image 29.5
Chlamydia trachomatis pneumonia, severe and bilateral, in a 5-week-old. Courtesy of Edgar O.
Ledbetter, MD, FAAP.

ERRNVPHGLFRVRUJ
104 Botulism and Infant ­Botulism

30 are ubiquitous in soils and dust worldwide and


have been isolated from the home vacuum
Clostridial Infections cleaner dust of patients with infant botulism.
Botulism and Infant Epidemiology
­Botulism • Infant botulism (annual average, 96
(Clostridium botulinum) ­labor­atory-confirmed cases from 2006–2011;
median age, 16 weeks) results after ingested
Clinical Manifestations spores of C botulinum or related neurotoxi-
Botulism is a neuroparalytic disorder charac- genic clostridial species germinate, multiply,
terized by an acute, afebrile, symmetric, and produce botulinal toxin in the large
descending, flaccid paralysis. Paralysis is intestine through transient colonization of
caused by blockade of neurotransmitter release the intestinal microflora. Cases can occur
at the voluntary motor and autonomic neuro- in breastfed infants at the time of first intro-
muscular junctions. Four naturally occurring duction of nonhuman milk substances; the
forms of human botulism exist: infant, food- source of spores is usually not identified.
borne, wound, and adult intestinal coloniza- Honey has been identified as an avoidable
tion. Iatrogenic botulism results from injection source of spores. No case of infant botulism
of excess therapeutic botulinal toxin. Onset has been proven to be attributable to con-
of symptoms occurs abruptly within hours sumption of corn syrup. Rarely, intestinal
or evolves gradually over several days and botulism can occur in older children and
includes diplopia, dysphagia, dysphonia, and adults, usually after intestinal surgery and
dysarthria. Cranial nerve palsies are followed exposure to antimicrobial agents.
by symmetric, descending, flaccid paralysis of
• Foodborne botulism (annual average,
somatic musculature in patients who remain
17 cases from 2006–2010; median age,
fully alert. Infant botulism, which occurs pre-
53 years) results when food that carries
dominantly in infants younger than 6 months
spores of C botulinum is preserved or stored
(range, 1 day to 12 months), is preceded by or
improperly under anaerobic conditions that
begins with constipation and manifests as
permit germination, multiplication, and
decreased movement, loss of facial expression,
toxin production. Illness follows ingestion
poor feeding, weak cry, diminished gag reflex,
of the food containing preformed botulinal
ocular palsies, loss of head control, and pro-
toxin. Home-processed foods are, by far, the
gressive descending generalized weakness and
most common cause of foodborne botulism
hypotonia. Sudden infant death could result
in the United States, followed by rare out-
from rapidly progressing infant botulism.
breaks associated with commercially pro-
Etiology cessed and restaurant-associated foods.
Botulism occurs after absorption of botulinal • Wound botulism (annual average,
toxin into the circulation from a mucosal or 26 ­laboratory-confirmed cases in 2006–2010;
wound surface. Seven antigenic toxin types median age, 46 years) results when C botuli­
(A–G) of Clostridium botulinum have been num contaminates traumatized tissue, ger-
identified. The most common serotypes of minates, multiplies, and produces toxin.
C botulinum associated with naturally occur- Gross trauma or crush injury can be a pre-
ring illness are types A, B, E, and, rarely, F. disposing event. During the last decade, self-
Non-botulinum species of Clostridium rarely injection of contaminated black tar heroin
produce these neurotoxins and cause disease. has been associated with most cases.
A few cases of infant botulism have been
caused by Clostridium butyricum (type E) and Immunity to botulinal toxin does not develop
Clostridium baratii (type F). C botulinum spores in botulism. Botulism is not transmitted from
person to person.

ERRNVPHGLFRVRUJ
Botulism and Infant ­Botulism 105

Incubation Period • Antitoxin for infant botulism. Human-


Infant botulism, 3 to 30 days from ingestion; derived antitoxin should be given immedi-
foodborne botulism, 12 to 48 hours (range, ately. Human botulism immune globulin for
6 hours–8 days); wound botulism, 4 to 14 days intravenous use (BabyBIG) is licensed by the
from injury. US Food and Drug Administration for treat-
ment of infant botulism caused by C botuli­
Diagnostic Tests num type A or B. BabyBIG is produced and
A toxin neutralization bioassay in mice is distributed by the California Department of
used to detect botulinal toxin in serum, stool, Public Health (www.infantbotulism.org).
enema fluid, gastric aspirate, or suspect foods. BabyBIG significantly decreases days of
Enriched selective media is required to isolate mechanical ventilation, days of intensive
C botulinum from stool and foods. The care unit stay, and total length of hospital
­diag­nosis of infant botulism is made by dem- stay by almost 1 month and leads to cost
onstrating botulinal toxin or botulinal toxin– ­saving. BabyBIG is first-line therapy for nat-
producing organisms in feces or enema fluid or urally occurring infant botulism. Equine-
toxin in serum. Although toxin can be demon- derived heptavalent botulism antitoxin was
strated in serum in some infants (13% in one licensed by the Food and Drug Administra-
large study), stool is the best specimen for tion in 2013 for treatment of adult and pedi-
­diagnosis; enema effluent can also be useful. If atric botulism and is available through the
constipation makes obtaining a stool specimen Centers for Disease Control and Prevention.
difficult, an enema of sterile, nonbacteriostatic Botulism antitoxin has been used to treat
water should be given promptly. Wound botu- patients with type F infant botulism where
lism is confirmed by demonstrating organisms the antitoxin is not contained in BabyBIG.
in the wound or tissue or toxin in the serum. • Antitoxin for noninfant forms of botulism.
To increase the likelihood of diagnosis in food- Immediate administration of antitoxin is
borne botulism, all suspect foods should be the key to successful therapy because anti-
collected, and serum and stool or enema speci- toxin treatment ends the toxemia and stops
mens should be obtained from all people with further uptake of toxin. However, because
suspected illness. In foodborne cases, serum botulinal neurotoxin becomes internalized
specimen test results may be positive for toxin in the nerve ending, administration of anti-
as long as 12 days after admission. Because toxin does not reverse paralysis. On suspi-
results of laboratory bioassay testing may cion of foodborne botulism, the state health
require several days, treatment with antitoxin department should be contacted immedi-
should be initiated urgently for all forms of ately to discuss and report. Botulism anti-
botulism on the basis of clinical suspicion. toxin contains antitoxin against all 7 (A–G)
The most prominent electromyographic find- botulinal toxin types and is provided by the
ing is an incremental increase of evoked muscle Centers for Disease Control and Prevention
potentials at high-frequency nerve stimulation with a treatment protocol.
(20–50 Hz), but this is infrequently needed
for diagnosis. • Antimicrobial agents. Antimicrobial ther-
apy is not prescribed in infant botulism.
Treatment Aminoglycoside agents can potentiate the
• Meticulous supportive care, particularly paralytic effects of the toxin and should be
respiratory and nutritional support, consti- avoided. Penicillin or metronidazole can be
tutes a fun­damental aspect of therapy in all given to patients with wound botulism after
forms of botulism. Recovery from botulism antitoxin has been administered. The role of
may take weeks to months. antimicrobial therapy in the adult intestinal
colonization form of botulism, if any, has
not been established.

ERRNVPHGLFRVRUJ
106 Botulism and Infant ­Botulism

Image 30.1
A photomicrograph of spore forms of Clostridium botulinum type A (Gram stain). These C botulinum
bacteria were cultured in thioglycolate broth for 48 hours at 35°C (95°F). The bacterium C botulinum
produces a nerve toxin that causes the rare but serious paralytic illness botulism. Courtesy of Centers
for Disease Control and Prevention/Dr George Lombard.

Image 30.2
Botulism, foodborne. Number of reported cases, by year—United States, 1992–2012. Courtesy of
Morbidity and Mortality Weekly Report.

ERRNVPHGLFRVRUJ
Botulism and Infant ­Botulism 107

Image 30.3
Botulism, infant. Number of reported cases, by year—United States, 1992–2012. Courtesy of Morbidity
and Mortality Weekly Report.

Image 30.4
An infant with mild botulism depicting the loss of facial expression. This infant also had a weak
cry, poor feeding, diminished gag reflex, and hypotonia. Infant botulism most often occurs in
infants younger than 6 months. Copyright Charles Prober.

ERRNVPHGLFRVRUJ
108 Botulism and Infant ­Botulism

Image 30.5
Wound botulism in the compound fracture of
the right arm of a 14-year-old boy. The patient
fractured his right ulna and radius and subse­
quently developed wound botulism. Courtesy of
Centers for Disease Control and Prevention.

Image 30.6
Infantile botulism in a 4-month-old boy with a
6-day history of progressive weakness, consti­
pation, decreased appetite, and weight loss.
The infant had been afebrile, was breastfed,
Image 30.7 and had not received honey. He was intubated
Botulism with ocular muscle paralysis in a within 24 hours of admission and remained on
preadolescent girl. She also had respiratory a ventilator for 26 days. Stool specimens were
muscle weakness but did not require ventilatory positive for Clostridium botulinum type A.
support. Courtesy of Hugh Moffet, MD. Copyright Larry I. Corman.

ERRNVPHGLFRVRUJ
Clostridial Myonecrosis 109

31 often in those with underlying malignancy,


neutrophil dysfunction, or diseases associated
Clostridial Myonecrosis with bowel ischemia.
(Gas Gangrene)
Incubation Period
Clinical Manifestations
From injury, 1 to 4 days.
Onset is heralded by acute pain at the site of
the wound, followed by edema, increasing Diagnostic Tests
exquisite tenderness, exudate, and progression Anaerobic cultures of wound exudate, involved
of pain. Systemic findings initially include soft tissue and muscle, and blood should be
tachycardia disproportionate to the degree of performed. Because Clostridium species are
fever, pallor, diaphoresis, hypotension, renal ubiquitous, their recovery from a wound is not
failure, and then, later, alterations in mental diagnostic unless typical clinical manifesta-
status. Crepitus is suggestive but not pathog­ tions are present. A Gram-stained smear of
nomonic of Clostridium infection and is not wound discharge demonstrating characteristic
always present. Diagnosis is based on clinical gram-positive bacilli and few, if any, polymor-
manifestations including the characteristic phonuclear leukocytes suggests clostridial
appearance of necrotic muscle at surgery. infection. Tissue specimens (not swab speci-
Untreated gas gangrene can lead to dissemi- mens) for anaerobic culture must be obtained
nated myonecrosis, suppurative visceral infec- to confirm the diagnosis. Because some patho-
tion, septicemia, and death within hours. genic Clostridium species are exquisitely oxy-
gen sensitive, care should be taken to optimize
Etiology
anaerobic growth conditions. A radiograph
Clostridial myonecrosis is caused by Clostrid­ of the affected site can demonstrate gas in the
ium species, most often Clostridium perfrin­ tissue, but this is a nonspecific finding. Occa-
gens. These organisms are large, gram-positive, sionally, blood culture results are positive and
spore-forming, anaerobic bacilli with blunt are considered diagnostic.
ends. Other Clostridium species (eg, Clostrid­
ium sordellii, Clostridium septicum, Clostrid­ Treatment
ium novyi) have also been associated with Prompt and complete surgical excision of
myonecrosis. Disease manifestations are necrotic tissue and removal of foreign material
caused by potent clostridial exotoxins (eg, are essential. Repeated surgical debridement
C sordellii with medical abortion; C septicum may be required. Management of shock, fluid
with malignancy). Mixed infection with other and electrolyte imbalance, hemolytic anemia,
gram-positive and gram-negative bacteria and other complications is crucial. High-dose
is common. penicillin G should be administered intrave-
nously. Clindamycin, metronidazole, mero­
Epidemiology
penem, ertapenem, and chloramphenicol can
Clostridial myonecrosis usually results from be considered as alternative drugs for patients
contamination of open wounds involving with a serious penicillin allergy or for treat-
­muscle. The sources of Clostridium species ment of polymicrobial infections. The combi-
are soil, contaminated foreign bodies, and nation of penicillin G and clindamycin may
human and animal feces. Dirty surgical or be superior to penicillin alone because of the
traumatic wounds, particularly those with theoretical benefit of clindamycin inhibiting
retained ­foreign bodies or significant amounts toxin synthesis. Hyperbaric oxygen may be
of devitalized tissue, predispose to disease. beneficial, but efficacy data from adequately
Nontraumatic gas gangrene occurs rarely in controlled clinical studies are not available.
people who are immunocompromised, most

ERRNVPHGLFRVRUJ
110 Clostridial Myonecrosis

Image 31.1
Gram stain of a tissue aspirate from a patient with clostridial omphalitis showing the charac­teristic
morphology of Clostridia bacilli, erro­neously stained gram-negative, and sparse polymorphonuclear
leukocytes.

Image 31.2
Clostridial omphalitis in an infant with myone­crosis of the abdominal wall (periumbilical). Early and
complete surgical excision of necrotic tissue and careful management of shock, fluid balance, and
other complications are crucial for survival.

ERRNVPHGLFRVRUJ
CLOSTRIDIUM DIFFICILE 111

32 older than 5 years and adults. Hospitals, nurs-


ing homes, and child care facilities are major
Clostridium difficile reservoirs for C difficile. Risk factors for acqui-
Clinical Manifestations sition of the bacteria include prolonged hospi-
talization and exposure to an infected person
Clostridium difficile is associated with several in the hospital or the community. Risk factors
syndromes as well as with asymptomatic car- for C difficile disease include antimicrobial
riage. Mild to moderate illness is characterized therapy, repeated enemas, gastric acid sup­
by watery diarrhea, low-grade fever, and mild pression therapy, prolonged nasogastric tube
abdominal pain. Pseudomembranous entero- placement, gastrostomy and jejunostomy tubes,
colitis is characterized by diarrhea with mucus underlying bowel disease, gastrointestinal
in feces, abdominal cramps and pain, fever, tract surgery, renal insufficiency, and humoral
and systemic toxicity. Occasionally, children immunocompromise. C difficile colitis has
have marked abdominal tenderness and disten- been associated with exposure to almost every
tion with minimal diarrhea (toxic megacolon). antimicrobial agent. Hospitalization of chil-
The colonic mucosa often contains 2- to 5-mm, dren for C difficile colitis is increasing. The
raised, yellowish plaques. Disease often begins NAP1 strain, a more virulent strain of C diffi­
while the child is hospitalized receiving anti- cile with variations in toxin genes, is associated
microbial therapy but can occur up to 10 weeks with severe disease, has emerged as a cause of
after therapy cessation. Community-associated outbreaks among adults, and has been reported
C difficile disease is less common but is increas- in children.
ing in frequency. The illness usually, but not
always, is associated with antimicrobial ther- Incubation Period
apy or prior hospitalization. Complications, Unknown; colitis usually develops 5 to 10 days
which occur more commonly in older adults, after initiation of antimicrobial therapy.
can include toxic megacolon, intestinal perfo-
ration, systemic inflammatory response syn- Diagnostic Tests
drome, and death. Severe or fatal disease is The diagnosis of C difficile disease is based
more likely to occur in neutropenic children on the presence of diarrhea and detection of
with leukemia, infants with Hirschsprung C ­difficile toxins in a diarrheal specimen.
­disease (congenital megacolon), and patients ­Isolation of the organism or toxin detection
with inflammatory bowel disease. Colonization from the stool of a patient who is not having
with C difficile, including toxin-producing liquid stools (unless toxic megacolon is sus-
strains, occurs in children younger than 5 years pected) should not be performed. Endoscopic
and is most common in infants. It is unclear findings of pseudomembranes and hyperemic,
how frequently C difficile causes disease in friable rectal mucosa suggest pseudomembra-
infants younger than 1 year. nous enterocolitis. The most common testing
Etiology method for C difficile toxins is the commer-
cially available enzyme immunoassay (EIA),
Clostridium difficile is a spore-forming, which detects toxins A and B. Although EIAs
­obligate anaerobic, gram-positive bacillus. are rapid and performed easily, their sensitivity
­Disease is related to A and B toxins produced is relatively low. The cell culture cytotoxicity
by these organisms. assay, which also tests for toxin in stool, is
Epidemiology more sensitive but requires more labor and
has a slow turnaround time, limiting its use­
C difficile can be isolated from soil and is fulness in the clinical setting. Two-step testing
­commonly found in the hospital environment. algorithms that use sensitive but nonspecific
C difficile is acquired from the environment or (detects toxigenic and nontoxigenic strains)
from stool of other colonized or infected peo- glutamate dehydrogenase EIA combined with
ple by the fecal-oral route. Intestinal coloniza- confirmatory toxin testing of positive results
tion rates in healthy infants can be as high as can also be used. Molecular assays using
50% but usually are less than 5% in children nucleic acid amplification tests (NAATs) have

ERRNVPHGLFRVRUJ
112 CLOSTRIDIUM DIFFICILE

been developed; NAATs combine good sensi- ronidazole is indicated as initial therapy for
tivity and specificity, provide results to clini- patients with severe disease (ie, hospitalized
cians in times comparable with EIAs, and are in an intensive care unit, pseudomembranous
not required to be part of a 2- or 3-step algo- enterocolitis by endoscopy, or significant
rithm. Many children’s hospitals are convert- underlying intestinal tract disease) and for
ing to NAAT technology to diagnose C difficile patients who do not respond to oral metro­
infection, but more data are needed in children nidazole. Vancomycin for intravenous use
before this technology can be used routinely as can be prepared for oral use. Intravenously
a stand-alone test. The predictive value of a administered vancomycin is not effective for
positive NAAT result in a child younger than C ­difficile infection. Therapy with metronida-
5 years is unknown because carriage of toxi- zole or vancomycin or the combination should
genic strains often occurs in these children. be administered for at least 10 days.
Because colonization with C difficile in infants
Up to 25% of patients experience a relapse after
is common, testing for other causes of diarrhea
discontinuing therapy, but infection usually
is always recommended in these patients.
responds to a second course of the same treat-
C ­difficile toxin degrades at room temperate
ment. Metronidazole should not be used for
and can be undetectable within 2 hours after
treatment of a second recurrence or for chronic
collection of a stool specimen. Tests of cure
therapy because neurotoxicity is possible.
should not be performed.
Tapered or pulse regimens of vancomycin are
Treatment recommended under this circumstance. Fidax-
Precipitating antimicrobial therapy should be omicin and nitazoxanide have been approved
discontinued as soon as possible. Antimicro- for treatment of C difficile–associated diarrhea
bial therapy for C difficile infection is always in adults, but no pediatric data are available
indicated for symptomatic patients. C difficile for fidaxomicin. Nitazoxanide is also an effec-
is susceptible to metronidazole and vancomy- tive therapy in adults. Drugs that decrease
cin. Metronidazole, orally, is the drug of choice intestinal motility should not be administered.
for initial treatment of children and adoles- ­Follow-up testing for toxin is not recom-
cents with mild to moderate diarrhea and for mended. Fecal transplant (intestinal micro­
first relapse. Oral vancomycin or vancomycin biota transplantation) appears to be effective
administered by enema plus intravenous met- in adults; there are limited data in pediatrics.

Image 32.1
Clostridium difficile is a gram-positive, spore-forming bacteria that can be part of the normal intestinal
flora in as many as 50% of children younger than 2 years. It is a cause of pseudo­membranous
enterocolitis and antibiotic-associated diarrhea in older children and adults. Courtesy of AAP News.

ERRNVPHGLFRVRUJ
CLOSTRIDIUM DIFFICILE 113

Image 32.2
This photograph depicts Clostridium difficile colonies after 48 hours’ growth on a blood agar plate
(magnification x4.8). Courtesy of Centers for Disease Control and Prevention/Dr Holdeman.

Image 32.3
This micrograph depicts gram-positive Clostridium difficile from a stool sample culture obtained using
a 0.1-µm filter. People can become infected if they touch items or surfaces that are contaminated with
C difficile spores and then touch their mouths or mucous membranes. Health care workers can spread
the bacteria to other patients or contaminate surfaces through hand contact. Courtesy of Lois Higg/
Courtesy of Centers for Disease Control and Prevention.

Image 32.4
The right-hand panel shows the typical pseudo­membranes of Clostridium difficile colitis; the left-hand
panel shows the histology, with the pseudomembrane structure at the top middle (arrows). Courtesy of
Carol J. Baker, MD, FAAP.

ERRNVPHGLFRVRUJ
114 CLOSTRIDIUM PERFRINGENS FOOD POISONING

33 during slow cooling, when stored at tempera-


tures from 20°C to 60°C (68°F–140°F), and
Clostridium perfringens ­during inadequate reheating. At an optimum
Food Poisoning temperature, C perfringens has one of the
­fastest rates of growth of any bacterium. Ill-
Clinical Manifestations ness results from consumption of food con-
Clostridium perfringens foodborne illness is taining high numbers of vegetative organisms
characterized by a sudden onset of watery (>105 colony-forming units [CFU]/g) followed
­diarrhea and moderate to severe, cramping, by enterotoxin production in the intestine.
midepigastric pain. Vomiting and fever are
Beef, poultry, gravies, and dried or precooked
uncommon. Symptoms usually resolve within
foods are common sources. Ingestion of the
24 hours. The short incubation period, short
organism is most commonly associated with
duration, and absence of fever in most patients
foods prepared by restaurants or caterers or
differentiate C perfringens foodborne disease
in institutional settings (eg, schools, camps)
from shigellosis and salmonellosis, and the
where food is prepared in large quantities,
infrequency of vomiting and longer incubation
cooled slowly, and stored inappropriately for
period contrast with the clinical features of
prolonged periods. Illness is not transmissible
foodborne disease associated with heavy
from person to person.
­metals, Staphylococcus aureus enterotoxins,
Bacillus cereus emetic toxin, and fish and shell- Incubation Period
fish toxins. Diarrheal illness caused by B cereus
6 to 24 hours; usually 8 to 12 hours.
diarrheal enterotoxins can be indistinguishable
from that caused by C perfringens. Enteritis Diagnostic Tests
necroticans (also known as pigbel) results from Because the fecal flora of healthy people
hemorrhagic necrosis of the midgut and is a ­commonly includes C perfringens, counts of
cause of severe illness and death attributable C ­perfringens of 106 CFU/g of feces or greater
to C perfringens food poisoning caused by obtained within 48 hours of onset of illness are
­Clostridium β toxin. Rare cases have been required to support the diagnosis in ill people.
reported in the Highlands of Papua, in New The diagnosis also can be supported by detec-
Guinea, and in Thailand; malnutrition is an tion of enterotoxin in stool. C perfringens can
important risk factor. be confirmed as the cause of an outbreak if
Etiology 106 CFU/g are isolated from stool or entero-
toxin is demonstrated in the stool of 2 or more
Typical food poisoning is caused by a heat-
ill people or when the concentration of organ-
labile C perfringens enterotoxin. C perfringens
isms is at least 105/g in the epidemiologically
type A, which produces α toxin and entero-
implicated food. Although C perfringens is an
toxin, commonly causes foodborne illness.
­a naerobe, special transport conditions are
Enteritis necroticans is caused by C perfringens
unnecessary. Stool specimens, rather than rec-
type C, which produces α and β toxins
tal swab specimens, should be obtained, trans-
and enterotoxin.
ported in ice packs, and tested within 24 hours.
Epidemiology
Treatment
C perfringens is a gram-positive, spore-forming
Oral rehydration or, occasionally, intravenous
bacillus that is ubiquitous in the environment
fluid and electrolyte replacement may be indi-
and the intestinal tracts of humans and ani-
cated to prevent or treat dehydration. Antimi-
mals and is commonly present in raw meat and
crobial agents are not indicated.
poultry. Spores of C perfringens that survive
cooking can germinate and multiply rapidly

ERRNVPHGLFRVRUJ
CLOSTRIDIUM PERFRINGENS FOOD POISONING 115

Image 33.1
Image 33.2
This photomicrograph reveals numbers of
This photomicrograph reveals Clostridium
Clostridium perfringens bacteria grown in
perfringens grown in Schaedler broth using
Schaedler broth and subsequently stained using
Gram stain. Courtesy of Centers for Disease
Gram stain (magnification x1,000). C perfringens
Control and Prevention/Don Stalons.
is a spore-forming, heat-resistant bacterium that
can cause foodborne disease. The spores persist
in the environment and often contaminate raw
food materials. These bacteria are found in
mammalian feces and soil. Courtesy of Centers
for Disease Control and Prevention/Don Stalons.

Image 33.3
Clostridium perfringens, an anaerobic, gram-positive, spore-forming bacillus, causes a broad spectrum
of pathology, including food poisoning. In Papua New Guinea, C perfringens is a cause of severe illness
and death called necrotizing enteritis necroticans (locally known as pigbel). Courtesy of Hugh Moffet, MD.

Image 33.4
This slide shows hemorrhagic necrosis of the intestine in a patient with Clostridium perfringens sepsis.
Courtesy of Dimitris P. Agamanolis, MD.

ERRNVPHGLFRVRUJ
116 Coccidioidomycosis

34 Epidemiology

Coccidioidomycosis Coccidioides species are found mostly in soil


in areas of the southwestern United States
Clinical Manifestations with endemic infection, including California,
Primary pulmonary infection is acquired by Arizona, New Mexico, west and south Texas,
inhaling fungal conidia and is asymptomatic southern Nevada, and Utah; northern Mexico;
or self-limited in 60% of infected children. and throughout certain parts of Central and
Constitutional symptoms, including fatigue South America. In areas with endemic coccidi-
and weight loss, are common and can persist oidomycosis, clusters of cases can follow dust-
for weeks or months. Symptomatic disease generating events, such as storms, seismic
can resemble influenza or community- events, archaeologic digging, or recreational
acquired pneumonia, with malaise, fever, activities. Most cases occur without a known
cough, myalgia, arthralgia, headache, and preceding event. The incidence of reported
chest pain. ­Pleural effusion, empyema, and coccidioidomycosis cases has increased sub-
mediastinal involvement are more common stantially over the past decade and a half, rising
in children than adults. Acute infection can from 5.3 per 100,000 population in the area of
only be ­associated with cutaneous abnor­ endemicity (Arizona, California, Nevada, New
malities, such as erythema multiforme, an Mexico, and Utah) in 1998 to 42.6 per 100,000
­erythematous maculopapular rash, or ery- in 2011. Infection is thought to provide lifelong
thema nodosum. Chronic pulmonary lesions immunity. Person-to-person transmission of
are rare, but approximately 5% of infected peo- coccidioidomycosis does not occur except in
ple develop asymptomatic pulmonary radio- rare instances of cutaneous infection with
graphic residua (eg, cysts, nodules, cavitary actively draining lesions, donor-derived trans-
lesions, coin lesions). Nonpulmonary primary mission via an infected organ, and congenital
infection is rare and usually follows trauma infection following in utero exposure. Preexist-
associated with contamination of wounds by ing impairment of T lymphocyte–mediated
arthroconidia. Cutaneous lesions and soft tis- immunity is a factor for severe primary coccid-
sue infections often are accompanied by ioidomycosis, disseminated disease, or relapse
regional ­lymphadenitis. of past infection. Other people at risk of severe
or disseminated disease include people of Afri-
Disseminated (extrapulmonary) infection can or Filipino ancestry, women in the third
occurs in less than 0.5% of infected people; trimester of pregnancy, and infants.
common sites of dissemination include skin,
bones and joints, and the central nervous sys- Incubation Period
tem (CNS). Meningitis is invariably fatal if Typically 1 to 4 weeks; disseminated infection
untreated. Congenital infection is rare. can develop years after primary infection.
Etiology Diagnostic Tests
Coccidioides species are dimorphic fungi. Diagnosis of coccidioidomycosis is best estab-
Molecular studies have divided the genus lished using serologic, histopathologic, and
­Coccidioides into 2 species: Coccidioides culture methods. Serologic tests are useful in
­immitis, confined mainly to California, and the diagnosis and management of infection.
Coccidioides posadasii, encompassing the The immunoglobulin (Ig) M response can be
remaining areas of distribution of the fungus detected by enzyme immunoassay (EIA) or
within certain deserts of the southwestern immunodiffusion methods. In approximately
United States, northern Mexico, and regions 50% and 90% of primary infections, IgM is
of Central and South America. detected in the first and third weeks, respec-
tively. IgG response can be detected by immu-
nodiffusion, EIA, or complement fixation (CF)
tests. Immunodiffusion and CF tests are highly

ERRNVPHGLFRVRUJ
Coccidioidomycosis 117

specific. Complement fixation antibodies in pain, severe malaise, inability to work or attend
serum are usually of low titer and are transient school, intense night sweats, or symptoms that
if the disease is asymptomatic or mild. Persis- persist for more than 2 months. Fluconazole or
tent high titers (≥1:16) occur with severe disease itraconazole is recommended for 3 to
and almost always in disseminated infection. 6 months. Repeated patient encounters every
Cerebrospinal fluid antibodies are also detect- 1 to 3 months for up to 2 years, to document
able by immunodiffusion or CF testing. radiographic resolution or to identify pulmo-
Increasing serum and cerebrospinal fluid titers nary or extrapulmonary complications, are
indicate progressive disease, and decreasing recommended. For diffuse pneumonia, defined
titers usually suggest improvement. Comple- as bilateral reticulonodular or military infil-
ment fixation titers may not be reliable in trates, amphotericin B or high-dose flucon-
patients who are immunocompromised. azole is recommended. Amphotericin B is
Because clinical laboratories use different more frequently used in the presence of severe
­diagnostic test kits, positive results should be hypoxemia or rapid clinical deterioration.
confirmed in a reference laboratory. The length of therapy for diffuse pneumonia
should be 1 year.
Spherules are as large as 80 µm in diameter
and can be visualized with magnification Oral itraconazole or fluconazole is the recom-
x100 to x400 in infected body fluid specimens mended initial therapy for disseminated infec-
(eg, pleural fluid, bronchoalveolar lavage) and tion not involving the CNS. Amphotericin B
biopsy specimens of skin lesions or organs. The is recommended as alternative therapy if
presence of a mature spherule with endospores lesions are progressing or are in critical loca-
is pathognomonic of infection. Isolation of tions, such as the vertebral column. In patients
Coccidioides species in culture establishes the experiencing failure of conventional amphoter-
diagnosis. Culture of organisms is possible on icin B deoxycholate therapy or experiencing
a variety of artificial media but is potentially drug-related toxicities, a lipid formulation of
hazardous to laboratory personnel because amphotericin B can be substituted.
spherules can convert to arthroconidia-bearing
Consultation with a specialist for treatment
mycelia on culture plates. An EIA test for
of patients with CNS disease caused by
urine, serum, plasma, or bronchoalveolar
­Coccidioides species is recommended. Oral
lavage fluid is available from a US laboratory
fluconazole is recommended for treatment of
for detection of Coccidioides antigen. Antigen
patients with CNS infection. Patients who
can be detected in more severe forms of disease
respond to azole therapy should continue this
(sensitivity 71%), but cross-reactions occur in
treatment indefinitely. For CNS infections that
patients with histoplasmosis, blastomycosis,
are unresponsive to oral azoles or are associ-
or paracoccidioidomycosis.
ated with severe basilar inflammation, intra-
Treatment thecal amphotericin B deoxycholate can be
Antifungal therapy for uncomplicated primary used to augment the azole therapy. A subcuta-
infection in people without risk factors for neous reservoir can facilitate administration
severe disease is controversial. Although most into the cisternal space or lateral ventricle. The
cases will resolve without therapy, some role of newer azole antifungal agents, such as
experts believe treatment may reduce illness voriconazole and posaconazole, in treatment
duration or risk for severe complications. Most of coccidiomycosis has not been established.
experts recommend treatment of coccidioido- The duration of antifungal therapy is variable
mycosis for people at risk of severe disease or and depends on the site(s) of involvement,
people with severe primary infection. Severe ­clinical response, and mycologic and immuno-
primary infection is manifested by CF titers of logic test results. In general, therapy is con­
1:16 or greater, infiltrates involving more than tinued until clinical and laboratory evidence
half of one lung or portions of both lungs, indicates active infection has resolved. Treat-
weight loss of greater than 10%, marked chest ment for disseminated coccidioidomycosis is

ERRNVPHGLFRVRUJ
118 Coccidioidomycosis

at least 6 months but, for some patients, may Surgical debridement or excision of lesions in
be extended to 1 year or longer. The role of bone, pericardium, and lung has been advo-
­subsequent suppressive azole therapy is uncer- cated for localized, symptomatic, persistent,
tain, except for patients with CNS infection, resistant, or progressive lesions. In some local-
­osteomyelitis, or underlying HIV infection or ized infections with sinuses, fistulae, or
solid organ transplant recipients, for whom abscesses, amphotericin B has been instilled
suppressive therapy is lifelong. Women should locally or used for irrigation of wounds.
be advised to avoid pregnancy while receiving
fluconazole, which may be teratogenic.

Image 34.1 Image 34.2


Spherule with endospores of Coccidioides Spherule of Coccidioides immitis with
immitis (periodic acid–Schiff reaction). Courtesy endospores (calcofluor stain). Courtesy of
of Centers for Disease Control and Prevention. Centers for Disease Control and Prevention.

Image 34.3
Coccidioidomycosis. Number of reported cases—United States and US territories, 2012. Courtesy of
Morbidity and Mortality Weekly Report.

ERRNVPHGLFRVRUJ
Coccidioidomycosis 119

Image 34.5
Primary pulmonary coccidioidomycosis in an
Image 34.4
11-year-old boy who recovered spontaneously.
Pneumonia due to Coccidioides immitis in the
The acute disease is usually self-limited in
upper lobe of the left lung of a 5½-month-old.
otherwise healthy children. The patient also had
The organism was isolated from gastric aspirate,
erythema nodosum lesions over the tibial area.
and complement fixation test result was elevated.

Image 34.7
Histopathology of coccidioidomycosis of lung.
Mature spherule with endospores of Coccidioides
immitis and intense infiltrate of neutrophils
(hematoxylin-eosin stain). Courtesy of Centers for
Image 34.6 Disease Control and Prevention/Dr Lucille K. Georg.
Erythema nodosum in a preadolescent girl with
primary pulmonary coccidioidomycosis.

Image 34.9
Coccidioidomycosis of the tongue in an adult
male. Courtesy of Edgar O. Ledbetter, MD, FAAP.

Image 34.8
Spondylitis due to Coccidioides immitis in 2-year-
old white boy with disseminated disease.

ERRNVPHGLFRVRUJ
120 Coccidioidomycosis

Image 34.10
Disseminated coccidioidomycosis with
osteomyelitis of the distal radius and ulna in a
preadolescent white boy. B

C
Image 34.12
Erythema nodosum lesions on skin of the Image 34.11
back due to hypersensitivity to antigens of A 15-year-old Hispanic girl who originally
Coccidioides immitis. Courtesy of Centers presented with forehead lesions without other
for Disease Control and Prevention/Lucille K. symptoms. At the third visit, she had dissemi­
Georg, MD. nated coccidioidomycosis disease and had
developed extensive cutaneous lesions all
over her body with severe nasal involvement.
Courtesy of Sabiha Hussain, MD.

ERRNVPHGLFRVRUJ
Coccidioidomycosis 121

Image 34.13 Image 34.14


Chest radiograph of a previously healthy A chest tube was inserted emergently in the
14-year-old boy who had a several month history patient in Image 34.15, and his right lung was
of intermittent fever, weight loss, and chest pain expanded. Courtesy of Jeffrey R. Starke, MD.
and recent onset of exercise intolerance. His
pyopneumothorax was caused by Coccidioides
immitis. He lived in West Texas near the Mexican
border. Courtesy of Jeffrey R. Starke, MD.

Image 34.15
After 7 days of hospitalization. The patient in
images 34.13 and 34.14 had a video-assisted
thoracostomy followed by an open thoracotomy
for decortication procedure. This photograph
demonstrated the copious fluid and thick
fibrinous exudate of a chronic empyema found
at surgery. Courtesy of Jeffrey R. Starke, MD.

ERRNVPHGLFRVRUJ
122 Coronaviruses, Including SARS and MERS

35 Infants and children younger than 12 years


who develop SARS typically present with fever,
Coronaviruses, Including cough, and rhinorrhea. Associated lymphope-
SARS and MERS nia is less severe, and radiographic changes
are milder and generally resolve more quickly
Clinical Manifestations than in adolescents and adults. Adolescents
Human coronaviruses (HCoVs) 229E, OC43, who develop SARS have clinical courses more
NL63, and HKU1 are associated most fre- closely resembling those of adult disease, pre-
quently with the common cold, an upper senting with fever, myalgia, headache, and
­respiratory tract infection characterized by chills. They are also more likely to develop
­rhinorrhea, nasal congestion, sore throat, ­dyspnea, hypoxemia, and worsening chest
sneezing, and cough that can be associated radiographic findings.
with fever. Symptoms are self-limiting and
MERS-CoV, the HCoV associated with Middle
­t ypically peak on day 3 or 4 of illness. Human
East respiratory syndrome (MERS), can also
coronavirus infections can also be associated
cause severe disease. MERS-CoV is associated
with acute otitis media or asthma exacerba-
with a severe respiratory illness similar to
tions. Less frequently, they are associated with
SARS-CoV, although a spectrum of disease,
lower respiratory tract infections, including
including asymptomatic infections and mild
bronchiolitis, croup, and pneumonia, primarily
disease, can occur. Patients commonly present
in infants and immunocompromised children
with fever, myalgia, chills, shortness of breath,
and adults.
and cough. Approximately 25% of patients also
SARS-CoV, the HCoV responsible for the experience vomiting, diarrhea, or abdominal
2002–2003 global outbreak of severe acute pain. Rapid deterioration of oxygenation with
respiratory syndrome (SARS), was associated progressive unilateral or bilateral airspace
with more severe symptoms, although a spec- infiltrates on chest imaging may follow, requir-
trum of disease, including asymptomatic infec- ing mechanical ventilation. The case-fatality
tions and mild disease, occurred. SARS-CoV rate is high, estimated at nearly 50%. To date,
disproportionately affected adults, who typi- most infections have been reported in male
cally presented with fever, myalgia, headache, adults with comorbidities, such as diabetes,
malaise, and chills followed by a nonproduc- chronic renal disease, hypertension, and
tive cough and dyspnea generally 5 to 7 days chronic cardiac disease.
later. Approximately 25% of infected adults
Etiology
developed watery diarrhea. Twenty percent
developed worsening respiratory distress Coronaviruses are enveloped, nonsegmented,
requiring intubation and ventilation. The over- single-stranded, positive-sense RNA viruses
all associated mortality rate was approximately named after their corona- or crownlike surface
10%, with most deaths occurring in the third projections observed on electron microscopy
week of illness. The case-fatality rate in people that correspond to large surface spike proteins.
older than 60 years approached 50%. Typical Coronaviruses are classified in the Nidovirales
laboratory abnormalities included lymphope- order. Coronaviruses are host specific and can
nia and increased lactate dehydrogenase and infect humans as well as a variety of different
creatine kinase concentrations. Most had animals, causing diverse clinical syndromes.
­progressive unilateral or bilateral ill-defined Four distinct genera have been described:
airspace infiltrates on chest imaging. Pneumo- Alphacoronavirus, Betacoronavirus, Gamma­
thoraces and other signs of barotrauma were coronavirus, and Deltacoronavirus. Human
common in critically ill patients receiving coronaviruses 229E and NL63 belong to the
mechanical ventilation. genus Alphacoronavirus; HCoVs OC43 and
HKU1 belong to lineage A of the genus Beta­
SARS-CoV infections in children are less coronavirus; SARS-CoV belongs to lineage B of
severe than in adults; notably, no infant or the genus Betacoronavirus; and MERS-CoV
child deaths from SARS-CoV infection were belongs to lineage C of the genus Betacoronavirus.
documented in the 2002–2003 global outbreak.

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Coronaviruses, Including SARS and MERS 123

Epidemiology cases in the United States. Human-to-human


Coronaviruses were first recognized as animal transmission, including clusters of cases, has
pathogens in the 1930s. Thirty years later, been observed, but there is no evidence of
HCoVs 229E and OC43 were identified as ­sustained human-to-human transmission in
human pathogens, along with other corona­ the community.
virus strains that were not investigated further The modes of transmission for 229E, OC43,
and for which little is known about their NL63, and HKU1 have not been well studied.
­prevalence and associated disease syndromes. However, on the basis of studies of other respi-
In 2003, SARS-CoV was identified as a novel ratory tract viruses, it is likely transmission
virus responsible for the 2002–2003 global occurs primarily via a combination of droplet
­outbreak of SARS, which lasted for 9 months, and direct and indirect contact spread. For
caused 8,096 reported cases, and resulted in SARS-CoV, studies suggest droplet and direct
774 deaths. No SARS-CoV infections have contact spread are likely the most common
been reported worldwide since early 2004. modes of transmission, although evidence of
Most experts believe SARS-CoV evolved from indirect contact and aerosol spread also exist.
a natural reservoir of SARS-CoV–like viruses The modes of transmission for MERS-CoV
in bats through civet cats. Whether or not a are still being studied.
large-scale reemergence of SARS will occur is
unknown. Finding a novel HCoV sparked a Human coronaviruses 229E and OC43 are
renewed interest in HCoV research, and 2 years most likely to be transmitted during the first
later, NL63 and HKU1 were identified as newly few days of illness, when symptoms and respi-
recognized HCoVs. Investigations have ratory viral loads are at their highest. Further
revealed that NL63 was present in archived study is needed to confirm that this holds true
human respiratory tract specimens as early as for the NL63 and HKU1 viruses. SARS-CoV is
1981 and HKU1 as early as 1995. most likely to be transmitted during the second
week of illness, when symptoms and respira-
In 2012, MERS-CoV was identified as a novel tory viral loads peak. The peak communicable
virus associated with the death of a 60-year- period or kinetics for MERS-CoV are not
old man from Saudi Arabia with acute pneu- yet known.
monia and renal failure. As of June 11, 2014,
699 ­laboratory-confirmed cases and 209 deaths Incubation Period
had been reported. MERS-CoV is thought to Human coronaviruses, 2 to 5 days; SARS-CoV,
have evolved from a natural reservoir of MERS- 2 to 10 days; MERS-CoV, 2 to 14 days.
CoV–like viruses in bats. An animal source for
MERS-CoV has not yet been determined, but Diagnostic Tests
recent studies demonstrated MERS-CoV The 2002–2003 SARS global outbreak garnered
genetic sequences in dromedary camels. renewed interest in better understanding the
etiology of respiratory tract infections, and
Human coronaviruses 229E, OC43, NL63,
some clinical laboratories have since started
and HKU1 can be found worldwide. They cause
offering comprehensive respiratory molecular
most disease in the winter and spring months
diagnostic testing for HCoVs using reverse
in temperate climates. Seroprevalence data for
transcriptase-polymerase chain reaction assays.
these HCoVs suggest exposure is common in
Specimens obtained from the upper and lower
early childhood, with approximately 90% of
respiratory tract are the most appropriate sam-
adults being seropositive for 229E, OC43, and
ples for HCoV detection. The yield from lower
NL63 and 60% being seropositive for HKU1.
respiratory tract specimens is higher for SARS-
In contrast, SARS-CoV infection has not been
CoV and MERS-CoV. Stool and serum samples
detected in humans since early 2004. MERS-
are also frequently positive using reverse
CoV has been reported in people who reside in
­transcriptase-polymerase chain reaction assays
or have traveled to the Middle East or who have
in patients with SARS-CoV and have been
had contact with a person with the infection
­positive in some patients with MERS-CoV. For
from the Middle East, including travel-related
229E and OC43, specimens are most likely to

ERRNVPHGLFRVRUJ
124 Coronaviruses, Including SARS and MERS

be positive during the first few days of illness. Treatment


The optimal timing of specimen collection for Infections attributable to HCoVs are generally
MERS-CoV is still being studied. treated with supportive care. SARS-CoV and
Serologic testing is a useful tool for diagnosis MERS-CoV infections are more serious. Ste-
for SARS and MERS, although these tests are roids, type 1 interferons, convalescent plasma,
not available widely. Although acute and con- ribavirin, and lopinavir/ritonavir were all used
valescent sera are optimal, a single serum spec- clinically to treat patients with SARS, albeit
imen collected 2 or more weeks from symptom without evidence of efficacy. In vitro data indi-
onset may help with the diagnosis of SARS or cate that cyclosporin A and interferon alfa
MERS because these infections are so rare. The inhibits MERS-CoV replication. No treatment
CDC should be contacted for additional infor- efficacy of antiviral agent for MERS-CoV has
mation on serologic testing. been demonstrated.

Image 35.1
Coronaviruses are a group of viruses that have a halo or crownlike (corona) appearance when
viewed in an electron microscope. SARS-CoV was the etiologic agent of the 2003 severe acute
respiratory syndrome (SARS) outbreak. Additional specimens are being tested to learn more about
this coronavirus and its etiologic link with SARS. Courtesy of Centers for Disease Control and
Prevention/Dr Fred Murphy.

Image 35.2
Microscopic appearance of control (A) and infected (B) Vero E6 cells, demonstrating cytopathic effects.
The cytopathic effect of SARS-CoV on Vero E6 was evident within 24 hours after infection. Courtesy of
Centers for Disease Control and Prevention/Emerging Infectious Diseases.

ERRNVPHGLFRVRUJ
Coronaviruses, Including SARS and MERS 125

Image 35.3
Electron micrograph of a coronavirus. Pleomorphic virions average 100 nm in diameter and are
covered with club-shaped knobs.

Image 35.4
This scanning electron micrograph (SEM) revealed the thickened, layered edge of severe acute
respiratory syndrome–infected Vero E6 culture cells. The thickened edges of the infected cells
were ruffled and appeared to comprise layers of folded plasma membranes. Note the layered cell
edge (arrows) seen by SEM. Virus particles (arrowheads) are extruded from the layered surfaces.
Courtesy of Centers for Disease Control and Prevention/Dr Mary Ng Mah Lee, National University
of Singapore.

ERRNVPHGLFRVRUJ
126 CRYPTOCOCCUS NEOFORMANS AND CRYPTOCOCCUS GATTII INFECTIONS

36 Epidemiology

Cryptococcus neoformans C neoformans var neoformans and C neoformans


var grubii are isolated primarily from soil con-
and Cryptococcus gattii taminated with pigeon or other bird droppings
Infections and cause most human infections, especially
(Cryptococcosis) infections in immunocompromised hosts.
C neoformans infects 5% to 10% of adults with
Clinical Manifestations AIDS, but infection is rare in HIV-infected
Primary infection is acquired by inhalation children. C gattii (formerly C neoformans var
of aerosolized Cryptococcus fungal elements gattii) is associated with trees and surrounding
found in contaminated soil and is often asymp- soil and has emerged as a pathogen producing
tomatic or mild. Pulmonary disease is charac- a respiratory syndrome with or without neuro-
terized by cough, chest pain, and constitutional logic findings in people from British Columbia,
symptoms. Chest radiographs can reveal soli- Canada, the Pacific Northwest region of the
tary or multiple masses; patchy, segmental, United States, and, occasionally, other regions
or lobar consolidation (often multifocal); or of the United States. A high frequency of dis-
nodular or reticulonodular interstitial changes. ease has also been reported in Aboriginal peo-
Pulmonary cryptococcosis can present as acute ple in Australia and in the central province of
respiratory distress syndrome and mimic Papua New Guinea. C gattii causes disease in
pneumocystis pneumonia. Hematogenous immunocompetent and immunocompromised
­dissemination to the central nervous system, people, including children. Person-to-person
bones, skin, and other sites can occur, is transmission does not occur.
uncommon, and almost always occurs in chil-
Incubation Period
dren with defects in T lymphocyte–mediated
immunity (eg, children with leukemia or lym- C neoformans, unknown; C gattii, 8 weeks to
phoma, congenital immunodeficiency, HIV 13 months.
infection, or AIDS; children taking cortico­ Diagnostic Tests
steroids; children who have undergone solid
organ transplantation). Usually, several sites Definitive diagnosis requires isolation of the
are infected, but manifestations of involvement organism from body fluid or tissue specimens.
at one site predominate. Cryptococcal menin- Blood should be cultured by lysis-centrifugation.
gitis, the most common and serious form of Differentiation between C neoformans and
cryptococcal disease, often follows an indolent C gattii can be made by the use of the selective
course. Clinical findings are characteristic of medium l-canavanine glycine bromothymol
meningitis, meningoencephalitis, or space- blue agar. Sabouraud dextrose agar is useful
occupying lesions but sometimes can manifest for isolation of Cryptococcus organisms from
only as subtle, nonspecific findings such as sputum, bronchopulmonary lavage, tissue, or
fever, headache, or behavioral changes. Cryp- cerebrospinal fluid (CSF) specimens. In refrac-
tococcal fungemia without apparent organ tory or relapse cases, susceptibility testing can
involvement occurs in patients with HIV be helpful, although antifungal resistance is
­infection but is rare in children. uncommon. A large quantity of CSF is needed
to recover the organism because CSF may con-
Etiology tain only a few organisms. Cerebrospinal fluid
Although there are more than 30 species of cell count and protein and glucose concentra-
Cryptococcus, only 2 species, Cryptococcus tions can be normal. Encapsulated yeast cells
­neoformans (var neoformans and var grubii) can be visualized using India ink or other
and Cryptococcus gattii are regarded as stains of CSF and bronchoalveolar lavage spec-
human pathogens. imens, but this method has limited sensitivity.
Focal pulmonary or skin lesions can be biop-
sied for fungal staining and culture.

ERRNVPHGLFRVRUJ
CRYPTOCOCCUS NEOFORMANS AND CRYPTOCOCCUS GATTII INFECTIONS 127

The latex agglutination test, lateral flow assay, antigen is not useful to monitor response to
and enzyme immunoassay for detection of therapy in patients with cryptococcal menin­
cryptococcal capsular polysaccharide antigen gitis. Patients with less severe disease can be
in CSF are excellent rapid diagnostic tests for treated with fluconazole or itraconazole, but
those with suspected meningitis. Antigen is data on use of these drugs for children with
detected in CSF or serum specimens from C neoformans infection are limited. Another
more than 98% of patients with cryptococcal potential treatment option for HIV-infected
meningitis; however, antigen test results can patients with less severe disease or patients in
be falsely negative when antigen concentra- whom amphotericin B treatment is not possible
tions are low or very high (prozone effect), is combination therapy with fluconazole and
if infection is caused by unencapsulated flucytosine. The combination of fluconazole
strains, or if the patient is less severely and flucytosine has superior efficacy compared
­immunocompromised. with fluconazole alone. Echinocandins are not
active against cryptococcal infections and
Treatment
should not be used.
Amphotericin B deoxycholate in combination
with oral flucytosine is indicated as initial ther- Increased intracranial pressure occurs fre-
apy for patients with meningeal and other seri- quently despite microbiologic response and
ous cryptococcal infections. Serum flucytosine is often associated with clinical deterioration.
concentrations should be maintained between Significant elevation of intracranial pressure
30 and 80 mcg/mL. Patients with meningitis is a major source of morbidity and should be
should receive combination therapy for at least managed with frequent repeated lumbar punc-
2 weeks followed by consolidation therapy with tures or placement of a lumbar drain.
fluconazole for a minimum of 8 weeks or until Children with HIV infection who have com-
CSF culture is sterile. Alternatively, the ampho- pleted initial therapy for cryptococcosis should
tericin B deoxycholate and flucytosine com­ receive long-term suppressive therapy with
bination can be continued for 6 to 10 weeks. fluconazole. Oral itraconazole daily or ampho-
Lipid formulations of amphotericin B can be tericin B deoxycholate, 1 to 3 times weekly, are
used as a substitute for amphotericin B deoxy- alternatives. Discontinuing chronic suppressive
cholate in children with renal impairment. If therapy for cryptococcosis (after 1 year or lon-
flucytosine cannot be administered, amphoter- ger of secondary prophylaxis) can be consid-
icin B alone is an acceptable alternative and is ered in asymptomatic children 6 years or older
administered for 4 to 6 weeks. A lumbar punc- who are receiving antiretroviral therapy, have
ture should be performed after 2 weeks of ther- sustained (≥6 months) increases in CD4+ T
apy to document microbiologic clearance. The lymphocyte counts to 100 cells/mm3 or greater,
20% to 40% of patients in whom culture result and have an undetectable viral load for at least
is positive after 2 weeks of therapy will require 3 months. Most experts would not discontinue
a more prolonged treatment course. When secondary prophylaxis for patients younger
infection is refractory to systemic therapy, than 6 years.
intraventricular amphotericin B can be admin-
istered. Monitoring of serum cryptococcal

ERRNVPHGLFRVRUJ
128 CRYPTOCOCCUS NEOFORMANS AND CRYPTOCOCCUS GATTII INFECTIONS

Image 36.1
This photomicrograph depicts Cryptococcus Image 36.2

neoformans using a light India ink staining Cryptococcus neoformans, thin-walled


preparation. Courtesy of Centers for Disease encapsulated yeast in cerebrospinal fluid
Control and Prevention/Dr Leanor Haley. (India ink preparation, original magnification
of cerebrospinal fluid x450).

Image 36.4
Image 36.3
This photomicrograph depicted numbers of Cryptococcosis of the liver (original magnification
Cryptococcus neoformans fungi, the etiologic x810) in an immunodeficient patient with
agents responsible for the disease cryptococco­ disseminated disease. The mucinous capsules
sis. This slide was created from a lung specimen are prominent. Courtesy of Edgar O. Ledbetter,
and stained using the hematoxylin-eosin staining MD, FAAP.
technique. Courtesy of Centers for Disease
Control and Prevention/Lucille K. Georg, MD.

Image 36.6
This micrograph depicts the histopathologic
changes associated with cryptococcosis of the
lung using mucicarmine stain. Cryptococcosis,
caused by the fungal pathogen Cryptococcus
neoformans, is transmitted through inhalation of
Image 36.5 airborne yeast cells or biospores. At risk are
Cryptococcus meningitis. Cystic lesions resulting those who are immunocompromised, especially
from accumulation of organisms in perivascular those with HIV infection. Courtesy of Centers for
spaces. Courtesy of Dimitris P. Agamanolis, MD. Disease Control and Prevention/Dr Leanor Haley.

ERRNVPHGLFRVRUJ
Cryptosporidiosis 129

37 ant, multistep treatment processes are often


used to remove (eg, filter) and inactivate
Cryptosporidiosis (eg, ultraviolet treatment) oocysts to protect
Clinical Manifestations public drinking water supplies. Typical filtra-
tion systems used for swimming pools are only
Frequent, nonbloody, watery diarrhea is the partially effective in removing oocysts from
most common manifestation of cryptosporidi- contaminated water. As a result, Cryptospori­
osis, although infection can be asymptomatic. dium species have become the leading cause of
Other symptoms include abdominal cramps, recreational water-associated outbreaks, being
fatigue, fever, vomiting, anorexia, and weight associated with 69% of 35 treated recreational
loss. In infected immunocompetent adults water-associated outbreaks with identified
and children, diarrheal illness is self-limited, infectious causes.
usually lasting 2 to 3 weeks. Infected immuno-
compromised hosts, such as children with a In addition to waterborne transmission,
solid organ transplant or advanced HIV dis- humans can acquire infections from livestock;
ease, can experience profuse diarrhea lasting from animals found in petting zoos, particu-
weeks to months; this can lead to malnutrition larly preweaned calves; or from pets. Person-
and wasting. Delay in diagnosis and treatment to-person transmission occurs as well and can
can be associated with death. Elevated tacroli- cause outbreaks in child care centers, in which
mus concentrations have been reported in up to 70% of attendees reportedly have been
solid organ transplant patients, thought to infected. Cryptosporidium species can also
be related to altered drug metabolism in the cause traveler’s diarrhea.
small intestine and resulting in acute kidney
Incubation Period
injury. Extraintestinal cryptosporidiosis (ie,
disease in the lungs, biliary tract, or, rarely, Usually 3 to 14 days, with oocyst shedding
pancreas) has been reported in people who ceasing in immunocompetent people 2 weeks
are ­immunocompromised. after symptom resolution. In immunocompro-
mised people, oocyst shedding can continue
Etiology for months.
Cryptosporidium species are oocyst-forming
Diagnostic Tests
coccidian protozoa. Oocysts are excreted in
feces of an infected host and transmitted via Routine laboratory examination of stool for
the fecal-oral route. Cryptosporidium hominis, ova and parasites might not include testing
which predominantly infects people, and for Cryptosporidium species, so testing for
­Cryptosporidium parvum, which infects peo- the organism should be requested specifically.
ple, preweaned calves, and other mammals, The direct immunofluorescent antibody
are the primary Cryptosporidium species that method for detection of oocysts in stool is the
infect humans. current test of choice for diagnosis of crypto-
sporidiosis. The detection of oocysts on micro-
Epidemiology scopic examination of stool specimens is also
Extensive waterborne disease outbreaks have diagnostic. The formalin ethyl acetate stool
been associated with contamination of drink- concentration method is recommended before
ing water and recreational water (eg, swim- staining the stool specimen with a modified
ming pools, lakes, interactive fountains). Kinyoun acid-fast stain. Oocysts generally
The incidence of cryptosporidiosis has been are small (4–6 µm in diameter). Enzyme
increasing in the United States since 2005; the immunoassays and immune chromatographic
total (confirmed and probable) number of tests (point-of-care rapid tests) for detecting
annually reported cases in 2012 was 7,956. In antigen in stool are available commercially,
children, the incidence of cryptosporidiosis is but confirmation of results may be indicated.
greatest during summer and early fall, corre- Because shedding can be intermittent, at least
sponding to the outdoor swimming season. 3 stool specimens collected on separate days
Because oocysts are extremely chlorine toler- should be examined before considering test

ERRNVPHGLFRVRUJ
130 Cryptosporidiosis

results to be negative. Organisms can also be improvement in CD4+ T lymphocyte count


identified in intestinal biopsy tissue or sam- associated with antiretroviral therapy can
pling of intestinal fluid. lead to symptom resolution and cessation of
oocyst shedding. For this reason, administra-
Treatment
tion of combination antiretroviral therapy is
Generally, immunocompetent people need no the primary treatment for cryptosporidiosis
specific therapy. A 3-day course of nitazoxa­ in patients with HIV infection. Given the seri-
nide oral suspension has been approved by the ousness of this infection in immunocompro-
US Food and Drug Administration for treat- mised individuals, use of nitazoxanide can
ment of all people 1 year and older with diar- be considered in immunocompromised HIV-
rhea associated with cryptosporidiosis. infected children in conjunction with combi-
The nitazoxanide dose for healthy children nation antiretroviral therapy for immune
not infected with HIV is based on age. The restoration. The recommended nitazoxanide
appropriate treatment of cryptosporidiosis dosing is the same as for immunocompetent
in children who are solid organ transplant people. Paromomycin, or a combination of
recipients is not known, but longer courses of paromomycin and azithromycin, might be
nitazoxanide (generally >14 days) have been effective, but few data regarding efficacy
recommended. In HIV-infected patients, are available.

Image 37.1
Oocysts of Cryptosporidium parvum (modified Kinyoun acid-fast stain). Monoclonal antibody-based
stain for oocytes in stool and an enzyme immunoassay for detecting antigen in stool are available
commercially. This image shows that the staining can be variable. In particular, infec­tions that are
resolving can be accompanied by increasing numbers of nonacid-fast oocysts or “ghosts.” Courtesy
of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Cryptosporidiosis 131

Image 37.2
This micrograph of a direct fecal smear is stained to detect Cryptosporidium species, an intracellular
protozoan parasite. Using a modified cold Kinyoun acid-fast staining technique and under an oil
immersion lens, Cryptosporidium species oocysts, which are acid-fast, stain red, and yeast cells,
which are not acid-fast, stain green. Ma P, Soave R. Three-step stool examination for cryptosporidiosis
in 10 homosexual men with protracted watery diarrhea. J Infect Dis. 1983;147(5):824–828. Reprinted
with permission from Oxford University Press.

Image 37.3
Histopathology of cryptosporidiosis, intestine. Plastic-embedded, toluidine blue-stained section shows
numerous Cryptosporidium organisms at luminal surfaces of epithelial cells. Courtesy of Centers for
Disease Control and Prevention/Dr Edwin P. Ewing Jr.

Image 37.4
Cryptosporidium, a spore-forming coccidian protozoan, can be seen on the brush border of intestinal
mucosa. Cryptosporidium does not invade below the epithelial layer of the mucosa, so fecal
leukocytes are absent.

ERRNVPHGLFRVRUJ
132 Cryptosporidiosis

Image 37.5
Cryptosporidiosis of gallbladder in a patient with AIDS. Histopathologic features of gallbladder
epithelium include numerous Cryptosporidium organisms along luminal surfaces of epithelial cells.
Courtesy of Centers for Disease Control and Prevention/Dr Edwin P. Ewing Jr.

Image 37.6
Incidence—United States and US Territories, 2012. Courtesy of Morbidity and Mortality Weekly Report.

ERRNVPHGLFRVRUJ
Cryptosporidiosis 133

Image 37.7
Life cycle of Cryptosporidium. Sporulated oocysts, containing 4 sporozoites, are excreted by the
infected host through feces and possibly other routes, such as respiratory secretions (1). Transmission
of Cryptosporidium parvum occurs mainly through contact with contaminated water (eg, drinking
or recreational water). Occasionally, food sources, such as chicken salad, may serve as vehicles
for transmission. Many outbreaks in the United States have occurred in water parks, community
swimming pools, and child care centers. Zoonotic transmission of C parvum occurs through exposure
to infected animals or exposure to water contaminated by feces of infected animals (2). Following
ingestion (and possibly inhalation) by a suitable host (3), excystation (a) occurs. The sporozoites are
released and parasitize epithelial cells (b, c) of the gastrointestinal tract or other tissues. In these
cells, the parasites undergo asexual multiplication (schizogony or merogony) (d, e, f) and then sexual
multiplication (gametogony), producing microgamonts (male) (g) and macrogamonts (female) (h). On
fertilization of the macrogamonts by the microgametes (i), oocysts (j, k) develop that sporulate in the
infected host. Two different types of oocysts are produced: the thick-walled, which is commonly
excreted from the host (j), and the thin-walled (k), which is primarily involved in autoinfection. Oocysts
are infective on excretion, thus permitting direct and immediate fecal-oral transmission. Note that
oocysts of Cyclospora cayetanensis, another important coccidian parasite, are unsporulated at the
time of excretion and do not become infective until sporulation is completed. Refer to the life cycle
of C cayetanensis for further details. Courtesy of Centers for Disease Control and Prevention/
Alexander J. da Silva, PhD/Melanie Moser.

ERRNVPHGLFRVRUJ
134 Cutaneous Larva Migrans

38 Epidemiology

Cutaneous Larva Migrans Cutaneous larva migrans is a disease of chil-


dren, utility workers, gardeners, sunbathers,
Clinical Manifestations and others who come in contact with soil con-
Nematode larvae produce pruritic, reddish taminated with cat and dog feces. In the United
papules at the site of skin entry, a condition States, the disease is most prevalent in the
referred to as creeping eruption. As the larvae Southeast. Cases in the United States can also
migrate through skin, advancing several milli- be imported by travelers returning from tropi-
meters to a few centimeters a day, intensely cal and subtropical areas.
pruritic serpiginous tracks or bullae are Diagnostic Tests
formed. This condition is most often caused by
larvae of the dog and cat hookworm Ancylos­ The diagnosis is made clinically, and biopsies
toma braziliense but can be caused by other typically are not indicated. Biopsy specimens
nematodes, including Strongyloides and human typically demonstrate an eosinophilic inflam-
hookworm species. Larval activity can con- matory infiltrate, but the migrating parasite is
tinue for several weeks or months, but the not visualized. Eosinophilia and increased
infection is self-limiting. Cutaneous larva immunoglobulin E serum concentrations
migrans is a clinical diagnosis based on occur in some cases. Larvae have been detected
advancing serpiginous tracks in the skin with in sputum and gastric washings in patients
associated intense pruritus. Rarely, in infec- with pneumonitis. Enzyme immunoassay or
tions with certain species of parasites, larvae Western blot analysis using antigens of A cani­
may penetrate deeper tissues and cause pneu- num have been developed in research laborato-
monitis (Löffler syndrome), which can be ries, but these assays are not available for
severe. Occasionally, the larvae of Ancylostoma routine diagnostic use.
caninum can reach the intestine and cause Treatment
eosinophilic enteritis.
The disease is usually self-limited, with sponta-
Etiology neous cure after several weeks or months.
Infective larvae of cat and dog hookworms (ie, Orally administered albendazole or ivermectin
A braziliense and A caninum) are the usual is the recommended therapy.
causes. Other skin-penetrating nematodes are
occasional causes.

Image 38.2
Cutaneous larva migrans lesions of the foot of
Image 38.1
a 10-year-old girl. In the United States, this dog
Cutaneous larva migrans lesions on lower leg and cat hookworm infection is most commonly
(caused by hookworm larvae of Ancylostoma seen in the Southeast. These raised, serpiginous,
braziliense and Ancylostoma caninum). pruritic, migrating eruptions may extend rapidly.
Copyright Gary Williams, MD.

ERRNVPHGLFRVRUJ
Cutaneous Larva Migrans 135

Image 38.3
Cutaneous larva migrans infection of the foot in an adolescent male. Courtesy of George Nankervis, MD.

Image 38.4
Adult who noted a migrating skin lesion on left thigh for 2 weeks. Copyright Larry I. Corman.

Image 38.5
Cutaneous larva migrans 48 hours after treatment. Orally administered albendazole or ivermectin is the
recommended therapy.

ERRNVPHGLFRVRUJ
136 Cyclosporiasis

39 known hosts for C cayetanensis. Direct person-


to-person transmission is unlikely because
Cyclosporiasis excreted oocysts take days to weeks under
Clinical Manifestations favorable environmental conditions to sporu-
late and become infective. The oocysts are
Watery diarrhea is the most common symptom resistant to most disinfectants used in food and
of cyclosporiasis; diarrhea can be profuse and water processing and can remain viable for
protracted. Anorexia, nausea, vomiting, sub- prolonged periods in cool, moist environments.
stantial weight loss, flatulence, abdominal
cramping, myalgia, and prolonged fatigue can Incubation Period
occur. Low-grade fever occurs in approxi- Typically 1 week (range 2–14 days).
mately 50% of patients. Biliary tract disease has
been reported. Infection is usually self-limited, Diagnostic Tests
but untreated people may have remitting, Diagnosis is made by identification of oocysts
relapsing symptoms for weeks to months. (8–10 μm in diameter) in stool, intestinal fluid/
Asymptomatic infection has been most com- aspirate, or intestinal biopsy specimens.
monly documented in settings where cyclospo- Oocysts may be shed at low levels, even by peo-
riasis is endemic. ple with profuse diarrhea. This makes critical
Etiology repeated stool examinations, sensitive recovery
methods (eg, concentration procedures), and
Cyclospora cayetanensis is a coccidian proto- detection methods that highlight the organism.
zoan; oocysts (rather than cysts) are passed in Oocysts are autofluorescent and are variably
stools. acid fast after modified acid fast staining of
Epidemiology stool specimens.
C cayetanensis is known to be endemic in Treatment
many resource-limited countries and has been Trimethoprim-sulfamethoxazole, typically for
reported as a cause of traveler’s diarrhea. Food- 7 to 10 days, is the drug of choice. People
and waterborne outbreaks have been reported. infected with HIV may need long-term main-
Most outbreaks in the United States and Can- tenance therapy.
ada have been associated with consumption of
imported fresh produce. Humans are the only

Image 39.1
Four Cyclospora oocysts from fresh stool fixed
in 10% formalin (acid-fast stain). Compared with
Image 39.2
wet mount preparations, the oocysts are less
Four Cyclospora oocysts from fresh stool fixed
perfectly round and have a wrinkled appearance.
in 10% formalin and stained with safranin,
Most important, the staining is variable among
showing the uniform staining of oocysts by
the 4 oocysts. Courtesy of Centers for Disease
this method. Courtesy of Centers for Disease
Control and Prevention.
Control and Prevention.

ERRNVPHGLFRVRUJ
Cyclosporiasis 137

Image 39.3
Cyclospora cayetanensis. When freshly passed in stools, the oocyst is not infective (1) (thus,
direct fecal-oral transmission cannot occur; this differentiates Cyclospora from another important
coccidian parasite, Cryptosporidium). In the environment (2), sporulation occurs after days or weeks
at temperatures between 22°C and 32°C (71.6°F–89.6°F), resulting in division of the sporont into
2 sporocysts, each containing 2 elongate sporozoites (3). Fresh produce and water can serve as
vehicles for transmission (4) and the sporulated oocysts are ingested (in contaminated food or
water) (5). The oocysts excyst in the gastrointestinal tract, freeing the sporozoites which invade the
epithelial cells of the small intestine (6). Inside the cells, they undergo asexual multiplication and
sexual development to mature into oocysts, which will be shed in stools (7). The potential mechan­
isms of contamination of food and water are still under investigation. Some of elements of this figure
were created based on an illustration by Ortega YR, Sterling CR, Gilman RH. Cyclospora cayetanensis.
Adv Parasitol. 1998;40:399–418. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
138 Cytomegalovirus Infection

40 deterioration (progression) of their hearing


loss. Between 55% and 75% of clinically appar-
Cytomegalovirus Infection ent and clinically silent newborns, respectively,
Clinical Manifestations who ultimately develop congenital CMV-­
associated SNHL will not have hearing loss
Manifestations of acquired human cytomega- detectable within the first month of life,
lovirus (CMV) infection vary with age and ­i llustrating the high frequency of late-onset
host immunocompetence. Asymptomatic SNHL in these children. For this reason, tar-
infections are the most common, particularly geted CMV testing of neonates who fail their
in children. An infectious mononucleosis-like uni­versal newborn hearing screen will not
syndrome with prolonged fever and mild detect most neonates who are at risk of CMV-­
­hepatitis, occurring in the absence of hetero- associated hearing loss. Approximately 20% of
phile antibody production (“monospot nega- all hearing loss at birth and 25% of all hearing
tive”), can occur in adolescents and adults. loss at 4 years of age are attributable to congen-
Pneumonia, colitis, retinitis, and a syndrome ital CMV infection. As such, all children with
characterized by fever, thrombocytopenia, congenital CMV infection should be regularly
­leukopenia, and mild hepatitis can occur in evaluated for early detection and intervention
immunocompromised hosts, including people as appropriate.
receiving treatment for malignant neoplasms,
people infected with HIV, and people receiving Infection acquired from maternal cervical
immunosuppressive therapy for organ or secretions during the intrapartum period, or
hematopoietic stem cell transplantation. Less in the postpartum period from human milk,
commonly, patients treated with biologic is usually not associated with clinical illness
response can exhibit CMV end-organ disease, in term neonates. In preterm neonates, how-
such as retinitis and hepatitis. ever, postpartum infection resulting from
human milk or from transfusion from CMV-­
Congenital infection has a spectrum of clinical seropositive donors has been associated with
manifestations but usually is not evident at systemic infections, including hepatitis, inter-
birth (“clinically silent” congenital CMV infec- stitial pneumonia, and hematologic abnor­
tion). Approximately 10% of neonates with malities, including thrombocytopenia and
­congenital CMV infection exhibit clinical leukopenia, and a viral sepsis syndrome.
­findings that are evident at birth (congenital
CMV disease), with manifestations including Etiology
intrauterine growth restriction, jaundice, Human CMV, also known as human herpes­
­purpura, hepatosplenomegaly, microcephaly, virus 5, is a double-stranded DNA virus and a
intracerebral (typically periventricular) calci­ member of the herpesvirus family (Herpes­
fications, and retinitis; developmental delays viridae), β-herpesvirus subfamily (Betaherpes-
are common among these neonates in later virinae), and Cytomegalovirus genus.
infancy and early childhood. Death attribut-
able to congenital CMV is estimated to occur Epidemiology
in 3% to 10% of neonates with congenital dis- Cytomegalovirus is highly species specific, and
ease. Sensorineural hearing loss (SNHL) is the only human CMV has been shown to infect
most common sequela following congenital humans and cause disease. The virus is ubiqui-
CMV infection, with SNHL occurring in up to tous and has numerous strain types (exhibits
50% of children with congenital disease at birth extensive genetic diversity). Transmission
and up to 15% of those with clinically silent occurs horizontally (by direct person-to-person
CMV infection. Congenital CMV infection is contact with virus-containing secretions),
the leading nongenetic cause of SNHL in chil- ­vertically (from mother to neonate before,
dren in the United States. Progressive SNHL ­during, or after birth), and via transfusions
can occur following symptomatic or asymp- of blood, platelets, and white blood cells from
tomatic congenital CMV infection, with 50% infected donors. Cytomegalovirus can also
of affected children continuing to have further be transmitted with organ or hematopoietic

ERRNVPHGLFRVRUJ
Cytomegalovirus Infection 139

stem cell transplantation. Infections have no Vertical transmission of CMV to a neonate


­seasonal predilection. Cytomegalovirus per- occurs in one of the following periods: in utero
sists in latent form after a primary infection, by transplacental passage of maternal blood-
and intermittent virus shedding and symptom- borne virus, at birth by passage through an
atic infection can occur throughout the life- infected maternal genital tract, or postnatally
time of the infected person, particularly under by ingestion of CMV-positive human milk or
conditions of immunosuppression. Reinfection by transfusion. Between 0.5% and 1% of all live-
with other strains of CMV can occur in sero- born neonates are infected in utero and excrete
positive hosts. CMV at birth, making this the most common
congenital viral infection in the United States.
Horizontal transmission is probably the result
In utero fetal infection can occur in women
of exposure to saliva and genital secretions
with no preexisting CMV immunity (primary
from infected individuals, but contact with
maternal infection) or in women with preexist-
infected urine can also have a role. Spread of
ing antibody to CMV (nonprimary maternal
CMV in households and child care centers is
infection) by acquisition of a different viral
well documented. Excretion rates from urine
strain during pregnancy or by reactivation of
or saliva in children 1 to 3 years of age who
an existing maternal infection. Congenital
attend child care centers usually range from
infection and associated sequelae can occur
30% to 40% but can be as high as 70%. These
irrespective of the trimester of pregnancy when
children frequently excrete high quantities of
the mother is infected, but severe sequelae are
virus. Young children can transmit CMV to
more commonly associated with primary
their parents, including mothers who may
maternal infection acquired during the first
be pregnant, and other caregivers, including
half of gestation. Damaging fetal infections
child care staff. In adolescents and adults,
following nonprimary maternal infection have
­sexual transmission occurs, as evidenced by
been reported, and acquisition of a different
detection of virus in seminal and cervical flu-
viral strain during pregnancy in women with
ids. As such, CMV is considered to be a sexu-
preexisting CMV antibody can cause clinically
ally transmitted infection.
apparent congenital disease with sequelae. It
Healthy cytomegalovirus-seropositive people is estimated that more than two-thirds of neo-
have latent CMV in their leukocytes and tis- nates with congenital CMV infection in the
sues; hence, blood transfusions and organ United States are born to women with non­
transplantation can result in transmission. primary infection, and the contribution of
Severe CMV disease following transfusion or nonprimary maternal infection as a cause of
organ transplantation is more likely to occur damaging congenital CMV infection is
if the recipient is immunosuppressed and believed to be common in populations with
CMV-seronegative or is a preterm neonate. higher maternal CMV seroprevalence than
In contrast, among nonautologous hemato­ that of women in the United States. Thus, the
poietic stem cell transplant recipients, CMV-­ definition of protective immunity in congenital
seropositive recipients who receive transplants CMV infection remains contentious.
from seronegative donors are at greatest risk
Cervical excretion of CMV is common among
of disease when exposed to CMV after trans-
seropositive women, resulting in exposure
plant, perhaps secondary to the failure of
of many neonates to CMV at birth. Cervical
transplanted graft to provide immunity to
excretion rates are higher among young moth-
the recipient. Latent CMV can reactivate in
ers in lower socioeconomic groups. Similarly,
immunosuppressed people and result in
although disease can occur in seronegative
­disease if immunosuppression is severe (eg,
neonates fed CMV-infected human milk, most
patients with AIDS, solid organ or hemato­
neonates who acquire CMV from ingestion of
poietic stem cell transplant recipients).
infected human milk do not develop clinical
illness or sequelae, most likely because of the
presence of passively transferred maternal

ERRNVPHGLFRVRUJ
140 Cytomegalovirus Infection

a­ ntibody. Among neonates who acquire infec- detection of CMV in urine, oral fluids, respira-
tion from maternal cervical secretions or tory tract secretions, blood, or cerebrospinal
human milk, preterm neonates born before fluid obtained within 2 to 4 weeks of birth. The
32 weeks’ gestation are at greater risk of CMV analytic sensitivity of CMV detection by PCR
disease than are full-term neonates. assay of dried blood spots is low, limiting use
of this type of specimen for screening for con-
Incubation Period
genital CMV infection. A positive PCR assay
Horizontally transmitted CMV infections, result from a neonatal dried blood spot con-
unknown; 3 to 12 weeks and 1 to 4 months firms congenital infection, but a negative
after blood transfusion and organ transplan­ result does not exclude congenital infection.
tation, respectively. Differentiation between intrauterine and peri-
natal infection is difficult at later than 2 to
Diagnostic Tests
4 weeks of age unless clinical manifestations
The diagnosis of CMV disease is confounded of the former are present. A strongly positive
by the ubiquity of the virus, high rate of CMV-specific IgM during early infancy can
asymp­tomatic excretion, frequency of reacti- be suggestive of congenital CMV infection;
vated infections, development of serum immu- however, IgM serologic methods commonly
noglobulin (Ig) M CMV-specific antibody in have reduced specificity and frequently result
some episodes of reactivation, reinfection with in false-positive results.
different strains of CMV, and concurrent infec-
tion with other pathogens. Treatment
Intravenous ganciclovir is the drug of choice
Virus can be isolated in cell culture from urine,
for induction and maintenance treatment of
oral fluids, peripheral blood leukocytes, human
retinitis caused by acquired or recurrent
milk, semen, cervical secretions, and other
CMV infection in immunocompromised
tissues and body fluids. Recovery of virus from
adult patients, including HIV-infected patients,
a target organ provides strong evidence that
and for prophylaxis and treatment of CMV
the disease is caused by CMV. Shell vial culture
disease in adult transplant recipients. Valganci-
and immunofluorescence antibody stain for
clovir, the oral prodrug of ganciclovir, is also
immediate early antigen provides results
approved for treatment (induction and mainte-
within days. A presumptive diagnosis of CMV
nance) of CMV retinitis in immunocompro-
infection beyond the neonatal period has been
mised adult patients, including HIV-infected
associated with a 4-fold antibody titer increase
patients, and for prevention of CMV disease in
in paired serum specimens or by demonstra-
kidney, kidney-pancreas, or heart transplant
tion of virus excretion. Viral DNA can be
recipients aged 4 months and older at high risk
detected by polymerase chain reaction (PCR)
for CMV disease. Ganciclovir and valganciclo-
assay in tissues and some fluids, such as cere-
vir are also used to treat CMV infections of
brospinal fluid, urine, and saliva. Detection of
other sites (esophagus, colon, lungs) and for
CMV DNA by PCR assay in blood does not
preemptive treatment of immunosuppressed
indicate acute infection or disease, especially
adults with CMV antigenemia or viremia.
in immunocompetent people. Detection of
Oral valganciclovir is available in tablet and
pp65 antigen or quantification of viral DNA
powder for oral solution formulations.
(eg, by quantitative PCR assay) in white blood
cells is often used to detect infection in immu- Neonates with symptomatic congenital CMV
nocompromised hosts. Various serologic disease with or without central nervous system
assays, including immunofluorescence, latex involvement have improved audiologic and
agglutination, and enzyme, are available for neurodevelopmental outcomes at 2 years of
detecting CMV-specific antibodies. age when treated with oral valganciclovir for
6 months. The dose should be adjusted each
Amniocentesis has been used in several small
month to account for weight gain. Significant
series of patients to establish the diagnosis of
neutropenia occurs in one-fifth of neonates
intrauterine infection. Following delivery,
treated with oral valganciclovir and in two-
proof of congenital infection requires virologic

ERRNVPHGLFRVRUJ
Cytomegalovirus Infection 141

thirds of neonates treated with parenteral (with high rates of limiting nephrotoxicity) but
­ganciclovir. Absolute neutrophil counts may be advantageous for some patients with
should be performed weekly for 6 weeks, then HIV infection, including people with disease
at 8 weeks, then monthly for the duration of caused by ganciclovir-resistant virus or who
­antiviral treatment; serum aminotransferase are unable to tolerate ganciclovir.
concentration should be measured monthly
Cytomegalovirus establishes lifelong persis-
during treatment.
tent infection, and as such, it is not eliminated
Preterm neonates with intrapartum-acquired from the body with antiviral treatment of
CMV infection can have end-organ disease CMV disease. Until immune reconstitution is
(eg, pneumonitis, hepatitis, thrombocytope- achieved with antiretroviral therapy, chronic
nia). Antiviral treatment has not been studied suppressive therapy should be administered to
in this population. In hematopoietic stem cell HIV-infected patients with a history of CMV
transplant recipients, the combination of intra- end-organ disease (eg, retinitis, colitis, pneu-
venous immunoglobulin or CMV intravenous monitis) to prevent recurrence. All patients
immunoglobulin and ganciclovir, adminis- who have had anti-CMV maintenance therapy
tered intravenously, has been reported to be discontinued should continue to undergo regu-
synergistic in treatment of CMV pneumonia. lar ophthalmologic monitoring at a minimum
Valganciclovir and foscarnet can also be used of 3- to 6-month intervals for early detection
for treatment and maintenance of CMV retini- of CMV relapse as well as immune reconstitu-
tis in adults with AIDS. Foscarnet is more toxic tion uveitis.

Image 40.1
Cells with intranuclear inclusions in the urine of infant with congenital cytomegalovirus disease.

Image 40.2
A 3-week-old with congenital cytomegalovirus infection with purpuric skin lesions and
hepatosplenomegaly. Courtesy of Edgar O. Ledbetter, MD, FAAP.

ERRNVPHGLFRVRUJ
142 Cytomegalovirus Infection

Image 40.3
A baby girl was delivered prematurely, at 30 weeks’ gestation, by emergency cesarean delivery
because of deceleration and no acceleration on fetal heart rate monitoring. In addition, she had
severe intrauterine growth restriction, oligohydramnios, and increased peak systolic velocity of the
middle cerebral artery on Doppler ultrasonography. The 39-year-old mother (gravida 7, para 5) had
been well during pregnancy. On examination, the neonate was found to have respiratory distress,
an extensive rash (A), and hepatomegaly. The rash consisted of purple-to-magenta, nonblanching
macules that were 0.5 to 1.0 cm in diameter, as well as papules and petechiae covering her entire
body. Laboratory investigation revealed anemia (hemoglobin level, 25 g/L [reference range,
121–191 g/L]) and thrombocytopenia (platelet count, 13,000/mm3 [13 x 109/L [reference range,
195,000–450,000/mm3 (195–434 x 109/L)]). Results of cytomegalovirus (CMV) IgM and IgG tests
and serum and plasma DNA polymerase chain reaction assays were positive. Tests for parvovirus
B19 and rubella IgM antibodies were negative. Despite aggressive care, the child did not survive.
Postmortem examination confirmed disseminated CMV infection. Extramedullary hematopoiesis
was present throughout the body, including the skin (B). Dermal hematopoiesis can occur in utero
as a result of severe anemia, congenital rubella, parvovirus infection, or CMV infection. From The New
England Journal of Medicine, Congenital Cytomegalovirus Infection, 362, 833. Copyright © 2010.
Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Image 40.5
This 1-day-old, who was small for gestational
Image 40.4
age, had microcephaly, hepatomegaly, jaundice,
Cytomegalovirus infection, congenital, with
and a “blueberry muffin” rash. The neonate also
characteristic “blueberry muffin” lesions.
developed thrombocytopenia and disseminated
Copyright David Clark.
intravascular coagulation. The neonate died at
48 hours of age. Kidney and lung tissue culture
tested positive for cytomegalovirus. Copyright
Larry I. Corman.

ERRNVPHGLFRVRUJ
Cytomegalovirus Infection 143

Image 40.7
Infant in Image 40.6 with lethal cytomegalovirus
disease with radiographic changes in long
Image 40.6 bones of osteitis characterized by fine vertical
Infant with lethal congenital cytomegalovirus metaphyseal striations. Courtesy of Edgar O.
disease with purpuric skin lesions and striking Ledbetter, MD, FAAP.
hepatosplenomegaly. Courtesy of Edgar O.
Ledbetter, MD, FAAP.

Image 40.9
Characteristic white perivascular infiltrates in the
retina of an infant with congenital cytomegalo­
Image 40.8 virus infection. Courtesy of George Nankervis, MD.
Widespread “brushfire retinitis” in an infant
with congenital cytomegalovirus infection. The
perivascular infiltrates and diffuse hemorrhage
may result in complete blindness whenever
macular involvement occurs. Courtesy of
George Nankervis, MD.

ERRNVPHGLFRVRUJ
144 Cytomegalovirus Infection

Image 40.10
Axial T2-weighted magnetic resonance image
demonstrates periventricular germinolytic cysts
(arrows). Also note the periventricular white
matter hyperintensities that are representative
of demyelination and gliosis. Image 40.11
Cytomegalovirus infection with periventricular
calcification. Courtesy of Benjamin Estrada, MD.

Image 40.12
Histopathology of cytomegalovirus infection Image 40.13
of brain capillary endothelial cell. Courtesy of Congenital cytomegalovirus encephalitis.
Centers for Disease Control and Prevention/ Microcephaly and cerebral calcification.
Dr Haraszti. Courtesy of Dimitris P. Agamanolis, MD.

Image 40.14
Histopathologic features of cytomegalovirus infection of the kidney. Intranuclear inclusions are
surrounded by a halo and the nuclear membrane, giving an “owl eye” appearance. Courtesy of
Centers for Disease Control and Prevention/Dr Haraszti.

ERRNVPHGLFRVRUJ
Dengue 145

41 DENV. After this short period, infection with


a different strain may predispose to more
Dengue severe disease. A person has a lifetime risk of
Clinical Manifestations up to 4 DENV infections.
Dengue has a wide range of clinical presenta- Epidemiology
tions, from asymptomatic infection to classic Dengue virus is primarily transmitted to
dengue fever and severe dengue (ie, dengue humans through the bite of infected Aedes
hemorrhagic fever or dengue shock syndrome). aegypti (and, less commonly, Aedes albopictus
Approximately 5% of patients develop severe or Aedes polynesiensis) mosquitoes. Humans
dengue, which is more common with second are the main amplifying host of DENV and
or other subsequent infections. Less common the main source of virus for Aedes mosquitoes.
clinical syndromes include myocarditis, pan- A sylvatic nonhuman primate DENV trans-
creatitis, hepatitis, and neuroinvasive disease. mission cycle exists in parts of Africa and
Dengue begins with a nonspecific, acute febrile Southeast Asia but rarely crosses to humans.
illness lasting 2 to 7 days (febrile phase), often During the approximately 7 days of viremia,
accompanied by muscle, joint, or bone pain; DENV can be transmitted following receipt
headache; retro-orbital pain; facial erythema; of blood products, donor organs, or tissue;
injected oropharynx; macular or maculopapu- ­percutaneous exposure to blood; and exposure
lar rash; leukopenia; and petechiae or other in utero or at parturition.
minor bleeding manifestations. During fever Dengue is a major public health problem in
defervescence, usually on days 3 through 7 of the tropics and subtropics; an estimated 50 to
illness, an increase in vascular permeability in 100 million dengue cases occur annually in
parallel with increasing hematocrit (hemocon- more than 100 countries, and 40% of the
centration) may occur. The period of clinically world’s population lives in areas with DENV
significant plasma leakage usually lasts 24 to transmission. In the United States, dengue is
48 hours (critical phase), followed by a con­ endemic in Puerto Rico, the Virgin Islands,
valescent phase with gradual improvement and American Samoa. In addition, millions of
and stabilization of the hemodynamic status. US travelers, including children, are at risk
Warning signs of progression to severe dengue because dengue is the leading cause of febrile
occur in the late febrile phase and include per- illness among travelers returning from the
sistent vomiting, severe abdominal pain, muco- Caribbean, Latin America, and South Asia.
sal bleeding, difficulty breathing, early signs Outbreaks with local DENV transmission
of shock, and a rapid decline in platelet count have occurred in Texas, Hawaii, and Florida
with an increase in hematocrit. Patients with in the last decade. However, although 16 states
nonsevere disease begin to improve during the have A aegypti and 35 states have A albopictus
critical phase, but people with clinically signi­ mosquitoes, local dengue transmission is
ficant plasma leakage attributable to increased uncommon. Dengue occurs in children and
vascular permeability develop severe disease adults; it is most likely to cause severe disease
with pleural effusions or ascites, hypovolemic in young children, pregnant women, and
shock, and hemorrhage. patients with chronic diseases (eg, asthma,
Etiology sickle cell anemia, diabetes mellitus).
Four related RNA viruses of the genus Incubation Period
­Flavivirus, dengue viruses (DENV) 1, 2, 3, 3 to 14 days before symptom onset. Infected
and 4, cause symptomatic (~25%) and asymp- people, symptomatic and asymptomatic, can
tomatic infections. Infection with one DENV transmit DENV to mosquitoes 1 to 2 days
type produces lifelong immunity against that before symptoms develop and during viremia
type and a short period of cross-protection (approximately 7 days).
against infection with the other 3 types of

ERRNVPHGLFRVRUJ
146 Dengue

Diagnostic Tests symptoms) and convalescent (>15 days after


Laboratory confirmation of the clinical onset of symptoms) samples confirms recent
­diagnosis of dengue can be made on a single infection. A single anti-DENV IgG antibody
serum specimen obtained during the febrile titer of 1:1280 or greater is highly suggestive
phase of the illness by testing for DENV of a dengue diagnosis.
by detection of DENV RNA by reverse Treatment
transcriptase-­polymerase chain reaction
No specific antiviral therapy exists for dengue.
assay, detection of DENV nonstructural
During the febrile phase, patients should stay
­protein 1 antigen by immunoassay, or testing
well hydrated and avoid use of aspirin (acetyl-
for anti-DENV immunoglobulin (Ig) M anti-
salicylic acid), salicylate-containing drugs,
bodies by enzyme immunoassay (EIA). Dengue
and other nonsteroidal anti-inflammatory
virus is detectable by reverse transcriptase-
drugs (eg, ibuprofen) to minimize the potential
polymerase chain reaction or nonstructural
for bleeding. Additional supportive care is
protein 1 antigen EIAs from the beginning of
required if the patient becomes dehydrated or
the febrile phase until day 7 to 10 after illness
develops signs of severe disease at the time of
onset, but anti-DENV IgM antibodies are not
fever defervescence.
detectable until at least 5 days after illness
onset. Other tests, such as IgG anti-DENV Early recognition of shock and intensive sup-
EIA and hemagglutination inhibition assay, portive therapy can reduce risk of death from
are not as specific. Anti-DENV IgG antibody approximately 10% to less than 1% in severe
remains elevated for life after DENV infection dengue. During the critical phase, mainte-
and is often falsely positive in people with prior nance of fluid volume and hemodynamic sta-
infection with or immunization against other tus is crucial to management of severe cases.
flaviviruses (eg, West Nile virus, Japanese Patients should be monitored for early signs of
encephalitis virus, yellow fever virus). A 4-fold shock, occult bleeding, and resolution of
or greater increase in anti-DENV IgG antibody plasma leak to avoid prolonged shock, end-
titers between the acute (≤ 5 days after onset of organ damage, and fluid overload.

Image 41.1
Distribution of dengue, western hemisphere. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Dengue 147

Image 41.2
Distribution of dengue, eastern hemisphere. Courtesy of Centers for Disease Control and Prevention.

Image 41.3
Dengue virus infection. Number of reported cases, by age group—United States, 2012. Courtesy of
Morbidity and Mortality Weekly Report.

ERRNVPHGLFRVRUJ
148 Dengue

Image 41.4
Dengue and dengue hemorrhagic fever. Number of reported cases, by location of residence—
United States and US territories, 2012. Courtesy of Morbidity and Mortality Weekly Report.

Image 41.5
This transmission electron micrograph depicts a number of round dengue virus particles that were
revealed in this tissue specimen. Courtesy of Centers for Disease Control and Prevention/Frederick
Murphy, Cynthia Goldsmith.

ERRNVPHGLFRVRUJ
Diphtheria 149

42 an appropriate antimicrobial agent usually are


not communicable 48 hours after treatment is
Diphtheria initiated. Transmission results from intimate
Clinical Manifestations contact with patients or carriers. People who
travel to areas where diphtheria is endemic or
Respiratory tract diphtheria usually occurs as people who come into contact with infected
membranous nasopharyngitis or obstructive travelers from such areas are at increased risk
laryngotracheitis. Membranous pharyngitis of being infected with the organism; rarely,
associated with a bloody nasal discharge fomites and raw milk or milk products can
should suggest diphtheria. Local infections are serve as vehicles of transmission. Severe dis-
associated with a low-grade fever and gradual ease occurs more often in people who are
onset of manifestations over 1 to 2 days. Less unimmunized or inadequately immunized.
commonly, diphtheria presents as cutaneous, Fully immunized people may be asymptomatic
vaginal, conjunctival, or otic infection. Cuta- carriers or have mild sore throat. The incidence
neous diphtheria is more common in tropical of respiratory diphtheria is greatest during
areas and among the urban homeless. Exten- autumn and winter, but summer epidemics
sive neck swelling with cervical lymphadenitis can occur in warm climates in which skin
(bull neck) is a sign of severe disease. Life- infections are prevalent. During the 1990s,
threatening complications of respiratory diph- ­epidemic diphtheria occurred throughout
theria include upper airway obstruction caused independent states of the former Soviet Union,
by extensive membrane formation; myocardi- with case-fatality rates ranging from 3% to 23%.
tis, which is often associated with heart block; Diphtheria remains endemic in these countries
and cranial and peripheral neuropathies. Pala- as well as in countries in Africa, Latin Amer-
tal palsy, characterized by nasal speech, fre- ica, Asia, the Middle East, and parts of Europe,
quently occurs in pharyngeal diphtheria. where childhood immunization coverage with
Etiology diphtheria toxoid–containing vaccines is sub-
optimal. During 2012, one probable case of
Diphtheria is caused by toxigenic strains of
diphtheria was reported in the United States,
Corynebacterium diphtheriae. In industrialized
representing the first case since 2003. Cases of
countries, toxigenic strains of Corynebacterium
cutaneous diphtheria likely still occur in the
ulcerans are emerging as an important cause
United States, but only respiratory tract cases
of a diphtherialike illness. C diphtheriae is an
are included for national notification.
irregularly staining, gram-positive, nonspore-
forming, nonmotile, pleomorphic bacillus Incubation Period
with 4 biotypes (mitis, intermedius, gravis, and 2 to 5 days (range, 1–10 days).
belfanti). All biotypes of C diphtheriae may be
toxigenic or nontoxigenic. The toxin inhibits Diagnostic Tests
protein synthesis in all cells, resulting in myo- Specimens for culture should be obtained from
carditis, acute tubular necrosis, and delayed the nose or throat and any mucosal or cutane-
peripheral nerve conduction. Nontoxigenic ous lesion. Material should be obtained from
strains of C diphtheriae can cause sore throat beneath the membrane, or a portion of the
and, rarely, other invasive infections, including membrane itself should be submitted for
endocarditis and foreign body infections. ­culture. Because special medium is required
Epidemiology for isolation, laboratory personnel should be
notified that C diphtheriae is suspected.
Humans are the sole reservoir of C diphtheriae. ­Specimens collected for culture can be placed
Organisms are spread by respiratory tract in any transport medium (eg, Amies, Stuart)
droplets and by contact with discharges from or in a sterile container and transported at 4°C
skin lesions. In untreated people, organisms (39.2°F) or in silica gel packs to a reference
can be present in discharges from the nose ­laboratory for culture. All C diphtheriae
and throat and from eye and skin lesions for 2
to 6 weeks after infection. Patients treated with

ERRNVPHGLFRVRUJ
150 Diphtheria

i­ solates should be sent through the state health • Antimicrobial therapy. Erythromycin
department to the Centers for Disease Control administered orally or parenterally for
and Prevention. 14 days, aqueous penicillin G administered
intravenously for 14 days, or penicillin G
Treatment
procaine administered intramuscularly for
• Antitoxin. Because the condition of patients 14 days constitutes acceptable therapy. Anti-
with diphtheria can deteriorate rapidly, a microbial therapy is required to stop toxin
single dose of equine antitoxin should be production, to eradicate the C diphtheriae
administered on the basis of clinical diagno- organism, and to prevent transmission, but
sis, even before culture results are available. it is not a substitute for antitoxin, which is
Antitoxin and its indications for use and the primary therapy. Elimination of the
instructions for administration are available organism should be documented 24 hours
through the Centers for Disease Control and after completion of treatment by 2 consecu-
Prevention. To neutralize toxin from the tive negative cultures from specimens taken
organism as rapidly as possible, intravenous 24 hours apart.
administration of the antitoxin is preferred.
Before intravenous administration of anti- • Immunization. Active immunization
toxin, tests for sensitivity to horse serum against diphtheria should be undertaken
should be performed, initially with a scratch during convalescence from diphtheria; dis-
test. Allergic reactions of variable severity to ease does not necessarily confer immunity.
horse serum can be expected in 5% to 20% • Cutaneous diphtheria. Thorough cleansing
of patients. The dose of antitoxin depends of the lesion with soap and water and
on the site and size of the diphtheria mem- administration of an appropriate antimicro-
brane, duration of illness, and degree of bial agent for 10 days are recommended.
toxic effects; presence of soft, diffuse cervical
lymphadenitis suggests moderate to severe
toxin absorption. Antitoxin is probably of
no value for cutaneous disease.

Image 42.1
Pharyngeal diphtheria with membranes covering
the tonsils and uvula in a 15-year-old girl. Tonsillar
and pharyngeal diphtheria may need to be differ­
entiated from group A streptococcal pharyngitis,
Image 42.2
infectious mononucleosis, Vincent angina, acute
toxoplasmosis, thrush, and leuke­mia, as well Bull neck appearance of diphtheritic cervical
as other, less common entities, including lymphadenopathy in a 13-year-old boy.
tularemia and acute cytomegalovirus infection.

ERRNVPHGLFRVRUJ
Diphtheria 151

Image 42.3
A 5-year-old Latin American boy with nasal
diphtheria. Courtesy of Paul Wehrle, MD.
Image 42.4
Chest radiograph of a 2-year-old boy with
laryngotracheal diphtheria. Diphtheritic
pneumonia was obscured by hyperaeration on
chest radiograph at time of admission to hospital
due to laryngotracheal membranous obstruction.
Courtesy of Edgar O. Ledbetter, MD, FAAP.

Image 42.6
Diphtheria pneumonia (hemorrhagic) with
bronchiolar membranes (hematoxylin-eosin
Image 42.5 stain). From the patient in images 42.4 and 42.5.
Diphtheritic pneumonia 3 days after the Courtesy of Edgar O. Ledbetter, MD, FAAP.
admission radiograph in Image 42.4 following a
tracheostomy complicated by early pneumo­
thorax. Unfortunately, the tracheal membrane
was not visualized at the time of tracheostomy
and diphtheria antitoxin therapy was not
prescribed. Courtesy of Edgar O. Ledbetter,
MD, FAAP.

Image 42.7
This is a close-up of a diphtheria skin lesion
caused by the organism Corynebacterium
diphtheriae. Courtesy of Centers for Disease
Control and Prevention/Dr Brodsky.

ERRNVPHGLFRVRUJ
152 Diphtheria

Image 42.8
A diphtheria skin lesion on the leg. Corynebacterium diphtheriae can not only affect the respiratory,
cardiovascular, renal, and neurologic systems, but the cutaneous system as well, where it sometimes
manifests as an open, isolated wound. Courtesy of Centers for Disease Control and Prevention.

Image 42.9
Nasal membrane of diphtheria in a preschool-aged white boy. Courtesy of George Nankervis, MD.

ERRNVPHGLFRVRUJ
Diphtheria 153

Image 42.10
Number of reported cases, by year—United States, 1982–2012. Courtesy of Morbidity and Mortality
Weekly Report.

Image 42.11
Baby graves dating from the 1890s in a central Mississippi family cemetery. Diphtheria was a
common cause of these infant deaths prior to the introduction of a toxoid vaccine around 1921.
In the preantibiotic era, treatment was limited to comfort care or tracheotomy. Vaccination of children
and adults has reduced the number of diphtheria cases in the United States. However, reluctance to
immunize children sets the stage for another generation of rows of tiny memories. Courtesy of Will
Sorey, MD.

ERRNVPHGLFRVRUJ
154 EHRLICHIA, ANAPLASMA, AND RELATED INFECTIONS

43 complications in some children after severe


disease, and more commonly with Ehrlichia
Ehrlichia, Anaplasma, infections. Fatal infections have been reported
and Related Infections more commonly for Ehrlichia chaffeensis infec-
(Human Ehrlichiosis, Anaplasmosis, and tions (approximately 1%–3%) than for anaplas-
Related Infections) mosis (<1%). Typically, E chaffeensis presents
with more severe disease than does Anaplasma
Clinical Manifestations phagocytophilum. People with underlying
Infections by members of the bacterial family immunosuppression are at greater risk of
Anaplasmataceae (genera Anaplasma, severe disease.
Ehrlichia, Neorickettsia, and the proposed
Ehrlichia and Anaplasma species do not cause
genus Neoehrlichia) cause human illness with
vasculitis or endothelial cell damage character-
similar signs, symptoms, and clinical courses.
istic of some other rickettsial diseases. How-
All are acute, systemic, febrile illnesses, with
ever, because of the nonspecific presenting
common systemic manifestations, including
symptoms, Rocky Mountain spotted fever
fever, headache, chills, malaise, myalgia, and
should be considered. The recently discovered,
nausea. More variable symptoms include
tick-borne Heartland virus can also present
arthralgia, vomiting, diarrhea, cough, and
similarly.
­confusion. Rash is more common in Ehrlichia
infections than Anaplasma infections and is Etiology
more common in children (up to 60% of cases).
In the United States, human ehrlichiosis and
More severe manifestations of these diseases
anaplasmosis are caused by at least 4 different
can include acute respiratory distress syn-
species of obligate intracellular bacteria:
drome, encephalopathy, meningitis, dissemi-
E chaffeensis, Ehrlichia ewingii, Ehrlichia
nated intravascular coagulation, spontaneous
muris–like agent, and A phagocytophilum
hemorrhage, and renal failure. Significant labo-
(Table 43.1). Ehrlichia and Anaplasma species
ratory findings in Anaplasma and Ehrlichia
are gram-negative cocci with tropisms for
infections may include leukopenia, lymphope-
­different white blood cell types. E muris is
nia, thrombocytopenia, hyponatremia, and
­suspected to cause disease in Russia and
elevated serum hepatic transaminase concen-
Japan. Neorickettsia sennetsu may cause illness
trations. Cerebrospinal fluid abnormalities
in Asia, while the organism designated as
(ie, pleocytosis with a predominance of lym-
Neoehrlichia mikurensis has been found in
phocytes and increased total protein con­
­various European and Asian countries.
centration) are common. Neorickettsiosis is
characterized by lymphadenopathy, a sign that Epidemiology
is not commonly seen with infections by other The reported incidences of E chaffeensis and
members of this bacterial family. As with A phagocytophilum infections during 2012
ehrlichiosis and anaplasmosis, patients with were 3.8 and 8.0 cases per million population,
neoehrlichiosis often have had leukocytosis respectively. These diseases are under-­
and elevated C-reactive protein concentrations, recognized, and selected active surveillance
but liver transaminase levels are usually within programs have shown the incidence to be sub-
normal ranges. Most cases of neoehrlichiosis stantially higher in some areas with endemic
have been in people with underlying immuno- infection. Most cases of E chaffeensis and
suppressive conditions. E ewingii infection are reported from the
Without treatment, symptoms typically last 1 south central and southeastern United States,
to 2 weeks, but prompt antimicrobial therapy as well as East Coast states. Ehrlichiosis caused
will shorten the duration and reduce the risk of by E chaffeensis and E ewingii are associated
serious manifestations and sequelae. Following with the bite of the lone star tick (Amblyomma
infection, fatigue may last several weeks; some americanum). To date, cases attributable to the
reports suggest the occurrence of neurologic new E muris–like agent have been reported

ERRNVPHGLFRVRUJ
EHRLICHIA, ANAPLASMA, AND RELATED INFECTIONS 155

only from Minnesota and Wisconsin. Most the first presentation before antibiotic therapy
cases of human anaplasmosis have been has been initiated. Polymerase chain reaction
reported from the upper Midwest and north- assays for anaplasmosis and ehrlichiosis are
east United States (eg, Wisconsin, Minnesota, available commercially. Sequence confirmation
Connecticut, New York) and northern Califor- of the amplified product provides specific iden-
nia. In most of the United States, A phagocyto­ tification and is often necessary to identify
philum is transmitted by the black-legged tick infection with certain species (eg, E ewingii;
(Ixodes scapularis), which is also the vector for E muris–like agent in the United States).
Lyme disease (Borrelia burgdorferi) and babe-
Identification of stained peripheral blood
siosis (Babesia microti). This tick is also sus-
smears to look for classic clusters of organism
pected to be a vector for the E muris–like agent.
known as morulae may occasionally indicate
In the western United States, the western black-
infection with Anaplasmataceae, but this
legged tick (Ixodes pacificus) is the main vector
method is generally insensitive and is not rec-
for A phagocytophilum. Various mammalian
ommended as a first-line diagnostic tool. In
wildlife reservoirs for the agents of human
many patients, serologic testing can be used to
ehrlichiosis and anaplasmosis have been identi-
demonstrate evidence of a 4-fold change in
fied, including white-tailed deer and wild
immunoglobulin (Ig) G–specific antibody titer
rodents. In other parts of the world, other
by indirect immunofluorescence antibody
­bacterial species of this family are transmitted
assay between paired serum specimens. Cross-
by the endemic tick vectors for that area. An
reactivity between species can make it difficult
exception is N sennetsu, which occurs in Asia
to interpret the causative agent in areas where
and is transmitted through ingestion of
geographic distributions overlap. Detection
infected trematodes residing in fish.
of IgG antibodies in acute and convalescent
Reported cases of symptomatic ehrlichiosis sera is recommended when assessing acutely
and anaplasmosis are characteristically in infected patients. E ewingii and E muris–like
older people, with age-specific incidences agent infections are best confirmed by molecu-
greatest in people older than 40 years. How- lar detection methods.
ever, seroprevalence data indicate that expo-
Treatment
sure to E chaffeensis may be common in
children. In the United States, most human Doxycycline is the drug of choice for treat-
infections occur between April and September, ment of human ehrlichiosis and anaplasmosis,
and the peak occurrence is from May through regardless of patient age, and has also been
July. Coinfections of anaplasmosis with other shown to be effective for the other Anaplasma-
tick-borne diseases, including babesiosis and taceae infections. Ehrlichiosis and anaplasmo-
Lyme disease, may cause illnesses that are sis can be severe or fatal in untreated patients
more severe or of longer duration than a sin- or patients with predisposing conditions; ini-
gle infection. tiation of therapy early in the course of disease
helps minimize complications of illness. Most
Incubation Period patients begin to respond within 48 hours of
E chaffeensis, 5 to 14 days; A phagocytophilum, initiating doxycycline treatment. Treatment
5 to 21 days. with trimethoprim-sulfamethoxazole has been
linked to more severe outcome and is contrain-
Diagnostic Tests
dicated. Treatment should continue for at least
Detection of specific DNA in a clinical speci- 3 days after defervescence; the standard course
men by polymerase chain reaction assay is a of treatment is 5 to 10 days. Unequivocal evi-
sensitive and specific means for early diagno- dence of clinical improvement is generally
sis. Whole blood anticoagulated with ethylene- within 7 days, although some symptoms (eg,
diaminetetraacetic acid should be collected at headache, malaise) can persist for weeks.

ERRNVPHGLFRVRUJ
156
Table 43.1
Human Ehrlichiosis, Anaplasmosis, and Related Infections
Disease Causal Agent Major Target Cell Tick Vector Geographic Distribution
Ehrlichiosis caused by Ehrlichia E chaffeensis Usually monocytes Lone star tick (­Amblyomma US: Predominantly southeast, south
chaffeensis (also known as human americanum) central, and East Coast states; has
monocytic ehrlichiosis, or HME) been reported outside US

EHRLICHIA, ANAPLASMA, AND RELATED INFECTIONS


Anaplasmosis (also known as Anaplasma Usually granulocytes Black-legged tick (Ixodes US: Northeastern and upper Midwest-
human granulocytic anaplasmosis, ­phagocytophilum scapularis) or Western black- ern states and northern California;
or HGA) legged tick (Ixodes pacificus) Europe and Asia
Ehrlichiosis caused by Ehrlichia E ewingii Usually granulocytes Lone star tick US: Southeastern, south central, and
ewingii (A americanum) Midwestern states; Africa, Asia
Ehrlichiosis caused by Ehrlichia E muris–like agent Unknown; suspected in I scapularis is identified as a US: Minnesota, Wisconsin
muris–like agent monocytes possible vector.
Ehrlichiosis caused by E muris E muris sensu stricto Unknown; suspected in Ixodes persulcatus, Ixodes Asia
monocytes ovatus
Thrombocytic anaplasmosis Anaplasma platys Platelets Rhipicephalus sanguineus Venezuela
(suspected)
Ehrlichiosis caused by Ehrlichia E canis Monocytes R sanguineus (suspected) Venezuela
canis
Neorickettsiosis, sennetsu fever, Neorickettsia Monocytes Ingestion of infected Japan, Malaysia, Laos
glandular fever ­sennetsu t­ rematodes residing in fish
Neoehrlichiosis Candidatus Unknown Ixodes ricinus, Ixodes Europe and Asia
­Neoehrlichia ­persulcatus, Haemaphysalis
­mikurensis flava
EHRLICHIA, ANAPLASMA, AND RELATED INFECTIONS 157

Image 43.2
Bone marrow examination (Wright stain,
magnification x1,000). Intraleukocytic morulae of
Ehrlichia can be seen (arrow) within monocytoid
cells. Courtesy of Emerging Infectious Diseases.
Image 43.1
The intracytoplasmic inclusion, or morula, of
human monocytic ehrlichiosis in a cytocentrifuge
preparation of cerebrospinal fluid from a patient
with central nervous system involvement.
Copyright Richard Jacobs, MD.

Image 43.4
The petechial and vasculitic rash of human
monocytic ehrlichiosis in the patient in Image
43.3. Copyright Richard Jacobs, MD.

Image 43.3
Human monocytic ehrlichiosis (HME). A
semicomatose 16-year-old girl with leukopenia,
lymphopenia, thrombocytopenia, and elevated
transaminase levels. The HME polymerase chain Image 43.5
reaction and serologic test results were positive The same characteristic rash of human
for HME. Copyright Richard Jacobs, MD. monocytic ehrlichiosis in the patient in images
43.3 and 43.4. The differential diagnosis of this
rash includes Rocky Mountain spotted fever,
meningococcemia, and Stevens-Johnson
syndrome. Other tick-borne diseases, such as
Lyme disease, babesiosis, Colorado tick fever,
relapsing fever, and tularemia, may need to be
considered. Kawasaki disease has also caused
some diagnostic confusion. Copyright Richard
Jacobs, MD.

ERRNVPHGLFRVRUJ
158 EHRLICHIA, ANAPLASMA, AND RELATED INFECTIONS

Image 43.6
Etiologic agents of ehrlichiosis. Photomicro­graphs
of human white blood cells infected with the agent
of human granulocytic ehrlichiosis (Anaplasma
phagocytophilum, formerly Ehrlichia phago­
cytophila) and the agent of human monocytic
ehrlichiosis (Ehrlichia chaffeensis). Courtesy of
Centers for Disease Control and Prevention.

Image 43.7
Ehrlichiosis, Anaplasma phagocytophilum. Number of reported cases, by county—United States,
2012. Courtesy of Morbidity and Mortality Weekly Report.

ERRNVPHGLFRVRUJ
EHRLICHIA, ANAPLASMA, AND RELATED INFECTIONS 159

Image 43.8
Ehrlichiosis, Ehrlichia chaffeensis. Number of reported cases, by county—United States, 2012.
Courtesy of Morbidity and Mortality Weekly Report.

Image 43.9
This is a female lone star tick, Amblyomma americanum, and is found in the southeastern and ­mid-
Atlantic United States. This tick is a vector of several zoonotic diseases, including human monocytic
ehrlichiosis, southern tick-associated rash illness, tularemia, and Rocky Mountain spotted fever.
Courtesy of Centers for Disease Control and Prevention/Michael L. Levin, PhD.

ERRNVPHGLFRVRUJ
160 Enterovirus (­Nonpoliovirus)

44 Enterovirus D68 (EV-D68) was first identified


in California in 1962 and has been associated
Enterovirus with mild to severe respiratory illness in
(­Nonpoliovirus) infants, children, and teenagers. In August
(Group A and B Coxsackieviruses, 2014, clusters of disease caused by EV-D68,
­Echoviruses, Numbered Enteroviruses) prominently associated with exacerbation of
asthma, were noted in Kansas City, MO, and
Clinical Manifestations Chicago, IL, with subsequent spread through-
Nonpolio enteroviruses (EVs) are responsible out the country. By the end of October 2014,
for significant and frequent illnesses in infants EV-D68 had been detected in 48 states, with
and children and result in protean clinical more than 1,100 patients. Almost all confirmed
manifestations. The most common manifes­ cases were among children, many of whom had
tation is nonspecific febrile illness, which, asthma or a history of wheezing. Nine children
in young infants, may lead to evaluation for died, although the contribution of EV-D68 to
bacterial sepsis. Other manifestations can the fatal outcome is unknown. Additionally, a
include (1) respiratory: coryza, pharyngitis, poliolike, acute neurologic syndrome was
herpangina, stomatitis, bronchiolitis, pneu­ reported in a few children with a history of
monia, and pleurodynia; (2) skin: hand-foot- recent respiratory illnesses, some of which
and-mouth disease, onychomadesis (periodic were caused by EV-D68. Illness consisted of
shedding of nails), and nonspecific exanthems; spinal fluid pleocytosis and acute onset of limb
(3) neurologic: aseptic meningitis, encephalitis, weakness and changes on magnetic resonance
and motor paralysis (acute flaccid paralysis); imaging of the spinal cord demonstrating non-
(4) gastrointestinal/genitourinary: vomiting, enhancing lesions restricted to the gray matter.
diarrhea, abdominal pain, hepatitis, pancreati- As of December 2014, 94 children with acute
tis, and orchitis; (5) eye: acute hemorrhagic flaccid myelitis have been reported in 33 states.
conjunctivitis and uveitis; (6) heart: myoperi-
Patients with humoral and combined immune
carditis; and (7) muscle: pleurodynia and other
deficiencies can develop persistent central ner-
skeletal myositis. Neonates, especially those
vous system infections, a dermatomyositis-like
who acquire infection in the absence of sero-
syndrome, or disseminated infection. Severe
type-specific maternal antibody, are at risk
neurologic or multisystem disease is reported
of severe disease, including viral sepsis, menin-
in hematopoietic stem cell and solid organ
goencephalitis, myocarditis, ­hepatitis, coagu-
transplant recipients, children with malig­
lopathy, and pneumonitis. Infection with EV 71
nancies, and patients treated with anti-CD20
is associated with hand-foot-and-mouth dis-
monoclonal antibody.
ease, herpangina, and, in a small proportion
of cases, severe neurologic disease, including Etiology
brainstem encephalomyelitis, paralytic dis-
The EVs comprise a genus in the Picornaviri-
ease, and other neurologic manifestations;
dae family of RNA viruses. The nonpolio EVs
­secondary pulmonary edema/hemorrhage
include more than 100 distinct serotypes for-
and cardiopulmonary collapse can occur,
merly subclassified as group A coxsackievi-
­occasionally resulting in fatalities and sequelae.
ruses, group B coxsackieviruses, echoviruses,
Other ­noteworthy but not exclusive serotype
and newer numbered EVs. A more recent
asso­ciations include coxsackieviruses A6 and
­classification system groups these nonpolio
A16 with hand-foot-and-mouth disease, cox-
EVs into 4 species (EV-A, -B, -C, and -D) on
sackievirus A6 with atypical rashes, coxsackie­
the basis of genetic similarity; polioviruses are
virus A24 variant and EV 70 with acute
members of EV-C. Echoviruses 22 and 23 have
hemorrhagic conjunctivitis, and coxsackievi-
been reclassified as human parechoviruses 1
ruses B1 through B5 with pleurodynia and
and 2, respectively.
­myopericarditis.

ERRNVPHGLFRVRUJ
Enterovirus (­Nonpoliovirus) 161

Epidemiology is present. Patients with EV 71 neurologic dis-


Humans are the only known reservoir for ease often have negative results of PCR assay
human EVs, although some primates can and culture of CSF (even in the presence of
become infected. Enterovirus infections are CSF pleocytosis) and blood; PCR assay and
common and distributed worldwide. They are culture of throat or rectal swab or vesicle fluid
spread by fecal-oral and respiratory routes specimens are more frequently positive. Poly-
and from mother to newborn prenatally, in the merase chain reaction assays for detection of
peripartum period, and, possibly, via breast- EV RNA are available at many reference and
feeding. Enteroviruses can survive on environ- commercial laboratories for CSF, blood, and
mental surfaces for periods long enough to other specimens. Polymerase chain reaction
allow transmission from fomites. Hospital assay is more rapid and more sensitive than
nursery and other institutional outbreaks can isolation of EVs in cell culture and can detect
occur. Infection incidence, clinical attack rates, all EVs, including serotypes that are difficult to
and disease severity are typically greatest in cultivate in viral culture. Sensitivity of culture
young children, and infections occur more ranges from 0% to 80% depending on serotype
frequently in tropical areas and where poor and cell lines used. Many group A coxsackievi-
sanitation, poor hygiene, and overcrowding ruses grow poorly or not at all in vitro. Culture
are present. Most EV infections in temperate usually requires 3 to 8 days to detect growth.
climates occur in the summer and fall (June Acute infection with a known EV serotype
through October in the northern hemisphere), can be determined at reference laboratories by
but seasonal patterns are less evident in the demonstration of a change in neutralizing or
tropics. Epidemics of EV meningitis, EV 71– other serotype-specific antibody titer between
associated hand-foot-and-mouth disease with acute and convalescent serum specimens or
neurologic and cardiopulmonary complica- detection of serotype-specific immunoglobu-
tions (particularly in southeastern Asia), and lin M, but serologic assays are relatively insen-
EV 70– and coxsackievirus A24–associated sitive and lack specificity.
acute hemorrhagic conjunctivitis (especially in Treatment
tropical regions) occur. Fecal viral shedding
No specific antiviral therapy is available for
can persist for several weeks or months after
EV infections. Intravenous immunoglobulin
onset of infection, but respiratory tract shed-
may be beneficial for chronic EV meningoen-
ding is usually limited to 1 to 3 weeks or less.
cephalitis in patients who are immunodefi-
Infection and viral shedding can occur without
cient. Intravenous immunoglobulin has also
signs of clinical illness.
been used for life-threatening neonatal EV
Incubation Period infections, severe EV infections in transplant
3 to 6 days for all except acute hemorrhagic recipients and people with malignancies, sus-
conjunctivitis, which is 24 to 72 hours. pected viral myocarditis, and EV 71 neurologic
disease, but proof of efficacy is lacking. Inter-
Diagnostic Tests ferons occasionally have been used for treat-
Enteroviruses can be detected by reverse ment of EV-associated myocarditis, without
­transcriptase-polymerase chain reaction (PCR) definitive proof of efficacy. The antiviral drug,
assay and culture from a variety of specimens, pleconaril, has activity against EVs (but likely
including stool, rectal, throat and conjunctival not parechoviruses) but is not available com-
swabs, nasopharyngeal aspirates, tracheal aspi- mercially. Other agents with activity against
rates, blood, urine, tissue biopsy specimens, EVs are in development (eg, pocapavir).
and cerebrospinal fluid (CSF) when meningitis

ERRNVPHGLFRVRUJ
162 Enterovirus (­Nonpoliovirus)

Image 44.1
Vesicular eruptions in hand (A), foot (B), and
mouth (C) of a 6-year-old boy with coxsackievirus
A6 infection. Several of his fingernails shed (D) 2 Image 44.2
months after the pictures were taken. Courtesy of Enterovirus infection in a preschool-aged girl.
Centers for Disease Control and Prevention/ Hand-foot-and-mouth disease lesions are caused
Emerging Infectious Diseases. by coxsackievirus A16 and enterovirus 71.

Image 44.4
Enterovirus infection (hand-foot-and-mouth
disease) affecting the feet.

Image 44.3
Enterovirus infection (hand-foot-and-mouth
disease) affecting the hands.

Image 44.5
Enterovirus infection (hand-foot-and-mouth
disease) with typical papulovesicular lesions over
the Achilles tendon area.

ERRNVPHGLFRVRUJ
Enterovirus (­Nonpoliovirus) 163

Image 44.7
Enterovirus infection (hand-foot-and-mouth
disease). This rash, commonly seen over the
buttocks, often appears macular, maculopapular,
or papulovesicular and may be petechial.
Image 44.6
Enterovirus infection (hand-foot-and-mouth
disease) affecting the anterior buccal mucosa.
These lesions are generally less painful than
herpes simplex lesions.

Image 44.8
Enterovirus infection (hand-foot-and-mouth
disease). The rash may also be seen on the trunk.

Image 44.9
Characteristic papulovesicular lesions on the
palm of a 2-year-old boy with hand-foot-and-
mouth disease, a coxsackievirus A infection,
most often A16, or enterovirus 71. Courtesy of
George Nankervis, MD.

Image 44.10
Characteristic papulovesicular lesions of hand-
foot-and-mouth disease in a 2-year-old boy.
Courtesy of George Nankervis, MD.

ERRNVPHGLFRVRUJ
164 Enterovirus (­Nonpoliovirus)

Image 44.12
Herpangina (coxsackievirus) lesions on the
posterior palate of a young adult male.
Image 44.11
Coxsackievirus lesions are usually found in the
Newborn with generalized enteroviral exanthem.
posterior aspect of the oropharynx and may
Copyright Michael Rajnik, MD, FAAP.
progress rapidly to painful ulceration.

Image 44.14
Image 44.13
Skin lesions on the neck and chest of a young
Skin lesions on the side of a young girl’s face due
girl due to echovirus 9. Echoviruses comprise
to echovirus 9. Courtesy of Centers for Disease
1 of 5 serotypes, which make up the genus
Control and Prevention.
Enterovirus, and are associated with illnesses,
including aseptic meningitis, nonspecific rashes,
encephalitides, and myositis. Courtesy of Centers
for Disease Control and Prevention.

Image 44.15
A 4-year-old white girl with pharyngeal inflamma­
tion and palatal lesions of hand-foot-and-mouth Image 44.16
disease, a coxsackievirus A infection. Copyright This 7-year-old white girl presented with low-
Larry Frenkel, MD. grade fever, malaise, sore throat, and these
interesting, slightly raised oral lesions opposite
the first molar. She also had approximately 10
maculopapular lesions on each buttock and a
few on each foot. She had classic hand-foot-and-
mouth disease. Coxsackievirus A16 was grown
from throat and rectal swabs. Courtesy of Neal
Halsey, MD.

ERRNVPHGLFRVRUJ
Epstein-Barr Virus ­Infections 165

45 early in life among boys, nodular B lymphocyte


lymphomas (often with central nervous
Epstein-Barr Virus ­system involvement), and profound hypo­
­Infections gammaglobulinemia.
(Infectious Mononucleosis)
Epstein-Barr virus–associated lymphoprolif-
Clinical Manifestations erative disorders result in a number of complex
syndromes in patients who are immunocom-
Infectious mononucleosis is the most common
promised, such as transplant recipients or
presentation of Epstein-Barr virus (EBV)
­people infected with HIV. The highest inci-
­infection. It typically manifests as fever, phar-
dence of these disorders occurs in liver and
yngitis with petechiae, exudative pharyngitis,
heart transplant recipients, in whom the
lymphadenopathy, hepatosplenomegaly, and
­proliferative states range from benign lymph
atypical lymphocytosis. The spectrum of
node hypertrophy to monoclonal lymphomas.
­diseases is wide, ranging from asymptomatic
Other EBV syndromes are of greater impor-
to fatal infection. Infections are commonly
tance outside the United States. Epstein-Barr
unrecognized in infants and young children.
virus is present in virtually 100% of people
Rash can occur and is more common in
with endemic Burkitt lymphoma, found pri-
patients treated with ampicillin or amoxicillin,
marily in Central Africa, in contrast to 20%
as well as with other penicillins. Central ner-
of people with sporadic Burkitt lymphoma
vous system manifestations include aseptic
(found in abdominal lymphoid tissue pre­
meningitis, encephalitis, myelitis, optic
dominantly in North America and Europe).
­neuritis, cranial nerve palsies, transverse
Epstein-Barr virus is found in nasopharyngeal
myelitis, “Alice in ­Wonderland” syndrome,
carcinoma in Southeast Asia and the Inuit
and Guillain-Barré syndrome. Hematologic
­populations. Epstein-Barr virus has also been
complications include splenic rupture, throm-
associated with Hodgkin disease (B lympho-
bocytopenia, agranulocytosis, hemolytic
cyte tumor), non-Hodgkin lymphomas (B
­anemia, and hemophagocytic lymphohistio­
and T lymphocyte), gastric carcinoma “lym-
cytosis (also called hemophagocytic syn-
phoepitheliomas,” and a variety of common
drome). Pneumonia, orchitis, and myocarditis
epithelial ­malignancies.
are infrequently observed. Early in the course
of primary infection, up to 20% of circulating Chronic fatigue syndrome is not related to EBV
B lymphocytes are infected with EBV. Repli­ infection; however, fatigue lasting weeks to a
cation of EBV in B lymphocytes results in few months may follow up to 10% of cases of
T ­lymphocyte proliferation and inhibition of classic infectious mononucleosis.
B lymphocyte proliferation by T lymphocyte
Etiology
cytotoxic responses. Fatal disseminated
­infection or B or T lymphocyte lymphomas Epstein-Barr virus (also known as human
can occur in children with no detectable ­herpesvirus 4) is a gammaherpesvirus of the
immunologic abnormality, as well as in chil- Lymphocryptovirus genus and is the most
dren with congenital or acquired cellular ­common cause of infectious mononucleosis
immune deficiencies. (>90% of cases).
Epstein-Barr virus is associated with several Epidemiology
other distinct disorders, including X-linked Humans are the only known reservoir of EBV,
lymphoproliferative syndrome, posttrans­ and approximately 90% of US adults have been
plantation lymphoproliferative disorders, infected. Close personal contact is usually
Burkitt lymphoma, nasopharyngeal carci- required for transmission. The virus is viable in
noma, and undifferentiated B or T lymphocyte saliva for several hours outside the body, but
lymphomas. The syndrome is characterized the role of fomites in transmission is unknown.
by several phenotypic expressions, including Epstein-Barr virus can also be transmitted by
occurrence of fatal infectious mononucleosis blood transfusion or transplantation. Infection

ERRNVPHGLFRVRUJ
166 Epstein-Barr Virus ­Infections

is commonly contracted early in life, particu- serologic tests are based on quantitative immu-
larly among members of lower socioeconomic nofluorescent antibody assays performed dur-
groups, in which intrafamilial spread is com- ing various stages of mononucleosis and its
mon. Endemic infectious mononucleosis is resolution, although detection of antibodies
common in group settings of adolescents, such by enzyme immunoassays is usually performed
as in educational institutions. No seasonal pat- by clinical laboratories. Serologic testing for
tern has been documented. Intermittent excre- EBV is useful, particularly for evaluating
tion in saliva may occur throughout life after patients who have heterophile-negative infec-
acute infection. tious mononucleosis and for cases in which
the infectious mononucleosis syndrome is not
Incubation Period
completely present.
30 to 50 days.
Isolation of EBV from oropharyngeal secre-
Diagnostic Tests tions by culture in cord blood cells is possible,
Routine diagnosis depends on serologic testing. but techniques for performing this procedure
Nonspecific tests for heterophile antibody, usually are not available in routine diagnostic
including the Paul-Bunnell test and slide laboratories, and viral isolation does not neces-
agglutination reaction test, are available most sarily indicate acute infection. Polymerase
commonly. The heterophile antibody response chain reaction (PCR) assay for detection of
is primarily immunoglobulin (Ig) M, which EBV DNA in serum, plasma, and tissue and
appears during the first 2 weeks of illness and reverse transcriptase-polymerase chain reac-
gradually disappears over a 6-month period. tion assay for detection of EBV RNA in lym-
The results of heterophile antibody tests are phoid cells, tissue, or body fluids are available
often negative in children younger than 4 years, commercially and may be useful in evaluation
but heterophile antibody tests identify approxi- of immunocompromised patients and in com-
mately 85% of cases of classic infectious mono- plex clinical problems.
nucleosis in older children and adults. An Treatment
absolute increase in atypical lymphocytes dur-
ing the second week of illness with infectious Patients suspected to have infectious mono­
mononucleosis is a characteristic but nonspe- nucleosis should not be given ampicillin or
cific finding. However, the finding of greater amoxicillin, which cause nonallergic morbilli-
than 10% atypical lymphocytes together with a form rashes in a high proportion of patients.
positive heterophile antibody test result in the Although therapy with short-course cortico­
classical illness pattern is considered diagnos- steroids may have a beneficial effect on acute
tic of acute infection. symptoms, because of potential adverse effects,
their use should be considered only for patients
Multiple specific serologic antibody tests for with marked tonsillar inflammation with
EBV infection are available. The most com- impending airway obstruction, massive spleno-
monly performed test is for antibody against megaly, myocarditis, hemolytic anemia, or
the viral capsid antigen (VCA). IgG antibodies hemophagocytic lymphohistiocytosis. Decreas-
against VCA occur in high titer early in infec- ing immunosuppressive therapy is beneficial
tion and persist for life. Testing for presence of for patients with EBV-induced posttransplant
IgM anti-VCA antibody and the absence of lymphoproliferative disorders.
antibodies to Epstein-Barr nuclear antigen
(EBNA) identifies active and recent infections. Contact and collision sports should be avoided
Because serum antibody against EBNA is not until the patient is recovered fully from infec-
present until several weeks to months after tious mononucleosis and the spleen is no lon-
onset of infection, a positive anti-EBNA result ger palpable. In the setting of acute infectious
excludes an active primary infection. Testing mononucleosis, participation in strenuous and
for antibodies against early antigen is not contact situations can result in splenic rupture.
­routinely performed. In selected cases, early After 21 days, limited noncontact aerobic activ-
antigen testing is useful. Epstein-Barr virus ity can be allowed if there are no symptoms

ERRNVPHGLFRVRUJ
Epstein-Barr Virus ­Infections 167

and no overt splenomegaly. Clearance to par- the athlete is asymptomatic and has no overt
ticipate in contact or collision sports is appro- splenomegaly. Repeat monospot or EBV sero-
priate after 4 weeks after onset of symptoms if logic testing is not recommended.

Image 45.1
Atypical lymphocyte in a peripheral blood smear
of a patient with infectious mononucleosis. This
Image 45.2
lymphocyte is larger than normal lymphocytes,
Bilateral cervical lymphadenopathy in an 8-year-
with a higher ratio of cytoplasm to nucleus. The
old boy with Epstein-Barr virus disease who
cytoplasm is vacuolated and basophilic. This may
remained relatively asymptomatic. Courtesy of
also be present in cytomegalovirus infections.
Edgar O. Ledbetter, MD, FAAP.

Image 45.3
Cervical lymphadenopathy in a 7-year-old girl with infectious mononucleosis.

Image 45.4
This morbilliform rash arose in a patient with infectious mononucleosis after amoxicillin was prescribed.
This is a nonallergic cutaneous eruption. Courtesy of Centers for Disease Control and Prevention/Dr
Thomas F. Sellers, Emory University.

ERRNVPHGLFRVRUJ
168 Epstein-Barr Virus ­Infections

Image 45.6
A preadolescent child with infectious mono­
nucleosis with petechiae on the soft palate and
uvula without exudation.

Image 45.5
Image 45.7
Epstein-Barr virus encephalitis. Axial fluid atten­
A conjunctival hemorrhage of the right eye of a
uated inversion recovery magnetic resonance
patient with infectious mononucleosis. At times,
image shows basal ganglia hyperintensity (arrows).
noninfectious conjunctivitis, as well as other
corneal abnormalities, may manifest itself due to
the body’s systemic response to viral infections,
such as infectious mononucleosis. Courtesy of
Centers for Disease Control and Prevention/Dr
Thomas F. Sellers, Emory University.

Image 45.8
Schematic representation of the evolution of antibodies to various Epstein-Barr virus antigens in
patients with infectious mononucleosis. Reproduced with permission from American Society for
Microbiology. Epstein-Barr virus. In: Rose NR, de Macario EC, Folds JD, eds. Manual of Clinical
Laboratory Immunology. 5th ed. Washington, DC: American Society for Microbiology; 1997:634–643.

ERRNVPHGLFRVRUJ
ESCHERICHIA COLI AND OTHER GRAM-NEGATIVE BACILLI 169

46 infant formula, and respiratory therapy equip-


ment, especially among very preterm neonates
Escherichia coli and Other who require prolonged neonatal intensive
Gram-Negative Bacilli care management. Predisposing factors in
(Septicemia and Meningitis in Neonates) ­neonatal gram-negative bacterial infections
include maternal intrapartum infection, gesta-
Clinical Manifestations tion less than 37 weeks, low birth weight, and
Neonatal septicemia or meningitis caused by prolonged rupture of membranes. Metabolic
Escherichia coli and other gram-negative bacilli abnormalities (eg, galactosemia), fetal hypoxia,
cannot be differentiated clinically from septi- and acidosis have been implicated as predis-
cemia or meningitis caused by other organ- posing factors. Neonates with defects in the
isms. The early signs of sepsis can be subtle integrity of skin or mucosa (eg, myelomenin-
and similar to signs observed in noninfectious gocele) or abnormalities of gastrointestinal or
processes. Signs of septicemia include fever, genitourinary tracts are at increased risk of
temperature instability, heart rate abnormali- gram-­negative bacterial infections. In neonatal
ties, grunting respirations, apnea, cyanosis, intensive care units, systems for respiratory
lethargy, irritability, anorexia, vomiting, jaun- and metabolic support, invasive or surgical
dice, abdominal distention, cellulitis, and diar- procedures, indwelling vascular access cath-
rhea. Meningitis, especially early in the course, eters, and frequent use of broad-spectrum
can occur without overt signs suggesting cen- ­antimicrobial agents enable selection and
tral nervous system involvement. Some gram-­ ­proliferation of strains of gram-negative
negative bacilli, such as Citrobacter koseri, bacilli that are resistant to multiple anti­
Cronobacter (formerly Enterobacter) sakazakii, microbial agents.
Serratia marcescens, and Salmonella species,
Multiple mechanisms of resistance in gram-
are associated with brain abscesses in neonates
negative bacilli can be present simultaneously.
with meningitis caused by these organisms.
Resistance resulting from production of
Etiology ­chromosomally encoded or plasmid-derived
AmpC β-lactamases or from plasmid-mediated
E coli strains, often those with the K1 capsular
extended-spectrum β-lactamases (ESBLs),
polysaccharide antigen, are the most common
occurring primarily in E coli, Klebsiella spe-
cause of septicemia and meningitis in neo-
cies, and Enterobacter species but reported in
nates. Other important gram-negative bacilli
many other gram-negative species, has been
causing neonatal septicemia include Klebsiella
associated with nursery outbreaks, especially
species, Enterobacter species, Proteus species,
in very low birth weight neonates. Organisms
Citrobacter species, Salmonella species, Pseu­
that produce ESBLs are typically resistant to
domonas species, Acinetobacter species, and
penicillins, cephalosporins, and monobactams
Serratia species. Nonencapsulated strains of
and can be resistant to aminoglycosides.
Haemophilus influenzae and anaerobic gram-
­Carbapenems-resistant strains have emerged
negative bacilli are rare causes.
among Enterobacteriaceae, especially Klebsiella
Epidemiology pneumoniae, Pseudomonas aeruginosa, and
The source of E coli and other gram-negative Acinetobacter species. Extended-spectrum
bacterial pathogens in neonatal infections β-lactamase– and carbapenemase-producing
­during the first few days of life typically is the bacteria often carry additional genes confer-
maternal genital tract. Reservoirs for gram- ring resistance to aminoglycosides and sulfon-
negative bacilli can also be present within the amides, as well as fluoroquinolones.
health care environment. Acquisition of gram- Incubation Period
negative organisms can occur through person-
Variable, ranging from birth to several
to-person transmission from hospital nursery
weeks after birth or longer in very low birth
personnel and from nursery environmental
weight, preterm neonates with prolonged
sites, such as sinks, countertops, powdered
­hospitalizations.

ERRNVPHGLFRVRUJ
170 ESCHERICHIA COLI AND OTHER GRAM-NEGATIVE BACILLI

Diagnostic Tests with ampicillin or cefotaxime; meningitis


Diagnosis is established by growth of E coli or caused by an ampicillin-resistant isolate is
other gram-negative bacilli from blood, cere- treated with cefotaxime with or without an
brospinal fluid (CSF), or other, usually sterile aminoglycoside. Combination therapy with
sites. Special screening and confirmatory labo- cefotaxime and an aminoglycoside antimicro-
ratory procedures are required to detect some bial agent is used for empirical therapy and
multidrug-resistant gram-negative organisms. until CSF is sterile. Some experts continue
Molecular diagnostics are increasingly being combination therapy for a longer duration.
used for identification of pathogens; specimens Expert advice from an infectious disease
should be saved for resistance testing. ­specialist can be helpful for management
of ­meningitis.
Treatment
The drug of choice for treatment of infections
Initial empiric treatment for suspected early- caused by ESBL-producing organisms is
onset gram-negative septicemia in neonates meropenem, which is active against gram-­
is ampicillin and an aminoglycoside. An alter- negative aerobic organisms with chromo­
native regimen of ampicillin and an extended- somally mediated AmpC β-lactamases or
spectrum cephalosporin (eg, cefotaxime) can ESBL-producing strains, except carbapenemase-
be used, but rapid emergence of cephalosporin- producing strains, especially some K pneu­
resistant organisms, especially Enterobacter moniae isolates. Of the aminoglycosides,
species, Klebsiella species, and Serratia species, ­a mikacin retains the most activity against
and increased risk of colonization or infection ESBL-producing strains. An amino­glycoside
with ESBL-producing Enterobacteriaceae can or cefepime can be used if the organism is
occur when use is routine in a neonatal unit. ­susceptible. Expert advice from an infectious
Hence, routine use of an extended-spectrum disease specialist can help in management of
cephalosporin is not recommended unless ESBL-producing gram-negative infections in
gram-negative bacterial meningitis is sus- neonates. The treatment of infections caused
pected. The proportion of E coli bloodstream by carbapenemase-producing gram-negative
infections with onset within 72 hours of life organisms is guided by expert advice from an
that are resistant to ampicillin is high among infectious disease specialist.
very low birth weight neonates. These E coli
infections are almost invariably susceptible to All neonates with gram-negative meningitis
gentamicin, although monotherapy with an should undergo repeat lumbar puncture to
aminoglycoside is not recommended. ensure sterility of the CSF after 24 to 48 hours
of therapy. If CSF remains culture positive,
Once the causative agent and in vitro anti­ choice and doses of antimicrobial agents
microbial susceptibility pattern are known, should be evaluated, and another lumbar
nonmeningeal infections should be treated ­puncture should be performed after another
with ampicillin, an appropriate aminoglyco- 48 to 72 hours. Duration of therapy is based
side, or an extended-spectrum cephalosporin on clinical and bacteriologic response of the
(eg, cefotaxime). Many experts would treat patient and the site(s) of infection; the usual
nonmeningeal infections caused by Entero­ duration of therapy for uncomplicated bac­
bacter species, Serratia species, or Pseudo­ teremia is 10 to 14 days, and for meningitis,
monas species and some other, less commonly minimum duration is 21 days. All neonates
occurring gram-negative bacilli with a with gram-negative meningitis should undergo
β-lactam antimicrobial agent and an amino- careful follow-up examinations, including
glycoside. For ampicillin-susceptible CSF ­testing for hearing loss, neurologic abnormali-
­isolates of E coli, meningitis can be treated ties, and developmental delay.

ERRNVPHGLFRVRUJ
ESCHERICHIA COLI AND OTHER GRAM-NEGATIVE BACILLI 171

Image 46.2
Icteric premature neonate with septicemia and
perineal and abdominal wall cellulitis due to
Escherichia coli.

Image 46.1
Computed tomography scan of the head of a
neonate 3 weeks after therapy for Escherichia coli
meningitis demonstrating widespread destruction
of cerebral cortex secondary to vascular thrombosis.
Neonate was blind, deaf, and globally intellec­tually
disabled and had diabetes insipidus. Courtesy of Image 46.4
Carol J. Baker, MD, FAAP. Sepsis and pneumonia with empyema due to
Escherichia coli. This newborn died at 12 hours
of age.

Image 46.3
Infant with Escherichia coli septicemia and
perineal cellulitis, scrotal necrosis, and abdominal
wall abscesses below the navel that required
surgical drainage and antibiotics.
Image 46.5
Pneumonia due to Klebsiella pneumoniae with
prebronchoscopy lung abscess. Courtesy of
Edgar O. Ledbetter, MD, FAAP.

ERRNVPHGLFRVRUJ
172 ESCHERICHIA COLI AND OTHER GRAM-NEGATIVE BACILLI

Image 46.6
Pneumonia due to Klebsiella pneumoniae with Image 46.7

lung abscess. Cavitation with air-fluid level shown Klebsiella pneumoniae pneumonia in a 4-month-
postbronchoscopy drainage. Repeat broncho­ old with spontaneous tension pneumothorax.
scopy was required for further drainage. Courtesy of Edgar O. Ledbetter, MD, FAAP.
Courtesy of Edgar O. Ledbetter, MD, FAAP.

Image 46.8
Image 46.9
A 5-week-old girl with Klebsiella pneumoniae
Bullous, necrotic, umbilicated lesions in infant with
sepsis and meningitis with bilateral saphenous
septicemia due to Pseudomonas aeruginosa.
vein thrombophlebitis (illness began with
diarrhea). Copyright Martin G. Myers, MD.

Image 46.10
Skin lesions due to Pseudomonas aeruginosa in child with neutropenia and septicemia.

ERRNVPHGLFRVRUJ
ESCHERICHIA COLI AND OTHER GRAM-NEGATIVE BACILLI 173

Image 46.11
Sepsis due to Pseudomonas aeruginosa with early ecthyma gangrenosum.

Image 46.13
Image 46.12 Gram stain of Escherichia coli in the cerebro­
Sepsis due to Pseudomonas aeruginosa with spinal fluid of a neonate with meningitis.
rapidly progressing ecthyma gangrenosum.

Image 46.14
Escherichia coli on sheep blood agar. Courtesy of Julia Rosebush, DO; Robert Jerris, PhD; and
Theresa Stanley, M(ASCP).

ERRNVPHGLFRVRUJ
174 ESCHERICHIA COLI DIARRHEA

47 • Diarrhea caused by enteropathogenic E coli


(EPEC) is watery. Although usually mild,
Escherichia coli Diarrhea diarrhea can result in dehydration and
(Including Hemolytic Uremic Syndrome) even death. Illness occurs almost exclusively
Clinical Manifestations in children younger than 2 years and pre-
dominantly in resource-limited countries,
At least 5 pathotypes of diarrhea-producing sporadically or in epidemics. In resource-
Escherichia coli strains have been identified. limited countries, EPEC may be associated
Clinical features of disease caused by each with high case fatality. Chronic EPEC
pathotype are summarized in Table 47.1. ­diarrhea can be persistent and result in
• Shiga toxin-producing E coli (STEC) ­wasting or growth retardation. Entero­
­organisms are associated with diarrhea, pathogenic E coli infection is uncommon
hemorrhagic colitis, and hemolytic uremic in breastfed infants.
syndrome (HUS). Shiga toxin-producing • Diarrhea caused by enterotoxigenic E coli
E coli O157:H7 is the serotype most often (ETEC) is a 1- to 5-day, self-limited illness
implicated in outbreaks and is consistently of moderate severity, typically with watery
a virulent STEC serotype, but other sero- stools and abdominal cramps. Enterotoxi-
types can also cause illness. Shiga toxin-­ genic E coli is common in infants in resource-
producing E coli illness typically begins limited countries and in travelers to those
with nonbloody diarrhea. Stools usually countries. Enterotoxigenic E coli infection
become bloody after 2 or 3 days, representing is rarely diagnosed in the United States.
the onset of hemorrhagic colitis. Severe However, outbreaks and studies with small
abdominal pain is typically short lived, and numbers of patients have demonstrated that
low-grade fever is present in approximately ETEC infection is occasionally acquired in
one-third of cases. In people with presump- the United States.
tive diagnoses of intussusception, appendici-
tis, inflammatory bowel disease, or ischemic • Diarrhea caused by enteroinvasive E coli
colitis, disease caused by E coli O157:H7 and is clinically similar to diarrhea caused by
other STEC should be considered. Shigella species. Although dysentery can

Table 47.1
Classification of Escherichia coli Associated With Diarrhea
Mechanism of
Pathotype Epidemiology Type of Diarrhea Pathogenesis
Shiga toxin-producing Hemorrhagic colitis Bloody or non- Shiga toxin production,
E coli (STEC) and hemolytic uremic bloody large bowel attachment,
syndrome in all ages coagulopathy
Enteropathogenic Acute and chronic Watery Small bowel adherence
E coli (EPEC) endemic and epidemic and effacement
diarrhea in infants
Enterotoxigenic E coli Infant diarrhea in Watery Small bowel adherence,
(ETEC) resource-limited coun- heat-stable/heat-labile
tries and traveler’s diar- enterotoxin production
rhea in all ages
Enteroinvasive E coli Diarrhea with fever in Bloody or non- Adherence, mucosal
(EIEC) all ages bloody; dysentery invasion and inflamma-
tion of large bowel
Enteroaggregative Acute and chronic diar- Watery, occasion- Small and large bowel
E coli (EAEC) rhea in all ages ally bloody adherence, enterotoxin
and cytotoxin production

ERRNVPHGLFRVRUJ
ESCHERICHIA COLI DIARRHEA 175

occur, diarrhea is usually watery without infected symptomatic people. Shiga toxin-­
blood or mucus. Patients are often febrile, producing E coli is shed in feces of cattle and,
and stools can contain leukocytes. to a lesser extent, sheep, deer, and other rumi-
nants. Human infection is acquired via con-
• Enteroaggregative E coli (EAEC) organisms
taminated food or water or via direct contact
cause watery diarrhea and are common in
with an infected person, a fomite, or a carrier
people of all ages in industrialized as well
animal or its environment. Many food vehicles
as resource-limited countries. Enteroaggre-
have caused E coli O157 outbreaks, including
gative E coli has been associated with pro-
undercooked ground beef (a major source), raw
longed diarrhea (≥14 days). Asymptomatic
leafy greens, and unpasteurized milk and juice.
infection can be accompanied by subclinical
Outbreak investigations have also implicated
inflammatory enteritis, which can cause
petting zoos, drinking water, and ingestion of
growth disturbance.
recreational water. The infectious dose is low;
• Sequelae of STEC infection: Hemolytic thus, person-to-person transmission is com-
­uremic syndrome is a serious sequela of mon in households and has occurred in child
STEC enteric infection. E coli O157:H7 is the care centers. Less is known about the epidemi-
STEC serotype most commonly associated ology of STEC strains other than O157:H7.
with HUS, which is defined by the triad of Among children younger than 5 years, the
microangiopathic hemolytic anemia, throm- ­incidence of HUS is highest in 1-year-olds and
bocytopenia, and acute renal dysfunction. lowest in infants. A severe outbreak of bloody
Children younger than 5 years are at highest diarrhea and HUS occurred in Europe in 2011;
risk of HUS, which occurs in approximately the outbreak was attributed to an EAEC strain
15% of children infected with STEC. Hemo- of serotype O104:H4 that had acquired the
lytic uremic syndrome typically develops Shiga toxin 2a-encoding phage. This experi-
7 days (up to 2 weeks; rarely, 2–3 weeks) after ence highlights the importance of considering
onset of diarrhea. More than 50% of children serotypes other than O157:H7 in outbreaks
with HUS require dialysis, and 3% to 5% die. and cases of HUS.
Patients with HUS can develop neurologic
With the exception of EAEC, non-STEC
complications (eg, seizures, coma, cerebral
pathotypes are most commonly associated
vessel thrombosis). Children presenting
with disease in resource-limited countries,
with an elevated white blood cell count (>20
where food and water supplies commonly are
x ­109/mL) or oliguria or anuria are at higher
contaminated and facilities and supplies for
risk of poor outcome, as are, seemingly para-
hand hygiene are suboptimal. For young chil-
doxically, children with hematocrit close to
dren in resource-limited countries, transmis-
normal rather than low. Most who survive
sion of ETEC, EPEC, and other diarrheal
have a very good prognosis, which can be
pathogens via contaminated weaning foods
predicted by normal creatinine clearance
(sometimes by use of untreated drinking water
and no proteinuria or hypertension 1 or
in the foods) is also common. Enterotoxigenic
more years after HUS.
E coli diarrhea occurs in people of all ages but
Etiology is especially frequent and severe in infants in
resource-limited countries. Enterotoxigenic
Five pathotypes of diarrhea-producing E coli
E coli is a major cause of traveler’s diarrhea.
have been distinguished by pathogenic and
Enteroaggregative E coli is increasingly recog-
clinical characteristics. Each pathotype com-
nized as a cause of diarrhea in the United
prises characteristic serotypes, indicated by
States.
somatic (O) and flagellar (H) antigens.
Incubation Period
Epidemiology
For most E coli strains, 10 hours to 6 days; for
Transmission of most diarrhea-associated
E coli O157:H7, 3 to 4 days (range, 1–8 days).
E coli strains is from food or water contami-
nated with human or animal feces or from

ERRNVPHGLFRVRUJ
176 ESCHERICHIA COLI DIARRHEA

Diagnostic Tests E coli O157 and O111 lipopolysaccharides is


Diagnosis of infection caused by diarrhea-­ available at the Centers for Disease Control
associated E coli other than STEC is difficult and Prevention for outbreak investigations
because tests are not widely available to and for patients with HUS.
­dis­tinguish these pathotypes from normal Treatment
E coli strains present in stool flora. Culture-­
Orally administered electrolyte-containing
independent tests are necessary to detect non-
solutions are usually adequate to prevent or
O157:H7 STEC infections. Newly licensed
treat dehydration and electrolyte abnormali-
multiplex polymerase chain reaction assays can
ties. Antimotility agents should not be admin-
detect a variety of enteric infections, including
istered to children with inflammatory or
ETEC and STEC. Several commercially avail-
bloody diarrhea. Patients with proven or
able, sensitive, specific, and rapid assays for
­suspected STEC infection should be fully but
Shiga toxins in stool or broth culture of stool,
­prudently rehydrated as soon as clinically
including enzyme immunoassays and immu-
­feasible. Careful monitoring of patients with
nochromatographic assays, have been approved
hemorrhagic colitis (including complete blood
by the US Food and Drug Administration. All
cell count with smear, blood urea nitrogen,
stool specimens submitted for routine testing
and creatinine concentrations) is recom-
from patients with acute community-acquired
mended to detect changes suggestive of HUS.
diarrhea should be cultured simultaneously
If patients have no laboratory evidence of
for E coli O157:H7 and tested with an assay that
hemolysis, thrombocytopenia, or nephropathy
detects Shiga toxins. Most E coli O157:H7 iso-
3 days after resolution of diarrhea, their risk of
lates can be identified presumptively when
developing HUS is low. In resource-limited
grown on sorbitol-containing selective media.
countries, nutritional rehabilitation should
Shiga toxin-producing E coli should also be be provided as part of case management algo-
sought in stool specimens from all patients rithms for diarrhea where feasible. Feeding,
diagnosed with postdiarrheal HUS. However, including breastfeeding, should be continued
the absence of STEC does not preclude the for young children with E coli enteric infection.
diagnosis of probable STEC-associated HUS
• Antimicrobial therapy: Most experts advise
because HUS is typically diagnosed a week or
not prescribing antimicrobial therapy for
more after onset of diarrhea, when the organ-
children with E coli O157:H7 enteritis or a
ism may not be detectable by conventional
clinical or epidemiologic picture strongly
methods. Selective enrichment followed by
suggestive of STEC infection. Empirical
immunomagnetic separation can markedly
self-treatment of diarrhea for travelers to
increase the sensitivity of STEC detection, so
a resource-limited country is effective,
this testing is especially useful for patients
and azithromycin or a fluoroquinolone
who were not tested early in their diarrheal
has been the most reliable agent for therapy;
illness. The test is available at some state public
the choice of therapy depends on the patho-
health laboratories and at the Centers for
gen and local antibiotic resistance patterns.
­Disease Control and Prevention. DNA probes
Rifaximin may be used for people 12 years
are also available in reference and research
and older.
laboratories. Serologic diagnosis using enzyme
immunoassay to detect serum antibodies to

ERRNVPHGLFRVRUJ
ESCHERICHIA COLI DIARRHEA 177

Image 47.1
Escherichia coli in the intestine of an 8-month-old
suffering from chronic diarrhea (fluorescent
antibody stain). In a small number of individuals
(mostly children <5 years and the elderly), E coli
can cause hemolytic uremic syndrome, in which
the red blood cells are destroyed and the kidneys
fail. Courtesy of Centers for Disease Control and
Prevention.

Image 47.2
Transmission electron micrograph of Escherichia
coli O157:H7. Courtesy of Centers for Disease
Control and Prevention/Peggy S. Hayes.

Image 47.3
Enterohemorrhagic Escherichia coli O157:H7. Number of reported cases in the United States and
US territories, 2003. Courtesy of Morbidity and Mortality Weekly Report.

ERRNVPHGLFRVRUJ
178 ESCHERICHIA COLI DIARRHEA

Image 47.4
Shiga toxin-producing Escherichia coli. Number of reported cases—United States and US territories,
2012. Courtesy of Morbidity and Mortality Weekly Report.

Image 47.5
Hemolytic uremic syndrome, postdiarrheal. Number of reported cases—United States and US
territories, 2012. Courtesy of Morbidity and Mortality Weekly Report.

ERRNVPHGLFRVRUJ
Fungal Diseases 179

48 neous barriers. A list of these fungi and the


pertinent underlying host conditions, reser-
Fungal Diseases voirs or routes of entry, clinical manifestations,
In addition to the mycoses discussed in indi- diagnostic laboratory tests, and treatments can
vidual chapters (ie, aspergillosis, blastomycosis, be found in Table 48.1. Taken as a group, few
candidiasis, coccidioidomycosis, cryptococco- in vitro antifungal susceptibility data are avail-
sis, histoplasmosis, paracoccidioidomycosis, able on which to base treatment recommen­
sporotrichosis), uncommonly encountered dations for these uncommon invasive fungal
fungi can cause infection in infants and infections, especially in children. Consultation
­children with immunosuppression or other with a pediatric infectious disease specialist
underlying conditions. Children can acquire experienced in the diagnosis and treatment
infection with these fungi through inhalation of invasive fungal infections should be consid-
via the respiratory tract or through direct ered when caring for a child infected with one
­inoculation after traumatic disruption of cuta- of these mycoses.

Table 48.1
Additional Fungal Diseases
Under­ Reservoir(s) Common Diagnostic
Disease lying Host or Route(s) Clinical Laboratory
and Agent Condition(s) of Entry ­Manifestations Test(s) Treatment
Hyalohyphomycosis
Fusarium Granulocytope- Respiratory Pulmonary infil- Culture of blood Voriconazole or
­species nia; hematopoi- tract; sinuses; trates; cutaneous or tissue L-AMBa
etic stem cell skin lesions, sinusitis; ­specimen
transplantation; disseminated
severe immu- infection
nocompromise
Malassezia Immunosup- Skin Central line–­ Culture of blood, Removal of
species pression; pre- associated blood- catheter tip, or catheters and
term birth; stream infection; tissue specimen temporary ces-
exposure to interstitial pneu- (requires special sation of lipid
parenteral monitis; urinary laboratory han- infusion; L-AMBa
nutrition that tract infection; dling)
includes fat meningitis
­emulsions
Penicilliosis
Penicillium HIV infection Respiratory Pneumonitis; inva- Culture of blood, Itraconazoleb or
marneffei and exposure tract sive dermatitis; bone marrow, or L-AMB
to southeast disseminated tissue; histo-
Asia infection pathologic
examination of
tissue
Phaeohyphomycosis
Alternaria None or trauma Respiratory Sinusitis; cutane- Culture and Voriconazole or
­species or immunosup- tract; skin ous lesions histopathologic high-dose
pression examination of L-AMBa
tissue
Bipolaris None, trauma, Environment Sinusitis; dissemi- Culture and Voriconazole,
­species immunosup- nated infection histopathologic itraconazole,b or
pression, or examination of L-AMBa; surgi-
chronic tissue cal excision
­sinusitis

ERRNVPHGLFRVRUJ
180 FUNGAL DISEASES

Table 48.1
Additional Fungal Diseases (continued)
Under— Reservoir(s) Common Diagnostic
Disease lying Host or Route(s) Clinical Laboratory
and Agent Condition(s) of Entry ­Manifestations Test(s) Treatment
Phaeohyphomycosis (continued)
Curvularia Immunosup- Environment Allergic fungal Culture and Allergic fungal
­species pression; sinusitis; invasive histopathologic sinusitis: sur-
altered skin dermatitis; dis- examination of gery and corti-
integrity; seminated tissue costeroids
asthma or nasal ­infection
polyps; chronic Invasive
sinusitis ­disease:
­voriconazole,
itraconazole,b or
L-AMBa
Exophiala spe- None or trauma Environment Sinusitis; cutane- Culture and Voriconazole,c
cies, Exserohi- or immunosup- ous lesions; histopathologic itraconazole,b
lum species pression ­disseminated examination of L-AMB, or surgi-
infection; meningi- tissue cal excision
tis associated with
contaminated
steroid for epidural
use
Pseudallesche- None or trauma Environment Pneumonia; dis- Culture and Voriconazoled or
ria boydii or immunosup- seminated infec- histopathologic itraconazole
(­Scedosporium pression tion; osteomyelitis examination of
apiospermum) or septic arthritis; tissue
endocarditis
Scedosporium
species
Trichosporonosis
Trichosporon Immunosup- Normal flora of Bloodstream infec- Blood culture; Voriconazole
species pression; cen- gastrointesti- tion; endocarditis; histopathologic
tral venous nal tract pneumonitis; examination of
catheter ­disseminated tissue; urine
infection culture
Mucormycosis (Formerly Zygomycosis)
Rhizopus; Immunosup- Respiratory Rhinocerebral Histopathologic High dose of
Mucor; Lich- pression; tract; skin infection; pulmo- examination of L-AMB for initial
theimia (for- hematologic nary infection; tissue and therapy; surgical
merly Absidia) malignant neo- disseminated ­culture excision as fea-
species; Rhizo- plasm; renal infection; skin and sible; posacon-
mucor species failure; diabetes gastrointestinal azolee for
mellitus; iron tract less maintenance
overload ­commonly therapy (Vori-
­syndromes conazole has no
activity.)

Abbreviation: L-AMB, liposomal amphotericin B (if the patient is a neonate or young infant, or if L-AMP is not available, amphotericin B,
D AMP, can be substituted).
a Consider use of a lipid-based formulation of amphotericin B.
b Itraconazole has been shown to be effective for cutaneous disease in adults, but safety and efficacy have not been established in children

younger than 12 years.


c Voriconazole demonstrates activity in vitro, but limited clinical data are available for children.
d Itraconazole may be the treatment of choice, but data on safety and effectiveness in children are limited.
e Posaconazole demonstrates activity in vitro, but few clinical data are available for children.

ERRNVPHGLFRVRUJ
Fungal Diseases 181

Image 48.1
Cerebral mucormycosis in a patient with acute
lymphoblastic leukemia. Occlusion of the basilar
artery and infarct of the pons. The patient had Image 48.2
jaundice. Courtesy of Dimitris P. Agamanolis, MD. Extensive cerebral necrosis in a patient with
mucormycosis. Courtesy of Dimitris P.
Agamanolis, MD.

Image 48.3
This slide describes the histopathologic changes
seen in zygomycosis due to Rhizopus arrhizus
using fluorescent antibody stain technique. R Image 48.4
arrhizus, the most common Rhizopus species, This micrograph reveals a conidia-laden
is known to be the cause of zygomycosis, an conidiophore of the fungus Bipolaris hawaiiensis.
angiotropic disease, which means it tends to Bipolaris species are known to be one of the
invade the blood vessels, thereby facilitating its causative agents of the fungal illness
systemic dissemination. Courtesy of Centers for phaeohyphomycosis, which can be superficially
Disease Control and Prevention/Dr William confined to the skin or systemically disseminated
Kaplan. and involve the brain, lungs, and bones. Courtesy
of Centers for Disease Control and Prevention.

Image 48.5
Scanning electron micrograph of Curvularia
geniculata. Courtesy of Centers for Disease
Control and Prevention/Robert Simmons/Janice
Haney Carr.

ERRNVPHGLFRVRUJ
182 Fungal Diseases

Image 48.6
Note the fine branching tubes of the fungus Exserohilum rostratum, which is the cause of phaeohy­pho­
mycosis. Phaeohyphomycosis is a fungal infection characterized by superficial and deep tissue involve­
ment caused by dematia­ceous, dark-walled fungi that form pigmented hyphae, or fine branching tubes,
and yeastlike cells in the infected tissues. Courtesy of Centers for Disease Control and Prevention/
Libero Ajello, MD.

Image 48.7
This micrograph depicts multiple conidia-laden conidiophores and phialides of a Penicillium marneffei
fungal organism. Penicillium species are known to cause penicilliosis, which usually affects immuno­
compromised individuals, such as those with AIDS or undergoing chemotherapy. P marneffei is normally
acquired though inhalation of airborne spores. Courtesy of Centers for Disease Control and Prevention/
Libero Ajello, MD.

Image 48.8
This photomicrograph reveals the conidiophores with conidia of the fungus Pseudallescheria boydii
from a slide culture. P boydii is pathogenic in humans, especially those who are immunocompromised,
causing infections in almost all body regions, and which are classified under the broad heading of
pseudallescheriasis. Courtesy of Centers for Disease Control and Prevention/Libero Ajello, MD.

ERRNVPHGLFRVRUJ
FUSOBACTERIUM INFECTIONS 183

49 neurologic signs may indicate the presence


of cerebral venous sinus thrombosis (eg, cav-
Fusobacterium Infections ernous sinus thrombosis), meningitis, or
(Including Lemierre Disease) brain abscess.
Clinical Manifestations Jugular vein septic thrombophlebitis or throm-
Fusobacterium necrophorum and Fusobacte­ bosis can be completely vasoocclusive. Surgical
rium nucleatum can be isolated from oropha- debridement of necrotic tissue may be neces-
ryngeal specimens in healthy people, are sary for patients who do not respond to anti­
frequent components of human dental plaque, microbial therapy. Some children with JVT
and may lead to periodontal disease. Invasive associated with Lemierre disease have evidence
disease attributable to Fusobacterium species of thrombophilia at diagnosis. These findings
has been associated with otitis media, tonsil­ often resolve over several months and can indi-
litis, gingivitis, and oropharyngeal trauma, cate response to the inflammatory, prothrom-
including dental surgery. Ten percent of cases botic process associated with infection rather
of invasive Fusobacterium infections are than an underlying hypercoagulable state.
­associated with concomitant Epstein-Barr Etiology
virus infection. Risk can be increased after
­macrolide use. Fusobacterium species are anaerobic, nonspore-
forming, gram-negative bacilli. Human infec-
Invasive infection with Fusobacterium species tion usually results from F necrophorum subsp
can lead to life-threatening disease. Otogenic funduliforme, but infections with other species,
infection is the most frequent primary source including F nucleatum, Fusobacterium gonidi­
in children and can be complicated by menin- aformans, Fusobacterium naviforme, Fusobac­
gitis and thrombosis of dural venous sinuses. terium mortiferum, and Fusobacterium varium,
Invasive infection following tonsillitis was have been reported. Infection with Fusobacte­
described early in the 20th century and was rium species, alone or in combination with
referred to as postanginal sepsis or Lemierre other oral anaerobic bacteria, may result in
disease. Lemierre disease most often occurs Lemierre disease.
in adolescents and young adults and is charac-
terized by internal jugular vein septic throm- Epidemiology
bophlebitis or thrombosis (JVT), evidence Fusobacterium species are commonly found
of septic embolic lesions in lungs or other in soil and the respiratory tracts of animals,
­sterile sites, and isolation of Fusobacterium including cattle, dogs, fowl, goats, sheep, and
species from blood or other normally sterile horses, and can be isolated from the orophar-
sites. Lemierre-like syndromes have also been ynx of healthy people. Fusobacterium infec-
reported following infection with Arcanobac­ tions are most common in adolescents and
terium haemolyticum, Bacteroides species, young adults, but infections, including fatal
anaerobic Streptococcus species, other anaero- cases of Lemierre disease, have been reported
bic bacteria, and methicillin-susceptible and in infants and young children. Those with
-resistant strains of Staphylococcus aureus. sickle cell disease or diabetes mellitus may
Fever and sore throat are followed by severe be at greater risk of infection.
neck pain (anginal pain) that can be accompa-
nied by unilateral neck swelling, trismus, and Diagnostic Tests
dysphagia. Patients with classic Lemierre dis- Fusobacterium species can be isolated using
ease have a sepsis syndrome with multiple conventional liquid anaerobic blood culture
organ dysfunction. Metastatic complications media. However, the organism grows best
from septic embolic phenomena associated on semisolid media for fastidious anaerobic
with suppurative JVT are common and may organisms or blood agar supplemented with
manifest as disseminated intravascular coagu- vitamin K, hemin, menadione, and a reducing
lation, pleural empyema, pyogenic arthritis, agent. Many strains fluoresce chartreuse green
or osteomyelitis. Persistent headache or other under ultraviolet light. Most Fusobacterium

ERRNVPHGLFRVRUJ
184 FUSOBACTERIUM INFECTIONS

organisms are indole positive. The accurate activity against microaerophilic streptococci
identification of anaerobes to the species level that can coinfect some patients. Clindamycin
has become important with the increasing inci- is generally an effective agent. Fusobacterium
dence of microorganisms that are resistant to species are intrinsically resistant to gentamicin,
multiple drugs. Sequencing of the 16S rRNA fluoroquinolone agents, and, typically, macro-
gene and phylogenetic analysis can identify lides. Tetracyclines have limited activity. Up to
anaerobic bacteria to the genus or taxonomic 50% of F nucleatum and 20% of F necrophorum
group level and, frequently, to the species level. isolates produce β-lactamases, rendering them
resistant to penicillin, ampicillin, and some
The diagnosis of Lemierre disease should be
cephalosporins.
considered in ill-appearing febrile children
and adolescents with sore throat and exquisite Because Fusobacterium infections are often
neck pain over the angle of the jaw. Anaerobic polymicrobial, broad-spectrum therapy­fre-
blood culture in addition to aerobic blood cul- quently is necessary. Therapy has been advo-
ture should be performed to detect invasive cated with a penicillin-β-lactamase ­inhibitor
Fusobacterium species infection. Computed combination (ampicillin-sulbactam or
tomography and magnetic resonance imaging ­piperacillin-tazobactam) or a carbapenem
are more sensitive than ultrasonography to (meropenem, imipenem, or ertapenem) or
document JVT early in the course of illness combination therapy with metronidazole or
and to better identify thrombus extension. clindamycin in addition to other agents active
against aerobic oral and respiratory tract
Treatment
patho­gens (cefotaxime, ceftriaxone, or cefuro­
Fusobacterium species may be susceptible to xime). Duration of antimicrobial therapy
metronidazole, clindamycin, chloramphenicol, depends on the anatomic location and severity
carbapenems (meropenem or imipenem), of infection but is usually several weeks. Surgical
cefoxitin, and ceftriaxone. Resistance to anti- intervention involving debridement or incision
microbial agents has increased in anaerobic and drainage of abscesses may be necessary.
bacteria during the last decade, and suscepti- Antico­agulation therapy has been used in adults
bility is no longer predictable. Susceptibility and children with JVT and cavernous sinus
testing is indicated for all clinically significant thrombosis. In cases with extensive thrombo-
anaerobic isolates. Metronidazole is the treat- sis, anticoagulation therapy may decrease the
ment preferred by many experts but lacks risk of clot extension and shorten recovery time.

Image 49.1
Image 49.2
Vincent stomatitis has been confused with
This photomicrograph shows Fusobacterium
diphtheria, although this infection is usually a
nucleatum after being cultured in a thioglycollate
mixed infection, including fusiform and spirochetal
medium for 48 hours. Courtesy of Centers for
anaerobic bacteria including Fusobacterium,
Disease Control and Prevention.
and is associated with severe pain and halitosis.
Note ulceration of the soft palate with surround­
ing erythema. Courtesy of Edgar O. Ledbetter,
MD, FAAP.

ERRNVPHGLFRVRUJ
FUSOBACTERIUM INFECTIONS 185

Image 49.3 Image 49.4


This is a photomicrograph of Fusobacterium This photograph demonstrates the morphology
russii cultured in a thioglycollate medium for of 4 colonies of Fusobacterium fusiforme bacteria
48 hours. Like the genus Bacteroides, Fusobac­ that were grown on blood agar medium for
terium species are anaerobic, gram-negative 48 hours. Fusobacterium fusiforme is a spindle-
bacteria that are normal inhabiters of the oral shaped gram-negative bacteria that colonizes
cavity, intestine, and female genital tract. the gingival sulcus of the human oral cavity and
Fusobacterium species are most commonly has also been isolated from infections of the
associated with head and neck, pulmonary, upper respiratory tract. Courtesy of Centers for
and wound infections. Courtesy of Centers for Disease Control and Prevention/V. R. Dowell
Disease Control and Prevention/V. R. Dowell Jr, MD.
Jr, MD.

Image 49.5
An abdominal computed tomography scan of a
15-year-old football linebacker who presented
with high fever, abdominal pain, and emesis for
5 days showing abscess collections in the liver.
Aspiration of 3 discrete abscess areas grew only
Fusobacterium nucleatum. Courtesy of Carol J.
Baker, MD, FAAP.

Image 49.6
80 mL of purulent material was aspirated from
the liver abscess of the patient in Image 49.5.
Courtesy of Carol J. Baker, MD, FAAP.

ERRNVPHGLFRVRUJ
186 GIARDIA INTESTINALIS (­FORMERLY GIARDIA LAMBLIA AND GIARDIA DUODENALIS) INFECTIONS

50 an infected person or through ingestion of


fecally contaminated water or food. Most
Giardia intestinalis ­community-wide epidemics have resulted
(­formerly Giardia lamblia from a contaminated drinking water supply;
outbreaks associated with recreational water
and Giardia duodenalis) have also been reported. Outbreaks resulting
Infections from person-to-person transmission occur in
(Giardiasis) child care centers or institutional care settings,
where staff and family members in contact
Clinical Manifestations
with infected children or adults become
Symptomatic infection with Giardia intestina­ infected themselves. Although less common,
lis causes a broad spectrum of clinical mani­ outbreaks associated with food or food han-
festations. Children can have occasional days dlers have also been reported. Surveys con-
of acute watery diarrhea with abdominal pain, ducted in the United States have identified
or they may experience a protracted, intermit- overall prevalence rates of Giardia organisms
tent, often debilitating disease characterized in stool specimens that range from 5% to 7%,
by passage of foul-smelling stools associated with variations depending on age, geographic
with anorexia, flatulence, and abdominal dis- location, and seasonality. Duration of cyst
tention. Anorexia, combined with malabsorp- excretion is variable but can range from weeks
tion, can lead to significant weight loss, failure to months. Giardiasis is communicable for as
to thrive, and anemia. Humoral immunodefi- long as the infected person excretes cysts.
ciencies predispose to chronic symptomatic
G intestinalis infections. Asymptomatic infec- Incubation Period
tion is common; approximately 50% to 75% of 1 to 3 weeks.
people who acquired infection in outbreaks
occurring in child care settings and in the Diagnostic Tests
community were asymptomatic. Commercially available, sensitive, and specific
enzyme immunoassay and direct fluorescence
Etiology
antibody assays are the standard tests used
G intestinalis is a flagellate protozoan that for diagnosis of giardiasis in the United States.
exists in trophozoite and cyst forms; the Enzyme immunoassay has a sensitivity of up
­infective form is the cyst. Infection is limited to 95% and a specificity of 98% to 100% when
to the small intestine and biliary tract. compared with microscopy. Direct fluores-
cence antibody assay has the advantage that
Epidemiology
organisms are visualized. Diagnosis has
Giardiasis is the most common intestinal ­traditionally been based on the microscopic
­ arasitic infection of humans identified in the
p identification of trophozoites or cysts in stool
United States and globally with a worldwide specimens; this requires an experienced
distribution. Approximately 20,000 cases are microscopist, and sensitivity can be subopti-
reported in the United States each year, with mal. Stool needs to be examined as soon as
highest incidence reported among children 1 to possible or placed immediately in a preserva-
9 years of age, adults 35 to 44 years of age, and tive, such as neutral-buffered 10% formalin
residents of northern states. Peak onset of ill- or polyvinyl alcohol. A single direct smear
ness occurs annually during early summer examination of stool has a sensitivity of 75%
through early fall. Humans are the principal to 95%. Sensitivity is higher for diarrheal stool
reservoir of infection, but Giardia organisms specimens because they contain higher concen-
can infect dogs, cats, beavers, rodents, sheep, trations of organisms. Sensitivity of micros-
cattle, nonhuman primates, and other animals. copy is increased by examining 3 or more
G intestinalis assemblages are quite species- specimens collected every other day. Commer-
specific, such that the organisms that affect cially available stool collection kits in child-
nonhumans are usually not infectious to proof containers are convenient for preserving
humans. People become infected directly from stool specimens collected at home. When

ERRNVPHGLFRVRUJ
GIARDIA INTESTINALIS (­FORMERLY GIARDIA LAMBLIA AND GIARDIA DUODENALIS) INFECTIONS 187

g­ iardiasis is suspected clinically but the organ- (occurs in 20%–40% of patients), immune
ism is not found on repeated stool examina- s­ uppression, insufficient treatment, or drug
tion, inspection of duodenal contents obtained resistance. If reinfection is suspected, a second
by direct aspiration or by using a commercially course of the same drug should be effective.
available string test (eg, Entero-Test) may be Treatment with a different class of drug is
diagnostic. Rarely, duodenal biopsy is required ­recommended for resistant giardiasis. Other
for diagnosis. treatment options include combination of a
nitroimidazole plus quinacrine for at least
Treatment
2 weeks or high-dose courses of the origi-
Some infections are self-limited, and treatment nal agent.
is not required. Dehydration and electrolyte
abnormalities can occur and should be cor- Patients who are immunocompromised
rected. Metronidazole, nitazoxanide, and because of hypogammaglobulinemia or
tinid­azole are the drugs of choice. Metronida- ­lymphoproliferative disease are at higher risk
zole (if used for a 5-day course) is the least of giardiasis, and it is more difficult to treat in
expensive of these therapies. A 5- to 10-day these patients. Among HIV-infected children
course of metronidazole has an efficacy of 80% without AIDS, effective combination and anti-
to 100% in pediatric patients, but poor palat- parasitic therapy are the major initial treat-
ability has been noted for metronidazole sus- ments for these infections. Especially in
pension. A 1-time dose of tinidazole, for HIV-infected children without AIDS, combi-
children 3 years and older, has a similar efficacy nation antiretroviral therapy should be part
in pediatric patients and has fewer adverse of the primary initial treatment for giardiasis.
effects than does metronidazole. A 3-day Patients with AIDS often respond to standard
course of nitazoxanide oral suspension also therapy; however, in some cases, additional
has similar efficacy to metronidazole and has treatment is required. If giardiasis is refractory
the advantage(s) of treating other intestinal to standard treatment among patients with
parasites and is approved for use in children AIDS, high doses, longer treatment duration,
1 year and older. or combination therapy may be appropriate.

Symptom recurrence after completing anti­


microbial treatment can be attributable to
­reinfection, post-Giardia lactose intolerance

Image 50.1
Three trophozoites of Giardia intestinalis (A, trichrome stain; B and C, iron hematoxylin stain). Each cell
has 2 nuclei with a large, central karyosome. Cell length is 9 to 21 µm. Trophozoites are usually seen in
fresh diarrheal stool or in duodenal mucus. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
188 GIARDIA INTESTINALIS (­FORMERLY GIARDIA LAMBLIA AND GIARDIA DUODENALIS) INFECTIONS

Image 50.3

Image 50.2 Giardia intestinalis cysts (trichrome stain). Person-


Photomicrograph of a Giardia intestinalis cyst to-person transmission is the most common
seen using a trichrome stain. G intestinalis is the mode of transmission of giardiasis.
protozoan organism that causes the disease
giardiasis, a diarrheal disorder directly affecting
the small intestine. Courtesy of Centers for
Disease Control and Prevention.

Image 50.4
Giardiasis. Incidence—United States and US territories, 2012. Courtesy of Morbidity and Mortality
Weekly Report.

ERRNVPHGLFRVRUJ
GIARDIA INTESTINALIS (­FORMERLY GIARDIA LAMBLIA AND GIARDIA DUODENALIS) INFECTIONS 189

Image 50.5
Cysts are resistant forms and responsible for transmission of giardiasis. Cysts and trophozoites can
be found in the feces (diagnostic stages) (1). The cysts are hardy and can survive several months in
cold water. Infection occurs by the ingestion of cysts in contaminated water or food or by the fecal-
oral route (hands or fomites) (2). In the small intestine, excystation releases trophozoites (each cyst
produces 2 trophozoites) (3). Trophozoites multiply by longitudinal binary fission, remaining in the
lumen of the proximal small bowel, where they can be free or attached to the mucosa by a ventral
sucking disk (4). Encystation occurs as the parasites transit toward the colon. The cyst is the stage
found most commonly in nondiarrheal feces (5). Because the cysts are infectious when passed in
the stool or shortly afterward, person-to-person transmission is possible. While animals are infected
with Giardia, their importance as a reservoir is unclear. Courtesy of Centers for Disease Control
and Prevention/Alexander J. da Silva, PhD/Melanie Moser.

ERRNVPHGLFRVRUJ
190 Gonococcal Infections

51 from mucosal sites can involve skin and


joints (arthritis-dermatitis syndrome; dis-
Gonococcal Infections seminated gonococcal infection) and occurs
Clinical Manifestations in up to 3% of untreated people with mucosal
gonorrhea. Bacteremia can result in a macu-
Gonococcal infections in newborns, infants, lopapular rash with necrosis, tenosynovitis,
children, and adolescents occur in 3 distinct and migratory arthritis. Arthritis may be
age groups. reactive (sterile) or septic in nature. Menin-
• Infection in the newborn usually involves gitis and endocarditis occur rarely.
the eyes. Other possible manifestations of Etiology
neonatal gonococcal infection include scalp
abscess (which can be associated with fetal Neisseria gonorrhoeae is a gram-negative,
scalp monitoring) and disseminated disease ­oxidase-positive diplococcus.
with bacteremia, arthritis, or meningitis. Epidemiology
Vaginitis and urethritis may occur as well.
Gonococcal infections only occur in humans.
• In children beyond the newborn period, The source of the organism is exudate and
including prepubertal children, gonococcal secretions from infected mucosal surfaces;
infection may occur in the genital tract and N gonorrhoeae is communicable as long as a
is almost always transmitted sexually. Vagi- person harbors the organism. Transmission
nitis is the most common manifestation in results from intimate contact, such as sexual
prepubertal females. Progression to pelvic acts, parturition, and, very rarely, household
inflammatory disease (PID) appears to be exposure in prepubertal children. Sexual abuse
less common in this age group than in older should be strongly considered when genital,
adolescents. Gonococcal urethritis is pos- rectal, or pharyngeal colonization or infection
sible but uncommon in prepubertal males. is diagnosed in prepubertal children beyond
Anorectal and tonsillopharyngeal infection the newborn period. N gonorrhoeae infection
can also occur in prepubertal children and is the second most commonly reported sexu-
is often asymptomatic. ally transmitted infection in the United States,
following Chlamydia trachomatis infection. In
• In sexually active adolescent and young
2012, a total of 334,826 cases of gonorrhea were
adult females, gonococcal infection of the
reported in the United States, a rate of 108 cases
genital tract is often asymptomatic. Com-
per 100,000 population. The reported rate of
mon clinical syndromes include urethritis,
diagnosis is highest in females 15 through
endocervicitis, and salpingitis. In males,
24 years of age. Among males, the rate is high-
infection is often symptomatic, and the
est in those 20 through 24 years of age. In 2012,
­primary site is the urethra. Infection of the
the rate of gonorrhea among black people was
rectum and pharynx can occur alone or
15 times the rate among white people. Rates
with genitourinary tract infection in either
were 4 times higher among American Indian/
gender. Rectal and pharyngeal infections
Alaska Native people, 3 times higher among
are often asymptomatic. Extension from
Native Hawaiian/Pacific Islander people, and
primary genital mucosal sites in males can
2 times higher among Hispanic people than
lead to epididymitis; in females, it can lead
among whites. Disparities in gonorrhea rates
to bartholinitis, PID with resultant tubal
are observed by sexual behavior. Among
scarring, and perihepatitis (Fitz-Hugh–­
males who have sex with males, very high
Curtis syndrome). Even asymptomatic
­proportions of positive gonorrhea pharyngeal,
­infection in females can progress to PID,
urethral, and rectal test results, as well as
with tubal scarring that can result in ectopic
­coinfection with other sexually transmitted
pregnancy, infertility, or chronic pelvic pain.
infections and HIV, have been found.
Infection involving other mucous mem-
branes can produce conjunctivitis, pharyn- Incubation Period
gitis, or proctitis. Hematogenous spread
2 to 7 days.

ERRNVPHGLFRVRUJ
Gonococcal Infections 191

Diagnostic Tests swab specimens, male or female urine speci-


Microscopic examination of Gram-stained mens, or liquid cytology specimens. Use of
smears of exudate from the conjunctivae, less-invasive specimens, such as urine or vagi-
vagina of prepubertal girls, male urethra, skin nal swab specimens, increases feasibility of
lesions, synovial fluid, and, when clinically routine testing of sexually active adolescents
warranted, cerebrospinal fluid (CSF) can be by their primary care physicians and in other
useful in the initial evaluation. Identification clinical settings. Nucleic acid amplification
of gram-negative intracellular diplococci in tests also permit dual testing of specimens for
these smears can be helpful, particularly if the C trachomatis and N gonorrhoeae. The Centers
organism is not recovered in culture. However, for Disease Control and Prevention (CDC)
because of low sensitivity, a negative smear recommends the vaginal swab specimen as
result should not be considered sufficient for the preferred means of screening females and
ruling out infection. N gonorrhoeae can be urine as the preferred means for screening
­isolated from normally sterile sites, such as males for N gonorrhoeae infection.
blood, CSF, or synovial fluid, using nonselec- For identifying N gonorrhoeae from nongenital
tive chocolate agar with incubation in 5% to sites, culture is the most widely used test and
10% carbon dioxide. Selective media that allows for antimicrobial susceptibility testing
inhibit normal flora and nonpathogenic to aid in management should infection persist
­Neisseria organisms are used for cultures following initial therapy. Nucleic acid ampli­
from nonsterile sites, such as the cervix, fication tests are not cleared by the US Food
vagina, rectum, urethra, and pharynx. Speci- and Drug Administration for N gonorrhoeae
mens for N gonorrhoeae culture from mucosal testing on rectal or pharyngeal swabs. Many
sites should be inoculated immediately onto commercial laboratories have validated gonor-
appropriate agar because the organism is rhea NAAT performance on rectal or pharyn-
extremely sensitive to drying and tempera- geal swab specimens. Some NAATs have the
ture changes. potential to cross-react with nongonococcal
Caution should be exercised when interpreting ­Neisseria species that are commonly found in
the significance of isolation of Neisseria organ- the throat, leading to false-positive test results.
isms because N gonorrhoeae can be confused A limited number of nonculture tests are
with other Neisseria species that colonize the approved by the Food and Drug Administra-
genitourinary tract or pharynx. At least 2 tion for conjunctival specimens.
­confirmatory bacteriologic tests involving • Sexual abuse. In all prepubertal children
­different biochemical principles should be beyond the newborn period and in adoles-
­performed by the laboratory. Interpretation cents who have gonococcal infection but
of culture of N gonorrhoeae from the pharynx report no prior sexual activity, sexual abuse
of young children necessitates particular cau- must be considered to have occurred until
tion because of the high carriage rate of non- proven otherwise. Health care professionals
pathogenic ­Neisseria species and the serious have a responsibility to report suspected
implications of such a culture result. sexual abuse to the state child protective
Nucleic acid amplification tests (NAATs) are services agency if there is “reasonable cause
far superior in overall performance compared to suspect abuse.” Cultures should be per-
with other N gonorrhoeae culture and non­ formed on genital, rectal, and pharyngeal
culture diagnostic methods to test genital and swab specimens for all patients before anti-
nongenital specimens, but performance varies microbial treatment is given. All gonococcal
by NAAT type. These tests include polymerase isolates from such patients should be pre-
chain reaction, transcription-mediated ampli- served. Nonculture gonococcal tests, includ-
fication, and strand-displacement amplifica- ing Gram stain, DNA probes, enzyme
tion. Most commercially available products are immunoassays, or NAATs of oropharyngeal,
now approved for testing male urethral swab rectal, or genital tract swab specimens in
specimens, female endocervical or vaginal children, cannot be relied on as the sole

ERRNVPHGLFRVRUJ
192 Gonococcal Infections

method for diagnosis of gonococcal infec- that persist after treatment or whose symptoms
tion for this purpose because false-positive recur shortly after treatment should be reevalu-
results can occur. Culture remains the pre- ated by culture for N gonorrhoeae, and any
ferred method for urethral specimens from gonococci isolated should be tested for anti­
boys and extragenital specimens (pharynx microbial susceptibility.
and rectum) in boys and girls.
Because patients may be reinfected by a new or
Treatment untreated partner within a few months after
The rapid emergence of antimicrobial resis- diagnosis and treatment, practitioners should
tance has led to a limited number of approved advise all adolescents and adults diagnosed
therapies for gonococcal infections. Resistance with gonorrhea to be retested approximately
to penicillin and tetracycline is widespread, 3 months after treatment. Patients who do not
and as of 2007, the CDC no longer recom- receive a test of reinfection at 3 months should
mends the use of fluoroquinolones for gonor- be tested whenever they are seen for care
rhea because of the increased prevalence of within the next 12 months. All patients with
quinolone-resistant N gonorrhoeae in the presumed or proven gonorrhea should be
United States. This leaves cephalosporins as ­evaluated for concurrent syphilis, HIV, and
the only recommended antimicrobial class C trachomatis infections.
for the treatment of gonococcal infections. Specific recommendations for management
Over the past decade, the minimum inhibitory and antimicrobial therapy are as follows:
concentrations for oral cefixime activity
against N gonorrhoeae strains circulating in • Neonatal disease. Infants with clinical
the United States and other countries has ­evidence of ophthalmia neonatorum, scalp
increased, suggesting that resistance to this abscess, or disseminated infections attri­b­
drug is emerging. As of 2012, the CDC no utable to N gonorrhoeae should be hos­
­longer recommends the use of cefixime as a pitalized. Cultures of blood, eye discharge,
first-line treatment for gonococcal infection. and other potential sites of infection, such
Ceftriaxone, intramuscularly, once, with as CSF, should be performed on specimens
azithromycin, once, or doxycycline, twice from infants to confirm the diagnosis and
daily for 7 days, is the recommended treatment to determine antimicrobial susceptibility.
for all gonococcal infections, regardless of Tests for concomitant infection with
age. Azithromycin is preferred to doxycycline C ­trachomatis, congenital syphilis, and
because of the convenience of single-dose HIV infection should be performed.
­t herapy and because gonococcal resistance to Results of the maternal test for hepatitis B
tetracycline appears to be greater than resis- surface antigen should be confirmed. The
tance to azithromycin. mother and her partner(s) also need appro-
priate examination and treatment for
Test-of-cure samples are not required in N ­gonorrhoeae.
­adolescents or adults with uncomplicated
­gonorrhea who are asymptomatic after being • Nondisseminated neonatal infections.
treated with a recommended antimicrobial ­Recommended antimicrobial therapy
regimen that includes ceftriaxone alone. If an for ophthalmia neonatorum caused by
alternative regimen is used for treatment of N ­gonorrhoeae is a single one-time dose
pharyngeal gonorrhea infection, the CDC of ceftriaxone, intravenously or intramuscu-
­recommends a test of cure 14 days after treat- larly. Infants with gonococcal ophthalmia
ment is completed, ideally using culture so should receive eye irrigations with saline
that antimicrobial susceptibility testing may solution immediately and at frequent inter-
be performed. If culture is not available, the vals until discharge is eliminated. Topical
CDC recommends testing with a NAAT. If antimicrobial treatment alone is inadequate
the NAAT result remains positive, every effort and unnecessary when recommended sys-
should be made to obtain a culture for suscep- temic antimicrobial treatment is given.
tibility testing. Patients who have symptoms

ERRNVPHGLFRVRUJ
Gonococcal Infections 193

Infants with gonococcal ophthalmia should alternative regimens for treating gonorrhea
be hospitalized and evaluated for dissemi- among people who have documented severe
nated infection (sepsis, arthritis, meningitis). cephalosporin allergy, consultation with
an expert in infectious diseases may be
• Disseminated neonatal infections and
­warranted.
scalp abscesses. Recommended therapy for
arthritis, septicemia, or abscess is ceftriax- • Pharyngeal infection is generally more
one, intravenously or intramuscularly, for ­difficult to treat than anogenital infection;
7 days. Cefotaxime, intravenously every therefore, single-dose ceftriaxone and
12 hours, is recommended for infants with azithromycin are recommended. Children
hyperbilirubinemia. If meningitis is docu- or adolescents with HIV infection should
mented, treatment should be continued for receive the same treatment for gonococcal
a total of 10 to 14 days. infection as children without HIV infection.
• Gonococcal infections in children beyond • Acute PID. N gonorrhoeae and C trachomatis
the neonatal period and adolescents. are implicated in many cases of PID; most
Patients with uncomplicated infections of cases have a polymicrobial etiology. No
the vagina, endocervix, urethra, or anorec- ­reliable clinical criteria distinguish gonococ-
tum and a history of severe adverse reac- cal from nongonococcal-associated PID.
tions to cephalosporins (eg, anaphylaxis, Hence, broad-spectrum treatment regimens
­ceftriaxone-induced hemolysis, Stevens- are recommended.
Johnson syndrome, toxic epidermal necroly-
• Acute epididymitis. Sexually transmitted
sis) should consult an expert in infectious
organisms, such as N gonorrhoeae or
diseases. In adults, dual treatment with a
C ­trachomatis, can cause acute epididymitis
single dose of gemifloxacin, plus oral
in sexually active adolescents and young
azithromycin, or dual treatment with a
adults but rarely, if ever, cause acute
­single dose of ­intramuscular gentamicin
­epididymitis in prepubertal children. The
plus oral azithromycin, are potential thera-
recommended regimen for epididymitis is
peutic options. However, there are no data
single-dose ceftriaxone plus doxycycline,
on the efficacy of these regimens in children
for 14 days.
or adolescents. Because data are limited on

Image 51.2
Image 51.1 This photomicrograph reveals the histopathology
Gram stain of cervical discharge in an adolescent in an acute case of gonococcal urethritis
who has gonococcal cervicitis. Note multiple (Gram stain). This image demonstrates the
intracellular diplococci. In children with suspected nonrandom distribution of gonococci among
abuse, it is imperative the gonococcus be polymorpho­nuclear neutrophils. Note there are
cultured and identified to distinguish pathogens intracellular and extracellular bacteria in the
from normal flora. field of view. Courtesy of Centers for Disease
Control and Prevention/Joe Miller.

ERRNVPHGLFRVRUJ
194 Gonococcal Infections

Image 51.3
Neisseria gonorrhoeae on chocolate agar. Colonies appear off-white with no discoloration of the agar.
Courtesy of Julia Rosebush, DO; Robert Jerris, PhD; and Theresa Stanley, M(ASCP).

Image 51.4
Gonorrhea. Incidence—United States and US territories, 2012. Courtesy of Morbidity and Mortality
Weekly Report.

ERRNVPHGLFRVRUJ
Gonococcal Infections 195

Image 51.5
Gonorrhea. Incidence, by sex—United States, 1997–2012. Courtesy of Morbidity and Mortality
Weekly Report.

Image 51.6 Image 51.7


An infant with gonococcal ophthalmia. In-hospital An 8-day-old with gonococcal ophthalmia.
evaluation and treatment is recommended for Therapy for Chlamydia trachomatis is recom­
infants with gonococcal ophthalmia. Copyright mended, as concomitant infection may occur.
Martin G. Myers, MD. Copyright Martin G. Myers, MD.

ERRNVPHGLFRVRUJ
196 Gonococcal Infections

Image 51.8
This newborn has gonococcal ophthalmia neona­
torum caused by a maternally transmitted gono­ Image 51.9
coc­cal infection. Unless preventive measures are Profuse, purulent vaginal discharge in an
taken, it is estimated that gonococcal ophthalmia 18-month-old girl who has gonococcal
neonatorum will develop in 28% of neonates born vulvovaginitis. In preadolescent children, this
to women with gonorrhea. It affects the corneal infection is almost always associated with
epithelium, causing microbial keratitis, ulceration, sexual abuse. Identification of the species of
and perforation. Courtesy of Centers for Disease cultured gonococci is imperative in suspected
Control and Prevention/J. Pledger. cases of sexual abuse.

Image 51.10 Image 51.11


This colposcopic view of this patient’s cervix This male presented with purulent penile dis­charge
revealed an eroded ostium due to Neisseria due to gonorrhea with an overlying penile pyo­
gonorrhoeae infection. A chronic N gonorrhoeae derma lesion. Pyoderma involves the forma­tion
infection can lead to complications that can be of a purulent skin lesion, as in this case, located
apparent, such as this cervical inflammation, and on the glans penis and overlying the sexually
some can be quite insipid, giving the impression transmitted infection gonorrhea. Courtesy of
that the infection has subsided while treatment is Centers for Disease Control and Prevention/
still needed. Courtesy of Centers for Disease Joe Miller.
Control and Prevention.

Image 51.12
This patient presented with gonococcal urethritis and gonococcal conjunctivitis of the right eye. If
untreated, Neisseria gonorrhoeae may spread to the bloodstream and throughout the body. Courtesy
of Centers for Disease Control and Prevention/Joe Miller.

ERRNVPHGLFRVRUJ
Gonococcal Infections 197

Image 51.13
Image 51.14
Gonococcemia with maculopapular and Adolescent with septic arthritis of left ankle
petechial skin lesions, most commonly seen with petechial and necrotic skin lesions on the
on the hands and feet. feet. Blood culture results were positive for
Neisseria gonorrhoeae.

Image 51.16
This patient presented with symptoms later
diagnosed as due to gonococcal pharyngitis.
Image 51.15 Gonococcal pharyngitis is a sexually transmitted
An acute gonococcal skin lesion with cutaneous infection acquired through oral sex with an
necrosis over the elbow of a 19-year-old male infected partner. Most throat infections caused
with gonococcal septicemia. Courtesy of George by gonococci have no symptoms, but some can
Nankervis, MD. suffer from mild to severe sore throat. Courtesy
of Centers for Disease Control and Prevention/
Dr N. J. Flumara, Dr Gavin Hart.

Image 51.17
Disseminated gonococcal infection. Courtesy of Gary Overturf, MD.

ERRNVPHGLFRVRUJ
198 Granuloma Inguinale

52
Incubation Period
8 to 80 days.
Granuloma Inguinale
Diagnostic Tests
(Donovanosis)
The causative organism is difficult to culture,
Clinical Manifestations and diagnosis requires microscopic demon-
Initial lesions of this sexually transmitted stration of dark-staining intracytoplasmic
infection are single or multiple subcutaneous K granulomatis (also called Donovan bodies)
nodules that gradually ulcerate. These non- on Wright or Giemsa staining of a crush prepa-
tender, granulomatous ulcers are beefy red and ration from subsurface scrapings of a lesion or
highly vascular and bleed readily on contact. tissue. The microorganism can also be detected
Lesions usually involve the genitalia without by histologic examination of biopsy specimens.
regional adenopathy, but anal infections occur Lesions should be cultured for Haemophilus
in 5% to 10% of patients; lesions at distant sites ducreyi to exclude chancroid. Granuloma
(eg, face, mouth, liver) are rare. Subcutaneous inguinale is often misdiagnosed as carcinoma,
extension into the inguinal area results in which can be excluded by histologic examina-
induration that can mimic inguinal adenopa- tion of tissue or by response of the lesion to
thy (ie, “pseudobubo”). Verrucous, necrotic, antimicrobial agents.
and fibrous lesions may occur as well. Fibrosis
Treatment
manifests as sinus tracts, adhesions, and
lymphedema, resulting in extreme genital Doxycycline for at least 21 days and until the
deformity. Urethral obstruction can occur. lesions are completely healed is the treatment
of choice. Azithromycin orally, once per week
Etiology for at least 3 weeks and until all lesions have
Granuloma inguinale, also called donovanosis, completely healed, is an alternative regimen.
is caused by Klebsiella granulomatis (formerly Trimethoprim-sulfamethoxazole, ciprofloxa-
known as Calymmatobacterium granulomatis), cin, and erythromycin may be used in appro-
an intracellular gram-negative bacillus. priate patients. Gentamicin can be added if no
improvement is evident after several days of
Epidemiology
therapy. Partial healing is usually noted within
Indigenous granuloma inguinale occurs very 7 days of initiation of therapy. Relapse can
rarely in the United States and most industrial- occur, especially if the antimicrobial agent is
ized nations. The disease is endemic in some stopped before the primary lesion has healed
tropical and developing areas, including India, completely. Complicated or long-standing
Papua New Guinea, the Caribbean, central infection can require surgical intervention.
Australia, and southern Africa. The incidence
of infection seems to correlate with sustained Patients should be evaluated for other sexually
high temperatures and high relative humidity. transmitted infections, such as gonorrhea,
Infection is usually acquired by sexual inter- syphilis, chancroid, chlamydia, hepatitis B
course, most commonly with a person with virus, and HIV infections. Initiation or com-
active infection but possibly also from a person pletion of the series of vaccines for hepatitis B
with asymptomatic rectal infection. Young and human papillomavirus should be given, if
children can acquire infection by contact with appropriate for the age group.
infected secretions. The period of communi­
cability extends throughout the duration of
active lesions or rectal colonization.

ERRNVPHGLFRVRUJ
Granuloma Inguinale 199

Image 52.1
Giemsa-stained Klebsiella granulomatis (Donovan Image 52.2
bodies) of granuloma inguinale. Courtesy of This patient’s penile lesions were due to
Robert Jerris, MD. gram-negative Klebsiella granulomatis, formerly
known as Calymmatobacterium granulomatis.
K granulomatis cause granuloma inguinale, or
donovanosis, a sexually transmitted infection
that is a slowly progressive, ulcerative condition
of the skin and lymphatics of the genital and
perianal area. A definitive diagnosis is achieved
when a tissue smear test result is positive for the
presence of K granulomatis (Donovan bodies).
Courtesy of Centers for Disease Control
and Prevention/Joe Miller; Source: Dr Cornelio
Arevalo, Venezuela.

Image 52.3
Granuloma inguinale accompanied by perianal
skin ulceration due to the bacterium Klebsiella
granulomatis (formerly Calymmatobacterium
granulomatis). The ulcerations are, for the most
part, painless and granulomatous in nature (ie,
chronic inflammation). Courtesy of the Centers Image 52.4
for Disease Control and Prevention/Joe Miller; Granuloma inguinale accompanied by perianal
Source: Dr Cornelio Arevalo, Venezuela. skin ulceration due to the bacterium Klebsiella
granulomatis (formerly Calymmatobacterium
granulomatis). The ulcerations are, for the most
part, painless and granulomatous in nature (ie,
chronic inflammation). Courtesy of Centers for
Disease Control and Prevention/Dr Thomas F.
Sellers/Emory University.

ERRNVPHGLFRVRUJ
200 HAEMOPHILUS INFLUENZAE INFECTIONS

53 include sickle cell disease, asplenia, HIV infec-


tion, certain immunodeficiency syndromes, and
Haemophilus influenzae malignant neoplasms. Historically, invasive
Infections Hib was more common in black, Alaska Native,
Apache, and Navajo ­children; boys; child care
Clinical Manifestations attendees; children living in crowded condi-
Haemophilus influenzae type b (Hib) causes tions; and children who were not ­breastfed.
pneumonia, bacteremia, meningitis, epiglottitis,
Since introduction of Hib conjugate vaccines
septic arthritis, cellulitis, otitis media, purulent
in the United States, the incidence of invasive
pericarditis, and, less commonly, endocarditis,
Hib disease has decreased by 99% to fewer
endophthalmitis, osteomyelitis, peritonitis,
than 1 cases per 100,000 children younger than
and gangrene. Nontype b–­encapsulated strains
5 years. In 2012, 30 cases of invasive type b
present in a similar manner to type b infections.
­disease were reported in children younger
Nontypable strains more commonly cause
than 5 years. In the United States, invasive Hib
infections of the respiratory tract (eg, otitis
disease occurs primarily in unimmunized or
media, sinusitis, pneumonia, conjunctivitis)
under-immunized children and among infants
and, less often, bacteremia, meningitis, chorio-
too young to have completed the primary
amnionitis, and neonatal septicemia.
immunization series. H influenzae type b
Etiology remains an important pathogen in many
H influenzae is a pleomorphic gram-negative resource-limited countries where Hib vaccines
coccobacillus. Encapsulated strains express 1 are not routinely available. The epidemiology
of 6 antigenically distinct capsular polysaccha- of invasive H influenzae disease in the United
rides (a–f); nonencapsulated strains lack cap- States has shifted in the postvaccination era.
sule genes and are designated nontypable. Nontypable H influenzae now causes most
invasive H influenzae disease in all age groups.
Epidemiology From 1999 through 2008, the annual incidence
The mode of transmission is person to person of invasive nontypable H influenzae disease
by inhalation of respiratory tract droplets or was 1.73 per 100,000 children younger than
by direct contact with respiratory tract secre- 5 years. Nontypable H influenzae causes
tions. In neonates, infection is acquired intra- approximately 50% of episodes of acute otitis
partum by aspiration of amniotic fluid or by media and sinusitis in children and is a com-
contact with genital tract secretions containing mon cause of recurrent otitis media. The rate
the organism. Pharyngeal colonization by of nontypable H influenzae infections in boys
H ­influenzae is relatively common, especially is twice that in girls and peaks in the late fall.
with nontypable and nontype b capsular-type In some North American indigenous popula-
strains. Similar to findings in the pre-Hib vaccine tions, H influenzae type a (Hia) has emerged
era, in resource-limited countries where Hib as a significant cause of invasive disease. The
vaccine has not been routinely implemented, 2002–2012 incidence of Hia in Alaska Native
the major reservoir of Hib is young infants and children younger than 5 years was 18 per
toddlers, who carry the organism in the upper 100,000 per year (vs 0.5/100,000 in nonnative
respiratory tract. Before introduction of effec- children). The incidence was highest in south-
tive Hib conjugate vaccines, Hib was the most western Alaska Native children younger than
common cause of bacterial meningitis in chil- 5 years (72/100,000/y). Similarly, Hia has
dren in the United States. The peak incidence emerged among northern Canadian indige-
of invasive Hib infections occurred between 6 nous children, who experienced an incidence
and 18 months of age. In contrast, the peak age of 102 per 100,000 per year in children younger
for Hib epiglottitis was 2 to 4 years of age. than 2 years. There has been an ongoing lower
Unimmunized children younger than 4 years level of Hia disease in Navajo children younger
are at increased risk of invasive Hib disease. than 5 years (20/100,000/y, 1988–2003). Inva-
Factors that predispose to invasive disease sive disease has also been caused by other
encapsulated nontype b strains.

ERRNVPHGLFRVRUJ
HAEMOPHILUS INFLUENZAE INFECTIONS 201

Incubation Period Hib isolate is susceptible. Treatment of other


Unknown. invasive H influenzae infections is similar.
Therapy is continued for 7 to 10 days and ­longer
Diagnostic Tests in complicated infections. Dexamethasone is
The diagnosis of invasive disease is established beneficial for treatment of infants and children
by growth of H influenzae from cerebrospinal with Hib meningitis to diminish the risk of
fluid, blood, synovial fluid, pleural fluid, or peri­ hearing loss, if given before or concurrently
cardial fluid. Gram stain of an infected body with the first dose of antimicrobial agent(s).
fluid specimen can facilitate presumptive diag- Epiglottitis is a medical emergency. An airway
nosis. All H influenzae isolates associated with must be established promptly via controlled
invasive infection should be serotyped. Although intubation. Infected pleural or pericardial
the potential for suboptimal sensitivity and fluid should be drained.
specificity exists with slide agglutination sero- For empiric treatment of acute otitis media in
typing depending on reagents used, slide children younger than 2 years or in children
agglu­tination serotyping and genotyping by 2 years or older with severe disease, oral
polymerase chain reaction are acceptable ­a moxicillin is recommended for 10 days. A
methods for capsule typing. If polymerase chain 7-day course is considered for children 2
reaction capsular typing is not available locally, through 5 years of age, and a 5-day course
isolates should be submitted to the state health can be used for older children. In the
department or to a reference ­laboratory for testing. United States, approximately 30% to 40% of
Otitis media attributable to H influenzae is H ­influenzae ­isolates produce β-lactamase,
diag­nosed by culture of tympanocentesis fluid; so amoxicillin may fail, necessitating use of
organisms isolated from other respiratory tract a β-lactamase–resistant agent, such as
swab specimens (eg, throat, ear drainage) may amoxicillin-­clavulanate, or an oral cephalo­
not be the same as those from middle-ear culture. sporin, such as cefdinir, cefuroxime, or cefpo-
doxime. Azithromycin is recommended for
Treatment children with an allergy to β-lactam antibiot-
Initial therapy for children with H influenzae ics. In vitro susceptibility testing of isolates
meningitis is intravenous cefotaxime or ceftri- from middle-ear fluid specimens helps guide
axone. Ampicillin should be substituted if the therapy in complicated or persistent cases.

Image 53.1
Image 53.2
Gram stain of cerebrospinal fluid (culture positive Haemophilus influenzae on chocolate agar. This
for Haemophilus influenzae type b). organism thrives on chocolate agar because of
the supplication of factors X and V required for its
growth. Individual colonies appear gray in color
and sometimes mucoid or glistening in quality.
Courtesy of Julia Rosebush, DO; Robert Jerris,
PhD; and Theresa Stanley, M(ASCP).

ERRNVPHGLFRVRUJ
202 HAEMOPHILUS INFLUENZAE INFECTIONS

Image 53.4
Image 53.3
Aggregatibacter (formerly Haemophilus)
This photograph depicts the colonial morphology
aphrophilus on chocolate agar. Colonies appear
displayed by gram-negative Haemophilus
to grow down into the plate. This organism, a
influenzae bacteria, which was grown on a medium
member of the A (H) aphrophilus, Actinobacillus
of chocolate agar for a 24-hour period at a
actinomycetemcomitans, Cardiobacterium
temperature of 37°C (98.6°F). Invasive disease
hominis, Eikenella corrodens, and Kingella
caused by H influenzae type b can affect many
species (HACEK) group, is associated with brain
organ systems. The most common types of
abscesses and endocarditis. Courtesy of Julia
invasive disease are pneumonia, occult febrile
Rosebush, DO; Robert Jerris, PhD; and Theresa
bacteremia, meningitis, epiglottitis, septic arthri­tis,
Stanley, M(ASCP).
cellulitis, otitis media, purulent pericarditis, and
other, less common infections, such as endocar­
ditis and osteomyelitis. Courtesy of Centers for
Disease Control and Prevention/Amanda Moore,
MT; Todd Parker, PhD; Audra Marsh.

Image 53.5
Haemophilus influenzae, invasive disease. Incidence by serotype among persons younger than 5
years—United States, 1999–2012. Courtesy of Morbidity and Mortality Weekly Report.

ERRNVPHGLFRVRUJ
HAEMOPHILUS INFLUENZAE INFECTIONS 203

Image 53.7
Image 53.6 A 16-month-old girl with periorbital and facial
Haemophilus influenzae type b periorbital cellulitis caused by Haemophilus influenzae
cellulitis. Courtesy of Neal Halsey, MD. type b. The patient had no history of trauma.
Copyright Martin G. Myers, MD.

Image 53.8
A 10-month-old white boy with periorbital
cellulitis due to Haemophilus influenzae type b. Image 53.9

Copyright Martin G. Myers, MD. Haemophilus influenzae type b cellulitis of the


face proved by positive subcutaneous aspirate
cultures and blood cultures. The cerebrospinal
fluid culture was negative. (This is the first of 3
preschool boys from the same child care center
who were examined within a period of 72 hours.)

Image 53.10
The second of 3 preschool-aged boys with Image 53.11

Haemophilus influenzae type b cellulitis of the A classic presentation of Haemophilus influenzae


face proved by positive subcutaneous aspirate type b (Hib) facial cellulitis in a 10-month-old
cultures and blood cultures. white girl. This once-common infection has been
nearly eliminated among children who have been
immunized with the Hib vaccine. Courtesy of
George Nankervis, MD.

ERRNVPHGLFRVRUJ
204 HAEMOPHILUS INFLUENZAE INFECTIONS

Image 53.12
Haemophilus influenzae type b cellulitis of the
arm proved by positive blood culture. Image 53.13
Haemophilus influenzae type b cellulitis of the
foot proved by positive blood culture.

Image 53.15
Acute Haemophilus influenzae type b epiglottitis
with striking erythema and swelling of the epiglot­
Image 53.14
tis. Courtesy of Edgar O. Ledbetter, MD, FAAP.
Acute epiglottitis due to Haemophilus influenzae
type b proved by blood culture. The swollen
inflamed epiglottis looks like the shadow of a
thumb on the lateral neck radiograph.

Image 53.17
Retrocardiac Haemophilus influenzae type b
pneumonia proved by blood culture. Note the air
bronchogram.

Image 53.16
Haemophilus influenzae type b pneumonia,
bilateral, in a patient with acute epiglottitis (proved
by blood culture). This is the same patient as in
Image 53.15.

ERRNVPHGLFRVRUJ
HAEMOPHILUS INFLUENZAE INFECTIONS 205

Image 53.19
Haemophilus influenzae type b bilateral
Image 53.18 pneumonia, empyema, and purulent pericarditis.
Air bronchogram of fulminant Haemophilus Pericardiostomy drainage is important in pre­
influenzae type b pneumonia of the right lung in a venting cardiac restriction.
child with congenital heart disease. Blood culture
was positive. Courtesy of Edgar O. Ledbetter,
MD, FAAP.

Image 53.21

Image 53.20 A 2-year-old boy with Haemophilus influenzae


Haemophilus influenzae type b sepsis with gan­ type b meningitis and subdural empyema. Note
grene of the hand. Courtesy of Neal Halsey, MD. the prominent anterior fontanelle secondary to
increased intracranial pressure. Copyright Martin
G. Myers, MD.

Image 53.22
Magnetic resonance image showing subdural
empyema that developed in a patient with
Haemophilus influenzae type b meningitis.
Image 53.23
Magnetic resonance image showing localized
cerebritis and vasculitis in a patient with
Haemophilus influenzae type b meningitis.

ERRNVPHGLFRVRUJ
206 HAEMOPHILUS INFLUENZAE INFECTIONS

Image 53.24
Magnetic resonance image showing cerebral infarction in a patient who had Haemophilus influenzae
type b (Hib) meningitis. The routine administration of Hib vaccine has virtually eliminated this type of
devastating illness in the United States.

Image 53.25
Haemophilus influenzae meningitis in a 4-month-old who was evaluated in the morning for a
well-child visit with normal clinical findings. By afternoon, the child had necrosis of the hands and feet
and died 12 hours later. This is the brain of the infant 24 hours after the well-child visit. No immunologic
deficit was diagnosed. Copyright Jerri Ann Jenista, MD.

ERRNVPHGLFRVRUJ
Hantavirus Pulmonary Syndrome 207

54 Etiology

Hantavirus Pulmonary Hantaviruses are RNA viruses of the Bunya-


viridae family. Sin Nombre virus is the major
Syndrome cause of HPS in the western and central
Clinical Manifestations regions of the United States. Bayou virus, Black
Creek Canal virus, Monongahela virus, and
Hantaviruses cause 2 distinct clinical syndromes: New York virus are responsible for sporadic
hantavirus pulmonary syndrome (HPS), a cases in Louisiana, Texas, Florida, New York,
­noncardiogenic pulmonary edema observed and other areas of the eastern United States.
in the western hemisphere; and hemorrhagic Hantavirus serotypes associated with HPS in
fever with renal syndrome, which occurs South and Central America include Andes
worldwide. The prodromal illness of HPS is 3 virus, Oran virus, Laguna Negra virus, and
to 7 days and is characterized by fever; chills; Choclo virus. During the past decade, Brazil,
headache; myalgia of the shoulders, lower back, Chile, and Argentina have reported most of
and thighs; nausea; vomiting; diarrhea; dizzi- the HPS cases in the Americas.
ness; and, sometimes, cough. Respiratory tract
symptoms or signs usually do not occur during Epidemiology
the prodrome, but pulmonary edema and severe Rodents, the natural hosts for hantaviruses,
hypoxemia appear abruptly after the onset of acquire lifelong, asymptomatic, chronic infec-
cough and dyspnea. The disease then progresses tion with prolonged viruria and virus in saliva,
over a number of hours. In severe cases, per­ urine, and feces. Humans acquire infection
sistent hypotension caused by myocardial dys- through direct contact with infected rodents,
function is present. In fatal cases, death occurs rodent droppings, or rodent nests or through
in 1 to 2 days following hospitalization. the inhalation of aerosolized virus particles
Extensive bilateral interstitial and alveolar from rodent urine, droppings, or saliva. Rarely,
­pulmonary edema and pleural effusions are infection may be acquired from rodent bites or
the result of a diffuse pulmonary capillary contamination of broken skin with excreta.
leak and appear to be immune mediated in Person-to-person transmission of hantaviruses
the endothelial cells of the microvasculature. has not been demonstrated in the United States
Endotracheal intubation and assisted ventila- but has been reported in Chile and Argentina.
tion are usually required for only 2 to 4 days, At-risk activities include handling or trapping
with resolution heralded by onset of diuresis rodents, cleaning or entering closed or rarely
and rapid clinical improvement. used rodent-infested structures, cleaning feed
storage or animal shelter areas, hand plowing,
The severe myocardial depression is different and living in a home with an increased density
from that of septic shock, with low cardiac of mice. For backpackers or campers, sleeping
indices and stroke volume index, normal in a structure also inhabited by rodents has
­pulmonary wedge pressure, and increased been associated with HPS. Weather conditions
­systemic vascular resistance. Poor prognostic resulting in exceptionally heavy rainfall and
indicators include persistent hypotension, improved rodent food supplies can result in a
marked hemoconcentration, a cardiac index large increase in the rodent population with
of less than 2, and abrupt onset of lactic acido- more frequent contact between humans and
sis with a serum lactate concentration of infected mice, resulting in an increase in
greater than 4 mmol/L (36 mg/dL). human disease. Most cases occur during the
The mortality rate for patients with HPS is spring and summer, with the geographic
between 30% and 40%. Asymptomatic and ­location determined by the habitat of the
milder forms of disease are rare. Limited rodent carrier.
­information suggests clinical manifestations Sin Nombre virus is transmitted by the deer
and prognosis are similar in adults and chil- mouse, Peromyscus maniculatus; Black Creek
dren. Serious sequelae are uncommon. Canal virus is transmitted by the cotton rat,
Sigmodon hispidus; Bayou virus is transmitted

ERRNVPHGLFRVRUJ
208 Hantavirus Pulmonary Syndrome

by the rice rat, Oryzomys palustris; and New ments and the Centers for Disease Control
York virus is transmitted by the white-footed and Prevention) and Western blot assays use
mouse, Peromyscus leucopus. recombinant antigens and have a high degree
of specificity for detection of IgG and IgM
Incubation Period
­a ntibody. Finally, immunohistochemistry in
1 to 6 weeks. tissues (staining of capillary endothelial cells
of the lungs and almost every organ in the
Diagnostic Tests
body) obtained from autopsy can also establish
Characteristic laboratory findings include neu- the diagnosis ­retrospectively.
trophilic leukocytosis with immature granulo-
cytes, including more than 10% immunoblasts, Treatment
thrombocytopenia, and increased hematocrit. Patients with suspected HPS should be trans-
Sin Nombre virus RNA has been detected by ferred immediately to a tertiary care facility
reverse transcriptase-polymerase chain reac- where supportive management of pulmonary
tion assay of peripheral blood mononuclear edema, severe hypoxemia, and hypotension
cells and other clinical specimens from the can occur during the first critical 24 to
early phase of the disease, frequently before 48 hours. In severe forms, early mechanical
the hospitalization. Viral RNA is not readily ventilation and inotropic and pressor support
detected in bronchoalveolar lavage fluids. are necessary. Extracorporeal membrane oxy-
genation should be considered when pulmo-
Hantavirus-specific immunoglobulin (Ig) M
nary wedge pressure and cardiac indices have
and IgG antibodies are often present at the
deteriorated and may provide short-term sup-
onset of clinical disease, and serologic testing
port for the severe capillary leak syndrome in
is the method of choice for diagnosis. IgG can
the lungs. Ribavirin is active in vitro against
be negative in rapidly fatal cases. Rapid diag-
hantaviruses, including Sin Nombre virus.
nosis can facilitate immediate appropriate
However, 2 clinical studies of intravenous
­supportive therapy and early transfer to a
­ribavirin failed to show benefit in treatment
­tertiary care facility. Enzyme immunoassay
of HPS in the cardiopulmonary stage.
(available through many state health depart-

Image 54.2
Image 54.1
Characteristics of Sin Nombre virus. Sin Nombre
Transmission electron micrograph of Sin Nombre
virus belongs to the family Bunyaviridae and
virus, a frequent cause of hantavirus pulmonary
contains 3 genomic RNA segments of negative
syndrome. Courtesy of Centers for Disease
polarity. The virion of Sin Nombre virus is spheri­
Control and Prevention/Photo credit: Cynthia
cal and is 80 to 120 nm in diameter. The virion
Goldsmith.
contains 2 glycoproteins, G1 and G2, located on
the outer surface, which are the nucleoprotein
and the viral polymerase. Courtesy of Centers
for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Hantavirus Pulmonary Syndrome 209

Image 54.3
Rodentborne hantavirus infections causing hemorrhagic fever with renal syndrome (HFRS) occur
throughout most of Europe and Russia. The clinical manifestations of hantavirus infection vary and
depend largely on the strain of the infecting virus. Classic HFRS is characterized by fever, acute renal
failure, hypotension, hemor­rhage, and vascular leakage. Acute tubular necrosis in a renal biopsy
specimen is shown in this photo­graph. Courtesy of Centers for Disease Control and Prevention/
Emerging Infectious Diseases.

Image 54.5
Deer mouse (Peromyscus maniculatus). The
deer mouse is a carrier of Sin Nombre virus,
Image 54.4
an etiologic agent of hantavirus pulmonary
Transmission of hantaviruses. The virus is hori­
syndrome. Courtesy of Centers for Disease
zontally transmitted between rodents through
Control and Prevention.
intraspecific aggressive behaviors, such as biting.
The virus is transmitted to humans from aerosol­
ized rodent excreta, particularly urine. Transmis­
sion to humans can also occur from inhalation
of secondary aerosols and from rodent bites or
other direct contact of infectious material with
mucous membranes or broken skin. Courtesy
of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
210 Hantavirus Pulmonary Syndrome

Image 54.6
This photograph depicts a cotton rat, Sigmodon hispidus, whose habitat includes the southeastern
United States and way down into Central and South America. Its body is larger than the deer mouse,
Peromyscus maniculatus, and measures about 5 to 7 inches, which includes the head and body; the
tail measures an additional 3 to 4 inches. Its hair is longer and coarser than P maniculatus and is a
grayish-brown color, sometimes grayish-black. The cotton rat prefers overgrown areas with shrubs
and tall grasses. The cotton rat is a hantavirus carrier that becomes a threat when it enters human
habitation in rural and suburban areas. Hantavirus pulmonary syndrome (HPS) is a deadly disease
transmitted by infected rodents through urine, droppings, or saliva. Humans can contract the disease
when they breathe in aerosolized virus. All hantaviruses known to cause HPS are carried by western
hemisphere rats and mice of the family Muridae, subfamily Sigmodontinae. Courtesy of Centers for
Disease Control and Prevention/James Gathany.

Image 54.7
Hantavirus pulmonary syndrome. Number of reported cases by survival status and year in the United
States, 1997–2006. Courtesy of Morbidity and Mortality Weekly Report.

ERRNVPHGLFRVRUJ
Hantavirus Pulmonary Syndrome 211

Image 54.9
Histopathologic features of lung in hantavirus
Image 54.8 pulmonary syndrome include interstitial
Hantavirus pulmonary syndrome in a 16-year-old pneumonitis and intra-alveolar edema. Courtesy
boy with a 36-hour history of fever, myalgia, and of Centers for Disease Control and Prevention/
shortness of breath. Diffuse interstitial infiltrates Dr Sherif R. Zaki.
with Kerley B lines. Diffuse nodular confluent
alveolar opacities with some consolidation con­
sistent with adult respiratory distress syndrome.
Hantavirus serology confirmatory by immuno­
globulin M at 1:6,400. Patient recovered with
supportive care including inhaled nitric oxide.
Copyright David Waagner.

Image 54.11
This photograph shows liver tissue from a patient
with hantavirus pulmonary syndrome. Courtesy
of Centers for Disease Control and Prevention.

Image 54.10
Radiographic findings of hantavirus pulmonary
syndrome. Findings usually include interstitial
edema, Kerley B lines, hilar indistinctness, and
peribronchial cuffing with normal cardiothoracic
ratios. Hantavirus pulmonary syndrome begins
with minimal changes of interstitial pulmonary
edema and rapidly progresses to alveolar edema
with severe bilateral involvement. Pleural Image 54.12
effusions are common and are often large This photograph shows splenic tissue from a
enough to be evident radiographically. Courtesy patient with hantavirus pulmonary syndrome
of Centers for Disease Control and Prevention. (HPS). In HPS splenic histopathology, one will
note a lymphohistiocytic infiltrate throughout the
red pulp region and concentrated to some extent
in the periarteriolar white pulp area as well.
Courtesy of Centers for Disease Control and
Prevention.

ERRNVPHGLFRVRUJ
212 Hantavirus Pulmonary Syndrome

Image 54.13
Common laboratory findings. Notable hematologic findings include low platelet count, immunoblasts,
left shift on white blood cell count differential, elevated white blood cell count, and elevated hematocrit.
The large atypical lymphocyte shown here is an example of one of the laboratory findings that, when
combined with a bandemia and dropping platelet count, are characteristic of hantavirus pulmonary
syndrome. Notable blood chemistry findings include low albumin, elevated lactate dehydrogenase,
elevated aspartate aminotransferase, and elevated alanine aminotransferase. Courtesy of Centers for
Disease Control and Prevention.

Image 54.14
Clinical course of hantavirus pulmonary syndrome starts with a febrile prodrome that may ultimately
lead to hypotension and end-organ failure. The onset of the immune response precedes severe organ
failure, which is thought to be immunopathologic in nature. Hypotension does not result in shock until
the onset of respiratory failure, but this may reflect the severe physiological effect of lung edema.
Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
HELICOBACTER PYLORI ­INFECTIONS 213

55 are asymptomatic, 20% of people have macro-


scopic (ie, visual) and microscopic findings of
Helicobacter pylori ulceration, and an estimated 1% have features
­Infections of neoplasia.
Clinical Manifestations Incubation Period
Helicobacter pylori causes chronic active gastri- Unknown.
tis and can result in duodenal and, to a lesser
Diagnostic Tests
extent, gastric ulcers. Persistent infection with
H pylori increases the risk of gastric cancer. In H pylori infection can be diagnosed by culture
children, H pylori infection can result in gas- of gastric biopsy tissue on nonselective or
troduodenal inflammation that can manifest as selective media at 37°C (98.6°F) under micro-
epigastric pain, nausea, vomiting, hemateme- aerobic conditions for 3 to 7 days. The organ-
sis, and guaiac-positive stools. Symptoms can ism can also be identified by polymerase chain
resolve within a few days or can wax and wane. reaction or fluorescence in situ hybridization
Extraintestinal conditions in children that of gastric biopsy tissue. Organisms can usually
have been associated with H pylori infection be visualized on histologic sections with
can include iron deficiency anemia and short ­Warthin-Starry silver, Steiner, Giemsa, or
stature. However, most infections are thought Genta staining. Because of production of urease
to be asymptomatic. Moreover, there is no clear by organisms, urease testing of a gastric speci-
association between infection and recurrent men can give a rapid and specific microbiologic
abdominal pain, in the absence of peptic ulcer diagnosis. Each of these tests requires endos-
disease. The organism can persist in the stom- copy and biopsy. The first H pylori breath test
ach for years or for life. H pylori infection is not for children 3 to 17 years of age became avail-
associated with secondary gastritis (eg, autoim- able in 2012. A stool antigen test (by enzyme
mune, associated with nonsteroidal anti- immunoassay) is also available and can be used
inflammatory agents). for children of any age, especially before and
after treatment. Each of these commercially
Etiology available tests for active infection (ie, breath or
H pylori is a gram-negative, spiral, curved, stool tests) has a high sensitivity and s­ pecificity.
or U-shaped microaerophilic bacillus that
Treatment
has single or multiple flagella at one end.
The organism is catalase, oxidase, and Treatment is recommended for infected
­urease ­positive. patients who have peptic ulcer disease (cur-
rently or in the past 1–5 years), gastric mucosa–
Epidemiology associated lymphoid tissue-type lymphoma, or
H pylori organisms have been isolated from early gastric cancer. Screening for and treat-
humans and other primates. An animal reser- ment of infection, if found, can be considered
voir for human transmission has not been for children with one or more primary relatives
demonstrated. Organisms are thought to be with gastric cancer, children who are in a high-
transmitted from infected humans by the risk group for gastric cancer (eg, immigrants
­fecal-oral, gastro-oral, and oral-oral routes. from resource-limited countries or countries
Nearly half of the world’s population is with high rates of gastric cancer), or children
infected with H pylori, with a disproportion- who have unexplained iron deficiency anemia.
ally high prevalence rate in resource-limited Treatment may also be considered if infection
countries. Infection rates are low in children is found at the time of diagnostic endoscopy.
in resource-rich, industrialized countries,
A number of treatment regimens have been
except in children from lower socioeconomic
evaluated and are approved for use in adults;
groups. Most infections are acquired in the
the safety and efficacy of these regimens in
first 5 years of life and can reach prevalence
pediatric patients have not been established.
rates of up to 80% in resource-limited coun-
First-line eradication regimens include triple
tries. Approximately 70% of infected people

ERRNVPHGLFRVRUJ
214 HELICOBACTER PYLORI ­INFECTIONS

therapy with a proton pump inhibitor (PPI) include bismuth subsalicylate plus metronida-
plus amoxicillin plus clarithromycin or metro- zole plus tetracycline plus either a PPI or an
nidazole, or bismuth salts plus amoxicillin plus H2-receptor antagonist (eg, cimetidine, famoti-
metronidazole. An alternative sequential regi- dine, nizatidine, ranitidine), or bismuth sub­
men that may be more effective includes dual citrate potassium plus metronidazole plus
therapy with amoxicillin and a PPI for 5 days, tetracycline plus omeprazole. A breath or stool
followed by 5 days of triple therapy (a PPI plus test may be performed as follow-up to docu-
clarithromycin and metronidazole). These regi- ment organism eradication 4 to 8 weeks after
mens are effective in eliminating the organism, completion of therapy, although the stool anti-
healing the ulcer, and preventing recurrence. gen test result can remain positive for up to
Alternate therapies in people 8 years and older 90 days after treatment.

Image 55.1 Image 55.2


Histology of the gastric mucosa demonstrates A biopsy of gastric mucosa stained with Warthin-
the characteristic curved organisms in the gastric Starry silver stain showing Helicobacter pylori
glands. Courtesy of H. Cody Meissner, MD, organisms. Courtesy of Brian Oliver, MD.
FAAP.

Image 55.3
Helicobacter pylori infection is a known risk factor for gastritis and duodenal ulcers in children and
adults. Rarely, and primarily in older adulthood, H pylori is also associated with a gastric lymphoma
of the mucosal-associated lymphoid tissue. The gold standard for the diagnosis of H pylori infection
of the stomach is endoscopy with biopsy. Endoscopy may show a nodular gastritis of the antrum.
Courtesy of H. Cody Meissner, MD, FAAP.

ERRNVPHGLFRVRUJ
Hemorrhagic Fevers Caused by Arenaviruses 215

56 Etiology

Hemorrhagic Fevers Arenaviruses are single-stranded RNA viruses.


The major arenavirus HFs occurring in the
Caused by Arenaviruses western hemisphere are caused by the Tacaribe
Clinical Manifestations serocomplex of arenaviruses: Argentine HF
caused by Junin virus, Bolivian HF caused by
Arenaviruses are responsible for several hem- Machupo virus, and Venezuelan HF caused by
orrhagic fevers (HFs): LCMV-LASV complex Guanarito virus. A fourth arenavirus, Sabia
(formerly Old World) arenavirus HFs include virus, has been recognized to cause 2 unrelated
Lassa fever and the recently described Lujo cases of naturally occurring HF in Brazil and
virus infections; Tacaribe complex (formerly 2 laboratory-acquired cases. Chapare virus
New World) arenavirus HFs include Argentine, has been isolated from a fatal human case in
Bolivian, Brazilian, Venezuelan, and Chapare Bolivia. The LCMV-LASV complex of arena­
virus infection. Lymphocytic choriomeningitis viruses includes Lassa virus, which causes
virus is an arenavirus that generally induces Lassa fever in West Africa, as well as Lujo
less severe disease, although it can cause HFs virus, which was described in southern Africa
in immunosuppressed patients; it is discussed during an outbreak characterized by fatal
in a separate chapter. Disease associated with human-to-human transmission. Several other
arenaviruses ranges in severity from mild, arenaviruses are known only from their rodent
acute, febrile infections to severe illnesses in reservoirs in both hemispheres.
which vascular leak, shock, and multiorgan
dysfunction are prominent features. Fever, Epidemiology
headache, myalgia, conjunctival suffusion, Arenaviruses are maintained in nature by
retro-orbital pain, facial flushing, bleeding, ­association with specific rodent hosts, in which
and abdominal pain are common early symp- they produce chronic viremia and viruria. The
toms in all infections. Thrombocytopenia, principal routes of infection are inhalation
­leukopenia, axillary petechiae, generalized and contact of mucous membranes and skin
lymphadenopathy, and encephalopathy are (ie, through cuts, scratches, or abrasions) with
usually present in Argentine HF, Bolivian HF, urine and salivary secretions from these persis-
and Venezuelan HF, and exudative pharyngitis tently infected rodents. Ingestion of food con-
often occurs in Lassa fever. Mucosal bleeding taminated by rodent excrement may also cause
occurs in severe cases as a consequence of vas- disease transmission. All arenaviruses are
cular damage, thrombocytopenia, and platelet infectious as aerosols, and arenaviruses caus-
dysfunction. Proteinuria is common, but renal ing HF should be considered highly hazardous
failure is unusual. Increased serum concentra- to people working with any of these viruses in
tions of aspartate transaminase can portend a the laboratory. Laboratory-acquired infections
severe or possibly fatal outcome of Lassa fever. have been documented with Lassa, Machupo,
Shock develops 7 to 9 days after onset of illness Junin, and Sabia viruses. The geographic distri-
in more severely ill patients with these infec- bution and habitats of the specific rodents that
tions. Upper and lower respiratory tract symp- serve as reservoir hosts largely determine the
toms can develop in people with Lassa fever. areas with endemic infection and the popula-
Encephalopathic signs, such as tremor, altera- tions at risk. Before a vaccine became available
tions in consciousness, and seizures, can occur in Argentina, several hundred cases of Argen-
in South American HFs and in severe cases of tine HF occurred annually in agricultural
Lassa fever. Transitory deafness is reported in workers and inhabitants of the Argentine
30% of early convalescents of Lassa fever. The ­pampas. The Argentine HF vaccine is not
mortality rate in South American HFs is 15% licensed in the United States. Epidemics of
to 30%. Bolivian HF occurred in small towns between
1962 and 1964; sporadic disease activity in
the countryside has continued since then.

ERRNVPHGLFRVRUJ
216 Hemorrhagic Fevers Caused by Arenaviruses

­ enezuelan HF was first identified in 1989 and


V fatal cases. The IgG antibody response is
occurs in rural north-central Venezuela. Lassa delayed. Diagnosis can be made retrospectively
fever is endemic in most of West Africa, where by immunohistochemistry in formalin-fixed
rodent hosts live in proximity with humans, tissues obtained from autopsy.
causing thousands of infections annually. Lassa
Treatment
fever has been reported in the United States
and Western Europe in people who have trav- Intravenous ribavirin substantially decreases
eled to West Africa. the mortality rate in patients with severe Lassa
fever, particularly if they are treated during the
Incubation Period first week of illness. For Argentine HF, trans­
6 to 17 days. fusion of immune plasma in defined doses of
neutralizing antibodies is the standard specific
Diagnostic Tests
treatment when administered during the first
Viral nucleic acid can be detected in acute 8 days from onset of symptoms. Intravenous
­disease by reverse transcriptase-polymerase ribavirin has been used with success to abort a
chain reaction assay. These viruses can be iso- Sabia laboratory infection and to treat Bolivian
lated from blood of acutely ill patients as well HF patients and the only Lujo infection survi-
as from various tissues obtained postmortem, vor. Ribavirin did not reduce mortality when
but isolation should be attempted only under initiated 8 days or more after onset of Argen-
Biosafety level 4 conditions. Virus antigen is tine HF symptoms. Whether ribavirin treat-
detectable by enzyme immunoassay in acute ment initiated early in the course of the disease
specimens and postmortem tissues. Virus-­ has a role in the treatment of Argentine HF
specific immunoglobulin (Ig) M antibodies remains unknown. Meticulous fluid balance
are present in the serum during acute stages is an important aspect of supportive care in
of illness but may be undetectable in rapidly each of the HFs.

Image 56.1
Image 56.2
This photomicrograph shows hepatitis caused Electron micrograph of Arenaviridae Tacaribe
by the Lassa virus (toluidine-blue azure II stain). complex arenaviruses. Arenaviridae are RNA
The Lassa virus, which can cause altered liver viruses whose particles are spherical and
morphology with hemorrhagic necrosis and have an average diameter of 110 to 130 nm.
inflammation, is a member of the family Arenaviridae members are zoonotic, which
Arenaviridae and is a single-stranded RNA, means in nature, they are found in reservoir
zoonotic, or animal-borne pathogen. Courtesy animal hosts—primarily rodents. Courtesy of
of Centers for Disease Control and Prevention/ Centers for Disease Control and Prevention/
Dr Fred Murphy; Sylvia Whitfield. E. L. Palmer.

ERRNVPHGLFRVRUJ
Hemorrhagic Fevers Caused by Arenaviruses 217

Image 56.3
This transmission electron micrograph depicts virions (viral particles) that are members of the genus
Arenavirus. Arenaviruses include lympho­cytic choriomeningitis virus and the agents of 5 hemorrhagic
fevers, including West African Lassa fever virus and Bolivian hemorrhagic fever, also known as
Machupo virus. Spread to humans occurs through inhalation of airborne particulates originating
from rodent excrement, which can occur during the simple act of sweeping a floor. Courtesy of
Centers for Disease Control and Prevention/Charles Humphrey.

Image 56.4
Electron photomicrograph of the Machupo virus. Machupo virus is a member of the arenavirus
family, isolated in the Beni province of Bolivia in 1963; viral hemorrhagic fever. Courtesy of Centers
for Disease Control and Prevention/Dr W. Winn.

ERRNVPHGLFRVRUJ
218 Hemorrhagic Fevers Caused by Bunyaviruses

57 Rift Valley fever (RVF), in most cases, is a


­self-limited, undifferentiated febrile illness.
Hemorrhagic Fevers Occasionally, hemorrhagic fever with shock
Caused by Bunyaviruses and icteric hepatitis, encephalitis, or retini-
tis develops.
Clinical Manifestations
Etiology
Bunyaviruses are vectorborne infections
(except for hantavirus) that often result in Bunyaviridae are single-stranded RNA viruses
severe febrile disease with multisystem involve- with different geographic distributions
ment. Human infection by bunyaviruses can depending on their vector or reservoir.
be associated with high rates of morbidity ­Hemorrhagic fever syndromes are associated
and mortality. In the United States, disease with viruses from 3 genera: hantaviruses,
attributable to a bunyavirus is most likely ­Nairovirus (CCHF virus), and Phlebovirus
caused by hantavirus or members of the (RVF, Heartland virus in the United States,
­California ­serogroup. sandfly fever viruses in Europe, and severe
fever with thrombocytopenia syndrome virus
Hemorrhagic fever with renal syndrome in China). Old World hantaviruses (Hantaan,
(HFRS) is a complex, multiphasic disease Seoul, Dobrava, and Puumala viruses) cause
­characterized by vascular instability and HFRS, and New World hantaviruses (Sin
­varying degrees of renal insufficiency. Fever, ­Nombre and related viruses) cause hantavirus
flushing, conjunctival injection, headache, pulmonary syndrome.
blurred vision, abdominal pain, and lumbar
pain are followed by hypotension, oliguria, Epidemiology
and, subsequently, polyuria. Petechiae are The epidemiology of these diseases is mainly
­frequent, but more serious bleeding mani­ a function of the distribution and behavior
festations are rare. Shock and acute renal of their reservoirs and vectors. All genera
­insufficiency may occur. Nephropathia epi- except hantaviruses are associated with
demica (attributable to Puumala virus) occurs ­arthropod vectors, and hantavirus infections
in Europe and presents as a milder disease are associated with airborne exposure to
with acute influenza-like illness, abdominal infected wild rodents, primarily via inhalation
pain, and proteinuria. Acute renal dysfunction of virus-contaminated urine, droppings, or
also occurs, but hypotensive shock or require- nesting ­materials.
ment for dialysis is rare. However, more severe
forms of HFRS (ie, attributable to Dobrava-­ Classic HFRS occurs throughout much of Asia
Belgrade virus) also occur in Europe. and Eastern and Western Europe, with up to
100,000 cases per year. The most severe form of
Crimean-Congo hemorrhagic fever (CCHF) the disease is caused by the prototype Hantaan
is a multisystem disease characterized by hepa- virus and Dobrava-Belgrade viruses in rural
titis and profuse bleeding. Fever, headache, and Asia and Europe, respectively; Puumala virus
myalgia are followed by signs of a diffuse capil- is associated with milder disease (nephropathia
lary leak syndrome with facial suffusion, con- epidemica) in Western Europe. Seoul virus is
junctivitis, icteric hepatitis, proteinuria, and distributed worldwide in association with
disseminated intravascular coagulation asso­ ­Rattus species and can cause a disease of vari-
ciated with petechiae and purpura on the skin able severity. Person-to-person transmission
and mucous membranes. A hypotensive crisis never has been reported with HFRS.
often occurs after the appearance of frank
hemorrhage from the gastrointestinal tract, Crimean-Congo hemorrhagic fever occurs in
nose, mouth, or uterus. Mortality rates range much of sub-Saharan Africa, the Middle East,
from 20% to 35%. areas in West and Central Asia, and the Bal-
kans. Crimean-Congo hemorrhagic fever virus
is transmitted by ticks and occasionally by

ERRNVPHGLFRVRUJ
Hemorrhagic Fevers Caused by Bunyaviruses 219

c­ ontact with viremic livestock and wild antibodies typically develop early in convales-
­animals at slaughter. Health care–associated cence in CCHF and RVF but could be absent
transmission of CCHF is a frequent and seri- in rapidly fatal cases of CCHF. In HFRS, IgM
ous hazard. and IgG antibodies are usually detectable at
the time of onset of illness or within 48 hours,
Rift Valley fever occurs throughout sub-­
when it is too late for virus isolation and poly-
Saharan Africa and has caused large epidemics
merase chain reaction assay. IgM antibodies
in Egypt in 1977 and 1993–1995, Mauritania in
or rising IgG titers in paired serum specimens,
1987, Saudi Arabia and Yemen in 2000, Kenya
as demonstrated by enzyme immunoassay, are
in 1997 and 2006–2007, Madagascar in 1990
diagnostic; neutralizing antibody tests provide
and 2008, and South Africa in 2010. The virus
greater virus-strain specificity but are rarely
is arthropodborne and is transmitted from
utilized. Diagnosis can be made retrospectively
domestic livestock to humans by mosquitoes.
by immunohistochemistry assay of formalin-
The virus can also be transmitted by aerosol
fixed tissues obtained from necropsy.
and by direct contact with infected aborted
tissues or freshly slaughtered infected animal Treatment
carcasses. Person-to-person transmission has Ribavirin administered intravenously to
not been reported. patients with HFRS within the first 4 days of
Incubation Period illness may be effective in decreasing renal dys-
function, vascular instability, and mortality.
Crimean-Congo hemorrhagic fever and RVF,
However, intravenous ribavirin is not available
2 to 10 days; HFRS, 7 to 42 days.
commercially in the United States. Health care
Diagnostic Tests professionals who need to obtain intravenous
ribavirin should contact the manufacture. Sup-
Crimean-Congo hemorrhagic fever and RVF
portive therapy for HFRS should include treat-
viruses can be cultivated readily (in a Biosafety
ment of shock, monitoring of fluid balance,
level 4 laboratory) from blood and tissue speci-
dialysis for complications of renal failure, con-
mens of infected patients. Polymerase chain
trol of hypertension during the oliguric phase,
reaction assays performed with appropriate
and early recognition of possible myocardial
safety precautions are usually sensitive on
failure with appropriate therapy.
­samples obtained during the acute phase of
CCHF and RVF but less for HFRS. Detection Oral and intravenous ribavirin given to
of viral antigen by enzyme immunoassay is a patients with CCHF has been associated
useful alternative for CCHF and RVF. Serum with milder disease, although no controlled
immunoglobulin (Ig) M and IgG virus-specific studies have been performed.

ERRNVPHGLFRVRUJ
220 Hemorrhagic Fevers Caused by Bunyaviruses

Image 57.2
Isolated male patient diagnosed with Crimean-
Congo hemorrhagic fever, a tick-borne
hemorrhagic fever with documented person-to-
person transmission and a case-fatality rate of
approximately 30%. This widespread virus has
been found in Africa, Asia, the Middle East, and
eastern Europe. Courtesy of Centers for Disease
Control and Prevention/Dr B.E. Henderson.

Image 57.1
Electron micrograph of the Rift Valley fever virus,
which is a member of the genus Phlebovirus in
the family Bunyaviridae, first reported in livestock
in Kenya around 1900. Courtesy of Centers for
Disease Control and Prevention/Dr Fred Murphy.

Image 57.3
Intubated patient with Crimean-Congo hemorrhagic fever, Republic of Georgia, 2009, showing
massive ecchymoses on the upper extremities that extend to the chest. Courtesy of Emerging
Infectious Diseases.

ERRNVPHGLFRVRUJ
Hemorrhagic Fevers Caused by Filoviruses: Ebola and Marburg 221

58 ­ sually resulting from viral- or bacterial-


u
induced septic shock and multiorgan system
Hemorrhagic Fevers failure. Approximately 30% of pregnant women
Caused by Filoviruses: with Ebola virus disease present with sponta-
neous abortion and vaginal bleeding. Maternal
Ebola and Marburg mortality approaches 90% when infection
Clinical Manifestations occurs during the third trimester. All neonates
Information on Ebola and Marburg virus born to mothers with active Ebola virus disease
infections is primarily derived from adult to date have died. The exact cause of the neo­
­populations. More is known about Ebola virus natal deaths is unknown, but high viral loads
disease than Marburg virus disease, although of Ebola virus have been documented in amni-
the same principles apply generally to all filo­ otic fluid, placental tissue, and fetal tissues of
viruses that cause human disease. Asymptom- stillborn neonates.
atic cases of human filovirus infections have Etiology
been reported, and symptomatic disease ranges
The Filoviridae (from the Latin filo meaning
from mild to severe; case fatality rates for
thread, referring to their filamentous shape)
severely affected people range from 25% to
are single-stranded, negative-sense RNA
90% (approximately 70% in the 2014 outbreak).
viruses. Four of the 5 species of virus in the
Onset in children and adults begins with non-
Ebola virus genus and both of the known
specific signs and symptoms, including fever,
­species of virus in the Marburg virus genus
headache, myalgia, abdominal pain, and weak-
are associated with human disease. All of the
ness, followed several days later by vomiting,
known human pathogenic filoviruses are
diarrhea, and unexplained bleeding or bruis-
endemic only in sub-Saharan Africa.
ing. Respiratory symptoms are more common
in children, and central nervous system mani- Epidemiology
festations are more common in adults. A fleet-
Fruit bats are believed to be the animal
ing maculopapular rash on the torso or face
­reservoir for Ebola virus. Human infection is
after approximately 4 to 5 days of illness can
believed to occur from inadvertent exposure
occur. Conjunctival injection or subconjunc­
to infected bat excreta or saliva following entry
tival hemorrhage can be present. Hepatic
into roosting areas in caves, mines, and forests.
­dysfunction, with elevations in aspartate
Nonhuman primates, especially gorillas and
­transaminase markedly higher than alanine
chimpanzees, and other wild animals can also
transaminase, and metabolic derangements,
become infected from bat contact and serve as
including hypokalemia, hyponatremia, hypo-
intermediate hosts that transmit filoviruses to
calcemia, and hypomagnesemia, are common.
humans through contact with their blood and
In the most severe cases, microvascular insta-
body fluids, usually associated with hunting
bility ensues around the end of the first week
and medical work. For unclear reasons, filo­
of disease. Although hemostasis is impaired,
virus outbreaks tend to occur after prolonged
hemorrhagic manifestations develop in a
dry seasons.
minority of patients. In the 2001 Uganda
Sudan Ebola virus outbreak, all children with Although filoviruses are the most transmissible
laboratory-confirmed Ebola virus disease were of all hemorrhagic fever viruses, secondary
febrile, and only 16% had hemorrhage. The attack rates in households are generally still
most common hemorrhagic manifestations only 15% to 20% in African communities and
consist of bleeding from the gastrointestinal are lower if proper universal and contact pre-
tract, sometimes with oozing from the mucous cautions are maintained. Human-to-human
membranes or venipuncture sites in the late transmission usually occurs through oral,
stages. Central nervous system manifestations mucous membrane, or nonintact skin exposure
and renal failure are frequent in end-stage to body fluids of a symptomatic person with
­disease. In fatal cases, death typically occurs filovirus disease, most often in the context of
around 10 to 12 days after symptom onset, providing care to a sick family or community

ERRNVPHGLFRVRUJ
222 Hemorrhagic Fevers Caused by Filoviruses: Ebola and Marburg

member (community transmission) or patient virus ­disease can be diagnosed by testing of


(health care–associated transmission). Funeral blood by reverse transcriptase-polymerase
rituals that entail touching of the corpse have chain reaction assay, enzyme-linked immuno-
also been implicated, as has transmission sorbent assay for viral antigens or immuno-
through breastfeeding from infected mothers. globulin (Ig) M, and cell culture, with the latter
Health care–associated transmission is highly being attempted only under Biosafety level
unlikely if rigorous infection control practices 4 conditions. Viral RNA is generally detectable
are in place in health care facilities. Ebola is by reverse transcriptase-polymerase chain
not spread through the air, by water, or, in reaction assay within 3 to 10 days after the
­general, by food. Respiratory spread of virus onset of symptoms. Postmortem diagnosis
does not occur. can be made via immunohistochemistry
­testing of skin, liver, or spleen. Local or state
The degree of viremia appears to correlate with
public health department officials must be
the clinical state. People are most infectious
­contacted and can facilitate testing at a
late in the course of severe disease, especially
regional certified laboratory or at the Centers
when copious vomiting, diarrhea, or bleeding
for Disease Control and Prevention.
is present. Transmission during the incubation
period, when the person is asymptomatic, is Treatment
not believed to occur. Virus may persist in a People suspected of having Ebola or Marburg
few immunologically protected sites for several virus infection should immediately be placed
weeks after clinical recovery, including in tes- in isolation, and public health officials should
ticles/semen, human milk, and chambers of be notified. Management of patients with filo-
the eye (resulting in transient uveitis and other virus disease is primarily supportive, including
ocular problems). Because of the risk of sexual oral or intravenous fluids with electrolyte
transmission, abstinence or use of condoms is repletion, vasopressors, blood products, total
recommended for 3 months after recovery. parenteral nutrition, and antimalarial and
The 2014 West Africa Ebola outbreak is the antibiotic medications when coinfections are
largest since the virus was first identified in suspected or confirmed. Volume losses can be
1976 and the first in that region of the conti- enormous (10 L/d in adults), and some centers
nent. A simultaneous outbreak of Ebola report better results with repletion using lac-
occurred in the Democratic Republic of the tated Ringer injection rather than normal
Congo (formerly Zaire), but this outbreak was saline solution in management of adult patients
caused by a different species than the species in the United States. When antibiotics are used
causing the outbreak in West Africa. to empirically treat sepsis, these should be
active against intestinal microbiota that can
Incubation Period be translocated from the gut into the blood of
8 to 10 days (range, 2–21 days). patients with filovirus disease. Nonsteroidal
anti-inflammatory drugs, aspirin, and intra-
Diagnostic Tests muscular injections should be avoided because
The diagnosis of Ebola virus infection should of the risk of bleeding.
be considered in a person who develops a fever
Ribavirin has no efficacy against filoviruses
within 21 days of travel to an endemic area.
and should not be used. Corticosteroids should
Because initial clinical manifestations are
not be administered except for replacement in
­difficult to distinguish from those of more
suspected or confirmed adrenal insufficiency
common febrile diseases, prompt laboratory
or refractory septic shock.
testing is imperative in a suspected case. Filo­

ERRNVPHGLFRVRUJ
Hemorrhagic Fevers Caused by Filoviruses: Ebola and Marburg 223

Image 58.1
This colorized negative stained transmission electron micrograph, captured by F.A. Murphy in 1968,
depicts a number of Marburg virus virions, which had been grown in an environment of tissue culture
cells. Marburg hemorrhagic fever is a rare, severe type of hemorrhagic fever that affects humans and
nonhuman primates. Caused by a genetically unique zoonotic (ie, animalborne) RNA virus of the
Filovirus family, its recognition led to the creation of this virus family. The 4 species of Ebola virus are
the only other known members of the Filovirus family. After an incubation period of 5 to 10 days, onset
of the disease is sudden and is marked by fever, chills, headache, and myalgia. Around the fifth day
after the onset of symptoms, a maculopapular rash, most prominent on the trunk (ie, chest, back,
stomach), may occur. Nausea, vomiting, chest pain, a sore throat, abdominal pain, and diarrhea may
then appear. Symptoms become increasingly severe and may include jaundice, inflammation of the
pancreas, severe weight loss, delirium, shock, liver failure, and multiorgan dysfunction. Because
many of the signs and symptoms of Marburg hemorrhagic fever are similar to those of other infectious
diseases, such as malaria or typhoid fever, diagnosis of the disease can be difficult, especially if only
a single case is involved. Courtesy of Centers for Disease Control and Prevention/Frederick Murphy,
MD.

Image 58.2
This electron micrograph shows a thin section containing the Ebola virus, the causative agent for
African hemorrhagic fever. Courtesy of Centers for Disease Control and Prevention/Frederick Murphy, MD.

ERRNVPHGLFRVRUJ
224 Hemorrhagic Fevers Caused by Filoviruses: Ebola and Marburg

Image 58.3
This map illustrates the geographic distribution, as of October 10, 2014, of the West African Ebola
outbreak and demarcates some of the salient focal points involved in the epidemiologic investigation
of what became an international epidemic, including the location of Ebola treatment units, field
laboratories, transit centers, and hospitals. Also indicated were the regions where there were newly
active and previously active cases and areas where there were no suspected cases. The 2014 Ebola
outbreak is one of the largest Ebola outbreaks in history and the first in West Africa. At the time of this
map’s creation, countries classified as sustaining “widespread transmission” included Guinea, Liberia,
and Sierra Leone. Countries exhibiting “localized transmission” included Nigeria (Port Harcourt and
Lagos), Spain (Madrid), and the United States (Dallas, TX). Finally, Senegal exhibited a single case in
its capital city of Dakar. Courtesy of World Health Organization.

Image 58.4
Under a high magnification of x400, this hematoxylin-eosin–stained photomicrograph depicts the
cytoarchitectural changes found in a liver tissue specimen extracted from a patient with Ebola virus
infection in the Democratic Republic of the Congo. This particular view reveals an acidophilic necrosis
leading to the formation of a Councilman body and cytoplasmic inclusions. A steatotic (fatty change)
vesicle was caught in the process of formation. Courtesy of Centers for Disease Control and Prevention/
Dr Yves Robin and Dr Jean Renaudet, Arbovirus Laboratory at the Pasteur Institute in Dakar, Senegal;
World Health Organization.

ERRNVPHGLFRVRUJ
Hemorrhagic Fevers Caused by Filoviruses: Ebola and Marburg 225

Image 58.5
This photomicrograph revealed the cytoarchitectural histopathologic changes detected in a lung
biopsy tissue section from a patient with Marburg virus infection who was treated in Johannesburg,
South Africa. Note the necrotic changes indicated by the breakdown of the alveolar walls resulting in
pulmonary edema. There is also the presence of numerous alveolar macrophages due to the Filovirus
infiltrate. Courtesy of Centers for Disease Control and Prevention/Dr J. Lyle Conrad.

Image 58.6
This patient with Marburg virus infection presented with a measleslike rash located on her back and
was hospitalized in Johannesburg, South Africa, in 1975. This type of maculopapular rash, which
can appear on patient with Marburg virus infection around the fifth day after the onset of symptoms,
may usually be found on the patient’s chest, back, and stomach. This patient’s skin blanched under
pressure, which is a common characteristic of a Marburg virus rash. Courtesy of Centers for Disease
Control and Prevention/Dr J. Lyle Conrad.

ERRNVPHGLFRVRUJ
226 Hepatitis A

59 of states and communities, disappeared after


introduction of targeted immunization in 1999.
Hepatitis A Rates in the United States were 1.0 per 100,000
Clinical Manifestations population in 2007, which was the year hepati-
tis A vaccine was recommended for routine use
Hepatitis A characteristically is an acute, self- in all US children 12 through 23 months of age,
limited illness associated with fever, malaise, and declined to 0.4 per 100,000 in 2011. The
jaundice, anorexia, and nausea. Symptomatic 1,398 HAV cases in 2011 represented the lowest
hepatitis A virus (HAV) infection occurs in number ever recorded; rates have plateaued
approximately 30% of infected children younger since then. An increasing proportion of adults
than 6 years; few of these children will have in the United States are susceptible to hepatitis
jaundice. Among older children and adults, A because of reduced exposure to HAV earlier
infection is usually symptomatic and typically in life. The mean age of people hospitalized
lasts several weeks, with jaundice occurring for HAV infection has increased significantly
in 70% or more. Signs and symptoms typically between 2002 and 2011 (mean age of 37.6 years
last less than 2 months, although 10% to 15% of in 2002–2003, compared with 45.5 years in
symptomatic people have prolonged or relaps- 2010–2011).
ing disease lasting as long as 6 months. Fulmi-
nant hepatitis is rare but is more common in Among reported cases of hepatitis A, recog-
people with underlying liver disease. Chronic nized risk factors include close personal
infection does not occur. ­contact with a person infected with HAV,
international travel, household or personal
Etiology contact with a child who attends a child care
Hepatitis A virus is an RNA virus classified as center, household or personal contact with a
a member of the Picornaviridae family, genus newly arriving international adoptee, a recog-
Hepatovirus. nized foodborne outbreak, men who have
sex with men, and use of illegal drugs. In
Epidemiology
approximately two-thirds of reported cases,
The most common mode of transmission is the source cannot be determined. Fecal-oral
person to person, resulting from fecal contam­ spread from people with asymptomatic infec-
ination and oral ingestion (ie, the fecal-oral tions, particularly young children, likely
route). In resource-limited countries where accounts for many of these cases with an
infection is endemic, most people are infected unknown source. Transmission by blood
during the first decade of life. In the United ­transfusion or from mother to newborn (ie,
States, hepatitis A was one of the most fre- vertical transmission) seldom occurs.
quently reported vaccine-preventable diseases
in the prevaccine era, but incidence of disease Before availability of vaccine, most HAV
attributable to HAV has declined significantly ­infection and illness occurred in the context
since hepatitis A vaccine was licensed in 1995. of community-wide epidemics, in which infec-
These declining rates have been accompanied tion was primarily transmitted in households
by a shift in age-specific rates. Historically, and extended-family settings. Community-
the highest rates occurred among children 5 wide epidemics have not been observed in
to 14 years of age and the lowest rates occurred recent years. Common-source foodborne out-
among adults older than 40 years. Beginning breaks occur; waterborne outbreaks are rare.
in the late 1990s, national age-specific rates Waterborne outbreaks are usually associated
declined more rapidly among children than with sewage-contaminated or inadequately
among adults; as a result, in recent years, rates treated water. Health care–associated trans-
have been similar among all age groups. In mission is unusual, but, very rarely, outbreaks
addition, the previously observed unequal have occurred in neonatal intensive care units
­geographic distribution of hepatitis A inci- from neonates infected through transfused
dence in the United States, with the highest blood who subsequently transmitted HAV
rates of disease occurring in a limited number to other neonates and staff.

ERRNVPHGLFRVRUJ
Hepatitis A 227

In child care centers, recognized symptomatic Diagnostic Tests


(icteric) illness occurs primarily among adult Serologic tests for HAV-specific total (ie,
contacts of children. Most infected children immunoglobulin [Ig] G and IgM) anti-HAV
younger than 6 years are asymptomatic or are available commercially. The presence of
have nonspecific manifestations. Hence, spread serum IgM anti-HAV indicates current or
of HAV infection within and outside a child recent infection, although false-positive results
care center often occurs before recognition of can occur. IgM anti-HAV is detectable in up to
the index case(s). Outbreaks have occurred 20% of vaccinees when measured 2 weeks after
most commonly in large child care centers and hepatitis A immunization. In most infected
specifically in facilities that enroll children people, serum IgM anti-HAV becomes detect-
in ­diapers. able 5 to 10 days before onset of symptoms and
Patients infected with HAV are most infectious declines to undetectable concentrations within
during the 1 to 2 weeks before onset of jaundice 6 months after infection. People who test posi-
or elevation of liver enzymes, when concentra- tive for IgM anti-HAV more than 1 year after
tion of virus in the stool is highest. The risk infection have been reported. IgG anti-HAV
of transmission subsequently diminishes and is detectable shortly after appearance of IgM.
is minimal by 1 week after onset of jaundice. A positive total anti-HAV (ie, IgM and IgG)
However, HAV can be detected in stool for test result with a negative IgM anti-HAV test
­longer periods, especially in neonates and result indicates immunity from past infection
young children. or vaccination. Polymerase chain reaction
assays for hepatitis A are available.
Incubation Period
Treatment
Average 28 days (range, 15–50 days).
Supportive.

Image 59.1
An electron micrograph of the hepatitis A virus, an RNA virus classified as a member of the
picornavirus group. Courtesy of Centers for Disease Control and Prevention/Betty Partin.

ERRNVPHGLFRVRUJ
228 Hepatitis A

Image 59.2
Estimated prevalence of hepatitis A virus. Centers for Disease Control and Prevention National Center
for Emerging and Zoonotic Infectious Diseases (NCEZID) Division of Global Migration and Quarantine
(DGMQ).

Image 59.3
Hepatitis, viral. Incidence, by year—United States, 1982–2012. Courtesy of Morbidity and Mortality
Weekly Report.

ERRNVPHGLFRVRUJ
Hepatitis A 229

Image 59.4
Hepatitis A. Incidence, by county—United States, 2012. Courtesy of Morbidity and Mortality Weekly
Report.

Image 59.6
Hepatitis A infection has caused this man’s skin
Image 59.5 and the whites of his eyes to turn yellow. Other
Acute hepatitis A infection with scleral icterus in a symptoms of hepatitis A can include loss of
10-year-old boy. Courtesy of Edgar O. Ledbetter, appetite, abdominal pain, nausea or vomiting,
MD, FAAP. fever, headaches, and dark urine. Courtesy of
Centers for Disease Control and Prevention/
Dr Thomas F. Sellers; Emory University.

ERRNVPHGLFRVRUJ
230 Hepatitis B

60 will die prematurely from HBV-related hepato-


cellular carcinoma (HCC) or cirrhosis. Risk
Hepatitis B factors for developing HCC include long dura-
Clinical Manifestations tion of infection, male gender, elevation of
serum alanine aminotrans­ferase (ALT),
People acutely infected with hepatitis B virus HBeAg positivity, degree of histologic injury of
(HBV) may be asymptomatic or symptomatic. the liver, replicative state of the virus (HBV
The likelihood of developing symptoms of DNA levels), presence of cirrhosis, and con-
acute hepatitis is age dependent: less than 1% comitant infection with ­hepatitis C virus or
of infants younger than 1 year, 5% to 15% of HIV.
children 1 through 5 years of age, and 30% to
50% of people older than 5 years are symptom- The clinical course of untreated chronic HBV
atic, although few data are available for adults infection varies according to the population
older than 30 years. The spectrum of signs and studied, reflecting differences in age at acqui­
symptoms is varied and includes subacute ill- sition, rate of loss of HBeAg, and, possibly,
ness with nonspecific symptoms (eg, anorexia, HBV genotype. Most children have asymptom-
nausea, malaise), clinical hepatitis with jaun- atic infection. Perinatally infected children
dice, or fulminant hepatitis. Extrahepatic usually have normal ALT concentrations and
­manifestations, such as arthralgia, arthritis, minimal or mild liver histologic abnormalities,
macular rashes, thrombocytopenia, polyar­ with detectable HBeAg and high HBV DNA
teritis nodosa, glomerulonephritis, or papular concentrations (≥20,000 IU/mL) for years to
acrodermatitis (Gianotti-Crosti syndrome), decades after initial infection (“immune toler-
can occur early in the course of illness and can ant phase”). Children with chronic HBV may
precede jaundice. Acute HBV infection cannot exhibit growth impairment. Chronic HBV
be distinguished from other forms of acute infection acquired during later childhood or
viral hepatitis on the basis of clinical signs and adolescence is usually accompanied by more
symptoms or nonspecific laboratory findings. active liver disease and increased serum ami-
notransferase concentrations. Patients with
Chronic HBV infection is defined as presence detectable HBeAg (HBeAg-positive chronic
of any one of hepatitis B surface antigen (HBsAg), hepatitis B) usually have high concentrations
HBV DNA, or hepatitis B e antigen (HBeAg) of HBV DNA and HBsAg in serum and are
in serum for at least 6 months. Chronic HBV more likely to transmit infection. Because
infection is likely in the presence of HBsAg, HBV-associated liver injury is thought to be
nucleic acid, HBV DNA, or HBeAg in serum immune mediated, in people coinfected with
from a person who tests negative for antibody HIV and HBV, the return of immune compe-
of the immunoglobulin (Ig) M subclass to tence with antiretroviral treatment of HIV
­hepatitis B core antigen (anti-HBc). infection may lead to a reactivation of HBV-
Age at the time of infection is the primary related liver inflammation and damage. Over
determinant of risk of progressing to chronic time (years to decades), HBeAg becomes unde-
infection. Up to 90% of infants infected peri­ tectable in many chronically infected people.
natally or in the first year of life will develop This transition is often accompanied by devel-
chronic HBV infection. Between 25% and 50% opment of antibody to HBeAg (anti-HBe) and
of children infected between 1 and 5 years of decreases in serum HBV DNA and serum ami-
age become chronically infected, whereas 5% notransferase concentrations and may be pre-
to 10% of infected older children and adults ceded by a temporary exacerbation of liver
develop chronic HBV infection. Patients who disease. These patients have inactive chronic
become HBV infected while immunosup- infection but still may have exacerbations of
pressed or with an underlying chronic illness hepatitis. Serologic reversion (reappearance of
(eg, end-stage renal disease) have an increased HBeAg) is more common if loss of HBeAg is
risk of developing chronic infection. In the not accompanied by development of anti-HBe;
absence of treatment, up to 25% of infants and reversion with loss of anti-HBe can also occur.
children who acquire chronic HBV infection

ERRNVPHGLFRVRUJ
Hepatitis B 231

Some patients who lose HBeAg may continue exposure to infectious body fluids; sharing
to have ongoing histologic evidence of liver or using nonsterilized needles, syringes, or
damage and moderate to high concentrations glucose monitoring equipment or devices;
of HBV DNA (HBeAg-negative chronic hepa­ ­sexual contact with an infected person; peri­
titis B). Patients with histologic evidence of natal exposure to an infected mother; and
chronic HBV infection, regardless of HBeAg household exposure to a person with chronic
status, remain at higher risk of death attri­b­ HBV infection. The risk of HBV acquisition
utable to liver failure compared with HBV- when a susceptible child bites a child who has
infected people with no histologic evidence of chronic HBV infection is unknown. A theo-
liver inflammation and fibrosis. Other factors retic risk exists if HBsAg-positive blood enters
that may adversely influence the natural his- the oral cavity of the biter, but transmission by
tory of chronic infection include male gender, this route has not been reported. Transmission
high HBV DNA level, elevation of serum ami- by transfusion of contaminated blood or blood
notransferase concentrations, HBeAg positiv- products is rare in the United States because
ity, race, alcohol use, and coinfection with of routine screening of blood donors and viral
hepatitis C virus, hepatitis D virus, or HIV. inactivation of certain blood products
before administration.
Resolved hepatitis B is defined as clearance
of HBsAg, normalization of serum amino- Perinatal transmission of HBV is highly effi-
transferase concentrations, and development cient and usually occurs from blood exposures
of antibody to HBsAg (anti-HBs). Chronically during labor and delivery. In utero transmis-
infected adults clear HBsAg and develop anti- sion accounts for less than 2% of all vertically
HBs at the rate of 1% to 2% annually; during transmitted HBV infections in most studies.
childhood, the annual clearance rate is less Without postexposure prophylaxis, the risk
than 1%. Reactivation of resolved chronic infec- of a neonate acquiring HBV from an infected
tion is possible if these patients become immu- mother as a result of perinatal exposure is 70%
nosuppressed and is also well reported among to 90% for neonates born to mothers who are
HBsAg-positive patients receiving antitumor HBsAg and HBeAg positive; the risk is 5% to
necrosis factor agents or disease-modifying 20% for neonates born to HBsAg-positive but
antirheumatic drugs (12% of patients). HBeAg-negative mothers.
Etiology Person-to-person spread of HBV can occur in
Hepatitis B virus is a DNA-containing, 42-nm- settings involving interpersonal contact over
diameter hepadnavirus. Important compo- extended periods, such as in a household with a
nents of the viral particle include an outer person with chronic HBV infection. In regions
lipoprotein envelope containing HBsAg and of the world with a high prevalence of chronic
an inner nucleocapsid consisting of anti-HBc. HBV infection, transmission between children
Viral polymerase activity can be detected in in household settings may account for a sub-
preparations of plasma containing HBV. stantial amount of transmission. The precise
mechanisms of transmission from child to
Epidemiology child are unknown; however, frequent inter-
Hepatitis B virus is transmitted through personal contact of nonintact skin or mucous
infected blood or body fluids. Although HBsAg membranes with blood-containing secretions,
has been detected in multiple body fluids, open skin lesions, or blood-containing saliva
including human milk, saliva, and tears, only are potential means of transmission. Trans­
blood, serum, semen, vaginal secretions, and mission from sharing inanimate objects, such
cerebrospinal, synovial, pleural, pericardial, as razors or toothbrushes, can also occur. Hep-
peritoneal, and amniotic fluids are considered atitis B virus can survive in the environment
the most potentially infectious. People with for 7 or more days but is inactivated by com-
chronic HBV infection are the primary reser- monly used disinfectants, including household
voirs for infection. Common modes of trans- bleach diluted 1:10 with water. Hepatitis B virus
mission include percutaneous and mucosal is not transmitted by the fecal-oral route.

ERRNVPHGLFRVRUJ
232 Hepatitis B

Transmission among children born in the endemicity, where the prevalence of chronic
United States is unusual because of high cover- HBV infection is 8% or greater. Historically, in
age with hepatitis B vaccine starting at birth. these regions, most new infections occurred as
The risk of HBV transmission is higher in chil- a result of perinatal or early childhood infec-
dren who have not completed a vaccine series, tions. In regions of intermediate HBV ende-
children undergoing hemodialysis, institution- micity, where the prevalence of HBV infection
alized children with developmental disabilities, is 2% to 7%, multiple modes of transmission (ie,
and children emigrating from countries with perinatal, household, sexual, injection drug
endemic HBV (eg, Southeast Asia, China, use, and health care–associated) contribute to
Africa). Person-to-person transmission has the burden of infection. In countries of low
been reported in child care settings, but risk endemicity, where chronic HBV infection prev-
of transmission in child care facilities in the alence is less than 2% (including the United
United States has become negligible as a result States) and where routine immunization has
of high infant hepatitis B immunization rates. been adopted, new infections are increasingly
among unimmunized age groups. Many people
Acute HBV infection is most commonly
born in countries with high endemicity live in
reported among adults 30 through 49 years of
the United States. Infant immunization pro-
age in the United States. Since 1990, the inci-
grams in some of these countries have, in
dence of acute HBV infection has declined in
recent years, greatly reduced the seropreva-
all age categories, with a 98% decline in chil-
lence of HBsAg, but many other countries with
dren younger than 19 years and a 93% decline
endemic HBV have yet to implement wide-
in young adults 20 through 29 years of age,
spread routine childhood hepatitis B immuni-
with most of the decline among people 20
zation programs.
through 24 years of age. Among patients with
acute hepatitis B interviewed in 2010, groups Incubation Period
constituting the largest proportion of acute Acute infection, 90 days (range, 45–160 days).
hepatitis B cases included users of injection
drugs, people with multiple heterosexual part- Diagnostic Tests
ners, men who have sex with men, and people Serologic antigen tests are available commer-
who reported surgery during the 6 weeks to cially to detect HBsAg and HBeAg. Serologic
6 months before onset of symptoms. Others assays are also available for detection of anti-
at increased risk include people with occupa- HBs, anti-HBc (total), IgM anti-HBc, and anti-
tional exposure to blood or body fluids, staff HBe. In addition, nucleic acid amplification
of institutions and nonresidential child care testing, gene-amplification techniques (eg,
programs for children with developmental dis- polymerase chain reaction assay, branched
abilities, patients undergoing hemodialysis, DNA methods), and hybridization assays are
and sexual or household contacts of people available to detect and quantify HBV DNA.
with an acute or chronic infection. Approxi- Tests to quantify HBsAg and HBeAg are cur-
mately 68% of infected people who were rently being developed but are not yet com­
­interviewed in 2010 did not have a readily mercially available. Hepatitis B surface antigen
­identifiable risk characteristic. Hepatitis B is detectable during acute infection. If HBV
virus infection in adolescents and adults is infection is self-limited, HBsAg disappears in
associated with other sexually transmitted most patients within a few weeks to several
infections. Outbreaks in nonhospital health months after infection, followed by appearance
care settings, including assisted-living facilities of anti-HBs. The time between disappearance
and nursing homes, highlight the increased of HBsAg and appearance of anti-HBs is
risk among people with diabetes mellitus termed the window period of infection. Dur-
undergoing assisted blood glucose monitoring. ing the window period, the only marker of
The prevalence of HBV infection and patterns acute infection is IgM anti-HBc, which is
of transmission vary markedly throughout highly specific for establishing the diagnosis
the world (Table 60.1). Approximately 45% of of acute infection. However, IgM anti-HBc
­people worldwide live in regions of high HBV is not usually present in neonates infected

ERRNVPHGLFRVRUJ
Hepatitis B 233

­ erinatally. People with chronic HBV infection


p be referred to a specialist in management of
have circulating HBsAg and circulating total chronic HBV infection for further manage-
anti-HBc; on rare occasions, anti-HBs is also ment and ­treatment.
present. Anti-HBs and total anti-HBc are
The goal of treatment in chronic HBV infection
­present in people with resolved infection,
is to prevent progression to cirrhosis, hepatic
whereas anti-HBs alone is present in people
failure, and HCC. Current indications for
immunized with hepatitis B vaccine. Transient
treatment of chronic HBV infection include
HBsAg antigenemia can occur following
evidence of ongoing hepatitis B viral replica-
receipt of hepatitis B vaccine, with HBsAg
tion, as indicated by the presence for longer
being detected as early as 24 hours after and
than 6 months of serum HBV DNA greater
up to 2 to 3 weeks following administration of
than 20,000 IU/mL without HBeAg positivity,
the vaccine. The presence of HBeAg in serum
greater than 2,000 IU/mL with HBeAg positi­
correlates with higher concentrations of HBV
vity, and elevated serum ALT concentrations
and greater infectivity. Tests for HBeAg and
for longer than 6 months or evidence of
HBV DNA are useful in selection of candidates
chronic hepatitis on liver biopsy. Children
to receive antiviral therapy and to monitor
without necroinflammatory liver disease and
response to ­t herapy.
children with immunotolerant chronic HBV
Treatment infection (ie, normal ALT concentrations
No specific therapy for acute HBV infection despite presence of HBV DNA) usually do not
is available, and acute HBV infection usually warrant antiviral therapy. Treatment response
does not warrant referral to a hepatitis special- is measured by biochemical, virologic, and his-
ist. However, acute HBV infection may be dif- tologic response. An important consideration
ficult to distinguish from reactivation of HBV, in the choice of treatment is to avoid selection
so if reactivation is a possibility, referral to a of antiviral-resistant mutations.
hepatitis specialist would be warranted. The US Food and Drug Administration has
Children and adolescents who have chronic approved 3 nucleoside analogues (entecavir,
HBV infection are at risk of developing serious lamivudine, and telbivudine), 2 nucleotide
liver disease, including primary HCC, with ­analogues (tenofovir and adefovir), and
advancing age and, therefore, should receive 2 ­interferon alfa drugs (interferon alfa-2b and
hepatitis A vaccine. Although the peak inci- pegylated interferon alfa-2a) for treatment of
dence of primary HCC attributable to HBV chronic HBV infection in adults. Tenofovir,
infection is in the fifth decade of life, HCC entecavir, and pegylated interferon alfa-2a are
occurs in children as young as 6 years who preferred in adults as first-line therapy because
become infected perinatally or in early child- of the lower likelihood of developing antiviral
hood. Several algorithms have been published resistance mutations over long-term therapy.
describing the initial evaluation, monitoring, Of these, Food and Drug Administration
and criteria for treatment. Children with ­licensure in the pediatric population is as fol-
chronic HBV infection should be screened lows: interferon, 1 year and older; lamivudine,
periodically for hepatic complications using 3 months and older; adefovir, 12 years and
serum aminotransferase tests, α-fetoprotein older; telbivudine, 16 years and older; and
concentration, and abdominal ultrasono­g­ ­entecavir, 16 years and older. Pediatric trials of
raphy. Definitive recommendations on the telbivudine, tenofovir, pegylated interferon,
­frequency and indications for specific tests and entecavir are currently underway. The
are not yet available because of lack of data optimal agent(s) and duration of therapy for
on their reliability in predicting sequelae. chronic HBV infection in children remain
Patients with serum ALT concentrations unclear. There are few large randomized, con-
­persistently exceeding the upper limit of trolled trials of antiviral therapies for chronic
­normal and patients with an increased serum hepatitis B in childhood. Studies indicate
α-fetoprotein concentration or abnormal approximately 17% to 58% of children with
­findings on abdominal ultrasonography should increased serum aminotransferase concentra-
tions who are treated with interferon alfa-2b

ERRNVPHGLFRVRUJ
234 Hepatitis B

for 6 months lose HBeAg, compared with cebo (23% vs 13%). Resistance to lamivudine
approximately 8% to 17% of untreated controls. can develop while on treatment and may occur
Response to interferon alfa is better for chil- early. The optimal duration of lamivudine
dren from Western countries (20%–58%) as therapy is not known, but a minimum of 1 year
compared with Asian countries (17%). Children is required. For those who have not yet serore­
from Asian countries with HBV infection are verted but do not have resistant virus, therapy
more likely to have acquired infection perina- beyond 1 year may be beneficial (ie, continued
tally, have a prolonged immune tolerant phase seroreversions). However, the high rates of
of infection, and be infected with HBV geno- lamivudine resistance (~70% after 3 years of
type C. All 3 of these factors are associated therapy) have decreased enthusiasm for the use
with lower response rates to interferon alfa, of this drug. Combination therapy with lamiv­
which is less effective for chronic infections udine and interferon alfa has been studied with
acquired during early childhood, especially mixed results, as compared with monotherapy
if serum aminotransferase concentrations are with interferon alfa. Children coinfected with
normal. Children with chronic HBV infection HIV and HBV should receive the lamivudine
who were treated with lamivudine had higher dose approved for treatment of HIV. Consulta-
rates of virologic response (loss of detectable tion with health care professionals with exper-
HBV DNA and loss of HBeAg) after 1 year of tise in treating chronic hepatitis B in children
treatment than did children who received pla- is recommended.

Table 60.1
Estimated International Hepatitis B Surface Antigen Prevalencea

Region Estimated HBsAg Prevalenceb


North America 0.1%
Mexico and Central America 0.3%
South America 0.7%
Western Europe 0.7%
Australia and New Zealand 0.9%
Caribbean (except Haiti) 1.0%
Eastern Europe and North Asia 2.8%
South Asia 2.8%
Middle East 3.2%
Haiti 5.6%
East Asia 7.4%
Southeast Asia 9.1%
Africa 9.3%
Pacific Islands 12.0%
Abbreviation: HBsAg, hepatitis B surface antigen.
a Centers for Disease Control and Prevention. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infec-

tion in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part II: immunization of adults.
MMWR Recomm Rep. 2006;55(RR-16):1–33.
b Level of hepatitis B virus endemicity defined as high (≥8%), intermediate (2%–7%), and low (<2%).

ERRNVPHGLFRVRUJ
Hepatitis B 235

Image 60.1
This electron micrograph reveals the presence of hepatitis B virus (HBV). Infectious HBV virions are
also known as Dane particles. These particles measure 42 nm in their overall diameter and contain a
DNA-based core that is 27 nm in diameter. Courtesy of Centers for Disease Control and Prevention.

Image 60.2
Transmission electron micrograph of hepatitis B virions, also known as Dane particles. Courtesy of
Centers for Disease Control and Prevention/Erskine Palmer, MD.

Image 60.3
This transmission electron micrograph revealed the presence of hepatitis B virions. Courtesy of
Centers for Disease Control and Prevention/Erskine Palmer, MD.

ERRNVPHGLFRVRUJ
236 Hepatitis B

Image 60.4
World map for hepatitis B endemicity. Courtesy of Centers for Disease Control and Prevention.

Image 60.5
Hepatitis, viral. Incidence, by year—United States, 1982–2012. Courtesy of Morbidity and Mortality
Weekly Report.

ERRNVPHGLFRVRUJ
Hepatitis B 237

Image 60.7
Section of liver damaged by hepatitis B virus.
Note the enlarged cells and blistering of the
capsular surface. Copyright Anthony Demetris,
MD, Director, Division of Transplantation
Pathology, University of Pittsburgh Medical Center.
Image 60.6
This female Cambodian patient presented with a
distended abdomen due to a hepatoma resulting
from chronic hepatitis B infection. Courtesy of
Centers for Disease Control and Prevention/
Patricia Walker, MD, Regions Hospital, MN.

Image 60.8
Typical serologic course of acute hepatitis B virus (HBV) infection with progression to chronic HBV
infection. From Centers for Disease Control and Prevention. Recommendations for identification and
public health management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep.
2008;57(RR-8):1–20.

ERRNVPHGLFRVRUJ
238 Hepatitis C

61 s­ ubstantial burden of disease still exists in the


United States because of the propensity of
Hepatitis C HCV to establish chronic infection and the
Clinical Manifestations high incidence of acute HCV infection through
the 1980s. The prevalence of HCV infection in
Signs and symptoms of hepatitis C virus the general population of the United States is
(HCV) infection are indistinguishable from estimated at 1.3%, equating to an estimated
those of hepatitis A or hepatitis B virus infec- 3.2 million people in the United States who
tions. Acute disease tends to be mild and have chronic HCV infection. The seropreva-
­insidious in onset, and most infections are lence of HCV in children was approximately
asymptomatic. Jaundice occurs in fewer than 0.1%, although the numbers of HCV infections
20% of patients, and abnormalities in serum in the younger age groups were too small for
aminotransferase concentrations are generally reliable estimates. Worldwide, the prevalence
less pronounced than abnormalities in patients of chronic HCV infection is highest in Africa,
with hepatitis B virus infection. Persistent especially Egypt.
infection with HCV occurs in up to 80% of
infected children, even in the absence of bio- Hepatitis C virus is primarily spread by paren-
chemical evidence of liver disease. Most chil- teral exposure to blood of HCV-infected peo-
dren with chronic infection are asymptomatic. ple. The most common risk factors for adults
Although chronic hepatitis develops in approx- to acquire infection are injection drug use,
imately 70% to 80% of infected adults, limited multiple sexual partners, or receipt of blood
data indicate chronic hepatitis and cirrhosis products before 1992. The current risk of HCV
occur less commonly in children, in part infection after blood transfusion in the United
because of the usually indolent nature of States is estimated to be 1 per 2 million units
­infection in pediatric patients. Liver failure transfused because of exclusion of high-risk
secondary to HCV infection is the leading donors since 1992 and of HCV-positive units
indication for liver transplantation among after antibody testing as well as screening
adults in the United States. of pools of blood units. The most common
route of infection in children is maternal-
Etiology fetal ­transmission.
Hepatitis C virus is a small, single-stranded
Approximately 60% of chronic HCV cases
RNA virus and is a member of the Flavivirus
are in injection drug users who have shared
family. At least 6 HCV genotypes exist with
needles or injection paraphernalia; almost all
multiple subtypes.
infected people are outside the pediatric age
Epidemiology range. Data from recent multicenter, population-
The incidence of acute symptomatic HCV based cohort studies indicate approximately
infection in the United States was 0.2 per one-third of young injection drug users 18 to
100,000 population in 2005; after asymptom- 30 years of age are infected with HCV. Approx-
atic infection and underreporting were con­ imately half of the 18,000 people with hemo-
sidered, approximately 20,000 new cases were philia who received transfusions before
estimated to have occurred. For all age groups, adoption of heat treatment of clotting factors
the incidence of HCV infection has markedly in 1987 are HCV seropositive. Also, more
decreased in the United States since the 1990s recently appreciated has been the number of
and has remained low since 2006. However, infections acquired in the health care setting,
there was a 45% increase in reported cases of especially nonhospital clinics where infection
acute HCV in the United States in 2011 com- control and needle and intravenous hygienic
pared with 2004 through 2010. This increase procedures have not been practiced strictly.
was mostly seen in white, nonurban young Prevalence is high among people with frequent
people with a history of using injection drugs but smaller direct percutaneous exposures,
and opioid agonists such as oxycodone. A such as patients receiving hemodialysis (10%–
20%). Transmission among family contacts is

ERRNVPHGLFRVRUJ
Hepatitis C 239

uncommon but can occur from direct or plasma within 1 to 2 weeks after exposure to
­inapparent percutaneous or mucosal exposure the virus and weeks before onset of liver
to blood. enzyme abnormalities or appearance of anti-
HCV. Assays for detection of HCV RNA are
Seroprevalence among pregnant women in the
commonly used in clinical practice to identify
United States has been estimated at 1% to 2%.
anti-HCV–positive patients who are viremic,
The risk of perinatal transmission averages
for identifying infection in neonates/infants
5% to 6% and transmission occurs only from
early in life (ie, perinatal transmission) when
women who are HCV RNA positive at the
maternal antibody interferes with ability to
time of delivery. Maternal coinfection with
detect antibody produced by the neonate/
HIV has been associated with increased risk
infant, and for monitoring patients receiving
of perinatal transmission of HCV, with trans-
antiviral therapy. However, false-positive and
mission rates between 10% and 20%; transmis-
false-negative results of nucleic acid amplifica-
sion depends in part on the amount of HCV
tion tests can occur from improper handling,
RNA in the mother’s blood. Although HCV
storage, and contamination of test specimens.
RNA has been detected in colostrum, the risk
Viral RNA may be detected intermittently in
of HCV transmission is similar in breastfed
acute infection (ie, in the first 6 or 12 months
and formula-fed neonates and infants.
following infection); thus, a single negative
Incubation Period assay result is not conclusive if performed
­during this acute infection period. Highly
Average, 6 to 7 weeks (range, 2 weeks–6 months);
­sensitive quantitative assays for measuring
time from exposure to development of viremia,
the concentration of HCV RNA have largely
1 to 2 weeks.
replaced qualitative assays. The clinical value of
Diagnostic Tests these quantitative assays appears to be primar-
The 2 types of tests available for laboratory ily as a prognostic indicator for patients under-
diagnosis of HCV infections are immuno­ going or about to undergo antiviral therapy.
globulin (Ig) G antibody enzyme immuno­ Treatment
assays for HCV and nucleic acid amplification
Patients diagnosed with HCV infection should
tests to detect HCV RNA. Assays for IgM to
be referred to a pediatric hepatitis specialist for
detect early or acute infection are not available.
clinical monitoring and consideration of anti-
Third-generation enzyme immunoassays are at
viral treatment. Therapy is aimed at inhibiting
least 97% sensitive and more than 99% specific.
HCV replication, eradicating infection, and
In June 2010, the US Food and Drug Adminis-
improving the natural history of disease. Ther-
tration approved for use in people 15 years and
apies are expensive and can have significant
older the OraQuick rapid blood test, which
adverse reactions. Response to treatment varies
uses a test strip that produces a blue line within
depending on the genotype with which the
20 minutes if anti-HCV antibodies are present.
person is infected. Genotype 1 is the most com-
False-negative results early in the course of
mon genotype in North America. Genotypes 1
acute infection can result from any of the HCV
and 4 respond less well than genotypes 2 and 3
serologic tests because of the prolonged inter-
to antiviral therapy. Currently, the only Food
val between exposure and onset of illness and
and Drug Administration–approved treatment
seroconversion. Within 15 weeks after exposure
for HCV in children 3 to 17 years of age consists
and within 5 to 6 weeks after onset of hepatitis,
of a combination of peginterferon and ribavi-
80% of patients will have positive test results
rin. The few studies of peginterferon and riba-
for serum anti-HCV antibody. Among neo-
virin combination therapy in children suggest
nates born to anti-HCV–positive mothers,
that children have fewer adverse events com-
­passively acquired maternal antibody may
pared with adults; however, all treatment regi-
­persist for up to 18 months.
mens are associated with adverse events. Major
Nucleic acid amplification tests for qualitative adverse effects of combination therapy in pedi-
detection of HCV RNA are available. Hepatitis atric patients include influenza-like symptoms,
C virus RNA can be detected in serum or hematologic abnormalities, neuropsychiatric

ERRNVPHGLFRVRUJ
240 Hepatitis C

symptoms, thyroid abnormalities, ocular comorbid conditions, including childhood


abnormalities including ischemic retinopathy c­ ancer, iron overload, or thalassemia, are pres-
and uveitis, and growth disturbances. The ent. Pediatricians need to be alert to concomi-
recent data for combination antivirals without tant infections, alcohol abuse, and concomitant
significant adverse effects in adults suggest use of drugs, such as acetaminophen and some
that, ultimately, pediatric patients with HCV antiretroviral agents (eg, stavudine), in patients
infection will also have effective therapies. with HCV infection. Children with chronic
infection should be followed closely, including
All patients with chronic HCV infection
sequential monitoring of serum aminotrans-
should be immunized against hepatitis A and
ferase concentrations, because of the potential
hepatitis B. Among children, progression of
for chronic liver disease.
liver disease appears to be accelerated when

Image 61.1
Hepatitis, viral. Incidence, by year—United States, 1982–2012. Courtesy of Morbidity and Mortality
Weekly Report.

ERRNVPHGLFRVRUJ
Hepatitis C 241

Image 61.2
Pie chart showing causes of chronic liver disease in residents of Jefferson County, AL. Hepatitis B
and hepatitis C viruses contributed to most cases of chronic liver disease in this population. Courtesy
of Centers for Disease Control and Prevention.

Image 61.3
Prevalence of chronic hepatitis C infection. Centers for Disease Control and Prevention National Center
for Emerging and Zoonotic Infectious Diseases (NCEZID) Division of Global Migration and Quarantine
(DGMQ).

ERRNVPHGLFRVRUJ
242 Hepatitis D

62 among people with chronic HBV infection.


High-prevalence areas include parts of Eastern
Hepatitis D Europe, South America, Africa, Central Asia
Clinical Manifestations (particularly Pakistan), and the Middle East.
In the United States, HDV infection is most
Hepatitis D virus (HDV) causes infection only commonly found in people who abuse injec-
in people with acute or chronic hepatitis B tion drugs, people with hemophilia, and people
virus (HBV) infection. Hepatitis D virus who have emigrated from areas with endemic
requires HBV as a helper virus for replication HDV ­infection.
and cannot produce infection in the absence
of HBV. The importance of HDV infection lies Incubation Period
in its ability to convert an asymptomatic or Approximately 2 to 8 weeks; when HBV and
mild chronic HBV infection into fulminant HDV viruses infect simultaneously, average
or more severe or rapidly progressive disease. 90 days (range, 45–160).
Acute coinfection with HBV and HDV usually
causes an acute illness indistinguishable from Diagnostic Tests
acute HBV infection alone, except that the People with chronic HBV infection are at risk
­likelihood of fulminant hepatitis can be as high of HDV coinfection. Accordingly, their care
as 5%. should be supervised by an expert in hepatitis
Etiology treatment, and consideration should be given
to testing for anti-HDV immunoglobulin (Ig)
Hepatitis D virus measures 36 to 43 nm in G antibodies using a commercially available
diameter and consists of an RNA genome and test if they have increased transaminase con-
a delta protein antigen, both of which are centrations, particularly if they recently came
coated with hepatitis B surface antigen. from a country with high prevalence of HDV.
Epidemiology Anti-HDV may not be present until several
weeks after onset of illness, and acute and
Hepatitis D virus infection is present world- ­convalescent sera can be required to confirm
wide, in all age groups, and an estimated the diagnosis. In a person with anti-HDV,
18 million people are infected with the virus. the absence of IgM hepatitis B core antibody,
Over the past 20 years, HDV prevalence has which is indicative of chronic HBV infection,
decreased significantly in Western and South- suggests the person has chronic HBV infection
ern Europe because of long-standing hepatitis and superinfection with HDV. Presence of
B immunization programs, although HDV anti-HDV IgG antibodies does not prove
remains a significant health problem in active infection; thus, HDV RNA testing
resource-limited countries. At least 8 geno- should be performed for diagnostic and
types of HDV have been described, each with ­t herapeutic considerations. Patients with
a typical geographic pattern, with genotype 1 ­circulating HDV RNA should be staged for
being the predominant type in Europe and severity of liver disease, have surveillance for
North America. Hepatitis D virus can cause development of hepatocellular carcinoma, and
an infection at the same time as the initial be considered for treatment. Presence of anti-
HBV infection (coinfection), or it can infect HDV IgM is of lesser utility because it is pres-
a person already chronically infected with ent in acute and chronic HDV infections.
HBV (superinfection). Acquisition of HDV
is by parenteral, percutaneous, or mucous Treatment
membrane inoculation. Hepatitis D virus can Hepatitis D virus has proven difficult to treat.
be acquired from blood or blood products, However, data suggest pegylated interferon
through injection drug use, or by sexual alfa may result in up to 40% of patients having
­contact, but only if HBV is also present. a sustained response to treatment. Clinical
­Trans­mission from mother to newborn is trials suggest at least a year of therapy may
uncommon. Intrafamilial spread can occur be associated with sustained responses, and

ERRNVPHGLFRVRUJ
Hepatitis D 243

longer courses may be warranted if the patient nation therapy with a direct-acting antiviral
is able to tolerate therapy. Further study of agent needs to be performed before treatment
pegylated interferon monotherapy or as combi- of HDV can be routinely advised.

ERRNVPHGLFRVRUJ
244 Hepatitis E

63 accounts for a significant proportion of fetal


loss and perinatal mortality. Hepatitis E is also
Hepatitis E transmitted through blood product transfu-
Clinical Manifestations sion. Transfusion-transmitted hepatitis E
occurs primarily in countries with endemic
Hepatitis E virus (HEV) infection causes an disease and is rarely reported in areas without
acute illness with symptoms including jaun- endemic infection. In the United States, sero-
dice, malaise, anorexia, fever, abdominal pain, logic studies have demonstrated that approxi-
and arthralgia. Disease is more common mately 20% of the population has
among adults than among children and is more immunoglobulin (Ig) G against HEV. However,
severe in pregnant women, in whom mortality symptomatic HEV infection in the United
rates can reach 10% to 25% during the third States is uncommon and generally occurs in
trimester. Chronic HEV infection is rare and people who acquire HEV genotype 1 infection
has been reported only in recipients of solid after traveling to countries with endemic HEV.
organ transplants and people with severe Nonetheless, a number of people without a
immunodeficiency. travel history have been diagnosed with acute
Etiology HEV, and evidence for the infection should be
sought in cases of acute hepatitis without an
Hepatitis E virus is a spherical, nonenveloped,
etiology. Acute HEV can masquerade as drug-
positive-sense RNA virus. It is classified in the
induced liver injury.
genus Hepevirus of the family Hepeviridae.
There are 4 major recognized genotypes with Diagnostic Tests
a single known serotype. Testing for IgM and IgG anti-HEV is available
Epidemiology through some research and commercial refer-
ence laboratories. Because anti-HEV assays are
Hepatitis E virus is the most common cause of
not approved by the US Food and Drug
viral hepatitis in the world. Globally, an esti-
Administration and their performance charac-
mated 20 million HEV infections occur annu-
teristics are not well defined, results should be
ally, resulting in 3.4 million cases of acute
interpreted with caution, particularly in cases
hepatitis and 70,000 deaths. In developing
lacking a discrete onset of illness associated
countries, ingestion of fecally contaminated
with jaundice or with no recent history of
water is the most common route of HEV trans-
travel to a country with endemic infection.
mission, and large waterborne outbreaks occur
Definitive diagnosis may be made by demon-
frequently. Sporadic HEV infection has been
strating viral RNA in serum or stool by means
reported throughout the world and is common
of reverse transcriptase-polymerase chain reac-
in Africa and the Indian subcontinent. Unlike
tion assay, which is available only in research
the other agents of viral hepatitis, certain HEV
settings (with prior approval through the Cen-
genotypes (genotypes 3 and 4) also have zoo-
ters for Disease Control and Prevention).
notic hosts, such as swine, and can be trans-
Because virus circulates in the body for a rela-
mitted by eating undercooked pork. Hepatitis
tively short period, the inability to detect HEV
E virus genotypes 1 and 2 exclusively infect
in serum or stool does not eliminate the possi-
humans. Person-to-person transmission
bility that the person was infected with HEV.
appears to be much less efficient than with hep-
atitis A virus but occurs in sporadic and out- Treatment
break settings. Mother-to-newborn Supportive care.
transmission of HEV occurs frequently and

ERRNVPHGLFRVRUJ
Hepatitis E 245

Image 63.1
This electron micrograph depicts hepatitis E
viruses. Hepatitis E virus was classified as a
member of the Caliciviridae family but has been
reclassified in the genus Hepevirus of the family
Hepeviridae. There are 4 major recognized
genotypes with a single known serotype.
Hepatitis E virus, the major etiologic agent of
Image 63.2
enterically transmitted non-A, non-B hepatitis
Electron micrograph of nonhuman primate
worldwide, is a spherical, nonenveloped, single-
(marmoset) passaged hepatitis E virus (HEV)
stranded RNA virus that is approximately 32
(Nepal isolate). Virus is aggregated with con­va­
to 34 nm in diameter. Courtesy of Centers for
lescent antisera to HEV and negatively stained in
Disease Control and Prevention.
phosphotungstic acid. Particle size ranges from
27 to 30 nm. Courtesy of Centers for Disease
Control and Prevention.

Image 63.3
Distribution of hepatitis E infection, 2010. Centers for Disease Control and Prevention National Center
for Emerging and Zoonotic Infectious Diseases (NCEZID) Division of Global Migration and Quarantine
(DGMQ).

ERRNVPHGLFRVRUJ
246 Herpes Simplex

64 of life; neonates with CNS disease usually pre­


sent with illness between the second and third
Herpes Simplex weeks of life.
Clinical Manifestations Children beyond the neonatal period and
Neonatal. In newborns, herpes simplex infec- adolescents. Most primary herpes simplex
tion can manifest as 3 syndromes: (1) dissemi- childhood infections beyond the neonatal
nated disease involving multiple organs, most period are asymptomatic.
prominently liver and lungs, and, in 60% to
Gingivostomatitis, which is the most com-
75% of cases, also involving the central nervous
mon clinical manifestation of herpes simplex
system (CNS); (2) CNS disease, with or with-
during childhood, is caused by herpes simplex
out skin involvement; or (3) disease localized
virus type 1 (HSV-1) and is characterized by
to the skin, eyes, or mouth (SEM disease).
fever, irritability, tender submandibular adeno­
Approximately 25% of cases of neonatal herpes
pathy, and an ulcerative enanthem involving
simplex manifest as disseminated disease,
the gingiva and mucous membranes of the
30% of cases manifest as CNS disease, and 45%
mouth, often with perioral vesicular lesions.
of cases manifest as SEM disease. More than
80% of neonates with SEM disease have skin Genital herpes, which is the most common
vesicles; those without have infection limited manifestation of primary herpes simplex infec-
to the eyes or oral mucosa. Approximately two- tion in adolescents and adults, is characterized
thirds of neonates with disseminated or CNS by vesicular or ulcerative lesions of the male
disease have skin lesions, but these lesions may or female genital organs, perineum, or both.
not be present at the time of onset of ­symptoms. Until recent years, genital herpes was most
Disseminated infection should be considered often caused by herpes simplex virus type 2
in neonates with sepsis syndrome, negative (HSV-2), but HSV-1 now accounts for more
bacteriologic culture results, severe liver dys- than half of all cases of ­genital herpes in the
function, or consumptive coagulopathy. Her- United States. Most cases of primary genital
pes simplex should also be considered as a herpes infection in males and females are
causative agent in neonates with fever, a vesi­ asymptomatic and are not ­recognized by the
cular rash, or abnormal cerebrospinal fluid infected person or diagnosed by a health care
(CSF) findings, especially in the presence of professional.
seizures or during a time of year when entero-
Eczema herpeticum can develop in patients
viruses are not circulating in the community.
with atopic dermatitis who are infected with
Although asymptomatic herpes simplex infec-
herpes simplex. Examination may reveal skin
tion is common in older children, it rarely, if
with punched-out erosions, hemorrhagic
ever, occurs in neonates.
crusts, or vesicular lesions.
Neonatal herpetic infections are often severe,
In patients who are immunocompromised,
with attendant high mortality and morbidity
severe local lesions and, less commonly, dis-
rates, even when antiviral therapy is promptly
seminated herpes simplex infection with gen-
administered. Recurrent skin lesions are
eralized vesicular skin lesions and visceral
­common in surviving neonates, occurring in
involvement can occur.
approximately 50% of survivors, often within
1 to 2 weeks of discontinuing the initial treat- After primary infection, herpes simplex per-
ment course. sists for life in a latent form. The site of latency
for the virus causing herpes labialis is the
Initial signs of herpes simplex infection most
­trigeminal ganglion, and the usual site of
often develop within the first month of life.
latency for genital herpes is the sacral dorsal
Neonates with disseminated disease and SEM
root ganglia, although any of the sensory gan-
disease have an earlier age of onset, typically
glia can be involved depending on the site
presenting between the first and second weeks
of primary infection. Reactivation of latent

ERRNVPHGLFRVRUJ
Herpes Simplex 247

virus most commonly is asymptomatic. When Herpes simplex infection can also cause
symptomatic, recurrent HSV-1 herpes labialis ­aseptic meningitis with nonspecific clinical
manifests as single or grouped vesicles in the manifestations that are usually mild and self-
perioral region, usually on the vermilion limited. Such episodes of meningitis are usu-
­border of the lips (typically called “cold sores” ally associated with genital HSV-2 infection.
or “fever blisters”). Symptomatic recurrent A number of unusual CNS manifestations of
genital herpes manifests as vesicular lesions herpes simplex have been described, including
on the penis, scrotum, vulva, cervix, buttocks, Bell palsy, atypical pain syndromes, trigeminal
perianal areas, thighs, or back. Among immu- neuralgia, ascending myelitis, transverse
nocompromised patients, genital HSV-2 myelitis, postinfectious encephalomyelitis,
­recurrences are more frequent and of longer and recurrent (Mollaret) meningitis.
duration. Recurrences may be heralded by a
Etiology
prodrome of burning or itching at the site
of an incipient recurrence, identification of Herpes simplex viruses are enveloped, double-
which can be useful in instituting antiviral stranded, DNA viruses. At least 9 herpesvirus
therapy early. species, including HSV, infect humans. Two
distinct types exist: HSV-1 and HSV-2. Infec-
Conjunctivitis and keratitis can result from tions with HSV-1 usually involve the face and
primary or recurrent herpes simplex infection. skin above the waist; however, an increasing
Herpetic whitlow consists of single or multiple number of genital herpes cases are attributable
vesicular lesions on the distal fingers. Herpes to HSV-1. Infections with HSV-2 usually
simplex infection can be a precipitating fac- involve the ­genitalia and skin below the waist
tor in erythema multiforme, and recurrent in sexually active adolescents and adults. How-
erythema multiforme is often caused by ever, HSV-1 and HSV-2 can be found in either
­symptomatic or asymptomatic herpes simplex area and both cause herpes disease in neonates.
recurrences. Wrestlers can develop herpes As with all human herpesviruses, HSV-1 and
gladiatorum if they become infected with HSV-2 establish latency following primary
­herpes simplex. infection, with periodic reactivation to cause
Herpes simplex encephalitis (HSE) occurs recurrent symptomatic disease or asymptom-
in children beyond the neonatal period or in atic viral ­shedding.
adolescents and adults and can result from Epidemiology
primary or recurrent HSV-1 infection. One-
fifth of HSE cases occur in the pediatric age Herpes simplex infections are ubiquitous
group. Symptoms and signs usually include and can be transmitted from people who are
fever, alterations in the state of consciousness, symptomatic or asymptomatic with primary
personality changes, seizures, and focal neuro- or recurrent infections.
logic findings. Encephalitis commonly has an Neonatal. The incidence of neonatal herpes
acute onset with a fulminant course, leading to simplex infection is estimated to range from
coma and death in untreated patients. Herpes 1 in 3,000 to 1 in 20,000 live births. Herpes
simplex encephalitis usually involves the tem- simplex virus is transmitted to a neonate
poral lobe; thus, temporal lobe abnormalities most often during birth through an infected
on imaging studies or electroencephalography maternal genital tract but can be caused by
in the context of a consistent clinical picture an ascending infection through ruptured or
should increase the suspicion of HSE. Magnetic apparently intact amniotic membranes. Intra-
resonance imaging is the most sensitive neuro- uterine infections causing congenital malfor-
imaging modality to demonstrate temporal mations have been implicated in rare cases.
lobe involvement. Cerebrospinal fluid pleo­ Other, less common sources of neonatal infec-
cytosis with a predominance of lymphocytes tion include postnatal transmission from a
is typical. parent or other caregiver, most often from a
nongenital infection (eg, mouth, hands).

ERRNVPHGLFRVRUJ
248 Herpes Simplex

The risk of HSV transmission to a neonate fore, genital HSV isolates from children should
born to a mother who acquires primary genital be typed to differentiate between HSV-1 and
infection near the time of delivery is estimated HSV-2.
to be 25% to 60%. In contrast, the risk to a
The incidence of HSV-2 infection correlates
­neonate born to a mother shedding HSV as a
with the number of sexual partners and with
result of reactivation of infection acquired dur-
acquisition of other sexually transmitted infec-
ing the first half of pregnancy or earlier is less
tions. After primary genital infection, which is
than 2%. Distinguishing between primary and
often asymptomatic, some people experience
recurrent herpes simplex infections in women
frequent clinical recurrences, and others have
by history or physical examination alone may
no clinically apparent recurrences. Genital
be impossible because primary and recurrent
HSV-2 infection is more likely to recur than
genital infections may be asymptomatic or
is genital HSV-1 infection.
associated with nonspecific findings (eg, vagi-
nal discharge, genital pain, shallow ulcers). Inoculation of abraded skin occurs from direct
History of maternal genital herpes simplex contact with herpes simplex virus shed from
infection is not helpful in diagnosing neonatal oral, genital, or other skin sites. This contact
herpes simplex disease because more than can result in herpes gladiatorum among wres-
three-quarters of neonates who contract herpes tlers, herpes rugbiaforum among rugby play-
simplex infection are born to women with ers, or herpetic whitlow of the fingers in any
no history or clinical findings suggestive of exposed person.
genital herpes simplex infection during or
­preceding ­pregnancy. Incubation Period
For infection beyond the neonatal period,
Children beyond the neonatal period and
range from 2 days to 2 weeks.
adolescents. Twenty-six percent of US children
have serologic evidence of HSV-1 infection by Diagnostic Tests
7 years of age. Patients with primary gingivo- Herpes simplex grows readily in cell culture.
stomatitis or genital herpes usually shed virus Special transport media are available that allow
for at least 1 week and, occasionally, for several transport to local or regional laboratories for
weeks. Patients with symptomatic recurrences culture. Cytopathogenic effects typical of her-
shed virus for a shorter period, typically 3 to pes simplex infection are usually observed 1 to
4 days. Intermittent asymptomatic reactivation 3 days after inoculation. Methods of culture
of oral and genital herpes is common and likely confirmation include fluorescent antibody
occurs throughout the remainder of a person’s staining, enzyme immunoassays, and mono-
life. The greatest concentration of virus is shed layer culture with typing. Cultures that remain
during symptomatic primary infections and negative by day 5 likely will continue to remain
the lowest concentration of virus is shed during negative. Polymerase chain reaction (PCR)
asymptomatic reactivation. assay can often detect herpes simplex DNA in
Infections with HSV-1 usually result from CSF from neonates with CNS infection (neo­
direct contact with virus shed from visible or natal herpes simplex CNS disease) and from
microscopic orolabial lesions or in infected older children and adults with HSE and is
oral secretions. Infections with HSV-2 usually the diagnostic method of choice for CNS
result from direct contact with virus shed from ­herpes simplex involvement. Polymerase
visible or microscopic genital lesions or in gen- chain reaction assay of CSF can yield negative
ital secretions during sexual activity. Genital results in cases of HSE, especially early in the
herpes simplex infections increase the risk of disease course. In difficult cases in which
acquisition of HIV. Genital infections caused repeated CSF PCR assay results are negative,
by HSV-1 in children can result from autoinoc- histologic examination and viral culture of a
ulation of virus from the mouth. Sexual abuse brain tissue biopsy specimen is the most defi­n­
should always be considered in prepubertal itive method of confirming the diagnosis of
children with genital HSV-2 infections. There- HSE. Detection of intrathecal antibody against

ERRNVPHGLFRVRUJ
Herpes Simplex 249

herpes simplex can also assist in the diagnosis. of multinucleated giant cells and eosinophilic
Viral cultures of CSF from a patient with HSE intranuclear inclusions typical of herpes sim-
are usually negative. plex (eg, with Tzanck test) has low sensitivity
and should not be performed.
For diagnosis of neonatal herpes simplex
­infection, the following specimens should be Herpes simplex PCR assay and cell culture
obtained: swab specimens from the mouth, are the preferred tests for detecting herpes
nasopharynx, conjunctivae, and anus (“surface ­simplex in genital ulcers or other mucocuta­
cultures”) for herpes simplex culture (a single neous lesions consistent with genital herpes.
swab can be used) and, if desired, for herpes The sensitivity of viral culture is low and
simplex PCR assay; specimens of skin vesicles declines rapidly as lesions begin to heal.
for herpes simplex culture and, if desired, for ­Polymerase chain reaction assays for herpes
PCR assay; CSF sample for herpes simplex PCR simplex DNA are more sensitive and are
assay; whole blood sample for herpes simplex increasingly used in many settings. Failure
PCR assay; and whole blood sample for mea- to detect herpes simplex in genital lesions by
suring alanine aminotransferase. The perfor- culture or PCR assay does not indicate an
mance of PCR assay on skin and mucosal absence of herpes simplex infection because
specimens from neonates has not been studied; viral shedding is ­intermittent.
if used, surface or skin PCR assays should be
Type-specific and type-common antibodies
performed in addition to surface cultures. Pos-
to herpes simplex develop during the first
itive culture results obtained from any of the
­several weeks after infection and persist inde­
surface sites more than 12 to 24 hours after
finitely. The median time to seroconversion is
birth indicate viral replication and are sug­
21 days with the Focus type-specific enzyme-
gestive of neonatal infection rather than con-
linked immunosorbent assay, and more than
tamination after intrapartum exposure. As
95% of people seroconvert by 12 weeks follow-
with any PCR assay, false-negative and false-
ing infection. Although type-specific HSV-2
positive results can occur. Whole blood PCR
antibody usually indicates previous anogenital
assay may be of benefit in diagnosis of neonatal
infection, the presence of HSV-1 antibody
herpes simplex disease, but its use should not
does not reliably distinguish anogenital from
supplant standard diagnostic studies (ie, sur-
orolabial infection because a substantial pro-
face cultures and CSF PCR assay). Any of the
portion of initial genital infections are caused
3 syndromes of neonatal herpes simplex can
by HSV-1. Type-specific serologic tests can be
have associated viremia, so a positive whole
useful in confirming a clinical diagnosis of
blood PCR assay should not be used to deter-
genital herpes caused by HSV-2. There is
mine extent of disease; similarly, no data exist
­growing evidence that type-specific antibody
to support use of serial blood PCR assay to
avidity testing may prove useful for evaluating
monitor response to therapy. Rapid diagnostic
risk of maternal transmission of herpes sim-
techniques are also available, such as direct
plex to neonates. Serologic testing is not useful
fluorescent antibody staining of vesicle scrap-
in ­neonates.
ings or enzyme immunoassay detection of her-
pes simplex antigens. These techniques are as Several glycoprotein G–based type-specific
specific but slightly less sensitive than culture. assays including at least one that can be used as
Typing herpes simplex strains differentiates a point-of-care test. The sensitivities and speci-
between HSV-1 and HSV-2 isolates. Radio- ficities of these tests for detection of HSV-2 IgG
graphs and clinical manifestations can suggest antibody vary from 90% to 100%; false-negative
herpes simplex pneumonitis, and elevated results may occur, especially early after infec-
transaminase values can suggest herpes sim- tion, and false-positive results can occur, espe-
plex hepatitis; both occur commonly in neo­ cially in patients with low likelihood of herpes
natal herpes simplex disseminated disease. simplex infection.
Histologic examination of lesions for presence

ERRNVPHGLFRVRUJ
250 Herpes Simplex

Treatment All neonates with neonatal herpes simplex


Acyclovir is the drug of choice for many herpes ­ isease, regardless of syndrome, should have
d
simplex infections (Table 64.1). Valacyclovir an ophthalmologic examination and neuro­
is an L-valyl ester of acyclovir that is metabo- imaging to establish baseline brain anatomy.
lized to acyclovir after oral administration, All neonates with CNS involvement should
resulting in higher serum concentrations than have a repeat lumbar puncture performed
are achieved with oral acyclovir and similar near the end of therapy to document that the
serum concentrations as are achieved with CSF is negative for herpes simplex DNA on
intravenous administration of acyclovir. Fam- PCR assay; if this remains positive, consulta-
ciclovir is converted rapidly to penciclovir tion with an infectious diseases specialist
after oral administration. is ­warranted.

Neonatal. Parenteral acyclovir is the recom- Oral acyclovir suppressive therapy for the
mended treatment for neonatal herpes simplex 6 months following treatment of acute neonatal
infections, regardless of manifestations and herpes simplex infection improves neurodevel-
clinical findings. The duration of therapy is opmental outcomes in infants with herpes sim-
14 days in SEM disease and a minimum of plex CNS disease and prevents skin recurrences
21 days in CNS disease or disseminated disease. in infants with any disease classification of
The best outcomes in terms of morbidity and neonatal herpes simplex. Infants with ocular
mortality are observed among neonates with involvement attributable to herpes simplex
SEM disease. Approximately 50% of neonates infection should receive a topical ophthalmic
surviving neonatal herpes simplex experience antiviral drug. An ophthalmologist should be
cutaneous recurrences, with the first skin involved in the management and treatment of
recurrence often occurring within 1 to 2 weeks acute neonatal ocular herpes simplex infection.
of stopping intravenous acyclovir treatment.

Table 64.1
Recommended Therapy for Herpes Simplex Infectionsa

Infection Drugb
Neonatal Parenteral acyclovir
Keratoconjunctivitis Trifluridinec
OR
Iododeoxyuridine
OR
Topical ganciclovir
Genital Acyclovir
OR
Famciclovir
OR
Valacyclovir
Mucocutaneous (immunocompromised or primary gingivostomatitis) Acyclovir
OR
Famciclovir
OR
Valacyclovir
Acyclovir-resistant (severe infections, immunocompromised) Parenteral foscarnet
Encephalitis Parenteral acyclovir
a See text for details.
b Famciclovir and valacyclovir are approved by the US Food and Drug Administration for treatment of adults.
c Treatment of herpes simplex ocular infection should involve an ophthalmologist.

ERRNVPHGLFRVRUJ
Herpes Simplex 251

Genital infection apy, which has the additional advantage of


decreasing the risk of genital HSV-2 trans-
• Primary. Many patients with first-episode
mission to susceptible partners.
genital herpes initially have mild clinical
manifestations but may go on to develop In adults with frequent genital herpes sim-
severe or prolonged symptoms with viral plex recurrences, daily oral acyclovir sup-
reactivation. Therefore, most patients with pressive therapy is effective for decreasing
initial genital herpes should receive antiviral the frequency of symptomatic recurrences
therapy. In adults, acyclovir and valacyclovir and improving quality of life. After approxi-
decrease the duration of symptoms and viral mately 1 year of continuous daily therapy,
shedding in primary genital herpes. Oral acyclovir should be discontinued, and the
acyclovir therapy, initiated within 6 days recurrence rate should be assessed. If fre-
of onset of disease, shortens the duration quent recurrences are observed, additional
of illness and viral shedding by 3 to 5 days. suppressive therapy should be considered.
Valacyclovir and famciclovir do not seem Acyclovir appears to be safe for adults
to be more effective than acyclovir but offer receiving the drug for more than 15 years,
the advantage of less frequent dosing. Intra- but longer-term effects are unknown.
venous acyclovir is indicated for patients
with a severe or complicated primary infec- Acyclovir or valacyclovir may be adminis-
tion that requires hospitalization followed tered orally to pregnant women with first-
by oral antiviral therapy to complete at least episode genital herpes or severe recurrent
10 days of total therapy. herpes, and acyclovir should be given intra-
venously to pregnant women with severe
• Recurrent. Antiviral therapy for recurrent
herpes simplex infection. Pregnant women
genital herpes can be administered episodi-
or women of childbearing age with genital
cally to ameliorate or shorten the duration
herpes should be encouraged to inform their
of lesions or continuously as suppressive
health care professionals and those who will
therapy to decrease the frequency of recur-
care for the newborn (Table 64.2).
rences. Many people prefer suppressive ther-

Table 64.2
Maternal Infection Classification by Genital Herpes ­Simplex
Viral Type and Maternal Serologic Test Resultsa

Classification of PCR/Culture From Maternal HSV-1 and HSV-2


­Maternal Infection Genital Lesion IgG Antibody Status
Documented first-episode Positive, either virus Both negative
­primary infection
Documented first-episode Positive for HSV-1 Positive for HSV-2 AND negative
nonprimary ­infection for HSV-1
Positive for HSV-2 Positive for HSV-1 AND negative
for HSV-2
Assumed first-episode Positive for HSV-1 OR HSV-2 Not available
(­primary or ­nonprimary) Negative OR not availableb Negative for HSV-1 and/or HSV-2,
infection OR not available
Recurrent infection Positive for HSV-1 Positive for HSV-1
Positive for HSV-2 Positive for HSV-2
Abbreviations: HSV, herpes simplex virus; IgG, immunoglobulin G; PCR, polymerase chain reaction (assay).
a To be used for women without a clinical history of genital herpes.
b When a genital lesion is strongly suspicious for HSV, clinical judgment should supersede the virologic test results for the conservative

purposes of this neonatal management algorithm. Conversely, if, in retrospect, the genital lesion was not likely to be caused by HSV and the
PCR assay culture result is negative, departure from the evaluation and management in this conservative algorithm may be warranted.

ERRNVPHGLFRVRUJ
252 Herpes Simplex

Mucocutaneous Other herpes simplex infections


• Immunocompromised hosts. Intravenous • Central nervous system. Patients with HSE
acyclovir is effective for treatment of should be treated for 21 days with intrave-
­mucocutaneous herpes simplex infection. nous acyclovir. Patients who are comatose
Acyclovir-resistant strains of HSV have or semicomatose at initiation of therapy
been isolated from immunocompromised have a poorer outcome. For people with Bell
people receiving prolonged treatment with palsy, the combination of acyclovir and
acyclovir. Under these circumstances, pro- prednisone may be considered.
gressive disease may be observed despite
• Ocular. Treatment of eye lesions should be
acyclovir therapy. Foscarnet is the drug
undertaken in consultation with an ophthal-
of choice for disease caused by acyclovir-­
mologist. Several topical drugs, such as 1%
resistant HSV isolates.
trifluridine, 0.1% iododeoxyuridine, and
• Immunocompetent hosts. Limited data 0.15% ganciclovir, have proven efficacy for
are available on effects of acyclovir on the superficial keratitis. Topical corticosteroids,
course of primary or recurrent nongenital by themselves, are contraindicated in sus-
mucocutaneous herpes simplex infection in pected herpes simplex conjunctivitis; how-
immunocompetent hosts. Therapeutic ben- ever, ophthalmologists may choose to use
efit has been noted in a limited number of corticosteroids in conjunction with antiviral
children with primary gingivostomatitis drugs to treat locally invasive infections.
treated with oral acyclovir. Slight therapeu-
tic benefit of oral acyclovir therapy has been
demonstrated among adults with recurrent
herpes labialis.

Image 64.2
Tzanck test showing multinucleated giant
cells (magnification x100). Courtesy of Robert
Jerris, MD.

Image 64.1
This negatively stained transmission
electron micrograph reveals the presence of
numerous herpesvirus virions, members of the
Herpesviridae virus family. Courtesy of Centers
for Disease Control and Prevention/Dr Fred
Murphy; Sylvia Whitfield.

ERRNVPHGLFRVRUJ
Herpes Simplex 253

Image 64.3
Image 64.4
This micrograph depicts results indicating the
Multinucleated giant cells formed by the fusion
presence of herpes simplex virus in a Tzanck test
of keratinocytes are often present in association
specimen from a penile lesion. A Tzanck test
with herpes simplex infection. Courtesy of Daniel
involves extracting a sample of tissue from the
P. Krowchuk, MD, FAAP.
base of a vesicle to look for multinucleated giant
cells. Courtesy of Centers for Disease Control
and Prevention/Joe Miller.

Image 64.6
Image 64.5 Herpes simplex stomatitis, primary infection.
The cytopathic effect of herpes simplex virus
develops rapidly in cell culture. Cytopathogenic
effects can usually be seen in 1 to 3 days after
tissue-culture inoculation.

Image 64.7
Herpes simplex stomatitis, primary infection of Image 64.8
the anterior oral mucous membranes. Tongue Herpes simplex stomatitis, primary infection with
lesions are also common with primary herpes extension to the face.
simplex infections.

ERRNVPHGLFRVRUJ
254 Herpes Simplex

Image 64.10
Recurrent herpes simplex infection of the face,
most pronounced in the periorbital area.

Image 64.9
Recurrent herpes simplex periorbital, ear, and
facial vesicles. Copyright Martha Lepow.

Image 64.12
Eczema herpeticum on the face of a boy with
eczema and primary herpetic gingivostomatitis,
day 3 to 4 of the onset. The herpetic lesions
spread over a period of 2 to 3 days to extensive
covering of the skin, and systemic therapy with
acyclovir was provided. The patient recovered
Image 64.11 after a prolonged hospital stay for secondary
Herpes simplex infection in a child with eczema nosocomial bacterial infections. Copyright Jerri
with Kaposi varicelliform eruption and Stevens- Ann Jenista, MD.
Johnson syndrome.

Image 64.13
Image 64.14
A neonate born with “sucking blisters” on hand
who developed neonatal herpes simplex lesions Herpes simplex infection at a diphtheria, tetanus,
at the site. The patient responded well while and pertussis vaccine injection site reflecting
receiving treatment with acyclovir. Copyright Jerri self-inoculation. Courtesy of Edgar O. Ledbetter,
Ann Jenista, MD. MD, FAAP.

ERRNVPHGLFRVRUJ
Herpes Simplex 255

Image 64.16
An adolescent girl with herpetic whitlow secon­d­
Image 64.15 ary to orolabial lesions with self-inoculation.
Herpetic whitlow in a 10-year-old boy with Copyright Martin G. Myers, MD.
recurrent herpes simplex infection.

Image 64.18
Neonatal herpes simplex infection with
disseminated vesicular lesions.

Image 64.17
A 7-month-old boy with eczema and suppurative Image 64.19

drainage from otitis media complicated by herpes Neonatal herpes skin lesions of the face. A pre­
simplex infection (Kaposi varicelliform eruption). mature 14-day-old developed vesicular lesions
Courtesy of George Nankervis, MD. over the right eye and face on days 11 to 14 of
life. Herpes simplex virus type 2 was recovered
from viral culture of the vesicular fluid. Kerato­
conjunctivitis was diagnosed by ophthalmology
and the neonate was treated with topical antiviral
eyedrops in addition to intravenous acyclovir. The
neonate was born via a spontaneous vaginal
delivery with a vertex presentation. Membranes
had ruptured 8 hours prior to delivery. There was
no history of genital herpes or fever blisters in
either parent. The lesions were concentrated on
the face and head, the presenting body parts in
delivery. Copyright Barbara Jantausch, MD, FAAP.

ERRNVPHGLFRVRUJ
256 Herpes Simplex

Image 64.20
Neonatal herpes skin lesions of the head and
face. This is the same patient as shown in
Image 64.19. Copyright Barbara Jantausch,
MD, FAAP. Image 64.21
A 2-hour-old girl with characteristic vesicular and
ulcerative lesions below the umbilicus and over
the genital area that grew herpes simplex type 1.
Courtesy of Neal Halsey, MD.

Image 64.23
Postneonatal herpes simplex encephalitis.
Image 64.22
Hemorrhagic necrosis of the temporal lobes.
Computed tomography scan of a patient
Courtesy of Dimitris P. Agamanolis, MD.
with herpes simplex encephalitis with temporal
lobe changes.

Image 64.25
Image 64.24
Burned out neonatal herpes simplex encephalitis.
Herpes simplex encephalitis. Viral intranuclear
Severe atrophy and distortion of the cerebral hemi­
inclusions. Courtesy of Dimitris P. Agamanolis, MD.
spheres. Courtesy of Dimitris P. Agamanolis, MD.

ERRNVPHGLFRVRUJ
Herpes Simplex 257

Image 64.26 Image 64.27


Herpes simplex esophagitis. Courtesy of Dimitris This male presented with primary vesiculopapular
P. Agamanolis, MD. herpes genitalis lesions on his glans penis and
penile shaft. When signs of herpes genitalis
occur, they typically appear as one or more
blisters on or around the genitals or rectum. The
blisters break, leaving tender ulcers (sores) that
may take 2 to 4 weeks to heal the first time they
occur. Courtesy of Centers for Disease Control
and Prevention/Dr N. J. Flumara; Dr Gavin Hart.

Image 64.28
A 15-year-old white girl with recurrent facial and
ocular herpes simplex infection. Courtesy of Larry
Frenkel, MD.

Image 64.29
Herpetic whitlow in a 6-year-old boy with a
history of herpes labialis. Courtesy of Benjamin
Estrada, MD.

Image 64.30
Herpes simplex infection is characterized by
clustered vesicles on an erythematous base.
Courtesy of Daniel P. Krowchuk, MD, FAAP.

Image 64.31
A 15-year-old girl with a primary herpes simplex
infection of the genital area. Courtesy of Larry
Frenkel, MD.

ERRNVPHGLFRVRUJ
258 Histoplasmosis

65 fever, failure to thrive, and hepatosplenomegaly;


if untreated, malnutrition, diffuse adenopathy,
Histoplasmosis pneumonitis, mucosal ulceration, pancytope-
Clinical Manifestations nia, disseminated intravascular coagulopathy,
and gastrointestinal tract bleeding can ensue.
Histoplasma capsulatum causes symptoms in Central nervous system involvement is com-
fewer than 5% of infected people. Clinical mon. Chronic PDH generally occurs in adults
­manifestations are classified according to site with immune suppression and is characterized
(pulmonary or disseminated), duration (acute, by prolonger fever, night sweats, weight loss,
subacute, or chronic), and pattern (primary or and fatigue; signs include hepatosplenomegaly,
reactivation) of infection. Most symptomatic mucosal ulcerations, adrenal insufficiency,
patients have acute pulmonary histoplasmosis, and pancytopenia. Clinicians should be alert
a self-limited illness characterized by fever, to the risk of disseminated endemic mycoses
chills, nonproductive cough, and malaise. in patients receiving tumor necrosis factor-α
­Typical radiographic finding in mild infections antagonists and disease-modifying antirheu-
is an area of focal pneumonitis associated with matic drugs.
hilar or mediastinal adenopathy; high inocu-
lum exposure can result in diffuse interstitial Etiology
or reticulonodular pulmonary infiltrates. Most H capsulatum var capsulatum is a thermally
patients recover without treatment 2 to 3 weeks dimorphic, endemic fungus that grows in the
after onset of symptoms. Exposure to a large environment as a microconidia-bearing mold
inoculum of conidia can cause severe pulmo- but converts to its yeast phase at 37°C (98.6°F).
nary infection associated with high fevers, H capsulatum var duboisii is the cause of
hypoxemia, diffuse reticulonodular infiltrates, ­African histoplasmosis and is found only in
and acute respiratory distress syndrome. Medi- central and western Africa.
astinal involvement, usually a complication of
pulmonary histoplasmosis, includes mediasti- Epidemiology
nal lymphadenitis, which can cause airway H capsulatum is encountered in most parts
encroachment in young children. Inflamma- of the world (including Africa, the Americas,
tory syndromes (pericarditis and rheumato- Asia, and Europe) and is highly endemic in the
logic syndromes) can also develop; erythema central United States, particularly the Missis-
nodosum can occur in adolescents and adults. sippi, Ohio, and Missouri river valleys. Infec-
Primary cutaneous infections after trauma are tion is acquired following inhalation of conidia
rare. Chronic cavitary pulmonary histoplas- that are aerosolized by disturbance of soil or
mosis is extremely rare in children. abandoned structures contaminated with bat
Disseminated histoplasmosis can be self-­ guano or bird droppings. The inoculum size,
limited or progressive. Progressive dissemi- strain virulence, and immune status of the
nated histoplasmosis (PDH) can occur in host affect the severity of the ensuing illness.
otherwise healthy infants and children younger Infections occur sporadically, in outbreaks
than 2 years or in older children with primary when weather conditions (dry and windy)
or acquired cellular immune dysfunction. ­predispose to spread of conidia, or in point-
­Progressive disseminated histoplasmosis can source epidemics after exposure to activities
be a rapidly progressive illness following acute that disturb contaminated sites. In regions
infection or can be a more chronic, slowly with endemic disease, recreational and
­progressive disease. Progressive disseminated ­occu­pational activities, such as playing in
histoplasmosis in adults occurs most often in ­hollow trees, caving, construction, excavation,
people with underlying immune deficiency demolition, farming, and cleaning of contami-
(eg, HIV/AIDS, solid organ transplant, hema- nated buildings, have been associated with
tologic malignancy, biologic response modifiers ­outbreaks. Person-to-person transmission
including tumor necrosis factor antagonists) or does not occur. Prior infection confers partial
in people older than 65 years. Early manifesta- immunity; reinfection can occur but requires
tions of PDH in children include prolonged a larger ­inoculum.

ERRNVPHGLFRVRUJ
Histoplasmosis 259

Incubation Period is more specific than the complement fixa-


Variable; usually 1 to 3 weeks. tion test, but the complement fixation test is
more sensitive.
Diagnostic Tests
Treatment
Culture is the definitive method of diagnosis.
H capsulatum organisms from bone marrow, Immunocompetent children with uncompli-
blood, sputum, and tissue specimens grow on cated or mild-to-moderate acute pulmonary
standard mycologic media in 1 to 6 weeks. The histoplasmosis may not require antifungal
lysis-centrifugation method is preferred for therapy because infection is usually self-­
blood cultures. A DNA probe for H capsulatum limited. However, if the patient does not
permits rapid identification of cultured isolates. improve within 4 weeks, itraconazole should
Demonstration of typical intracellular yeast be given for 6 to 12 weeks.
forms by examination with Gomori methe­n­ For severe or disseminated infections, a lipid
amine silver or other stains of tissue, blood, formulation of amphotericin B followed by
bone marrow, or bronchoalveolar lavage speci- itraconazole is recommended. Itraconazole is
mens strongly supports the diagnosis of histo- preferred over other azoles by most experts.
plasmosis when clinical, epidemiologic, and Although safety and efficacy of itraconazole
other laboratory studies are compatible. for use in children have not been established,
Detection of H capsulatum antigen in serum, anecdotal experience has found it to be well
urine, bronchoalveolar lavage fluid, or cerebro- tolerated and effective. Serum trough con­
spinal fluid using a quantitative immunoassay centrations of itraconazole should be 1 or
is possible with a rapid, commercially available greater but less than 10 mcg/mL. Concentra-
diagnostic test. Antigen detection in blood and tions should be checked after 2 weeks of ther-
urine specimens is most sensitive for severe, apy to ensure adequate drug exposure.
acute pulmonary infections and for progressive For severe, acute pulmonary infections, treat-
disseminated infections. Results are often tran- ment with a lipid formulation of amphotericin B
siently positive early in the course of acute, is recommended for 1 to 2 weeks. After ­clinical
self-limited pulmonary infections. A negative improvement occurs, itraconazole is recom-
test result does not exclude infection. If the mended for an additional 12 weeks. Methyl-
result is initially positive, the antigen test is prednisolone during the first 1 to 2 weeks of
also useful for monitoring treatment response therapy may be considered if severe respiratory
and, thereafter, promptly identifying relapse complications develop.
or reexposure to H capsulatum conidia. Cross-
reactions occur in patients with blastomycosis, All patients with chronic pulmonary histo­
coccidioidomycosis, paracoccidioidomycosis, plasmosis should be treated. Mild to moderate
and penicilliosis; clinical and epidemiologic cases should be treated with itraconazole for 1
distinctions aid in differentiating these entities. to 2 years. Severe cases should be treated ini-
tially with a lipid formulation amphotericin B
Serologic testing is available and is most useful followed by itraconazole for the same duration.
in patients with subacute or chronic pulmonary
disease. A 4-fold increase in yeast-phase or Mediastinal and inflammatory manifestations
mycelial-phase complement fixation titers or of infection generally do not need to be treated
a single titer of 1:32 or greater in either test is with antifungal agents. However, mediastinal
strong presumptive evidence of active or recent adenitis that causes obstruction of a bronchus,
infection in patients exposed to or residing the esophagus, or another mediastinal struc-
within regions of endemicity. Cross-reacting ture may improve with a brief course of corti-
antibodies can result from Aspergillus species, costeroids. In these instances, itraconazole
Blastomyces dermatitidis, and Coccidioides should be used concurrently and continued
species infections. The immunodiffusion test for 6 to 12 weeks. Dense fibrosis of mediastinal

ERRNVPHGLFRVRUJ
260 Histoplasmosis

structures without an associated granuloma- When the child has demonstrated substantial
tous inflammatory component does not clinical improvement and a decline in the
respond to antifungal therapy, and surgical serum concentration of Histoplasma antigen,
intervention may be necessary for severe cases. oral itraconazole is administered for 12 weeks.
Pericarditis and rheumatologic syndromes may Prolonged therapy for up to 12 months may
respond to treatment with nonsteroidal anti- be required for patients with severe disease,
inflammatory agents. primary immunodeficiency syndromes, or
acquired immunodeficiency that cannot be
For treatment of moderately severe to severe
reversed, or patients who experience relapse
PDH in an infant or child, a lipid formulation
despite appropriate therapy.
of amphotericin B is the drug of choice and
is usually given for a minimum of 2 weeks.

Image 65.2
Image 65.1 Asexual spores (conidia). Tuberculate macroco­
Pulmonary histiocyte containing numerous yeast nidia of Histoplasma capsulatum (toluidine blue
cells of Histoplasma capsulatum. Courtesy of stain). Microconidia are also present. Courtesy
Centers for Disease Control and Prevention/ of Centers for Disease Control and Prevention.
Dr J.T. McClellan, Lexington, KY.

Image 65.4
Image 65.3
Methenamine silver stain reveals Histoplasma
This photomicrograph reveals a conidiophore
capsulatum fungi. Courtesy of Centers for
of the fungus Histoplasma capsulatum.
Disease Control and Prevention.
H capsulatum grows in soil and material con­
taminated with bat or bird droppings. Spores
become airborne when contaminated soil is
disturbed. Breathing the spores causes pulmonary
histoplasmosis. Courtesy of Centers for Disease
Control and Prevention/Libero Ajello, MD.

ERRNVPHGLFRVRUJ
Histoplasmosis 261

Image 65.5
Image 65.6
Pictured is a Sabhi agar plate culture of the
These 2 slant cultures grew Histoplasma
fungus Histoplasma capsulatum grown at 20°C
capsulatum colonies (left tube: Sabouraud agar;
(68°F). Positive histoplasmin skin tests occur in
right tube: Sabhi agar). H capsulatum is the
as many as 80% of the people living in areas
most common cause of fungal respiratory
where H capsulatum is common, such as the
infections globally. While most infections are
eastern and central United States. Courtesy of
mild, 10% of cases can be life-threatening, such
Centers for Disease Control and Prevention/Dr
as inflammation of the pericardium and fibrosis
William Kaplan.
of major blood vessels. Courtesy of Centers for
Disease Control and Prevention.

Image 65.7
A 10-year-old boy with calcified left hilar lymph Image 65.8
nodes secondary to histoplasmosis. A preadolescent with calcified left hilar lymph
nodes bilaterally secondary to histoplasmosis.

Image 65.9
Histoplasma capsulatum in peripheral blood
smear. Copyright Martha Lepow.
Image 65.10
Computed tomography scan showing single
pulmonary nodule of histoplasmosis. Courtesy of
Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
262 Histoplasmosis

Image 65.12
Gross pathology specimen of lung showing
cut surface of fibrocaseous nodule due to
Histoplasma capsulatum. Copyright American
Society for Clinical Pathology.

Image 65.11
Chest radiograph showing miliary densities in
both lung fields plus a thin-walled cavity with
a fluid level. Copyright American Society for
Clinical Pathology.

Image 65.13
Computed tomography scan of lungs showing classic snowstorm appearance of acute histoplasmo­sis.
Courtesy of Centers for Disease Control and Prevention.

Image 65.14
This partially calcified fibrocaseous nodule depicts the histopathologic changes associated with
histoplasmosis of the lung. Courtesy of Centers for Disease Control and Prevention/Martin Hicklin, MD.

ERRNVPHGLFRVRUJ
Histoplasmosis 263

Image 65.15
This micrograph depicts the histopathologic changes associated with histoplasmosis of the lung.
Courtesy of Centers for Disease Control and Prevention/Martin Hicklin, MD.

Image 65.16
This micrograph depicts the histopathologic changes associated with histoplasmosis of the spleen
(Gridley stain). Courtesy of Centers for Disease Control and Prevention/Martin Hicklin, MD.

ERRNVPHGLFRVRUJ
264 Hookworm Infections

66 selected foci of South America. N americanus


is predominant in the western hemisphere,
Hookworm Infections sub-Saharan Africa, Southeast Asia, and a
(Ancylostoma duodenale and Necator number of Pacific islands. Larvae and eggs
­americanus) ­survive in loose, sandy, moist, shady, well-­
aerated, warm soil (optimal temperature 23°C–
Clinical Manifestations
33°C [73°F–91°F]). Hookworm eggs from stool
Patients with hookworm infection are often hatch in soil in 1 to 2 days as rhabditiform lar-
asymptomatic; however, chronic hookworm vae. These larvae develop into infective filari-
infection is a common cause of moderate to form larvae in soil within 5 to 7 days and can
severe hypochromic, microcytic anemia in persist for 3 to 4 weeks. Percutaneous infection
people living in tropical developing countries, occurs after exposure to infectious larvae. A
and heavy infestation can cause hypoprotein- duodenale transmission can occur by oral
emia with edema. Chronic hookworm infec- ingestion and, possibly, through human milk.
tion in children can lead to physical growth Untreated infected patients can harbor worms
delay, deficits in cognition, and developmental for 5 years or longer.
delay. After contact with contaminated soil,
initial skin penetration of larvae, often involv- Incubation Period
ing the feet, can cause a stinging or burning The time from exposure to development of
sensation followed by pruritus and a papulo­ noncutaneous symptoms is 4 to 12 weeks.
vesicular rash that may persist for 1 to 2 weeks.
Pneumonitis associated with migrating larvae Diagnostic Tests
(Löffler-like syndrome) is uncommon and Microscopic demonstration of hookworm eggs
­usually mild, except in heavy infections. Col- in feces is diagnostic. Adult worms or larvae
icky abdominal pain, nausea, diarrhea, and are rarely seen. Approximately 5 to 8 weeks are
marked eosinophilia can develop 4 to 6 weeks required after infection for eggs to appear in
after exposure. Blood loss secondary to hook- feces. A direct stool smear with saline solution
worm infection develops 10 to 12 weeks after or potassium iodide saturated with iodine is
initial infection, and symptoms related to adequate for diagnosis of heavy hookworm
­serious iron deficiency anemia can develop in infection; light infections require concentra-
long-standing moderate or heavy hookworm tion techniques. Quantification techniques
infections. Pharyngeal itching, hoarseness, (eg, Kato test, Beaver direct smear, or Stoll egg-
nausea, and vomiting can develop shortly counting techniques) to determine the clinical
after oral ingestion of infectious Ancylostoma significance of infection and the response to
duodenale ­larvae. treatment may be available from state or refer-
ence laboratories.
Etiology
Necator americanus is the major cause of Treatment
­hookworm infection worldwide, although Albendazole, mebendazole, and pyrantel
A duodenale is also an important hookworm pamoate are all effective treatments. In 1-year-
in some regions. Mixed infections can also olds, the World Health Organization recom-
occur. Both are roundworms (nematodes) mends reducing the albendazole dose to half
with similar life cycles. of that given to older children and adults.
Reexamination of stool specimens 2 weeks
Epidemiology
after therapy to determine whether worms
Humans are the only reservoir. Hookworms have been eliminated is helpful for assessing
are prominent in rural, tropical, and subtropi- response to therapy. Retreatment is indicated
cal areas where soil contamination with human for persistent infection. Nutritional supple-
feces is common. Although the prevalence of mentation, including iron, is important when
both hookworm species is equal in many areas, severe anemia is present. Severely affected chil-
A duodenale is the predominant species in the dren may also require blood transfusion.
Mediterranean region, northern Asia, and

ERRNVPHGLFRVRUJ
Hookworm Infections 265

Image 66.1
Hookworm (Necator americanus) ova in stool preparation.

Image 66.2
Hookworm eggs examined on wet mount (eggs of Ancylostoma duodenale and Necator americanus
cannot be distinguished morphologically). Diagnostic characteristics: 57 to 76 µm by 35 to 47 µm, oval
or ellipsoidal, thin shell. The embryo (right) has begun cellular division and is at an early developmental
stage (gastrula). Courtesy of Centers for Disease Control and Prevention.

Image 66.3
Hookworm filariform larva (wet preparation). Courtesy of Centers for Disease Control and Prevention/
Dr Mae Melvin.

ERRNVPHGLFRVRUJ
266 Hookworm Infections

Image 66.4
This micrograph reveals the head of the
hookworm Necator americanus and its mouth’s Image 66.5
cutting plates (magnification x400). The hook­ This unstained micrograph reveals the
worm uses these sharp cutting teeth to grasp Ancylostoma duodenale hookworm’s mouth
firmly to the intestinal wall and, while remaining parts (magnification x125). Courtesy of Centers
fastened in place, ingests the host’s blood, for Disease Control and Prevention/Dr Mae
obtaining its nutrients in this fashion. Courtesy Melvin.
of Centers for Disease Control and Prevention/
Dr Mae Melvin.

Image 66.6
Eggs are passed in the stool (1) and, under favorable conditions (moisture, warmth, shade), larvae
hatch in 1 to 2 days. The released rhabditiform larvae grow in the feces or the soil (2), and, after 5 to
10 days (and 2 molts), they become filariform (third-stage) larvae that are infective (3). These infective
larvae can survive 3 to 4 weeks in favorable environmental conditions. On contact with the human
host, the larvae penetrate the skin and are carried through the veins to the heart and then to the lungs.
They penetrate into the pulmonary alveoli, ascend the bronchial tree to the pharynx, and are swallowed
(4). The larvae reach the small intestine, where they reside and mature into adults. Adult worms live in
the lumen of the small intestine, where they attach to the intestinal wall with resultant blood loss by
the host (5). Most adult worms are eliminated in 1 to 2 years, but longevity records can reach several
years. Some Ancylostoma duodenale larvae, following penetration of the host skin, can become
dormant (in the intestine or muscle). In addition, infection by A duodenale may also occur by the oral
and transmammary route. Necator americanus, however, requires a transpulmonary migration phase.
Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Hookworm Infections 267

Image 66.7
This child with hookworm shows visible signs of edema and was diagnosed with anemia as well.
Courtesy of Centers for Disease Control and Prevention/Dr Myron Schultz.

Image 66.8
This enlargement shows hookworms, Ancylostoma caninum, attached to the intestinal mucosa.
Barely visible larvae penetrate the skin (often through bare feet), are carried to the lungs, go through
the respiratory tract to the mouth, are swallowed, and eventually reach the small intestine. This journey
takes about a week. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
268 Human Herpesvirus 6 (Including Roseola) and 7

67 Following primary infection, HHV-6 and


HHV-7 remain latent and can reactivate.
Human Herpesvirus 6 The clinical circumstances and manifestations
(Including Roseola) and 7 of reactivation in healthy people are unclear.
Illness associated with HHV-6 reactivation
Clinical Manifestations has been described primarily among recipients
Clinical manifestations of primary infection of solid organ and hematopoietic stem cell
with human herpesvirus 6 (HHV-6) include transplants. Among the clinical findings
roseola (exanthem subitum) in approximately ­associated with HHV-6 reactivation in these
20% of infected children, with the other 80% patients are fever, rash, hepatitis, bone marrow
having an undifferentiated febrile illness with- suppression, graft rejection, pneumonia, and
out rash or localizing signs. Human herpes­ encephalitis. A few cases with central nervous
virus 6 infection is often accompanied by system symptoms have been reported in asso-
cervical and characteristic occipital lymphade- ciation with HHV-7 reactivation in immuno-
nopathy, gastrointestinal tract or respiratory compromised hosts, but clinical findings are
tract signs, and inflamed tympanic mem- less frequently with HHV-7 than with HHV-6
branes. Fever is usually high (temperature reactivation.
>39.5°C [103.0°F]) and persists for 3 to 7 days.
Etiology
Approximately 20% of all emergency depart-
ment visits for febrile children 6 through 12 Human herpesviruses 6 and 7 are lympho-
months of age are attributable to HHV-6. tropic agents that are closely related members
­Roseola is distinguished by the erythematous of the Herpesviridae family, subfamily
maculopapular rash that appears once fever ­Betaherpesvirinae. Among the human herpes-
resolves and can last hours to days. Febrile viruses, HHV-6 and HHV-7 are most closely
­seizures, sometimes leading to status epilepti- related to cytomegalovirus. Human herpes­
cus, are the most common complication and viruses 6 and 7 establish lifelong infection
reason for hospitalization among children after initial exposure. There are 2 species of
with primary HHV-6 infection. Approximately HHV-6, HHV-6A and HHV-6B. Essentially
10% to 15% of children develop febrile seizures, all primary infections in children are caused
predominantly between the ages of 6 and by HHV-6B, except infections in some parts
18 months. Other neurologic manifestations of Africa. Among congenital HHV-6 infec-
that can accompany primary infection include tions, however, as many as one-third may be
a bulging fontanelle and encephalopathy or caused by HHV-6A.
encephalitis. Hepatitis is a rare manifestation.
Epidemiology
Approximately 5% of mononucleosis cases are
attributable to HHV-6. Congenital HHV-6 Human herpesviruses 6 and 7 cause ubiquitous
infection, which occurs in approximately 1% infections in children worldwide. Humans
of newborns, has not been linked to any are the only natural host. Nearly all children
­clinical disease. acquire HHV-6 infection within the first
2 years of life, probably resulting from asymp-
The clinical manifestations occurring with tomatic shedding of infectious virus in secre-
human herpesvirus 7 (HHV-7) infections are tions of a healthy family member or other
indistinct. Most primary infections are asymp- close contact. During the acute phase of pri-
tomatic or mild. Some initial infections can mary infection, HHV-6 and HHV-7 can be
present as typical roseola and may account for isolated from peripheral blood mononuclear
second or recurrent cases of roseola. Febrile cells and from saliva of some children. Viral
illnesses associated with seizures have also DNA subsequently can be detected throughout
been documented to occur during primary life by polymerase chain reaction assay in mul-
HHV-7 infection. Some investigators suggest tiple body sites. Although HHV-6 and HHV-7
the association of HHV-7 with these clinical can be detected in blood mononuclear cells,
manifestations results from the ability of salivary glands, lung, and skin, only HHV-6
HHV-7 to reactivate latent HHV-6.

ERRNVPHGLFRVRUJ
Human Herpesvirus 6 (Including Roseola) and 7 269

is found in brain and only HHV-7 is found in Diagnostic Tests


mammary glands. Virus-specific maternal Multiple assays for detection of HHV-6 and
antibody, which is uniformly present in the HHV-7 have been developed, but few are avail-
sera of neonates at birth, provides transient able commercially, and many do not differenti-
partial protection. As maternal antibody ate between new, past, and reactivated infection.
­concentration decreases during the first year These tests have limited utility in clinical practice.
of life, the infection rate increases rapidly,
peaking between 6 and 24 months of age. Serologic tests include immunofluorescent
Essentially all children are seropositive for anti­body, neutralization, immunoblot, and
HHV-6 by 4 years of age. Infections occur enzyme immunoassays. A 4-fold increase in
throughout the year. Occasional outbreaks serum antibody concentration alone does not
of roseola occur. necessarily indicate new infection because an
increase in titer may also occur with reactiva-
Human herpesvirus 7 infection usually occurs tion and in association with other infections,
later in childhood than HHV-6 infection. especially other Betaherpesvirinae infections.
The seroprevalence of HHV-7 is approximately Detection of specific immunoglobulin (Ig) M
85% in adults. Contact with infected respira- antibody is not reliable for diagnosing new
tory tract secretions of healthy people is the infection. These antibody assays do not differ-
probable mode of transmission of HHV-7 to entiate HHV-6A from HHV-6B infections.
young children. Human herpesvirus 7 has Reference laboratories offer diagnostic testing
been detected in human milk, peripheral for HHV-6 and HHV-7 infections by detection
blood mononuclear cells, cervical secretions, of viral DNA in blood and cerebrospinal fluid
and other body sites. Congenital HHV-7 infec- specimens. However, detection of HHV-6 DNA
tion has not been demonstrated by the exami- or HHV-7 DNA in peripheral blood mononu-
nation of large numbers of cord blood samples clear cells, other body fluids, and tissues gener-
for HHV-7 DNA. ally does not differentiate between new infec­tion
Incubation Period and persistence of virus from past infection.
For HHV-6, 9 to 10 days; for HHV-7, unknown. Treatment
Supportive.

Image 67.1
Thin-section electron micrograph image of human herpesvirus 7, which, like human herpesvirus 6, can
cause roseola. Virions consist of a darkly staining core within the capsid that is surrounded by a
proteinaceous tegument layer and enclosed within the viral envelope. Courtesy of Centers for Disease
Control and Prevention.

ERRNVPHGLFRVRUJ
270 Human Herpesvirus 6 (Including Roseola) and 7

Image 67.3
An 8-month-old with a temperature between
38°C and 39°C (101°F and 103°F) for 3 consec­
utive days. The child appeared well, with no
additional symptoms aside from mild irritability
and decreased appetite. After cessation of the
fever, the patient developed a maculopapular
rash heavy on the trunk, but, aside from this, the
patient still appeared well. The rash resolved in
the next 48 hours. The clinical course and rash
are compatible with roseola. Copyright Stan
Image 67.2 Block, MD, FAAP.
A 13-month-old white boy developed high fever
that persisted for 4 days without recognized
cause. The child appeared relatively well and
the fever subsided to be followed by a maculo­
papular rash that began on the trunk and spread
to involve the face and extremities. The course
was typical for roseola infantum. Courtesy of
George Nankervis, MD.

Image 67.5
Clinical course and rash compatible with roseola.
Copyright Stan Block, MD, FAAP.

Image 67.4
A Hispanic female toddler with the exanthem of
roseola following several days of high fever.
Courtesy of Larry Frenkel, MD.

ERRNVPHGLFRVRUJ
Human Herpesvirus 8 271

68 approximately 30% to 80%. Low rates of


­seroprevalence, generally less than 5%, have
Human Herpesvirus 8 been reported in the United States, Northern
Clinical Manifestations and Central Europe, and most areas of Asia.
Higher rates, however, occur in specific geo-
Human herpesvirus 8 (HHV-8) is the etiologic graphic regions, among adolescents and adults
agent associated with Kaposi sarcoma (KS), with or at high risk of acquiring HIV infection,
primary effusion lymphoma, and multicentric injection drug users, and internationally
Castleman disease. More recently, a syndrome adopted children coming from some Eastern
termed KS herpesvirus-associated inflamma- European countries.
tory cytokine syndrome, which ­presents as a
systemic inflammatory illness, has been Acquisition of HHV-8 in areas with endemic
described in adults with HHV-8 infection in infection frequently occurs before puberty,
the United States. Human herpesvirus 8 is one likely by oral inoculation of saliva of close
of the triggers of hemophagocytic lymphohis- ­contacts, especially secretions of mothers and
tiocytosis. In regions with endemic HHV-8, siblings. Virus is shed frequently in saliva of
the following primary infection syndrome infected people and becomes latent for life in
in immunocompetent children has been peripheral blood mononuclear cells, primarily
described: fever and a maculopapular rash, CD19+ B lymphocytes, and lymphoid tissue. In
often accompanied by upper respiratory tract areas where infection is not endemic, sexual
signs. Primary infection among immunocom- transmission appears to be the major route of
promised people and men who have sex with infection, especially among men who have sex
men tends to have more severe manifestations with men. Studies from areas with endemic
that include pancytopenia, fever, rash, lymph- infection have suggested transmission can
adenopathy, splenomegaly, diarrhea, arthral- occur by blood transfusion, but in the United
gia, disseminated disease, and KS. In parts of States, such evidence is lacking. Transplanta-
Africa, among children with and without HIV tion of infected donor organs has been docu-
infection, KS is a frequent, aggressive malig- mented to result in HHV-8 infection in the
nancy. In the United States, KS is rare in chil- recipient. Human herpesvirus 8 DNA has been
dren but occurs commonly in those severely detected in blood drawn at birth from neonates
immunocompromised by HIV. Among organ born to HHV-8 seropositive mothers, but verti-
transplant recipients and other immunosup- cal transmission is rare.
pressed patients, KS is an important cause of
Incubation Period
cancer-related deaths. Primary effusion lym-
phoma is rare among children. Multicentric Unknown.
Castleman disease has been described in Diagnostic Tests
immunosuppressed and immunocompetent
children, but the proportion of cases attribut- Nucleic acid amplification testing and serologic
able to infection with HHV-8 is unknown. assays for HHV-8 are available, and new assays
with greater clinical utility are being devel-
Etiology oped. Polymerase chain reaction assays can
Human herpesvirus 8 is a member of the fam- be used on peripheral blood and tissue biopsy
ily Herpesviridae, the Gammaherpesvirinae specimens of patients with HHV-8–associated
subfamily, and the Rhadinovirus genus and is disease, such as KS. Detection of HHV-8 in
related closely to herpesvirus saimiri of mon- peripheral blood specimens by polymerase
keys and Epstein-Barr virus. chain reaction assay has been used to support
the diagnosis of KS and to identify exacerba-
Epidemiology tions of HHV-8–associated diseases, primarily
In areas of Africa, the Amazon basin, the multicentric Castleman disease and KS herpes-
­Mediterranean, and the Middle East, HHV-8 virus-associated inflammatory cytokine
is endemic and seroprevalence ranges from

ERRNVPHGLFRVRUJ
272 Human Herpesvirus 8

s­ yndrome. However, HHV-8 DNA detection in Treatment


the peripheral blood does not ­differentiate No antiviral treatment is approved for HHV-8
between latent and active repli­cating infection. disease. Ganciclovir has been shown to inhibit
Currently available serologic assays measuring HHV-8 replication in the only randomized
antibodies to HHV-8 include immunofluores- trial of an antiviral drug for this infection.
cence assay, enzyme immunoassays, and Valacyclovir and famciclovir more modestly
­Western blot assays using recombinant HHV-8 reduce HHV-8 replication. Retrospective
proteins. These serologic assays can detect cohort studies suggest antiretroviral therapy
latent and lytic infection, but each has chal- (particularly zidovudine and nelfinavir) may
lenges with accuracy or convenience, thereby inhibit HHV-8 replication in patients infected
limiting use in the diagnosis and management with HIV.
of acute disease.

ERRNVPHGLFRVRUJ
Human Immunodeficiency Virus Infection 273

69 classifies all HIV-infected children younger


than 13 years according to clinical stage of dis-
Human Immunodeficiency ease (Box 69.2) and immunologic status
Virus Infection (Table 69.1). For purposes of surveillance of
HIV disease, the CDC has updated the immu-
Clinical Manifestations nologic classification system; however, some
HIV infection results in a wide array of clini- clinical guidelines continue to make use of the
cal manifestations and varied natural history. 1994 CDC immunologic classification. This
HIV type 1 (HIV-1) is much more common in pediatric classification system emphasizes the
the United States than is HIV type 2 (HIV-2). importance of the CD4+ T-lymphocyte count
Unless otherwise specified, this chapter and percentage as critical immunologic param-
addresses HIV-1 infection. eters and as markers of prognosis. Data on
plasma HIV-1 RNA concentration (viral load)
AIDS is the name given to an advanced stage
are not included in this classification.
of HIV infection. The Centers for Disease
­Control and Prevention (CDC) uses a case With timely diagnostic testing and appropriate
­definition that comprises AIDS-defining con- treatment, clinical manifestations of HIV-1
ditions for surveillance (Box 69.1). The CDC infection and occurrence of AIDS-defining

Box 69.1
1993 Revised Case Definition of AIDS-Defining ­Conditions
for Adults and Adolescents 13 Years and Older

• Candidiasis of bronchi, trachea, or lungs


• Candidiasis, esophageal
• Cervical cancer, invasive
• Coccidioidomycosis, disseminated or extrapulmonary
• Cryptococcosis, extrapulmonary
• Cryptosporidiosis, chronic intestinal (>1 mo duration)
• Cystoisosporiasis (isosporiasis), chronic intestinal (>1 mo duration)
• Cytomegalovirus disease (other than liver, spleen, or nodes)
• Cytomegalovirus retinitis (with loss of vision)
• Encephalopathy, HIV related
• Herpes simplex: chronic ulcer(s) (>1 mo duration) or bronchitis, pneumonitis, or esophagitis
• Histoplasmosis, disseminated or extrapulmonary
• Kaposi sarcoma
• Lymphoma, Burkitt (or equivalent term)
• Lymphoma, immunoblastic (or equivalent term)
• Lymphoma, primary or brain
• Mycobacterium avium complex or Mycobacterium kansasii infection, disseminated or
­extrapulmonary
• Mycobacterium tuberculosis infection, any site, pulmonary or extrapulmonary
• Mycobacterium, other species or unidentified species infection, disseminated or
­extra­pulmonary
• Pneumocystis jiroveci pneumonia
• Pneumonia, recurrent
• Progressive multifocal leukoencephalopathy
• Salmonella septicemia, recurrent
• Toxoplasmosis of brain
• Wasting syndrome attributable to HIV
• CD4+ T-lymphocyte count <200/µL (0.20 x 109/L) or CD4+ T-lymphocyte percentage <15%

Abbreviations: AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus.


Modified from Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance
case definition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992;41(RR-17):1–19.

ERRNVPHGLFRVRUJ
274
Box 69.2
Clinical Categories for Children Younger Than 13 Years With HIV Infection

Category N: Not Symptomatic


Children who have no signs or symptoms considered to be the result of HIV infection or have only 1 of the conditions listed in Category A.

Human Immunodeficiency Virus Infection


Category A: Mildly Symptomatic
• Children with 2 or more of the conditions listed but none of the conditions listed • Dermatitis
in categories B and C • Parotitis
• Lymphadenopathy (≥0.5 cm at more than 2 sites; bilateral at 1 site) • Recurrent or persistent upper respiratory tract infection, sinusitis,
• Hepatomegaly or otitis media
• Splenomegaly

Category B: Moderately Symptomatic


• Children who have symptomatic conditions other than those listed • Herpes simplex bronchitis, pneumonitis, or esophagitis with
for category A or C that are attributed to HIV infection onset before 1 mo of age
• Anemia (hemoglobin <8 g/dL [<80 g/L]), neutropenia (white blood • Herpes zoster (shingles) involving at least 2 distinct episodes or
cell count <1,000/μL [<1.0 x 109/L]), and/or thrombocytopenia (platelet count more than 1 dermatome
<100 x 103/μL [<100 x 109/L]) persisting for ≥30 d • Leiomyosarcoma
• Bacterial meningitis, pneumonia, or sepsis (single episode) • Lymphoid interstitial pneumonia or pulmonary lymphoid hyper-
• Candidiasis, oropharyngeal (thrush), persisting (>2 mo) in children plasia complex
older than 6 mo • Nephropathy
• Cardiomyopathy • Nocardiosis
• Cytomegalovirus infection, with onset before 1 mo of age • Persistent fever (lasting >1 mo)
• Diarrhea, recurrent or chronic • Toxoplasmosis, onset before 1 mo of age
• Hepatitis • Varicella, disseminated (complicated chickenpox)
• Herpes simplex stomatitis, recurrent (>2 episodes within 1 y)

Box 69.2
Clinical Categories for Children Younger Than 13 Years With HIV Infection, continued

Category C: Severely Symptomatic


• Serious bacterial infections, multiple or recurrent (ie, any combination • Histoplasmosis, disseminated (at a site other than or in addition to
of at least 2 culture-confirmed infections within a 2-y period), of the following lungs or cervical or hilar lymph nodes)
types: septicemia, pneumonia, meningitis, bone or joint infection, or abscess of • Kaposi sarcoma
an internal organ or body cavity (excluding otitis media, superficial skin or muco- • Lymphoma, primary, in brain

Human Immunodeficiency Virus Infection


sal abscesses, and indwelling catheter-related infections) • Lymphoma, small, noncleaved cell (Burkitt), or immunoblastic; or
• Candidiasis, esophageal or pulmonary (bronchi, trachea, lungs) large-cell lymphoma of B-lymphocyte or unknown immunologic
• Coccidioidomycosis, disseminated (at site other than or in addition to lungs or phenotype
cervical or hilar lymph nodes) • Mycobacterium tuberculosis, disseminated or extrapulmonary
• Cryptococcosis, extrapulmonary • Mycobacterium, other species or unidentified species infection,
• Cryptosporidiosis or cystoisosporiasis with diarrhea persisting >1 mo disseminated (at a site other than or in addition to lungs, skin, or
cervical or hilar lymph nodes)
• Cytomegalovirus disease with onset of symptoms after 1 mo of age
• Pneumocystis jiroveci pneumonia
(at a site other than liver, spleen, or lymph nodes)
• Progressive multifocal leukoencephalopathy
• Encephalopathy (at least 1 of the following progressive findings present for at • Salmonella (nontyphoid) septicemia, recurrent
least 2 mo in the absence of a concurrent illness other than HIV infection that • Toxoplasmosis of the brain with onset at or after 1 mo of age
could explain the findings): (1) failure to attain or loss of developmental mile- • Wasting syndrome in the absence of a concurrent illness other
stones or loss of intellectual ability, verified by standard developmental scale or than HIV infection that could explain the following findings: (1) per-
neuropsychologic tests; (2) impaired brain growth or acquired microcephaly sistent weight loss >10% of baseline; (2) downward crossing of at
demonstrated by head circumference measurements or brain atrophy demon- least 2 of the following percentile lines on the weight-for-age chart
strated by computed tomography or magnetic resonance imaging (serial imaging (eg, 95th, 75th, 50th, 25th, 5th) in a child 1 y or older; OR (3) <5th
required for children <2 y); (3) acquired symmetric motor deficit manifested by 2 percentile on weight-for-height chart on 2 consecutive measure-
or more of the following: paresis, pathologic reflexes, ataxia, or gait disturbance ments, ≥30 days apart; PLUS
• Herpes simplex infection causing a mucocutaneous ulcer that persists for greater (1) chronic diarrhea (ie, at least 2 loose stools per day for >30 d);
than 1 mo or bronchitis, pneumonitis, or esophagitis for any duration affecting a OR
child older than 1 mo (2) documented fever (for >30 d, intermittent or constant)

Modified from Centers for Disease Control and Prevention. 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age. Official authorized addenda: human immunodefi-
ciency virus infection codes and official guidelines for coding and reporting ICD-9-CM. MMWR Recomm Rep. 1994;43(RR-12):1–19.

275
276 Human Immunodeficiency Virus Infection

Table 69.1
HIV Infection Stage, Based on Age-Specific CD4+ T-Lymphocyte
Count or CD4+ T-Lymphocyte Percentage of Total Lymphocytesa
Age on Date of CD4 T-Lymphocyte Test
<1 y 1–5 y 6 y–Adult
Stagea Cells/µL % Cells/µL % Cells/µL %
1 ≥1,500 ≥30 ≥1,000 ≥26 ≥500 ≥26b
2 750–1,499 20–29 500–999 14–25 200–499 14–25
3 <750 <20 <500 <14 <200 <14
a The stage is based primarily on the CD4+ T-lymphocyte count; it is based on the CD4+ T-lymphocyte percentage only if the count is missing.
There are 3 situations in which the stage is not based on this table: (1) if the criteria for stage 0 are met, the stage is 0 regardless of criteria
for other stages (CD4+ T-lymphocyte test results and opportunistic illness diagnoses); (2) if the criteria for stage 0 are not met and a
stage-3–defining opportunistic illness has been diagnosed, the stage is 3 regardless of CD4+ T-lymphocyte test results; and (3) if the criteria
for stage 0 are not met and information on the above criteria for other stages is missing, the stage is U (unknown).
b The change in the upper CD4+ T-lymphocyte percentage threshold from 29% (as in the case definition of 2008) to 26% (as in the revision

above) is contingent on data being published that support it, to corroborate unpublished analyses of surveillance data.

illnesses are now rare among children in the Immune reconstitution inflammatory syndrome
United States and other industrialized coun- is a paradoxical clinical deterioration often
tries. Early clinical manifestations of pediatric seen in severely immunosuppressed ­people
HIV infection include unexplained fevers, that occurs shortly after the initiation of cART.
­generalized lymphadenopathy, hepatomegaly, Local or systemic symptoms develop secondary
splenomegaly, failure to thrive, persistent or to an inflammatory response as ­cell-mediated
recurrent oral and diaper candidiasis, recur- immunity is restored. Under­lying infection
rent diarrhea, parotitis, hepatitis, central with mycobacteria (including M tuberculosis),
­nervous system disease (eg, hyperreflexia, herpesviruses, and fungi (including Crypto­
hypertonia, floppiness, developmental delay), coccus species) predispose to immune recon­
lymphoid interstitial pneumonia, recurrent stitution inflammatory ­syndrome.
invasive bacterial infections, and other oppor-
Malignant neoplasms in children with HIV-1
tunistic infections (OIs) (eg, viral, fungal).
infection are relatively uncommon, but leio-
In the era of combination antiretroviral myosarcomas and non-Hodgkin B-cell lym-
t­ herapy (cART), there has been a substantial phomas of the Burkitt type (including some
decrease in frequency of all OIs. Frequency of that occur in the central nervous system)
different OIs in the pre-cART era varied by age, occur more commonly in children with HIV
pathogen, previous infection history, and infection than in immunocompetent children.
immunologic status. In the pre-cART era, the Kaposi sarcoma is rare in children in the
most common OIs observed among children United States but has been documented in
in the United States were infections caused by HIV-infected children who have emigrated
invasive encapsulated bacteria, Pneumocystis from sub-Saharan African countries. The inci-
jiroveci, varicella-zoster virus, cytomegalovirus dence of malignant neoplasms in HIV-infected
(CMV), human herpesvirus (herpes simplex), children has decreased during the cART era.
Mycobacterium avium complex, and Candida
The incidence of HIV encephalopathy is high
species. Less commonly observed opportunis-
among untreated HIV-infected infants and
tic pathogens included Epstein-Barr virus,
young children. In the United States, pediat-
Mycobacterium tuberculosis, Cryptosporidium
ric HIV encephalopathy has decreased sub-
species, Cystoisospora (formerly Isospora)
stantially in the cART era, although other
­species, other enteric pathogens, Aspergillus
neurologic signs and symptoms have been
species, and Toxoplasma gondii.
appreciated, such as myelopathy or peripheral
neuropathies, sometimes associated with anti-
retroviral therapy (ART).

ERRNVPHGLFRVRUJ
Human Immunodeficiency Virus Infection 277

Prognosis for survival is poor for untreated tered by the child. With advancing immuno-
neonates who acquired HIV infection through suppression, recall antibody responses,
mother-to-child transmission and who have including responses to vaccine-associated
high viral loads (ie, >100,000 copies/mL) and ­antigens, are slow and diminish in magnitude.
severe suppression of CD4+ T-lymphocyte A small proportion (<10%) of patients will
counts (Table 69.2). In these infants, AIDS- develop panhypogammaglobulinemia. In the
defining conditions developing during the first absence of treatment with cART, such patients
6 months of life, including P jiroveci pneumo- have a particularly poor prognosis.
nia (PCP), progressive neurologic disease, and
Etiology
severe wasting, are predictors of a poor out-
come. When cART regimens are begun early, As noted previously, 2 types of HIV cause
prognosis and survival rates improve dramati- ­disease in humans: HIV-1 and HIV-2. These
cally. Although deaths attributable to OIs have viruses are cytopathic lentiviruses belonging to
declined, non–AIDS-defining infections and the family Retroviridae, and they are related
multiorgan failure remain major causes of closely to simian immunodeficiency viruses
death. In the United States, mortality in a (SIVs), agents found in a variety of nonhuman
­longitudinal cohort of HIV-infected children primate species in sub-Saharan Africa. HIV-1
whose age at enrollment ranged from birth to species infecting humans have evolved from
21 years declined from 7.2 per 100 person years SIVs found in chimpanzees and gorillas,
in 1993 to 0.8 per 100 person years in 2006. The whereas HIV-2 evolved from an SIV in sooty
HIV mortality rate in 2006 was equivalent to mangabeys. Three distinct genetic groups of
that of the general US pediatric population HIV-1 exist worldwide: M (major), O (outlier),
younger than 5 years (0.8/100) in 2011. and N (new). Group M viruses are the most
prevalent worldwide and comprise 8 genetic
Although B-lymphocyte counts remain normal subtypes, or clades, known as A through H,
or are somewhat increased, humoral immune which each have distinct geographic distri­
dysfunction may precede or accompany cellu- bution. The HIV-1 genome is 10 kb in length
lar dysfunction. Polyclonal B-lymphocyte and has conserved and highly variable domains.
hyperactivation occurs as part of a spectrum Three principal genes (gag, pol, and env)
of chronic immune activation, leading to pro- encode the major structural and enzymatic
duction of immunoglobulins that are not proteins, and 6 accessory genes regulate gene
directed against specific pathogens encoun- expression and aid in assembly and release of

Table 69.2
Laboratory Diagnosis of HIV Infectiona
Test Comment
HIV DNA PCR Preferred test to diagnose HIV-1 subtype B infection in infants and children
younger than 18 mo; highly sensitive and specific by 2 wk of age and available;
performed on peripheral blood mononuclear cells. False-negative results can
occur in non-B subtype HIV-1 infections.
HIV p24 Ag Less sensitive, false-positive results during first month of life, variable results;
not recommended.
ICD p24 Ag Negative test result does not rule out infection; not recommended.
HIV culture Expensive, not easily available, requires up to 4 wk for results; not recommended.
HIV RNA PCR Preferred test to identify non-B subtype HIV-1 infections. Similar sensitivity
and specificity to HIV DNA PCR in infants and children younger than 18 mo,
but DNA PCR is generally preferred because of greater clinical experience
with that assay.
Abbreviations: Ag, antigen; HIV, human immunodeficiency virus; ICD, immune complex dissociated; PCR, polymerase chain reaction.
a Read JS; American Academy of Pediatrics Committee on Pediatric AIDS. Diagnosis of HIV-1 infection in children younger than 18 months in

the United States, Pediatrics. 2007;120(6):e1547–e1562. Reaffirmed April 2010. http://pediatrics.aappublications.org/cgi/content/full/120/6/


e1547. Accessed May 23, 2016.

ERRNVPHGLFRVRUJ
278 Human Immunodeficiency Virus Infection

infectious virions. The envelope glycoprotein mented with normal activities in households;
interacts with the CD4+ receptor and with 1 of transmission has been documented after con-
2 major coreceptors (CCR5 or CXCR4) on the tact of nonintact skin with blood-containing
host cell membrane. HIV-1 is a single-stranded body fluids. Moreover, transmission of HIV
RNA virus that requires the activity of a viral has not been documented in schools or child
enzyme, reverse transcriptase, to convert to care settings in the United States.
double-stranded DNA. A double-stranded
Children younger than 13 years accounted for
DNA copy of the viral genome then randomly
0.3% of all estimated HIV diagnoses in the
integrates into the host cell genome, where it
United States in 2011. Since the mid-1990s, the
persists as a provirus.
number of reported pediatric AIDS cases has
HIV-2, the second AIDS-causing virus, is pre- decreased significantly, primarily because of
dominantly found in West Africa, with the prevention of mother-to-child transmission of
highest rates of infection in Guinea-Bissau. HIV. This decrease in rate of mother-to-child
The prevalence of HIV-2 in the United States transmission of HIV in the United States was
is extremely low. HIV-2 is thought to have a attributable to the development and implemen-
milder disease course with a longer time to tation of antenatal HIV testing programs and
development of AIDS than HIV-1. Nonnucleo- other interventions to prevent transmission,
side reverse transcriptase inhibitors and at least including antiretroviral prophylaxis during
1 fusion inhibitor (enfuvirtide) are not effective the antepartum, intrapartum, and postnatal
against HIV-2, whereas nucleoside reverse periods; cesarean delivery before labor and
transcriptase inhibitors and protease inhibitors before rupture of membranes; and complete
have varying efficacy against HIV-2. avoidance of breastfeeding. Combination anti-
retroviral regimens during pregnancy have
Epidemiology
been associated with lower rates of mother-to-
Humans are the only known reservoir for child transmission than zidovudine monother-
HIV-1 and HIV-2. Latent virus persists in apy taken antenatally. Currently, in the United
peripheral blood mononuclear cells and in cells States, most HIV-infected pregnant women
of the brain, bone marrow, and genital tract receive 3-drug combination antiretroviral regi-
even when plasma viral load is undetectable. mens for treatment of their own HIV infection
Only blood, semen, cervicovaginal secretions, or, if criteria for treatment are not yet met, for
and human milk have been implicated epide- prevention of mother-to-child transmission of
miologically in transmission of infection. HIV (in which case the drugs can be stopped
after delivery). The CDC estimates perinatally
Established modes of HIV transmission
transmitted HIV cases in the United States
include sexual contact (vaginal, anal, or
have decreased from a peak of 1,650 in 1991 to
­orogenital); percutaneous blood exposure
57 in 2010.
(from contaminated needles or other sharp
instruments); mucous membrane exposure The risk of infection for a neonate born to an
to contaminated blood or other body fluids; HIV-seropositive mother who did not receive
mother-to-child transmission in utero, around interventions to prevent transmission is esti-
the time of labor and delivery, and postnatally mated to range from 22.6% to 25.5% in the
through breastfeeding; and transfusion with United States. Most mother-to-child transmis-
contaminated blood products. Cases of prob- sion occurs during the intrapartum period,
able HIV transmission from an HIV-infected with fewer transmission events occurring in
caregiver to an infant through feeding blood- utero and postnatally through breastfeeding.
tinged premasticated food have been reported Risk factors for mother-to-child transmission
in the United States. As a result of highly effec- of HIV can be categorized as follows: the
tive screening methods, transfusion of blood, amount of virus to which the child is exposed
blood components, and clotting factors has (a higher maternal viral load is associated with
virtually been eliminated as a cause of HIV a lower maternal CD4+ T-lymphocyte count
transmission in the United States since 1985. and with more advanced maternal clinical
Also, transmission of HIV has not been docu- ­disease or with recent seroconversion); the

ERRNVPHGLFRVRUJ
Human Immunodeficiency Virus Infection 279

duration of exposure (eg, duration of ruptured feed their infants exclusively for the first 6
membranes or of breastfeeding, vaginal versus months of life because the morbidity associated
cesarean delivery before labor and before rup- with formula feeding is unacceptably high. In
ture of membranes); and factors that facilitate addition, these women should be offered HIV
the transfer of virus from mother to child testing. The World Health Organization rec-
(eg, maternal breast pathologic lesions, infant ommended in 2010 that HIV-infected mothers
oral candidiasis). In addition to these factors, exclusively breastfeed their infants for the first
characteristics of the virus and the child’s 6 months of life. Introduction of complemen-
suscep­tibility to infection are important. Of tary foods should occur after 6 months of life,
note, although maternal viral load is a critical and breastfeeding should continue through
determinant affecting the likelihood of 12 months of life. Breastfeeding should be
mother-to-child transmission of HIV, trans- replaced only when a nutritionally adequate
missions have been observed across the entire and safe diet can be maintained without
range of maternal viral loads. The risk of human milk. In areas where ART is available,
mother-to-child transmission increases with infants should receive daily nevirapine prophy-
each hour increase in the duration of rupture laxis until 1 week after human milk consump-
of membranes, and the duration of ruptured tion stops, and mothers should receive ART
membranes should be considered when evalu- (consisting of an effective cART regimen) for
ating the need for obstetric interventions. the first 6 months of their infants’ lives. For
Cesarean delivery performed before onset of infants known to be HIV-infected, mothers are
labor and before rupture of membranes has encouraged to breastfeed exclusively for the
been shown to reduce mother-to-child intra- first 6 months of life and, after the introduction
partum transmission. Current US guidelines of complementary foods, should continue to
recommend cesarean delivery at 38 weeks’ breastfeed up to 2 years of age, as per recom-
­gestation, before onset of labor and before mendations for the general population.
­rupture of membranes, for HIV-infected
Although the rate of acquisition of HIV infec-
women with a viral load greater than 1,000 copies/
tion among infants has decreased significantly
mL (irrespective of use of ART during preg-
in the United States, the rate of new HIV infec-
nancy) and for women with unknown viral
tions during adolescence and young adulthood
load near the time of delivery. Cesarean deliv-
continues to increase. HIV infection in adoles-
ery for women with an undetectable viral load
cents occurs disproportionately among youth
is not routinely ­recommended.
of minority race or ethnicity. Transmission of
Postnatal transmission to neonates and young HIV to adolescents is attributable primarily to
infants occurs mainly through breastfeeding. sexual exposure and secondarily to illicit intra-
Worldwide, an estimated one-third to one-half venous drug use. It is estimated that, in 2011,
of cases of mother-to-child transmission of males accounted for approximately 77% and
HIV occurs as a result of breastfeeding. HIV 86% of adolescents 13 to 19 years of age and 20
genomes have been detected in cell-associated to 24 years of age, respectively, diagnosed with
and cell-free fractions of human milk. In the HIV infection. Young men who have sex with
United States, HIV-infected mothers are men are particularly at high risk of acquiring
advised not to breastfeed because safe alterna- HIV infection, and the rates of HIV infection
tives to human milk are available. Because in young men who have sex with men continue
human milk cell-associated HIV can be to increase. In the United States and 6 depen-
detected even in women receiving cART and dent areas in 2011, an estimated 77% and 91%
perinatal transmission still occurs among a of diagnoses of HIV infections among all ado-
small percentage of cART-receiving virologi- lescents and young adults 13 to 24 years of age
cally suppressed women, replacement (for- and among male adolescent and young adults
mula) feeding continues to be recommended 13 to 24 years of age, respectively, were attrib-
for US mothers receiving cART. In resource- uted to male-to-male sexual contact. In con-
limited locations, women whose HIV infection trast, 92% of diagnoses of HIV infection in 2011
status is unknown are encouraged to breast- among young adolescent and adult women

ERRNVPHGLFRVRUJ
280 Human Immunodeficiency Virus Infection

13 to 24 years of age were attributed to hetero- In the United States, the preferred test for
sexual contact. In 2010, there were an esti- ­ iagnosis of HIV infection in neonates is the
d
mated 39,035 adolescents and young adults HIV DNA polymerase chain reaction (PCR)
living with a diagnosis of HIV infection in the assay. The DNA PCR assay can detect 1 to 10
United States and 6 dependent areas; 63% were DNA copies of proviral DNA in peripheral
black (African American), 19% Hispanic/ blood mononuclear cells. Approximately 30%
Latino, and 15% non-Hispanic white. Rates of to 40% of HIV-infected neonates will have a
HIV infection among adolescents are particu- positive HIV DNA PCR assay result in samples
larly high in the Southeastern and Northeast- obtained before 48 hours of age. A positive
ern United States. Most HIV-infected result by 48 hours of age suggests in utero
adolescents and young adults are asymptom- transmission. Approximately 93% of infected
atic and, without testing, remain unaware of neonates have detectable HIV DNA by 2 weeks
their infection. Youth 13 to 24 years of age rep- of age, and approximately 95% of HIV-infected
resent 26% of new HIV infections annually, neonates have a positive HIV DNA PCR assay
and 60% are unaware they are infected. result by 1 month of age. A single HIV DNA
PCR assay has a sensitivity of 95% and a
Incubation Period
­specificity of 97% for samples collected from
Approximately 12 to 18 months of age for infected children 1 to 36 months of age.
untreated children (mother-to-child trans­
mission). However, some HIV-infected infants HIV isolation by culture is less sensitive, less
become ill in the first few months of life, available, and more expensive than the DNA
whereas others remain relatively asymptomatic PCR assay. Definitive results may take up to
for more than 5 years and, rarely, until early 28 days. This test is no longer recommended
adolescence. Following HIV acquisition in for routine diagnosis.
adolescents and adults, primary seroconversion Detection of the p24 antigen (including
syndrome can occur 7 to 14 days following immune complex dissociated) is less sensitive
viral acquisition and can last for 5 to 7 days. than the HIV DNA PCR assay or culture.
Diagnostic Tests False-positive test results occur in samples
obtained from neonates younger than 1 month.
Laboratory diagnosis of HIV-1 infection during This test generally should not be used, although
infancy is based on detection of the virus or newer assays have been reported to have sensi-
viral nucleic acid (see Table 69.2). Because tivities similar to HIV DNA PCR assays.
­neonates born to HIV-infected mothers
acquire maternal antibodies passively, antibody Plasma HIV RNA assays have also been used
assays are not informative for diagnosis of to diagnose HIV infection. However, a false-
infection in children younger than 24 months negative test result may occur in neonates
unless assay results are negative. In children receiving ART as prophylaxis. Although use
24 months and older, HIV antibody assays can of ART can reduce plasma viral loads to unde-
be used for diagnosis. Historically, 18 months tectable levels, results of DNA PCR assay,
was considered the age at which a positive anti- which detects cell-associated integrated HIV
body assay could accurately distinguish DNA, remain positive even among individuals
between presence of maternal and infant anti- with undetectable plasma viral loads.
bodies. However, using medical record data for In the absence of therapy, plasma viral loads
a cohort of HIV-uninfected infants born from among neonates who acquired HIV infection
2000 to 2007, it was demonstrated that clear- through mother-to-child transmission increase
ance of maternal HIV antibodies occurred later rapidly to very high levels (typically from sev-
than previously reported. Despite a median age eral hundred thousand to more than 1 million
of seroreversion of 13.9 months, 14% of children copies/mL) after birth, decreasing only slowly
remained seropositive after 18 months, 4.3% to a “set point” by approximately 2 years of age.
after 21 months, and 1.2% after 24 months. This is in contrast to infection in adults, in

ERRNVPHGLFRVRUJ
Human Immunodeficiency Virus Infection 281

whom viral load generally does not reach the • One negative HIV antibody test result
high levels that are seen in newly infected obtained at 6 months or older; AND
­neonates and for whom the set point occurs
• No other laboratory or clinical evidence of
approximately 6 months after acquisition of
HIV infection (ie, no subsequent positive
infection. An HIV RNA assay result with
results from virologic tests if tests were per-
only low-level viral copy number in an HIV-
formed and no AIDS-defining condition for
exposed neonate may indicate a false-positive
which there is no other underlying condition
result, reinforcing the importance of repeating
of immunosuppression)
any positive assay result to confirm the diag­
nosis of HIV infection in infancy. Like HIV In nonbreastfed children younger than
DNA PCR assays, the sensitivity of HIV RNA 18 months with negative HIV virologic test
assays for diagnosing infections in the first results, definitive exclusion of HIV is
week of life is low (25%–40%) because trans- based on
mission usually occurs around the time of
delivery. RNA assays provide quantitative • At least 2 negative HIV DNA or RNA viro-
results as a predictor of disease progression logic test results, from separate specimens,
rather than for routine diagnosis of HIV infec- obtained at 1 month or older and obtained
tion in neonates. RNA assays are also useful at 4 months or older; OR
in monitoring changes in viral load during • At least 2 negative HIV antibody test
the course of ART. results from separate specimens obtained
Diagnostic testing with HIV DNA or RNA at 6 months or older; AND
assays is recommended at 14 to 21 days of age • No other laboratory or clinical evidence of
and, if results are negative, again at 1 to HIV infection (ie, no subsequent positive
2 months of age and at 4 to 6 months of age. results from virologic tests if tests were per-
An infant is considered infected if 2 samples formed and no AIDS-defining condition for
from 2 different time points test positive by which there is no other underlying condition
DNA or RNA PCR assay. of immunosuppression).
Viral diagnostic testing in the first 2 days of In children with 2 negative HIV DNA PCR
life is recommended by some experts to allow test results, many clinicians will confirm
for early identification of neonates with pre- the absence of antibody (ie, loss of passively
sumed in utero infection. If testing is per- acquired natural antibody) to HIV on testing
formed shortly after birth, umbilical cord at 12 through 24 months of age (seroreversion).
blood should not be used because of possible In addition, some clinicians have a slightly
contamination with maternal blood. Obtaining more stringent requirement that the 2 separate
the sample as early as 14 days of age may antibody-negative blood samples obtained
­facilitate decisions about initiating ART. HIV- after 6 months of age be drawn at least
infected neonates should be transitioned from 1 month apart for a child to be considered
neonatal antiretroviral prophylaxis to cART HIV ­uninfected.
treatment. In nonbreastfed children younger
than 18 months with negative HIV virologic Immunoassays (IAs) are used widely as the
test results, presumptive exclusion of HIV initial test for serum HIV antibody or for
infection is based on p24 antigen and HIV antibody. These tests
are highly sensitive and specific. Repeated IA
• Two negative HIV DNA or RNA virologic testing of initially reactive specimens is com-
test results, from separate specimens, mon practice and is followed by additional
each obtained at 2 weeks or older and testing to establish the diagnosis of HIV. A
one obtained at 4 weeks or older; OR positive HIV antibody test result (reactive IA
• One negative HIV DNA or RNA virologic followed by positive Western blot or HIV-1/
test result from a specimen obtained at HIV-2 antibody differentiation assay) in a
8 weeks or older; OR child 18 months or older almost always indi-
cates infection, although passively acquired

ERRNVPHGLFRVRUJ
282 Human Immunodeficiency Virus Infection

maternal antibody can, rarely, persist beyond decline HIV testing and allowing a provider-
18 months of age. HIV antibody tests can be patient relationship conducive to optimal
performed on samples of blood or oral fluid; clinical and preventive care. Patients or peo-
antigen/antibody tests can be performed only ple responsible for the patient’s care should
on serum or plasma. Rapid tests for HIV anti- be notified orally that testing is planned,
bodies have been approved for use in the advised of the indication for testing and the
United States; these tests are used widely implications of positive and negative test
throughout the world, particularly to screen results, and offered an opportunity to ask
mothers of undocumented serostatus in mater- questions and to decline testing. With such
nity settings. As with laboratory IAs, addi- notification, the patient’s general consent
tional testing is required after a reactive rapid for medical care is considered sufficient for
test. Results from rapid tests are available diagnostic HIV testing. Although parental
within 20 minutes; however, IA results and involvement in an adolescent’s health care
follow-up testing might take 2 days or longer. may be desirable, it is not typically required
when the adolescent consents to HIV testing.
Neonates who acquire HIV infection through
However, laws on consent and confidential-
mother-to-child transmission commonly have
ity for HIV care differ among states. Public
high viral set points with progressive cellular
health statutes and legal precedents allow
immune dysfunction and immunosuppression
for evaluation and treatment of minors for
resulting from a decrease in the total number
sexually transmitted infections without
of circulating CD4+ T lymphocytes. Sometimes,
parental knowledge or consent, but not
T-lymphocyte counts do not decrease until
every state has explicitly defined HIV infec-
late in the course of infection. Changes in cell
tion as a condition for which testing or
populations frequently result in a decrease in
­treatment may proceed without parental
the normal CD4+ to CD8+ T-­lymphocyte ratio
consent. Health care professionals should
of 1.0 or greater. This nonspecific finding,
endeavor to respect an adolescent’s request
although characteristic of HIV-1 infection,
for privacy. HIV screening should be dis-
also occurs with other acute viral infections,
cussed with all adolescents and encouraged
including infections caused by CMV and
for adolescents who are sexually active. Pro-
Epstein-Barr virus, and tuberculosis. The risk
viding information about HIV infection,
of OIs correlates with the CD4+ T-lymphocyte
diagnostic testing, transmission including
percentage and count. The normal values for
secondary trans­mission, and implications
peripheral CD4+ T-lymphocyte counts are
of infection is an essential component of the
age related.
anticipatory guidance provided to all adoles-
• Adolescents and HIV testing. Routine cents as part of primary care. Access to clini-
screening should be offered to all adolescents cal care, preventive counseling, and support
at least once by 16 through 18 years of age. services is essential for people with positive
Use of any licensed HIV antibody test is HIV test results.
appropriate. For any positive test result,
Treatment
referral to an HIV specialist is appropriate
to confirm diagnosis and initiate manage- Because HIV treatment options and recom-
ment. Adolescents with behaviors that mendations change with time and vary with
increase risk of HIV acquisition (eg, multiple occurrence of antiretroviral drug resistance
sex partners, illicit drug use, men who have and adverse event profile, consultation with
sex with men) should be tested annually. an expert in pediatric HIV infection is recom-
mended in the care of HIV-infected infants,
• Consent for diagnostic testing. The CDC children, and adolescents. Current treatment
recommends that diagnostic HIV testing recommendations for HIV-infected children
and opt-out HIV screening should be part are available online (http://aidsinfo.nih.gov).
of routine clinical care in all health care Whenever possible, enrollment of HIV-
­settings for patients 13 through 64 years of infected children in clinical trials should
age, thus preserving the patient’s option to be encouraged.

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Human Immunodeficiency Virus Infection 283

Combination antiretroviral therapy is indi- symptomatic (CDC clinical category A or N


cated for most HIV-infected children. The or the following category B condition: single
principal objectives of therapy are to suppress episode of serious bacterial infection) and
viral replication maximally, to restore and have a CD4+ T-lymphocyte count greater
­preserve immune function, to reduce HIV- than 750 cells/mm3 and a viral load of
associated morbidity and mortality, to mini- 100,000 copies/mL or greater.
mize drug toxicity, to maintain normal growth
4. Children 5 years and older should receive
and development, and to improve quality of
cART if they (a) have AIDS or significant
life. Initiation of cART depends on the age of
HIV-related symptoms (CDC clinical cat-
the child and on a combination of virologic,
egories C and B [except for the following B
immunologic, and clinical criteria. Data
condition: single episode of serious bacterial
­indicate that very early initiation of therapy
infection]) or (b) have a CD4+ T-lymphocyte
reduces morbidity and mortality compared
count below 500 cells/mm3.
with starting treatment at onset of clinical
symptoms or immune suppression. Effective Starting cART should be considered for HIV-
administration of early therapy will maintain infected children from 1 to 3 years of age who
the viral load at low or undetectable concen­ are asymptomatic or have mild symptoms
trations and will reduce viral mutation (clinical category N or A, or the following clin-
and ­evolution. ical category B condition: single episode of
serious bacterial infection) and have a CD4+
Initiation of cART is recommended as follows:
T-lymphocyte percentage of 25% or greater and
1. HIV-infected infants 12 months or younger a viral load below 100,000 copies/mL. Initia-
should receive cART irrespective of clinical tion of cART should also be considered for
symptoms, immune status, or viral load. HIV-infected children 5 years and older who
are asymptomatic or have mild symptoms
2. Children from 1 to 3 years of age should
(clinical category N or A, or the following clin-
receive cART if they (a) have AIDS or signif-
ical category B condition: single episode of
icant HIV-related symptoms (CDC clinical
serious bacterial infection) and have a CD4+
categories C and B [except for the following
T-lymphocyte count above 500 cells/mm3 and a
category B condition: single episode of seri-
viral load below 100,000 copies/mL. The child
ous bacterial infection]), regardless of CD4+
and the child’s primary caregiver must be able
T-lymphocyte counts or plasma viral load
to adhere to the prescribed regimen.
values; (b) have a CD4+ T-lymphocyte per-
centage below 25% or CD4+ T-lymphocyte Initiation of treatment of adolescents generally
count below 1,000 cells/mm3, regardless of follows guidelines for adults, for whom initia-
symptoms or viral load; or (c) are asymp- tion of treatment is strongly recommended if
tomatic or mildly symptomatic (CDC clini- an AIDS-defining illness is present or if the
cal category A or N or the following category CD4+ T-lymphocyte count is below 500 cells/
B condition: single episode of serious bacte- mm3, or regardless of CD4+ T-lymphocyte
rial infection) and have a CD4+ T-lympho- count in patients with HIV-associated
cyte percentage of 25% or greater and a viral nephropathy or with hepatitis B virus infection
load of 100,000 copies/mL or greater. when treatment of hepatitis B virus is recom-
mended. Combination antiretroviral therapy
3. Children 3 to 5 years of age should receive
should be considered for patients with CD4+
cART if they (a) have AIDS or significant
T-lymphocyte counts above 500 cells/mm.
HIV-related symptoms (CDC clinical cat-
In general, cART with at least 3 active drugs
egories C and B [except for the following
is recommended for all HIV-infected individu-
category B condition: single episode of seri-
als requiring ART. Drug regimens most often
ous bacterial infection]); (b) have a CD4+
include 2 nucleoside reverse transcriptase
T-lymphocyte count at or below 750 cells/
inhibitors plus a protease inhibitor or a non-
mm3 or CD4+ T-lymphocyte percentage
nucleoside reverse transcriptase inhibitor
below 25%; or (c) are asymptomatic or mildly
(http://aidsinfo.nih.gov). Antiretroviral

ERRNVPHGLFRVRUJ
284 Human Immunodeficiency Virus Infection

r­ esistance testing (viral genotyping) is recom- pression of HIV replication in the blood to
mended before starting treatment. Suppression undetectable levels by cART has resulted in
of virus to undetectable levels is the desired relatively normal CD4+ and CD8+ T-lymphocyte
goal. A change in ART should be considered counts, leading to a dramatic decrease in the
if there is evidence of disease progression occurrence of most OIs. Limited data on the
(­v irologic, immunologic, or clinical), toxicity safety of discontinuing prophylaxis in HIV-
of or intolerance to drugs, initial presence infected children receiving cART are available;
or development of drug resistance, or availa­ however, prophylaxis should not be discontin-
bility of data suggesting the possibility of a ued in HIV-infected infants younger than
superior regimen. 1 year irrespective of the viral or immunologic
response. For older children, many experts
Intravenous immunoglobulin therapy has
consider discontinuing PCP prophylaxis on the
been used in combination with cART for
basis of CD4+ T-lymphocyte count for those
HIV-infected children with hypogamma­
who have received at least 6 months of effective
globulinemia (IgG <400 mg/dL [4.0 g/L]) and
cART as follows: for ­children 1 through 5 years
can be considered for HIV-infected children
of age, CD4+ T-­lymphocyte percentage of at
who have recurrent, serious bacterial infec-
least 15% or CD4+ T-­lymphocyte absolute count
tions, such as bacteremia, meningitis, or
of at least 500 cells/μL for more than 3 consecu-
­pneumonia. Trimethoprim-sulfamethoxazole
tive months; and for children 6 years or older,
prophylaxis may provide comparable protec-
CD4+ T-lymphocyte percentage of at least 15%
tion. Typically, neither form of prophylaxis is
or the CD4+ T-lymphocyte absolute count of at
necessary for patients receiving effective cART.
least 200 cells/μL for more than 3 consecutive
Early diagnosis, prophylaxis, and aggressive months. Subsequently, the CD4+ T-lymphocyte
treatment of OIs may prolong survival. This is absolute count or percentage should be reeval-
particularly true for PCP, which accounts for uated at least every 3 months. Prophylaxis
approximately one-third of pediatric AIDS should be reinstituted if the original criteria
diagnoses overall and may occur early in the for prophylaxis are reached again.
first year of life. Prophylaxis is not recom-
• Immunization recommendations. All
mended for neonates who meet criteria for
­recommended childhood immunizations
­presumptive or definitive HIV-uninfected
should be given to HIV-exposed infants. If
­status. Thus, for neonates with negative HIV
HIV infection is confirmed, guidelines for
diagnostic test results at 2 and 4 weeks of age,
the HIV-infected child should be followed.
PCP prophylaxis would not need to be initi-
Children with HIV infection should be
ated. Because mortality rates are high, PCP
immunized as soon as is age appropriate
chemoprophylaxis should be given to all HIV-
with inactivated vaccines. Inactivated influ-
exposed infants with indeterminate HIV infec-
enza vaccine should be given annually
tion status starting at 4 to 6 weeks of age but
according to the most current recommen­
can be stopped if the infant subsequently meets
dations. Additionally, live-virus vaccines
criteria for presumptive or definitive absence of
(measles-mumps-rubella [MMR] and vari-
HIV infection. All infants with HIV infection
cella) can be given to asymptomatic HIV-
should receive PCP prophylaxis through 1 year
infected children and adolescents without
of age regardless of immune status. The need
severe immunosuppression (ie, CD4+
for PCP prophylaxis for HIV-infected children
T-­lymphocyte percentage >15% for at least
1 year and older is determined by the degree of
6 months in children 1 through 5 years of
immunosuppression from CD4+ T-lymphocyte
age and CD4+ T-lymphocyte percentage
percentage and count.
>15% and a CD4+ T-lymphocyte count >200
Guidelines for prevention and treatment of lymphocytes/mm3 for a 6-month period in
OIs in children, adolescents, and adults pro- those 6 years and older). Severely immuno-
vide indications for administration of drugs compromised HIV-infected infants, chil-
for infection with M avium complex, CMV, dren, adolescents, and young adults should
T gondii, and other organisms. Successful sup- not receive measles virus–containing vac-

ERRNVPHGLFRVRUJ
Human Immunodeficiency Virus Infection 285

cine because vaccine-related pneumonia tration of these vaccines is provided in the


has been reported. The quadrivalent MMR- “Recommended Immunization Schedule
varicella vaccine should not be administered for Persons Aged 0 Through 18 Years”
to any HIV-infected infants, regardless of (http://redbook.solutions.aap.org/SS/
degree of immunosuppression, because of Immunization_Schedules.aspx).
lack of safety data in this population. Rota­
• Children who are HIV uninfected residing
virus vaccine can be given to HIV-exposed
in the household of an HIV-infected per-
and HIV-infected infants irrespective of
son. Members of households in which an
CD4+ T-lymphocyte percentage or count.
adult or child has HIV infection can receive
HIV-infected children should receive a dose
MMR vaccine because these vaccine viruses
of 23-valent polysaccharide pneumococcal
are not transmitted person to person. To
vaccine after 24 months of age, with a mini-
decrease the risk of transmission of influ-
mal interval of 8 weeks since the last conju-
enza to patients with symptomatic HIV
gate pneumococcal vaccine. Although HIV
infection, all household members 6 months
infection is not an indication for pneumo-
or older should receive yearly influenza
coccal vaccine, people at increased risk of
immunization. Immunization with varicella
meningococcal disease and who are 2 years
vaccine of siblings and susceptible adult
or older should receive a 2-dose primary
caregivers of patients with HIV infection is
series of the quadrivalent meningococcal
encouraged to prevent acquisition of wild-
vaccine at least 8 weeks apart. HIV-infected
type varicella-zoster virus infection, which
adolescents 11 through 18 years of age should
can cause severe disease in immunocompro-
receive all inactivated vaccines recom-
mised hosts. Transmission of varicella vac-
mended for this age group, including the
cine virus from an immunocompetent host
3-dose series of human papillomavirus
to a household contact is very uncommon.
­vaccine. The suggested schedule for adminis­

m
Ia
g

Image 69.2
Scanning electron micrograph of HIV type 1
Image 69.1 budding from cultured lymphocyte. Courtesy of
HIV type 1. Transmission electron micrograph. Centers for Disease Control and Prevention/
Cone-shaped cores are sectioned in various C. Goldsmith, P. Feorino, E. L. Palmer, W. R.
orientations. Viral genomic RNA is located in the McManus.
electron-dense wide end of core. Courtesy of
Centers for Disease Control and Prevention/
Dr Edwin P. Ewing Jr.

ERRNVPHGLFRVRUJ
286 Human Immunodeficiency Virus Infection

Image 69.3
Perinatally acquired AIDS cases, by age at diagnosis, 1982–2001, United States. Perinatally acquired
AIDS was diagnosed for nearly 40% of infected infants within the first year of life and for 22% within the
first 6 months. This distribution could change if more HIV-infected childbearing women become aware of
their HIV status and seek medical care early in their infants’ lives, when treatment could possibly prevent
the progres­sion from HIV infection to AIDS in their children. Courtesy of Centers for Disease Control
and Prevention.

Image 69.4
Diagnosis rates—United States and US territories, 2012. Courtesy of Morbidity and Mortality
Weekly Report.

ERRNVPHGLFRVRUJ
Human Immunodeficiency Virus Infection 287

Image 69.5
Percentage of diagnosed cases, by race/ethnicity—United States, 2012. Courtesy of Morbidity and
Mortality Weekly Report.

Image 69.6
HIV prevalence in adults, 2009. Centers for Disease Control and Prevention National Center for
Emerging and Zoonotic Infectious Diseases (NCEZID) Division of Global Migration and Quarantine
(DGMQ).

ERRNVPHGLFRVRUJ
288 Human Immunodeficiency Virus Infection

Image 69.7
Digital clubbing in a child with HIV infection and
lymphoid interstitial pneumonitis/pulmonary
lymphoid hyperplasia (LIP/PLH). Marked lympha­
denopathy, hepatosplenomegaly, and salivary
gland enlargement are also observed in many
children with LIP/PLH. The clinical course of LIP/
PLH is variable. Exacerbation of respiratory Image 69.8
distress and hypoxemia can occur in association Bilateral parotid gland enlargement in an HIV-
with intercurrent viral respiratory illnesses. Spon­ infected male child with lymphoid interstitial
taneous clinical remission is sometimes observed. pneumonitis/pulmonary lymphoid hyperplasia.
Copyright Baylor International Pediatric AIDS Note the presence of multiple lesions of mollus­
Initiative/Mark Kline, MD, FAAP. cum contagiosum, which are commonly seen in
patients with HIV, particularly those with a low
CD4 lymphocyte count. (See also Molluscum
Contagiosum.) Copyright Baylor International
Pediatric AIDS Initiative/Mark Kline, MD, FAAP.

Image 69.9
Severe molluscum contagiosum in a boy with
HIV infection. Some HIV-infected children
develop molluscum contagiosum lesions that
are unusually large or widespread. They are Image 69.10
often seated more deeply in the epidermis. (See Norwegian (crusted) scabies in a boy with HIV
also Molluscum Contagiosum.) Copyright infection. Generalized scaling and hyperkeratotic,
Baylor International Pediatric AIDS Initiative/Mark crusted plaques are present. (See also Scabies.)
Kline, MD, FAAP. Copyright Baylor International Pediatric AIDS
Initiative/Mark Kline, MD, FAAP.

ERRNVPHGLFRVRUJ
Human Immunodeficiency Virus Infection 289

Image 69.11 Image 69.12


An 8-year-old boy with HIV and tuberculous Herpes simplex infection in a girl with HIV
lymphadenitis (scrofula). Copious amounts of pus infection. Chronic or progressive herpetic skin
spontaneously drained from this lesion. In an lesions are observed occasionally in HIV-infected
immunocompromised child, other causes of children, although, unlike varicella-zoster virus
lymphadenitis include infections with gram- infections in these patients, herpes simplex
positive bacteria, atypical mycobacterium, and infections much less commonly cause
Bartonella henselae (cat-scratch disease); disseminated disease. (See also Herpes
malignant neoplasms such as lymphoma; Simplex.) Copyright Baylor International
masses such as branchial cleft cysts or cystic Pediatric AIDS Initiative/Mark Kline, MD, FAAP.
hygromas masquerading as lymph nodes; and
adenitis due to HIV itself. (See also Diseases
Caused by Nontuberculous Mycobacteria.)
Copyright Baylor International Pediatric AIDS
Initiative/Mark Kline, MD, FAAP.

Image 69.13
Herpes zoster (shingles) in a boy with HIV infection. Such cases can be complicated by chronicity or
dissemination. (See also Varicella-Zoster Virus Infections.) Copyright Baylor International Pediatric
AIDS Initiative/Mark Kline, MD, FAAP.

ERRNVPHGLFRVRUJ
290 Human Immunodeficiency Virus Infection

Image 69.14 Image 69.15


Severe cutaneous warts (human papillomavirus Pseudomembranous candidiasis in a person with
infection) in a boy with HIV infection. Copyright HIV infection. (See also Candidiasis.) Copyright
Baylor International Pediatric AIDS Initiative/Mark Baylor International Pediatric AIDS Initiative/Mark
Kline, MD, FAAP. Kline, MD, FAAP.

Image 69.17
Histopathology of toxoplasmosis of heart in fatal
Image 69.16
case of AIDS. Courtesy of Centers for Disease
A 9-year-old girl with HIV infection and cutaneous
Control and Prevention/Dr Edwin P. Ewing Jr.
Cryptococcus neoformans infection. Skin lesions
can be single or multiple and may appear as
small papules, pustules, nodules, or ulcers with
a base of granulation tissue. (See also Crypto­
coc­cus neoformans and Cryptococcus gattii
Infections.) Copyright Baylor International
Pediatric AIDS Initiative/Mark Kline, MD, FAAP.

Image 69.19
Histopathology of toxoplasmosis of the brain
in fatal case of AIDS. Courtesy of Centers for
Disease Control and Prevention/Dr Edwin P.
Ewing Jr.

Image 69.18
Toxoplasmosis of the heart in a patient with AIDS.
Courtesy of Centers for Disease Control and
Prevention/Dr Edwin P. Ewing Jr.

ERRNVPHGLFRVRUJ
Human Immunodeficiency Virus Infection 291

Image 69.21
Computed tomography scan of the brain of a
9-month-old girl with HIV infection and bilateral
calcifications of the basal ganglia. This finding in
an infant or young child strongly suggests HIV
infection. Copyright Baylor International Pediatric
Image 69.20 AIDS Initiative/Mark Kline, MD, FAAP.
Computed tomography scan of the brain of an
8-year-old boy with HIV infection and generalized
brain atrophy. Cerebral atrophy is commonly
observed among children with HIV-associated
encephalopathy, but it may also be observed
among children who are normal neurologically
and developmentally. Copyright Baylor Inter­
national Pediatric AIDS Initiative/Mark Kline,
MD, FAAP.

Image 69.23
A 7-year-old girl with HIV infection and a Kaposi
sarcoma lesion. This tumor is rarely diagnosed
among US children, with the occasional excep­
tions of children of Haitian descent with vertical
HIV infection or older adolescents. Kaposi
Image 69.22 sarcoma is observed more commonly among
Chest radiograph showing cardiomegaly in a HIV-infected children in some other geographic
5-year-old girl with HIV infection, cardiomyopathy, locales, including parts of Africa (eg, Zambia,
and congestive heart failure. Many HIV-infected Uganda) and Romania. Kaposi sarcoma has
children with congestive heart failure respond been linked to infection with a novel herpesvirus,
well to medical management. Copyright Baylor now known as human herpesvirus 8 or Kaposi
International Pediatric AIDS Initiative/Mark Kline, sarcoma–associated virus. Copyright Baylor
MD, FAAP. International Pediatric AIDS Initiative/Mark Kline,
MD, FAAP.

ERRNVPHGLFRVRUJ
292 Human Immunodeficiency Virus Infection

Image 69.24
This HIV patient presented with intraoral Kaposi sarcoma of the hard palate secondary to his AIDS
infection. Approximately 7.5% to 10% of AIDS patients display signs of oral Kaposi sarcoma, which
can range in appearance from small asymptomatic growths that are flat purple-red in color to larger
nodular growths. Courtesy of Centers for Disease Control and Prevention/Sol Silverman Jr, DDS,
University of California, San Francisco.

Image 69.25
This HIV-positive patient presented with an intraoral Kaposi sarcoma lesion with an overlying candi­
diasis infection. This AIDS patient exhibited a CD4+ T-cell count less than 200 and a high viral load.
Initially, the Kaposi sarcoma lesions are flattened and red, but as they age, they become raised and
darker, tending to a purple coloration. Courtesy of Centers for Disease Control and Prevention/Sol
Silverman Jr, DDS, University of California, San Francisco.

Image 69.26
This HIV-positive patient was exhibiting a chronic mucocutaneous herpes lesion for 1 month in
duration. Courtesy of Centers for Disease Control and Prevention/Sol Silverman Jr, DDS, University
of California, San Francisco.

ERRNVPHGLFRVRUJ
Human Immunodeficiency Virus Infection 293

Image 69.27
A 5-year-old African American boy with HIV syndrome with varicella. Courtesy of Larry Frenkel, MD.

Image 69.28
A 17-year-old Hispanic male with HIV syndrome with an ulcerative lesion on the plantar surface of the
left foot of several months’ duration. A viral culture was positive for human herpesvirus, which led to
the diagnosis of HIV. Courtesy of Larry Frenkel, MD.

ERRNVPHGLFRVRUJ
294 Influenza

70 viruses cause sporadic, mild influenza-like


ill­ness in children and antigens are not included
Influenza in influenza vaccines. The virus type or subtype
Clinical Manifestations may have an effect on the number of hospital-
izations and deaths that season. For example,
Influenza typically begins with sudden onset seasons with influenza A (H3N2) as the pre-
of fever, often accompanied by chills or rigors, dominant circulating strain have had 2.7-times
headache, malaise, diffuse myalgia, and non- higher average mortality rates than other seasons.
productive cough. Subsequently, respiratory The 2009 influenza A (H1N1) pandemic com-
tract signs, including sore throat, nasal conges- bined exceptional pediatric ­v irulence and lack
tion, rhinitis, and cough, become more promi- of immunity, which resulted in nearly 4 times
nent. Conjunctival injection, abdominal pain, as many pediatric deaths as usually recorded.
nausea, vomiting, and diarrhea are less com-
monly associated with influenza illness. In Influenza A viruses are subclassified into sub-
some children, influenza can appear as an types by 2 surface antigens, hemagglutinin (HA)
upper respiratory tract infection or as a febrile and neuraminidase (NA). Examples of these
illness with few respiratory tract symptoms. include H1N1 and H3N2 viruses. Specific anti-
Influenza is an important cause of otitis media. bodies to these various antigens, especially to
Acute myositis characterized by calf tenderness HA, are important determinants of immunity.
and refusal to walk has been described. In Minor antigenic variation within the same
infants, influenza can produce a sepsislike pic- influenza B type or influenza A subtypes is called
ture and can occasionally cause croup, bron- antigenic drift. Antigenic drift occurs contin-
chiolitis, or pneumonia. Although the large uously and results in new strains of influenza A
majority of children with influenza recover and B viruses, leading to seasonal epidemics.
fully after 3 to 7 days, previously healthy chil- On the basis of ongoing global surveillance data,
dren can have severe symptoms and complica- there have only been 5 times since 1986 that the
tions. In the 2013–2014 influenza season, 43% vaccine strains in the influenza vaccine have
of children hospitalized with influenza had not changed from the previous season. Anti-
no known underlying conditions. Neurologic genic shifts are major changes in influenza A
complications associated with influenza range viruses that result in new subtypes that contain
from febrile seizures to severe encephalopathy a new HA alone or with a new NA. Antigenic
and encephalitis with status epilepticus, with shift only occurs with influenza A viruses and
resulting neurologic sequelae or death. Reye can lead a to pandemic if the new strain can
syndrome, which is now a very rare condition, infect humans and be transmitted efficiently
has been associated with influenza infection from person to person in a sustained manner in
and the use of aspirin therapy during the ill- the setting of little or no preexisting immunity.
ness. Children with influenza or suspected
From April 2009 to August 2010, the World
influenza should not be given aspirin. Death
Health Organization declared such a pandemic
from influenza-associated myocarditis has
caused by influenza A (H1N1) virus. There
been reported. Invasive secondary infections
now have been 4 influenza pandemics caused
or coinfections with group A streptococcus,
by antigenic shift in the 20th and 21st centu-
Staphylococcus aureus (including methicillin-
ries. The 2009 pandemic was associated with
resistant S aureus), Streptococcus pneumoniae,
2 waves of substantial activity in the United
or other bacterial pathogens can result in
States, occurring in the spring and fall of 2009
severe disease and death.
and extending well into winter 2010. During
Etiology this time, more than 99% of virus isolates char-
acterized were the 2009 pandemic influenza A
Influenza viruses are orthomyxoviruses of
(H1N1) virus. As with previous antigenic shifts,
3 genera or types (A, B, and C). Epidemic dis-
the 2009 pandemic influenza A (H1N1) viral
ease is caused by influenza virus types A and B,
strain has replaced the previously circulating
and influenza A and B virus antigens are
seasonal influenza A (H1N1) strain.
included in influenza vaccines. Type C influenza

ERRNVPHGLFRVRUJ
Influenza 295

Humans of all ages are occasionally infected munity over the course of an influenza season.
with influenza A viruses of swine or avian Antigenic drift in the circulating strain(s) is
­origin. Human infections with swine viruses associated with seasonal epidemics. In temper-
have manifested as typical influenza-like ill- ate climates, seasonal epidemics usually occur
ness, and confirmation of infection caused by during winter months. Peak influenza activity
an influenza virus of swine origin has been in the United States can occur anytime from
discovered retrospectively during routine typ- November to May but most commonly occurs
ing of human influenza isolates. For example, between January and March. Community
influenza A (H3N2v) viruses with the matrix ­outbreaks can last 4 to 8 weeks or longer. Cir-
(M) gene from the 2009 H1N1 pandemic virus culation of 2 or 3 influenza virus strains in a
were first detected in people in 2011 and were community may be associated with a pro-
responsible for a multistate outbreak in sum- longed influenza season of 3 months or more
mer 2012. Most cases were associated with and bimodal peaks in activity. Influenza is
exposure to swine at agricultural fairs, and no highly contagious, especially among semi­
sustained human-to-human transmission was enclosed, institutionalized populations and
observed. Similarly, human infections with other ongoing, closed-group gatherings, such
avian influenza viruses are uncommon but as school and preschool or child care class-
may result in a spectrum of disease, including rooms. Patients may be infectious 24 hours
mild respiratory symptoms and conjunctivitis before onset of symptoms. Viral shedding in
to severe lower respiratory tract disease, acute nasal secretions usually peaks during the first
respiratory distress syndrome, and death. Most 3 days of illness and ceases within 7 days but
notable among avian influenza viruses are A can be prolonged in young children and immu-
(H5N1) and A (H7N9), both of which have been nodeficient patients for 10 days or even longer.
associated with severe disease and high case- Viral shedding is correlated directly with
fatality rates. Influenza A (H5N1) viruses degree of fever.
emerged as human infections in 1997 and have
Incidence of influenza in healthy children is
since caused human disease in Asia, Africa,
generally 10% to 40% each year, but illness rates
Europe, and the Middle East, areas where
as low as 3% have also been reported, depend-
these viruses are present in domestic or wild
ing on the circulating strain. Tens of thousands
birds. Influenza A (H7N9) infections were
of children visit clinics and emergency depart-
first detected in 2013 and have been associated
ments because of influenza illness each season.
with sporadic disease in China.
Influenza and its complications have been
Epidemiology reported to result in a 10% to 30% increase in
Influenza is spread from person to person, the number of courses of antimicrobial agents
­primarily by respiratory tract droplets created prescribed to children during the influenza
by coughing or sneezing. Contact with respira- season. Although bacterial coinfections with
tory tract droplet–contaminated surfaces fol- a variety of pathogens, including methicillin-
lowed by autoinoculation is another mode of resistant S aureus, have been reported, medical
transmission. During community outbreaks of care encounters for children with influenza
influenza, the highest incidence occurs among are an important cause of inappropriate anti-
school-aged children. Secondary spread to microbial use.
adults and other children within a family is Hospitalization rates among children younger
common. Incidence and disease severity than 2 years are similar to hospitalization rates
depend, in part, on immunity developed as a among people 65 years and older. Rates vary
result of previous experience (by natural dis- among studies (190–480 per 100,000 popula-
ease) or recent influenza immunization with tion) because of differences in methodology
the circulating strain or a related strain. Influ- and severity of influenza seasons. However,
enza A viruses, including 2 subtypes (H1N1 children younger than 24 months are consis-
and H3N2), and influenza B viruses circulate tently at a substantially higher risk of hospi­
worldwide, but the prevalence of each can vary talization than older children. Antecedent
among communities and within a single com- influenza infection is sometimes associated

ERRNVPHGLFRVRUJ
296 Influenza

with development of pneumococcal or staphy- son to person. Pandemics, therefore, can lead
lococcal pneumonia in children. Methicillin- to substantially increased morbidity and mor-
resistant staphylococcal community-acquired tality rates compared with seasonal influenza.
pneumonia, with a rapid clinical progression During the 20th century, there were 3 influenza
and a high fatality rate, has been reported in pandemics, in 1918 (H1N1), 1957 (H2N2), and
previously healthy children and adults with 1968 (H3N2). The pandemic in 1918 killed at
concomitant influenza infection. Rates of hos- least 20 million people in the United States and
pitalization and morbidity attributable to com- perhaps as many as 50 million people world-
plications, such as bronchitis and pneumonia, wide. The 2009 influenza A (H1N1) pandemic
are even greater in children with high-risk con- was the first in the 21st century, lasting from
ditions, including asthma, diabetes mellitus, April 2009 to August 2010; there were 18,449
hemodynamically significant cardiac disease, deaths among laboratory-confirmed influenza
immunosuppression, and neurologic and neu- cases. However, this is believed to represent
rodevelopmental disorders. Influenza virus only a fraction of the true number of deaths.
infection in neonates has also been associated On the basis of a modeling study from the
with considerable morbidity, including a sep- ­Centers for Disease Control and Prevention,
sislike syndrome, apnea, and lower respiratory it is estimated the 2009 influenza A (H1N1)
tract disease. pandemic was associated with between 151,700
and 575,400 deaths worldwide. Public health
Fatal outcomes, including sudden death, have
authorities have developed plans for pandemic
been reported in chronically ill and previously
preparedness and response to a pandemic in
healthy children. Since influenza-related pedi-
the United States. Pediatricians should be
atric deaths became nationally notifiable in
familiar with national, state, and institutional
2004, the number of deaths among children
pandemic plans, including recommendations
reported annually in nonpandemic seasons
for vaccine and antiviral drug use, health care
has ranged from 46 (2005–2006 season) to 171
surge capacity, and personal protective strate-
(2012–2013 season); during the 2009–2010
gies that can be communicated to patients and
­season, the number of pediatric deaths in the
families. Up-to-date information on pandemic
United States was 288. During the entire influ-
influenza can be found at www.flu.gov.
enza A (H1N1) pandemic period lasting from
April 2009 to August 2010, a total of 344 Diagnostic Tests
­laboratory-confirmed, influenza-associated Specimens for viral culture, reverse transcriptase-
pediatric deaths were reported. Influenza A polymerase chain reaction (RT-PCR), rapid
and B viruses have been associated with deaths influenza molecular assays, or rapid ­diagnostic
in children, most of which have occurred in tests should be obtained, if possible, during the
­children younger than 5 years. Almost half of first 72 hours of illness because the quantity of
children who die do not have a high-risk con­ virus shed decreases rapidly as illness pro-
dition as defined by the Advisory Committee gresses beyond that point. Specimens of naso-
on Immunization Practices. All influenza- pharyngeal secretions obtained by swab,
associated pediatric deaths are nationally aspirate, or wash should be placed in appropri-
­notifiable and should be reported to the ate transport media for culture. After inocula-
­Centers for Disease Control and Prevention tion into eggs or cell culture, influenza virus
through state health departments. can usually be isolated within 2 to 6 days.
Incubation Period Rapid diagnostic tests for identification of
influenza A and B antigens in respiratory
Usually 1 to 4 days, with a mean of 2 days.
tract specimens are available commercially,
Influenza Pandemics although their reported sensitivity (44%–97%)
and specificity (76%–100%) compared with
A pandemic is defined by emergence and
viral culture, RT-PCR, and rapid influenza
global spread of a new influenza A virus sub-
molecular assays are variable and differ by test
type to which the population has little or no
and specimen type. Additionally, many rapid
immunity and that spreads rapidly from per-
diagnostic antigen tests cannot distinguish

ERRNVPHGLFRVRUJ
Influenza 297

between influenza subtypes, a feature that can 10 to 14 days apart are required. Rapid influ-
be critical during seasons with strains that dif- enza molecular assays are becoming more
fer in antiviral susceptibility or relative viru- widely available. Reverse transcriptase-­
lence. Results of rapid diagnostic tests should polymerase chain reaction, viral culture tests,
be interpreted in the context of clinical find- and rapid influenza molecular assays offer
ings and local community influenza activity. potential for high sensitivity as well as specific-
Careful clinical judgment must be exercised ity and are recommended as the tests of choice.
because the prevalence of circulating influenza
Treatment
viruses influences the positive and negative
predictive values of these influenza screening In the United States, 2 classes of antiviral med-
tests. False-positive results are more likely to ications are currently approved for treatment
occur during periods of low influenza activity; or prophylaxis of influenza infections: neura­min­
false-negative results are more likely to occur idase inhibitors (oseltamivir and zana­mivir) and
during periods of peak influenza activity. Deci- adamantanes (amantadine and rimantadine).
sions on treatment and infection control can be Guidance for use of these 4 antiviral agents is
made on the basis of positive rapid diagnostic summarized in Table 70.1. Oseltamivir, an oral
test results. Positive results are helpful because drug, remains the antiviral drug of choice that
they may reduce additional testing to identify can be given to children as young as 2 weeks.
the cause of the child’s influenza-like illness. Given preliminary pharmacokinetic data and
Treatment should not be withheld in high-risk limited safety data, oseltamivir can be used to
patients awaiting RT-PCR test results. Serologic treat influenza in term and preterm newborns
diagnosis can be established retrospectively by from birth because benefits of therapy are likely
a 4-fold or greater increase in antibody titer in to outweigh possible risks of treatment. Zanami-
serum specimens obtained during the acute vir, an inhaled drug, is an acceptable alterna-
and convalescent stages of illness, as deter- tive but is more difficult to administer,
mined by hemagglutination inhibition testing, especially to young children.
complement fixation testing, neutralization
Widespread resistance to adamantanes has
testing, or enzyme immunoassay. However,
been documented among H3N2 and H1N1
serologic testing is rarely useful in patient
influenza viruses since 2005 (influenza B
management because 2 serum samples collected

Table 70.1
Antiviral Drugs for Influenzaa
Drug Treatment Chemoprophy-
(Trade Name) Virus Administration Indications laxis Indications Adverse Effects
Oseltamivir A and Oral Birth or 3 mo or older Nausea, vomiting
(Tamiflu) B olderb
Zanamivir A and Inhalation 7 y or older 5 y or older Bronchospasm
(Relenza) B
Amantadinec A Oral 1 y or older 1 y or older Central nervous
(Symmetrel) ­system, anxiety,
­gastrointestinal
Rimantadinec A Oral 13 y or older 1 y or older Central nervous
(Flumadine) ­system, anxiety,
­gastrointestinal
a For current recommendations about treatment and chemoprophylaxis of influenza, including specific dosing information, see www.cdc.
gov/flu/professionals/antivirals/index.htm or www.aapredbook.org/flu.
b Approved by the US Food and Drug Administration for children as young as 2 weeks. Given preliminary pharmacokinetic data and limited

safety data, oseltamivir can be used to treat influenza in term and preterm newborns from birth because benefits of therapy are likely to
outweigh possible risks of treatment.
c High levels of resistance to amantadine and rimantadine persist, and these drugs should not be used unless resistance patterns change

significantly. Antiviral susceptibilities of viral strains are reported weekly at www.cdc.gov/flu/weekly/fluactivitysurv.htm.

ERRNVPHGLFRVRUJ
298 Influenza

viruses i­ ntrinsically are not susceptible to be considered for symptomatic siblings of infants
­adamantanes). Since January 2006, neuramini- younger than 6 months or with underlying medi­
dase inhibitors (oseltamivir, zanamivir) have cal conditions that predispose them to compli-
been the only recommended influenza anti­ cations of influenza. Children with severe
viral drugs against influenza viruses. Resis- influenza should be ­evaluated carefully for pos-
tance to oseltamivir has been documented to sible coinfection with bacterial pathogens (eg,
be around 1%, at most, for any of the tested S aureus) that might require antimicrobial
influenza viral samples during the past few therapy. Clinicians who want to have influenza
years. Each year, options for treatment or isolates tested for susceptibility should contact
­chemoprophylaxis of influenza in the United their state health department.
States will depend on influenza strain resis-
The duration of treatment is 5 days for the
tance patterns.
neuraminidase inhibitors.
Therapy for influenza virus infection should be
The most common adverse effects of oseltami-
offered to any hospitalized child who has severe,
vir are nausea and vomiting. Zanamivir use
complicated, or progressive respiratory illness
has been associated with bronchospasm in
that may be influenza related, regardless of
some people and is not recommended for use
influenza-immunization status or whether onset
in patients with underlying airway disease.
of illness has been greater than 48 hours before
admission. Outpatient therapy should be offered Control of fever with acetaminophen or
for influenza infection of any severity in chil- another appropriate nonsalicylate-containing
dren at high risk of complications of influenza antipyretic agent may be important in young
infection, such as children younger than 2 years. children because fever and other symptoms of
Treatment may be considered for any other- influenza could exacerbate underlying chronic
wise healthy child with influenza infection for conditions. Children and adolescents with
whom a decrease in duration of clinical symp- influenza should not receive aspirin or any
toms is believed to be warranted by his or her salicylate-containing products because of the
pediatrician. Antiviral treatment should also potential risk of developing Reye syndrome.

Image 70.1 Image 70.2


Transmission electron micrograph of influenza A Colorized transmission electron micrograph of
virus, late passage. Courtesy of Centers for avian influenza A (H5N1) viruses (seen in gold)
Disease Control and Prevention/Dr Erskine Palmer. grown in Madin-Darby canine kidney epithelial
cells (seen in green). Avian influenza A viruses
do not usually infect humans; however, several
instances of human infections and outbreaks
have been reported since 1997. When such
infections occur, public health authorities monitor
these situations closely. Courtesy of Centers for
Disease Control and Prevention/Courtesy of
Cynthia Goldsmith; Jacqueline Katz; Sherif R. Zaki.

ERRNVPHGLFRVRUJ
Influenza 299

Image 70.3 Image 70.4


This negative-stained transmission electron Influenza, like many viral infections, is spread
micrograph depicts the ultrastructural details of by droplet transmission or direct contact with
an influenza virus particle, or virion. Courtesy of items recently contaminated by infected naso­
Centers for Disease Control and Prevention/ pharyn­geal secretions. Courtesy of Centers for
Erskine L. Palmer, MD/M. L. Martin, MD. Disease Control and Prevention.

Image 70.5
Properly donned disposable N95 filtering
facepiece respirator. To be properly donned,
the respirator must be correctly oriented on
the face and held in position with both straps.
The straps must be cor­rectly placed, with the
upper strap high on the head and the lower
strap below the ears. For persons with long Image 70.6
hair, the lower strap should be placed under Influenza-associated pediatric mortality.
(not over) the hair. The nose clip must be tightened Incidence—United States and US territories,
to avoid gaps between the respirator and the 2012. Courtesy of Morbidity and Mortality Weekly
skin. Facial hair should be removed before Report.
donning. Appropriate respirator donning could be
important in the event of an influenza epidemic.
Courtesy of Centers for Disease Control and
Prevention/Emerging Infectious Diseases and
Kristin J. Cummings.

ERRNVPHGLFRVRUJ
300 Influenza

Image 70.7
Antigenic drift. Each year’s flu vaccine contains 3 flu strains—2 A strains and 1 B strain—that can
change from year to year. After vaccination, the body produces infection-fighting antibodies against
the 3 flu strains in the vaccine. If a vaccinated individual is exposed to any of the 3 flu strains during the
flu season, the antibodies will latch onto the virus hemagglutinin (HA) antigens, preventing the flu virus
from attaching to healthy cells and infecting them. Influenza virus genes, made of RNA, are more prone
to mutations than genes made of DNA. If the HA gene changes, so can the antigen that it encodes,
causing it to change shape. If the HA antigen changes shape, antibodies that normally would match
up to it no longer can, allowing the newly mutated virus to infect the body’s cells. This type of genetic
mutation is called antigenic drift. Courtesy of National Institute of Allergy and Infectious Diseases.

ERRNVPHGLFRVRUJ
Influenza 301

Image 70.8
Antigenic shift. The genetic change that enables a flu strain to jump from one animal species to
another, including humans, is called antigenic shift. Antigenic shift can happen in 3 ways. Antigenic
shift 1: A duck or other aquatic bird passes a bird strain of influenza A to an intermediate host, such
as a chicken or pig. A person passes a human strain of influenza A to the same chicken or pig. When
the viruses infect the same cell, genes from the bird strain mix with genes from the human strain to
yield a new strain. The new strain can spread from the intermediate host to humans. Antigenic
shift 2: Without undergoing genetic change, a bird strain of influenza A can jump directly from a
duck or other aquatic bird to humans. Antigenic shift 3: Without undergoing genetic change, a
bird strain of influenza A can jump directly from a duck or other aquatic bird to an intermediate animal
host and then to humans. The new strain may further evolve to spread from person to person. If so,
an influenza pandemic could arise. Courtesy of National Institute of Allergy and Infectious Diseases.

ERRNVPHGLFRVRUJ
302 Influenza

Image 70.9
Recombination. An influenza virus contains 8 gene segments. One of the gene segments codes for the
surface antigen hemagglutinin (HA), and another codes for the surface antigen neuraminidase (NA).
Each year, researchers predict which flu strains will be most prevalent and select 3—2 influenza A
strains and 1 influenza B strain—to be included in that year’s vaccine. The goal of recombination is to
combine the desired HA and NA antigens from the target strain (flu strain 1) with genes from a
harmless strain that grows well in an egg (flu strain 2). The illustration details the following steps in
creating the vaccine: Flu strains 1 and 2 are injected into a fertilized chicken egg. The genes from flu
strain 1 multiply and mix with the genes from flu strain 2, forming as many as 256 possible gene
combinations. Researchers search the many combinations for the flu strain that contains the HA and
NA genes from flu strain 1 and remaining genes from flu strain 2 that ensures it is able to grow
efficiently in eggs. This new recombined flu strain and 2 other flu strains will make up next year’s
vaccine. Courtesy of National Institute of Allergy and Infectious Diseases.

ERRNVPHGLFRVRUJ
Influenza 303

Image 70.10 Image 70.11


Emergency hospital during 1918 influenza epide­mic, US Army Camp Hospital No. 45, Aix-Les-Bains,
Camp Funston, KS. Source: National Museum of France, influenza ward 1, 1918. Source: National
Health and Medicine, Armed Forces Institute of Museum of Health and Medicine, Armed Forces
Pathology, Washington, DC, Image NCP 1603. Institute of Pathology, Washington, DC, Image
Courtesy of Immunization Action Coalition. Reeve 14682. Courtesy of Immunization Action
Coalition.

Image 70.12
Influenza pneumonia in a 12-year-old boy
with respiratory failure. Courtesy of Benjamin
Estrada, MD.

Image 70.13
Influenza A with Staphylococcus aureus
pneumonia with empyema in a preschool-aged
child. Courtesy of Benjamin Estrada, MD.

Image 70.14
Influenza A with Staphylococcus aureus super­
infection in a 6-year-old. Note the presence of
bilateral pneumatoceles. Courtesy of Benjamin
Estrada, MD.

ERRNVPHGLFRVRUJ
304 Influenza

Image 70.15
Coronal T2-weighted magnetic resonance image of a 5-year-old with influenza-associated encepha­
lopathy demonstrating bilateral confluent signal hyperintensity in the white matter (arrows) and thalami
(asterisks). Courtesy of James Sejvar, MD.

Image 70.16
Pathologic findings from a patient with confirmed influenza A (H5N1) infection (hematoxylin-eosin stain,
magnification x40). A, Hyaline membrane formation lining the alveolar spaces of the lung and vascular
congestion with a few infiltrating lymphocytes in the interstitial areas. Reactive fibroblasts are also
present. B, An area of lung with proliferating reactive fibroblasts within the interstitial areas. Few
lymphocytes are seen, and no viral intranuclear inclusions are visible. C, Fibrinous exudates filling the
alveolar spaces, with organizing formation and few hyaline membranes. The surrounding alveolar
spaces contain hemorrhage. D, A section of spleen showing numerous atypical lymphoid cells
scattered around the white pulp. No viral intranuclear inclusions are seen. Courtesy of Centers for
Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Influenza 305

Image 70.17
Influenza viral antigens in bronchial epithelial
lining cells as seen by immunohistochemistry. Image 70.18
Courtesy of Centers for Disease Control Immunostaining for influenza B viral antigens.
and Prevention. Note intracellular viral antigens in these areas.
Courtesy of Centers for Disease Control
and Prevention.

Image 70.19
Focal myocarditis seen in the patient in Image
70.18 with influenza B infection. Note myocardial Image 70.20
necrosis associated with areas of mostly This is Image 70.19 of influenza B myocarditis at
mononuclear inflammation. Courtesy of Centers a higher magnification. Courtesy of Centers for
for Disease Control and Prevention. Disease Control and Prevention.

ERRNVPHGLFRVRUJ
306 Isosporiasis (now ­designated as ­Cystoisosporiasis)

71 2 days and, perhaps, more quickly in some set-


tings. Oocysts probably are resistant to most
Isosporiasis disinfectants and can remain viable for pro-
(now ­designated as longed periods in a cool, moist environment.
­Cystoisosporiasis) Incubation Period
Clinical Manifestations Uncertain, but ranges from 7 to 12 days in
reported cases associated with accidental
Watery diarrhea is the most common symptom
­laboratory exposures.
of cystoisosporiasis and can be profuse and
protracted, even in immunocompetent people. Diagnostic Tests
Manifestations are similar to those caused by
Identification of oocysts in feces or in duodenal
other enteric protozoa (eg, Cryptosporidium,
aspirates or finding developmental stages of the
Cyclospora species) and can include abdominal
parasite in biopsy specimens (eg, of the small
pain, cramping, anorexia, nausea, vomiting,
intestine) is diagnostic. Oocysts in stool are
weight loss, and low-grade fever. Eosinophilia
elongate and ellipsoidal (length, 25–30 µm).
can also occur. The proportion of infected
Oocysts can be shed in low numbers, even by
­people who are asymptomatic is unknown.
people with profuse diarrhea. This constraint
Severity of infection ranges from self-limiting
underscores the utility of repeated stool exami-
in immunocompetent hosts to debilitating
nations, sensitive recovery methods (eg, con-
and life threatening in immunocompromised
centration methods), and detection methods
patients, particularly people infected with
that highlight the organism (eg, oocysts stain
HIV. Infections of the biliary tract and reactive
bright red with modified acid-fast techniques
arthritis have also been reported.
and autofluoresce when viewed by ultraviolet
Etiology fluorescent microscopy).
Cystoisospora (formerly Isospora) belli is a Treatment
­coccidian protozoan; oocysts (rather than
Trimethoprim-sulfamethoxazole, typically for
cysts) are passed in stools.
7 to 10 days, is the drug of choice. Patients
Epidemiology who are immunocompromised may need
higher doses and a longer duration of therapy.
Infection occurs predominantly in tropical
Pyrimethamine (plus leucovorin, to prevent
and subtropical regions of the world and can
myelosuppression) is an alternative treatment
cause traveler’s diarrhea. Infection results
for people who cannot tolerate trimethoprim-
from ingestion of sporulated oocysts in con-
sulfamethoxazole. Ciprofloxacin is less effec-
taminated food or water. Humans are the only
tive than trimethoprim-sulfamethoxazole. In
known host for C belli and shed noninfective
adolescents and adults, maintenance therapy
oocysts in feces. These oocysts must mature
is recommended to prevent recurrent disease
(sporulate) outside the host in the environment
for people infected with HIV.
to become infective. Under favorable condi-
tions, sporulation can be completed in 1 to

ERRNVPHGLFRVRUJ
Isosporiasis (now ­designated as ­Cystoisosporiasis) 307

Image 71.1
Oocysts of Cystoisospora (formerly Isospora) belli (iodine stain). The oocysts are large (25–30 µm)
and have a typical ellipsoidal shape. When excreted, they are immature and contain 1 sporoblast
(A, B). The oocyst matures after excretion; the single sporoblast divides into 2 sporoblasts (C),
which develop cyst walls, becoming sporocysts, which eventually contain 4 sporozoites each.
Courtesy of Centers for Disease Control and Prevention.

Image 71.2
Oocysts of Cystoisospora (formerly Isospora) belli can also be stained with acid-fast stain and
visualized by epifluorescence on wet mounts, as illustrated. Three coccidian parasites that most
commonly infect humans, seen in acid-fast stained smears (A, C, F), bright-field differential inter­
ference contrast (B, D, G), and epifluorescence (E, H, C; Cryptosporidium parvum oocysts do not
­autofluoresce). Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
308 Isosporiasis (now ­designated as ­Cystoisosporiasis)

Image 71.3
At time of excretion, the immature oocyst usually contains 1 sporoblast (more rarely, 2) (1). In further
maturation after excretion, the sporoblast divides into 2 (the oocyst now contains 2 sporoblasts);
the sporoblasts secrete a cyst wall, thus becoming sporocysts; and the sporocysts divide twice to
produce 4 sporozoites each (2). Infection occurs by ingestion of sporocyst-containing oocysts. The
sporocysts excyst in the small intestine and release their sporozoites, which invade the epithelial
cells and initiate schizogony (3). On rupture of the schizonts, the merozoites are released, invade
new epithelial cells, and continue the cycle of asexual multiplication (4). Trophozoites develop into
schizonts that contain multiple merozoites. After a minimum of 1 week, the sexual stage begins with
the development of male and female gametocytes (5). Fertilization results in the development of
oocysts that are excreted in the stool (1). Cystoisospora (formerly Isospora) belli infects humans
and animals. Courtesy of Centers for Disease Control and Prevention/Alexander J. da Silva, PhD/
Melanie Moser.

ERRNVPHGLFRVRUJ
Kawasaki Disease 309

72 (10%–20%), meningismus with cerebrospinal


fluid pleocytosis (40%), pericardial effusion of
Kawasaki Disease at least 1 mm (<5%), gallbladder hydrops (<10%),
Clinical Manifestations and myocarditis manifested by congestive
heart failure (<5%). A persistent resting tachy-
Kawasaki disease (also called mucocutaneous cardia and the presence of an S3 gallop are
lymph node syndrome) is a self-limited vascu- often appreciated. Fine desquamation in the
litis characterized by fever and mucocutaneous groin area can occur in the acute phase of dis-
signs that is recognized across the globe. If ease (Fink sign). Inflammation or ulceration
untreated, approximately 20% of children will may be observed at the inoculation scar of
develop coronary artery abnormalities, includ- ­previous bacille Calmette-Guérin immuniza-
ing aneurysms. The illness is characterized by tion. Rarely, Kawasaki disease can present
fever and the following clinical features: bilat- with what appears to be “septic shock” with
eral bulbar conjunctival injection with limbic need for intensive care; these children often
sparing and without exudate; erythematous have significant thrombocytopenia at admis-
mouth and pharynx, strawberry tongue, and sion. Group A streptococcal or Staphylococcus
red, cracked lips; a polymorphous, generalized, aureus toxic shock syndrome should be
erythematous rash that can be morbilliform, excluded in such cases.
maculopapular, or scarlatiniform or can
resemble erythema multiforme; changes in The diagnosis of incomplete Kawasaki disease
the peripheral extremities consisting of indura- should be considered in patients with fever for
tion of the hands and feet with erythematous 5 days or longer plus the presence of 2 or more
palms and soles, often with later periungual of the characteristic features with supportive
desquamation; and acute, nonsuppurative, laboratory data (eg, erythrocyte sedimentation
usually unilateral, cervical lymphadenopathy rate ≥40 mm/h; C-reactive protein [CRP] con-
with at least 1 node 1.5 cm in diameter. Kawa- centration ≥3 mg/dL). If patients have purulent
saki disease diagnosis may be delayed in conjunctivitis, exudative pharyngitis, or sple-
patients who come to attention because of nomegaly, they are highly unlikely to have
fever and unilateral cervical lymphadenitis, Kawasaki disease. The proportion of children
which, mistakenly, is thought to be bacterial with Kawasaki disease with incomplete mani-
lymphadenitis; a distinguishing feature in festations is higher among infants younger
Kawasaki disease is that lymphadenitis is than 12 months. Infants with Kawasaki disease
unlikely to be necrotizing or suppurative by have a higher risk of developing coronary
imaging studies. For diagnosis of classic Kawa- artery aneurysms than do older children,
saki disease, patients should have fever for at ­making diagnosis and timely treatment espe-
least 5 days (or fever until the date of treatment cially important in this age group. Laboratory
if given before the fifth day of illness) and at findings in incomplete cases are similar to
least 4 of the 5 previously listed features with- findings in classic cases. Although laboratory
out alternative explanation for the findings. findings in Kawasaki disease are nonspecific,
Presence of a concurrent or preceding viral they may prove useful in increasing or decreas-
upper respiratory infection does not exclude ing the likelihood of incomplete Kawasaki
the diagnosis of Kawasaki disease. The epide- ­disease. Kawasaki disease should also be con-
miologic case definition also allows diagnosis sidered in any infant younger than 6 months
of incomplete Kawasaki disease when a patient with prolonged fever and no other explanation
has fewer than 4 principal clinical criteria in for the fever and in infants with shocklike syn-
the presence of fever and coronary artery drome in whom an inciting infection is not
abnormalities. Irritability, abdominal pain, confirmed. If coronary artery aneurysm, ecta-
diarrhea, and vomiting are common associated sia, or dilation is evident, a presumptive diag-
symptoms. Other findings include urethritis nosis of Kawasaki disease should be made. A
with sterile pyuria (70% of cases), mild anterior normal early echocardiographic study is typi-
uveitis (80%), mild elevation of hepatic trans- cal and does not exclude the diagnosis but
aminase levels (50%), arthritis or arthralgia may be useful in evaluation of patients with

ERRNVPHGLFRVRUJ
310 Kawasaki Disease

suspected incomplete Kawasaki disease. In In children with mild coronary artery dilation
one study, 80% of patients with Kawasaki or ectasia, coronary artery dimensions often
­disease who ultimately developed coronary return to baseline within 6 to 8 weeks after
artery disease had abnormalities on their onset of disease. Approximately 50% of coro-
admission echocardiogram. Most of these nary aneurysms (but only a small proportion
patients were evaluated before day 10 of fever. of giant aneurysms) regress to normal luminal
The American Heart Association algorithm size within 1 to 2 years, although this process
(Image 72.1) summarizes the approach for can be accompanied by development of coro-
diagnosis and treatment of suspected incom- nary stenosis.
plete Kawasaki disease.
The current case-fatality rate for Kawasaki
The average duration of fever in untreated ­disease in the United States and Japan is less
Kawasaki disease is 10 days; however, fever than 0.2%. The principal cause of death is
can last 2 weeks or longer. After fever resolves, ­myocardial infarction resulting from coronary
patients can remain anorectic or irritable with artery occlusion attributable to thrombosis or
decreased energy for 2 to 3 weeks. During this progressive stenosis. Rarely, a large coronary
phase, desquamation of fingers and toes and artery aneurysm may rupture during the acute
fine desquamation of other areas can occur. phase. The relative risk of mortality is highest
Recurrent disease develops in approximately within 6 weeks of onset of acute symptoms of
2% of patients months to years later. Kawasaki disease, but myocardial infarction
and sudden death can occur months to years
Coronary artery abnormalities are serious
after the acute episode. There is no current
sequelae of Kawasaki disease and may occur in
­evidence that the vasculitis of Kawasaki dis-
20% of untreated children. Increased risk of
ease predisposes to premature atherosclerotic
developing coronary artery abnormalities is
coronary artery disease, although this
associated with male gender; age younger than
seems ­plausible.
12 months or older than 8 years; fever for more
than 10 days; high baseline relative neutrophil Etiology
and band count (>80%); white blood cell count The etiology is unknown. Epidemiologic
>15,000/mm3; low hemoglobin concentration and clinical features strongly suggest an infec-
(<10 g/dL); hypoalbuminemia, hyponatremia, tious cause or trigger. Studies also suggest
or thrombocytopenia at presentation; fever genetic susceptibility.
persisting or occurring after intravenous
immunoglobulin (IVIG) administration; and Epidemiology
persistence of elevated CRP concentration for Peak age of occurrence in the United States
more than 30 days or recurrent CRP elevations. is between 18 and 24 months. Fifty percent of
Aneurysms of the coronary arteries have been patients are younger than 2 years, and 80%
demonstrated by echocardiography as early as are younger than 5 years; children older than
4 to 7 days after onset of illness but more typi- 8 years less commonly develop the disease, but
cally occur between 1 and 4 weeks after onset rare cases may occur even in adults. In chil-
of illness; onset later than 6 weeks is extremely dren younger than 6 months, the diagnosis is
uncommon. Giant coronary artery aneurysms often delayed because the symptom complex of
(internal diameter ≥8 mm) are highly predic- Kawasaki disease is incomplete and individual
tive of long-term complications. Aneurysms features can be subtle. The prevalence of coro-
occurring in other medium-sized arteries (eg, nary artery abnormalities is higher when diag-
iliac, femoral, renal, and axillary vessels) are nosis and treatment are delayed beyond the
uncommon and generally do not occur in the 10th day of illness. The male to female ratio
absence of significant coronary abnormalities. is approximately 1.5:1. In the United States,
In addition to coronary artery disease, carditis 4,000 to 5,500 cases are estimated to occur
can involve the pericardium, myocardium, or annually; the incidence is highest in children
endocardium, and mitral or aortic regurgita- of Asian ancestry. More cases, including
tion or both can develop. Carditis generally ­clusters, occur during winter and spring. No
resolves when fever resolves.

ERRNVPHGLFRVRUJ
Kawasaki Disease 311

evidence ­indicates person-to-person or common- portive care. Therapy should be initiated as


source spread, although the incidence is some- soon as the diagnosis is established or strongly
what higher in siblings of children with the suspected. Once the acute phase has subsided,
disease. therapy is directed at prevention of coronary
artery thrombosis. Specific recommendations
Incubation Period
for therapy include single, high-dose IVIG and
Unknown. high-dose aspirin therapy. Despite prompt
treatment with IVIG and aspirin, approxi-
Diagnostic Tests
mately 4% of patients develop coronary artery
No specific diagnostic test is available. The aneurysms if treatment is initiated before the
diagnosis is established by fulfillment of the onset of coronary artery abnormalities. Many
clinical criteria after consideration of other patients have fever in the 24 hours after com-
possible illnesses, such as staphylococcal or pleting the IVIG infusion. Persistent or recru-
streptococcal toxin-mediated disease; drug descent fever present 36 or more hours after
reactions (eg, Stevens-Johnson syndrome); the end of the IVIG infusion is used to define
viral infections, such as measles, adenovirus, IVIG-resistant cases. Up to 15% of Kawasaki
Epstein-Barr virus, parvovirus B19, or entero- patients are resistant to IVIG therapy. In these
virus; rickettsial exanthems; leptospirosis; situations, the diagnosis of Kawasaki disease
­systemic-onset juvenile idiopathic arthritis; should be reevaluated. If Kawasaki disease is
and reactive arthritis. The identification of a still considered to be most likely, retreatment
respiratory virus by molecular testing does not with IVIG and continued high-dose aspirin
­necessarily exclude the diagnosis of Kawasaki therapy is generally given.
disease in infants and children who otherwise
meet diagnostic criteria. Erythrocyte sedimen- Measles- and varicella-containing vaccines
tation rate and platelet count are usually nor- should be deferred for 11 months after receipt
mal within 6 to 8 weeks; CRP concentration of high-dose IVIG for treatment of Kawasaki
returns to normal much sooner. disease because of possible interference with
the immune response. The schedule for admin-
Treatment istration of inactivated childhood vaccines
Management during the acute phase is directed should not be interrupted.
at decreasing inflammation of the myocardium
and coronary artery wall and providing sup-

ERRNVPHGLFRVRUJ
312 Kawasaki Disease

Evaluation of suspected incomplete Kawasaki disease. (1) In the absence of gold standard for diagnosis, this algorithm cannot be evi-
dence based but rather represents the informed opinion of the expert committee. Consultation with an expert should be sought anytime
assistance is needed. (2) Infants ≤6 months old on day ≥7 of fever without other explanation should undergo laboratory testing and, if
evidence of systemic inflammation is found, an echocardiogram, even if the infants have no clinical criteria. (3) Patient characteristics
suggesting Kawasaki disease are provided in text. Characteristics suggesting disease other than Kawasaki disease include exudative
conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, or generalized adenopathy. Consider alternative
diagnoses. (4) Supplemental laboratory criteria include albumin ≤3.0 g/dL, anemia for age, elevation of alanine aminotransferase, plate-
lets after 7 d ≥450 000/mm3, white blood cell count ≥15 000/mm3, and urine ≥10 white blood cells/high-power field. (5) Can treat before
performing echocardiogram. (6) Echocardiogram is considered positive for purposes of this algorithm if any of 3 conditions are met: z
score of LAD or RCA ≥2.5, coronary arteries meet Japanese Ministry of Health criteria for aneurysms, or ≥3 other suggestive features
exist, including perivascular brightness, lack of tapering, decreased LV function, mitral regurgitation, pericardial effusion, or z scores in
LAD or RCA of 2–2.5. (7) If the echocardiogram is positive, treatment should be given to children within 10 d of fever onset and those
beyond day 10 with clinical and laboratory signs (CRP, ESR) of ongoing inflammation. (8) Typical peeling begins under nail bed of fingers
and then toes.
Reprinted from Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a
statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovas-
cular Disease in the Young, American Heart Association. Pediatrics. 2004;114(6):1708–1733.

Image 72.1
Evaluation of suspected incomplete Kawasaki disease.

ERRNVPHGLFRVRUJ
Kawasaki Disease 313

Image 72.2 Image 72.3


A child with Kawasaki disease with striking facial A child with Kawasaki disease with conjunctivitis.
rash and erythema of the oral mucous membrane. Note the absence of conjunctival discharge.

Image 72.4
Image 72.5
Characteristic distribution of erythroderma of
Generalized erythema and early perianal and
Kawasaki disease. The rash is accentuated in
palmar desquamation. This is the same patient
the perineal area in approximately two-thirds
as in Image 72.4.
of patients.

Image 72.6
Characteristic desquamation of the skin over the abdomen in a patient with Kawasaki disease. This is
the same patient as in images 72.4 and 72.5.

ERRNVPHGLFRVRUJ
314 Kawasaki Disease

Image 72.8
Image 72.7
Periungual desquamation of a patient with Characteristic cutaneous and mucous membrane
Kawasaki disease. This is the same patient as changes of Kawasaki disease. Courtesy of Neal
in images 72.4, 72.5, and 72.6. Halsey, MD.

Image 72.10
Bulbar conjunctivitis in a patient with Kawasaki
disease. Exudation is generally absent.

Image 72.9
Distal desquamation of Kawasaki disease.
Courtesy of Neal Halsey, MD.

Image 72.11
Erythematous lips and injection of the oropharyngeal membranes in a patient with Kawasaki disease.
Scarlet fever, toxic shock syndrome, staphylococcal scalded skin syndrome, and measles may be
confused with this disease.

ERRNVPHGLFRVRUJ
Kawasaki Disease 315

Image 72.12
A child with the characteristic desquamation of
the hands in a later stage of Kawasaki disease. Image 72.13
Copyright Charles Prober. Desquamation of the skin of the distal fingers
following Kawasaki disease in a 4-year-old boy.
Copyright Michael Rajnik, MD, FAAP.

Image 72.14
Desquamation of the skin of the toes following
Kawasaki disease. This is the same patient
as in Image 72.13. Copyright Michael Rajnik,
MD, FAAP.

Image 72.15
This white 1-year-old presented with fever,
generalized erythroderma, and conjunctivitis
compatible with Kawasaki disease. Courtesy of
George Nankervis, MD.

Image 72.16
Erythroderma of the palm of the hand of the child
in Image 72.15 with Kawasaki disease. Courtesy
of George Nankervis, MD.

ERRNVPHGLFRVRUJ
316 Kawasaki Disease

Image 72.17
Erythroderma of the plantar foot surface of the child in images 72.15 and 72.16 with Kawasaki disease.
Courtesy of George Nankervis, MD.

Image 72.18
A 7-year-old white girl with Kawasaki disease. Right arm. Courtesy of Larry Frenkel, MD.

ERRNVPHGLFRVRUJ
KINGELLA KINGAE INFECTIONS 317

73 Epidemiology

Kingella kingae Infections The usual habitat of K kingae is the posterior


pharynx. The organism more frequently colo-
Clinical Manifestations nizes young children than adults and can be
The most common infections attributable to transmitted among children in child care cen-
Kingella kingae are pyogenic arthritis, osteo- ters, occasionally causing clusters of cases.
myelitis, and bacteremia. The vast majority of Infection may be associated with preceding or
K kingae infections affect children, predomi- concomitant stomatitis or upper respiratory
nantly between 6 and 48 months of age, with tract infection.
most cases occurring in those younger than Incubation Period
2 years. K kingae is the most common cause
of skeletal infections in children younger than Variable.
3 years in some geographic locations. K kingae Diagnostic Tests
pyogenic arthritis is generally monoarticular
K kingae can be isolated from blood, synovial
and most commonly involves the knee, hip,
fluid, bone, cerebrospinal fluid, respiratory
or ankle. K kingae osteomyelitis most often
tract secretions, and other sites of infection.
involves the femur or tibia and also has an
Organisms grow better in aerobic conditions
unusual predilection for small bones, including
with supplemental carbon dioxide. In patients
the small bones of the foot. The clinical mani-
with K kingae pyogenic arthritis or osteomye­
festations of K kingae pyogenic arthritis and
litis, blood cultures are often negative. K kingae
osteomyelitis are similar to manifestations of
is difficult to isolate on routine solid media,
skeletal infection due to other bacterial patho-
and synovial fluid and bone aspirates from
gens in immunocompetent children, although
patients with suspected K kingae infection
a subacute course may be more common. A
should be inoculated into Bactec, BacT/Alert,
Brodie abscess of bone attributable to K kingae
or similar blood culture systems and held for
is uncommon. Bacteremia can occur in previ-
at least 7 days to maximize recovery. Conven-
ously healthy children and in children with
tional and real-time polymerase chain reaction
preexisting chronic medical problems. Chil-
methods have improved detection of K kingae.
dren with K kingae bacteremia present with
fever and frequently have concurrent findings Treatment
of respiratory or gastrointestinal tract disease.
K kingae is almost always highly susceptible
Other infections caused by K kingae include
to penicillins and cephalosporins, although
diskitis, endocarditis (K kingae belongs to the
β-lactamase production has been reported
HACEK group of organisms), meningitis,
in rare isolates. Nearly all isolates are also
and pneumonia.
­susceptible to aminoglycosides, macrolides,
Etiology ­trimethoprim-sulfamethoxazole, tetracyclines,
and fluoroquinolones. Virtually all isolates
K kingae is a gram-negative organism that
are resistant to glycopeptide antibiotics
belongs to the Neisseriaceae family. It is a
(­vancomycin and teicoplanin). Most cases of
­fastidious, facultative anaerobic, β-hemolytic
K kingae infection are treated with penicillin
small bacillus that appears as pairs or short
or ­a mpicillin-sulbactam or a second- or third-
chains with tapered ends and often resists
generation cephalosporin.
decolorization, sometimes resulting in mis-
identification as a gram-positive organism.

ERRNVPHGLFRVRUJ
318 KINGELLA KINGAE INFECTIONS

Image 73.1
Kingella kingae on blood agar. Smooth, gray colonies may pit the agar and are surrounded by a small
but distinct zone of β-hemolysis on blood agar. Courtesy of Julia Rosebush, DO; Robert Jerris, PhD;
and Theresa Stanley, M(ASCP).

Image 73.2
Kingella kingae on chocolate agar. Colonies appear after 2 to 4 days of incubation on blood and
chocolate agar. This species demonstrates β-hemolysis on blood agar. Courtesy of Julia Rosebush,
DO; Robert Jerris, PhD; and Theresa Stanley, M(ASCP).

ERRNVPHGLFRVRUJ
LEGIONELLA PNEUMOPHILA INFECTIONS 319

74 and are often related to contamination of the


hot water supply. In patients who develop
Legionella pneumophila pneumonia during or after their hospitaliza-
Infections tion, legionnaires’ disease should be considered
in the differential diagnosis. Legionnaires’ dis-
Clinical Manifestations ease occurs most commonly in people who are
Legionellosis is associated with 2 clinically elderly, are immunocompromised, or have
and epidemiologically distinct illnesses: underlying lung disease. Infection in children
­legionnaires’ disease and Pontiac fever. is rare and is usually asymptomatic or mild
Legionnaires’ disease varies in severity from and unrecognized. Severe disease has occurred
mild to severe pneumonia characterized by in children with malignant neoplasms, severe
fever, cough, and progressive respiratory dis- combined immunodeficiency, chronic granu­
tress. Legionnaires’ disease can be associated lomatous disease, organ transplantation, end-
with chills, myalgia, and gastrointestinal tract, stage renal disease, underlying pulmonary
­central nervous ­system, and renal manifesta- disease, and immunosuppression; in children
tions. Respiratory failure and death can occur. receiving systemic corticosteroids; and as a
Pontiac fever is a milder febrile illness without health care–associated infection in newborns.
pneumonia that occurs in epidemics and is
Incubation Period
characterized by an abrupt onset and a self-
limited, ­influenza-like illness. For legionnaires’ disease, 2 to 10 days; for
­Pontiac fever, 1 to 2 days.
Etiology
Diagnostic Tests
Legionella species are fastidious aerobic bacilli
that stain gram negative after recovery on Recovery of Legionella from respiratory tract
­buffered charcoal yeast extract media. At least secretions, lung tissue, pleural fluid, or other
20 different species have been implicated in normally sterile fluid specimens using buffered
human disease, but the most common species charcoal yeast extract media provides defini-
causing infections in the United States is tive evidence of infection, but the sensitivity
­Legionella pneumophila, with most isolates of culture is laboratory dependent. When a
belonging to serogroup 1. Multiplication of patient is suspected of having legionnaires’
Legionella organisms in water sources occurs disease, culture of a respiratory specimen
optimally in temperatures between 25ºC and should be conducted in addition to urine anti-
45ºC (77ºF and 113ºF). gen testing. Detection of Legionella antigen in
urine by commercially available immunoassays
Epidemiology is highly specific. Such tests are sensitive for
Legionnaires’ disease is acquired through L pneumophila serogroup 1. The bacterium
inhalation of aerosolized water contaminated can be demonstrated in specimens by direct
with L pneumophila. Person-to-person trans- immunofluorescent assay, but this test is less
mission has not been demonstrated. More sensitive and the specificity is technician
than 80% of cases are sporadic; the sources dependent and lower than culture or urine
of infection can be related to exposure to immunoassay. Genus-specific polymerase
L pneumophila–contaminated water in the chain reaction–based assays have been devel-
home, workplace, or hospitals or other medical oped that detect Legionella DNA in respiratory
facilities or to aerosol-producing devices in secretions as well as in blood and urine of some
public places. Outbreaks have been ascribed to patients with pneumonia. For serologic diag-
common-source exposure to contaminated nosis, a 4-fold increase in titer of antibodies to
cooling ­towers, evaporative condensers, pota- L pneumophila serogroup 1, measured by indi-
ble water systems, whirlpool spas, humidifiers, rect immunofluorescent antibody assay, con-
and respiratory therapy equipment. Outbreaks firms a recent infection. Convalescent serum
have occurred in hospitals, hotels, and other samples should be obtained 3 to 4 weeks after
large buildings, as well as on cruise ships. onset of symptoms; however, a titer increase
Health care–associated infections can occur can be delayed for 8 to 12 weeks. The positive

ERRNVPHGLFRVRUJ
320 LEGIONELLA PNEUMOPHILA INFECTIONS

predictive value of a single titer of 1:256 or another fluoroquinolone) is the drug of choice
greater is low and does not provide definitive for immunocompromised adults. Doxycycline
evidence of infection. Antibodies to several and trimethoprim-sulfamethoxazole are alter-
gram-negative organisms, including Pseudo­ native drugs. Duration of therapy is 5 to 10 days
monas species, Bacteroides fragilis, and for azithromycin and 14 to 21 days for other
­Campylobacter jejuni, can cause false-positive drugs. Longer courses of therapy are recom-
immunofluorescent antibody test results. mended for patients who are immunocompro-
mised or who have severe disease.
Treatment
Azithromycin is the drug of choice. Once
the condition of a patient is improving, oral
therapy can be substituted. Levofloxacin (or

Image 74.1
This Gram-stained micrograph reveals chains
and solitary gram-negative Legionella pneumo­
phila bacteria found within a sample taken from
a victim of the 1976 legionnaires’ disease out­
break in Philadelphia, PA. Legionnaires’ disease
is the more severe form of legionellosis and is Image 74.2
characterized by pneumonia, commencing 2 to Charcoal-yeast extract agar plate culture of
10 days after exposure. Pontiac fever is an acute- Legionella pneumophila. Courtesy of Centers
onset, flu-like, nonpneumonic illness, occurring for Disease Control and Prevention/Dr Jim Feeley.
within 1 to 2 days of exposure. Courtesy of
Centers for Disease Control and Prevention.

Image 74.4
Transmission electron micrograph of Legionella
pneumophila. Courtesy of Centers for Disease
Control and Prevention/Dr Francis Chandler.
Image 74.3
Legionella pneumophila multiplying inside a
cultured human lung fibroblast. Courtesy of
Centers for Disease Control and Prevention/
Dr Edwin P. Ewing Jr.

ERRNVPHGLFRVRUJ
LEGIONELLA PNEUMOPHILA INFECTIONS 321

Image 74.5
Legionellosis. Incidence, by year—United States, 1997–2012. Courtesy of Morbidity and Mortality
Weekly Report.

Image 74.6
An adult with pneumonia due to Legionella pneumophila. Legionella infections are rare in otherwise
healthy children. Although nosocomial infections and hospital outbreaks are reported, this infection
is not transmitted from person to person.

ERRNVPHGLFRVRUJ
322 LEGIONELLA PNEUMOPHILA INFECTIONS

Image 74.7
Imaging studies of a 42-year-old man with severe pneumonia caused by Legionella pneumophila
serogroup 11, showing lobar consolidation of the left lower lung lobe, with an air-bronchogram
within the homogeneous airspace consolidation. Consensual mild pleural effusion was documented
by a chest radiograph (A) and high-resolution computed tomography (B). A week after hospital
admission, repeat high-resolution computed tomography of the chest showed extensive and
homogeneous consolidation of left upper and lower lobes, accompanied by bilateral ground-glass
opacities (C and D). Courtesy of Emerging Infectious Diseases.

Image 74.8
This hematoxylin-eosin–stained micrograph of lung tissue biopsied from a patient with legionnaires’
diseases revealed the presence of an intra-alveolar exudate consisting of macrophages and poly­
morphonuclear leucocytes. The Legionella pneumophila bacteria are not stained in this preparation
(magnification x500). Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Leishmaniasis 323

75 bone marrow). The stereotypical clinical


manifestations include fever, weight loss,
Leishmaniasis pancytopenia, hypoalbuminemia, and
Clinical Manifestations hypergammaglobulinemia. Peripheral
lymphadenopathy is quite common in East
The 3 main clinical syndromes are as follows: Africa (eg, South Sudan). Some patients
• Cutaneous leishmaniasis. After inoculation in South Asia (the Indian subcontinent)
by the bite of an infected female ­Phlebotomus develop grayish discoloration of their skin;
species sand fly (approximately 2–3 mm this manifestation gave rise to the Hindi
long), parasites proliferate locally in mono- term kala-azar (“black sickness”). Untreated,
nuclear phagocytes, leading to an erythema- advanced cases of visceral leishmaniasis are
tous papule, which, typically, slowly enlarges almost always fatal, directly from the disease
to become a nodule and then an ulcerative or from complications such as secondary
lesion with raised, indurated borders. Ulcer- bacterial infections or hemorrhage. At the
ative lesions can become dry and crusted or other end of the spectrum, visceral infection
can develop a moist granulating base with can be asymptomatic or oligosymptomatic.
an overlying exudate. Lesions can, however, Latent visceral infection can activate years
persist as nodules or papules and can be to decades postexposure in people who
­single or multiple. Lesions are commonly become immunocompromised (eg, because
on exposed areas of the body (eg, face, of coinfection with HIV; posttransplantation
extremities) and may be accompanied by immunosuppression) or who receive immu-
satellite lesions, sporotrichoid-like nodules, nomodulatory therapy (eg, with an antitu-
and regional adenopathy. Clinical mani­ mor necrosis factor-α agent) because of
festations of Old World and New World other medical conditions.
(­American) cutaneous leishmaniasis are Etiology
similar. Spontaneous resolution of lesions
can take weeks to years—depending, in In the human host, Leishmania species are
part, on the Leishmania species/strain— obligate intracellular parasites of mononuclear
and usually results in a flat, atrophic scar. phagocytes. To date, approximately 20
­Leishmania species (in the Leishmania and
• Mucosal leishmaniasis (espundia) tradi- Viannia subgenera) are known to infect
tionally refers to a metastatic sequela of New humans. Cutaneous leishmaniasis is typically
World cutaneous infection, which results caused by Old World species Leishmania
from dissemination of the parasite from the ­tropica, Leishmania major, and Leishmania
skin to the naso-oropharyngeal mucosa; this aethiopica and by New World species Leish­
form of leishmaniasis is typically caused by mania mexicana, Leishmania amazonensis,
species in the Viannia subgenus. Mucosal Leishmania (Viannia) braziliensis, Leishmania
disease usually becomes evident months to (V) panamensis, Leishmania (V) guyanensis,
years after original cutaneous lesions heal; and Leishmania (V) peruviana. Mucosal leish-
however, mucosal and cutaneous lesions can maniasis is typically caused by species in the
be noted simultaneously, as some affected Viannia subgenus (especially L [V] braziliensis
people have subclinical cutaneous infection. but also L [V] panamensis and, sometimes,
Granulomatous inflammation may cause L [V] guyanensis). Most cases of visceral leish-
hypertrophy of the nose and lips. Untreated maniasis are caused by Leishmania donovani
mucosal leishmaniasis can progress to cause or Leishmania infantum (Leishmania chagasi
ulcerative destruction (eg, perforation of the is synonymous). L donovani and L infantum
nasal septum) and facial disfigurement. can also cause cutaneous leishmaniasis; how-
• Visceral leishmaniasis (kala-azar). After ever, people with typical cutaneous leishmani-
cutaneous inoculation by an infected sand asis caused by these organisms rarely develop
fly, the parasite spreads throughout the visceral leishmaniasis.
­reticuloendothelial system (eg, spleen, liver,

ERRNVPHGLFRVRUJ
324 Leishmaniasis

Epidemiology Diagnostic Tests


In most settings, leishmaniasis is a zoonosis, Definitive diagnosis is made by detecting the
with mammalian reservoir hosts, such as parasite in infected tissue by light-microscopic
rodents or dogs. However, some transmission examination of stained slides (eg, of aspirates,
cycles are anthroponotic; infected humans touch preparations, histologic sections), by
are the primary or only reservoir hosts of in vitro culture, or by molecular methods. In
L ­donovani in South Asia (potentially also cutaneous and mucosal disease, tissue can
in East Africa) and of L tropica. Congenital be obtained by a 3-mm punch biopsy, lesion
and parenteral transmission have also scrapings, or needle aspiration of the raised
been reported. nonnecrotic edge of the lesion. In visceral
leishmaniasis, although the sensitivity is
Overall, leishmaniasis is endemic in more
­highest for splenic aspiration (approximately
than 90 countries in the tropics, subtropics,
95%), the procedure can be associated with
and southern Europe. Visceral leishmaniasis
life-threatening hemorrhage; bone marrow
(an estimated 0.2–0.4 million new cases annu-
aspiration is safer. Other potential sources of
ally) is found in focal areas of more than
specimens include liver, lymph node, and, in
60 countries: in the Old World, in parts of
some patients (eg, those coinfected with HIV),
Asia (particularly South, Southwest, and
whole blood or buffy coat. Identification of the
­Central Asia), Africa (particularly East Africa),
Leishmania species may affect prognosis and
the Middle East, and southern Europe; in the
influence treatment decisions. The Centers
New World, particularly in Brazil, with scat-
for Disease Control and Prevention (CDC)
tered foci elsewhere. Most (>90%) of the
(www.cdc.gov/parasites/leishmaniasis) can
world’s cases of visceral leishmaniasis occur in
assist in all aspects of diagnostic testing. Sero-
South Asia (India, Bangladesh, and Nepal),
logic testing is not usually helpful in cases of
East Africa (Sudan, South Sudan, and Ethio-
cutaneous leishmaniasis but can provide sup-
pia), and Brazil. Cutaneous leishmaniasis is
portive evidence for the diagnosis of visceral
more common (an estimated total of 0.7–1.2
or mucosal leishmaniasis, particularly if the
million new cases annually) and more wide-
patient is immunocompetent.
spread than visceral leishmaniasis. Cutaneous
leishmaniasis is found in focal areas of more Treatment
than 90 countries: in the Old World, in parts of Systemic antileishmanial treatment is always
the Middle East, Asia (particularly Southwest indicated for patients with visceral or mucosal
and Central Asia), Africa (particularly North leishmaniasis, but not all patients with cuta­
and East Africa, with some cases elsewhere), neous leishmaniasis need to be treated. Con-
and southern Europe; in the New World, in sultation with infectious disease or tropical
parts of Mexico, Central America, and South medicine specialists or with staff of the CDC
America (not in Chile or Uruguay). Occasional Division of Parasitic Diseases and Malaria is
cases of cutaneous leishmaniasis have been recommended (telephone: 404/718-4745; e-mail:
acquired in Texas and Oklahoma. The geo- parasites@cdc.gov; CDC Emergency Opera-
graphic distribution of leishmaniasis cases tions Center [after business hours and on
identified in the United States reflects immi- ­weekends]: 770/488-7100). The relative merits
gration and travel patterns (eg, the locations of various treatment approaches or regimens
of popular tourist destinations in Latin for an individual patient should be considered,
­America and of various military activities). taking into account that the therapeutic
Incubation Period response may vary not only for different
­Leishmania species but also for the same
Ranges from weeks to years. In cutaneous
­species in different geographic regions. In
leishmaniasis, skin lesions typically appear
­addition, special considerations apply in the
within several weeks; in visceral, from 2 to
United States for the availability of particular
6 months.

ERRNVPHGLFRVRUJ
Leishmaniasis 325

medications. For example, the pentavalent of visceral ­leishmaniasis. The oral agent,


antimonial compound sodium stibogluconate ­ iltefosine, is approved for treatment of
m
is not commercially available but can be ­cutaneous and mucosal as well as visceral
obtained through the CDC Drug Service leishmaniasis but is limited to infection caused
(404/639-3670), under an investigational new by particular Leishmania species and for
drug protocol. Liposomal amphotericin B, patients 12 years and older who are not preg-
which is administered by intravenous nant or ­breastfeeding.
­infusion, is recommended for treatment

Image 75.1
Leishmania tropica amastigotes from a skin touch preparation. A, Still intact macrophage is practically
filled with amastigotes, several of which have a clearly visible nucleus and a kinetoplast (arrows). B,
Amastigotes are being freed from a rupturing macrophage. The patient has a history of travel to Egypt,
Africa, and the Middle East. Culture in Novy-MacNeal-Nicolle medium followed by isoenzyme analysis
identified the species as L tropica minor. Courtesy of Centers for Disease Control and Prevention.

Image 75.2
Leishmania donovani in bone marrow cell. Smear. Courtesy of Centers for Disease Control and
Prevention/L. L. Moore Jr, MD.

ERRNVPHGLFRVRUJ
326 Leishmaniasis

Image 75.3
This image depicts a mounted male Phlebotomus species fly, which, due to its resemblance, may be
mistaken for a mosquito. Phlebotomus species sand flies are bloodsucking insects that are very small
and sometimes act as the vectors for various diseases, such as leishmaniasis and bartonellosis (also
known as Carrión disease). Courtesy of Centers for Disease Control and Prevention/Donated by the
World Health Organization.

Image 75.4
Leishmaniasis is transmitted by the bite of female Phlebotomus species sand flies. The sand flies inject
the infective stage, promastigotes, during blood meals (1). Promastigotes that reach the puncture
wound are phagocytized by macrophages (2) and transform into amastigotes (3). Amastigotes multiply
in infected cells and affect different tissues, depending, in part, on the Leishmania species (4). This
originates the clinical manifestations of leishmaniasis. Sand flies become infected during blood meals
on an infected host when they ingest macrophages infected with amastigotes (5, 6). In the sand fly’s
midgut, the parasites differentiate into promastigotes (7), which multiply and migrate to the proboscis
(8). Courtesy of Centers for Disease Control and Prevention/Alexander J. da Silva, PhD/Blaine Mathison.

ERRNVPHGLFRVRUJ
Leishmaniasis 327

Image 75.5
Homes built in newly cleared forest areas (here, outside Rio de Janeiro) expose settlers to the sand
flies that transmit leishmaniasis. Courtesy of World Health Organization.

Image 75.6
A shantytown, another environment where Leishmania infection proliferates due to inadequate housing
and lack of sanitation. Courtesy of World Health Organization.

Image 75.7
Natural uncut forests are transmission sites for leishmaniasis. People who collect rubber or clear such
areas for agriculture are prone to infection. Courtesy of World Health Organization/TDR/Lainson/
Wellcome Trust.

ERRNVPHGLFRVRUJ
328 Leishmaniasis

Image 75.8
Cutaneous leishmaniasis, as in this boy from
Image 75.9
India, seldom disseminates in immunocompetent
persons. Multiple organisms can usually be found Cutaneous leishmaniasis. Infected sand fly inocu­
on biopsy of the border of a lesion. lation site with satellite lesions. The organism may
be demonstrated by punch biopsy of the margin
of a cutaneous lesion. This is the same child as in
Image 75.9.

Image 75.10
Skin ulcer due to leishmaniasis, hand of Central
American adult. Courtesy of Centers for Disease
Control and Prevention/Dr D.S. Martin. Image 75.11
Crater lesion of leishmaniasis, skin. Courtesy of
Centers for Disease Control and Prevention.

Image 75.12
Two young boys suffering visceral leishmaniasis, with distended abdomens due to hepatosple­no­
megaly. Courtesy of World Health Organization/TDR/Lainson/Wellcome Trust.

ERRNVPHGLFRVRUJ
Leishmaniasis 329

Image 75.13
A young girl with cutaneous leishmaniasis. Courtesy of World Health Organization.

Image 75.14
A young girl with cutaneous leishmaniasis with multiple cutaneous lesions. Courtesy of World
Health Organization.

ERRNVPHGLFRVRUJ
330 Leprosy

76 ing few bacilli. Lepromatous spectrum cases


have high antibody responses with little cell-
Leprosy mediated immunity to M leprae and several
Clinical Manifestations somewhat-diffuse lesions usually containing
numerous bacilli.
Leprosy (Hansen disease) is a curable infection
involving skin, peripheral nerves, mucosa of Serious consequences of leprosy occur from
the upper respiratory tract, and testes. The immune reactions and nerve involvement
clinical forms of leprosy reflect the cellular with resulting anesthesia, which can lead to
immune response to Mycobacterium leprae repeated unrecognized trauma, ulcerations,
and, in turn, the number, size, structure, and fractures, and even bone resorption. Injuries
bacillary content of the lesions. The organism can have a significant effect on life quality.
has unique tropism for peripheral nerves, and ­Leprosy is a leading cause of permanent physi-
all forms of leprosy exhibit nerve involvement. cal disability among communicable diseases
Leprosy lesions usually do not itch or hurt. worldwide. Eye involvement can occur, and
They lack sensation to heat, touch, and pain but patients should be examined by an ophthal-
otherwise may be difficult to distinguish from mologist. A diagnosis of leprosy should be
other common maladies. There can be madaro- ­considered in any patient with hypoesthetic or
sis (loss of eyelashes or eyebrows) and ocular anesthetic skin rash or skin patches, especially
problems. However, the stereotypical presenta- those that do not respond to ordinary thera-
tions of leonine facies with nasal deformity or pies, and among those with a history of resi-
clawed hands with loss of digits are manifesta- dence in areas with endemic leprosy or contact
tions of late-stage untreated disease that are with armadillos.
seldom seen today. Although the nerve injury
• Leprosy reactions. Acute clinical exacerba-
caused by leprosy is irreversible, early diagno-
tions reflect abrupt changes in the immuno-
sis and drug therapy can prevent sequelae.
logic balance. They are especially common
Leprosy manifests over a broad clinical and during initial years of treatment but can
histopathologic spectrum. In the United States, occur in the absence of therapy. Two major
the Ridley-Jopling scale is used to classify types of leprosy reactions (LRs) are seen:
patients according to the histopathologic type 1 (reversal reaction, LR-1) is predomi-
­features of their lesions and organization of nantly observed in borderline tuberculoid
the underlying granuloma. The scale includes and borderline lepromatous leprosy and is
tuberculoid, borderline tuberculoid, border- the result of a sudden increase in effective
line, borderline lepromatous, and lepromatous. cell-mediated immunity. Acute tenderness
A simplified scheme introduced by the World and swelling at the site of cutaneous and
Health Organization for circumstances in neural lesions with development of new
which pathologic examination and diagnosis lesions are major manifestations. Ulcer-
are unavailable is based purely on clinical skin ations can occur, but polymorphonuclear
examination. Under this scheme, leprosy is leukocytes are absent from the LR-1 lesion.
classified by the number of skin patches seen Fever and systemic toxicity are uncommon.
on skin examination, classifying disease as Type 2 (erythema nodosum leprosum, LR-2)
paucibacillary (1–5 lesions, usually tuberculoid occurs in borderline and lepromatous forms
or borderline tuberculoid) or multibacillary as a systemic inflammatory response. Ten-
(>5 lesions, usually borderline, borderline der, red dermal papules or nodules resem-
­lepromatous, or lepromatous). Patients in the bling erythema nodosum, along with high
tuberculoid spectrum have active cell-mediated fever, migrating polyarthralgia, painful
immunity with low antibody responses to swelling of lymph nodes and spleen, irido­
M leprae and few well-defined lesions contain- cyclitis, and, rarely, nephritis, can occur.

ERRNVPHGLFRVRUJ
Leprosy 331

Etiology Other areas of high endemicity include Angola,


Leprosy is caused by M leprae, an obligate Brazil, Central African Republic, Democratic
intracellular bacterium that can have variable Republic of Congo, Madagascar, Mozambique,
staining by Gram stain. It is best visualized the Republic of the Marshall Islands, South
using the Fite method. M leprae is the only Sudan, the Federated States of Micronesia,
­bacterium known to infect peripheral nerves. and the United Republic of Tanzania.

Epidemiology Incubation Period

Leprosy is considered a neglected tropical Usually 3 to 5 years (range, 1–20 years).


­disease and is most prevalent in tropical and Diagnostic Tests
subtropical zones. It is not highly infectious.
Histopathologic examination of skin biopsy by
Fewer than 5% of people appear to be geneti-
an experienced pathologist is the best method
cally susceptible to the infection. Accordingly,
of establishing the diagnosis and is the basis
spouses of leprosy patients are not likely to
for classification of leprosy. These specimens
develop leprosy, but biological parents, chil-
can be sent to the National Hansen’s Disease
dren, and siblings who are household contacts
(Leprosy) Program (NHDP) [800/642-2477;
of untreated patients with leprosy are at
www.hrsa.gov/hansensdisease] in formalin or
increased risk.
embedded in paraffin. Acid-fast bacilli may be
Transmission is thought to be through long- found in slit smears or biopsy specimens of
term close contact with an infected individual, skin lesions of patients with lepromatous forms
and it likely occurs through respiratory shed- but are rarely visualized from patients with
ding of infectious droplets by untreated cases tuberculoid and indeterminate forms of dis-
or individuals incubating subclinical infections. ease. A polymerase chain reaction assay for
The 9-banded armadillo (Dasypus novemcinc­ M leprae is available to assist diagnosis after
tus) and 6-banded armadillo (Euphractus consultation with the NHDP and can be per-
­sexcinctus) are the only known nonhuman formed on the basis of clinical suspicion.
­reservoirs of M leprae; zoonotic transmission
Treatment
is reported in the southern United States.
Like many other chronic infectious diseases, Leprosy is curable. The primary goal of therapy
onset of leprosy is increasingly associated is prevention of permanent nerve damage,
with use of anti-inflammatory ­autoimmune which can be accomplished by early diagnosis
therapies and immunologic senescence among and treatment. Combination antimicrobial
elderly patients. multidrug therapy can be obtained free of
charge from the NHDP in the United States
There are approximately 6,500 people with and from the World Health Organization
­leprosy living in the United States, with 3,300 in other countries. Certain criteria must be
under active medical management. During met for physicians wishing to obtain the
1994–2011, there were 2,323 new cases of lep- ­antimicrobial therapy from the NHDP
rosy. Over this period, a decline in the rate of (www.hrsa.gov/hansensdisease/diagnosis/
new diagnoses from 0.52 (1994–1996) to 0.43 recommendedtreatment.html).
(2009–2011) per million was observed. The
rate among foreign-born people decreased It is important to treat M leprae infections
from 3.66 to 2.29, whereas the rate among US- with more than 1 antimicrobial agent to
born people was 0.16 in both 1994–1996 and ­minimize development of antimicrobial-­
2009–2011. The majority of leprosy cases resistant organisms. Adults are treated with
reported in the United States occurred among dapsone, rifampin, and clofazimine. Resistance
residents of Texas, California, and Hawaii to all 3 drugs has been documented but is
or among immigrants or those who lived or rare. The infectivity of leprosy patients ceases
worked in leprosy-endemic countries. More within a few days of initiating standard multi-
than 65% of the world’s leprosy patients reside drug ­t herapy.
in South and Southeast Asia— primarily India.

ERRNVPHGLFRVRUJ
332 Leprosy

• Multibacillary leprosy (6 patches or more). Leprosy reactions should be treated aggres-


Dapsone and rifampin and clofazimine sively to prevent peripheral nerve damage.
for 24 months are recommended. Clarithro- Treatment with prednisone can be initiated.
mycin can be used in place of clofazimine All patients with leprosy should be educated
for children. Clofazimine is not available about signs and symptoms of neuritis and cau-
commercially; in the United States, it is tioned to report signs and symptoms of neuri-
available only as an investigational drug tis immediately so corticosteroid therapy can
for treatment of leprosy and is obtained be instituted. Patients should receive counsel-
through the NHDP. ing because of the social and psychological
effects of this disease.
• Paucibacillary leprosy (1–5 patches).
­Dapsone and rifampin for 12 months are Relapse of disease after completing multidrug
recommended. Before beginning anti­ therapy is rare (0.01%–0.14%); the presentation
microbial therapy, patients should be tested of new skin patches is usually attributable to a
for glucose-6-phosphate dehydrogenase late type 1 reaction. When it does occur, relapse
­deficiency, have baseline complete blood is usually attributable to reactivation of drug-
cell counts and liver function test results susceptible organisms. People with relapses of
documented, and be evaluated for any evi- disease require another course of multidrug
dence of tuberculosis infection, especially therapy. Therapy for patients with leprosy
if the patient is infected with HIV. Skin should be undertaken in consultation with
darkening typically resolves within several an expert in leprosy.
months of completing therapy.

Image 76.2
Hansen disease. A young Vietnamese boy
who spent 2 years in a refugee camp in the
Philippines presented with the nodular violaceous
skin lesion shown. The results of a biopsy of the
Image 76.1 lesion showed acid-fast organisms surrounding
A photomicrograph of Mycobacterium leprae blood vessels. A diagnosis of lepromatous
taken from a leprous skin lesion. M leprae is the leprosy was made and the child was treated
cause of leprosy, or Hansen disease. A slow- with a multidrug regimen. Copyright Barbara
multiplying bacterium, it mainly affects the skin, Jantausch, MD, FAAP.
nerves, and mucous membranes. In 1999,
the world incidence level was estimated to be
640,000; in 2000, 738,284 cases were identified.
In 2007, 101 new cases of leprosy were reported
in the United States. Courtesy of Centers for
Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Leprosy 333

Image 76.3
Erythema nodosum leprosum in a 29-year-old Asian man. Copyright Gary Williams.

Image 76.4
Erythema nodosum leprosum in the same patient
Image 76.5
as in Image 76.3. Copyright Gary Williams.
Erythema nodosum leprosum in the same
patient as in images 76.3 and 76.4. Copyright
Gary Williams.

Image 76.6
Lepromatous leprosy in an Asian man. Newly diagnosed cases are considered contagious until
treatment is established and should be reported to local and state public health departments.
Courtesy of Hugh Moffet, MD.

ERRNVPHGLFRVRUJ
334 Leprosy

Image 76.7
An adult male with lepromatous leprosy. Courtesy of Hugh Moffet, MD.

Image 76.8
Number of reported cases, by year—United States, 1992–2012. Courtesy of Morbidity and Mortality
Weekly Report.

ERRNVPHGLFRVRUJ
Leptospirosis 335

77 Epidemiology

Leptospirosis Leptospirosis is among the most globally


important zoonoses, affecting people in
Clinical Manifestations resource-rich and resource-limited countries
Leptospirosis is an acute febrile disease with in urban and rural contexts. It has been esti-
varied manifestations. The severity of disease mated that approximately 868,000 people
ranges from asymptomatic or subclinical to annually worldwide are currently infected
self-limited systemic illness (approximately (range, 327,000–1,520,000), with approximately
90% of patients) to life-threatening illness with 49,200 (range, 19,000–88,900) deaths occur-
jaundice, renal failure (oliguric or nonoliguric), ring each year. The reservoirs for Leptospira
myocarditis, hemorrhage (particularly pul­ species include a range of wild and domestic
monary), and refractory shock. Clinical pre- animals, primarily rats, dogs, and livestock
sentation may be monophasic or biphasic. (eg, cattle, pigs), that can shed organisms
Classically described biphasic leptospirosis asymptomatically for years. Leptospira organ-
has an acute septicemia phase, usually lasting isms excreted in animal urine can remain via-
1 week, when Leptospira organisms are present ble in moist soil or water for weeks to months
in blood, followed by a second immune-­ in warm climates. Humans usually become
mediated phase that does not respond to anti- infected via entry of leptospires through con-
biotic therapy. Regardless of its severity, the tact of mucosal surfaces (especially conjunc­
acute phase is characterized by nonspecific tivae) or abraded skin with contaminated
symptoms, including fever, chills, headache, environmental sources. Unusually, infection
nausea, and vomiting, occasionally accompa- may be acquired through direct contact with
nied by rash or conjunctival suffusion. Distinct infected animals or their tissues, infective
clinical findings include notable conjunctival urine or fluids from carrier animals, or urine-
suffusion without purulent discharge (30%– contaminated soil or water. Epidemic exposure
99% of cases) and myalgia of the calf and is associated with seasonal flooding and natu-
­lumbar regions (40%–100% of cases). Findings ral disasters, including hurricanes and mon-
commonly associated with the immune-­ soons. Populations in tropical regions of high
mediated phase include fever, aseptic menin­ endemicity likely encounter Leptospira organ-
gitis, and uveitis; between 5% and 10% of isms commonly during routine activities of
Leptospira-infected patients are estimated to daily living. People who are predisposed by
experience severe illness. Severe manifesta- occupation include abattoir and sewer workers,
tions include any combination of jaundice miners, veterinarians, farmers, and military
and renal dysfunction (Weil syndrome), pul- personnel. Recreational exposures and clusters
monary hemorrhage, cardiac arrhythmias, of disease have been associated with adventure
and cir­culatory collapse. The estimated case- travel; sporting events, including triathlons;
fatality rate from severe illness is 5% to 15%, and wading, swimming, or boating in contam-
although it can increase to greater than 50% inated water, particularly during flooding or
in patients with pulmonary hemorrhage. following heavy rainfall. Being submerged in
Asymptomatic or subclinical infection with or swallowing water during these activities is a
seroconversion is frequent, especially in set- common historical finding. Person-to-person
tings of endemic infection. transmission does not occur.

Etiology Incubation Period


Leptospirosis is caused by pathogenic spiro- 5 to 14 days; range, 2 to 30 days.
chetes of the genus Leptospira. Leptospires are Diagnostic Tests
classified by species and subdivided into more
than 250 antigenically defined serovars and Leptospira organisms can be isolated from
grouped into serogroups on the basis of anti- blood or cerebrospinal fluid during the early
genic relatedness. septicemic phase (first 7–10 days) of illness and
from urine specimens 14 days or more after

ERRNVPHGLFRVRUJ
336 Leptospirosis

illness onset. Specialized culture media are Treatment


required but are not routinely available in Intravenous penicillin is the drug of choice
most laboratories. Leptospira organisms can for patients with severe infection requiring
be grown on Leptospira semisolid medium hospitalization; penicillin has been shown to
(ie, Ellinghausen-McCullough-Johnson-­ be effective in shortening duration of fever as
Harris) from blood culture bottles used in late as 7 days into the course of illness. Penicil-
automated systems within 1 week of inocula- lin G decreases the duration of systemic symp-
tion. However, isolation of the organism may toms and persistence of associated laboratory
be difficult, requiring incubation for up to abnormalities and may prevent development
16 weeks, and the sensitivity of culture for of leptospiruria. As with other spirochetal
diagnosis is low. For these reasons, serum infections, a Jarisch-Herxheimer reaction
­specimens should always be obtained to facili- (an acute febrile reaction accompanied by
tate diagnosis. Antibodies can develop as early headache, myalgia, and an aggravated clinical
as 5 to 7 days after onset of illness and can be picture lasting less than 24 hours) can develop
measured by commercially available immuno- after initiation of penicillin therapy. Parenteral
assays. However, these assays have variable cefotaxime, ceftriaxone, and doxycycline have
sensitivity according to regional differences been demonstrated in randomized clinical
of the various Leptospira species and increases ­trials to be equal in efficacy to penicillin G for
in antibody titer may not be detected until treatment of severe leptospirosis. Severe cases
more than 10 days after onset, especially if also require appropriate supportive care,
antimicrobial therapy is initiated early. Anti- including fluid and electrolyte replacement.
body increases can be transient, delayed, or Patients with oliguric renal insufficiency and
absent in some patients. Microscopic aggluti- pulmonary hemorrhage syndrome require
nation, the gold standard serologic test, is prompt dialysis and mechanical ventilation,
­performed only in reference laboratories and respectively, to improve clinical outcome. For
requires seroconversion demonstrated between patients with mild disease, oral doxycycline
acute and convalescent specimens obtained has been shown to shorten the course of illness
at least 10 days apart. Immunohistochemical and decrease occurrence of leptospiruria;
and immunofluorescent techniques can ampicillin or amoxicillin can also be used to
detect ­leptospiral antigens in infected tissues. treat mild disease. Azithromycin has been
Polymerase chain reaction assays for detection demonstrated in a clinical trial to be as effec-
of Leptospira DNA in blood and urine have tive as doxycycline and can be used as an
been developed but are only available in ­a lternative in patients for whom doxycycline
research laboratories. is contraindicated (eg, pregnant women).

Image 77.1
Photomicrograph of leptospiral microscopic agglutination test with live antigen (darkfield microscopy
technique). Leptospirosis is a common global zoonotic disease of humans and several warm-blooded
animals, especially in subtropic regions of the world, caused by the spirochete bacteria Leptospira.
Courtesy of Centers for Disease Control and Prevention/Mrs M. Gatton.

ERRNVPHGLFRVRUJ
Leptospirosis 337

Image 77.2
Scanning electron micrograph of Leptospira interrogans strain RGA. Courtesy of Centers for Disease
Control and Prevention National Center for Infectious Disease/Rob Weyant/Janice Haney Carr.

Image 77.3
Leptospirosis rash in an adolescent male that shows the generalized vasculitis caused by this infection.

Image 77.4
Photomicrograph of kidney tissue, using a silver staining technique, revealing the presence of
Leptospira bacteria. Courtesy of Centers for Disease Control and Prevention/Martin Hicklin, MD.

ERRNVPHGLFRVRUJ
338 Leptospirosis

Image 77.5
Photomicrograph of liver tissue revealing the presence of Leptospira bacteria. Humans become
infected by swallowing water con­taminated by infected animals or through skin contact, especially
with mucosal surfaces, such as the eyes or nose, or with broken skin. The disease is not known to
be spread from person to person. Courtesy of Centers for Disease Control and Prevention/Martin
Hicklin, MD.

Image 77.6
A, Renal biopsy shows inflammatory cell infiltrate in the interstitium and focal denudation of tubular
epithelial cells (hematoxylin-eosin, original magnification x100). B, Immunostaining of fragmented
leptospire (arrowhead) and granular form of bacterial antigens (arrows) (original magnification x158).
Meites E, Jay MT, Deresinski S, et al. Reemerging leptospirosis, California. Emerg Infect Dis. 2004;
10(3):406–412.

ERRNVPHGLFRVRUJ
LISTERIA MONOCYTOGENES INFECTIONS 339

78 without parenchymal brain involvement and,


less commonly, brain abscess or endocarditis.
Listeria monocytogenes L monocytogenes can also cause rhombenceph-
Infections alitis (brainstem encephalitis) in otherwise
(Listeriosis) healthy adolescents and young adults. Out-
breaks of febrile gastroenteritis caused by
Clinical Manifestations food contaminated with a large inoculum of
Listeriosis is a relatively uncommon but severe L monocytogenes have been reported; this ill-
invasive infection caused by Listeria mono­cyto­ ness typically lasts 2 to 3 days. The prevalence
genes. Transmission predominantly is food- of stool carriage of L monocytogenes among
borne, and illness occurs most frequently among healthy, asymptomatic adults is estimated to
pregnant women and their fetuses or newborns, be 1% to 5%.
older adults, and people with impaired cell-
Etiology
mediated immunity resulting from underlying
illness or treatment (eg, organ transplant, L monocytogenes is a facultatively anaerobic,
hematologic malignancy, immunosuppression nonspore-forming, nonbranching, motile,
resulting from therapy with corticosteroid or gram-positive rod that multiplies intracellu-
antitumor necrosis factor agents, AIDS). larly. The organism grows readily on blood
­Pregnancy-associated infections can result in agar and produces incomplete hemolysis.
spontaneous abortion, fetal death, preterm L monocytogenes serotypes 1/2a, 4b, and 1/2b
delivery, and neonatal illness or death. In preg- cause most human cases of invasive listeriosis.
nant women, infections can be asymptomatic Unlike most bacteria, L monocytogenes grows
or associated with a nonspecific febrile illness well at refrigerator temperatures (4°C–10°C
with myalgia, back pain, and, occasionally, [39°F–50°F]).
gastrointestinal tract symptoms. Fetal infec- Epidemiology
tion results from transplacental trans­mission
following maternal bacteremia. Approximately L monocytogenes causes approximately
65% of pregnant women with Listeria infection 1,600 cases of invasive disease and 260 deaths
experience a prodromal illness before the diag- annually in the United States. This sapro-
nosis of listeriosis in their newborn. Amnio­ phytic organism is distributed widely in the
nitis during labor, brown staining of amniotic environment and is an important cause of ill-
fluid, or asymptomatic perinatal infection can ness in ruminants. Foodborne transmission
occur. Neonates can present with early-onset causes outbreaks and sporadic infections in
and late-onset syndromes similar to those of humans. Commonly incriminated foods
group B strepto­coccal disease. Preterm birth, include deli-style, ready-to-eat meats, parti­
pneumonia, and septicemia are common in cularly poultry, and unpasteurized milk and
early-onset disease (within the first week of soft cheeses, including Mexican-style cheese.
life), with fatality rates of 14% to 56%. An ery- The US incidence of listeriosis decreased
thematous rash with small, pale papules char- ­substantially ­during the 1990s, when US
acterized histologically by granulomas, termed ­regulatory agencies began enforcing rigorous
“granulomatosis infantisepticum,” can occur screening guidelines for L monocytogenes in
in severe newborn infection. Late-onset infec- processed foods. The last large outbreak in the
tions occur at 8 to 30 days of life following term United States occurred in 2011, resulting in
deliveries and usually result in meningitis with 143 hospitalizations, and was linked to con­
fatality rates of approximately 25%. Late-onset taminated ­cantaloupe.
infection may result from acquisition of the Incubation Period
organism during passage through the birth
canal or, rarely, from environmental sources. For pregnancy-associated cases, 2 to 4 weeks;
for nonpregnancy-associated cases, 1 to 14 days;
Clinical features characteristic of invasive for febrile gastroenteritis, 24 hours.
­listeriosis outside pregnancy or the neonatal
period are bacteremia and meningitis with or

ERRNVPHGLFRVRUJ
340 LISTERIA MONOCYTOGENES INFECTIONS

Diagnostic Tests intravenous ampicillin and an aminoglycoside,


L monocytogenes can be recovered readily on usually gentamicin, is recommended for severe
blood agar from cultures of blood, cerebrospi- infections, including meningitis, encephalitis,
nal fluid (CSF), meconium, placental or fetal endocarditis, and infections in neonates and
tissue specimens, amniotic fluid, and other immunocompromised patients. Use of an alter-
infected tissue specimens, including joint, native to an aminoglycoside that is active intra-
pleural, or peritoneal fluid. Gram stain of cellularly (eg, trimethoprim-sulfamethoxazole,
meconium, placental tissue, biopsy specimens a quinolone, linezolid, rifampin) is supported
of the rash of early-onset infection, or CSF by clinical reports in adults. In the penicillin-
from an infected patient may demonstrate allergic patient, trimethoprim-sulfamethoxazole
the organism. The organisms can be gram- or a quinolone has been used successfully as
variable and resemble diphtheroids, cocci, monotherapy for Listeria central nervous sys-
or diplococci. Laboratory misidentification tem infections. Cephalosporins are not active
is not uncommon, and the isolation of a against L monocytogenes. For bacteremia with-
“­diphtheroid” from blood or CSF should out associated central nervous system infec-
always alert one to the possibility that the tion, 14 days of treatment is sufficient. For
organism is L monocytogenes. L monocytogenes meningitis, most experts
­recommend 21 days of treatment. Longer
Treatment courses are necessary for patients with endo-
No controlled trials have established the carditis or parenchymal brain infection (cere­
drug(s) of choice or duration of therapy for britis, rhombencephalitis, brain abscess).
Listeria infection. Combination therapy using

Image 78.1
Listeria monocytogenes on blood agar. Courtesy of Julia Rosebush, DO; Robert Jerris, PhD; and
Theresa Stanley, M(ASCP).

ERRNVPHGLFRVRUJ
LISTERIA MONOCYTOGENES INFECTIONS 341

Image 78.2
Cerebrospinal fluid showing characteristic gram-positive rods (Gram stain). Listeriosis is a severe
but relatively uncommon infection. Listeriosis occurs most frequently among pregnant women and
their fetuses or newborns, people of advanced age, or immunocompro­mised people. Copyright
Martha Lepow, MD.

Image 78.3
Electron micrograph of a flagellated Listeria monocytogenes bacterium (magnification x41,250).
Courtesy of Centers for Disease Control and Prevention/Dr Balasubr Swaminathan; Peggy Hayes.

ERRNVPHGLFRVRUJ
342 LISTERIA MONOCYTOGENES INFECTIONS

Image 78.4
Listeriosis. Incidence—United States and US territories, 2012. Courtesy of Morbidity and Mortality
Weekly Report.

Image 78.5
Skin lesions present at birth in a neonate with congenital pneumonia. Listeria monocytogenes was
isolated from blood and skin lesion cultures.

ERRNVPHGLFRVRUJ
Lyme Disease 343

79 disseminated stage. Lymphocytic meningitis


can occur and often is associated with cranial
Lyme Disease neuropathy or papilledema; patients with lym-
(Lyme Borreliosis, Borrelia burgdorferi phocytic meningitis typically have a more sub-
­Infection) acute onset, lower temperature, and fewer
Clinical Manifestations white blood cells in cerebrospinal fluid (CSF)
than those with viral meningitis. Carditis,
Clinical manifestations of Lyme disease are which usually manifests as various degrees of
divided into 3 stages: early localized, early dis- heart block, can occur in children but is rela-
seminated, and late disease. Early localized dis- tively less common. Occasionally, people with
ease is characterized by a distinctive lesion, early Lyme disease have concurrent human
erythema migrans, at the site of a recent tick granulocytic anaplasmosis or babesiosis, which
bite. Erythema migrans is, by far, the most are transmitted by the same tick. Coinfection
common manifestation of Lyme disease in can present as more severe disease than Lyme
children. Erythema migrans begins as a red monoinfection, and the presence of a high
macule or papule that usually expands over fever with Lyme disease or inadequate response
days to weeks to form a large, annular, ery- to treatment should raise suspicion of concur-
thematous lesion that typically increases in size rent anaplasmosis or babesiosis. Certain labo-
to 5 cm or more in diameter, sometimes with ratory abnormalities, such as leukopenia,
partial central clearing. The lesion is usually thrombocytopenia, anemia, or abnormal
but not always painless, and it is not pruritic. hepatic transaminase concentrations, should
Localized erythema migrans can vary greatly raise concern for coinfection.
in size and shape and can be confused with
cellulitis; lesions may have a purplish discolor- Late disease occurs in patients who are not
ation or central vesicular or necrotic areas. A treated at an earlier stage of illness and most
classic bull’s-eye appearance with concentric commonly manifests as Lyme arthritis in chil-
rings appears in a minority of cases. Factors dren, which is characterized by inflammatory
that distinguish erythema migrans from local arthritis that is usually pauciarticular and
allergic reaction to a tick bite include larger affects large joints, particularly knees.
size (>5 cm), gradual expansion, lack of pruri- Although arthralgias can be present at any
tus, and slower onset. Constitutional symp- stage of Lyme disease, Lyme arthritis has
toms, such as malaise, headache, mild neck objective evidence of joint swelling. Arthritis
stiffness, myalgia, and arthralgia, often accom- can occur without a history of earlier stages of
pany the rash of early localized disease. Fever illness (including erythema migrans). Com-
can be present but is not universal and is pared with pyogenic arthritis, Lyme arthritis
­generally mild. tends to manifest with joint swelling or effu-
sion out of proportion to pain or disability
In early disseminated disease, multiple erythema and with lower peripheral blood neutrophilia
migrans lesions may appear several weeks after and erythrocyte sedimentation rate. Poly­
an infective tick bite and consist of secondary neuropathy, encephalopathy, and encephalitis
annular, erythematous lesions similar to, but are extremely rare manifestations of late dis-
usually smaller than, the primary lesion. Other ease. Children who are treated with antimicro-
manifestations of early disseminated illness bial agents in the early stage of disease almost
(which may occur with or without rash) are never develop late disease.
palsies of the cranial nerves (especially cranial
nerve VII), lymphocytic meningitis, and poly- Lyme disease does not cause a congenital infec-
radiculitis. Ophthalmic conditions (eg, con- tion syndrome. No evidence suggests Lyme
junctivitis, optic neuritis, keratitis, uveitis) can disease can be transmitted via human milk.
occur, usually in concert with other neurologic
Some patients with demonstrated Lyme disease
manifestations. Systemic symptoms, such as
have persistent subjective symptoms, such as
low-grade fever, arthralgia, myalgia, headache,
fatigue and arthralgia, after appropriate treat-
and fatigue, are also common during the early

ERRNVPHGLFRVRUJ
344 Lyme Disease

ment, a condition known as posttreatment Most cases of early Lyme disease occur
Lyme disease syndrome. Although the cause between April and October; more than 50%
is unknown, ongoing infection with Borrelia of cases occur during June and July. People
burgdorferi has not been demonstrated, and of all ages can be affected, but incidence in
long-term antibiotics have not been shown the United States is highest among children
to be beneficial. Patients with posttreatment 5 through 9 years of age and adults 55 through
Lyme disease syndrome usually respond to 59 years of age.
symptomatic treatment and recover gradually.
A lesion similar to erythema migrans known
“Chronic Lyme disease” is a nonspecific term as “southern tick-associated rash illness” or
that lacks a clinical definition. It is used by a STARI has been reported in south central
small minority of clinicians and patient advo- and southeastern states without endemic
cates to refer to patients with chronic, unex- B burgdorferi infection. The etiology and
plained syndromes usually characterized by appropriate treatment of this condition
pain and fatigue. Alternative diagnoses may remain unknown. Southern tick-associated
be responsible for symptoms and should be rash illness results from the bite of the lone
considered. In none of these situations is there star tick, Amblyomma americanum, which is
credible evidence that persistent infection abundant in southern states and is biologically
with B burgdorferi is demonstrable. incapable of transmitting B burgdorferi.
Patients with STARI may present with consti-
Etiology
tutional symptoms in addition to erythema
In the United States, Lyme disease is caused migrans; however, STARI has not been associ-
by the spirochete B burgdorferi sensu stricto. ated with any of the disseminated complica-
In Eurasia, B burgdorferi, Borrelia afzelii, and tions of Lyme disease.
Borrelia garinii cause borreliosis.
Clinical manifestations of Lyme disease in
Epidemiology eastern Canada, Europe, states of the former
Lyme disease primarily occurs in 2 distinct Soviet Union, China, and Japan vary some-
geographic regions of the United States. More what from manifestations seen in the United
than 90% of cases occur in New England and States. In particular, European Lyme disease
in the eastern Mid-Atlantic States, as far south may cause borrelial lymphocytoma and acro-
as Virginia. The disease also occurs, but with dermatitis chronica atrophicans and is more
lower frequency, in the upper Midwest, espe- likely to produce neurologic disease, whereas
cially Wisconsin and Minnesota. Transmission arthritis is uncommon. These differences are
also occurs at a low level on the West Coast, attributable to the different genospecies of
especially northern California. The occurrence ­Borrelia responsible for European Lyme dis-
of cases in the United States correlates with ease. The primary tick vector in Europe is
the distribution and frequency of infected tick ­Ixodes ricinus, and the primary tick vector in
vectors—Ixodes scapularis in the east and Asia is Ixodes ­persulcatus.
­Midwest and Ixodes pacificus in the west. In Incubation Period
Southern states, I scapularis ticks are rare
­compared with the northeast. Ticks that are From tick bite to appearance of single or mul-
present in Southern states do not commonly tiple erythema migrans lesions is 1 to 32 days
feed on competent reservoir mammals and are (median 11 days). Late manifestations can
less likely to bite humans because of different occur months after the tick bite.
questing habits. Reported cases from states Diagnostic Tests
without known enzootic risks may have been
The diagnosis of Lyme disease rests first and
acquired in states with endemic infection or
foremost on the recognition of a consistent
may be misdiagnoses resulting from false-­
clinical illness in people who have had plau­
positive serologic test results or results that
sible geographic exposure. Early localized
are misinterpreted as positive.

ERRNVPHGLFRVRUJ
Lyme Disease 345

Lyme disease is diagnosed clinically on tive, equivocal, or positive. If the first-tier


­recognition of an erythema migrans lesion. ELISA result is negative, the patient is con­
Although ­erythema migrans is not strictly sidered seronegative and no further testing is
pathognomonic for Lyme disease, it is highly indicated. If the result is equivocal or positive,
distinctive and characteristic. If a patient has a second-tier test is required. Although sensi-
a small lesion (<5-cm diameter) that resembles tive, the first-tier test is not specific and has a
erythema migrans, the patient can be followed rate of false-positive results that may exceed 5%
over several days to see if the lesion expands in clinically compatible cases and far higher in
to greater than 5 cm; this will improve the clinically nonsuggestive cases. This is partly
specificity of a clinical diagnosis. In areas because the test is not well standardized and
endemic for Lyme disease during the warm because there are antigenic components of
months of the year, it is expected that the vast B burgdorferi that are not specific to this spe-
majority of erythema migrans is attributable cies. In particular, other spirochetal infections,
to B burgdorferi infection, and early initiation normal spirochetes from our oral flora, other
of treatment is appropriate. acute infections, and certain autoimmune dis-
eases may be cross-reactive. The EIA or IFA
Diagnostic testing is based on serology; during
test is the important, helpful first-tier test but
early infection, the sensitivity is low and sero-
is too nonspecific to determine, in itself, a
logic testing is not recommended because only
patient’s serologic status.
approximately one-third of patients with soli-
tary erythema migrans lesions are seropositive. Serum specimens that yield positive or equivo-
Furthermore, immunoglobulin (Ig) M–based cal EIA results should then be tested by the
Lyme disease serologic testing carries a sub- second-tier standardized Western immuno­
stantial risk of false-positive results. Patients blot. This assay tests for the presence of anti-
who have multiple lesions of erythema migrans bodies to specific B burgdorferi antigens. Three
are also diagnosed clinically, although the like- IgM antibodies (to the 23/24, 39, and 41 kDa
lihood of seropositivity is higher. Diagnosis of polypeptides) and 10 IgG antibodies (to the 18,
disseminated Lyme disease requires a typical 23/24, 28, 30, 39, 41, 45, 60, 66, and 93 kDa poly-
clinical illness, plausible geographic exposure, peptides) are tested. The presence of at least
and a positive serologic test result. 2 IgM bands or 5 IgG bands is considered a
positive immunoblot result. Laboratory report-
The standard testing method for Lyme disease
ing practices can produce some confusion
is a 2-tier serologic assay. The initial test is
when physicians are interpreting results. It is
a quantitative screening for antibodies
common for clinical laboratories to report the
to a whole-cell sonicate or C6 antigen of
titers of all 13 bands and describe them as posi-
B ­burgdorferi. This test is performed using an
tive or negative; laboratories often print posi-
enzyme-linked immunosorbent assay (ELISA)
tive bands in bold, which frequently results in
or immunofluorescent antibody (IFA) test. It
misinterpretation of the overall result as posi-
should be noted that clinical laboratories vary
tive despite the fact that 4 or fewer IgG bands
somewhat in their description of this test. It
are present. The presence of 4 or fewer IgG
may be described as “Lyme ELISA,” “Lyme
bands is too nonspecific to meet criteria for
antibody screen,” “total Lyme antibody,” or
positivity. It is imperative the physician review
“Lyme IgG/IgM.” Many commercial labora­
the interpretive criteria for the test overall
tories offer enzyme immunoassay (EIA) or
rather than risk overinterpretation of what
IFA tests with reflex to Western immunoblot
may be a negative test result.
if the first-tier assay result is positive. This is
the most foolproof way of ordering the appro- The IgM assay is only useful for patients in
priate 2-tier test for Lyme disease. the first 30 days after symptom onset. The IgM
immunoblot should be disregarded (or, if
The initial EIA or IFA test result may be
­possible, not ordered to begin with) in patients
reported as a titer, but the role of the numerical
who have had symptoms for longer than
titer is solely to categorize the result as nega-

ERRNVPHGLFRVRUJ
346 Lyme Disease

4 to 6 weeks because false-positive IgM assay nervous system inflammatory processes; in


results are common, and most untreated particular, the presence of CSF antibodies to
patients with disseminated Lyme disease will B burgdorferi cannot confirm a diagnosis
have a positive IgG result by week 6 of illness. of Lyme disease if a different diagnosis is
Immunoblot testing should not be performed more plausible.
if the EIA result is negative or without a prior
The widespread practice of ordering serologic
EIA; the specificity of immunoblot testing
tests for patients with nonspecific symptoms,
diminishes if this test is performed alone. The
such as fatigue or arthralgia, or testing for
EIA and Western blot should not be thought
Lyme disease because of parental or patient
of as “screening” and “confirmatory,” respec-
pressure, is strongly discouraged. Almost all
tively. They are interdependent parts of an
positive serologic test results in these patients
overall testing method.
are false-positive results. In areas with endemic
A licensed, commercially available serologic infection, previous subclinical infection with
test (C6) that detects antibody to a peptide seroconversion may occur, and the patient’s
of the immunodominant conserved region symptoms may be merely coincidental. Patients
of the variable surface antigen (VlsE) of with active Lyme disease almost always have
B ­burgdorferi appears to have improved objective signs of infection (eg, erythema
­sensitivity for patients with early Lyme disease migrans, facial nerve palsy, arthritis). Non­
and Lyme disease acquired in Europe. How- specific symptoms commonly accompany
ever, when used alone, its specificity is lower these specific signs but almost never are the
than that of standard 2-tier testing. In the only evidence of Lyme disease.
future, the C6 EIA may replace immuno­
Some patients who are treated with anti­
blotting in the 2-tier method.
microbial agents for early Lyme disease
Polymerase chain reaction testing (using a never develop detectable antibodies against
­laboratory with excellent quality-control pro- B ­burgdorferi; they are cured and are not at
cedures) has been used to detect B burgdorferi risk of late disease. Development of antibodies
DNA in joint fluid. This test, however, is not in patients treated for early Lyme disease does
necessary for the diagnosis of Lyme arthritis, not indicate lack of cure or presence of per­
a late disseminated manifestation in which sistent infection. Ongoing infection without
patients are almost invariably seropositive. development of antibodies (“seronegative
For patients with persistent arthritis after a Lyme”) has not been demonstrated. Most
standard course of therapy, polymerase chain patients with early disseminated disease and
reaction testing of synovial fluid or tissue may virtually all patients with late disease have
help discriminate ongoing infection from antibodies against B burgdorferi. Once such
­a ntibiotic-refractory arthritis. Polymerase antibodies develop, they persist for many
chain reaction testing can also detect B burg­ years. Consequently, tests for antibodies should
dorferi in skin biopsy specimens of erythema not be repeated or used to assess the success
migrans lesions, although this invasive proce- of treatment.
dure is not recommended for routine clinical
Treatment
practice. Polymerase chain reaction has poor
sensitivity for CSF and blood specimens. Consensus practice guidelines for assessment,
treatment, and prevention of Lyme disease
Suspected central nervous system Lyme dis- have been published by the Infectious Diseases
ease can be confirmed by demonstration of Society of America and recommendations for
intrathecal production of antibodies against children are summarized in Table 79.1. Anti­
B ­burgdorferi, which is indicated by CSF/serum microbial therapy for nonspecific symptoms
IgG optical density ratio greater than 1.3 in or for asymptomatic seropositivity is discour-
specimens collected simultaneously. Cere­ aged. Doxycycline is the drug of choice for
brospinal fluid antibody tests, however, can treatment of early Lyme disease in children
be falsely positive in a variety of other central

ERRNVPHGLFRVRUJ
Lyme Disease 347

Table 79.1
Recommended Treatment of Lyme Disease in Children
Disease Category Drug(s) and Dosea
Early localized diseasea
8 y or older Doxycycline, 4 mg/kg per day, orally, divided into 2 doses
(maximum 200 mg/d) for 14 daysb
Younger than 8 y or unable Amoxicillin, 50 mg/kg per day, orally, divided into 3 doses
to tolerate doxycyclineb (maximum 1.5 g/d) for 14 days
OR
Cefuroxime, 30 mg/kg per day in 2 divided doses (maximum
1,000 mg/d or 1 g/d) for 14 days
Early disseminated and late disease
Multiple erythema migrans Same oral regimen as for early localized disease, for 14 days
Isolated facial palsy Same oral regimen as for early localized disease, for 14 days
(range 14–21 days)c,d
Arthritis Same oral regimen as for early localized disease, for 28 days
Recurrent arthritis Same oral regimen as for first-episode arthritis, for 28 days
OR
Preferred parenteral regimen:
Ceftriaxone sodium, 50–75 mg/kg, IV, once a day (maximum 2 g/d)
for 14 days (range 14–28 days)

Alternative parenteral regimen:


Penicillin, 200,000–400,000 U/kg per day, IV, given in divided
doses every 4 hours (maximum 18–24 million U/d) for 14 days
(range 14–28 days)
OR
Cefotaxime 150–200 mg/kg per day, IV, divided into 3 or 4 doses
(­maximum 6 g/d) for 14 days (range 14–28 days)
Antibiotic-refractory/­ Symptomatic therapy
persistent arthritise
Atrioventricular heart block Oral regimen as for early disease if asymptomaticf or not
or ­carditis ­hospitalized, for 14 days (range 14–21 days)
OR
Parenteral regimen initially for hospitalized patients, dosing as
for ­recurrent arthritis, for 14 days (range 14–21 days); oral therapy
can be substituted to complete the 14–21 day course.
Meningitis Ceftriaxoneg or alternatives of cefotaxime or penicilling: dosing as
for recurrent arthritis, for 14 days (range 10–21 days)
OR
Doxycycline, 4–8 mg/kg per day, orally, divided into 2 doses
(­maximum 100–200 mg) for 14 days (range 14-21 days)b
Encephalitis or other late Ceftriaxoneg or alternatives of cefotaxime or penicilling: dosing as
neurologic diseaseh for recurrent arthritis, for 14 days (range 14–28 days)
Abbreviation: IV, intravenously.
a For patients who are allergic to penicillin, alternatives are cefuroxime, azithromycin, and erythromycin.
b Tetracycline-based antimicrobial agents, including doxycycline, may cause permanent tooth discoloration for children younger than 8 years

if used for repeated treatment courses. However, doxycycline binds less readily to calcium compared with older tetracyclines, and in some
studies, doxycycline was not associated with visible teeth staining in younger children (see Tetracyclines).
c Corticosteroids should not be given.
d Treatment has no effect on the resolution of facial nerve palsy; its purpose is to prevent late disease.
e Arthritis is not considered persistent unless objective evidence of synovitis exists at least 2 months after completion of a course of

­parenteral therapy or of two 28-day courses of oral therapy. Some experts administer a second course of an oral agent before using an
IV-administered antimicrobial agent.
f Symptoms for heart block or carditis include syncope, dyspnea, or chest pain.
g For treatment of meningitis or encephalitis with ceftriaxone, cefotaxime, or penicillin, drug should be administered IV.
h Other late neurologic manifestations include peripheral neuropathy or encephalopathy.

ERRNVPHGLFRVRUJ
348 Lyme Disease

8 years and older and, unlike amoxicillin, also Patients with Lyme disease and simultaneously
treats patients with anaplasmosis. For children infected with Babesia microti (babesiosis),
younger than 8 years, amoxicillin is recom- Anaplasma phagocytophilum (human granulo-
mended. For patients who are allergic to peni- cytic anaplasmosis), or both should be treated
cillin, the alternative drug is cefuroxime. for each infection.
Erythromycin and azithromycin are less
Isolation of the Hospitalized Patient
­effective. Early Lyme disease should be treated
orally for 14 days. Standard precautions are recommended.

Image 79.2
Using darkfield microscopy technique, this
photomicrograph reveals the presence of
spirochetes, or corkscrew-shaped bacteria
known as Borrelia burgdorferi, which is the
pathogen responsible for causing Lyme disease
(magnification x400). B burgdorferi are helical-
shaped bacteria and are about 10 to 25 µm long.
These bacteria are transmitted to humans by the
bite of an infected deer tick. Courtesy of Centers
for Disease Control and Prevention.

Image 79.1
Photomicrograph of Borrelia burgdorferi, the
bacteria that cause Lyme disease. This is a spiral-
shaped bacteria that is frequently carried by deer
ticks of the genus Ixodes. When the deer tick
bites a human being, the bacteria are transmitted
to the human bloodstream. Courtesy of Centers
for Disease Control and Prevention.

Image 79.3
Two deer ticks of the Ixodes genus that transmit
Borrelia burgdorferi to humans. The engorged
tick on the right demonstrates increased size
from a blood meal. Both are magnified for this
photograph.

ERRNVPHGLFRVRUJ
Lyme Disease 349

Image 79.5
Despite engorgement, the deer tick is still small
and its size approximates the head of a small nail.
Image 79.4 The ticks that transmit Rickettsia rickettsii, usually
This photograph depicts a dorsal view of an the dog or lone star ticks, are larger, particularly
immature, or nymphal, lone star tick, Amblyomma when engorged.
americanum. Nymphal ticks are much smaller
than adult ticks, and people might not notice a
nymph until it has been feeding for a few days.
Nymphs are, therefore, more likely than adult
ticks to transmit diseases to people. Courtesy
of Centers for Disease Control and Prevention/
Amanda Loftis, MD; William Nicholson, MD; Will
Reeves, MD; Chris Paddock, MD.

Image 79.7
This photograph of a white-tailed deer,
Odocoileus virginianus, was taken during a Lyme
disease field investigation in 1993. White-tailed
deer are investigated during outbreaks of Lyme
disease because they serve as hosts to the ticks
which carry Borrelia burgdorferi, the bacteria
responsible for Lyme disease. Courtesy of
Centers for Disease Control and Prevention.

Image 79.6
This photograph depicts a white-footed mouse,
Peromyscus leucopus, which is a wild rodent
reservoir host of ticks, which are known to carry
Borrelia burgdorferi, the bacteria responsible for
Lyme disease. During their larval stage, Ixodidae,
or hard ticks, feed on small mammals, particularly
the white-footed mouse, which serves as the
primary reservoir for B burgdorferi. Courtesy of
Centers for Disease Control and Prevention.

Image 79.8
This photograph depicts a dorsal view of a
female lone star tick, Amblyomma americanum.
Note the characteristic lone star marking located
centrally on its dorsal surface, at the distal tip
of its scutum. Courtesy of Centers for Disease
Control and Prevention/Amanda Loftis, MD;
William Nicholson, MD; Will Reeves, MD; Chris
Paddock, MD/James Gathany.

ERRNVPHGLFRVRUJ
350 Lyme Disease

Image 79.9
Life cycle of black-legged ticks, which live for 2 years and have 3 feeding stages: larvae, nymph, and
adult. Tick eggs are laid in the spring and hatch as larvae in the summer. Larvae feed on mice, birds,
and other small animals in the summer and early fall. When a young tick feeds on an infected animal,
the tick takes bacteria into its body along with the blood meal, and it remains infected for the rest of
its life. After this initial feeding, the larvae become inactive as they grow into nymphs. The following
spring, nymphs seek blood meals to fuel their growth into adults. When the tick feeds again, it can
transmit the bacterium to its new host. Usually, the new host is another small rodent, but, sometimes,
the new host is a human. Most cases of human illness occur in the late spring and summer when the
tiny nymphs are most active and human outdoor activity is greatest. Adult ticks feed on large animals
and, sometimes, on humans. In the spring, adult female ticks lay their eggs on the ground, completing
the life cycle. Although adult ticks often feed on deer, these animals do not become infected. Deer are,
nevertheless, important in transporting ticks and maintaining tick populations. Courtesy of Centers for
Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Lyme Disease 351

Image 79.10
Incidence of reported confirmed cases, by county—United States, 2012. Courtesy of Morbidity and
Mortality Weekly Report.

Image 79.12
Erythema migrans lesion at the site of a tick bite
Image 79.11 characteristic of early localized Lyme disease. It
Lyme disease. The rash of erythema migrans in is annular with central clearing (ie, a target lesion),
a 4-year-old boy with infection due to Borrelia but in other cases, the initial lesion can be
burgdorferi. Copyright Richard Jacobs. uniformly erythematous and occasionally have
a vesicular or necrotic center, as illustrated in
Image 79.17. Systemic symptoms, such as fever,
myalgia, headache, or malaise, can occur at
this stage of infection.

ERRNVPHGLFRVRUJ
352 Lyme Disease

Image 79.13
The rash at the site of a tick bite on the lower leg is indicative of the variation in the initial rash of Lyme
disease. Central clearing is incomplete, and a central necrotic area is apparent at the presumed site of
the tick bite.

Image 79.14
The rash on the lower leg is similar to that in Image 79.17, but it does not have a necrotic center.

ERRNVPHGLFRVRUJ
Lyme Disease 353

Image 79.15
A 15-month-old girl with left facial nerve palsy complicating Lyme disease. Copyright Michael Rajnik,
MD, FAAP.

Image 79.16
Erythema migrans lesions in a 12-year-old boy who contracted Lyme disease in Maryland. Copyright
Michael Rajnik, MD, FAAP.

Image 79.17
A 14-year-old boy with multiple annular skin lesions and worsening headache associated with photo­
phobia. Results from a lumbar puncture revealed a cerebrospinal fluid pleocytosis and aseptic menin­
gitis. The characteristic erythema migrans skin lesions helped to determine the diagnosis of Lyme
disease. The patient was treated with intravenous ceftriaxone. Copyright Barbara Jantausch, MD, FAAP.

ERRNVPHGLFRVRUJ
354 Lyme Disease

Image 79.18
Borrelia burgdorferi synovitis with marked swelling and only mild tenderness. Arthritis usually occurs
within 1 to 2 months following the appearance of erythema migrans, and the knees are the most
commonly affected joints.

Image 79.19 Image 79.20


This photograph depicts the pathognomonic This photograph depicts the pathognomonic
erythematous rash in the pattern of a bull’s-eye, erythematous rash (erythema migrans) in the
which developed at the site of a tick bite on this pattern of a bull’s-eye, which developed at the
Maryland woman’s posterior right upper arm. site of a tick bite on this Maryland woman’s
Courtesy of Centers for Disease Control and posterior right upper arm. The expanding
Prevention/James Gathany. rash reflects migration of the spirochetes after
introduction of the organism during the tick bite.
Courtesy of Centers for Disease Control and
Prevention/James Gathany.

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Lymphatic Filariasis 355

80 Epidemiology

Lymphatic Filariasis The parasite is transmitted by the bite of


infected species of various genera of mosquitoes,
(Bancroftian, Malayan, and Timorian)
including Culex, Aedes, Anopheles, and
Clinical Manifestations ­Mansonia. W bancrofti, the most prevalent
Lymphatic filariasis is caused by infection with cause of lymphatic filariasis, is found in Haiti,
the filarial parasites, Wuchereria bancrofti, the Dominican Republic, Guyana, northeast
Brugia malayi, or Brugia timori. Adult worms Brazil, sub-Saharan and North Africa, and
cause lymphatic dilatation and dysfunction, Asia, extending from India through the Indo-
result in abnormal lymph flow, and, eventually, nesian archipelago to the western Pacific
may lead to lymphedema in the legs, scrotal islands. Humans are the only definitive host
area (for W bancrofti only), and arms. Recur- for the parasite. B malayi is found mostly in
rent secondary bacterial infections hasten pro- Southeast Asia and parts of India. B timori is
gression of lymphedema to the more severe restricted to certain islands at the eastern
form known as elephantiasis. Although the end of the Indonesian archipelago. Live adult
infection occurs commonly in young children worms release microfilariae into the blood-
living in lymphatic filariasis–endemic areas, stream. Adult worms live for an average of 5 to
chronic manifestations of infection, such as 8 years, and reinfection is common. Microfilar-
hydrocele and lymphedema, occur infrequently iae that can infect mosquitoes may remain in
in people younger than 20 years. Most filarial the patient’s blood for decades; individual
infections remain clinically asymptomatic but microfilaria have a life span up to 1.5 years. The
still commonly cause subclinical lymphatic adult worm is not transmissible from person
dilatation and dysfunction. Lymphadenopathy, to person or by blood transfusion, but micro­
most frequently of the inguinal, crural, and filariae may be transmitted by transfusion.
axillary lymph nodes, is the most common Incubation Period
clinical sign of lymphatic filariasis in children.
From acquisition to the appearance of micro­
When the adult worm dies, there is an acute
filariae in blood, 3 to 12 months, depending on
inflammatory response that progresses distally
the species of parasite.
(retrograde) along the affected lymphatic vessel,
usually in the limbs. Accompanying systemic Diagnostic Tests
symptoms, such as headache or fever, are
Microfilariae can generally be detected micro-
­generally mild. In postpubertal males, adult
scopically on blood smears obtained at night
W bancrofti organisms are most commonly
(10:00 pm–4:00 am), although variations in
found in the intrascrotal lymphatic vessels;
the periodicity of microfilaremia have been
thus, inflammation around dead or dying adult
described depending on the parasite strain
worms can present as funiculitis (inflamma-
and geographic location. Adult worms or
tion of the spermatic cord), epididymitis, or
microfilariae can be identified in tissue speci-
orchitis. A tender granulomatous nodule may
mens obtained at biopsy. Serologic enzyme
be palpable at the site of dying or dead adult
immunoassays are available, but interpretation
worms. Chyluria can occur as a manifestation
of results is affected by cross-reactions of filar-
of bancroftian filariasis. Tropical pulmonary
ial antibodies with antibodies against other
eosinophilia, characterized by cough, fever,
helminths. Assays for circulating parasite anti-
marked eosinophilia, and high serum immu-
gen of W bancrofti are available commercially
noglobulin E concentrations, is a rare mani­
but are not cleared by the US Food and Drug
festation of lymphatic filariasis.
Administration. Ultrasonography can be used
Etiology to visualize adult worms. Patients with lymph-
edema may no longer have microfilariae or
Filariasis is caused by 3 filarial nematodes:
filarial antibody present.
W bancrofti, B malayi, and B timori.

ERRNVPHGLFRVRUJ
356 Lymphatic Filariasis

Treatment including doxycycline, may cause permanent


The main goal of treatment of an infected per- tooth discoloration for children younger than
son is to kill the adult worm. Diethylcarbam- 8 years if used for repeated treatment courses.
azine citrate, which is microfilaricidal and For early forms of lymphedema, antifilarial
active against the adult worm, is the drug of chemotherapy has been shown to have limited
choice for lymphatic filariasis. Ivermectin is efficacy for reversing or stabilizing the lymph-
effective against the microfilariae of W ban­ edema. Doxycycline, in limited studies, has
crofti but has no effect on the adult parasite. been shown to decrease the severity of lymph-
Albendazole has demonstrated macrofilari- edema. Complex decongestive physiotherapy
cidal activity. In some studies, combination may be effective for treating lymphedema and
therapy with single-dose diethylcarbamazine requires strict attention to hygiene in the
citrate–albendazole or ivermectin-albendazole affected anatomic areas. Chyluria originating
has been shown to be more effective than any in the bladder responds to fulguration; chyluria
one drug alone in suppressing microfilaremia originating in the kidney usually cannot be
and is the basis for the World Health Organi­ corrected. Prompt identification and treatment
zation Global Programme to Eliminate Lym- of bacterial superinfections, particularly strep-
phatic Filariasis. Doxycycline (up to 6 weeks), tococcal and staphylococcal infections, and
a drug that targets the Wolbachia (intracellular careful treatment of intertriginous and ungual
rickettsial-like bacteria) endosymbiont, has fungal infections are important aspects of
been shown to be macrofilaricidal as well. ­t herapy for lymphedema.
­Tetracycline-based antimicrobial agents,

Image 80.2
This photomicrograph shows the inner body and
Image 80.1
cephalic space of a Brugia malayi microfilaria in a
Mansonella ozzardi, infectious agent of filariasis.
thick blood smear. B malayi, a nematode that can
Courtesy of Centers for Disease Control and
inhabit the lymphatics and subcutaneous tissues
Prevention/Dr Lee Moore.
in humans, is one of the causative agents for
lymphatic filariasis. The vectors for this parasite
are mosquito species from the genera Mansonia
and Aedes. Courtesy of Centers for Disease
Control and Prevention/Mae Melvin, MD.

Image 80.3
Microfilaria of Brugia malayi collected by the
Knott (centrifugation) concentration technique,
in 2% formalin wet preparation. Note the erythro­
cyte ghosts (for size comparison) and the clearly
visible sheath that extends beyond the anterior
and posterior ends of the microfilaria. (There are
4 sheathed species: Wuchereria bancrofti, Brugia
malayi, Brugia timori, and Loa loa.) Courtesy of
Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Lymphatic Filariasis 357

Image 80.4
Microfilariae of Loa loa (right) and Mansonella
perstans (left) in a patient in Cameroon (thick
blood smear; hematoxylin stain). L loa is sheathed,
with a relatively dense nuclear column; its tail
tapers and is frequently coiled, and nuclei extend
to the end of the tail. M perstans is smaller, has Image 80.5
no sheath, and has a blunt tail with nuclei Microfilaria of Wuchereria bancrofti from a patient
extending to the end of the tail. Courtesy of in Haiti (thick blood smear; hematoxylin stain).
Centers for Disease Control and Prevention. The microfilaria is sheathed, its body is gently
curved, and the tail is tapered to a point. The
nuclear column (ie, the cells that constitute the
body of the microfilaria) is loosely packed; the
cells can be visualized individually and do not
extend to the tip of the tail. The sheath is slightly
stained by hematoxylin. Courtesy of Centers for
Disease Control and Prevention.

Image 80.6
Elephantiasis of both legs due to filariasis. Luzon,
Philippines. Courtesy of Centers for Disease
Control and Prevention.

Image 80.7
Scrotal lymphangitis due to filariasis. Courtesy of
Centers for Disease Control and Prevention.

Image 80.8
Inguinal lymph nodes enlarged due to filariasis.
Courtesy of Centers for Disease Control and
Prevention.

ERRNVPHGLFRVRUJ
358 Lymphatic Filariasis

Image 80.9
The typical vector for Brugia malayi filariasis are mosquito species from the genera Mansonia and
Aedes. During a blood meal, an infected mosquito introduces third-stage filarial larvae onto the skin
of the human host, where they penetrate into the bite wound (1). They develop into adults that
commonly reside in the lymphatics (2). The adult worms resemble those of Wuchereria bancrofti but
are smaller. Female worms measure 43 to 55 mm in length by 130 to 170 µm in width, and males
measure 13 to 23 mm in length by 70 to 80 µm in width. Adults produce microfilariae, measuring
177 to 230 µm in length and 5 to 7 µm in width, that are sheathed and have nocturnal periodicity.
The microfilariae migrate into lymph and enter the bloodstream, reaching the peripheral blood (3).
A mosquito ingests the microfilariae during a blood meal (4). After ingestion, the microfilariae lose
their sheaths and work their way through the wall of the proventriculus and cardiac portion of the
midgut to reach the thoracic muscles (5). There, the microfilariae develop into first-stage larvae (6)
and, subsequently, into third-stage larvae (7). The third-stage larvae migrate through the hemocoel
to the mosquito’s proboscis (8) and can infect another human when the mosquito takes a blood
meal (1). Courtesy of Centers for Disease Control and Prevention.

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Lymphocytic ­Choriomeningitis 359

81 Etiology

Lymphocytic Lymphocytic choriomeningitis virus is a


­single-stranded RNA virus that belongs to
­Choriomeningitis the family Arenaviridae.
Clinical Manifestations Epidemiology
Child and adult infections are asymptomatic Lymphocytic choriomeningitis is a chronic
in approximately one-third of cases. Sympto­ infection of common house mice, which are
matic infection can result in a mild to severe often infected asymptomatically and chroni-
illness that includes fever, malaise, myalgia, cally shed virus in urine and other excretions.
retro-orbital headache, photophobia, anorexia, Congenital murine infection is common and
and nausea. Initial symptoms can last up to results in a normal-appearing litter with
1 week. A biphasic febrile course is common; chronic viremia and particularly high virus
after a few days without symptoms, the second excretion. In addition, pet hamsters, laboratory
phase can occur in up to half of symptomatic mice, guinea pigs, and colonized golden ham-
patients, consisting of neurologic manifesta- sters can have chronic infection and can be
tions that vary from aseptic meningitis to sources of human infection. Humans are
severe encephalitis. Transmission of lympho- infected by aerosol or by ingestion of dust
cytic choriomeningitis (LCM) virus through or food contaminated with the virus from
organ transplantation can result in fatal dis- the urine, feces, blood, or nasopharyngeal
seminated infection with multiple organ fail- secretions of infected rodents. The disease
ure. In the past, LCM virus caused up to 10% is observed more frequently in young adults.
to 15% of all cases of aseptic meningitis, and Human-to-human transmission has occurred
it was a common cause of aseptic meningitis during pregnancy from infected mothers to
during winter months. Arthralgia or arthritis, their fetuses and through solid organ trans-
respiratory tract symptoms, orchitis, and plantation from an undiagnosed, acutely LCM
­leukopenia develop occasionally. Recovery virus–infected organ donor. Several such clus-
without sequelae is the usual outcome. Lym- ters of cases have been described following
phocytic choriomeningitis virus infection transplantation, and index case was traced
should be suspected in presence of aseptic to a pet hamster purchased by the donor. A
meningitis or encephalitis during the fall/­ number of laboratory-acquired LCM virus
winter season; febrile illness, followed by infections have occurred through infected
brief remission, followed by onset of neurologic ­laboratory animals and contaminated tissue-
illness; and cerebrospinal fluid (CSF) findings culture stocks.
of lymphocytosis and hypoglycorrhachia.
Incubation Period
Infection during pregnancy has been associated
with spontaneous abortion. Congenital infec- Usually 6 to 13 days; occasionally 3 weeks.
tion can cause severe abnormalities, including Diagnostic Tests
hydrocephalus, chorioretinitis, intracranial
In patients with central nervous system disease,
calcifications, microcephaly, and mental retar-
mononuclear pleocytosis, often exceeding
dation. Congenital LCM etiology should be
1,000 cells/µL, is present in CSF. Hypogly­
considered when TORCH (toxoplasma, other
corrhachia can occur. Lymphocytic chorio-
[syphilis], rubella, cytomegalovirus, herpes
meningitis virus can usually be isolated from
simplex) infections are suspected. Patients with
CSF obtained during the acute phase of illness
immune abnormalities may experience severe
and, in severe disseminated infections, also
or fatal illness, as observed in patients receiv-
from blood, urine, and nasopharyngeal
ing organs from LCM virus–infected donors.
­secretion specimens. Reverse transcriptase-­
polymerase chain reaction assays can be used
on CSF. Serum specimens from the acute and
convalescent phases of illness can be tested

ERRNVPHGLFRVRUJ
360 Lymphocytic ­Choriomeningitis

for increases in antibody titers by enzyme suppressed patients, the seroconversion can


immunoassays. Demonstration of virus-­ take several weeks. Diagnosis can be made
specific immunoglobulin M antibodies in ­retrospectively by immunohistochemical assay
serum or CSF specimens is useful. In con­ of fixed tissues obtained from necropsy.
genital infections, diagnosis is usually sus-
Treatment
pected at the sequela phase, and diagnosis is
usually made by serologic testing. In immuno- Supportive.

Image 81.1
This transmission electron micrograph depicted 8 virions (viral particles) of a newly discovered virus,
which was determined to be a member of the genus Arenavirus. A cause of fatal hemorrhagic fever, it
was confirmed that this virus was responsible for causing illness in 5 South Africans, 4 of whom died
having succumbed to its devastating effects. Ultrastructurally, these round Arenavirus virions displayed
the characteristic “sandy” or granular capsid (ie, outer skin), an appearance from which the Latin
name, arena, was derived. Other members of the genus Arenavirus include the West African Lassa
virus, lymphocytic choriomeningitis, and Bolivian hemorrhagic fever, also known as Machupo virus, all
of which are spread to humans through their inhalation of airborne particulates originating from rodent
excrement, which can occur during the simple act of sweeping a floor. Courtesy of Centers for Disease
Control and Prevention/Charles Humphrey.

Image 81.2
Fundus photograph of a 9-month-old girl with congenital lymphocytic choriomeningitis virus infection.
Extensive chorioretinal scarring is visible. Hydrocephalus and periventricular calcification were visible on
computed tomography scan and magnetic resonance imaging. Copyright Leslie L. Barton, MD, FAAP.

ERRNVPHGLFRVRUJ
Malaria 361

82 • Renal failure caused by acute tubular necro-


sis (rare in children younger than 8 years).
Malaria
• Respiratory failure, without pulmonary
Clinical Manifestations edema.
The classic symptoms of malaria are high
• Metabolic acidosis, usually attributed to
fever with chills, rigor, sweats, and headache,
­lactic acidosis, hypovolemia, liver dysfunc-
which may be paroxysmal. If appropriate
tion, and impaired renal function.
­treatment is not administered, fever and
­paroxysms may occur in a cyclic pattern. • Severe anemia attributable to high para­
Depending on the infecting species, fever sitemia and hemolysis, sequestration of
­classically appears every other (Plasmodium infected erythrocytes to capillaries, and
falciparum, Plasmodium vivax, and Plasmo­ hemolysis of infected erythrocytes associ-
dium ovale) or every third day (Plasmodium ated with hypersplenism.
malariae), although, in general practice, this
• Vascular collapse and shock associated
pattern is infrequently observed, especially in
with hypothermia and adrenal insufficiency.
children. Other manifestations as the clinical
People with asplenia who become infected
disease progresses can include nausea, vomit-
may be at increased risk of more severe ill-
ing, diarrhea, cough, tachypnea, arthralgia,
ness and death.
myalgia, and abdominal and back pain.
­Anemia and thrombocytopenia, along with Syndromes primarily associated with P vivax
pallor and jaundice caused by hemolysis, are and P ovale infection are as follows:
common in severe illness. Hepatosplenomeg-
aly may be present. More severe disease may • Anemia attributable to acute parasitemia
occur in people without immunity acquired • Hypersplenism with danger of late splenic
as a result of previous infections, young chil- rupture
dren, and people who are pregnant or immu-
nocompromised. • Relapse of infection, for as long as 3 to
5 years after the primary infection, attribut-
Infection with P falciparum, 1 of the 5 Plasmo­ able to latent hepatic stages (hypnozoites)
dium species that infect humans, is potentially
fatal and most commonly manifests as a Syndromes associated with P malariae infec-
febrile nonspecific illness without localizing tion include
signs. Severe disease (most commonly caused • Chronic asymptomatic parasitemia for as
by P falciparum, although, recently, also caused long as decades after the primary infection
by P vivax from India, Southeast Asia, and
South America) can manifest as one of the • Nephrotic syndrome resulting from deposi-
­following clinical syndromes, each of which tion of immune complexes in the kidney
are medical emergencies, and can be fatal: Plasmodium knowlesi is a nonhuman primate
• Cerebral malaria, characterized by malaria parasite that can also infect humans.
unarousable coma, can manifest with a P knowlesi malaria has been commonly mis­
range of neurologic signs and symptoms, diagnosed as the more benign P malariae
including generalized seizures, signs of malaria. Disease can be characterized by
increased intracranial pressure (confusion very rapid replication of the parasite and
and progression to stupor, coma), and death. hyper­parasitemia resulting in severe disease.
Severe disease in patients with P knowlesi
• Hypoglycemia, which can present with infection should be treated aggressively
­metabolic acidosis and hypotension because hepatorenal failure and death have
­asso­ciated with hyperparasitemia or been documented.
result from quinine or quinidine-induced
hyperinsulinemia.

ERRNVPHGLFRVRUJ
362 Malaria

Congenital malaria resulting from perinatal planes flying from areas with endemic malaria
transmission occurs infrequently. Most con- have been the source of cases in people work-
genital cases have been caused by P vivax and ing or residing near international airports.
P falciparum; P malariae and P ovale account Local transmission also, rarely, occurs in the
for fewer than 20% of such cases. Manifesta- United States.
tions can resemble those of neonatal sepsis,
P vivax and P falciparum are the most com-
including fever and nonspecific symptoms
mon species worldwide. P vivax malaria is
of poor appetite, irritability, and lethargy.
prevalent on the Indian subcontinent and
Etiology in Central America. P falciparum malaria is
The genus Plasmodium includes species of prevalent in Africa, in Papua New Guinea,
intraerythrocytic parasites that infect a wide and on the island of Hispaniola (Haiti and the
range of mammals, birds, and reptiles. The Dominican Republic). P vivax and P ­falciparum
5 species that infect humans are P falciparum, species are the most common malaria species
P vivax, P ovale, P malariae, and P knowlesi. in southern and Southeast Asia, Oceania, and
Coinfection with multiple species is increasingly South America. P malariae, although much
recognized as polymerase chain reaction tech- less common, has a wide distribution. P ovale
nology is applied to the diagnosis of malaria. malaria occurs most often in West Africa but
has been reported in other areas. Cases of
Epidemiology human infections with P knowlesi reported,
Malaria is endemic throughout the tropical so far, have been from certain countries of
areas of the world and is acquired from the bite Southeast Asia like Borneo, Malaysia, Philip-
of the female nocturnal-feeding Anopheles pines, Thailand, the Thai-Burmese border,
genus of mosquito. Half of the world’s popula- ­Singapore, and ­Cambodia.
tion lives in areas where transmission occurs. Relapses may occur in P vivax and P ovale
Worldwide, 216 million cases and 655,000 malaria because of a persistent hepatic
deaths were reported in 2010. Most deaths (­hypnozoite) stage of infection. Recrudescence
occur in young children. Infection by the of P falciparum and P malariae infection
malaria parasite poses substantial risks to occurs when a persistent low-concentration
pregnant women, especially primigravidae, parasitemia causes recurrence of symptoms of
and their fetuses and can result in spontaneous the disease or when drug resistance prevents
abortion and stillbirth. Malaria also contrib- elimination of the parasite. In areas of Africa
utes significantly to low birth weight in coun- and Asia with hyperendemic infection,
tries where P falciparum is endemic. The risk repeated infection in people with partial
of malaria is highest, but variable, for travelers immunity results in a high prevalence of
to sub-Saharan Africa, Papua New Guinea, asymptomatic parasitemia.
the Solomon Islands, and Vanuatu; the risk is
intermediate on the Indian subcontinent and The spread of chloroquine-resistant P ­falciparum
is low in most of Southeast Asia and Latin strains throughout the world is of increasing
America. The potential for malaria transmis- concern. In addition, resistance to other anti-
sion is ongoing in areas where malaria was malarial drugs is also occurring in many areas
­previously eliminated if infected people return where the drugs are used widely. P falciparum
and the mosquito vector is still present. These resistance to sulfadoxine-­pyrimethamine is
conditions have resulted in recent cases in trav- common throughout Africa; mefloquine resis-
elers to areas such as Jamaica, the Dominican tance has been documented in Burma (Myan-
Republic, and the Bahamas. Transmission is mar), Laos, Thailand, Cambodia, China, and
possible in more temperate climates, including Vietnam; and emerging resistance to artemis-
areas of the United States where anopheline inin has been observed at the Cambodia-­
mosquitoes are present. Nearly all of the Thailand border. Chloroquine-resistant P vivax
approximately 1,500 annual reported cases has been reported in Indonesia, Papua New
in the United States result from infection Guinea, the Solomon Islands, Myanmar, India,
acquired abroad. Rarely, mosquitoes in air- and Guyana. Malaria symptoms can develop as

ERRNVPHGLFRVRUJ
Malaria 363

soon as 7 days after exposure in an area with for antigen detection is available in the United
endemic malaria to as late as several months States; however, this product has poor sensitiv-
after departure. More than 80% of cases diag- ity for detecting low-density P vivax infections.
nosed in the United States occur in people who Positive and negative rapid diagnostic test
have onset of symptoms after their return to results should be confirmed by microscopic
the United States. Beginning in 2012, the examination because low-level parasitemia
­Centers for Disease Control and Prevention may not be detected, false-positive results
has tested samples from US patients for molec- occur, and mixed infections may not be
ular markers associated with antimalarial drug detected accurately. Also, information about
resistance. Of the 65 P falciparum–positive the sensitivity of rapid diagnostic tests for the
samples, genetic polymorphisms were associ- 2 less common species of malaria, P ovale and
ated with pyrimethamine drug resistance in P malariae, is limited.
53 (82%), sulfadoxine resistance in 61 (94%),
Treatment
chloroquine resistance in 29 (45%), mefloquine
resistance in 1 (2%), and atovaquone resistance The choice of malaria chemotherapy is based
in 2 (3%); none had genetic polymorphisms on the infecting species, possible drug resis-
associated with artemisinin resistance. tance, and severity of disease. Severe malaria
is defined as any one or more of the following
Diagnostic Tests signs or symptoms: parasitemia greater than
Definitive diagnosis relies on identification of 5% of red blood cells, signs of central nervous
the parasite microscopically on stained blood system or other end-organ involvement, shock,
films. Thick and thin blood films should be acidosis, thrombocytopenia, or hypoglycemia.
examined. The thick film allows for concen­ Patients with severe malaria require intensive
tration of the blood to find parasites that may care and parenteral treatment with intravenous
be present in small numbers, whereas the thin quinidine until the parasite density decreases
film is most useful for species identification to less than 1% and they are able to tolerate
and determination of the degree of parasitemia oral therapy. Concurrent treatment with tetra-
(the percentage of erythrocytes harboring cycline, doxycycline, or clindamycin should
­parasites). If initial blood smear test results begin orally or intravenously if oral treatment
are negative for Plasmodium species but is not tolerated. Exchange transfusion for
malaria remains a possibility, the smear test severe disease is not efficacious.
should be repeated every 12 to 24 hours during
For patients with severe malaria in the United
a 72-hour period.
States who do not tolerate or cannot easily
Confirmation and identification of the species access quinidine, intravenous artesunate has
of malaria parasites on the blood smear is become available through a Centers for Disease
important in guiding therapy. Serologic testing Control and Prevention investigational new
is generally not helpful, except in epidemio- drug protocol. For patients with P falciparum
logic surveys. Polymerase chain reaction assay malaria, sequential blood smears to determine
is available in reference laboratories and many percentage of erythrocytes harboring parasites
state health departments. An approved test can be useful in monitoring treatment.

ERRNVPHGLFRVRUJ
364 Malaria

Image 82.1
This Giemsa-stained slide reveals a Plasmodium falciparum, Plasmodium ovale, Plasmodium malariae,
and Plasmodium vivax gametocyte. The male (microgametocytes) and female (macrogametocytes) are
ingested by an Anopheles mosquito during its blood meal. Known as the sporogonic cycle, while in the
mosquito’s stomach, the microgametes penetrate the macrogametes, generating zygotes. Courtesy of
Centers for Disease Control and Prevention/Steven Glenn, Laboratory & Consultation Division.

Image 82.2
This thin-film Giemsa-stained micrograph reveals growing Plasmodium vivax, Plasmodium malariae,
and Plasmodium ovale trophozoites. As the parasite increases in size, the ring morphology of the
early trophozoite disappears and becomes what is referred to as a mature trophozoite, which
undergoes further transformation, maturing into a schizont. Courtesy of Centers for Disease Control
and Prevention/Steven Glenn, Laboratory & Consultation Division.

ERRNVPHGLFRVRUJ
Malaria 365

Image 82.3
This thin-film Giemsa-stained micrograph reveals a ringform Plasmodium falciparum trophozoite.
As P falciparum trophozoites mature, they tend to retain their ringlike shape and, sometimes, trace
amounts of yellow pigment can be seen within the cytoplasm. In this case, the presence of debris can
make microscopic diagnosis more difficult. Courtesy of Centers for Disease Control and Prevention/
Steven Glenn, Laboratory & Consultation Division.

Image 82.4
Plasmodium falciparum ring-stage smears from patients. P falciparum rings have delicate cyto­plasm
and 1 or 2 small chromatin dots. Red blood cells (RBCs) that are infected are not enlarged; multiple
infection of RBCs is more common in P falciparum than in other species. Occasional appliqué forms
(rings appearing on the periphery of the RBC) can be present. A–C, Multiple infected RBCs with
appliqué forms in thin blood smears. D, Signet ring form. E, Double chromatin dot. F, A thick blood
smear showing many ringforms of P falciparum. Courtesy of Centers for Disease Control and
Prevention.

ERRNVPHGLFRVRUJ
366 Malaria

Image 82.5
This thin-film Giemsa-stained micrograph depicts a number of ringform Plasmodium falciparum
trophozoites. During the parasite’s development, the trophozoite represents an asexual, erythro­cytic
stage in which the organism loses its ring appearance and begins to accumulate pigment, which is
yellow to black in coloration. Courtesy of Centers for Disease Control and Prevention/Steven Glenn,
Laboratory & Consultation Division.

Image 82.6
Plasmodium ovale ring-stage parasites (smears from patients). P ovale rings have sturdy cyto­plasm
and large chromatin dots. Red blood cells (RBCs) are normal to slightly enlarged (x1.25), may be
round to oval, and are sometimes fim­briated. Schüffner dots are visible under optimal conditions.
A–B, P ovale rings in thin blood smears. A, Fimbriation of the infected RBC. B, Schüffner dots. C–D,
Rings of P ovale in thick blood smears. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Malaria 367

Image 82.7
Plasmodium vivax gametocytes (smears from patients). P vivax gametocytes are round to oval with
scattered brown pigment and may almost fill the red blood cell. Red blood cells are enlarged 1.5 to
2 times and may be distorted. Under optimal conditions, Schüffner dots may appear more fine than
those seen in Plasmodium ovale. Courtesy of Centers for Disease Control and Prevention.

Image 82.8
This thin-film Giemsa-stained micrograph depicts a mature Plasmodium vivax schizont containing
16 merozoites. Note the similarities seen in this platelet artifact to characteristics displayed by a
late-staged malarial schizont containing a number of merozoites. Maturing schizonts will eventually
rupture and release their cache of merozoites into the blood. Courtesy of Centers for Disease Control
and Prevention/Steven Glenn, Laboratory Training & Consultation Division.

Image 82.9
Plasmodium malariae ring-stage parasites (smears from patients). P malariae rings have sturdy
cytoplasm and a large chromatin dot. The red blood cells are normal to smaller than normal (x0.075)
in size. A–C, Ringforms in thin blood smears. D, A thick blood smear showing 2 rings (lower right) and
a gametocyte. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
368 Malaria

Image 82.10
Malaria-endemic countries in the western hemisphere. Centers for Disease Control and Prevention.

Image 82.11
Malaria-endemic countries in the eastern hemisphere. Centers for Disease Control and Prevention
National Center for Emerging and Zoonotic Infectious Diseases (NCEZID) Division of Global Migration
and Quarantine (DGMQ).

ERRNVPHGLFRVRUJ
Malaria 369

Image 82.12
Number of reported cases—United States and US territories, 2012. Courtesy of Morbidity and
Mortality Weekly Report.

Image 82.13
This photograph depicts an Anopheles funestus mosquito partaking in a blood meal from its human
host. Note the blood passing through the proboscis, which has penetrated the skin and entered a
miniscule cutaneous blood vessel. The A funestus mosquito, which, along with A gambiae, is 1 of the
2 most important malaria vectors in Africa, where more than 80% of the world’s malarial disease and
deaths occurs. Courtesy of Centers for Disease Control and Prevention/James Gathany.

ERRNVPHGLFRVRUJ
370 Malaria

Image 82.14
The malaria parasite life cycle involves 2 hosts. During a blood meal, a malaria-infected female
Anopheles species mosquito inoculates sporozoites into the human host (1). Sporozoites infect liver
cells (2) and mature into schizonts (3), which rupture and release merozoites (4). (Of note, in
Plasmodium vivax and Plasmodium ovale, a dormant stage [hypnozoites] can persist in the liver and
cause relapses by invading the bloodstream weeks, or even years, later.) After this initial replication in
the liver (exoerythrocytic schizogony) (A), the parasites undergo asexual multiplication in the
erythrocytes (erythrocytic schizogony) (B). Merozoites infect red blood cells (5). The ring-stage
trophozoites mature into schizonts, which rupture, releasing merozoites (6). Some parasites
differentiate into sexual erythrocytic stages (gametocytes) (7). Blood stage parasites are responsible
for the clinical manifestations of the disease. The gametocytes, male (microgametocytes) and female
(macrogametocytes), are ingested by an Anopheles species mosquito during a blood meal (8). The
parasite multiplication in the mosquito is known as the sporogonic cycle (C). While in the mosquito’s
stomach, the microgametes penetrate the macrogametes, generating zygotes (9). The zygotes, in turn,
become motile and elongated (ookinetes) (10) and invade the midgut wall of the mosquito, where they
develop into oocysts (11). The oocysts grow, rupture, and release sporozoites (12), which make their
way to the mosquito’s salivary glands. Inoculation of the sporozoites into a new human host
perpetuates the malaria life cycle (1). Courtesy of Centers for Disease Control and Prevention/
DPDx/Alexander J. da Silva, PhD, Melanie Moser.

ERRNVPHGLFRVRUJ
Malaria 371

Image 82.16
Histopathology of malaria exoerythrocytic forms
in liver. Courtesy of Centers for Disease Control
and Prevention/Dr Mae Melvin.

Image 82.15
The edema exhibited by this African child was
brought on by nephrosis associated with malaria.
Infection with one type of malaria, Plasmodium
falciparum, if not promptly treated, may cause
kidney failure. Swelling of the abdomen, eyes,
feet, and hands are some of the symptoms of
nephrosis brought on by the damaged kidneys. Image 82.17
Courtesy of Centers for Disease Control and Histopathology of malaria of brain. Mature
Prevention/Dr Myron Schultz. schizonts. Courtesy of Centers for Disease
Control and Prevention/Dr Martin D. Hicklin.

Image 82.18
A photomicrograph of placental tissue revealing Image 82.19
the presence of the malarial parasite Plasmodium Severe Plasmodium vivax malaria, Brazilian
falciparum. Maternal or placental malaria Amazon. Hand of a 2-year-old (patient no. 1) with
predisposes the newborn to a low birth weight, severe anemia (hemoglobin level 3.6 g/dL) and
premature delivery, and increased mortality, showing intense pallor, compared with the hand
and the mother to maternal anemia. Courtesy of a healthy physician. Courtesy of Emerging
of Centers for Disease Control and Prevention/ Infectious Diseases.
Edwin P. Ewing Jr, MD.

ERRNVPHGLFRVRUJ
372 Measles

83 by 20 years of age. The childhood and adoles-


cent immunization program in the United
Measles States has resulted in a greater than 99%
Clinical Manifestations decrease in the reported incidence of measles
and interruption of endemic disease transmis-
Measles is an acute viral disease characterized sion since measles vaccine was first licensed
by fever, cough, coryza, and conjunctivitis, in 1963.
followed by a maculopapular rash beginning
on the face and spreading cephalocaudally and From 1989 to 1991, the incidence of measles
centrifugally. During the prodromal period, a in the United States increased because of
pathognomonic enanthema (Koplik spots) low immunization rates in preschool-aged
may be present. Complications include otitis ­children, especially in urban areas. Following
media, bronchopneumonia, laryngotracheo- improved coverage in preschool-aged children
bronchitis (croup), and diarrhea and occur and implementation of a routine second dose
commonly in young children and immuno- of measles-mumps-rubella vaccine for chil-
compromised hosts. Acute encephalitis often dren, the incidence of measles declined to
results in permanent brain damage and occurs extremely low levels (<1 case per 1 million
in approximately 1 of every 1,000 cases. In the ­population). In 2000, an independent panel
postmeasles-elimination era, death, predomi- of internationally recognized experts unani-
nantly resulting from respiratory and neuro- mously agreed that measles was no longer
logic complications, has occurred in 1 to 3 of endemic in the United States. From 2001
every 1,000 cases in the United States. Case- through 2012, a median of 60 measles cases
fatality rates are increased in children younger were reported annually (range, 37–220). In
than 5 years and immunocompromised chil- 2008, 2011, and 2013, the numbers of reported
dren. Sometimes, the characteristic rash does cases were 140, 220, and 189, respectively; these
not develop in immunocompromised patients. larger numbers of cases were attributable to
an increase in the number of importations
Subacute sclerosing panencephalitis (SSPE) is or spread from importations. The number of
a rare degenerative central nervous system measles outbreaks (≥3 cases linked in time and
­disease characterized by behavioral and intel- space) that occurred ranged from 2 to 16 per
lectual deterioration and seizures that occur 7 year. In the first half of 2014, 514 measles cases
to 11 years after wild-type measles (incidence, from 16 outbreaks were reported in 20 states.
4 to 11 per 100,000 measles cases). Widespread Forty-eight separate importations occurred;
measles immunization has led to the virtual 81% were in unvaccinated people, 12% of those
disappearance of SSPE in the United States. infected had an unknown vaccination status
Etiology (78% of those were adults), and 7% of those
infected were vaccinated (including 5% with
Measles virus is an enveloped RNA virus with
2 or more doses). Among the unvaccinated
one serotype, classified as a member of the genus
people who became infected, 87% cited per-
Morbillivirus in the Paramyxoviridae family.
sonal belief exemptions for not being immu-
Epidemiology nized, 3% were unvaccinated travelers 6
months to 2 years of age, and 5% were too
The only natural host of measles virus is
young to be vaccinated. This is the largest
humans. Measles is transmitted by direct
number of measles cases in the United States
­contact with infectious droplets or, less com-
since 1994.
monly, by airborne spread. Measles is one of
the most highly communicable of all infectious Vaccine failure occurs in as many as 5% of
diseases. In temperate areas, the peak inci- ­people who have received a single dose of vac-
dence of infection usually occurs during late cine at 12 months or older. Although waning
winter and spring. In the prevaccine era, immunity after immunization may be a factor
most cases of measles in the United States in some cases, most cases of measles in previ-
occurred in preschool- and young school-aged ously immunized children seem to occur in
children, and few people remained susceptible people in whom response to the vaccine was

ERRNVPHGLFRVRUJ
Measles 373

inadequate (ie, primary vaccine failures). This of measles IgM assays varies by timing of
was the main reason a 2-dose vaccine schedule ­specimen collection, immunization status of
was routinely recommended for children and the case, and the assay. IgM capture assays
high-risk adults. often have positive results on the day of rash
onset. However, up to 20% of assays for IgM
Patients are contagious from 4 days before
may be negative in the first 72 hours after rash
the rash to 4 days after appearance of the rash.
onset. IgM is detectable for at least 1 month
Immunocompromised patients who may
after rash onset in unimmunized people but
have prolonged excretion of the virus in respi-
might be absent or present only transiently in
ratory tract secretions can be contagious for
people immunized with 1 or 2 vaccine doses. In
the duration of the illness. Patients with SSPE
populations with high vaccine coverage, such
are not contagious.
as the United States, it is recommended that
Incubation Period ­diagnostic testing for measles include serologic
and virologic testing. People with febrile rash
8 to 12 days from exposure to onset; in family
illness who are seronegative for measles IgM
studies, average interval between rash in the
should be tested for rubella using the same
index case is 14 days (range, 7–21 days).
specimens. Genotyping of viral isolates allows
Diagnostic Tests determination of patterns of importation and
Measles virus infection can be diagnosed by transmission, and genome sequencing can be
a positive serologic test result for measles used to differentiate between wild-type and
immunoglobulin (Ig) M antibody, a significant vaccine virus infection in those who have been
increase in measles IgG antibody concentra- immunized recently. All cases of suspected
tion in paired acute and convalescent serum measles should be immediately reported to
specimens (at least 10 days apart) by any stan- the local or state health department.
dard serologic assay, or isolation of measles Treatment
virus or identification of measles RNA (by
No specific antiviral therapy is available. Vita-
reverse transcriptase-polymerase chain reac-
min A treatment of children with measles in
tion assay) from clinical specimens, such as
developing countries has been associated with
throat or nasopharyngeal secretions. The sim-
decreased morbidity and mortality rates. Low
plest method of establishing the diagnosis of
serum concentrations of vitamin A have also
measles is testing for IgM antibody on a single
been found in children in the United States. All
serum specimen obtained during the first
children with measles should receive vitamin
encounter with a person suspected of having
A, regardless of their country of residence,
disease; if the result is positive, it is a good
once daily for 2 days.
measure for a presumptive case. The sensitivity

Image 83.1
This electron micrograph reveals a paramyxovirus measles virus and virions of the polyomavirus,
simian virus 40. Courtesy of Centers for Disease Control and Prevention/Dr Erskine Palmer.

ERRNVPHGLFRVRUJ
374 Measles

Image 83.2
Measles. Incidence, by year—United States, 1977–2012. Courtesy of Morbidity and Mortality
Weekly Report.

Image 83.3
Child with measles who exhibited an appearance
of feeling miserable. Image 83.4
Measles. This is the same patient as in
Image 83.3.

ERRNVPHGLFRVRUJ
Measles 375

Image 83.5
Image 83.6
Characteristic confluent measles rash over the Measles with Koplik spots.
back of this child.

Image 83.7 Image 83.8


Koplik spots of measles in a 7-year-old white boy. This child with measles is displaying the
Courtesy of Larry Frenkel, MD. characteristic red, blotchy pattern on his face and
body during the third day of the rash. Courtesy of
Centers for Disease Control and Prevention.

Image 83.9
This child with measles is showing the
characteristic red, blotchy rash on his buttocks Image 83.10
and back during the third day of the rash. This was a patient who presented with Koplik
Measles is an acute, highly communicable viral spots on the palate due to preeruptive measles
disease with prodromal fever, conjunctivitis, on day 3 of the illness. Measles is an acute,
coryza, cough, and Koplik spots on the buccal highly communicable viral disease with fever,
mucosa. A red, blotchy rash appears around conjunctivitis, coryza, cough, and Koplik spots.
day 3 of the illness, first on the face and then Koplik spots are small, red, irregularly shaped
becoming generalized. Courtesy of Centers for spots with blue-white centers found on the
Disease Control and Prevention. mucosal surface of the oral cavity. Courtesy of
Centers for Disease Control and Prevention/
Heinz F. Eichenwald, MD.

ERRNVPHGLFRVRUJ
376 Measles

Image 83.12
The near-confluent exanthem of measles in a
2-year-old white boy. Courtesy of Paul Wehrle,
MD.

Image 83.11
Measles in a 7-year-old white boy. Courtesy of
Paul Wehrle, MD.

Image 83.14
Measles pneumonia in a 6-year-old with acute
lymphoblastic leukemia. The child died of
respiratory failure.
Image 83.13
This late 1960s photograph shows a Nigerian
mother and her child, who was recovering from
measles. Note the skin is sloughing on the child
as he heals from his measles infection. This child
was among many who were cared for in camps
set up during the Centers for Disease Control
and Prevention–led refugee relief effort during the
Nigerian-Biafran war. Measles was a constant
threat in these camps. Sloughing of the skin in
recovering measles patients was often extensive
and resembled that of a burn victim. Due to their
Image 83.15
weakened state, children like the one shown here
needed nursing care to avoid subsequent Measles pneumonia with interstitial mononuclear
infections. Courtesy of Centers for Disease cell infiltration, multinucleated giant cells, and
Control and Prevention/Dr Lyle Conrad. hyaline membranes (hematoxylin-eosin stain,
original magnification x250).

ERRNVPHGLFRVRUJ
Measles 377

Image 83.16
Measles encephalitis in an immunosuppressed
patient who underwent renal transplantation with
viral intranuclear inclusion. Courtesy of Dimitris P.
Agamanolis, MD. Image 83.17
This coronal T2-weighted magnetic resonance
image shows swelling and hyperintensity of the
right parietal occipital cortex (arrows) in a patient
with measles encephalitis.

Image 83.18
A child with measles rash and conjunctivitis. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
378 Meningococcal Infections

84 term neurologic deficits, such as impaired


school performance, behavioral problems,
Meningococcal Infections and attention-deficit/hyperactivity disorder.
Clinical Manifestations Etiology
Invasive infection usually results in meningitis Neisseria meningitidis is a gram-negative
(~50% of cases), bacteremia (~35%–40% of ­diplococcus with at least 13 serogroups based
cases), or both. Bacteremic pneumonia is on capsular type.
uncommon (~9% of cases). Onset can be insi­d­
ious and nonspecific but is typically abrupt, Epidemiology
with fever, chills, malaise, myalgia, limb pain, Strains belonging to groups A, B, C, W, and Y
prostration, and a rash that can initially be are most commonly implicated in invasive
macular, maculopapular, petechial, or purpuric ­disease worldwide. Serogroup A has been
(meningococcemia). The maculopapular and ­frequently associated with epidemics outside
petechial rash is indistinguishable from the the United States, primarily in sub-Saharan
rash caused by some viral infections. Purpura Africa. A serogroup A meningococcal conju-
can also occur in severe sepsis caused by other gate vaccine was introduced in the “meningitis
bacterial pathogens. In fulminant cases, pur- belt” of sub-Saharan Africa in December 2010.
pura, limb ischemia, coagulopathy, pulmonary This novel vaccine is highly effective and has
edema, shock, coma, and death can ensue the potential to end epidemic meningitis as a
within hours despite appropriate therapy. Signs public health concern in sub-Saharan Africa.
and symptoms of meningococcal meningitis An increase in cases of serogroup W menin­
are indistinguishable from those associated gococcal disease has been associated with the
with acute meningitis caused by other menin- hajj pilgrimage in Saudi Arabia. Since 2002,
geal pathogens (eg, Streptococcus pneumoniae). serogroup W meningococcal disease has been
In severe and fatal cases of meningococcal reported in sub-Saharan African countries
meningitis, raised intracranial pressure is a during epidemic seasons. More recently, sero-
predominant presenting feature. The overall group W outbreaks have occurred in South
case-fatality rate for meningococcal disease is America. Prolonged outbreaks of serogroup B
10% to 15% and is somewhat higher in adoles- meningococcal disease have occurred in New
cents than infants. Death is more common in Zealand, France, and Oregon. More recently,
those with coma, hypotension, leukopenia, several clusters of serogroup B meningococcal
and thrombocytopenia and absence of menin- disease have occurred on college campuses in
gitis. Less common manifestations of menin- the United States. Serogroup X causes a sub-
gococcal infection include conjunctivitis, stantial number of cases of meningococcal
febrile occult bacteremia, septic arthritis, and ­disease in parts of Africa but is rare on
chronic meningococcemia. Invasive infections other continents.
can be complicated by arthritis, myocarditis,
pericarditis, and endophthalmitis. A self-­ The incidence of meningococcal disease varies
limiting postinfectious inflammatory syn- over time and by age and location. During the
drome occurs in fewer than 10% of cases 4 or past 60 years, the annual incidence of menin-
more days after onset of meningococcal infec- gococcal disease in the United States has varied
tion and most commonly presents as fever, from less than 0.3 to 1.5 cases per 100,000 pop-
arthritis, or vasculitis. Iritis, scleritis, conjunc- ulation. Incidence cycles have occurred over
tivitis, pericarditis, and polyserositis are less multiple years. Since the early 2000s, annual
common manifestations of postinfectious incidence rates have decreased, and since 2005,
inflammatory ­syndrome. only an estimated 800 to 1,000 US cases have
been reported annually. The reasons for this
Sequelae associated with meningococcal ­disease decrease, which preceded introduction of
occur in 11% to 19% of survivors and include meningococcal polysaccharide-protein conju-
hearing loss, neurologic disability, digit or limb gate vaccine into the immunization schedule,
amputations, and skin scarring. In addition, are not known but may be related to immunity
some patients may also experience subtle long-

ERRNVPHGLFRVRUJ
Meningococcal Infections 379

of the population to circulating meningococcal electrophoresis, and pulsed-field gel electro-


strains and changes in behavioral risk factors phoresis of enzyme-restricted DNA fragments
(eg, smoking and exposure to secondhand can be useful epidemiologic tools during a sus-
smoke among adolescents and young adults). pected outbreak to detect concordance among
invasive strains.
Distribution of meningococcal serogroups
in the United States has shifted in the past Incubation Period
2 decades. Serogroups B, C, and Y each account 1 to 10 days (usually <4 days).
for approximately 30% of reported cases, but
serogroup distribution varies by age, location, Diagnostic Tests
and time. Approximately three-quarters of Cultures of blood and cerebrospinal fluid are
cases among adolescents and young adults are indicated for patients with suspected invasive
caused by serogroups C, W, or Y and poten- meningococcal disease. Culture of a petechial
tially are preventable with available vaccines. or purpuric lesion scraping, synovial fluid,
In infants and children younger than 5 years, and other, usually sterile body fluid specimens
60% of cases are caused by serogroup B and, yield the organism in some patients. A Gram
therefore, are not preventable with vaccines stain of a petechial or purpuric scraping, cere-
licensed in the United States for those ages. brospinal fluid, and buffy coat smear of blood
Since introduction in the United States of can be helpful. Because N meningitidis can be
­Haemophilus influenzae type b and pneumo- a component of the nasopharyngeal flora,
coccal polysaccharide-protein conjugate vac- ­isolation of N meningitidis from this site is not
cines for infants, N meningitidis has become helpful diagnostically. A serogroup-specific
the leading cause of bacterial meningitis in polymerase chain reaction (PCR) test to detect
children and remains an important cause N meningitidis from clinical specimens is used
of septicemia. The peak incidence occurs in routinely in the United Kingdom and some
infants. Other peaks occur in adolescents and European countries, where up to 56% of cases
young adults 16 through 21 years of age and are confirmed by PCR testing alone. This test
adults older than 65 years. Close contacts of is particularly useful in patients who receive
patients with meningococcal disease are at antimicrobial therapy before cultures are
increased risk of becoming infected. Patients obtained. In the United States, PCR-based
with persistent complement component defi- assays are available in some research and pub-
ciencies (eg, C5–C9, properdin, factor H or lic health laboratories. A recently described
factor D deficiencies) or anatomic or functional multiplex PCR assay appears to have a sensi­
asplenia are at increased risk of invasive and tivity and specificity approaching 100% for
recurrent meningococcal disease. Asymptom- detection of serogroups A, B, C, W, and Y.
atic colonization of the upper respiratory tract Case definitions for invasive meningococcal
provides the source from which the organism disease are given in Box 84.1.
is spread. The highest rates of meningococcal
colonization occur in older adolescents and Treatment
young adults. Transmission occurs from per- The priority in management of meningococcal
son to person through droplets from the respi- disease is treatment of shock in meningo­coc­
ratory tract and requires close contact. cemia and of raised intracranial pressure
Outbreaks occur in communities and institu- in severe cases of meningitis. Empirical
tions, including child care centers, schools, ­t herapy for suspected meningococcal disease
colleges, and military recruit camps. However, should include an extended-spectrum
most cases of meningococcal disease are ­cephalosporin, such as cefotaxime or ceftri­
­sporadic, with fewer than 5% associated axone. Once the microbiologic diagnosis is
with outbreaks. The attack rate for household established, definitive treatment with peni­
contacts is 500 to 800 times the rate for the cillin G (300,000 U/kg/d), ampicillin, or an
general population. Serologic typing, multi­ extended-spectrum cephalosporin is recom-
locus sequence typing, multilocus enzyme mended. ­Ceftriaxone clears nasopharyngeal

ERRNVPHGLFRVRUJ
380 Meningococcal Infections

Box 84.1
Surveillance Case Definitions for Invasive Meningococcal Disease

Confirmed Case

A clinically compatible case and isolation of Neisseria meningitidis from a usually sterile site; for
example
• Blood
• Cerebrospinal fluid
• Synovial fluid
• Pleural fluid
• Pericardial fluid
• Isolation from skin scraping of petechial or purpuric lesions

Probable Case

A clinically compatible case with either a positive result of antigen test or immunohistochemistry
of formalin-fixed tissue or a positive polymerase chain reaction test of blood or cerebrospinal
fluid, without a positive sterile site culture.

Suspect

• A clinically compatible case and gram-negative diplococcic in any sterile fluid, such as
­cerebrospinal fluid, synovial fluid, or scraping from a petechial or purpuric lesion
• Clinical purpura fulminans without a positive culture

carriage effectively after one dose and allows t­ ravelers from areas where penicillin resistance
outpatient management for completion of has been reported, cefotaxime, ceftriaxone, or
­t herapy when appropriate. For patients with chloramphenicol is recommended. In menin-
a life-threatening penicillin allergy charac­ gococcemia, early and rapid fluid resuscitation
terized by anaphylaxis, chloramphenicol is and early use of inotropic and ventilatory sup-
recommended, if available. If chlorampheni- port may reduce mortality. The postinfectious
col is not available, meropenem can be used, inflammatory syndromes associated with
although the rate of cross-reactivity in meningococcal disease often respond to non-
­penicillin-allergic adults is 2% to 3%. For steroidal anti-inflammatory drugs.

Image 84.1
This micrograph depicts the presence of aerobic gram-negative Neisseria meningitidis diplococcal
bacteria (magnification x1,150). Meningococcal disease is an infection caused by a bacterium called
N meningitidis or meningococcus. Courtesy of Centers for Disease Control and Prevention/Dr Brodsky.

ERRNVPHGLFRVRUJ
Meningococcal Infections 381

Image 84.2
Meningococcal disease. Incidence, by year—United States, 1982–2012. Courtesy of Morbidity and
Mortality Weekly Report.

Image 84.3
Areas with frequent epidemics of meningococcal meningitis. Centers for Disease Control and
Prevention National Center for Emerging and Zoonotic Infectious Diseases (NCEZID) Division of
Global Migration and Quarantine (DGMQ).

ERRNVPHGLFRVRUJ
382 Meningococcal Infections

Image 84.5
The arm of the boy shown in Image 84.4, which
Image 84.4
demonstrates striking extremity involvement and
Young boy with meningococcemia that demon­
characteristic angular lesions. Copyright Martin
strates striking involvement of the extremities with
G. Myers, MD.
sparing of the trunk. Copyright Martin G. Myers,
MD.

Image 84.7
Meningococcemia. This image shows the lower
Image 84.6
extremities of the patient in Image 84.6.
Meningococcemia showing striking involvement
of the extremities with relative sparing of the skin
of the child’s body surface.

Image 84.9
Characteristic, angular, necrotic lesions on the
Image 84.8
foot of infant boy with meningococcemia (after
Papular skin lesions of early meningococcemia.
2 days of intravenous penicillin treatment).

ERRNVPHGLFRVRUJ
Meningococcal Infections 383

Image 84.10
Preschool-aged girl with meningococcal pan­
Image 84.11
ophthal­mitis. An infant sibling had meningococcal
This 6-month-old boy presented with fever and
meningitis 1 week prior to the onset of this
erythema and tenderness over the ankle. Blood
child’s illness.
culture and needle aspirate of the cellulitis grew
Neisseria meningitidis. Courtesy of Neal Halsey, MD.

Image 84.13
Patient shown in Image 84.12 with marked
purpura of the left foot.

Image 84.12
Meningococcemia in an adolescent female with
disseminated intravascular coagulation.

Image 84.15
Patient shown in images 84.12, 84.13, and 84.14
with cutaneous necrosis.

Image 84.14
Patient shown in images 84.12 and 84.13 with
gangrene of the toes.

ERRNVPHGLFRVRUJ
384 Meningococcal Infections

Image 84.17
Adrenal hemorrhage in a patient with gram-
negative sepsis, a major complication of
meningococcal disease with increased mortality.
Courtesy of Dimitris P. Agamanolis, MD.

Image 84.16
Hemorrhagic adrenal glands from a 2-year-old
who had the characteristic histopathology of
Waterhouse-Friderichsen syndrome at autopsy.
Courtesy of George Nankervis, MD.

Image 84.19
Meningococcemia in an infant boy. Courtesy of
Ed Fajardo, MD.

Image 84.18
Fatal meningococcal meningitis with purulent
exudate in the subarachnoid space covering
the cerebral convexities. Courtesy of Dimitris P.
Agamanolis, MD.

ERRNVPHGLFRVRUJ
Human Metapneumovirus 385

85 may occur throughout the year. In otherwise


healthy infants, the duration of viral shedding
Human Metapneumovirus is 1 to 2 weeks. Prolonged shedding (months)
Clinical Manifestations has been reported in severely immunocompro-
mised hosts.
Since its discovery in 2001, human meta­
pneumovirus (hMPV) has been shown to Serologic studies suggest most children are
cause acute respiratory tract illness in people infected at least once by 5 years of age. The
of all ages. Human metapneumovirus is one of population incidence of hospitalizations
the leading causes of bronchiolitis in infants ­attributable to hMPV is generally thought
and also causes pneumonia, asthma exacerba- to be lower than that attributable to RSV but
tions, croup, and upper respiratory tract infec- comparable to that of influenza and para­
tions with concomitant acute otitis media in influenza virus 3 in children younger than
children. Human metapneumovirus is also 5 years. Large studies have shown that hMPV
associated with acute exacerbations of chronic is detected in 6% to 7% of children with lower
obstructive pulmonary disease and pneumonia respiratory illnesses who are hospitalized or
in adults. Otherwise healthy young children seen in the outpatient and emergency depart-
infected with hMPV usually have mild or ments. Overall annual rates of hospitalization
­moderate symptoms, but some young children associated with hMPV infection are about
have severe disease requiring hospitalization. 1 per 1,000 children younger than 5 years, 2 per
Human metapneumovirus infection in 1,000 infants 6 to 11 months of age, and 3 per
­immunosuppressed people can result in 1,000 infants younger than 6 months. Coinfec-
severe ­disease, and fatalities have been tion with RSV and other respiratory viruses
reported in hematopoietic stem cell or lung can occur.
transplant recipients. Preterm birth and
Incubation Period
­underlying cardiopulmonary disease are
likely risk factors, but degree of risk associated An estimated 3 to 5 days.
with these conditions is not fully defined. Diagnostic Tests
Recurrent infection occurs throughout life
and, in previously healthy people, is usually Human metapneumovirus can be difficult to
mild or ­asymptomatic. isolate in cell culture. Reverse transcriptase-
polymerase chain reaction assays are the diag-
Etiology nostic method of choice for hMPV. Several
Human metapneumovirus is a single-stranded, reverse transcriptase-­polymerase chain reac-
negative-sense RNA virus of the family Para- tion assays for hMPV are available commer-
myxoviridae. Four major genotypes of virus cially. Immunofluorescence assays using
have been ­identified with 2 major antigenic monoclonal antibodies for hMPV antigen are
subgroups (designated A and B). These differ- also available, with reported sensitivities vary-
ent subgroups cocirculate each year. ing from 65% to 90%.

Epidemiology Treatment
Humans are the only source of infection. Treatment is supportive and includes hydration
Transmission studies have not been reported, and careful clinical assessment of respiratory
but spread is likely to occur by direct or close status, including measurement of oxygen
contact with contaminated secretions. Health ­saturation, use of supplemental oxygen, and,
care–associated infections have been reported. if ­necessary, mechanical ventilation. Anti­
Human metapneumovirus infections usually microbial agents are not indicated in the
occur annually ­during winter and early spring ­treatment of infants hospitalized with uncom-
in temperate climates, coinciding or overlap- plicated hMPV bronchiolitis or pneumonia
ping with the latter half of the respiratory syn- unless evidence exists for the presence of a
cytial virus (RSV) season. Sporadic infection ­concurrent bacterial infection.

ERRNVPHGLFRVRUJ
386 Microsporidia Infections

86 role in transmission is unknown. Data suggest


the possibility of zoonotic transmission.
Microsporidia Infections
(Microsporidiosis) Incubation Period
Unknown.
Clinical Manifestations
Patients with intestinal infection have watery, Diagnostic Tests
nonbloody diarrhea, generally without fever. Infection with gastrointestinal Microsporida
Abdominal cramping can occur. Data suggest species can be documented by identification of
asymptomatic infection is more common than organisms in biopsy specimens from the small
previously thought. Symptomatic intestinal intestine. Microsporida species spores can also
infection is most common in immunocompro- be detected in formaldehyde solution–fixed
mised people, especially in organ transplant stool specimens or duodenal aspirates stained
recipients and people who are infected with with a chromotrope-based stain and examined
HIV with low CD4+ lymphocyte counts, in by an experienced microscopist. Chemofluo-
whom infection often results in chronic diar- rescent agents like calcofluor, as well as Gram,
rhea. The clinical course can be complicated acid-fast, periodic acid-Schiff, Warthin-Starry
by malnutrition and progressive weight loss. silver, and Giemsa stains, can also be used to
Chronic infection in immunocompetent peo- detect organisms in tissue sections. Organisms
ple is rare. Other clinical syndromes that can are not often noticed because they are small
occur in HIV-infected and immunocompro- (1–4 μm), stain poorly, and evoke minimal
mised patients include keratoconjunctivitis, inflammatory response. Stool concentration
encephalitis, sinusitis, dermatitis, myositis, techniques do not improve the ability to detect
osteomyelitis, nephritis, hepatitis, cholangitis, E bieneusi spores. Polymerase chain reaction
peritonitis, prostatitis, urethritis, cystitis, dis- assay can also be used for diagnosis. Identifica-
seminated disease, pulmonary disease, cardiac tion for classification purposes and diagnostic
disease, and wasting syndrome. confirmation of species requires transmission
electron microscopy or molecular techniques.
Etiology
Microsporidia are obligate intracellular, Treatment
s­ pore-forming organisms classified as fungi. Restoration of immune function is critical
Enterocytozoon bieneusi and Encephalitozoon for control of any microsporidia infection.
intestinalis are the most commonly reported For a limited number of patients, albendazole,
pathogens in humans and are most often asso- fumagillin, metronidazole, atovaquone, and
ciated with chronic diarrhea in HIV-infected nitazoxanide have been reported to decrease
people. Multiple genera, including Encephalito­ diarrhea but without eradication of the
zoon, Enterocytozoon, Nosema, Pleistophora, ­organism. Albendazole is the drug of choice
Trachipleistophora, Anncaliia, Vittaforma, and for infections caused by E intestinalis but is
Microsporida, have been implicated in human ineffective against E bieneusi and Vittaforma
infection, as have unclassified species. corneae infections, which may respond to
fumagillin. However, fumagillin is associated
Epidemiology
with bone marrow toxicity, recurrence of diar-
Most microsporidia infections are transmitted rhea is common after therapy is discontinued,
by oral ingestion of spores. Microsporidia and the drug is not available in the United
spores are commonly found in surface water, States. In patients infected with HIV, anti­
and human strains have been identified in retroviral therapy, which is associated with
municipal water supplies and ground water. improvement in the CD4+ T-lymphocyte count,
Several studies indicate waterborne transmis- can modify the course of disease favorably
sion occurs. Person-to-person spread by the and should be considered as a main part of
fecal-oral route also occurs. Spores have also the treatment plan. None of these therapies
been detected in other body fluids, but their have been studied in children.

ERRNVPHGLFRVRUJ
Microsporidia Infections 387

Image 86.2
Transmission electron micrograph showing
developing forms of Encephalitozoon intestinalis
inside a parasitophorous vacuole (red arrows)
with mature spores (black arrows). Microspori­
diosis, parasite. Courtesy of Centers for Disease
Control and Prevention.

Image 86.1
Transmission electron micrographs showing
developmental intracellular stages of micro­
sporidia. Courtesy of Centers for Disease
Control and Prevention.

Image 86.3
Transmission electron micrograph of a mature microsporidia spore. Black arrows indicate the
electron dense cell wall and red arrows, the coils of polar tubule. Although polymerase chain
reaction can be used for diagnosis, serologic tests are unreliable. Courtesy of Centers for Disease
Control and Prevention.

ERRNVPHGLFRVRUJ
388 Microsporidia Infections

Image 86.4
The infective form of microsporidia is the resistant spore and it can survive for a long time in the
environment (1). The spore extrudes its polar tubule and infects the host cell (2). The spore injects
the infective sporoplasm into the eukaryotic host cell through the polar tubule (3). Inside the cell,
the sporoplasm undergoes extensive multiplication by merogony (binary fission) (4) or schizogony
(multiple fission). This development can occur in direct contact with the host cell cytoplasm (eg,
Enterocytozoon bieneusi) or inside a vacuole termed parasitophorous vacuole (eg, Enterocytozoon
intestinalis). Free in the cytoplasm or inside a parasitophorous vacuole, microsporidia develop by
sporogony to mature spores (5). During sporogony, a thick wall is formed around the spore that
provides resistance to adverse environmental conditions. When the spores increase in number and
completely fill the host cell cytoplasm, the cell membrane is disrupted and releases the spores to
the surroundings (6). These free mature spores can infect new cells, thus continuing the cycle.
Courtesy of Centers for Disease Control and Prevention/Alexander J. da Silva, PhD/Melanie Moser.

ERRNVPHGLFRVRUJ
Molluscum Contagiosum 389

87 Diagnostic Tests

Molluscum Contagiosum The diagnosis can usually be made clinically


from the characteristic appearance of the
Clinical Manifestations lesions. Wright or Giemsa staining of cells
Molluscum contagiosum is a benign viral expressed from the central core of a lesion
infection of the skin with no systemic manifes- reveals characteristic intracytoplasmic inclu-
tations. It is usually characterized by 1 to sions. Electron microscopic examination of
20 discrete, 2- to 5-mm–diameter, flesh-colored these cells identifies typical poxvirus particles.
to translucent, dome-shaped papules, some Adolescents and young adults with genital
with central umbilication. Lesions commonly molluscum contagiosum should be tested for
occur on the trunk, face, and extremities but sexually transmitted infections.
are rarely generalized. Molluscum contagiosum Treatment
is a self-limited epidermal infection that usu-
ally resolves spontaneously in 6 to 12 months There is no consensus on management of
but may take as long as 4 years to disappear ­molluscum contagiosum in children and
completely. An eczematous reaction encircles ­adolescents. Genital lesions should be treated
lesions in approximately 10% of patients. Peo- to prevent spread to sexual contacts. Treatment
ple with eczema, immunocom­promising con- of nongenital lesions is mainly for cosmetic
ditions, and HIV infection tend to have more reasons. Lesions in healthy people are typically
widespread and prolonged ­eruptions. self-limited, and treatment may not be neces-
sary. However, therapy may be warranted to
Etiology alleviate discomfort, including itching; reduce
The cause is a poxvirus, which is the sole mem- autoinoculation; limit transmission of the
ber of the genus Molluscipoxvirus. virus to close contacts; reduce cosmetic
­concerns; and prevent secondary infection.
Epidemiology Physical destruction of the lesions is the most
Humans are the only known source of the rapid and effective means of curing molluscum
virus, which is spread by direct contact, contagiosum. Modalities available include
­including sexual contact, or by fomites. Verti- curettage, cryotherapy with liquid nitrogen,
cal transmission has been suggested in case electrodesiccation, and chemical agents
reports of neonatal molluscum contagiosum designed to initiate a local inflammatory
infection. Lesions can be disseminated by response (eg, podophyllin, tretinoin, can­
­autoinoculation. Infectivity is generally low, tharidin, 25%–50% trichloroacetic acid, lique-
but occasional outbreaks have been reported, fied phenol, silver nitrate, tincture of iodine,
including outbreaks in child care centers. The potassium hydroxide). Cidofovir is a cytosine
period of communicability is unknown. nucleotide analogue with in vitro activity
against molluscum contagiosum; cidofovir
Incubation Period should be reserved for extreme cases because of
2 to 7 weeks, but can be as long as 6 months. potential carcinogenicity and known toxicities.
Solitary genital lesions in children are usually
not acquired by sexual transmission but rather
other modes of direct contact with the virus,
including ­autoinoculation.

ERRNVPHGLFRVRUJ
390 Molluscum Contagiosum

Image 87.2
Image 87.1 A central dimple or umbilication is the hallmark
Molluscum contagiosum lesions adjacent to of molluscum contagiosum. The lesions of
nasal bridge. Copyright Edgar K. Marcuse, MD. molluscum contagiosum vary in size from 1 to
6 mm and, unlike venereal warts, are smooth
and pearly and have an umbilicated center.

Image 87.3
Molluscum contagiosum is characterized by one Image 87.4
or more translucent or white papules. A molluscum contagiosum lesion with
Intracytoplasmic inclusions may be seen with characteristic umbilication.
Wright or Giemsa staining of material expressed
from the core of a lesion.

Image 87.5
Pearly papules on the forehead and eyelid in a child with molluscum contagiosum lesions, which
commonly occur on the face.

ERRNVPHGLFRVRUJ
Molluscum Contagiosum 391

Image 87.6
This 10-year-old girl has had multiple small bumps on the face for the past month. These started as a
solitary papule on her eyebrow but spread over several weeks. They have developed a small pointed
core and are an embarrassment to the child. School pictures are pending. The family demands
treatment. There is a family history of keloids. The family was counseled on the limited treatment
options due to the potential for permanent scarring and keloid formation. Consultation with a
dermatologist was arranged at the parents’ request. Courtesy of Will Sorey, MD.

Image 87.7
A 15-year-old boy with HIV with numerous and widespread molluscum contagiosum lesions. Courtesy
of Larry Frenkel, MD.

Image 87.8
This healthy 5-year-old boy with widespread molluscum was started on home treatment with a topical
liquid salicylic acid preparation. He developed itchy crusted erosions around the treated lesions.
Topical therapy was discontinued and a topical antibiotic ointment was prescribed with rapid clearing
of the irritant dermatitis. Courtesy of H. Cody Meissner, MD, FAAP.

ERRNVPHGLFRVRUJ
392 Mumps

88 ­ revaccine era to 2 per 100,000 in 1988. After


p
implementation of the 2-dose measles-mumps-
Mumps rubella vaccine recommendation in 1989,
Clinical Manifestations mumps further declined to extremely low
­levels, with an incidence of 0.1 per 100,000 by
Mumps is a systemic disease characterized by 1999. From 2000 to 2005, seasonality was no
swelling of one or more of the salivary glands, longer evident, and there were fewer than 300
usually the parotid glands. Approximately reported cases per year (incidence of 0.1 per
one-third of infections do not cause clinically 100,000), representing a greater than 99%
apparent salivary gland swelling and can be reduction in disease incidence. In early 2006,
asymptomatic (subclinical) or manifest pri- a large-scale mumps outbreak occurred in the
marily as respiratory tract infection. More than Midwestern United States, with 6,584 reported
50% of people with mumps have cerebrospinal cases (incidence of 2.2 per 100,000). Most of
fluid pleocytosis, but fewer than 10% have the cases occurred among people 18 through
symptoms of viral meningitis. Orchitis is a 24 years of age, many of whom were college
commonly reported complication after students who had received 2 doses of mumps
puberty, although sterility rarely results. Rare vaccine. Another outbreak in 2009–2010
complications include arthritis, thyroiditis, affected more than 3,500 people, mainly
mastitis, glomerulonephritis, myocarditis, ­students in grades 6 through 12 who were
endocardial fibroelastosis, thrombocytopenia, members of traditional observant religious
cerebellar ataxia, transverse myelitis, encepha- communities in New York and New Jersey
litis, pancreatitis, oophoritis, and permanent and who had received 2 doses of measles-
hearing impairment. Infection in adults is mumps-rubella vaccine. Two doses of the
more likely to result in complications. Whether mumps vaccine are approximately 88% effec-
first trimester maternal mumps causes spon­ tive in preventing disease. The period of
taneous abortion or intrauterine fetal death is ­maximum communicability begins several
uncertain, and this does not result in congeni- days before parotitis onset. The recommended
tal malformation. isolation period is for 5 days after onset of
Etiology parotid swelling.
Mumps is an RNA virus in the Paramyxoviri- Incubation Period
dae family. Other infectious causes of parotitis 16 to 18 days, but occasionally 12 to 25 days
include Epstein-Barr virus, cytomegalovirus, after exposure.
parainfluenza virus, influenza A virus, entero-
viruses, lymphocytic choriomeningitis virus, Diagnostic Tests
HIV, nontuberculous mycobacteria, and gram- Despite the outbreaks in 2006 and 2009–2010,
positive and, less often, gram-negative bacteria. mumps remains an uncommon infection in
Epidemiology the United States, and parotitis has other eti-
ologies, including other infectious agents. Peo-
Mumps occurs worldwide, and humans are ple with parotitis without other apparent cause
the only known natural hosts. The virus is should undergo diagnostic testing to confirm
spread by contact with infectious respiratory mumps virus as the cause or to diagnose other
tract secretions and saliva. Mumps virus is etiologies. Mumps can be confirmed by detec-
the only known cause of epidemic parotitis. tion of mumps virus nucleic acid via reverse
Historically, the peak incidence of mumps was transcriptase-polymerase chain reaction assay
between January and May and among children in specimens from buccal swabs (Stensen duct
younger than 10 years. Mumps vaccine was exudates), throat washings, saliva, or spinal
recommended for routine childhood immuni- fluid; by detection of mumps-specific immuno-
zation in 1977. After implementation of the globulin (Ig) M antibody; or by a significant
one-dose mumps vaccine recommendation, increase between acute and convalescent titers
the incidence of mumps in the United States
declined from 50 to 251 per 100,000 in the

ERRNVPHGLFRVRUJ
Mumps 393

in serum mumps IgG antibody titer deter- acute and convalescent specimens. Emphasis
mined by standard quantitative or semi­ should be placed on obtaining clinical speci-
quantitative serologic assay. mens within 1 to 3 days after onset of parotitis.
In immunized people, a negative IgM result
Confirming the diagnosis of mumps in highly
does not rule out mumps.
immunized populations is challenging because
the IgM response may be absent or short lived; Treatment
acute IgG titers might already be high, so no There is no antiviral therapy, so therapy
significant increase can be detected between is ­supportive.

Image 88.1
Electron micrograph of the mumps virus. The mumps virus is a member of the Paramyxoviridae family
and is enveloped by a helical ribonucleic-protein capsid, which has a Herring-body–like appearance.
Courtesy of Centers for Disease Control and Prevention/Dr F. A. Murphy.

Image 88.2
Thin-section electron micrograph of mumps virus. Filamentous nucleocapsids can be seen within
viral particles and juxtaposed along the viral envelope. Courtesy of Centers for Disease Control
and Prevention/Courtesy of A. Harrison and F. A. Murphy.

ERRNVPHGLFRVRUJ
394 Mumps

Image 88.3
Mumps. Incidence, by year—United States, 1987–2012. Courtesy of Morbidity and Mortality
Weekly Report.

Image 88.5
This is a photograph of a patient with bilateral
swelling in the submaxillary regions due to
mumps. Prior to vaccine licensure in 1967,
Image 88.4 100,000 to 200,000 mumps cases are estimated
Mumps with parotid and submandibular involve­ to have occurred in the United States each
ment bilaterally. The differential diagnosis for year. Courtesy of Centers for Disease Control
acute infectious parotitis includes cytomegalo­virus, and Prevention/Dr Heinz F. Eichenwald.
parainfluenza viruses, lymphocytic choriomenin­
gitis, coxsackieviruses and other enteroviruses,
HIV, nontuberculous mycobac­terium, and certain
bacteria. Copyright Martha Lepow.

ERRNVPHGLFRVRUJ
Mumps 395

Image 88.6
Mumps parotitis with cervical and presternal edema and erythema that resolved spontaneously.

Image 88.7
Swelling and erythema of the Stensen duct in a 10-year-old white boy with mumps parotitis. Courtesy
of Paul Wehrle, MD.

Image 88.8
Mumps orchitis in a 6-year-old boy. This complication is unusual in prepubertal boys. The highest risk
for orchitis is in males between 15 and 29 years of age.

ERRNVPHGLFRVRUJ
396 MYCOPLASMA PNEUMONIAE AND OTHER MYCOPLASMA SPECIES INFECTIONS

89 Several other Mycoplasma species colonize


mucosal surfaces of humans and can produce
Mycoplasma pneumoniae disease in children. Mycoplasma hominis
and Other Mycoplasma ­infection has been reported in neonates
(­especially at scalp electrode monitor site) and
Species Infections children (immunocompetent and immuno-
Clinical Manifestations compromised). Intra-abdominal abscesses,
Mycoplasma pneumoniae is a frequent cause septic arthritis, endocarditis, pneumonia,
of upper and lower respiratory tract infections meningoencephalitis, brain abscess, and surgi-
in children, including pharyngitis, acute bron- cal wound infections have all been reported.
chitis, and pneumonia. Acute otitis media is Etiology
uncommon. Bullous myringitis, once consid-
Mycoplasmas, including M pneumoniae, are
ered pathognomonic for mycoplasma, is now
pleomorphic bacteria that lack a cell wall.
known to occur with other pathogens as well.
Mycoplasmas cannot be detected using
Coryza, sinusitis, and croup are rare. Symp-
light microscopy.
toms are variable and include cough, malaise,
fever, and, occasionally, headache. Acute bron- Epidemiology
chitis and upper respiratory tract illness caused
Mycoplasmas are ubiquitous in animals and
by M pneumoniae are generally mild and self-
plants, but M pneumoniae causes disease only
limited. Approximately 10% of infected school-
in humans. M pneumoniae is transmissible
aged children will develop pneumonia with
by respiratory droplets during close contact
cough and widespread rales on physical exami-
with a symptomatic person. Outbreaks have
nation within days after onset of constitutional
been described in hospitals, military bases,
symptoms. Cough is often initially nonproduc-
colleges, and summer camps. Occasionally,
tive but later can become productive. Cough
M pneumoniae causes ventilator-associated
can persist for 3 to 4 weeks and can be accom-
pneumonia. M pneumoniae is a leading cause
panied by wheezing. Approximately 10% of
of pneumonia in school-aged children and
children with M pneumoniae infection will
young adults but is an infrequent cause of
exhibit a rash, which is most often maculopap-
­community-acquired pneumonia in pre­school-
ular. Radiographic abnormalities are variable.
aged children. In the United States, an esti-
Bilateral diffuse infiltrates or focal abnormali-
mated 2 million infections are caused by
ties, such as consolidation, effusion, or hilar
M pneumoniae each year; approximately
adenopathy, can occur.
20% of hospitalized community-acquired
Unusual manifestations include nervous system pneumonia cases may be caused by
disease (eg, aseptic meningitis, encephalitis, M ­pneumoniae. Infections occur throughout
acute disseminated encephalomyelitis, cere­ the world, in any season, and in all geographic
bellar ataxia, transverse myelitis, peripheral settings. In family studies, approximately 30%
neuropathy), as well as myocarditis, pericar­ of household contacts develop pneumonia.
ditis, arthritis, erythema nodosum, polymor- Asymptomatic carriage after infection may
phous mucocutaneous eruptions (including occur for weeks to months. Immunity after
classic and atypical Stevens-Johnson syndrome), infection is not long lasting.
hemolytic anemia, thrombocytopenic purpura,
Incubation Period
and hemophagocytic syndromes. In patients
with sickle cell disease, Down syndrome, 2 to 3 weeks (range, 1 to 4 weeks).
immunodeficiencies, and chronic cardiorespi- Diagnostic Tests
ratory disease, severe pneumonia with pleural
effusion can develop. Acute chest syndrome M pneumoniae can be grown in special
and pneumonia have been associated with enriched broth followed by passage to SP4 agar
M pneumoniae in patients with sickle cell media or on commercially available mixed liq-
­disease. Infection has also been associated uid broth/agar slant media, but most clinical
with exacerbations of asthma. facilities lack the capacity to perform this

ERRNVPHGLFRVRUJ
MYCOPLASMA PNEUMONIAE AND OTHER MYCOPLASMA SPECIES INFECTIONS 397

c­ ulture. Serologic tests using immunofluores- respiratory tract for several weeks after acute
cence and enzyme immunoassays that detect infection, even after appropriate antimicrobial
M pneumoniae–specific immunoglobulin (Ig) therapy. Polymerase chain reaction assay of
M and IgG antibodies are available commer- body fluids for M hominis is available at refer-
cially. IgM antibodies are not generally ence laboratories.
­detectable within the first 7 days after onset
Treatment
of symptoms. IgM antibody titer peaks at
approximately 3 to 6 weeks and persists for 2 to Evidence of benefit of antimicrobial therapy for
3 months after infection. Although the pres- nonhospitalized children with lower respira-
ence of IgM antibodies may indicate recent tory tract disease attributable to M pneumoniae
M pneumoniae infection, false-positive test is limited. Some data suggest benefit of appro-
results occur and may not indicate current priate antimicrobial therapy in hospitalized
infection. Serologic diagnosis is best made by children. Antimicrobial therapy is not recom-
demonstrating a 4-fold or greater increase in mended for preschool-aged children with
antibody titer between acute and convalescent ­community-acquired pneumonia because
serum specimens. Measurement of serum cold viral pathogens are responsible for the great
hemagglutinin titer has limited value. majority of cases. There is no evidence that
treatment of other possible manifestations of
Polymerase chain reaction (PCR) tests for M ­pneumoniae infection (eg, upper respiratory
M pneumoniae are available commercially tract infection, extrapulmonary infection) with
and are increasingly replacing other tests antimicrobial agents alters the course of illness.
because PCR tests performed on respiratory Macrolides, including azithromycin, clarithro-
tract specimens (nasal wash, nasopharyngeal mycin, and erythromycin, are the preferred
swab, pharyngeal swab) have sensitivity and antimicrobial agents for treatment of pneumo-
specificity between 80% and 100%, yield posi- nia in school-aged children who have moderate
tive results earlier in the course of illness than to severe infection and those with underlying
serologic tests, and are rapid. Identification of conditions, such as sickle cell disease. Fluoro-
M ­pneumoniae by PCR or culture in a patient quinolones and doxycycline are also effective
with compatible clinical manifestations sug- in adolescents. Macrolide-resistant strains are
gests causation; attributing a nonclassic clinical increasingly common.
disorder to Mycoplasma is problematic, how-
ever, because M pneumoniae can colonize the

Image 89.1
A, Typical structure of a common gram-negative bacterium (Pseudomonas aeruginosa) and its
flagellum, as seen on electron microscopy. B, Pleomorphic structure of Mycoplasma pneumoniae,
as seen on electron microscopy. The bacterium is indicated by the black pointer. Mycoplasmas,
including M pneumoniae, lack a cell wall.

ERRNVPHGLFRVRUJ
398 MYCOPLASMA PNEUMONIAE AND OTHER MYCOPLASMA SPECIES INFECTIONS

Image 89.2
A preadolescent boy with bilateral perihilar infiltration and right lower lobe pneumonia and pleural
effusion due to Mycoplasma pneumoniae. Courtesy of Edgar O. Ledbetter, MD, FAAP.

Image 89.3
Right lateral radiograph of the patient in Image 89.2 with pneumonia and pleural effusion. Pleural
effusions associated with Mycoplasma pneumoniae infections generally resolve spontaneously
without drainage. Courtesy of Edgar O. Ledbetter, MD, FAAP.

Image 89.4
Preadolescent boy with bilateral perihilar infiltrates caused by Mycoplasma pneumoniae.

ERRNVPHGLFRVRUJ
MYCOPLASMA PNEUMONIAE AND OTHER MYCOPLASMA SPECIES INFECTIONS 399

Image 89.5
Lateral radiograph of the patient in Image 89.4 with pneumonia caused by Mycoplasma pneumoniae.

Image 89.6
Histopathologic study of Mycoplasma pneumoniae–infected lung tissue. The respiratory bronchiole
is surrounded by an inflammatory mononuclear cell response. The intraluminal site is approximately
30% occluded by mucus and white blood cells. M pneumoniae is a common cause of pneumonia
and tracheobronchitis in school-aged children and adolescents.

ERRNVPHGLFRVRUJ
400 MYCOPLASMA PNEUMONIAE AND OTHER MYCOPLASMA SPECIES INFECTIONS

Image 89.7
Erythema multiforme associated with mycoplasma infection. This 10-year-old boy presented with fever
and macular lesions on the face, chest, arms, and back, as well as facial swelling. He had a 4-day
period of increasing cough and low-grade fever prior to the onset of the skin lesions and facial
swelling. Chest radiograph revealed mild increased infiltrates in the right lung. Cold agglutinins were
markedly elevated and he had a greater than 4-fold rise in complement fixation antibody to
Mycoplasma pneumoniae. Courtesy of Neal Halsey, MD.

Image 89.8
Erythema multiforme rash (Stevens-Johnson syndrome) associated with Mycoplasma pneumoniae
infection in a preadolescent girl. Copyright Charles Prober, MD.

ERRNVPHGLFRVRUJ
Nocardiosis 401

90 Epidemiology

Nocardiosis Nocardia species are ubiquitous environmental


saprophytes, living in soil, organic matter, and
Clinical Manifestations water. Infections caused by Nocardia species
Immunocompetent children typically develop are typically the result of environmental expo-
cutaneous or lymphocutaneous disease with sure through inhalation of soil or dust particles
pustular or ulcerative lesions that remain local- or through traumatic inoculation with a soil-
ized after soil contamination of a skin injury. contaminated object. Person-to-person and
Invasive disease occurs most commonly in animal-to-human transmission does not occur.
people with chronic granulomatous disease, Incubation Period
organ transplantation, HIV infection, or
­disease requiring long-term systemic cortico- Unknown.
steroid therapy. Infection has occurred in Diagnostic Tests
adults receiving tumor necrosis factor inhibi-
Isolation of Nocardia species from body fluid,
tors, especially infliximab. In immunocom­
abscess material, or tissue provides a definitive
promised children, infection characteristically
diagnosis. Isolation of Nocardia species can
begins in the lungs, and illness can be acute,
require extended incubation periods because
subacute, or chronic. Pulmonary disease com-
of their slow growth. Recovery of Nocardia
monly manifests as rounded nodular infiltrates
species from tissue can be improved if the labo-
that can undergo cavitation. Hematogenous
ratory is requested to observe cultures for 3
spread may occur from the lungs to the brain
to 4 weeks in an appropriate liquid medium.
(single or multiple abscesses), in skin (pustules,
Stained smears of sputum, body fluids, or pus
pyoderma, abscesses, mycetoma), or, occasion-
demonstrating beaded, branching rods that
ally, in other organs. Some experts recommend
stain weakly gram positive and partially acid
neuroimaging in patients with pulmonary dis-
fast by the modified Kinyoun method suggest
ease attributable to the frequency of concurrent
the diagnosis. Brown-Brenn tissue Gram-stain
central nervous system disease, which can ini-
method and Grocott-Gomori methenamine
tially be asymptomatic. Nocardia organisms
silver stains are recommended to demonstrate
can be recovered from patients with cystic
microorganisms in tissue specimens. Serologic
fibrosis, but their role as a lung pathogen in
tests for Nocardia species are not useful.
these patients is not clear.
Treatment
Etiology
Trimethoprim-sulfamethoxazole or a sulfon-
Nocardia species are gram-positive, filamen-
amide alone (eg, sulfisoxazole, sulfamethoxa-
tous bacteria that belong to a group informally
zole) has been the drug of choice for mild
known as the aerobic actinomycetes. Other
infections. Sulfonamides that are less urine
members of this group include Actinomadura
soluble, such as sulfadiazine, should be
madurae, one of several species that are the
avoided. For immunocompromised patients
causative agent of actinomycetoma; Rhodococcus
and patients with severe disease, disseminated
equi; and Gordonia bronchialis. In the United
disease, or central nervous system involve-
States, the most prevalent species isolated from
ment, combination therapy for the first 4 to
human sources are from the Nocardia asteroides
12 weeks is recommended. Suggested combina-
complex (Nocardia nova, Nocardia farcinica,
tions include trimethoprim-sulfamethoxazole
Nocardia cyriacigeorgica, and Nocardia absces­
plus amikacin, meropenem or imipenem, or
sus). Primary cutaneous infection is most often
ceftriaxone. Immunocompetent patients with
associated with Nocardia brasiliensis. Other,
primary lymphocutaneous disease usually
less common pathogenic species include
respond after 6 to 12 weeks of therapy. Drain-
­Nocardia brevicatena, Nocardia otitidiscav­
age of abscesses is beneficial. Immunocom­
iarum, Nocardia pseudobrasiliensis, Nocardia
promised patients and patients with serious
transvalensis complex, and Nocardia veterana.
disease should be treated for 6 to 12 months
and for at least 3 months after apparent cure

ERRNVPHGLFRVRUJ
402 Nocardiosis

because of the propensity for relapse. Patients (N brasiliensis and N abscessus), imipenem, or
with AIDS may need even longer therapy, meropenem, may be beneficial. A case series
and suppressive therapy should be considered including a small number of patients demon-
for life. strated that linezolid may be effective for treat-
ment of some invasive infections.
If infection does not respond to trimetho­prim-
sulfamethoxazole, other agents, such as cla­
rithromycin (N nova), amoxicillin-clavulanate

Image 90.1
Image 90.2
Nocardia asteroides (Gram stain). Courtesy of
This gram-positive aerobic Nocardia asteroides
Edgar O. Ledbetter, MD, FAAP.
slide culture reveals chains of aerial mycelia.
The filamentous structure of these bacteria tend
toward a branching pattern terminating in a rod
or coccoid-shaped morphologic appearance.
Courtesy of Centers for Disease Control and
Prevention/Lucille K. Georg, MD.

Image 90.3
Note the presence of the gram-positive acid-fast
Nocardia brasiliensis bacteria using a modified
Fite-Faraco stain. Courtesy of Centers for
Disease Control and Prevention/Dr Lucille Georg.

Image 90.4
Nocardia asteroides colonies (white, chalklike
colonies on blood agar plate).

Image 90.5
Nocardia asteroides colony (tissue acid-fast stain).

ERRNVPHGLFRVRUJ
Nocardiosis 403

Image 90.7
Cutaneous nocardiosis of forearm in an
Image 90.6
immunocompetent preschool-aged boy.
Cutaneous Nocardia asteroides lesion in a
10-year-old boy with no evidence of disseminated
disease. Courtesy of Edgar O. Ledbetter, MD,
FAAP.

Image 90.9
Image 90.8
Cutaneous nocardiosis of lower leg of Nocardia pneumonia, bilateral, in an immuno­
immunocompetent preschool-aged girl. compromised child. Invasive nocardiosis is
unusual in immunocompetent children.

Image 90.10
This photomicrograph depicts the histopathologic
changes due to nocardiosis of a mesenteric
lymph node. Courtesy of Centers for Disease
Control and Prevention/Dr Martin Hicklin.
Image 90.11
Hispanic school-aged child with chronic rash on
the lower left ankle. Histopathology confirmed
Nocardia brasiliensis. Courtesy of Preeti Jaggi, MD.

ERRNVPHGLFRVRUJ
404 Norovirus and Other Human Calicivirus ­Infections

91 Asymptomatic norovirus excretion is common


in children. Outbreaks tend to occur in closed
Norovirus and Other populations (eg, long-term care facilities,
Human Calicivirus schools, cruise ships). Transmission is person
to person via fecal-oral or vomitus-oral routes,
­Infections through contaminated food or water, or by
Clinical Manifestations contaminated environmental surfaces. Noro­
Abrupt onset of vomiting accompanied by virus is recognized as the most common cause
watery diarrhea, abdominal cramps, and of foodborne illness and foodborne disease
­nausea are characteristic of norovirus gastro- outbreaks in the United States. Common-
enteritis. Acute diarrhea without vomiting can source outbreaks have been described after
also occur. Symptoms last from 24 to 60 hours, ingestion of ice, shellfish, and a variety of
but longer courses of illness can occur, parti­ ready-to-eat foods, including salads, berries,
cularly among young children. Systemic mani- and bakery products, usually contaminated by
festations, including fever, myalgia, malaise, infected food handlers. Norovirus has been
anorexia, and headache, may accompany gas- detected in raw or unpasteurized milk or milk
trointestinal tract symptoms. Since introduc- products. Viral excretion may start before
tion of rotavirus vaccines, noroviruses have onset of symptoms, peaks several days after
become the leading cause of gastroenteritis in exposure, and can persist for 3 weeks or more.
the United States. Prolonged excretion has been reported in
immunocompromised hosts. Infection occurs
Etiology year-round but is more common during winter.
Noroviruses are 27- to 40-nm, RNA viruses Incubation Period
of the family Caliciviridae. This family has at
least 5 genera (Lagovirus, Nebovirus, Vesivirus, 12 to 48 hours.
Sapovirus, and Norovirus), with noroviruses Diagnostic Tests
and Sapovirus species often referred to as
A multiplex nucleic acid–based assay for the
human caliciviruses. Noroviruses are currently
detection of gastrointestinal pathogens, which
divided into 6 genogroups (1–6), of which 3
includes norovirus, is approved by the US Food
(1, 2, and 4) can cause human illness.
and Drug Administration, although it may not
Epidemiology be widely available. An enzyme immunoassay
Noroviruses are a major cause of sporadic cases kit is also approved for preliminary identifica-
and outbreaks of gastroenteritis. Norovirus tion of norovirus. Most state and local public
causes an estimated 1 in 15 US residents to health laboratories use real-time reverse
become ill each year, with 56,000 to 71,000 ­transcriptase-polymerase chain reaction assay
hospitalizations and 570 to 800 deaths. Noro­ for detection of norovirus RNA in stool.
viruses have become the predominant agent Treatment
of pediatric viral gastroenteritis in the United
Supportive therapy includes oral or intrave-
States. Sapovirus infections are reported
nous rehydration solutions to replace and
among children with sporadic acute diarrhea,
maintain fluid and electrolyte balance.
although, increasingly, Sapovirus species have
been recognized as a cause of outbreaks.

ERRNVPHGLFRVRUJ
Onchocerciasis 405

92 Incubation Period

Onchocerciasis 12 to 18 months from larval inoculation to


microfilariae in the skin, but can be as long
(River Blindness, Filariasis)
as 3 years.
Clinical Manifestations
Diagnostic Tests
The disease involves skin, subcutaneous
Direct examination of a 1- to 2-mg shaving or
­tissues, lymphatic vessels, and eyes. Sub­
biopsy specimen of the epidermis and upper
cutaneous, nontender nodules that can be up
dermis (usually taken from the posterior iliac
to several centimeters in diameter containing
crest area) can reveal microfilariae. Microfilar-
male and female worms develop 6 to 12 months
iae are not found in blood. Adult worms may
after initial infection. In patients in Africa,
be demonstrated in excised nodules that have
nodules tend to be found on the lower torso,
been sectioned and stained. A slit lamp exami-
pelvis, and lower extremities, whereas in
nation of an involved eye may reveal motile
patients in Central and South America, the
microfilariae in the anterior chamber or
nodules are more often located on the upper
“snowflake” corneal lesions. Eosinophilia is
body (head and trunk) but can occur on the
common. Specific serologic tests and poly-
extremities. After the worms mature, fertilized
merase chain reaction techniques for detection
females produce microfilariae that migrate to
of microfilariae in skin are only available in
the dermis and may cause a papular dermatitis.
research laboratories.
Pruritus is often highly intense, resulting in
patient-inflicted excoriations over the affected Treatment
areas. After a period of years, skin can become
Ivermectin, a microfilaricidal agent, is the
lichenified and hypopigmented or hyperpig-
drug of choice for treatment of onchocerciasis.
mented. Microfilariae may invade ocular
Treatment decreases dermatitis and the risk of
­structures, leading to inflammation of the
developing severe ocular disease but does not
­cornea, iris, ciliary body, retina, choroid, and
kill the adult worms (which can live for more
optic nerve. Loss of visual acuity and blindness
than a decade) and, thus, is not curative. One
can result if the disease is untreated.
single oral dose of ivermectin should be given
Etiology every 6 to 12 months until asymptomatic.
Adverse reactions to treatment are caused by
Onchocerca volvulus is a filarial nematode.
death of microfilariae and can include rash,
Epidemiology edema, fever, myalgia, and, rarely, asthma
O volvulus has no significant animal reservoir. exacerbation and hypotension. Such reactions
Microfilariae in human skin infect Simulium are more common in people with higher
species flies (blackflies) when they take a blood skin loads of microfilaria and decrease with
meal and then, in 10 to 14 days, develop into repeated treatment in the absence of reexpo-
infectious larvae that are transmitted with sub- sure. Precautions to ivermectin treatment
sequent bites. Blackflies breed in fast-flowing include pregnancy, central nervous system
streams and rivers (hence, the colloquial name ­disorders, and high levels of circulating Loa loa
for the disease, river blindness). The disease microfilaremia. Treatment of patients with
occurs primarily in equatorial Africa, but small high levels of circulating L loa microfilaremia
foci are found in southern Mexico, Guatemala, with ivermectin can sometimes result in fatal
northern South America, and Yemen. Preva- encephalopathy. The American Academy of
lence is greatest among people who live near Pediatrics notes that ivermectin is usually
vector breeding sites. The infection is not ­compatible with breastfeeding. A 6-week
transmissible by person-to-person contact or course of doxycycline can be used to kill
blood transfusion. adult worms through depletion of the endo-
symbiotic rickettsia-like bacteria, which appear

ERRNVPHGLFRVRUJ
406 Onchocerciasis

to be required for survival of O volvulus. ­ onpregnant adults. Doxycycline treatment


n
This approach may be used as adjunctive should be initiated several days after treatment
­t herapy for children 8 years or older and with ­ivermectin.

Image 92.1 Image 92.2


This is a glycerin mount photomicrograph of the These are Simulium species of flies, or blackflies,
microfilarial pathogen Onchocerca volvulus in a vector of the disease onchocerciasis, or river
its larval form. Courtesy of Centers for Disease blindness. Courtesy of World Health Organization.
Control and Prevention/Ladene Newton.

Image 92.4
Histopathologic features of Onchocerca nodule in
onchocerciasis. Courtesy of Centers for Disease
Control and Prevention/Dr Mae Melvin.

Image 92.3
As an adult, this Simulium species larva, or
blackfly, is a vector of the disease onchocercia­
sis, or river blindness. The blackfly larva is usually
a filter-feeder, feeding on nutrients extracted from
passing currents. Prior to entering the pupal
stage, a Simulium species larva passes through
6 larval stages and then encases itself in a silken,
submerged cocoon. Courtesy of Centers for
Disease Control and Prevention/Dr Martin Hicklin.

ERRNVPHGLFRVRUJ
Human Papillomaviruses 407

93 scrotum, or anal or perianal area. In females,


these lesions can occur on the vulva, anal or
Human Papillomaviruses perianal area, and, less commonly, in the
Clinical Manifestations vagina or on the cervix. Warts usually are
painless, although they can cause itching,
Human papillomaviruses (HPVs) are a large burning, local pain, or bleeding.
family of viruses. Most HPV infections are not
apparent. However, HPVs can cause benign Anogenital low-grade squamous intraepithe-
epithelial proliferation (warts) of the skin and lial lesions can result from persistent infection
mucous membranes and are associated with with low-risk and high-risk HPV types,
cancers. Human papillomaviruses can be whereas high-grade squamous intraepithelial
grouped into cutaneous and genital (mucosal) lesions result from persistent infection with
types. The cutaneous types cause nongenital high-risk HPV types. High-grade squamous
warts, including common skin warts, plantar intraepithelial lesions are considered precan-
warts, flat warts, threadlike (filiform) warts, cers. In the cervix, these lesions are detected
and epidermodysplasia verruciformis. Some through routine screening with cytologic test-
mucosal types (low risk) are associated with ing (Papanicolaou [Pap] test); tissue biopsy is
warts or papillomas of mucous membranes, required to make the diagnosis. In the past,
including the upper respiratory tract, anogeni- cervical lesions have been called dysplasias
tal, oral, nasal, and conjunctival areas. Other (mild, moderate, severe) or cervical intraepi-
mucosal types (high risk) are associated with thelial neoplasia (CIN grades 1, 2, or 3, with
cancers and precancers, including cervical, only grades 2 or 3 being considered cancer
anogenital, and oropharyngeal cancers. ­precursors). Endocervical glandular precancer,
adenocarcinoma in situ, also may result from
Common skin warts are dome-shaped with high-risk HPV types. Invasive cancers associ-
conical projections that give the surface a ated with HPV include cervical, vaginal, vul-
rough appearance. They are usually painless var, penile, anal, and oropharyngeal.
and multiple, commonly occurring on the
hands and around or under the nails. When Juvenile recurrent respiratory papillomatosis
small dermal vessels become thrombosed, is a rare condition characterized by recurring
black dots appear in the warts. papillomas in the larynx or other areas of
the upper respiratory tract. This condition is
Plantar warts on the foot are often larger most commonly diagnosed in children aged 2
than warts at other sites and may not project to 5 years and manifests as voice change (eg,
through much of the skin surface. They can hoarseness), stridor, or abnormal cry. Respir­a­
be painful when walking and are character- tory papillomas can cause respiratory tract
ized by marked hyperkeratosis, sometimes obstruction in young children. Adult onset
with black dots. has also been described.
Flat warts (“juvenile warts”) are commonly Epidermodysplasia verruciformis is a rare,
found on the face and extremities of children inherited disorder believed to be a conse-
and adolescents. They are usually small, quence of a deficiency of cell-mediated immu-
­multiple, and flat topped; seldom exhibit nity resulting in an abnormal susceptibility to
­papillomatosis; and, rarely, cause pain. Fili- certain HPV types and manifesting as chronic
form warts occur on the face and neck. Cuta- cutaneous HPV infection and frequent devel-
neous warts are benign. opment of skin cancer. Lesions may resemble
Anogenital warts, also called condylomata flat warts but are often similar to tinea versi-
acuminata, are skin-colored warts with a pap- color, covering the torso and upper extremities.
ular, flat, or cauliflowerlike surface that range Most appear during the first decade of life, but
in size from a few millimeters to several centi- malignant transformation, which occurs in
meters; these warts often occur in groups. In 30% to 60% of affected people, is usually
males, these warts may be found on the penis, delayed until adulthood.

ERRNVPHGLFRVRUJ
408 Human Papillomaviruses

Etiology requires decades of persistent infection.


Human papillomaviruses are DNA viruses Human papillomavirus is also the cause of
of the Papillomaviridae family, which can be most vulvar, vaginal, penile, and anal cancers,
grouped into cutaneous and mucosal types. as well as a significant percentage of oropha-
In children, the most common lesions from ryngeal cancers. Nearly 27,000 US cases of
cutaneous HPVs are hand and foot warts. HPV-related cancers are diagnosed annually.
Mucosal HPVs infect the genital tract and The risk of development of cancer precursor
other mucosal surfaces and are grouped into lesions is greater in people with HIV infection
low-risk and high-risk types based on their and cellular immune deficiencies.
association with cancers. Low-risk types 6 Rarely, infection is transmitted to a neonate
and 11 are associated with about 90% of con­ through the birth canal during delivery or
dylomata acuminata, recurrent respiratory from nongenital sites. Respiratory papilloma-
papillomatosis, and conjunctival papillomas. tosis is believed to be acquired by aspiration of
High-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, infectious maternal secretions intrapartum.
56, 58, 59, 68, 69, 73, and 82) can cause low- When anogenital warts are identified in a child
grade cervical cell abnormalities, high-grade who is beyond infancy but is prepubertal, sex-
cervical cell abnormalities that are precursors ual abuse must be considered.
to cancer, and anogenital cancers. High-risk
HPV types are detected in 99% of cervical can- Incubation Period
cers. Type 16 is the cause of approximately 50% Estimated range, 3 months to several years.
of cervical cancers worldwide, and types 16 and Human papillomavirus acquired intrapartum
18 together account for approximately 70% of by neonates may never cause clinical disease
cervical cancers. Type 16 is also the cause of or become apparent over several years.
most HPV-related oropharyngeal cancers.
Diagnostic Tests
Epidemiology
Most cutaneous and anogenital warts are
Human papillomavirus types involved in ­diagnosed clinically. Respiratory papillomato-
­common hand and foot warts are quite differ- sis is diagnosed using endoscopy and biopsy.
ent from mucosal types. Nongenital hand and Cytologic screening (Pap test) and, sometimes,
foot warts commonly occur among school- HPV testing of cervical specimens will identify
aged children; the prevalence rate is as high women requiring follow-up with colposcopy
as 50%. These can be acquired through casual and biopsy. Vulvar, vaginal, penile, and anal
contact and facilitated through minor skin lesions may be identified using visual inspec-
trauma. Autoinoculation can result in spread tion; in some cases, cytologic screening (Pap
of lesions. The intense and often widespread test) is used and suspicious lesions are biopsied.
appearance of cutaneous warts in patients For all anogenital lesions, diagnosis is made on
with compromised cellular immunity suggests the basis of histologic findings.
that alterations in T-lymphocyte immunity
impair clearance. Although cytologic and histologic changes can
be suggestive of HPV, these findings are not
Genital HPV infections are transmitted diagnostic of HPV. Detection of HPV infection
­primarily by skin-to-skin contact, usually is based on detection of viral nucleic acid
through sexual intercourse; other genital (DNA or RNA) or capsid protein. Clinical tests
­contact has been associated with transmission. for high-risk HPV may be used in combination
In US females, the highest prevalence of infec- with Pap testing for cervical cancer screening
tion is in 20- to 24-year-olds. Most infections in women 30 years or older and for triage of
are subclinical and clear within 2 years. Persis- equivocal Pap test abnormalities (atypical
tent infection with high-risk types of HPV is squamous cells of undetermined significance)
associated with development of cervical cancer, in women 21 years or older. These HPV tests
resulting in approximately 12,000 new US cases are not recommended for use in adolescents
and 4,000 deaths annually. Cervical cancer is or men.
a rare outcome of infection that generally

ERRNVPHGLFRVRUJ
Human Papillomaviruses 409

Treatment Cancer precursor lesions that are identified


Treatment of HPV infection is directed toward in the cervix (ie, high-grade squamous intra­
eliminating lesions. Treatment of anogenital epithelial lesions, adenocarcinoma in situ)
warts may differ from treatment of cutaneous and elsewhere in the genital tract require exci-
nongenital warts. Regression of nongenital sion or destruction. Overtreatment of cervical
and genital warts occurs in approximately 30% lesions can cause substantial economic, emo-
of cases within 6 months. Most methods of tional, and reproductive adverse effects, includ-
treatment of cutaneous warts use chemical or ing higher risk of preterm birth. Management
physical destruction of the infected epithelium, of invasive cervical and other anogenital and
including cryotherapy with liquid nitrogen, oropharyngeal cancers requires a specialist
laser or surgical removal of warts, application and should be conducted according to exist-
of salicylic acid products, or application of ing guidance.
­topical immune-modulating agents. Daily Respiratory papillomatosis is difficult to treat
treatment with tretinoin has been useful for and is best managed by an experienced otolar-
widespread flat warts in children. Care must yngologist. Local recurrence is common, and
be taken to avoid a deleterious cosmetic result repeated surgical procedures for removal are
with therapy. often necessary. Extension or dissemination of
Treatments for genital warts are characterized respiratory papillomas from the larynx into the
as patient applied or provider administered. trachea, bronchi, or lung parenchyma is rare
No one treatment is superior to another. but can result in increased morbidity and
­Interventions include ablation or excisional ­mortality; carcinoma can occur rarely. Intra­
treatments, antiproliferative methods, and lesional interferon, indole-3-carbinole, photo-
immune-modulating therapy. Many agents dynamic therapy, intralesional mumps vaccine,
used for treatment have not been tested for and intralesional cidofovir have been used as
safety and efficacy in children, and some are investigational treatments, but the efficacy of
contraindicated in pregnancy. Although most these therapies is uncertain. Oral warts can be
forms of therapy are successful for initial removed through cryotherapy, electrocautery,
removal of warts, treatment may not eradicate or surgical excision.
HPV infection from the surrounding tissue.
Recurrences are common and may be attribut-
able to reactivation rather than reinfection.

Image 93.1
Digitate human papillomavirus wart with fingerlike projections on a child’s index finger. Copyright
Gary Williams.

ERRNVPHGLFRVRUJ
410 Human Papillomaviruses

Image 93.2
Image 93.3
Human papillomavirus warts on the foot of an Laryngeal papillomas may cause hoarseness.
immunocompromised 14-year-old boy. Copyright Although rare, they can occur in infants of
Gary Williams. mothers infected with human papillomavirus.

Image 93.5
Massive condyloma acuminata (genital warts) in a
10-year-old girl who had been sexually abused.
These genital warts are commonly caused by
Image 93.4 human papillomavirus, especially types 6 and 11.
A 13-month-old girl with condyloma acuminata
around the anus from sexual abuse (sodomy).
Copyright Martin G. Myers, MD.

Image 93.6
This HIV-positive patient was exhibiting signs of a Image 93.7
secondary condyloma acuminata infection (ie, This patient with condylomata acuminata
venereal warts). This intraoral eruption of presented with soft, wartlike growths on the
condyloma acuminata was caused by human penis (12 hours postpodophyllin application).
papillomavirus (HPV). Although oral HPV is a rare Condylomata acuminata refers to an epidermal
occurrence, HIV reduces the body’s immune manifestation caused by epidermotropic human
response and, therefore, such secondary papillomavirus. The most commonly affected
infections can manifest themselves. Courtesy of areas are the penis, vulva, vagina, cervix, perineum,
Centers for Disease Control and Prevention/Sol and perianal area. Courtesy of Centers for
Silverman Jr, DDS. Disease Control and Prevention/Susan Lindsley.

ERRNVPHGLFRVRUJ
Paracoccidioidomycosis 411

94 Diagnostic Tests

Paracoccidioidomycosis Round, multiple-budding cells with a distin-


guishing pilot’s wheel appearance can be seen
(South American Blastomycosis)
in preparations of sputum, bronchoalveolar
Clinical Manifestations lavage specimens, scrapings from ulcers, and
Disease occurs primarily in adults, in whom material from lesions or in tissue biopsy speci-
the site of initial infection is the lungs. Disease mens. Several procedures, including wet or
is infrequent in children, in whom approxi- KOH wet preparations, or histologic staining
mately 5% to 10% of all cases occur. Clinical are adequate for visualization of fungal ele-
patterns can include subclinical infection or ments. The mycelia form of P brasiliensis
progressive disease that can be acute-subacute can be cultured on most enriched media. Its
(juvenile type) or chronic (adult type). In both appearance is not distinctive. A number of
forms, constitutional symptoms, such as fever, serologic tests are available; quantitative
malaise, anorexia, and weight loss, are com- immunodiffusion is the preferred test. The
mon. In the juvenile form, the initial pulmo- antibody titer by immunodiffusion usually
nary infection is usually asymptomatic, and is 1:32 or greater in acute infection.
manifestations are related to dissemination Treatment
of infection to the reticuloendothelial system,
Amphotericin B is preferred by many experts
resulting in enlarged lymph nodes and involve-
for initial treatment of severe paracoccidioi­
ment of liver, spleen, and bone marrow. Skin
domycosis. An alternative is intravenous
lesions are observed regularly and are typically
­trimethoprim-sulfamethoxazole. Children
located on the face, neck, and trunk. Involve-
treated initially by the intravenous route can
ment of bones, joints, and mucous membranes
transition to orally administered therapy after
is less common. Enlarged lymph nodes occa-
clinical improvement has been observed, usu-
sionally coalesce and form abscesses or fistulas.
ally after 3 to 6 weeks.
The chronic form of the illness can be localized
to the lungs or can disseminate. Oral mucosal Oral therapy with itraconazole is the treatment
lesions are observed in 50%. Skin involvement of choice for less severe or localized infection
is common but occurs in a smaller proportion and to complete treatment when amphotericin
than in patients with the acute-subacute form. B is used initially. Prolonged therapy for 6 to
Infection can be latent for years before caus- 12 months is necessary to minimize the relapse
ing illness. rate. Children with severe disease can require a
longer course. Voriconazole is as well tolerated
Etiology
and as effective as itraconazole in adults, but
Paracoccidioides brasiliensis is a thermally data for its use in children with paracoccidioi-
dimorphic fungus with yeast and mycelia phases. domycosis are not available. Trimethoprim-
Epidemiology sulfamethoxazole orally is an alternative, but
treatment must be continued for 2 years or
The infection occurs in Latin America, from ­longer to lessen the risk of relapse, which occurs
Mexico to Argentina. The natural reservoir in 10% to 15% of optimally treated patients.
is unknown, although soil is suspected. The
mode of transmission is unknown, but trans- Serial serologic testing by quantitative
mission most likely occurs via inhalation of immuno­diffusion is useful for monitoring the
contaminated soil or dust; person-to-person response to therapy. The expected response is a
transmission does not occur. progressive decline in titers after 1 to 3 months
of treatment with stabilization at a low titer.
Incubation Period
Highly variable; range, 1 month to many years.

ERRNVPHGLFRVRUJ
412 Paracoccidioidomycosis

Image 94.2
Image 94.1 Histopathologic features of paracoccidioido­
Histopathologic features of paracoccidioido­ mycosis, liver. Minute buds on several cells of
myco­sis. Budding cell of Paracoccidioides Paracoccidioides brasiliensis (methenamine silver
brasiliensis (methenamine silver stain). Courtesy stain). Courtesy of Centers for Disease Control
of Centers for Disease Control and Prevention. and Prevention/Dr Lucille K. Georg.

Image 94.4
Image 94.3
This micrograph depicts the histopathologic
Histopathology of paracoccidioidomycosis.
changes associated with paracoccidioidomycosis
Budding cells of Paracoccidioides brasiliensis
due to Paracoccidioides brasiliensis. This is the
(methenamine silver stain). Courtesy of Centers
only etiological agent for the disease paracoc­­
for Disease Control and Prevention/Dr Lucille
cidioido­mycosis. The P brasiliensis fungus is
K. Georg.
geographically restricted to areas of South
and Central America. A cell of P brasiliensis is
centrally located. Courtesy of Centers for Disease
Control and Prevention/Dr Lucille K. Georg.

Image 94.5
Histopathologic features of paracoccidioido­
mycosis from skin sample. Cells of Paracoc­
cidioides brasiliensis are visible. Courtesy of
Image 94.6
Centers for Disease Control and Prevention/
Histopathologic features of paracoccidioido­
Dr Lucille K. Georg.
mycosis, skin. Budding cell of Paracoccidioides
brasiliensis within multinucleated giant cell.
Courtesy of Centers for Disease Control
and Prevention/Dr Lucille K. Georg.

ERRNVPHGLFRVRUJ
Paragonimiasis 413

95 P westermani, present in imported crab. The


adult flukes of P westermani are up to 12 mm
Paragonimiasis long and 7 mm wide and occur throughout
Clinical Manifestations Asia. A triploid parthenogenetic form of ­
P westermani, which is larger, produces more
There are 2 major forms of paragonimiasis: eggs, and elicits greater disease, has been
disease attributable to Paragonimus ­westermani, described in Japan, Korea, Taiwan, and parts
Paragonimus heterotrema, Paragonimus of eastern China. P heterotrema occurs in
­africanus, Paragonimus uterobilateralis, and Southeast Asia and adjacent parts of China.
Paragonimus kellicotti causing primary pulmo-
nary disease with or without extrapulmonary Extrapulmonary paragonimiasis (ie, visceral
manifestations, and disease attributable to larva migrans) is caused by larval stages of
other species of Paragonimus, most notably P skrjabini and Paragonimus miyazakii. The
Paragonimus skrjabini, for which humans are worms rarely mature in infected human tis-
accidental hosts and manifestations generally sues. P skrjabini occurs in China, whereas
are extrapulmonary, resulting in a larva P miyazakii occurs in Japan. Paragonimus
migrans syndrome similar to that caused by ­mexicanus and Paragonimus ecuadoriensis
Toxocara canis. The former disease is especially occur in Mexico, Costa Rica, Ecuador, and
likely to have an insidious onset and a chronic Peru. P kellicotti, a lung fluke of mink and
course. Pulmonary disease is associated with opossums in the United States, can also cause
chronic cough and dyspnea, but most infec- infection in humans.
tions are probably inapparent or result in
Epidemiology
mild symptoms. Heavy infestations cause
­paroxysms of coughing, which often produce Transmission occurs when raw or undercooked
blood-tinged sputum that is brown because freshwater crabs or crayfish containing larvae
of the presence of Paragonimus species eggs. (metacercariae) are ingested. Numerous
Hemoptysis can be severe. Pleural effusion, cases have been associated with ingestion of
pneumothorax, bronchiectasis, and pulmonary uncooked crawfish during river raft trips in
fibrosis with clubbing can develop. Extrapul- the Midwestern United States. The metacer­
monary manifestations also may involve liver, cariae excyst in the small intestine and pen-
spleen, abdominal cavity, intestinal wall, intra-­ etrate the abdominal cavity, where they remain
abdominal lymph nodes, skin, and central for a few days before migrating to the lungs.
­nervous system, with meningoencephalitis, P westermani and P heterotrema mature within
seizures, and space-occupying tumors attri­b­ the lungs over 6 to 10 weeks, when they begin
utable to invasion of the brain by adult flukes, egg production. Eggs escape from pulmonary
usually occurring within a year of pulmonary capsules into the bronchi and exit from the
infection. Symptoms tend to subside after human host in sputum or feces. Eggs hatch in
approximately 5 years but can persist for as freshwater within 3 weeks, giving rise to mira-
many as 20 years. cidia. Miracidia penetrate freshwater snails and
emerge several weeks later as cercariae, which
Extrapulmonary paragonimiasis is associated encyst within the muscles and viscera of fresh-
with migratory allergic subcutaneous nodules water crustaceans before maturing into infec-
containing juvenile worms. Pleural effusion is tive metacercariae. A less common mode of
common, as is invasion of the brain. transmission that may also occur is human
Etiology infection through the ingestion of raw pork,
usually from wild pigs, containing the juvenile
In Asia, classical paragonimiasis is caused by stages of Paragonimus species (described as
adult flukes and eggs of P westermani and occurring in Japan).
P heterotrema. In Africa, the adult flukes and
eggs of P africanus and P uterobilateralis pro- Humans are accidental (“dead-end”) hosts
duce the disease, whereas in North America, for P skrjabini and P miyazakii in visceral
the endemic species is P kellicotti. In North larva migrans. These flukes cannot mature
America, disease has also been caused by in humans and, hence, do not produce eggs.

ERRNVPHGLFRVRUJ
414 Paragonimiasis

Paragonimus species also infect a variety of elements. Chest radiographs can appear nor-
other mammals, such as canids, mustelids, mal or resemble radiographs from patients
felids, and rodents, which serve as animal with tuberculosis. Misdiagnosis is likely unless
­reservoir hosts. paragonimiasis is suspected.
Incubation Period Treatment
Variable; egg production begins by approxi- Praziquantel in a 2-day course is the treatment
mately 8 weeks after ingestion of P westermani of choice and is associated with high cure rates
metacercariae. as demonstrated by disappearance of egg pro-
duction and radiographic lesions in the lungs.
Diagnostic Tests
The drug is also effective for some extrapulmo-
Microscopic examination of stool, sputum, nary manifestations. An alternative drug for
pleural effusion, cerebrospinal fluid, and other patients unable to take praziquantel is tricla-
tissue specimens may reveal eggs. A Western bendazole; it is not commercially available but
blot serologic antibody test based on P wester­ may be obtained from the Centers for Disease
mani antigen, available at the Centers for Dis- Control and Prevention under an investiga-
ease Control and Prevention, is sensitive and tional drug protocol. For patients with central
specific; antibody concentrations detected by nervous system paragonimiasis, a short course
immunoblot decrease slowly after the infection of steroids may be beneficial in addition to
is cured by treatment. Charcot-Leyden crystals the praziquantel.
and eosinophils in sputum are useful diagnostic

Image 95.1
Paragonimus westermani ova in stool preparation
(original magnification x400).

Image 95.2
Ovum of Paragonimus westermani. The average
ovum size is 85 by 53 µm (range, 68–118 µm
by 39–67 µm). They are yellow-brown and
ovoid or elongate, with a thick shell, and often
asymmetric, with one end slightly flattened. At
the large end, the operculum is clearly visible.
The opposite (abopercular) end is thickened.
The ova of P westermani are excreted unem­
Image 95.3
bryonated and may be found in the stool or
Eating raw or undercooked crabs or crayfish sputum. Courtesy of Centers for Disease
can result in human paragonimiasis, a parasitic Control and Prevention.
disease caused by Paragonimus westermani
and Paragonimus heterotrema. Courtesy of
Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Paragonimiasis 415

Image 95.4
Life cycle of Paragonimus westermani. The eggs are excreted unembryonated in the sputum or,
alternately, they are swallowed and passed with stool (1). In the external environment, the eggs
become embryonated (2), and miracidia hatch and seek the first intermediate host, a snail, and
penetrate its soft tissues (3). Miracidia go through several developmental stages inside the snail (4):
sporocysts (4a), rediae (4b), with the latter giving rise to many cercariae (4c), which emerge from the
snail. The cercariae invade the second intermediate host, a crustacean such as a crab or crayfish,
where they encyst and become metacercariae. This is the infective stage for the mammalian host (5).
Human infection with P westermani occurs by eating inadequately cooked or pickled crab or crayfish
that harbor metacercariae of the parasite (6). The metacercariae excyst in the duodenum (7), penetrate
through the intestinal wall into the peritoneal cavity, then through the abdominal wall and diaphragm
into the lungs, where they become encapsulated and develop into adults (8) (7.5–12 mm by 4–6 mm).
The worms can also reach other organs and tissues, such as the brain and striated muscles, respec­
tively. However, when this takes place, completion of the life cycles is not achieved because the eggs
laid cannot exit these sites. Time from infection to oviposition is 65 to 90 days. Infections may persist
for 20 years in humans. Animals such as pigs, dogs, and a variety of feline species can also harbor
P westermani. Courtesy of Centers for Disease Control and Prevention/Alexander J. da Silva, PhD/
Melanie Moser.

ERRNVPHGLFRVRUJ
416 Parainfluenza Viral ­Infections

96 respiratory tract disease. Seasonal patterns of


infection are distinct, predictable, and cyclic
Parainfluenza Viral in temperate regions. Different serotypes have
­Infections distinct epidemiologic patterns. Parainfluenza
virus 1 tends to produce outbreaks of respira-
Clinical Manifestations tory tract illness, usually croup, in the autumn
Parainfluenza viruses (PIVs) are the major of every other year. Parainfluenza virus 2 can
cause of laryngotracheobronchitis (croup) but also cause outbreaks of respiratory tract illness
also upper respiratory tract infection, bronchi- in the autumn, often in conjunction with PIV1
olitis, and pneumonia. Parainfluenza virus 1 outbreaks, but PIV2 outbreaks tend to be less
(PIV1) and, to a lesser extent, 2 (PIV2) are the severe, irregular, and less common. Parainflu-
most common pathogens associated with enza virus 3 is endemic and usually is promi-
croup. Parainfluenza virus 3 (PIV3) is most nent during spring and summer in temperate
commonly associated with bronchiolitis and climates but often continues into autumn,
pneumonia in infants and young children. especially in years when autumn outbreaks
Infections with parainfluenza virus 4 (PIV4) of PIV1 or PIV2 are absent. Infections with
are less well characterized, but studies using PIV4 are recognized less commonly and can
sensitive molecular assays suggest they may be be associated with illnesses ranging from mild
more common than previously appreciated. to severe.
Rarely, PIVs have been isolated from patients
The age of primary infection varies with sero-
with parotitis, aseptic meningitis, encephalitis,
type. Primary infection with all types usually
or Guillain-Barré syndrome. Parainfluenza
occurs by 5 years of age. Infection with PIV3
virus infections can exacerbate symptoms of
occurs more often in infants and is a promi-
chronic lung disease and asthma in children
nent cause of bronchiolitis and pneumonia in
and adults. In children with immunodeficiency
this age group. By 12 months of age, 50% of
and recipients of hematopoietic stem cell
infants have acquired PIV3 infection. Infec-
­transplants, PIVs can cause refractory infec-
tions between 1 and 5 years of age more com-
tions with persistent shedding, severe pneumo-
monly are associated with PIV1 and, to a lesser
nia with viral dissemination, and even fatal
extent, PIV2. Age at acquisition of PIV4 infec-
disease, most commonly caused by PIV3. Para-
tion is not well defined. Rates of PIV-associated
influenza virus infections do not confer com-
hospitalizations for children vary depending
plete protective immunity; reinfections can
on clinical syndrome, PIV type, and patient age.
occur with all serotypes and at any age, but
reinfections usually cause a mild illness limited Immunocompetent children with primary PIV
to the upper respiratory tract. infection can shed virus for up to 1 week before
onset of clinical symptoms and for 1 to 3 weeks
Etiology
after symptoms have disappeared, depending
Parainfluenza viruses are enveloped, single- on serotype. Severe lower respiratory tract
stranded, negative-sense RNA viruses classi- ­disease with prolonged shedding of the virus
fied in the family Paramyxoviridae. Four can develop in immunodeficient people. In
antigenically distinct types—1, 2, 3, and 4 these patients, infection may spread beyond the
(with 2 subtypes, 4A and 4B)—that infect respiratory tract to the liver and lymph nodes.
humans have been identified.
Incubation Period
Epidemiology
2 to 6 days.
Parainfluenza viruses are transmitted from
person to person by direct contact and expo- Diagnostic Tests
sure to contaminated nasopharyngeal secre- Parainfluenza viruses may be isolated from
tions through respiratory tract droplets and nasopharyngeal secretions, usually within 4
fomites. Parainfluenza virus infections can be to 7 days of culture inoculation or earlier by
sporadic or associated with outbreaks of acute use of centrifugation of the specimen onto

ERRNVPHGLFRVRUJ
Parainfluenza Viral ­Infections 417

a monolayer of susceptible cells (shell vial Treatment


assay). Highly sensitive reverse transcriptase-­ Specific antiviral therapy is not available. Most
polymerase chain reaction assays are also infections are self-limited and require no treat-
available commercially for detection and ment. Monitoring for hypoxia and hypercapnia
­differentiation of PIVs. Rapid antigen identifi- in more severely affected children with lower
cation techniques, including immunofluores- respiratory tract disease is useful. For laryngo-
cence assays, can be used to detect the viruses tracheobronchitis, racemic epinephrine aerosol
in nasopharyngeal secretions, but sensitivities is commonly given to severely affected hospi-
of the tests vary. Serologic diagnosis, made talized patients with croup. Parenteral, oral,
retrospectively by a significant increase in and nebulized corticosteroids have been dem-
­antibody titer between serum specimens onstrated to lessen the severity and duration of
obtained during acute infection and con­ symptoms and hospitalization in patients with
valescence, is less useful. moderate to severe laryngotracheobronchitis.
Oral steroids are also effective for outpatients
with less severe croup. Management is other-
wise supportive.

Image 96.1
Electron micrograph of parainfluenza virus.
Image 96.2
Copyright Charles Prober.
Transmission electron micrograph of parainflu­enza
virus showing 2 intact particles and a free fila­
men­tous nucleocapsid. Courtesy of Centers for
Disease Control and Prevention/Dr Erskine Palmer.

Image 96.3
This electron micrograph depicts the paramyxovirus 4A nucleocapsid with its herringbone-shaped
RNA core. Courtesy of Centers for Disease Control and Prevention/Dr Fred Murphy.

ERRNVPHGLFRVRUJ
418 Parainfluenza Viral ­Infections

Image 96.5
Parainfluenza laryngotracheitis in a 2-year-old
boy. Courtesy of Benjamin Estrada, MD.

Image 96.4
Fatal croup. Edema, congestion, and inflam­
mation of larynx and pharynx. Courtesy of
Dimitris P. Agamanolis, MD.
Image 96.6
Parainfluenza laryngotracheitis with the steeple
sign in a 2-year-old. Courtesy of Benjamin
Estrada, MD.

Image 96.7
Parainfluenza pneumonia in a 2-year-old boy. Courtesy of Benjamin Estrada, MD.

ERRNVPHGLFRVRUJ
Parainfluenza Viral ­Infections 419

Image 96.8
Erythema multiforme minor in a 2-year-old boy with parainfluenza. Courtesy of Larry Frenkel, MD.

Image 96.9
Erythema multiforme minor in a 2-year-old boy with parainfluenza. Courtesy of Larry Frenkel, MD.

ERRNVPHGLFRVRUJ
420 Parasitic Diseases

97 living in the United States and aboriginal peo-


ple living in Alaska and the Canadian Arctic.
Parasitic Diseases Physicians and clinical laboratory personnel
Many parasitic diseases have traditionally need to be aware of where these infections can
been considered exotic and, therefore, fre- be acquired, their clinical presentations, and
quently are not included in differential diag­ methods of diagnosis and should advise people
noses of patients in the United States, Canada, how to prevent infection (Table 97.1).
and Europe. Nevertheless, a number of these Consultation and assistance in diagnosis and
organisms are endemic in industrialized coun- management of parasitic diseases are available
tries, and, overall, parasites are among the from the Centers for Disease Control and
most common causes of morbidity and mor­ ­Prevention, state health departments, and
tality in various and diverse geographic loca- ­university departments or divisions of geo-
tions worldwide. Outside the tropics and graphic medicine, tropical medicine, pediat-
subtropics, parasitic diseases are particularly ric infectious diseases, global health, and
common among tourists returning to their public health. Important human parasitic
own countries, immigrants from areas with infections are discussed in individual chapters;
highly endemic infection, and people who are the diseases are arranged alphabetically. The
immunocompromised. Some of these infec- recommendation for drugs is found in the
tions disproportionately affect impoverished ­disease-specific chapters.
populations, such as black and Hispanic people

ERRNVPHGLFRVRUJ
Table 97.1


Parasitic Diseases Not Covered Elsewhere
Directly
Commu- Diagnostic
nicable Laboratory Causative
Where Infection Definitive ­Intermediate Modes of Human (Person Tests in Form of Manifestations
Disease/Agent May Be Acquired Host Host Infection to Person) Humans Parasite in Humans
Angiostrongylus Widespread in Rats Snails and Eating improperly No Eosinophils in Larval Eosinophilia,
cantonensis the tropics, par- slugs cooked infected mol- CSF; rarely, worms meningo­
(neurotropic ticularly Pacific lusks or food contami- identification of encephalitis
­disease) Islands, Southeast nated by mollusk larvae in CSF or
Asia, Central and secretions containing at autopsy; sero-
South America, larvae; prawns, fish, logic test
the Caribbean, and land crabs that

Parasitic Diseases
and the United have ingested infected
States mollusks also may
be infectious.
Angiostrongylus Central and South Rodents Snails and Eating improperly/ No Gel diffusion; Larval Abdominal pain,
costaricensis America slugs poorly cooked infected identification of worms eosinophilia
(gastrointestinal mollusks or food larvae and eggs
tract disease) ­contaminated by in tissue
­mollusk secretions
containing larvae
Anisakiasis Cosmopolitan, Marine Certain salt- Eating uncooked or No Identification of Larval Acute gastroin­
most common mammal water fish, inadequately treated recovered larvae worms testinal tract
where eating raw squid, and infected marine fish in granulomas or ­disease
fish is practiced octopus vomitus
Opisthorchis East Asia, Eastern Humans, Certain fresh- Eating uncooked No Eggs in stool or Larvae Abdominal pain;
(Clonorchis) Europe, Russian cats, water snails infected freshwater fish duodenal fluid and hepatobiliary
sinensis, Opis- Federation dogs, mature disease
thorchis viverrini, other flukes Cholangio­
Opisthorchis mammals carcinoma

421
felineus (flukes)
422
Table 97.1
Parasitic Diseases Not Covered Elsewhere (continued)
Directly
Commu- Diagnostic
nicable Laboratory Causative
Where Infection Definitive ­Intermediate Modes of Human (Person Tests in Form of Manifestations
Disease/Agent May Be Acquired Host Host Infection to Person) Humans Parasite in Humans
Dracunculiasis Foci in Africa Humans Crustacea Drinking water infested No Identification of Adult Emerging round-
(Dracunculus Global eradication (copepods) with infected cope- emerging or female worm; inflamma-
medinensis) nearly achieved pods adult worm in worm tory response;

Parasitic Diseases
(guinea worm) subcutaneous systemic and
tissues local blister or
ulcer in skin
Fasciolopsiasis East Asia Humans, Certain fresh- Eating uncooked No Eggs or worm Larvae Diarrhea, consti-
(Fasciolopsis pigs, dogs water snails, infected plants in feces or and pation, vomiting,
buski) plants ­duodenal fluid mature anorexia, edema
worms of face and legs,
ascites
Intestinal Philippines, Humans, Fish Ingestion of uncooked Uncertain Eggs and para- Larvae Protein-losing
­capillariasis ­Thailand fish-eating infected fish site in feces and enteropathy,
(Capillaria birds mature diarrhea, malab-
­philippinensis) worms sorption, ascites,
emaciation

Abbreviation: CSF, cerebrospinal fluid.


Parasitic Diseases 423

Image 97.1
Opisthorchis (formerly Clonorchis) sinensis (Chinese liver fluke) egg. These are small, operculated
eggs, 27 to 35 µm by 11 to 20 µm. The operculum, at the smaller end of the egg, is convex and rests
on a visible “shoulder.” At the opposite (larger, abopercular) end, a small knob or hooklike protrusion
is often visible (as is the case here). The miracidium is visible inside the egg. (Also referred to as
opisthorchiasis.) Courtesy of Centers for Disease Control and Prevention/Dr Mae Melvin.

Image 97.2
Fasciola hepatica eggs (wet mounts with iodine). The eggs are ellipsoidal. They have a small, barely
distinct operculum (A, B, upper end of the eggs). The operculum can be opened (egg C), for example,
when a slight pressure is applied to the coverslip. The eggs have a thin shell that is slightly thicker at
the abopercular end. They are passed unembryonated. The size ranges from 120 to 150 µm by 63 to
90 µm. Fascioliasis is caused by the sheep liver fluke infecting the liver and biliary system. Courtesy of
Centers for Disease Control and Prevention.

Image 97.3
Dracunculiasis. The female Dracunculus medinensis (guinea worm) induces a painful blister (A); after
rupture of the blister, the worm emerges as a whitish filament (B) in the center of a painful ulcer, which
is often secondarily infected. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
424 Parasitic Diseases

Image 97.4
Saggital and axial T2-weighted magnetic resonance images of a focal lesion of the cervical spine in an
18-year-old patient with spinal cord involvement of infection with Gnathostoma spinigerum, a nema­
tode found throughout Asia that can be acquired by humans through consumption of undercooked
shellfish or meat. Courtesy of James Sejvar, MD.

Image 97.5
Eggs and larva of Angiostrongylus costaricensis. In humans, eggs and larvae are not normally excreted
but remain sequestered in tissues. Eggs and larvae (occasionally adult worms) of A costaricensis can
be identified in biopsy or surgical specimens of intestinal tissue. The larvae need to be distinguished
from larvae of Strongyloides stercoralis; however, the presence of granulomas containing thin-shelled
eggs or larvae serve to distinguish A costaricensis infections. The larval infection can cause mesenteric
arteritis and abdominal pain, occurring primarily in people in Central and South America. Courtesy of
Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Parasitic Diseases 425

Image 97.6
Fasciola hepatica (life cycle). Immature eggs are discharged in the biliary ducts and in the stool (1).
Eggs become embryonated in water (2) and release miracidia (3), which invade a suitable snail
intermediate host (4), including many species of the genus Lymnaea. In the snail, the parasites
undergo several developmental stages (sporocysts [4a], rediae [4b], and cercariae [4c]). The
cercariae are released from the snail (5) and encyst as metacercariae on aquatic vegetation or
other surfaces. Mammals acquire the infection by eating vegetation containing metacercariae.
Humans can become infected by ingesting metacercariae-containing freshwater plants, especially
watercress (6). After ingestion, the metacercariae excyst in the duodenum (7) and migrate through
the intestinal wall, the peritoneal cavity, and the liver parenchyma into the biliary ducts, where they
develop into adults (8). In humans, maturation from metacercariae into adult flukes takes approxi­
mately 3 to 4 months. The adult flukes (F hepatica, up to 30 by 13 mm; Fasciola gigantica, up to
75 mm) reside in the large biliary ducts of the mammalian host. F hepatica infect various animal
species, mostly herbivores. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
426 Parasitic Diseases

Image 97.7
Dracunculus medinensis. Humans become infected by drinking unfiltered water containing
copepods (small crustaceans) that are infected with larvae of D medinensis (1). Following ingestion,
the copepods die and release the larvae, which penetrate the host stomach and intestinal wall and
enter the abdominal cavity and retroperitoneal space (2). After maturation into adults and copulation,
the male worms die and the females (length, 70–120 cm) migrate in the subcutaneous tissues toward
the skin surface (3). Approximately 1 year after infection, the female worm induces a blister on the
skin, generally on the distal lower extremity, which ruptures. When this lesion comes into contact with
water, a contact that the patient seeks to relieve the local discomfort, the female worm emerges and
releases larvae (4). The larvae are ingested by a copepod (5) and after 2 weeks (and 2 molts) have
developed into infective larvae (6). Ingestion of the copepods closes the cycle. Courtesy of Centers
for Disease Control and Prevention/Alexander J. da Silva, PhD/Melanie Moser.

ERRNVPHGLFRVRUJ
Parasitic Diseases 427

Image 97.8
Heterophyes heterophyes. Adults release embryonated eggs each with a fully developed
miracidium, and eggs are passed in the host’s feces (1). After ingestion by a suitable snail (first
intermediate host), the eggs hatch and release miracidia, which penetrate the snail’s intestine (2).
Genera Cerithidia and Pironella are important snail hosts in Asia and the Middle East, respectively.
The miracidia undergo several developmental stages in the snail (sporocysts [2a], rediae [2b], and
cercariae [2c]). Many cercariae are produced from each redia. The cercariae are released from the
snail (3) and encyst as metacercariae in the tissues of a suitable freshwater or brackish water fish
(second intermediate host) (4). The definitive host becomes infected by ingesting undercooked or
salted fish containing metacercariae (5). After ingestion, the metacercariae excyst, attach to the
mucosa of the small intestine (6), and mature into adults (measuring 1.0–1.7 mm by 0.3–0.4 mm) (7).
In addition to humans, various fish-eating mammals (eg, cats, dogs) and birds can be infected by H
heterophyes (8). Geographic distribution: Egypt, the Middle East, and Far East. Courtesy of Centers
for Disease Control and Prevention/Alexander J. da Silva, PhD/Melanie Moser.

ERRNVPHGLFRVRUJ
428 Parasitic Diseases

Image 97.9
Anisakiasis is caused by the accidental ingestion of larvae of the nematodes (roundworms) Anisakis
simplex or Pseudoterranova decipiens. Adult stages of Anisakis simplex or P decipiens reside in the
stomach of marine mammals, where they are embedded in the mucosa, in clusters. Unembryonated
eggs produced by adult females are passed in the feces of marine mammals (1). The eggs become
embryonated in water, and first-stage larvae are formed in the eggs. The larvae molt, becoming
second-stage larvae (2a), and, after the larvae hatch from the eggs, they become free-swimming (2b).
Larvae released from the eggs are ingested by crustaceans (3). The ingested larvae develop into third-
stage larvae that are infective to fish and squid (4). The larvae migrate from the intestine to the tissues
in the peritoneal cavity and grow up to 3 cm in length. On the host’s death, larvae migrate to the
muscle tissues and, through predation, are transferred from fish to fish. Fish and squid maintain third-
stage larvae that are infective to humans and marine mammals (5). When fish or squid containing third-
stage larvae are ingested by marine mammals, the larvae molt twice and develop into adult worms.
The adult females produce eggs that are shed by marine mammals (6). Humans become infected by
eating raw or undercooked infected marine fish (7). After ingestion, the Anisakis larvae penetrate the
gastric and intestinal mucosa, causing the symptoms of anisakiasis. Courtesy of Centers for Disease
Control and Prevention/Alexander J. da Silva, PhD/Melanie Moser.

ERRNVPHGLFRVRUJ
Parasitic Diseases 429

Image 97.10
Life cycle of Angiostrongylus cantonensis. Courtesy of Centers for Disease Control and Prevention/
Emerging Infectious Diseases.

ERRNVPHGLFRVRUJ
430 Parvovirus B19

98 (arthralgia and arthritis in adults in the


absence of other manifestations of EI),
Parvovirus B19 chronic erythroid hypoplasia with severe
(Erythema Infectiosum, Fifth Disease) ­a nemia in immunodeficient patients, and
Clinical Manifestations ­transient aplastic crisis lasting 7 to 10 days in
patients with hemolytic anemias (eg, sickle
Infection with human parvovirus B19 is cell disease, autoimmune hemolytic anemia).
­recognized most often as erythema infectio- For children with other conditions associated
sum (EI), or fifth disease, which is character- with low hemoglobin concentrations, including
ized by a distinctive rash that may be preceded hemorrhage, severe anemia, and thalassemia,
by mild systemic symptoms, including fever parvovirus B19 infection will not result in
in 15% to 30% of patients. The facial rash can aplastic crisis but might result in prolongation
be intensely red with a “slapped cheek” appear- of recovery from the anemia resulting from
ance that often is accompanied by circumoral these conditions. Patients with transient
pallor. A symmetric, macular, lacelike, and, ­aplastic crisis may have a prodromal illness
often, pruritic rash also occurs on the trunk, with fever, malaise, and myalgia, but rash
moving peripherally to involve the arms, is usually absent. Human parvovirus B19
­buttocks, and thighs. The rash can fluctuate ­infection sometimes has been associated with
in intensity and recur with environmental decreases in numbers of platelets, lymphocytes,
changes, such as temperature and exposure to and ­neutrophils.
sunlight, for weeks to months. A brief, mild,
nonspecific illness consisting of fever, malaise, Human parvovirus B19 infection occurring
myalgia, and headache often precedes the during pregnancy can cause fetal hydrops,
­characteristic exanthema by approximately 7 to intrauterine growth restriction, isolated pleural
10 days. Arthralgia and arthritis occur in fewer and pericardial effusions, and death, but the
than 10% of infected children but commonly virus does not cause congenital anomalies.
among adults, especially women. Knees are The risk of fetal death is between 2% and 6%
involved most often in children, but symmetric when infection occurs during pregnancy. The
polyarthropathy of knees, fingers, and other greatest risk appears to occur during the first
joints can occur in adults. half of pregnancy.

Human parvovirus B19 can also cause asymp- Etiology


tomatic infections. Other manifestations Human parvovirus B19 is a small, nonenvel-
(Table 98.1) include a mild respiratory tract oped, single-stranded DNA virus in the family
­i llness with no rash, a rash atypical for EI that Parvoviridae, genus Erythrovirus. There are
may be rubelliform or petechial, papular-­ 3 distinct genotypes. Parvovirus B19 replicates
purpuric gloves-and-socks syndrome (painful in human erythrocyte precursors. Human
and pruritic papules, petechiae, and purpura ­parvovirus B19–associated red blood cell apla-
of hands and feet, often with fever and an sia is related to caspase-mediated apoptosis of
enanthem), polyarthropathy syndrome erythrocyte precursors.

Table 98.1
Clinical Manifestations of Human Parvovirus B19 Infection
Conditions Usual Hosts
Erythema infectiosum (fifth disease) Immunocompetent children
Polyarthropathy syndrome Immunocompetent adults (more common in women)
Chronic anemia/pure red cell aplasia Immunocompromised hosts
Transient aplastic crisis People with hemolytic anemia (ie, sickle cell anemia)
Hydrops fetalis/congenital anemia Fetus (first 20 weeks of pregnancy)
Petechial, papular-purpuric gloves-and- Immunocompetent adults
socks ­syndrome

ERRNVPHGLFRVRUJ
Parvovirus B19 431

Epidemiology Diagnostic Tests


Parvovirus B19 is distributed worldwide and Parvovirus B19 cannot be propagated in stan-
is a common cause of infection in humans, dard cell culture. In the immunocompetent
who are the only known hosts. Modes of host, detection of serum parvovirus B19–
­trans­mission include contact with respiratory specific immunoglobulin (Ig) M antibodies
tract secretions, percutaneous exposure to is the preferred diagnostic test for parvovirus
blood or blood products, and vertical trans­ B19–associated rash illness. A positive IgM test
mission from mother to fetus. Human parvo­ result indicates infection probably occurred
virus B19 infections are ubiquitous, and cases within the previous 2 to 3 months. On the basis
of EI can occur sporadically or in outbreaks of immunoassay results, IgM antibodies can
in elementary or junior high schools during be detected in 90% or more of patients at the
late winter and early spring. Secondary spread time of the EI rash and by the third day of ill-
among sus­ceptible household members is ness in patients with transient aplastic crisis.
­common, with infection occurring in appro­x­ Serum IgG antibodies appear by approximately
imately 50% of susceptible contacts in some day 2 of EI and persist for life. These assays are
studies. The transmission rate in schools is available through commercial laboratories;
lower, but infection can be an occupational however, their sensitivity and specificity can
risk for school and child care personnel, with vary, particularly for IgM. The optimal method
approximately 20% of susceptible contacts for detecting transient aplastic crisis or chronic
becoming infected. In young children, anti- infection in the immunocompromised patient
body seroprevalence is generally 5% to 10%. is demonstration of high titer of viral DNA
In most communities, approximately 50% of by polymerase chain reaction (PCR) assays.
young adults and, often, more than 90% of Because parvovirus B19 DNA can be detected
elderly people are seropositive. The annual at low levels by PCR assay in serum for months
seroconversion rate in women of childbearing and even years after the acute viremic phase,
age has been reported to be approximately 1.5%. detection does not necessarily indicate acute
Timing of the presence of high-titer parvovirus infection. Low levels of parvovirus B19 DNA
B19 DNA in serum and respiratory tract secre- can also be detected by PCR in tissues (skin,
tions indicates that people with EI are infec- heart, liver, bone marrow), independent of
tious before and after rash onset or joint active disease.
symptoms. In contrast, patients with aplastic
Treatment
crises are contagious from before the onset of
symptoms for at least a week after onset. Symp- For most patients, only supportive care is
toms of papular-purpuric gloves-and-socks ­indicated. Patients with aplastic crisis may
syndrome can occur in association with require transfusion. For treatment of chronic
­v iremia and before development of antibody infection in immunodeficient patients, intra­
response, and affected patients should be venous immunoglobulin therapy is often
­considered infectious. ­effective and should be considered. Some
cases of parvovirus B19 infection concurrent
Incubation Period with hydrops fetalis have been treated success-
Usually 4 to 14 days, but can be as long as fully with intrauterine blood transfusions of
21 days. the fetus.

ERRNVPHGLFRVRUJ
432 Parvovirus B19

Image 98.1
Parvovirus B19 infection with a generalized rash in a 9-year-old boy. Courtesy of Benjamin Estrada, MD.

Image 98.2
Parvovirus B19 infection (erythema infectiosum, fifth disease) with typical facial erythema, com­monly
referred to as the “slapped cheek” sign.

Image 98.3
Parvovirus B19 infection. Characteristic lacelike
pattern on the back of the leg. This is the same
patient as in Image 98.2.

Image 98.4
Parvovirus B19 infection (erythema infectiosum,
fifth disease) in a 5-year-old girl.

ERRNVPHGLFRVRUJ
Parvovirus B19 433

Image 98.5
Parvovirus B19 infection (erythema infectiosum, fifth disease). This is the same child as in Image 98.4.

Image 98.6
Close-up view of the lacelike pattern of fifth disease in a 6-year-old girl. Courtesy of George Nankervis,
MD.

Image 98.7
Characteristic “slapped cheek” appearance of the face in a child who has fifth disease. The
characteristic rash is also present on the arms.

ERRNVPHGLFRVRUJ
434 Parvovirus B19

Image 98.9
Stocking glove purpura. This 18-year-old girl
awoke one morning with asymptomatic
Image 98.8
symmetric purpura of the hands and feet, which
An 8-year-old white girl with the facial erythema spread to involve the proximal extremities. The
of erythema infectiosum. Courtesy of Larry exanthem faded over 7 to 10 days. Although an
Frenkel, MD. enanthem is not usually reported with parvovirus
infection, she also developed some erythema of
the buccal mucosa and white plaques on a red
base on the dorsum of the tongue. Courtesy of
H. Cody Meissner, MD, FAAP.

Image 98.10
This healthy 6-year-old girl developed an asymptomatic symmetric red papular eruption on her face,
extremities, and trunk, which became confluent on her face 1 week earlier. Courtesy of H. Cody
Meissner, MD, FAAP.

ERRNVPHGLFRVRUJ
PASTEURELLA INFECTIONS 435

99 exposure can be identified. Although rare,


human-to-human transmission has been
Pasteurella Infections ­documented vertically from mother to neo-
Clinical Manifestations nate, horizontally from colonized humans,
and by contaminated blood products.
The most common manifestation in children
is cellulitis at the site of a bite or scratch of a Incubation Period
cat, dog, or other animal. Cellulitis typically Usually less than 24 hours.
develops within 24 hours of the injury and
includes swelling, erythema, tenderness, and Diagnostic Tests
serous or sanguinopurulent discharge at the The isolation of Pasteurella species from skin
site. Regional lymphadenopathy, chills, and lesion drainage or other sites of infection
fever can occur. Local complications, such as (eg, blood, joint fluid, cerebrospinal fluid, spu-
abscesses and tenosynovitis, are frequent, tum, pleural fluid, suppurative lymph nodes)
but septic arthritis and osteomyelitis are also is diagnostic. Pasteurella species are some-
reported. Less common manifestations of what fastidious but may be cultured on several
infection include septicemia, meningitis, media generally used in clinical laboratories,
­endocarditis, respiratory tract infections including sheep blood and chocolate agars.
(eg, pneumonia, pulmonary abscesses, pleural Although they resemble several other organ-
empyema), appendicitis, hepatic abscess, isms morphologically, laboratory identification
­peritonitis, and ocular infections (eg, corneal to the genus level is generally not difficult.
ulcers, endophthalmitis). People with liver
­disease, solid organ transplant, or underlying Treatment
host defense abnormalities are predisposed to The drug of choice is penicillin. Other oral
bacteremia with Pasteurella multocida. agents that are usually effective include
­a mpicillin, amoxicillin, cefuroxime, cefixime,
Etiology
cefpodoxime, doxycycline, and fluoroquino-
Members of the genus Pasteurella are nonmo- lones. Pasteurella species are usually resistant
tile, facultatively anaerobic, mostly catalase to vancomycin, clindamycin, and erythromy-
and oxidase positive, gram-negative cocco­ cin. For patients who are allergic to β-lactam
bacilli that are primarily respiratory tract agents, azithromycin or trimethoprim-­
pathogens in animals. The most common sulfamethoxazole are alternative choices.
human pathogen is P multocida subsp multo­ For suspected polymicrobial infected bites,
cida (­causing >50% of infections). oral amoxicillin-clavulanate or, for severe
Epidemiology infection, intravenous ampicillin-sulbactam
or piperacillin-tazobactam can be given. The
Pasteurella species are found in the oral flora duration of therapy is usually 7 to 10 days for
of 70% to 90% of cats, 25% to 50% of dogs, and local infections and 10 to 14 days for more
many other animals. Transmission can occur severe infections. Antimicrobial therapy
from the bite or scratch or licking of a previous should be continued for 4 to 6 weeks for bone
wound by a cat or dog or, less commonly, and joint infections. Wound drainage or
from another animal. Rarely, respiratory tract debridement may be necessary.
spread occurs from animals to humans; in a
significant proportion of cases, no animal

ERRNVPHGLFRVRUJ
436 PASTEURELLA INFECTIONS

Image 99.1 Image 99.2


This photograph depicts the colonial morphology Pasteurella multocida on chocolate agar. Colo­
displayed by gram-negative Yersinia pestis bac­ nies are small, gray, smooth, and nonhemolytic.
teria, which was grown on a medium of sheep Courtesy of Julia Rosebush, DO; Robert Jerris,
blood agar for a 72-hour period at a temperature PhD; and Theresa Stanley, M(ASCP).
of 37°C (98.6°F). Courtesy of Centers for Disease
Control and Prevention/Todd Parker, MD, and
Audra Marsh.

Image 99.3
Pasteurella multocida cellulitis secondary to multiple cat bites about the face of a 1-year-old. Courtesy
of George Nankervis, MD.

Image 99.4
Right forearm of 1-year-old boy bitten by a stray cat. The child developed fever, redness, and swelling
10 hours after the bite. He was taking amoxicillin for otitis media at the time of the bite. The child
responded to treatment with intravenous cefuroxime, although the fever persisted for 36 hours.
Pasturella multocida was cultured from purulent material obtained from the wound the day after
admission. Courtesy of Larry I. Corman, MD.

ERRNVPHGLFRVRUJ
Pediculosis Capitis 437

100 combs, hairbrushes, and hats, is uncommon.


Away from the scalp, head lice survive fewer
Pediculosis Capitis than 2 days at room temperature, and their
(Head Lice) eggs generally become nonviable within a
Clinical Manifestations week and cannot hatch at a lower ambient
­temperature than that near the scalp.
Itching is the most common symptom of head
lice infestation, but many children are asymp- Incubation Period
tomatic. Adult lice or eggs (nits) are found on From the laying of eggs to hatching of first
the hair and are most readily apparent behind nymph, 8 to 9 days, varying from 7 to 12 days,
the ears and near the nape of the neck. Excor­ but shorter in hot climates. Lice mature to the
iations and crusting caused by secondary adult stage 9 to 12 days later. Adult females
­bacterial infection may occur and are often then may lay eggs (nits), but only if the female
associated with regional lymphadenopathy. has mated.
Head lice usually deposit their eggs on a hair
shaft 4 mm or less from the scalp. Because Diagnostic Tests
hair grows at a rate of approximately 1 cm per Identification of eggs (nits), nymphs, and lice
month, the duration of infestation can be esti- with the naked eye is possible; diagnosis can be
mated by the distance of the nit from the scalp. confirmed by using a hand lens, dermatoscope
(epiluminescence microscope), or traditional
Etiology
microscope. Nymphal and adult lice shun light,
Pediculus humanus capitis is the head louse. move rapidly, and conceal themselves. Wetting
Nymphs and adult lice feed on human blood. the hair with water, oil, or a conditioner and
Epidemiology using a fine-tooth comb may improve ability to
diagnose infestation and shorten examination
In the United States, head lice infestation is time. It is important to differentiate nits from
most common in children attending child care dandruff, benign hair casts (a layer of follicular
and elementary school. Head lice infestation cells that may slide easily off the hair shaft),
is not a sign of poor hygiene or influenced by plugs of desquamated cells, external hair
hair length. All socioeconomic groups are debris, and fungal infections of the hair.
affected. In the United States, infestations are Because nits remain affixed to the hair firmly,
less common in black children than in children even if dead or hatched, the mere presence of
of other races and ethnicities. Head lice are nits is not a sign of an active infestation.
not a health hazard because they are not
responsible for spread of any disease. Head lice Treatment
are only able to crawl; therefore, transmission A number of effective pediculicidal agents
occurs mainly by direct head-to-head contact are available to treat head lice infestation
with hair of infested people. Transmission by (Table 100.1). Safety is a major concern with
contact with personal belongings, such as pediculicides because the infestation itself

Table 100.1
Topical Pediculicides for the Treatment of Head Lice
Product Availability Cost Estimatea
Permethrin 1% lotion (Nix) Over the counter $
Pyrethrins + piperonyl butoxide (Rid) Over the counter $
Malathion 0.5% (Ovide) Prescription $$$$
Benzyl alcohol 5% (Ulesfia) Prescription $$–$$$$b
Spinosad 0.9% suspension (Natroba) Prescription $$$$
Ivermectin 0.5% lotion (Sklice) Prescription $$$$
a $, <$25; $$, $26–$99; $$$, $100–$199; $$$$, $200–$299.
b Cost varies by length of hair, which affects number of units of product required.

ERRNVPHGLFRVRUJ
438 Pediculosis Capitis

presents minimal risk to the host. Pediculicides ulicide, malathion, benzyl alcohol lotion,
should be used only as directed and with care. ­spinosad suspension, or ivermectin lotion
Instructions on proper use of any product should be used. When lice are resistant to all
should be explained carefully. Therapy can be topical agents, oral ivermectin may be used.
started with over-the-counter 1% permethrin Drugs that have residual activity may kill
or with a pyrethrin combined with piperonyl nymphs as they emerge from eggs. Pediculi-
butoxide product; both have good safety pro- cides that are not sufficiently ovicidal usually
files. However, resistance to these compounds require more than one application. Ideally,
has been documented in the United States. retreatment should occur after the eggs that
For treatment failures not attributable to are present at initial treatment have hatched
improper use of an over-the-counter pedi­c­ but before any new eggs have been produced.

Image 100.1
Head louse, baby louse, and hair. Copyright Gary Williams, MD.

Image 100.2 Image 100.3


Nits on the hair shafts. Copyright Edward K. Nits on the hair shaft. Copyright Edgar K.
Marcuse, MD. Marcuse, MD.

ERRNVPHGLFRVRUJ
Pediculosis Capitis 439

Image 100.4
Pediculosis (head lice) with nits and excoriations of the scalp. Courtesy of Centers for Disease Control
and Prevention.

Image 100.5
An 8-year-old girl with an earache. This child complained of otalgia. During the course of otoscopic
evaluation, she was noted to have a very large number of nits in her hair as well as active lice. On
questioning, she stated she has had itching of the scalp. She was treated with topical permethrin with
temporary resolution. Reinfestation occurred after sharing a riding helmet with a cousin. Courtesy of
Will Sorey, MD.

ERRNVPHGLFRVRUJ
440 Pediculosis Capitis

Image 100.6
The life cycle of the head louse has 3 stages: egg, nymph, and adult. Eggs: Nits are head lice eggs.
They are hard to see and are often confused for dandruff or hair spray droplets. Nits are laid by the
adult female and are cemented at the base of the hair shaft nearest the scalp (1). They are 0.8 by 0.3
mm, oval, and, usually, yellow to white. Nits take about 1 week to hatch (range, 6–9 days). Viable eggs
are usually located within 6 mm of the scalp. Nymphs: The egg hatches to release a nymph (2). The nit
shell then becomes a more visible dull yellow and remains attached to the hair shaft. The nymph looks
like an adult head louse but is about the size of a pin head. Nymphs mature after 3 molts (3, 4) and
become adults about 7 days after hatching. Adults: The adult louse is about the size of a sesame
seed, has 6 legs (each with claws), and is tan to grayish-white (5). In persons with dark hair, the adult
louse will appear darker. Females are usually larger than males and can lay up to 8 nits per day. Adult
lice can live up to 30 days on a person’s head. To live, adult lice need to feed on blood several times
daily. Without blood meals, the louse will die within 1 to 2 days off the host. Courtesy of Centers for
Disease Control and Prevention/Alexander J. da Silva, PhD/Melanie Moser.

ERRNVPHGLFRVRUJ
Pediculosis Corporis 441

101 room temperature. In contrast with head lice,


body lice are well-recognized vectors of disease
Pediculosis Corporis (eg, epidemic typhus, trench fever, epidemic
(Body Lice) relapsing fever, bacillary angiomatosis).
Clinical Manifestations Incubation Period
Intense itching, particularly at night, is com- From laying eggs to hatching of first nymph, 1
mon with body lice infestations. Bites manifest to 2 weeks. Lice mature and are capable of
as small erythematous macules, papules, and reproducing 9 to 19 days after hatching.
excoriations primarily on the trunk. In heavily
bitten areas, typically around the midsection, Diagnostic Tests
the skin can become thickened and discolored. Identification of eggs, nymphs, and lice with
Secondary bacterial infection of the skin the naked eye is possible; diagnosis can be
(­pyoderma) caused by scratching is common. ­confirmed by using a hand lens, dermatoscope
(epiluminescence microscope), or a traditional
Etiology
microscope. Adult and nymphal body lice are
Pediculus humanus humanus (or corporis) is seldom seen on the body because they are gen-
the body louse. Nymphs and adult lice feed on erally sequestered in clothing.
human blood.
Treatment
Epidemiology
Treatment consists of improving hygiene and
Body lice are generally restricted to people regular changes of clean clothes and bedding.
­living in crowded conditions without access Infested materials can be decontaminated by
to regular bathing or changes of clothing washing in hot water (at least 53.5°C [128.3°F]),
(eg, refugees, victims of war or natural disas- by machine drying at hot temperatures, by
ters, homeless people). Under these conditions, dry cleaning, or by pressing with a hot iron.
body lice can spread rapidly through direct Temperatures exceeding 53.5°C (128.3°F) for
contact or contact with contaminated clothing 5 minutes are lethal to lice and eggs. Pediculi-
or bedding. Body lice live in clothes or bed- cides are not usually necessary if materials are
ding, lay their eggs on or near the seams of laundered at least weekly. Some people with
clothing, and move to the skin to feed. Body much body hair may require full-body treat-
lice cannot survive away from a blood source ment with a pediculicide because lice and eggs
for longer than approximately 5 to 7 days at may adhere to body hair.

Image 101.1
This body louse, Pediculus humanus humanus, was photographed during a 1972 study of
migrant labor camp disease vectors. Body lice, family Pediculidae, are parasitic insects that live
on the body and in the clothing or bedding of infested humans. Infestation is common and is found
worldwide. Itching and rash are common with lice infestation. Courtesy of Centers for Disease
Control and Prevention.

ERRNVPHGLFRVRUJ
442 Pediculosis Corporis

Image 101.2
This 2006 image depicted 5 body lice, Pediculus humanus humanus, which, from left to right, include
3 nymphal-staged lice, beginning with a stage N1, then N2, and, thirdly, an N3-staged nymph, followed
by an adult male louse and, finally, an adult female louse. Courtesy of Centers for Disease Control and
Prevention/Joseph Strycharz, PhD; Kyong Sup Yoon, PhD; Frank Collins, PhD.

Image 101.3
This is a piece of clothing, the seams of which contained lice eggs from the body louse Pediculus
humanus humanus. The most important factor in the control of body lice infestation is the ability
to change and wash clothing. Courtesy of Centers for Disease Control and Prevention/Reed &
Carnrick Pharmaceuticals.

ERRNVPHGLFRVRUJ
Pediculosis Pubis 443

102 36 hours, and their eggs can remain viable


for up to 10 days under suitable environmen-
Pediculosis Pubis tal conditions.
(Pubic Lice, Crab Lice)
Incubation Period
Clinical Manifestations
From the laying of eggs to the hatching of
Pruritus of the anogenital area is a common first nymph, 6 to 10 days. Adult lice become
symptom in pubic lice infestations (“crabs” capable of reproducing approximately 2 to
or “phthiriasis”). The parasite is found most 3 weeks after hatching.
frequently in the pubic region, but infestation
can involve the eyelashes, eyebrows, beard, Diagnostic Tests
axilla, perianal area, and, rarely, scalp. A char- Identification of eggs (nits), nymphs, and lice
acteristic sign of heavy pubic lice infestation is with the naked eye is possible; the diagnosis
the presence of bluish or slate-colored macules can be confirmed by using a hand lens, micro-
(maculae ceruleae) on the chest, abdomen, scope, or dermatoscope.
or thighs.
Treatment
Etiology
All areas of the body with coarse hair should
Phthirus pubis is the pubic or crab louse. be examined for evidence of pubic lice infesta-
Nymphs and adult lice feed on human blood. tion. Lice and their eggs can be removed man-
ually, or the hairs can be shaved to eliminate
Epidemiology
infestation immediately. Caution should be
Pubic lice infestations are more prevalent in used when inspecting, removing, or treating
adults and are usually transmitted through lice on or near the eyelashes. Pediculicides
sexual contact. Transmission by contaminated used to treat other kinds of louse infestations
items, such as towels, is uncommon. Pubic are effective for treatment of pubic lice.
lice on the eyelashes or eyebrows of children Retreatment is recommended as for head lice.
may be evidence of sexual abuse, although For treatment of pubic lice infestation of eye-
other modes of transmission are possible. lashes, an ophthalmic-grade petrolatum oint-
Infested people should be examined for other ment is applied to the eyelashes 2 to 4 times
sexually transmitted infections. Adult pubic daily for 8 to 10 days.
lice can survive away from a host for up to

ERRNVPHGLFRVRUJ
444 Pediculosis Pubis

Image 102.1
Pediculosis, the infestation of humans by lice, has been documented for millennia. Three species of
lice infest humans: Pediculus humanus humanus, the body louse; Pediculus humanus capitis, the
head louse; and Pthirus pubis, the pubic or crab louse. The hallmark of louse infestation is pruritus
at the site of bites. Lice are more active at night, frequently disrupting the sleep of the host, which
is the derivation of the term “feeling lousy.” Adult pubic lice can survive without a blood meal for
36 hours. Unlike head lice, which may travel up to 23 cm per minute, pubic lice are sluggish, traveling
a maximum of 10 cm per day. Viable eggs on pubic hairs may hatch up to 10 days later. Pubic louse
infestation is localized most frequently to the pubic and perianal regions but may spread to the
mustache, beard, axillae, eyelashes, or scalp hair. Infestation is usually acquired through sexual
contact, and the finding of pubic lice in children (often limited to the eyelashes) should raise concern
for possible sexual abuse. Courtesy of H. Cody Meissner, MD, FAAP.

Image 102.2
Image 102.3
Pubic lice (Phthirus pubis) in the eyelashes of This photograph reveals the presence of pubic
a 3-year-old boy. The diagnosis can be con­ or crab lice, Pthirus pubis, with reddish-brown
firmed by the use of a hand lens or microscope. feces. Pubic lice are generally found in the
Copyright Gary Williams. genital area on pubic hair but may occasionally
be found on other coarse body hair, such as leg
hair, armpit hair, mustache, beard, eyebrows,
and eyelashes. Courtesy of Centers for Disease
Control and Prevention/Reed & Carnrick
Pharmaceuticals.

ERRNVPHGLFRVRUJ
Pertussis (­Whooping Cough) 445

103 ­trachomatis, Chlamydophila pneumoniae,


­Bordetella bronchiseptica (the cause of kennel
Pertussis cough), Bordetella holmesii, and certain respi-
(­Whooping Cough) ratory tract viruses, particularly adenoviruses
and respiratory syncytial viruses.
Clinical Manifestations
Epidemiology
Pertussis begins with mild upper respiratory
tract symptoms similar to the common cold Humans are the only known hosts of B ­pertussis.
(catarrhal stage) and progresses to cough and Transmission occurs by close contact with
then usually to paroxysms of cough (paroxys- cases via aerosolized droplets. Cases occur
mal stage), characterized by inspiratory whoop year-round, typically with a late summer-
and commonly followed by vomiting. Fever is autumn peak. Neither infection nor immuni-
absent or minimal. Symptoms wane gradually zation provides lifelong immunity. Lack of
over weeks to months (convalescent stage). natural booster events and waning immunity
Cough illness in immunized children and since the most recent immunization, parti­c­
adults can range from typical to mild and ularly when acellular pertussis vaccine is
unrecognized. The duration of classic pertussis used for the entire immunization series, are
is 6 to 10 weeks. Approximately half of adoles- responsible for increased cases reported in
cents with pertussis cough for 10 weeks or school-aged children, adolescents, and adults.
­longer. Complications among adolescents and Additionally, waning maternal immunity and
adults include syncope, weight loss, sleep reduced transplacental antibody in mothers
­disturbance, incontinence, rib fractures, and who have not received tetanus, diphtheria,
pneumonia; among adults, complications acellular pertussis vaccine during pregnancy
increase with age. Pertussis is most severe contribute to an increase in pertussis in very
when it occurs during the first 6 months of young infants. More than 41,000 cases of per-
life, particularly in preterm and unimmunized tussis were reported in the United States in
or underimmunized infants. Disease in infants 2012, the highest in people older than 50 years.
younger than 6 months can be atypical with Up to 80% of previously immunized household
a short catarrhal stage, followed by gagging, contacts of symptomatic cases are infected
gasping, bradycardia, or apnea (67%) as with pertussis. Symptoms in these contacts
­prominent early manifestations; absence of vary from asymptomatic infection to classic
whoop; and prolonged convalescence. Sudden pertussis. Older siblings (including adoles-
unexpected death can be caused by pertussis. cents) and adults with mild or unrecognized
Complications among infants include pneu­ atypical disease are important sources of
monia (23%) and pulmonary hypertension, as ­pertussis for infants and young children.
well as complications related to severe cough- Infected people are most contagious during
ing spells, such as subdural or conjunctival the catarrhal stage through the third week
bleeding and hernia, and severe coughing after onset of paroxysms. Factors affecting
spells leading to hypoxia and complications the length of communicability include age,
such as seizures (2%), encephalopathy (<0.5%), immunization status or previous infection,
apnea, and death. More than two-thirds of and appropriate antimicrobial therapy.
infants with pertussis are hospitalized. Case-
Incubation Period
fatality rates are approximately 1% in infants
younger than 2 months and less than 0.5% in 7 to 10 days; range, 5 to 21 days.
infants 2 through 11 months of age. Diagnostic Tests
Etiology Culture is considered the gold standard for
Pertussis is caused by a fastidious, gram-­ laboratory diagnosis of pertussis. Although
negative, pleomorphic bacillus, Bordetella culture is 100% specific, it is not optimally
­pertussis. Other causes of sporadic prolonged ­sensitive because B pertussis is a fastidious
cough illness include Bordetella parapertussis, organism. Culture requires collection of an
Mycoplasma pneumoniae, Chlamydia appropriate nasopharyngeal specimen,

ERRNVPHGLFRVRUJ
446 Pertussis (­Whooping Cough)

obtained by aspiration or with Dacron (poly- often absent in adolescents and adults with
ethylene terephthalate) or calcium alginate pertussis. A markedly elevated white blood
swabs. Specimens must be placed into special cell count is associated with a poor prognosis
transport media immediately and not allowed in young infants.
to dry while being transported promptly to the
Treatment
laboratory. Culture results can be negative if
taken from a previously immunized person, if Antimicrobial agents administered during
antimicrobial therapy has been started, if more the catarrhal stage may ameliorate the disease.
than 2 weeks has elapsed since cough onset, or Clinicians should begin antimicrobial therapy
if the specimen is not handled appropriately. prior to test results if the clinical history is
strongly suggestive of pertussis or the patient
Polymerase chain reaction (PCR) assay is is at high risk of severe or complicated disease
now the most commonly used laboratory (eg, young infants). After the cough is estab-
method for detection of B pertussis because lished, antimicrobial agents have no discern-
of its improved sensitivity and more rapid ible effect on the course of illness but are
turnaround time. The PCR test requires col­ recommended to limit spread of organisms
lection of an adequate nasopharyngeal speci- to others. A 5-day course of azithromycin is
men. Calcium alginate swabs are inhibitory appropriate for treatment. Azithromycin
to PCR and should not be used for PCR tests. should be used with caution in people with
The PCR test has optimal sensitivity during long QT syndrome and proarrhythmic con­
the first 3 weeks of cough, is unlikely to be ditions. Resistance of B pertussis to macrolide
­useful if antimicrobial therapy has been given antimicrobial agents has been reported,
for more than 5 days, and lacks sensitivity in but rarely. Penicillins and first- and second-­
previously immunized people. Unacceptably generation cephalosporins are not effective
high rates of false-positive results are reported against B pertussis.
from some laboratories, and pseudo-outbreaks
linked to contaminated specimens have also Antimicrobial agents used for infants younger
been reported. The Centers for Disease Control than 6 months require special consideration.
and Prevention has released a best practices An association between orally administered
document to guide pertussis PCR assays erythromycin and azithromycin with infantile
(www.cdc.gov/pertussis/clinical/diagnostic- hypertrophic pyloric stenosis has been
testing/diagnosis-pcr-bestpractices.html) as reported in neonates younger than 1 month.
well as a video demonstrating optimal speci- Azithromycin is the drug of choice for treat-
men collection. Multiple DNA target sequences ment or prophylaxis of pertussis in neonates
are required to distinguish between Bordetella younger than 1 month in whom the risk
species. Direct fluorescent antibody testing is of developing severe pertussis and life-­
no longer recommended. threatening complications outweighs the
potential risk of infantile hypertrophic
Commercial serologic tests for pertussis pyloric stenosis.
­infection can be helpful for diagnosis,
­especially later in illness and in adolescents Trimethoprim-sulfamethoxazole is an alter­
and adults. In the absence of recent immuni­ native for patients older than 2 months who
zation, an ­elevated serum immunoglobulin cannot tolerate macrolides or who are infected
(Ig) G ­antibody to pertussis toxin (PT) after with a macrolide-resistant strain, but studies
2 weeks of onset of cough is suggestive of evaluating trimethoprim-sulfamethoxazole
recent B ­pertussis infection. An increasing as treatment for pertussis are limited.
titer, a ­single IgG anti-PT value of approxi-
Young infants are at increased risk of respira-
mately 100 IU/mL or greater, or a decreasing
tory failure, secondary bacterial pneumonia,
titer, if obtained later in the illness, are con­
and cardiopulmonary failure and death from
sidered diagnostic.
severe pulmonary hypertension. Hospitalized
An increased white blood cell count attribut- young infants with pertussis should be man-
able to absolute lymphocytosis is suggestive of aged in a setting where these complications
pertussis in infants and young children but is can be recognized and managed urgently.

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Pertussis (­Whooping Cough) 447

Image 103.1
Colonies of Bordetella pertussis growing on Bordet-Gengou agar. Courtesy of Edgar O. Ledbetter,
MD, FAAP.

Image 103.2
Pertussis. Incidence, by year—United States, 1982–2012. Courtesy of Morbidity and Mortality
Weekly Report.

ERRNVPHGLFRVRUJ
448 Pertussis (­Whooping Cough)

Image 103.3
Pertussis. Number of reported cases, by age group—United States, 2012. Courtesy of Morbidity and
Mortality Weekly Report.

Image 103.4
Thick bronchopulmonary secretions of pertussis
in an infant. Copyright Charles Prober, MD.

Image 103.5
A preschool-aged boy with pertussis. Thick
respiratory secretions were produced by a
paroxysmal coughing spell. Courtesy of Edgar O.
Ledbetter, MD, FAAP.

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Pertussis (­Whooping Cough) 449

Image 103.7
A 4-week-old with pertussis pneumonia with
pulmonary air trapping and progressive atelec­
tasis confirmed at autopsy. The neonate acquired
the infection from the mother shortly after birth.
Segmented and lobar atelectasis are not uncom­
Image 103.6
mon complications of pertussis.
Bilateral subconjunctival hemorrhages and thick
nasal mucus in an infant with pertussis.

Image 103.8 Image 103.9


Bronchiolar plugging in the neonate in Image 103.7 Bordetella pertussis bacteria enmeshed in
who died of pertussis pneumonia. Neonates, the cilia of respiratory epithelial cells lining a
infants, and children often acquire pertussis bronchiole in an infant with fatal pertussis
from an infected adult or sibling contact. (hematoxylin-eosin stain, original magnification
x100). Courtesy of Christopher Paddock, MD.

Image 103.10
Plugging and alveolar dilatation of pertussis
pneumonia in an infant who died. Courtesy of
Edgar O. Ledbetter, MD, FAAP.

Image 103.11
Pertussis pneumonia in a 7-year-old who
was exhausted from persistent coughing.
Obliteration of cardiac borders on the chest
radiograph is a common radiographic change
of pertussis pneumonia.

ERRNVPHGLFRVRUJ
450 Pertussis (­Whooping Cough)

Image 103.12
This image depicts a malnourished female infant who presented to a clinic suffering from what was
diagnosed as pertussis. Pertussis is a highly communicable, vaccine-preventable disease caused by
Bordetella pertussis, a gram-negative coccobacillus, that lasts for many weeks and typically afflicts
children with severe coughing, whooping, and posttussive vomiting. Courtesy of Centers for Disease
Control and Prevention.

Image 103.13
Umbilical hernia more prominent as a result of persistent pertussis cough in a 4-month-old boy.
Courtesy of Benjamin Estrada, MD.

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Pertussis (­Whooping Cough) 451

Image 103.14
This child has pertussis (whooping cough). He has severe coughing spasms, which are often followed
by a whooping sound. It is difficult for him to stop coughing and catch his breath. Courtesy of Centers
for Disease Control and Prevention.

Image 103.15
Pertussis pneumonia in a 2-month-old 2 days Image 103.16
after hospital admission. His mother had been The infant in Image 103.15 required mechanical
coughing since shortly after delivery. Courtesy of ventilation because of respiratory failure.
Carol J. Baker, MD, FAAP. Courtesy of Carol J. Baker, MD, FAAP.

ERRNVPHGLFRVRUJ
452 Pinworm Infection

104 Incubation Period

Pinworm Infection From ingestion of an egg until an adult gravid


female migrates to the perianal region, 1 to
(Enterobius vermicularis)
2 months or longer.
Clinical Manifestations
Diagnostic Tests
Although some people are asymptomatic,
Diagnosis is made when adult worms are visu-
­pinworm infection (enterobiasis) can cause
alized in the perianal region, which is best
pruritus ani and, rarely, pruritus vulvae.
examined 2 to 3 hours after the child is asleep.
­Bac­terial superinfections can result from
No egg shedding occurs inside the intestinal
scratching and excoriation of an area.
lumen; thus, very few ova are present in stool,
Although pinworms have been found in the
so examination of stool specimens for ova and
lumen of the appendix and, in some cases,
parasites is not recommended. Alternatively,
these intraluminal parasites have been associ-
diagnosis is made by touching the perianal
ated with acute appendicitis, pinworms have
skin with transparent (not translucent) adhe-
also been observed in histologically normal
sive tape to collect any eggs that may be pres-
appendixes. Many clinical findings, such as
ent; the tape is then applied to a glass slide and
grinding of teeth at night, weight loss, and
examined under a low-power microscopic lens.
enuresis, have been attributed to pinworm
Specimens should be obtained on 3 consecutive
infections, but proof of a causal relationship
mornings when the child first awakens. Eosin-
has not been established. Urethritis, vaginitis,
ophilia is unusual and should not be attributed
salpingitis, or pelvic peritonitis may occur
to pinworm infection.
from aberrant migration of an adult worm
from the perineum. Treatment
Etiology Because pinworms are largely innocuous, the
risk versus benefit of treatments should be
Enterobius vermicularis is a nematode or
weighed. Drugs of choice for treatment are
roundworm.
­pyrantel pamoate and albendazole, which are
Epidemiology given in a single dose and repeated in 2 weeks
Enterobiasis occurs worldwide and commonly because none of these drugs are completely
clusters within families. Prevalence rates are effective against the egg or developing larvae
higher in preschool- and school-aged children, stages. Pyrantel pamoate is available without
in primary caregivers of infected children, and prescription. Reinfection with pinworms
in institutionalized people; up to 50% of these occurs easily; prevention should be discussed
populations may be infected. when treatment is given. Infected people
should bathe in the morning; bathing removes
Egg transmission occurs by the fecal-oral route a large proportion of eggs. Frequently changing
directly or indirectly via contaminated hands the infected child’s underclothes, bedclothes,
or fomites such as shared toys, bedding, cloth- and bedsheets may decrease the egg contami-
ing, toilet seats, and baths. Female pinworms nation of the local environment and risk of
usually die after depositing up to 10,000 fertil- reinfection. Specific personal hygiene measures
ized eggs within 24 hours on the perianal skin. (eg, exercising hand hygiene before eating or
Reinfection occurs by autoinfection, from pin- preparing food, keeping fingernails short,
worms crawling into the rectum after hatching, avoiding scratching of the perianal region,
or by infection following ingestion of eggs from avoiding nail biting) may decrease risk of
another person. A person remains infectious as ­autoinfection and continued transmission.
long as female nematodes are discharging eggs All household members should be treated as
on perianal skin. Eggs usually remain infective a group in situations in which multiple or
in an indoor environment for 2 to 3 weeks. repeated symptomatic infections occur.
Humans are the only known natural hosts; ­Vaginitis is self-limited and does not require
dogs and cats do not harbor E vermicularis. separate treatment.

ERRNVPHGLFRVRUJ
Pinworm Infection 453

Image 104.1
A, B, Enterobius egg(s). C, Enterobius eggs on cellulose tape preparation. Courtesy of Centers for
Disease Control and Prevention.

Image 104.2
Adult pinworm (Enterobius vermicularis) in the perianal area of a 14-year-old boy. Perianal inspection
2 to 3 hours after the child goes to sleep may reveal pinworms that have migrated outside of the
intestinal tract. Copyright Gary Williams.

Image 104.3
Enterobius vermicularis in the lumen of the appendix of a 10-year-old. Pinworms can be found in the
lumen of the appendix, but most evidence indicates they do not cause acute appendicitis. Courtesy
of Benjamin Estrada, MD.

ERRNVPHGLFRVRUJ
454 Pinworm Infection

Image 104.4
Eggs are deposited on perianal folds (1). Self-infection occurs by transferring infective eggs to the
mouth with hands that have scratched the perianal area (2). Person-to-person transmission can also
occur through handling of contaminated clothes or bed linens. Enterobiasis may also be acquired
through surfaces in the environment that are contaminated with pinworm eggs (eg, curtains,
carpeting). Some small number of eggs may become airborne and inhaled. These could be swallowed
and follow the same development as ingested eggs. Following ingestion of infective eggs, the larvae
hatch in the small intestine (3) and the adults establish themselves in the colon (4). The time interval
from ingestion of infective eggs to oviposition by the adult females is about 1 month. The life span of
the adults is about 2 months. Gravid females migrate nocturnally outside the anus and oviposit while
crawling on the skin of the perianal area (5). The larvae contained inside the eggs develop (the eggs
become infective) in 4 to 6 hours under optimal conditions (1). Retroinfection, or the migration of
newly hatched larvae from the anal skin back into the rectum, may occur, but the frequency with
which this happens is unknown. Courtesy of Centers for Disease Control and Prevention.

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Pityriasis Versicolor 455

105 Incubation Period

Pityriasis Versicolor Unknown.


(Tinea Versicolor) Diagnostic Tests
Clinical Manifestations The presence of symmetrically distributed,
faintly scaling macules and patches of varying
Pityriasis versicolor (formerly tinea versicolor)
color concentrated on the upper back and chest
is a common and benign superficial infection
is diagnostic. The “evoked scale” sign consists
of the skin. It classically occurs in adolescence
of stretching or scraping involved skin, which
and involves the upper trunk and neck. Infants
elicits a visible layer of thin scale. Involved
and children are more likely to exhibit facial
areas fluoresce yellow-green under Wood lamp
involvement. The condition can occur at any
evaluation. Potassium hydroxide wet mount
age and may involve other areas, including the
preparation of scraped scales reveals the classic
scalp, genital area, and thighs. Symmetric
“spaghetti and meatballs” short hyphae and
involvement with ovoid discrete or coalescent
clusters of yeast forms. Because this yeast is a
lesions of varying size is typical; these macules
common inhabitant of the skin, culture from
or patches vary in color, even in the same per-
the surface is nondiagnostic. Growth requires
son. White, pink, tan, or brown coloration is
media enriched with sterile olive oil or another
often surmounted by faint dusty scales. Com-
long-chain fatty acid.
mon conditions confused with this disorder
include pityriasis alba, vitiligo, seborrheic der- Treatment
matitis, pityriasis rosea, progressive macular
Multiple topical and systemic agents are effi­
hypopigmentation, pityriasis lichenoides, and
cacious, and recommendations vary substan-
secondary syphilis.
tially. The most cost-effective treatments are
Etiology selenium sulfide shampoo/lotion and clotrima-
zole cream for 2 to 3 weeks. Effective topical
The cause of pityriasis versicolor is Malassezia
agents include ketoconazole, bifonazole,
species, a group of lipid-dependent yeasts that
miconazole, econazole, oxiconazole, clotrima-
exist on healthy skin in yeast phase and cause
zole, terbinafine, and ciclopirox, as well as
clinical lesions only when substantial growth
zinc pyrithione shampoo. Systemic therapies,
of hyphae occurs. Lesions fail to tan during the
including fluconazole and ketoconazole, are
summer and are relatively darker during the
easy to use and are effective. Single doses do
winter, hence the term versicolor.
not appear to be as efficacious as multiple doses
Epidemiology over several days or weeks. Although oral
Pityriasis versicolor can occur in any climate agents are easier to use, they are not necessarily
or age group but tends to favor adolescents and more effective and have possible serious side
young adults, particularly in tropical climates. effects. For uncomplicated cases, most experts
Moisture, heat, and the presence of lipids from recommend initiating therapy with topical
the sebaceous glands seem to encourage hyphal agents; selenium sulfide shampoo used for 3 to
overgrowth. These organisms can also cause 7 days for 5 to 10 minutes and then showered
systemic infections in neonates, particularly off; or a topical azole applied twice daily for 2
those receiving total parenteral nutrition with to 3 weeks. Systemic therapy is reserved for
lipids, and folliculitis, particularly in immuno- resistant infection or extensive involvement.
compromised individuals. Repigmentation may not occur for several
months after treatment.

ERRNVPHGLFRVRUJ
456 Pityriasis Versicolor

Image 105.1 Image 105.2


The spores and pseudohyphae of Malassezia Note the yeastlike fungal cells and short hyphae
furfur (a yeast that can cause pityriasis versicolor) of Malassezia furfur in skin scale from a patient
resemble spaghetti and meatballs on a with pityriasis versicolor. Usually, M furfur grows
potassium hydroxide slide. sparsely without causing a rash. In some
individuals, it grows more actively for reasons
unknown, resulting in pale brown, flaky patches
on the trunk, neck, or arms, a condition called
pityriasis versicolor (formerly called tinea
versicolor). Courtesy of Centers for Disease
Control and Prevention/Dr Lucille K. Georg.

Image 105.3
Pityriasis versicolor. Courtesy of Edgar K.
Marcuse, MD.
Image 105.4
This photomicrograph of a skin scale reveals the
presence of the fungus Malassezia furfur. Usually,
M furfur grows sparsely without causing a rash.
In some individuals, it grows more actively for
reasons unknown, resulting in pale brown, flaky
patches on the trunk, neck, or arms, a condition
called pityriasis versicolor (formerly called tinea
versicolor). Courtesy of Centers for Disease
Control and Prevention.

Image 105.5
Pityriasis versicolor in a 16-year-old boy. Courtesy
of Gary Williams, MD/Dr Lucille K. Georg.

ERRNVPHGLFRVRUJ
Plague 457

106 occurred in 1924. Rarely, humans can develop


primary pneumonic plague following exposure
Plague to domestic cats with respiratory tract plague
Clinical Manifestations infections. Plague occurs worldwide with
­enzootic foci in parts of Asia, Africa, and the
Naturally acquired plague most commonly Americas. Most human plague cases are
manifests in the bubonic form, with acute reported from rural, underdeveloped areas
onset of fever and painful swollen regional and mainly occur as isolated cases or in small,
lymph nodes (buboes). Buboes most commonly focal clusters. Since 2000, more than 95% of
develop in the inguinal region but also occur the approximately 22,000 cases reported to the
in axillary or cervical areas. Less commonly, World Health Organization have been from
plague manifests in the septicemic form countries in sub-Saharan Africa. In the United
(ie, hypotension, acute respiratory distress, States, plague is endemic in western states,
purpuric skin lesions, intravascular coagulo­p­ with most (approximately 85%) of the 37 cases
athy, organ failure) or as pneumonic plague reported from 2006 through 2010 being from
(ie, cough, fever, dyspnea, and hemoptysis) New Mexico, Colorado, Arizona, and Califor-
and, rarely, as meningeal, pharyngeal, ocular, nia. Cases of peripatetic plague have been iden-
or gastrointestinal plague. Abrupt onset of tified in states without endemic plague, such as
fever, chills, headache, and malaise are charac- Connecticut (2008) and New York (2002).
teristic in all cases. Occasionally, patients
have symptoms of mild lymphadenitis or Incubation Period
prominent gastrointestinal tract symptoms, 2 to 8 days for bubonic plague; 1 to 6 days for
which may obscure the correct diagnosis. primary pneumonic plague.
When left untreated, plague will often progress
to overwhelming sepsis with renal failure, Diagnostic Tests
acute respiratory distress syndrome, instability, Y pestis has a bipolar (safety-pin) appearance
diffuse intravascular coagulation, necrosis of when stained with Wright-Giemsa or Wayson
distal extremities, and death. Plague has been stains. A positive fluorescent antibody test
referred to as the black death. result for the presence of Y pestis in direct
Etiology smears or cultures of blood, bubo aspirate,
­sputum, or another clinical specimen provides
Plague is caused by Yersinia pestis, a pleo­ presumptive evidence of Y pestis infection.
morphic, bipolar-staining, gram-negative Diagnosis of plague is usually confirmed by
­coccobacillus. culture of Y pestis from blood, bubo aspirate,
Epidemiology sputum, or another clinical specimen. Auto-
mated blood culture identification systems
Plague is a zoonotic infection primarily can misidentify Y pestis. Many clinical labor­
­maintained in rodents and their fleas. Humans atories provide preliminary identification of
are incidental hosts who typically develop Yersinia species, with definitive identification
bubonic or primary septicemic manifestations performed at state or federal laboratory. Isola-
through the bite of infected rodent fleas or tion of Yersinia species from an automated
direct contact with tissues of infected animals. ­system should trigger additional evaluation
Secondary pneumonic plague arises from to determine whether the clinical presentation
hematogenous seeding of the lungs with is consistent with plague. A single positive
Y ­pestis in patients with untreated bubonic serologic test result from passive hemaggluti-
or septicemic plague. Primary pneumonic nation assay or enzyme immunoassay in an
plague is acquired by inhalation of respiratory unimmunized patient who has not previously
tract droplets from a human or animal with had plague also provides presumptive evidence
pneumonic plague. Only the pneumonic form of infection. Seroconversion, defined as a 4-fold
has been shown to be transmitted from person difference in antibody titer between 2 serum
to person, and the last known case of person- specimens obtained at least 2 weeks apart, also
to-person transmission in the United States confirms the diagnosis of plague. Polymerase

ERRNVPHGLFRVRUJ
458 Plague

chain r­ eaction assay and immunohisto­ higher treatment failure rates. Fluoroquino-
chemical staining for rapid diagnosis of lones have been shown to be highly effective in
Y ­pestis are available in some reference or animal and in vitro studies, and levofloxacin
­public health laboratories. has been approved for treatment of plague.
The usual duration of antimicrobial treatment
Treatment
is 7 to 10 days or several days after fever has
For children, gentamicin and streptomycin resolved. Fluoroquinolones, especially those
administered intramuscularly or intravenously with higher cerebrospinal fluid penetration
appear to be equally effective. Tetracycline, (ie, levofloxacin), should be used for plague
doxycycline, chloramphenicol, and meningitis in the United States, but chloram-
­trimethoprim-sulfamethoxazole are alternative phenicol is also effective. Drainage of abscessed
drugs. Trimethoprim-sulfamethoxazole buboes may be necessary; drainage material is
should not be used as monotherapy to treat infectious until effective antimicrobial therapy
pneumonic or septicemic plague because of has been administered.

Image 106.1
This photograph depicts the colonial morphology displayed by gram-negative Yersinia pestis bac­teria,
which were grown on a medium of sheep blood agar for a 48-hour period at a temperature of 37°C
(98.6°F). There is a tena­cious nature of these colonies when touched by an inoculation loop, and they
tend to form “stringy,” sticky strands. Morphologic characteristics after 48 hours of Y pestis colonial
growth include an average colonial diameter of 1.0 to 2.0 mm and an opaque coloration that ranges
from gray-white to yellowish. If permitted to continue growing, Y pestis colonies take on what is
referred to as a “fried egg” appearance, which becomes more prominent as the colonies age. Older
colonies also display what is termed a “hammered copper” texture to their surfaces. Courtesy of
Centers for Disease Control and Prevention/Pete Seidel.

Image 106.2
Yersinia pestis on sheep blood agar, 72 hours. Y pestis grows well on most standard laboratory media,
after 48 to 72 hours, gray-white to slightly yellow opaque raised, irregular “fried egg” morphology;
alternatively, colonies may have a “hammered copper” shiny surface. Courtesy of Centers for Disease
Control and Prevention/Courtesy of Larry Stauffer, Oregon State Public Health Laboratory.

ERRNVPHGLFRVRUJ
Plague 459

Image 106.4
Plague bubo aspirate. Courtesy of Gary Overturf,
Image 106.3 MD.
Yersinia pestis is a small (0.5 x 1.0 µm) gram-
negative bacillus (magnification x1,000). Bipolar
staining occurs when using Wayson, Wright,
Giemsa, or methylene blue stain and may
occasionally be seen in Gram-stained prepara­
tions. Courtesy of Centers for Disease Control
and Prevention/Courtesy of Larry Stauffer,
Oregon State Public Health Laboratory.

Image 106.6
Dark-stained bipolar ends of Yersinia pestis can
clearly be seen in this Wright stain of blood from
a plague victim. The actual cause of the disease
is the plague bacillus, Y pestis. It is a nonmotile,
nonspore-forming, gram-negative, nonlactose-
fermenting, bipolar, ovoid, safety-pin–shaped
bacterium. Courtesy of Centers for Disease
Image 106.5 Control and Prevention.
Bubo aspirate (Gram stain) showing many gram-
negative bacilli, Yersinia pestis.

Image 106.7
Inguinal plague buboes in an 8-year-old boy. If left untreated, bubonic plague often becomes
septicemic, with meningitis occurring in 6% of cases.

ERRNVPHGLFRVRUJ
460 Plague

Image 106.9
Small hemorrhages on the skin of a plague
victim. Capillary fragility is one of the manifes­
tations of a plague infection, evident here on
the leg of an infected patient. Courtesy of Centers
for Disease Control and Prevention.

Image 106.8
This patient acquired a plague infection through
abrasions on his upper right leg. Bubonic plague
is transmitted through the bite of an infected
flea or, as in this case, exposure to inoculated
material through a break in the skin. Symptoms
include swollen, tender lymph glands known as
buboes. Courtesy of Centers for Disease Control
and Prevention/Dr Jack Poland.

Image 106.11
This patient presented with symptoms of plague
that included gangrene of the right foot causing
necrosis of the toes. Courtesy of Centers for
Image 106.10
Disease Control and Prevention/William
Right hand of a plague patient displaying acral
Archibald.
gangrene. Gangrene is one of the manifestations
of plague and is the origin of the term black death
given to plague throughout the ages. Dissemi­
nated intravascular coagulation is not uncommon
in septicemic plague. Courtesy of Centers for
Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Plague 461

Image 106.12
This anteroposterior radiograph reveals a bilaterally progressive plague infection involving both lung
fields. The first signs of plague are fever, headache, weakness, and rapidly devel­oping pneumonia
with shortness of breath, chest pain, cough, and, sometimes, bloody or watery sputum, eventually
progressing for 2 to 4 days into respiratory failure and shock. Courtesy of Centers for Disease Control
and Prevention/Dr Jack Poland.

Image 106.13
Photomicrograph of lung tissue (Giemsa stain) from a patient with fatal human plague, revealing
pneumonia and an abundance of Yersinia pestis organisms. Courtesy of Centers for Disease Control
and Prevention.

Image 106.14 Image 106.15

Histopathology of lung in fatal human plague. This photomicrograph depicts the histopathologic
Area of marked fibrinopurulent pneumonia. changes in lung tissue in a case of fatal human
Courtesy of Centers for Disease Control and plague pneumonia (hematoxylin-eosin stain,
Prevention/Dr Marshall Fox. magnification x160). Note the presence of many
polymorphonuclear leukocytes, capillary engorge­
ment, and intra-alveolar debris, all indicative of an
acute infection. Courtesy of Centers for Disease
Control and Prevention/Dr Marshall Fox.

ERRNVPHGLFRVRUJ
462 Plague

Image 106.16
Plague. Number of reported cases among humans by year in the United States, 1973–2003.
The World Health Organization reports 1,000 to 3,000 cases of plague each year globally.
Courtesy of Morbidity and Mortality Weekly Report.

Image 106.18
This image shows the roof rat or black rat, Rattus
rattus, a carrier of the plague bacterium, Yersinia
Image 106.17 pestis. The roof rat can be differentiated from the
This photograph depicts an adult male Diamanus Norway (brown) rat by its smaller size; its body is
montana flea, formerly known as Oropsylla generally 16 to 20 cm (6–8 inches) in length with
montana. This flea is a common ectoparasite of a 19- to 25-cm (7- to 10-inch) tail. It is a climber
the rock squirrel, Citellus variegatus, and, in the and nests largely in buildings and trees. Courtesy
western United States, is an important vector for of Centers for Disease Control and Prevention.
the bacterium Yersinia pestis, the pathogen
responsible for causing plague. Courtesy of
Centers for Disease Control and Prevention/
John Montenieri.

ERRNVPHGLFRVRUJ
Plague 463

Image 106.19
This photograph shows a ground squirrel that died due to a plague infection, Yersinia pestis. Field
rodents, such as western ground squirrels and prairie dogs, may be a threat when their burrows are
beside labor camps and residential areas because they and their fleas are carriers of the plague
bacteria. Courtesy of Centers for Disease Control and Prevention.

Image 106.20
The long-tailed weasel, Mustela frenata, here seen in its winter pelage, is a carrier of plague vectors.
Long-tailed weasels have been identified as carriers of fleas inoculated with Yersinia pestis, the plague
bacteria. This animal was found during a 1975 plague and Colorado tick fever study. Courtesy of
Centers for Disease Control and Prevention.

Image 106.21
The bobcat, Felis rufus, can be a source of plague infection for humans. People involved in trapping
and skinning wild carnivores, especially bobcats, should be extremely cautious about exposure to
Yersinia pestis vectors. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
464 Pneumococcal Infections

107 infants, young children, elderly people, and


black, Alaska Native, and some American
Pneumococcal Infections Indian populations. The incidence and severity
Clinical Manifestations of infections are increased in people with
­congenital or acquired humoral immuno­
Streptococcus pneumoniae is a common cause deficiency, HIV infection, absent or deficient
of invasive bacterial infections in children, splenic function (eg, sickle cell disease, con­
including febrile bacteremia. Pneumococci genital or surgical asplenia), diabetes mellitus,
are also a common cause of acute otitis media chronic liver disease, chronic renal failure or
(AOM), sinusitis, community-acquired pneu- nephrotic syndrome, or abnormal innate
monia, pleural empyema, and conjunctivitis. immune responses. Children with cochlear
As of 2008, S pneumoniae remained the most implants have high rates of pneumococcal
common cause of bacterial meningitis and sub- meningitis, as do children with congenital or
dural hygromas in infants and children from acquired cerebrospinal fluid (CSF) leaks.
2 months of age in the United States. Pneumo- Other categories of children at presumed
cocci occasionally cause mastoiditis, perior- high risk or at moderate risk of developing
bital cellulitis, endocarditis, osteomyelitis, invasive pneumococcal disease (IPD) are
pericarditis, peritonitis, pyogenic arthritis, ­outlined in Table 107.1. Since introduction of
soft tissue infection, overwhelming septicemia pneumococcal conjugate vaccine (PCV7 [2000]
in patients with splenic dysfunction, and neo- and PCV13 [2010]), racial disparities have
natal septicemia. Hemolytic uremic syndrome diminished; however, rates of IPD among
can accompany complicated invasive disease some American Indian (Alaska Native and
(eg, pneumonia with pleural empyema). Apache) populations remain more than 5-fold
Etiology higher than the rate among children in the
general US population.
S pneumoniae organisms (pneumococci) are
lancet-shaped, gram-positive, catalase-negative From 1998 to 2007, the incidence of vaccine-
diplococci. More than 90 pneumococcal type invasive pneumococcal infections
­serotypes have been identified on the basis of decreased by 99%, and the incidence of all
unique polysaccharide capsules. IPD decreased by 76% in children younger
than 5 years. In adults 65 years and older, IPD
Epidemiology
caused by PCV7 serotypes decreased 92% com-
Pneumococci are ubiquitous, with many pared with baseline and all serotype invasive
­people having transient colonization of the disease by 37%. The reduction in cases in these
upper respiratory tract. In children, nasopha- latter groups indicates the significant indirect
ryngeal carriage rates range from 21% in benefits of PCV7 immunization by interrup-
­industrialized countries to more than 90% tion of transmission of pneumococci from
in resource-­limited countries. Transmission ­children to adults. Further reductions in dis-
is from person to person by respiratory drop- ease in children of all ages, also associated
let contact. The period of communicability with herd protection, have been demonstrated
may be as long as the organism is present in to date for at least 3 of the additional 6 sero-
respiratory tract secretions but is probably less types in PCV13, including serotype 19A.
than 24 hours after effective antimicrobial
therapy is begun. Among young children who Incubation Period
acquire a new pneumococcal serotype in the Varies by type of infection but can be as short
nasopharynx, illness (eg, otitis media) occurs as 1 to 3 days.
in approximately 15%, usually within a few days
Diagnostic Tests
of acquisition. Viral upper respiratory tract
infections, including influenza, can predispose Recovery of S pneumoniae from a normally
to pneumococcal infection and transmission. sterile site (eg, blood, CSF, peritoneal fluid,
Pneumococcal infections are most prevalent middle ear fluid, joint fluid) or from a suppura-
during winter months. Incidence is highest in tive focus confirms the diagnosis. The finding

ERRNVPHGLFRVRUJ
Pneumococcal Infections 465

Table 107.1
Underlying Medical Conditions That Are Indications for
­Pneumococcal Immunization Among Children, by Risk Groupa
Risk Group Condition
Immunocompetent children Chronic heart diseaseb
Chronic lung diseasec
Diabetes mellitus
Cerebrospinal fluid leaks
Cochlear implant
Children with functional or Sickle cell disease and other hemoglobinopathies
anatomic asplenia Chronic or acquired asplenia, or splenic dysfunction
Children with immuno­ HIV infection
compromising conditions Chronic renal failure and nephrotic syndrome
Diseases associated with treatment with immunosuppressive drugs
or radiation therapy, including malignant neoplasms, leukemias,
lymphomas, and Hodgkin disease; or solid organ transplantation
Congenital immunodeficiencyd
a Centers for Disease Control and Prevention. Licensure of a 13-valent pneumococcal conjugate vaccine (PCV13) and recommendations for
use among children. Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep. 2010;59(9):258–261.
b Particularlycyanotic congenital heart disease and cardiac failure.
c Including asthma if treated with prolonged high-dose oral corticosteroids.
d Include B-(humoral) or T-lymphocyte deficiency; complement deficiencies, particularly C1, C2, C3, and C4 deficiency; and phagocytic

disorders (excluding chronic granulomatous disease).

of lancet-shaped gram-positive organisms or meningeal site. Accordingly, current


and white blood cells in expectorated sputum ­definitions by the Clinical and Laboratory
or pleural exudate suggests pneumococcal Standards Institute for susceptibility and
pneumonia or pleural empyema in older nonsusceptibility are provided in Table 107.2
­children and adults. Recovery of pneumococci for nonmeningeal and meningitis presenta-
by culture of an upper respiratory tract swab tions. If the patient has a nonmeningeal
specimen is of no diagnostic significance. infection caused by an isolate that is non­
­Real-time polymerase chain reaction assay susceptible to penicillin, cefotaxime, and
using lytA is investigational but may be spe- ceftriaxone, susceptibility testing to other
cific and significantly more sensitive than agents, such as clindamycin, erythromycin,
­culture of pleural fluid, CSF, and blood, par­ trimethoprim-sulfamethoxazole, linezolid,
ticularly in patients who have received recent meropenem, and vancomycin, should
antimicrobial ­t herapy. be performed.
• Susceptibility testing. All S pneumoniae Quantitative minimum inhibitory concen-
isolates from normally sterile body fluids tration testing using reliable methods, such
(eg, CSF, blood, middle ear fluid, pleural as broth microdilution or antimicrobial
fluid, joint fluid) should be tested for anti­ ­gradient strips (E-test), should be performed
microbial susceptibility to determine the on isolates from children with invasive
minimum inhibitory concentration of infections. When quantitative testing
­penicillin, cefotaxime or ceftriaxone, and ­methods are not available or for isolates
clindamycin. Cerebrospinal fluid isolates from noninvasive infections, the qualitative
should also be tested for susceptibility to screening test using a 1-mcg oxacillin disk
vancomycin and meropenem. Nonsuscep- on an agar plate reliably identifies all peni­
tible includes intermediate and resistant cillin-susceptible pneumococci using men-
isolates. Breakpoints vary depending on ingitis breakpoints (ie, disk-zone diameter
whether an isolate is from a nonmeningeal of ≥20 mm). Organisms with an oxacillin

ERRNVPHGLFRVRUJ
466 Pneumococcal Infections

Table 107.2
Clinical and Laboratory Standards Institute D­ efinitions
of In vitro Susceptibility and Nonsusceptibility of
­Nonmeningeal and Meningeal Pneumococcal Isolates
Nonsusceptible, mcg/mL
Susceptible,
Drug and Isolate Location mcg/mL Intermediate Resistant
Penicillin (oral)a ≤0.06 0.12–1.0 ≥2.0
Penicillin (intravenous)b
Nonmeningeal ≤2.0 4.0 ≥8.0
Meningeal ≤0.06 None ≥0.12
Cefotaxime OR ceftriaxone
Nonmeningeal ≤1.0 2.0 ≥4.0
Meningeal ≤0.5 1.0 ≥2.0
a Without meningitis.
b Treated with intravenous penicillin.
From Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: 18th Informational Supple-
ment. CLSI Publication No. M100-S23. Wayne, PA: Clinical and Laboratory Standards Institute; 2013.

disk-zone size of less than 20 mm are poten- not be given alone because bactericidal con-
tially nonsusceptible for treatment of menin- centrations in CSF are difficult to sustain,
gitis and require quantitative susceptibility and clinical experience to support use of
testing. The oxacillin disk test is used as a vancomycin as monotherapy is minimal.
screening test for resistance to β-lactam Rifampin also should not be given as mono-
drugs (ie, penicillins and cephalosporins). therapy because resistance can develop dur-
ing therapy. Meropenem alone can be given
Treatment
as an alternative drug.
S pneumoniae strains that are nonsusceptible
to penicillin G, cefotaxime, ceftriaxone, and Once results of susceptibility testing are
other antimicrobial agents using meningitis available, therapy should be modified. Van-
breakpoints have been identified throughout comycin should be discontinued and peni-
the United States and worldwide but are cillin or cefotaxime or ceftriaxone should be
uncommon using nonmeningeal breakpoints. continued if the organism is susceptible; if
Recommendations for treatment of pneumo- the isolate is penicillin nonsusceptible, cefo-
coccal infections are as follows: taxime or ceftriaxone should be continued.
If the organism is nonsusceptible to penicil-
• Bacterial meningitis possibly or proven lin and cefotaxime or ceftriaxone, consulta-
to be caused by S pneumoniae. Combina- tion with an infectious disease specialist
tion therapy with vancomycin and cefotax- should be considered.
ime or ceftriaxone should be administered
initially to all infants and children 1 month • Dexamethasone. For infants and children
or older with definite or probable bacterial 6 weeks and older, adjunctive therapy with
meningitis because of the possibility of dexamethasone may be considered after
S pneumoniae resistant to penicillin, cefo- weighing the potential benefits and possible
taxime, and ­ceftriaxone. risks. If used, dexamethasone should be
given before or concurrently with the first
For children with serious hypersensitivity dose of antimicrobial agents.
reactions to β-lactam antimicrobial agents
(ie, penicillins and cephalosporins), the • Nonmeningeal invasive pneumococcal
combination of vancomycin and rifampin infections requiring hospitalization.
should be considered. Vancomycin should For nonmeningeal invasive infections in

ERRNVPHGLFRVRUJ
Pneumococcal Infections 467

­ re­v iously healthy children who are not crit-


p high-dose amoxicillin is recommended,
ically ill, antimicrobial agents currently used except in select cases in which the option of
to treat infections with S pneumoniae and observation without antimicrobial therapy is
other potential pathogens should be initiated warranted. Optimal duration of therapy is
at the usually recommended dosages. For uncertain. For younger children and chil-
critically ill infants and children with inva- dren with severe disease at any age, a 10-day
sive infections potentially attributable to course is recommended; for children 6 years
S pneumoniae, vancomycin, in addition to and older with mild or moderate disease, a
empirical antimicrobial therapy (ie, cefotax- duration of 5 to 7 days is appropriate.
ime or ceftriaxone or others), can be con­
Patients who fail to respond to initial
sidered. Such patients include those with
­ anagement should be reassessed at 48
m
presumed septic shock, severe pneumonia
to 72 hours to confirm the diagnosis of
with empyema, or significant hypoxia or
AOM and exclude other causes of illness. If
myopericardial involvement. If vancomycin
AOM is confirmed in the patient managed
is administered, it should be discontinued
initially with observation, amoxicillin
as soon as antimicrobial susceptibility
should be given. If the patient has failed
test results demonstrate effective alterna-
­initial anti­bacterial therapy, a change in
tive agents.
antibacterial agent is indicated. Suitable
If the organism has in vitro resistance to alternative agents should be active against
penicillin, cefotaxime, and ceftriaxone, penicillin-­nonsusceptible pneumococci as
­t herapy should be modified on the basis well as β-lactamase–producing Haemophilus
of clinical response, susceptibility to other ­influenzae and Moraxella catarrhalis. Such
antimicrobial agents, and results of follow- agents include high-dose oral amoxicillin-
up cultures of blood and other infected body clavulanate; oral cefdinir, cefpodoxime, or
fluids. Consultation with an infectious dis- cefuroxime; or intramuscular ceftriaxone in
ease specialist should be considered. a 3-day course. Macrolide resistance among
S pneumoniae is high, so clarithromycin and
• Nonmeningeal invasive pneumococcal
azithromycin are not generally considered
infections in the immunocompromised
appropriate alternatives for initial therapy.
host. The preceding recommendations for
management of possible pneumococcal Myringotomy or tympanocentesis should
infections requiring hospitalization also be considered for children failing to respond
apply to immunocompromised children. to second-line therapy and for severe cases
Vancomycin should be discontinued as soon to obtain cultures to guide therapy. For
as antimicrobial susceptibility test results ­multidrug-resistant strains of S pneumoniae,
indicate effective alternative antimicrobial use of levofloxacin or other agents should
agents are available. be considered in consultation with an expert
in infectious diseases.
• Acute otitis media. According to clinical
practice guidelines of the American • Sinusitis. Antimicrobial agents effective for
­Academy of Pediatrics and the American treatment of AOM are also likely to be effec-
Academy of Family Physicians on AOM, tive for acute sinusitis and are recommended.

ERRNVPHGLFRVRUJ
468 Pneumococcal Infections

Image 107.2
Image 107.1
This is a photomicrograph of Streptococcus
Streptococcus pneumoniae, 24-hour sheep pneumoniae grown from a blood culture (Gram
blood agar plate, with alpha hemolysis. Courtesy stain). Courtesy of Centers for Disease Control
of Robert Jerris, MD. and Prevention/Dr Mike Miller.

Image 107.3
Streptococcus pneumoniae (pneumococcus) in a
Gram stain of cerebrospinal fluid. Courtesy of H.
Cody Meissner, MD, FAAP.
Image 107.4
Periorbital cellulitis with purulent exudate
from which Streptococcus pneumoniae and
Haemophilus influenzae type b were grown on
culture. S pneumoniae was isolated on blood
culture. The cerebrospinal fluid culture result
was negative.

Image 107.5
A 3½-year-old boy with acute suppurative otitis
media and mastoiditis due to Streptococcus
pneumoniae. Note the protuberance of the right Image 107.6
external ear secondary to mastoid swelling. Streptococcus pneumoniae mastoiditis in a
Courtesy of George Nankervis, MD. 7-year-old girl. Courtesy of Benjamin Estrada, MD.

ERRNVPHGLFRVRUJ
Pneumococcal Infections 469

Image 107.8
Image 107.7 Streptococcus pneumoniae submental abscess
Streptococcus pneumoniae sepsis with purpura in a 5-year-old girl with dysgammaglobulinemia.
fulminans in a child who had undergone sple­ There is an increased incidence of pneumococcal
nectomy for refractory idiopathic thrombocyto­ disease in immunocompromised children.
penic purpura. Courtesy of Edgar O. Ledbetter, MD, FAAP.

Image 107.9
Perionychial abscess caused by Streptococcus
pneumoniae in a child with acute lymphoblastic
leukemia.
Image 107.10
Segmental (nodular) pneumonia due to
Streptococcus pneumoniae.

Image 107.12
Streptococcus pneumoniae pneumonia of the
upper lobe of the right lung. The blood culture
Image 107.11
result was positive, and the infant had a prompt
Segmental (nodular) pneumonia due to
response to penicillin therapy.
Streptococcus pneumoniae.

ERRNVPHGLFRVRUJ
470 Pneumococcal Infections

Image 107.13
Pneumococcal pneumonia with pleural effusion on the right. Courtesy of Edgar O. Ledbetter,
MD, FAAP.

Image 107.15
Pneumonia with right subpleural empyema due
to Streptococcus pneumoniae in a child with
sickle cell disease.

Image 107.14
Pneumococcal pneumonia with massive effusion
pushing the mediastinal structures into the left
area of the chest. A delayed clinical response to
treatment was not surprising. Courtesy of Edgar
O. Ledbetter, MD, FAAP.

Image 107.16
Streptococcus pneumoniae in pleural exudate
(Gram stain).

ERRNVPHGLFRVRUJ
Pneumococcal Infections 471

Image 107.18
Streptococcus pneumoniae pneumonia with
pneumatocele formation in the left lung. Courtesy
of Benjamin Estrada, MD.

Image 107.17
Pneumonia and purulent pericarditis due to
Streptococcus pneumoniae in a previously
healthy infant. Despite clinical improvement with
penicillin therapy and repeated needle aspiration
of the pericardial space, the infant died of
constrictive pericarditis.

Image 107.20
Skull opened at autopsy revealing purulent
inflammation of leptomeninges beneath reflected
dura in a patient who died of pneumococcal
meningitis. Courtesy of Centers for Disease
Control and Prevention/Dr Edwin P. Ewing Jr.

Image 107.19
An axial T1-weighted magnetic resonance
image following contrast shows frontal subdural
hygromas (arrows). Also note the enhancing left
thalamic infarction secondary to penetrating
artery spasm (arrowhead) in a patient with
pneumococcal meningitis.

Image 107.21
A ventral view of the brain depicting purulent
exudate from fatal Streptococcus pneumoniae
meningitis. Courtesy of Centers for Disease
Control and Prevention.

ERRNVPHGLFRVRUJ
472 PNEUMOCYSTIS JIROVECI INFECTIONS

108 in life, with more than 85% of healthy children


acquiring antibody by 20 months of age. In
Pneumocystis jiroveci resource-limited countries and in times of
Infections famine, PCP can occur in epidemics, primarily
affecting malnourished infants and children.
Clinical Manifestations Epidemics have also occurred among preterm
Symptomatic infection is extremely rare in neonates. In industrialized countries, PCP
healthy people. Disease in immunocompro- occurs almost entirely in immunocompro-
mised infants and children can produce a mised people with deficient cell-mediated
respiratory illness characterized by dyspnea, immunity, particularly people with HIV infec-
tachypnea, significant oxygen desaturation, tion, recipients of immunosuppressive therapy
nonproductive cough, and fever. The intensity after solid organ transplantation or treatment
of these signs and symptoms vary and, in for malignant neoplasm, and children with
some immunocompromised children and congenital immunodeficiency syndromes.
adults, the onset can be acute and fulminant. Although decreasing in frequency because of
Chest radiographs often show bilateral diffuse effective prophylaxis and antiretroviral ther-
interstitial or alveolar disease; rarely, lobar, apy, PCP remains one of the most common
miliary, cavitary, and nodular lesions or serious opportunistic infections in infants and
even no lesions are seen. Most children with children with perinatally acquired HIV infec-
Pneumocystis pneumonia (PCP) are signifi- tion and adolescents with advanced immuno-
cantly hypoxic. The mortality rate in immuno- suppression. Although onset of disease can
compromised patients ranges from 5% to 40% occur at any age, including rare instances dur-
in treated patients and approaches 100% with- ing the first month of life, PCP most commonly
out therapy. occurs in HIV-infected children in the first
year of life, with peak incidence at 3 through
Etiology
6 months of age. The single most important
Originally considered a protozoan, Pneumo­ factor in susceptibility to PCP is the status of
cystis is now classified as a fungus on the basis cell-mediated immunity of the host, reflected
of DNA sequence analysis. Human Pneumo­ by a marked decrease in CD4+ T-lymphocyte
cystis now is called Pneumocystis jiroveci, while count and percentage. The mode of transmis-
Pneumocystis carinii is used for organisms sion is unknown. Animal studies have demon-
infecting rats. P carinii f sp hominis or “human strated animal-to-animal transmission by the
P carinii” are sometimes still used to refer to airborne route. Although reactivation of latent
human Pneumocystis. P jiroveci is an atypical infection with immunosuppression has been
fungus, with several morphologic and biologic proposed as an explanation for disease after
similarities to protozoa, including susceptibil- the first 2 years of life, animal models of PCP
ity to a number of antiprotozoal agents but do not support the existence of latency. Studies
resistance to most antifungal agents. In addi- of patients with AIDS with more than one
tion, the organism exists as 2 distinct morpho- ­episode of PCP suggest reinfection rather than
logic forms: the 5- to 7-μm–diameter cysts, relapse. In patients with cancer, the disease can
which contain up to 8 intracystic bodies, and occur during remission or relapse. The period
the smaller, 1- to 5-μm–diameter trophozoite of communicability is unknown.
or trophic form.
Incubation Period
Epidemiology
Unknown, but possibly a median of 53 days
Pneumocystis species are ubiquitous in mam- from exposure to clinically apparent infection.
mals worldwide, particularly rodents, and have
a tropism for growth on respiratory tract epi- Diagnostic Tests
thelium. Pneumocystis isolates recovered from A definitive diagnosis of PCP is made by
mice, rats, and ferrets differ genetically from ­v isualization of organisms (Pneumocystis cysts)
each other and from human P jiroveci. Asymp- in lung tissue or respiratory tract secretion
tomatic or mild human infection occurs early specimens. The most sensitive and specific

ERRNVPHGLFRVRUJ
PNEUMOCYSTIS JIROVECI INFECTIONS 473

diagnostic procedures involve specimen ties, hypoglycemia, hyperglycemia, hypo­


­collection from open lung biopsy and, in older tension, cardiac arrhythmias, fever, and
children, transbronchial biopsy. However, neutropenia. Atovaquone is approved for oral
bronchoscopy with bronchoalveolar lavage, treatment of mild to moderate PCP in adults
induction of sputum in older children and who are intolerant of TMP-SMX. Experience
­adolescents, and intubation with deep endo­ with use of atovaquone in children is limited,
tracheal aspiration are less invasive, can be although atovaquone-azithromycin appears
diagnostic, and are sensitive in patients who to be as effective as TMP-SMX for preventing
have a large number of Pneumocystis organ- serious bacterial infections as well as PCP.
isms. Methenamine silver, toluidine blue O, Adverse reactions to atovaquone are limited
calcofluor white, and fluorescein-conjugated to rash, nausea, and diarrhea.
monoclonal antibody are the most useful
Corticosteroids appear to be beneficial in treat-
stains for identifying the thick-walled cysts
ment of HIV-infected adults with moderate to
of P ­jiroveci. Extracystic trophozoite forms
severe PCP (as defined by a Pao2 of <70 mm Hg
can also be identified with special stains. The
in room air or an arterial-alveolar gradient of
sensitivity of all microscopy-based methods
>35 mm Hg). Studies have shown that use of
depends on the skill of the laboratory techni-
corticosteroids can lead to reduced acute respi-
cian. Polymerase chain reaction assays for
ratory failure, decreased need for ventilation,
detecting P jiroveci infection have been shown
and reduced mortality in children with PCP.
to be highly sensitive and cost-effective even
Although no controlled studies of the use of
with noninvasive specimens, such as oral wash
corticosteroids in young children have been
or expectorated sputum.
performed, most experts would recommend
Treatment corticosteroids as part of therapy for children
The drug of choice is trimethoprim-­ with moderate to severe PCP disease.
sulfamethoxazole (TMP-SMX), usually Coinfection with other organisms, such as
­administered intravenously. Oral therapy cytomegalovirus or pneumococcus, has
should be reserved for patients with mild been reported in HIV-infected children.
­disease who do not have malabsorption or ­Children with dual infections can have
diarrhea and for patients with a favorable more severe ­disease.
­clinical response to initial intravenous therapy.
Duration of therapy is 14 to 21 days. The rate Chemoprophylaxis is highly effective in pre-
of adverse reactions to TMP-SMX (eg, rash, venting PCP among some high-risk groups.
neutropenia, anemia, thrombocytopenia, renal Prophylaxis against a first episode of PCP is
toxicity, hepatitis, nausea, vomiting, diarrhea) indicated for many patients with significant
is higher in HIV-infected children than in immunosuppression, including people with
non–HIV-infected patients. It is not necessary HIV infection and people with primary or
to discontinue therapy for most mild adverse acquired cell-mediated immunodeficiency.
reactions. At least half of the patients with Prophylaxis for PCP is recommended for
more severe reactions (excluding anaphylaxis) ­children who have received hematopoietic
requiring interruption of therapy will subse- stem cell transplants or solid organ transplants;
quently tolerate TMP-SMX if rechallenged children with hematologic malignancies
after the reaction resolves. (eg, leukemia, lymphoma) and some non­
Intravenously administered pentamidine is an hematologic malignancies; children with
alternative drug for children and adults who severe cell-mediated immunodeficiency,
cannot tolerate TMP-SMX or who have severe including children who received adrenocor­
disease and have not responded to TMP-SMX ticotropic hormone for treatment of infantile
after 5 to 7 days of therapy. Pentamidine is spasm; and children who are otherwise immu-
associated with a high incidence of adverse nosuppressed and who have had a previous
reactions, including pancreatitis, diabetes ­episode of PCP. In general, for this diverse
­mellitus, renal toxicity, electrolyte abnormali- group of immunocompromised hosts, the risk

ERRNVPHGLFRVRUJ
474 PNEUMOCYSTIS JIROVECI INFECTIONS

of PCP increases with duration and intensity of The recommended drug regimen for PCP
chemotherapy, with other immunosuppressive ­ rophylaxis for all immunocompromised
p
therapies, and with coinfection with immuno- patients is TMP-SMX, administered orally on
suppressive viruses (eg, cytomegalovirus) and 3 consecutive days each week. Alternatively,
rates of PCP for similar patients in a given TMP-SMX can be administered daily, 7 days a
locale. Consequently, the recommended dura- week. For patients who cannot tolerate TMP-
tion of PCP prophylaxis will vary depending SMX, alternative choices include oral atova-
on individual circumstances. quone or dapsone.

Image 108.1
Pneumocystis jiroveci organisms in tracheal
aspirate (Gomori methenamine silver stain).
Courtesy of Russell Byrnes.

Image 108.2
Pneumocystis jiroveci pneumonia. This pathogen
is an important cause of pulmonary infections in
patients who are immunocompromised. Charac­
teristic signs and symptoms include dyspnea at
rest, tachypnea, nonproductive cough, fever, and
hypoxia with an increased oxygen requirement.
The intensity of the signs and symptoms can vary,
and onset may be acute and fulminant. Chest
radiographs frequently demonstrate diffuse
bilateral interstitial or alveolar disease. This is
a chest radiograph from a 5-year-old boy
­demonstrating bilateral perihilar infiltrates due to
P jiroveci. Courtesy of Beverly P. Wood, MD,
MSEd, PhD, FAAP.

Image 108.3
An infant with bilateral Pneumocystis jiroveci
pneumonia. Courtesy of Benjamin Estrada, MD.

ERRNVPHGLFRVRUJ
PNEUMOCYSTIS JIROVECI INFECTIONS 475

Image 108.4
Foamy intra-alveolar exudate in lung biopsy specimen from a patient with Pneumocystis jiroveci
pneumonia (hematoxylin-eosin stain).

Image 108.5
Pneumocystis jiroveci pneumonia with hyperaeration in an infant with congenital agammaglobulinemia.

Image 108.6
Pneumocystis jiroveci in the lung. Frothy exudate in alveolar spaces. Courtesy of Dimitris P.
Agamanolis, MD.

ERRNVPHGLFRVRUJ
476 Poliovirus Infections

109 population immunity. In addition, rare cases


of vaccine-associated paralytic poliomyelitis
Poliovirus Infections (VAPP) occur in recipients of oral poliovirus
Clinical Manifestations vaccine (OPV) or their close contacts. People
with primary β-lymphocyte immunodefi­
Approximately 72% of poliovirus infections in ciencies are at increased risk of VAPP and
susceptible children are asymptomatic. Non- of chronic infection (immunodeficiency-­
specific illness with low-grade fever and sore associated vaccine-derived polioviruses).
throat (minor illness) occurs in 24% of people With recent progress in the World Health
who become infected. Viral meningitis, some- Organization Global Polio Eradication Initia-
times with paresthesias, occurs in 1% to 5% of tive, more cases of paralytic disease are caused
patients a few days after the minor illness has by vaccine-related viruses (VAPP and circu­
resolved. Rapid onset of asymmetric acute flac- lating vaccine-derived polioviruses) than by
cid paralysis with areflexia of the involved limb wild polioviruses.
occurs in fewer than 1% of infections; residual
paralytic disease occurs in approximately two- Epidemiology
thirds of people with acute motor neuron dis- Humans are the only natural reservoir for
ease. The classical case of paralytic polio begins poliovirus. Spread is by contact with feces
with a minor illness characterized by fever, and respiratory secretions. Infection is more
sore throat, headache, nausea, constipation, or common in infants and young children and
malaise for several days, followed by a symptom- occurs at an earlier age among children living
free period of 1 to 3 days. Rapid onset of para­l­ in poor hygienic conditions. In temperate cli-
ysis then follows, but paralysis can occur mates, poliovirus infections are most common
­w ithout this prodrome. Typically, paralysis is during summer and autumn; in the tropics,
asymmetric and affects the proximal muscles the seasonal pattern is less pronounced.
more than the distal muscles. Cranial nerve
involvement (bulbar poliomyelitis, often show- The last reported case of poliomyelitis attrib­
ing a tripod sign) and paralysis of respiratory utable to indigenously acquired, naturally
tract muscles can occur. Sensation is usually occurring wild poliovirus in the United States
intact. Findings in cerebrospinal fluid are char- occurred in 1979 during an outbreak among
acteristic of viral meningitis, with mild pleocy- unimmunized people that resulted in 10 para-
tosis and lymphocytic predominance. Adults lytic cases. The only identified imported case of
who contracted paralytic poliomyelitis during paralytic poliomyelitis since 1986 occurred in
childhood can develop the noninfectious post- 1993 in a child transported to the United States
polio syndrome 15 to 40 years later. Postpolio for medical care. Since 1986, all other cases
syndrome is characterized by slow and irre- acquired in the United States have been VAPP
versible exacerbation of weakness, most likely cases attributable to OPV. From 1980 to 1997,
occurring in those muscle groups involved the average annual number of cases of VAPP
during the original infection. Muscle and joint reported in the United States was 8. Implemen-
pain are also common. The prevalence of post- tation of an all–inactivated poliovirus vaccine
polio syndrome is unclear, but the estimated schedule in 2000 halted the occurrence of
range is 25% to 40%. VAPP cases in the United States. In 2005,
­however, a healthy, unimmunized young adult
Etiology from the United States acquired VAPP in
Polioviruses are classified as members of the ­Central America, most likely from an infant
family Picornaviridae, genus Enterovirus, in grandchild of the host family who had recently
the species enterovirus C, and include 3 sero- been immunized with OPV. In 2005, a type 1
types (1, 2, and 3). Acute paralytic disease vaccine-derived poliovirus was identified in
may be caused by naturally occurring (wild) the stool of an asymptomatic, unimmunized,
polioviruses or by circulating vaccine-derived immunodeficient child in Minnesota. Subse-
polioviruses as a result of sustained person-to- quently, poliovirus infections in 7 other unim-
person circulation in the absence of adequate munized children (35% of all children tested)

ERRNVPHGLFRVRUJ
Poliovirus Infections 477

within the index patient’s community were with significant β-lymphocyte immune defi-
documented. None of the infected children had ciencies have excreted immunodeficiency-­
paralysis. Phylogenetic analysis suggested the associated vaccine-derived polioviruses for
vaccine-derived poliovirus circulated in the periods of more than 20 years.
community for approximately 2 months before
Incubation Period
the infant’s infection was detected and the
­initiating OPV dose had been given (likely in Nonparalytic poliomyelitis, 3 to 6 days;
another country) before the index child’s birth. ­paralytic poliomyelitis, 7 to 21 days to paralysis
In 2009, a woman with long-standing common- (range, 3–35 days).
variable immunodeficiency was diagnosed
Diagnostic Tests
with VAPP and died of polio-associated com-
plications. Molecular characterization of the Poliovirus can be detected in specimens from
poliovirus isolate suggested the infection likely the pharynx and feces, less commonly from
occurred approximately 12 years earlier, coin- urine, and, rarely, from cerebrospinal fluid by
ciding with OPV immunization of her child. isolation in cell culture or reverse transcriptase-
Circulation of indigenous wild polio­v irus polymerase chain reaction. Two or more stool
strains ceased in the United States several and throat swab specimens for enterovirus
decades ago, and the risk of contact with isolation or detection should be obtained
imported wild polioviruses has decreased in at least 24 hours apart from patients with sus-
parallel with the success of the global eradica- pected paralytic poliomyelitis as early in the
tion program. Of the 3 poliovirus serotypes, course of illness as possible (within 14 days of
type 2 wild poliovirus appears to have been symptom onset). Fecal material is most likely
eradicated globally, with the last naturally to yield virus in cell culture. However, poliovi-
occurring case detected in 1999 in India. No rus may be excreted intermittently, and a single
cases of type 3 wild poliovirus were detected negative test result does not rule out infection.
during 2013, suggesting this type is also on the Because OPV is no longer available in the
verge of eradication. Type 1 poliovirus now United States, the chance of exposure to
accounts for all polio cases attributable to ­vaccine-type polioviruses is remote. If a polio-
wild poliovirus. virus is isolated in the United States, the isolate
Communicability of poliovirus is greatest should be reported immediately to the state
shortly before and after onset of clinical illness, health department and sent to the Centers for
when the virus is present in the throat and Disease Control and Prevention for further
excreted in high concentrations in feces. Virus testing. The diagnostic test of choice for con-
persists in the throat for approximately 1 to firming poliovirus disease is viral culture of
2 weeks after onset of illness and is excreted in stool and throat swab specimens. Interpreta-
feces for 3 to 6 weeks. Patients are potentially tion of acute and convalescent serologic test
contagious as long as fecal excretion persists. results can be difficult because of high levels
In recipients of OPV, virus also persists in the of population immunity.
throat for 1 to 2 weeks and is excreted in feces Treatment
for several weeks or, in rare cases, for more
than 2 months. Immunocompromised patients Supportive.

ERRNVPHGLFRVRUJ
478 Poliovirus Infections

Image 109.2
A physician examines a tank respirator, also
known as an iron lung, during a polio epidemic.
The iron lung encased the thoracic cavity
externally in an airtight chamber. The chamber
was used to create a negative pressure around
the thoracic cavity, thereby causing air to rush
into the lungs to equalize intrapulmonary pres­
sure. Courtesy of Centers for Disease Control
Image 109.1 and Prevention.
Electron micrograph of the poliovirus. Poliovirus
is a species of Enterovirus, which is a genus in
the family of Picornaviridae and an RNA virus.
Courtesy of Centers for Disease Control and
Prevention/Fred Murphy, MD, and Sylvia Whitfield.

Image 109.3
Made of stainless steel and still in good working order, this Emerson Respirator, also known as an
iron lung, was used by polio patients whose ability to breath was paralyzed due to this crippling viral
disease. This iron lung was donated to the David J. Sencer Centers for Disease Control and Prevention
Museum by the family of polio patient Barton Hebert of Covington, LA, who had used the device from
the late 1950s until his death in 2003. Iron lungs encase the thoracic cavity externally in an airtight
chamber. The chamber is used to create a negative pressure around the thoracic cavity, thereby
causing air to rush into the lungs to equalize intrapulmonary pressure. Courtesy of Centers for
Disease Control and Prevention/Jim Gathany.

ERRNVPHGLFRVRUJ
Poliovirus Infections 479

Image 109.4
This 1952 photo of a Los Angeles, CA, hospital
respiratory ward shows polio patients in iron
lungs—machines that were necessary to help
them breathe. Courtesy of Centers for Disease
Control and Prevention.

Image 109.5
Images like this were used to encourage polio
vaccination. Courtesy of Centers for Disease
Control and Prevention.

Image 109.6
Cheshire Home for Handicapped Children,
Freetown, Sierra Leone. Courtesy of World Health
Organization/Immunization Action Coalition.

Image 109.8
A young girl with bulbar polio with tripod sign
attempts to sit upright. Copyright Martin G.
Myers, MD.

Image 109.7
This child is displaying a deformity of her right
lower extremity caused by the poliovirus.
Courtesy of Centers for Disease Control
and Prevention.

ERRNVPHGLFRVRUJ
480 Poliovirus Infections

Image 109.10
A photomicrograph of the cervical spinal cord in
the region of the anterior horn revealing polio
type 3 degenerative changes. The poliovirus
has an affinity for the anterior horn motor neurons
of the cervical and lumbar regions of the spinal
cord. Death of these cells causes muscle
weakness of those muscles once innervated
Image 109.9 by the now-dead neurons. Courtesy of Centers
Axial T2-weighted magnetic resonance image for Disease Control and Prevention/Dr Karp,
shows cervical spinal cord hyperintensity Emory University.
involving the central gray matter (arrow).

Image 109.11
A photomicrograph of skeletal muscle tissue revealing myotonic dystrophic changes as a result of
polio type 3. When spinal neurons die, wallerian degeneration takes place, resulting in muscle
weakness of those muscles once innervated by the now-dead neurons (denervated). The degree
of paralysis is directly correlated to the number of deceased neurons. Courtesy of Centers for
Disease Control and Prevention/Dr Karp, Emory University.

ERRNVPHGLFRVRUJ
Prion Diseases: ­Transmissible Spongiform Encephalopathies 481

110 United Kingdom, also preclinical with a find-


ing of PrPTSE in spleen, was attributed to treat-
Prion Diseases: ment with potentially vCJD-contaminated,
­Transmissible Spongiform UK-sourced fractionated plasma products. The
best-known TSEs affecting animals include
Encephalopathies scrapie of sheep, BSE, and a chronic wasting
Clinical Manifestations disease of North American deer, elk, and
Transmissible spongiform encephalopathies moose. Except for vCJD, no other human
(TSEs), or prion diseases, constitute a group TSE has been attributed to infection with an
of rare, rapidly progressive, universally fatal agent of animal origin.
neurodegenerative diseases of humans and Creutzfeldt-Jakob disease manifests as a
­animals that are characterized by neuronal ­rapidly progressive neurologic disease with
degeneration, spongiform change, gliosis, and escalating defects in memory, personality,
accumulation of abnormal misfolded protease- and other higher cortical functions. At pre­
resistant prion protein (PrP) (protease-resistant sentation, approximately one-third of patients
prion protein [PrP-res], variably called scrapie have cerebellar dysfunction, including ataxia
prion protein [PrPSc] or, as suggested by the and dysarthria. Iatrogenic CJD can also mani-
World Health Organization, TSE-associated fest as dementia with cerebellar signs. Myoclo-
PrP [PrPTSE]) that distributes diffusely nus develops in at least 80% of affected patients
through­out the brain or forms plaques of at some point in the course of disease. Death
­various morphology. usually occurs in weeks to months (median,
Human TSEs include several diseases: 4–5 months); approximately 10% to 15% of
Creutzfeldt-Jakob disease (CJD), Gerstmann- patients with sporadic CJD survive for more
Sträussler-Scheinker syndrome, fatal familial than 1 year.
and sporadic fatal insomnia, kuru, and variant Variant CJD is distinguished from classic
CJD (vCJD, presumably caused by the agent CJD by younger age of onset, early “psychiat-
of bovine spongiform encephalopathy [BSE], ric” manifestations, and other features, such
commonly called “mad cow disease”). Classic as painful sensory symptoms, delayed onset
CJD can be sporadic (~85% of cases), familial of overt neurologic signs, relative absence of
(~15% of cases), or iatrogenic (<1% of cases). diagnostic EEG changes, and a more prolonged
Sporadic CJD is most commonly a disease of duration of illness (median, 13–14 months). In
older adults (median age of death in the United vCJD, a high proportion of people exhibit high
States, 68 years) but also, rarely, has been signal abnormalities on T2-weighted brain
described in adolescents older than 13 years magnetic resonance imaging in the pulvinar
and young adults. Iatrogenic CJD has been region of the posterior thalamus (known as the
acquired through intramuscular injection of pulvinar sign). In vCJD, the neuropathologic
contaminated cadaveric pituitary hormones examination reveals numerous florid plaques
(growth hormone and human gonadotropin), (surrounded by vacuoles) and exceptionally
dura mater allografts, corneal transplantation, striking accumulation of PrPTSE in the brain.
and use of contaminated instrumentation at In addition, PrPTSE is detectable in the tonsils
neurosurgery or during depth-electrode elec- and other lymphoid tissues of patients
troencephalographic (EEG) recording. In 1996, with vCJD.
an outbreak of vCJD linked to exposure to
­tissues from BSE-infected cattle was reported Etiology
in the United Kingdom. Since the end of 2003, The infectious particle or prion responsible for
4 presumptive cases of transfusion-transmitted human and animal prion diseases is believed
vCJD have been reported: 3 clinical cases, as to be a misfolded form of a normal ubiquitous
well as 1 probable asymptomatic case in which PrP found on the surface of neurons and many
PrPTSE was detected in spleen and lymph nodes other cells in humans and animals. The precise
but not brain tissues. A fifth iatrogenic vCJD protein structure and mechanism of propaga-
infection in a hemophiliac patient in the tion is unknown. It is generally postulated

ERRNVPHGLFRVRUJ
482 Prion Diseases: ­Transmissible Spongiform Encephalopathies

that sporadic CJD arises from a spontaneous during their residencies as children in Saudi
­structural change into the pathogenic form of Arabia. Authorities suspect the Japanese
the normal cellular protease-sensitive host- patient was infected during a short visit of
encoded glycoprotein (PrPC or PrP-sen). 24 days to the United Kingdom in 1990,
Prion propagation is postulated to occur by 12 years before the onset of vCJD. Most
a “recruitment” reaction (the nature of which patients with vCJD were younger than
is under investigation), in which abnormal 30 years, and several were adolescents. All
­PrPTSE serves as a template or lattice for the but 3 of the primary 174 United Kingdom
conversion of neighboring PrPC molecules patients with noniatrogenic vCJD died before
into misfolded protein with high potential 60 years of age; all but 14 patients died before
to ­aggregate. 50 years of age; and 151 patients (87%) died
before age 40 years. The median age at death
Epidemiology
of the 174 primary vCJD cases was 27 years.
Classic CJD is rare, occurring in the United The ages at death of the 3 iatrogenic vCJD
States at a rate of approximately 1 case per transfusion transmission cases were 32, 69,
1 million people annually. The onset of disease and 75 years. On the basis of animal inocula-
peaks at ages 60 through 74 years. Case-control tion studies, comparative PrP immunoblotting,
studies of sporadic CJD have not identified and epidemiologic investi­gations, almost all
any consistent environmental risk factor. No cases of vCJD are believed to have resulted
statistically significant increase in cases of from exposure to tissues from cattle infected
­sporadic CJD has been observed in people with BSE. As noted, 3 clinically symptomatic
­previously treated with blood, blood compo- patients and 1 patient with no clinical signs of
nents, or plasma derivatives. The incidence of the disease are believed to have been infected
sporadic CJD is not increased in patients with with vCJD through trans­f usion of nonleu­
several diseases associated with frequent expo- koreduced red blood cells, and 1 hemophiliac
sure to blood or blood products, suggesting patient, also with no clinical signs of TSE, was
that the risk of transfusion transmission of probably infected through injections of human
classic CJD, if any, is very low and appropri- plasma–derived clotting ­factors.
ately regarded as theoretical. Creutzfeldt-Jakob
disease has not been reported in neonates born Incubation Period
to infected mothers. Familial or genetic form Iatrogenic CJD varies by route of exposure
of TSEs, inherited as autosomal-dominant (range, 14 months–>30 years).
­disorder, is associated with a variety of muta-
Diagnostic Tests
tions of the PrP-encoding gene (PRNP) located
on chromosome 20. Familial CJD onset of The diagnosis of human prion diseases can be
­disease is approximately 10 years earlier than made with certainty only by neuropathologic
sporadic CJD. examination of affected brain tissue, usually
obtained at autopsy. In most patients with clas-
As of June 2014, the total number of vCJD sic CJD, a characteristic 1 to 2 cycles per second
cases reported was 177 patients in the United triphasic sharp-wave discharge on EEG tracing
Kingdom, 27 in France, 5 in Spain, 4 in Ireland, is regarded as indicative of CJD. The likelihood
4 in the United States, 3 in the Netherlands, 2 of finding this abnormality is enhanced when
in Portugal, 2 in Italy, 2 in Canada, and 1 each serial EEG recordings are obtained. A protein
in Taiwan, Japan, and Saudi Arabia. Two of assay that detects the 14-3-3 protein in cerebro-
the 4 patients in the United States, 2 of the 4 in spinal fluid (CSF) has been reported to be rea-
Ireland, and 1 each of the patients in France sonably sensitive, although not specific, as a
and Canada are believed to have acquired marker for CJD. Measurement of the tau pro-
vCJD during prolonged residence in the United tein level in addition to the detection of 14-3-3
Kingdom. The Centers for Disease Control and protein in CSF has been reported to increase
Prevention and Health Canada have concluded the specificity of CSF testing for CJD. Specific
that one of the vCJD patients in the United disease marker PrPTSE was demonstrated in
States and in Canada probably were infected CSF of 80% of CJD cases, but, currently, testing

ERRNVPHGLFRVRUJ
Prion Diseases: ­Transmissible Spongiform Encephalopathies 483

for this marker can be performed only on an CSF, PRNP gene sequencing, Western blot
investigational basis in a few laboratories using analysis to identify and characterize PrPTSE ,
sophisticated techniques for detecting minute and histologic processing of brain tissues
amounts of the protein. No validated blood with expert neuropathologic consultation,
test is available, but a prototype test for vCJD are offered by the National Prion Disease
that captures, enriches, and detects disease-­ Pathology Surveillance Center (telephone,
associated PrP from whole blood using stain- ­216/368-0587; www.cjdsurveillance.com). 
less steel powder is being investigated. A
Treatment
progressive neurologic syndrome in a person
bearing a pathogenic mutation of the PRNP No treatment in humans slows or stops the
gene is presumed to be prion disease. Because progressive neurodegeneration in prion dis-
no unique nucleic acid has been detected in eases. Experimental treatments are being
prions causing TSEs, genome amplification ­studied. Supportive therapy is necessary to
studies, such as polymerase chain reaction, are manage dementia, spasticity, rigidity, and
not possible. Consideration of brain biopsies ­seizures occurring during the course of the
for patients with possible CJD should be given illness. Psychological support may help fami-
when other potentially treatable diseases lies of affected people. Genetic counseling
remain in the differential diagnosis. Complete is indicated in familial disease, taking into
postmortem examination of the brain is account that penetrance has been variable in
encouraged to confirm the clinical diagnosis some families in which people with a PRNP
and to detect emerging forms of CJD, such mutation survived to an advanced age without
as vCJD. State-of-the-art diagnostic testing, neurodegenerative disease.
including assays of 14-3-3 and tau proteins in

Image 110.1
Number of deceased variant Creutzfeldt-Jakob disease patients worldwide (150 from the United
Kingdom and 15 outside the United Kingdom) by year of death, June 2005. Courtesy of Emerging
Infectious Diseases.

ERRNVPHGLFRVRUJ
484 Prion Diseases: ­Transmissible Spongiform Encephalopathies

Image 110.3
Histopathologic changes in frontal cerebral
cortex of the patient who died of variant
Image 110.2
Creutzfeldt-Jakob disease in the United States.
Cattle, such as pictured here, which are affected
Marked astroglial reaction is shown, occasionally
by bovine spongiform encephalopathy (BSE),
with relatively large florid plaques surrounded
experience progressive degeneration of the
by vacuoles (arrow in inset) (hematoxylin-eosin
nervous system. Behavioral changes in temper­
stain, original magnification x40). Courtesy of
ament (eg, nervousness, aggression), abnormal
Belay ED, Sejvar JJ, Shieh WJ, et al. Variant
posture, incoordination and difficulty in rising,
Creutzfeldt-Jakob disease death, United States.
decreased milk production, or weight loss
Emerg Infect Dis. 2005;11(9):1351–1354.
despite continued appetite are followed by
death in cattle affected by BSE. Courtesy of
Centers for Disease Control and Prevention/
US Department of Agriculture–Animal and Plant
Health Inspection Service, APHIS/Dr Art Davis.

Image 110.5
This micrograph of brain tissue reveals the
Image 110.4 cytoarchitectural histopathologic changes found
Immunohistochemical staining of cerebellar in bovine spongiform encephalopathy (BSE). The
tissue of the patient who died of variant presence of vacuoles (ie, microscopic “holes” in
Creutzfeldt-Jakob disease in the United States. the gray matter) gives the brain of BSE-affected
Stained amyloid plaques are shown with cows a spongelike appearance when tissue
surrounding deposits of abnormal prion protein sections are examined in the laboratory. Courtesy
(immunoalkaline phosphatase stain, naphthol of Centers for Disease Control and Prevention/
fast red substrate with light hematoxylin US Department of Agriculture–Animal and Plant
counterstain; original magnification x158). Health Inspection Service, APHIS/Dr Al Jenny.
Courtesy of Belay ED, Sejvar JJ, Shieh WJ, et al.
Variant Creutzfeldt-Jakob disease death, United
States. Emerg Infect Dis. 2005;11(9):1351–1354.

ERRNVPHGLFRVRUJ
Q FEVER (COXIELLA BURNETII INFECTION) 485

111 ally asymptomatic in animals. Many different


species can be infected, although cattle, sheep,
Q Fever (Coxiella burnetii and goats are the primary reservoirs for human
Infection) infection. Tick vectors may be important for
maintaining animal and bird reservoirs but
Clinical Manifestations are not thought to be important in transmis-
Approximately 50% of acute Q fever infections sion to humans. Humans typically acquire
are asymptomatic. Two types of disease, acute infection by inhalation of fine-particle aerosols
and chronic, exist, and both can present as of C burnetii generated from birthing fluids or
fever of unknown origin. Q fever in children other excreta of infected animals or through
is typically characterized by abrupt onset of inhalation of dust contaminated by these
fever often accompanied by chills, headache, ­materials. Infection can occur by exposure to
weakness, cough, and other nonspecific sys- contaminated materials, such as wool, straw,
temic symptoms. Illness is usually self-limited, bedding, or laundry. Windborne particles con-
although a relapsing febrile illness lasting for taining infectious organisms can travel a half
several months has been documented. Gastro- mile or more, contributing to sporadic cases
intestinal tract symptoms, such as diarrhea, for which no apparent animal contact can be
vomiting, abdominal pain, and anorexia, are demonstrated. Unpasteurized dairy products
reported in 50% to 80% of children. Rash has can contain the organism. Seasonal trends
also been observed in some patients with occur in farming areas with predictable fre-
Q fever. Q fever pneumonia usually manifests quency, and the disease often coincides with
as mild cough, respiratory distress, and chest the livestock birthing season in spring.
pain. Chest radiographic patterns are variable.
Incubation Period
More severe manifestations of acute Q fever are
rare but include hepatitis, hemolytic uremic 14 to 22 days (range, 9 to 39 days), depending
syndrome, myocarditis, pericarditis, cerebelli- on inoculum size. Chronic Q fever can develop
tis, encephalitis, meningitis, hemophagocyto- months or years after initial infection.
sis, lymphadenitis, acalculous cholecystitis,
Diagnostic Tests
and rhabdomyolysis. Chronic Q fever is rare
in children but can present as blood culture–­ Serologic evidence of a 4-fold increase in phase
negative endocarditis, chronic relapsing or 2 immunoglobulin (Ig) G by immunofluores-
multifocal osteomyelitis, or chronic hepatitis. cent assay tests between paired sera taken 3 to
Children who are immunocompromised or 6 weeks apart is the diagnostic gold standard
have underlying valvular heart disease may for diagnosis of acute Q fever. Polymerase
be at higher risk of chronic Q fever. chain reaction (PCR) testing on blood or serum
may be useful within 2 weeks of symptom
Etiology onset and before antibiotic administration.
Coxiella burnetii, the cause of Q fever, was Although a positive PCR assay result can
f­ ormerly considered to be a Rickettsia organ- ­confirm the diagnosis, a negative PCR result
ism but is a gram-negative intracellular bacte- does not exclude Q fever. A single high serum
rium that belongs to the order Legionellaceae. phase 2 IgG titer (≥1:128) by immunofluores-
The infectious form of C burnetii is highly cent assay in convalescent serum may be
resistant to heat, desiccation, and disinfectant ­considered evidence of probable infection.
chemicals and can persist for long periods in Confirmation of chronic Q fever is based on an
the environment. C burnetii is classified as a increasing phase 1 IgG titer (typically ≥1:1,024)
category B bioterrorism agent. that is often higher than the phase 2 IgG titer
and an iden­tifiable nidus of infection (eg,
Epidemiology endocarditis, vascular infection, osteomyelitis,
Q fever is a zoonotic infection that has been chronic ­hepatitis). Detection of C burnetii in
reported worldwide, including every state in tissues by immunohistochemistry or PCR
the United States. C burnetii infection is usu- assay can also confirm a diagnosis of chronic

ERRNVPHGLFRVRUJ
486 Q FEVER (COXIELLA BURNETII INFECTION)

Q fever. Isolation of C burnetii from blood can Doxycycline is the drug of choice for severe
be performed only in special laboratories infections. Children younger than 8 years with
because of the potential hazard to labora- mild illness, pregnant women, and patients
tory workers. allergic to doxycycline can be treated with
­trimethoprim-sulfamethoxazole.
Treatment
Acute Q fever is generally a self-limited illness, Chronic Q fever is much more difficult to
and many patients recover without antimicro- treat, and relapses can occur despite appro­
bial therapy. However, early treatment is priate therapy, necessitating repeated courses
extremely effective in shortening illness dura- of therapy. The recommended therapy for
tion and symptom severity and is recom- chronic Q fever endocarditis is a combination
mended. Patients with suspected Q fever of doxycycline and hydroxychloroquine for a
should be treated empirically because labora- minimum of 18 months. Surgical replacement
tory results are often negative early in illness. of the infected valve may be necessary in
some patients.

Image 111.1
Q fever, acute and chronic. Number of reported cases—United States and US territories, 2012.
Courtesy of Morbidity and Mortality Weekly Report.

ERRNVPHGLFRVRUJ
Q FEVER (COXIELLA BURNETII INFECTION) 487

Image 111.2
These domestic sheep were lying on a hillside in Glencolmcille, County Donegal, Ireland, with the
Atlantic Ocean in the background. In 2004, Ireland had almost 7 million domestic sheep. That year,
the Irish state exported approximately 51,500 tons of sheep meat valued at 165 million euros. While
important to national economies, livestock industries can present health hazards for producers and
consumers. Diseases that can be transmitted from animals to humans are called zoonoses. Q fever,
Coxiella burnetii, is a disease passed to humans from sheep. People working around domestic sheep
should consider getting vaccinated against this disease. The disease can be acquired from the
inhalation of aerosolized barnyard dust should it contain infected dried urine, manure particles, or dried
fluids from the birth of calves or lambs. Domestic animals present problems not only for their handlers
(ie, farmers) but also for consumers when animals are used for food. Food products made from
animals include not only meat but meat derivatives that are added to sweets and other foods and,
therefore, are less obvious to consumers. Courtesy of Centers for Disease Control and Prevention/
Edwin P. Ewing Jr, MD.

Image 111.3
Chest radiograph of patient at time of admission to hospital, before intubation, demonstrating
extensive bilateral airspace disease. The first cases of Q fever in Nova Scotia were recognized in 1979
during a study of atypical pneumonia. This observation led to a series of studies that showed Q fever
was common in Nova Scotia (50–60 cases per year in a population of ~950,000) and the epidemiology
was unique; exposure to infected parturient cats or newborn kittens was the major risk factor for
infection. At about the same time, cat-related outbreaks were noted in neighboring Prince Edward
Island and New Brunswick. In the early 1990s, cases began to decline but, to our knowledge, since
1999, Q fever in this area has not been systematically studied. Courtesy of Marrie TJ, Campbell N,
McNeil SA, Webster D, Hatchette TF. Q fever update, Maritime Canada. Emerg Infect Dis. 2008;
14(1):67–69.

ERRNVPHGLFRVRUJ
488 Rabies

112 by bite has not been documented in the United


States, although the virus has been isolated
Rabies from saliva of infected patients.
Clinical Manifestations Wildlife rabies perpetuates throughout all 50
Infection with rabies virus and other Lyssavi­ United States except Hawaii, which remains
rus species characteristically produces an “rabies free.” Wildlife, including bats, rac-
acute illness with rapidly progressive central coons, skunks, foxes, coyotes, and bobcats,
nervous system manifestations, including are the most important potential sources of
­a nxiety, radicular pain, dysesthesia or pruritus, infection for humans and domestic animals
hydrophobia, and dysautonomia. Some in the United States. Rabies in small rodents
patients may have paralysis. Illness almost (squirrels, hamsters, guinea pigs, gerbils, chip-
invariably progresses to death. Three unim­ munks, rats, mice) and lagomorphs (rabbits,
munized people have recovered from clinical pikas, hares) is rare. Rabies may occur in
rabies in the United States. The differential woodchucks or other large rodents in areas
diagnosis of acute encephalitic illnesses of where raccoon rabies is common. The virus is
unknown cause or with features of Guillain- present in saliva and is transmitted by bites
Barré syndrome should include rabies. or, rarely, by contamination of mucosa or skin
lesions by saliva or other potentially infectious
Etiology material (eg, neural tissue). Worldwide, most
Rabies virus is an RNA virus classified in the rabies cases in humans result from dog bites
Rhabdoviridae family, Lyssavirus genus. The in areas where canine rabies is enzootic. Most
genus Lyssavirus currently contains 12 species rabid dogs, cats, and ferrets shed virus for a
with 2 additional putative species divided into few days before there are obvious signs of ill-
3 phylogroups. ness. No case of human rabies in the United
States has been attributed to a dog, cat, or fer-
Epidemiology
ret that has remained healthy throughout the
Understanding the epidemiology of rabies standard 10-day period of confinement after
has been aided by viral variant identification an ­exposure.
using monoclonal antibodies and nucleotide
sequencing. In the United States, human cases Incubation Period
have decreased steadily since the 1950s, reflect- In humans, average 1 to 3 months, but range
ing widespread immunization of dogs and the from days to years.
availability of effective prophylaxis after expo-
Diagnostic Tests
sure to a rabid animal. From 2000 through
July 2013, 31 of 43 cases of human rabies Infection in animals can be diagnosed by
reported in the United States were acquired ­demonstration of the presence of rabies virus
indigenously. Among the 31 indigenously antigen in brain tissue using a direct fluores-
acquired cases, all but 4 were associated with cent antibody test. Suspected rabid animals
bats. Despite the large focus of rabies in rac- should be euthanized in a manner that pre-
coons in the eastern United States, only 3 serves brain tissue for appropriate laboratory
human deaths have been attributed to the rac- diagnosis. Virus can be isolated in suckling
coon rabies virus variant. Historically, 2 cases mice or in tissue culture from saliva, brain,
of human rabies were attributable to probable and other specimens and can be detected by
aerosol exposure in laboratories, and 2 unusual identification of viral antigens or nucleotide
cases have been attributed to possible airborne sequences in affected tissues. Diagnosis in
exposures in caves inhabited by millions of ­suspected human cases can be made post­
bats, although alternative infection routes mortem by immunofluorescent or immuno­
­cannot be discounted. Transmission has also histochemical examination of brain tissue
occurred by transplantation of organs, corneas, or by detection of viral nucleotide sequences.
and other tissues from patients dying of undi- Antemortem diagnosis can be made by direct
agnosed rabies. Person-to-person transmission fluorescent antibody test on skin biopsy

ERRNVPHGLFRVRUJ
Rabies 489

s­ pecimens from the nape of the neck, by isola- Treatment


tion of the virus from saliva, by detection of Once symptoms develop, neither rabies vaccine
antibody in serum in unvaccinated people nor rabies immune globulin is useful. There is
and cerebrospinal fluid in all people, and by no specific treatment. Ten people have survived
detection of viral nucleotide sequences in rabies in association with incomplete rabies
saliva, skin, or other tissues. No single test vaccine schedules. Since 2004, 3 girls, each of
is sufficiently sensitive because of the unique whom had not received rabies postexposure
nature of rabies pathobiology. Laboratory per- prophylaxis, survived rabies. A combination
sonnel and state or local health departments of sedation and intensive medical intervention
should be consulted before submission of may be valuable adjunctive therapy.
­specimens to the Centers for Disease Control
and Prevention so appropriate collection and
transport of materials can be arranged.

Image 112.1
Electron micrograph of the rabies virus. This electron micrograph shows the rabies virus, as well
as Negri bodies or cellular inclusions. Courtesy of Centers for Disease Control and Prevention/
Dr Fred Murphy.

ERRNVPHGLFRVRUJ
490 Rabies

Image 112.2
Rabies, animal. Number of reported cases, by county—United States, 2012. Courtesy of Morbidity and
Mortality Weekly Report.

Image 112.3
Raccoons can be vectors of the rabies virus, Image 112.4
transmitting the virus to humans and other Approximately one-third of reported animal rabies
animals. Rabies virus belongs to the order is attributed to the wild skunk population. Wild
Mononegavirales. Raccoons continue to be the animals accounted for 93% of reported animal
most frequently reported rabid wildlife species cases of rabies in 2000. Skunks were responsible
and involved 37.7% of all animal-transmitted for 30.1% of this number. Courtesy of Centers for
cases during 2000. Courtesy of Centers for Disease Control and Prevention.
Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Rabies 491

Image 112.5
This bat, Artibeus jamaicensis, is also known as
the Jamaican fruit bat. Most of the recent human
Image 112.6
rabies cases in the United States have been
This rabid dog has saliva dripping from the
caused by rabies virus that was transmitted
mouth, which is a primary indicator for the
through a bat vector. Courtesy of Centers for
presence of rabies. Before 1960, the majority
Disease Control and Prevention/Dr R. Keith Sikes.
of cases were in domestic animals. In more
recent years, more than 90% of all animal cases
reported occur in wildlife. Courtesy of Centers
for Disease Control and Prevention.

Image 112.8
Image 112.7 Characteristic Negri bodies are present within a
Close-up of a dog’s face during late-stage Purkinje cell of the cerebellum in this patient who
“dumb” paralytic rabies. Animals with dumb died of rabies. Courtesy of Centers for Disease
rabies appear depressed, lethargic, and Control and Prevention/Dr Makonnen Fekadu.
uncoordinated. Gradually, they become
completely paralyzed. When their throat and
jaw muscles are paralyzed, the animals will drool
and have difficulty swallowing. Courtesy of
Centers for Disease Control and Prevention.

Image 112.10
This micrograph depicts the histopathologic
Image 112.9 changes associated with rabies encephalitis
Photomicrograph of brain tissue from a rabies (hematoxylin-eosin stain). Note the Negri bodies,
encephalitis patient (hematoxylin-eosin stain). which are cellular inclusions found most
His­topathologic brain tissue from a rabies patient frequently in the pyramidal cells of hippocampus
displaying the pathognomonic finding of Negri proprius, and the Purkinje cells of the cerebellum.
bodies within the neuronal cytoplasm (hematoxylin- They are also found in the cells of the medulla and
eosin stain). Courtesy of Centers for Disease various other ganglia. Courtesy of Centers for
Control and Prevention/Dr Daniel P. Perl. Disease Control and Prevention/Dr Daniel P. Perl.

ERRNVPHGLFRVRUJ
492 Rat-bite Fever

113 fever refers to infection after ingestion of


unpasteurized milk, water, or food con­
Rat-bite Fever taminated with S moniliformis and may be
Clinical Manifestations associated with an outbreak of disease.
S minus is transmitted by bites of rats and
Rat-bite fever is caused by Streptobacillus mice. S ­moniliformis infection accounts for
moniliformis or Spirillum minus. S ­moniliformis most cases of rat-bite fever in the United States;
infection (streptobacillary or Haverhill fever) S minus infections occur primarily in Asia.
is characterized by relapsing fever, rash, and
migratory polyarthritis. There is an abrupt Incubation Period
onset of fever, chills, muscle pain, vomiting, For S moniliformis, usually less than 7 days
headache, and, rarely (unlike S minus), lymph- (range, 3 days–3 weeks); for S minus, 7 to
adenopathy. A maculopapular, purpuric, or 21 days.
petechial rash develops, predominantly on the
peripheral extremities, including the palms Diagnostic Tests
and soles, typically within a few days of fever S moniliformis is a fastidious, slow-growing
onset. The bite site usually heals promptly organism isolated from specimens of blood,
and exhibits no or minimal inflammation. synovial fluid, aspirates from abscesses, or
Non­suppurative migratory polyarthritis or material from the bite lesion by inoculation
arthralgia follows in approximately 50% of into bacteriologic media enriched with blood,
patients. Symptoms of untreated infection serum, or ascitic fluid. Cultures should be held
resolve within 2 weeks, but fever can occa­ up to 3 weeks if S moniliformis is suspected.
sionally relapse for weeks or months. Com­ Sodium polyanethol sulfonate, present in
plications include soft tissue and solid-organ most blood culture media, is inhibitory to
abscesses, septic arthritis, pneumonia, endo- S moniliformis; therefore, sodium polyanethol
carditis, myocarditis, and meningitis. The case- sulfonate–free media should be used. S minus
fatality rate is 7% to 13% in untreated patients, has not been recovered on artificial media but
and fatal cases have been reported in young can be visualized by darkfield microscopy in
children. With S minus infection (sodoku), a wet mounts of blood, exudate of a lesion, and
period of initial apparent healing at the site of lymph nodes. Blood specimens should also be
the bite is usually followed by fever and ulcer- viewed with Giemsa or Wright stain. S minus
ation at the site, regional lymphangitis and can be recovered from blood, lymph nodes, or
lymphadenopathy, and a distinctive rash of local lesions by intraperitoneal inoculation of
red or purple plaques. Arthritis is rare. Infec- mice or guinea pigs. S moniliformis has been
tion with S minus is rare in the United States. detected using a nucleic acid amplification–
Etiology based assay.

The causes of rat-bite fever are S moniliformis, Treatment


a microaerophilic, gram-negative, pleomorphic Penicillin administered intravenously or intra-
bacillus, and S minus, a small, gram-negative, muscularly for 7 to 10 days is the treatment for
spiral organism with bipolar flagellar tufts. rat-bite fever caused by either agent. Initial
Epidemiology intravenous penicillin for 5 to 7 days followed
by oral penicillin for 7 days has also been
Rat-bite fever is a zoonotic illness. The natu- ­successful. Limited experience exists for
ral habitat of S moniliformis and S minus ­a mpicillin, cefuroxime, and cefotaxime.
is the upper respiratory tract of rodents. ­Doxycycline or streptomycin can be substi-
S ­moniliformis is transmitted by bites or tuted when a patient has a serious allergy to
scratches from or exposure to oral secretions penicillin. Patients with endocarditis should
of infected rats (eg, kissing pet rodents); other receive intravenous high-dose penicillin G for
rodents (eg, mice, gerbils, squirrels, weasels) at least 4 weeks. The addition of streptomycin
and rodent-eating animals, including cats and or gentamicin for initial therapy may be useful.
dogs, can also transmit the infection. Haverhill

ERRNVPHGLFRVRUJ
Rat-bite Fever 493

Image 113.2
Five days after being bitten by a rat, the child in
Image 113.1 developed fever, chills, and head­
ache, followed 5 days later by a papulovesicular
rash on the hands and feet. Streptobacillus
moniliformis was isolated from blood cultures,
and the patient responded to intravenous
penicillin therapy without complication. Courtesy
of George Nankervis, MD.

Image 113.1
Rat-bite wounds on the finger of a 5-year-old
white boy 12 hours after the bite appear non­
inflammatory. Because of fever, chills, headache,
and rash 5 days later, blood cultures were
obtained that grew Streptobacillus moniliformis.
Courtesy of George Nankervis, MD.

Image 113.4
Close-up view of the rash of the same infant
as in Image 113.3 who was bitten on the
right cheek by a rat. Sodoku, or rat-bite fever
caused by Spirillum minus, rarely occurs in
the United States.

Image 113.3
The rash of rat-bite fever (Streptobacillus
moniliformis) in an infant bitten by a rat on the
right side of the face while sleeping.

ERRNVPHGLFRVRUJ
494 Respiratory Syncytial Virus

114 Reinfection with RSV throughout life is


­common. Recurrent RSV infection in older
Respiratory Syncytial children and adults usually manifests as mild
Virus upper respiratory tract illness. Serious disease
involving the lower respiratory tract can
Clinical Manifestations develop in older children and adults, especially
Respiratory syncytial virus (RSV) causes acute in immunocompromised people, people with
respiratory tract infections in people of all cardiopulmonary disease, and elderly people,
ages and is one of the most common diseases particularly those with comorbidities.
of early childhood. Most patients are infected
Etiology
during the first year of life, with virtually
all having been infected at least once by the Respiratory syncytial virus is an enveloped,
second birthday; the majority experience nonsegmented, negative-strand RNA virus of
upper respiratory tract symptoms, and 20% the family Paramyxoviridae. The virus uses
to 30% develop lower respiratory tract disease attachment (G) and fusion (F) surface glyco-
(eg, bronchiolitis, pneumonia) with the first proteins for virus entry; these surface proteins
infection. Signs and symptoms of bronchiolitis lack neuraminidase and hemagglutinin acti­v­
typically begin with rhinitis and cough, which ities. Only one serotype is known, but
progress to increased respiratory effort with ­variations in the surface proteins (especially
tachypnea, wheezing, rales, crackles, inter­ attachment protein G) result in the classifica-
costal or subcostal retractions, grunting, and tion of viruses in 2 major subgroups, desig-
nasal flaring. During the first few weeks of life, nated A and B.
particularly among preterm neonates, infec-
Epidemiology
tion with RSV can produce minimal respira-
tory tract signs; lethargy, irritability, and poor Humans are the only source of infection.
feeding, sometimes accompanied by apneic Respiratory syncytial virus is usually trans­
episodes, are often presenting manifestations mitted by direct or close contact with con­
in these neonates. Most previously healthy neo- taminated secretions, which may occur from
nates who develop RSV bronchiolitis do not exposure to large-particle droplets at short
require hospitalization, and even those who ­distances (typically <3 to 6 feet) or from fomi-
are hospitalized improve with supportive care, tes. Viable RSV can persist on environmental
with discharge after 2 or 3 days. Approximately surfaces for several hours and for 30 minutes
1% to 3% of all infants in the first 12 months of or more on hands. Infection among health care
life will be hospitalized because of RSV lower personnel and others can occur by hand-to-eye
respiratory tract disease. Most RSV hospital- or hand-to-nasal epithelium self-inoculation
izations occur in the first 3 months of life. Fac- with contaminated secretions. Enforcement of
tors that increase the risk of severe RSV lower infection control policies is critical to decrease
respiratory tract illness include extreme pre- the risk of health care–associated transmission
maturity; cyanotic or complicated congenital of RSV, especially to hematopoietic stem cell
heart disease, especially conditions associated or solid organ transplant recipients or patients
with pulmonary hypertension; chronic lung with cardiopulmonary abnormalities or immu-
disease of prematurity (formerly called bron- nocompromised conditions that can be severe
chopulmonary dysplasia); and certain immu- and fatal. Children with HIV infection experi-
nodeficiency states. Fewer than 100 deaths in ence extended viral shedding and, sometimes,
young children are attributable to complica- prolonged illness but usually do not exhibit
tions of RSV infection annually. The associa- enhanced disease.
tion between RSV bronchiolitis early in life Respiratory syncytial virus occurs in annual
and subsequent asthma remains poorly under- epidemics during winter and early spring in
stood. Respiratory syncytial virus bronchiolitis temperate climates. Spread among household
can be associated with short-term or long-term and child care contacts, including adults,
complications that include recurrent wheezing is common. The period of viral shedding is
and abnormalities in pulmonary function.

ERRNVPHGLFRVRUJ
Respiratory Syncytial Virus 495

usually 3 to 8 days but can last longer, especially testing for multiple respiratory viruses with
in young infants and immunosuppressed peo- one test. Because of the increased sensitivity of
ple, in whom shedding may continue for as RT-PCR testing, these tests may be preferred
long as 3 to 4 weeks. in many clinical settings. However, these tests
should be interpreted with caution, especially
Incubation Period
when a multiplex assay identifies the presence
4 to 6 days; range, 2 to 8 days. of nucleic acid from more than one virus,
because genetic material from some viruses
Diagnostic Tests
(eg, rhinovirus, adenovirus, bocavirus) may
Rapid diagnostic assays, including immuno­ persist in the airway for many weeks after
fluorescent and enzyme immunoassay tech- ­cessation of shedding of infectious virus. As
niques for detection of viral antigen in many as 25% of asymptomatic children test
nasopharyngeal specimens, are available positive for respiratory viruses using RT-PCR
­commercially for RSV and are generally reli- assays in population-based studies.
able in infants and young children. In children,
the sensitivity of these assays in comparison Respiratory syncytial virus isolation from
with culture varies between 53% and 96%, with respiratory tract secretions in cell culture
most in the 80% to 90% range. The sensitivity requires 1 to 5 days (shell vial techniques
may be lower in older children and is quite can produce results within 24–48 hours),
poor in adults because adults typically shed but results and sensitivity vary among lab­
low concentrations of RSV. As with all antigen oratories. Experienced viral laboratory per­
detection assays, the predictive value is high sonnel should be consulted for optimal
during the peak season, but false-positive methods of collection and transport of speci-
test results are more likely to occur when mens, which include keeping the specimen
the incidence of disease is low, such as in the cold but unfrozen during transport, rapid
summer in temperate areas. Therefore, antigen specimen processing, and ­stabilization in
detection assays should not be the only basis virus transport media. Con­ventional sero-
on which the beginning and end of monthly logic testing of acute and con­valescent serum
immunoprophylaxis is determined. In most specimens cannot be relied on to confirm
outpatient and inpatient settings, specific viral infection in young infants, in whom sensitiv-
testing has little effect on management and ity may be low.
routine testing is not recommended. Treatment
One disadvantage of targeted antigen detection Primary treatment of young children hospi­
relative to comprehensive virologic assessment talized with bronchiolitis is supportive and
(culture or reverse transcriptase-polymerase should include hydration, careful assessment
chain reaction [RT-PCR] assay) is that coin­ of respiratory status, measurement of oxygen
fections may not be detected. Up to 30% of saturation, suction of the upper airway, and,
children with RSV bronchiolitis may be coin- if necessary, intubation and mechanical ven­
fected with another respiratory tract pathogen, tilation. Clinicians may choose not to adminis-
such as human metapneumovirus, rhinovirus, ter supplemental oxygen if the oxyhemoglobin
bocavirus, adenovirus, coronavirus, influenza saturation exceeds 90% in infants and children
virus, or parainfluenza virus. Whether children hospitalized with bronchiolitis. Continuous
with bronchiolitis who are coinfected with measurement of oxygen saturation may detect
more than one virus experience more severe transient fluctuations in oxygenation that are
disease is not clear. not clinically significant, prolong oxygen use,
and delay discharge.
Molecular diagnostic tests using RT-PCR
assays are available commercially and increase Ribavirin has in vitro antiviral activity against
RSV detection rates over viral isolation or RSV, and aerosolized ribavirin therapy has
­antigen detection assays, especially in older been associated with a small but statistically
children and adults. Many commercial tests significant increase in oxygen saturation dur-
are designed as multiplex assays to facilitate ing the acute infection in several small studies.

ERRNVPHGLFRVRUJ
496 Respiratory Syncytial Virus

However, a consistent decrease in need for • Antimicrobial therapy. Antimicrobial


mechanical ventilation, decrease in length of ­t herapy is not indicated for infants with RSV
stay in the pediatric intensive care unit, or bronchiolitis or pneumonia unless there is
reduction in days of hospitalization among evidence of concurrent bacterial infection.
ribavirin recipients has not been demonstrated.
• Other therapies. Chest physiotherapy
• α- and β-adrenergic agents. β-Adrenergic should not be used in infants and children
agents are not recommended for care of first- with a diagnosis of bronchiolitis. Nebulized
time wheezing associated with RSV bronchi- hypertonic saline (3%) appears to be safe and
olitis. Evidence does not support the use of effective at improving the symptoms of mild
nebulized epinephrine in hospitalized chil- to moderate bronchiolitis after 24 hours of
dren with bronchiolitis or for outpatient use and in reducing hospital length of stay in
management of children with bronchiolitis. settings where the duration of stay is likely
to exceed 3 days. Hypertonic saline has not
• Corticosteroid therapy. Controlled clinical
been shown to be effective over the short
trials among children with bronchiolitis
term for patients managed in the emergency
have demonstrated that corticosteroids do
department or when length of hospitaliza-
not reduce hospital admissions or length of
tion is brief.
stay for inpatients. Corticosteroid treatment
is not recommended for infants and children
with RSV bronchiolitis.

Image 114.1
Electron micrograph of a respiratory syncytial virus. The virion is variable in shape and size
(average diameter between 120 and 300 nm). Respiratory syncytial virus is the most common cause
of bronchiolitis and pneumonia among infants younger than 1 year. Courtesy of Centers for
Disease Control and Prevention/E. L. Palmer.

ERRNVPHGLFRVRUJ
Respiratory Syncytial Virus 497

Image 114.2
The characteristic cytopathic effect of respiratory syncytial virus in tissue culture includes the formation
of large multinucleated syncytial cells.

Image 114.3
Respiratory syncytial virus bronchiolitis and pneumonia. Note the bilateral infiltrates and striking
hyperaeration. Copyright Martha Lepow.

Image 114.4
An anteroposterior radiograph of a 2-month-old girl with respiratory syncytial virus bronchiolitis. Note
the wide intercostal spaces, hyperaeration of the lung fields, and flattening of the diaphragm. Courtesy
of Benjamin Estrada, MD.

ERRNVPHGLFRVRUJ
498 Rickettsial Diseases

115 gram-negative bacteria that are obligate


­intracellular pathogens and cannot be grown
Rickettsial Diseases in cell-free media.
Clinical Manifestations Epidemiology
Rickettsial diseases comprise infections caused Rickettsial diseases have arthropod vectors
by bacterial species of the genera Rickettsia including ticks, flies, mites, and lice. The
(endemic and epidemic typhus and spotted ­continued identification of new pathogenic
fever group rickettsioses), Orientia (scrub rickettsial agents, such as Rickettsia phillipi
typhus), Ehrlichia (ehrlichiosis), Anaplasma (364D) in California in 2010 and Rickettsia
(anaplasmosis), Neoehrlichia, and ­Neorickettsia. parkeri in many states, will require ongoing
Rickettsial infections have many features in research to confirm the burden of human ill-
common, including ness. Humans are incidental hosts, except for
the agent of classic epidemic typhus, for which
• Fever, rash (especially in spotted fever and humans are the principal reservoir and the
typhus group rickettsiae), headache, myal- human body louse is the vector; however, other
gia, and respiratory tract symptoms are vectors and reservoirs exist even for this dis-
prominent features. ease. Rickettsial life cycles typically involve
• Local primary eschars occur with some arthropod and mammalian reservoirs, and
­rickettsial diseases, commonly with spotted transmission occurs as a result of environ­
fever rickettsioses, rickettsialpox, and mental or occupational exposure. Geographic
scrub typhus. and seasonal occurrences of rickettsial diseases
are related to specific arthropod vector life
• Systemic capillary and small vessel endo­ cycles, activities, and distributions.
thelial damage (ie, vasculitis) with increased
microvascular permeability is the primary Incubation Periods
pathologic feature of most severe spotted Vary according to organism.
fever and typhus group rickettsial infections.
Diagnostic Tests
• Rickettsial diseases can become life threat- Group-specific antibodies are detectable in
ening rapidly. Risk factors for severe disease the serum of many people 7 to 14 days after
include glucose-6-phosphate dehydroge- onset of illness, but slower antibody responses
nase deficiency, male gender, and treatment commonly occur in some diseases. The utility
with sulfonamides. of serologic diagnoses in acute illness is limited
Immunity against reinfection by the same in these infections because of their short incu-
agent after natural infection is usually of long bations; a negative serologic test result never
duration, except in the case of scrub typhus. excludes infection in the acute phase of clinical
Among the 4 groups of rickettsial diseases, illness. Various serologic tests for detecting
some cross-immunity is usually conferred antirickettsial antibodies are available. The
by infections within groups but not between indirect immunofluorescent antibody assay is
groups. Reinfection of humans with Ehrlichia recommended in most circumstances because
species and Anaplasma species has not of its relative sensitivity and specificity. Treat-
been described. ment early in the course of illness can blunt or
delay serologic responses. In laboratories with
Etiology experienced personnel, immunohistochemical
The rickettsiae causing human disease include staining and polymerase chain reaction testing
Rickettsia species, Orientia tsutsugamushi, of skin biopsy specimens from patients with
Ehrlichia species, Anaplasma phagocytophilum, rash or eschar can help to diagnose rickettsial
Neorickettsia sennetsu, and Neoehrlichia miku­ infections early in the course of disease. Weil-
rensis. Rickettsiae are small, coccobacillary Felix tests are not recommended. The use of
tick panels is discouraged.

ERRNVPHGLFRVRUJ
Rickettsial Diseases 499

Treatment is most effective when individuals are treated


Prompt and specific therapy is important for appropriately during the first week of illness.
optimal outcome. The drug of choice for rick- If the disease remains untreated during the
ettsioses is doxycycline. The duration of treat- second week, therapy is less effective in pre-
ment is 7 to 14 days. Antimicrobial treatment venting complications.

ERRNVPHGLFRVRUJ
500 Rickettsialpox

116 occurs. The disease is not communicable


but occurs occasionally among families or
Rickettsialpox ­people cohabiting a house mouse mite–infested
Clinical Manifestations dwelling.
Rickettsialpox is a febrile, eschar-associated Incubation Period
illness that is characterized by generalized, 6 to 15 days.
relatively sparse, erythematous, papulovesicu-
lar eruptions on the trunk, face, and extremi- Diagnostic Tests
ties (less often on palms and soles) or on R akari can be isolated in cell culture from
mucous membranes of the mouth. The rash blood and eschar biopsy specimens during
develops 1 to 4 days after onset of fever and 3 to the acute stage of disease, but culture is not
10 days after appearance of an eschar at the site attempted routinely. Because antibodies to
of the bite of a house mouse mite. Regional R akari have extensive cross-reactivity with
lymph nodes in the area of the primary eschar antibodies against Rickettsia rickettsii (the
typically become enlarged. Without specific cause of Rocky Mountain spotted fever) and
antimicrobial therapy, systemic disease lasts other spotted fever group rickettsiae, an indi-
approximately 7 to 10 days; manifestations rect immunofluorescent antibody assay for
include fever, headache, malaise, and myalgia. R rickettsii can be used to demonstrate a 4-fold
Less frequent manifestations include anorexia, or greater change in antibody titers between
vomiting, conjunctivitis, nuchal rigidity, and acute and convalescent serum specimens taken
photophobia. The disease is mild compared 2 to 6 weeks apart. Use of R akari antigen is
with Rocky Mountain spotted fever, and no recommended for a more accurate serologic
rickettsialpox-associated deaths have been diagnosis but may only be available in special-
described; however, disease is occasionally ized research laboratories. Direct fluorescent
severe enough to warrant hospitalization. antibody or immunohistochemical testing of
Etiology formalin-fixed, paraffin-embedded eschars
or papulovesicle biopsy specimens can detect
Rickettsialpox is caused by Rickettsia akari, a rickettsiae in the samples and are useful
gram-negative intracellular bacillus, which is ­diagnostic techniques, but because of cross-
classified with the spotted fever group rickett- reactivity, these assays are not able to confirm
siae and related antigenically to other members the etiologic agent. Use of polymerase chain
of that group. reaction for detection of rickettsial DNA with
Epidemiology subsequent sequence identification can con-
firm R akari infection.
The natural host for R akari in the United
States is Mus musculus, the common house Treatment
mouse. The disease is transmitted by the Doxycycline is the drug of choice in all age
house mouse mite, Liponyssoides sanguineus. groups and is effective when given for 3 to
Disease risk is heightened in areas infested 5 days. Doxycycline will shorten the course
with mice and rats. The disease can occur of disease; symptoms typically resolve within
wherever the hosts, pathogens, and humans 12 to 48 hours after initiation of therapy.
coexist but is most frequently reported in Relapse is rare. There are limited data describ-
large urban settings. In the United States, ing the utility of other antimicrobials, includ-
­rickettsialpox has been described predomi- ing azithromycin and fluoroquinolones.
nantly in northeastern metropolitan centers, Chloramphenicol is an alternative drug but
especially New York. It has also been con- is not available as an oral formulation in the
firmed in many other countries, including United States. Untreated rickettsialpox usually
­Croatia, Ukraine, Turkey, ­Russia, South will resolve within 2 to 3 weeks.
Korea, and Mexico. All age groups can be
affected. No seasonal pattern of disease

ERRNVPHGLFRVRUJ
Rickettsialpox 501

Image 116.1 Image 116.2


Eschar on the posterior right calf of patient with Multiple papulovesicular lesions involving the
rickettsialpox. This type of lesion is not seen with upper trunk on a patient with rickettsialpox.
Rocky Mountain spotted fever. Courtesy of Courtesy of Emerging Infectious Diseases.
Emerging Infectious Diseases.

ERRNVPHGLFRVRUJ
502 Rocky Mountain ­Spotted Fever

117 ­ earing loss; peripheral neuropathy; bladder


h
and bowel incontinence; cerebellar, vestibular,
Rocky Mountain and motor dysfunction) and nonneurologic
­Spotted Fever (disability from limb or digit amputation)
sequelae. Patients treated early in the course of
Clinical Manifestations symptoms may have a mild illness, with fever
Rocky Mountain spotted fever (RMSF) is a resolving in the first 48 hours of treatment.
systemic, small-vessel vasculitis that often
Etiology
involves a characteristic rash. Fever, myalgia,
severe headache, photophobia, nausea, vomit- Rickettsia rickettsii, an obligate, intracellular,
ing, and anorexia are typical presenting symp- gram-negative bacillus and a member of the
toms. Abdominal pain and diarrhea are often spotted fever group of rickettsiae, is the caus-
present and can obscure the diagnosis. The ative agent. The primary targets of infection in
rash usually begins within the first 6 days of mammalian hosts are endothelial cells lining
symptoms as erythematous macules or macu- the small blood vessels of all major tissues
lopapules. The rash usually appears first on and organs.
the wrists and ankles, often spreading within
Epidemiology
hours proximally to the trunk and distally to
the palms and soles. Although early develop- The pathogen is transmitted to humans by the
ment of a rash is a useful diagnostic sign, the bite of a tick of the Ixodidae family (hard ticks).
rash can be atypical or absent in up to 20% of Ticks and their small mammal hosts serve as
cases. It may be difficult to visualize in patients reservoirs of the pathogen in nature. Other
with dark skin. A petechial rash is typically a wild animals and dogs have been found with
late finding and indicates progression to severe antibodies to R rickettsii, but their role as
disease. Lack of a typical rash is a risk factor ­natural reservoirs is not clear. People with
for misdiagnosis and poor outcome. Hepato- occupational or recreational exposure to the
megaly and splenomegaly occur in 33% of tick vector (eg, pet owners, animal handlers,
patients. Meningeal signs with a positive people who spend more time outdoors) are at
Kernig and Brudzinski sign can occur. increased risk of acquiring the organism. Peo-
ple of all ages can be infected. The period of
Thrombocytopenia, hyponatremia (observed highest incidence in the United States is from
in 20% of cases), and elevated liver transami- April to September, although RMSF can occur
nase concentrations develop in many cases, are year-round in certain areas with endemic dis-
frequently mild in the early stages of disease, ease. Laboratory-acquired infection has occa-
and worsen as disease progresses. White blood sionally resulted from accidental inoculation
cell count is typically normal, but leukopenia and aerosol contamination. Transmission has
and anemia can occur. If not treated, the ill- occurred, on rare occasions, by blood transfu-
ness can last as long as 3 weeks and can be sion. Mortality is highest in males, people
severe, with prominent central nervous sys- older than 50 years, children 5 to 9 years of
tem, cardiac, pulmonary, gastrointestinal age, and people with no recognized tick bite or
tract, and renal involvement; disseminated attachment. In approximately half of pediatric
intravascular coagulation; and shock leading RMSF cases, there is no recall of a recent tick
to death. Rocky Mountain spotted fever can bite. Factors contributing to delayed diagnosis
progress rapidly, even in previously healthy include absence of rash or difficulty in its rec-
people. Delay in appropriate antimicrobial ognition, especially in individuals with darker
treatment beyond the fifth day of symptoms complexions; initial presentation before the
is associated with severe disease and poor out- fourth day of illness; and onset of illness dur-
comes. Case-­fatality rates of untreated RMSF ing months of low incidence.
range from 20% to 80%, with a median time
to death of 8 days. Significant long-term Rocky Mountain spotted fever is widespread
sequelae are ­common in patients with severe in the United States, with a reported annual
RMSF, including neurologic (paraparesis; incidence that has increased 8-fold from

ERRNVPHGLFRVRUJ
Rocky Mountain ­Spotted Fever 503

1.8 cases per 1 million people in 2000 to 14.3 cases visualization of rickettsiae in tissues. The gold
per 1 million in 2012, or about 4,500 cases per standard for serologic diagnosis of RMSF is the
year. Despite its name, RMSF is not common indirect fluorescent antibody test. A negative
in the Rocky Mountain area. Most cases are serologic test result does not exclude a diag­
reported in the south Atlantic, southeastern, nosis of RMSF. Immunoglobulin (Ig) G and
and south central states, although most states IgM antibodies begin to increase around day
in the contiguous United States record cases 7 to 10 after onset of symptoms; an elevated
each year. The principal recognized vectors acute titer may represent past exposure rather
of R rickettsii are Dermacentor variabilis (the than acute infection. Mildly elevated antibody
American dog tick) in the eastern and central titers can be an incidental finding in a signifi-
United States and Dermacentor andersoni (the cant proportion of the general population in
Rocky Mountain wood tick) in the western some regions. IgM antibodies can remain
United States. Another common tick through- ­elevated for months and are not highly specific
out the world that feeds on dogs, Rhipicephalus for acute RMSF. A 4-fold or greater rise in
sanguineus (the brown dog tick), has been antigen-­specific IgG between acute and conva-
­confirmed as a vector of R rickettsii in Arizona lescent sera obtained 2 to 6 weeks apart con-
and Mexico and may play a role in other firms the diagnosis. Cross-reactivity may be
regions. Transmission parallels the tick season observed between antibodies to other spotted
in a given geographic area. Rocky Mountain fever group rickettsiae.
spotted fever also occurs in Canada, Mexico,
Treatment
Central America, and South America.
Doxycycline is the treatment of choice for
Incubation Period RMSF in patients of any age, and this drug
Approximately 1 week; range, 2 to 14 days. should be initiated as soon as RMSF is sus-
pected. Use of antibiotics other than doxy­
Diagnostic Tests
cycline increases the risk of mortality.
Rocky Mountain spotted fever may be diag- Treatment is most effective if started in the
nosed by the detection of R rickettsii DNA in first few days of symptoms; treatment started
acute whole blood and serum specimens by after the fifth day of symptoms is less likely
polymerase chain reaction assay. The speci- to prevent death or other adverse outcomes.
men should preferably be obtained within the Chloramphenicol is an alternative treatment
first week of symptoms and before (or within but should be considered only in rare cases,
24 hours of) initiation of antimicrobial ther- such as severe doxycycline allergies or during
apy, and a negative result does not exclude pregnancy. Antimicrobial treatment should be
RMSF infection. Diagnosis can also be con- continued until the patient has been afebrile
firmed by the detection of rickettsial DNA in for at least 3 days and has demonstrated clini-
biopsy or autopsy specimens by polymerase cal improvement; the usual duration of therapy
chain reaction assay or immunohistochemical is 7 to 10 days.

ERRNVPHGLFRVRUJ
504 Rocky Mountain ­Spotted Fever

Image 117.1
Spotted fever rickettsiosis. Number of reported cases, by county—United States, 2012. Courtesy of
Morbidity and Mortality Weekly Report.

Image 117.3
Image 117.2
This photograph depicts a dorsal view of a
This is a female lone star tick, Amblyomma
male Rocky Mountain wood tick, Dermacentor
americanum, which is found in the southeastern
andersoni. This tick species is a known North
and mid-Atlantic United States. This tick is a
American vector of Rickettsia rickettsii, which is
vector of several zoonotic diseases, including
the etiologic agent of Rocky Mountain spotted
human monocytic ehrlichiosis and Rocky
fever. Courtesy of Centers for Disease Control
Mountain spotted fever. Courtesy of Centers
and Prevention/Christopher Paddock, MD.
for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Rocky Mountain ­Spotted Fever 505

Image 117.4
This image depicts a male brown dog tick, Rhipicephalus sanguineus, from a superior, or dorsal, view
looking down on this hard tick’s scutum, which entirely covers its back, identifying it as a male. In the
female, the dorsal abdomen is only partially covered, thereby offering room for abdominal expansion
when she becomes engorged with blood while ingesting her blood meal obtained from her host.
Courtesy of Centers for Disease Control and Prevention/James Gathany; William Nicholson.

Image 117.6
Image 117.5
Rocky Mountain spotted fever. Sixth day of rash
Rocky Mountain spotted fever in an 8-year-old
without treatment. This is the same patient as in
boy. Sixth day of rash without treatment.
Image 117.5.

Image 117.7
Rocky Mountain spotted fever. Sixth day of rash without treatment. This is the same patient as in
images 117.5 and 117.6.

ERRNVPHGLFRVRUJ
506 Rocky Mountain ­Spotted Fever

Image 117.8
A 2-year-old boy with obtundation, disorientation, and petechial rash of Rocky Mountain spotted fever,
with facial and generalized edema secon­dary to generalized vasculitis. Rocky Mountain spotted fever
is the most severe and frequently reported rickettsial illness in the United States.

Image 117.9
Image 117.10
This is the same patient as in Image 117.8 showing
This is the same patient as in images 117.8 and
petechial rash and edema of the upper extremity.
117.9 showing petechiae and edema of foot.
The rickettsiae multiply in the endothelial cells of
small blood vessels, resulting in vasculitis.

Image 117.11
This 8-year-old girl presented with a history of “chickenpox” for 11 days. She had numerous lesions on
her chest, face, arms, and proximal legs. There were subcutaneous erythematous lesions on the
hands, and she had 5 or 6 lesions on her feet. The diagnosis of Rocky Mountain spotted fever was
confirmed serologically, and she was treated without any complications. Courtesy of Neal Halsey, MD.

ERRNVPHGLFRVRUJ
Rocky Mountain ­Spotted Fever 507

Image 117.12
A child’s right hand and wrist displaying the
spotted rash and edema of Rocky Mountain
spotted fever. Courtesy of Centers for Disease
Control and Prevention.

Image 117.13
The soles of the feet as well as the palms of
the hands are typically involved in patients
with Rocky Mountain spotted fever.

Image 117.14 Image 117.15


A 4-year-old girl with Rocky Mountain spotted Immunohistochemical analysis shows the
fever acquired in Panama that was misdiagnosed presence of spotted fever group rickettsiae
as meningococcemia. Autopsy findings included (brown) in vessels of the brain of a patient with
myocarditis, interstitial nephritis, pneumonitis, fatal Rocky Mountain spotted fever (magnification
and encephalitis. Histologic and immunohis­to­ x400). Courtesy of Centers for Disease Control
chemical evaluation of heart tissue. A, Lympho­ and Prevention/Emerging Infectious Diseases
histiocytic inflammatory cell infiltrates in the and Marylin Hidalgo.
myocardium (hematoxylin-eosin stain, original
magnification x25). B, Immunohistochemical
detection of spotted fever group rickettsiae (red)
in perivascular infiltrates of heart (immunoalkaline
phosphatase with naphthol-fast red substrate
and hematoxylin counterstain, original magnifi­
cation x250). Courtesy of Centers for Disease
Control and Prevention/Emerging Infectious
Diseases and Dora Estripeaut.

ERRNVPHGLFRVRUJ
508 Rotavirus Infections

118 families and institutions is common. Rarely,


common-source outbreaks from contaminated
Rotavirus Infections water or food have been reported.
Clinical Manifestations In temperate climates, rotavirus disease is
Infection begins with acute onset of fever most prevalent during the cooler months.
and vomiting followed 24 to 48 hours later by Before licensure of rotavirus vaccines in
watery diarrhea. Symptoms generally persist North America in 2006 and 2008, the annual
for 3 to 8 days. In moderate to severe cases, rotavirus epidemic usually started during the
dehydration, electrolyte abnormalities, and autumn in Mexico and the southwest United
acidosis can occur. In certain immunocom­ States and moved eastward, reaching the
promised children, including children with northeast United States and Maritime prov-
congenital cellular immunodeficiencies or inces by spring. The seasonal pattern of disease
severe combined immunodeficiency and is less pronounced in tropical climates, with
­children who are hematopoietic stem cell or rotavirus infection being more common dur-
solid organ transplant recipients, persistent ing the cooler, drier months.
infection and diarrhea can develop.
The epidemiology of rotavirus disease in the
Etiology United States has changed dramatically since
rotavirus vaccines became available. A bien-
Rotaviruses are segmented, double-stranded
nial pattern has emerged, with small, short
RNA viruses belonging to the family
seasons beginning in late winter or early spring
­Reoviridae, with at least 7 distinct antigenic
(eg, 2009, 2011, 2013) alternating with years
groups (A–G). Group A viruses are the major
with extremely low circulation (eg, 2008, 2010,
causes of rotavirus diarrhea worldwide. Sero-
2012). The overall burden of rotavirus disease
typing is based on the 2 surface proteins, VP7
has declined dramatically. Beginning in 2008,
glycoprotein (G) and VP4 protease-cleaved
annual hospitalizations for rotavirus disease
hemagglutinin (P). Prior to introduction of
among US children younger than 5 years
the rotavirus vaccine, G types 1 through 4
declined by approximately 75%, with an esti-
and 9 and P types 1A[8] and 1B[4] were most
mated 40,000 to 50,000 fewer rotavirus hospi-
common in the United States.
talizations nationally each year. In the United
Epidemiology States, a full series of vaccine has been found
The epidemiology of rotavirus disease in the to be approximately 85% to 90% effective
United States has changed following the intro- against rotavirus disease resulting in hospital-
duction of rotavirus vaccines. Prior to wide- ization. The vaccines are also highly effective
spread vaccine use, rotavirus was the most against rotavirus disease resulting in emer-
common cause of acute gastroenteritis in gency department care and in office visits
young children, an important cause of acute attributable to rotavirus.
gastroenteritis in children attending child Incubation Period
care, and the most common cause of health
1 to 3 days.
care–associated diarrhea in young children.
Rotavirus is present in high titer in stools of Diagnostic Tests
infected patients several days before and sev-
It is not possible to diagnose rotavirus infec-
eral days after onset of clinical disease. Trans-
tion by clinical presentation or nonspecific
mission is by the fecal-oral route. Rotavirus
laboratory tests. Enzyme immunoassays,
can be found on toys and hard surfaces in
immunochromatography, and latex aggluti­
child care centers, indicating fomites may
nation assays for group A rotavirus antigen
serve as a mechanism of transmission. Res­
detection in stool are available commercially.
piratory transmission likely plays a minor
Enzyme immunoassays are used most widely
role in disease transmission. Spread within
because of their high sensitivity and specificity.

ERRNVPHGLFRVRUJ
Rotavirus Infections 509

Rotavirus can also be identified in stool by Treatment


electron microscopy, by electrophoresis and No specific antiviral therapy is available. Oral
­silver staining, by standard or real-time reverse or parenteral fluids and electrolytes are given
transcriptase-polymerase chain reaction assay to prevent or correct dehydration.
for detection of viral genomic RNA, and by
viral culture.

Image 118.1
Transmission electron micrograph of intact rotavirus particles, double-shelled. Distinctive rim of
radiating capsomeres. Courtesy of Centers for Disease Control and Prevention/Dr Erskine Palmer.

Image 118.2
Doctor examining a child dehydrated from rotavirus infection. In developing countries, rotavirus
causes approximately 600,000 deaths each year in children younger than 5 years. Courtesy of
World Health Organization.

ERRNVPHGLFRVRUJ
510 Rubella

119 Etiology

Rubella Rubella virus is an enveloped, positive-stranded


RNA virus classified as a Rubivirus in the
Clinical Manifestations ­Togaviridae family.
• Postnatal rubella. Many cases of postnatal Epidemiology
rubella are subclinical. Clinical disease is
usually mild and characterized by a gen­ Humans are the only source of infection. Post-
eralized erythematous maculopapular rash, natal rubella is transmitted primarily through
lymphadenopathy, and slight fever. The rash direct or droplet contact from nasopharyngeal
starts on the face, becomes generalized in secretions. The peak incidence of infection is
24 hours, and lasts a median of 3 days. during late winter and early spring. Approxi-
Lymphadenopathy, which can precede rash, mately 25% to 50% of infections are asymptom-
often involves posterior auricular or sub­ atic. Immunity from wild-type or vaccine virus
occipital lymph nodes, can be generalized, is usually prolonged, but reinfection on rare
and lasts between 5 and 8 days. Conjunctivi- occasions has been demonstrated and, rarely,
tis and palatal enanthema have been noted. has resulted in CRS. Although volunteer stud-
Transient polyarthralgia and polyarthritis ies have demonstrated rubella virus in naso-
rarely occur in children but are common in pharyngeal secretions from 7 days before to a
adolescents and adults, especially females. maximum of 14 days after onset of rash, the
Encephalitis (1 in 6,000 cases) and thrombo- period of maximal communicability extends
cytopenia (1 in 3,000 cases) are complications. from a few days before to 7 days after onset of
rash. A small number of infants with congeni-
• Congenital rubella syndrome. Maternal tal rubella continue to shed virus in nasopha-
rubella during pregnancy can result in ryngeal secretions and urine for 1 year or more
­miscarriage, fetal death, or a constellation and can transmit infection to susceptible con-
of congenital anomalies (congenital rubella tacts. Rubella virus has been recovered in high
syndrome [CRS]). The most commonly titer from lens aspirates in children with con-
described anomalies or manifestations genital cataracts for several years.
­associated with CRS are ophthalmologic
(cataracts, pigmentary retinopathy, Before widespread use of rubella vaccine,
microph­t halmos, congenital glaucoma), rubella was an epidemic disease, occurring in
­cardiac (patent ductus arteriosus, periph- 6- to 9-year cycles, with most cases occurring
eral pul­monary artery stenosis), auditory in children. In the postvaccine era, most cases
(sensorineural hearing impairment), or in the mid-1970s and 1980s occurred in young
­neurologic (behavioral disorders, menin­ unimmunized adults in outbreaks on college
goencephalitis, microcephaly, cognitive campuses and in occupational settings. More
impairments). ­Neonatal manifestations of recent outbreaks have occurred in people born
CRS include intrauterine growth restriction, outside the United States or among underim-
interstitial pneumonitis, radiolucent bone munized populations. The incidence of rubella
disease, hepatosplenomegaly, thrombocyto- in the United States has decreased by more
penia, and dermal erythropoiesis (so-called than 99% from the prevaccine era.
blueberry muffin lesions). Mild forms of the The United States was determined to no longer
disease can be associated with few or no have endemic rubella in 2004, and from 2004
obvious clinical manifestations at birth. through 2012, 79 cases of rubella and 6 cases
Congenital defects occur in up to 85% of of CRS, including 3 cases in 2012, were
cases if maternal infection occurs during reported in the United States; all of the cases
the first 12 weeks of gestation, 50% if infec- were import associated or from unknown
tion occurs during 13 to 16 weeks of gesta- sources. A national serologic survey from 1999
tion, and 25% if infection occurs during the to 2004 indicated that among children and
end of the second trimester. Natural rubella adolescents 6 through 19 years of age, sero­
infection in pregnancy can cause autism prevalence was approximately 95%. Studies of
spectrum disorder in the neonate.

ERRNVPHGLFRVRUJ
Rubella 511

rubella and CRS in the United States have inhibition rubella antibody test, which was
­identified that seronegativity is higher among previously the most commonly used method
people born outside the United States or from of serologic screening for rubella infection,
areas with poor vaccine coverage; the risk of has generally been supplanted by a number
CRS is highest among these populations. of equally or more sensitive assays for deter-
mining rubella immunity, including enzyme
In 2003, the Pan American Health Organiza-
immunoassays and latex agglutination tests.
tion (PAHO) adopted a resolution calling for
Diagnosis of congenital rubella infection in
elimination of rubella and CRS in the Ameri-
children older than 1 year is difficult; serologic
cas by 2010. All countries with endemic
testing is usually not diagnostic, and viral
rubella in the Americas implemented the rec-
­isolation, although confirmatory, is possible
ommended PAHO strategy by the end of 2008.
in only a small proportion of congenitally
The strategy consists of achieving high levels
infected children of this age.
of measles-rubella vaccination coverage in
the routine immunization program. The last A false-positive IgM test result may be caused
confirmed endemic case in the Americas was by a number of factors, including rheumatoid
­diagnosed in Argentina in February 2009. factor, parvovirus IgM, and heterophile anti-
In September 2010, PAHO announced that bodies. The presence of high-avidity IgG or
the region of the Americas had achieved the lack of increase in IgG titers can be useful in
rubella and CRS elimination goals on the identifying false-positive rubella IgM results.
basis of surveillance data, but documentation Low-avidity IgG is associated with recent pri-
of elimination is ongoing. mary rubella infection, whereas high-avidity
IgG is associated with past infection or rein­
Incubation Period
fection. The avidity assay is only performed
Usually 16 to 18 days; range, 14 to 21 days. at reference laboratories.
Diagnostic Tests Rubella virus can be isolated most consistently
Detection of rubella-specific immunoglobulin from throat or nasal specimens (and less con-
(Ig) M antibody usually indicates recent post- sistently, urine) by inoculation of appropriate
natal infection or congenital infection in a cell culture. Detection of rubella virus RNA
newborn, but false-negative and false-positive by real time reverse-transcriptase polymerase
results occur. Most postnatal cases are IgM- chain reaction from a throat or nasal swab or
positive by 5 days after symptom onset, and urine sample with subsequent genotyping
most congenital cases are IgM-positive at of strains may be valuable for diagnosis and
birth and up to 3 months later. For diagnosis molecular epidemiology. Most postnatal cases
of postnatally acquired rubella, a 4-fold or are positive virologically on the day of symp-
greater increase in antibody titer between acute tom onset, and most congenital cases are posi-
and convalescent periods indicates infection. tive virologically at birth
Congenital infection can also be confirmed Treatment
by stable or increasing serum concentrations
of rubella-specific IgG over the first 7 to Supportive.
11 months of life. The hemagglutination-­

ERRNVPHGLFRVRUJ
512 Rubella

Image 119.1
Rubella. Incidence, by year—United States, 1982–2012. Courtesy of Morbidity and Mortality
Weekly Report.

Image 119.2
This 5-year-old Hawaiian boy developed the fine macular rash noted on his face and chest. He had
serologically confirmed rubella. Courtesy of Neal Halsey, MD.

ERRNVPHGLFRVRUJ
Rubella 513

Image 119.3
Rubella rash on a child’s back (1978). The distribution is similar to that of measles, although the lesions
are less intensely red. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
514 Rubella

Image 119.4
Rubella rash (face) in a previously unimmunized
female. Adenovirus and enterovirus infections
can cause exanthema that mimics rubella.
Serologic testing is important if the patient
is pregnant.
Image 119.5
During a rubella outbreak in Hawaii, this
adolescent presented with a 2-day history of
fever, malaise, rash, and lymphadenopathy,
including these postauricular lymph nodes.
Courtesy of Neal Halsey, MD.

Image 119.6
Young adult male with postrubella thrombo­
cytopenic purpura with large blueberry muffin
skin lesions.

Image 119.7
Newborn with congenital rubella rash. Courtesy
of Immunization Action Coalition.

Image 119.9
A 4-year-old boy with congenital rubella
syndrome with unilateral microphthalmos and
cataract formation in the left eye.
Image 119.8
This photograph shows the cataracts in an
infant’s eyes due to congenital rubella syndrome.
Rubella is a viral disease that can affect suscep­
tible persons of any age. Although generally a
mild rash, if contracted in early pregnancy,
there can be a high rate of fetal wastage or
birth defects, known as congenital rubella
syndrome. Courtesy of Centers for Disease
Control and Prevention.

ERRNVPHGLFRVRUJ
Rubella 515

Image 119.10
Radiograph of the chest and upper abdomen of an infant with congenital rubella pneumonia with
hepatosplenomegaly.

Image 119.11
Radiolucent changes in the metaphyses of the long bones of the upper extremity of an infant with
congenital rubella.

Image 119.12
Radiograph of the lower extremity of the same patient as in Image 119.11 with metaphyseal radiolucent
changes, which are found in 10% to 20% of infants with congenital rubella.

ERRNVPHGLFRVRUJ
516 SALMONELLA INFECTIONS

120 infection can occur in association with more


severe clinical symptoms and signs, sustained
Salmonella Infections bacteremia, and meningitis. Diarrhea (resem-
Clinical Manifestations bling pea soup) or constipation can be early
features. Relative bradycardia (pulse rate
Nontyphoidal Salmonella organisms cause a slower than would be expected for a given
spectrum of illness ranging from asymptom- body temperature) has been considered a
atic gastrointestinal tract carriage to gastro­ ­common feature of typhoid fever in adults,
enteritis, bacteremia, and focal infections, but in children, this is rare.
including meningitis, brain abscess, and
­osteomyelitis. The most common illness Etiology
­associated with nontyphoidal Salmonella Salmonella organisms are gram-negative bacilli
­infection is gastroenteritis, in which diarrhea, that belong to the family Enterobacteriaceae.
abdominal cramps, and fever are common More than 2,500 Salmonella serovars have
manifestations. The site of infection is usually been described; most serovars causing human
the distal small intestine as well as the colon. disease are classified within O serogroups A
Sustained or intermittent bacteremia can through E. Salmonella ser Typhi is classified
occur, and focal infections are recognized in in O serogroup D, along with many other
as many as 10% of patients with nontyphoidal ­common serovars, including Enteritidis and
Salmonella ­bacteremia. Dublin. In 2011, the most commonly reported
In the United States, the incidence of invasive human isolates in the United States were
Salmonella infection is highest among infants. ­Salmonella serovars Enteritidis, Typhimurium,
Certain Salmonella serovars (eg, Dublin, Newport, Javiana, and Heidelberg; these 5
Typhi, Choleraesuis), although rare, are serovars generally account for nearly half of
more likely to result in invasive infection than all Salmonella infections in the United States.
­gastroenteritis. However, in recent years in The relative prevalence of other serovars varies
sub-Saharan Africa, certain serovars of non­ by country. Approximately 75% to 95% of the
typhoidal ­Salmonella have been reported to be serovars associated with invasive pediatric dis-
common. Notably, these highly lethal African ease in sub-Saharan Africa are S Typhimurium
nontyphoidal Salmonella organisms are geneti- (Table 120.1).
cally distinct from their serovar counterparts
causing pediatric disease in industrialized Epidemiology
countries and exhibit a very high lethality The principal reservoirs for nontyphoidal
(an estimate mortality of 20%); two-thirds of ­Salmonella organisms include birds, mammals,
patients present without gastroenteritis or a reptiles, and amphibians. However, it is believed
history of antecedent diarrhea. that some of the African serotypes associated
Salmonella enterica serovars Typhi, Paratyphi with invasive human disease have a human,
A, Paratyphi B, and Paratyphi C can cause rather than animal, reservoir. The major food
a protracted bacteremic illness referred to, vehicles of transmission to humans in industri-
respectively, as typhoid and paratyphoid fever alized countries include food of ­animal origin,
and, collectively, as enteric fevers. In older such as poultry, beef, eggs, and dairy products.
­children, the onset of enteric fever is typically Multiple other food vehicles (eg, fruits, vegeta-
gradual, with manifestations such as fever, bles, peanut butter, frozen potpies, powdered
constitutional symptoms (eg, headache, mal- infant formula, cereal, ­bakery products) have
aise, anorexia, lethargy), abdominal discomfort been implicated in ­outbreaks in the United
and tenderness, hepatomegaly, splenomegaly, States and Europe, presumably when the food
dactylitis, rose spots, and change in mental was contaminated by contact with an infected
status. In infants and toddlers, invasive infec- animal product or a human carrier. Other
tion with enteric fever serovars can manifest modes of transmission include ingestion of
as a mild, nondescript febrile illness accompa- contaminated water or contact with infected
nied by self-limited bacteremia, or invasive animals, mainly poultry (eg, chicks, chickens,

ERRNVPHGLFRVRUJ
SALMONELLA INFECTIONS 517

Table 120.1
Nomenclature for Salmonella Organisms

Complete Namea Serotypeb Antigenic Formula


S entericaa subsp enterica ser Typhi Typhi 9,12,[Vi]:d:-
S enterica subsp enterica ser Typhimurium Typhimurium [1],4,[5],12:i:1,2
S enterica subsp enterica ser Newport Newport 6,8,[20]:e,h:1,2
S enterica subsp enterica ser Paratyphi A Paratyphi A [1],2,12:a:[1,5]
S enterica subsp enterica ser Enteritidis Enteritidis [1],9,12:g,m:-
a
Species and subspecies are determined by biochemical reactions. Serotype is determined based on antigenic make-up. In the
­current ­taxonomy, only 2 species are recognized, Salmonella enterica and Salmonella bongori. S enterica has 6 subspecies, of which
­subspecies I (enterica) contains the overwhelming majority of all Salmonella pathogens that affect humans, other mammals, and birds.
b
Many Salmonella pathogens that previously were considered species (and, therefore, were written italicized with a small case first letter)
now are considered serotypes (also called serovars). Serotypes are now written nonitalicized with a capital first letter (eg, Typhi,
Typhimurium, Enteritidis). The serotype of Salmonella is determined by its O (somatic) and H (flagellar) antigens and whether Vi
is expressed.

ducks), reptiles or amphibians (eg, pet turtles, Age-specific incidences for nontyphoidal
iguanas, lizards, snakes, frogs, toads, newts, S­ almonella infection are highest in children
salamanders), and rodents (eg, hamsters, mice) younger than 4 years. In the United States,
or other mammals (eg, hedgehogs). Reptiles rates of invasive infections and mortality are
and amphibians that live in tanks or aquari- higher in infants, elderly people, and people
ums can contaminate the water. Small turtles with hemoglobinopathies (including sickle
with a shell length of less than 4 inches are a cell disease) and immunocompromising
well-known source of human Salmonella infec- ­con­ditions (eg, malignant neoplasms). Most
tions. Because of this risk, the US Food and reported cases are sporadic, but widespread
Drug Administration has banned the interstate outbreaks, including health care–associated
sale and distribution of these turtles since 1975. and institutional outbreaks, have been
Animal-derived pet foods and treats have also reported. The incidence of foodborne cases
been linked to Salmonella infections, especially of nontyphoidal Salmonella gastroenteritis
among young children. has diminished little in recent years.
Unlike nontyphoidal Salmonella serovars, Every year, nontyphoidal Salmonella organ-
the enteric fever serovars (Salmonella Typhi, isms are one of the most common causes of
Paratyphi A, Paratyphi B [sensu stricto]) are laboratory-confirmed cases of enteric disease
restricted to human hosts, in whom they cause reported by the Foodborne Diseases Active
clinical and subclinical infections. Chronic Surveillance Network.
human carriers (mostly involving chronic
A risk of transmission of infection to others
infection of the gallbladder but occasionally
persists for as long as an infected person
involving infection of the urinary tract) con­
excretes nontyphoidal Salmonella organisms.
stitute the reservoir in areas with endemic
Twelve weeks after infection with the most
infection. Infection with enteric fever serovars
common nontyphoidal Salmonella serovars,
implies ingestion of a food or water vehicle
approximately 45% of children younger than
contaminated by a chronic carrier or person
5 years excrete organisms, compared with 5%
with acute infection. Although typhoid fever
of older children and adults; antimicrobial
(300–400 cases annually) and paratyphoid
therapy can prolong excretion. Approximately
fever (~150 cases annually) are uncommon in
1% of adults continue to excrete nontyphoidal
the United States, these infections are highly
Salmonella organisms for more than 1 year.
endemic in many resource-limited countries,
particularly in Asia. Consequently, most
typhoid fever and paratyphoid fever infections
in residents of the United States are usually
acquired during international travel.

ERRNVPHGLFRVRUJ
518 SALMONELLA INFECTIONS

Incubation Period If antimicrobial therapy is initiated in


For nontyphoidal Salmonella gastroenteritis, patients with gastroenteritis, amoxicillin or
12 to 36 hours (range, 6–72 hours). For enteric trimethoprim-­sulfamethoxazole is recom-
fever, 7 to 14 days (range, 3–60 days). mended for susceptible strains. Resistance
to these antimicrobial agents is becoming
Diagnostic Tests more common, especially in resource-limited
Isolation of Salmonella organisms from cul- ­countries. In areas where ampicillin and
tures of stool, blood, urine, bile (including ­trimethoprim-sulfamethoxazole resistance
­duodenal fluid–containing bile), and material is common, a fluoroquinolone or azithro­
from foci of infection is diagnostic. Gastro­ mycin is usually effective. For patients with
enteritis is diagnosed by stool culture. Diag- localized invasive disease (eg, osteomyelitis,
nostic tests to detect Salmonella antigens by abscess, meningitis) or bacteremia in people
enzyme immunoassay, latex agglutination, infected with HIV, empirical therapy with
and monoclonal antibodies have been devel- ­ceftriaxone is recommended. Once anti­
oped, as have commercial immunoassays microbial susceptibility test results are avail-
that detect antibodies to antigens of enteric able, ampicillin or ceftriaxone for susceptible
fever serovars. Gene-based polymerase chain strains is ­recommended.
reaction diagnostic tests are also available in For invasive, nonfocal infections, such as
research laboratories. Multiplex polymerase ­bacteremia or septicemia, caused by nonty-
chain reaction platforms for detection of phoidal Salmonella or for enteric fever caused
­multiple viral, parasitic, and bacterial patho- by Salmonella Typhi, Paratyphi A, and Para­
gens, including Salmonella, have been licensed typhi B, 14 days of therapy is recommended,
for diagnostic use. although shorter courses (7–10 days) have
If enteric fever is suspected, blood, bone been effective. Therapy with a fluoroquinolone
­marrow, or bile culture is diagnostic because or azithromycin orally can be considered in
organisms are often absent from stool. The patients with uncomplicated infections for
­sensitivity of blood culture and bone marrow nontyphoidal Salmonella. For enteric fever
culture in children with enteric fever is approx- caused by Salmonella Typhi, therapy should
imately 60% and 90%, respectively. The combi- be administered parenterally for 14 days. For
nation of a single blood culture plus culture localized invasive disease (eg, osteomyelitis,
of bile (collected from a bile-stained duodenal meningitis), at least 4 to 6 weeks of therapy
string) is 90% sensitive in detecting Salmonella is recommended. Drugs of choice, route of
Typhi infection in children with clinical administration, and duration of therapy are
enteric fever. based on susceptibility of the organism, site
of infection, host, and clinical response. Multi-
Treatment drug-resistant isolates of Salmonella Typhi and
Antimicrobial therapy is usually not indicated Paratyphi A (exhibiting resistance to ampicil-
for patients with asymptomatic infection or lin, chloramphenicol, and trimethoprim-­
uncomplicated (noninvasive) gastroenteritis sulfamethoxazole) and strains with decreased
caused by nontyphoidal Salmonella serovars susceptibility to fluoroquinolones are common
because therapy does not shorten the duration in South and Southeast Asia and are increas-
of diarrheal disease and can prolong duration ingly found in travelers to areas with endemic
of fecal excretion. Although of unproven ben- infection. Invasive salmonellosis attributable
efit, antimicrobial therapy is recommended to strains with decreased fluoroquinolone sus-
for gastroenteritis caused by nontyphoidal ceptibility is associated with greater risk for
­Salmonella serovars in people at increased risk treatment failure. Azithromycin is an effective
of invasive disease, including infants younger alternative for people with uncomplicated
than 3 months and people with chronic gastro- infections. Relapse of nontyphoidal Salmonella
intestinal tract disease, malignant neoplasms, infection can occur, particularly in immuno-
hemoglobinopathies, HIV infection, or other compromised patients, who may require longer
immunosuppressive illnesses or therapies. duration of treatment and retreatment.

ERRNVPHGLFRVRUJ
SALMONELLA INFECTIONS 519

The propensity to become a chronic Salmonella Corticosteroids may be beneficial in patients


Typhi carrier (excretion >1 year) following with severe enteric fever, which is character-
acute typhoid infection correlates with preva- ized by delirium, obtundation, stupor, coma,
lence of cholelithiasis, increases with age, and or shock. These drugs should be reserved for
is greater in females than males. Chronic car- critically ill patients in whom relief of mani­
riage in children is uncommon. The chronic festations of toxemia may be lifesaving. The
carrier state may be eradicated by 4 weeks of usual regimen is high-dose dexamethasone
oral therapy with ciprofloxacin or norfloxacin, given intravenously.
antimicrobial agents that are highly concen-
trated in bile. High-dose parenteral ampicillin
can also be used if 4 weeks of oral fluoroquino-
lone therapy is not well tolerated.

Image 120.1
Salmonella species grown on blood agar plate. Courtesy of Rita Yee, MT(ASCP) SM.

Image 120.2
This image depicts the colonial growth pattern displayed by Salmonella enterica subsp arizonae grown
on blood agar, also known as S arizonae or Arizona hinshawii. Salmonella species are gram-negative,
aerobic, rod-shaped, zoonotic bacteria that can infect people, birds, reptiles, and other animals.
Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
520 SALMONELLA INFECTIONS

Image 120.3
Salmonellosis and shigellosis. Incidence, by year—United States, 1982–2012. Courtesy of Morbidity
and Mortality Weekly Report.

Image 120.4
Typhoid fever. Number of reported cases, by year, 1982–2012. Courtesy of Morbidity and Mortality
Weekly Report.

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SALMONELLA INFECTIONS 521

Image 120.5
This 2005 photograph depicts a young boy holding a box turtle, portraying a look of wonder­ment
mixed with curiosity, as the turtle looks on with almost a sense of nonchalance. The impor­tance of
this image lies in the reality that turtles carry Salmonella. The sale of turtles less than 4 inches in length
has been banned in the United States since 1975. The ban by the US Food and Drug Administration
has prevented an estimated 100,000 cases of salmonellosis annually in children. Courtesy of Centers
for Disease Control and Prevention/James Gathan.

Image 120.7
A young African American child with sickle cell
disease and Salmonella sepsis with swelling of
Image 120.6 the hands. Probable diagnosis: acute sickle cell
African dwarf frog. Salmonella infection can be dactylitis with septicemia. Copyright Martin G.
acquired through contact with reptiles and Myers, MD.
amphibians in homes, petting zoos, parks, child
care facilities, and other locations. Courtesy of
Centers for Disease Control and Prevention.

Image 120.9
Typhoid fever cholecystitis with an ulceration and
perforation of the gallbladder into the jejunum.
Salmonella ser Typhi, the bacterium responsible
for causing typhoid fever, has a preference for the
Image 120.8 gallbladder and, if present, will colonize the surface
A young child with sickle cell dactylitis of the of gallstones, which is how people become long-
foot and Salmonella sepsis. This is the same term carriers of the disease. Courtesy of Centers
patient as in Image 120.7. Copyright Martin G. for Disease Control and Prevention/Armed Forces
Myers, MD. Institute of Pathology, Charles N. Farmer.

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522 SALMONELLA INFECTIONS

Image 120.10
Osteomyelitis due to Salmonella infection of the
humeral shaft (diaphysis) in a 14-year-old African
American boy with sickle cell disease.

Image 120.11
Osteomyelitis (chronic) due to Salmonella
infection of the proximal femur.

Image 120.12
Osteomyelitis due to Salmonella infection of the distal tibia.

Image 120.13
A computed tomography scan showing a large brain abscess in the posterior parietal region as a
complication of Salmonella meningitis in a neonate.

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SALMONELLA INFECTIONS 523

Image 120.15
Image 120.14
Histopathologic changes in brain tissue due A photomicrograph demonstrating the histo­
to Salmonella ser Typhi meningitis. Salmonella patho­logic changes in brain tissue due to
septicemia has been associated with subsequent Salmonella ser Typhi bacteria. Salmonella
infection of virtually every organ system, and the septicemia has been associated with subse­
nervous system is no exception. Courtesy of quent infection of virtually every organ system,
Centers for Disease Control and Prevention/ and the nervous system is no exception. Here
Armed Forces Institute of Pathology, Charles we see an acute inflammatory encephalitis due
N. Farmer. to S Typhi bacteria. Courtesy of Centers for
Disease Control and Prevention.

Image 120.16
Salmonella pneumonia with empyema in a 3-year-old girl with congenital neutropenia who required
chest tube drainage and prolonged antibiotic treatment to control extensive pneumonia due to a
nontyphoidal Salmonella species. Courtesy of Edgar O. Ledbetter, MD, FAAP.

ERRNVPHGLFRVRUJ
524 Scabies

121 predominantly in an acral distribution, but


lesions can extend, to a lesser degree, onto
Scabies the torso.
Clinical Manifestations Etiology
Scabies is characterized by an intensely pruri­ The mite Sarcoptes scabiei subsp hominis is the
tic, erythematous, papular eruption caused by cause of scabies. The adult female burrows in
burrowing of adult female mites in upper layers the stratum corneum of the skin and lays eggs.
of the epidermis, creating serpiginous burrows. Larvae emerge from the eggs in 2 to 4 days and
Itching is most intense at night. In older chil- molt to nymphs and then to adults, which mate
dren and adults, the sites of predilection are and produce new eggs. The entire cycle takes
interdigital folds, flexor aspects of wrists, exten­ approximately 10 to 17 days. S scabiei subsp
sor surfaces of elbows, anterior axillary folds, canis, acquired from dogs (with clinical
waistline, thighs, navel, genitalia, areolae, mange), can cause a self-limited and mild
abdomen, intergluteal cleft, and buttocks. In infestation in humans usually involving the
children younger than 2 years, the eruption is area in direct contact with the infested animal
generally vesicular and often occurs in areas that will resolve without specific treatment.
usually spared in older children and adults,
such as the scalp, face, neck, palms, and soles. Epidemiology
The eruption is caused by a hypersensitivity Humans are the source of infestation. Trans-
reaction to the proteins of the parasite. mission usually occurs through prolonged
Characteristic scabietic burrows appear as close, personal contact. Because of the large
gray or white, tortuous, threadlike lines. Exco- number of mites in exfoliating scales, even
riations are common, and most burrows are minimal contact with a patient with crusted
obliterated by scratching before a patient seeks scabies can result in transmission; transmis-
medical attention. Occasionally, 2- to 5-mm sion from a patient with crusted scabies can
red-brown nodules are present, particularly on also occur through contamination of items
covered parts of the body, such as the genitalia, such as clothing, bedding, and furniture. Infes-
groin, and axilla. These scabies nodules are a tation acquired from dogs and other animals is
granulomatous response to dead mite antigens uncommon, and these mites do not replicate in
and feces; the nodules can persist for weeks humans. Scabies of human origin can be trans-
and even months after effective treatment. mitted as long as the patient remains infested
Cutaneous secondary bacterial infection can and untreated, including during the interval
occur and is usually caused by Streptococcus before symptoms develop. Scabies is endemic
pyogenes or Staphylococcus aureus. in many countries and occurs worldwide in
cycles thought to be 15 to 30 years long. Scabies
Crusted (Norwegian) scabies is an uncommon affects people from all socioeconomic levels
clinical syndrome characterized by a large without regard to age, gender, or standards of
num­ber of mites and widespread, crusted, personal hygiene. Scabies in adults often is
hyperkeratotic lesions. Crusted scabies usually acquired sexually.
occurs in people with debilitating conditions
or developmental disabilities or who are Incubation Period
immunocompromised. Crusted scabies can Without previous exposure, 4 to 6 weeks; if
also occur in otherwise healthy children after previously infested, 1 to 4 days.
long-term use of topical corticosteroid therapy.
Diagnostic Tests
Postscabetic pustulosis is a reactive phenom- Diagnosis is typically made by clinical exami-
enon that may follow successful treatment nation. Diagnosis can be confirmed by identi­
of primary infestation with scabies. Affected fication of the mite or mite eggs or scybala
infants and young children manifest episodic (feces) from scrapings of papules or intact
crops of sterile, pruritic papules and pustules ­burrows, preferably from the terminal portion

ERRNVPHGLFRVRUJ
Scabies 525

where the mite is generally found. Mineral oil, their entire body below the head. Because
microscope immersion oil, or water applied to s­ cabies can affect the face, scalp, and neck in
skin facilitates collection of scrapings. A broad- infants and young children, treatment of the
blade scalpel is used to scrape the burrow. entire head, neck, and body in this age group is
Scrapings and oil can be placed on a slide required. Special attention should be given to
under cover glass and examined microscopi- trimming fingernails and ensuring application
cally under low power. Adult female mites of medication to these areas. A Cochrane
average 330 to 450 µm in length. Skin scrapings review found oral ivermectin is effective for
provide definitive evidence of infection but treating scabies but less effective than topical
have low sensitivity. Handheld dermoscopy permethrin. Because ivermectin is not ovicidal,
(epiluminescence microscopy) has been used it is given as 2 doses, 1 week apart. Alternative
to identify in vivo the pigmented mite parts or drugs include 10% crotamiton cream or lotion
air bubbles corresponding to infesting mites or unapproved 5% to 10% precipitated sulfur
within the stratum corneum. compounded into petrolatum. Because scabi-
etic lesions are the result of a hypersensitivity
Treatment
reaction to the mite, itching may not subside
Topical permethrin 5% cream or oral ivermec- for several weeks despite successful treatment.
tin are effective agents for treatment of scabies. The use of oral antihistamines and topical
Most experts recommend starting with topical ­corticosteroids can help relieve this itching.
5% permethrin cream, particularly for infants, Topical or systemic antimicrobial therapy is
young children (not approved for children indicated for secondary bacterial infections
younger than 2 months), and pregnant or of the excoriated lesions. Because of safety
­nursing women. Permethrin cream should be ­concerns and availability of other treatments,
removed by bathing after 8 to 14 hours. Chil- lindane lotion should not be used as a first-line
dren and adults with infestation should apply agent in the treatment of scabies.
lotion or cream containing this scabicide over

Image 121.2
Image 121.1 Linear papulovesicular burrows often contain
This is a Sarcoptes scabiei subsp hominis, or itch female scabies mites when examined in mineral
mite, which is the cause of scabies. Females are oil, which confirms the diagnosis of scabies, as
0.3- to 0.4-mm long and 0.25- to 0.35-mm wide. shown here.
Male mites are slightly more than half that size.
Scabies is a highly contagious infestation of the
skin caused by a mite affecting humans and
animals. Scabies is usually transmitted by
intimate interpersonal contact, often sexual in
nature, but trans­mission through casual contact
can occur. Courtesy of Centers for Disease
Control and Prevention/Reed & Carnrick
Pharmaceuticals.

ERRNVPHGLFRVRUJ
526 Scabies

Image 121.3
Life cycle. Sarcoptes scabiei undergoes 4 stages in its life cycle: egg, larva, nymph, and adult.
Females deposit eggs at 2- to 3-day intervals as they burrow through the skin (1). Eggs are oval and
0.1 to 0.15 mm in length (2) and incubation time is 3 to 8 days. After the eggs hatch, the larvae migrate
to the skin surface and burrow into the intact stratum corneum to construct almost invisible, short
burrows called molting pouches. The larval stage, which emerges from the eggs, has only 3 pairs of
legs (3), and this form lasts 2 to 3 days. After larvae molt, the resulting nymphs have 4 pairs of legs (4).
This form molts into slightly larger nymphs before molting into adults. Larvae and nymphs may often
be found in molting pouches or in hair follicles and look similar to adults, only smaller. Adults are round,
saclike, eyeless mites. Females are 0.3- to 0.4-mm long and 0.25- to 0.35-mm wide, and males are
slightly more than half that size. Mating occurs after the nomadic male penetrates the molting pouch
of the adult female (5). Impregnated females extend their molting pouches into the characteristic
serpentine burrows, laying eggs in the process. The impregnated females burrow into the skin and
spend the remaining 2 months of their lives in tunnels under the surface of the skin. Males are rarely
seen. They make a temporary gallery in the skin before mating. Transmission occurs by the transfer
of ovigerous females during personal contact. Mode of transmission is primarily person-to-person
contact, but transmission may also occur via fomites (eg, bedding, clothing). Mites are found predom­
inantly between the fingers and on the wrists. The mites hold onto the skin using suckers attached to
the 2 most anterior pairs of legs. Courtesy of Centers for Disease Control and Prevention/Alexander J.
da Silva, PhD/Melanie Moser.

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Scabies 527

Image 121.4
A 2-year-old girl with scabies who was adopted from an orphanage in Eastern Europe. Courtesy of
Daniel P. Krowchuk, MD, FAAP.

Image 121.5
Papulopustules and a widespread eczematous eruption, which represents a hypersensitivity reaction
to a scabies infestation.

ERRNVPHGLFRVRUJ
528 Scabies

Image 121.6
Older children, adolescents, and adults with scabies exhibit erythematous papules, nodules, or
burrows in the interdigital webs, as in this patient.

Image 121.7
A 12-year-old with itching in the axillae and groin for 2 weeks. She recently returned from a family
camping trip, where she shared a tent with “dozens of cousins.” Since returning home, she has had
itching in the armpits and in her pubic area. She now has papules and pustules on the fingers, toes,
and her gluteal furrow. The family is reluctant to inquire about relatives with similar lesions. Examination
of scrapings of the lesions indicated a few oval structures suggestive of scabies eggs. She responded
to treatment with topical sulfur and oil in lieu of pesticide-based therapy. Courtesy of Will Sorey, MD.

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Schistosomiasis 529

122 Cercarial dermatitis (swimmer’s itch) is often


caused by larvae of schistosome parasites of
Schistosomiasis birds or other wildlife. These larvae can
Clinical Manifestations ­penetrate human skin but eventually die in
the dermis and do not cause systemic disease.
Infections are established by skin penetration Skin manifestations include pruritus at the
of infecting larvae (cercariae, shed by fresh­ penetration site a few hours after water expo-
water snails), which can be accompanied by sure, followed in 5 to 14 days by an intermit-
a transient, pruritic, papular rash (cercarial tent pruritic, sometimes papular, eruption.
dermatitis). After penetration, the parasites In previously sensitized people, more intense
enter the bloodstream, migrate through the papular eruptions may occur for 7 to 10 days
lungs, and eventually mature into adult worms after ­exposure.
that reside in the venous plexus that drains
the intestines or, in the case of Schistosoma Etiology
haematobium, the urogenital tract. Four to The trematodes (flukes) S mansoni, S ­japonicum,
8 weeks after exposure, an acute serum sick- Schistosoma mekongi, and Schistosoma inter­
nesslike illness (Katayama fever) can develop calatum cause intestinal schistosomiasis, and
that manifests as fever, malaise, cough, rash, S haematobium causes urogenital disease. All
abdominal pain, hepatosplenomegaly, diar- species have similar life cycles. Swimmer’s
rhea, nausea, lymphadenopathy, and eosino- itch is typically caused by various schistosome
philia. The severity of symptoms associated species that are parasitic only for birds and
with infection is related to the worm burden. wild mammals.
People with low to moderate worm burdens
may have only subclinical disease or relatively Epidemiology
mild manifestations, such as growth stunting Persistence of schistosomiasis depends on the
or anemia. Higher worm burdens are associ- presence of an appropriate snail as an inter­
ated with a range of symptoms caused pri­ mediate host. Eggs excreted in stool (S mansoni,
marily by inflammation and fibrosis triggered S japonicum, S mekongi, and S intercalatum) or
by the immune response to eggs produced urine (S haematobium) into freshwater hatch
by adult worms. Severe forms of intestinal into motile miracidia, which infect snails. After
schistosomiasis (Schistosoma mansoni and development and asexual replication in snails,
Schistosoma japonicum infections) can result cercariae emerge and penetrate the skin of
in hepatosplenomegaly, abdominal pain, humans in contact with water. Children are
bloody diarrhea, portal hypertension, ascites, commonly first infected when they accompany
esophageal varices, and hematemesis. Uro­ their mothers to lakes, ponds, and other open
genital schistosomiasis (S haematobium freshwater sources. School-aged children are
­infections) can result in the bladder becoming typically the most heavily infected people in
inflamed and fibrotic. Urinary tract symptoms the community because of prolonged wading
and signs include dysuria, urgency, terminal and swimming in infected waters. They are
microscopic and gross hematuria, secondary also important in maintaining transmission
urinary tract infections, hydronephrosis, and through behaviors such as uncontrolled def-
nonspecific pelvic pain. S haematobium is ecation and urination. Communicability lasts
­associated with lesions of the lower genital as long as infected snails are in the environ-
tract (vulva, vagina, and cervix) in women, ment or live eggs are excreted in the urine and
prostatitis and hematospermia in men, and feces of humans into freshwater sources with
certain forms of bladder cancer. Other organ appropriate snails. In the case of S japonicum,
systems can be involved; for example, eggs animals play an important zoonotic role (as a
can embolize in the lungs, causing pulmonary source of eggs) in maintaining the life cycle.
hypertension. Less commonly, eggs can lodge Infection is not transmissible by person-to-­
in the central nervous system, causing severe person contact or blood transfusion.
neurologic complications.

ERRNVPHGLFRVRUJ
530 Schistosomiasis

The distribution of schistosomiasis is focal examined by a concentration technique may


and limited by the presence of appropriate be needed before eggs are found, or eggs
snail vectors, infected human reservoirs, and may be seen in a biopsy of the rectal mucosa.
freshwater sources. S mansoni occurs through- S ­haematobium is diagnosed by examining
out tropical Africa, in parts of several urine for eggs. Egg excretion in urine often
­Caribbean islands, and in areas of Venezuela, peaks between 12:00 noon and 3:00 pm. Biopsy
Brazil, Suriname, and the Arabian Peninsula. of the bladder mucosa can be used to diagnose
S ­japonicum is found in China, the Philippines, this infection. Serologic tests, available through
and Indonesia. S haematobium occurs in the Centers for Disease Control and Prevention
Africa and the Middle East. S mekongi is and some commercial laboratories, can be
found in Cambodia and Laos. S intercalatum helpful for detecting light infections. However,
is found in West and Central Africa. Adult results of these antibody-based tests remain
worms of S mansoni can live as long as 30 years positive for many years and are not useful in
in the human host. Thus, schistosomiasis can differentiating ongoing infection from past
be diagnosed in patients many years after infection or reinfection.
they have left an area with endemic infection.
Swimmer’s itch can be difficult to differentiate
Immunity is incomplete, and reinfection
from other causes of dermatitis. A skin biopsy
occurs commonly. Swimmer’s itch can occur
may demonstrate larvae, but their absence does
in all regions of the world after exposure to
not exclude the diagnosis.
freshwater, brackish water, or salt water.
Treatment
Incubation Period
The drug of choice for schistosomiasis caused
Approximately 4 to 6 weeks for S japonicum,
by any species is praziquantel; the alternative
6 to 8 weeks for S mansoni, and 10 to 12 weeks
drug for S mansoni is oxamniquine, although
for S haematobium.
this drug is not available in the United States
Diagnostic Tests (it is used in some areas of Brazil). Praziquantel
Eosinophilia is common and may be intense in does not kill developing worms; therapy given
Katayama fever (acute schistosomiasis). Infec- within 4 to 8 weeks of exposure should be
tion with S mansoni and other species (except repeated 1 to 2 months later to improve the rate
S haematobium) is determined by microscopic of parasitologic cure. Swimmer’s itch is a self-
examination of stool specimens to detect char- limited disease that may require symptomatic
acteristic eggs, but results may be negative if treatment of the rash. More intense reactions
performed too early in the course of infection. may require a course of oral corticosteroids.
In light infections, several stool specimens

Image 122.1
This micrograph depicts an egg from a Schistosoma haematobium trematode parasite (magnification
x500). Note the egg’s posteriorly protruding terminal spine, unlike the spinal remnant, which protrudes
from the lateral wall of the Schistosoma japonicum egg. These eggs are eliminated in an infected human’s
feces or urine and, under optimal conditions in a watery environment, the eggs hatch and release mira­
cidia, which then penetrate a specific snail intermediate host. Once inside the host, the S haematobium
parasite passes through 2 developmental generations of sporocysts and Is released by the snail into
its environment as cercariae. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Schistosomiasis 531

Image 122.2
A–D, Schistosoma haematobium eggs. In this species, the eggs are large and have a prominent
terminal spine at the posterior end (length, 112–170 µm). B, The miracidium is shown inside the egg.
Courtesy of Centers for Disease Control and Prevention.

Image 122.3
Geographic distribution of schistosomiasis. Centers for Disease Control and Prevention National
Center for Emerging and Zoonotic Infectious Diseases (NCEZID) Division of Global Migration and
Quarantine (DGMQ).

ERRNVPHGLFRVRUJ
532 Schistosomiasis

Image 122.4
Life cycle. Eggs are eliminated with feces or urine (1). Under optimal conditions, the eggs hatch and
release miracidia (2), which swim and penetrate specific snail intermediate hosts (3). The stages in
the snail include 2 generations of sporocysts (4) and the production of cercariae (5). On release
from the snail, the infective cercariae swim, penetrate the skin of the human host (6), and shed their
forked tail, becoming schistosomulae (7). The schistosomulae migrate through several tissues and
stages to their residence in the veins (10). Adult worms in humans reside in the mesenteric venules
in various locations, which, at times, seem to be specific for each species (10). For instance,
Schistosoma japonicum is more frequently found in the superior mesenteric veins draining the small
intestine (A), and Schistosoma mansoni occurs more often in the superior mesenteric veins draining
the large intestine (B). However, both species can occupy either location, and they are capable of
moving between sites, so it is not possible to state unequivocally that one species only occurs in
one location. Schistosoma haematobium most often occurs in the venous plexus of the bladder (C),
but it can also be found in the rectal venules. The females (size 7–20 mm; males slightly smaller)
deposit eggs in the small venules of the portal and perivesical systems. The eggs are moved
progressively toward the lumen of the intestine (S mansoni and S japonicum) and of the bladder
and ureters (S haematobium) and are eliminated with feces or urine, respectively (1). Pathology of
S mansoni and S japonicum schistosomiasis includes Katayama fever, presinusoidal egg granulomas,
Symmers pipestem periportal fibrosis, portal hypertension, and occasional embolic egg granulomas
in the brain or spinal cord. Pathology of S haematobium schistosomiasis includes hematuria, scarring,
calcification, squamous cell carcinoma, and occasional embolic egg granulomas in the brain or spinal
cord. Human contact with water is, thus, necessary for infection by schistosomes. Various animals,
such as dogs, cats, rodents, pigs, horses, and goats, serve as reservoirs for S japonicum, and dogs
for S mekongi. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Schistosomiasis 533

Image 122.5
A boy with swollen abdomen due to schistosomiasis with hepatosplenomegaly. Courtesy of
Immunization Action Coalition.

Image 122.6
Schistosome dermatitis, or swimmer’s itch, occurs when skin is penetrated by a free-swimming, fork-
tailed infective cercaria. On release from the snail host, the infective cercariae swim, penetrate the skin
of the human host, and shed their forked tail, becoming schistosomulae. The schistosomulae migrate
through several tissues and stages to their residence in the veins. Courtesy of Centers for Disease
Control and Prevention.

Image 122.7
A–C, Cross-section of different human tissues showing Schistosoma species eggs. A, Schistosoma
mansoni eggs in intestinal wall. B, Schistosoma japonicum eggs in colon. C, S japonicum eggs in liver.
Courtesy of Centers for Disease Control and Prevention.

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534 Schistosomiasis

Image 122.8
A–B, Cross-section of different human tissues showing Schistosoma species eggs. Schistosoma
species in liver and bladder, respectively. Courtesy of Centers for Disease Control and Prevention.

Image 122.9 Image 122.10


Histopathology of the bladder shows eggs of This micrograph reveals signs of schistosomiasis
Schistosoma haematobium surrounded by infection of the liver, also known as pipestem
intense infiltrates of eosinophils and other inflam­ cirrhosis (magnification x500). Pipestem cirrhosis
matory cells. Courtesy of Centers for Disease occurs when schistosomes infect the liver
Control and Prevention/Edwin P. Ewing Jr, MD. (ie, hepatic schistosomiasis), which causes
scarring to occur, thereby entrapping parasites
and their ova in and around the hepatic portal
circulatory vessels. Courtesy of Centers for
Disease Control and Prevention.

Image 122.11
Histopathology of Schistosomiasis haematobia,
bladder. Histopathology of the bladder shows
eggs of S haematobium surrounded by intense
infiltrates of eosinophils. Courtesy of Centers for
Disease Control and Prevention/Edwin P. Ewing
Jr, MD.

ERRNVPHGLFRVRUJ
SHIGELLA INFECTIONS 535

123 the colonic mucosa and can cause small blood


vessel and renal damage, leading to hemolytic
Shigella Infections uremic syndrome.
Clinical Manifestations Epidemiology
Shigella species primarily infect the large Humans are the natural host for Shigella
­intestine, causing clinical manifestations that organisms, although other primates can be
range from watery or loose stools with mini- infected. The primary mode of transmission
mal or no constitutional symptoms to more is fecal-oral, although transmission can also
severe symptoms, including high fever, abdom- occur via contact with a contaminated inani-
inal cramps or tenderness, tenesmus, and mate object, ingestion of contaminated food
mucoid stools with or without blood. Shigella or water, or sexual contact. Houseflies may
­dysenteriae serotype 1 often causes a more also be vectors through physical transport of
severe illness than other shigellae with a higher infected feces. Ingestion of as few as 10 organ-
risk of complications, including septicemia, isms, depending on the species, is sufficient
pseudomembranous colitis, toxic megacolon, for infection to occur. Prolonged organism
intestinal perforation, hemolysis, and hemo- survival in water (up to 6 months) and food
lytic uremic syndrome. Infection attributable (up to 30 days) can occur with Shigella. Chil-
to S dysenteriae 1 has become rare in industri- dren 5 years or younger in child care settings
alized countries. Generalized seizures have and their caregivers, people living in crowded
been reported among young children with conditions, and men who have sex with men
shigellosis attributable to any serotype; are at increased risk of infection. Infections
although the pathophysiology and incidence attributable to S flexneri, S boydii, and
are poorly understood, such seizures are S ­dysenteriae are more common in older chil-
­usually self-limited and associated with high dren and adults than are infections attributable
fever or electrolyte abnormalities. Septicemia to S sonnei in the United States; nonetheless,
is rare during the course of illness and is more than 25% of cases caused by each species
caused by Shigella organisms or by other are reported among children younger than
gut flora that gain access to the bloodstream 5 years. Travel to resource-limited countries
through intestinal mucosa damaged during with inadequate sanitation can place travelers
shigellosis. Septicemia occurs most often in at risk of infection. Even without antimicrobial
neonates, malnourished children, and people therapy, the carrier state usually ceases within
with S dysenteriae 1 infection. Reactive arthri- 1 to 4 weeks after onset of illness; long-term
tis with possible extraarticular manifestations carriage is uncommon and does not correlate
is a rare complication that can develop weeks with underlying intestinal dysfunction.
or months after shigellosis, especially in
patients expressing HLA-B27. Incubation Period

Etiology 1 to 3 days; range, 1 to 7 days.

Shigella species are facultative aerobic, gram- Diagnostic Tests


negative bacilli in the family Enterobacteriaceae. Isolation of Shigella organisms from feces or
Four species (with more than 40 serotypes) rectal swab specimens containing feces is
have been identified. Among Shigella isolates ­diagnostic; sensitivity is improved by testing
reported in the United States in 2012, approx­ stool as soon as possible after it is passed. The
imately 81% were Shigella sonnei, 17% were presence of fecal lactoferrin (or fecal leuko-
­Shigella flexneri, 1% was Shigella boydii, and cytes) demonstrated on a methylene-blue–
less than 1% was other species. In resource-­ stained stool smear is fairly sensitive for the
limited countries, especially in Africa and diagnosis of colitis but is not specific for
Asia, S flexneri predominates, and S ­dysenteriae ­shigellosis. Although bacteremia is rare,
often causes outbreaks. Shiga toxin is ­produced blood should be cultured in children who
by S dysenteriae 1, which enhances virulence at are severely ill, immunocompromised, or
­malnourished. Multiplex polymerase chain

ERRNVPHGLFRVRUJ
536 SHIGELLA INFECTIONS

reaction platforms for detection of multiple resistant to ciprofloxacin, and 1.1% was resis-
bacterial, viral, and parasitic pathogens, tant to ceftriaxone. Ciprofloxacin and ceftriax-
including Shigella, are commercially available. one resistance is increasing around the world.
Treatment For cases in which treatment is required
Although severe dehydration is rare with and susceptibilities are unknown or an
­shigellosis, correction of fluid and electrolyte ­ampicillin- and trimethoprim-sulfamethoxazole–
losses, preferably by oral rehydration solutions, resistant strain is isolated, parenteral ceftriax­
is the mainstay of treatment. Most clinical one for 2 to 5 days, a fluoroquinolone (eg,
infections with S sonnei are self-limited (48– ­ciprofloxacin) for 3 days, or azithromycin for
72 hours), and mild episodes do not require 3 days should be administered. Oral cephalo-
antimicrobial therapy. Available evidence sug- sporins (eg, cefixime) have been used suc­
gests antimicrobial therapy is somewhat effec- cessfully in ­treating shigellosis in adults. For
tive in shortening duration of diarrhea and susceptible strains, ampicillin or trimethoprim-
hastening eradication of organisms from feces. ­sulfamethoxazole for 5 days is effective; amoxi-
Treatment is recommended for patients with cillin is not effective because of its rapid
severe disease or with underlying immuno­ absorption from the gastrointestinal tract.
suppressive conditions; in these patients, The oral route of therapy is recommended
empiric therapy should be given while awaiting except for seriously ill patients.
culture and susceptibility results. Antimicro- Antidiarrheal compounds that inhibit intes­
bial susceptibility testing of clinical isolates is tinal peristalsis are contraindicated because
indicated because resistance to antimicrobial they can prolong the clinical and bacteriologic
agents is common and susceptibility data course of disease and can increase the rate
can guide appropriate therapy. In 2012 in the of complications.
United States, approximately 25% of Shigella
species were resistant to ampicillin, 43% were Nutritional supplementation, including vita-
resistant to trimethoprim-sulfamethoxazole, min A and zinc orally daily, can be given to
4% were resistant to azithromycin, 2% were hasten clinical resolution in geographic areas
where children are at risk of malnutrition.

Image 123.1
Culture of Shigella sonnei grown on a blood agar plate. Courtesy of Rita Yee, MT(ASCP) SM.

ERRNVPHGLFRVRUJ
SHIGELLA INFECTIONS 537

Image 123.2
Gram stain of Shigella sonnei from Image 123.1 (magnification x100). Courtesy of Rita Yee, MT(ASCP)
SM.

Image 123.3
Salmonellosis and shigellosis. Incidence, by year—United States, 1982–2012. Courtesy of Morbidity
and Mortality Weekly Report.

ERRNVPHGLFRVRUJ
538 SHIGELLA INFECTIONS

Image 123.4
Characteristic bloody mucoid stool of a child with shigellosis.

Image 123.5
Fecal leukocytes (shigellosis) (methylene-blue stain). The presence of fecal leukocytes suggests
a bacterial diarrhea, although not specific for Shigella infection. Courtesy of Edgar O. Ledbetter,
MD, FAAP.

ERRNVPHGLFRVRUJ
Smallpox (Variola) 539

124 involve the forearms, trunk, and legs, with the


greatest concentration of lesions on the face
Smallpox (Variola) and distal extremities. Most patients will have
The last naturally occurring case of smallpox lesions on the palms and soles. With rash
occurred in Somalia in 1977, followed by 2 cases onset, fever decreases but does not resolve.
in 1978 after a photographer was infected dur- Lesions begin as macules that progress to
ing a laboratory exposure and later transmitted ­papules, followed by firm vesicles and then
smallpox to her mother in the United King- deep-seated, hard pustules described as
dom. In 1980, the World Health Assembly “pearls of pus.” Each stage lasts 1 to 2 days.
declared that smallpox (variola virus) had been By the sixth or seventh day of rash, lesions
eradicated successfully worldwide. The United may begin to umbilicate or become confluent.
States discontinued routine childhood immu- Lesions increase in size for approximately 8 to
nization against smallpox in 1972 and routine 10 days, after which they begin to crust. Once
immunization of health care professionals in all the crusts have separated, 3 to 4 weeks
1976. Immunization of US military personnel after the onset of rash, the patient is no longer
continued until 1990. Following eradication, infectious. Variola minor strains cause a dis-
2 World Health Organization reference labora- ease that is indistinguishable clinically from
tories were authorized to maintain stocks of variola major, except it causes less severe sys-
variola virus. As a result of terrorism events temic symptoms, more rapid rash evolution,
on September 11, 2001, and concern that the reduced scarring, and fewer fatalities.
virus and the expertise to use it as a weapon of Varicella (chickenpox) is the condition most
bioterrorism may have been misappropriated, likely to be mistaken for smallpox. Generally,
the smallpox immunization policy was revis- children with varicella do not have a febrile
ited. In 2002, the United States resumed immu- prodrome, but adults can have a brief, mild
nization of military personnel deployed to prodrome. Although the 2 diseases are con-
certain areas of the world, and in 2003, the fused easily in the first few days of the rash,
United States initiated a civilian smallpox smallpox lesions develop into pustules that
immunization program for first responders are firm and deeply embedded in the dermis,
to facilitate preparedness and response to a whereas varicella lesions develop into super­
possible smallpox bioterrorism event. ficial vesicles. Because varicella erupts in crops
Clinical Manifestations of lesions that evolve quickly, lesions on any
one part of the body will be in different stages
People infected with variola major strains of evolution (papules, vesicles, and crusts),
develop a severe prodromal illness character- whereas all smallpox lesions on any one part of
ized by high fever (38.9°C–40.0°C [102°F–104°F]) the body are in the same stage of development.
and constitutional symptoms, including mal- The rash distribution of the 2 diseases differs;
aise, severe headache, backache, abdominal varicella most commonly affects the face and
pain, and prostration, lasting for 2 to 5 days. trunk, with relative sparing of the extremities,
Infected children can suffer from vomiting and lesions on the palms or soles are rare.
and seizures during this prodromal period.
Most patients with smallpox are severely ill Variola major in unimmunized people is asso-
and bedridden during the febrile prodrome. ciated with case-fatality rates of 30% during
The prodromal period is followed by develop- epidemics of smallpox. The mortality rate is
ment of lesions on mucosa of the mouth or highest in pregnant women, children younger
pharynx, which may not be noticed by the than 1 year, and adults older than 30 years.
patient. This stage occurs less than 24 hours
In addition to the typical presentation of small-
before onset of rash, which is usually the first
pox (≥90% of cases), there are 2 uncommon
recognized manifestation of infectiousness.
forms of variola major: hemorrhagic (charac-
With onset of oral lesions, the patient becomes
terized by a hemorrhagic diathesis prior to
infectious and remains so until all skin crust
onset of the typical smallpox rash [early hem-
lesions have separated. The rash typically
orrhagic smallpox] or by ­hemorrhage into skin
begins on the face and rapidly progresses to

ERRNVPHGLFRVRUJ
540 Smallpox (Variola)

lesions and disseminated intravascular coagu- rates for smallpox were considerably lower
lation [late hemorrhagic smallpox]) and malig- than for measles and similar to or lower than
nant or flat type (in which the skin lesions do rates for varicella.
not progress to the pustular stage but remain
Incubation Period
flat and soft). Each variant occurs in approxi-
mately 5% of cases and is associated with a 95% 7 to 17 days; mean, 12 days.
to 100% mortality rate.
Diagnostic Tests
Etiology Variola virus can be detected in vesicular or
Variola is a member of the Poxviridae family pustular fluid by a number of different meth-
(genus Orthopoxvirus). Other members of this ods, including electron microscopy, immuno-
genus that can infect humans include monkey- histochemistry, culture, or polymerase chain
pox virus, cowpox virus, and vaccinia virus. reaction assay. Only polymerase chain reaction
In 2003, an outbreak of monkeypox linked to assay can diagnose infection with variola virus
prairie dogs exposed to rodents imported from definitively; all other methods simply screen
Ghana occurred in the United States. for orthopoxviruses. Diagnostic evaluation
includes exclusion of varicella-zoster virus or
Epidemiology other common conditions that cause a vesicu-
Humans are the only natural reservoir for lar or pustular rash illness.
­variola virus (smallpox). Smallpox is spread
Treatment
most commonly in droplets from the orophar-
ynx of infected people, although rare transmis- There is no known effective antiviral therapy
sion from aerosol spread has been reported. available to treat smallpox. Infected patients
Infection from direct contact with lesion should receive supportive care. Cidofovir, a
­material or indirectly via fomites, such as nucleotide analogue of cytosine, has demon-
clothing and bedding, has also been reported. strated antiviral activity against certain ortho-
Because most patients with smallpox are poxviruses in vitro and in animal models. Its
extremely ill and bedridden, spread is generally effectiveness in treatment of variola in humans
limited to household contacts and health care is unknown.
professionals. Secondary household attack

Image 124.1
A transmission electron micrograph of a tissue section containing variola virus. Smallpox is a serious,
highly contagious, and, sometimes, fatal infectious disease. There is no specific treatment for smallpox
disease, and the only prevention is vaccination. Courtesy of Centers for Disease Control and Prevention/
Fred Murphy; Sylvia Whitfield.

ERRNVPHGLFRVRUJ
Smallpox (Variola) 541

Image 124.2
Smallpox in a 2-year-old boy demonstrating commonplace greater density of lesions on the face as
compared with the child’s body. Courtesy of Paul Wehrle, MD.

Image 124.3
Variola minor lesions on the face of a 2-year-old Latin American boy. Courtesy of Paul Wehrle, MD.

ERRNVPHGLFRVRUJ
542 Smallpox (Variola)

Image 124.4
A 7-year-old boy residing in India with smallpox
lesions in a typical centripetal distribution.
Courtesy of Paul Wehrle, MD.

Image 124.5
This young girl in Bangladesh was infected with
smallpox in 1973. Freedom from smallpox was
declared in Bangladesh in December 1977
when a World Health Organization International
Commission officially certified that smallpox had
been eradicated from that country. Courtesy of
Centers for Disease Control and Prevention/
James Hicks.

Image 124.6
This photograph reveals the back of a Nigerian
child with smallpox. Note the pustules are Image 124.7
centripetal in distribution, radiating from their Numerous healing smallpox lesions on the feet of
densest area of eruption on the upper back and a young child. Courtesy of Edgar O. Ledbetter,
outward along the extremities. All the skin lesions MD, FAAP.
are at the same stage of development. Courtesy
of Centers for Disease Control and Prevention/
Dr Lyle Conrad.

ERRNVPHGLFRVRUJ
Smallpox (Variola) 543

Image 124.9
Day 4 of smallpox eruption in a young child.
People with smallpox become infectious with
Image 124.8 the onset of exanthema and remain most
Day 2 of smallpox eruption in a young child. infectious throughout the initial 7 to 10 days
Courtesy of Centers for Disease Control of the rash. Courtesy of Centers for Disease
and Prevention. Control and Prevention.

Image 124.10
Multiple secondary vaccinia lesions from autoinoculation in a 5-year-old white girl, one of the more
common complications of smallpox vaccination. Courtesy of George Nankervis, MD.

ERRNVPHGLFRVRUJ
544 Smallpox (Variola)

Image 124.11
The child on the left has a contact vaccinia lesion next to her left eye from her twin sister (August 24,
1974; photographed August 31, 1974). After receiving a smallpox vaccination, it is imperative the
recipient take precautions to avoid transmitting the virus to another person, called contact vaccinia,
or to other regions of his or her own body, called autoinoculation. Courtesy of Centers for Disease
Control and Prevention/James Mitchell, MD/California Emergency Preparedness Office (Calif/EPO).

Image 124.12
Due to progressive vaccinia, this patient required a graft to correct the necrotic vaccination site.
Progressive vaccinia (formerly called vaccinia gangrenosum) is one of the most severe complications
of smallpox vaccination, and it is almost always life-threatening. Those who are most susceptible to
this condition are the immunosuppressed. Courtesy of Centers for Disease Control and Prevention/
Allen W. Mathies, MD/California Emergency Preparedness Office (Calif/EPO), Immunization Branch.

ERRNVPHGLFRVRUJ
Sporotrichosis 545

125 The related species Sporothrix brasiliensis,


­Sporothrix globosa, and Sporothrix mexicana
Sporotrichosis also cause human infection.
Clinical Manifestations Epidemiology
There are 3 cutaneous patterns described for S schenckii is a ubiquitous organism that has
sporotrichosis. The classic lymphocutaneous worldwide distribution but is most common
process with multiple nodules is most com- in tropical and subtropical regions of Central
monly seen in adults. Inoculation occurs at a and South America and parts of North Amer-
site of minor trauma, causing a painless pap- ica and Japan. The fungus is isolated from soil
ule that enlarges slowly to become a nodular and plant material, including hay, straw, sphag-
lesion that can develop a violaceous hue or num moss, and decaying vegetation. Thorny
can ulcerate. Secondary lesions follow the plants, such as roses and Christmas trees, are
same evolution and develop along the lym- commonly implicated because pricks from
phatic distribution proximal to the initial their thorns or needles inoculate the organism
lesion. A localized cutaneous form of sporo­ from the soil or moss around the bush or tree.
trichosis, also called fixed cutaneous form, is People engaging in gardening or farming are
most commonly seen in children and presents at risk of infection. Inhalation of conidia can
as a solitary crusted papule or papuloulcerative lead to pulmonary disease. Zoonotic spread
or nodular lesion in which lymphatic spread from infected cats or scratches from digging
is not observed. The extremities and face are animals, such as armadillos, has led to cutane-
the most common sites of infection. A dis­ ous disease.
seminated cutaneous form with multiple
lesions is rare, usually occurring in children Incubation Period
who are immunocompromised. 7 to 30 days after cutaneous inoculation, but
Extracutaneous sporotrichosis is uncommon, can be as long as 3 months.
with cases occurring primarily in immuno- Diagnostic Tests
compromised patients or, in adults, those
Culture of Sporothrix species from a tissue,
who are alcoholic or have chronic obstructive
wound drainage, or sputum specimen is diag-
pulmonary disease. Osteoarticular infection
nostic. Culture of Sporothrix species from a
results from hematogenous spread or local
blood specimen is definite evidence for the
inoculation. The most commonly affected
disseminated form of infection associated with
joints are the knee, elbow, wrist, and ankle.
immunodeficiency. Histopathologic examina-
Pulmonary sporotrichosis clinically resembles
tion of tissue may not be helpful because the
tuberculosis and occurs after inhalation or
organism seldom is abundant. Special fungal
aspiration of aerosolized conidia. Dissemi-
stains to visualize the oval or cigar-shaped
nated disease generally occurs after hema­
organism are required. Serologic testing and
togenous spread from primary skin or lung
polymerase chain reaction assay show promise
infection. Disseminated sporotrichosis can
for accurate and specific diagnosis but are
involve multiple foci (eg, eyes, pericardium,
available only in research laboratories.
genitourinary tract, central nervous system)
and occurs predominantly in immunocom­ Treatment
promised patients. Pulmonary and dissemi-
Sporotrichosis does not usually resolve with-
nated forms of sporotrichosis are uncommon
out treatment. Itraconazole is the drug of
in ­children.
choice for children with lymphocutaneous
Etiology and localized cutaneous disease. The duration
of therapy is 2 to 4 weeks after all lesions have
Sporothrix schenckii is a thermally dimorphic
resolved. Saturated solution of potassium
fungus that grows as a mold or mycelial form
iodide is an alternative therapy. Oral flucon-
at room temperature and as a yeast at 35°C
azole should be used only if the patient cannot
to 37°C (95°F–99°F) and in host tissues.
tolerate other agents.
S schenckii is a complex of at least 6 species.

ERRNVPHGLFRVRUJ
546 Sporotrichosis

Amphotericin B is recommended as the initial may be required for lifelong therapy in chil-
therapy for visceral or disseminated sporotri- dren with HIV infection. Pulmonary and dis-
chosis in children. After clinical response to seminated infections respond less well than
amphotericin B therapy is documented, itra- cutaneous infection, despite prolonged therapy.
conazole can be substituted and should be Surgical debridement or excision may be neces-
­continued for at least 12 months. Itraconazole sary to resolve cavitary pulmonary disease.

Image 125.2
Image 125.1
This micrograph is taken from a slant culture Sporothrix schenckii, mold phase (48-hour potato
of Sporothrix schenckii during its yeast phase. dextrose agar, lactophenol cotton blue prepara­
Courtesy of Centers for Disease Control tion); small tear-shaped conidia forming rosette­
and Prevention/Dr Lucille K. Georg. like clusters. Courtesy of Centers for Disease
Control and Prevention.

Image 125.3
Image 125.4
This is an image of a Sabhi agar plate culture of
This patient’s arm shows the effects of the fungal
Sporothrix schenckii grown at 20°C (68°F). S
disease sporotrichosis, caused by the fungus
schenckii is the causative agent for the fungal
Sporothrix schenckii. Courtesy of Centers for
infection sporotrichosis, also known as “rose
Disease Control and Prevention/Dr Lucille
handler’s disease,” which affects individuals
K. Georg.
who handle thorny plants, sphagnum moss,
or baled hay. Courtesy of Centers for Disease
Control and Prevention.

ERRNVPHGLFRVRUJ
Sporotrichosis 547

Image 125.5
Sporothrix schenckii was cultured from the biopsy specimen from an abscessed cervical lymph node
of this 10-year-old boy. Test results on stained smears of purulent material aspirated from a cervical
lymph node were negative.

Image 125.6 Image 125.7


Anterior cervical sporotrichosis lesions of an Cutaneous sporotrichosis of the face in a
adolescent sister of the patient in Image 125.5. preschool-aged child. Courtesy of Edgar O.
Ledbetter, MD, FAAP.

ERRNVPHGLFRVRUJ
548 Staphylococcal Infections

126 superantigen that stimulates production of


tumor necrosis factor and other mediators that
Staphylococcal Infections cause capillary leak, leading to hypotension
Clinical Manifestations and multiorgan failure. Staphylococcal TSS is
characterized by acute onset of fever, general-
Staphylococcus aureus ized erythroderma, rapid-onset hypotension,
Staphylococcus aureus causes a variety of and signs of multisystem organ involvement,
­localized and invasive suppurative infections including profuse watery diarrhea, vomiting,
and 3 toxin-mediated syndromes: toxic shock conjunctival injection, and severe myalgia
syndrome (TSS), scalded skin syndrome, and (Box 126.1). Although approximately 50% of
food poisoning. Localized infections include reported cases of staphylococcal TSS occur in
cellulitis, skin and soft tissue abscesses, pus­ menstruating females using tampons, non-
tulosis, impetigo (bullous and nonbullous), menstrual TSS cases occur after childbirth or
paronychia, mastitis, ecthyma, erythroderma, abortion, after surgical procedures, and in
hordeola, furuncles, carbuncles, peritonsillar association with cutaneous lesions. Toxic
abscesses (quinsy), omphalitis, parotitis, shock syndrome can also occur in males and
lymphadenitis, and wound infections. S aureus females without a readily identifiable focus of
also causes invasive infections with bacteremia infection. Prevailing clones (eg, USA300) of
associated with foreign bodies, including intra- community-associated methicillin-resistant
vascular catheters or grafts, peritoneal cath- S aureus (MRSA) rarely produce TSS toxin.
eters, cerebrospinal fluid (CSF) shunts, spinal People with TSS, especially menses-associated
instrumentation or intramedullary rods, pres- illness, are at risk of a recurrent episode.
sure equalization tubes, pacemakers and other Staphylococcal scalded skin syndrome (SSSS)
intracardiac devices, and prosthetic joints. is a toxin-mediated disease caused by circula-
Bacteremia can be complicated by septicemia; tion of exfoliative toxins A and B. Manifesta-
osteomyelitis; arthritis; endocarditis; pneumo- tions of SSSS are age related and include Ritter
nia; pleural empyema; pericarditis; soft tissue, disease (generalized exfoliation) in the neo-
muscle, or visceral abscesses; septic thrombo- nate, a tender scarlatiniform eruption and
phlebitis of small and large vessels; and other localized bullous impetigo in older children,
foci of infection. Primary S aureus pneumonia or a combination of these with thick white/
can also occur after aspiration of organisms brown flaky desquamation of the entire skin,
from the upper respiratory tract and is typi- especially on the face and neck, in older infants
cally associated with mechanical ventilation or and toddlers. The hallmark of SSSS is the
viral infections in the community (eg, influ- toxin-mediated cleavage of the stratum granu-
enza). Meningitis is rare unless accompanied losum layer of the epidermis (ie, Nikolsky
by an intradermal foreign body (eg, ventri­ sign). Healing occurs without scarring. Bacter­
culoperitoneal shunt) or a congenital or emia is rare, but dehydration and superinfec-
acquired defect in the dura. S aureus infections tion can occur with extensive exfoliation.
can be fulminant and are often associated with
metastatic foci and abscess formation, requir- Coagulase-Negative Staphylococci
ing drainage, foreign body removal, and pro-
Most coagulase-negative staphylococci (CoNS)
longed antimicrobial therapy to achieve cure.
isolates from patient specimens represent con-
Certain chronic diseases, such as diabetes
tamination of culture material. Of the isolates
­mellitus, malignancy, prematurity, immuno­
that do not represent contamination, most
deficiency, nutritional disorders, surgery, and
come from infections associated with health
transplantation, increase the risk for severe
care, such as patients with obvious disruptions
S aureus ­infections.
of host defenses caused by surgery, medical
Staphylococcal TSS, a toxin-mediated disease, device insertion, immunosuppression, or
is caused by strains producing TSS toxin-1 or developmental maturity (eg, very low birth
possibly other related staphylococcal entero- weight neonates). Coagulase-negative staphylo-
toxins. Toxic shock syndrome toxin-1 acts as a cocci are the most common cause of late-onset

ERRNVPHGLFRVRUJ
Staphylococcal Infections 549

Box 126.1
Staphylococcus aureus Toxic Shock Syndrome: Clinical Case Definition

Clinical Findings
• Fever: temperature 38.9°C (102.0°F) or greater
• Rash: diffuse macular erythroderma
• Desquamation: 1–2 wk after onset, particularly on palms, soles, fingers, and toes
• Hypotension: systolic pressure 90 mm Hg or less for adults; lower than fifth percentile for
age for children younger than 16 y; orthostatic drop in diastolic pressure of 15 mm Hg or
greater from lying to sitting; orthostatic syncope or orthostatic dizziness
• Multisystem organ involvement: 3 or more of
1. Gastrointestinal tract: vomiting or diarrhea at onset of illness
2. Muscular: severe myalgia or creatinine phosphokinase concentration greater than twice
the upper limit of reference range
3. Mucous membrane: vaginal, oropharyngeal, or conjunctival hyperemia
4. Renal: serum urea nitrogen or serum creatinine concentration greater than twice the upper
limit of reference range or urinary sediment with 5 white blood cells/high-power field or
greater in the absence of urinary tract infection
5. Hepatic: total bilirubin, aspartate transaminase, or alanine transaminase concentration
greater than twice the upper limit of reference range
6. Hematologic: platelet count 100,000/mm3 or less
7. Central nervous system: disorientation or alterations in consciousness without focal
­neurologic signs when fever and hypotension are absent

Laboratory Criteria
• Negative results on the following tests, if obtained:
1. Blood, throat, or cerebrospinal fluid cultures; blood culture may be positive for
­Staphylococcus aureus
2. Serologic tests for Rocky Mountain spotted fever, leptospirosis, or measles

Case Classification
• Probable: a case that meets the laboratory criteria and in which 4 of 5 clinical findings are
present
• Confirmed: a case that meets laboratory criteria and all 5 of the clinical findings, including
desquamation, unless the patient dies before desquamation occurs

Adapted from Wharton M, Chorba TL, Vogt RL, Morse DL, Buehler JW. Case definitions for public health surveillance. MMWR Recomm Rep.
1990;39(RR-13):1–43.

bacteremia and septicemia among preterm described. Coagulase-negative staphylococci


neonates, typically neonates weighing less can also enter the bloodstream from the respi-
than 1,500 g at birth, and of episodes of health ratory tract of mechanically ventilated preterm
care–associated bacteremia in all age groups. neonates or from the gastrointestinal tract of
­Coagulase-negative staphylococci are respon- neonates with necrotizing enterocolitis. Some
sible for bacteremia in children with intravas- species of CoNS are associated with urinary
cular catheters or those with vascular grafts or tract infection, including Staphylococcus
intracardiac patches, prosthetic cardiac valves, ­saprophyticus in adolescent females and young
or pacemaker wires. Infection may also occur adult women, often after sexual intercourse,
associated with other indwelling foreign bod- and Staphylococcus epidermidis and Staphylo­
ies, including CSF shunts, peritoneal catheters, coccus haemolyticus in hospitalized patients
or prosthetic joints. Mediastinitis after open- with urinary tract catheters. In general, CoNS
heart surgery, endophthalmitis after intrao­c­ infections have an indolent clinical course in
ular trauma, and omphalitis and scalp children with intact immune function, even
abscesses in preterm neonates have been in children who are immunocompromised.

ERRNVPHGLFRVRUJ
550 Staphylococcal Infections

Etiology menses, menstrual and nonmenstrual cases


Staphylococci are catalase-positive, gram-­ of TSS continue to occur and are reported
positive cocci that appear microscopically as with similar frequency. Risk factors for TSS
grapelike clusters. There are 32 species that include absence of antibody to TSS toxin-1 and
are related closely on the basis of DNA base focal S aureus infection with a TSS toxin-1–­
composition, but only 17 species are indigenous producing strain. Toxic shock syndrome
to humans. S aureus is the only species that toxin-1–producing strains can be part of nor-
produces coagulase, although not all S aureus mal flora of the anterior nares or vagina, and
produce coagulase. Of the 16 CoNS species, colonization at these sites is believed to result
S epidermidis, S haemolyticus, S saprophyticus, in protective antibody in more than 90% of
Staphylococcus schleiferi, and Staphylococcus adults. Health care–associated TSS can occur
lugdunensis are most often associated with and most often follows surgical procedures.
human infections. Staphylococci are ubiqui- In postoperative cases, the organism generally
tous and can survive extreme conditions of originates from the patient’s own flora.
drying, heat, and low-oxygen and high-salt Transmission of S aureus
environments. S aureus has many surface pro-
teins, including the microbial surface compo- S aureus is most often transmitted by direct
nents recognizing adhesive matrix molecule contact in community settings and indirectly
receptors, which allow the organism to bind from patient to patient via transiently colo-
to tissues and foreign bodies coated with fibro- nized hands of health care professionals in
nectin, fibrinogen, and collagen. This permits health care settings. Health care professionals
a low inoculum of organisms to adhere to and family members who are colonized with
sutures, catheters, prosthetic valves, and S aureus in the nares or on skin can also serve
other devices. Many CoNS produce an exo- as a reservoir for transmission. Contaminated
polysaccharide slime biofilm that makes these environmental surfaces and objects can also
organisms, as they bind to medical devices play a role in transmission of S aureus,
(eg, catheters), relatively inaccessible to host although their contribution for spread is
defenses and antimicrobial agents. ­probably minor. Although not routinely
­transmitted by the droplet route, S aureus can
Epidemiology be dispersed into the air over short distances.
­Dissemination of S aureus from people with
Staphylococcus aureus
nasal carriage, including infants, is related
S aureus, which is second only to CoNS as a to density of colonization, and increased dis-
cause of health care–associated bacteremia, is semination occurs during viral upper respira-
one of the most common causes of health care– tory tract infections. Additional risk factors
associated pneumonia and is responsible for for health care–associated acquisition of
most health care–associated surgical site infec- S aureus include illness requiring care in
tions. S aureus colonizes the skin and mucous ­neonatal or pediatric intensive care or burn
membranes of 30% to 50% of healthy adults units, surgical procedures, prolonged hospital-
and children. The anterior nares, throat, axilla, ization, local epidemic of S aureus infection,
perineum, vagina, and rectum are usual sites and the presence of indwelling catheters or
of colonization. Rates of carriage of more than prosthetic devices.
50% occur in children with desquamating skin
disorders or burns and in people with frequent S aureus Colonization and Disease
needle use (eg, diabetes mellitus, hemodialysis, Nasal, skin, vaginal, and rectal carriage are
illicit drug use, allergy shots). the primary reservoirs for S aureus. Although
S aureus–mediated TSS was recognized in domestic animals can be colonized, data sug-
1978, and many early cases were associated gest colonization is acquired from humans.
with tampon use. Although changes in tam- Adults who carry MRSA in the nose preopera-
pon composition and use have resulted in a tively are more likely to develop surgical site
decreased proportion of cases associated with infections after general, cardiac, orthopedic,

ERRNVPHGLFRVRUJ
Staphylococcal Infections 551

or solid organ transplant surgery than are MRSA infections since 1999 without change
patients who are not carriers. Heavy cutaneous in the frequency of MSSA infections. Health
colonization at an insertion site is the single care–associated MRSA strains are difficult
most important predictor of intravenous to treat because they are usually multidrug
­catheter-related infections for short-term resistant and are predictably susceptible
­percutaneously inserted catheters. For hemo­ only to vancomycin, linezolid, and agents
dialysis patients with S aureus skin coloniza- not approved by the US Food and Drug
tion, the incidence of central line–associated Administration for use in children.
bloodstream infection is 6-fold higher than
for patients without skin colonization. After Community-Associated MRSA
head trauma, adults who are nasal carriers of Unique clones of MRSA are responsible for
S aureus are more likely to develop S aureus community-associated infections in healthy
pneumonia than are noncolonized patients. children and adults without typical risk factors
for health care–associated MRSA infections.
Health Care–Associated Methicillin-­ The most frequent manifestation of community-
Resistant S aureus (MRSA) associated MRSA infections is skin and soft
Methicillin-resistant S aureus has been tissue infection, but invasive disease also
endemic in most US hospitals since the 1980s, occurs. Antimicrobial susceptibility patterns
recently accounting for more than 60% of of these strains differ from those of health
health care–associated S aureus infections in care–associated MRSA strains. Although
intensive care units reported to the Centers for ­community-associated MRSA are resistant
Disease Control and Prevention (CDC). Health to all β-lactam antimicrobial agents except
care–associated MRSA strains are resistant to ceftaroline, they are typically susceptible to
β-lactamase–resistant (BLR) β-lactam antimi- multiple other antimicrobial agents, including
crobial agents and cephalosporins (except the trimethoprim-sulfamethoxazole, gentamicin,
fifth-generation cephalosporin, ceftaroline), as and doxycycline; clindamycin susceptibility
well as to antimicrobial agents of several other is variable. A review of prescribing patterns
classes (multidrug resistance). Methicillin-­ among 25 pediatric hospitals has demon-
susceptible S aureus (MSSA) strains can be strated clindamycin to be the most commonly
heterogeneous for methicillin resistance. prescribed antimicrobial agent for non–life-
threatening MRSA infections. However, atten-
Risk factors for nasal carriage of health care–
tion to local resistance rates of S aureus to
associated MRSA include hospitalization
clindamycin is imperative because community-
within the previous year, recent (within the
associated MRSA and MSSA isolates with
previous 60 days) antimicrobial use, prolonged
intrinsic or inducible resistance to clindamycin
hospital stay, frequent contact with a health
exceeding 20% have been reported by some
care environment, presence of an intravas­
institutions. Community-associated MRSA
cular or peritoneal catheter or tracheal tube,
infections have occurred in settings where
increased number of surgical procedures, or
there is crowding; frequent skin-to-skin con-
frequent contact with a person with one or
tact; body piercing; sharing of personal items,
more of the preceding risk factors. A dis-
such as towels and clothing; and poor personal
charged patient known to have had coloniza-
hygiene, such as occurs among athletic teams,
tion with MRSA should be assumed to have
in correctional facilities, and in military train-
continued colonization when rehospitalized
ing facilities. However, most community-­
because carriage can persist for years.
associated MRSA infections occur in people
Methicillin-resistant S aureus, health care– without direct links to those settings, including
and community-associated strains, and healthy term neonates. Transmission of
­methicillin-resistant CoNS are responsible ­community-associated MRSA from an infected
for a large portion of infections acquired in classmate or teammate has been described in
health care settings. A review of 25 pediatric child care centers and among sports teams,
hospitals demonstrated a 10-fold increase in respectively. Although community-associated

ERRNVPHGLFRVRUJ
552 Staphylococcal Infections

MRSA arose from the community, in many crine glands. The frequency of health care–­
health care settings, these clones are overtak- associated CoNS infections increased steadily
ing health care–associated MRSA strains as a until 2000, when these infections seem to have
cause of health care–associated MRSA infec- plateaued. Newborns, infants, and children in
tions, making usefulness of the epidemiologic intensive care units, including neonatal inten-
terms “health care–associated” and “commu- sive care units, have the highest incidence of
nity-associated” of less value. CoNS bloodstream infections. Coagulase-­
negative staphylococci can be introduced at
Vancomycin-Intermediate S aureus the time of medical device placement, through
Strains of MRSA with intermediate suscepti- mucous membrane or skin breaks, through
bility to vancomycin (minimum inhibitory loss of bowel wall integrity (eg, necrotizing
concentration [MIC], 4–8 mcg/mL) have been enterocolitis in very low birth weight neo-
isolated from people (historically, dialysis nates), or during catheter manipulation. Less
patients) who had received multiple courses of often, health care professionals with environ-
vancomycin for a MRSA infection. Extensive mental CoNS colonization on hands transmit
vancomycin use allows vancomycin-intermediate the organism. The roles of the environment or
S aureus (VISA) strains to develop. These fomites in CoNS transmission are not known.
strains may emerge during therapy. Control
Most CoNS strains are methicillin resistant
measures recommended by the CDC have
and account for health care–associated infec-
included using proper methods to detect VISA,
tions associated with indwelling foreign bodies
using appropriate infection-control measures,
and in the neonatal population. Methicillin-
and adopting measures to ensure appropriate
resistant strains are resistant to all β-lactam
vancomycin use. Although rare, outbreaks of
drugs, including cephalosporins (except cef-
VISA and heteroresistant VISA have been
taroline), and, usually, several other drug
reported in France, Spain, and Japan.
classes. Once these strains become endemic
Vancomycin-Resistant S aureus in a hospital, eradication is difficult, even
when strict infection-prevention practices
In 2002, two isolates of vancomycin-resistant are followed.
S aureus (VRSA [MIC, ≥16 mcg/mL]) were
identified in adults from 2 different states. Incubation Period
As of May 2014, VRSA had been isolated in Variable. For toxin-mediated SSSS, 1 to 10 days;
13 adults from 4 states. Each of these adults for postoperative TSS, as short as 12 hours.
with VRSA infections had underlying medical Menstrual-related cases can develop at any
conditions, a history of MRSA infections, and time during menses.
prolonged exposure to vancomycin. No spread
of VRSA beyond case patients has been docu- Diagnostic Tests
mented. A concern is that most automated Gram-stained smears of material from skin
antimicrobial susceptibility testing methods lesions or pyogenic foci showing gram-positive
commonly used in the United States were cocci in clusters can provide presumptive evi-
unable to detect vancomycin resistance in dence of infection. Isolation of organisms from
these isolates. culture of otherwise sterile body fluid is the
Coagulase-Negative Staphylococci method for definitive diagnosis. Newer molec-
ular assays are available for direct detection
Coagulase-negative staphylococci are com- of S aureus from blood culture bottles. Non­
mon inhabitants of the skin and mucous amplified molecular assays, such as peptide
­membranes. Virtually all neonates have colo­ nucleic acid fluorescent in situ hybridization,
nization at multiple sites by 2 to 4 days of age. and nucleic acid amplification tests, such as BD
The most frequently isolated CoNS organism GeneOhm Staph SR (BD Molecular Diagnos-
is S epidermidis. Different species colonize tics) and Xpert MRSA/SA BC (Cepheid), are
­specific areas of the body. S haemolyticus is approved for detection and identification of
found on areas of skin with numerous apo- S aureus, including MRSA, in positive blood

ERRNVPHGLFRVRUJ
Staphylococcal Infections 553

cultures. S aureus is almost never a contami- Quantitative antimicrobial susceptibility test-


nant when isolated from a blood culture. ing should be performed for all staphylococci,
­Coagulase-negative staphylococci isolated including CoNS, isolated from normally sterile
from a single blood culture are commonly sites. Health care–associated MRSA heteroge-
­dismissed as “contaminants.” In a very preterm neous or heterotypic strains appear susceptible
neonate (ie, <32 weeks’ gestation), an immuno- by disk testing. However, when a parent strain
compromised person, or a patient with an is cultured on methicillin-containing media,
indwelling catheter or prosthetic device, resistant subpopulations are apparent.
repeated isolation of the same strain of CoNS
A large proportion of community-associated
(by antimicrobial susceptibility results or
S aureus strains are methicillin resistant, and
molecular techniques) from blood cultures or
a high percentage (>90% in some centers) of
another normally sterile body fluid suggests
health care–associated S aureus from children
true infection, but genotyping more strongly
are methicillin and multidrug resistant. More
supports the diagnosis. For central line–­
than 90% of health care–associated CoNS
associated bloodstream infection, quantitative
strains are methicillin-resistant. Because of
blood cultures from the catheter will have 5
the high rates of community-associated MRSA
to 10 times more organisms than cultures
infections in the United States, clindamycin
from a peripheral blood vessel. Criteria that
has become an often-used drug for treatment
suggest CoNS as pathogens rather than con-
of nonlife-threatening presumed S aureus
taminants include
infections. Routine antimicrobial susceptibility
• Two or more positive blood cultures from testing of S aureus strains historically did not
different collection sites include a method to detect strains susceptible
to clindamycin that rapidly become clinda­mycin-
• A single positive culture from blood and
resistant when exposed to this agent. This
another sterile site (eg, CSF, joint) with
clindamycin-inducible resistance can be
­identical antimicrobial susceptibility
detected by the D zone test. When a MRSA
­patterns for each isolate
isolate is determined to be erythromycin resis-
• Growth in a continuously monitored blood tant and clindamycin susceptible by routine
culture system within 15 hours of incubation methods, the D zone test is performed. Many
automated platforms for susceptibility testing
• Clinical findings of infection now include testing for inducible clindamycin
• An intravascular catheter that has been in resistance. Methicillin-resistant S aureus iso-
place for 3 days or more lates that demonstrate clindamycin-inducible
resistance will be reported by the laboratory as
• Similar or identical genotypes among all clindamycin resistant, and the patient should
isolates not be treated with clindamycin. All S aureus
S aureus–mediated TSS is a clinical diagnosis. strains with an MIC to vancomycin of 4 mcg/
S aureus grows in culture of blood specimens mL or greater should be confirmed and further
from fewer than 5% of patients with TSS. characterized. Early detection of VISA is criti-
­Specimens for culture should be obtained from cal to trigger aggressive infection-control mea-
an identified focal site of infection because sures (Box 126.2).
these sites will usually yield the organism. S aureus and CoNS strain genotyping has
Because approximately one-third of isolates of become a necessary adjunct for determining
S aureus from nonmenstrual cases produce whether several isolates from one patient or
toxins other than TSS toxin-1, and TSS toxin-1– from different patients are the same. Typing, in
producing organisms can be present as normal conjunction with epidemiologic information,
flora, TSS-1 production by an isolate is not use- can facilitate identification of the source,
ful diagnostically. extent, and mechanism of transmission in an
outbreak. Antimicrobial susceptibility testing
is the most readily available method for typing
by a phenotypic characteristic. A number of

ERRNVPHGLFRVRUJ
554 Staphylococcal Infections

Box 126.2
Recommendations for Detecting Staphylococcus aureus
With Decreased Susceptibility to Vancomycin

Definitions
• Vancomycin-susceptible S aureus
MIC ≤2 mcg/mL
• VISA
MIC 4 – 8 mcg/mL
Not transferable to susceptible strains
• VRSA
MIC ≥16 mcg/mL
Potentially transferable to susceptible strains
• Confirmation of VISA and VRSA
Possible VISA and VRSA isolates should be retested using vancomycin screen plates or a
  validated MIC method.
VISA and VRSA isolates should be reported to the local health department or CDC.

Abbreviations: CDC, Centers for Disease Control and Prevention; MIC, minimum inhibitory concentration; VISA, vancomycin-intermediate
Staphylococcus aureus; VRSA, vancomycin-resistant Staphylococcus aureus.
For information on control of spread of VISA and VRSA, e-mail SEARCH@cdc.gov or visit www.cdc.gov/hai.

molecular typing methods are available for cated skin and soft tissue infection with
S aureus. The primary method currently used abscess, drainage or debridement and systemic
by the CDC is pulsed-field gel electrophoresis. antibiotic therapy are warranted; therapy
should be focused on the pathogen identified.
Treatment

Skin and Soft Tissue Infection Invasive Staphylococcal Infections

Skin and soft tissue infections, such as diffuse Empirical therapy for serious suspected
impetigo or cellulitis attributable to MSSA, can ­staphylococcal infection is vancomycin plus
be treated with oral penicillinase-resistant a semisynthetic β-lactam (eg, nafcillin).
β-lactam drugs, such as a first- or second-­ Clindamycin is bacteriostatic and should not
generation cephalosporin. However, the be used for initial treatment of endovascular
­continued increase in prevalence of community- infection. Serious MSSA infections require
associated MRSA throughout the United States intravenous therapy with a BLR β-lactam
limits the utility of β-lactams as empirical ­a ntimicrobial agent, such as nafcillin or oxacil-
agents. For the penicillin-allergic patient lin, because most S aureus strains produce
and in cases in which MRSA is considered, β-lactamase enzymes and are resistant to
­trimethoprim-sulfamethoxazole, doxycycline ­penicillin and ampicillin (Table 126.1).
in children 8 years and older, or clindamycin ­Vancomycin is not recommended for treatment
can be used if the isolate is susceptible. Trime- of serious MSSA infections because outcomes
thoprim-sulfamethoxazole should not be used are inferior compared with cases in which
as a single agent in the initial treatment of cel- ­a ntistaphylococcal β-lactams are used and to
lulitis. Topical mupirocin is recommended for minimize emergence of vancomycin resistance.
localized impetigo. First- or second-generation cephalosporins
(eg, cefazolin) or vancomycin are less effective
The most frequent manifestation of community- than nafcillin or oxacillin for treatment of
associated MRSA infection is skin and soft MSSA endocarditis or meningitis. A patient
tissue infection. Image 126.1 shows the ­initial with MSSA infection (and no evidence of
management of skin and soft tissue infections ­endocarditis or central nervous system [CNS]
suspected to be caused by community-­ infection) who has a nonserious allergy to
associated MRSA. For patients with compli-

ERRNVPHGLFRVRUJ

Table 126.1
Parenteral Antimicrobial Agent(s) for Treatment of ­Bacteremia and Other Serious Staphylococcus aureus Infections
Susceptibility Antimicrobial Agents Comments
I. Initial empiric therapy (organism of unknown susceptibility)
Drugs of choice Vancomycin (15 mg/kg, every 6 h) + For life-threatening infections (ie, septicemia, endocarditis, CNS infection);
­nafcillin or oxacillin ­linezolid could be substituted for vancomycin if the patient has received several
recent courses of vancomycin.
Vancomycin (15 mg/kg, every 6–8 h) For nonlife-threatening infection without signs of sepsis (eg, skin infection,
­cellulitis, osteomyelitis, pyarthrosis) when rates of MRSA colonization and

Staphylococcal Infections
­infection in the community are substantial
Clindamycin For nonlife-threatening infection without signs of sepsis when rates of MRSA
­colonization and infection in the community are substantial and prevalence of
clindamycin resistance is low
II. Methicillin-susceptible, penicillin-resistant S aureus
Drugs of choice Nafcillin or oxacillina
Cefazolin
Alternatives Clindamycin Only for patients with a serious penicillin allergy and clindamycin-susceptible
strain
Vancomycin Only for patients with a serious penicillin and cephalosporin allergy
Ampicillin + sulbactam For patients with polymicrobial infections caused by susceptible isolates

III. MRSA (oxacillin MIC, ≥4 mcg/mL)


A. Health care–associated (multidrug resistant)
Drugs of choice Vancomycin ± gentamicina
Alternatives: susceptibility test- Trimethoprim-sulfamethoxazole
ing results available before alter- Linezolidb
native drugs are used
Quinupristin-dalfopristinb

555
556
Table 126.1
Parenteral Antimicrobial Agent(s) for Treatment of ­Bacteremia and Other
Serious Staphylococcus aureus Infections (continued)
Susceptibility Antimicrobial Agents Comments
III. MRSA (oxacillin MIC, ≥4 mcg/mL) (continued)
B. Community-associated (not multidrug resistant)
Drugs of choice Vancomycin ± gentamicina For life-threatening infections or endovascular infections, including those
­complicated by venous thrombosis
Clindamycin (if strain susceptible) For pneumonia, septic arthritis, osteomyelitis, skin or soft tissue infections
Trimethoprim-sulfamethoxazole For skin or soft tissue infections
Alternatives Vancomycin For serious infections

Staphylococcal Infections
Linezolid For serious infections caused by clindamycin-resistant isolates in patients with
renal dysfunction or those intolerant of vancomycin
IV. Vancomycin-intermediate S aureus (MIC, 4 –16 mcg/mL)b
Drugs of choice Optimal therapy is not known. Dependent on in vitro susceptibility test results
Linezolidb
Ceftaroline
Daptomycinc
Quinupristin-dalfopristinb
Tigecycline
Alternatives Vancomycin + linezolid ± gentamicin
Vancomycin + trimethoprim-sulfa-
methoxazolea
Abbreviations: CNS, central nervous system; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus.
a
Gentamicin should be considered for addition to the therapeutic regimen for endocarditis without prosthetic devices or CNS infection; gentamicin and rifampin should be added for endocarditis of a prosthetic device or
infections with a vancomycin-intermediate S aureus strain. Addition of rifampin is recommended for other device-related infections (eg, spinal instrumentation, prosthetic joint). Some experts recommend achieving vancomy-
cin trough concentrations between 15 and 20 mcg/mL for serious MRSA infections until the patient has improved and blood cultures are sterile. Consultation with an infectious diseases specialist should be considered to
determine which agent to use and duration of use.
b
Linezolid, ceftaroline, quinupristin-dalfopristin, and tigecycline are agents with activity in vitro and efficacy in adults with multidrug-resistant, gram-positive organisms, including S aureus. Because experience with these
agents in children is limited, consultation with an infectious diseases specialist should be considered before use.
c
Daptomycin is active in vitro against multidrug-resistant, gram-positive organisms, including S aureus, but has not been evaluated in children. Daptomycin is approved by the US Food and Drug Administration only for treat-
ment of complicated skin and skin structure infections and for S aureus bloodstream infections. Daptomycin is ineffective for treatment of pneumonia and is not indicated in patients 18 years and older.
Staphylococcal Infections 557

­ enicillin can be treated with a first- or second-


p tered foci of infection, and, for MRSA strains,
generation cephalosporin or with clindamycin, should consider the vancomycin MIC and the
if the S aureus strain is susceptible. achievable vancomycin trough concentrations.
Intravenous vancomycin is recommended Completion of the course with an oral drug
for treatment of serious infections caused by can be considered if adherence can be ensured
staphylococcal strains resistant to BLR and endocarditis or CNS infection is not a
β-lactam antimicrobial agents (eg, MRSA, ­consideration. For endocarditis and CNS infec-
all CoNS). For life-threatening S aureus tion, parenteral therapy is recommended for
­infections, initial therapy should include the entire treatment. Drainage of abscesses and
­vancomycin and a BLR β-lactam antimicro- removal of foreign bodies are desirable and are
bial agent (eg, nafcillin). For hospital-acquired almost always required for medical treatment
CoNS infections, vancomycin is the drug of to be effective. In some cases, multiple debride-
choice. Subsequent therapy should be deter- ment procedures are necessary for children
mined by antimicrobial susceptibility results. with MRSA osteoarticular infection.
Guidelines for management of serious skin or
Duration of therapy for central line–associated
soft tissue infection, complicated pneumonia
bloodstream infections is controversial and
or empyema, CNS infection, osteomyelitis,
depends on consideration of a number of
and endocarditis caused by MRSA are avail-
­factors, including the organism (S aureus vs
able (www.idsociety.org/IDSA_Practice_
CoNS), the type and location of the catheter,
Guidelines).
the site of infection (exit site vs tunnel vs line),
Vancomycin Treatment Failure and the feasibility of using an alternative vascular
­Vancomycin-Intermediate S aureus Infection access site at a later date, and the presence or
absence of a catheter-related thrombus. Infec-
Vancomycin-intermediate S aureus infection is
tions are more difficult to treat when associated
rare in children. For seriously ill patients with
with a thrombus, thrombophlebitis, or intra-
a history of recurrent MRSA infections or for
atrial thrombus. Data detailing outcomes of
patients failing vancomycin therapy in whom
treatment of serious MRSA infections in adults
VISA strains are a consideration, initial ther-
does not support the addition of gentamicin or
apy could include linezolid or trimethoprim-
rifampin to vancomycin because of an increase
sulfamethoxazole, with or without gentamicin.
in adverse effects and lack of greater efficacy of
If antimicrobial susceptibility results docu-
the combination versus monotherapy, but the
ment multidrug resistance, alternative agents,
addition of rifampin can be considered in the
such as quinupristin-dalfopristin, daptomycin
setting of a foreign body–associated infection.
(not approved for pneumonia), ceftaroline, or
If a central line can be removed, there is no
tigecycline, could be considered.
demonstrable thrombus, and bacteremia
Duration of Therapy for Invasive Infections resolves promptly, a 5-day course of therapy
seems appropriate for CoNS infections in the
Duration of therapy for serious MSSA or immunocompetent host.
MRSA infections depends on the site and
severity of infection but is usually 4 weeks or A longer course is suggested if the patient is
more for endocarditis, osteomyelitis, necro­ immunocompromised or the organism is
tizing pneumonia, or disseminated infection, S aureus; experts differ on recommended
assuming a documented clinical and microbio- ­duration, but many suggest a minimum of
logic response. The duration of bacteremia for 14 days provided there is no evidence of a
patients with staphylococcal infection can ­metastatic focus. If the patient needs a new
­t ypically be 3 to 4 days for MSSA and 7 to 9 central line, waiting 48 to 72 hours after bac­
days for MRSA. In assessing whether modifi­ teremia has apparently resolved before inser-
cation of therapy is necessary, clinicians should tion is optimal. If a tunneled catheter is needed
consider whether the patient is clinically for ongoing care, in situ treatment of the infec-
improving, should identify and drain seques- tion can be attempted. If the patient responds

ERRNVPHGLFRVRUJ
558 Staphylococcal Infections

to antimicrobial therapy with immediate reso- parentally administered β-lactam antistaphy-


lution of the S aureus bacteremia, treatment lococcal antimicrobial agent and a protein
should be continued for 10 to 14 days parenter- ­synthesis-inhibiting drug, such as clindamy-
ally. Antimicrobial lock therapy of tunneled cin, at maximum dosages. Vancomycin
central lines may result in a higher rate of should be substituted for BLR penicillins or
­catheter salvage in adults with CoNS infec- cephalosporins in regions where community-
tions, but experience with this approach is associated MRSA infections are common.
­limited in children. If blood culture results Once the organism is identified and suscepti-
remain positive for more than 2 days for bilities are known, therapy for S aureus should
S aureus or 3 to 5 days for CoNS or if the clini- be modified, but an active antimicrobial agent
cal illness fails to improve, the central line should be continued for 10 to 14 days. Admin-
should be removed, parenteral therapy should istration of antimicrobial agents can be
be continued, and the patient should be evalu- changed to the oral route once the patient is
ated for metastatic foci of infection. Vegeta- tolerating oral alimentation. Total duration
tions or a thrombus in the heart or great vessels of therapy is based on the usual duration of
should always be considered when a central established foci of infection (eg, osteomyelitis).
line becomes infected and should be suspected Aggressive drainage and irrigation of acces-
more strongly if blood cultures remain positive sible sites of purulent infection should be per-
for more than 2 days or if there are other clini- formed as soon as possible. All foreign bodies,
cal manifestations associated with endocardi- including those recently inserted during sur-
tis. Transesophageal echocardiography, if gery, should be removed if possible. Intrave-
feasible, is the most sensitive technique for nous immunoglobulin (IVIG) can be
identifying vegetations, but transthoracic considered in patients with severe staphylo­
echocardiography is generally adequate for coccal TSS unresponsive to other therapeutic
children younger than 10 years and those measures because IVIG may neutralize circu-
weighing less than 60 kg. lating toxin. The optimal IVIG regimen is
unknown. Staphylococcal scalded skin syn-
Management of S aureus Toxin-Mediated drome in infants should be treated with a par-
Diseases enteral BLR β-lactam antimicrobial agent or,
As summarized in Box 126.3, the first priority if MRSA is a consideration, vancomycin.
in management of S aureus TSS is aggressive ­Transition to an oral agent can be considered
fluid management as well as management of in non-neonates who have demonstrated
respiratory or cardiac failure, if present. Ini- ­excellent clinical and microbiologic response
tial antimicrobial therapy should include a to parenteral therapy.

Box 126.3
Management of Staphylococcal Toxic Shock Syndrome

• Fluid management to maintain adequate venous return and cardiac filling pressures to prevent
end-organ damage
• Anticipatory management of multisystem organ failure
• Parenteral antimicrobial therapy at maximum doses
——Kill organism with bactericidal cell wall inhibitor (eg, β-lactamase–resistant antistaphylococ-
cal antimicrobial agent).
——Reduce enzyme or toxin production with protein synthesis inhibitor (eg, clindamycin).
• Intravenous immunoglobulin therapy may be considered for infection refractory to several
hours of aggressive therapy or in the presence of an undrainable focus or persistent oliguria
with pulmonary edema.

ERRNVPHGLFRVRUJ
Staphylococcal Infections 559

PRESENTATION
Folliculitis/pustular lesions, furuncle/carbuncle, abscess, “insect/spider
bite,” cellulitis

FIRST STEP
• Incision and drainage (when indicated)
• Obtain specimen(s) for culture and susceptibility.

NEXT STEP
Classify severity

MILD MODERATE SEVERE


Afebrile Febrile, ill but Toxic appearance CRITICALLY ILL
Previously healthy previously healthy OR
Immunocompromisea
OR
Limb-threatening
infection

Incision and
drainage alone may
be adequate.

• Incision and If extensive area • Hospitalize • Hospitalize


drainage of involvement, • Emergent • Emergent
• Oral antimicrobial clinically incision and incision and
therapy concerning drainage as drainage as
—TMP-SMXb systemic indicated indicated
—Clindamycinc symptoms, or • Empiric van- • Empiric van-
—Doxycycline compliance and comycin or comycin
(if ≥8 y) follow-up of clindamycinc PLUS
care uncertain until culture nafcillin ± other
• Follow-up at 48 h
results known agents

a
Immunocompromise = any chronic condition except asthma or eczema.
b
TMP-SMX = trimethoprim-sulfamethoxazole, if group A streptococcus unlikely.
c
Consider prevalence of clindamycin-susceptible methicillin-susceptible Staphylococcus aureus and D test–negative
community-associated methicillin-resistant S aureus strains in the community.

Image 126.1
Algorithm for initial management of skin and soft tissue infections caused by community-associated
Staphylococcus aureus.

ERRNVPHGLFRVRUJ
560 Staphylococcal Infections

Image 126.2 Image 126.3


Staphylococcus aureus on blood agar. Colonies Staphylococcus epidermidis on blood agar. In
have a golden or cream-colored appearance, are contrast to Staphylococcus aureus and other
opaque, and produce β-hemolysis on blood agar. coagulase-negative Staphylococcus species,
Courtesy of Julia Rosebush, DO; Robert Jerris, this organism produces a white colony with little
PhD; and Theresa Stanley, M(ASCP). or no pigmentation. Courtesy of Julia Rosebush,
DO; Robert Jerris, PhD; and Theresa Stanley,
M(ASCP).

Image 126.4
A Staphylococcus aureus isolate tested by the
Etest gradient diffusion method with vancomycin, Image 126.5
daptomycin, and linezolid on Mueller-Hinton-IH D zone test for clindamycin-induced resistance
agar. The minimum inhibitory concentration of by Staphylococcus aureus. The left shows a
each agent is determined by the intersection of negative result and the right shows a positive
the organism growth with the strip as measured one. Courtesy of Sarah Long, MD, FAAP.
using the scale inscribed on the strip. Used with
permission from Clinical Infectious Diseases.

Image 126.7
Image 126.6 Skin desquamation in a 7-year-old black boy with
Skin desquamation in a 7-year-old boy with staphylococcal scarlatiniform eruption. Courtesy
staphylococcal scalded skin syndrome. Courtesy of Benjamin Estrada, MD.
of Benjamin Estrada, MD.

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Staphylococcal Infections 561

Image 126.8
Skin desquamation of the hand in a 7-year-old Image 126.9

boy with staphylococcal scalded skin syndrome. Newborn with pustulosis of the perineum
Courtesy of Benjamin Estrada, MD. and genitalia due to Staphylococcus aureus.
Copyright Michael Rajnik, MD, FAAP.

Image 126.10
Staphylococcal bullous impetigo lesions about
the eyes, nose, and mouth in a 6-year-old black Image 126.11

boy. Also note the secondary anterior cervical An infant with orbital cellulitis and ethmoid
lymphadenopathy. Courtesy of George sinusitis due to Staphylococcus aureus.
Nankervis, MD. Copyright Martin G. Myers, MD.

Image 126.12
A 3-week-old with an orbital abscess and
Image 126.13
bacteremia caused by methicillin-resistant
Staphylococcus aureus. Incision and drainage Periorbital cellulitis due to Staphylococcus
of the abscess and parenteral vancomycin aureus–infected lesion adjacent to the orbit (most
resulted in full recovery. likely secondary to a recent insect bite). Courtesy
of Edgar O. Ledbetter, MD, FAAP.

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562 Staphylococcal Infections

Image 126.14
Orbital abscess with proptosis of the globe due Image 126.15
to Staphylococcus aureus in a 12-year-old boy. Pyomyositis of the cheek of a 1-year-old girl
Delayed surgical drainage contributed to caused by Staphylococcus aureus. Copyright
permanent visual impairment due to central Michael Rajnik, MD, FAAP.
retinal vascular involvement. The patient also
had left ethmoid and maxillary sinusitis.

Image 126.17
Cervical adenitis with abscess formation due
Image 126.16
to Staphylococcus aureus. Delay in seeking
Staphylococcus aureus abscess of the lobe
medical care resulted in spontaneous drainage
of the left ear secondary to ear piercing in an
of  the abscess.
adolescent girl. Courtesy of Edgar O. Ledbetter,
MD, FAAP.

Image 126.18
Subauricular cervical adenitis Staphylococcus
aureus in a 2-year-old boy. Courtesy of Neal
Image 126.19
Halsey, MD.
Abscess of axillary lymph node due to
Staphylococcus aureus.

ERRNVPHGLFRVRUJ
Staphylococcal Infections 563

Image 126.20
Posttraumatic paronychia due to Staphylococcus Image 126.21
aureus of the left great toe of an infant. Courtesy Cellulitis (inguinal) due to Staphylococcus aureus.
of Edgar O. Ledbetter, MD, FAAP. Courtesy of Neal Halsey, MD.

Image 126.22
A 15-year-old with Fanconi syndrome with Image 126.23
Staphylococcus aureus infection at the finger- Chronic osteomyelitis of the right tibia due to
stick site. Copyright Martin G. Myers, MD. Staphylococcus aureus.

Image 126.24
Osteomyelitis of the calcaneus due to
Staphylococcus aureus with no history of injury.

Image 126.25
Vertebral osteomyelitis in a 13-year-old with
a 6-week history of back pain. Magnetic reso­
nance imaging revealed osteolytic changes of the
anterior segments of the first and second lumbar
vertebrae. A culture of the biopsy specimen grew
methicillin-resistant Staphylococcus aureus.

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564 Staphylococcal Infections

Image 126.27
Staphylococcal scalded skin syndrome.
Epidermolytic toxins A and B are the components
of Staphylococcus aureus thought to cause
this syndrome.

Image 126.26
Cerebral infarct in a patient with bacterial endo­
carditis. Courtesy of Dimitris P. Agamanolis, MD.

Image 126.29
Infant with staphylococcal scalded skin
syndrome with sheets of skin desquamation.

Image 126.28
Staphylococcal scalded skin syndrome with a
positive Nikolsky sign.

Image 126.30
Staphylococcal scalded skin syndrome.
Epidermolytic exotoxin results in superficial,
generalized desquamation. Courtesy of Edgar O.
Ledbetter, MD, FAAP.

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Staphylococcal Infections 565

Image 126.31
Staphylococcal pneumonia, primary, with rapid Image 126.32
progression and empyema. The infant had only Staphylococcal pneumonia, primary, with rapid
mild respiratory distress and paralytic ileus progression with empyema. This is the same
without fever when first examined. patient as in Image 126.30. Courtesy of Edgar O.
Ledbetter, MD, FAAP.

Image 126.33
Pneumonia due to Staphylococcus aureus
with right lower lobe infiltrate in a preschool-aged
child (day 1). Courtesy of Edgar O. Ledbetter,
MD, FAAP. Image 126.34
Staphylococcal pneumonia with massive
empyema demonstrating the rather rapid
progression typical of staphylococcal infection.
This is the same patient as in Image 126.32
(day 4). Courtesy of Edgar O. Ledbetter, MD,
FAAP.

Image 126.35
Staphylococcus aureus pelvic abscess in a
14-year-old white girl demonstrated by
computed tomography scan. Courtesy of
Benjamin Estrada, MD.

ERRNVPHGLFRVRUJ
566 Staphylococcal Infections

Image 126.36
Staphylococcus aureus necrotizing fasciitis in
an 8-month-old girl. Courtesy of Benjamin
Image 126.37
Estrada, MD.
Staphylococcus aureus cervical abscess in
an 8-month-old girl demonstrated by
computed tomography scan. Courtesy of
Benjamin Estrada, MD.

Image 126.38
Pyoderma due to Staphylococcus aureus in a
young infant.

Image 126.39
A 6-year-old boy with peritonsillar abscess
(quinsy) due to Staphylococcus aureus. Pain on
swallowing and drooling are common symptoms.
Copyright Martin G. Myers, MD.

Image 126.40
Digit and palm desquamation in a 15-year-old
boy during staphylococcal toxic shock
syndrome convalescence. Courtesy of Benjamin
Estrada, MD.

ERRNVPHGLFRVRUJ
Staphylococcal Infections 567

Image 126.41
Characteristic erythroderma of the hand of the patient in Image 126.40 with staphylococcal toxic
shock syndrome.

Image 126.42
Facial erythroderma secondary to Staphylococ­cus aureus toxic shock syndrome in a woman who was
obtunded and hypotensive on admission.

Image 126.43
Erythroderma that blanches on pressure in a patient with toxic shock syndrome. The mortality rate for
staphylococcal toxic shock syndrome is lower than that of streptococcal toxic shock syndrome.

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568 Group A Streptococcal Infections

127 purpura fulminans, osteomyelitis, myositis,


puerperal sepsis, surgical wound infection,
Group A Streptococcal mastoiditis, and neonatal omphalitis. Invasive
Infections GAS infections are often associated with bacte-
remia with or without a local focus of infection
Clinical Manifestations and can present as streptococcal toxic shock
The most common group A streptococcal syndrome (TSS) or necrotizing fasciitis. Necro-
(GAS) infection is acute pharyngotonsillitis tizing fasciitis can follow minor or unrecog-
(pharyngitis), which is heralded by sore nized trauma, often involves an extremity,
throat with tonsillar inflammation and, often, and presents as pain out of proportion to
tender cervical lymphadenopathy. Pharyngitis examination findings. An association between
can be accompanied by palatal petechiae or a GAS infection and sudden onset of obsessive-­
strawberry tongue. Purulent complications of compulsive behaviors, prepubertal anorexia
pharyngitis usually occur in patients not nervosa, or tic disorders—pediatric autoim-
treated with antimicrobial agents and include mune neuropsychiatric disorders associated
otitis media, sinusitis, peritonsillar or retro- with streptococcal infections, also known as
pharyngeal abscesses, and suppurative cervi- pediatric acute-onset neuropsychiatric syn-
cal adenitis. Nonsuppurative complications drome—has been proposed, but carefully
include acute rheumatic fever (ARF) and acute ­performed prospective studies have not shown
glomerulonephritis. The goal of antimicrobial there is a specific relationship between these
therapy for GAS pharyngitis is to reduce acute disorders and GAS infections.
morbidity, complications, and transmission to
Streptococcal TSS is caused by toxin-­producing
close contacts.
GAS strains and typically manifests as an acute
Scarlet fever occurs most often in association illness characterized by fever, generalized
with pharyngitis and, rarely, with pyoderma erythroderma, rapid-onset hypotension, and
or an infected wound. Scarlet fever is usually signs of multiorgan involvement, including
a mild disease in the modern era and has a rapidly progressive renal failure (Box 127.1).
characteristic confluent erythematous sand­ Evidence of local soft tissue infection (eg, cellu-
paperlike rash that is caused by one or more litis, myositis, necrotizing fasciitis) associated
of several erythrogenic exotoxins produced with severe, rapidly increasing pain is com-
by group A streptococci. Other than occur- mon, but streptococcal TSS can occur without
rence of rash, the epidemiologic features, an identifiable focus of infection or with foci
symptoms, signs, sequelae, and treatment such as pneumonia with or without empyema,
of scarlet fever are the same as those of strep­ osteomyelitis, pyarthrosis, or endocarditis.
tococcal pharyngitis.
Etiology
Acute streptococcal pharyngitis is uncommon More than 120 distinct serotypes or genotypes
in children younger than 3 years. Instead, they of group A β-hemolytic streptococci (Strep­
present with rhinitis and then develop a pro- tococcus pyogenes) have been identified based
tracted illness with moderate fever, irritability, on M-protein serotype or M-protein gene
and anorexia (streptococcal fever or strepto- sequence (emm types). Because of a variety of
coccosis). The second most common site of factors, including M nontypability and emm
GAS infection is skin. Streptococcal skin infec- sequence variation within given M types, emm
tions (eg, pyoderma, impetigo) can be followed typing is generally more discriminating than
by acute glomerulonephritis, which occasion- M-protein serotyping. Epidemiologic studies
ally occurs in epidemics. Acute rheumatic fever suggest an association between certain sero-
is not a sequela of GAS skin infection. types (ie, types 1, 3, 5, 6, 18, 19, and 24) and
Other manifestations of GAS infections include rheumatic fever, but a specific rheumatogenic
erysipelas, cellulitis (including perianal), vagini- factor has not been identified. Several sero-
tis, bacteremia, pneumonia, endocarditis, peri- types (ie, types 49, 55, 57, and 59) are more
carditis, septic arthritis, necrotizing fasciitis, commonly associated with pyoderma and

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Group A Streptococcal Infections 569

Box 127.1
Streptococcal Toxic Shock Syndrome: Clinical Case Definitiona

I. Isolation of group A streptococcus (Streptococcus pyogenes)


A. From a normally sterile site (eg, blood, cerebrospinal fluid, peritoneal fluid, tissue
biopsy specimen)
B. From a nonsterile site (eg, throat, sputum, vagina, open surgical wound, superficial
skin lesion)
II. Clinical signs of severity
A. Hypotension: systolic pressure 90 mm Hg or less in adults or lower than the fifth percentile
for age in children
AND
B. Two or more of the following signs:
• Renal impairment: creatinine concentration 177 µmol/L (2 mg/dL) or greater for adults
or at least 2 times the upper limit of reference range for ageb
• Coagulopathy: platelet count 100,000/mm3 or less or disseminated intravascular
­coagulation
• Hepatic involvement: elevated alanine transaminase, aspartate transaminase, or total
bilirubin concentrations at least 2 times the upper limit of reference range for age
• Adult respiratory distress syndrome
• A generalized erythematous macular rash that may desquamate
• Soft tissue necrosis, including necrotizing fasciitis or myositis, or gangrene

a
An illness fulfilling criteria IA and IIA and IIB can be defined as a definite case. An illness fulfilling criteria IB and IIA and IIB can be defined
as a probable case if no other cause for the illness is identified.
b
In patients with preexisting renal or hepatic disease, concentrations of 2-fold or greater elevation over patient’s baseline.
Adapted from The Working Group on Severe Streptococcal Infections. Defining the group A streptococcal toxic shock syndrome. Rationale
and consensus definition. JAMA. 1993;269(3):390–391.

acute glomerulonephritis. Other serotypes care centers, contact sports (eg, wrestling),
(ie, types 1, 6, and 12) are associated with phar- boarding schools, and military installations
yngitis and acute glomerulonephritis. Most facilitates transmission. Foodborne outbreaks
cases of streptococcal TSS are caused by strains of pharyngitis occur rarely and are a conse-
producing at least one of several different pyro- quence of human contamination of food in
genic exotoxins, most commonly streptococcal conjunction with improper food preparation
pyrogenic exotoxin A. These toxins act as or refrigeration procedures.
super­antigens that stimulate production of
Streptococcal pharyngitis occurs at all ages but
tumor necrosis factor and other inflammatory
is most common among school-aged children
mediators that cause capillary leak and other
and adolescents, peaking at 7 to 8 years of age.
physiologic changes, leading to hypotension
Group A streptococcal pharyngitis and pyo-
and organ damage.
derma are substantially less common in adults
Epidemiology than in children.
Pharyngitis usually results from contact with Geographically, GAS pharyngitis and pyo-
the respiratory tract secretions of a person who derma are ubiquitous. Pyoderma is more
has GAS pharyngitis. Fomites and household ­common in tropical climates and warm sea-
pets, such as dogs, are not vectors of GAS sons, presumably because of antecedent insect
infection. Pharyngitis and impetigo (and their bites and other minor skin trauma. Strepto­
nonsuppurative complications) can be associ- coccal pharyngitis is more common during
ated with crowding, which is often present in late autumn, winter, and spring in temperate
socioeconomically disadvantaged populations. climates, in part because of close person-to-
The close contact that occurs in schools, child person contact in schools. Communicability

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570 Group A Streptococcal Infections

of patients with streptococcal pharyngitis In the United States, the incidence of invasive
is highest during acute infection and, when GAS infections is highest in infants and the
untreated, gradually diminishes over a period elderly. Fatal cases in children are not com-
of weeks. Patients are not considered to be mon. Before use of varicella vaccine, varicella
­contagious beginning 24 hours after initiation was the most commonly identified predispos-
of appropriate antimicrobial therapy. ing factor for invasive GAS infection. Other
factors increasing risk include exposure to
Throat culture surveys of healthy asymptom-
other children and household crowding. The
atic children during school outbreaks of phar-
portal of entry is unknown in most invasive
yngitis have yielded group A streptococci
GAS infections but is presumed to be skin or
prevalence rates as high as 25%. These surveys
mucous membranes. Such infections rarely
identified children who were pharyngeal car­
follow symptomatic GAS pharyngitis. An
riers. Carriage of group A streptococci can
­association between use of nonsteroidal
persist for many months, but risk of trans­
­a nti-inflammatory drugs and invasive GAS
mission from carriers to others is low.
infections in children with varicella has been
The incidence of ARF in the United States described, but a causal relationship has not
decreased sharply during the 20th century, been established.
and rates of this nonsuppurative sequela are
The incidence of streptococcal TSS is highest
low. Focal outbreaks of ARF in school-aged
among young children and the elderly,
children occurred in several areas in the 1990s,
although streptococcal TSS can occur at
and small clusters continue to be reported
any age. Of all cases of invasive streptococcal
­periodically. The highest rates of ARF are in
infections in children, fewer than 5% are asso-
Utah, Hawaii, New York, and Pennsylvania,
ciated with streptococcal TSS. Among chil-
most likely related to circulation of rheumato-
dren, streptococcal TSS has been reported
genic strains. Their occurrence reemphasizes
with focal lesions (eg, varicella, cellulitis,
the importance of diagnosing GAS pharyngitis
trauma, osteomyelitis), pneumonia, and
and treating with a recommended antimicro-
­bacteremia without a defined focus. Mortal-
bial regimen.
ity rates are substantially lower for children
In streptococcal impetigo, the organism is than for adults with streptococcal TSS.
­usually acquired by direct contact from
Incubation Period
another person. Group A streptococcal colo­
nization of healthy skin usually precedes For streptococcal pharyngitis, 2 to 5 days; for
­development of impetigo, but group A strep­ impetigo, 7 to 10 days; for streptococcal TSS,
tococci do not penetrate intact skin. Impetigi- unknown, but can be as short as 14 hours in
nous lesions occur at the site of breaks in skin some cases (eg, childbirth, penetrating trauma).
(eg, insect bites, burns, traumatic wounds, var- Diagnostic Tests
icella lesions). After development of impetigi-
nous lesions, the upper respiratory tract often Children with pharyngitis and obvious viral
becomes colonized with group A streptococci. symptoms (eg, rhinorrhea, cough, hoarseness)
Infection of surgical wounds and postpartum should not be tested or treated for GAS infec-
(puerperal) sepsis usually result from trans- tion. Laboratory confirmation is required for
mission through direct contact. Health care cases in children without viral symptoms
workers who are anal or vaginal carriers and because many will not have GAS pharyngitis.
people with skin infection can transmit GAS A specimen should be obtained by vigorous
organisms to surgical and obstetric patients, swabbing of a pair of swabs on tonsils and the
resulting in health care–associated outbreaks. posterior pharynx for culture or rapid antigen
Infections in neonates result from intrapartum testing. It is recommended that a throat swab
or contact transmission; in the latter situation, with a negative rapid antigen test result from
infection can begin as omphalitis, cellulitis, or children be submitted to the laboratory for
necrotizing fasciitis. isolation of group A streptococci; the second
swab can be used for this purpose. Culture

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Group A Streptococcal Infections 571

on sheep blood agar can confirm GAS infec- tive predictive value than testing performed
tion, with latex agglutination differentiating in a clinical setting. Because of the high speci-
group A streptococci from other β-hemolytic ficity of rapid tests, a positive test result does
streptococci. False-negative culture results not require throat culture confirmation.
occur in fewer than 10% of symptomatic Rapid diagnostic tests using techniques such
patients when an adequate throat swab speci- as polymerase chain reaction and chemilumi-
men is obtained and cultured by trained nescent DNA probes have been developed. The
­personnel. Recovery of group A streptococci US Food and Drug Administration recently
from the pharynx does not distinguish patients approved an isothermal nucleic acid amplifica-
with true streptococcal infection (defined by a tion test for detection of group A streptococci
serologic response to extracellular antigens from throat swab specimens. These tests may
[eg, streptolysin O]) from streptococcal carri- be as sensitive as standard throat cultures on
ers who have an intercurrent viral pharyngitis. sheep blood agar. The diagnosis of ARF is
The number of colonies of group A strepto- based on the Jones criteria (Box 127.2).
cocci on an agar culture plate also does not
reliably differentiate true infection from car- Indications for Group A Streptococcal
riage. Cultures that are negative for group A ­ esting
T
streptococci after 18 to 24 hours should be Factors to be considered in the decision to
incubated for a second day to optimize recov- obtain a throat swab specimen for testing
ery of organisms. ­children with pharyngitis are the patient’s age,
signs and symptoms, season, and family and
Several rapid diagnostic tests for GAS pharyn-
community epidemiology, including contact
gitis are available. Most are based on nitrous
with a person with GAS infection or presence
acid extraction of GAS carbohydrate antigen
in the family of a person with a history of ARF
from organisms obtained by throat swab.
or of poststreptococcal glomerulonephritis.
­Specificities of these tests are generally high,
Group A streptococcal pharyngitis and, there-
but the reported sensitivities vary consider-
fore, ARF are uncommon in children younger
ably (ie, false-negative results occur). As with
than 3 years, but outbreaks of GAS pharyngitis
throat swab cultures, sensitivity of these tests
have been reported in young children in child
is highly dependent on the quality of the
care settings. The risk of ARF is so remote in
throat swab specimen, experience of the per-
young children in industrialized countries that
son performing the test, and rigor of the cul-
diagnostic studies for GAS pharyngitis are not
ture method used for comparison. The US
generally indicated. Children with manifesta-
Food and Drug Administration has cleared a
tions highly suggestive of viral infection, such
variety of rapid tests for use in home settings.
as coryza, conjunctivitis, hoarseness, cough,
Parents should be informed that their use is
anterior stomatitis, discrete ulcerative oral
discouraged, and clinicians should be aware
lesions, or diarrhea, are unlikely to have GAS
that such testing may have an even lower nega-
pharyngitis and generally should not be tested.

Box 127.2
Jones Criteria for Diagnosis of Acute Rheumatic Fevera
Major Criteria Minor Criteria Supporting Evidence
Carditis Clinical findings: Fever, arthralgiab Positive throat culture or rapid test
Polyarthritis Laboratory findings: Elevated for GAS antigen

Chorea acute phase reactants; ­prolonged OR


P–R interval Elevated or rising streptococcal
Erythema marginatum
antibody test
Subcutaneous nodules

Abbreviation: GAS, group A streptococcal.


a
Diagnosis requires 2 major criteria or 1 major and 2 minor criteria with supporting evidence of antecedent group A streptococcal infection.
b
Arthralgia is not a minor criterion in a patient with arthritis as a major criterion.

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572 Group A Streptococcal Infections

In contrast, children with acute onset of sore members have pharyngitis or other GAS infec-
throat and clinical signs and symptoms such tions, simultaneous cultures of all household
as pharyngeal exudate, pain on swallowing, members and treatment of all people with
fever, and enlarged tender anterior cervical ­positive cultures or rapid antigen test results
lymph nodes or exposure to a person with may be of value.
GAS pharyngitis are more likely to have GAS
infection and should have a rapid antigen test, Testing for Group A Streptococci in
and a throat culture if rapid test result is nega- ­Nonpharyngitis Infections
tive, performed and treatment initiated if a Cultures of impetiginous lesions often yield
test result is positive. streptococci and staphylococci, and deter­
mination of the primary pathogen is generally
Testing Contacts for Group A Streptococcal not possible. Culture is performed when it is
Infection necessary to determine susceptibility of the
Indications for testing contacts for GAS Staphylococcus aureus organisms. In suspected
­infection vary according to circumstances. invasive GAS infections, cultures of blood and
Testing asymptomatic household contacts for of focal sites of possible infection are indicated.
GAS infection is not recommended except In necrotizing fasciitis, imaging studies can
when the contacts are at increased risk of delay, rather than facilitate, establishing the
developing sequelae of GAS infection, ARF, diagnosis. Clinical suspicion of necrotizing
or acute glomerulonephritis; if test results are fasciitis should prompt surgical evaluation
positive, contacts should be treated. with intervention, including debridement of
deep tissues with Gram stain and culture of
Follow-up Throat Cultures surgical specimens.
Posttreatment throat swab cultures are indi-
Streptococcal TSS is diagnosed on the basis
cated only for patients who are at particularly
of clinical findings and isolation of group A
high risk of ARF or have active symptoms
streptococci (see Box 127.2). Blood culture
compatible with GAS pharyngitis. Repeated
results are positive for S pyogenes in approxi-
courses of antimicrobial therapy are not indi-
mately 50% of patients with streptococcal TSS.
cated for asymptomatic patients with cultures
Culture results from a focal site of infection are
positive for group A streptococci; the excep-
also usually positive and can remain so for
tions are people who have had or whose family
several days after appropriate antimicrobial
members have had ARF or other uncommon
agents have been initiated. S pyogenes species is
epidemiologic circumstances, such as a com-
uniformly susceptible to β-lactam antimicro-
munity outbreak of ARF or acute poststrepto-
bial agents (penicillins and cephalosporins),
coccal glomerulonephritis.
and susceptibility testing is only needed for
Patients who have repeated episodes of non–­β -lactam agents, such as erythromycin or
­ haryngitis at short intervals and in whom
p clindamycin, to which S pyogenes can be resis-
GAS infection is documented by culture or tant. A significant increase in antibody titers
antigen detection test present a special prob- to streptolysin O, deoxyribonuclease B, or
lem. Most often, these people are chronic GAS other streptococcal extracellular enzymes 4
carriers who are experiencing frequent viral to 6 weeks after infection can help to confirm
illnesses and for whom repeated testing and the diagnosis if culture results are negative.
use of antimicrobial agents are unnecessary. In
Treatment
assessing such patients, inadequate adherence
to oral treatment should also be considered. Pharyngitis
Although relatively uncommon, macrolide and Penicillin V is the drug of choice for treatment
azalide resistance among GAS strains occurs, of GAS pharyngitis. A clinical GAS isolate
resulting in erythromycin, clarithromycin, or resistant to penicillin or cephalosporin has
azithromycin treatment failures. Testing never been documented. Prompt administra-
asymptomatic household contacts is usually tion of penicillin shortens the clinical course,
not helpful. However, if multiple household decreases risk of suppurative sequelae and

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Group A Streptococcal Infections 573

transmission, and prevents ARF even when higher rates of gastrointestinal tract adverse
given up to 9 days after illness onset. For all effects compared with clarithromycin or
patients with ARF, a complete course of peni- azithromycin. Group A streptococcal strains
cillin or another appropriate antimicrobial resistant to macrolides or azalides have been
agent for GAS pharyngitis should be given to highly prevalent in some areas of the world
eradicate group A streptococci from the throat, and have resulted in treatment failures. In
even if group A streptococci are not recovered recent years, macrolide resistance rates in
in the initial throat culture. Orally adminis- most areas of the United States have been 5%
tered amoxicillin as a single dose daily for to 10%, but resistance rates up to 20% have
10 days is as effective as orally administered been reported, and continued monitoring is
penicillin V or amoxicillin given multiple necessary. Tetracyclines, sulfonamides (includ-
times per day for 10 days and comes as a more ing trimethoprim-sulfamethoxazole), and
palatable suspension. This regimen has been ­fluoroquinolones should not be used for
endorsed by the American Heart Association ­treating GAS pharyngitis.
in its guidelines for the treatment of GAS
Children who have a recurrence of GAS phar-
­pharyngitis and the prevention of ARF.
yngitis shortly after completing a full course
Treatment failures may occur more often of a recommended oral antimicrobial agent
with oral penicillin than with intramuscular can be retreated with the same antimicrobial
penicillin G benzathine because of inadequate agent, an alternative oral drug, or an intra­
adherence to oral therapy. In addition, short- muscular dose of penicillin G benzathine,
course treatment (<10 days) for GAS pharyn­ especially if inadequate adherence to oral
gitis, particularly with penicillin V, is ­t herapy is suspected. Alternative drugs include
associated with inferior bacteriologic eradi­ a narrow-spectrum cephalosporin (ie, cepha-
cation rates. Intramuscular penicillin G lexin), amoxicillin-clavulanate, clindamycin,
­benzathine is appropriate therapy. It ensures a macrolide, or azalide. Expert opinions dif-
adequate blood concentrations and avoids the fer about the most appropriate therapy in
problem of adherence, but administration is this circumstance.
painful. Discomfort is less if the preparation
Management of a patient who has repeated
of penicillin G benzathine is brought to room
and frequent episodes of acute pharyngitis
temperature before intramuscular injection.
associated with positive laboratory tests for
Mixtures containing shorter-acting penicillins
group A streptococci is problematic. To
(eg, penicillin G procaine) in addition to peni-
­determine whether the patient is a long-term
cillin G benzathine have not been demon-
streptococcal pharyngeal carrier who is experi-
strated to be more effective than penicillin G
encing repeated episodes of intercurrent viral
benzathine alone but are less painful when
pharyngitis (which is the situation in most
administered. For patients who have a history
cases), the following should be determined:
of nonanaphylactic allergy to penicillin, a
whether the clinical findings are more sugges-
10-day course of a narrow-spectrum (first-­
tive of group A streptococci or a virus as the
generation) oral cephalosporin (ie, cephalexin)
cause; whether epidemiologic factors in the
is indicated. Patients with immediate (ana­
community support group A streptococci or
phylactic) or type 1 hypersensitivity to penicil-
a virus as the cause; the nature of the clinical
lin should be treated with oral clindamycin
response to the antimicrobial therapy (in true
(30 mg/kg per day in 3 divided doses; maxi-
GAS pharyngitis, response to therapy is usu-
mum, 900 mg/d for 10 days) rather than a
ally 24 hours or less); and whether laboratory
cephalosporin.
test results are positive for GAS infection
An oral macrolide or azalide (eg, erythro­ between episodes of acute pharyngitis (sug-
mycin, clarithromycin, azithromycin) is also gesting the patient is a carrier). Measurement
acceptable for patients who are allergic to peni- of a serial serologic response to GAS extracel-
cillins. Therapy for 10 days is indicated except lular antigens (eg, antistreptolysin O) should
for azithromycin, which is indicated for 5 days. be discouraged.
Erythromycin is associated with substantially

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574 Group A Streptococcal Infections

Pharyngeal Carriers localized disease. With multiple lesions or


Antimicrobial therapy is not indicated for with nonbullous impetigo in multiple family
most GAS pharyngeal carriers. The few specific members, child care groups, or athletic teams,
situations in which eradication of carriage may impetigo should be treated with oral antimi-
be indicated include a local outbreak of ARF crobials active against group A streptococci
or poststreptococcal glomerulonephritis, an and S aureus.
outbreak of GAS pharyngitis in a closed or
Toxic Shock Syndrome
semiclosed community, a family history of
ARF, or multiple (“ping-pong”) episodes of Most aspects of management are the same
documented symptomatic GAS pharyngitis for TSS caused by group A streptococci or by
occurring within a family for many weeks S aureus (Box 127.3 and Box 127.4). Paramount
despite appropriate therapy. are immediate aggressive fluid replacement
management of respiratory and cardiac failure,
Group A streptococcal carriage can be diffi- if present, and aggressive surgical debridement
cult to eradicate with conventional anti­ of any deep-seated infection. Because S pyo­
microbial therapy. A number of antimicrobial genes and S aureus TSSs are ­difficult to distin-
agents, including clindamycin, cephalosporins, guish clinically, initial anti­microbial therapy
­a moxicillin-clavulanate, azithromycin, or a should include an anti­staphylococcal agent and
combination that includes penicillin V or peni- a protein synthesis–inhibiting antimicrobial
cillin G benzathine with rifampin for the last agent, such as clinda­mycin. The addition of
4 days of treatment, have been demonstrated clindamycin to penicillin is recommended for
to be more effective than penicillin alone in serious GAS infections because the antimicro-
eliminating chronic streptococcal carriage. bial activity of clindamycin is not affected by
Of these drugs, oral clindamycin for 10 days inoculum size, has a long postantimicrobial
has been reported to be most effective. Docu- effect, and acts on bacteria by inhibiting pro-
mented eradication of the carrier state is help- tein synthesis. Inhibition of protein synthesis
ful in the evaluation of subsequent episodes of results in suppression of ­synthesis of the S pyo­
acute pharyngitis; however, carriage can recur genes antiphagocytic M-protein and bacterial
after reacquisition of GAS infection, as some toxins. Clindamycin should not be used alone
individuals appear to be “carrier prone.” as initial antimicrobial therapy in life-threat-
ening situations because, in the United States,
Nonbullous Impetigo
1% to 2% of GAS strains are resistant to
Local mupirocin or retapamulin ointment may clindamycin. Higher resistance rates have been
be useful for limiting person-to-person spread reported for strains associated with invasive
of nonbullous impetigo and for eradicating infection and may be as high as 10%.

Box 127.3
Management of Streptococcal Toxic Shock S
­ yndrome Without
Necrotizing Fasciitis

• Fluid management to maintain adequate venous return and cardiac filling pressures to prevent
end-organ damage
• Anticipatory management of multisystem organ failure
• Parenteral antimicrobial therapy at maximum doses with the capacity to
——Kill organism with bactericidal cell wall inhibitor (eg, β-lactamase–resistant antimicrobial
agent).
——Decrease enzyme, toxin, or cytokine production with protein synthesis inhibitor (eg,
clindamycin).
• IVIG may be considered for infection refractory to several hours of aggressive therapy or in the
presence of an undrainable focus or persistent oliguria with pulmonary edema.

Abbreviation: IVIG, intravenous immunoglobulin.

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Group A Streptococcal Infections 575

Box 127.4
Management of Streptococcal Toxic Shock Syndrome With
Necrotizing Fasciitis

• Immediate surgical evaluation


——Exploration or incisional biopsy for diagnosis and culture
——Resection of all necrotic tissue
• Repeated resection of tissue may be needed if infection persists or progresses.

Once GAS infection has been confirmed, meningitis, arthritis, osteomyelitis, erysipelas,
­antimicrobial therapy should be tailored to necrotizing fasciitis, and neonatal omphalitis.
penicillin and clindamycin. Intravenous ther- Treatment is often prolonged.
apy should be continued until the patient is
afebrile and stable hemodynamically and Prevention of Sequelae
blood is sterile as evidenced by negative cul- Acute rheumatic fever and acute glomerulone-
ture results. The total duration of therapy is phritis are serious nonsuppurative sequelae
based on duration established for the primary of GAS infections. During epidemics of GAS
site of infection. infections on military bases in the 1950s,
­rheumatic fever developed in 3% of untreated
Aggressive drainage and irrigation of acces-
patients with acute GAS pharyngitis. The cur-
sible sites of infection should be performed
rent incidence after endemic infections is not
as soon as possible. If necrotizing fasciitis is
known but is believed to be substantially less
suspected, immediate surgical exploration or
than 1%. The risk of ARF can be eliminated
biopsy is crucial to identify and debride the
almost completely by adequate treatment of
deep soft-tissue infection.
the antecedent GAS infection; however, rare
The use of intravenous immunoglobulin can cases have occurred even after apparently
be considered as adjunctive therapy of strepto- appropriate therapy. The effectiveness of
coccal TSS or necrotizing fasciitis if the patient ­antimicrobial therapy for preventing acute
is severely ill. poststreptococcal glomerulonephritis after
pyoderma or pharyngitis has not been estab-
Other Infections lished. Suppurative sequelae, such as periton-
Parenteral antimicrobial therapy is required sillar abscesses and cervical adenitis, are
for severe infections, such as endocarditis, usually prevented by treatment of the pri-
pneumonia, empyema, abscess, septicemia, mary infection.

ERRNVPHGLFRVRUJ
576 Group A Streptococcal Infections

Image 127.1
Streptococcus pyogenes, 24-hour sheep blood
agar plate showing β hemolysis. Courtesy of
Robert Jerris, MD. Image 127.2
Electron micrograph (magnification x70,000) of
an ultrathin section of Streptococcus pyogenes.
Courtesy of Centers for Disease Control and
Prevention/Dr Vincent A. Fischetti, Rockefeller
University.

Image 127.3
Group A streptococcal pharyngitis with inflamma­
tion of the tonsils and uvula. Courtesy of Centers
for Disease Control and Prevention.
Image 127.4
Note inflammation of the oropharynx with pete­
chiae on the soft palate, small red spots caused
by group A streptococcal pharyngitis. Courtesy
of Centers for Disease Control and Prevention.

Image 127.5
Protracted nasopharyngitis is the most common
presentation of group A streptococcal infection
in toddlers. Inflammation of the skin beneath the
nares is often present, as in this child.
Image 127.6
Cervical lymphadenitis, unilateral, in a 6-year-old
boy. The lymph node aspirate culture result was
positive for group A streptococci, while the throat
culture result was negative.

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Group A Streptococcal Infections 577

Image 127.8
Fluctuant, abscessed posterior cervical lymph
node in a 4-year-old boy with impetigo of the
Image 127.7 scalp, prepped with povidone-iodine for needle
Cervical lymphadenitis, unilateral. This is the aspiration for drainage and culture. Aspirate
same patient as in Image 127.6. culture result was positive for group A
streptococci. Courtesy of Edgar O. Ledbetter,
MD, FAAP.

Image 127.9
Posterior cervical lymph node aspiration in the
same patient as in Image 127.8. Culture result Image 127.10
was positive for group A streptococci. Courtesy Bilateral cervical lymphadenitis. The throat
of Edgar O. Ledbetter, MD, FAAP. culture result was negative, but a lymph node
aspirate culture result was positive for group A
streptococci, which obviated the need for further
diagnostic studies.

Image 127.11
A 13-year-old white boy with group A
streptococcal erysipelas of the left cheek.
Copyright Martin G. Myers, MD.

ERRNVPHGLFRVRUJ
578 Group A Streptococcal Infections

Image 127.12 Image 127.13

Facial erysipelas in a 1-year-old white boy. Group A streptococcal cellulitis. Ink marks show
Courtesy of George Nankervis, MD. the progression of cellulitis during the early hours
of penicillin treatment.

Image 127.15
Image 127.14
Group A streptococcal cellulitis (erysipelas) of
Group A streptococcal cellulitis and arthritis of the right leg in a school-aged child secondary to
the left ankle in a 4-year-old white girl. Copyright impetigo. Courtesy of George Nankervis, MD.
Michael Rajnik, MD, FAAP.

Image 127.16 Image 127.17


Group A streptococcal necrotizing fasciitis Necrotizing fasciitis of the left upper arm and
complicating varicella in a 3-year-old white girl. shoulder secondary to group A streptococcus.
Courtesy of George Nankervis, MD. Courtesy of Charles Prober.

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Group A Streptococcal Infections 579

Image 127.18
Desquamation of the skin of the hand following a group A streptococcal infection (pharyngitis) in a
13-year-old black girl. Copyright Michael Rajnik, MD, FAAP.

Image 127.19
Desquamation of the hands of the patient in Image 127.18. Copyright Michael Rajnik, MD, FAAP.

Image 127.21
The characteristic inflammatory changes in the
Image 127.20 tongue (ie, the strawberry tongue) of scarlet fever.
Pastia lines in the antecubital space of a 12-year- Courtesy of Paul Wehrle, MD.
old white boy with scarlet fever. Courtesy of
George Nankervis, MD.

ERRNVPHGLFRVRUJ
580 Group A Streptococcal Infections

Image 127.23
Erythema marginatum in a 12-year-old white girl.
Although a characteristic rash of rheumatic
fever, it is noted in fewer than 3% of cases. Its
serpiginous border and evanescent nature serve
Image 127.22 to distinguish it from erythema migrans lesions
A 4½-year-old white boy with the rash and of Lyme disease. Copyright Martin G. Myers, MD.
strawberry tongue of scarlet fever. Courtesy of
George Nankervis, MD.

Image 127.25
Erythema marginatum lesions on the anterior
trunk of a 5-year-old white boy with acute
Image 127.24
poststreptococcal rheumatic fever. Courtesy
Beau lines in the toenails of a child following a of George Nankervis, MD.
severe, protracted group A streptococcal illness.
Copyright Michael Rajnik, MD, FAAP.

Image 127.26
Streptococcus pyogenes pneumonia in a 3-year-old girl. Courtesy of Benjamin Estrada, MD.

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Group A Streptococcal Infections 581

Image 127. 27
Purpura fulminans in a 6-year-old girl with Streptococcus pyogenes septicemia. Courtesy of Benjamin
Estrada, MD.

Image 127.28
Purpura fulminans in a 6-year-old girl with Streptococcus pyogenes septicemia. Courtesy of Benjamin
Estrada, MD.

Image 127.29
Purpura fulminans in a 6-year-old girl with Streptococcus pyogenes septicemia. Courtesy of Benjamin
Estrada, MD.

ERRNVPHGLFRVRUJ
582 Group B Streptococcal Infections

128 l­ ate-onset infections in neonates and infants.


Capsular polysaccharides and surface pilus
Group B Streptococcal islands are important virulence factors and
Infections are potential vaccine candidates.
Clinical Manifestations Epidemiology
Group B streptococci are a major cause of peri- Group B streptococci are common inhabitants
natal infections, including bacteremia, endo- of the human gastrointestinal and genitouri-
metritis, chorioamnionitis, and urinary tract nary tracts. Less commonly, they colonize the
infections in pregnant women, and systemic pharynx. The colonization rate in pregnant
and focal infections in neonates and young women ranges from 15% to 35%. Colonization
infants. Invasive disease in neonates is catego- during pregnancy can be constant or inter­
rized on the basis of chronologic age at onset. mittent. Before recommendations were made
Early-onset disease usually occurs within the for prevention of early-onset group B strep­
first 24 to 36 hours of life (range, 0–6 days) and tococcal (GBS) disease through maternal
is characterized by signs of systemic infection, ­intrapartum antimicrobial prophylaxis, the
respiratory distress, apnea, shock, pneumonia, incidence was 1 to 4 cases per 1,000 live births;
and, less often, meningitis (5%–10% of cases). early-onset disease accounted for approxi-
Late-onset disease, which typically occurs at 3 mately 75% of cases in neonates and occurred
to 4 weeks of age (range, 7–89 days), commonly in approximately 1 to 2 neonates per 100
manifests as occult bacteremia or meningitis ­colonized women. Following widespread
(approximately 30% of cases); other focal infec- implementation of maternal intrapartum anti-
tions, such as osteomyelitis, septic arthritis, microbial prophylaxis, the incidence of early-
necrotizing fasciitis, pneumonia, adenitis, and onset disease has decreased by approximately
cellulitis, occur less commonly. Approximately 80% to an estimated 0.24 cases per 1,000 live
50% of survivors of early- or late-onset menin- births in 2012. The use of intrapartum chemo-
gitis have long-term neurologic sequelae prophylaxis has had no measurable effect on
(encephalomalacia, cortical blindness, cerebral late-onset GBS disease (0.32 cases per 1,000 live
palsy, visual impairment, hearing deficits, or births in 2012). The case-fatality ratio in term
learning disabilities). Late, late-onset disease neonates ranges from 1% to 3% but is higher in
occurs beyond 89 days of age, usually in very preterm neonates (estimated at 20% for early-
preterm infants requiring prolonged hospital- onset disease and 5% for late-onset disease).
ization. Group B streptococci also cause sys- Approximately 70% of early-onset and 50%
temic infections in nonpregnant adults with of late-onset cases still afflict term neonates.
one or more underlying medical conditions,
Transmission from mother to neonate occurs
such as diabetes mellitus, chronic liver or renal
shortly before or during delivery. After deliv-
disease, malignancy, or other immunocompro-
ery, person-to-person transmission can occur.
mising conditions and in adults 65 years and
Although uncommon, GBS infection can be
older.
acquired in the nursery from health care
Etiology ­professionals (probably via breaks in hand
hygiene) or visitors and, more commonly, in
Group B streptococci (Streptococcus agalactiae)
the community (colonized family members
are gram-positive, aerobic diplococci that typi-
or caregivers). The risk of early-onset disease
cally produce a narrow zone of β hemolysis
is increased in preterm neonates (<37 weeks’
on 5% sheep blood agar. These organisms are
­gestation), neonates born after the amniotic
divided into 10 types on the basis of capsular
membranes have been ruptured 18 hours or
polysaccharides (Ia, Ib, II, and III–IX). Types
more, and neonates born to women with high
Ia, Ib, II, III, and V account for approximately
genital GBS inoculum, intrapartum fever
95% of cases in neonates and infants in the
(­temperature ≥38°C [100.4°F]), chorioamnio­
United States. Type III is the predominant
nitis, GBS bacteriuria during the current preg-
cause of early-onset meningitis and most

ERRNVPHGLFRVRUJ
Group B Streptococcal Infections 583

nancy, or a previous newborn with invasive Treatment


GBS disease. A low or an undetectable mater- Ampicillin plus an aminoglycoside is the
nal concentration of capsular type-specific empirical treatment of choice for a newborn
serum antibody of the infecting strain is also with presumptive early-onset GBS infection.
a predisposing factor for neonatal infection. For initial treatment of late-onset disease,
Other risk factors are intrauterine fetal moni- ampicillin and an aminoglycoside or cefotax-
toring and maternal age younger than 20 years. ime are recommended. Penicillin G alone is
Black race is an independent risk factor for the drug of choice when group B streptococcus
early-onset and late-onset disease. Although has been identified as the cause of the infection
the incidence of early-onset disease has and when clinical and microbiologic responses
declined in all racial groups since the 1990s, have been documented. Ampicillin is an
rates have consistently been higher among acceptable alternative therapy. Except for
black neonates (0.38 cases per 1,000 live births ­meningitis or bone/joint infection, the dura-
in 2012) compared with white neonates (0.19 cases tion of treatment is 10 days. Septic arthritis or
per 1,000 live births in 2012), with the highest osteomyelitis requires treatment for 3 to
incidence observed among preterm black 4 weeks; endocarditis or ventriculitis requires
­neonates. The reason for this racial/­ethnic dis- treatment for at least 4 weeks.
parity is not known. The period of communi-
cability is unknown but can extend throughout For neonates and infants with meningitis
the duration of colonization or disease. Infants attributable to group B streptococcus, high-
can remain colonized for ­several months after dose penicillin G is the drug of choice, and
birth and after treatment for systemic infec- ampicillin is an acceptable alternative. The
tion. Recurrent GBS disease affects an esti- duration of therapy is 2 to 3 weeks. Some
mated 1% to 3% of appropriately treated infants. experts believe a second lumbar puncture
approximately 24 to 48 hours after initiation
Incubation Period of therapy assists in management and prog­
Early-onset disease, fewer than 7 days (typi- nosis. If CSF sterility is not achieved, a com­
cally <24 hours); for late-onset and late, late- plicated course (eg, cerebral infarcts,
onset disease, unknown. encephalomalacia) can be expected; also,
an increasing protein concentration suggests
Diagnostic Tests
an intracranial complication (eg, infarction,
Gram-positive cocci in pairs or short chains ventricular obstruction). Additional lumbar
by Gram stain of body fluids that are typically punctures are indicated if response to therapy
sterile (eg, cerebrospinal fluid [CSF], pleural is in doubt, neurologic abnormalities persist,
fluid, joint fluid) provide presumptive evidence or focal neurologic deficits occur. Failed hear-
of infection. Growth of the organism from cul- ing screen, abnormal neurologic examination,
tures of blood, CSF, or, if present, a suppurative and certain cranial imaging abnormalities at
focus is necessary to establish the diagnosis. discharge predict an adverse long-term out-
come. Consultation with a specialist in pediat-
ric infectious diseases is often useful.

ERRNVPHGLFRVRUJ
584 Group B Streptococcal Infections

Image 128.1
Streptococcus agalactiae on blood agar.
Courtesy of Julia Rosebush, DO; Robert Jerris,
PhD; and Theresa Stanley, M(ASCP).

Image 128.2
Bilateral, severe group B streptococcal
pneumonia in a neonate. Courtesy of David
Clark, MD.

Image 128.3
Streptococcus agalactiae necrotizing fasciitis in a
3-month-old. Courtesy of Benjamin Estrada, MD.

Image 128.4
Magnetic resonance imaging after group B
streptococcal meningitis.

Image 128.5
Neonatal group B streptococcal septic arthritis
of the right shoulder joint and osteomyelitis of
the right proximal humerus. Courtesy of Neal
Halsey, MD.

Image 128.6
Neonatal group B streptococcal septic arthritis
(left shoulder joint) and osteomyelitis of the left
proximal humerus. Courtesy of Edgar O.
Ledbetter, MD, FAAP.

ERRNVPHGLFRVRUJ
Group B Streptococcal Infections 585

Image 128.7
Necrotizing fasciitis of the periumbilical area. Group B streptococcus, Staphylococcus aureus, and
anaerobic streptococci were isolated at the time of surgical debridement. Courtesy of Edgar O.
Ledbetter, MD, FAAP.

Image 128.8
A term 3-week-old who had poor feeding and irritability followed 2 hours later by fever to 38.1°C
(100.6°F). On admission to the hospital 3 hours later, he required fluid resuscitation and intravenous
antibiotic therapy. His spinal fluid was within normal limits, but the blood culture grew group B
streptococcus. At admission, the physical examination revealed the classic facial and submandibular
erythema, tenderness, and swelling characteristic of group B streptococcal cellulitis. Courtesy of Nate
Serazin, MD, and C. Mary Healy, MD.

Image 128.9
A term 3-day-old neonate with fatal group B streptococcus sepsis and peripheral gangrene. Courtesy
of Carol J. Baker, MD, FAAP.

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586 Non–Group A or B ­Streptococcal and ­Enterococcal Infections

129 is the group C subspecies most often associated


with human infections. Streptococci that are
Non–Group A or B non–β-hemolytic (α-hemolytic or nonhemo-
­Streptococcal and lytic) on blood agar plates include Streptococ­
cus pneumoniae, a member of the Streptococcus
­Enterococcal Infections mitis group; the Streptococcus bovis group;
Clinical Manifestations and viridans streptococci clinically relevant
Streptococci other than Lancefield groups A in humans, which include 5 Streptococcus
or B can be associated with invasive disease in ­species groups (the anginosus group, the mitis
infants, children, adolescents, and adults. The group, the sanguinis group, the salivarius
principal clinical syndromes of groups C and group, and the mutans group). The anginosus
G streptococci are septicemia, upper and lower group includes S anginosus, Streptococcus
respiratory tract infections, skin and soft tissue ­constellatus, and Streptococcus intermedius.
infections, septic arthritis, meningitis with a This group can have variable hemolysis, and
parameningeal focus, brain abscess, and endo- approximately one-third possess group A, C,
carditis with various clinical manifestations. F, or G antigens. Nutritionally variant strepto-
Group F streptococcus is an infrequent cause cocci, once thought to be viridans streptococci,
of invasive infection. Viridans streptococci are now are classified in the genera Abiotrophia
the most common cause of bacterial endocar- and Granulicatella.
ditis in children, especially children with con- The genus Enterococcus (previously included
genital or valvular heart disease, and these with Lancefield group D streptococci) contains
organisms have become a common cause of at least 18 species, with Enterococcus faecalis
bacteremia in neutropenic patients with cancer and Enterococcus faecium accounting for most
and in the first 2 weeks after bone marrow human enterococcal infections. Outbreaks and
transplantation. Among the viridans strepto- health care–associated spread with Enterococ­
cocci, organisms from the Streptococcus angi­ cus gallinarum have also occurred occasionally.
nosus group often cause localized infections, Nonenterococcal group D streptococci include
such as brain or dental abscesses or abscesses S bovis and Streptococcus equinus, both mem-
in other sites, including lymph nodes, liver, bers of the bovis group.
and lung. Enterococci are associated with
­bacteremia in neonates and bacteremia, Epidemiology
device-associated infections, intra-abdominal The habitats that non-group A and B strepto-
abscesses, and urinary tract infections in older cocci and enterococci occupy in humans
children and adults. include the skin (groups C and G), oropharynx
(groups C and G and the mutans group),
Etiology
­gastrointestinal tract (groups C and G, the
Changes in taxonomy and nomenclature of bovis group, and Enterococcus species), and
the Streptococcus genus have evolved with vagina (groups C, D, and G and Enterococcus
advances in molecular technology. Among species). Typical human habitats of different
gram-positive organisms that are catalase neg- species of viridans streptococci are the oro-
ative and display chains by Gram stain, the pharynx, epithelial surfaces of the oral cavity,
genera associated most often with human dis- teeth, skin, and gastrointestinal and geni­
ease are Streptococcus and Enterococcus. The tourinary tracts. Intrapartum transmission
genus Streptococcus has been subdivided into is responsible for most cases of early-onset
7 species groups on the basis of 16S rRNA gene ­neonatal infection caused by non-group A
sequencing. Members of the genus that are and B streptococci and enterococci. Environ-
β-hemolytic on blood agar plates include mental contamination or transmission via
­Streptococcus pyogenes, Streptococcus agalac­ hands of health care professionals can lead
tiae and groups C and G streptococci, all in to colonization of patients. Groups C and G
the Streptococcus pyogenes species group. streptococci have been known to cause food-
­Streptococcus dysgalactiae subsp equisimilis borne outbreaks of pharyngitis.

ERRNVPHGLFRVRUJ
Non–Group A or B ­Streptococcal and ­Enterococcal Infections 587

Incubation Period bination of high-dose penicillin or vancomycin


Unknown. and an aminoglycoside can enhance bacteri-
cidal ­activity.
Diagnostic Tests
Enterococci exhibit uniform resistance to
Diagnosis is established by culture of usually cephalosporins, and isolates resistant to van­
sterile body fluids with appropriate biochemi- comycin, especially E faecium, are increasing
cal testing and serologic analysis for definitive in prevalence. In general, children with a
identification. Antimicrobial susceptibility ­central line–associated bloodstream infection
testing of isolates from usually sterile sites caused by enterococci should have the device
should be performed to guide treatment of removed promptly.
infections caused by viridans streptococci or
enterococci. The proportion of vancomycin- Systemic enterococcal infections, such as
resistant enterococci among hospitalized ­endocarditis or meningitis, should be treated
patients can be as high as 30%. with ampicillin (if the isolate is susceptible) or
vancomycin in combination with an amino­
Treatment glycoside. Gentamicin is the aminoglycoside
Penicillin G is the drug of choice for groups recommended for achieving synergy. Genta­
C and G streptococci. Other agents with good micin should be discontinued if in vitro sus-
activity include ampicillin, cefotaxime, van­ ceptibility testing demonstrates high-level
comycin, and linezolid. The combination of resistance, in which case synergy cannot be
gentamicin with a β-lactam antimicrobial achieved. The role of combination therapy for
agent (eg, penicillin, ampicillin) or vancomy- treating central line–associated bloodstream
cin may enhance bactericidal activity needed infections is uncertain. Linezolid or dapto­
for treatment of life-threatening infections mycin are options for treatment of infections
(eg, endocarditis, meningitis). caused by vancomycin-resistant E faecium.
Isolates of vancomycin-resistant enterococci
Many viridans streptococci remain highly that are also resistant to linezolid have been
­susceptible to penicillin. Strains with a mini- described. Resistance to linezolid among
mum inhibitory concentration greater than ­vancomycin-resistant enterococci isolates can
0.12 mcg/mL and less than or equal to 0.5 mcg/ also develop during prolonged treatment.
mL are considered relatively resistant by Although most vancomycin-resistant isolates
­criteria in the American Heart Association of E faecalis and E faecium are daptomycin
guidelines for determining treatment of strep- susceptible, daptomycin is only approved for
tococcal endocarditis. Strains with a penicillin use in adults and experience in children is
minimum inhibitory concentration greater ­limited. Daptomycin should not be used to
than 0.5 mcg/mL are considered resistant. treat pneumonia, as tissue levels are poor and
Nonpenicillin antimicrobial agents with good daptomycin is inactivated by surfactants.
activity against viridans streptococci include
cephalosporins (especially ceftriaxone), vanco- • Endocarditis. Guidelines for antimicrobial
mycin, linezolid, daptomycin, and tigecycline, therapy in adults have been formulated by
although pediatric experience with daptomy- the American Heart Association and should
cin and tigecycline is limited. Abiotrophia and be consulted for regimens that are appropri-
Granulicatella organisms can exhibit relative ate for children and adolescents.
or high-level resistance to penicillin. The com-

ERRNVPHGLFRVRUJ
588 Non–Group A or B ­Streptococcal and ­Enterococcal Infections

Image 129.1 Image 129.2


Viridans streptococcus group on blood agar. Enterococcus faecalis on sheep blood agar.
This organism produces a zone of a hemolysis, Small, gray, flat nonhemolytic colonies with
rendering the colonies greenish in color. No smooth edges are seen. Courtesy of Julia
zone of inhibition is seen surrounding the P disc, Rosebush, DO; Robert Jerris, PhD; and
distinguishing it from Streptococcus pneumoniae. Theresa Stanley, M(ASCP).
Courtesy of Julia Rosebush, DO; Robert Jerris,
PhD; and Theresa Stanley, M(ASCP).

Image 129.3 Image 129.4


Conjunctival (palpebral) petechiae in an Brain from a neonate with Enterococcus faecalis
adolescent girl with Streptococcus viridans meningitis showing copious purulent exudate
subacute bacterial endocarditis. covering the meninges. Courtesy of Edgar O.
Ledbetter MD, FAAP.

Image 129.5
A conjunctival hemorrhage in an adolescent
female with enterococcal endocarditis. Courtesy Image 129.6
of George Nankervis, MD. A patient with Osler nodes from viridans
streptococcus bacterial endocarditis. Copyright
Martin G. Myers, MD.

ERRNVPHGLFRVRUJ
Non–Group A or B ­Streptococcal and ­Enterococcal Infections 589

Image 129.8
A Janeway lesion on the sole of the same patient
as in Image 129.5 with enterococcal endocarditis.
Image 129.7
Courtesy of George Nankervis, MD.
Osler nodes on the fingers and a Janeway lesion
in the palm of the same patient as in Image 129.5
with enterococcal endocarditis. Courtesy of
George Nankervis, MD.

Image 129.10
Janeway lesions in a 13-year-old girl with
viridans streptococcus endocarditis. Courtesy
of Benjamin Estrada, MD.

Image 129.9
Hemorrhagic retinitis with Roth spots in
the adolescent female in Image 129.5 with
enterococcal endocarditis. Courtesy of
George Nankervis, MD.

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590 Non–Group A or B ­Streptococcal and ­Enterococcal Infections

Image 129.11
Computed tomography scan showing a large liver abscess in a previously healthy 5-year-old white girl
with abdominal pain and nausea. Cultures were positive for Milleri group streptococci. Courtesy of
Preeti Jaggi, MD.

Image 129.12
A liver abscess in a 7-year-old boy from which viridans streptococci were isolated. Courtesy of
Benjamin Estrada, MD.

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Strongyloidiasis 591

130 cats, and other animals can serve as reservoirs.


Transmission involves penetration of skin by
Strongyloidiasis filariform larvae from contact with contami-
(Strongyloides stercoralis) nated soil. Infections rarely can be acquired
Clinical Manifestations from intimate skin contact or from inadvertent
coprophagy, such as from ingestion of contam-
Most infections with Strongyloides stercoralis inated food or within institutional settings.
are asymptomatic. When symptoms occur, Adult females release eggs in the small intes-
they are most often related to larval skin tine, where they hatch as first-stage (rhabditi-
­invasion, tissue migration, or the presence of form) larvae that are excreted in feces. A small
adult worms in the intestine. Infective (filari- percentage of larvae molt to the infective (filar-
form) larvae are acquired from skin contact iform) stage during intestinal transit, at which
with contaminated soil, producing transient point they can penetrate the bowel mucosa or
pruritic papules at the site of penetration. perianal skin, thus maintaining the life cycle
­Larvae migrate to the lungs and can cause a within a single person (autoinfection). Because
transient pneumonitis or Löffler-like syn- of this capacity for autoinfection, people can
drome. After ascending the tracheobronchial remain infected for decades after leaving an
tree, larvae are swallowed and mature into area with endemic infection.
adults within the gastrointestinal tract. Symp-
toms of intestinal infection include nonspe- Incubation Period
cific abdominal pain, malabsorption, vomiting, Unknown.
and diarrhea. Larval migration from defecated
stool can result in migratory pruritic skin Diagnostic Tests
lesions in the perianal area, buttocks, and Strongyloidiasis can be difficult to diagnose in
upper thighs, which may present as serpigi- immunocompetent people because excretion
nous, erythematous tracks called larva currens. of larvae in feces is highly variable and often of
Immunocompromised people, most often low intensity. At least 3 consecutive stool speci-
those receiving glucocorticoids for underlying mens should be examined microscopically for
malignancy or autoimmune disease, people characteristic larvae (not eggs), but stool con-
receiving biologic response modifiers, and centration techniques may be required to
­people infected with human T-lymphotropic establish the diagnosis. The use of agar plate
virus 1, are at risk of Strongyloides hyperinfec- culture methods can have greater sensitivity
tion syndrome and disseminated disease, in than fecal microscopy, and examination of
which larvae migrate via the systemic circula- duodenal contents obtained using the string
tion to distant organs, including the brain, test (Entero-Test) or a direct aspirate through
liver, kidney, heart, and skin. This condition, a flexible endoscope may also demonstrate
which is frequently fatal, is characterized by ­larvae. Eosinophilia (blood eosinophil count
fever, abdominal pain, diffuse pulmonary infil- >500/µL) is common in chronic infection but
trates, and septicemia or meningitis caused by can be absent in hyperinfection syndrome.
enteric gram-negative bacilli. Serodiagnosis is sensitive and should be
­considered in all people with unexplained
Etiology
eosinophilia, especially if immunomodulatory
S stercoralis is a nematode (roundworm). therapy is being considered.
Epidemiology In disseminated strongyloidiasis, filariform
Strongyloidiasis is endemic in the tropics larvae can be isolated from sputum or bron-
and subtropics, including the southeastern choalveolar lavage fluid as well as spinal fluid.
United States, wherever suitable moist soil and Gram-negative bacillary meningitis is a com-
improper disposal of human waste coexist. mon associated finding in disseminated disease
Humans are the principal hosts, but dogs, and carries a high mortality rate.

ERRNVPHGLFRVRUJ
592 Strongyloidiasis

Treatment it is associated with lower cure rates. Prolonged


Ivermectin is the treatment of choice for or repeated treatment may be necessary in
chronic (asymptomatic) strongyloidiasis and ­people with hyperinfection and disseminated
hyperinfection with disseminated disease. strongyloidiasis, and relapse can occur.
An alternative agent is albendazole, although

Image 130.1
Strongyloides stercoralis larvae (low-power magnification).

Image 130.2
Adult female of Strongyloides stercoralis collected in bronchial fluid of a patient with disseminated
disease (scale bar = 400 µm). Courtesy of Centers for Disease Control and Prevention/Emerging
Infectious Diseases.

ERRNVPHGLFRVRUJ
Strongyloidiasis 593

Image 130.3
The Strongyloides life cycle is complex among helminths with its alternation between free-living and
parasitic cycles and its potential for autoinfection and multiplication within the host. Two types of
cycles exist. Free-living cycle: The rhabditiform larvae passed in the stool (1) (see Parasitic cycle) can
molt twice and become infective filariform larvae (direct development) (6) or molt 4 times and become
free-living adult males and females (2) that mate and produce eggs (3), from which rhabditiform larvae
hatch (4). The latter, in turn, can develop (5) into a new generation of free-living adults (as represented
in 2) or into infective filariform larvae (6). The filariform larvae penetrate the human host skin to initiate
the parasitic cycle. Parasitic cycle: Filariform larvae in contaminated soil penetrate human skin (6)
and are transported to the lungs, where they penetrate the alveolar spaces; they are carried through
the bronchial tree to the pharynx, are swallowed, and then reach the small intestine (7). In the small
intestine they molt twice and become adult female worms (8). The females live threaded in the
epithelium of the small intestine and by parthenogenesis produce eggs (9), which yield rhabditiform
larvae. The rhabditiform larvae can be passed in the stool (1) (see Free-living cycle) or can cause
autoinfection (10). In autoinfection, the rhabditiform larvae become infective filariform larvae, which can
penetrate the intestinal mucosa (internal autoinfection) or the skin of the perianal area (external
autoinfection); in either case, the filariform larvae may follow the previously described route, being
carried successively to the lungs, bronchial tree, pharynx, and small intestine, where they mature into
adults; or they may disseminate widely in the body. To date, occurrence of autoinfection in humans
with helminthic infections is recognized only in Strongyloides stercoralis and Capillaria philippinensis
infections. In the case of Strongyloides, autoinfection may explain the possibility of persistent
infections for many years in persons who have not been in an endemic area and of hyperinfections
in immunodepressed individuals. Courtesy of Centers for Disease Control and Prevention/Alexander
J. da Silva, PhD/Melanie Moser.

ERRNVPHGLFRVRUJ
594 Syphilis

131 sure (10–90 days) and heal spontaneously in


a few weeks. Chancres are sometimes not
Syphilis ­recognized clinically and are sometimes still
Clinical Manifestations present during the secondary stage of syphilis.
The secondary stage (or “secondary syphilis”),
Congenital Syphilis beginning 1 to 2 months later, is characterized
Intrauterine infection with Treponema pallidum by rash, mucocutaneous lesions, and lymph-
can result in stillbirth, hydrops fetalis, or pre- adenopathy. The polymorphic maculopapular
term birth or can be asymptomatic at birth. rash is generalized and typically includes the
Infected neonates and infants can have hepa­ palms and soles. In moist areas around the
tosplenomegaly, snuffles (copious nasal secre- vulva or anus, hypertrophic papular lesions
tions), lymphadenopathy, mucocutaneous (condyloma lata) can occur and can be con-
lesions, pneumonia, osteochondritis and pseu- fused with condyloma acuminata secondary
doparalysis, edema, rash, hemolytic anemia, to human papillomavirus infection. General-
or thrombocytopenia at birth or within the ized lymphadenopathy, fever, malaise, spleno-
first 4 to 8 weeks of age. Skin lesions or moist megaly, sore throat, headache, alopecia, and
nasal secretions of congenital syphilis are arthralgia can be present. Secondary syphilis
highly infectious. However, organisms are can be mistaken for other conditions because
rarely found in lesions more than 24 hours its signs and symptoms are nonspecific. This
after treatment has begun. Untreated infants, stage also resolves spontaneously without
regardless of whether they have manifestations treatment in approximately 3 to 12 weeks,
in early infancy, can develop late manifesta- ­leaving the infected person completely asymp-
tions, which usually appear after 2 years of age tomatic. A variable latent period follows but
and involve the central nervous system, bones is sometimes interrupted during the first few
and joints, teeth, eyes, and skin. Some conse- years by recurrences of symptoms of second-
quences of intrauterine infection may not ary syphilis. Latent syphilis is defined as the
become apparent until many years after birth, period after infection when patients are sero­
such as interstitial keratitis (5–20 years of age), reactive but demonstrate no clinical manifes­
eighth cranial nerve deafness (10–40 years of tations of disease. Latent syphilis acquired
age), Hutchinson teeth (peg-shaped, notched within the preceding year is referred to as
central incisors), anterior bowing of the shins, early latent syphilis; all other cases of latent
frontal bossing, mulberry molars, saddle nose, syphilis are late latent syphilis (>1 year’s
rhagades (perioral fissures), and Clutton joints ­duration). Patients who have latent syphilis
(symmetric, painless swelling of the knees). of unknown duration should be managed
The first 3 manifestations are referred to as the ­clinically as if they have late latent syphilis.
Hutchinson triad. Late manifestations can be The tertiary stage of infection occurs 15 to
prevented by treatment of early infection. 30 years after the initial infection and can
include gumma formation (soft, noncancerous
Acquired Syphilis growths that can destroy tissue), cardiovascu-
Infection with T pallidum in childhood or lar involvement (including aortitis), or neuro-
adulthood can be divided into 3 stages. The syphilis. Neurosyphilis is defined as infection
primary stage (or “primary syphilis”) appears of the central nervous system with T pallidum.
as one or more painless indurated ulcers Manifestations of neurosyphilis can include
(­chancres) of the skin or mucous membranes syphilitic meningitis, uveitis, and (typically
at the site of inoculation. Lesions most com- years after infection) dementia and posterior
monly appear on the genitalia but can appear spinal cord degeneration (tabes dorsalis).
elsewhere, depending on the sexual contact ­Neurosyphilis can occur at any stage of infec-
responsible for transmission (eg, oral). These tion, especially in people infected with HIV
lesions appear, on average, 3 weeks after expo- and neonates with congenital syphilis.

ERRNVPHGLFRVRUJ
Syphilis 595

Etiology infection). In 2008, approximately 520,900


T pallidum is a thin, motile spirochete that is adverse outcomes were estimated to be caused
extremely fastidious, surviving only briefly by maternal syphilis worldwide, including
outside the host. The organism has not been approximately 212,300 stillbirths (gestational
successfully cultivated on artificial media. age >28 weeks) or early fetal deaths (gestational
age 22–28 weeks), 91,800 neonatal deaths,
Epidemiology 65,300 neonates born preterm or with low
Syphilis, which is rare in much of the industri- birth weight, and 151,500 infected newborns.
alized world, persists in the United States and Acquired syphilis is almost always contracted
in resource-limited countries. The incidence through direct sexual contact with ulcerative
of acquired and congenital syphilis increased lesions of the skin or mucous membranes of
dramatically in the United States during the infected people. Open, moist lesions of the
late 1980s and early 1990s but decreased subse- ­primary or secondary stages are highly infec-
quently; in 2000, the incidence was the lowest tious. Relapses of secondary syphilis with
since reporting began in 1941. Since 2001, how- infectious mucocutaneous lesions have been
ever, the rate of primary and secondary syphi- observed 4 years after primary infection.
lis has increased, primarily among men who
have sex with men. Among women, the rate Sexual abuse must be suspected in any young
of primary and secondary syphilis increased child with acquired syphilis. In most cases,
during 2005–2008, with a concomitant identification of acquired syphilis in children
increase in cases of congenital syphilis; rates must be reported to state child protective ser-
of primary and secondary syphilis among vice agencies. Physical examination for signs
women and congenital syphilis have since of sexual abuse and forensic interviews may be
decreased. The highest rates of primary and conducted under the auspices of a pediatrician
secondary syphilis and congenital syphilis are with expertise in child abuse or at a local child
in the Southern United States. Late or limited advocacy center.
prenatal care and failure of health care profes- Incubation Period
sionals to follow maternal syphilis screening
recommendations have been shown to contrib- For primary syphilis, 3 weeks (range, 10–90 days).
ute to the incidence of congenital syphilis. In Diagnostic Tests
adults, infection with HIV is common among
individuals with syphilis, particularly among Definitive diagnosis is made when spirochetes
men who have sex with men. Primary and sec- are identified by microscopic darkfield exami-
ondary rates of syphilis are highest in black, nation of lesion exudate, nasal discharge, or
non-Hispanic people and in males compared tissue, such as placenta, umbilical cord, or
with females. autopsy specimens. Specimens should be
scraped from moist mucocutaneous lesions
Congenital syphilis is contracted from an or aspirated from a regional lymph node.
infected mother via transplacental trans­ ­Specimens from mouth lesions can contain
mission of T pallidum at any time during nonpathogenic treponemes that can be difficult
­pregnancy or, possibly, at birth from contact to distinguish from T pallidum by darkfield
with maternal lesions. Among women with microscopy. Although such testing can pro-
untreated early syphilis, as many as 40% of vide a definitive diagnosis, serologic testing is
pregnancies result in spontaneous abortion, also necessary.
stillbirth, or perinatal death. Infection can be
transmitted to the fetus at any stage of mater- Presumptive diagnosis is possible using non-
nal disease. The rate of transmission is 60% treponemal and treponemal serologic tests.
to 100% during primary and secondary syphi- Use of only one type of test is insufficient for
lis and slowly decreases with later stages of diagnosis because false-positive nontrepone-
maternal infection (approximately 40% with mal test results occur with various medical
early latent infection and 8% with late latent conditions, and treponemal test results remain
positive long after syphilis has been treated

ERRNVPHGLFRVRUJ
596 Syphilis

adequately (making the diagnosis of reinfec- the nontreponemal test result after treatment
tion difficult) and can be falsely positive with usually demonstrates adequate therapy,
other spirochetal diseases. whereas a sustained 4-fold increase in titer
(eg, from 1:8 to 1:32) after treatment suggests
Standard nontreponemal tests for syphilis
reinfection or relapse. The nontreponemal
include the Venereal Disease Research Labor­
test titer usually decreases 4-fold within 6 to
atory (VDRL) slide test and the rapid plasma
12 months after therapy for primary or second-
reagin (RPR) test. These tests measure anti-
ary syphilis and usually becomes nonreactive
body directed against lipoidal antigen from
within 1 year after successful therapy if the
T pallidum, antibody interaction with host
infection (primary or secondary syphilis) was
tissues, or both. These tests are inexpensive
treated early. The patient usually becomes sero-
and performed rapidly and provide semiquan-
negative within 2 years even if the initial titer
titative results. Quantitative results help define
was high or the infection was congenital. Some
disease activity and monitor response to ther-
people will continue to have low stable non-
apy. Nontreponemal test results (eg, VDRL,
treponemal antibody titers despite effective
RPR) can be falsely negative (ie, nonreactive)
therapy. This serofast state is more common in
in early primary syphilis, latent acquired
patients treated for latent or tertiary syphilis.
­syphilis of long duration, and late congenital
syphilis. Occasionally, a nontreponemal test Treponemal tests in use include the T pallidum
performed on serum samples containing high particle agglutination (TP-PA) test, T pallidum
concentrations of antibody against T pallidum enzyme immunoassay (TP-EIA), T pallidum
will be weakly reactive or falsely negative, a chemiluminescent assay (TP-CIA), and fluo-
reaction termed the prozone phenomenon. rescent treponemal antibody absorption
Diluting serum results in a positive test. Rapid (FTA-ABS) test. People who have reactive
plasma reagin titers are generally higher than trepone­mal test results usually remain reactive
VDRL titers; thus, when nontreponemal tests for life, even after successful therapy. However,
are used to monitor treatment response, the 15% to 25% of patients treated during the pri-
same specific test (eg, VDRL, RPR) must be mary stage revert to being serologically non­
used throughout the follow-up period, prefer- reactive after 2 to 3 years. Treponemal test
ably performed by the same laboratory, to antibody titers correlate poorly with disease
ensure comparability of results. activity and should not be used to assess
response to therapy.
A reactive nontreponemal test result from a
patient with typical lesions indicates a pre- Treponemal tests are also not 100% specific for
sumptive diagnosis of syphilis and the need syphilis; positive reactions occur variably in
for treatment. However, any reactive nontre­p­ patients with other spirochetal diseases, such
onemal test result must be confirmed by one as yaws, pinta, leptospirosis, rat-bite fever,
of the specific treponemal tests to exclude a relapsing fever, and Lyme disease. Nontre­p­
false-positive test result. False-positive results onemal tests can be used to differentiate
can be caused by certain viral infections Lyme disease from syphilis because the VDRL
(eg, Epstein-Barr virus infection, hepatitis, test is nonreactive in Lyme disease.
varicella, measles), lymphoma, tuberculosis,
The Centers for Disease Control and Preven-
malaria, endocarditis, connective tissue dis-
tion recommends syphilis serologic screening
ease, pregnancy, abuse of injection drugs,
with a nontreponemal test, such as the RPR
­laboratory or technical error, or Wharton
or VDRL test, to identify people with possible
jelly contamination when umbilical cord
untreated infection; this screening is followed
blood specimens are used. Treatment should
by confirmation using one of several available
not be delayed while awaiting the results of
treponemal tests. Some clinical laboratories
the treponemal test results if the patient is
and blood banks have begun to screen samples
symptomatic or at high risk of infection. A
using treponemal EIA tests rather than begin-
sustained 4-fold decrease in titer, equivalent to
ning with a nontreponemal test; the reasons for
a change of 2 dilutions (eg, from 1:32 to 1:8), of
this change in sequence of the screening relate

ERRNVPHGLFRVRUJ
Syphilis 597

to cost. However, this “reverse-sequence Testing During Pregnancy


screening” approach is associated with high All women should be screened serologically for
rates of false-positive results, and in 2011, the syphilis early in pregnancy with a nontrepone-
Centers for Disease Control and Prevention mal test (RPR or VDRL) and preferably again
reaffirmed its long-standing recommendation at delivery. In areas of high prevalence of syph-
that nontreponemal tests be used to screen for ilis and in patients considered at high risk of
syphilis and treponemal testing be used to con- syphilis, a nontreponemal serum test at the
firm syphilis as the cause of nontreponemal beginning of the third trimester (28 weeks of
reactivity. The traditional algorithm performs gestation) and at delivery is indicated. For
well in identifying people with active infection women treated for syphilis during pregnancy,
who require further evaluation and treatment follow-up nontreponemal serologic testing is
while minimizing false-positive results in low- necessary to assess the efficacy of therapy.
prevalence populations. All patients who have Low-titer false-positive nontreponemal anti-
syphilis should be tested for HIV infection body test results occasionally occur in preg-
and other sexually transmitted infections. nancy. A positive nontreponemal antibody test
result should be confirmed with a treponemal
Cerebrospinal Fluid Tests
antibody test (eg, TP-PA, TP-EIA, TP-CIA,
Cerebrospinal fluid (CSF) abnormalities in FTA-ABS). In most cases, if the treponemal
patients with neurosyphilis include increased antibody test result is negative, the nontrepo-
protein concentration, increased white blood nemal test result is falsely positive, and no
cell (WBC) count, or a reactive CSF-VDRL test ­f urther evaluation is necessary. However, in
result. The CSF-VDRL is highly specific but is patients with early syphilis, the nontreponemal
insensitive. Thus, the CSF-VDRL test results test result can be positive before the trepone-
should be interpreted cautiously because a mal test result. Therefore, retesting in 2 to
­negative result on a VDRL test of CSF does 4 weeks and later, if clinically indicated, should
not exclude a diagnosis of neurosyphilis. be considered for high-risk pregnant women
­A lternatively, a reactive CSF-VDRL test in with a positive nontreponemal test and a nega-
the CSF of neonates can be the result of non- tive treponemal test. Some laboratories are
treponemal immunoglobulin G antibodies screening pregnant women using an EIA
that cross the blood-brain barrier. The CSF treponemal test, but this “reverse-sequence”
leukocyte count is usually elevated in neuro- screening approach is not recommended.
syphilis (>5 WBCs/mm3) in a non-neonate. Pregnant women with reactive treponemal EIA
Cerebrospinal fluid test results obtained dur- screening tests should have confirmatory test-
ing the neonatal period can be difficult to ing with a nontreponemal test. Subsequent
interpret; normal values differ by gestational evaluation and possible treatment of the neo-
age and are higher in preterm neonates. Values nate should follow the mother’s RPR or VDRL
as high as 21 WBCs/mm3 or protein up to result and her management, as outlined in
130 mg/dL can occur in term neonates. Image 131.1. Any woman who delivers a still-
Although the FTA-ABS test of CSF is less born neonate after 20 weeks’ gestation should
­specific than the CSF-VDRL test, some experts be tested for syphilis.
recommend using the FTA-ABS test, believing
it to be more sensitive than the CSF-VDRL test. Evaluation of Neonates and Infants for
A ­positive CSF FTA-ABS result can support the ­Congenital Infection During the Newborn
diagnosis of neurosyphilis but, by itself, can- Period and First Months of Life
not establish the diagnosis. Fewer data exist No newborn should be discharged from the
for the TP-PA test for CSF, and none exist for hospital without determination of the mother’s
the RPR test; these tests should not be used serologic status for syphilis at least once during
for CSF ­evaluation. pregnancy and also at delivery. All neonates
born to seropositive mothers require a careful
examination and a nontreponemal syphilis
test obtained from the neonate. The test

ERRNVPHGLFRVRUJ
598 Syphilis

­ erformed on the neonate should be the same


p Cerebrospinal Fluid Testing
as that performed on the mother to enable Cerebrospinal fluid should be examined in all
comparison of titer results. A negative mater- patients with neurologic or ophthalmic signs or
nal RPR or VDRL test result at delivery does symptoms, evidence of active tertiary syphilis
not exclude congenital syphilis, although such (eg, aortitis and gumma), treatment failure, or
a situation is uncommon. The diagnostic and HIV infection with late latent syphilis.
therapeutic approach to neonates being evalu-
ated for congenital syphilis is summarized in Treatment
Image 131.1 and depends on identification of Parenteral penicillin G remains the preferred
maternal syphilis, adequacy of maternal drug for treatment of syphilis at any stage.
­t herapy, maternal serologic response to ther- ­Recommendations for penicillin G use and
apy, comparison of maternal and neonatal duration of therapy vary, depending on the
serologic titers, and the findings on the neo- stage of disease and clinical manifestations.
nate’s physical examination. On the basis Parenteral penicillin G is the only documented
of maternal history and initial findings, the effective therapy for patients who have neuro-
evaluation includes laboratory tests (liver syphilis, congenital syphilis, or syphilis during
­f unction tests, complete blood cell and platelet pregnancy and is recommended for HIV-
counts, a CSF-VDRL, and CSF cell count and infected patients. Such patients should always
protein concentration), long-bone and chest be treated with penicillin, even if desensitiza-
radiography, and an ophthalmologic exam­ tion for penicillin allergy is necessary.
ination. Neonates with an abnormal physical
examination consistent with congenital syphi- Congenital Syphilis: Neonates in the First
lis, born to mothers with no or inadequate Month of Life
therapy, and whose mothers received therapy The diagnostic and therapeutic approach to
less than 4 weeks before delivery will need neonates delivered to mothers with syphilis
CSF evaluation to establish the diagnosis of is outlined in Image 131.1. For proven or prob-
neurosyphilis and aid in planning follow-up able congenital syphilis (on the basis of the
evaluations. Additional recommendations for neonate’s physical examination and radio-
neonate evaluation are found in Image 131.1. graphic and laboratory test results), the pre-
Other causes of elevated CSF values should be ferred treatment is aqueous crystalline
considered when a neonate is being evaluated penicillin G, administered intravenously
for congenital syphilis. Neonates born to for 10 days. The dosage should be based on
mothers who are coinfected with syphilis chro­nologic age rather than gestational age.
and HIV do not require different evaluation, Alternatively, procaine penicillin G, intramus-
therapy, or follow-up for syphilis than is rec- cularly, can be administered as a single daily
ommended for all neonates. dose for 10 days; no treatment failures have
occurred with this formulation despite its low
Evaluation and Treatment of Older Infants
CSF concentrations. When the neonate is at
and Children
risk of ­congenital syphilis because of inade-
Children who are identified as having reactive quate maternal treatment or response to treat-
serologic tests for syphilis should have mater- ment (or reinfection) during pregnancy but the
nal serologic test results and records reviewed ­neonate’s physical examination, radiographic
to assess whether they have congenital or imaging, and laboratory analyses are normal
acquired syphilis. The recommended evalua- (including neonate RPR/VDRL titer the same
tion includes CSF analysis for CSF-VDRL as or less than 4-fold the maternal RPR/VDRL),
­testing, cell count, and protein concentration; some experts would treat with a single dose of
complete blood cell count, differential, and penicillin G benzathine intramuscularly, but
platelet count; and other tests as indicated clin- most would still prefer 10 days of treatment. If
ically (eg, long-bone or chest radiography, liver more than 1 day of therapy is missed, the entire
function tests, abdominal ultrasonography, course should be restarted. Data supporting
ophthalmologic examination, auditory brain- use of other antimicrobial agents (eg, ampicil-
stem response testing, neuroimaging studies). lin) for treatment of congenital syphilis are not

ERRNVPHGLFRVRUJ
Syphilis 599

available. When possible, a full 10-day course Syphilis in Pregnancy


of penicillin is preferred, even if ampicillin Regardless of stage of pregnancy, women
was initially provided for possible sepsis. should be treated with penicillin according
Neonates who have a normal physical exami- to the dosage schedules appropriate for the
nation and a serum quantitative nontrepone- stage of syphilis as recommended for non­
mal serologic titer less than 4-fold higher than pregnant patients. For penicillin-allergic
the maternal titer (eg, 1:16 is 4-fold higher than patients, no proven alternative therapy has
1:4) are at minimal risk of syphilis if they are been established. A pregnant woman with a
born to mothers who completed appropriate history of penicillin allergy should be treated
penicillin treatment for syphilis during preg- with penicillin after desensitization. Desensi­
nancy and more than 4 weeks before delivery tization should be performed in consultation
and the mother had no evidence of reinfection with a specialist and only in facilities in which
or relapse. Although a full evaluation may be emergency assistance is available.
unnecessary, these neonates should be treated
Early Acquired Syphilis (Primary, Secondary,
with a single intramuscular injection of peni-
Early Latent Syphilis)
cillin G benzathine because fetal treatment
failure can occur despite adequate maternal A single intramuscular dose of penicillin G
treatment during pregnancy. Alternatively, benzathine is the preferred treatment for
these neonates can be examined carefully, ­children and adults. All children should
­preferably monthly, until their nontreponemal have a CSF examination before treatment to
serologic test results are negative. exclude a diagnosis of neurosyphilis. Evalu­
ation of CSF in adolescents and adults is
Neonates who have a normal physical exami- ­necessary only if clinical signs or symptoms
nation and a serum quantitative nontrepone- of neurologic or ophthalmic involvement are
mal serologic titer the same as or lower than present. Neurosyphilis should be considered
the maternal titer and whose mother’s treat- in the differential diagnosis of neurologic dis-
ment was adequate before pregnancy and ease in HIV-infected people.
whose mother’s nontreponemal serologic titer
remained low and stable before and during For nonpregnant adults and adolescents who
pregnancy and at delivery (VDRL <1:2; RPR are allergic to penicillin, doxycycline or tetra-
<1:4) require no evaluation. Some experts, cycline should be given for 14 days. Clinical
however, would treat with penicillin G ben­ studies (along with biologic and pharmacologic
zathine as a single intramuscular injection if considerations) suggest ceftriaxone once daily,
follow-up is uncertain. intramuscularly or intravenously, for 10 to
14 days (for adolescents and adults) is effective
Congenital Syphilis: Older Infants for early-acquired syphilis, but the optimal
and ­Children dose and duration of therapy have not been
Because establishing the diagnosis of neuro- defined. Single-dose therapy with ceftriaxone
syphilis is difficult, infants older than 1 month is not effective, as has been documented in
who possibly have congenital syphilis or who ­several geographic areas.
have neurologic involvement should be treated Close follow-up of people receiving any alter-
with intravenous aqueous crystalline penicil- native therapy is essential. When follow-up
lin for 10 days (Table 131.1). This regimen cannot be ensured, especially for children
should also be used to treat children older younger than 8 years, consideration must be
than 2 years who have late and previously given to hospitalization and desensitization
untreated congenital syphilis. If the patient followed by administration of penicillin G.
has no clinical manifestations of disease, the
CSF examination is normal, and the result of Syphilis of More Than 1 Year’s Duration
the CSF-VDRL test is negative, some experts (Late Latent Syphilis and Late Syphilis)
would treat with 3 weekly doses of penicillin Penicillin G benzathine should be given intra-
G benzathine. muscularly, weekly, for 3 successive weeks.
In patients who are allergic to penicillin,

ERRNVPHGLFRVRUJ
Table 131.1

600 Syphilis
Recommended Treatment for Syphilis in People Older Than 1 Month
Status Children Adults
Congenital syphilis Aqueous crystalline penicillin G, 200,000–
300,000 U/kg/d, IV, administered as 50,000 U/kg,
every 4–6 h for 10 da
Primary, secondary, Penicillin G benzathine,c 50,000 U/kg, IM, up to Penicillin G benzathine, 2.4 million U, IM, in a single dose
and early latent the adult dose of 2.4 million U in a single dose OR
­syphilisb If allergic to penicillin and not pregnant, doxycycline, 100 mg, orally, twice a
day for 14 d
OR
Tetracycline, 500 mg, orally, 4 times/d for 14 d

Late latent syphilisd Penicillin G benzathine, 50,000 U/kg, IM, up to the Penicillin G benzathine, 7.2 million U total, administered as 3 doses of 2.4 mil-
adult dose of 2.4 million U, administered as 3 sin- lion U, IM, each at 1-wk intervals
gle doses at 1-wk intervals (total 150,000 U/kg, up OR
to the adult dose of 7.2 million U) If allergic to penicillin and not pregnant, doxycycline, 100 mg, orally, twice a
day for 4 wk
OR
Tetracycline, 500 mg, orally, 4 times/d for 4 wk

Tertiary … Penicillin G benzathine 7.2 million U total, administered as 3 doses of


2.4 million U, IM, at 1-wk intervals
If allergic to penicillin and not pregnant, consult an infectious diseases expert.

Neurosyphilise Aqueous crystalline penicillin G, 200,000– Aqueous crystalline penicillin G, 18–24 million U per day, administered as
300,000 U/kg/d, IV, every 4–6 h for 10–14 d, in 3–4 million U, IV, every 4 h for 10–14 df
doses not to exceed the adult dose OR
Penicillin G procaine,c 2.4 million U, IM, once daily PLUS probenecid, 500 mg,
orally, 4 times/d, both for 10–14 df

Abbreviations: IM, intramuscularly; IV, intravenously.


a
If the patient has no clinical manifestations of disease, the cerebrospinal fluid (CSF) examination is normal, and the CSF Venereal Disease Research Laboratory test result is negative, some experts would treat with
up to 3 weekly doses of penicillin G benzathine, 50,000 U/kg, IM. Some experts also suggest giving these patients a single dose of penicillin G benzathine, 50,000 U/kg, IM, after the 10-day course of intravenous
­aqueous penicillin.
b
Early latent syphilis is defined as being acquired within the preceding year.
c
Penicillin G benzathine and penicillin G procaine are approved for intramuscular administration only.
d
Late latent syphilis is defined as syphilis beyond 1 year’s duration.
e
Patients who are allergic to penicillin should be desensitized.
f
Some experts administer penicillin G benzathine, 2.4 million U, IM, once per week for up to 3 weeks after completion of these neurosyphilis treatment regimens.
Syphilis 601

­ oxycycline or tetracycline for 4 weeks should


d Chlamydia trachomatis, HIV, and hepatitis B.
be given only with close serologic and clinical If injection drug use is suspected, the mother
follow-up. Limited clinical studies suggest may also be at risk of hepatitis C virus infec-
­ceftriaxone might be effective, but the optimal tion. All recent sexual contacts of people with
dose and duration have not been defined. acquired syphilis should be evaluated for
Patients who have syphilis and who demon- other sexually transmitted infections as well
strate any of the following criteria should as syphilis. Partners who were exposed within
have a prompt CSF examination: 90 days preceding the diagnosis of primary,
secondary, or early latent syphilis in the index
1. Neurologic or ophthalmic signs or ­symptoms
patient should be treated presumptively for
2. Evidence of active tertiary syphilis syphilis, even if they are seronegative.
(eg, aortitis, gumma, iritis, uveitis)
All patients with syphilis should be tested for
3. Serologic treatment failure other sexually transmitted infections, includ-
ing N gonorrhoeae, C trachomatis, HIV, and
If dictated by circumstances and patient or hepatitis B. Patients who have primary syphilis
parent preferences, a CSF examination may should be retested for HIV after 3 months if
be performed for patients who do not meet the first HIV test result is negative. For HIV-
these criteria. Some experts recommend per- infected patients with syphilis, careful follow-
forming a CSF examination on all patients up is essential. Patients infected with HIV who
who have latent syphilis and a nontreponemal have early syphilis may be at increased risk of
serologic test result of 1:32 or greater or if the neurologic complications and higher rates of
patient is HIV infected and has a serum CD4+ treatment failure with currently recommended
T-­lymphocyte count of 350 or less. The risk regimens. Children with acquired primary,
of asymptomatic neurosyphilis in these cir- secondary, or latent syphilis should be evalu-
cumstances is increased approximately 3-fold. ated for possible sexual assault or abuse.
If a CSF examination is performed and the
results indicate abnormalities consistent with Follow-up and Management
neurosyphilis, the patient should be treated
for neurosyphilis. Congenital Syphilis
All neonates and infants who have reactive
Neurosyphilis serologic tests for syphilis or were born to mothers
The recommended regimen for adults is ­aqueous who were seroreactive at delivery should receive
crystalline penicillin G, intravenously, for 10 to careful follow-up evaluations during regularly
14 days. If adherence to therapy can be ensured, scheduled well-child care ­v isits at 2, 4, 6, and
patients may be treated with an alternative 12 months of age. Serologic nontreponemal
­regimen of daily intramuscular penicillin G tests should be performed every 2 to 3 months
procaine plus oral probenecid for 10 to 14 days. until the nontreponemal test becomes non­
Some experts recommend following both of reactive or the titer has decreased at least 4-fold
these regimens with penicillin G benzathine (ie, 1:16 to 1:4). Nontreponemal antibody titers
intramuscularly, weekly, for 1 to 3 doses. For should decrease by 3 months of age and should
children, intravenous aqueous crystalline be nonreactive by 6 months of age if the infant
­penicillin G for 10 to 14 days is ­recommended. was infected and adequately treated or was not
infected and ­initially seropositive because of
If the patient has a history of allergy to penicil- transplacentally acquired maternal antibody.
lin, consideration should be given to desensiti- The serologic response after therapy may be
zation, and the patient should be managed in slower for infants treated after the neonatal
consultation with an allergy specialist. period. Patients with increasing titers or with
persistent stable titers 6 to 12 months after ini-
Other Considerations
tial treatment should be reevaluated, including
Mothers of neonates with congenital syphilis a CSF examination, and treated with a 10-day
should be tested for other sexually transmitted course of parenteral penicillin G, even if they
infections, including Neisseria gonorrhoeae, were treated previously.

ERRNVPHGLFRVRUJ
602 Syphilis

Treponemal tests should not be used to evalu- Indications for Retreatment


ate treatment response because results for an
Primary/Secondary Syphilis
infected child can remain positive despite
effective therapy. Passively transferred mater- If clinical signs or symptoms persist or recur or
nal treponemal antibodies can persist in a if a 4-fold increase in titer of a nontreponemal
child until 15 months of age. A reactive trepo- test occurs, evaluate CSF and HIV status and
nemal test after 18 months of age is diagnostic repeat therapy. If the nontreponemal titer fails
of congenital syphilis. If the nontreponemal to decrease 4-fold within 6 months after ther-
test is nonreactive at this time, no further apy, evaluate for HIV; repeat therapy unless
­evaluation or treatment is necessary. If the follow-up for continued clinical and serologic
nontreponemal test is reactive at 18 months of assessment can be ensured. Some experts rec-
age, the child should be evaluated (or reevalu- ommend CSF evaluation.
ated) fully and treated for congenital syphilis.
Latent Syphilis
Treated infants with congenital neurosyphilis In the following situations, CSF examination
and initially positive results of CSF-VDRL tests should be performed and retreatment should
or abnormal CSF cell counts or protein con­ be provided:
centrations should undergo repeated clinical
evaluation and CSF examination at 6-month • Titers increase at least 4-fold (ie, 1:4 to 1:16).
intervals until their CSF examination is normal.
• An initially high titer (>1:32) fails to
A reactive CSF-VDRL test or abnormal CSF
decrease at least 4-fold (ie, 1:32 to 1:8)
indices that cannot be attributed to another
within 12 to 24 months.
ongoing illness at the 6-month interval are
indications for retreatment. Neuroimaging • Signs or symptoms attributable to syphi-
studies, such as magnetic resonance imaging, lis develop.
should be considered in these children.
In all these instances, retreatment should be
Acquired Syphilis performed with 3 weekly injections of penicil-
lin G benzathine, intramuscularly, unless CSF
Treated pregnant women with syphilis should
examination indicates neurosyphilis is present,
have quantitative nontreponemal serologic
at which time treatment for neurosyphilis
tests repeated at 28 to 32 weeks of gestation,
should be initiated. Retreated patients should
at delivery, and according to recommendations
be treated with the schedules recommended
for the stage of disease. Serologic titers may
for patients with syphilis for more than 1 year.
be repeated monthly in women at high risk of
In general, only one retreatment course is indi-
reinfection or in geographic areas where the
cated. The possibility of reinfection or concur-
prevalence of syphilis is high. The clinical and
rent HIV infection should always be considered
antibody response should be appropriate for
when retreating patients with early syphilis,
stage of disease, but most women will deliver
and repeat HIV testing should be performed
before their serologic response to treatment
in such cases.
can be assessed definitively. Inadequate mater-
nal treatment is likely if clinical signs of infec- Patients with neurosyphilis associated with
tion are present at delivery or if maternal acquired syphilis must have periodic sero-
antibody titer is 4-fold higher than the pre- logic testing, clinical evaluation at 6-month
treatment titer. Fetal treatment is considered intervals, and repeat CSF examinations. If the
inadequate if delivery occurs within 28 days CSF white blood cell count has not decreased
of maternal therapy. after 6 months or if the CSF white blood cell
count or protein are not within reference
range after 2 years, retreatment should be
­considered. Cerebrospinal fluid abnormalities
may persist for extended periods in HIV-
infected people with neurosyphilis. Close
­follow-up is ­warranted.

ERRNVPHGLFRVRUJ
Syphilis 603

Abbreviations: RPR, rapid plasma reagin; VDRL, Venereal Disease Research Laboratory.
a
Treponema pallidum particle agglutination (TP-PA), fluorescent treponemal antibody absorption (FTA-ABS), T pallidum enzyme immu-
noassay (TP-EIA), or microhemagglutination test for antibodies to T pallidum (MHA-TP).
b
Test for HIV antibody. Neonates of HIV-infected mothers do not require different evaluation or treatment for syphilis.
c
A 4-fold change in titer is the same as a change of 2 dilutions. For example, a titer of 1:64 is 4-fold greater than a titer of 1:16, and a titer
of 1:4 is 4-fold lower than a titer of 1:16. When comparing titers, the same type of nontreponemal test should be used (eg, if the initial
test was an RPR, the follow-up test should also be an RPR).
d
Women who maintain a VDRL titer 1:2 or less or an RPR 1:4 or less beyond 1 year after successful treatment are considered serofast.
e
Complete blood cell and platelet count; cerebrospinal fluid examination for cell count, protein, and quantitative VDRL; other tests as
clinically indicated (eg, chest radiographs, long-bone radiographs, eye examination, liver function tests, neuroimaging, auditory brain-
stem response).
f
Treatment (option 1 or option 2, below), with most experts recommending treatment option 1. If a single dose of benzathine penicillin G
is used, the neonate must be fully evaluated, full evaluation must be normal, and follow-up must be certain. If any part of the neonate’s
evaluation is abnormal or not performed, or if the CSF analysis is rendered uninterpretable, a 10-day course of penicillin is required.
g
Some experts would consider a single intramuscular injection of benzathine penicillin (treatment option 2), particularly if follow-up is not
certain.
Treatment Options
1. Aqueous penicillin G, 50,000 U/kg, intravenously, every 12 hours (1 week of age or younger) or every 8 hours (older than 1 week); or
procaine penicillin G, 50,000 U/kg, intramuscularly, as a single daily dose for 10 days. If 24 or more hours of therapy is missed, the
entire course must be restarted.
2. Benzathine penicillin G, 50,000 U/kg, intramuscularly, single dose.

Image 131.1
Algorithm for evaluation and treatment of neonates born to mothers with reactive serologic tests
for syphilis.

ERRNVPHGLFRVRUJ
604 Syphilis

Image 131.2
This electron micrograph shows Treponema pallidum on cultures of cotton-tail rabbit epithelium cells.
Courtesy of Centers for Disease Control and Prevention.

Image 131.3
Syphilis, primary and secondary. Incidence, by race/ethnicity—United States, 1997–2012. Courtesy of
Morbidity and Mortality Weekly Report.

ERRNVPHGLFRVRUJ
Syphilis 605

Image 131.4
Syphilis, congenital. Incidence among infants, by year of birth—United States, 1982–2012. Courtesy of
Morbidity and Mortality Weekly Report.

Image 131.5
Syphilis, primary and secondary. Incidence—United States and US territories, 2012. Courtesy of
Morbidity and Mortality Weekly Report.

ERRNVPHGLFRVRUJ
606 Syphilis

Image 131.6
Syphilis, primary and secondary. Incidence, by sex—United States, 1997–2012. Courtesy of Morbidity
and Mortality Weekly Report.

Image 131.8
Congenital syphilis with desquamation over
the hand. Courtesy of Charles Prober.

Image 131.7
A newborn with congenital syphilis. Note the
marked generalized desquamation.

ERRNVPHGLFRVRUJ
Syphilis 607

Image 131.10
Image 131.9 The face of a newborn displaying pathologic
Upper extremities of a patient with early morphology indicative of congenital syphilis
periostitis and radiolucency of the distal radius with striking mucous membrane involvement.
and ulna bilaterally. Courtesy of Edgar O. Courtesy of Centers for Disease Control
Ledbetter, MD, FAAP. and Prevention/Dr Norman Cole.

Image 131.11
Congenital syphilis with metaphyseal destruction of distal humerus, radius, and ulna.

Image 131.12
Congenital syphilis with proximal tibial metaphysitis (Wimberger sign).

ERRNVPHGLFRVRUJ
608 Syphilis

Image 131.13
Congenital syphilis with pneumonia alba. The
infant survived with penicillin treatment. Image 131.14
This pathologic condition of the lungs, know
as pneumonia alba, is caused by congenital
syphilis. The lungs are enlarged, heavy, uniformly
firm, and yellow-white in color. Seventy percent
of all pregnant women with untreated primary
syphilis may transmit the infection to their
fetuses. Courtesy of Centers for Disease
Control and Prevention/Susan Lindsley.

Image 131.15
This photograph depicts the presence of a
diffuse stromal haze in the cornea of a female
patient, known as interstitial keratitis, which
was due to her late-staged congenital syphilitic
condition. Interstitial keratitis, which is an
inflammation of the cornea’s connective tissue
elements and usually affects both eyes, can
occur as a complication brought on by congenital
Image 131.16
or acquired syphilis. Interstitial keratitis usually
Hutchinson teeth, a late manifestation of
occurs in children older than 2 years. Courtesy
congenital syphilis. Changes occur in secondary
of Centers for Disease Control and Prevention.
dentition. The central incisors are smaller than
normal and have sloping sides. Courtesy of
Edgar O. Ledbetter, MD, FAAP.

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Syphilis 609

Image 131.18
This image shows an extensive chancre located
on the penile shaft due to a primary syphilitic
infection caused by Treponema pallidum. The
primary stage of syphilis is usually marked by the
appearance of a single lesion, called a chancre.
Image 131.17 The chancre is usually firm, round, small, and
Condyloma latum in a 7-year-old girl who has painless. It appears at the spot where T pallidum
been sexually abused. These whitish gray, moist entered the body and lasts 3 to 6 weeks, healing
lesions are caused by Treponema pallidum and on its own. Courtesy of Centers for Disease
are highly contagious. Control and Prevention/Susan Lindsley.

Image 131.19
A 16-year-old girl with rash of secondary syphilis noticed at 3 months’ gestation of her pregnancy.
The sign and symptoms of secondary syphilis generally occur 6 to 8 weeks after the primary infection
when primary lesions have usually healed.

ERRNVPHGLFRVRUJ
610 Syphilis

Image 131.20
Secondary syphilis in a different patient than Image 131.20 with discrete palmar lesions. The diagnosis
was suspected because of the palmar lesions.

ERRNVPHGLFRVRUJ
Tapeworm Diseases 611

132 Europe. T saginata asiatica is common in


China, Taiwan, and Southeast Asia. Taeniasis
Tapeworm Diseases is acquired by eating undercooked beef
(Taeniasis and Cysticercosis) (T ­saginata) or pork (T solium). T saginata
Clinical Manifestations ­asiatica is acquired by eating viscera of
infected pigs that contain encysted larvae.
• Taeniasis. Infection with adult tapeworms Infection is often asymptomatic.
is often asymptomatic; however, mild
­gastrointestinal tract symptoms, such as Cysticercosis in humans is acquired by ingest-
nausea, diarrhea, and pain, can occur. ing eggs of the pork tapeworm (T solium),
­Tapeworm segments can be seen migrating through direct fecal-oral contact with a person
from the anus or in feces. harboring the adult tapeworm, or through
ingestion of fecally contaminated food. Auto-
• Cysticercosis. Manifestations depend on infection is possible. Eggs are only found in
the location and number of pork tapeworm human feces because humans are the obligate
larval cysts (cysticerci) and the host definitive host. Eggs liberate oncospheres in
response. Cysticerci can be found anywhere the intestine that migrate through the blood
in the body. The most common and serious and lymphatics to tissues throughout the
manifestations are caused by cysticerci in body, including the CNS, where the onco-
the central nervous system (CNS). Larval spheres develop into cysticerci. Although most
cysts of Taenia solium in the brain (neuro- cases of cysticercosis in the United States have
cysticercosis) can cause seizures, behavioral been imported, cysticercosis can be acquired
disturbances, obstructive hydrocephalus, in the United States from tapeworm carriers
and other neurologic signs and symptoms. who emigrated from an area with endemic
Neurocysticercosis is the leading infectious infection and still have T solium intestinal-
cause of epilepsy in the developing world. stage infection. T saginata and T saginata
The host reaction to degenerating cysticerci ­asiatica do not cause cysticercosis.
can produce signs and symptoms of menin-
gitis. Cysts in the spinal column can cause Incubation Period
gait disturbance, pain, or transverse myeli- For taeniasis (time from ingestion of the larvae
tis. Subcutaneous cysticerci produce palpa- until segments are passed in the feces), 2 to
ble nodules, and ocular involvement can 3 months; for cysticercosis, several years.
cause visual impairment.
Diagnosis
Etiology
Diagnosis of taeniasis (adult tapeworm infec-
Taeniasis is caused by intestinal infection by tion) is based on demonstration of the pro­
the adult tapeworm, Taenia saginata (beef glottids or ova in feces or the perianal region.
tapeworm) or T solium (pork tapeworm). However, these techniques are insensitive.
­Taenia saginata asiatica causes taeniasis in ­Species identification of the parasite is based
Asia. Human cysticercosis is caused only by on the different structures of gravid proglottids
the larvae of T solium (Cysticercus cellulosae). and scolex. Diagnosis of neurocysticercosis
Epidemiology typically requires imaging of the CNS and
serologic testing. Computed tomography scan-
These tapeworm diseases have worldwide ning or magnetic resonance imaging of the
­distribution. Prevalence is high in areas with brain or spinal cord is used to demonstrate
poor sanitation and human fecal contamina- lesions compatible with cysticerci. Antibody
tion in areas where cattle graze or swine are assays that detect specific antibodies to larval
fed. Most cases of T solium infection in the T solium in serum and cerebrospinal fluid are
United States are imported from Latin America useful to confirm the diagnosis but can have
or Asia, although the disease is prevalent in limited sensitivity if few cysticerci are present.
sub-Saharan Africa as well. High rates of In the United States, antibody tests are avail-
T saginata infection occur in Mexico, parts able through the Centers for Disease Control
of South America, East Africa, and central

ERRNVPHGLFRVRUJ
612 Tapeworm Diseases

and Prevention and a few commercial labora­ it has fewer drug-drug interactions with
tories. In general, antibody tests are more anticonvulsants. Coadministration of corti-
­sensitive with serum specimens than with costeroids during antiparasitic therapy may
­cerebrospinal fluid specimens. Serum antibody decrease adverse effects if more extensive
assay results are often negative in children with viable CNS cysticerci are suspected, and a
solitary parenchymal lesions but usually are prolonged course may be required for some
positive in patients with multiple lesions. forms of the disease (eg, basal, subarach-
noid). Corticosteroids can affect the tissue
Treatment
concentrations of albendazole. Arachnoidi-
• Taeniasis. Praziquantel is highly effective tis, vasculitis, or diffuse cerebral edema
for eradicating infection with the adult tape- (­c ysticercal encephalitis) is treated with
worm, and niclosamide is an alternative. ­corticosteroid therapy until the cerebral
Niclosamide is not approved for treatment edema is controlled.
of T solium infection but is approved for
treatment of T saginata infection. How- The medical and surgical management of
ever, niclosamide is not available in the cysticercosis can be highly complex and
United States. often needs to be conducted in consultation
with a neurologist or neurosurgeon. Seizures
• Cysticercosis. Neurocysticercosis treatment may recur for months or years. Anticonvul-
should be individualized on the basis of the sant therapy is recommended until there is
number, location, and viability of cysticerci neuroradiologic evidence of resolution and
as assessed by neuroimaging studies seizures have not occurred for 1 to 2 years.
(­magnetic resonance imaging or computed Calcification of cysts may require prolonged
tomography scan) and the clinical manifes- or indefinite use of anticonvulsants. Intra-
tations. Management is generally aimed at ventricular cysticerci and hydrocephalus
symptoms and should include anticonvul- usually require surgical therapy. Intraven-
sants for patients with seizures and insertion tricular cysticerci can often be removed by
of shunts for patients with hydrocephalus. endoscopic surgery, which is the treatment
Two antiparasitic drugs—albendazole and of choice. If cysticerci cannot be removed
praziquantel—are available. Although both easily, hydrocephalus should be corrected
drugs are cysticercidal and hasten radiologic with placement of intraventricular shunts.
resolution of cysts, most symptoms result Ocular cysticercosis is treated by surgical
from the host inflammatory response and excision of the cysticerci. Ocular and spinal
can be exacerbated by treatment. Most cysticerci generally are not treated with
experts recommend therapy with alben­ anthelmintic drugs, which can exacerbate
dazole or praziquantel for patients with inflammation. An ophthalmic examination
­non­enhancing or multiple cysticerci. Alben- should be performed before treatment to
dazole is preferred over praziquantel because rule out intraocular cysticerci.

ERRNVPHGLFRVRUJ
Tapeworm Diseases 613

Image 132.1

The eggs of Taenia solium and Taenia saginata are indistinguishable from each other, as well as from
other members of the Taeniidae family. The eggs measure 30 to 35 µm in diameter and are radially
striated. The internal oncosphere contains 6 refractile hooks. Taenia species eggs in unstained wet
mounts. Courtesy of Centers for Disease Control and Prevention.

Image 132.2
Taenia saginata. Courtesy of Gary Overturf, MD.

ERRNVPHGLFRVRUJ
614 Tapeworm Diseases

Image 132.3
Cysticercosis is an infection of humans and pigs with the larval stages of the parasitic cestode,
Taenia solium. This infection is caused by ingestion of eggs shed in the feces of a human tapeworm
carrier (1). Pigs and humans become infected by ingesting eggs or gravid proglottids (2). Humans are
infected by ingestion of food contaminated with feces or by autoinfection. In the latter case, a human
infected with adult T solium can ingest eggs produced by that tapeworm through fecal contamination
or, possibly, from proglottids carried into the stomach by reverse peristalsis. Once eggs are ingested,
oncospheres hatch in the intestine (3), invade the intestinal wall, and migrate to striated muscles, as
well as the brain, liver, and other tissues, where they develop into cysticerci. In humans, cysts can
cause serious sequelae if they localize in the brain, resulting in neurocysticercosis. The parasite life
cycle is completed, resulting in human tapeworm infection when humans ingest undercooked pork
containing cysticerci (4). Cysts evaginate and attach to the small intestine by their scolex (5). Adult
tapeworms develop (up to 2–7 m in length and produce <1,000 proglottids, each with ~50,000 eggs)
and reside in the small intestine for years (6). Courtesy of Centers for Disease Control and Prevention/
Alexander J. da Silva, PhD/Melanie Moser.

Image 132.4
Neurocysticercosis in an 11-year-old Asian girl apparent on computed tomography scan. Courtesy of
Benjamin Estrada, MD.

ERRNVPHGLFRVRUJ
Tapeworm Diseases 615

Image 132.5
Cerebral neurocysticercosis with diffuse, scat­tered, ring-enhancing lesions throughout the brain
parenchyma with focal edema evident on computed tomography scan. Courtesy of David Waagner.

Image 132.6
A young boy with a seizure. Magnetic resonance imaging of the brain revealed a ringlike lesion
characteristic of neurocysticercosis. Copyright Barbara Ann Jantausch, MD, FAAP.

ERRNVPHGLFRVRUJ
616 Other Tapeworm ­Infections

133 ­ iarrhea, abdominal pain, or, rarely, megalo-


d
blastic anemia secondary to vitamin B12 defi-
Other Tapeworm ciency. Infection with other related species of
­Infections fish tapeworm are associated with consump-
(Including Hydatid Disease) tion of anadromous or saltwater fish, such as
salmon. ­Diagnosis is made by recognition of
Most tapeworm infections are asymptomatic, the ­characteristic proglottids or eggs passed in
but nausea, abdominal pain, and diarrhea have stool. Therapy with praziquantel is effective;
been observed in people who are heavily infected. niclosamide is an alternative but is not avail-
Etiologies, Diagnosis, and Treatment able in the United States.

Hymenolepis nana Echinococcus granulosus and Echinococcus


This tapeworm, also called the dwarf tapeworm multilocularis
because it is the smallest of the adult human The larval forms of these tapeworms cause
tapeworms, can complete its entire life cycle ­c ystic echinococcosis, also known as hydatid
within humans. New infection can be acquired disease, and alveolar echinococcosis, respec-
by ingestion of eggs passed in feces of infected tively. The distribution of Echinococcus granu­
people or of infected arthropods (fleas). More losus is related to sheep or cattle herding.
problematic is autoinfection, which perpetu- Areas of high prevalence include parts of
ates infection in the host, because eggs can ­Central and South America, East Africa,
hatch within the intestine and reinitiate the ­Eastern Europe, the Middle East, the Mediter-
life cycle, leading to development of new ranean region, China, and Central Asia. The
worms and a large worm burden. Diagnosis is parasite is also endemic in Australia and New
made by recognition of the characteristic eggs Zealand. In the United States, small foci of
passed in stool. Praziquantel is the treatment endemic transmission have been reported in
of choice, with nitazoxanide as an alternative Arizona, California, New Mexico, and Utah,
drug. If infection persists after treatment, and a strain of the parasite is adapted to
retreatment with praziquantel is indicated. wolves, moose, and caribou in Alaska and
Canada. Dogs, coyotes, wolves, dingoes, and
Dipylidium caninum jackals can become infected by swallowing
This tapeworm is the most common and protoscolices of the parasite within hydatid
­w idespread adult tapeworm of dogs and cats. cysts in the organs of sheep or other inter­
Dipylidium caninum infects children when mediate hosts. Dogs pass embryonated eggs
they inadvertently swallow a dog or cat flea, in their stools, and sheep become infected
which serves as the intermediate host. Diag­ by swallowing the eggs. If humans swallow
nosis is made by finding the characteristic Echinococcus eggs, they can become inadver-
eggs or motile proglottids in stool. Proglottids tent intermediate hosts, and cysts can develop
resemble rice kernels. Therapy with praziquan- in various organs, such as the liver, lungs,
tel is effective. Niclosamide is an alternative ­k idneys, and spleen. Cysts caused by larvae
therapeutic option but is not available in the of E granulosus usually grow slowly (1 cm in
United States. diameter per year) and eventually can contain
several liters of fluid. If a cyst ruptures, ana-
Diphyllobothrium latum (and related species) phylaxis and multiple secondary cysts from
Fish are one of the intermediate hosts of the seeding of protoscolices can result. Clinical
Diphyllobothrium latum tapeworm, also called diagnosis is often difficult. A history of con-
fish tapeworm. Consumption of infected, raw tact with dogs in an area with endemic
freshwater fish (including trout and pike) ­infection is helpful. Cystic lesions can be
leads to infection. Three to 5 weeks are needed ­demonstrated by radiography, ultrasonogra-
for the adult tapeworm to mature and begin phy, or computed tomography of various
to lay eggs. The worm sometimes causes organs. Serologic ­testing, available at the
mechanical obstruction of the bowel or ­Centers for Disease Control and Prevention,

ERRNVPHGLFRVRUJ
Other Tapeworm ­Infections 617

is helpful, but ­false-negative results occur; con- are at risk of anaphylactic reactions to cyst
versely, tests at ­commercial laboratories may c­ ontents. Treatment with albendazole generally
provide false-positive results. Treatment should be initiated days to weeks before sur-
depends on ultra­sonographic staging and may gery or PAIR and continued for several weeks
include watchful waiting, antiparasitic therapy, to months afterward.
PAIR (puncture aspiration, injection of proto-
Echinococcus multilocularis, a species for which
scolicidal agents, and reaspiration), surgical
the life cycle involves foxes, dogs, and rodents,
excision, or no treatment. In uncomplicated
causes alveolar echinococcosis, which is char-
cases, treatment of choice is PAIR. Contraindi-
acterized by invasive growth of the larvae in
cations to PAIR include communication of the
the liver with occasional metastatic spread.
cyst with the biliary tract (eg, bile staining after
Alveolar echinococcosis is limited to the
initial aspiration), superficial cysts, and heavily
northern hemisphere and usually is diagnosed
septated cysts. Surgical therapy is indicated for
in people 50 years or older. The disease has
complicated cases and requires meticulous care
been reported frequently from Western China.
to prevent spillage, including preparations such
The preferred treatment is surgical removal of
as soaking of surgical drapes in hypertonic
the entire larval mass. In nonresectable cases,
saline. In general, the cyst should be removed
continuous treatment with albendazole has
intact because leakage of contents is associated
been associated with clinical improvement.
with a higher rate of complications. Patients

Image 133.1
Dog tapeworm, Dipylidium caninum, in the stool
of a healthy 7-month-old boy. Courtesy of Carol
Image 133.2
J. Baker, MD, FAAP.
Proglottids of Dipylidium caninum. Such
proglottids (average mature size, 12 x 3 mm) have
2 genital pores, one in the middle of each lateral
margin. Proglottids may be passed singly or in
chains and, occasionally, may be seen dangling
from the anus. They are pumpkin seed–shaped
when passed and often resemble rice grains
when dried. Courtesy of Centers for Disease
Control and Prevention.

Image 133.3
Three adult Hymenolepis nana tapeworms. Each
tapeworm (length, 15–40 mm) has a small,
rounded scolex at the anterior end, and
proglottids can be distinguished at the posterior,
wider end. Courtesy of Centers for Disease
Control and Prevention.

ERRNVPHGLFRVRUJ
618 Other Tapeworm ­Infections

Image 133.5
Image 133.4 Echinococcus cyst in the right lobe of the liver in
Fluid-filled echinococcus cyst in the lungs of an a 27-year-old man. Note the striking elevation of
adolescent male. Courtesy of Edgar O. Ledbetter, the right hemidiaphragm. Courtesy of Edgar O.
MD, FAAP. Ledbetter, MD, FAAP.

Image 133.6
Hydatid sand. Fluid aspirated from a hydatid cyst will show multiple protoscolices (size, approximately
100 µm), each of which has typical hooklets. The protoscolices are normally invaginated (left), and
evaginate (middle, then right) when put in saline. Courtesy of Centers for Disease Control and
Prevention.

Image 133.7
Echinococcus abscess of liver in an adult, the most common site of abscess formation.

ERRNVPHGLFRVRUJ
Tetanus 619

134 Epidemiology

Tetanus Tetanus occurs worldwide and is more com-


mon in warmer climates and during warmer
(Lockjaw)
months, in part because of higher frequency
Clinical Manifestations of contaminated wounds associated with those
Tetanus can manifest in 4 overlapping locations and seasons. The organism, a normal
­clinical forms: generalized, neonatal, local, inhabitant of soil and animal and human
and cephalic. ­intestines, is ubiquitous in the environment,
especially where contamination by excreta is
• Generalized tetanus (lockjaw) is a neuro- common. Organisms multiply in wounds, rec-
logic disease manifesting as trismus and ognized or unrecognized, and elaborate toxins
severe muscular spasms, including risus in the presence of anaerobic conditions. Con-
­sardonicus. Onset is gradual, occurring taminated wounds, especially wounds with
over 1 to 7 days, and symptoms progress to devitalized tissue and deep-puncture trauma,
severe, painful generalized muscle spasms, are at greatest risk. Neonatal tetanus is com-
which are often aggravated by any external mon in many developing countries where
stimulus. Autonomic dysfunction, manifest- ­pregnant women are not immunized appro­
ing as diaphoresis, tachycardia, labile blood priately against tetanus and nonsterile umbili-
pressure, and arrhythmias, is often present. cal cord care practices are followed. More than
Severe spasms persist for 1 week or more 250,000 deaths from neonatal tetanus were
and subside over several weeks in people estimated to have occurred worldwide each
who recover. year between 2000 and 2003. Widespread
active immunization against tetanus has
• Neonatal tetanus is a form of generalized
­modified the epidemiology of disease in the
tetanus occurring in newborns lacking
United States, where 40 or fewer cases have
­protective passive immunity because their
been reported annually since 1999. Tetanus
mothers are not immune.
is not transmissible from person to person.
• Local tetanus manifests as local muscle
Incubation Period
spasms in areas contiguous to a wound.
Usually within 8 days (range, 3–21 days); neo-
• Cephalic tetanus is a dysfunction of cranial natal tetanus, usually 7 days (range, 4–14 days).
nerves associated with infected wounds on
the head and neck. Local and cephalic teta- Diagnostic Tests
nus can precede generalized tetanus. The diagnosis of tetanus is made clinically by
Etiology excluding other causes of tetanic spasms, such
as hypocalcemic tetany, phenothiazine reac-
Clostridium tetani is a spore-forming, obligate tion, strychnine poisoning, and conversion
anaerobic, gram-positive bacillus. This organ- disorder. Attempts to culture C tetani are
ism is a wound contaminant that causes nei- ­associated with poor yield, and a negative
ther tissue destruction nor an inflammatory ­culture does exclude disease. A protective
response. The vegetative form of C tetani pro- serum antitoxin concentration should not
duces a potent plasmid-encoded exotoxin be used to exclude the diagnosis of tetanus.
(­tetanospasmin), which binds to gangliosides
at the myoneural junction of skeletal muscle Treatment
and on neuronal membranes in the spinal Human tetanus immune globulin (TIG),
cord, blocking inhibitory impulses to motor given in a single dose, is recommended for
neurons. The action of tetanus toxin on the treatment. Available preparations must be
brain and sympathetic nervous system is less given intramuscularly. Infiltration of part
well documented. of the dose locally around the wound is
­recommended, although the efficacy of this

ERRNVPHGLFRVRUJ
620 Tetanus

approach has not been proven. In countries S­ upportive care and pharmacotherapy to


where human TIG is not available, equine ­control tetanic spasms are of major impor-
­tetanus antitoxin may be available. Equine tance. Oral (or intravenous) metronidazole is
antitoxin is administered after appropriate effective in decreasing the number of vegeta-
testing for sensitivity and desensitization if tive forms of C tetani and is the antimicrobial
necessary. This product is no longer available agent of choice. Parenteral penicillin G is an
in the United States. Intravenous immuno­ alternative treatment. Therapy for 7 to 10 days
globulin contains antibodies to tetanus and is ­recommended.
can be considered for treatment.
Active immunization against tetanus should
All wounds should be cleaned and debrided always be undertaken during convalescence
properly, especially if extensive necrosis is from tetanus. Because of the extreme potency
present. In neonatal tetanus, wide excision of tiny amounts of toxin, tetanus disease may
of the umbilical stump is not indicated. not result in immunity.

Image 134.1
This Gram-stained photomicrograph depicts
gram-positive Clostridium tetani, which had been
Image 134.2
cultivated on a blood agar plate over 48 hours
(magnification x956). Courtesy of Centers for Trismus in an adult with tetanus. Courtesy of
Disease Control and Prevention/Dr Holdeman. Charles Prober, MD.

Image 134.3
Severe muscular spasms with trismus in an Image 134.4
infant who acquired neonatal tetanus from The face of an infant with neonatal tetanus with
contamination of the umbilical stump. risus sardonicus. Copyright Martin G. Myers, MD.

ERRNVPHGLFRVRUJ
Tetanus 621

Image 134.5
This neonate is displaying a body rigidity produced by Clostridium tetani exotoxin. Neonatal tetanus
may occur in neonates born without protective passive immunity, when the mother is not immune. It
usually occurs through infection of the unhealed umbilical stump, particularly when the stump is cut
with an unsterile instrument. Courtesy of Centers for Disease Control and Prevention.

Image 134.6
A preschool-aged boy with tetanus with severe Image 134.7

muscle contractions, generalized, caused by This patient is displaying a body posture known
tetanospasmin action in the central nervous as opisthotonos due to Clostridium tetani
system. Courtesy of Centers for Disease Control exotoxin. Generalized tetanus, the most
and Prevention. common type (about 80%), usually presents
with a descending pattern, starting with trismus
or lockjaw, followed by stiffness of the neck,
difficulty in swallowing, and rigidity of abdominal
muscles. Courtesy of Centers for Disease Control
and Prevention.

Image 134.8
A preschool-aged boy with localized tetanus
secondary to the parent attempting to drain
an impetigo lesion with a mesquite thorn
contaminated with tetanus spores. Courtesy
of Edgar O. Ledbetter, MD, FAAP.

ERRNVPHGLFRVRUJ
622 Tinea Capitis

135 Etiology

Tinea Capitis The prime causes of the disease are fungi of the
genus Trichophyton, including Trichophyton
(­Ringworm of the Scalp)
tonsurans (commonly associated with black dot
Clinical Manifestations tinea capitis) and Trichophyton schoenleinii
Dermatophytic fungal infections of the scalp (commonly associated with favus). An endemic
have 3 major forms: black dot, gray patch, form of gray patch tinea capitis is caused by
and favus. Black dot tinea capitis is the most Microsporum canis.
common manifestation in the United States. Epidemiology
It begins as an erythematous scaling patch
Black dot tinea capitis is predominantly a
over the scalp that slowly enlarges and is
­disease of young African American school-
often recognized only when hair loss becomes
aged children but has been reported in all
noticeable. The name comes from the areas of
racial and ethnic groups as well as in infants
alopecia in which the hair is broken off flush
and postmenopausal female caregivers. Gray
with the scalp, giving the appearance of black
patch tinea capitis is rare in North America,
dots. Inflammation, which may be accom­
as is favus, which remains more common in
panied by tender lymphadenopathy, can be
areas such as Iran, China, and Nigeria. Patho-
prominent. Scarring with permanent alopecia
genic dermatophytes can be transmitted to
can occur in the absence of treatment. Gray
affected people by other humans, animals
patch tinea capitis also begins as a well-­
(especially pet cats or dogs), or the environ-
demarcated erythematous, scaling patch over
ment. The organism remains viable for pro-
the scalp and spreads centrifugally. Lesions
longed periods on fomites (eg, brushes, combs),
can be singular or multiple and are accompa-
and the rate of asymptomatic carriage and
nied by hair breakage a few millimeters above
infected individuals among family members
the scalp. Favus (tinea favosa) primarily mani-
of index cases is high. The role of asymptom-
fests as a perifollicular erythema of the scalp
atic carriers is unclear, but they may serve
that can progress to yellow crusting known
as a reservoir of infection within families,
as scutula, which can coalesce into confluent,
schools, and ­communities.
adherent masses overlying severe hair loss.
Incubation Period
Both black dot and gray patch tinea capitis
can evolve into kerion, a boggy erythematous Unknown; thought to be 1 to 3 weeks.
nodule lacking hair, which can become sup­
Diagnostic tests
purative and drain. Kerion can be mistaken
for a primary bacterial abscess or cellulitis The presence of alopecia, scale, and neck
because it represents an extreme inflammatory lymphadenopathy makes the diagnosis of tinea
response to the fungus. However, secondary capitis almost certain, and most clinicians will
bacterial infection can also occur. As with choose to treat empirically prior to laboratory
other forms of tinea, a dermatophytic or id confirmation. Dermoscopic evaluation of areas
reaction can develop and can involve a papular, of alopecia with a lighted magnifier may show
vesicular, or eczemalike eruption that is often comma- or corkscrew-shaped hairs. Hairs and
pruritic and may be extensive, involving the scale obtained by gentle scraping of a moist-
face, trunk, or extremities. When this reaction ened area of the scalp with a blunt scalpel,
develops following initiation of therapy, it is toothbrush, brush, or tweezers are used for
sometimes mistaken for a drug eruption. potassium hydroxide wet mount examination.
The dermatophyte test medium is also a reli-
Tinea capitis can be confused with atopic der- able, simple, and inexpensive method of
matitis, seborrheic dermatitis, psoriasis, bacte- ­diagnosing tinea capitis. Skin scrapings from
rial folliculitis or abscess, trichotillomania, lesions are inoculated directly onto culture
alopecia areata, head lice, and scarring alopecia. medium and incubated at room temperature.

ERRNVPHGLFRVRUJ
Tinea Capitis 623

After 1 to 2 weeks, a phenol red indicator in the griseofulvin is considered standard of care for
agar will turn from yellow to red in the area M canis infections, many experts believe that
surrounding a dermatophyte colony. When terbinafine for 6 weeks is a better choice for
necessary, the diagnosis can also be con- T tonsurans infections because of the shorter
firmed by culture on Sabouraud dextrose duration of therapy required for cure. Shorter
agar, although this often requires incubation (usually 4 weeks) courses of terbinafine are
for 3 to 4 weeks. equal or superior to longer-term griseofulvin
therapy for T tonsurans infection. Fluconazole
Scalp scales and hairs can be scraped or
is the only oral antifungal that is approved
plucked from the scalp for immediate evalua-
by the US Food and Drug Administration for
tion using potassium hydroxide preparation
children younger than 2 years, and azole agents
mounts. Arthroconidia can be visualized
have also been used for tinea capitis.
within the hair shaft in endothrix infections,
such as T tonsurans, while ectothrix infections, Topical treatment can be useful as an adjunct
such as M canis, exhibit conidia on the outside to systemic therapy to decrease carriage of
of the hair shaft. In both forms, septate hyphae ­v iable conidia. Selenium sulfide, ketoconazole,
may be visualized in scrapings from the scalp or ciclopirox shampoos can be applied 2 to
surface. Wood lamp evaluation is only useful 3 times per week and left in place for 5 to 10
if a Microsporum infection is present, in which minutes; duration of therapy should continue
case affected areas will fluoresce yellow-green. for at least 2 weeks. Some experts recommend
­continuing topical treatments until clinical
Treatment
and mycologic cure occurs.
Optimal treatment of tinea capitis is contro­
versial. Experts generally use higher doses of Kerion is managed by antifungal therapy;
griseofulvin than have been approved by the ­corticosteroid therapy (oral or intralesional)
US Food and Drug Administration. Griseo­ has not been shown to be superior to anti­
fulvin is approved by the FDA for children fungal therapy alone. Unless secondary bac­
2 years or older, is available in liquid or tablet terial infection has occurred, treatment with
form, can be dosed on a daily basis, and should antibiotics is generally unnecessary.
be taken with fatty foods. Although high-dose

Image 135.1
Microsporum audouinii. Microsporum canis, a zoophilic dermatophyte often found in cats and
dogs, is a common cause of tinea corporis and tinea capitis in humans. Other dermatophytes are
included in the genera Epidermophyton and Trichophyton. Courtesy of Centers for Disease Control
and Prevention.

ERRNVPHGLFRVRUJ
624 Tinea Capitis

Image 135.2
A 6-year-old boy with hair loss on the top of his head for the past 2 weeks. The area is slightly pruritic
and has increased in size. Mom recalls a scaly patch developing a few days after having his head
shaved. Wood lamp evaluation result was negative. Culture of the area was positive for Trichophyton
tonsurans. He responded well to 6 weeks of therapy with griseofulvin. He had no residual scarring or
hair loss. Courtesy of Will Sorey, MD.

Image 135.3
A 3-year-old boy with a tinea lesion on the occiput for 1 month. The mother had been applying a
topical antifungal agent, but the lesion became progressively larger. The patient was treated
successfully with griseofulvin. Copyright Larry I. Corman.

Image 135.4
This patient had ringworm of the scalp, or tinea capitis, due to Microsporum nanum when first
examined in 1964. Tinea capitis is an infection of the scalp with mold-like fungi called dermatophytes.
This type of fungus thrives in warm, moist areas. Susceptibility to tinea infection is increased by poor
hygiene, prolonged moist skin, and minor skin or scalp injuries. Courtesy of Centers for Disease
Control and Prevention/Dr Lucille K. Georg.

ERRNVPHGLFRVRUJ
Tinea Capitis 625

Image 135.5
An 8-year-old boy with a bald spot, hair loss, and enlarging posterior cervical lymph node for 2 weeks.
The node was described as tender, not fluctuant, and without erythema of the overlying scalp. The
area of hair loss was boggy and fluctuant. The patient responded well to treatment with griseofulvin.
Copyright Stan Block, MD, FAAP.

Image 135.6
Tinea capitis in the hairline of an 8-year-old boy. Copyright Stan Block, MD, FAAP.

Image 135.7
A 2½-year-old boy with a kerion secondary to chronic, progressive tinea capitis. Copyright
Martin G. Myers, MD.

ERRNVPHGLFRVRUJ
626 Tinea Corporis

136 Incubation Period

Tinea Corporis Typically 1 to 3 weeks, but can be shorter.


(Ringworm of the Body) Diagnostic Tests
Clinical Manifestations Fungi responsible for tinea corporis can be
detected by microscopic examination of a
Superficial tinea infections of the nonhairy
potas­sium hydroxide wet mount of skin
(glabrous) skin, termed tinea corporis, involve
­scrapings. Use of dermatophyte test medium
the face, trunk, or limbs. The lesion is often
is also a reliable, simple, and inexpensive
ring-shaped or circular (hence, the lay term,
method of diagnosing tinea corporis. Skin
ringworm), slightly erythematous, and well
scrapings from lesions are inoculated directly
demarcated with a scaly, vesicular, or pustular
onto culture medium and incubated at room
border and central clearing. Small confluent
temperature. After 1 to 2 weeks, a phenol red
plaques or papules, as well as multiple lesions,
indicator in the agar will turn from yellow to
can occur, particularly in wrestlers (tinea
red in the area surrounding a dermatophyte
­gladiatorum). Lesions can be mistaken for
colony. When necessary, the diagnosis can also
­psoriasis, pityriasis rosea, nummular eczema,
be ­confirmed by culture on Sabouraud dextrose
erythema annulare centrifugum, or atopic,
agar, although this often requires incubation
seborrheic, or contact dermatitis. A frequent
for 3 to 4 weeks. Histopathologic diagnosis using
source of confusion is an alteration in the
periodic acid–Schiff reaction and polymerase
appearance of lesions as a result of application
chain reaction diagnostic tools are available
of a topical corticosteroid preparation, termed
but are expensive and, ­generally, unnecessary.
tinea incognito. Such patients can also develop
Majocchi granuloma (trichophytic granuloma), Treatment
a follicular fungal infection associated with a
Topical application of a miconazole, clotri­m­
granulomatous dermal reaction. In patients
azole, terbinafine (12 years and older),
with diminished T-lymphocyte function
­tolnaftate, or ciclopirox (10 years and older)
(eg, HIV infection), skin lesions may appear
preparation twice a day or of a ketoconazole,
as grouped papules or pustules unaccompanied
econazole, naftifine, oxiconazole, sertacon-
by scaling or erythema.
azole, butenafine (12 years and older), or
A pruritic, fine, papular or vesicular eruption ­sulconazole preparation once a day is recom-
(dermatophytic or id reaction) involving the mended. Although clinical resolution can be
trunk, hands, or face, caused by a hypersensi- evident within 2 weeks of therapy, continuing
tivity response to infecting fungus, can accom- therapy for another 2 to 4 weeks is generally
pany skin lesions. Tinea corporis can occur in recommended. If significant clinical improve-
association with tinea capitis, and examination ment is not observed after 4 to 6 weeks of
of the scalp should be performed. ­treatment, an alternate diagnosis should be
considered. Topical preparations of antifungal
Etiology medication mixed with high-potency cortico-
The prime causes of the disease are fungi of the steroids should not be used; in addition, local
genus Trichophyton, especially Trichophyton and systemic adverse events from the cortico-
tonsurans, Trichophyton rubrum, and steroids can occur.
Trichoph­yton mentagrophytes; the genus
If lesions are extensive or unresponsive to
­Microsporum, especially Microsporum canis;
­topical therapy, griseofulvin can be adminis-
and Epidermo­phyton floccosum. Microsporum
tered orally for 6 weeks. Oral itraconazole,
gypseum can also occasionally cause infection.
­fluconazole, and terbinafine are alternative
Epidemiology effective options for more severe cases. If
These causative fungi occur worldwide and are Majocchi granulomas are present, oral anti­
transmissible by direct contact with infected fungal therapy is recommended because topi-
humans, animals, soil, or fomites. Fungi in cal therapy is unlikely to penetrate deeply
lesions are communicable. enough to eradicate infection.

ERRNVPHGLFRVRUJ
Tinea Corporis 627

Image 136.1
This photomicrograph reveals a number of macroconidia of the dermatophytic fungus Epidermophyton
floccosum. E floccosum is known to be a cause of dermatophytosis leading to tinea corporis (ringworm),
tinea cruris (jock itch), tinea pedis (athlete’s foot), and onychomy­cosis or tinea unguium, a fungal
infection of the nail bed. Courtesy of Centers for Disease Control and Prevention/Libero Ajello, MD.

Image 136.2
Image 136.3
Tinea corporis lesion in a 10-year-old girl.
Courtesy of Gary Williams, MD. Tinea corporis of the arm. This 6-year-old girl had
enlarging skin lesion that had been present for a
week. Copyright Larry I. Corman.

Image 136.4
Tinea corporis of the face. These annular erythematous lesions have a scaly center. Courtesy of
Charles Prober, MD.

ERRNVPHGLFRVRUJ
628 Tinea Corporis

Image 136.5
Tinea corporis of the chin on a 6-year-old girl with enlarging lesions. The patient was successfully
treated with clotrimazole. Copyright Larry I. Corman.

Image 136.6
A 16-month-old with a pruritic patch on his trunk. It has gotten larger over the past 3 days. He has
a cat with dandruff and hair loss. The cat sleeps on his bed during the sunny part of the day. The
child was treated with antifungal cream. The cat was evaluated by a veterinarian and cultured
positive for Microsporum canis. This represents tinea corporis, commonly called ringworm.
Courtesy of Will Sorey, MD.

Image 136.7
Generalized tinea corporis in a 5-year-old girl.

ERRNVPHGLFRVRUJ
Tinea Cruris 629

137 should be evaluated for this possibility, with


careful evaluation of the interdigital web
Tinea Cruris spaces. Onychomycosis is also a possible asso-
(Jock Itch) ciation, particularly in adolescents and adults.
Clinical Manifestations Incubation Period
Tinea cruris is a common superficial fungal Estimated to be 1 to 3 weeks.
disorder of the groin and upper thighs. Con-
comitant tinea pedis has been reported in Diagnostic Tests
patients with tinea cruris as well as previous Fungi responsible for tinea cruris may be
episodes of tinea cruris. The eruption is usually detected by microscopic examination of a
bilaterally symmetric and sharply marginated, potassium hydroxide wet mount of scales.
often with polycyclic borders. Involved skin is Use of dermatophyte test medium is also a
erythematous and scaly and varies from red to ­reliable, simple, and inexpensive method of
brown; occasionally, the eruption is accompa- diagnosing tinea cruris. Skin scrapings from
nied by central clearing and can have a vesicu- lesions are inoculated directly onto culture
lopapular border. In chronic infections, the medium and incubated at room temperature.
margin can be subtle, and lichenification can After 1 to 2 weeks, a phenol red indicator in
be present. Tinea cruris skin lesions can be the agar will turn from yellow to red in the
extremely pruritic. The appearance of tinea area surrounding a dermatophyte colony.
cruris can be altered in patients who have When necessary, the diagnosis can also be
­erroneously been treated with topical cortico- ­confirmed by culture on Sabouraud dextrose
steroids (tinea incognito), including dimin- agar, although this often requires incubation
ished erythema, absence of typical scaling for 3 to 4 weeks. Polymerase chain reaction
border, and development of folliculitis assay is a more expensive diagnostic tool that
(­Majocchi [trichophytic] granuloma). These generally is not required. A characteristic
lesions should be differentiated from candi­ coral-red ­fluorescence under Wood light can
diasis, intertrigo, seborrheic dermatitis, identify the presence of erythrasma (an erup-
­psoriasis, atopic dermatitis, irritant or allergic tion of reddish brown patches attributable to
contact dermatitis (generally caused by the ­presence of C minutissimum) and, thus,
­t herapeutic agents applied to the area), and exclude tinea cruris.
erythrasma. The latter is a superficial bacte-
rial infection of the skin caused by Coryne­ Treatment
bacterium minutissimum. Twice-daily topical application for 4 to 6 weeks
of a clotrimazole, miconazole, terbinafine
Etiology
(12 years and older), tolnaftate, or ciclopirox
The fungi Epidermophyton floccosum, (10 years and older) preparation rubbed or
­Trichophyton rubrum, and Trichophyton sprayed onto the affected areas and surround-
­mentagrophytes are the most common causes. ing skin is effective. Once-daily therapy with
Trichophyton tonsurans, Trichophyton verru­ topical econazole, ketoconazole, naftifine,
cosum, and Trichophyton interdigitale have ­oxiconazole, butenafine (12 years and older),
also been identified. or sulconazole preparation is also effective.
Tinea pedis, if present, should be treated
Epidemiology
­concurrently.
Tinea cruris occurs predominantly in adoles-
cent and adult males, mainly via indirect Topical preparations of antifungal medication
­contact from desquamated epithelium or hair. mixed with high-potency corticosteroids
Moisture, close-fitting garments, friction, and should be avoided because of the potential for
obesity are predisposing factors. Direct or indi- prolonged infections and local and systemic
rect person-to-person transmission can occur. adverse corticosteroid-induced events. Loose-
This infection commonly occurs in association fitting, washed cotton underclothes to decrease
with tinea pedis, and all infected patients chafing; avoidance of hot baths; and use of an

ERRNVPHGLFRVRUJ
630 Tinea Cruris

absorbent powder can be helpful adjuvants to to eradicate infection. Because many condi-
therapy. Griseofulvin, given orally for 6 weeks, tions mimic tinea cruris, a differential diagno-
may be effective in unresponsive cases. If sis should be considered if primary treatments
Majocchi granulomas are present, oral anti­ fail, and a fungal culture should be performed
fungal therapy is recommended, as topical if the diagnosis is in question.
therapy is unlikely to penetrate deeply enough

Image 137.1
Symmetric, confluent, annular, scaly red, and hyperpigmented plaques. This 10-year-old girl developed
a chronic itchy eruption on the groin that spread to the anterior thighs. A potassium hydroxide prepara­
tion showed hyphae, and she was treated successfully with topical antifungal cream.

ERRNVPHGLFRVRUJ
Tinea Pedis and Tinea Unguium 631

138 throughout a household among family mem-


bers and is communicable for as long as infec-
Tinea Pedis and tion is present.
Tinea Unguium Incubation Period
(Athlete’s Foot, Ringworm of the Feet)
Estimated to be approximately 1 to 3 weeks.
Clinical Manifestations
Diagnostic Tests
Tinea pedis manifests as a fine scaly or vesi­c­
ulopustular eruption that is commonly pru- Tinea pedis usually is diagnosed by clinical
ritic. Lesions can involve all areas of the foot manifestations and can be confirmed by
but usually are patchy in distribution, with a ­microscopic examination of a potassium
predisposition to fissures and scaling between hydroxide wet mount of cutaneous scrapings.
toes, particularly in the third and fourth inter- Use of dermatophyte test medium is a reliable,
digital spaces or distributed around the sides simple, and inexpensive method of diagnosing
of the feet. Toenails can be infected and can tinea pedis and tinea unguium. Skin scrapings
be thickened with subungual debris and yel- from lesions are inoculated directly onto the
low or white discoloration (tinea unguium culture medium and incubated at room tem-
[onycho­mycosis]). Toenails can be the source perature. After 1 to 2 weeks, a phenol red indi-
for recurrent tinea pedis. Tinea pedis must cator in the agar will turn from yellow to red
be differentiated from dyshidrotic eczema, in the area surrounding a dermatophyte col-
atopic dermatitis, contact dermatitis, juvenile ony. When necessary, the diagnosis can also be
plantar dermatosis, palmoplantar kerato- confirmed by culture on Sabouraud dextrose
derma, and erythrasma (an eruption of reddish agar, although this often requires incubation
brown patches caused by Corynebacterium for 3 to 4 weeks. Infection of the nail can be
minutissimum). Tinea pedis commonly occurs verified by direct microscopic examination
in association with tinea cruris and onycho­ with potassium hydroxide, fungal culture of
mycosis (tinea unguium). Dermatophyte desquamated subungual material, or fungal
­infections commonly affect otherwise healthy stain of a nail clipping fixed in formalin. Peri-
people, but immunocompromised people have odic acid-Schiff reaction has the highest sen­
increased susceptibility. sitivity for detecting fungus but does not
identify the associated species and cannot
Tinea pedis and many other fungal infections ­necessarily differentiate other mold infections
can be accompanied by a hypersensitivity from dermatophyte infections.
­reaction to the fungi (the dermatophytid or
id reaction), with resulting papular or papulo- Treatment
vesicular eruptions on the palms and the sides Topical application of terbinafine, twice
of fingers and, occasionally, by an erythema- daily; ciclopirox; or an azole agent (clotri­m­
tous vesicular eruption on the extremities, azole, miconazole, econazole, oxiconazole,
trunk, and face. sertaconazole, ketoconazole), once or twice
daily, is usually adequate for milder cases of
Etiology
tinea pedis. Acute vesicular lesions can be
The fungi Trichophyton rubrum, Trichophyton treated with intermittent use of open wet
mentagrophytes, and Epidermophyton flocco­ ­compresses (eg, with Burow [aluminum ace-
sum are the most common causes of tinea pedis. tate topical] solution, 1:80). Dermatophyte
Epidemiology infections in other locations, if present,
should be treated concurrently.
Tinea pedis is a common infection worldwide
in adolescents and adults but is less common in Tinea pedis that is severe, chronic, or refrac-
young children. Fungi are acquired by contact tory to topical treatment can be treated with
with skin scales containing fungi or with fungi oral therapy. Oral itraconazole or terbinafine
in damp areas, such as swimming pools, locker is the most effective, with griseofulvin next
rooms, and showers. Tinea pedis can spread and fluconazole least effective. Id (hypersen­
sitivity response) reactions are treated by wet

ERRNVPHGLFRVRUJ
632 Tinea Pedis and Tinea Unguium

compresses, topical corticosteroids, occasion- nail; however, even topical therapy for 48 weeks
ally systemic corticosteroids, and eradication typically has a cure rate less than 20%. Topical
of the primary source of infection. ciclopirox (8%) can be applied to affected
toenail(s) once daily in combination with a
Recurrence is prevented by proper foot hygiene,
comprehensive nail management program.
which includes keeping the feet dry and cool,
Studies in adults have demonstrated the best
gentle cleaning, drying between the toes, use
cure rates after therapy with oral itraconazole
of absorbent antifungal foot powder, frequent
or terbinafine; however, safety and effective-
airing of affected areas, and avoidance of occlu­
ness in children has not been established.
sive footwear and nylon socks or other fabrics
Recurrences are common. Removal of the
that interfere with dissipation of moisture.
nail plate followed by use of oral therapy dur-
In people with onychomycosis (tinea unguium), ing the period of regrowth can help to affect
topical therapy should only be used when the a cure in resistant cases.
infection is confined to the distal ends of the

Image 138.1
This patient presented with ringworm or tinea pedis of the toes, which is also known as athlete’s foot.
Tinea pedis is a fungal infection of the feet, principally involving the toe webs and soles. Athlete’s foot
can be caused by the fungi Epidermophyton floccosum or by numerous members of the Trichophyton
genus. Courtesy of Centers for Disease Control and Prevention/Dr Lucille K. Georg.

Image 138.2
This patient presented with ringworm of the foot (tinea pedis) due to the dermatophytic fungus
Trichophyton rubrum. Individuals who practice generally poor hygiene, wear enclosed footwear
such as tennis shoes, endure prolonged wetting of the skin (ie, sweating during exercise), and
suffer with minor skin or nail injuries are more prone to suffer from tinea infections. Courtesy of
Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
Tinea Pedis and Tinea Unguium 633

Image 138.3
Tinea pedis and tinea unguium.

Image 138.4
Tinea pedis and tinea unguium. Courtesy of Gary Williams, MD.

Image 138.5
Tinea pedis and tinea unguium infection. This is the same patient as in Image 138.4. Courtesy of Gary
Williams, MD.

ERRNVPHGLFRVRUJ
634 Toxocariasis

139 grounds. Eggs become infective after 2 to


4 weeks in the environment and may persist
Toxocariasis long term in the soil. Direct contact with dogs
(Visceral Toxocariasis [previously Visceral is of secondary importance because eggs are
Larva Migrans]; Ocular Toxocariasis not infective immediately when shed in the
[­previously Ocular Larva Migrans])
feces. Infection risk is highest in hot, humid
Clinical Manifestations regions where eggs persist in soil.
The severity of symptoms depends on the Incubation Period
­number of larvae ingested and the degree of Unknown.
the inflammatory response. Most people who
are infected are asymptomatic. Characteristic Diagnostic Tests
manifestations of visceral toxocariasis include Hypereosinophilia and hypergammaglobu-
fever, leukocytosis, eosinophilia, hypergamma- linemia associated with increased titers of
globulinemia, wheezing, abdominal pain, and ­isohemagglutinin to the A and B blood group
hepatomegaly. Other manifestations include antigens are presumptive evidence of infection.
malaise, anemia, cough, and, in rare instances, An enzyme immunoassay for Toxocara anti-
pneumonia, myocarditis, and encephalitis. bodies in serum, available at the Centers for
Atypical manifestations include hemorrhagic Disease Control and Prevention and some
rash and seizures. When ocular invasion commercial laboratories, can provide confir-
(resulting in endophthalmitis or retinal granu- matory evidence of toxocariasis but does not
lomas) occurs, other evidence of infection is distinguish between past and current, active
usually lacking, suggesting the visceral and infection. This assay is specific and sensitive
ocular manifestations are distinct syndromes. for diagnosis of visceral toxocariasis but is less
Etiology sensitive for diagnosis of ocular toxocariasis.
Microscopic identification of larvae in a liver
Toxocariasis is caused by Toxocara species, biopsy specimen is diagnostic, but this finding
which are common roundworms of dogs and is rare. A liver biopsy negative for larvae, how-
cats (especially puppies or kittens), specifically ever, does not exclude the diagnosis.
Toxocara canis and Toxocara cati. In the United
States, most cases are caused by T canis. Other Treatment
nematodes of animals can also cause this syn- Albendazole is the recommended drug for
drome, although rarely. treatment of toxocariasis. Alternative drugs
Epidemiology include mebendazole and ivermectin, although
mebendazole is no longer available in the
On the basis of a nationally representative United States. In severe cases with myocarditis
­survey, 14% of the US population has serologic or involvement of the central nervous system,
evidence of Toxocara infection. Visceral toxo- corticosteroid therapy should be considered.
cariasis typically occurs in children 2 to 7 years Correcting the underlying causes of pica helps
of age, often with a history of pica, but can prevent reinfection.
occur in older children and adults. Ocular
­toxocariasis usually occurs in older children Antiparasitic treatment of ocular toxocariasis
and adolescents. Humans are infected by inges- may not be effective. Inflammation may be
tion of soil containing infective eggs of the decreased by topical or systemic corticosteroids
­parasite. Eggs may be found wherever dogs and secondary damage decreased with ophthal­
and cats defecate, often in sandboxes and play- mologic surgery.

ERRNVPHGLFRVRUJ
Toxocariasis 635

Image 139.1
Eggs of Toxocara canis. These eggs are passed in dog feces, especially puppy feces. Humans do not
produce or excrete eggs; therefore, eggs are not a diagnostic finding in human toxocariasis. The egg
to the left is fertilized but not yet embryonated, while the egg to the right contains a well-developed
larva. The latter egg would be infective if ingested by a human (frequently, a child). Courtesy of Centers
for Disease Control and Prevention.

Image 139.2
Visceral toxocariasis (previously visceral larva migrans) with Toxocara canis larvae on liver biopsy.

Image 139.3
Toxocara canis. Fundus damage from larval invasion. Courtesy of Hugh Moffet, MD.

ERRNVPHGLFRVRUJ
636 Toxocariasis

Image 139.4
Toxocara canis accomplishes its life cycle in dogs, with humans acquiring the infection as accidental
hosts. Following ingestion by dogs, the infective eggs yield larvae that penetrate the gut wall and
migrate into various tissues, where they encyst if the dog is older than 5 weeks. In younger dogs, the
larvae migrate through the lungs, bronchial tree, and esophagus; adult worms develop and oviposit
in the small intestine. In older dogs, the encysted stages are reactivated during pregnancy and infect
by the transplacental and transmammary routes of the puppies, in whose small intestine adult worms
become established. Thus, infective eggs are excreted by lactating adult female dogs and puppies.
Humans are paratenic hosts who become infected by ingesting infective eggs in contaminated soil.
After ingestion, the eggs yield larvae that penetrate the intestinal wall and are carried by the circulation
to a wide variety of tissues (liver, heart, lungs, brain, muscle, eyes). While the larvae do not undergo
any further development in these sites, they can cause severe local reactions that are the basis of
toxocariasis. Courtesy of Centers for Disease Control and Prevention/Alexander J. da Silva, PhD/
Melanie Moser.

ERRNVPHGLFRVRUJ
TOXOPLASMA GONDII ­INFECTIONS 637

140 occasionally have a mononucleosis-like illness


associated with a macular rash and hepato-
Toxoplasma gondii splenomegaly. The clinical course is usually
­Infections benign and self-­limited. In a subset of immu-
(Toxoplasmosis) nocompetent individuals and in immunocom-
promised patients, primary infection presents
Clinical Manifestations with persistent fever, myocarditis, myositis,
Congenital Infection hepatitis, peri­carditis, pneumonia, encephalitis
with and without brain abscesses, and skin
Although most children with congenital lesions. These manifestations and a more
­infection are born without clinical manifesta- aggressive clinical course, including life-
tions, visual or hearing impairment, learning threatening pneumonia, have been docu-
disabilities, or intellectual disability (mental mented in patients who acquired primary
retardation) will become apparent in a large toxoplasmosis in certain tropical countries in
proportion several months to years later. Major South America, such as French Guiana, Brazil,
clinical signs at birth include chorioretinitis and Colombia. Toxoplasmosis should be
cerebral calcifications and hydrocephalus; they included in the differential diagnosis of ill trav-
can be present alone or in combination. The elers who return home with these unexplained
concomitant presence of these 3 signs (“classic syndromes.
triad”) is rare but highly suggestive of congeni-
tal toxoplasmosis. More than 70% of congeni- Ocular toxoplasmosis also occurs in the setting
tally infected children develop chorioretinitis of postnatally acquired infection. In Brazil and
later in life. Additional signs of congenital Canada, up to 17% of patients diagnosed with
toxoplasmosis at birth include microcephaly, postnatally acquired toxoplasmosis have toxo-
seizures, hearing loss, strabismus, a maculo- plasmic chorioretinitis. Acute ocular involve-
papular rash, generalized lymphadenopathy, ment manifests as blurred vision, eye pain,
hepatomegaly, splenomegaly, jaundice, pneu- decreased visual acuity, floaters, scotoma, pho-
monitis, diarrhea, hypothermia, anemia, tophobia, or epiphora. The most common late
­petechiae, and thrombocytopenia. As a con­ finding is chorioretinitis, which can result in
sequence of intrauterine infection, menin­ vision loss. Ocular disease can become reacti-
goencephalitis with cerebrospinal fluid (CSF) vated years after the initial infection in healthy
abnormalities can develop. Some severely and immunocompromised people.
affected fetuses and newborns die in utero or
within a few days of birth. Cerebral calcifica- Reactivation of Chronic Infection in
tions can be demonstrated by plain radiograph, ­Immunocompromised Patients
ultrasonography, or computed tomography In chronically infected immunodeficient
(CT) imaging of the head. Computed tomo­ patients, including people with HIV infection,
graphy is the radiologic technique of choice reactivation of T gondii can result in life-
because it is the most sensitive for calcifications threatening encephalitis, pneumonitis, toxo-
and can reveal brain abnormalities when plasmic chorioretinitis (a posterior uveitis),
plain radiographic or ultrasonographic studies fever of unknown origin, or disseminated
are normal. ­toxoplasmosis. In patients with AIDS, toxo-
plasmic encephalitis (TE) is the most common
Postnatally Acquired Primary Infection cause of encephalitis and typically presents
Toxoplasma gondii infection acquired after with acute to subacute neurologic or psychiat-
birth is asymptomatic in most immunocompe- ric symptoms and multiple ring-enhancing
tent patients. When symptoms develop, they brain lesions. In these patients, a clear
may be nonspecific and can include fever, improvement in their symptoms and signs
­malaise, headache, sore throat, arthralgia, within 7 to 10 days of beginning empiric anti-
and myalgia. Lymphadenopathy, frequently toxoplasma drugs is considered diagnostic
cervical, is the most common sign. Patients of TE. However, immunocompromised

ERRNVPHGLFRVRUJ
638 TOXOPLASMA GONDII ­INFECTIONS

patients without AIDS (eg, transplant or Epidemiology


­cancer patients, patients taking immunosup- T gondii is worldwide in distribution and
pressive drugs) who are chronically infected infects most species of warm-blooded animals.
with T gondii and who present with multiple The seroprevalence of T gondii infection (a
ring-enhancing brain lesions should undergo reflection of the chronic infection and mea-
an immediate brain biopsy to confirm the sured by the presence of T gondii–specific
diag­nosis. Toxoplasmic encephalitis can also immunoglobulin [Ig] G antibodies) varies by
­present as a single brain lesion by magnetic geographic locale and the socioeconomic strata
resonance imaging (MRI) or as a diffuse and of the population. The age-adjusted seropreva-
rapidly progressive process in the setting of lence of infection in the United States has been
apparently negative brain MRI studies. Mag- estimated at 11% among women 15 to 44 years
netic resonance imaging is superior to CT for old. Members of the feline family are definitive
the diagnosis of TE and can detect lesions not hosts. Cats generally acquire the infection
revealed by CT. Seropositive hematopoietic by ingestion of infected animals (eg, mice),
stem cell and solid organ transplant patients uncooked household meats, soil organic mat-
are at risk of their latent T gondii infection ter, and water or food contaminated with their
being reactivated. In these patients, toxo­ own oocysts. The parasite replicates sexually
plasmosis may manifest as pneumonia, in the feline small intestine. Cats may begin
­unexplained fever or seizures, myocarditis, to excrete millions of oocysts in their stools
hepatosplenomegaly, lymphadenopathy, or 3 to 30 days after primary infection and may
skin lesions, in addition to brain abscesses shed oocysts for 7 to 14 days. After excretion,
and diffuse encephalitis. T gondii–seropositive oocysts require a maturation phase (sporula-
solid organ donors (D+) can transmit the para- tion) of 1 to 5 days in temperate climates before
site via the allograft to seronegative recipients they are infective by the oral route. Sporulated
(R–). Thirty percent of D+/R– heart transplant oocysts survive for long periods under most
recipients develop toxoplasmosis in the absence ordinary environmental conditions, eg, sur­
of anti-T gondii prophylaxis. viving in moist soil for months and even years.
Etiology Intermediate hosts (including sheep, pigs, and
cattle) can have tissue cysts in the brain, myo-
T gondii is a protozoan and obligate intracellu-
cardium, skeletal muscle, and other organs.
lar parasite. T gondii organisms exist in nature
These cysts remain viable for the lifetime of
in 3 primary clonal lineages (types 1, 2, and 3)
the host. Humans usually become infected by
and several infectious forms (tachyzoite, tissue
consumption of raw or undercooked meat that
cysts containing bradyzoites, and oocysts con-
contains cysts or by accidental ingestion of
taining sporozoites). The tachyzoite and host
sporulated oocysts from soil or in contami-
immune response are responsible for symp-
nated food or water. A large outbreak linked
toms observed during the acute infection or
epidemiologically to contamination of a
during reactivation of a latent infection in
municipal water supply has also been reported.
immunocompromised patients. The tissue
Risk factors associated with acute infection in
cyst is responsible for latent infection and is
the United States are eating raw ground beef,
usually present in brain, skeletal muscle, car-
rare lamb, or locally produced cured, dried, or
diac tissue, and eyes of humans and other ver-
smoked meat, raw oyster, clams or mussels;
tebrate animals. It is the tissue cyst form that
working with meat; drinking unpasteurized
is transmitted through ingestion of under-
goat milk; and owning 3 or more kittens.
cooked or raw meat. The oocyst is present in
Drinking untreated water was also found to
the small intestine of cats and other members
have a trend toward increased risk for acute
of the feline family; it is responsible for trans-
infection in the United States. Up to 50% of
mission through ingestion of soil, water, or
acutely infected people do not recall identifi-
food contaminated with cat feces that contain
able risk factors or symptoms. Thus, T gondii
the organism.
infection and toxoplasmosis may occur even

ERRNVPHGLFRVRUJ
TOXOPLASMA GONDII ­INFECTIONS 639

in patients without a suggestive epidemiologic at PAMF-TSL ≤512) indicates infection of at


history or illness. Only appropriate laboratory least 6 months’ duration. Detectable T gondii–
testing can establish or exclude the diagnosis of specific IgM antibodies can indicate recent
T gondii infection or toxoplasmosis. There is no infection, chronic infection, or a false-positive
evidence of human-to-human transmission reaction. Sera with positive T gondii–specific
except through vertical transmission, blood IgM test results can be sent to PAMF-TSL for
products, or organ transplantation. confirmatory testing and to establish whether
the patient has an acute or a chronic infection.
Transmission of T gondii has been documented
Enzyme immunoassays are the most sensitive
in the setting of solid organ (eg, heart, kidney,
tests for IgM, and indirect fluorescent antibody
liver) or hematopoietic stem cell transplantation
tests are the least sensitive tests for detecting
from a seropositive donor with latent infection
IgM. Immunoglobulin M–specific antibodies
to an R–. Infection has rarely occurred as a
can be detected 2 weeks after infection (IgG-
result of a laboratory accident or from blood
specific antibodies are usually negative during
or blood product transfusion. In most cases,
this period), achieve peak concentrations in
congenital transmission occurs as a result of
1 month, decrease thereafter, and usually
primary maternal infection during gestation.
become undetectable within 6 to 9 months.
In utero infection rarely occurs as a result of
However, in some people, a positive IgM test
reactivated parasitemia during pregnancy in
result may persist for years without apparent
chronically infected immunocompromised
clinical significance. In adults, a positive
women. The incidence of congenital toxoplas-
IgM test should be followed by confirmatory
mosis in the United States has been estimated
testing at a laboratory with special expertise
to be 1 in 1,000 to 1 in 10,000 live births.
in Toxoplasma serology when determining
Incubation Period the timing of infection is important clinically
(eg, in a pregnant woman).
Approximately 7 days; range, 4 to 21 days.
Laboratory tests that have been found to be
Diagnostic Tests
helpful in determining timing of infection in
Serologic tests are the primary means of diag- patients with positive IgM test results include
nosing primary and latent infection. Poly- an IgG avidity test, the differential agglutina-
merase chain reaction (PCR) testing of body tion (AC/HS) test, and IgA- and IgE-specific
fluids and staining of a biopsy specimen with antibody tests. The presence of high-avidity
T gondii–specific immunoperoxidase are IgG antibodies indicates infection occurred
­valuable for confirming the diagnosis of at least 12 to 16 weeks prior. The presence of
­toxoplasmosis. Laboratories with special low-avidity antibodies is not a reliable indica-
­expertise in Toxoplasma serologic assays and tion of more recent infection, and treatment
their inter­pretation, such as the Palo Alto may affect the maturation of IgG avidity and
­Medical ­Foundation Toxoplasma Serology prolong the presence of low-avidity antibodies.
­Laboratory (PAMF-TSL, CA) are useful to A nonacute pattern in the AC/HS test is usually
­clinicians and nonreference laboratories. indicative of an infection that was acquired at
Immunoglobulin G–specific antibodies least 12 months before the serum was obtained.
achieve a peak concentration 1 to 2 months Tests to detect IgA and IgE antibodies, which
after infection and remain positive indefinitely. decrease to undetectable concentrations sooner
The vast majority of patients will have low-­ than IgM antibodies do, are also useful for
positive IgG antibody titers 6 months after the diagnosis of congenital infections and infec-
acute infection. To determine the approximate tions in pregnant women, for whom more
time of infection in IgG-positive adults, spe- ­precise information about the duration of
cific IgM antibody determinations should be infection is needed. T gondii–specific IgA
performed. The lack of T gondii–specific IgM and IgE antibody tests are available in Toxo­
antibodies in a person with low-positive titers plasma reference laboratories but, generally,
of IgG antibodies (eg, a Sabin-Feldman dye test not in other laboratories. Diagnosis of

ERRNVPHGLFRVRUJ
640 TOXOPLASMA GONDII ­INFECTIONS

­ oxoplasma infection during pregnancy should


T agglutination assay [ISAGA] method), and IgA
be made on the basis of results of serologic tests should be performed for all newborns
assays performed in a reference laboratory. suspected of having congenital toxoplasmosis.
Infected newborns can have any combination
Polymerase chain reaction assay and T gondii–
of positive or negative IgM and IgA antibodies.
specific immunoperoxidase staining can be
Although placental leak can occasionally lead
attempted with virtually any body fluid or
to false-positive IgM or IgA reactions in the
­tissue, depending on the clinical scenario.
newborn, repeat testing at approximately age
Specimens on which PCR assay can be per-
10 days can help confirm the diagnosis because
formed include amniotic fluid, CSF, whole
the half-life of these immunoglobulins is short
blood, bronchoalveolar lavage fluid, vitreous
and the titers in a neonate who is not infected
fluid, aqueous humor, peritoneal fluid, ascitic
should decrease rapidly. The sensitivity of
fluid, pleural fluid, bone marrow, and urine.
T gondii–specific IgM as determined by an
Essentially any tissue can be stained with
immunosorbent agglutination assay is 87% in
T gondii–specific immunoperoxidase; the
newborns born to mothers not treated during
­presence of extracellular antigens and a sur-
gestation; sensitivity for IgA antibodies is 77%;
rounding inflammatory response are also diag-
and when both are taken into consideration,
nostic of toxoplasmosis. A positive PCR test
the sensitivity increases to 93%. The indirect
result in tissue must be interpreted with cau-
fluorescent assay or enzyme immunoassay
tion because it does not distinguish reactiva-
for IgM should not be relied on to diagnose
tion from inactive chronic latent infection.
congenital infection.
Special Situations If the mother was not tested during pregnancy,
Prenatal a maternal serum sample should also be tested
for IgG and IgM, and the AC/HS test should be
A definitive diagnosis of congenital toxoplas- performed as soon as it is feasible. Maternal
mosis can be made prenatally by detecting test results can help in the interpretation of
­parasite DNA in amniotic fluid by PCR assay. newborn test results. In newborns with clinical
Isolation of the parasite by mouse or tissue cul- signs, peripheral blood, CSF, and urine speci-
ture inoculation can also be attempted from mens should be assayed for T gondii by PCR
amniotic fluid. Serial fetal ultrasonographic assay in a reference laboratory. Evaluation of
examinations can be performed in cases of the newborn should include ophthalmologic,
suspected congenital infection to detect any auditory, and neurologic examinations; lum-
increase in size of the lateral ventricles of the bar puncture; and CT of the head. An attempt
central nervous system or other signs of fetal may be made to isolate T gondii by mouse
infection, such as brain, hepatic, or splenic ­inoculation from placenta, umbilical cord
­calcifications. Some states routinely screen blood, CSF, urine, or peripheral blood speci-
all newborns for the presence of antibody to mens. Examination of the placenta by histo-
T gondii. logic tools and PCR assay can be helpful, but
a positive result does not necessarily indicate
Postnatal
the newborn is infected.
Congenital toxoplasmosis should be considered
in neonates born to women suspected of hav- Congenital infection is confirmed serologically
ing or who have been diagnosed with primary by persistently positive IgG titers beyond the
T gondii infection during gestation, women first 12 months of life. Conversely, in an unin-
infected shortly before conception (eg, within fected infant, a continuous decrease in IgG
3 months of conception), immunocompro- titer before 12 months without detection of
mised women with serologic evidence of past IgM or IgA antibodies will occur. Transpla­
infection with T gondii, or any neonate with centally transmitted IgG antibody usually
clinical signs or laboratory abnormalities sug- becomes undetectable by 6 to 12 months of age.
gestive of congenital infection. Toxoplasma- Congenital toxoplasmosis can be confirmed
specific IgG, IgM (by the immunosorbent before 12 months of age in infants with the

ERRNVPHGLFRVRUJ
TOXOPLASMA GONDII ­INFECTIONS 641

f­ ollowing laboratory test results: a persistently ­ resent as diffuse encephalitis without space-
p
positive or increasing IgG antibody concen­ occupying lesions on brain MRI. Prompt rec-
tration compared with the mother; a positive ognition of this syndrome and confirmation of
Toxoplasma-specific IgM (after 5 days of life) or the diagnosis by PCR testing in CSF is crucial
IgA assay (after 10 days of life); a positive PCR because these patients usually exhibit a rapidly
test result in CSF, peripheral blood, or urine; progressive and fatal clinical course.
or a positive IgG antibody test accompanied by
Diagnosis of TE in immunocompromised
clinical signs in a newborn born to a mother
patients other than HIV-infected people
who was infected during gestation.
requires confirmation by brain biopsy or PCR
Immunocompromised Patients testing of CSF. In these patients, other organ-
isms, such as invasive mold infections and
Immunocompromised patients (eg, patients
nocardiosis, should be considered before
with AIDS, solid organ transplant recipients,
beginning an empiric anti-T gondii therapy.
patients with cancer, people taking immuno-
suppressive drugs) who are infected latently Neonates born to women who are infected
with T gondii have variable titers of IgG anti- simultaneously with HIV and T gondii should
body to T gondii but rarely have IgM antibody. be evaluated for congenital toxoplasmosis
Immunocompromised patients should be because of an increased likelihood of mater-
tested for T gondii–specific IgG before com- nal reactivation and congenital transmission
mencing immunosuppressive therapy or as in this setting. Expert advice is available at
soon as their status of immunosuppression the PAMF-TSL (www.pamf.org/serology;
is diagnosed to determine whether they are ­telephone 650/853-4828; e-mail toxolab@pamf.
chronically infected with T gondii and at risk org) and the National Collaborative Chicago-
of reactivation of latent infection. Active dis- Based Congenital Toxoplasmosis Study, IL;
ease in immunosuppressed patients may or www.uchospitals.edu/specialties/infectious-­
may not result in seroconversion and a 4-fold diseases/toxoplasmosis; telephone 773/834-
increase in IgG antibody titers; consequently, 4131; e-mail rmcleod@midway.uchicago.edu).
serologic diagnosis in these patients is often
difficult. Previously seropositive patients may Ocular Toxoplasmosis
have changes in their IgG titers in any direc- Toxoplasmic chorioretinitis is usually diag-
tion (increase, decrease, or no change) without nosed on the basis of characteristic retinal
any clinical relevance. In these patients, PCR lesions in conjunction with a positive serum
testing, histologic examination, and attempts T gondii–specific IgG test result. All patients
to isolate the parasite become the laboratory with eye disease should have an IgM test
methods of choice to diagnose toxoplasmosis. ­performed; if a positive IgM test result is
­confirmed at a reference laboratory and eye
In HIV-infected patients who are seropositive
lesions are consistent with toxoplasmic chorio-
for T gondii IgG, reactivation of their latent
retinitis, ocular disease is the result of an acute
infection is usually manifested by TE.
T gondii infection rather than reactivation of a
­Toxoplasmic encephalitis can be diagnosed
chronic infection. Patients who have atypical
presumptively on the basis of characteristic
retinal lesions or who fail to respond to anti-
clinical and radiographic findings. Magnetic
T gondii therapy should undergo examination
resonance imaging usually reveals the pres-
of vitreous fluid or aqueous humor by PCR,
ence of multiple brain-occupying and ring-­
and antibody testing (by using the Goldmann-
enhancing lesions. If there is no clinical
Witmer coefficient, which compares the levels
response within 10 days to an empiric trial
of intraocular antibody production to that of
of anti-T gondii therapy, demonstration of
serum, as measured by enzyme-linked immu-
T gondii organisms, antigen, or DNA in speci-
nosorbent assay or radioimmunoassay) should
mens such as blood, CSF, or bronchoalveolar
be considered.
fluid may be necessary to confirm the diag­
nosis. Toxoplasmic encephalitis can also

ERRNVPHGLFRVRUJ
642 TOXOPLASMA GONDII ­INFECTIONS

Treatment 5 years of age should have initiation of primary


Most cases of acquired infection in an immu- prophylaxis when CD4+ T-lymphocyte percen­
nocompetent host do not require specific tage falls below 15%. Alternative regimens
­a ntimicrobial therapy unless infection occurs and recommendations for discontinuation
during pregnancy or symptoms are severe or of prophylaxis after the CD4+ T-lymphocyte
persistent. When indicated (eg, chorioretinitis, count recovers in association with antiretro­
significant organ damage), the combination of viral therapy are available. Trimethoprim-­
pyrimethamine and sulfadiazine, with supple- sulfamethoxazole, when administered for
mental leucovorin (folinic acid) to minimize Pneumocystis jiroveci pneumonia (PCP)
pyrimethamine-associated hematologic toxic- ­prophylaxis, also provides prophylaxis against
ity, is the regimen most widely accepted for toxoplasmosis. Dapsone plus pyrimethamine
children and adults with acute symptomatic or atovaquone may also provide protection.
disease. Trimethoprim-sulfamethoxazole Children older than 12 months who need PCP
(TMP-SMX) has been reported to be equiva- prophylaxis and who are receiving an agent
lent to pyrimethamine and sulfadiazine in other than TMP-SMX or atovaquone should
the treatment of patients with toxoplasmic have serologic testing for Toxoplasma anti­
­chorioretinitis. In addition, pyrimethamine bodies because alternative drugs for PCP pro-
can be used in combination with clindamycin, phylaxis, such as pentamidine, are not effective
atovaquone, or azithromycin if the patient against T gondii. Severely immunosuppressed
does not tolerate sulfonamide compounds. children who are not receiving TMP-SMX or
Corticosteroids appear to be useful in manage- atovaquone and who are found to be seroposi-
ment of ocular complications, central nervous tive for Toxoplasma infection should receive
system disease (CSF protein >1,000 mg/dL), prophylaxis for PCP and toxoplasmosis (ie,
and focal lesions with substantial mass effects dapsone plus pyrimethamine).
in certain patients. Primary prophylaxis with TMP-SMX or
HIV-infected adolescents and children 6 years ­atovaquone is also recommended for previ-
or older who have completed initial therapy ously seropositive patients who undergo
(at least 6 weeks and clinical response) for TE ­a llogeneic hematopoietic stem cell or bone
should receive suppressive therapy to prevent marrow transplantation. In addition, D+/R–
recurrence until their CD4+ T-lymphocyte heart transplant recipients must also receive
count recovers above 200 cells/µL and their primary prophylaxis with TMP-SMX, atova-
HIV viral load is nondetectable for at least quone, or pyrimethamine. For immunocom-
6 months. HIV-infected children 1 through promised patients without HIV infection,
5 years of age should also receive suppressive suppressive therapy should be continued for
therapy after completion of initial therapy; life or until the patient is no longer signifi-
discontinuation may be considered after they cantly immunosuppressed.
have been on stable antiretroviral therapy for For symptomatic and silent congenital
longer than 6 months, are asymptomatic, ­infections, pyrimethamine combined with
and have demonstrated an increase in CD4+ sulfadiazine (supplemented with folinic acid)
T-­lymphocyte percentage above 15% for more is recommended as initial therapy. Duration
than 3 consecutive months. Prophylaxis should of therapy is prolonged and often is 1 year.
be reinstituted whenever these parameters are However, the optimal dosage and duration
not met. Regimens for primary treatment are are not established definitively and should be
also effective for suppressive therapy. determined in consultation with an infectious
Primary prophylaxis to prevent the first episode diseases specialist.
of toxoplasmosis is generally recommended for Treatment of primary T gondii infection in
HIV-infected adolescents and children 6 years pregnant women, including women with HIV
or older who are T gondii–seropositive and infection, is recommended. Appropriate spe-
have CD4+ T-lymphocyte counts less than cialists should be consulted for management.
100/µL. HIV-infected children 1 through

ERRNVPHGLFRVRUJ
TOXOPLASMA GONDII ­INFECTIONS 643

Spiramycin treatment of primary infection only as an investigational drug in the United


during gestation is used in an attempt to pre- States but may be obtained from the manufac-
vent transmission of T gondii from the mother turer following the advice of PAMF-TSL. If
to the fetus but does not treat the fetus if in fetal infection is confirmed at or after 18 weeks
utero infection has already occurred because of gestation or if the mother acquires infection
spiramycin does not cross the placenta. Mater- during the third trimester, consideration
nal therapy may decrease the severity of should be given to starting therapy with
sequelae in the fetus once congenital toxoplas- ­pyrimethamine and sulfadiazine.
mosis has occurred. Spiramycin is available

Image 140.1
Cysts of Toxoplasma gondii usually range in size from 5 to 50 µm in diameter. Cysts are usually
spherical in the brain but more elongated in cardiac and skeletal muscles. They may be found in
various sites throughout the body of the host but are most common in the brain and skeletal and
cardiac muscles. T gondii cyst in brain tissue (hematoxylin-eosin stain). Courtesy of Centers for
Disease Control and Prevention.

Image 140.2
Histopathology of toxoplasmosis of the brain in fatal AIDS. Pseudocyst contains numerous tachyzoites
of Toxoplasma gondii. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
644 TOXOPLASMA GONDII ­INFECTIONS

Image 140.3
Histopathology of toxoplasmosis of the heart in
fatal AIDS. Within a myocyte is a pseudocyst
containing numerous tachyzoites of Toxoplasma
gondii. Several myocardial contraction bands and
scattered inflammatory cells are visible. Courtesy
of Centers for Disease Control and Prevention.

Image 140.4
A 12-day-old white boy with congenital
toxoplasmosis with marked hepatosplenomegaly.
Courtesy of George Nankervis, MD.

Image 140.5
Infant girl with congenital toxoplasmosis with
hepatosplenomegaly. Courtesy of Edgar O.
Ledbetter, MD, FAAP.

Image 140.6
A computed tomography scan of an infant with
congenital toxoplasmosis demonstrating multiple
intracranial calcifications. Courtesy of Larry
Frenkel, MD.

Image 140.7
Congenital infection evident on a computed
tomography scan of the head that shows diffuse
calcifications and hydrocephaly. Courtesy of
Charles Prober, MD.

ERRNVPHGLFRVRUJ
TOXOPLASMA GONDII ­INFECTIONS 645

Image 140.8
A 3-day-old boy presented with a seizure. His Image 140.9
computed tomography scan demonstrated Toxoplasma gondii retinitis. Note well-defined
hydrocephalus and periventricular calcification, areas of choroidoretinitis with pigmentation and
suggestive of congenital infection, such as irregular scarring.
toxoplasmosis, rubella, cytomegalovirus, or
herpes simplex. Toxoplasma serology was
positive and the neonate was treated for
congenital toxoplasmosis with pyrimethamine,
sulfadiazine, and folinic acid. Copyright Barbara
Jantausch, MD, FAAP.

Image 140.11
A 12-year-old boy with chorioretinal scar with
surrounding retinitis in the left eye nasal to the
disk measuring a one-quarter disc diameter
adjacent to the scar with mild overlying mild
vitritis. No lesions in the macula. Findings typical
of toxoplasmosis. Courtesy of Vicki Chen, MD.

Image 140.10
Peripheral chorioretinitis in an infant with
congenital toxoplasmosis. Courtesy of George
Nankervis, MD.

ERRNVPHGLFRVRUJ
646 TOXOPLASMA GONDII ­INFECTIONS

Image 140.12
Pathways for infection with Toxoplasma gondii. The only source for the production of T gondii oocysts
is the feline intestinal tract. Humans usually acquire the disease by direct ingestion of oocysts from
contaminated sources (eg, soil, cat litter, garden vegetables) or the ingestion of tissue cysts present in
undercooked tissues from infected animals. Fetal infection occurs most commonly following acute
maternal infection in pregnancy, but it can also occur following reactivation of latent infection in
immunocompromised women. Pathways leading to human disease (solid arrow); pathways leading
to feline infection (dashed arrow).

ERRNVPHGLFRVRUJ
Trichinellosis 647

141 (especially bear, boar, seal, and walrus) are


now the most common sources of infection.
Trichinellosis The disease is not transmitted from person
(Trichinella spiralis and Other Species) to ­person.
Clinical Manifestations Incubation Period
The clinical spectrum of infection ranges from Usually less than 1 month.
inapparent to fulminant and fatal illness, but
most infections are asymptomatic. The severity Diagnostic Tests
of disease is proportional to the infective dose. Eosinophilia up to 70%, in conjunction with
During the first week after ingesting infected compatible symptoms and dietary history,
meat, a person may experience abdominal ­suggests the diagnosis. Increases in concen­
­discomfort, nausea, vomiting, or diarrhea as trations of muscle enzymes, such as creatinine
excysted larvae infect the intestine. Two to phosphokinase and lactic dehydrogenase,
8 weeks later, as progeny larvae migrate into occur. Identification of larvae in suspect meat
tissues, fever, myalgia, periorbital edema, can be the most rapid source of diagnostic
­urticarial rash, and conjunctival and subun- information. Encapsulated larvae in a skeletal
gual hemorrhages can develop. In severe infec- muscle biopsy specimen (particularly deltoid
tions, myocarditis, neurologic involvement, and gastrocnemius) can be visualized micro-
and pneumonitis can occur in 1 or 2 months. scopically beginning 2 weeks after infection
Larvae may remain viable in tissues for years; by examining hematoxylin-eosin–stained
calcification of some larvae in skeletal muscle slides or sediment from digested muscle tissue.
usually occurs within 6 to 24 months and may Serologic tests are available through commer-
be detected on radiographs. cial and state laboratories and the Centers for
Disease Control and Prevention. Serum anti-
Etiology
body titers generally take 3 or more weeks to
Infection is caused by nematodes (roundworms) become positive and can remain positive for
of the genus Trichinella. At least 5 ­species years. Testing paired acute and convalescent
­capable of infecting only warm-blooded serum specimens is usually diagnostic.
­animals have been identified. Worldwide,
Trichinella spiralis is the most common cause Treatment
of human infection. Albendazole and mebendazole have com­
parable efficacy for treatment of trichinellosis
Epidemiology
(trichinosis). However, albendazole and
Infection is enzootic worldwide in carnivores mebendazole are less effective for Trichinella
and omnivores, especially scavengers. Infection larvae already in the muscles. Mebendazole
occurs as a result of ingestion of raw or insuffi- is no longer available in the United States.
ciently cooked meat containing encysted larvae Coadministration of corticosteroids with
of Trichinella species. Commercial and home- mebendazole or albendazole is often recom-
raised pork remain a source of human infec- mended when systemic symptoms are severe.
tions, but meats other than pork, such as Corticosteroids can be lifesaving when the
venison, horse meat, and, particularly, meats ­central nervous system or heart is involved.
from wild carnivorous or omnivorous game

ERRNVPHGLFRVRUJ
648 Trichinellosis

Image 141.2
Image 141.1 Adult Trichinella species reside in the intestinal
Trichinella larvae in a sample of infected meat tract of the mammalian host; larvae can be found
(light microscopy, magnification x100). Courtesy encapsulated in muscle tissue. Diagnosis is
of Emerging Infectious Diseases. usually made serologically or based on obser­
vation of the larvae in muscle tissue following
biopsies or autopsies. Trichinella spiralis larvae
in muscle tissue. Courtesy of Centers for
Disease Control and Prevention.

Image 141.3
Trichinellosis. Number of reported cases, by year—United States, 1982–2012. Courtesy of Morbidity
and Mortality Weekly Report.

ERRNVPHGLFRVRUJ
Trichinellosis 649

Image 141.4
This patient with trichinellosis (trichinosis) had periorbital swelling, muscle pain, diarrhea, and 28%
(0.28) eosinophils. Courtesy of Centers for Disease Control and Prevention/Dr Thomas F. Sellers,
Emory University.

Image 141.5
Here the parasitic disease trichinellosis (trichi­no­
sis) is manifested by splinter hemorrhages under
the fingernails. Trichinellosis is caused by eating
raw or undercooked pork infected with the larvae
of a species of worm called Trichinella. Initial
symptoms include nausea, diarrhea, vomiting, Image 141.6

fatigue, fever, and abdominal discom­fort. Courtesy Larvae of Trichinella spiralis in skeletal muscle
of Centers for Disease Control and Prevention/ biopsy.
Dr Thomas F. Sellers, Emory University.

Image 141.7
Trichinella spiralis organisms on cross-section
of muscle biopsy of the patient in images 141.4
and 141.5. Courtesy of Edgar O. Ledbetter,
MD, FAAP.

ERRNVPHGLFRVRUJ
650 Trichinellosis

Image 141.8
Trichinellosis (trichinosis) is acquired by ingesting meat containing cysts (encysted larvae) (1) of
Trichinella. After exposure to gastric acid and pepsin, the larvae are released (2) from the cysts and
invade the small bowel mucosa, where they develop into adult worms (3) (female, 2.2 mm in length;
males, 1.2 mm in length; life span in the small bowel, 4 weeks). After 1 week, the females release
larvae (4) that migrate to the striated muscles, where they encyst (5). Trichinella pseudospiralis, how­
ever, do not encyst. Encystment is completed in 4 to 5 weeks and the encysted larvae may remain
viable for several years. Ingestion of the encysted larvae perpetuates the cycle. Rats and rodents
are primarily responsible for maintaining the endemicity of this infection. Carnivorous or omnivorous
animals, such as pigs or bears, feed on infected rodents or meat from other animals. Different animal
hosts are implicated in the life cycle of the different species of Trichinella. Humans are accidentally
infected when eating improperly processed meat of these carnivorous animals (or eating food con­
taminated with such meat). Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
TRICHOMONAS VAGINALIS INFECTIONS 651

142 experienced 14- to 19-year-old girls in the


United States was 3.6%. It commonly coexists
Trichomonas vaginalis with other conditions, particularly with
Infections ­Neisseria gonorrhoeae and Chlamydia
(Trichomoniasis) ­trachomatis infections and bacterial vaginosis.
Transmission results almost exclusively from
Clinical Manifestations sexual contact, and the presence of T vaginalis
Trichomonas vaginalis infection is asymptom- in a child or preadolescent beyond the perina-
atic in 70% to 85% of infected people. Clinical tal period is considered highly suspicious for
manifestations in symptomatic pubertal or sexual abuse. T vaginalis infection can increase
postpubertal females consist of a diffuse vagi- the acquisition and transmission of HIV.
nal discharge, odor, and vulvovaginal pruritus
Incubation Period
and irritation. Dysuria and, less often, lower
abdominal pain can occur. Vaginal discharge Typically 1 week (range, 5–28 days).
may be any color but is classically yellow-green, Diagnostic Tests
frothy, and malodorous. The vulva and vaginal
mucosa can be erythematous and edematous. Diagnosis in a symptomatic female is typically
The cervix can be inflamed and is sometimes established by careful and immediate examina-
covered with numerous punctate cervical hem- tion of a wet-mount preparation of vaginal dis-
orrhages and swollen papillae, referred to as charge. The jerky motility of the protozoan and
strawberry cervix (colpitis macularis). This the movement of the flagella are distinctive.
finding occurs in fewer than 5% of infected Microscopy has 50% to 65% sensitivity for
females but is highly suggestive of trichomo- T vaginalis diagnosis in females and is less
niasis. Clinical manifestations in symptomatic ­sensitive in males; test sensitivity declines if
men include urethritis and, rarely, epididymitis the evaluation is delayed. The presence of
or prostatitis. Reinfection is common, and symptoms and the identification of the organ-
resistance to treatment is rare but increasing. ism are related directly to the number of
Rectal infections are uncommon, and oral organisms present. The nucleic acid amplifi­
infections have not been described. cation test is the most sensitive means of diag-
nosing T vaginalis infection and is encouraged
T vaginalis infections in pregnant women for detection in females and males. The Aptima
have been associated with premature rupture T vaginalis assay (Hologic, Inc, Marlborough,
of the membranes and preterm delivery. Peri- MA) is commercially available for testing vagi-
natal infection can occur in up to 5% of neo- nal specimens, endocervical specimens, female
nates of infected mothers. T vaginalis infection urine, and liquid cytology specimens. The BD
in female newborns may cause vaginal dis- ProbeTec T vaginalis QX Amplified DNA Assay
charge during the first weeks of life but is (BD Diagnostics, Baltimore, MD) can detect
­usually self-limited, resolving as maternal T vaginalis from endocervical, vaginal, or
­hormones are metabolized. female urine specimens. Culture of T vaginalis
Etiology in diamond media or other trichomoniasis-
specific culture systems (eg, InPouch, Biomed
T vaginalis is a flagellated protozoan approxi- Diagnostics, White City, OR) is a sensitive and
mately the size of a leukocyte. It requires specific method of diagnosis in females but has
adherence to host cells for survival. lower sensitivity in males.
Epidemiology Two point-of-care tests are available for testing
Although formal surveillance programs are female vaginal swab specimens in settings
not in place, several studies suggest that where no microscope is available and rapid
T ­vaginalis infection is the most common results are desirable. The OSOM Trichomonas
­curable sexually transmitted infection in the Test (Sekisui Diagnostics, LLC, Lexington,
United States and globally. Prevalence in a MA) is a Clinical Laboratory Improvement
nationally representative sample of sexually Amendments–waived, antigen-detection,

ERRNVPHGLFRVRUJ
652 TRICHOMONAS VAGINALIS INFECTIONS

point-of-care test that uses immunochromato- do not achieve therapeutic concentrations in


graphic capillary flow dipstick technology. the urethra or perivaginal glands. Sexual
Results are available within 10 minutes. The ­partners should be treated, even if asymptom-
BD Affirm VPIII (Becton, Dickinson and atic, because reinfection is a major factor in
Company, Franklin Lakes, NJ) is a nucleic treatment failures. T vaginalis strains with
acid probe test for T vaginalis, Gardnerella decreased susceptibility to metronidazole
­vaginalis, and Candida albicans. Although have been reported; most of these infections
the Affirm VPIII is considered a point-of-care respond to tinidazole or higher doses of metro-
diagnostic tool, test results are available in nidazole. If treatment failure occurs and rein-
45 minutes. Vaginal specimens can also be fection is excluded, metronidazole twice daily
sent to a clinical laboratory for Affirm VPIII for 7 days should be used. If treatment failure
testing. Both of these vaginitis tests are reported occurs following this regimen, a course of met-
to be more sensitive than microscopy (63% ronidazole or tinidazole may be used. If several
when compared with culture) and to have a 1-week regimens have failed in a person who is
specificity of 99%. False-positive results may unlikely to have nonadherence or reinfection,
occur in populations with a low prevalence testing of the organism for metronidazole and
of disease. tinidazole susceptibility is recommended.
Treatment People infected with T vaginalis should be eval-
Treatment of adults with metronidazole, in uated for other sexually transmitted infections,
a single dose, results in cure rates of approxi- including syphilis, gonorrhea, chlamydia, HIV,
mately 90% to 95%. Treatment with tinidazole and hepatitis B. For newborns, infection with
in a single dose appears to be similar or even T vaginalis acquired maternally is self-limited,
superior to metronidazole. Topical vaginal and treatment is generally not recommended.
preparations should not be used because they

Image 142.2
This phase contrast wet mount micrograph of
a vaginal discharge revealed the presence of
Trichomonas vaginalis protozoa. T vaginalis,
Image 142.1
a flagellate, is the most common pathogenic
Two trophozoites of Trichomonas vaginalis protozoan of humans in industrialized countries.
obtained from in vitro culture (Giemsa stain). This protozoan resides in the female lower genital
Courtesy of Centers for Disease Control tract and the male urethra and prostate, where it
and Prevention. replicates by binary fission. Courtesy of Centers
for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
TRICHOMONAS VAGINALIS INFECTIONS 653

Image 142.3
Trichomonas vaginalis resides in the female lower genital tract and the male urethra and prostate (1),
where it replicates by binary fission (2). The parasite does not appear to have a cyst form and does
not survive well in the external environ­ment. T vaginalis is transmitted among humans, its only known
host, primarily by sexual inter­course (3). Courtesy of Centers for Disease Control and Prevention/
Alexander J. da Silva, PhD/Melanie Moser.

Image 142.4
This patient presented with a strawberry cervix (colpitis macularis) due to a Trichomonas vaginalis
infection, or trichomoniasis. The term strawberry cervix is used to describe the appearance of the
cervix due to the presence of T vaginalis protozoa. The cervical mucosa reveals punctate hemorrhages
along with accompanying vesicles or papules. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
654 TRICHOMONAS VAGINALIS INFECTIONS

Image 142.6
This Gram-stained micrograph of a urethral
discharge revealed the presence of trichomonads
and gram-negative rods. Trichomonas vaginalis,
a flagellate, is the most common pathogenic
protozoan of humans in industrialized countries.
Image 142.5
This protozoan resides in the female lower genital
This was a case of Trichomonas vaginitis revealing tract and the male urethra and prostate, where it
a copious purulent discharge emanating from the replicates by binary fission. Courtesy of Centers
cervical os. Trichomonas vaginalis, a flagellate, is for Disease Control and Prevention.
the most common pathogenic protozoan of humans
in industrialized countries. This protozoan resides
in the female lower genital tract and the male
urethra and prostate, where it replicates by binary
fission. Courtesy of Centers for Disease Control
and Prevention.

Image 142.7
An asymptomatic vaginal discharge in a premenarcheal girl who has other signs of the effects of
estrogen is most likely due to physiological leukorrhea. The discharge is caused by the desquamation
of vaginal epithelial cells in response to the effect of estrogen on the vaginal mucosa. Prior to puberty,
the vaginal mucosa is atrophic, the pH of vaginal secretions is 6.5 to 7.5, and the bacterial flora are
mixed. Following the onset of puberty, Lactobacillus becomes the predominant organism in the
vagina. These gram-positive bacilli metabolize sloughed epithelial cells, producing lactic acid and
decreasing the pH of the vagina to less than 4.5. Courtesy of H. Cody Meissner, MD, FAAP.

ERRNVPHGLFRVRUJ
Trichuriasis 655

143 hookworm species. Humans are the natural


reservoir. Eggs require a minimum of 10 days
Trichuriasis of incubation in the soil before they are infec-
(Whipworm Infection) tious. The disease is not communicable from
Clinical Manifestations person to person.

Disease caused by the whipworm Trichuris Incubation Period


trichiura is generally proportional to the inten- Approximately 12 weeks.
sity of the infection. Although most infected
children are asymptomatic, those with heavy Diagnostic Tests
infestations can develop a colitis that mimics Eggs may be found on direct examination of
inflammatory bowel disease and can lead to stool, although diagnosis of light to moderate
anemia, physical growth restriction, and club- infections may require concentration techniques.
bing. T trichiura dysentery syndrome is more
intense and characterized by abdominal pain, Treatment
tenesmus, and bloody diarrhea with mucus; it Albendazole, ivermectin, or mebendazole
can be associated with rectal prolapse. administered for 3 days provides only moder-
ate rates of cure. Albendazole is considered
Etiology
the treatment of choice in the United States
T trichiura, the human whipworm, is the because mebendazole is no longer available.
­causative agent. Adult worms are 30 to 50 mm Reexamination of stool specimens 2 weeks
long with a large, threadlike anterior end that after therapy to determine whether the worms
embeds in the mucosa of the large intestine. have been eliminated is helpful for assessing
the effectiveness of therapy. A recent study sug-
Epidemiology
gests combination therapy with mebendazole
The parasite is the second most common and ivermectin is associated with a higher cure
­soil-transmitted helminth in the world, occur- rate than any currently available monotherapy.
ring mainly in tropical regions with poor
­sanitation. It is coendemic with Ascaris and

Image 143.1
Trichuris trichiura ova. A–C, Atypical Trichuris species eggs. Courtesy of Centers for Disease Control
and Prevention.

ERRNVPHGLFRVRUJ
656 Trichuriasis

Image 143.2
This micrograph of an adult Trichuris female human whipworm reveals that its size in centimeters
is approximately 4 cm. The female Trichuris trichiura worms begin to oviposit in the cecum and
ascending colon 60 to 70 days after infection. Female worms in the cecum shed between 3,000
and 20,000 eggs per day. The life span of the adults is about 1 year. Courtesy of Centers for
Disease Control and Prevention.

Image 143.3
Trichuris trichiura life cycle. The unembryonated eggs are passed with the stool (1). In the soil, the
eggs develop into a 2-cell stage (2) and an advanced cleavage stage (3) and then they embryonate (4);
eggs become infective in 15 to 30 days. After ingestion (soil-contaminated hands or food), the eggs
hatch in the small intestine and release larvae (5) that mature and establish themselves as adults in
the colon (6). The adult worms (~4 cm in length) live in the cecum and ascending colon. The adult
worms are fixed in that location, with the anterior portions threaded into the mucosa. The females
begin to oviposit 60 to 70 days after infection. Female worms in the cecum shed between 3,000 and
20,000 eggs per day. The life span of the adults is about 1 year. Courtesy of Centers for Disease
Control and Prevention.

ERRNVPHGLFRVRUJ
African Trypanosomiasis 657

144 African (Gambian) form progresses more


slowly and is caused by T brucei gambiense.
African Trypanosomiasis The east and southern African (Rhodesian)
(African Sleeping Sickness) form is more acute and is caused by T brucei
Clinical Manifestations rhodesiense. Both are extracellular protozoan
hemoflagellates that live in blood and tissue
The clinical course of human African trypano- of the human host.
somiasis (sleeping sickness) has 2 stages: the
first is the hemolymphatic stage, in which the Epidemiology
parasite multiplies in subcutaneous tissues, Approximately 7,000 human cases are reported
lymph, and blood; once the parasite crosses annually worldwide, although only a few cases,
the blood-brain barrier and infects the central which are acquired in Africa, are reported
nervous system (CNS), the disease enters the every year in the United States. Transmission
second stage, known as the neurologic stage. is confined to an area in Africa between the
The rapidity of disease progression and clinical latitudes of 15° north and 20° south, corre-
manifestations vary with the infecting sub­ sponding precisely with the distribution of
species. With Trypanosoma brucei gambiense the tsetse fly vector (Glossina species). In
infection (West African sleeping sickness), West and Central Africa, humans are the
initial symptoms can be mild, with fever, main reservoir of T brucei gambiense, although
­muscle aches, and malaise. Pruritus, rash, the ­parasite can sometimes be found in domes-
weight loss, and generalized lymphadenopathy tic animals, such as dogs and pigs. In East
can occur. Posterior cervical lymphadenopathy Africa, wild animals, such as antelope, bush-
(Winterbottom sign) may be present. Central buck, and hartebeest, constitute the major
nervous system involvement typically develops ­reservoirs for sporadic infections with T brucei
1 to 2 years later with development of behav- ­rhodesiense, although cattle serve as reservoir
ioral changes, cachexia, headache, hallucina- hosts in local outbreaks. In addition to the bite
tions, delusions, and daytime somnolence of the tsetse fly, T brucei can also be transmit-
followed by nighttime insomnia. In contrast, ted congenitally and through blood transfu-
Trypanosoma brucei rhodesiense infection sions or organ transplantation, although these
(East African sleeping sickness) is an acute, modes are uncommon.
generalized illness that develops days to weeks
after parasite inoculation, with manifestations Incubation Period
including high fever, lymphadenopathy, rash, For T brucei rhodesiense infection, 3 to 21 days;
muscle and joint aches, thrombocytopenia, for T brucei gambiense infection, 5 to 14 days.
hepatitis, anemia, myocarditis, and, rarely,
laboratory evidence of disseminated intra­ Diagnostic Tests
vascular coagulopathy. A chancre may develop Diagnosis is made by identification of trypano-
at the site of the tsetse fly bite. Clinical menin- somes in specimens of blood, cerebrospinal
goencephalitis can develop as early as 3 weeks fluid (CSF), or fluid aspirated from a chancre
after onset of the untreated systemic illness. or lymph node or by inoculation of susceptible
Both forms of African trypanosomiasis have laboratory animals (mice) with heparinized
high fatality rates; without treatment, infected blood. Examination of CSF is critical to man-
patients usually die within weeks to months agement and should be performed using the
after clinical onset of disease caused by double-centrifugation technique. Concentra-
T ­brucei rhodesiense and within a few years tion and Giemsa staining of the buffy coat layer
from disease caused by T brucei gambiense. of peripheral blood can also be helpful and is
easier for T brucei rhodesiense because the den-
Etiology
sity of organisms in circulating blood is higher
Human African trypanosomiasis occurs in than for T brucei gambiense. T brucei gam­
sub-Saharan Africa. It is caused by the proto- biense is more likely to be found in lymph
zoan parasite T brucei, transmitted by blood- node aspirates. Identification of trypanosomes
feeding tsetse flies. The west and central or a white blood cell count of 6 or higher in the

ERRNVPHGLFRVRUJ
658 African Trypanosomiasis

CSF is the most widely used criteria for CNS involvement is present, the drug of choice for
involvement; elevated protein and an increase the acute hemolymphatic stage of infection
in immunoglobulin M also suggest second is pentamidine for T brucei gambiense infec-
stage disease. Serologic testing is available tion and suramin for T brucei rhodesiense
­outside the United States for T brucei gam­ infection. For treatment of infection with
biense; there is no serologic screening test for CNS involvement, the drug of choice is eflor­
T brucei rhodesiense. nithine for T brucei gambiense infection and
melarsoprol for T brucei rhodesiense infection.
Treatment
Suramin, eflornithine, and melarsoprol can be
The choice of drug used for treatment will be obtained from the Centers for Disease Control
dependent on the type and stage of African and Prevention.
trypanosomiasis. When no evidence of CNS

Image 144.1
Trypanosoma brucei gambiense in blood smear (Giemsa stain).

Image 144.2
Trypanosoma forms in blood smear from a patient with African trypanosomiasis (hematoxylin-
eosin stain).

ERRNVPHGLFRVRUJ
African Trypanosomiasis 659

Image 144.3
During a blood meal on the mammalian host, an infected tsetse fly (genus Glossina) injects metacyclic
trypomastigotes into skin tissue. The parasites enter the lymphatic system and pass into the blood­
stream (1). Inside the host, they transform into bloodstream trypomastigotes (2), are carried to other
sites throughout the body, reach other body fluids (eg, lymph, spinal fluid), and continue the replication
by binary fission (3). The entire life cycle of African trypanosomes is represented by extracellular
stages. The tsetse fly becomes infected with bloodstream trypomastigotes when taking a blood meal
on an infected mammalian host (4, 5). In the fly’s midgut, the parasites transform into procyclic trypo­
mastigotes, multiply by binary fission (6), leave the midgut, and transform into epimastigotes (7). The
epimastigotes reach the fly’s salivary glands and continue multiplication by binary fission (8). The
cycle in the fly takes approximately 3 weeks. Humans are the main reservoir for Trypanosoma brucei
gambiense, but this species can also be found in animals. Wild game animals are the main reservoir
of Trypanosoma brucei rhodesiense. Courtesy of Centers for Disease Control and Prevention/
Alexander J. da Silva, PhD/Melanie Moser.

ERRNVPHGLFRVRUJ
660 American Trypanosomiasis

145 with swallowing difficulties accompanied by


severe weight loss. Congenital Chagas disease
American Trypanosomiasis occurs in 1% to 10% of neonates born to
(Chagas Disease) infected mothers and is characterized by low
Clinical Manifestations birth weight, hepatosplenomegaly, myocarditis,
or meningoencephalitis with seizures and
The acute phase of Trypanosoma cruzi infection tremors. However, most neonates with congen-
lasts 2 to 3 months, followed by the chronic ital T cruzi infection have no signs or symp-
phase that, in the absence of successful anti- toms of disease. Reactivation of chronic T cruzi
parasitic treatment, is lifelong. The acute phase, infection with parasites found in the circulat-
when parasites circulate in the blood, is com- ing blood, which can be life threatening, may
monly asymptomatic or characterized by mild, occur in immunocompromised people, includ-
nonspecific symptoms. Young children are ing people infected with HIV and those who
more likely to exhibit symptoms than are are immunosuppressed after transplantation.
adults. In some patients, a red, indurated
­nodule known as a chagoma develops at the Etiology
site of the original inoculation, usually on the T cruzi, a protozoan hemoflagellate, is the cause.
face or arms. Unilateral edema of the eyelids,
known as the Romaña sign, may occur if the Epidemiology
portal of entry was the conjunctiva; it usually Parasites are transmitted in feces of infected
is not present. The edematous skin may be triatomine insects (sometimes called “kissing
­v iolaceous and associated with conjunctivitis bugs”; local Spanish/Portuguese names include
and enlargement of the ipsilateral preauricular vinchuca, chinche picuda, or barbeiro). The
lymph node. Fever, malaise, generalized bugs defecate during or after taking blood.
lymphadenopathy, and hepatosplenomegaly The bitten person is inoculated through inad-
can develop. In rare instances, acute myo­ vertent rubbing of insect feces containing the
carditis or meningoencephalitis can occur. parasite into the site of the bite or mucous
The symptoms of acute Chagas disease resolve membranes of the eye or mouth. The parasite
without treatment within 3 months, and can also be transmitted congenitally, during
patients pass into the chronic phase of the solid organ transplantation, through blood
infection, during which few or no parasites are transfusion, and by ingestion of food or drink
found in the blood. Most people with chronic contaminated by the vector’s excreta. Acciden-
T cruzi infection have no signs or symptoms tal laboratory infections can result from han-
and are said to have the indeterminate form dling parasite cultures or blood from infected
of chronic Chagas disease. In 20% to 30% of people or laboratory animals, usually through
cases, serious progressive sequelae affecting needlestick injuries. Vectorborne transmission
the heart or gastrointestinal tract develop years of the disease is limited to the Western hemi-
to decades after the initial infection (called sphere, predominantly Mexico and Central
determinate forms of chronic Chagas disease). and South America. The southern United
Chagas cardiomyopathy is characterized by States has established enzootic cycles of T cruzi
conduction system abnormalities, especially involving several triatomine vector species
right bundle branch block, and ventricular and mammalian hosts, such as raccoons,
arrhythmias and can progress to dilated ­opossums, rodents, and domestic dogs. Never-
­cardiomyopathy and congestive heart failure. theless, most T cruzi–infected individuals in
Patients with Chagas cardiomyopathy may the United States are immigrants from areas of
die suddenly from ventricular arrhythmias, Latin America with endemic infection. There
complete heart block, or emboli phenomena; are an estimated 300,000 individuals with
death may also occur from intractable conges- T cruzi infection in the United States. Assum-
tive heart failure. Although cardiac manifes­ ing a 1% to 5% risk of congenital transmission,
tations are more common, some patients with based on estimates of maternal infection,
chronic Chagas disease develop digestive dis- approximately 63 to 315 neonates are born
ease with dilatation of the colon or esophagus with Chagas disease in the United States every

ERRNVPHGLFRVRUJ
American Trypanosomiasis 661

year. Several transfusion- and transplantation-­ diagnosis of chronic T cruzi infection. The Pan
associated cases have been documented in the American Health Organization and World
United States. Health Organization recommend that samples
be tested using 2 assays of different formats
The disease is an important cause of morbidity
before diagnostic decisions are made.
and death in Latin America, where an estimated
8 million people are infected, of whom approx- The diagnosis of congenital Chagas disease can
imately 30% to 40% have or will develop cardio­ be made during the first 3 months of life by
myopathy or gastrointestinal tract disorders. identification of motile trypomastigotes by
direct microscopy of fresh anticoagulated
Incubation Period
blood specimens. Polymerase chain reaction
Acute phase, 1 to 2 weeks or longer; chronic testing has higher sensitivity than microscopy.
manifestations do not appear for years to All infants born to seropositive mothers
decades. should be screened using conventional sero-
logic testing after 9 months of age, when IgG
Diagnostic Tests
measurements reflect infant response rather
During the acute phase of disease, the parasite than maternal antibody.
is demonstrable in blood specimens by Giemsa
staining after a concentration technique or in Treatment
direct wet-mount or buffy coat preparations. Antitrypanosomal treatment is recommended
Molecular techniques and hemoculture in for all cases of acute and congenital Chagas
­special media (available at the Centers for disease, reactivated infection attributable to
­Disease Control and Prevention) also have immunosuppression, and chronic T cruzi
high sensitivity in the acute phase. The chronic infection in children younger than 18 years.
phase of T cruzi infection is characterized by Treatment of chronic T cruzi infection in
low-level parasitemia; the sensitivity of culture adults without advanced cardiomyopathy is
and polymerase chain reaction assay is gener- also generally recommended. The only drugs
ally less than 50%. Diagnosis in the chronic with proven efficacy are benznidazole and
phase relies on serologic tests to demonstrate nifurtimox; neither drug is approved by the
immunoglobulin (Ig) G antibodies against US Food and Drug Administration for use
T cruzi. Serologic tests include indirect immu- in the United States, but both drugs can be
nofluorescent and enzyme immunosorbent obtained from the Centers for Disease
assays; however, no single serologic test is ­Control and Prevention under compassionate
­sufficiently sensitive or specific for confirmed use protocols.

Image 145.1
A–E, Trypanosoma cruzi in blood smears (Giemsa stain). Courtesy of Centers for Disease Control
and Prevention.

ERRNVPHGLFRVRUJ
662 American Trypanosomiasis

Image 145.2 Image 145.3


This is a photomicrograph of Trypanosoma cruzi Dorsal view of a male triatomine bug, Triatoma
in a blood smear using Giemsa staining sanguisuga, one of the most important species in
technique. This protozoan parasite, T cruzi, is the the United States for Chagas disease
causative agent for Chagas disease, also known transmission. Courtesy of Centers for Disease
as American trypanosomiasis. It is estimated that Control and Prevention/Emerging Infectious
16 to 18 million people are infected with Chagas Diseases and Patricia L. Dorn.
disease and, of those infected, 50,000 will die
each year. Courtesy of Centers for Disease
Control and Prevention.

Image 145.4
Adult female “kissing bug” of the species Triatoma rubida, the most abundant triatomine species in
southern Arizona (scale bar = 1 cm). Chagas disease is endemic throughout Mexico and Central and
South America, with 7.7 million persons infected, 108.6 million persons considered at risk, 33.3 million
symptomatic cases, an annual incidence of 42,500 cases (through vectorial transmission), and 21,000
deaths every year. This disease is caused by the protozoan parasite Trypanosoma cruzi, which is
transmitted to humans by bloodsucking insects of the family Reduviidae (Triatominae). Although mainly
a vectorborne disease, Chagas disease can also be acquired by humans through blood transfusions
and organ transplantation, congenitally (from a pregnant woman to her baby), and through oral
contamination (eg, foodborne). Courtesy of Emerging Infectious Diseases/C. Hedgecock.

ERRNVPHGLFRVRUJ
American Trypanosomiasis 663

Image 145.5
A–C, Triatomine bug, Trypanosoma cruzi vector, defecating on the wound after taking a blood meal.
Courtesy of Centers for Disease Control and Prevention.

Image 145.6
An infected triatomine insect vector (or “kissing bug”) takes a blood meal and releases trypomastigotes
in its feces near the site of the bite wound. Trypomastigotes enter the host through the wound or
through intact mucosal membranes, such as the conjunctiva (1). Common triatomine vector species
for trypanosomiasis belong to the genera Triatoma, Rhodnius, and Panstrongylus. Inside the host, the
trypomastigotes invade cells, where they differentiate into intracellular amastigotes (2). The
amastigotes multiply by binary fission (3), differentiate into trypomastigotes, and then are released into
the circulation as bloodstream trypomastigotes (4). Trypomastigotes infect cells from a variety of
tissues and transform into intracellular amastigotes in new infection sites. Clinical manifestations can
result from this infective cycle. The bloodstream trypomastigotes do not replicate (different from
African trypanosomes). Replication resumes only when the parasites enter human or animal blood that
contains circulating parasites (5). The ingested trypomastigotes transform into epimastigotes in the
vector’s midgut (6). The parasites multiply and differentiate in the midgut (7) and differentiate into
infective metacyclic trypomastigotes in the hindgut (8). Trypanosoma cruzi can also be transmitted
through blood transfusions, organ transplantation, transplacentally, and in laboratory accidents.
Courtesy of Centers for Disease Control and Prevention/Alexander J. da Silva, PhD/Melanie Moser.

ERRNVPHGLFRVRUJ
664 Tuberculosis

146 patients with drug-resistant tuberculosis dis-


ease are indistinguishable from manifestations
Tuberculosis in patients with drug-susceptible disease.
Clinical Manifestations Etiology
Tuberculosis disease is caused by infection The causative agent is M tuberculosis complex,
with organisms of the Mycobacterium tuber­ a group of closely related acid-fast bacilli
culosis complex. Most infections caused by (AFB), which routinely includes the human
M tuberculosis complex in children and adoles- pathogens M tuberculosis, M bovis, and
cents are asymptomatic. When tuberculosis ­Mycobacterium africanum. M africanum is
disease occurs, clinical manifestations most rare in the United States, so clinical laborato-
often appear 1 to 6 months after infection (up ries do not distinguish it routinely. M bovis
to 18 months for osteoarticular disease) and can be distinguished from M tuberculosis in
include fever, weight loss or poor weight gain, reference laboratories, and although the spec-
growth delay, cough, night sweats, and chills. trum of illness caused by M bovis is similar to
Chest radiographic findings after infection that of M tuberculosis, the epidemiology, and
are rarely specific for tuberculosis and range treatment are different.
from normal to diverse abnormalities, such
as lymphadenopathy of the hilar, subcarinal, Definitions
paratracheal, or mediastinal nodes; atelectasis • Positive tuberculin skin test (TST) result.
or infiltrate of a segment or lobe; pleural effu- A positive TST result (Box 146.1) indicates
sion that can conceal small interstitial lesions; possible infection with M tuberculosis com-
interstitial cavities; or miliary-pattern infil- plex. Tuberculin reactivity appears 2 to
trates. In selected instances, computed tomog- 10 weeks after initial infection; the median
raphy or magnetic resonance imaging of the interval is 3 to 4 weeks. Bacille Calmette-
chest can resolve indistinct radiographic find- Guérin (BCG) immunization can produce
ings, but these methods are not necessary for a positive TST result.
routine diagnosis. Although cavitation is com-
mon in reactivation “adult” tuberculosis, cavi- • Positive interferon-gamma release assay
tation is uncommon in childhood tuberculosis. (IGRA) result. A positive IGRA result indi-
Necrosis and cavitation can result from a pro- cates probable infection with M tuberculosis
gressive primary focus in very young or immu- complex.
nocompromised patients and in the setting of
• Exposed person is a person who has had
lymphobronchial disease. Extrapulmonary
recent (ie, within 3 months) contact with
manifestations include meningitis and granu-
another person with suspected or confirmed
lomatous inflammation of the lymph nodes,
contagious tuberculosis disease and who
bones, joints, skin, and middle ear and mas-
has a negative TST or IGRA result, normal
toid. Gastrointestinal tuberculosis can mimic
physical examination, and chest radio-
inflammatory bowel disease. Renal tubercu­
graphic findings that are normal or not
losis and progression to disease from latent
­compatible with tuberculosis. Some exposed
M tuberculosis infection (LTBI) (“adult-type
people are or become infected (and, subse-
pulmonary tuberculosis”) are unusual in
quently, develop a positive TST or IGRA
younger children but can occur in adolescents.
result), while others do not; the 2 groups
In addition, chronic abdominal pain with
cannot be distinguished initially.
­peritonitis and intermittent partial intestinal
obstruction can be present in disease caused • Source case is the person who has transmit-
by Mycobacterium bovis. Congenital tubercu­ ted infection with M tuberculosis complex to
losis can mimic neonatal sepsis, or the infant another person who subsequently develops
may come to medical attention in the first LTBI or tuberculosis disease.
90 days of life with bronchopneumonia and
hepatosplenomegaly. Clinical findings in

ERRNVPHGLFRVRUJ
Tuberculosis 665

Box 146.1
Definitions of Positive Tuberculin Skin Test Results
in Infants, Children, and Adolescentsa

Induration ≥5 mm
Children in close contact with known or suspected contagious people with tuberculosis disease
Children suspected to have tuberculosis disease
• Findings on chest radiograph consistent with active or previous tuberculosis disease
• Clinical evidence of tuberculosis diseaseb
Children receiving immunosuppressive therapyc or with immunosuppressive conditions, includ-
ing HIV infection

Induration ≥10 mm
Children at increased risk of disseminated tuberculosis disease
• Children younger than 4 years
• Children with other medical conditions, including Hodgkin disease, lymphoma, diabetes
­mellitus, chronic renal failure, or malnutrition
Children with likelihood of increased exposure to tuberculosis disease
• Children born in high-prevalence regions of the world
• Children who travel to high-prevalence regions of the world
• Children frequently exposed to adults who are HIV infected, homeless, users of illicit drugs,
residents of nursing homes, incarcerated, or institutionalized

Induration ≥15 mm
Children 4 years or older without any risk factors

Abbreviations: BCG, bacille Calmette-Guérin; HIV, human immunodeficiency virus; TST, tuberculin skin test.
a These definitions apply regardless of previous BCG immunization; erythema alone at TST site does not indicate a positive test result.

Tests should be read at 48 to 72 hours after placement.


b Evidence by physical examination or laboratory assessment that would include tuberculosis in the working differential diagnosis

(eg, meningitis).
c Including immunosuppressive doses of corticosteroids or tumor necrosis factor α antagonists or blockers.

• Latent M tuberculosis infection is M tuber­ • Directly observed therapy (DOT) is an


culosis complex infection in a person who intervention by which medications are
has a positive TST or IGRA result, no physi- administered directly to the patient by a
cal findings of disease, and chest radiograph health care professional or trained third
findings that are normal or reveal evidence party (not a relative or friend) who observes
of healed infection (ie, calcification in the and documents that the patient ingests each
lung, hilar lymph nodes, or both). dose of medication.
• Tuberculosis disease is an infection in • Multidrug-resistant (MDR) tuberculosis
a person in whom symptoms, signs, or is infection or disease caused by a strain of
radiographic manifestations caused by M tuberculosis complex that is resistant to at
M ­tuberculosis complex are apparent; least isoniazid and rifampin, the 2 first-line
­disease can be pulmonary, extrapulmonary, drugs with greatest efficacy.
or both.
• Extensively drug-resistant tuberculosis is
• Contagious tuberculosis refers to tubercu- an infection or disease caused by a strain
losis disease typical of the lungs or airway of M tuberculosis complex that is resistant
in a person when there is the potential to to isoniazid and rifampin, at least one fluo-
transmit M tuberculosis to other people. roquinolone, and at least one of the follow-
ing parenteral drugs: amikacin, kanamycin,
or capreomycin.

ERRNVPHGLFRVRUJ
666 Tuberculosis

• Bacille Calmette-Guérin is a live-attenuated A diagnosis of LTBI or tuberculosis disease


vaccine strain of M bovis. BCG vaccine is in a young child is a public health sentinel
rarely administered to children in the event often representing recent transmission.
United States but is one of the most widely Transmission of M tuberculosis complex is air-
used vaccines in the world. An isolate of borne, with inhalation of droplet nuclei usually
BCG can be distinguished from wildtype produced by an adult or adolescent with conta-
M bovis only in a reference laboratory. gious pulmonary, endobronchial, or laryngeal
tuberculosis disease. M bovis is most often
Epidemiology
transmitted by unpasteurized dairy products,
Case rates of tuberculosis in all ages are higher but airborne human-to-human transmission
in urban, low-income areas and in nonwhite can occur. The duration of contagiousness of
racial and ethnic groups; more than 80% of an adult receiving effective treatment depends
reported cases in the United States occur in on drug susceptibilities of the organism, adher-
Hispanic and nonwhite people. In recent years, ence to an appropriate drug regimen by the
60% of all US cases have been in people born patient, the number of organisms in sputum,
outside the United States. Almost 75% of all and frequency of cough. Although contagious-
childhood tuberculosis is associated with some ness usually lasts only a few days to weeks
form of foreign contact of the child, parent, after initiation of effective drug therapy, it can
or a household member. Specific groups with last longer, especially when the adult patient
greater LTBI and disease rates include immi- has pulmonary cavities, does not adhere to
grants, international adoptees, refugees from medical therapy, or is infected with a drug-
or travelers to high-prevalence regions (eg, resistant strain. If the sputum smear result
Asia, Africa, Latin America, countries of the is negative for AFB on 3 separate specimens
former Soviet Union), homeless people, people at least 8 hours apart and the patient has
who use alcohol excessively or illicit drugs, improved clinically with resolution of cough,
and residents of correctional facilities and the treated person can be considered at low
other congregate settings. Increased risk of risk of transmitting M tuberculosis. Children
infection also occurs in children with expo- younger than 10 years with small pulmonary
sure to secondhand smoke. lesions (paucibacillary disease) and nonpro-
ductive cough are rarely contagious. Unusual
Infants and postpubertal adolescents are at
cases of adult-form pulmonary disease in
increased risk of progression of LTBI to
young children, particularly with lung cavities
­tuberculosis disease. Other predictive factors
and positive sputum-smear microscopy result
for development of disease include recent
for AFB, and cases of congenital tuberculosis
infection (within the past 2 years); immuno­
can be highly contagious.
deficiency, especially from HIV infection;
use of immunosuppressive drugs, such as Incubation Period
­prolonged or high-dose corticosteroid therapy
Latent M tuberculosis infection, 2 to 10 weeks
or chemotherapy; intravenous drug use; and
after exposure; tuberculosis disease, 6 to
certain diseases or medical conditions, includ-
24 months after exposure, but can be years
ing Hodgkin disease, lymphoma, diabetes
between initial M tuberculosis infection and
­mellitus, chronic renal failure, and malnutri-
subsequent disease.
tion. There have been reports of tuberculosis
disease in adolescents and adults being treated Diagnostic Tests
for arthritis, inflammatory bowel disease, and
other conditions with tumor necrosis factor α Assessing for Mycobacterium tuberculosis
antagonists or blockers, such as infliximab Disease
and etanercept. A positive TST or IGRA Patients testing positive for M tuberculosis
result should be accepted as indicative of infection should have a chest radiograph and
­infection in individuals receiving or about physical examination to assess for tuberculosis
to receive these ­medications. disease. Most experts recommend that infants
younger than 12 months who are suspected of

ERRNVPHGLFRVRUJ
Tuberculosis 667

having pulmonary or extrapulmonary tuber- be reliably distinguished from other mycobac-


culosis disease (ie, have a positive TST and teria in stained specimens. Regardless of
clinical history, physical examination signs, or results of the AFB smears, each specimen
chest radiograph abnormalities consistent with should be cultured.
tuberculosis disease), with or without neuro-
Because M tuberculosis complex organisms
logic signs, should have a lumbar puncture to
are slow growing, detection of these organisms
evaluate for tuberculous meningitis. Some
may take as long as 10 weeks using solid media;
experts also recommend performing a lumbar
use of liquid media allows detection within 1 to
puncture in children 12 through 23 months of
6 weeks and usually within 3 weeks. Even with
age with tuberculosis disease, with or without
optimal culture techniques, M tuberculosis
neurologic findings. Children 24 months and
complex organisms are isolated from fewer
older with tuberculosis disease require a lum-
than 50% of children and 75% of infants with
bar puncture only if they have neurologic
pulmonary tuberculosis diagnosed by other
signs or symptoms.
clinical criteria. Current methods for species
Laboratory isolation of M tuberculosis complex identification of isolates from culture include
by culture from specimens of sputum, gastric molecular probes, genetic sequencing, mass
aspirates, bronchial washings, pleural fluid, spectroscopy, and biochemical tests. M bovis
cerebrospinal fluid (CSF), urine, or other body is usually suspected because of pyrazinamide
fluids or a tissue biopsy specimen establishes resistance, which is characteristic of almost
the diagnosis. Children older than 5 years and all M bovis isolates, but further biochemical
adolescents can frequently produce sputum or molecular testing is required to distinguish
spontaneously or by induction with aerosolized M bovis from M tuberculosis.
hypertonic saline. Successful collections of
Several nucleic acid amplification tests for
induced sputum from infants with pulmonary
rapid diagnosis of tuberculosis are available.
tuberculosis are theoretically possible, but this
Nucleic acid amplification tests have varying
requires special expertise. The best specimen
sensitivity and specificity for sputum, gastric
for diagnosis of pulmonary tuberculosis in any
aspirate, CSF, and tissue specimens, with false-
child or adolescent in whom cough is absent or
negative and false-positive results reported.
nonproductive and sputum cannot be induced
Further research is needed before nucleic acid
is an early-morning gastric aspirate. Gastric
amplification tests can be routinely recom-
aspirate specimens should be obtained with a
mended for the diagnosis of tuberculosis in
nasogastric tube on awakening the child and
children when specimens other than sputum
before ambulation or feeding, and the acid pH
are submitted to the laboratory.
of the gastric secretions should be neutralized
as soon as possible. Aspirates collected on For a child with clinically suspected tuberculo-
3 separate mornings should be submitted for sis disease, finding the culture-positive source
testing by staining and culture. Fluorescent case supports the child’s presumptive diagnosis
staining methods for specimen smears are and provides the likely drug susceptibility of
more sensitive than AFB smears and are pre- the child’s organism. Culture material should
ferred. The overall diagnostic yield of micros- be collected from children with evidence of
copy of gastric aspirates and induced sputum tuberculosis disease, especially when an isolate
is low in children with clinically suspected from a source case is not available, the pre-
­pulmonary tuberculosis, and false-positive sumed source case has drug-resistant tuber­
smear results caused by the presence of non­ culosis, the child is immunocompromised or
tuberculous mycobacteria can occur. Histo- ill enough to require hospital admission, or
logic examination for and demonstration of the child has extrapulmonary disease. Tradi-
AFB and granulomas in biopsy specimens tional methods of determining drug suscepti-
from lymph node, pleura, mesentery, liver, bility require bacterial isolation. Several new
bone marrow, or other tissues can be useful, molecular methods of rapidly determining
but M tuberculosis complex organisms cannot drug resistance directly from clinical samples

ERRNVPHGLFRVRUJ
668 Tuberculosis

are available in reference laboratories and are Classification of TST results is based on epide-
expected to be used in hospital laboratories in miologic and clinical factors. Interpretation of
the near future. the size of induration (mm) as a positive result
varies with the person’s risk of LTBI and like­
Testing for M tuberculosis Infection lihood of progression to tuberculosis disease.
Tuberculin Skin Test Current guidelines from the Centers for
­Disease Control and Prevention (CDC),
The TST is an indirect method for detecting ­American Thoracic Society, and American
M tuberculosis infection. It is one of 2 methods Academy of Pediatrics, which recommend
for diagnosing LTBI in asymptomatic people, interpretation of TST findings on the basis
the other method being IGRA. Both methods of an individual’s risk stratification, are
rely on specific cellular sensitization after ­summarized in Box 146.1. Prompt clinical
infection. Conditions that decrease lympho- and radiographic evaluation of all children
cyte numbers or functionality can reduce and adolescents with a positive TST result
the sensitivity of these tests. The routine is ­recommended.
(ie, Mantoux) technique of administering
the skin test consists of 5 tuberculin units of Generally, interpretation of TST results in
purified protein derivative (0.1 mL) injected BCG vaccine recipients who are known con-
intradermally using a 27-gauge needle and a tacts of a person with tuberculosis disease or
1.0-mL syringe into the volar aspect of the who are at high risk of tuberculosis disease is
­forearm. Creation of a palpable wheal 6 to the same as for people who have not received
10 mm in diameter is crucial to accurate test- BCG vaccine. After BCG immunization, dis-
ing. Administration of TSTs and interpretation tinguishing between a positive TST result
of results should be performed by trained and caused by pathogenic M tuberculosis complex
experienced health care personnel because infection and that caused by BCG is difficult.
administration and interpretation by unskilled Reactivity of the TST after receipt of BCG
people and family members are unreliable. ­vaccine does not occur in some patients. The
The recommended time for assessing the TST size of the TST reaction attributable to BCG
result is 48 to 72 hours after administration. immunization depends on many factors,
The diameter of induration in millimeters is including age at BCG immunization, quality
measured transversely to the long axis of the and strain of BCG vaccine used, number of
forearm. Positive TST results are defined in doses of BCG vaccine received, nutritional and
Box 146.1, and induration can persist for sev- immunologic status of the vaccine recipient,
eral weeks in some patients. frequency of TST administration, and time
lapse between immunization and TST. Evi-
Lack of reaction to a TST does not exclude dence that increases the probability that a
LTBI or tuberculosis disease. Approximately ­positive TST result is attributable to LTBI
10% to 40% of immunocompetent children includes known contact with a person with
with culture-documented tuberculosis disease contagious tuberculosis, a family history of
do not initially react to a TST. Host factors, tuberculosis disease, a long interval (>5 years)
such as young age, poor nutrition, immuno- since neonatal BCG immunization, and a TST
suppression, viral infections (especially reaction of 15 mm or greater.
­measles, varicella, and influenza), recent
M tuberculosis infection, and disseminated Blood-Based Testing with Interferon-Gamma
tuberculosis disease can decrease TST reactiv- Release Assays
ity. Many children and adults coinfected with
QuantiFERON-TB Gold In-Tube and T-SPOT.
HIV and M tuberculosis complex do not react
TB are IGRAs and are the preferred tests for
to a TST. Control skin tests to assess cutane-
tuberculosis infection in asymptomatic chil-
ous energy are not recommended routinely
dren 5 years and older who have been vacci-
because the diagnostic significance of sensi­
nated with BCG. These tests measure ex vivo
tivity and anergy to the control antigens
interferon-gamma production from T lympho-
is unknown.
cytes in response to stimulation with antigens

ERRNVPHGLFRVRUJ
Tuberculosis 669

specific to M tuberculosis complex, which the CDC for all indications in which TST
includes M tuberculosis and M bovis. However, would be used, and some experts prefer IGRAs
the IGRA antigens used are not found in BCG. for use in adults. The published experience
As with TSTs, IGRAs cannot distinguish testing children with IGRAs demonstrates
between latent infection and disease, and a that IGRAs consistently perform well in chil-
negative result from these tests cannot exclude dren 5 years and older, and some data support
the possibility of tuberculosis disease in a their use for children as young as 3 years. The
patient with suggestive findings. The sensitivity negative predictive value of IGRAs is not
of IGRA tests is similar to that of TSTs for known, but if the IGRA result is negative and
detecting infection in adults and older children the TST result is positive in an asymptomatic
who have untreated culture-confirmed tuber- child, the diagnosis of LTBI is unlikely. A
culosis. In many clinical settings, the specific- ­negative result for a TST or an IGRA should
ity of IGRAs is higher than that for the TST be considered as especially unreliable in infants
because the antigens used are not found in younger than 3 months.
BCG or most pathogenic nontuberculous
At this time, neither an IGRA nor the TST can
mycobacteria (ie, are not found in Mycobacte­
be considered the gold standard for diagnosis
rium avium complex but are found in Myco­
of LTBI. Current recommendations for use of
bacterium kansasii, Mycobacterium szulgai,
IGRAs in children for LTBI are shown in
and Mycobacterium marinum). Interferon-
Box 146.2 and Image 146.1.
gamma release assays are recommended by
Box 146.2
Tuberculin Skin Test and Interferon-Gamma Release Assay
­Recommendations for Infants, Children, and Adolescentsa

Children for whom immediate TST or IGRA is indicatedb


• Contacts of people with confirmed or suspected contagious tuberculosis (contact
­investigation)
• Children with radiographic or clinical findings suggesting tuberculosis disease
• Children immigrating from countries with endemic infection (eg, Asia, Middle East, Africa,
Latin America, countries of the former Soviet Union), including international adoptees
• Children with travel histories to countries with endemic infection and substantial contact with
indigenous people from such countriesc
Children who should have annual TST or IGRA
• Children infected with HIV infection (TST only)

Children at increased risk of progression of LTBI to tuberculosis disease


Children with other medical conditions, including diabetes mellitus, chronic renal failure,
­malnutrition, or congenital or acquired immunodeficiencies, and children receiving TNF
­antagonists deserve special consideration. Without recent exposure, these people are not
at increased risk of acquiring Mycobacterium tuberculosis infection. Underlying immune
­deficiencies associated with these conditions would theoretically enhance the possibility for
progression to severe disease. Initial histories of potential exposure to tuberculosis should
be included for all of these patients. If these histories or local epidemiologic factors suggest
a possibility of exposure, immediate and periodic TST or IGRA should be considered.
A TST or IGRA should be performed before initiation of immunosuppressive therapy,
including prolonged systemic corticosteroid administration, organ transplantation,
use of TNF-α antagonists or blockers, or other immunosuppressive therapy in any
child requiring these treatments.

Abbreviations: BCG, Bacille Calmette-Guérin; HIV, human immunodeficiency virus; IGRA, interferon-gamma release assay; LTBI, latent
Mycobacterium tuberculosis infection; TNF, tumor necrosis factor; TST, tuberculin skin test.
a BCG immunization is not a contraindication to a TST.
b Beginning as early as 3 months of age for TST and 3 years of age for IGRAs for LTBI and disease.
c If the child is well and has no history of exposure, the TST or IGRA should be delayed for up to 10 weeks after return.

ERRNVPHGLFRVRUJ
670 Tuberculosis

• Children with a positive result from an tuberculosis disease in children are based on
IGRA should be considered infected with thorough and expedient contact investigations
M tuberculosis complex. A negative IGRA rather than nonselective skin testing of large
result cannot be interpreted universally as populations. Contact investigations are public
absence of infection. health interventions that should be coordi-
nated through the local public health depart-
• Indeterminate IGRA results have several
ment. Only children deemed to have increased
possible causes that could be related to
risk of contact with people with contagious
the patient, assay, or assay performance.
tuberculosis or children with suspected tuber-
Indeterminate results do not exclude
culosis disease should be considered for a
M tuberculosis infection and may necessitate
TST or IGRA. Household investigation of
repeat testing, possibly with a different test.
­children for tuberculosis is indicated whenever
Indeterminate IGRA results should not be
a TST or IGRA result of a household member
used to make clinical decisions.
converts from negative to positive (indicating
Use of Tests for M tuberculosis Infection recent ­infection).

A TST or IGRA should be performed in HIV Infection


­children who are at increased risk of infection
Children with HIV infection are considered
with M tuberculosis. Universal testing with
at high risk of tuberculosis, and an annual
TST or IGRA, including programs based at
TST beginning at 3 through 12 months of age
schools, child care centers, and camps that
is ­recommended, or, if older, when HIV infec-
include populations at low risk, is discouraged
tion is diagnosed. Children who have tubercu-
because it results in a low yield of positive
losis disease should be tested for HIV infection.
results or a large proportion of false-positive
The clinical manifestations and radiographic
results, leading to an inefficient use of health
appearance of tuberculosis disease in children
care resources. However, using a questionnaire
with HIV infection tend to be similar to those
to determine risk factors for LTBI can be effec-
in immunocompetent children, but manifes­
tive in health care settings. Simple question-
tations in these children can be more severe
naires can identify children with risk factors
and unusual and can include extrapulmonary
for LTBI (Box 146.3) who should then have a
involvement of multiple organs. In HIV-
TST or IGRA performed. Risk assessment for
infected patients, a TST induration of 5 mm
tuberculosis should be performed at the first
or greater is considered a positive result; how-
health care encounter with a child and every
ever, a negative TST result attributable to HIV-
6 months thereafter for the first year of life
related immunosuppression can also occur.
(eg, 2 weeks and 6 and 12 months of age). After
An IGRA test can also be used, but a negative
1 year of age, risk assessment for tuberculosis
result does not exclude tuberculosis. Specimens
should be performed at the time of routine
for culture should be obtained from all HIV-
care, annually if possible. The most reliable
infected children with suspected tuberculosis.
strategies for identifying LTBI and preventing

Box 146.3
Validated Questions for Determining Risk of Latent M ­ ycobacterium
tuberculosis Infection in Children in the United States

Has a family member or contact had tuberculosis disease?


Has a family member had a positive tuberculin skin test result?
Was your child born in a high-risk country (countries other than the United States, Canada,
­Australia, New Zealand, or Western and North European countries)?
Has your child traveled (had contact with resident populations) to a high-risk country for longer
than 1 week?

ERRNVPHGLFRVRUJ
Tuberculosis 671

Organ Transplant Patients Guérin can cause suppurative lymphadenitis


The risk of tuberculosis in organ transplant in the regional lymph node drainage of the
patients is several-fold greater than in the inoculation site of a healthy child and can
­general population. A careful history of cause disseminated disease in children with
­previous exposure to tuberculosis should be severe forms of immunodeficiency.
taken from all transplant candidates, including Sensitivity to purified protein derivative
details about previous TST results and expo- ­tuberculin antigen persists for years in most
sure to individuals with active tuberculosis. instances, even after effective treatment. The
All transplant candidates should undergo durability of positive IGRA results has not
­evaluation by TST or IGRA for LTBI. A posi- been determined. Studies seeking to show
tive result of either test should be taken as reversion of TST or IGRA results after treat-
­evidence of M tuberculosis infection. ment of LTBI or tuberculosis disease have had
inconclusive findings. Currently, repeat testing
Patients Receiving Immunosuppressive
with TST or IGRA has no known clinical util-
­Therapies, Including Tumor Necrosis Factor
ity for assessing the effectiveness of treatment
Antagonists or Blockers
or for diagnosing new infection in patients who
Patients should be screened for risk factors for were previously infected with M tuberculosis
M tuberculosis complex infection and have a TST and who are reexposed.
or IGRA performed before the initiation ther-
apy of systemic corticosteroids, antimetabolite Treatment
agents, and tumor necrosis factor antagonists Specific Drugs
or blockers (ie, infliximab and etanercept). A
positive result of either test should be taken as Antituberculosis drugs kill or inhibit multipli-
evidence of M tuberculosis infection. cation of M tuberculosis complex organisms,
thereby arresting progression of infection and
Other Considerations preventing most complications. Chemotherapy
does not cause rapid disappearance of already
Testing for tuberculosis at any age is not
caseous or granulomatous lesions (eg, medias-
required before administration of live virus
tinal lymphadenitis). Recommendations and
vaccines. Measles vaccine can temporarily
the more commonly reported adverse reactions
­suppress tuberculin reactivity for at least 4 to
of major antituberculosis drugs are summa-
6 weeks. If indicated, a TST can be applied at
rized in Table 146.1 and Box 146.4. For treat-
the same visit during which these vaccines are
ment of tuberculosis disease, these drugs must
administered. The effects of vaccination on
always be used in recommended combination
IGRA characteristics have not been deter-
and dosage to minimize emergence of drug-
mined; the same precautions as for TST
resistant strains. Use of nonstandard regimens
should be followed. The effect of live virus
for any reason (eg, drug allergy, drug resis-
­varicella, yellow fever, and live-attenuated
tance) should be undertaken only in consulta-
influenza vaccines on TST reactivity and
tion with an expert in treating tuberculosis.
IGRA results is not known. In the absence
of data, the same spacing recommendation • Isoniazid is bactericidal, rapidly absorbed,
should be applied to these vaccines as and well tolerated and penetrates into body
described for measles-mumps-rubella vaccine. fluids, including CSF. Isoniazid is metabo-
There is no evidence that inactivated vaccines, lized in the liver and excreted primarily
polysaccharide-protein conjugate vaccines, or through the kidneys. Hepatotoxic effects are
recombinant or subunit vaccines or toxoids rare in children but can be life threatening.
interfere with clinical interpretation of TST Caution should be used in storing and
or IGRAs. administering isoniazid because accidental
or deliberate overdose is dangerous. In chil-
Chest radiographic findings of a granuloma,
dren and adolescents given recommended
calcification, or adenopathy can be caused by
doses, peripheral neuritis or seizures caused
infection with M tuberculosis complex but
by inhibition of pyridoxine metabolism are
not by BCG immunization. Bacille Calmette-

ERRNVPHGLFRVRUJ
672 Tuberculosis

Table 146.1
Recommended Usual Treatment Regimens for Drug-­Susceptible
Tuberculosis in Infants, Children, and Adolescents
Infection or Disease Category Regimen Remarks
Latent Mycobacterium tuber­
culosis infection (positive TST
or IGRA result, no disease)a

• Isoniazid susceptible 9 mo of isoniazid, once a day If daily therapy is not possible,


DOT twice a week can be
used for 9 mo.

• Isoniazid resistant 4 mo of rifampin, once a day If daily therapy is not possible,


DOT twice a week can be
used for 4 mo.
• Isoniazid-rifampin ­resistant Consult a tuberculosis
­specialist
Pulmonary and 2 mo of isoniazid, rifampin, Some experts recommend a
­extrapulmonary pyrazinamide, and ethambutol 3-drug initial regimen (isonia-
(except meningitis)b daily or twice weekly, followed zid, rifampin, and pyrazin-
by 4 mo of isoniazid and amide) if the risk of drug
rifampinc by DOT d for drug- resistance is low. DOT is
susceptible M tuberculosis highly desirable.

9–12 mo of isoniazid and If hilar adenopathy only and


rifampin for drug-susceptible the risk of drug resistance is
Mycobacterium bovis low, a 6-mo course of isonia-
zid and rifampin is sufficient.

Drugs can be given 2 or 3


times/wk under DOT.
Meningitis 2 mo of isoniazid, rifampin, For patients who may have
pyrazinamide, and an amino- acquired tuberculosis in
glycoside or ethionamide, ­geographic areas where
once a day, followed by ­resistance to streptomycin
7–10 mo of isoniazid and is common, kanamycin,
rifampin, once a day or ­amikacin, or capreomycin
twice a week (9–12 mo total) can be used instead of
for drug-susceptible ­streptomycin.
M tuberculosis

At least 12 mo of therapy
without pyrazinamide for
drug-susceptible M bovis

Abbreviations: DOT, directly observed therapy; HIV, human immunodeficiency virus; IGRA, interferon-gamma release assay; TST, tuberculin
skin test.
a See text for additional acceptable or alternative regimens.
b Duration of therapy may be longer for HIV-infected people, and additional drugs and dosing intervals may be indicated.
c Medications should be administered daily for the first 2 weeks to 2 months of treatment and then can be administered 2 to 3 times

per week by DOT. (Twice-weekly therapy is not recommended for HIV-infected people).
d If initial chest radiograph shows pulmonary cavities and sputum culture after 2 months of therapy remains positive, the continuation

phase is extended to 7 months, for a total treatment duration of 9 months.

ERRNVPHGLFRVRUJ
Tuberculosis 673

Box 146.4
People at Increased Risk of Drug-Resistant Tuberculosis Infection or Disease

People with a history of treatment for tuberculosis disease (or whose source case for the contact
received such treatment)
Contacts of a patient with drug-resistant contagious tuberculosis disease
People from countries with high prevalence of drug-resistant tuberculosis
Infected people whose source case has positive smears for acid-fast bacilli or cultures after
2 months of appropriate antituberculosis therapy and patients who do not respond to a
­standard treatment regimen
Residence in geographic area with a high percentage of drug-resistant isolates

rare, and most do not need pyridoxine c­ hildren receiving antiretroviral therapy
­supplements. Pyridoxine supplementation that restricts the use of rifampin because of
is recommended for exclusively breastfed drug interactions; however, experience in
infants and for children and adolescents on children is limited. Major toxicities of rifa­
meat- and milk-deficient diets; children butin include leukopenia, gastrointestinal
with nutritional deficiencies, including all tract upset, polyarthralgia, rash, increased
symptomatic HIV-infected children; and transaminase concentrations, and skin and
pregnant adolescents and women. For secretion discoloration (pseudojaundice).
infants and young children, isoniazid tab- Anterior uveitis has been reported among
lets can be ­pulverized. children receiving rifabutin as prophylaxis
or as part of a combination regimen for
• Rifampin is a bactericidal agent in the
treatment, usually when administered at
­rifamycin class of drugs that is absorbed
high doses. Rifabutin also increases hepatic
rapidly and penetrates into body fluids,
metabolism of many drugs but is a less
including CSF. Other drugs in the rifamycin
potent inducer of cytochrome P450 enzymes
class approved for treating tuberculosis are
than rifampin and has fewer problematic
rifabutin and rifapentine. Rifampin is
drug interactions than rifampin. However,
metabolized by the liver and can alter the
adjustments in doses of rifabutin and coad-
pharmacokinetics and serum concentrations
ministered antiretroviral drugs may be
of many other drugs. Rare adverse effects
­necessary for certain combinations. Rifapen-
include hepatotoxicity, influenza-like symp-
tine is a long-acting rifamycin that permits
toms, pruritus, and thrombocytopenia.
weekly dosing in selected adults and adoles-
Rifampin is excreted in bile and urine and
cents, but its evaluation in younger pediatric
can cause orange urine, sweat, and tears,
patients has been limited.
with discoloration of soft contact lenses.
Rifampin can make oral contraceptives • Pyrazinamide attains therapeutic CSF
­ineffective, so nonhormonal birth-control ­concentrations, is detectable in macro-
methods should be adopted when rifampin phages, is administered orally, and is
is administered to sexually active female ­metabolized by the liver. Administration of
adolescents and adults. For infants and pyrazinamide for the first 2 months with
young children, the contents of the capsules isoniazid and rifampin allows for 6-month
can be suspended in cherry-flavored syrup regimens in immunocompetent patients
or sprinkled on semisoft foods (eg, pudding). with drug-­susceptible tuberculosis. Almost
M tuberculosis complex isolates that are all isolates of M bovis are resistant to pyra-
resistant to rifampin are almost always zinamide, precluding therapy for this patho-
­resistant to isoniazid. Rifabutin is a suitable gen. In daily doses of 40 mg/kg per day or
alternative to rifampin in HIV-infected less, ­pyrazinamide seldom has hepatotoxic

ERRNVPHGLFRVRUJ
674 Tuberculosis

effects and is well tolerated by children. medications. Isoniazid, rifampin, strepto-


Some adolescents and many adults develop mycin and related drugs, and fluoroquino-
arthralgia and hyperuricemia because of lones can be administered parenterally.
inhibition of uric acid excretion. Pyrazin-
amide must be used with caution in people Treatment Regimens for Latent
with underlying liver disease; when admin- M ­tuberculosis Infection (LTBI)
istered with rifampin, pyrazinamide is Isoniazid Therapy for LTBI
­associated with somewhat higher rates of
hepatotoxicity. A 9-month course of isoniazid is the preferred
regimen in the United States for treatment of
• Ethambutol is well absorbed after oral LTBI in most children. Isoniazid given to
administration, diffuses well into tissues, adults who have LTBI (ie, no clinical or radio-
and is excreted in urine. However, concen- graphic abnormalities suggesting tuberculosis
trations in CSF are low. At 20 mg/kg per day, disease) provides substantial protection
ethambutol is bacteriostatic, and its primary (54%–88%) against development of tuberculosis
therapeutic role is to prevent emergence of disease for at least 20 years. Among children,
drug resistance. Ethambutol can cause efficacy approaches 100% if adherence to ther-
reversible or irreversible optic neuritis, but apy is high. Unfortunately, many studies have
reports in children with normal renal func- shown the adherence rate to be 50% to 75% over
tion are rare. Children who are receiving 9 months when families give isoniazid on their
ethambutol should be monitored monthly own. All infants and children who have LTBI
for visual acuity and red-green color dis- but no evidence of tuberculosis disease and
crimination if they are old enough to coop- who have never received antituberculosis ther-
erate. Use of ethambutol in young children apy should be considered for isoniazid unless
whose visual acuity cannot be monitored resistance to isoniazid is suspected (ie, known
requires consideration of risks and benefits, exposure to a person with isoniazid-resistant
but it can be used routinely to treat tubercu- tuberculosis) or a specific contraindication
losis disease in infants and children unless exists. Isoniazid, in this circumstance, is thera-
otherwise contraindicated. peutic and prevents development of disease.
A physical examination and chest radiograph
• The less commonly used (ie, second-line)
should be performed prior to initiation of iso-
antituberculosis drugs have limited useful-
niazid therapy to exclude tuberculosis disease.
ness because of decreased effectiveness and
greater toxicity and should only be used in Duration of Isoniazid Therapy for LTBI
consultation with a specialist familiar with
childhood tuberculosis. Ethionamide is an For infants, children, and adolescents, ­including
orally administered antituberculosis drug those with HIV infection or other immuno­
that is well tolerated by children, achieves compromising conditions, the recommended
therapeutic CSF concentrations, and may duration of isoniazid therapy in the United
be useful for treatment of people with States is 9 months. Physicians who treat LTBI
­meningitis or drug-resistant tuberculosis. should educate patients and their families
Fluoroquinolones have antituberculosis about the adverse effects of isoniazid, provide
activity and can be used in special cir­ written information about adverse drug effects,
cumstances, including drug-resistant and prescribe it in monthly allocations with
­organisms, but are not US Food and Drug clinic visits scheduled for periodic face-to-face
Adminis­tration (FDA) approved for this monitoring. Successful completion of therapy
indication. Because some fluoroquinolones is based on total number of doses taken. When
are approved by the FDA for use only in adherence with daily therapy with isoniazid
­people 18 years and older, their use in cannot be ensured, twice-a-week DOT can be
younger patients neces­sitates careful assess- considered. The twice-weekly regimen should
ment of the potential risks and benefits. not be prescribed unless each dose is docu-
Occasionally, a patient cannot tolerate oral mented by DOT. Routine determination of
serum transaminase concentrations during

ERRNVPHGLFRVRUJ
Tuberculosis 675

the 9 months of therapy for LTBI is not indi- experts recommend isoniazid be used to treat
cated except for children and adolescents LTBI in children unless the child has had con-
who have concurrent or recent liver or biliary tact with a person known to have isoniazid-
disease, are pregnant or in the first 12 weeks’ resistant tuberculosis or the infection was
postpartum, are having clinical evidence of acquired in a locale known to have a high
hepatotoxic effects, or are concurrently taking ­prevalence of isoniazid resistance. If the source
other hepatotoxic drugs (eg, anticonvulsant case is found to have isoniazid-resistant,
or HIV agents). If therapy is completed suc- rifampin-susceptible organisms, isoniazid
cessfully, there is no need to perform addi- should be discontinued and rifampin should
tional tests or chest radiographs unless a new be given daily for a total course of 4 months.
exposure to tuberculosis is documented or Some experts would choose to treat children
the child develops a clinical illness consistent younger than 12 years with rifampin daily for
with tuberculosis. 6 months. Rifampin can also be used when
isoniazid cannot be given because of patient
Isoniazid-Rifapentine Therapy for LTBI intolerance or when isoniazid is unavailable.
In 2011, on the basis of a large clinical trial, the Optimal therapy for children with LTBI caused
CDC recommended a 12-week, once-weekly by organisms with resistance to isoniazid and
dose of isoniazid and rifapentine, given under rifampin (ie, MDR) is not known. In these
DOT by a health department, as an alter­native ­circumstances, fluoroquinolones alone and
regimen for treating LTBI in people 12 years multidrug regimens have been used, but the
or older. This regimen was shown to be at least safety and the efficacy of these empiric regi-
as effective with fewer adverse reactions than mens have not been assessed in clinical trials.
9 months of isoniazid given by self-supervision. Drugs to consider include pyrazinamide, a
Children between 2 and 11 years of age were ­fluoroquinolone, and ethambutol, depending
enrolled in the trial, and the regimen was on susceptibility of the isolate. Consultation
shown to be safe and well tolerated. However, with a tuberculosis specialist is indicated.
efficacy of this regimen in this age group could
not be determined. This regimen should not Treatment of Tuberculosis Disease
be used routinely for children younger than The goal of treatment is to achieve killing of
12 years but can be considered when the like­ replicating organisms in the tuberculous lesion
lihood of completing another regimen is low. in the shortest possible time. Achievement of
This regimen should not be used in children this goal minimizes the possibility of develop-
younger than 2 years. ment of resistant organisms. The major prob-
lem limiting successful treatment is poor
Additional Regimens for Treatment of LTBI adherence to prescribed treatment regimens.
Additional possible regimens for treatment The use of DOT decreases the rates of relapse,
of LTBI are 3 months of daily isoniazid and treatment failures, and drug resistance; there-
rifampin or 2 months of daily rifampin and fore, DOT is strongly recommended for treat-
pyrazinamide when given as part of rifampin, ment of all children and adolescents with
isoniazid, pyrazinamide, and ethambutol tuberculosis disease in the United States.
(RIPE) therapy for suspected tuberculosis
For tuberculosis disease, a 6-month, 4-drug
­disease (which is subsequently determined to
regimen consisting of RIPE for the first 2 months
be M tuberculosis infection only).
and isoniazid and rifampin for the remaining
Therapy for Contacts of Patients With 4 months is recommended for treatment of
­Isoniazid-Resistant M tuberculosis and pulmonary disease, pulmonary disease with
When Isoniazid Cannot Be Given hilar adenopathy, and hilar adenopathy disease
in infants, children, and adolescents when an
The incidence of isoniazid resistance among MDR case is not suspected as the source of
M tuberculosis complex isolates from US infection or when drug-­susceptibility results
patients is approximately 9%. Risk factors for are available from the patient or the likely source
drug resistance are listed in Box 146.4. Most case. Some experts would administer 3 drugs

ERRNVPHGLFRVRUJ
676 Tuberculosis

(isoniazid, rifampin, pyrazinamide) as the ini- circumstances of international travel or adop-


tial regimen if a source case has been identified tion. If this information is not available, a 4- or
with known pansusceptible M tuberculosis or 5-drug initial regimen is recommended with
if the presumed source case has no risk factors close monitoring for clinical response.
for drug-resistant M tuberculosis. For children
Most cases of pulmonary tuberculosis in
with hilar adenopathy in whom drug resistance
c­ hildren that are caused by an isoniazid-­
is not a consideration, a 6-month regimen of
resistant but rifampin- and pyrazinamide-­
only isoniazid and rifampin is considered ade-
susceptible strain of M tuberculosis complex
quate by some experts. If the chest radiograph
can be treated with a 6-month regimen of
shows one or more pulmonary cavities and
rifampin, pyrazinamide, and ethambutol. For
sputum culture result remains positive after
cases of MDR tuberculosis disease, the treat-
2 months of therapy, the duration of therapy
ment regimen needed for cure should include
should be extended to 9 months.
at least 4 or 5 antituberculosis drugs to which
In the 6-month regimen with 4-drug therapy, the organism is susceptible. Bedaquiline was
RIPE is given once a day for at least the first recently approved by the FDA as treatment for
2 weeks by DOT daily (at least 5 days per week). adults with MDR tuberculosis for whom an
An alternative to daily dosing between 2 weeks effective 4-drug regimen could not be insti-
and 2 months of treatment is to give these tuted without the use of bedaquiline; unfortu-
drugs twice or 3 times a week by DOT (except nately, currently, there are no safety, efficacy,
in HIV-infected people, in whom twice-weekly or pharmacokinetic data for children for this
dosing is not recommended). After the initial drug. Therapy for MDR tuberculosis is admin-
2-month period, a DOT regimen of isoniazid istered for 12 to 24 months from the time of
and rifampin given 2 or 3 times a week is culture conversion to negativity. An injectable
acceptable. Several alternative regimens drug, such as kanamycin or capreomycin,
with differing durations of daily therapy and should be used for the first 4 to 6 months of
total therapy have been used successfully in treatment, as tolerated. Regimens in which
adults and children. These alternative regi- drugs are administered 2 or 3 times per week
mens should be prescribed and managed by are not recommended for drug-resistant dis-
a specialist in tuberculosis. ease; daily DOT is critical to prevent emer-
gence of additional resistance. An expert in
Therapy for Drug-Resistant Tuberculosis ­Disease drug-resistant tuberculosis should be con-
Drug resistance is more common in the follow- sulted for all drug-­resistant cases.
ing groups: people previously treated for tuber-
culosis disease; people born in areas with a Extrapulmonary Tuberculosis Disease
high prevalence of drug resistance, such as In general, extrapulmonary tuberculosis—with
Russia and the nations of the former Soviet the exception of meningitis—can be treated
Union, Asia, Africa, and Latin America; and with the same regimens as used for pulmonary
contacts, especially children, with tuberculosis tuberculosis. For suspected drug-susceptible
disease whose source case is a person from tuberculous meningitis, daily treatment with
one of these groups. When resistance to drugs isoniazid, rifampin, pyrazinamide, and ethion-
other than isoniazid is likely, initial therapy amide, if possible, or an aminoglycoside should
should be adjusted by adding at least 2 drugs be initiated. When susceptibility to all drugs is
to match the presumed drug susceptibility established, the ethionamide or aminoglyco-
­pattern until drug susceptibility results are side can be discontinued. Pyrazinamide is
available. If an isolate from the pediatric case given for a total of 2 months, and isoniazid and
under treatment is not available, drug suscep­ rifampin are given for a total of 9 to 12 months.
tibilities can be inferred by the drug suscepti- Isoniazid and rifampin can be given daily or 2
bility pattern of isolates from the adult source or 3 times per week after the first 2 months of
case. Data for guiding drug selection may not treatment if the child has responded well.
be available for foreign-born children or in

ERRNVPHGLFRVRUJ
Tuberculosis 677

Other Treatment Considerations Evaluation and Monitoring of Therapy in


­ hildren and Adolescents
C
Corticosteroids
Careful monthly monitoring of clinical and
The evidence supporting adjuvant treatment
bacteriologic responses to therapy is impor-
with corticosteroids for children with tuber­
tant. With DOT, clinical evaluation is an
culosis disease is incomplete. Corticosteroids
­integral component of each visit for drug
are definitely indicated for children with
administration. For patients with pulmonary
­tuberculous meningitis because corticoste-
tuberculosis, chest radiographs should be
roids decrease rates of mortality and long-term
obtained after 2 months of therapy to evaluate
neurologic impairment. Corticosteroids can
response. Even with successful 6-month regi-
be considered for children with pleural and
mens, hilar adenopathy can persist for 2 to
pericardial effusions (to hasten reabsorption
3 years; normal radiographic findings are not
of fluid), severe miliary disease (to mitigate
necessary to discontinue therapy. Follow-up
alveolocapillary block), endobronchial disease
chest radiography beyond termination of suc-
(to relieve obstruction and atelectasis), and
cessful therapy is not usually necessary unless
abdominal tuberculosis (to decrease the risk
clinical deterioration occurs.
of strictures). Corticosteroids should be given
only when accompanied by appropriate anti­ If therapy has been interrupted, the date of
tuberculosis therapy. Most experts consider completion should be extended. Although
2 mg/kg per day of prednisone (maximum, guidelines cannot be provided for every situa-
60 mg/d) or its equivalent for 4 to 6 weeks tion, factors to consider when establishing
­followed by tapering. the date of completion include length of inter-
ruption of therapy, time during therapy (early
Tuberculosis Disease and HIV Infection or late) when interruption occurred, and the
Most HIV-infected adults with drug-­susceptible patient’s clinical, radiographic, and bacterio-
tuberculosis respond well to standard treat- logic status before, during, and after interrup-
ment regimens when appropriate therapy is tion of therapy. The total doses administered
initiated early. However, optimal therapy for by DOT should be calculated to guide the
tuberculosis in children with HIV infection duration of therapy. Consultation with a spe-
has not been established. Treating tuberculosis cialist in tuberculosis is advised.
in an HIV-infected child is complicated by
Untoward effects of isoniazid therapy, including
antiretroviral drug interactions with the rifa-
severe hepatitis in otherwise healthy infants,
mycins and overlapping toxicities. Therapy
children, and adolescents, are rare. Routine
always should include at least 4 drugs initially,
determination of serum transaminase con­
should be administered daily via DOT, and
centrations is not recommended. However, for
should be continued for at least 6 months. Iso-
children with severe tuberculosis disease, espe-
niazid, rifampin, and pyrazinamide, usually
cially children with meningitis or disseminated
with ethambutol or an aminoglycoside, should
disease, transaminase concentrations should
be given for at least the first 2 months. Etham-
be monitored approximately monthly during
butol can be discontinued once drug-resistant
the first several months of treatment. Other
tuberculosis disease is excluded. Rifampin may
indications for testing include having concur-
be contraindicated in people who are receiving
rent or recent liver or biliary disease, being
antiretroviral therapy. Rifabutin can be sub­
pregnant or in the first 12 weeks’ postpartum,
stituted for rifampin in some circumstances.
having clinical evidence of hepatotoxic effects,
Consultation with a specialist who has experi-
or concurrently using other hepatotoxic drugs
ence in managing HIV-infected patients with
(eg, anticonvulsant or HIV agents). In most
tuberculosis is advised.
other circumstances, monthly clinical evalua-
tions to observe for signs or symptoms of hepa-
titis and other adverse effects of drug therapy
without routine monitoring of transaminase

ERRNVPHGLFRVRUJ
678 Tuberculosis

concentrations is appropriate follow-up. In fetus. Because streptomycin can cause ototoxic


all cases, regular physician-patient contact to effects in the fetus, it should not be used unless
assess drug adherence, efficacy, and adverse administration is essential for effective treat-
effects is an important aspect of management. ment. The effects of other second-line drugs on
Patients should be provided with written the fetus are unknown, and ethionamide has
instructions and advised to call a physician been demonstrated to be teratogenic, so its use
immediately if symptoms of adverse events, during pregnancy is contraindicated.
in particular hepatotoxicity (eg, nausea, vomit-
Although isoniazid is secreted in human milk,
ing, abdominal pain, jaundice), develop.
no adverse effects of isoniazid on nursing neo-
Immunizations nates and infants have been demonstrated.
Breastfed neonates and infants do not require
Patients who are receiving treatment for tuber-
pyridoxine supplementation unless they are
culosis can be given measles and other age-
receiving isoniazid. The isoniazid dosage of a
appropriate, attenuated, live virus vaccines
breastfed baby whose mother is taking isonia-
unless they are receiving high-dose systemic
zid does not require adjustment for the small
corticosteroids, are severely ill, or have other
amount of drug in the milk.
specific contraindications to immunization.
Congenital Tuberculosis
Tuberculosis During Pregnancy
and ­Breastfeeding Women who have only pulmonary tuberculosis
are not likely to infect the fetus but can infect
Tuberculosis treatment during pregnancy is
their newborn after delivery. Congenital tuber-
complex. If tuberculosis disease is diagnosed
culosis is rare, but in utero infections can occur
during pregnancy, a regimen of isoniazid,
after maternal bacillemia.
rifampin, and ethambutol is recommended.
Pyrazinamide is commonly used in a 3- or If a newborn is suspected of having congenital
4-drug regimen, but safety during pregnancy tuberculosis, a TST, chest radiography, lumbar
has not been established. At least 6 months puncture, and appropriate cultures and radiog-
of therapy is indicated for drug-susceptible raphy should be performed promptly. The TST
tuberculosis disease if pyrazinamide is used; result is usually negative in newborns with
at least 9 months of therapy is indicated if congenital or perinatally acquired infection.
­pyrazinamide is not used. Prompt initiation Hence, regardless of the TST result, treatment
of therapy is mandatory to protect mother of the newborn should be initiated promptly
and fetus. with isoniazid, rifampin, pyrazinamide, and an
aminoglycoside (eg, amikacin). The placenta
Asymptomatic pregnant women with a posi-
should be examined histologically for granulo-
tive TST or IGRA result, normal chest radio-
mata and AFB, and a specimen should be cul-
graphic findings, and recent contact with a
tured for M tuberculosis complex. The mother
contagious person should be considered for
should be evaluated for presence of pulmonary
isoniazid therapy. The recommended duration
or extrapulmonary disease, including genito-
of therapy is 9 months. Therapy in these cir-
urinary tuberculosis. If the physical examina-
cumstances should begin after the first trimes-
tion and chest radiographic findings support
ter. Pyridoxine supplementation is indicated
the diagnosis of tuberculosis disease, the new-
for all pregnant and breastfeeding women
born should be treated with regimens recom-
receiving isoniazid.
mended for tuberculosis disease. If meningitis
Isoniazid, ethambutol, and rifampin are rela- is confirmed, corticosteroids should be added.
tively safe for the fetus. The benefit of etham- Drug susceptibility testing of the organism
butol and rifampin for therapy of tuberculosis recovered from the mother or household con-
disease in the mother outweighs the risk to the tact, newborn, or both should be performed.

ERRNVPHGLFRVRUJ
Tuberculosis 679

Management of the Newborn Whose Mother t­ herapy, the mother wears a mask, and the
(or Other Household Contact) Has LTBI or mother understands and is willing to adhere
Tuberculosis Disease to infection-control measures. Once the
Management of the newborn is based on cat- newborn is receiving isoniazid, separation is
egorization of the maternal (or household not necessary unless the mother (or house-
­contact) infection. Although protection of the hold contact) has possible MDR tuberculosis
newborn from exposure and infection is of disease or has poor adherence to treatment
paramount importance, contact between new- and DOT is not possible. If the mother is
born and mother should be allowed when pos- suspected of having MDR tuberculosis dis-
sible. Differing circumstances and resulting ease, an expert in tuberculosis disease treat-
recommendations are as follows: ment should be consulted. Women with
drug-susceptible tuberculosis disease who
• Mother (or household contact) has a posi- have been treated appropriately for 2 or more
tive TST or IGRA result and normal chest weeks and who are not considered conta-
radiographic findings. If the mother (or gious can breastfeed.
household contact) is asymptomatic, no
­separation is required. The mother is usually If congenital tuberculosis is excluded, isoni-
a candidate for treatment of LTBI after the azid is given until the infant is 3 or 4 months
initial postpartum period. The newborn of age, when a TST should be performed. If
needs no special evaluation or therapy. the TST result is positive, the infant should
Because of the newborn’s exquisite suscep­ be reassessed for tuberculosis disease. If
tibility, and because the mother’s positive tuberculosis disease is excluded in an infant
TST result could be a marker of an unrecog- with a positive TST result, isoniazid alone
nized case of contagious tuberculosis within should be continued for a total of 9 months.
the household, other household members The infant should be evaluated monthly
should have a TST or IGRA and further ­during treatment for signs of illness or poor
evaluation; this should not delay the new- growth. If the TST result is negative at 3 to
born’s discharge from the hospital. These 4 months of age and the mother (or house-
mothers can breastfeed their newborns. hold contact) has good adherence and
response to treatment and is no longer con-
• Mother (or household contact) has clinical tagious, isoniazid should be discontinued.
signs and symptoms or abnormal findings
on chest radiograph consistent with tuber- • Mother (or household contact) has a
culosis disease. Cases of suspected or ­positive TST or IGRA and abnormal
proven tuberculosis disease in mothers ­findings on chest radiography but no evi-
(or household contacts) should be reported dence of tuberculosis disease. If the chest
immediately to the local health department, radiograph of the mother (or household
and investigation of all household members ­contact) appears abnormal but is not sug­
should start as soon as possible. If the gestive of tuberculosis disease and the his-
mother has tuberculosis disease, the new- tory, physical examination, and sputum
born should be evaluated for congenital smear indicate no evidence of tuberculosis
tuberculosis, and the mother should be disease, the newborn can be assumed to be
tested for HIV infection. The mother (or at low risk of M tuberculosis infection and
household contact) and newborn should be need not be separated from the mother (or
separated until the mother (or household household contact). The mother and her
contact) has been evaluated and, if tubercu- newborn should receive follow-up care
losis disease is suspected, until the mother and the mother should be treated for LTBI.
(or household contact) and newborn are Other household members should have a
receiving appropriate antituberculosis TST or IGRA and further evaluation.

ERRNVPHGLFRVRUJ
680 Tuberculosis

BCG No Yes
vaccinated? Age <5 yrs?

No Yes

TST
preferred
Likely to
return for
TST reading?

Yes No

Either TST
or IGRA
acceptable
Negative result - Positive result -
IGRA Testing complete Testing complete
preferred unless criteria A* unless criteria B**
met, then IGRA are met, then IGRA
Negative TST - Positive TST -
Testing complete Testing complete
unless criteria A* unless criteria B**
met, then IGRA are met, then IGRA

Negative result – Positive result – *Criteria A


Indeterminate 1) High clinical suspicion for TB disease
testing complete testing complete
and/or
2) High risk for infection, progression
or poor outcome
Repeat IGRA
**Criteria B
1) Additional evidence needed to
ensure adherence and/or
Negative result – Positive result – 2) child healthy and at low risk and/or
testing complete testing complete 3) NTM suspected

Abbreviations: BCG, Bacille Calmette-Guérin; IGRA, interferon-gamma release assay; NTM, nontuberculous mycobacteria;
TB, tuberculosis; TST, tuberculin skin test.

Image 146.1
Guidance on strategy for use of tuberculin skin test and interferon-gamma release assay by age and
bacille Calmette-Guérin immunization status.

Image 146.2
Image 146.3
This photomicrograph reveals Mycobacterium This is a close-up of a Mycobacterium
tuberculosis bacteria using acid-fast Ziehl- tuberculosis culture revealing this organism’s
Neelsen stain (magnification x1,000). The ­ colonial morphology. Courtesy of Centers for
acid-fast stains depend on the ability of Disease Control and Prevention/Dr George
mycobacteria to retain dye when treated with P. Kubica.
mineral acid or an acid-alcohol solution, such
as the Ziehl-Neelsen, or the Kinyoun stains
that are carbolfuchsin methods specific for
M tuberculosis. Courtesy of Centers for Disease
Control and Prevention/Dr George P. Kubica.

ERRNVPHGLFRVRUJ
Tuberculosis 681

Image 146.4
Estimated tuberculosis incidence rates, 2009. Courtesy of Centers for Disease Control and Prevention.

Image 146.5
Distribution of countries and territories reporting at least one case of extensively drug-resistant
tuberculosis as of 2010. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
682 Tuberculosis

Image 146.6
Tuberculosis. Incidence—United States and US territories, 2012. Courtesy of Morbidity and Mortality
Weekly Report.

Image 146.7
Tuberculosis. Incidence, by race/ethnicity—United States, 2002–2012. Courtesy of Morbidity and
Mortality Weekly Report.

ERRNVPHGLFRVRUJ
Tuberculosis 683

Image 146.9
Image 146.8
Miliary tuberculosis. Courtesy of Gary Overturf, Tuberculosis, miliary, in a 29-year-old woman
MD. 4 months after delivery. Tuberculosis may
exacerbate during pregnancy.

Image 146.10
A young child with a positive tuberculin skin test Image 146.11
reaction with erythema and induration. Courtesy Young man with Mycobacterium tuberculosis
of Martin G. Myers, MD. cervical lymphadenitis. Copyright Martin G.
Myers, MD.

Image 146.13
Image 146.12 A 3-month-old with tuberculosis. The child had
Young woman with Mycobacterium tuberculosis a fever when first examined. Chest radiograph
cervical lymphadenitis. Copyright Martin G. revealed right upper lobe consolidation. A purified
Myers, MD. protein derivative was placed and was positive.
Mycobacterium tuberculosis grew from gastric
aspirate culture. Copyright Barbara Jantausch,
MD, FAAP.

ERRNVPHGLFRVRUJ
684 Tuberculosis

Image 146.14
Mycobacterium tuberculosis infection with
Image 146.15
paratracheal lymph nodes. Courtesy of Martha
A 1-year-old with endobronchial tuberculosis with
Lepow, MD.
pulmonary consolidation.

Image 146.17
Image 146.16 A 10-month-old with radiographic changes of
A 13-year-old boy with tuberculosis. The patient miliary tuberculosis.
had a 1-week history of shortness of breath and
sharp pain on his right side while riding his
bicycle. A purified protein derivative revealed 20
by 25 mm of induration at 72 hours. The chest
computed tomography scan revealed right hilar
adenopathy and a primary complex in the right
peripheral lung field. Copyright Barbara
Jantausch, MD, FAAP.

Image 146.18
Miliary tuberculosis with pulmonary cavitation
(right lung).

ERRNVPHGLFRVRUJ
Tuberculosis 685

Image 146.19
Tuberculosis of the spine with paravertebral
abscess (Pott disease). Image 146.20
Tuberculous spondylitis in a 14-year-old boy
demonstrated by magnetic resonance imaging.
Courtesy of Benjamin Estrada, MD.

Image 146.22
Cavitary tuberculosis in a 15-year-old boy
Image 146.21
delineated by computed tomography scan.
Cavitary tuberculosis in a 15-year-old boy.
Courtesy of Benjamin Estrada, MD.
Courtesy of Benjamin Estrada, MD.

Image 146.23
Tuberculosis. Caseation and Langhans giant cells in a lymph node. Courtesy of Dimitris P. Agamanolis,
MD.

ERRNVPHGLFRVRUJ
686 Diseases Caused by Nontuberculous Mycobacteria

147 local MAC symptoms can worsen temporarily.


This immune reconstitution syndrome usually
Diseases Caused by Non­ occurs 2 to 4 weeks after initiation of antiretro-
tuberculous Mycobacteria viral therapy. Symptoms can include worsen-
(Environmental Mycobacteria, Mycobacteria ing fever, swollen lymph nodes, local pain, and
Other Than Mycobacterium tuberculosis) laboratory ­abnormalities.
Clinical Manifestations Etiology
Several syndromes are caused by nontuber­ Of the more than 130 species of NTM that have
culous mycobacteria (NTM). In children, the been identified, only a few account for most
most common of these syndromes is cervical human infections. The species most commonly
lymphadenitis. Cutaneous infection can follow infecting children in the United States are
soil- or water-contaminated traumatic wounds, MAC, Mycobacterium fortuitum, M abscessus,
surgeries, or cosmetic procedures (eg, tattoos, and Mycobacterium marinum (Table 147.1).
pedicures, body piercings). Less common Several new species, which can be detected by
­syndromes include soft tissue infection, osteo- nucleic acid amplification testing but cannot be
myelitis, otitis media, catheter-associated grown by routine culture methods, have been
bloodstream infections, and pulmonary infec- identified in lymph nodes of children with cer-
tions, especially in adolescents with cystic vical adenitis. Nontuberculous mycobacteria
fibrosis. Nontuberculous mycobacteria, espe- disease in patients with HIV infection is usu-
cially Mycobacterium avium complex (MAC ally caused by MAC. M fortuitum, Mycobac­
[including M avium and Mycobacterium terium chelonae, Mycobacterium smegmatis,
avium-intracellulare complex]) and Mycobac­ and M abscessus are commonly referred to as
terium abscessus, can be recovered from spu- “rapidly growing” mycobacteria. The rapidly
tum in 10% to 20% of adolescents and young growing mycobacteria have sufficient growth
adults with cystic fibrosis and can be associated within 3 to 5 days so identification can be
with fever and declining clinical status. Dis- achieved, whereas MAC, M marinum, and
seminated infections are almost always associ- Mycobacterium szulgai usually require several
ated with impaired cell-mediated immunity, weeks before sufficient growth occurs for iden-
as found in children with congenital immune tification. Rapidly growing mycobacteria have
defects (eg, interleukin-12 deficiency, NF- been implicated in wound, soft tissue, bone,
kappa-B essential modulator mutation and pulmonary, central venous catheter, and middle-
related disorders, interferon-gamma receptor ear infections. Other mycobacterial species
defects), hematopoietic stem cell transplants, that usually are not pathogenic have caused
or advanced HIV infection. Disseminated infections in immunocompromised hosts or
MAC is rare in HIV-infected children during have been associated with the presence of a
the first year of life, but the frequency foreign body.
increases with increasing age and declining
Epidemiology
CD4+ T-­lymphocyte counts (<50 cells/µL, in
children older than 6 years). Manifestations Many NTM species are ubiquitous in nature
of disseminated NTM infections depend on and are found in soil, food, water, and animals.
the species and route of infection but include Tap water is the major reservoir for Mycobac­
fever, night sweats, weight loss, abdominal terium kansasii, Mycobacterium lentiflavum,
pain, fatigue, diarrhea, and anemia. These Mycobacterium xenopi, Mycobacterium simiae,
signs and symptoms are also found in and health care–associated infections attribut-
advanced immuno­suppressed HIV-infected able to the rapidly growing mycobacteria,
children without disseminated MAC. For M abscessus and M fortuitum. Outbreaks have
­HIV-infected children who have disseminated been associated with contaminated water used
MAC, respiratory symptoms and isolated for pedicures and inks used for tattooing. For
­pulmonary disease are uncommon. In HIV- M marinum, water in a fish tank or aquarium
infected patients developing immune restora- or an injury in a saltwater environment is the
tion with initiation of antiretroviral therapy,

ERRNVPHGLFRVRUJ
Diseases Caused by Nontuberculous Mycobacteria 687

Table 147.1
Diseases Caused by Nontuberculous Mycobacterium Species
Less Common Species in
Clinical Disease Common Species the United States
Cutaneous infection M chelonae, M fortuitum, M ulceransa
M abscessus, M marinum
Lymphadenitis MAC, M haemophilum, M kansasii, M fortuitum,
M lentiflavum M malmoenseb
Otologic infection M abscessus M fortuitum
Pulmonary infection MAC, M kansasii, M abscessus M xenopi, M malmoense,b
M szulgai, M fortuitum, M simiae
Catheter-associated infection M chelonae, M fortuitum M abscessus
Skeletal infection MAC, M kansasii, M fortuitum M chelonae, M marinum,
M abscessus, M ulceransa
Disseminated MAC M kansasii, M genavense,
M haemophilum, M chelonae
Abbreviation: MAC, Mycobacterium avium complex.
a Not endemic in the United States.
b Found primarily in Northern Europe.

major source of infection. The environmental associated with polyethylene ear tubes and
reservoir for M abscessus and MAC causing use of contaminated equipment or water. A
pulmonary infection is unknown. Although waterborne route of transmission has been
many people are exposed to NTM, it is implicated for MAC infection in some immu-
unknown why some exposures result in acute nodeficient hosts. Buruli ulcer disease is a skin
or chronic infection. Usual portals of entry for and bone infection caused by Mycobacterium
NTM infection are believed to be abrasions ulcerans, an emerging disease causing signifi-
in the skin (eg, cutaneous lesions caused by cant morbidity and disability in tropical areas
M marinum), penetrating trauma (needles and such as Africa, Asia, South America, Australia,
organic material most often associated with and the western Pacific.
M abscessus and M fortuitum), surgical sites
Incubation Period
(especially for central vascular catheters), oro-
pharyngeal mucosa (the presumed portal of Variable.
entry for cervical lymphadenitis), gastrointes­
Diagnostic Tests
tinal or respiratory tract for disseminated
MAC, and respiratory tract (including tympa- Definitive diagnosis of NTM disease requires
nostomy tubes for otitis media). Pulmonary isolation of the organism. Consultation with
disease and rare cases of mediastinal adenitis the laboratory should occur to ensure culture
and endobronchial disease do occur. Nontu- specimens are handled correctly. Because these
berculous mycobacteria can be an important organisms are commonly found in the envi-
pathogen in patients with cystic fibrosis and is ronment, contamination of cultures or tran-
an emerging pathogen in individuals receiving sient colonization can occur. Caution must be
biologic response modifiers, such as antitumor exercised in interpretation of cultures obtained
necrosis factor α. Most infections remain from nonsterile sites, such as gastric washing
localized at the portal of entry or in regional specimens, endoscopy material, a single expec-
lymph nodes. Dissemination to distal sites pri- torated sputum sample, or urine specimens,
marily occurs in immunocompromised hosts. and also when the species cultured is usually
No definitive evidence of person-to-person nonpathogenic (eg, Mycobacterium terrae com-
transmission of NTM exists. Outbreaks of plex, Mycobacterium gordonae). An acid-fast
­otitis media caused by M abscessus have been bacilli smear-positive sample and repeated

ERRNVPHGLFRVRUJ
688 Diseases Caused by Nontuberculous Mycobacteria

i­ solation on culture media of a single species immune status, and the need to treat a patient
from any site are more likely to indicate disease presumptively for tuberculosis while awaiting
than culture contamination or transient colo- culture reports that subsequently reveal NTM.
nization. Diagnostic criteria for NTM lung
For NTM lymphadenitis in otherwise healthy
disease in adults include 2 or more separate
children, especially when the disease is caused
sputum samples that grow NTM or one bron-
by MAC, complete surgical excision is curative.
chial alveolar lavage specimen that grows
Antimicrobial therapy has been shown to pro-
NTM. These criteria have not been validated in
vide no additional benefit. Therapy with clar-
children and apply best to MAC, M kansasii,
ithromycin or azithromycin combined with
and M abscessus. Nontuberculous mycobacte-
ethambutol or rifampin or rifabutin may be
ria isolates from draining sinus tracts or
beneficial for children in whom surgical exci-
wounds are almost always significant clinically.
sion is incomplete or for children with recur-
Recovery of NTM from sites that are usually
rent disease (Table 147.2).
sterile, such as cerebrospinal fluid, pleural
fluid, bone marrow, blood, lymph node aspi- Isolates of rapidly growing mycobacteria
rates, middle ear or mastoid aspirates, or (M fortuitum, M abscessus, and M chelonae)
­surgically excised tissue, is the most reliable should be tested in vitro against drugs to
diagnostic test. With radiometric or nonradio- which they are commonly susceptible and that
metric broth techniques, blood cultures are have been used with some therapeutic success
highly sensitive in recovery of disseminated (eg, amikacin, imipenem, sulfamethoxazole
MAC and other blood-borne NTM species. or trimethoprim-sulfamethoxazole, cefoxitin,
Disseminated MAC disease should prompt a ciprofloxacin, clarithromycin, linezolid,
search for underlying immunodeficiency. ­doxycycline). Clarithromycin and at least
one other agent is the treatment of choice for
Patients with NTM infection, such as
cutaneous (disseminated) infections attribut-
M ­marinum or MAC cervical lymphadenitis,
able to M chelonae or M abscessus. Indwelling
can have a positive tuberculin skin test result
foreign bodies should always be removed, and
because the purified protein derivative prepa-
surgical debridement for serious localized dis-
ration, derived from M tuberculosis, shares a
ease is optimal. The choice of drugs, dosages,
number of antigens with NTM species. These
and duration should be reviewed with a con-
tuberculin skin test reactions usually measure
sultant experienced in the management of
less than 10 mm of induration but can measure
NTM ­infections.
more than 15 mm. The interferon-gamma
release assays use 2 or 3 antigens to detect For patients with cystic fibrosis and isolation
infection with M tuberculosis. Although of MAC species, treatment is suggested only
these antigens are not found on M avium-­ for those with clinical symptoms not attribut-
intracellulare complex and most other NTM able to other causes, worsening lung function,
species, cross reactions can occur with infec- and chest radiographic progression. The deci-
tion caused by M kansasii, M marinum, and sion to embark on therapy should take into
M szulgai. consideration susceptibility testing results and
should involve consultation with an expert in
Treatment
cystic fibrosis care. M abscessus is difficult to
Many NTM are relatively resistant in vitro to treat, and the role of therapy in clinical benefit
antituberculosis drugs. In vitro resistance to is unknown.
these agents, however, does not necessarily
correlate with clinical response, especially In patients with AIDS and in other immuno-
with MAC infections. The approach to therapy compromised people with disseminated MAC
should be directed by the species causing the infection, multidrug therapy is recommended.
infection, the results of drug-susceptibility Clinical isolates of MAC are usually resistant
testing, the site(s) of infection, the patient’s to many of the approved antituberculosis
drugs, including isoniazid, but are susceptible
to clarithromycin and azithromycin and often

ERRNVPHGLFRVRUJ
Diseases Caused by Nontuberculous Mycobacteria 689

Table 147.2
Treatment of Nontuberculous Mycobacteria Infections in Children
Organism Disease Initial Treatment
Slowly Growing Mycobacterium Species
MAC, M haemophi- Lymphadenitis Complete excision of lymph nodes; if excision
lum, M lentiflavum incomplete or disease recurs, clarithromycin or
azithromycin plus ethambutol or rifampin (or
­rifabutin)
Pulmonary infection Clarithromycin or azithromycin plus ethambutol
with rifampin or rifabutin (pulmonary resection in
some patients who fail to respond to drug therapy).
For severe disease, an initial course of amikacin or
streptomycin is often included. Clinical data in
adults support that 3-times-weekly therapy is as
effective as daily therapy, with less toxicity for adult
patients with mild to moderate disease. For patients
with advanced or cavitary disease, drugs should be
given daily.
Disseminated See text.
M kansasii Pulmonary infection Rifampin plus ethambutol with isoniazid daily. If
rifampin resistance is detected, a 3-drug regimen
based on drug susceptibility testing should be
used.
Osteomyelitis Surgical debridement and prolonged antimicrobial
therapy using rifampin plus ethambutol with
­isoniazid
M marinum Cutaneous infection None, if minor; rifampin, trimethoprim-­
sulfamethoxazole, clarithromycin, or doxycyclinea
for moderate disease; extensive lesions may
require surgical debridement. Susceptibility testing
is not routinely required.
M ulcerans Cutaneous and bone Daily intramuscular streptomycin and oral rifampin
infections for 8 weeks; excision to remove necrotic tissue, if
present; disability prevention
Rapidly Growing Mycobacterium Species
M fortuitum group Cutaneous infection Initial therapy for serious disease is amikacin plus
meropenem, IV, followed by clarithromycin, doxycy-
clinea or trimethoprim-sulfamethoxazole, or cipro-
floxacin, orally, on the basis of in vitro susceptibility
testing; may require surgical excision. Up to 50% of
isolates are resistant to cefoxitin.
Catheter infection Catheter removal and amikacin plus meropenem,
IV; clarithromycin, trimethoprim-sulfamethoxazole,
or ciprofloxacin, orally, on the basis of in vitro sus-
ceptibility testing
M abscessus Otitis media; cutane- There is no reliable antimicrobial regimen because
ous infection of variability in drug susceptibility. Clarithromycin
plus initial course of amikacin plus cefoxitin or
meropenem; may require surgical debridement on
the basis of in vitro susceptibility testing (50% are
amikacin resistant).

ERRNVPHGLFRVRUJ
690 Diseases Caused by Nontuberculous Mycobacteria

Table 147.2
Treatment of Nontuberculous ­Mycobacteria
­Infections in Children (continued)
Organism Disease Initial Treatment
Rapidly Growing Mycobacterium Species (continued)
M abscessus Pulmonary infection Serious disease, clarithromycin, amikacin, and
(­continued) (in cystic fibrosis) cefoxitin or meropenem on the basis of susceptibil-
ity testing; may require surgical resection.
M chelonae Catheter infection Catheter removal and tobramycin (initially) plus
clarithromycin
Disseminated cuta- Tobramycin and meropenem or linezolid (initially)
neous infection plus clarithromycin
Abbreviations: IV, intravenously; MAC, Mycobacterium avium complex.
a Tetracycline-based antimicrobial agents, including doxycycline, may cause permanent tooth discoloration for children younger than 8 years

if used for repeated treatment courses. However, doxycycline binds less readily to calcium compared with older tetracyclines, and, in some
studies, doxycycline was not associated with visible teeth staining in younger children. Only 50% of isolates of M marinum are susceptible
to doxycycline.

are susceptible to combinations of ethambutol, regimen is yet to be determined. Treatment


rifabutin or rifampin, and amikacin or strep­ of disseminated MAC infection should be
tomycin. Susceptibility testing to these other undertaken in consultation with an infectious
agents has not been standardized and, thus, diseases expert.
is not recommended routinely. The optimal

Image 147.2
Atypical mycobacterial lymphadenitis.

Image 147.1
Atypical mycobacterial tuberculosis
(lymphadenitis) with ulceration.

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Diseases Caused by Nontuberculous Mycobacteria 691

Image 147.3
Disseminated atypical mycobacterial tuberculosis
with generalized cutaneous lesions in a boy with
Image 147.4
acute lymphoblastic leukemia in remission.
The same patient as in Image 147.3 with atypical
mycobacterial tuberculosis osteomyelitis of the
right middle finger.

Image 147.5
Mycobacterium avium-intracellulare complex
infection of the lymph node in a patient with AIDS
(Ziehl-Neelsen stain). Courtesy of Centers for
Disease Control and Prevention/Dr Edwin P.
Ewing Jr.

Image 147.6
An 18-month-old with culture- and polymerase
chain reaction–confirmed Buruli ulcer of the right
ear. She had briefly visited St Leonards, Australia,
in 2001. The initial lesion resembled a mosquito
or other insect bite. Courtesy of Centers for
Disease Control and Prevention/Emerging
Infectious Diseases and Paul D. R. Johnson.

Image 147.7
A 4-year-old white boy with an atypical
mycobacterial infection involving left preauricular
lymph nodes. Courtesy of Ed Fajardo, MD.

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692 Diseases Caused by Nontuberculous Mycobacteria

Image 147.8
Approximately 21% of adults in the United States
report having at least one permanent tattoo.
Outbreaks caused by nontuberculous myco­
bacteria (NTM) have been reported infrequently Image 147.9
after tattooing. One such report describes An 18-year-old woman presented with a large,
charac­teristics of tattoo-associated NTM fluctuant, violaceous plaque on her right cheek
infection clusters in 4 states during 2011–2012. In (A). Her right tragus had been profes­sionally
January 2012, public health officials in New York pierced 6 months earlier, and streaking had
reviewed reports of Mycobacterium developed along the angle of her jaw 1 month
chelonae skin infections in 14 residents who after the piercing. A biopsy specimen showed
received tattoos in the last quarter of 2011. All granulomatous inflammation. The tissue culture
infections were associated with use of the same grew Mycobacterium fortuitum. From The New
nationally distributed, prediluted gray ink England Journal of Medicine, Piercing-Related
manufactured by Company A. In February 2012, Nontuberculous Mycobacterial Infection, 362,
the Centers for Disease Control and Prevention 2012. Copyright © 2010. Massachusetts Medical
disseminated an Epi-X public health alert to Society. Reprinted with permission from
identify additional tattoo-associated NTM skin Massachusetts Medical Society.
infections. A con­firmed case was defined as a
patient with persis­tent inflammatory reaction
localized within the margins of a new tattoo
received between May 1, 2011, and February 10,
2012, and isolation of NTM from a wound or skin
biopsy. Results of this study showed 22 cases
were identified from 4 states: Colorado, Iowa,
New York, and Washington. Nineteen of the 22
cases (86%) were caused by M chelonae, the
others by Mycobacterium abscessus.
Investigations found the use of ink con­taminated
with NTM before distribution or just before
tattooing likely led to infections in each of
the reported clusters. Copy­right Paige Brase,
used with permission.

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Tularemia 693

148 source of infection. In the United States,


human infection is usually associated with
Tularemia direct contact with one of these species or
Clinical Manifestations with the bite of arthropod vectors such as ticks
and deerflies. Infection has been reported in
Most patients with tularemia have abrupt onset commercially traded hamsters and in a child
of fever, chills, myalgia, and headache. Illness bitten by a pet hamster. Infection can also be
usually conforms to one of several tularemic acquired following ingestion of contaminated
syndromes. Most common is the ulceroglan- water or inadequately cooked meat or inhala-
dular syndrome characterized by a maculo- tion of contaminated aerosols generated during
papular lesion at the entry site with subsequent lawn mowing, brush cutting, or certain farm-
ulceration and slow healing, associated with ing activities, such as baling contaminated
painful, acutely inflamed regional lymph nodes hay. At-risk people have occupational or recre-
that can drain spontaneously. The glandular ational exposure to infected animals or their
syndrome (regional lymphadenopathy with no habitats, such as rabbit hunters and trappers,
ulcer) is also common. Less common disease people exposed to certain ticks or biting
syndromes are pneumonic (flu-like symptoms, insects, and laboratory technicians working
often without chest radiograph abnormalities), with F tularensis, which is highly infectious
oculoglandular (severe conjunctivitis and pre- and may be aerosolized when grown in culture.
auricular lymphadenopathy), oropharyngeal In the United States, most cases occur during
(severe exudative stomatitis, pharyngitis, or May through September. Approximately two-
tonsillitis and cervical lymphadenopathy), thirds of cases occur in males, and one-quarter
vesicular skin lesions that can be mistaken of cases occur in children 1 to 14 years of age.
for herpes simplex or varicella-zoster virus Tularemia has been reported in all US states
cutaneous infections, typhoidal (systemic except Hawaii. Six states accounted for 59% of
infection, high fever, hepatomegaly, spleno- reported cases: Missouri (19%), Arkansas (13%),
megaly, and, possibly, septicemia), and intes­ Oklahoma (9%), Massachusetts (7%), South
tinal (intestinal pain, vomiting, and diarrhea). Dakota (5%), and Kansas (5%). During 2001–
Pneumonic tularemia, characterized by fever, 2010, 1,208 cases were reported (median, 126.5
dry cough, chest pain, and hilar adenopathy, cases per year; range, 90–154). Organisms can
is normally associated with farming or lawn be present in blood during the first 2 weeks of
maintenance activities that create aerosols disease and in cutaneous lesions for as long as
and dust. This would also be the anticipated 1 month if untreated. Person-to-person trans-
syndrome after intentional aerosol release mission has not been reported.
of organisms.
Incubation Period
Etiology
3 to 5 days; range, 1 to 21 days.
Francisella tularensis is a small, weakly stain-
ing, gram-negative pleomorphic coccobacillus. Diagnostic Tests
Two subspecies cause human infection in Diagnosis is established most often by sero-
North America, F tularensis subsp tularensis logic testing. Most clinical laboratories are not
(type A), and F tularensis subsp holarctica equipped to perform the generally accepted
(type B). Type A is generally is considered diagnostic tests for tularemia, and suspect
more virulent, although either can be lethal, samples may need to be processed by a desig-
especially if inhaled. nated reference laboratory. Patients do not
Epidemiology develop antibodies until the second week of
illness. A single serum antibody titer of 1:128
F tularensis can infect more than 100 animal or greater determined by microagglutination
species; vertebrates considered most important (MA) or of 1:160 or greater determined by tube
in enzootic cycles are rabbits, hares, and agglutination (TA) is consistent with recent or
rodents, especially muskrats, voles, beavers, past infection and constitutes a presumptive
and prairie dogs. Domestic cats are another diagnosis. Confirmation by serologic testing

ERRNVPHGLFRVRUJ
694 Tularemia

requires a 4-fold or greater titer change presumptively by polymerase chain reaction


between serum samples obtained at least or direct fluorescent antibody assays. Because
2 weeks apart, with one of the specimens hav- of its propensity for causing laboratory-
ing a minimum titer of 1:128 or greater by MA acquired infections, laboratory personnel
or 1:160 or greater by TA. Nonspecific cross- should be alerted when F tularensis infection
reactions can occur with specimens contain- is suspected.
ing heterophile antibodies or antibodies to
Treatment
­Brucella species, Legionella species, or other
gram-negative bacteria. However, cross-­ Gentamicin, intravenously or intramuscularly,
reactions rarely result in MA or TA titers that is the drug of choice for the treatment of
are diagnostic. Some clinical laboratories can ­tularemia in children. Duration of therapy
presumptively identify F tularensis in ulcer usually is 7 to 10 days. A 5- to 7-day course
exudate or aspirate material by polymerase may be sufficient in mild disease, but a longer
chain reaction assay or direct fluorescent anti- course is required for more severe illness
body assay. Immunohistochemical staining is (eg, meningitis). Ciprofloxacin is an alterna-
specific for detection of F tularensis in fixed tive for mild disease. Doxycycline is another
tissues; however, this method is not available alternative agent but is associated with a
in most clinical laboratories. Isolation of higher rate of relapses, and longer courses
F tularensis from specimens of blood, skin, (14 days) of therapy should be used. Suppura-
ulcers, lymph node drainage, gastric washings, tion of lymph nodes can occur despite anti­
or respiratory tract secretions is best achieved microbial therapy. F tularensis is resistant to
by inoculation of cysteine-enriched media. β-lactam drugs and ­carbapenems.
Suspect growth on culture can be identified

Image 148.1
Francisella tularensis. Colony characteristics when grown on chocolate agar or Martin-Lewis or
Thayer-Martin medium include colony size of 1 to 3 mm, gray-white at 48 to 72 hours. Courtesy
of Centers for Disease Control and Prevention/Courtesy of Larry Stauffer, Oregon State Public
Health Laboratory.

ERRNVPHGLFRVRUJ
Tularemia 695

Image 148.2
Tularemia. Number of reported cases—United States and US territories, 2012. Courtesy of Morbidity
and Mortality Weekly Report.

Image 148.3
Spatial distributions of isolates from the AI and AII subpopulations of Francisella tularensis subsp
tularensis relative to (A) distribution of tularemia vectors Dermacentor variabilis, Dermacentor
andersoni, Amblyomma americanum, and Chrysops discalis and (B) distribution of tularemia hosts
Sylvilagus nuttallii and S floridanus. Courtesy of Emerging Infectious Diseases.

ERRNVPHGLFRVRUJ
696 Tularemia

Image 148.4
Francisella tularensis is maintained in nature by interactions between animals and the ticks and flies
that bite them. In recent years, more cases have been reported in humans from ticks and deerflies
than from direct contact with wild animals. Spread occurs from wild-animal reservoirs to domestic
animals, especially cats, and transmission to humans results from animal or insect bites, the handling
of infected animal tissues, or inhalation of aerosolized organisms during activities such as landscaping
or lawn mowing. From The New England Journal of Medicine, Case 31-2010 — A 29-Year-Old Woman
with Fever after a Cat Bite, 363:1560-1568 © 2010. Massachusetts Medical Society. Reprinted with
permission from Massachusetts Medical Society.

Image 148.5
An 8-year-old boy with 7 days of fever unresponsive to ceftriaxone was examined because of occipital
and posterior cervical lymphadenitis. The cervical lymph node had spontaneously drained purulent
material. A culture of the node aspirate was positive for Francisella tularensis. Courtesy of Richard
Jacobs, MD.

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Tularemia 697

Image 148.6
Image 148.7
Tularemic ulcer on the thumb. Irregular ulceration Tularemic ulcer on the shoulder. Tularemia has
occurred at the site of entry of Francisella been reported in all states except Hawaii.
tularensis. Courtesy of Centers for Disease Courtesy of Gary Overturf, MD.
Control and Prevention/Courtesy Emory
University, Dr Sellers.

Image 148.8
Tularemia is a relatively rare infection that can manifest with painful cervical adenitis. This boy had a
tick bite on his scalp that developed an ulcer followed by a large postauricular node. His tularemia titer
results were positive and he responded to treatment with gentamycin.

Image 148.9
Tularemia pneumonia. Posteroanterior chest radiograph showing pneumonia and pleural effusion in
the lower lobe of the right lung; the pneumonia was unresponsive to ceftriaxone, azithromycin, and
nafcillin. The patient had a history of tick bite and a high fever for 8 days, and his tularemia agglutinin
titer was 1:2,048. An outbreak of pneumonic tularemia should prompt consideration of bioterrorism.

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698 Endemic Typhus

149 Incubation Period

Endemic Typhus 6 to 14 days.


(Murine Typhus) Diagnostic Tests
Clinical Manifestations Antibody titers determined with R typhi anti-
gen by an indirect fluorescent antibody assay,
Endemic typhus resembles epidemic (louse-
enzyme immunoassay, or latex agglutination
borne) typhus but usually has a less abrupt
test peak around 4 weeks after infection, but
onset with less severe systemic symptoms.
results of these tests are often negative early in
In young children, the disease can be mild.
the course of illness. A 4-fold immunoglobulin
Fever, present in almost all patients, can be
(Ig) G titer change between acute and conva-
accompanied by a persistent, usually severe,
lescent serum specimens taken 2 to 3 weeks
headache and myalgia. Nausea and vomiting
apart is diagnostic. Although more prone to
also develop in approximately half of patients.
false-positive results, immunoassays demon-
A rash typically appears on day 4 to 7 of illness,
strating increases in specific IgM antibody can
is macular or maculopapular, lasts 4 to 8 days,
aid in distinguishing clinical illness from pre-
and tends to remain discrete, with sparse
vious exposure if interpreted with a concurrent
lesions and no hemorrhage. Rash is present in
IgG test; use of IgM assays alone is not recom-
approximately 50% of patients. Illness seldom
mended. Serologic tests may not differentiate
lasts longer than 2 weeks; visceral involvement
murine typhus from epidemic (louseborne)
is uncommon. Laboratory findings include
typhus, R felis infection, or infection with
thrombocytopenia, elevated liver transami-
­spotted fever rickettsiosis, such as Rickettsia
nases, and hyponatremia. Fatal outcome is
rickettsii, without antibody cross-absorption
rare except in untreated severe disease.
for indirect fluorescent antibody or western
Etiology blotting analyses, which are not available
Endemic typhus is caused by Rickettsia typhi ­routinely. Routine hospital blood cultures are
and Rickettsia felis. not suitable for culture of R typhi. Molecular
diagnostic assays on infected whole blood and
Epidemiology skin biopsies can distinguish endemic typhus
Rats, in which infection is unapparent, are the and other rickettsioses and are performed at
natural reservoirs for R typhi. The primary the Centers for Disease Control and Preven-
vector for transmission among rats and to tion. Immunohistochemical procedures on
humans is the rat flea, Xenopsylla cheopis, formalin-fixed skin biopsy tissues can also be
although other fleas and mites have been performed at the Centers for Disease Control
­implicated. Cat fleas and opossums have been and Prevention.
implicated as the source of some cases of Treatment
endemic typhus caused by R felis. Infected flea
feces are rubbed into broken skin or mucous Doxycycline is the treatment of choice for
membranes or are inhaled. The disease is endemic typhus, regardless of patient age,
worldwide in distribution and tends to occur administered intravenously or orally. Treat-
most commonly in adults, in males, and during ment should be continued for at least 3 days
the months of April to October in the United after defervescence and evidence of clinical
States; in children, males and females are improvement is documented, and the total
affected equally. Exposure to rats and their treatment course is usually for 7 to 14 days.
fleas is the major risk factor for infection, ­Fluoroquinolones or chloramphenicol are
although a history of such exposure is often alternative medications but may not be
absent. Endemic typhus is rare in the United as ­effective.
States, with most cases occurring in southern
California, southern Texas, the southeastern
Gulf Coast, and Hawaii.

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Endemic Typhus 699

Image 149.1
A Norway rat, Rattus norvegicus, in a Kansas
City, MO, corn storage bin. R norvegicus is Image 149.2
known to be a reservoir of bubonic plague A healthy 8-year-old boy had 5 days of fever,
(transmitted to man by the bite of a flea or other severe headache, and malaise before this rash
insect), endemic typhus fever, rat-bite fever, and began. He had been exposed to numerous cats
a few other dreaded diseases. Courtesy of with fleas before the onset of illness. Courtesy of
Centers for Disease Control and Prevention. Carol J. Baker, MD, FAAP.

Image 149.3
The same boy as in Image 149.2 who had rash involving palms and soles as well as pancyto­penia. He
recovered completely with doxycycline therapy. Courtesy of Carol J. Baker, MD, FAAP.

ERRNVPHGLFRVRUJ
700 Epidemic Typhus

150 of Europe, and Central and South America,


particularly in refugee camps and jails of
Epidemic Typhus resource-limited countries. Epidemic typhus
(Louseborne or Sylvatic Typhus) is most common during winter, when condi-
Clinical Manifestations tions favor person-to-person transmission of
the vector, the body louse. Rickettsiae are pres-
Clinically, epidemic typhus should be con­ ent in the blood and tissues of patients during
sidered when people in crowded conditions the early febrile phase but are not found in
develop abrupt onset of high fever, chills, and secretions. Direct person-to-person spread of
myalgia accompanied by severe headache and the disease does not occur in the absence of
malaise. Although epidemic typhus patients the louse vector. In the United States, sporadic
often develop a rash by day 4 to 7 after the start human cases associated with close contact with
of illness, rash may not always be present and infected flying squirrels (Glaucomys volans),
should not be relied on for diagnosis. When their nests, or their ectoparasites are occasion-
present, the rash usually begins on the trunk, ally reported in the eastern United States.
spreads to the limbs, and generally spares the Cases have been reported in people who reside
face, palms, and soles. The rash is typically or work in flying squirrel–infested dwellings,
macular to maculopapular but, in advanced even when direct contact is not reported. Fly-
stages, can become petechial or hemorrhagic. ing squirrel–associated disease, called sylvatic
There is no eschar, as is often present in many typhus, typically presents with a similar illness
other rickettsial diseases. Abdominal com- to that observed with body louse–transmitted
plaints (eg, stomach pain, nausea) and changes infection. Illness can be severe, although fatali-
in mental status are common, and delirium or ties are uncommonly reported with sylvatic
coma can occur. Myocardial and renal failure typhus; the later development of Brill-Zinsser
can occur when the disease is severe. The case- disease has been confirmed in at least one case
fatality rate in untreated people is as high as of untreated sylvatic typhus. Amblyomma ticks
30%. Mortality is less common in children, in the Americas and in Ethiopia have been
and the rate increases with advancing age. shown to carry R prowazekii, but their vector
Untreated patients who recover typically have potential is unknown.
an illness lasting 2 weeks. Brill-Zinsser disease
is a relapse of epidemic typhus that can occur Incubation Period
years after the initial episode. Factors that reac- 1 to 2 weeks.
tivate the rickettsiae are unknown, but relapse
is often milder and of shorter duration. Diagnostic Tests
Epidemic typhus may be diagnosed by the
Etiology
detection of R prowazekii DNA in acute blood
Epidemic typhus is caused by Rickettsia and serum specimens by polymerase chain
­prowazekii. reaction assay. The specimen should preferably
Epidemiology be taken within the first week of symptoms
and before (or within 24 hours of) doxycycline
Humans are the primary reservoir of the administration; a negative result does not
organism, which is transmitted from person exclude R prowazekii infection. Diagnosis may
to person by the human body louse, Pediculus also be determined by detection of rickettsial
humanus corporis. Infected louse feces are DNA in biopsy or autopsy specimens by poly-
rubbed into broken skin or mucous mem- merase chain reaction assay or immunohisto-
branes or are inhaled. All ages are affected. chemical visualization of rickettsiae in tissues.
Poverty, crowding, and poor sanitary condi- The gold standard for serologic diagnosis of
tions contribute to the spread of body lice and, epidemic typhus is a 4-fold increase in immu-
hence, the disease. Cases of epidemic typhus noglobulin (Ig) G antibody titer by the indirect
are rare in the United States but have occurred fluorescent antibody test. IgG and IgM anti-
throughout the world, including the colder, bodies begin to increase by day 7 to 10 after
mountainous areas of Asia, Africa, some parts

ERRNVPHGLFRVRUJ
Epidemic Typhus 701

onset of symptoms; thus, an elevated acute Treatment


titer can represent past exposure rather than Doxycycline is the drug of choice to treat epi­
acute infection. Low-level elevated antibody demic typhus, regardless of patient age, admin-
titers can be an incidental finding in a signifi- istered intravenously or orally. Treatment
cant proportion of the general population in should be continued for at least 3 days after
some regions. IgM antibodies may remain ele- defervescence and evidence of clinical improve­
vated for months and are not highly specific ment is documented, and the total treatment
for acute epidemic typhus. A confirmed case, course is usually for 5 to 10 days. Other broad-
therefore, is one that shows a 4-fold or greater spectrum antibiotics, including ciprofloxacin,
increase in antigen-specific IgG between acute are not recommended and may be more likely
and convalescent sera obtained 2 to 6 weeks to result in fatal outcome. Chloramphenicol
apart. Cross-reactivity may be observed to may be used in cases of ­absolute contraindica-
antibodies to Rickettsia typhi (the agent of tion of doxycycline. To halt the spread of dis-
endemic typhus), Rickettsia rickettsii (the ease to other people, louse-infested patients
agent of Rocky Mountain spotted fever), and should be treated with cream or gel pediculi-
other spotted fever group rickettsiae. Testing cides containing pyrethrins or permethrin;
of acute and convalescent sera by enzyme malathion is prescribed most often when pyre-
immunoassays or dot blot immunoassay tests throids fail. In epidemic situations in which
can also be used for assessing presence of anti- antimicrobial agents may be limited (eg, refu-
body but is less useful for quantifying changes gee camps), a single dose of doxycycline may
in titer. provide effective treatment, especially when
combined with delousing efforts.

Image 150.1
Charles-Jules-Henri Nicolle (1866–1936), a physician, microbiologist, novelist, philosopher, and
historian. From 1903 until his death in 1936, he was director of the Institut Pasteur in Tunis, Tunisia.
Nicolle’s many accomplishments include the discovery that epidemic typhus is transmitted by body
lice (Pediculus humanis corporis), discovery of the phenomenon of inapparent infection, and, possibly,
the first isolation of human influenza virus after experimental transmission. Nicolle made many other
fundamental contributions to knowledge of infectious diseases. He was awarded the 1928 Nobel Prize
in Physiology or Medicine for his discovery about typhus transmission, made in the summer of 1909.
Courtesy of Centers for Disease Control and Prevention/Emerging Infectious Diseases/David M. Morens.

ERRNVPHGLFRVRUJ
702 Epidemic Typhus

Image 150.2
This image depicts an adult female body louse, Pediculus humanus, and 2 larval young, which serve
as the vector of epidemic typhus. Courtesy of Centers for Disease Control and Prevention/World
Health Organization.

Image 150.3
Human body lice in clothes. Courtesy of Centers for Disease Control and Prevention/Emerging
Infectious Diseases and Cédric Foucault.

ERRNVPHGLFRVRUJ
Varicella-Zoster Virus Infections 703

151 Varicella-zoster virus (VZV) establishes


latency in sensory (dorsal root, cranial nerve,
Varicella-Zoster Virus and autonomic, including enteric) ganglia dur-
Infections ing infection. Latency in sensory ganglia can
occur as a result of primary infection with
Clinical Manifestations wild-type VZV in an unvaccinated individual
Primary infection results in varicella (chicken- or infection with wild-type VZV in a previ-
pox), manifesting in unvaccinated people as a ously vaccinated individual or after vaccination
generalized, pruritic, vesicular rash typically with vaccine-strain VZV. Reactivation results
consisting of 250 to 500 lesions in varying in herpes zoster (“shingles”), characterized by
stages of development (papules, vesicles) and grouped vesicular skin lesions in the distribu-
resolution (crusting), low-grade fever, and tion of 1 to 3 sensory dermatomes, frequently
other systemic symptoms. Complications accompanied by pain or itching localized to
include bacterial superinfection of skin lesions the area. Postherpetic neuralgia, pain that
with or without bacterial sepsis, pneumonia, persists after resolution of the zoster rash, can
central nervous system involvement (acute cer- last for weeks to months. Childhood zoster
ebellar ataxia, encephalitis, stroke/vasculopathy), tends to be milder than disease in adults and is
thrombocytopenia, and other rare complica- rarely associated with postherpetic neuralgia.
tions, such as glomerulonephritis, arthritis, Zoster can occasionally become disseminated
and hepatitis. Primary viral pneumonia is not in immunocompromised patients, with lesions
common among immunocompetent children appearing outside the primary dermatomes
but is the most common complication in and resulting in visceral complications. Vari-
adults. Varicella tends to be more severe in cella-zoster virus reactivation may occur less
infants, adolescents, and adults than in chil- frequently in the absence of skin rash (zoster
dren. Before the introduction of routine immu- sine eruptione [or herpete]); these patients
nization against varicella in the United States, can present with aseptic meningitis or enceph-
an average of 100 to 125 people died of chicken- alitis as well as with gastrointestinal tract
pox each year. Breakthrough varicella cases involvement. Visceral zoster can arise from
can occur in immunized children and are usu- reactivation of latent VZV in the enteric (gas-
ally mild and clinically modified. Reye syn- trointestinal) nervous system. Some, but not
drome can follow cases of varicella, although all, of these patients may eventually develop a
this outcome has become rare since the recom- zosteriform skin rash.
mendation not to use salicylate-containing
The attenuated VZV in the varicella vaccine
compounds (eg, aspirin, bismuth-subsalicylate)
may establish latent infection and reactivate
for children during varicella illness. In immu-
as herpes zoster. However, prelicensure data
nocompromised children, progressive, severe
from immunocompromised children indicate
varicella may occur with continuing eruption
risk of developing zoster is lower among vac-
of lesions and high fever, persisting into the
cine recipients than among children who have
second week of illness, and visceral dissemina-
experienced natural varicella. Postlicensure
tion (ie, encephalitis, hepatitis, and pneumo-
studies have also documented a lower risk of
nia) can develop. Hemorrhagic varicella is
herpes zoster among healthy children who
more common among immunocompromised
received varicella vaccines compared with
patients than among immunocompetent hosts.
unvaccinated children.
In children with HIV infection, recurrent
­varicella or disseminated herpes zoster can Fetal infection after maternal varicella during
develop. Severe and even fatal varicella has the first or early second trimester of pregnancy
been reported in otherwise healthy children occasionally results in fetal death or varicella
receiving courses of high-dose corticosteroids embryopathy, characterized by limb hypopla-
(>2 mg/kg/d of prednisone or equivalent) for sia, cutaneous scarring, eye abnormalities, and
treatment of asthma and other illnesses. The damage to the central nervous system (congen-
risk is especially high when corticosteroids ital varicella syndrome). The incidence of con-
are given during the incubation period. genital varicella syndrome among neonates

ERRNVPHGLFRVRUJ
704 Varicella-Zoster Virus Infections

born to mothers who experience gestational (­secondary family cases) often have more
varicella is approximately 1% to 2% when infec- skin lesions than the index case. Health care–­
tion occurs between 8 and 20 weeks of gesta- associated transmission is well-documented
tion. Rarely, cases of congenital varicella in pediatric units, but transmission is rare in
syndrome have been reported in neonates of newborn nurseries.
women infected after 20 weeks’ gestation, the
In temperate climates in the prevaccine era,
latest occurring at 28 weeks. Children infected
varicella was a childhood disease with a
with VZV in utero can develop zoster early in
marked seasonal distribution, with peak
life without having had extrauterine varicella.
­incidence during late winter and early spring
Varicella infection has a higher case-fatality
and among children younger than 10 years.
rate in neonates when the mother develops
High rates of vaccine coverage in the United
varicella from 5 days before to 2 days after
States have effectively eliminated discernible
delivery because there is little opportunity for
seasonality of varicella. In tropical climates,
development and transfer of antibody from
the epidemiology of varicella is different;
mother to neonate and the neonate’s cellular
acquisition of disease occurs at later ages,
immune system is immature. When varicella
resulting in a higher proportion of adults
develops in a mother more than 5 days before
being susceptible to varicella. Following imple-
delivery and gestation is 28 weeks or more, the
mentation of universal immunization in the
severity of disease in the newborn is modified
United States in 1995, varicella declined in all
by transplacental transfer of VZV-specific
age groups, resulting in herd protection. In
maternal immunoglobulin (Ig) G antibody.
areas with active surveillance and with high
Etiology vaccine coverage, the rate of varicella disease
Varicella-zoster virus (also known as human decreased by approximately 90% between 1995
herpesvirus 3) is a member of the Herpesviridae and 2005. Since recommendation of a routine
family, the subfamily Alphaherpesvirinae, and second dose of vaccine in 2006, the incidence
the genus Varicellovirus. of varicella has declined further. The age of
peak varicella incidence is shifting from chil-
Epidemiology dren younger than 10 years to children 10
Humans are the only source of infection for through 14 years of age, although the incidence
this highly contagious virus. Humans are in this and all age groups is lower than in the
infected when the virus comes in contact prevaccine era. Immunity to varicella generally
with the mucosa of the upper respiratory tract is lifelong. Cellular immunity is more impor-
or the conjunctiva of a susceptible person. tant than humoral immunity for limiting the
­Person-to-person transmission occurs by the extent of primary infection with VZV and for
airborne route and from direct contact with preventing reactivation of virus with herpes
patients with vesicular VZV lesions (varicella zoster. Symptomatic reinfection is uncommon
and herpes zoster); vesicles contain infectious in immunocompetent people, in whom asymp-
virus that can be aerosolized. Skin lesions tomatic reinfection is more frequent. Asymp-
appear to be the major source of transmissible tomatic primary infection is unusual.
VZV; transmission from infected respiratory Since 2007, coverage with 1 or more doses of
tract secretions is possible but probably less varicella vaccine among 19- through 35-month-
common than from skin vesicles. There is no old children in the United States has been
evidence of VZV spread from fomites; the greater than 90%. As of 2013, more than 78%
virus is extremely labile and is unable to sur- of 13- to 17-year-olds have received 2 doses of
vive for long in the environment. In utero varicella vaccine. This should not be confused
infection occurs as a result of transplacental as evidence of an increasing rate of break-
passage of virus during maternal VZV viremia. through disease or vaccine failure.
Varicella-zoster virus infection in a household
member usually results in infection of almost Immunocompromised people with primary
all susceptible people in that household. Chil- (varicella) or recurrent (herpes zoster) infec-
dren who acquire their infection at home tion are at increased risk of severe disease.

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Varicella-Zoster Virus Infections 705

Severe varicella and disseminated zoster are Diagnostic Tests


more likely to develop in children with con- Diagnostic tests for VZV are summarized in
genital T-lymphocyte defects or AIDS than Table 151.1. Vesicular fluid or a scab can be
in people with B-lymphocyte abnormalities. used to identify VZV using a polymerase chain
Other groups of pediatric patients who can reaction (PCR) assay test, which is currently
experience more severe or complicated disease the diagnostic method of choice. This testing
include infants, adolescents, patients with can be used to distinguish between wild-type
chronic cutaneous or pulmonary disorders, and vaccine-strain VZV (genotyping). During
and patients receiving systemic corticosteroids, the acute phase of illness, VZV can also be
other immunosuppressive therapy, or long- identified by PCR assay of saliva or buccal
term salicylate therapy. swabs, from unimmunized and immunized
Patients are contagious from 1 to 2 days before patients, although VZV is more likely to be
onset of the rash until all lesions have crusted. detected in vesicular fluid or scabs. Varicella-
zoster virus can be demonstrated by direct
Incubation Period fluorescent ­antibody assay, using scrapings of
14 to 16 days (range, 10–21 days) after exposure a vesicle base during the first 3 to 4 days of the
to rash. The incubation period can be pro- eruption or by viral isolation in cell culture
longed for up to 28 days after receipt of varicella- from vesicular fluid. Viral culture and direct
zoster immune globulin or intravenous fluorescent antibody assay are less sensitive
­immunoglobulin. Varicella can develop than PCR assay, and neither test has the capac-
between 2 and 16 days after birth in neonates ity to distinguish vaccine-strain from wild-
born to mothers with active varicella. type viruses. A significant increase in serum

Table 151.1
Diagnostic Tests for Varicella-Zoster Virus Infection
Test Specimen Comments
PCR Vesicular swabs or scrap- Very sensitive method. Specific for VZV. Methods
ings, scabs from crusted have been designed that distinguish vaccine strain
lesions, biopsy tissue, from wild-type (see text).
CSF
DFA Vesicle scraping, swab of Specific for VZV. More rapid and more sensitive
lesion base (must include than culture, less sensitive than PCR.
cells)
Viral culture Vesicular fluid, CSF, Distinguishes VZV from herpes simplex. Cost, lim-
biopsy tissue ited availability, requires up to a week for result.
Least sensitive method.
Tzanck test Vesicle scraping, swab of Observe multinucleated giant cells with inclusions.
lesion base (must include Not specific for VZV. Less sensitive and accurate
cells) than DFA.
Serology (IgG) Acute and convalescent Specific for VZV. Commercial assays generally have
serum specimens for IgG low sensitivity to reliably detect vaccine-induced
immunity. gpELISA and FAMA are the only IgG
methods that can readily detect vaccine serocon-
version, but these tests are not commercially avail-
able.
Capture IgM Acute serum specimens Specific for VZV. IgM inconsistently detected. Not
for IgM reliable method for routine confirmation, but positive
result indicates current/recent VZV activity.
Requires special equipment.
Abbreviations: CSF, cerebrospinal fluid; DFA, direct fluorescent antibody; FAMA, fluorescent antibody to membrane antigen (assay);
gpELISA, glycoprotein enzyme-linked immunoassay; IgG, immunoglobulin G; IgM, immunoglobulin M; PCR, polymerase chain reaction; VZV,
varicella-zoster virus.

ERRNVPHGLFRVRUJ
706 Varicella-Zoster Virus Infections

varicella IgG antibody between acute and con- Some experts recommend oral acyclovir or
valescent samples by any standard serologic valacyclovir for pregnant women with vari-
assay can confirm a diagnosis retrospectively. cella, especially during the second and third
These antibody tests are reliable for diagnosing trimesters. Intravenous acyclovir is recom-
natural infection in healthy hosts but may not mended for the pregnant patient with serious
be reliable in immunocompromised people. complications of varicella.
However, diagnosis of VZV infection by sero-
Intravenous acyclovir therapy is recommended
logic testing is seldom necessary. Commer-
for immunocompromised patients, including
cially available enzyme immunoassay tests
patients being treated with high-dose cortico-
usually are not sufficiently sensitive to reliably
steroid therapy for more than 14 days. Therapy
demonstrate a vaccine-induced antibody
initiated early in the course of the illness, espe-
response; routine postvaccination serologic
cially within 24 hours of rash onset, maximizes
testing is not recommended. IgM tests are not
benefit. Oral acyclovir should not be used to
reliable for routine confirmation or ruling out
treat immunocompromised children with vari-
of acute infection. All VZV IgM assays are
cella because of poor oral bioavailability. Some
prone to false-positive results, but in the pres-
experts have used valacyclovir, with its
ence of a rash, positive results can indicate cur-
improved bioavailability compared with oral
rent or recent VZV infection or reactivation.
acyclovir, in selected immunocompromised
Treatment patients perceived to be at low to moderate risk
The decision to use antiviral therapy and the of developing severe varicella, such as HIV-
route and duration of therapy should be deter- infected patients with relatively normal num-
mined by specific host factors, extent of infec- bers of CD4+ T lymphocytes and children with
tion, and initial response to therapy. Antiviral leukemia in whom careful follow-up is
drugs have a limited window of opportunity to ensured. Famciclovir is available for treatment
affect the outcome of VZV infection. In immu- of VZV infections in adults, but its efficacy and
nocompetent hosts, most virus replication has safety have not been established for children.
stopped by 72 hours after onset of rash; the Although VariZIG or, if not available, intrave-
duration of replication may be extended in nous immunoglobulin given shortly after
immunocompromised hosts. Oral acyclovir or exposure can prevent or modify the course of
valacyclovir is not recommended for routine disease, immunoglobulin preparations are not
use in otherwise healthy children with vari- effective treatment once disease is established.
cella. Administration within 24 hours of onset Infections caused by acyclovir-resistant VZV
of rash in healthy children results in only a strains, which are generally rare and limited to
modest decrease in symptoms. Oral acyclovir immunocompromised hosts, should be treated
or valacyclovir should be considered for other- with parenteral foscarnet.
wise healthy people at increased risk of moder-
ate to severe varicella, such as unvaccinated Children with varicella should not receive
people older than 12 years, people with chronic salicylates or salicylate-containing products
cutaneous or pulmonary disorders, people because administration of salicylates to such
receiving long-term salicylate therapy, and children increases the risk of Reye syndrome.
people receiving short, intermittent, or aero­ Salicylate therapy should be stopped in an
solized courses of corticosteroids. Some unimmunized child who is exposed to ­varicella.
experts also recommend use of oral acyclovir
or valacyclovir for secondary household cases
in which the disease is usually more severe
than in the primary case.

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Varicella-Zoster Virus Infections 707

Image 151.1
Varicella (chickenpox). Number of reported cases—Illinois, Michigan, Texas, and West Virginia,
1996–2012. Courtesy of Morbidity and Mortality Weekly Report.

Image 151.2
Congenital varicella with short-limb syndrome
and scarring of the skin. The mother had varicella
during the first trimester of pregnancy. Copyright
David Clark, MD.

Image 151.3
Varicella embryopathy with involvement of the
brain. Atrophy of the left cerebral hemisphere.
Courtesy of Dimitris P. Agamanolis, MD.

ERRNVPHGLFRVRUJ
708 Varicella-Zoster Virus Infections

Image 151.5
This child acquired her infection from a younger
sibling. Varicella lesions are apparent on the
palate. This is the same child as in Image 151.4.

Image 151.4
School-aged girl with varicella who acquired it
from a younger sibling, who had a more mild
clinical course with fewer lesions.

Image 151.7
Varicella with scleral lesions and bulbar
conjunctivitis.

Image 151.8
Image 151.6 An adolescent white girl with varicella lesions in
School-aged child with varicella who acquired it various stages. This is the same patient as in
from a younger sibling. This is the same child as Image 151.7.
in images 151.4 and 151.5 who had calamine
lotion applied by the parents for itching. She
recovered without incident.

ERRNVPHGLFRVRUJ
Varicella-Zoster Virus Infections 709

Image 151.9
Varicella with secondary thrombocytopenic Image 151.10
purpura. Varicella with secondary thrombocytopenic
purpura in the same Latin American child as in
Image 151.9.

Image 151.11
Hemorrhagic varicella in a 6-year-old white boy
with eczema. Image 151.12
Hemorrhagic, disseminated, and fatal varicella
with lesions over the anterior chest of a 7-month-
old. Courtesy of David Ascher, MD/Howard
Johnson, MD.

ERRNVPHGLFRVRUJ
710 Varicella-Zoster Virus Infections

Image 151.14
Varicella complicated by necrotizing fasciitis.
A blood culture result was positive for group A
Streptococcus. The disease responded to
antibiotics and surgical debridement followed
by primary surgical closure.

Image 151.13
Diffuse varicella pneumonia bilaterally shown in
the chest radiograph of a patient with Hodgkin
disease. Courtesy of George Nankervis, MD.

Image 151.16
Herpes zoster lesions in an otherwise healthy
Image 151.15
child. The lesions were not particularly painful, as
Varicella and necrotizing fasciitis in a patient is often the case for immunocompetent children
shortly after surgical debridement. with herpes zoster, particularly in the absence of
trigeminal nerve involvement.

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Varicella-Zoster Virus Infections 711

Image 151.17
Close-up of the varicella-zoster lesions of the
patient in Image 151.16.

Image 151.18
Herpes zoster in an otherwise healthy child.

Image 151.19
Varicella zoster in a 7-year-old girl. The patient
had an erythematous vesicular skin rash on the
face on first examination. The dermatologic
distribution suggested the diagnosis of herpes
zoster. This image was taken 3 days after
acyclovir therapy was initiated. The lesions were
crusting. The child had no prior history of
recurring infections and was growing well.
Copyright Barbara Jantausch, MD, FAAP.

Image 151.20
Herpes zoster. Trigeminal nerve involvement.
There may be significant pain associated with
lesions in the trigeminal nerve distribution.
Courtesy of David Ascher, MD/Howard Johnson,
MD.

Image 151.21
Herpes zoster (shingles). Courtesy of C. W. Leung.

ERRNVPHGLFRVRUJ
712 Cholera

152 of V cholerae ­non-O1/non-O139 are associated


with sporadic cases of gastroenteritis, sepsis,
Vibrio Infections and rare cases of wound infection.
Cholera Epidemiology
(Vibrio cholerae) Since the early 1800s, there have been 7 cholera
pandemics. The current pandemic began in
Clinical Manifestations
1961 and is caused by V cholerae O1 biovar El
Cholera is characterized by voluminous watery Tor. Molecular epidemiology shows this pan-
diarrhea and rapid onset of life-threatening demic has occurred in 3 successive waves,
dehydration. Hypovolemic shock can occur with each one spreading from South Asia to
within hours of the onset of diarrhea. Stools other regions in Asia, Africa, and the Western
have a characteristic rice-water appearance, are Pacific Islands (Oceania). In 1991, epidemic
white-tinged, and contain small flecks of mucus cholera caused by toxigenic V cholerae O1
and high concentrations of sodium, potassium, biovar El Tor appeared in Peru and spread to
chloride, and bicarbonate. Vomiting is a com- most countries in South, Central, and North
mon feature of cholera. Fever and abdominal America, causing more than 1 million cases of
cramps are usually absent. In addition to dehydra­ cholera before subsiding. In 2010, V cholerae
tion and hypovolemia, common complications O1 biovar El Tor was introduced into Haiti,
of cholera include hypokalemia, metabolic aci- initiating a massive epidemic of cholera. In the
dosis, and hypoglycemia, parti­cularly in chil- United States, sporadic cases resulting from
dren. Although severe cholera is a distinctive travel to or ingestion of contaminated food
illness characterized by profuse diarrhea and transported from regions with endemic cholera
rapid dehydration, most people infected with are reported, including several cases imported
toxigenic Vibrio cholerae O1 have no symptoms from Hispaniola since 2010.
or mild to moderate diarrhea lasting 3 to 7 days.
Humans are the only documented natural host,
Etiology but free-living V cholerae organisms can ­persist
V cholerae is a curved or comma-shaped, in the aquatic environment. Infection is primar-
motile, gram-negative rod. There are more ily acquired by ingestion of large numbers of
than 200 V cholerae serogroups, some of which organisms from contaminated water or food
carry the cholera toxin gene. Although those (particularly raw or undercooked shellfish, raw
serogroups with the cholera toxin gene and or partially dried fish, or moist grains or vegeta-
others without the cholera toxin gene can cause bles held at ambient temperature). People with
acute watery diarrhea, only toxin-producing low gastric acidity and with blood group O are
serogroups O1 and O139 cause epidemic chol- at increased risk of severe cholera infection.
era, with O1 causing the vast majority of cases Incubation Period
of cholera. V cholerae O1 is classified into
2 ­biotypes, classical and V cholerae biovar El 1 to 3 days (range, few hours to 5 days).
Tor, and 2 major serotypes, Ogawa and Inaba. Diagnostic Tests
Since 1992, toxigenic V cholerae serogroup
O139 has been recognized as a cause of epi- V cholerae can be cultured from fecal speci-
demic cholera in Asia. Aside from the sub­ mens (preferred) or vomitus plated on thio­
stitution of the O139 for the O1 antigen, the sulfate citrate–bile salts–sucrose agar. Because
organism is almost identical to V cholerae O1 most laboratories in the United States do not
biovar El Tor. All other serogroups of V chol­ culture routinely for V cholerae or other Vibrio
erae are collectively known as V cholerae non- organisms, clinicians should request appro­
O1/non-O139. Toxin-producing strains of priate cultures for clinically suspected cases.
V cholerae non-O1/non-O139 can cause spo- Isolates of V cholerae should be sent to a state
radic cases of severe dehydrating diarrheal health department laboratory for confirmation
­i llness but have not caused large outbreaks of and then forwarded to the Centers for Disease
epidemic cholera. Nontoxin-producing strains Control and Prevention for confirmation,

ERRNVPHGLFRVRUJ
Cholera 713

s­ erogrouping, and detection of the cholera 0.5%. Rehydration therapy should be based on
toxin gene. Tests to detect serum antibodies to World Health Organization standards, with
V cholerae, such as the vibriocidal assay and the goal of replacing the estimated fluid deficit
an anticholera toxin enzyme-linked immuno- within 3 to 4 hours of initial presentation.
assay, are available at the Centers for Disease In patients with severe dehydration, isotonic
Control and Prevention. Both assays require intravenous fluids should be used, and lactated
submission of acute and convalescent serum Ringer injection is the widely preferred option.
specimens. A 4-fold increase in vibriocidal or For patients without severe dehydration, oral
anticholera toxin antibody titers between acute rehydration therapy using World Health Orga-
and convalescent sera suggests the diagnosis nization reduced-osmolality oral rehydration
of cholera. Several commercial tests for rapid solution (ORS) has been the standard, but data
antigen detection of V cholerae O1 and O139 in suggest rice-based ORS or amylase-resistant
stool specimens have been developed. These starch ORS is more effective.
V cholerae O1 and O139 rapid diagnostic tests
Prompt initiation of antimicrobial therapy
have sensitivities ranging from approximately
decreases the duration and volume of diar-
80% to 97% and specificities of approximately
rhea and shedding of viable bacteria. Anti­
70% to 90%. Rapid diagnostic tests are not a
microbial therapy should be considered for
substitute for stool culture but potentially pro-
people who are moderately to severely ill.
vide a rapid presumptive indication of a sus-
The choice of antimicrobial therapy should
pect cholera outbreak in regions where stool
be made on the basis of the age of the patient
culture is not immediately available.
as well as ­prevailing patterns of antimicrobial
Treatment resistance. In cases in which prevailing pat-
Appropriate rehydration therapy is the corner- terns of resistance are unknown, antimicro-
stone of management of cholera and reduces bial susceptibility testing should be performed
the mortality of severe cholera to less than and monitored.

Image 152.2
Image 152.1
Vibrio cholerae (Leifson flagella stain, digitally This fly, Musca domestica, was photographed
colorized). Courtesy of Centers for Disease during a 1972 study of disease carriers and
Control and Prevention/Dr William A. Clark. pests of migrant labor camps. Annoying
houseflies may spread typhoid, cholera,
dysentery, and diarrhea. They can carry these
disease-causing organisms from garbage,
sewage, and fecal matter to food or to a
person’s hands or lips. Courtesy of Centers
for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
714 Cholera

Image 152.3 Image 152.4


In 1991, 17 persons in the United States were Typical Vibrio cholerae–contaminated water
infected with Vibrio cholerae related to travel to supply. Ingestion of V cholerae–contaminated
Latin America. Of these, only 6 had actually water is a typical mode of pathogen trans­mis­
traveled there (1 to Peru, 1 to Columbia, and 4 sion. Courtesy of Centers for Disease Control
to Ecuador). The other 11 were family members and Prevention.
in the United States who ate crab brought back
from Latin America in the 4 travelers’ suitcases.
Courtesy of Centers for Disease Control
and Prevention.

Image 152.5
Number of reported cases—United States and US territories, 2012. Courtesy of Morbidity and
Mortality Weekly Report.

ERRNVPHGLFRVRUJ
Cholera 715

Image 152.6
An adult cholera patient with “washerwoman’s hand” sign. Due to severe dehydration, cholera
manifests itself in decreased skin turgor, which produces the so-called washerwoman’s hand sign.
Courtesy of Centers for Disease Control and Prevention.

Image 152.7
Intestinal biopsy showing Vibrio cholerae causing increased mucus production. V cholerae is
transmitted to humans through the ingestion of contaminated food or water and produces a cholera
toxin that acts on the intestinal mucosa and causes severe diarrhea. Courtesy of Centers for Disease
Control and Prevention.

Image 152.8
Here, a cup of typical rice-water stool from a cholera patient shows flecks of mucus that have settled
to the bottom. These stools are inoffensive, with a faint fishy odor. They are isotonic with plasma and
contain high levels of sodium, potassium, and bicarbonate. They also contain extraordinary quantities
of Vibrio cholerae bacterial organisms. Courtesy of Centers for Disease Control and Prevention.

ERRNVPHGLFRVRUJ
716 OTHER VIBRIO INFECTIONS

153 are highest. Gastroenteritis usually follows


ingestion of raw or undercooked seafood,
Other Vibrio Infections ­especially oysters, clams, crabs, and shrimp.
Clinical Manifestations Wound infections can result from exposure of
a preexisting wound to contaminated seawater
Illnesses attributable to nontoxigenic species or from punctures resulting from handling of
of the Vibrionaceae family are considered contaminated shellfish. Exposure to contami-
­v ibriosis. This includes infections attributable nated water during natural disasters, such as
to toxigenic Vibrio cholerae O75 and O141, hurricanes, has resulted in wound infections.
nontoxigenic V cholerae O1, members of the Person-to-person transmission of infection has
Vibrionaceae family that are not in the genus not been reported. People with liver disease,
Vibrio (eg, Grimontia hollisae), and other low gastric acidity, and immunodeficiency
­Vibrio species. Associated clinical syndromes have increased susceptibility to infection
include gastroenteritis, wound infection, and with Vibrio species. Infections associated
septicemia. Gastroenteritis is the most com- with noncholera Vibrio organisms became
mon syndrome and is characterized by acute nationally notifiable in January 2007.
onset of watery stools and crampy abdominal
pain. Approximately half of those afflicted Incubation Period
will have low-grade fever, headache, and chills; Gastroenteritis, typically 24 hours (range,
approximately 30% will have vomiting. Sponta- 5–92 hours).
neous recovery follows in 2 to 5 days. Primary
septicemia is uncommon but can develop in Diagnostic Tests
immunocompromised people with preceding Vibrio organisms can be isolated from stool of
gastroenteritis or wound infection. Wound patients with gastroenteritis, from blood speci-
infections can be severe in people with liver mens, and from wound exudates. Extraintesti-
disease or who are immunocompromised. nal specimens can be cultured according to
­Septicemia and hemorrhagic bullous or necro­ standard laboratory practice because Vibrio
tic skin lesions can be seen in people with species grow well on most nonselective plating
infections caused by Vibrio vulnificus, with media with sodium chloride, such as blood or
associated high morbidity and mortality rates. chocolate agar. Because identification of the
Etiology organism requires special techniques, labora-
tory personnel should be notified when infec-
Vibrio organisms are facultatively anaerobic, tion with Vibrio species is suspected.
motile, gram-negative bacilli that are tolerant
of salt. The most commonly reported nontoxi- Treatment
genic Vibrio species associated with diarrhea Most episodes of diarrhea are mild and
are Vibrio parahaemolyticus and V cholerae self-limited and do not require treatment
non-O1/non-O139. V vulnificus typically causes other than oral rehydration. Antimicrobial
primary septicemia and severe wound infec- therapy can benefit people with severe diar-
tions; the other species can also cause these rhea, wound infection, or septicemia. Septi­
syndromes. Vibrio alginolyticus typically cemia with or without hemorrhagic bullae
causes wound infections. should be treated with a third-generation
Epidemiology ­cephalosporin plus doxycycline. In children
younger than 8 years, a combination of
Vibrio species are natural inhabitants of trimethoprim-­sulfamethoxazole and an
marine and estuarine environments. In ­a minoglycoside is an alternative regimen.
­temperate climates, most noncholera Vibrio Wound infections require surgical debride-
infections occur during summer and autumn ment of necrotic tissue, if present.
months, when Vibrio populations in seawater

ERRNVPHGLFRVRUJ
OTHER VIBRIO INFECTIONS 717

Image 153.1
Vibriosis. Number of reported cases—United States and US territories, 2012. Courtesy of Morbidity
and Mortality Weekly Report.

ERRNVPHGLFRVRUJ
718 West Nile Virus

154 WNV encephalitis or acute flaccid paralysis


often have residual neurologic deficits. Among
West Nile Virus patients with neuroinvasive disease, the overall
Clinical Manifestations case-fatality rate is approximately 10% but is
significantly higher in WNV encephalitis and
An estimated 70% to 80% of people infected myelitis than in WNV meningitis.
with West Nile virus (WNV) are asymptom-
atic. Most symptomatic people experience an Most women known to have been infected
acute systemic febrile illness that often includes with WNV during pregnancy have delivered
headache, myalgia, or arthralgia; gastrointes­ neonates without evidence of infection or
tinal tract symptoms and a transient maculo- ­clinical abnormalities. In the single known
papular rash are also commonly reported. instance of confirmed congenital WNV infec-
Fewer than 1% of infected people develop tion, the mother developed WNV encephalitis
neuroin­vasive disease, which typically mani- at 27 weeks’ gestation, and the neonate was
fests as meningitis, encephalitis, or acute flac- born with cystic destruction of cerebral tissue
cid p­ aralysis. West Nile virus meningitis is and chorioretinitis. If WNV disease is diag-
indistinguishable clinically from aseptic men- nosed during pregnancy, a detailed examina-
ingitis caused by most other viruses. Patients tion of the fetus and of the newborn should
with WNV encephalitis usually present with be ­performed.
seizures, mental status changes, focal neuro-
Etiology
logic deficits, or movement disorders. West
Nile virus acute flaccid paralysis is often clini- West Nile virus is an RNA virus of the Flavi-
cally and pathologically identical to poliovirus-­ viridae family (genus Flavivirus) that is related
associated poliomyelitis, with damage of ante- antigenically to St. Louis encephalitis and Japa-
rior horn cells, and may progress to respiratory nese encephalitis viruses.
paralysis requiring mechanical ventilation. Epidemiology
West Nile virus–associated Guillain-Barré
­syndrome has also been reported and can West Nile virus is an arthropodborne virus
be distinguished from WNV acute flaccid (arbovirus) that is transmitted in an enzootic
paralysis by clinical manifestations and elec- cycle between mosquitoes and amplifying ver-
trophysiologic testing. Cardiac dysrhythmias, tebrate hosts, primarily birds. West Nile virus
myocarditis, rhabdomyolysis, optic neuritis, is transmitted to humans primarily through
uveitis, chorioretinitis, orchitis, pancreatitis, bites of infected Culex mosquitoes. Humans
and hepatitis have been described rarely after usually do not develop a level or duration of
WNV infection. viremia sufficient to infect mosquitoes. There-
fore, humans are dead-end hosts. However,
Routine clinical laboratory results are generally person-to-person WNV transmission can
nonspecific in WNV infections. In patients occur through blood transfusion and solid
with neuroinvasive disease, cerebrospinal organ transplantation. Intrauterine and prob-
fluid (CSF) examination generally shows lym- able breastfeeding transmission is rare. Trans-
phocytic pleocytosis, but neutrophils can pre- mission through percutaneous and mucosal
dominate early in the illness. Brain magnetic exposure has occurred in laboratory workers
resonance imaging is frequently normal, but and occupational settings.
signal abnormalities may be seen in the basal
ganglia, thalamus, and brainstem with WNV West Nile virus transmission has been docu-
encephalitis and in the spinal cord with WNV mented on every continent except Antarctica.
acute flaccid paralysis. Since the 1990s, the largest outbreaks of WNV
neuroinvasive disease have occurred in the
Most patients with WNV nonneuroinvasive Middle East, Europe, and North America.
disease or meningitis recover completely, but West Nile virus was first detected in the west-
fatigue, malaise, and weakness can linger for ern hemisphere in New York, NY, in 1999 and
weeks or months. Patients who recover from subsequently spread across the continental

ERRNVPHGLFRVRUJ
West Nile Virus 719

United States and Canada. From 1999 through bodies are detectable in most WNV-infected
2012, 16,196 cases of WNV neuroinvasive dis- patients within 7 days of symptom onset. For
ease were reported in the United States, includ- patients in whom serum collected within
ing 605 (4%) among children younger than 10 days of illness lacks detectable IgM, testing
18 years. The national incidence of WNV should be repeated on a convalescent-phase
­neuroinvasive disease peaked in 2002 (1.02 sample. IgG antibody is generally detectable
per 100,000) and 2003 (0.98). During 2004 shortly after IgM and can persist for years.
through 2011, annual incidence was relatively Plaque-reduction neutralization tests can be
low (median, 0.31; range, 0.13–0.50), but in 2012, performed to measure virus-specific neutraliz-
the national incidence of WNV neuroinvasive ing antibodies and to discriminate between
disease increased to 0.92 per 100,000. West cross-reacting antibodies from closely related
Nile virus remains the leading cause of neuro- flaviviruses. A 4-fold or greater increase in
invasive arboviral disease in the United States; virus-specific neutralizing antibodies between
in 2013, 2,469 cases of WNV neuroinvasive acute- and convalescent-phase serum speci-
disease were reported, more than 20 times mens collected 2 to 3 weeks apart may be used
the number of neuroinvasive disease cases to confirm recent WNV infection.
reported than for all other domestic arbovi-
Viral culture and WNV nucleic acid ampli­
ruses combined.
fication tests can be performed on acute-phase
In temperate and subtropical regions, most serum, CSF, or tissue specimens. However, by
human WNV infections occur in summer or the time most immunocompetent patients
early autumn. Although all age groups and present with clinical symptoms, WNV RNA
both genders are susceptible to WNV infection, is usually no longer detectable; thus, poly-
the incidence of severe disease (ie, encephalitis merase chain reaction assay is not recom-
and death) is highest among adults older than mended for diagnosis in immunocompetent
60 years. Chronic renal failure, history of can- hosts. The sensitivity of these tests is likely
cer, history of alcohol abuse, diabetes, and higher in immunocompromised patients.
hypertension has been associated with devel- Immunohistochemical staining can detect
oping severe WNV disease (eg, hospitalization) WNV antigens in fixed tissue, but negative
or acquiring encephalitis. results are not ­definitive.
Incubation Period West Nile virus disease should be considered
2 to 6 days; range, 2 to 14 days and up to 21 days in the differential diagnosis of febrile or acute
in immunocompromised people. neurologic illnesses associated with recent
exposure to mosquitoes, blood transfusion, or
Diagnostic Tests solid organ transplantation and of illnesses in
Detection of anti-WNV immunoglobulin (Ig) neonates whose mothers were infected with
M antibodies in serum or CSF is the most WNV during pregnancy or while breastfeed-
­common way to diagnose WNV infection. The ing. In addition to other, more common causes
presence of anti-WNV IgM is usually good of aseptic meningitis and encephalitis, other
evidence of recent WNV infection but can arboviruses should also be considered in the
indicate infection with another closely related differential diagnosis.
flavivirus. Because anti-WNV IgM can persist Treatment
in the serum of some patients for longer than
1 year, a positive test result may occasionally Management of WNV disease is supportive.
reflect past infection. Detection of WNV IgM Although various therapies have been evalu-
in CSF is generally indicative of recent neuro- ated or used for WNV disease, none has shown
invasive infection. West Nile virus IgM anti- specific benefit thus far.

ERRNVPHGLFRVRUJ
720 West Nile Virus

Image 154.1
Transmission electron micrograph of West Nile virus. Courtesy of Centers for Disease Control
and Prevention/Institut Pasteur.

Image 154.2
Reported incidence of neuroinvasive West Nile virus disease by county in the United States, 1999–
2004. Reported to Centers for Disease Control and Prevention by states through April 21, 2005.
Courtesy of Emerging Infectious Diseases.

ERRNVPHGLFRVRUJ
West Nile Virus 721

Image 154.3
Arboviral diseases, West Nile virus. Incidence of reported cases of neuroinvasive disease, by age
group—United States, 2012. Courtesy of Morbidity and Mortality Weekly Report.

Image 154.4
A blood-engorged female Aedes albopictus
mosquito feeding on a human host. Under
experimental conditions, the A albopictus Image 154.5

mosquito, also known as the Asian tiger Four patients with West Nile virus fever and
mosquito, has been found to be a vector of West erythematous, maculopapular rashes on the
Nile virus. Aedes is a genus of the Culicinae back (top left), flank (top right), posterior thigh
family of mosquitoes. Courtesy of Centers for (bottom left), and back (bottom right). Ferguson
Disease Control and Prevention/James Gathany. DD, Gershman K, LeBailly A, Petersen LR.
Characteristics of the rash associated with West
Nile virus fever. Clin Infect Dis. 2005;41(8):1204–
1207. Reprinted with permission from Oxford
University Press.

ERRNVPHGLFRVRUJ
722 West Nile Virus

Image 154.6
West Nile virus–associated flaccid paralysis.
Saggital (A) and axial (B) T2-weighted magnetic Image 154.7
resonance images of the cervical spinal cord in a Three Mollaret-like cells are present (center), with
patient with acute asymmetric upper extremity a neutrophil (upper left) and a lymphocyte (upper
weakness and subjective dyspnea. A, Diffuse right) in cerebrospinal fluid from a patient with
cervical cord signal abnormality. B, Abnormal West Nile virus encephalitis, confirmed by
signal in the anterior horn region. Courtesy of reverse-transcription polymerase chain reaction
Emerging Infectious Diseases. and serologic testing (Papanicolaou stain,
magnification x500). Courtesy of Centers for
Disease Control and Prevention.

Image 154.8
Staining of West Nile virus antigen in the cyto­plasm
of a Purkinje cell in the cerebellum (immuno­his­
tochemistry, magnification x40). Courtesy of
Centers for Disease Control and Prevention.

Image 154.9
Histopathologic features of West Nile virus (WNV)
in human tissues. A and B show inflam­ma­tion,
microglial nodules, and variable necrosis that
occur during WNV encephalitis; C shows WNV
antigen (red) in neurons and neuro­nal processes
using an immunohistochemical stain; D is an
electron micrograph of WNV in the endoplas­mic
reticulum of a nerve cell (arrow) (bar = 100 nm).
These 4 images are from a fatal case of WNV
infection in a 39-year-old African American
female. Courtesy of Emerging Infectious Diseases.

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YERSINIA ENTEROCOLITICA AND YERSINIA PSEUDO­TUBERCULOSIS INFECTIONS 723

155 Etiology

Yersinia enterocolitica The genus Yersinia consists of 11 species of


gram-negative bacilli. Y enterocolitica,
and Yersinia pseudo­ Y ­pseudotuberculosis, and Yersinia pestis are
tuberculosis Infections the 3 most recognized human pathogens.
Y enterocolitica bioserotypes most often asso­
(Enteritis and Other Illnesses)
ciated with human illness are 1B/O:8, 2/O:5,27,
Clinical Manifestations 2/O:9, 3/O:3, and 4/O:3, with bioserotype 4/O:3
now predominating as the most common type
Yersinia enterocolitica causes several age-­
in the United States. Virulence can be attrib-
specific syndromes and a variety of other, less
uted to adhesion or invasion genes, entero­
commonly reported clinical illnesses. Infection
toxins, iron-scavenging genomic islands, and
with Y enterocolitica typically manifests as
secretion systems. Highly pathogenic Yersinia
fever and diarrhea in young children; stool
are known to carry a 70 kb pYV virulence plas-
often contains leukocytes, blood, and mucus.
mid, which encodes a type 3 secretion system
Relapsing disease and, rarely, necrotizing
that is activated at human body temperatures
enterocolitis have also been described. In
and promotes entry into lymph tissues and
older children and adults, a pseudoappendicitis
subsequent evasion of host defense mechanisms.
syndrome (ie, fever, abdominal pain, tender-
ness in the right lower quadrant of the abdomen, Epidemiology
and leukocytosis) predominates. Bacteremia
Yersinia infections are uncommonly reported
with Y enterocolitica most often occurs in
in the United State. Y enterocolitica and
infants younger than 1 year and in older chil-
Y ­pseudotuberculosis are isolated most often
dren with predisposing conditions, such as
during the cool months of temperate climates.
excessive iron storage (eg, deferoxamine use,
According to the Foodborne Disease Active
sickle cell disease, β-thalassemia) and immu-
Surveillance Network, during 2012, 3.3
nosuppressive states. Focal manifestations of
­laboratory-confirmed infections per 1 million
Y enterocolitica are uncommon and include
people were reported to surveillance sites.
pharyngitis, meningitis, osteomyelitis, pyo­
­During Foodborne Disease Active Surveillance
myositis, conjunctivitis, pneumonia, pleural
Network surveillance from 1996 to 2009, 47%
empyema, endocarditis, acute peritonitis,
of infections were in children younger than
abscesses of the liver and spleen, and primary
5 years; 28% were hospitalized, and 1% died.
cutaneous infection. Postinfectious sequelae
In contrast, the average annual incidence of
with Y enterocolitica infection include erythema
Y pseudotuberculosis was 0.04 cases per 1 mil-
nodosum, reactive arthritis, and proliferative
lion people; the median age was 47 years, 72%
glomerulonephritis. These sequelae occur most
were hospitalized, and 11% died. Two-thirds of
often in older children and adults, particularly
Y pseudotuberculosis isolates were recovered
people with HLA-B27 antigen.
from blood.
Major manifestations of Yersinia pseudotuber­
The principal reservoir of Y enterocolitica is
culosis infection include fever, scarlatiniform
swine; feral Y pseudotuberculosis has been
rash, and abdominal symptoms. Acute pseudo-
­isolated from ungulates (deer, elk, goats,
appendiceal abdominal pain is common,
sheep, cattle), rodents (rats, squirrels, beaver),
resulting from ileocecal mesenteric adenitis
rabbits, and many bird species. Infection with
or terminal ileitis. Other findings include diar-
Y enterocolitica is believed to be transmitted
rhea, erythema nodosum, septicemia, and ster-
by ingestion of contaminated food (raw or
ile pleural and joint effusions. Clinical features
incompletely cooked pork products, tofu, and
can mimic those of Kawasaki disease (mucocu-
unpasteurized or inadequately pasteurized
taneous lymph node syndrome); in Hiroshima,
milk), by contaminated surface or well water,
Japan, nearly 10% of children with a diagnosis
by direct or indirect contact with animals,
of Kawasaki disease have serologic or culture
and, rarely, by transfusion with contaminated
evidence of Y pseudotuberculosis infection.

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724 YERSINIA ENTEROCOLITICA AND YERSINIA PSEUDO­TUBERCULOSIS INFECTIONS

packed red blood cells and by person-to-person generally available only in reference or research
transmission. Cross-contamination has been laboratories. Characteristic ultrasonographic
documented to lead to infection in infants if features demonstrating edema of the wall of
their caregivers handle raw pork intestines the terminal ileum and cecum help to distin-
(ie, chitterlings) and do not cleanse their hands guish pseudoappendicitis from appendicitis
adequately before handling the infant or the and can help avoid exploratory surgery.
infant’s toys, bottles, or pacifiers.
Treatment
Incubation Period Neonates, immunocompromised hosts, and
4 to 6 days; range, 1 to 14 days. Organisms are all patients with septicemia or extraintestinal
typically excreted for 2 to 3 weeks. disease require treatment for Yersinia infection.
Parenteral therapy with a third-generation
Diagnostic Tests
cephalosporin is appropriate, and evaluation
Y enterocolitica and Y pseudotuberculosis can of cerebrospinal fluid should be performed
be recovered from stool, throat swab speci- for infected neonates. Otherwise healthy non-
mens, mesenteric lymph nodes, peritoneal neonates with enterocolitis can be treated
fluid, and blood. Y enterocolitica has also been symptomatically. Other than decreasing the
isolated from synovial fluid, bile, urine, cere- duration of fecal excretion of Y enterocolitica
brospinal fluid, sputum, pleural fluid, and and Y pseudotuberculosis, a clinical benefit of
wounds. Stool cultures generally yield bacteria antimicrobial therapy for immunocompetent
during the first 2 weeks of illness, regardless patients with enterocolitis, pseudoappendici-
of the nature of gastrointestinal tract mani­ tis syndrome, or mesenteric adenitis has not
festations. Yersinia organisms are not sought been established. In addition to third-­
routinely in stool specimens by most labora­ generation cephalosporins, Y enterocolitica
tories in the United States. Consequently, and Y ­pseudotuberculosis are usually sus­
­laboratory personnel should be notified when ceptible to trimethoprim-sulfamethoxazole,
Yersinia infection is suspected so stool can be aminoglycosides, fluoroquinolones, chloram-
cultured on suitable media (cefsulodin-irgasan-­ phenicol, tetracycline, or doxycycline.
novobiocin agar). Infection can also be con- Y ­enterocolitica isolates are usually resistant
firmed by demonstrating increases in serum to first-generation cephalosporins and
antibody titer after infection, but these tests are most penicillins.

Image 155.1
A photomicrograph of Yersinia enterocolitica using flagella staining technique. Symptoms of yersiniosis
are fever, abdominal pain, and diarrhea (often bloody), and Y enterocolitica is the cause of most
Yersinia-related illnesses in the United States (mostly in children). Courtesy of Centers for Disease
Control and Prevention.

ERRNVPHGLFRVRUJ
YERSINIA ENTEROCOLITICA AND YERSINIA PSEUDO­TUBERCULOSIS INFECTIONS 725

Image 155.2
Yersinia kristensenii on cefsulodin-irgasan-novobiocin agar. Colonies appear light rose in color with a
darker, reddish center. Courtesy of Julia Rosebush, DO; Robert Jerris, PhD; and Theresa Stanley,
M(ASCP).

Image 155.3
Multiple erythema nodosum lesions over both lower extremities of a 10-year-old girl following a
Yersinia enterocolitica infection. This immunoreactive complication may also occur in association with
Campylobacter jejuni infections, tuberculosis, leprosy, coccidioidomycosis, histoplasmosis, and other
infectious diseases. Courtesy of George Nankervis, MD.

ERRNVPHGLFRVRUJ
ERRNVPHGLFRVRUJ
INDEX 727

Index Abscesses
abdominal
Page numbers followed by f indicate a figure. from actinomycosis, 1
Page numbers followed by i indicate an image. from Bacteroides infection, 53
Page numbers followed by t indicate a table. from Prevotella infection, 53
actinomycotic, 2i
A from Bacteroides infection, 53
from blastomycosis, 64
Abdominal abscess brain
from Bacteroides infection, 53 from Arcanobacterium haemolyticum infections,
from Prevotella infection, 53 33
Abdominal actinomycosis, 1 from Bacteroides infection, 53
Abdominal cramps from Escherichia coli, 169
from Bacillus cereus, 49 from Lemierre disease, 183
from Clostridium difficile, 111 from melioidosis from Burkholderia pseudomallei,
from cryptosporidiosis, 129 73
from cyclosporiasis, 136 from Prevotella infection, 53
from human calicivirus infections, 404 hepatic, from Pasteurella infections, 435
from microsporidia infections, 386 intra-abdominal, from non–group A or B strepto­
from Salmonella infections, 516 coccal and enterococcal infections, 586
from Shigella infections, 535 liver, 11i
Abdominal discomfort from amebiasis, 7
from Balantidium coli infection, 56 from Yersinia enterocolitica, 723
from Clostridium difficile, 111 lung
from trichinellosis, 647 from Bacteroides infection, 53
from Yersinia pseudotuberculosis infection, 723 from Burkholderia infections, 73
Abdominal distention from nocardiosis, 401
from Escherichia coli, 169 from Prevotella infection, 53
from Giardia intestinalis infections, 186 orbital, 561i
Abdominal pain from paracoccidioidomycosis, 411
from anthrax, 18 paravertebral, 685i
from babesiosis, 45 peritonsillar
from Blastocystis hominis infections, 62 from Arcanobacterium haemolyticum infections,
from brucellosis, 70 33
from Campylobacter infections, 76 from Bacteroides infection, 53
from cystoisosporiasis, 306 from group A streptococcal infections, 568
from dengue, 145 from Prevotella infection, 53
from enterovirus infections, 160 from Prevotella infection, 53
from Escherichia coli diarrhea, 174 prostatic, from melioidosis from Burkholderia
from Giardia intestinalis infections, 186 pseudomallei, 73
from hemorrhagic fever, 221 pulmonary, from Pasteurella infections, 435
from hemorrhagic fever with renal syndrome, 218 from rat-bite fever, 492
from hepatitis E, 244 retropharyngeal, from group A streptococcal
from hookworm infections, 264 infections, 568
from influenza, 294 scalp
from isosporiasis, 306 from staphylococcal infections, 549
from malaria, 361 from tinea capitis, 622
from nontuberculous mycobacteria, 686 spleen, from Yersinia enterocolitica, 723
from Q fever, 485 Acalculous cholecystitis from Q fever, 485
from Rocky Mountain spotted fever, 502 Acanthamoeba keratitis, 13, 14, 17i
from schistosomiasis, 529 Acanthamoeba species, 13, 15i
from smallpox, 539 Acid-fast bacillus (AFB), 664
from Strongyloides, 591 smear for nontuberculous mycobacteria, 687
from tapeworm infections, 616 Acid-fast staining for cyclosporiasis, 136i
from Trichomonas vaginalis infections, 651 Acidosis from rotavirus infections, 508
from trichuriasis, 655 Acid-Schiff stain for microsporidia infections, 386
from tuberculosis, 664 Acinetobacter, 169
Abortion Acquired syphilis, 594
lymphocytic choriomeningitis and, 359 follow-up and management of, 602
mumps and, 392 primary stage, 594
syphilis and, 595 secondary stage, 594
tertiary stage, 594

ERRNVPHGLFRVRUJ
728 INDEX

Actinobacillus actinomycetemcomitans, 3i African trypanosomiasis (African sleeping sickness),


Actinomadura madurae, 401 657–659
Actinomyces, 2, 2i clinical manifestations of, 657
Actinomyces cervical abscess, 1, 3i diagnostic tests for, 657–658
Actinomyces israelii, 1, 2i epidemiology of, 657
Actinomycosis, 1–3 etiology of, 657
abdominal, 1 incubation period of, 657
amoxicillin for, 2 pentamidine for, 658
ampicillin for, 2 suramin for, 658
chronic pulmonary, 3i treatment of, 658
clindamycin for, 2 Agranulocytosis from Epstein-Barr virus, 165
clinical manifestations of, 1 AIDS from Cryptococcus neoformans infections, 126
diagnostic tests for, 1–2 Airspace disease, 487i
doxycycline for, 2 Allergic bronchopulmonary aspergillosis, 38, 40
epidemiology of, 1 Allergic sinusitis from aspergillosis, 38, 40
erythromycin for, 2 Alopecia areata, tinea capitis and, 622
etiology of, 1 Alphacoronavirus, 122
incubation period of, 1 Alveolar disease from Pneumocystis jiroveci infections, 472
penicillin G for, 2 Amblyomma americanum, 159i, 344, 349i, 504i
tetracycline for, 2 Amebiasis, 7–12, 9i–12i
treatment of, 2 chloroquine phosphate for, 8
Actinomycotic abscesses, 2i, 3i clinical manifestations of, 7
Acute bronchitis from Chlamydophila pneumoniae, 95 diagnostic tests for, 8
Acute follicular adenovirus conjunctivitis, 5i epidemiology of, 7
Acute hemorrhagic conjunctivitis from enterovirus etiology of, 7
infections, 160 incubation period of, 7
Acute hemorrhagic fever from arboviruses, 24 intestinal, 7, 8
Acute idiopathic polyneuritis, as complication of viral invasive extraintestinal, 12i
Campylobacter infections, 76 iodoquinol for, 8
Acute myositis from influenza, 294 luminal amebicide for, 8
Acute peritonitis from Yersinia enterocolitica, 723 metronidazole for, 8
Acute pharyngitis from Arcanobacterium haemolyticum paromomycin for, 8
infections, 33 tinidazole for, 8
Acute pulmonary histoplasmosis, 258 treatment of, 8
Acute respiratory distress syndrome from plague, 457 Amebic keratitis, 13–17, 16i
Acute respiratory tract illness clinical manifestations of, 13
from Mycoplasma pneumoniae infections, 396 diagnostic tests for, 14
from respiratory syncytial virus, 494 epidemiology of, 13–14
Acute rheumatic fever, 568, 571 etiology of, 13
Acute transient pneumonitis from Ascaris lumbricoides fluconazole for, 14
infections, 35 incubation period of, 14
Adenitis, 93 itraconazole for, 14
from group B streptococcal infections, 582 treatment of, 14
Adenocarcinoma in situ, 407 Amebic meningoencephalitis, 13–17, 16i
Adenopathy amphotericin B for, 14
from rat-bite fever, 492 clinical manifestations of, 13
Adenoviral pneumonia, 5i diagnostic tests for, 14
Adenovirus infections, 4–6, 5i–6i epidemiology of, 13–14
cidofovir for, 5 etiology of, 13
clinical manifestations of, 4 fluconazole for, 14
diagnostic tests for, 4–5 incubation period of, 14
epidemiology of, 4 itraconazole for, 14
etiology of, 4 treatment of, 14
incubation period of, 4 Ameboma from amebiasis, 7
treatment of, 5 American trypanosomiasis (Chagas disease), 660–663
Adolescence, acquisition of HIV during, 279 benznidazole for, 661
Aedes aegypti, 27, 145, 145 clinical manifestations of, 660
Aedes albopictus, 27, 145 diagnostic tests for, 661
Aedes polynesiensis, 145 epidemiology of, 660–661
Aerobic cultures for Bacteroides and Prevotella infections, etiology of, 660
53 incubation period of, 661
Aerosol treatment for respiratory syncytial virus, 495 nifurtimox for, 661
treatment of, 661

ERRNVPHGLFRVRUJ
INDEX 729

Amniocentesis for cytomegalovirus infection, 140 Antemortem diagnosis for rabies, 488
Amnionitis from Listeria monocytogenes infections, 339 Anterior uveitis from Kawasaki disease, 309
Anaerobic cultures of wound exudate for clostridial Anthrax, 18–23
myonecrosis, 109 ciprofloxacin for, 19
Anal infections from granuloma inguinale, 198 clindamycin for, 19
Anaplasma infections, 154–159 clinical manifestations of, 18
clinical manifestations of, 154 cutaneous, 18, 21i, 22i
diagnostic tests for, 155 diagnostic tests for, 19
doxycycline for, 155 doxycycline for, 19
epidemiology of, 154–155 epidemiology of, 18–19
etiology of, 154 etiology of, 18
incubation period of, 155 fluoroquinolone for, 19
treatment of, 155 incubation period of, 19
Anaplasma phagocytophilum, 45, 154–155, 158i, 348 inhalational, 18
Anaplasmosis, 156t injection, 18
Ancylostoma braziliense, 134 linezolid for, 20
Ancylostoma caninum, 134, 267i meropenem for, 20
Ancylostoma duodenale, 264, 266i oropharyngeal, 18
Anemia penicillin for, 19
from African trypanosomiasis, 657 treatment of, 19–20
hemolytic Antigen detection tests
from Epstein-Barr virus, 165, 166 for Histoplasma capsulatum, 259
from syphilis, 594 for malaria, 363
hypochromic microcytic, 264 for respiratory syncytial virus, 495
from malaria, 361 Antigenic drift from influenza, 294, 300i
megaloblastic, from tapeworm infections, 616 Antigenic shift from influenza, 294, 301i
from Mycoplasma pneumoniae infections, 396 Anti-HDV immunoglobulin G antibodies for hepatitis
from nontuberculous mycobacteria, 686 D, 242
from parvovirus B19, 430 Anti-HEV immunoglobulin G antibodies for hepatitis
from Rocky Mountain spotted fever, 502 E, 244
from toxocariasis, 634 Anti-HEV immunoglobulin M antibodies for hepatitis
Aneurysms from Kawasaki disease, 309–310 E, 244
Angiostrongylus cantonensis, 421t, 429i Antimicrobial-associated diarrhea from Clostridium
Angiostrongylus costaricensis, 421t, 424i difficile, 112
Animal feces as cause of Escherichia coli diarrhea, 175 Antimicrobial susceptibility testing for non–group A or B
Anisakiasis, 421t, 428i streptococcal and enterococcal infections, 587
Anisakis simplex, 428i Anxiety from rabies, 488
Annular erythematous lesions, 627i Apnea
Anogenital HPV infection, 407, 408 from Escherichia coli, 169
low-grade squamous intraepithelial lesions, 407 from group B streptococcal infections, 582
high-grade squamous intraepithelial lesions, 407 from pertussis, 445
Anogenital warts, 407 Apneic episodes from respiratory syncytial virus, 494
Anopheles funestus, 369i Appendicitis from Pasteurella infections, 435
Anorectal infection from gonococcal infections, 190 Arboviruses, 24–32
Anorexia clinical manifestations of, 24–25, 24t
from anthrax, 18 diagnostic tests for, 27
from babesiosis, 45 epidemiology of, 25, 27
from brucellosis, 70 etiology of, 25
from cryptosporidiosis, 129 incubation period of, 27
from cyclosporiasis, 136 treatment of, 27
from cystoisosporiasis, 306 Arcanobacterium haemolyticum infections, 33–34, 34i, 183
from Escherichia coli, 169 aminoglycosides for, 33
from Giardia intestinalis infections, 186 associated rash, 34i
from group A streptococcal infections, 568 clinical manifestations of, 33
from hepatitis A, 226 diagnostic tests for, 33
from hepatitis B, 230 epidemiology of, 33
from hepatitis E, 244 erythromycin for, 33
from isosporiasis, 306 etiology of, 33
from lymphocytic choriomeningitis, 359 incubation period of, 33
from rickettsialpox, 500 parenteral penicillin for, 33
from Rocky Mountain spotted fever, 502 treatment of, 33
from Salmonella infections, 516

ERRNVPHGLFRVRUJ
730 INDEX

Arcanobacterium haemolyticum pharyngitis, 34i Aseptic meningitis


Areflexia as complication of viral Campylobacter from arboviruses, 25
infections, 76 from Epstein-Barr virus, 165
Arenaviruses, hemorrhagic fevers from, 215–217, 217i from herpes simplex infections, 247
clinical manifestations of, 215 from leptospirosis, 335
diagnostic tests for, 216 from Mycoplasma pneumoniae infections, 396
epidemiology of, 215–216 from parainfluenza viral infections, 416
etiology of, 215 from West Nile virus, 718
incubation period of, 216 Aspartate transaminase in Lassa fever, 215
ribavirin for, 216 Aspergillomas, 41i
treatment of, 216 from aspergillosis, 38
Argentine hemorrhagic fever, 215–216 Aspergillosis, 38–42, 40i
Arthralgia allergic bronchopulmonary, 38
from babesiosis, 45 amphotericin B for, 39
from brucellosis, 70 clinical manifestations of, 38
from Ehrlichia and Anaplasma infections, 154 diagnostic tests for, 39
from hepatitis B, 230 epidemiology of, 38
from hepatitis E, 244 etiology of, 38
from Kawasaki disease, 309 incubation period of, 39
from Lyme disease, 343 invasive, 38
from lymphocytic choriomeningitis, 359 pulmonary, 40i
from malaria, 361 treatment of, 39–40
from parvovirus B19, 430 voriconazole for, 39
from rat-bite fever, 492 Aspergillus flavus, 38
Arthritis. See also Reactive arthritis; Septic arthritis Aspergillus fumigatus, 38, 42i
from Bacteroides infection, 53 Aspergillus nidulans, 38
from brucellosis, 70 Aspergillus niger, 38
group A streptococcal, 578i Aspergillus pneumonia, 40i
from hepatitis B, 230 Aspergillus terreus, 38
from Kawasaki disease, 311 Aspiration pneumonia
Lyme, 343, 346 from Bacteroides infection, 53
from lymphocytic choriomeningitis, 359 from Prevotella infection, 53
from meningococcal infections, 378 Asthma
migratory, from gonococcal infections, 190 from human coronaviruses, 122
from mumps, 392 from human metapneumovirus, 385
from Mycoplasma pneumoniae infections, 396 from parainfluenza viral infections, 416
from parvovirus B19, 430 Astrovirus infections, 43–44, 44i
from Prevotella infection, 53 clinical manifestations of, 43
pyogenic, from pneumococcal infections, 464 diagnostic tests for, 43
from rat-bite fever, 492 epidemiology of, 43
recurrent, from Lyme disease, 347 etiology of, 43
treatment for, 575 incubation period of, 43
from varicella-zoster infections, 703 treatment of, 43
from viral Campylobacter infections, 76 Asymptomatic cyst excreter, 8
Artibeus jamaicensis as carrier of rabies virus, 491i Asymptomatic infection, 226
Ascaris lumbricoides infections, 35–37, 36i, 37i Ataxia
albendazole for, 35 as complication of viral Campylobacter infections, 76
clinical manifestations of, 35 from Creutzfeldt-Jakob disease, 481
diagnostic tests for, 35 Atelectasis from tuberculosis, 664
epidemiology of, 35 Athlete’s foot (tinea pedis), 631–633, 632i, 633i
etiology of, 35 clinical manifestations of, 631
incubation period of, 35 clotrimazole for, 631
intravenous fluids for, 35 diagnosis of, 631
ivermectin for, 35 econazole for, 631
mebendazole for, 35 epidemiology of, 631
nitazoxanide for, 35 etiology of, 631
treatment of, 35 fluconazole for, 631
Ascending myelitis from herpes simplex virus, 247 itraconazole for, 631
Ascites miconazole for, 631
from anthrax, 18 terbinafine for, 631–632
from dengue, 145 treatment of, 631–632

ERRNVPHGLFRVRUJ
INDEX 731

Atopic dermatitis, 530 Bacterial meningitis, 466


from tinea capitis, 622 Bacterial sepsis from enterovirus infections, 160
from tinea pedis, 631 Bacterial vaginosis, 51–52, 52i
from tinea unguium, 631 clindamycin for, 52
Atypical mycobacterial tuberculosis, 690i clinical manifestations of, 51
Autoimmune gastritis from Helicobacter pylori infections, diagnostic tests for, 51–52
213 epidemiology of, 51
Axillary petechiae etiology of, 51
from Argentine hemorrhagic fever, 215 incubation period of, 51
from Bolivian hemorrhagic fever, 215 metronidazole for, 52
from Venezuelan hemorrhagic fever, 215 treatment of, 52
Bacteroides fragilis, 53, 54i, 55i, 320
B Bacteroides infections, 53–55, 54i, 183
antimicrobial therapy for, 53
Babesia duncani, 45 ampicillin for, 53
Babesia microti, 45, 46i, 155, 348 β-lactam penicillin for, 53
Babesiosis, 45–48 clindamycin for, 53
atovaquone for, 46 clinical manifestations of, 53
azithromycin for, 46 diagnostic tests for, 53
clindamycin for, 46 epidemiology of, 53
clinical manifestations of, 45 etiology of, 53
diagnostic tests for, 45–46 incubation period of, 53
epidemiology of, 45 metronidazole for, 54
etiology of, 45 penicillin G for, 53
incubation period of, 45 treatment of, 53–54
Lyme disease and, 343 Balamuthia mandrillaris, 13–14, 17i
oral quinine for, 46 Balantidium coli infections (balantidiasis), 56–57, 56i
treatment of, 46 clinical manifestations of, 56
Bacille Calmette-Guérin, 666 diagnostic tests for, 56
Bacillus anthracis, 18–19 epidemiology of, 56
photomicrograph of, 20i etiology of, 56
Bacillus cereus infections, 49–50, 50i, 114 incubation period of, 56
antimicrobial therapy for, 49 iodoquinol for, 56
clinical manifestations of, 49 metronidazole for, 56
diagnostic tests for, 49 tetracycline for, 56
epidemiology of, 49 treatment of, 56
etiology of, 49 Bancroftian filariasis, 355–358
incubation period of, 49 Bartonella henselae (cat-scratch disease), 88–92, 89i
treatment of, 49–50 antimicrobial therapy for, 89
vancomycin for, 50 azithromycin for, 89
Bacillus cereus subsp mycoides, 50i ciprofloxacin for, 89
Back pain clinical manifestations of, 88
from Listeria monocytogenes infections, 339 diagnostic tests for, 89
from malaria, 361 doxycycline for, 89
from smallpox, 539 epidemiology of, 88
Bacteremia etiology of, 88
from Bacillus cereus, 49 granuloma of finger of, 91i
from Burkholderia infections, 73 incubation period of, 89
from gonococcal infections, 190 parenteral gentamicin for, 89
from group A streptococcal infections, 568 rifampin for, 89
from group B streptococcal infections, 582 treatment of, 89
from Haemophilus influenzae, 200 trimethoprim-sulfamethoxazole for, 89
from non–group A or B streptococcal and Bartonella henselae, 88
enterococcal infections, 586 Baylisascaris infections, 58–61, 59i, 60i
from Pasteurella infections, 435 albendazole for, 58
from Shigella infections, 535 anthelmintic treatment for, 58
from staphylococcal infections, 548 clinical manifestations of, 58
from Yersinia enterocolitica, 723 corticosteroid therapy for, 58
Bacterial antigens in leptospirosis, 338i diagnostic tests for, 58
Bacterial endocarditis, 564i epidemiology of, 58
Bacterial infections etiology of, 58
from human immunodeficiency virus infection, 276 treatment of, 58
from pediculosis corporis, 437

ERRNVPHGLFRVRUJ
732 INDEX

Baylisascaris procyonis, 58, 59i, 60i Bloating from Blastocystis hominis infections, 62
Beau lines, 580i Blood agar plate culture of Bacillus cereus, 50i
Beaver direct smear for hookworm infections, 264 Blood cultures
Behavioral disturbances for pneumococcal infections, 467
from cysticercosis, 611 for staphylococcal infections, 552
from tapeworm diseases, 611 Blood smears for meningococcal infections, 379
Bell palsy from herpes simplex virus, 247 Blood specimen for sporotrichosis, 545
Betacoronavirus, 122 Blueberry muffin lesions from congenital rubella, 510
Bicarbonate agar plate culture of Bacillus cereus, 50i Blurred vision from Toxoplasma gondii infections, 637
Bilateral conjunctivitis, as complication of viral Bocavirus, 66
Campylobacter infections, 76 Body lice (pediculosis corporis), 441, 442i
Bilateral diffuse interstitial disease from Pneumocystis clinical manifestations of, 441
jiroveci infections, 472 diagnostic tests for, 441
Bilateral parotid gland enlargement from HIV infection, epidemiology of, 441
288 etiology of, 441
Bilateral subconjunctival hemorrhages, in infant with incubation period of, 441
pertussis, 449i pediculicides for, 441
Bilateral varicella pneumonia, 710i treatment of, 441
Biliary colic from Ascaris lumbricoides infections, 35 Bolivian hemorrhagic fever, 215
Biliary tract disease from cyclosporiasis, 136 Bone marrow
Biopsy specimens for Histoplasma capsulatum, 259
for onchocerciasis, 405 suppression from human herpesvirus 6 and 7, 268
for tuberculosis, 667 Bordetella bronchiseptica, 445
Bites Bordetella holmesii, 445
cat, 436i Bordetella parapertussis, 445
rat, 493i Bordetella pertussis, 445, 447i, 449i
tick, 351i Borrelia afzelii, 344
Black Creek Canal virus, 207 Borrelia burgdorferi infection (Lyme disease), 68, 155,
Black death, 457 343–354, 348i
Black dot ringworm, 622 antimicrobial therapy for, 346
Blackfly larva, 406i from babesiosis, 45
Black sickness, 323 clinical manifestations of, 343–344
Bladder cancer from Schistosoma haematobium, 529 diagnostic tests for, 344–346
Bladder incontinence from Rocky Mountain spotted fever doxycycline for, 346
(RMSF), 502 epidemiology of, 344
Blastocystis hominis infections, 62–63, 62i etiology of, 344
clinical manifestations of, 62 incubation period of, 344
diagnostic tests for, 62 synovitis, 354i
epidemiology of, 62 treatment of, 346–348
etiology of, 62 Borrelia garinii, 344
incubation period of, 62 Borrelia hermsii, 67, 68i, 69i
life cycle of, 63i Borrelia infections (relapsing fever), 67–69, 68i
metronidazole for, 62 clinical manifestations of, 67
nitazoxanide for, 62 diagnostic tests for, 68
treatment of, 62 doxycycline for, 68
Blastomyces dermatitidis, 65i, 259 epidemiology of, 67
from blastomycosis, 64 erythromycin for, 68
Blastomycosis, 64–65, 65i etiology of, 67
amphotericin B for, 64 incubation period of, 68
clinical manifestations of, 64 penicillin G for, 68
cutaneous, 65i tetracycline for, 68
diagnostic tests for, 64 treatment of, 68
epidemiology of, 64 Borrelia parkeri, 67
etiology of, 64 Borrelia recurrentis, 67
fluconazole for, 64 Borrelia turicatae, 67
incubation period of, 64 Botulism, 104, 106i–108i
itraconazole for, 64 foodborne, 104
treatment of, 64 infant, 104, 108i
voriconazole for, 64 intestinal, 94
Bleeding ocular muscle paralysis in, 108i
from Crimean-Congo hemorrhagic fever, 218 wound, 104, 108i
from hemorrhagic fevers, 215 Bovine spongiform encephalopathy, 481, 484i
Blindness from onchocerciasis, 405 Bowel dilation from Balantidium coli infection, 56

ERRNVPHGLFRVRUJ
INDEX 733

Bowel incontinence from Rocky Mountain spotted fever incubation period of, 219
(RMSF), 502 ribavirin for, 219
Bowel obstruction from tapeworm infections, 616 treatment of, 219
Brain abscesses Bunyaviruses, 218–220
from Arcanobacterium haemolyticum infections, 33 Burkholderia cepacia, 73, 74i
from Bacteroides infection, 53 ceftazidime for, 74
from Escherichia coli, 169 chloramphenicol for, 74
from Lemierre disease, 183 doxycycline for, 74
from melioidosis from Burkholderia pseudomallei, 73 imipenem for, 74
from Prevotella infection, 53 meropenem for, 74
Brain lesions from candidiasis, 79–80 trimethoprim-sulfamethoxazole for, 74
Brazilian hemorrhagic fever, 215 Burkholderia gladioli, 73
Breastfeeding Burkholderia infections, 73–75, 74i
postnatal transmission of human immunodeficiency clinical manifestations of, 73
virus through, 278–279 diagnostic tests for, 74
tuberculosis during, 673, 678 epidemiology of, 73–74
Breath tests for Helicobacter pylori infections, 213 etiology of, 73
Brill-Zinsser disease from epidemic typhus, 700 incubation period of, 74
Bronchiectasis from paragonimiasis, 413 treatment of, 74
Bronchiolar plugging in infant with pertussis, 449i Burkholderia mallei, 73
Bronchiolitis Burkholderia oklahomensis, 73
from adenovirus infections, 4 Burkholderia pseudomallei, 73, 75i
from human metapneumovirus, 385 Burkholderia thailandensis, 73
from influenza, 294 Burkitt lymphoma from Epstein-Barr virus, 165
from parainfluenza viral infections, 416
from respiratory syncytial virus, 494 C
Bronchitis, acute, from Chlamydophila pneumoniae, 95
Bronchoscopy for Pneumocystis jiroveci infections, 473 Cachexia from African trypanosomiasis, 657
Brucella abortus, 70 Calcium alginate swab for pertussis, 446
Brucella canis, 70 Caliciviridae, 404
Brucella ceti, 70 Calymmatobacterium granulomatis, 198, 199i
Brucella granuloma, 71i Campylobacter coli, 76
Brucella inopinata, 70 Campylobacter fetus, 76, 78i
Brucella melitensis, 70, 71i Campylobacter hyointestinalis, 76
Brucella pinnipedialis, 70 Campylobacter infections, 76–78
Brucella suis, 70 aminoglycosides for, 77
Brucellosis, 70–72 azithromycin for, 77
antimicrobial therapy for, 71 cephalosporins for, 77
clinical manifestations of, 70 ciprofloxacin for, 77
diagnostic tests for, 70–71 clinical manifestations of, 76
doxycycline for, 71 diagnostic tests for, 77
epidemiology of, 70 epidemiology of, 76
etiology of, 70 erythromycin for, 77
gentamicin for, 71 etiology of, 76
incubation period of, 70 imipenem for, 77
rifampin for, 71 incubation period of, 77
tetracycline for, 71 meropenem for, 77
treatment of, 71 treatment of, 77
trimethoprim-sulfamethoxazole for, 71 Campylobacter jejuni, 76, 77i, 320
Brugia malayi, 355, 356i Campylobacter lari, 76
Brugia timori, 355 Campylobacter upsaliensis, 76
Bubo aspirate for plague, 457 Cancer precursor lesions from human papillomaviruses,
Bubonic plague, 457, 459i 409
Bulbar conjunctivitis, 314i, 708i Candida albicans, 79, 83i
Bulbar polio, 479i Candida albicans esophagitis, 87i
Bullous impetigo, 561i Candida diaper dermatitis, 86i
Bunyaviridae Candida dubliniensis, 79
description of, 25 Candida glabrata, 79
hemorrhagic fevers from, 218–220, 220f Candida granulomatous lesions, 86i
clinical manifestations of, 218 Candida guilliermondii, 79
diagnostic tests for, 219 Candida krusei, 79
epidemiology of, 218–219 Candida lusitaniae, 79
etiology of, 218 Candida parapsilosis, 79

ERRNVPHGLFRVRUJ
734 INDEX

Candida tropicalis, 79, 83i Cellulitis


Candidemia from candidiasis, 79 from Arcanobacterium haemolyticum infections, 33
Candidiasis, 79–87 from Bacteroides infection, 53
amphotericin B for, 80–81 from group A streptococcal infections, 568
anidulafungin for, 81 from group B streptococcal infections, 582
caspofungin for, 81 from Haemophilus influenzae, 200
chronic, 87i from Pasteurella infections, 435
ciclopirox for, 80 periorbital, 468i, 561i
clinical manifestations of, 79 from Prevotella infection, 53
clotrimazole for, 80 from staphylococcal infections, 548
congenital, 84i, 85i from tinea capitis, 622
cutaneous, 78i Central catheter infections from nontuberculous
diagnostic tests for, 79–80 mycobacteria, 686
disseminated, 79 Central line–associated bloodstream infection from
econazole for, 80 Bacillus cereus, 49
epidemiology of, 79 Central nervous system (CNS) disease
etiology of, 79 from Baylisascaris infections, 58
fluconazole for, 80, 81–82 from herpes simplex infections, 252
incubation period of, 79 from human immunodeficiency virus infection, 276
invasive, 79–80 manifestations from rabies, 488
ketoconazole for, 80 Cephalic tetanus, 619
micafungin for, 81 Cercarial dermatitis from schistosomiasis, 529
miconazole for, 80 Cerebellar ataxia
mucocutaneous, 79, 86i, 87i from mumps, 392
naftifine for, 80 from Mycoplasma pneumoniae infections, 396
nystatin for, 80 from varicella-zoster infections, 703
oral, 79 Cerebellitis from Q fever, 485
oral nystatin suspension for, 80 Cerebral calcifications from Toxoplasma gondii infections,
treatment of, 80–82 637
vaginal, 79 Cerebral malaria, 361
Candiduria from candidiasis, 79 Cerebral neurocysticercosis, 615i
Capillaria philippinensis, 422t Cerebrospinal fluid (CSF) specimen
Carbuncles from staphylococcal infections, 548 for arboviruses, 27
Cardiac dysrhythmias from West Nile virus, 718 for Creutzfeldt-Jakob disease, 482
Cardiomyopathy from American trypanosomiasis, 660 Cerebrospinal fluid tests
Carditis for syphilis, 597, 598
from Kawasaki disease, 310 Cervical adenitis, 562i
from Lyme disease, 343 from Bacteroides infection, 53
Cataracts in congenital rubella, 514i from Prevotella infection, 53
Cat bite, Pasteurella infections in, 436i Cervical candidiasis, 79
Cat-scratch disease (Bartonella henselae), 88–92, 89i Cervical lymphadenitis, 576i, 577i
antimicrobial therapy for, 89 from nontuberculous mycobacteria, 686
azithromycin for, 89 Cervical lymphadenopathy
ciprofloxacin for, 89 from Epstein-Barr virus infections, 167
clinical manifestations of, 88, 89i from Kawasaki disease, 309
diagnostic tests for, 89 from tularemia, 693
doxycycline for, 89 Cervical lymph nodes, 625i
epidemiology of, 88 aspiration of, 577i
etiology of, 88 Cervicitis from Chlamydia trachomatis, 99
granuloma of finger of, 91i Cervicofacial infections from actinomycosis, 1
incubation period of, 89 Cesarean delivery, in reducing risk of HIV transmission,
parenteral gentamicin for, 89 278–279
rifampin for, 89 Chagas disease (American trypanosomiasis), 660–663
treatment of, 89 clinical manifestations of, 660
trimethoprim-sulfamethoxazole for, 89 diagnostic tests for, 661
Cavernous sinus thrombosis from Lemierre disease, 183 epidemiology of, 660–661
Cavitary tuberculosis, 685i etiology of, 660
Cell cultures incubation period of, 661
for adenovirus infections, 4 nifurtimox for, 661
for enterovirus infections, 161 treatment of, 661
for herpes simplex virus, 248 Chagoma from American trypanosomiasis, 660
for poliovirus infections, 477 Chancre from African trypanosomiasis, 657

ERRNVPHGLFRVRUJ
INDEX 735

Chancroid, 93–94, 94i Chlamydia trachomatis genitourinary tract infection, 99


azithromycin for, 93 doxycycline for, 101
ceftriaxone for, 93 erythromycin for, 101
clinical manifestations of, 93 levofloxacin for, 101
diagnostic tests for, 93 ofloxacin for, 101
epidemiology of, 93 Chlamydophila pneumoniae, 95, 445
etiology of, 93 antimicrobial therapy for, 95
incubation period of, 93 azithromycin for, 96
treatment of, 93 clarithromycin for, 96
ulcer, 93, 94i clinical manifestations of, 95
Chapare hemorrhagic fever, 215 diagnostic tests for, 95–96
Chemoprophylaxis doxycycline for, 96
for candidiasis, 82 epidemiology of, 95
for Pneumocystis jiroveci infections, 473 erythromycin for, 96
Chemotherapy for tuberculosis, 666 etiology of, 95
Chest pain fluoroquinolones for, 96
from Cryptococcus neoformans infections, 126 incubation period of, 95
from tularemia, 693 levofloxacin for, 96
Chest radiographs macrolides for, 96
for Chlamydophila pneumoniae, 95 moxifloxacin for, 96
for Chlamydophila psittaci, 98i tetracycline for, 96
for paragonimiasis, 414 treatment of, 96
for Q fever, 485 Chlamydophila psittaci (psittacosis), 97–98, 98i
for severe acute respiratory syndrome, 122 azithromycin for, 98
Chickenpox. See Varicella-zoster virus (VZV) infections clinical manifestations of, 97
Chikungunya viruses, 25, 26t, 28i diagnostic tests for, 97
global spread of, 30i doxycycline for, 98
Chills epidemiology of, 97
from babesiosis, 45 erythromycin for, 98
from Ehrlichia and Anaplasma infections, 154 etiology of, 97
from epidemic typhus, 700 incubation period of, 97
from hantavirus pulmonary syndrome, 207 tetracycline for, 98
from influenza, 294 treatment of, 98
from legionnaires’ disease, 319 Chloroquine-resistant Plasmodium falciparum, 362
from leptospirosis, 33 Chloroquine-resistant Plasmodium vivax, 362
from malaria, 361 Choclo virus, 207
from meningococcal infections, 378 Cholangitis from Ascaris lumbricoides infections, 35
from Pasteurella infections, 435 Cholera (Vibrio cholerae), 712–713, 713i, 714i
from plague, 457 antimicrobial therapy for, 713
from Q fever, 485 clinical manifestations of, 712
from rat-bite fever, 492 diagnostic tests for, 712–713
from severe acute respiratory syndrome, 122 epidemiology of, 712
from tuberculosis, 664 etiology of, 712
from tularemia, 693 incubation period of, 712
Chlamydial conjunctivitis, 103i parenteral rehydration for, 713
erythromycin for, 101 treatment of, 713
ethylsuccinate for, 101 Chorioamnionitis
Chlamydial pneumonia, 103i from group B streptococcal infections, 582
azithromycin for, 101 from Haemophilus influenzae, 200
erythromycin for, 101 Chorioretinitis
ethylsuccinate for, 101 from lymphocytic choriomeningitis, 359
Chlamydia pneumoniae. See Chlamydophila pneumoniae from Toxoplasma gondii infections, 637
Chlamydia trachomatis, 99–103, 102i, 104i, 190, 191–193, from West Nile virus, 718
445, 651 Chromotrope-based stain for microsporidia infections,
from bacterial vaginosis, 51 386
clinical manifestations of, 99 Chronic asymptomatic parasitemia, 361
diagnostic tests for, 100–101 Plasmodium malariae infection and, 361
epidemiology of, 99–100 Chronic cardiorespiratory disease, Mycoplasma
etiology of, 99 pneumoniae infections and, 396
incubation period of, 100 Chronic cavitary pulmonary histoplasmosis, 258
treatment of, 101 Chronic granulomatous disease, 73–74
Chronic meningococcemia from meningococcal
infections, 378

ERRNVPHGLFRVRUJ
736 INDEX

Chronic mucocutaneous candidiasis, 79–80, 87i etiology of, 116


Chronic pulmonary actinomycosis, 3i fluconazole for, 117
Chronic sinusitis incubation period of, 116
from Bacteroides infection, 53 itraconazole for, 117
from Prevotella infection, 53 pulmonary, 119i
Cirrhosis from hepatitis C virus (HCV), 238 treatment of, 117–118
Citrobacter, 169 Colitis
Citrobacter koseri, 169 from cytomegalovirus infection, 138
Clonorchis sinensis, 421t from Trichuriasis trichiura, 655
Clostridial myonecrosis (gas gangrene), 109–110 Colorado tick fever, disease caused by arboviruses in
chloramphenicol for, 109 Western hemisphere, 26t
clindamycin for, 109 Coma
clinical manifestations of, 109 from epidemic typhus, 700
diagnostic tests for, 109 from meningococcal infections, 378
epidemiology of, 109 Common cold
ertapenem for, 109 from adenovirus infections, 4
etiology of, 109 from human coronaviruses, 122
incubation period of, 109 from pertussis, 445
meropenem for, 109 Community-acquired pneumonia
metronidazole for, 109 Chlamydophila pneumoniae presenting as, 95
penicillin G for, 109 from pneumococcal infections, 464
treatment of, 109 Complement fixation assay for Chlamydophila psittaci, 97
Clostridial omphalitis, 110i Complex decongestive physiotherapy for lymphatic
Clostridium baratii, 104 filariasis, 356
Clostridium botulinum, 104–108 Computed tomography (CT) scan
antitoxin for, 105 for Fusobacterium infections, 184
clinical manifestations of, 104 for tapeworm diseases, 611
diagnostic tests for, 105 Concentration techniques for trichuriasis, 655
epidemiology of, 104 Condylomata acuminata, 407, 410i
etiology of, 104 Condyloma lata, 594, 609i
incubation period of, 105 Confusion
treatment of, 105 from amebic keratitis, 13
Clostridium butyricum, 104 from amebic meningoencephalitis, 13
Clostridium difficile, 111–113, 112i Congenital candidiasis, 84i, 85i
antimicrobial therapy for, 112 Congenital disease from American trypanosomiasis, 660
clinical manifestations of, 111 Congenital heart disease from respiratory syncytial virus,
diagnostic tests for, 111–112 494
epidemiology of, 111 Congenital hepatosplenomegaly, 644i
etiology of, 111 Congenital immunodeficiency from Cryptococcus
fidaxomicin for, 112 neoformans infections, 126
incubation period of, 111 Congenital infection from cytomegalovirus infection, 138
metronidazole for, 112 Congenital lymphocytic choriomeningitis, 359, 360i
nitazoxanide for, 112 Congenital malaria, 362
treatment of, 112 Congenital rubella syndrome (CRS), 510, 514i
vancomycin for, 112 Congenital syphilis, 594, 605i, 606i
Clostridium novyi, 109 aqueous crystalline penicillin G for, 598
Clostridium perfringens evaluation of newborn infants for, 597–598
clostridial myonecrosis caused by, 109 follow-up and management of, 598
food poisoning caused by, 49, 114–115, 115i penicillin G benzathine for, 598
Clostridium septicum, 109 penicillin G procaine for, 598
Clostridium sordellii, 109 treatment for, 598–599, 600t
Clostridium tetani, 619, 621i Congenital toxoplasmosis, 637, 640, 644i–645i
Clue cells, 52i Congenital tuberculosis, 664, 678
Clutton joints, 594 Congenital varicella syndrome, 703, 707i
from syphilis, 594 Conidia, inhalation of, in aspergillosis, 38
Coagulase-negative staphylococci, 548–550, 552 Conjunctival hemorrhage, 168i
Coccidioides immitis infection, 116, 118i–121i from non–group A or B streptococcal and
Coccidioides posadasii, 116 enterococcal infections, 588i
Coccidioidomycosis, 116–121, 119i–121i from trichinellosis, 647
amphotericin B for, 117 Conjunctival injection
clinical manifestations of, 116 from babesiosis, 45
diagnostic tests for, 116–117 from influenza, 294
epidemiology of, 116 Conjunctival (palpebral) petechiae, 588i

ERRNVPHGLFRVRUJ
INDEX 737

Conjunctival suffusion from Q fever, 485


from hemorrhagic fever, 215 from schistosomiasis, 529
from leptospirosis, 335 from severe acute respiratory syndrome, 122
Conjunctivitis, 103i, 377i from toxocariasis, 634
from acute follicular adenovirus, 4, 5i from tuberculosis, 664
acute hemorrhagic, 160 from tularemia, 693
from adenovirus infections, 4 Cowpox, 540
from Crimean-Congo hemorrhagic fever, 218 Coxiella burnetii, 485
from enterovirus infections, 160 Coxsackievirus lesions, 163i, 164i
from gonococcal infections, 190 Cranial nerve palsies
from Haemophilus influenzae, 200 from Clostridium botulinum, 104
from herpes simplex virus, 247 from Epstein-Barr virus, 165
from Kawasaki disease, 313i Creeping eruption from cutaneous larva migrans, 134
from measles, 372, 377i Crepitus from clostridial myonecrosis, 109
from meningococcal infections, 378 Creutzfeldt-Jakob disease, 484i
from pneumococcal infections, 464 classic, 481
from rubella, 510 clinical manifestations of, 481
from tularemia, 693 diagnostic tests for, 482–483
from Yersinia enterocolitica, 723 epidemiology of, 482
Constipation etiology of, 482
from Clostridium botulinum, 104 familial, 481
from Salmonella infections, 516 iatrogenic, 481
Contact dermatitis incubation period of, 482
from tinea pedis, 631 sporadic, 481
from tinea unguium, 631 treatment of, 483
Contagious tuberculosis, 665 variant, 481, 483i
Convalescent serum specimens Crimean-Congo hemorrhagic fever, 218–219, 220i
for lymphocytic choriomeningitis, 359 Cronobacter sakazakii, 161
for rickettsialpox, 500 Cross-reacting antibodies for Histoplasma capsulatum, 259
for Rocky Mountain spotted fever, 503 Croup
Corneal ulcer from Pasteurella infections, 435 from adenovirus infections, 4
Coronary aneurysms from Kawasaki disease, 309–310 fatal, 418i
Coronary artery occlusion from Kawasaki disease, 310 from human metapneumovirus, 385
Coronary artery thrombosis from Kawasaki disease, 311 from influenza, 294
Coronaviruses, 122–125, 124i, 125i from measles, 372
clinical manifestations of, 122 from parainfluenza viral infections, 416
diagnostic tests for, 123–124 Crusted scabies, 524
epidemiology of, 123 Cryotherapy for warts, 409
etiology of, 122 Cryptococcus gattii infections (cryptococcosis), 126–128,
incubation period of, 123 128i
treatment of, 124 amphotericin B deoxycholate for, 127
Corynebacterium diphtheriae, 149 clinical manifestations of, 126
Corynebacterium minutissimum, 629, 631 diagnostic tests for, 126–127
Corynebacterium ulcerans, 149 epidemiology of, 126
Coryza etiology of, 126
from measles, 372 fluconazole for, 127
from Mycoplasma pneumoniae infections, 396 flucytosine for, 127
Cotton rat, 210i incubation period of, 126
Cough itraconazole for, 127
from babesiosis, 45 treatment of, 127
from Borrelia infections, 67 Cryptococcus meningitis, 128i
from Chlamydophila pneumoniae, 95 Cryptococcus neoformans infections (cryptococcosis),
from Cryptococcus neoformans infections, 126 126–128, 128i
from hantavirus pulmonary syndrome, 207 amphotericin B for, 127
from human bocavirus, 66 clinical manifestations of, 126
from human coronaviruses, 122 diagnostic tests for, 126–127
from influenza, 294 epidemiology of, 126
from lymphatic filariasis, 355 etiology of, 126
from malaria, 361 fluconazole for, 127
from measles, 372 flucytosine for, 127
from paragonimiasis, 413 incubation period of, 126
from pertussis, 445 itraconazole for, 127
from Pneumocystis jiroveci infections, 472 treatment of, 127

ERRNVPHGLFRVRUJ
738 INDEX

Cryptosporidiosis, 129–133, 130i–133i Cysticercus cellulosae, 611


azithromycin for, 130 Cystic fibrosis pulmonary infections from Burkholderia
clinical manifestations of, 129 infections, 73–74
diagnostic tests for, 129–130 Cystoisospora belli, 306, 307i
epidemiology of, 129 Cystoisospora from HIV infection, 276
etiology of, 129 Cystoisosporiasis, 306–308, 307i
incubation period of, 129 ciprofloxacin for, 306
nitazoxanide for, 130 clinical manifestations of, 306
paromomycin for, 130 diagnostic tests for, 306
treatment of, 130 epidemiology of, 306
Cryptosporidium etiology of, 306
from HIV infection, 276 incubation period of, 306
life cycle of, 133i pyrimethamine for, 306
Cryptosporidium hominis, 129 treatment of, 306
Cryptosporidium parvum, 62, 129 trimethoprim-sulfamethoxazole for, 306
CSF pleocytosis, 359 Cytomegalovirus (CMV) infections, 138–144, 141i–144i
Ctenocephalides felis, 88 clinical manifestations of, 138
Culex tarsalis, 31i diagnostic tests for, 140
Cutaneous anthrax, 18, 21i, 22i epidemiology of, 138–140
Cutaneous blastomycosis, 65i etiology of, 138
Cutaneous candidiasis, congenital, 84i, 85i foscarnet for, 141
Cutaneous diphtheria, 149, 150 ganciclovir for, 140
Cutaneous larva migrans, 134–135, 134i, 135i from human immunodeficiency virus infection, 276
albendazole for, 134 incubation period of, 140
clinical manifestations of, 134 infant with, 141i
diagnostic tests for, 134 treatment of, 140–141
epidemiology of, 134 valganciclovir for, 140
etiology of, 134 white perivascular infiltrates in retina, 143i
treatment of, 134
Cutaneous leishmaniasis, 323, 328i, 329i D
Cutaneous nocardiosis, 403i
Cutaneous nongenital warts, 407 Dacron alginate swab for pertussis, 446
Cutaneous sporotrichosis, 547i Darkfield examination for syphilis, 595
Cutaneous warts (human papillomavirus infection), 290i, Darkfield microscopy in wet mounts for rat-bite fever, 492
407 Dasypus novemcinctus, 331
Cyanosis from Escherichia coli, 169 Dehydration
Cyanotic congenital heart disease from respiratory from Escherichia coli diarrhea, 174
syncytial virus, 494 from rotavirus infections, 508
Cyclospora cayetanensis, 136, 136i from Vibrio cholerae infections, 712
Cyclosporiasis, 136–137, 136i, 137i Delirium from epidemic typhus, 700
clinical manifestations of, 136 Deltacoronavirus, 122
diagnostic tests for, 136 Delusions from African trypanosomiasis, 657
epidemiology of, 136 Dementia from Creutzfeldt-Jakob disease, 481
etiology of, 136 Dengue, 145–148, 146i, 147i
incubation period of, 136 clinical manifestations of, 145
treatment of, 136 convalescent phase, 145
trimethoprim-sulfamethoxazole for, 136 critical phase, 145
Cyst(s) diagnostic tests for, 146
echinococcus, 618f epidemiology of, 145
from tapeworm diseases, 611, 616 etiology of, 145
Cysticercal encephalitis, 612 febrile phase, 145
Cysticercosis (tapeworm diseases), 611–615 incubation period of, 145
albendazole for, 612 treatment of, 146
anticonvulsants for, 612 Dengue fever, 145
clinical manifestations of, 611 Dengue hemorrhagic fever, 25, 26t, 145
corticosteroid therapy for, 612 Dengue shock syndrome, 145
diagnosis of, 611–612 Dental infection
epidemiology of, 611 from Bacteroides infection, 53
etiology of, 611 from Prevotella infection, 53
incubation period of, 611 Dermacentor andersoni, 503, 504i
ocular, 612 Dermacentor variabilis, 503
praziquantel for, 612 Dermal erythropoiesis from congenital rubella, 510
treatment of, 612

ERRNVPHGLFRVRUJ
INDEX 739

Dermatitis Diphtheria, 149–153, 150i–153i


atopic, 622 antimicrobial therapy for, 150
from onchocerciasis, 505 antitoxin for, 150
seborrheic, 622 clinical manifestations of, 149
from tinea corporis, 626 cutaneous, 150
Dermatophyte test diagnostic tests for, 149–150
for tinea cruris, 629 epidemiology of, 149
for tinea pedis, 631 etiology of, 149
for tinea unguium, 631 immunization for, 150
Diabetes mellitus incubation period of, 149
Burkholderia infections and, 74 penicillin G for, 150
from group B streptococcal infections, 582 pharyngeal, 150i
Diamanus montana flea, 462i treatment of, 150
Diaphoresis from clostridial myonecrosis, 109 Diphtheria pneumonia, 151i
Diarrhea Diphtheritic cervical lymphadenopathy, 150i
from anthrax, 18 Diphyllobothrium latum, 616
from astrovirus infections, 43 Dipylidium caninum, 616, 617i
from Bacillus cereus, 49, 114 Direct aspirate through endoscope for strongyloidiasis,
from Balantidium coli infection, 56 591
from Blastocystis hominis infections, 62 Direct fluorescent antibody (DFA) tests
from Campylobacter infections, 76 for pertussis, 446
from Chlamydophila psittaci, 97 for tularemia, 694
from Clostridium difficile, 111 for varicella-zoster infections, 705
from Clostridium perfringens food poisoning, 114 Direct immunofluorescence antibody test for cryptospo­
from cyclosporiasis, 136 ri­diosis, 129
from cystoisosporiasis, 306 Directly observed therapy (DOT) for tuberculosis, 665
from enterovirus infections, 160 Disseminated candidiasis, 79, 85i
from Escherichia coli, 169 Disseminated herpes simplex infection, 246
from Giardia intestinalis infections, 186 Disseminated histoplasmosis, 258
from hantavirus pulmonary syndrome, 207 Disseminated intravascular coagulation
from hookworm infections, 264 from African trypanosomiasis, 657
from human calicivirus infections, 404 from Ehrlichia and Anaplasma infections, 154
from influenza, 294 from histoplasmosis, 258
from isosporiasis, 306 from Lemierre disease, 183
from malaria, 361 from Rocky Mountain spotted fever, 502
from measles, 372 Disseminated neonatal gonococcal infections, 193, 197i
from microsporidia infections, 386 Disseminated nontuberculous mycobacterial cutaneous
from nontuberculous mycobacteria, 686 lesions, 691i
from psittacosis, 97 Disseminated sporotrichosis, 545
from Q fever, 485 Dizziness from hantavirus pulmonary syndrome, 207
from Rocky Mountain spotted fever, 502 Dobrava virus, 218
from rotavirus infections, 508 Donovan bodies, 198, 199i
from Salmonella infections, 516 Donovanosis, 198
from schistosomiasis, 529 Dot blot immunoassay for epidemic typhus, 701
from Shigella infections, 536 Double-centrifugation technique for African
from Strongyloides, 591 trypanosomiasis, 657
from tapeworm infections, 611, 616 Down syndrome, Mycoplasma pneumoniae infections
from trichinellosis, 647 and, 396
from trichuriasis, 655 Dracunculiasis, 422t, 423i
from Vibrio cholerae infections, 712 Dracunculus medinensis, 422t, 423i, 426i
from Vibrio infections, 716 Drug-resistant tuberculosis disease, therapy for, 676
from Yersinia enterocolitica, 723 Dumb paralytic rabies, 491i
from Yersinia pseudotuberculosis infection, 723 Duodenal ulcers from Helicobacter pylori infections, 214i
Diethylcarbamazine citrate (DEC) for lymphatic filariasis, Dwarf tapeworm, 616
356 Dysarthria from Creutzfeldt-Jakob disease, 481
Diffuse capillary leak syndrome from Crimean-Congo Dyshidrotic eczema
hemorrhagic fever, 218 from tinea pedis, 631
Diffuse intravascular coagulation from plague, 457 from tinea unguium, 631
Diffuse myalgia from influenza, 294 Dyspareunia from chancroid, 93
Digital clubbing from HIV infection, 288i Dysphagia from Lemierre disease, 183
Digital gangrene, 28i

ERRNVPHGLFRVRUJ
740 INDEX

Dyspnea from Chlamydophila psittaci, 97


from paragonimiasis, 413 from enterovirus infections, 160
from Pneumocystis jiroveci infections, 472 from Epstein-Barr virus, 165
from severe acute respiratory syndrome, 122 from herpes simplex virus, 247
Dysuria from human herpesvirus 6 and 7, 268
from chancroid, 93 from influenza, 294
from Schistosoma haematobium, 529 from Mycoplasma pneumoniae infections, 396
from Trichomonas vaginalis infections, 651 from parainfluenza viral infections, 416
from psittacosis, 97
E from Q fever, 485
from Rift Valley fever, 218
East African sleeping sickness, 657 from rubella, 510
Eastern equine encephalitis virus, disease caused by from toxocariasis, 634
arboviruses in Western hemisphere, 26t, 29i from Toxoplasma gondii infections, 637
Ebola virus, 221–225, 223i from varicella-zoster infections, 703
Echinococcus abscess, 618i from West Nile virus, 718
Echinococcus cyst, 618i Encephalitozoon intestinalis, 386, 387i
Echinococcus granulosus, 616–617 Encephalopathy
Echinococcus multilocularis, 616–617 from cat-scratch disease, 88
Echoviruses, 160 from Ehrlichia and Anaplasma infections, 154
Ecthyma from staphylococcal infections, 548 from human herpesvirus 6 and 7, 268
Eczema from molluscum contagiosum, 389 from influenza, 294
Eczema herpeticum from herpes simplex, 246, 254i from pertussis, 445
Edema Endemic typhus (flea-borne typhus or murine typhus),
from American trypanosomiasis, 660 698–699
from hookworm infections, 264, 267i clinical manifestations of, 698
from malaria, 371i diagnostic tests for, 698
from syphilis, 594 doxycycline for, 698
Ehrlichia (ehrlichiosis), 498 epidemiology of, 698
Ehrlichia canis ehrlichiosis, 156t etiology of, 698
Ehrlichia chaffeensis, 154–155, 159i incubation period of, 698
Ehrlichia ewingii, 154 treatment of, 698
Ehrlichia ewingii ehrlichiosis, 156t Endocardial fibroelastosis from mumps, 392
Ehrlichia infections, 154–159 Endocarditis, 38
clinical manifestations of, 154 from Arcanobacterium haemolyticum infections, 33
diagnostic tests for, 155 from Bacillus cereus, 49
doxycycline for, 155 from Bacteroides infection, 53
epidemiology of, 154–155 from brucellosis, 70
etiology of, 154 from Chlamydophila psittaci, 97
incubation period of, 155 from group A streptococcal infections, 568
treatment of, 155 from Haemophilus influenzae, 200
Ehrlichia muris, 154, 155 from non–group A or B streptococcal and
Ehrlichia muris ehrlichiosis, 156t enterococcal infections, 587
Ehrlichia phagocytophila, 158i from pneumococcal infections, 464
Ehrlichiosis, 156t from Prevotella infection, 53
Electrolyte abnormalities from rotavirus infections, 508 from psittacosis, 97
Electron micrograph for hepatitis B virus (HBV), 235i from rat-bite fever, 492
Electron microscopic examination treatment for, 575
for molluscum contagiosum, 389 from Yersinia enterocolitica, 723
for smallpox, 540 Endocervical swab for gonococcal infections, 191
Elephantiasis, 357i Endocervicitis from gonococcal infections, 190
from lymphatic filariasis, 355 Endocrinologic diseases from candidiasis, 79
Emetic syndrome from Bacillus cereus, 49 Endometritis
Empyema from Chlamydia trachomatis, 99
from actinomycosis, 1 from group B streptococcal infections, 582
from Bacteroides infection, 53 Endophthalmitis
from Lemierre disease, 183 from Bacillus cereus, 49
from Prevotella infection, 53 from Haemophilus influenzae, 200
from Yersinia enterocolitica, 723 from meningococcal infections, 378
Encephalitis from Pasteurella infections, 435
from adenovirus infections, 4 from staphylococcal infections, 549
from arboviruses, 24 from toxocariasis, 634
from astrovirus infections, 44i

ERRNVPHGLFRVRUJ
INDEX 741

Endoscopy Enterovirus (nonpoliovirus) infections, 160–164,


for amebiasis, 8 162i–164i
for candidiasis, 79 clinical manifestations of, 160
for Helicobacter pylori infections, 213 diagnostic tests for, 161
Endotracheal aspiration for Pneumocystis jiroveci epidemiology of, 161
infections, 473 etiology of, 160
Enlarged lymph nodes from paracoccidioidomycosis, 411 incubation period of, 161
Entamoeba dispar, 7 treatment of, 161
Entamoeba histolytica infections, 7–8, 9i Enzyme immunoassay (EIA) tests
Entamoeba moshkovskii, 7 for American trypanosomiasis, 661
Enteritis necroticans, 114 for Borrelia infections, 68
Enteritis (Yersinia enterocolitica and Yersinia pseudotuber­ for Clostridium difficile, 111
culosis infections), 723–725 for Crimean-Congo hemorrhagic fever, 219
aminoglycosides for, 724 for Cryptococcus neoformans infections, 127
chloramphenicol for, 724 for cryptosporidiosis, 129
clinical manifestations of, 723 for endemic typhus, 698
diagnostic tests for, 724 for epidemic typhus, 701
doxycycline for, 724 for Entamoeba histolytica, 8
epidemiology of, 723–724 for Giardia intestinalis infections, 186
etiology of, 723 for hantavirus pulmonary syndrome, 208
fluoroquinolones for, 724 for hepatitis C virus, 239
incubation period of, 724 for herpes simplex virus, 248
treatment of, 724 for human calicivirus infections, 404
trimethoprim-sulfamethoxazole for, 724 for human herpesvirus 8, 272
Enteroaggregative E coli (EAEC), 174t, 175 for Lyme disease, 345
Enterobacter, 169 for norovirus, 404
Enterobacteriaceae, 169, 170 for Rift Valley fever, 219
Enterobius vermicularis (pinworm infection), 452–454, for Sapovirus, 404
453i for syphilis, 596
albendazole for, 452 for toxocariasis, 634
clinical manifestations of, 452 Enzyme-linked immunosorbent assay (ELISA), for Lyme
diagnostic tests for, 452 disease, 345
epidemiology of, 452 Eosinophilia
etiology of, 452 from cystoisosporiasis, 306
incubation period of, 452 from hookworm infections, 264
pyrantel pamoate for, 452 from isosporiasis, 306
treatment of, 452 from lymphatic filariasis, 355
Enterococcal endocarditis, 588i from schistosomiasis, 529
Enterococcal infections, non–group A or B, 586–590 from toxocariasis, 634
ampicillin for, 587 for trichinellosis, 647
clinical manifestations of, 586 Eosinophilic enteritis from cutaneous larva migrans, 134
diagnostic tests for, 587 Eosinophilic meningoencephalitis from Baylisascaris
epidemiology of, 586 infections, 58
etiology of, 586 Epidemic keratoconjunctivitis, 4
gentamicin for, 587 Epidemic typhus (louseborne typhus), 700–702
incubation period of, 587 chloramphenicol for, 701
penicillin G for, 587 clinical manifestations of, 700
treatment of, 587 diagnostic tests for, 700–701
vancomycin for, 587 doxycycline for, 701
Enterococcus faecalis, 586, 588i epidemiology of, 700
Enterococcus faecium, 586 etiology of, 700
Enterocolitis, necrotizing, 549 incubation period of, 700
Enterocytozoon bieneusi, 386 pediculicides for, 701
Enterohemorrhagic Escherichia coli, 177i treatment of, 701
Enteroinvasive E coli (EIEC), 174t, 174–175 Epidermodysplasia verruciformis, 407
Enteropathogenic E coli (EPEC), 174, 174t Epidermolytic exotoxin, 564i
Entero-Test Epidermophyton floccosum, 626, 629, 631
for Giardia intestinalis infections, 187 Epididymitis
for strongyloidiasis, 591 acute, 193
Enterotoxigenic E coli (ETEC), 174, 174t from gonococcal infections, 190
Enteroviral exanthem, newborn with, 164i from lymphatic filariasis, 355
from Trichomonas vaginalis infections, 651

ERRNVPHGLFRVRUJ
742 INDEX

Epigastric pain from Helicobacter pylori infections, 213 Erythrasma


Epiglottis, swelling of, 204i from tinea pedis, 631
Epiglottitis from Haemophilus influenzae, 200–201 from tinea unguium, 631
Epilepsy from tapeworm diseases, 611 Erythroid hypoplasia from parvovirus B19, 430
Epitrochlear suppurative adenitis, 91i Escherichia coli diarrhea, 174–178, 177i
Epstein-Barr virus (EBV) (infectious mononucleosis), antimicrobial therapy for, 176
165–168, 167i, 168i azithromycin for, 176
amoxicillin for, 166 classification of, 174t
ampicillin for, 166 clinical manifestations of, 174–175
clinical manifestations of, 165 diagnostic tests for, 176
corticosteroid therapy for, 166 enteroaggregative, 174t, 175
diagnostic tests for, 166–167 enteroinvasive, 174–175, 174t
epidemiology of, 165–166 enteropathogenic, 174, 174t
etiology of, 166 enterotoxigenic, 174, 174t
Fusobacterium infections, 183 epidemiology of, 175
incubation period of, 166 etiology of, 175
treatment of, 166–167 incubation period of, 175
Epstein-Barr virus encephalitis, 168i Shiga toxin-producing, 174, 174t, 175
Equine tetanus antitoxin, 620 treatment of, 176
Erysipelas, 577i, 578i Escherichia coli (nondiarrheal), 169–173, 171i, 173i
treatment for, 575 aminoglycosides for, 169, 170
Erythema ampicillin for, 170
from dengue, 145 β-lactam antimicrobial agents for, 170
from tinea corporis, 626 cefotaxime for, 170
Erythema infectiosum (fifth disease, parvovirus B19), cephalosporins for, 169, 170
430–434, 432i clinical manifestations of, 169
clinical manifestations of, 430, 430t diagnostic tests for, 170
diagnostic tests for, 431 epidemiology of, 169
epidemiology of, 431 etiology of, 169
etiology of, 430 gentamicin for, 170
incubation period of, 431 incubation period of, 169
treatment of, 431 treatment of, 170
Erythema marginatum, 580i Esophageal candidiasis, 79
Erythema migrans lesions from Lyme disease, 343, 351i, Esophagitis, 38, 80
353i, 354i Ethmoid sinusitis, 561i
Erythema multiforme Euphractus sexcinctus, 331
from coccidioidomycosis, 116 Exanthem subitum from human herpesvirus 6 and 7, 268
from mycoplasma infection, 400i Exchange blood transfusions for babesiosis, 46
Erythema multiforme rash (Stevens-Johnson syndrome), Extensively drug-resistant tuberculosis, 665
400i Extracutaneous sporotrichosis, 545
Erythema nodosum, 119i, 120i, 725i Extrapulmonary paragonimiasis, 413
from Campylobacter infections, 76 Exudative pharyngitis
from cat-scratch disease, 88 from Epstein-Barr virus, 165
from coccidioidomycosis, 116 from Lassa fever, 215
from histoplasmosis, 258 Extrapulmonary tuberculosis, 676
from Yersinia enterocolitica, 723 Exudative stomatitis from tularemia, 693
from Yersinia pseudotuberculosis infection, 723
Erythema nodosum leprosum, 330, 333i F
Erythematous lips, with Kawasaki disease, 314i
Erythematous maculopapular rash Facial erysipelas from group A streptococcal infection,
from coccidioidomycosis, 116 578i
from measles, 372 Facial erythema from dengue, 145
Erythematous papules, 528i Failure to thrive from HIV infection, 276
Erythematous papulovesicular eruptions from Fasciola hepatica, 423i, 425i
rickettsialpox, 500 Fasciolopsiasis, 422t
Erythematous rash Fasciolopsis buski, 422t
from Kawasaki disease, 309 Fatal familial insomnia, 481
from Listeria monocytogenes infections, 339 Fatigue
Erythematous vesicular eruptions from babesiosis, 45
from tinea pedis, 631 from cryptosporidiosis, 129
from tinea unguium, 631 from cyclosporiasis, 136
from histoplasmosis, 258
from nontuberculous mycobacteria, 686
from West Nile virus, 718

ERRNVPHGLFRVRUJ
INDEX 743

Favus (tinea favosa), 622 from Pneumocystis jiroveci infections, 472


Febrile occult bacteremia from meningococcal infections, from poliovirus infections, 476
378 from psittacosis, 97
Febrile seizures from Q fever, 485
from human herpesvirus 6 and 7, 268 from rat-bite fever, 492
from influenza, 294 from rickettsialpox, 498
Fecal cultures from Rift Valley fever, 218
for Campylobacter infections, 76 from Rocky Mountain spotted fever, 502
for Vibrio cholerae infections, 712 from rotavirus infections, 508
Fecal leukocytes (shigellosis), 538i from Salmonella infections, 516
Felis rufus, 463i from schistosomiasis, 529
Fever from severe acute respiratory syndrome, 122
from African trypanosomiasis, 657 from Shigella infections, 535
from amebic keratitis, 13 from smallpox, 539
from amebic meningoencephalitis, 13 from toxocariasis, 634
from anthrax, 18 from Toxoplasma gondii infections, 637
from Arcanobacterium haemolyticum infections, 33 from trichinellosis, 647
from astrovirus infections, 43 from tuberculosis, 664
from Borrelia infections, 67 from tularemia, 693
from brucellosis, 70 from varicella-zoster infections, 703
from Campylobacter infections, 76 from Yersinia enterocolitica, 723
from cat-scratch disease, 88 from Yersinia pseudotuberculosis infection, 723
from Chlamydophila psittaci, 97 Fifth disease (parvovirus B19, erythema infectiosum),
from clostridial myonecrosis, 109 430–434
from Clostridium difficile, 111 clinical manifestations of, 430
from Clostridium perfringens food poisoning, 114 diagnostic tests for, 431
from Crimean-Congo hemorrhagic fever, 218 epidemiology of, 431
from cryptosporidiosis, 129 etiology of, 430
from cyclosporiasis, 136 incubation period of, 431
from cystoisosporiasis, 306 treatment of, 431
from dengue, 145 Filarial nematodes, 355
from endemic typhus, 698 Filariasis
from epidemic typhus, 700 bancroftian, 355–358
from Epstein-Barr virus, 165 Malayan, 355–358
from Escherichia coli, 169, 174 onchocerciasis, 405–406
from group A streptococcal infections, 568 Timorian, 355–358
from hantavirus pulmonary syndrome, 207 Filiform warts, 407
from hemorrhagic fever, 215 Filoviridae, 221
from hemorrhagic fever with renal syndrome, 218 Fish tapeworm, 616
from hepatitis A, 226 Fistulas from paracoccidioidomycosis, 411
from hepatitis E, 244 Fitz-Hugh–Curtis syndrome from gonococcal infections,
from histoplasmosis, 258 190
from human bocavirus, 66 Fixed cutaneous sporotrichosis, 545
from human herpesvirus 6 and 7, 268 Flaccid paralysis from arboviruses, 25
from influenza, 294 Flatulence
from isosporiasis, 306 from Blastocystis hominis infections, 62
from Kawasaki disease, 309 from cyclosporiasis, 136
from leishmaniasis, 323 from Giardia intestinalis infections, 186
from Lemierre disease, 183 Flat warts, 407
from leptospirosis, 335 Flaviviridae, 25
from Lyme disease, 343 Flavivirus, 145
from lymphatic filariasis, 355 Flea-borne typhus (endemic typhus, murine typhus),
from lymphocytic choriomeningitis, 359 698–699
from malaria, 361 clinical manifestations of, 698
from measles, 372 diagnostic tests for, 698
from meningococcal infections, 378 doxycycline for, 698
from Mycoplasma pneumoniae infections, 396 epidemiology of, 698
from nontuberculous mycobacteria, 686 etiology of, 698
from paracoccidioidomycosis, 411 incubation period of, 698
from parvovirus B19, 430 treatment of, 698
from Pasteurella infections, 435 Flukes, 529
from pertussis, 445 Fluorescein-conjugated monoclonal antibody stain for
from plague, 457 Pneumocystis jiroveci infections, 473

ERRNVPHGLFRVRUJ
744 INDEX

Fluorescent antibody test G


for herpes simplex virus, 248
Gagging from pertussis, 445
for plague, 457
Gag reflex from Clostridium botulinum, 104
Fluorescent staining for tuberculosis, 667
Gait disturbance from tapeworm diseases, 611
Fluorescent treponemal antibody absorption (FTA-ABS)
Gallbladder hydrops from Kawasaki disease, 309
for syphilis, 596
Gammacoronavirus, 122
Folliculitis, tinea capitis and, 622
Gardnerella vaginalis, in bacterial vaginosis, 51
Foodborne botulism, 104
Gas gangrene (clostridial myonecrosis), 109–110
Foodborne illness from Bacillus cereus, 49
clindamycin for, 109
Food poisoning
clinical manifestations of, 109
from Clostridium perfringens, 114–115, 115i
diagnostic tests for, 109
from staphylococcal infections, 548
epidemiology of, 109
Francisella tularensis, 693, 694i
etiology of, 109
Frontal bossing from syphilis, 594
incubation period of, 109
Fulguration for lymphatic filariasis, 356
meropenem for, 109
Fulminant colitis from amebiasis, 7
metronidazole for, 109
Fulminant hepatitis, 226, 230
penicillin G for, 109
Fungal diseases, 179–182, 179t–180t
treatment of, 109
Alternaria species, 179t
Gasping from pertussis, 445
Bipolaris species, 179t
Gastric aspirate specimen for tuberculosis, 667
Curvularia species, 180t
Gastric biopsy for Helicobacter pylori infections, 213
Exophiala species, 180t
Gastric cancer from Helicobacter pylori infections, 213
Exserohilum species, 180t
Gastric ulcers from Helicobacter pylori infections, 213
Fusarium species, 179t
Gastritis from Helicobacter pylori infections, 213
Lichtheimia species, 180t
Gastroenteritis
Malassezia species, 179t
from adenovirus infections, 4
Mucor species, 180t
from astrovirus infections, 43, 44i
Penicillium marneffei, 179t
from Salmonella infections, 516
Pseudallescheria boydii, 180t
from Vibrio infections, 712
Rhizomucor species, 180t
Gastrointestinal tract bleeding from histoplasmosis, 258
Rhizopus species, 180t
Gastrointestinal tract disease from anthrax, 18
Scedosporium species, 180t
Gastrointestinal tract symptoms
Trichosporon species, 180t
from Listeria monocytogenes infections, 339
Fungal culture for tinea pedis and tinea unguium, 631
from plague, 457
Fungal infection from tinea capitis, 622
Gene amplification for hepatitis B virus (HBV), 232
Fungal stain for sporotrichosis, 545
Generalized tetanus, 619
Funiculitis from lymphatic filariasis, 355
Genital herpes from herpes simplex virus (HSV), 246,
Furuncles from staphylococcal infections, 548
247–248, 251, 251t
Fusobacterium gonidiaformans, 183
Genitourinary tract manifestations from Chlamydia
Fusobacterium infections (Lemierre disease), 183–185,
trachomatis, 99
184i, 185i
Genital ulcer from chancroid, 93
carbapenem for, 184
Genotyping
cefoxitin for, 184
for measles, 373
ceftriaxone for, 184
for staphylococcal infections, 553
chloramphenicol for, 184
Geophagia/pica from Baylisascaris infections, 58
clindamycin for, 184
Gerstmann-Sträussler-Scheinker disease, 481
clinical manifestations of, 183
Gianotti-Crosti syndrome from hepatitis B, 230
diagnostic tests for, 183–184
Giardia duodenalis. See Giardia intestinalis infections
epidemiology of, 183
Giardia intestinalis infections, 62, 186–189, 187i–189i
etiology of, 183
clinical manifestations of, 186
metronidazole for, 184
diagnostic tests for, 186–187
treatment of, 184
epidemiology of, 186
Fusobacterium mortiferum, 183
etiology of, 186
Fusobacterium naviforme, 183
incubation period of, 186
Fusobacterium necrophorum, 183
metronidazole for, 187
Fusobacterium necrophorum subsp funduliforme, 183
nitazoxanide for, 187
Fusobacterium nucleatum, 183, 184i
quinacrine for, 187
Fusobacterium varium, 183
tinidazole for, 187
treatment of, 187
Giardia lamblia. See Giardia intestinalis infections
Giardiasis, 186–189

ERRNVPHGLFRVRUJ
INDEX 745

Giemsa-stained smear Granuloma inguinale, 198–199


for African trypanosomiasis, 657 antimicrobial therapy for, 198
for American trypanosomiasis, 661 azithromycin for, 198
for molluscum contagiosum, 389 ciprofloxacin for, 198
for Plasmodium malariae, 364i clinical manifestations of, 198
for Plasmodium ovale, 364i diagnostic tests for, 198
for Plasmodium vivax, 364i doxycycline for, 198
in Yersinia pestis, 459i epidemiology of, 198
Gingivitis from Fusobacterium infections, 183 erythromycin for, 198
Gingivostomatitis, 246 etiology of, 198
from herpes simplex virus, 246, 248 gentamicin for, 198
Glanders from Burkholderia mallei, 73 Giemsa-stained Donovan bodies of, 199i
Glandular fever, 156t incubation period of, 198
Glandular syndrome from tularemia, 693 perianal lesion, 199i
Glomerulonephritis treatment of, 198
from mumps, 392 trimethoprim-sulfamethoxazole for, 198
from varicella-zoster infections, 703 Granulomata from cat-scratch disease, 88
Gonococcal cervicitis, 193i Granulomatosis infantisepticum from Listeria monocyto­
Gonococcal conjunctivitis, 190, 196i genes infections, 339
Gonococcemia, 197i Granulomatous amebic encephalitis, 13
Gonococcal infections, 190–197 Granulomatous inflammation of lymph nodes from
antimicrobial therapy for, 192 tuberculosis, 664
azithromycin for, 192 Gray patch tinea capitis, 622
cefixime for, 192 Gross hematuria from Schistosoma haematobium, 529
cefotaxime for, 193 Group A coxsackieviruses, 160–161
ceftriaxone for, 192–193 Group A streptococcal arthritis, 578i
cephalosporins for, 192–193 Group A streptococcal cellulitis, 578i
clinical manifestations of, 190 Group A streptococcal infections, 568–581
diagnostic tests for, 191–192 from bacterial vaginosis, 51
doxycycline for, 192 cephalosporins for, 572
epidemiology of, 190 clinical manifestations of, 568
etiology of, 190 diagnostic tests for, 570–572
fluoroquinolones for, 192 epidemiology of, 569–570
incubation period of, 190 erythromycin for, 573
treatment of, 192–193 etiology of, 568–569
Gonococcal ophthalmia, 193, 195i, 196i incubation period of, 570
Gonococcal pharyngitis, 197i indications for testing, 571–572
Gonococcal urethritis from gonococcal infections, 190, penicillin G benzathine for, 573
196i penicillin V for, 572
Gonococcal vulvovaginitis, 196i sulfonamide for, 573
Gonorrhea from gonococcal infections, 190 tetracycline for, 573
Gordonia bronchialis, 401 treatment of, 572–575
Gram-negative bacilli, 169–173, 516 Group A streptococcal necrotizing fasciitis, 578i
clinical manifestations of, 169 Group A streptococcal pharyngitis, 576i
diagnostic tests for, 170 Group A streptococcus from influenza, 294
epidemiology of, 169 Group B coxsackieviruses, 160
etiology of, 169 Group B streptococcal infections, 582–585
incubation period of, 169 ampicillin for, 583
treatment of, 170 clinical manifestations of, 582
Gram stain diagnostic tests for, 583
for actinomycosis, 1 epidemiology of, 582–583
for anthrax, 19 etiology of, 582
for clostridial myonecrosis, 109 incubation period of, 583
for gonococcal infections, 191 penicillin G for, 583
for Haemophilus influenzae infections, 201 treatment of, 583
for Listeria monocytogenes infections, 340 Group B streptococcal meningitis, 584i
for meningococcal infections, 379 Group B streptococcal osteomyelitis, 584i
for microsporidia infections, 386 Group B streptococcal pneumonia, 584i
for plague, 457 Growth delay from tuberculosis, 664
for staphylococcal infections, 552 Growth retardation
of vaginal secretions in bacterial vaginosis, 51 from congenital rubella, 510
from trichuriasis, 655

ERRNVPHGLFRVRUJ
746 INDEX

Grunting respirations from Escherichia coli, 169 from Crimean-Congo hemorrhagic fever, 218
Guaiac-positive stools from Helicobacter pylori infections, from dengue, 145
213 from Ehrlichia and Anaplasma infections, 154
Guillain-Barré syndrome from endemic typhus, 698
as complication of viral Campylobacter infections, 76 from epidemic typhus, 700
from West Nile virus, 718 from hantavirus pulmonary syndrome, 207
from hemorrhagic fever, 215
H from influenza, 294
from Lemierre disease, 183
Haemophilus ducreyi, 93, 94i, 198 from leptospirosis, 335
Haemophilus influenzae infections, 169, 200–206, from Lyme disease, 343
201i–206i, 467 from lymphatic filariasis, 355
amoxicillin-clavulanate for, 201 from malaria, 361
amoxicillin for, 201 from Mycoplasma pneumoniae infections, 396
ampicillin for, 201 from parvovirus B19, 430
antimicrobial therapy for, 201 from plague, 457
cefdinir for, 201 from Q fever, 485
cefotaxime for, 201 from rat-bite fever, 492
cefpodoxime for, 201 from rickettsialpox, 500
ceftriaxone for, 201 from Rocky Mountain spotted fever, 502
cefuroxime for, 201 from Salmonella infections, 516
cephalosporin for, 201 from severe acute respiratory syndrome, 122
clinical manifestations of, 200 from smallpox, 539
dexamethasone for, 201 from tularemia, 693
diagnostic tests for, 201 from West Nile virus, 718
epidemiology of, 200 Head lice (pediculosis capitis), 437–440
etiology of, 200 clinical manifestations of, 437
incubation period of, 201 diagnostic tests for, 437
treatment of, 201 epidemiology of, 437
type a (Hia), 200 etiology of, 437
type b (Hib), 200, 203i incubation period of, 437
Haemophilus influenzae meningitis, 201, 206i oral ivermectin for, 438
Haemophilus influenzae type b (Hib), 200, 203i pediculicides for, 437
cellulitis, 203i, 204i permethrin for, 438
epiglottitis, 204i treatment of, 437–438
meningitis, 205i, 206i Health care–associated infections from Burkholderia
pneumonia, 204i, 205i infections, 73
sepsis, 205i Hearing impairment from mumps, 392
Hair loss from tinea capitis, 622 Heart failure from American trypanosomiasis, 660
Hallucinations from African trypanosomiasis, 657 Heart rate abnormalities from Escherichia coli, 169
Hansen disease. See Leprosy Helicobacter pylori infections, 213–214
Hantaan virus, 218 amoxicillin for, 214
Hantaviruses, 218 bismuth subcitrate potassium for, 214
Hantavirus pulmonary syndrome, 207–212, 208i–211i, bismuth subsalicylate for, 214
218 clarithromycin for, 214
clinical manifestations of, 207 clinical manifestations of, 213
diagnostic tests for, 208 diagnostic tests for, 213
epidemiology of, 207–208 epidemiology of, 213
etiology of, 207 etiology of, 213
incubation period of, 208 incubation period of, 213
ribavirin for, 208 metronidazole for, 214
treatment of, 208 omeprazole for, 214
Haverhill fever, 492 proton pump inhibitor for, 214
HBeAg for hepatitis B virus (HBV), 230 tetracycline for, 214
HBsAg for hepatitis B virus (HBV), 230, 234t treatment of, 213–214
Headaches Hematemesis
from African trypanosomiasis, 657 from anthrax, 18
from amebic keratitis, 13 from Helicobacter pylori infections, 213
from amebic meningoencephalitis, 13 Hemolytic anemia
from arboviruses, 24 from Epstein-Barr virus, 165, 166
from babesiosis, 45 from syphilis, 594
from brucellosis, 70

ERRNVPHGLFRVRUJ
INDEX 747

Hemolytic uremic syndrome, 174–178, 178i from dengue, 145


clinical manifestations of, 174–175 from enterovirus infections, 160
diagnostic tests for, 176 fulminant, 226, 230
epidemiology of, 175 from human herpesvirus 6 and 7, 268
from Escherichia coli diarrhea, 174 from human immunodeficiency virus infection, 276
etiology of, 175 from psittacosis, 97
incubation period of, 175 from Q fever, 485
from Q fever, 485 from varicella-zoster infections, 703
reported cases of postdiarrheal, 178i from West Nile virus, 718
from Shigella infections, 535 Hepatitis A, 226–229
treatment of, 176 acute, 229i
Hemophagocytic syndrome from Epstein-Barr virus, 165 clinical manifestations of, 226
Hemophagocytosis from Q fever, 485 diagnostic tests for, 227
Hemoptysis from paragonimiasis, 413 epidemiology of, 226
Hemorrhage etiology of, 226–227
from dengue, 145 incubation period of, 227
from parvovirus B19, 430 treatment of, 227
Hemorrhagic colitis from Escherichia coli diarrhea, 174 Hepatitis B, 230–237
Hemorrhagic cystitis from adenovirus infections, 4 acute infection, 230
Hemorrhagic fever(s) adefovir for, 233
acute, from arboviruses, 25 antiviral therapy for, 233
from arenaviruses, 215–217, 217i chronic infection, 230
clinical manifestations of, 215 clinical manifestations of, 230–231
diagnostic tests for, 216 diagnostic tests for, 232–233
epidemiology of, 215–216 entecavir for,
etiology of, 215 epidemiology of, 231–232
incubation period of, 216 etiology of, 231
treatment of, 216 hepatitis D and, 242
Argentine, 215 incubation period of, 232
Bolivian, 215 interferon-alfa for, 233
Brazilian, 215 lamivudine for, 233
from Bunyaviridae family viruses, 218–220, 220f resolved hepatitis B, 231
clinical manifestations of, 218 telbivudine for, 233
diagnostic tests for, 219 tenofovir for, 233
epidemiology of, 218–219 treatment of, 233–234
etiology of, 218 Hepatitis C, 238–241
incubation period of, 219 clinical manifestations of, 238
treatment of, 219 diagnostic tests for, 239
Chapare, 215 epidemiology of, 238–239
Crimean-Congo, 218–219, 220i etiology of, 238
from filoviruses, 221–225 incubation period of, 239
clinical manifestations of, 221 peginterferon-ribavirin for, 239
diagnostic tests for, 222 treatment of, 239–240
epidemiology of, 221–222 Hepatitis D, 242–243
etiology of, 221 clinical manifestations of, 242
incubation period of, 222 diagnostic tests for, 242
treatment of, 222 epidemiology of, 242
Lassa, 215 etiology of, 242
Lujo, 215 incubation period of, 242
with renal syndrome (HFRS), 218 pegylated interferon-alpha for, 242
Rift Valley fever, 218, 220i treatment of, 242–243
Venezuelan, 215 Hepatitis E, 244–245, 245i
Hemorrhagic necrosis from Clostridium perfringens food clinical manifestations of, 244
poisoning, 115i diagnostic tests for, 244
Hemorrhagic retinitis with Roth spots, 589i epidemiology of, 244
Hemorrhagic varicella, 703, 709i etiology of, 244
Hepatic abscess from Pasteurella infections, 435 incubation period of, 244
Hepatitis treatment of, 244
from African trypanosomiasis, 657 Hepatomegaly
from Chlamydophila psittaci, 97 from human immunodeficiency virus infection, 276
from Crimean-Congo hemorrhagic fever, 218 from toxocariasis, 634

ERRNVPHGLFRVRUJ
748 INDEX

Hepatosplenomegaly Histoplasma capsulatum, 258, 260i


from American trypanosomiasis, 660 Histoplasma capsulatum var capsulatum, 258
from babesiosis, 45 Histoplasma capsulatum var duboisii, 258
from Borrelia infections, 67 Histoplasmosis, 258–263
from brucellosis, 70 acute primary, 258
from congenital rubella, 510 acute pulmonary, 258
from cytomegalovirus infection, 138 amphotericin B for, 259
from Epstein-Barr virus, 165 antifungal therapy for, 259
from histoplasmosis, 258 clinical manifestations of, 258
from malaria, 361 diagnostic tests for, 259
from schistosomiasis, 529 epidemiology of, 258
from syphilis, 594 etiology of, 258
from Toxoplasma gondii infections, 637 incubation period of, 259
Hepevirus, 244 itraconazole for, 259
Herpangina (coxsackievirus) from enterovirus infections, pulmonary, 258–259
160, 164i snowstorm of acute, 262i
Herpes gladiatorum, 247 treatment of, 259–260
Herpes labialis from herpes simplex, 246 HIV. See Human immunodeficiency virus (HIV) infection
Herpes simplex encephalitis (HSE), 247, 256i Hoarseness from hookworm infections, 264
Herpes simplex esophagitis, 257i Hookworm infections, 264–267, 265i–267i
Herpes simplex infections, 246–257 albendazole for, 264
acyclovir for, 250–251 clinical manifestations of, 264
adolescent, 246 diagnostic tests for, 264
children beyond neonatal period, 248 epidemiology of, 264
clinical manifestations of, 246–247 etiology of, 264
corticosteroid therapy for, 252 incubation period of, 264
diagnostic tests for, 248–249 mebendazole for, 264
epidemiology of, 247–248 pyrantel pamoate for, 264
etiology of, 247 treatment of, 264
famciclovir for, 250, 251 Hordeola from staphylococcal infections, 548
from HIV infection, 289i HPV DNA testing, 408
genital, 246, 251 HPV RNA testing for human papillomaviruses, 408
incubation period of, 248 Human bocavirus, 66
mucocutaneous, 252 clinical manifestations of, 66
neonatal, 246, 247, 248, 250 diagnostic tests for, 66
postneonatal, 246, 248, 256i epidemiology of, 66
recurrent, 251, 254i etiology of, 66
treatment of, 250–252, 250t treatment of, 66
valacyclovir for, 250–251 Human calicivirus infections, 404
Herpes simplex lesions, 253i–257i clinical manifestations of, 404
neonatal, 255i diagnostic tests for, 404
Herpes simplex stomatitis, 253i epidemiology of, 404
Herpes simplex virus (HSV) etiology of, 404
acyclovir-resistant strains of, 250 incubation period of, 404
from bacterial vaginosis, 51 rehydration solutions for, 404
chancroid and, 93 treatment of, 404
trifluridine for, 251 Human coronaviruses, 122–125, 124i, 125i
valacyclovir for, 250–251 clinical manifestations of, 122
Herpes simplex virus (HSV) conjunctivitis, 247 diagnostic tests for, 123–124
Herpes simplex virus (HSV) encephalitis, 247 epidemiology of, 123
Herpes zoster (shingles), 289i etiology of, 122
Herpes zoster virus (HZV) infection, 710i incubation period of, 123
Herpetic whitlow from herpes simplex, 247, 255i, 257i treatment of, 124
Heterophil antibody tests for Epstein-Barr virus, 166 Human feces as cause of Escherichia coli diarrhea, 175
Heterophyes heterophyes, 427i Human granulocytic anaplasmosis, 156t
Hilar adenopathy, 684i Lyme disease and, 343
from tularemia, 693 Human herpesvirus 4. See Epstein-Barr virus (EBV)
Hirschsprung disease from Clostridium difficile, 111 Human herpesvirus 6 and 7, 268–270
Histologic examination for herpes simplex virus (HSV), clinical manifestations of, 268, 274–275, 276t
248 diagnostic tests for, 269
Histopathologic examination epidemiology of, 268–269
for leprosy, 330 etiology of, 268
for sporotrichosis, 545 incubation period of, 269

ERRNVPHGLFRVRUJ
INDEX 749

rash of human, 270i Hymenolepis nana from hydatid disease, 616, 617i
treatment of, 269 Hyperbaric oxygen for clostridial myonecrosis, 109
Human herpesvirus 8, 271–272 Hyperesthesia from babesiosis, 45
clinical manifestations of, 271 Hypergammaglobulinemia
diagnostic tests for, 271–272 from leishmaniasis, 323
epidemiology of, 271 from toxocariasis, 634
etiology of, 271 Hyperkeratosis, 407
famciclovir for, 272 Hypersplenism from malaria, 361
ganciclovir for, 272 Hyphae, 630i
incubation period of, 271 Hypoalbuminemia from leishmaniasis, 323
treatment of, 272 Hypochromic microcytic anemia from hookworm
valacyclovir for, 272 infections, 264
Human immunodeficiency virus (HIV) infection, Hypoesthesia from leprosy, 330
273–293, 285i–293i Hypoglycemia
antiretroviral therapy for, 276 from malaria, 361
from candidiasis, 79 from Vibrio cholerae infections, 712
cART, initiation of, 283 Hypokalemia from Vibrio cholerae infections, 712
case definition of AIDS-defining conditions, 273 Hypoproteinemia from hookworm infections, 264
chancroid and, 93 Hypotension
clinical manifestations of, 273, 277 from clostridial myonecrosis, 109
diagnostic tests for, 277t, 280–282, 286i–287i from hemorrhagic fever with renal syndrome, 218
epidemiology of, 278–280 Hypotonia from Clostridium botulinum, 104
etiology of, 277–278 Hypovolemic shock
immunization for, 284–285 from dengue, 145
immunoglobulin therapy, 284 from Vibrio cholerae infections, 712
incubation period of, 280 Hypoxemia from severe acute respiratory syndrome, 122
treatment of, 282–285
trimethoprim-sulfamethoxazole for, 284 I
tuberculosis disease and, 670, 677
type 1 and 2, 273, 285i IgG agglutinins for brucellosis, 71
Human metapneumovirus, 385 IgG antibody assays
antimicrobial agents for, 385 for Chlamydophila pneumoniae, 95
clinical manifestations of, 385 for Crimean-Congo hemorrhagic fever, 219
diagnostic tests for, 385 for hemorrhagic fever with renal syndrome, 216
epidemiology of, 385 IgG anti-DENV titer test for dengue, 146
etiology of, 385 IgG avidity test for Toxoplasma gondii, 639
incubation period of, 385 IgG immunoblot assays for Lyme disease, 345
treatment of, 385 IgM antibody testing
Human monocytic ehrlichiosis, 156t, 154, 157i, 158i, 159i for arboviral infections, 27
Human papillomaviruses, 407–410 for Chlamydophila pneumoniae, 95
clinical manifestations of, 407 for Crimean-Congo hemorrhagic fever, 219
diagnostic tests for, 408 for dengue, 146
epidemiology of, 408 for hemorrhagic fever, 219
etiology of, 408 for hemorrhagic fever with renal syndrome, 219
incubation period of, 408 for measles, 373
treatment of, 409 for Rift Valley fever, 219
Human plague, 457 IgM hepatitis B core antibody for hepatitis D, 242
Human plague pneumonia, 461i IgM immunoblot assays
Human tetanus immune globulin (TIG), 619 for Lyme disease, 345
Hutchinson teeth, 594, 608i IgM test for Toxoplasma gondii, 639
Hutchinson triad, 594 Ileocecal mesenteric adenitis from Yersinia pseudotuber­
Hyalohyphomycosis (fungal disease), 179t culosis infection, 723
Hybridization assays for hepatitis B virus (HBV), 232 Immune chromatography for cryptosporidiosis, 129
Hydatid disease (other tapeworm infections), 616–617 Immunizations. See Vaccines
albendazole for, 617 Immunoassay for adenovirus infections, 4
alveolar form of, 617 Immunodeficiencies, Mycoplasma pneumoniae infections
nitazoxanide for, 616 and, 396
praziquantel for, 616 Immunodeficiency disease from respiratory syncytial
Hydrocele from lymphatic filariasis, 355 virus, 494
Hydrocephalus Immunodiffusion test
from lymphocytic choriomeningitis, 359 for histoplasmosis, 259
from Toxoplasma gondii infections, 637 for paracoccidioidomycosis, 411

ERRNVPHGLFRVRUJ
750 INDEX

Immunofluorescent assays oseltamivir for, 297


for cytomegalovirus infection, 140 pandemics, 296
for human herpesvirus 8, 272 rimantadine for, 297
for human metapneumovirus, 385 treatment of, 297–298
for Legionella pneumophila infections, 319 types A, B and C, 294–295
for parainfluenza virus infections, 517 zanamivir for, 297, 298
for Q fever, 485 Influenza pneumonia, 303i
Immunohistochemical assay Inguinal lymph nodes enlarged, from filariasis, 357i
for epidemic typhus, 698 Inguinal plague buboes, 459i
for Q fever, 485 Inhalational anthrax, 18–19, 22i, 23i
Immunohistochemical examination of brain for rabies, Injection anthrax, 18
488 Interferon-gamma release assay (IGRA) for tuberculosis,
Immunohistochemical techniques for leptospirosis, 336 664
Immunohistochemical visualization for epidemic typhus, blood-based testing, 668–669
700 Internal jugular vein septic thrombophlebitis from
Immunologic disorders from candidiasis, 79 Lemierre disease, 183
Impetigo Interstitial keratitis, 594, 608i
from staphylococcal infections, 548 Interstitial pneumonitis from congenital rubella, 510
streptococcal, 570 Intestinal botulism, 104
Incision and drainage, in treating cat-scratch disease, 89 Intestinal capillariasis, 422t
Incomplete Kawasaki disease, 309 Intestinal perforation from Shigella infections, 535
Incontinence from pertussis, 445 Intestinal roundworms, 35
Indirect fluorescent antibody tests Intestinal tularemia, 693
for endemic typhus, 698 Intra-abdominal abscesses from non–group A or B
for epidemic typhus, 700 streptococcal and enterococcal infections, 586
Indirect hemagglutination assays Intracellular gram-negative diplococci, 191, 193i
for Burkholderia infections, 74 Intracerebral calcification from cytomegalovirus
Indirect immunofluorescent antibody (IFA) assays infection, 138
for American trypanosomiasis, 661 Intracranial calcifications from lymphocytic
for cat-scratch disease, 89 choriomeningitis, 359
for Ehrlichia and Anaplasma infections, 155 Intracytoplasmic Donovan bodies on Wright or Giemsa
for Lyme disease, 345 staining, dark staining of, for granuloma
for rickettsialpox, 498 inguinale, 198
for Rocky Mountain spotted fever, 500 Intramuscular ceftriaxone for otitis media, 467
Infant botulism, 104, 107i Intrauterine blood transfusions for parvovirus B19, 431
antitoxin for, 105 Intrauterine growth retardation from cytomegalovirus
from Clostridium botulinum, 104 infection, 138
Infectious mononucleosis (Epstein-Barr virus), 165–168, Intravenous fluids for Ascaris lumbricoides infections, 35
167i, 168i Invasive aspergillosis, 38
amoxicillin for, 166 Invasive candidiasis, 79–82
ampicillin for, 166 Invasive extraintestinal amebiasis, 12i
clinical manifestations of, 165 In vitro susceptibility and nonsusceptibility, definition
corticosteroid therapy for, 166 of, 466t
diagnostic tests for, 166–167 Iododeoxyuridine for herpes simplex virus (HSV), 252
epidemiology of, 165–166 Ipsilateral inguinal lymph nodes, 94i
etiology of, 166 Iridocyclitis from Borrelia infections, 67
Fusobacterium infections, 183 Iron lung, 478i
incubation period of, 166 Irritability
treatment of, 166–167 from Escherichia coli, 169
Inflammatory bowel disease from group A streptococcal infections, 568
from Clostridium difficile, 111 from respiratory syncytial virus, 494
from trichuriasis, 655 Isoniazid for tuberculosis, 671, 673, 674
Influenza, 294–305, 299i Isospora belli. See Cystoisospora belli
acetaminophen for, 298 Isosporiasis, 306–308, 307i
adamantanes for, 297 ciprofloxacin for, 306
amantadine for, 297 clinical manifestations of, 306
antiviral therapy for, 297t, 297–298 diagnostic tests for, 306
clinical manifestations of, 294 epidemiology of, 306
diagnostic tests for, 296–297 etiology of, 306
epidemiology of, 295–296 incubation period of, 306
etiology of, 294–295 pyrimethamine for, 306
incubation period of, 296 treatment of, 306
neuraminidase inhibitors for, 297 trimethoprim-sulfamethoxazole for, 306

ERRNVPHGLFRVRUJ
INDEX 751

Itching Kawasaki disease (mucocutaneous lymph node


from pediculosis capitis, 437 syndrome), 309–316, 723
from pediculosis corporis, 441 aspirin therapy for, 311
from scabies, 524 clinical manifestations of, 309–310
Ixodes pacificus, 155, 344 conjunctivitis and, 313i
Ixodes persulcatus, 344 desquamation of hands with, 313i
Ixodes ricinus, 344 diagnostic tests for, 311
Ixodes scapularis, 45, 155, 344 epidemiology of, 310–311
erythroderma of, 313i, 315i, 316i
J etiology of, 310
IVIG therapy for, 311
Japanese encephalitis virus, 32i incomplete, 309, 312i
disease caused by arboviruses in Western hemisphere, incubation period of, 311
26t treatment of, 311
Jarisch-Herxheimer reaction Keratitis
in Borrelia infections, 68 amebic, 13–17
in leptospirosis, 336 clinical manifestations of, 13
Jaundice diagnostic tests for, 14
from Borrelia infections, 67 epidemiology of, 13–14
from cytomegalovirus infection, 138 etiology of, 13
from Escherichia coli, 169 incubation period of, 14
from hepatitis A, 226 treatment of, 14
from hepatitis B, 230 from Bacillus cereus, 49
from hepatitis C virus, 238 from herpes simplex, 247
from hepatitis E, 244 interstitial, 594
from malaria, 361 Keratoconjunctivitis, epidemic, 4
from Toxoplasma gondii infections, 637 Keratomycosis, 80
Jock itch (tinea cruris), 629–630 Kerion, 622
butenafine for, 629 corticosteroid therapy for, 623
ciclopirox for, 629 griseofulvin for, 623
clinical manifestations of, 629 from tinea capitis, 622–623, 625i
clotrimazole for, 629 Kidney lesions from candidiasis, 79–80
diagnostic tests for, 629 Kingella kingae infections, 317–318, 318i
econazole for, 629 cephalosporin for, 317
epidemiology of, 629 clinical manifestations of, 317
etiology of, 629 diagnostic tests for, 317
griseofulvin for, 630 epidemiology of, 317
incubation period of, 629 etiology of, 317
ketoconazole for, 629 incubation period of, 317
miconazole for, 629 penicillin for, 317
naftifine for, 629 treatment of, 317
oxiconazole for, 629 Kissing bugs, 660, 662i
sulconazole for, 629 Klebsiella, 169
terbinafine for, 629 Klebsiella granulomatis, 198, 199i
tolnaftate for, 629 Klebsiella pneumoniae, 169, 171i, 172i
treatment of, 629–630 Koplik spots, 375i
Joint effusions from Yersinia pseudotuberculosis infection, from measles, 372
723 Kuru, 481
Jugular vein septic thrombosis from Lemierre disease, 183
Junin virus, 215
Juvenile plantar dermatosis
L
from tinea pedis, 631 La Crosse, disease caused by arboviruses in Western
from tinea unguium, 631 hemisphere, 26t
Juvenile recurrent respiratory papillomatosis, 407 Lacelike pattern of parvovirus B19 infections, 433i
Juvenile warts, 407 Lagovirus, 404
Laguna Negra virus, 207
K Larva currens, 591
Laryngeal candidiasis, 79
Kaposi sarcoma, 291i Laryngeal papillomas, 410i
from human herpesvirus 8, 271 Laryngitis from Chlamydophila pneumoniae, 95
from human immunodeficiency virus infection, 276, Laryngotracheitis from diphtheria, 149
292i Laryngotracheobronchitis from measles, 372
Katayama fever from schistosomiasis, 529 Laser surgery for warts, 409
Kato test for hookworm infections, 264

ERRNVPHGLFRVRUJ
752 INDEX

Lassa fever, 215 Leprosy, 330–334


ribavirin for, 216 clinical manifestations of, 330
Lassa virus, 215, 216i clofazimine for, 331
Latent syphilis, 594 dapsone for, 331
early, 594 diagnostic tests for, 331
late, 594 epidemiology of, 331
penicillin G benzathine for, 598 etiology of, 331
retreatment of, 602 incubation period of, 331
Latent M tuberculosis infection (LTBI), 664, 665 lepromatous, 330, 332i
diagnosis of, 666 multidrug therapy (MDT) for, 331
treatment of, 674–675 rifampin for, 331
Late-onset disease from group B streptococcal infections, treatment of, 331
582 tuberculoid, 330
Latex agglutination assay test Leptospira, 68, 335
for Cryptococcus neoformans infections, 127 Leptospirosis, 335–338
for cytomegalovirus infection, 140 amoxicillin for, 336
for endemic typhus, 698 ampicillin for, 336
Legionella pneumophila infections, 319–322, 320i, azithromycin for, 336
321i–322i ceftriaxone for, 336
azithromycin for, 320 clinical manifestations of, 335
clinical manifestations of, 319 diagnostic tests for, 335–336
diagnostic tests for, 319–320 doxycycline for, 336
doxycycline for, 320 epidemiology of, 335
epidemiology of, 319 etiology of, 335
etiology of, 319 incubation period of, 335
fluoroquinolones for, 320 penicillin for, 336
incubation period of, 319 penicillin G for, 336
levofloxacin for, 320 rash from, 337i
treatment of, 320 treatment of, 336
trimethoprim-sulfamethoxazole for, 320 Lesions
Legionellosis, 321i annular erythematous, 627i
Legionnaires’ disease, 319 blueberry muffin, from congenital rubella, 510
Leiomyosarcomas from HIV infection, 276 brain, from candidiasis, 80
Leishmania aethiopica, 323 Candida granulomatous, 86i
Leishmania amazonensis, 323 cavitary, from tuberculosis, 664
Leishmania braziliensis, 323 coxsackievirus, 160, 163i, 164i
Leishmania chagasi, 323 disseminated nontuberculous mycobacterial, 691i
Leishmania donovani, 323, 325i erythema migrans, from Lyme disease, 343–344, 351i,
Leishmania guyanensis, 323 353i
Leishmania infantum, 323 herpes simplex, 253i–257i
Leishmania major, 323 kidney, from candidiasis, 80
Leishmania mexicana, 323 liver, from candidiasis, 80
Leishmania panamensis, 323 lobar, from Pneumocystis jiroveci infections, 472
Leishmania peruviana, 323 miliary, from Pneumocystis jiroveci infections, 472
Leishmaniasis, 323–329 molluscum contagiosum, 389, 390i
clinical manifestations of, 323 mucocutaneous, from syphilis, 594
cutaneous, 323, 328i nodular, from Pneumocystis jiroveci infections, 472
diagnostic tests for, 324 osteolytic, from cat-scratch disease, 88
epidemiology of, 324 papular skin, 382i
etiology of, 323 papulovesicular, of rickettsialpox, 501i
incubation period of, 324 penile pyoderma, 196i
liposomal amphotericin B for, 325 perianal, 199i
miltefosine for, 325 from pityriasis versicolor, 455
mucosal, 323, 324 pruritic skin, from Strongyloides, 591
treatment of, 324–325 retinal, from candidiasis, 79
visceral, 323, 324 scalp, from tinea capitis, 622
Leishmania tropica, 323, 325i scaly
Lemierre syndrome from Arcanobacterium haemolyticum from tinea pedis, 631
infections, 33 from tinea unguium, 631
Leonine facies from leprosy, 330 skin, 164i
Lepromatous leprosy, 330, 333i, 334i from blastomycosis, 64
from Burkholderia infections, 74
from leprosy, 330–331

ERRNVPHGLFRVRUJ
INDEX 753

from syphilis, 594 Local tetanus, 619


from tinea cruris, 629 Lockjaw (tetanus), 619–621. See also Tetanus (lockjaw)
from varicella-zoster infections, 703 clinical manifestations of, 619
from Vibrio infections, 716 diagnostic tests for, 619
smallpox, 541i, 542i, 543–544i epidemiology of, 619
spleen, from candidiasis, 79–80 etiology of, 619
from sporotrichosis, 545 incubation period of, 619
tinea, 624i treatment of, 619–620
from tinea corporis, 626 Löffler syndrome
ulcerative chancroid, 94i from Ascaris lumbricoides infections, 35
Lesion scrapings for leishmaniasis, 324 from cutaneous larva migrans, 134
Lethargy from hookworm infections, 264
from amebic keratitis, 13 from Strongyloides, 591
from amebic meningoencephalitis, 13 Long-term sequelae from Rocky Mountain spotted fever
from Escherichia coli, 169 (RMSF), 502
from respiratory syncytial virus, 494 Louseborne typhus (epidemic typhus), 700–702
from Salmonella infections, 516 chloramphenicol for, 701
Leukemia from Cryptococcus neoformans infections, 126 clinical manifestations of, 700
Leukocytosis from toxocariasis, 634 diagnostic tests for, 700–701
Leukopenia doxycycline for, 701
from dengue, 145 epidemiology of, 700
from lymphocytic choriomeningitis, 359 etiology of, 700
from Rocky Mountain spotted fever, 502 incubation period of, 700
Liponyssoides sanguineus, 500 pediculicides for, 701
Listeria monocytogenes infections (listeriosis), 339–342, treatment of, 701
342i Low birth weight from American trypanosomiasis, 660
aminoglycosides for, 340 Lujo hemorrhagic fever, 215
ampicillin for, 340 Lujo virus, 215
cephalosporins for, 340 Lumbar pain from hemorrhagic fever with renal
clinical manifestations of, 339 syndrome, 218
diagnostic tests for, 340 Lumbar puncture for Cryptococcus neoformans
epidemiology of, 339 infections, 127
etiology of, 339 Lung abscess
gentamicin for, 340 from Bacteroides infection, 53
incubation period of, 339 from Burkholderia infections, 73
quinolone for, 340 from Prevotella infection, 53
treatment of, 340 Lung disease
trimethoprim-sulfamethoxazole for, 340 from parainfluenza viral infections, 416
Listeriosis (Listeria monocytogenes infections), 339–342, from respiratory syncytial virus, 494
342i Lung infection from sporotrichosis, 545
aminoglycosides for, 340 Lung tissue secretion specimens for Pneumocystis jiroveci
ampicillin for, 340 infections, 472
cephalosporins for, 340 Lyme arthritis, 343, 346
clinical manifestations of, 339 Lyme disease (Borrelia burgdorferi infection), 343–354
diagnostic tests for, 340 antimicrobial therapy for, 346
epidemiology of, 330 clinical manifestations of, 343–344
etiology of, 339 diagnostic tests for, 344–346
gentamicin for, 340 doxycycline for, 346
incubation period of, 339 epidemiology of, 344
treatment of, 340 etiology of, 344
trimethoprim-sulfamethoxazole for, 340 incubation period of, 344
Liver abscesses treatment of, 346–348, 347t
from amebiasis, 7, 11i Lymphadenitis
from Yersinia enterocolitica, 723 from Burkholderia infections, 73
Liver biopsy for toxocariasis, 634 from cat-scratch disease, 88, 90i
Liver disease cervical, 576i, 577i
from group B streptococcal infections, 582 from coccidioidomycosis, 116
from hepatitis C virus, 238 from plague, 457
from Pasteurella infections, 435 from Q fever, 485
Liver lesions from candidiasis, 79–80 from staphylococcal infections, 548
Lobar lesions from Pneumocystis jiroveci infections, 472

ERRNVPHGLFRVRUJ
754 INDEX

Lymphadenopathy, 91i, 355 Mad cow disease. See Bovine spongiform encephalopathy
from Arcanobacterium haemolyticum infections, 33 Magnetic resonance imaging (MRI)
bilateral cervical, 167i, 577i for Fusobacterium infections, 184
from brucellosis, 70 for tapeworm diseases, 611
from group A streptococcal infections, 568 Malabsorption from Strongyloides, 591
of hilar nodes from tuberculosis, 664 Malaise
from human immunodeficiency virus infection, 276 from African trypanosomiasis, 657
from leishmaniasis, 323 from brucellosis, 70
from Pasteurella infections, 435 from Campylobacter infections, 76
from rat-bite fever, 492 from Ehrlichia and Anaplasma infections, 154
from rubella, 510 from epidemic typhus, 700
from schistosomiasis, 529 from hepatitis A, 226
from syphilis, 594 from hepatitis B, 230
from tinea capitis, 622 from hepatitis E, 244
from Toxoplasma gondii infections, 637 from human calicivirus infections, 404
Lymphangitis from rat-bite fever, 492 from influenza, 294
Lymphatic filariasis, 355–358 from Lyme disease, 343
albendazole for, 356 from lymphocytic choriomeningitis, 359
clinical manifestations of, 355 from meningococcal infections, 378
diethylcarbamazine citrate-albendazole for, 356 from Mycoplasma pneumoniae infections, 396
diagnostic tests for, 355–356 from paracoccidioidomycosis, 411
epidemiology of, 355 from parvovirus B19, 430
etiology of, 355 from plague, 457
incubation period of, 355 from Salmonella infections, 516
ivermectin-albendazole for, 356 from schistosomiasis, 529
ivermectin for, 356 from severe acute respiratory syndrome, 122
treatment of, 356 from toxocariasis, 634
Lymphedema from lymphatic filariasis, 355 from Toxoplasma gondii infections, 637
Lymph node specimens for cat-scratch disease, 88 from West Nile virus, 718
Lymphocryptovirus, 165 Malaria, 361–371
Lymphocytic choriomeningitis, 359–360 antimalarial drugs for, 363
clinical manifestations of, 359 cerebral, 361
diagnostic tests for, 359–360 clindamycin for, 363
epidemiology of, 359 clinical manifestations of, 361–362
etiology of, 359 congenital, 362
incubation period of, 359 diagnostic tests for, 363
treatment of, 360 doxycycline for, 363
Lymphocytic choriomeningitis virus, 215 endemic countries, 368i
Lymphocytosis from Epstein-Barr virus, 165 epidemiology of, 362–363
Lymphogranuloma venereum (LGV) from Chlamydia etiology of, 362
trachomatis, 99, 101 quinidine for, 363
Lymphoid interstitial pneumonia from HIV infection, 276 tetracycline for, 363
Lymphopenia from severe acute respiratory syndrome, treatment of, 363
122 Malassezia furfur, 456i
Lyssavirus, 488 Malassezia species, 455
Lysis-centrifugation culture Malathion for pediculosis capitis, 438
for Cryptococcus neoformans infections, 126 Malayan filariasis, 355–358
for Histoplasma capsulatum, 259 Malnutrition
from cryptosporidiosis, 129
M from histoplasmosis, 258
Mansonella ozzardi, 356i
Machupo virus, 215, 217i Marburg virus, 221–225, 223i, 225i
Macrolides for Mycoplasma pneumoniae infections, 397 Mastitis from mumps, 392
Maculae ceruleae from pediculosis pubis, 443 Maternal rubella, 510
Macular rash Measles, 372–377, 374i, 375i
from dengue, 145 clinical manifestations of, 372
from hepatitis B, 230 diagnostic tests for, 373
Macules from pediculosis corporis, 441 epidemiology of, 372–373
Maculopapular exanthem from Arcanobacterium etiology of, 372
haemolyticum infections, 33 incubation period of, 373
Maculopapular rash rash in, 375i
from dengue, 145 treatment of, 373
with necrosis, from gonococcal infections, 190 Measles encephalitis, 377i

ERRNVPHGLFRVRUJ
INDEX 755

Measles-mumps-rubella (MMR) vaccine for HIV in Meningoencephalitis


children, 284 from African trypanosomiasis, 657
Measles pneumonia, 376i from American trypanosomiasis, 660
Mediastinitis, 549 from Toxoplasma gondii infections, 637
Megacolon Mental retardation from lymphocytic choriomeningitis,
from amebiasis, 7 359
from Shigella infections, 535 Mental status alterations
Megaloblastic anemia from tapeworm infections, 616 from Chlamydophila psittaci, 97
Melioidosis from Burkholderia pseudomallei, 73–74, 75i from psittacosis, 97
Membranous pharyngitis from Arcanobacterium Metabolic acidosis
haemolyticum infections, 33 from malaria, 361
Meningitis, 38 from Vibrio cholerae infections, 712
from adenovirus infections, 4 Methicillin-resistant CoNS, 551
from Arcanobacterium haemolyticum infections, 33 Methicillin-resistant Staphylococcus aureus (MRSA)
aseptic, 247 community-associated, 551–552
from Bacillus cereus, 49 epidemic strains of, 550
bacterial, 464 health care–associated, 551
from Bacteroides infection, 53 Microcephaly
from Borrelia infections, 67 from cytomegalovirus infection, 138
from brucellosis, 70 from lymphocytic choriomeningitis, 359
from cysticercosis, 611 Microfilariae, 355, 357i
from Ehrlichia and Anaplasma infections, 154 Microimmunofluorescent antibody test
from enterovirus infections, 160 for Chlamydophila pneumoniae, 95
from group B streptococcal infections, 582 for Chlamydophila psittaci, 97
from Haemophilus influenzae, 200 Microscopic agglutination for leptospirosis, 273
from herpes simplex virus, 247 Microsporidia infections (microsporidiosis), 386–388, 388i
from Lemierre disease, 183 albendazole for, 386
from Listeria monocytogenes infections, 339 atovaquone for, 386
meningococcal, 378, 381i clinical manifestations of, 386
from non–group A or B streptococcal and diagnostic tests for, 386
enterococcal infections, 586 epidemiology of, 386
from Pasteurella infections, 435 etiology of, 386
from pneumococcal infections, 464–465 fumagillin for, 386
from Prevotella infection, 53 incubation period of, 386
from Q fever, 485 metronidazole for, 386
from rat-bite fever, 492 nitazoxanide for, 386
from Salmonella infections, 516 treatment of, 386
from Strongyloides, 591 Microsporidiosis (microsporidia infections), 386–388, 388i
from tapeworm diseases, 611 albendazole for, 386
treatment for, 170, 575, 583 atovaquone for, 386
from tuberculosis, 664 clinical manifestations of, 386
viral, 476 diagnostic tests for, 386
from West Nile virus, 718 epidemiology of, 386
from Yersinia enterocolitica, 723 etiology of, 386
Meningococcal infections, 378–384 fumagillin for, 386
ampicillin for, 379 incubation period of, 386
antimicrobial therapy for, 379 metronidazole for, 386
cefotaxime for, 379–380 nitazoxanide for, 386
ceftriaxone for, 379–380 treatment of, 386
chloramphenicol for, 380 Microsporum audouinii, 623i
clinical manifestations of, 378 Microsporum canis, 622, 626
diagnostic tests for, 379 Migratory arthritis from gonococcal infections, 190
epidemiology of, 378–379 Migratory polyarthritis from rat-bite fever, 492
etiology of, 378 Mild neck stiffness from Lyme disease, 343
incubation period of, 379 Miliary disease from tuberculosis, 677
meropenem for, 380 Miliary lesions from Pneumocystis jiroveci infections, 472
penicillin G for, 379 Miliary tuberculosis, 683i
treatment of, 379–380 Miller Fisher syndrome, as complication of viral
Meningococcal meningitis, 378, 381i Campylobacter infections, 76
Meningococcemia, 378, 382i, 383i Molluscipoxvirus, 389
adrenal hemorrhage in, 384i
with cutaneous necrosis, 383i
with gangrene, 383i

ERRNVPHGLFRVRUJ
756 INDEX

Molluscum contagiosum, 288i, 389–391, 390i Muscle enzyme increase for trichinellosis, 647
cidofovir for, 389 Muscle pain from rat-bite fever, 492
clinical manifestations of, 389 Muscle spasms from tetanus, 619
diagnostic tests for, 389 Muscular spasms from tetanus, 619
epidemiology of, 389 Mustela frenata, 463i
etiology of, 389 Myalgias
incubation period of, 389 from babesiosis, 45
lesions of, 390i from brucellosis, 64
treatment of, 389 from Crimean-Congo hemorrhagic fever, 218
white papules and, 390i from cyclosporiasis, 136
Monkeypox, 540 from Ehrlichia and Anaplasma infections, 154
Monongahela virus, 207 from endemic typhus, 698
Moraxella catarrhalis, 467 from epidemic typhus, 700
Morbilliform rash, 167i from hemorrhagic fevers, 215
Motor dysfunction from Rocky Mountain spotted fever from legionnaires’ disease, 319
(RMSF), 502 from Lyme disease, 343
Motor neuron disease from poliovirus infections, 476 from lymphocytic choriomeningitis, 359
Mucocutaneous candidiasis, 79, 86i from parvovirus B19, 430
Mucocutaneous herpes simplex infections, 252 from rickettsialpox, 500
Mucocutaneous lesions from syphilis, 594 from Rocky Mountain spotted fever, 502
Mucocutaneous lymph node syndrome (Kawasaki from severe acute respiratory syndrome, 122
disease), 309–316, 723 from Toxoplasma gondii infections, 637
aspirin therapy for, 311 from trichinellosis, 647
clinical manifestations of, 309–310 from tularemia, 693
conjunctivitis and, 313i from West Nile virus, 718
desquamation of hands with, 313i Mycelial-phase antigens for Histoplasma capsulatum, 259
diagnostic tests for, 311 Mycetoma from nocardiosis, 401
epidemiology of, 310–311 Mycobacterial tuberculosis, 690i
etiology of, 310 Mycobacterium abscessus, 686–687
IVIG therapy for, 311 Mycobacterium avium, 276, 686
incomplete, 309 Mycobacterium avium-intracellulare infection, 688, 691i
incubation period of, 311 Mycobacterium bovis, 664, 672
treatment of, 311 Mycobacterium chelonae, 686
Mucoid stools from Shigella infections, 535 Mycobacterium fortuitum, 686
Mucormycosis, 180t Mycobacterium kansasii, 669
Mucosal bleeding from dengue, 145 Mycobacterium leprae, 330, 332i
Mucosal leishmaniasis (espundia), 323, 324 Mycobacterium marinum, 669, 686
Mucosal ulceration from histoplasmosis, 258 Mycobacterium simiae, 686
Mulberry molars from syphilis, 594 Mycobacterium tuberculosis, 664, 680i
Multibacillary leprosy, 332 from human immunodeficiency virus infection, 276
Multicentric Castleman disease from human herpesvirus Mycobacterium ulcerans, 687
8, 271 Mycoplasma hominis, in bacterial vaginosis, 51, 396
Multidrug-resistant (MDR) tuberculosis, 665 Mycoplasma pneumoniae infections, 396–400, 399i, 445
Multiple organ dysfunction from Lemierre disease, 183 antimicrobial therapy for, 397
Mumps, 392–393 azithromycin for, 397
clinical manifestations of, 392 clarithromycin for, 397
diagnostic tests for, 392–393 clinical manifestations of, 396
epidemiology of, 392 diagnostic tests for, 396–397
etiology of, 392 doxycycline for, 397
incubation period of, 392 epidemiology of, 396
treatment of, 393 erythromycin for, 396
Mumps orchitis, 395i etiology of, 396
Mumps parotitis, 395i fluoroquinolones for, 397
Murine typhus (flea-borne typhus, endemic typhus), incubation period of, 396
698–699 treatment of, 397
clinical manifestations of, 698 Mycoplasmas, 396
diagnostic tests for, 698 Myelitis from Epstein-Barr virus, 165
doxycycline for, 698 Myocardial dysfunction from hantavirus pulmonary
epidemiology of, 698 syndrome, 207
etiology of, 698 Myocardial failure from epidemic typhus, 700
incubation period of, 698 Myocardial infarction from Kawasaki disease, 310
treatment of, 698
Musca domestica, 713i

ERRNVPHGLFRVRUJ
INDEX 757

Myocarditis Necrosis of distal extremities from plague, 457


from African trypanosomiasis, 657 Necrotizing enterocolitis, 549
from American trypanosomiasis, 660 from Yersinia enterocolitica, 723
from Borrelia infections, 67 Necrotizing fasciitis, 585i, 710i
from Chlamydophila psittaci, 97 from Bacteroides infection, 53
from dengue, 145 from group A streptococcal infections, 568
from Epstein-Barr virus, 165, 166 from group B streptococcal infections, 585i
from influenza, 294 from Prevotella infection, 53
from Kawasaki disease, 309 from staphylococcal infections, 566i
from meningococcal infections, 378 treatment for, 575
from mumps, 392 Necrotizing pneumonia
from Mycoplasma pneumoniae infections, 396 from Bacteroides infection, 53
from psittacosis, 97 from Prevotella infection, 53
from Q fever, 485 Needle aspiration, in treating cat-scratch disease, 89
from rat-bite fever, 492 Neisseria gonorrhoeae, 190, 194i, 651
from toxocariasis, 634 from bacterial vaginosis, 51
from trichinellosis, 647 Neisseria meningitidis, 378–380, 380i
Myoclonus from Creutzfeldt-Jakob disease, 481 Nematode, filarial, 355
Myopericarditis from enterovirus infections, 160 Neoehrlichia mikurensis, 154
Myositis Neoehrlichiosis, 156t
from group A streptococcal infections, 568 Neonatal chlamydial conjunctivitis from Chlamydia
Myringitis from Mycoplasma pneumoniae infections, 396 trachomatis, 99
Myringotomy for otitis media, 467 Neonatal conjunctivitis from Chlamydia trachomatis, 99
Neonatal disease from gonococcal infections, 192
N Neonatal herpes simplex, 246, 247, 248, 250, 255i
Neonatal herpes simplex lesions, 255i
Naegleria fowleri, 13, 15i, 16i Neonatal herpetic infections from herpes simplex, 246
Nairovirus, 218 Neonatal meningitis
Nasal congestion from Escherichia coli, 169
from human coronaviruses, 122 Neonatal omphalitis
from influenza, 294 from group A streptococcal infections, 568
Nasal diphtheria, 151i treatment for, 575
Nasogastric suction for Ascaris lumbricoides infections, 35 Neonatal septicemia
Nasopharyngeal carcinoma from Epstein-Barr virus, 165 from Escherichia coli, 169, 171i
Nasopharyngeal specimen for pertussis, 445 from Haemophilus influenzae, 200
Nasopharyngitis from diphtheria, 149 from pneumococcal infections, 464
National Hansen’s Disease Program, 331 Neonatal tetanus, 619, 620i
Nausea. See also Vomiting Neorickettsia sennetsu, 154, 155
from anthrax, 18 Neorickettsiosis, 154, 156t
from babesiosis, 45 Nephritis
from Bacillus cereus, 49 from Chlamydophila psittaci, 97
from Balantidium coli infection, 56 from psittacosis, 97
from Blastocystis hominis infections, 62 Nephropathia epidemic, 218
from cyclosporiasis, 136 Nephrotic syndrome, 361
from cystoisosporiasis, 306 Neurocysticercosis, 611–612, 614i
from Ehrlichia and Anaplasma infections, 154 from tapeworm diseases, 611
from hantavirus pulmonary syndrome, 207 Neuroinvasive disease from arboviruses, 25
from Helicobacter pylori infections, 213 Neuroretinitis
from hepatitis A, 226 from Baylisascaris infections, 58
from hepatitis B, 230 from cat-scratch disease, 88
from hookworm infections, 264 Neurosyphilis, 594
from influenza, 294 aqueous crystalline penicillin G for, 598
from isosporiasis, 306 penicillin G procaine plus oral probenecid for, 601
from leptospirosis, 335 retreatment of, 602
from lymphocytic choriomeningitis, 359 from syphilis, 594
from malaria, 361 treatment for, 598, 600
from Rocky Mountain spotted fever, 502 New York virus, 207–208
from schistosomiasis, 529 Night sweats
from tapeworm diseases, 611 from brucellosis, 70
from trichinellosis, 647 from nontuberculous mycobacteria, 686
Nebovirus, 404 from tuberculosis, 664
Necator americanus, 264, 265i Nikolsky sign, 548
Neck pain from Lemierre disease, 183 Nits from pediculosis capitis, 437, 438i

ERRNVPHGLFRVRUJ
758 INDEX

Nocardia, 401, 402i Nonpulmonary primary infection from


Nocardia abscessus, 401 coccidioidomycosis, 116
Nocardia asteroides, 401, 402i Nonradiometric broth technique for nontuberculous
Nocardia brasiliensis, 401, 402i mycobacteria, 688
Nocardia brevicatena, 401 Nontreponemal tests for syphilis, 596
Nocardia cyriacigeorgica, 401 Nontuberculous mycobacteria, 686–692
Nocardia farcinica, 401 amikacin for, 688
Nocardia nova, 401 azithromycin for, 688
Nocardia otitidiscaviarum, 401 cefoxitin for, 688
Nocardia pneumonia, 403i ciprofloxacin for, 688
Nocardia pseudobrasiliensis, 401 clarithromycin for, 688
Nocardiosis, 401–403 clinical manifestations of, 686
amikacin for, 401 diagnostic tests for, 687–688
amoxicillin-clavulanate for, 402 doxycycline for, 688
ceftriaxone for, 401 epidemiology of, 686–687
clarithromycin for, 402 ethambutol for, 688
clinical manifestations of, 401 etiology of, 686
cutaneous, 403i imipenem for, 688
diagnostic tests for, 401 incubation period of, 687
epidemiology of, 401 linezolid for, 688
etiology of, 401 rifampin for, 688
imipenem for, 401 rifabutin for, 688
incubation period of, 401 sulfamethoxazole for, 688
linezolid for, 402 treatment of, 688–690, 689t–690t
meropenem for, 401 trimethoprim-sulfamethoxazole for, 688
sulfamethoxazole for, 401 Nontuberculous mycobacterial osteomyelitis, 691i
sulfisoxazole for, 401 Nontuberculous mycobacteria lymphadenitis, 688
sulfonamide for, 401 azithromycin for, 688
treatment of, 401–402 clarithromycin for, 688
trimethoprim-sulfamethoxazole for, 401 ethambutol for, 688
Nocardia transvalensis, 401 rifabutin for, 688
Nocardia veteran, 401 Norovirus, 404
Nodular lesions from Pneumocystis jiroveci infections, 472 clinical manifestations of, 404
Nomenclature for Salmonella organisms, 517t diagnostic tests for, 404
Nonbullous impetigo, treatment of, 574 epidemiology of, 404
Nondisseminated neonatal gonococcal infections, etiology of, 404
192–193 incubation period of, 404
Nongenital warts, 407 rehydration solutions for, 404
Non–group A or B streptococcal and enterococcal treatment of, 404
infections, 586–590 Norwegian scabies, 288i, 524
ampicillin for, 587 Nosema, 386
cephalosporin for, 587 Nuchal rigidity
clinical manifestations of, 586 from amebic keratitis, 13
daptomycin for, 587 from amebic meningoencephalitis, 13
diagnostic tests for, 587 Nucleic acid amplification (NAA) tests
epidemiology of, 586 for arboviruses, 27
etiology of, 586 for Chlamydia trachomatis, 97
gentamicin for, 587 for gonococcal infections, 191
incubation period of, 587 for hepatitis C virus, 239
linezolid for, 587 for human herpesvirus 8, 271
penicillin G for, 587 for tuberculosis, 667
tigecycline for, 587 for West Nile virus, 719
treatment of, 587 Nucleic acid detection
vancomycin for, 587 by DNA PCR assay for human immunodeficiency
Non-Hodgkin B-lymphocyte lymphomas from HIV virus, 280
infection, 276 for human immunodeficiency virus, 280
Nonmeningeal invasive pneumococcal infections Numbered enteroviruses, 160
in immunocompromised host, 467
requiring hospitalization, 466–467
Nonpolio enteroviruses (EVs), 160

ERRNVPHGLFRVRUJ
INDEX 759

O Orthopoxvirus, 540
Oryzomys palustris, 208
Obstructive hydrocephalus
Osler nodes, 588i, 589i
from cysticercosis, 611
Osteochondritis from syphilis, 594
from tapeworm diseases, 611
Osteolytic lesions from cat-scratch disease, 88
Ocular cysticercosis, 612
Osteomyelitis, 38, 563i
Ocular disease from Toxoplasma gondii infections, 637
from Arcanobacterium haemolyticum infections, 33
Ocular infections
from Bacillus cereus, 49
from Bacillus cereus, 49
from Bacteroides infection, 53
from herpes simplex infections, 252
from brucellosis, 70
from Pasteurella infections, 435
from group A streptococcal infections, 568
Ocular muscle paralysis, in botulism, 108i
from group B streptococcal infections, 582
Ocular palsies from Clostridium botulinum, 104
from Haemophilus influenzae, 200
Ocular toxoplasmosis from Toxoplasma gondii infections,
from Lemierre disease, 183
637, 641
from nontuberculous mycobacteria, 686
Ocular trachoma, 101
from Pasteurella infections, 435
Oculoglandular lymphadenopathy from tularemia, 693
from pneumococcal infections, 464
Odocoileus virginianus, 45, 349i
from Prevotella infection, 53
Oliguria from hemorrhagic fever with renal syndrome,
from Q fever, 485
218
from Salmonella infections, 516, 522i
Omphalitis from staphylococcal infections, 548
treatment for, 575
Onchocerca nodule, 406i
from Yersinia enterocolitica, 723
Onchocerca volvulus, 405
Otitis media, 467
Onchocerciasis, 405–406, 406i
from adenovirus infections, 4
clinical manifestations of, 405
from Bacteroides infection, 53
diagnostic tests for, 405
cefpodoxime for, 467
doxycycline for, 405
cefuroxime for, 467
epidemiology of, 405
from Chlamydophila pneumoniae, 95
etiology of, 405
from Fusobacterium infections, 183
incubation period of, 405
from group A streptococcal infections, 568
ivermectin for, 405
from Haemophilus influenzae, 200–201
treatment of, 405–406
from human coronaviruses, 122
Oophoritis from mumps, 392
from measles, 372
Open lung biopsy for Pneumocystis jiroveci infections, 473
from Mycoplasma pneumoniae infections, 396
Ophthalmologic examination for candidiasis, 79
from nontuberculous mycobacteria, 686
Ophthalmoplegia, as complication of viral Campylobacter
oral cefdinir for, 467
infections, 76
from Prevotella infection, 53
Opisthorchis felineus, 421t
Otomycosis, 38
Opisthorchis sinensis, 421t, 423i
Oxygen desaturation from Pneumocystis jiroveci
Opisthorchis viverrini, 421t
infections, 472
Optic neuritis from Epstein-Barr virus, 165
Oral candidiasis, 79, 80
from human immunodeficiency virus infection, 279 P
Oral poliovirus (OPV) vaccine, 476 Pain
Oral rehydration abdominal
for Vibrio cholerae infections, 713 from anthrax, 18
Oran virus, 207 from babesiosis, 45
Orbital abscess, 561i, 562i from Blastocystis hominis infections, 62
Orbital cellulitis, 561i from brucellosis, 70
from Arcanobacterium haemolyticum infections, 33 from Campylobacter infections, 76
Orchitis from cystoisosporiasis, 306
from lymphatic filariasis, 355 from dengue, 145
from lymphocytic choriomeningitis, 359 from enterovirus infections, 160
mumps and, 392 from Escherichia coli diarrhea, 174
from West Nile virus, 718 from Giardia intestinalis infections, 186
Organ transplant patients, tuberculosis and, 671 from hemorrhagic fever, 215
Orientia, 498 from hemorrhagic fever with renal syndrome, 218
Ornithodoros hermsii, 69i from hepatitis E, 244
Ornithodoros species, 67 from hookworm infections, 264
Ornithosis. See Psittacosis (Chlamydophila psittaci) from influenza, 294
Oropharyngeal anthrax, 18 from isosporiasis, 306
Oropharyngeal syndrome from tularemia, 693 from malaria, 361
Oropharynx inflammation, 576i from nontuberculous mycobacteria, 686

ERRNVPHGLFRVRUJ
760 INDEX

Pain, continued etiology of, 413


from Q fever, 485 extrapulmonary, 413
from Rocky Mountain spotted fever, 502 incubation period of, 414
from schistosomiasis, 529 praziquantel for, 414
from smallpox, 539 treatment of, 414
from Strongyloides, 591 Paragonimus africanus, 413
from tapeworm infections, 616 Paragonimus ecuadoriensis, 413
from Trichomonas vaginalis infections, 651 Paragonimus heterotrema, 413
from trichuriasis, 655 Paragonimus kellicotti, 413
from tuberculosis, 664 Paragonimus mexicanus, 413
from amebic keratitis, 13 Paragonimus miyazakii, 413
from amebic meningoencephalitis, 13 Paragonimus skrjabini, 413
back Paragonimus uterobilateralis, 413
from Listeria monocytogenes infections, 339 Paragonimus westermani, 413, 414i
from malaria, 361 Parainfluenza laryngotracheitis, 418i
from smallpox, 539 Parainfluenza pneumonia, 418i
chest Parainfluenza viral infections, 416–419, 417i
from Cryptococcus neoformans infections, 126 antiviral therapy for, 417
from tularemia, 693 clinical manifestations of, 416
on defecation from chancroid, 93 corticosteroid therapy for, 417
epigastric, from Helicobacter pylori infections, 213 diagnostic tests for, 416–417
muscle, from rat-bite fever, 492 epidemiology of, 416
from tapeworm diseases, 611 epinephrine for, 417
Pain syndromes from herpes simplex virus, 247 etiology of, 416
Palatal enanthem from rubella, 510 incubation period of, 416
Pallor steroids for, 417
from clostridial myonecrosis, 109 treatment of, 417
from malaria, 361 Paralysis
Palmar desquamation of Kawasaki disease, 313i from enterovirus infections, 160
Pancreatitis from rabies, 488
from Ascaris lumbricoides infections, 35 Paralytic poliomyelitis, 476
from dengue, 145 from poliovirus infections, 476
from mumps, 392 Parasitic diseases, 421i–429i
from West Nile virus, 718 Angiostrongylus cantonensis, 421t, 429i
Pancytopenia from histoplasmosis, 258 Angiostrongylus costaricensis, 421t, 424i
Panophthalmitis from Bacillus cereus, 49 anisakiasis, 421t
Papillomas Capillaria philippinensis, 422t
laryngeal, 410i Clonorchis sinensis, 421t
respiratory, 407 description of, 420
Papillomatosis dracunculiasis, 422t, 423i
respiratory, 407 fasciolopsiasis, 422t
respiratory tract, 407 intestinal capillariasis, 422t
Pap test for human papillomaviruses, 407 Opisthorchis felineus, 421t
Papular acrodermatitis from hepatitis B, 230 Opisthorchis sinensis, 421t
Papular rash, 609i Opisthorchis viverrini, 421t
Papular skin lesions, 382i Paravertebral abscess, 685i
Papules from pediculosis corporis, 441 Parenchymal brain infection from Listeria monocytogenes
Papulovesicular rash from hookworm infections, 264 infections, 339
Paracoccidioides brasiliensis, 411, 412i Paresthesias from poliovirus infections, 476
Paracoccidioidomycosis (South American blastomycosis), Parinaud oculoglandular syndrome from cat-scratch
411–412 disease, 88, 90i
amphotericin B for, 411 Paronychia
clinical manifestations of, 411 from Arcanobacterium haemolyticum infections, 33
diagnostic tests for, 411 from staphylococcal infections, 548
epidemiology of, 411 Parotitis
etiology of, 411 from human immunodeficiency virus infection, 276
incubation period of, 411 from melioidosis from Burkholderia pseudomallei, 73
itraconazole for, 411 mumps and, 392
treatment of, 411 from parainfluenza viral infections, 416
Paragonimiasis, 413–414 from staphylococcal infections, 548
clinical manifestations of, 413
diagnostic tests for, 414
epidemiology of, 413–414

ERRNVPHGLFRVRUJ
INDEX 761

Parvovirus B19 (erythema infectiosum, fifth disease), Pediculosis corporis (body lice), 441, 442i
430–434, 432i clinical manifestations of, 441
clinical manifestations of, 430, 430t diagnostic tests for, 441
diagnostic tests for, 431 epidemiology of, 441
epidemiology of, 431 etiology of, 441
etiology of, 430 incubation period of, 441
immunoglobulin therapy for, 431 pediculicides for, 441
incubation period of, 431 treatment of, 441
treatment of, 431 Pediculosis pubis (pubic lice), 443, 444i
Pasteurella infections, 435–436 clinical manifestations of, 443
amoxicillin-clavulanate for, 435 diagnostic tests for, 443
ampicillin for, 435 epidemiology of, 443
ampicillin-sulbactam for, 435 etiology of, 443
antimicrobial therapy for, 435 incubation period of, 443
azithromycin for, 435 pediculicides for, 443
cefixime for, 435 treatment of, 443
cefpodoxime for, 435 Pediculus humanus, 67, 69i, 700, 702i
cefuroxime for, 435 Pediculus humanus capitis, 437
clindamycin for, 435 Pediculus humanus corporis, 441
clinical manifestations of, 435 Pediculus humanus humanus, 441, 441i, 442i
diagnostic tests for, 435 Pelvic inflammatory disease (PID)
doxycycline for, 435 from Bacteroides infection, 53
epidemiology of, 435 from gonococcal infections, 190, 193
erythromycin for, 435 from Prevotella infection, 53
etiology of, 435 Pelvic pain from Schistosoma haematobium, 529
fluoroquinolones for, 435 Pelvic peritonitis from pinworm infection, 452
incubation period of, 435 Penicilliosis (fungal disease), 179t
penicillin for, 435 Penile pyoderma lesion, 196i
piperacillin-tazobactam for, 435 Perforation from amebiasis, 7
treatment of, 435 Perianal cellulitis from group A streptococcal infections,
trimethoprim-sulfamethoxazole for, 435 568
Pasteurella multocida, 435, 436i Perianal desquamation of Kawasaki disease, 313i
Pathognomonic enanthema from measles, 372 Perianal granuloma inguinale lesion, 199i
Paucibacillary leprosy, 332 Perianal infections
PCP prophylaxis for HIV children, 284 from Bacteroides infection, 53
PCR assay from Prevotella infection, 53
for Chlamydophila pneumoniae, 95 Pericardial effusion from Kawasaki disease, 309
for cytomegalovirus infection, 140 Pericarditis
for Entamoeba histolytica, 8 from Chlamydophila psittaci, 97
for epidemic typhus, 700 from group A streptococcal infections, 568
for human bocavirus, 66 from melioidosis from Burkholderia pseudomallei, 73
for human herpesvirus 8, 271 from meningococcal infections, 378
for Legionella pneumophila infections, 319 from Mycoplasma pneumoniae infections, 396
for malaria, 362 from pneumococcal infections, 464
for meningococcal infections, 379 from psittacosis, 97
for microsporidia infections, 386 from Q fever, 485
for Mycoplasma pneumoniae infections, 397 Perihepatitis
for pertussis, 446 from Chlamydia trachomatis, 99
for smallpox, 540 from gonococcal infections, 190
for tularemia, 694 Perinatal bacterial infections from group B streptococcal
Pediatric acute-onset neuropsychiatric syndrome, 568 infections, 582
Pediatric autoimmune neuropsychiatric disorders Perinatal death from syphilis, 595
associated with streptococcal infection, 568 Perinatal transmission of hepatitis B virus (HBV), 231
Pediculosis capitis (head lice), 437–440, 439i Periodic acid-Schiff stain for microsporidia infections,
clinical manifestations of, 437 386
diagnostic tests for, 437 Periodontal disease from Fusobacterium infections, 183
epidemiology of, 437 Perionychial abscess from Streptococcus pneumonia, 469i
etiology of, 437 Periorbital cellulitis, 468i, 561i
incubation period of, 437 from Haemophilus influenzae infections, 203i
oral ivermectin for, 438 from pneumococcal infections, 464
pediculicides for, 437, 437t from staphylococcal infections, 561i
permethrin for, 438 Periorbital edema from trichinellosis, 647
treatment of, 437–438

ERRNVPHGLFRVRUJ
762 INDEX

Peripheral neuropathy from Rocky Mountain spotted Pharynx swabbing for group A streptococcal infections,
fever, 502 570
Peritonitis Phlebovirus, 218
from Haemophilus influenzae, 200 Photophobia
from Pasteurella infections, 435 from amebic keratitis, 13
from pneumococcal infections, 464 from amebic meningoencephalitis, 13
Peritonsillar abscesses from babesiosis, 45
from Arcanobacterium haemolyticum infections, 33 from lymphocytic choriomeningitis, 359
from Bacteroides infection, 53 from rickettsialpox, 500
from group A streptococcal infections, 568 Phthirus pubis, 443, 444i
from Prevotella infection, 53 Pinworm infection (Enterobius vermicularis), 452–454
from staphylococcal infections, 566i albendazole for, 452
Periungual desquamation of Kawasaki disease, 314i clinical manifestations of, 452
Periventricular germinolytic cysts, 144i diagnostic tests for, 452
Peromyscus leucopus (white-footed mouse), 45, 208, 349i epidemiology of, 452
Peromyscus maniculatus (deer mouse), 207, 209i, 210i etiology of, 452
Person-to-person spread of hepatitis B virus (HBV), 231 incubation period of, 452
Pertussis pneumonia, 449i, 451i pyrantel pamoate for, 452
Pertussis (whooping cough), 445–451 treatment of, 452
antimicrobial therapy for, 446 Pityriasis rosea, pityriasis versicolor and, 455
azithromycin for, 446 Pityriasis versicolor (tinea versicolor), 455–456, 456i
clinical manifestations of, 445 bifonazole for, 455
diagnostic tests for, 445–446 ciclopirox for, 455
epidemiology of, 445 clinical manifestations of, 455
erythromycin for, 446 clotrimazole cream for, 455
etiology of, 445 diagnosis of, 455
incubation period of, 445 econazole for, 455
treatment of, 446 epidemiology of, 455
trimethoprim-sulfamethoxazole for, 446 etiology of, 455
Petechiae fluconazole for, 455
from Argentine hemorrhagic fever, 215 incubation period of, 455
from Bolivian hemorrhagic fever, 215 ketoconazole for, 455
from dengue, 145 miconazole for, 455
from hemorrhagic fever with renal syndrome, 218 oxiconazole for, 455
from parvovirus B19, 430 selenium sulfide for, 455
from Venezuelan hemorrhagic fever, 215 terbinafine for, 455
Phaeohyphomycosis, 179t–180t treatment of, 455
Pharyngeal carriers, treatment for, 574 zinc pyrithione for, 455
Pharyngeal diphtheria, 150i Plague, 457–463
Pharyngeal exudate from Arcanobacterium haemolyticum bubonic, 457
infections, 33 chloramphenicol for, 458
Pharyngeal infection, 193 clinical manifestations of, 457
Pharyngeal itching from hookworm infections, 264 diagnostic tests for, 457–458
Pharyngeal swab for gonococcal infections, 191 doxycycline for, 458
Pharyngitis epidemiology of, 457
from Chlamydophila pneumoniae, 95 etiology of, 457
from Chlamydophila psittaci, 97 fluoroquinolones for, 458
from enterovirus infections, 160 gangrene of, 460i
foodborne outbreaks of, 569 gentamicin for, 458
from gonococcal infections, 190 hemorrhages on skin of, 460i
from group A streptococcal infections, 568, 572–573 human, 457
from Lassa fever, 215 incubation period of, 457
from Mycoplasma pneumoniae infections, 396 pneumonic, 457
from non–group A or B streptococcal and primary pneumonic, 457
enterococcal infections, 586 secondary pneumonic, 457
from psittacosis, 97 septicemic, 457
streptococcal, 568 streptomycin for, 458
treatment for, 572–573 tetracycline for, 458
from tularemia, 693 treatment of, 458
from Yersinia enterocolitica, 723 trimethoprim-sulfamethoxazole for, 458
Pharyngoconjunctival fever from adenovirus infections, 4 Plantar warts, 407
Pharyngotonsillitis from group A streptococcal infections, Plaque-reduction neutralization tests for West Nile virus
568 (WNV), 719

ERRNVPHGLFRVRUJ
INDEX 763

Plasma HIV-1 RNA PCR assay for HIV, 280 from Chlamydophila pneumoniae, 95
Plasmodium falciparum, 361, 362, 364i, 365i, 366i from Chlamydophila psittaci, 98i
Plasmodium knowlesi, 361 community-acquired, from pneumococcal infections,
Plasmodium malariae, 361, 362, 364i 464
Plasmodium ovale, 361, 362, 364i, 366i from cytomegalovirus infection, 138
Plasmodium vivax, 361, 362, 364i, 367i diphtheria, 151i
Platelet count for Kawasaki disease, 311 from enterovirus infections, 160
Pleistophora, 386 from Epstein-Barr virus, 165
Pleocytosis from poliovirus infections, 476 from group A streptococcal infections, 568
Pleural effusions from group B streptococcal infections, 582, 584i
from Burkholderia infections, 73 from Haemophilus influenzae, 200, 204i
from dengue, 145 from histoplasmosis, 258
from hantavirus pulmonary syndrome, 207 from human herpesvirus 6 and 7, 268
from Mycoplasma pneumoniae infections, 396 from human metapneumovirus, 385
from paragonimiasis, 413 from influenza, 294
from tuberculosis, 664 from Legionella pneumophila infections, 321i
from Yersinia pseudotuberculosis infection, 723 from Listeria monocytogenes infections, 339
Pleural empyema from Pasteurella infections, 435 lymphoid interstitial, 276
Pleuritic pain from Borrelia infections, 67 from meningococcal infections, 378
Pleurodermal sinuses from actinomycosis, 1 from Mycoplasma pneumoniae infections, 396
Pleurodynia from enterovirus infections, 160 necrotizing
Pneumococcal infections, 464–471 from Bacteroides infection, 53
antimicrobial therapy for, 465, 466t from Prevotella infection, 53
cefotaxime for, 466 Nocardia, 403i
ceftriaxone for, 466 from parainfluenza viral infections, 416
children at risk of invasive, 465t from Pasteurella infections, 435
clinical manifestations of, 464 from pertussis, 445, 449i, 451i
dexamethasone for, 466 plague, 457, 461i
diagnostic tests for, 464–466 Pneumocystis jiroveci, 276, 474i
epidemiology of, 464 from Q fever, 485
etiology of, 464 from rat-bite fever, 492
incubation period of, 464 from respiratory syncytial virus, 494
penicillin G for, 466 segmental (nodular), 469i
treatment of, 466 staphylococcal, 565i
vancomycin for, 466 from toxocariasis, 634
Pneumococcal meningitis, 464 treatment for, 575
Pneumococcal pneumonia, 470i tularemia, 697i
Pneumocystis carinii, 472 varicella, 710i
Pneumocystis jiroveci infections, 472–475, 474i, 475i from varicella-zoster infections, 703
atovaquone for, 473 from Yersinia enterocolitica, 723
clinical manifestations of, 472 Pneumonic plague, 457
corticosteroid therapy for, 473 Pneumonic tularemia, 693
diagnostic tests for, 472–473 Pneumonitis
epidemiology of, 472 from Borrelia infections, 67
etiology of, 472 from hookworm infections, 264
incubation period of, 472 from Strongyloides, 591
pentamidine for, 473 from Toxoplasma gondii infections, 637
treatment of, 473–474 from trichinellosis, 647
trimethoprim-sulfamethoxazole for, 473 Pneumothorax from paragonimiasis, 413
Pneumocystis jiroveci pneumonia, 472, 474i, 475i, 642 Poliomyelitis, paralytic, 476
from human immunodeficiency virus infection, 276 Poliovirus infections, 476–480
Pneumonia clinical manifestations of, 476
from actinomycosis, 1 deformity caused by, 479i
from adenovirus infections, 4, 5i diagnostic tests for, 477
from Arcanobacterium haemolyticum infections, 33 epidemiology of, 476–477
aspiration etiology of, 476
from Bacteroides infection, 53 incubation period of, 477
from Prevotella infection, 53 photomicrograph of, 480i
from Bacillus cereus, 49 Polyarthralgia from rubella, 510
bilateral varicella, 710i Polyarthritis from rubella, 510
from Burkholderia infections, 73 Polyarthropathy syndrome from parvovirus B19, 430
from cat-scratch disease, 88 Polymorphonuclear pleocytosis, 14
from Chlamydia trachomatis, 99

ERRNVPHGLFRVRUJ
764 INDEX

Polymorphous mucocutaneous eruptions from Proglottids of Dipylidium caninum, 617i


Mycoplasma pneumoniae infections, 396 Progressive disseminated histoplasmosis (PDH), 258
Pontiac fever from Legionella pneumophila infections, 319 Proliferative glomerulonephritis from Yersinia
Poor feeding from respiratory syncytial virus, 494 enterocolitica, 723
Postherpetic neuralgia, 703 Prostatic abscess from melioidosis from Burkholderia
Postinfectious encephalomyelitis from herpes simplex pseudomallei, 73
virus, 247 Prostatitis from Trichomonas vaginalis infections, 651
Postnatal rubella, 510 Prostration
Postnatally acquired toxoplasmosis, 637, 640 from meningococcal infections, 378
Postoperative wound infection from smallpox, 539
from Bacteroides infection, 53 Protease-resistant prion protein, 481
from Prevotella infection, 53 Proteinuria
Postpolio syndrome from poliovirus infections, 476 from Crimean-Congo hemorrhagic fever, 218
Posttransplantation lymphoproliferative disorders from from hemorrhagic fevers, 215
Epstein-Barr virus, 165 Proteus, 169
Posttraumatic paronychia from staphylococcal infections, Protracted nasopharyngitis, 576i
563i Prozone phenomenon, 596
Potassium hydroxide wet mount Pruritic papules from parvovirus B19, 430
for pityriasis versicolor, 455 Pruritic skin lesions from Strongyloides, 591
for tinea capitis, 622 Pruritus
for tinea pedis, 631 from African trypanosomiasis, 657
for tinea unguium, 631 from Arcanobacterium haemolyticum infections, 33
Potassium iodide for sporotrichosis, 545 from cutaneous larva migrans, 134
Powassan encephalitis virus, disease caused by from hookworm infections, 264
arboviruses in Western hemisphere, 26t from pediculosis pubis, 443
Preauricular lymphadenopathy from tularemia, 693 from pinworm infection, 452
Pregnancy Pruritus vulvae from pinworm infection, 452
lymphocytic choriomeningitis during, 359 Pseudoappendiceal abdominal pain from Yersinia
parvovirus B19 during, 430 pseudotuberculosis infection, 723
rubella in, 510 Pseudoappendicitis syndrome from Yersinia enterocolitica,
syphilis in, 595 723
testing for syphilis in, 597 Pseudomembranous candidiasis from HIV infection, 290i
tuberculosis during, 678 Pseudomembranous enterocolitis from Clostridium
varicella-zoster infections during, 703, 706 difficile, 111
West Nile virus during, 718 Pseudomonas, 169
Prevotella infections, 53–54 Pseudomonas aeruginosa, 74, 169, 172i, 173i
antimicrobial therapy for, 53 Pseudoparalysis from syphilis, 594
ampicillin for, 53 Pseudoterranova decipiens, 428i
β-lactam penicillin for, 53 Psittacosis (Chlamydophila psittaci), 97–98, 98i
clindamycin for, 53 azithromycin for, 98
clinical manifestations of, 53 clinical manifestations of, 97
diagnostic tests for, 53 diagnostic tests for, 97
epidemiology of, 53 doxycycline for, 98
etiology of, 53 epidemiology of, 97
incubation period of, 53 erythromycin for, 98
metronidazole for, 54 etiology of, 97
penicillin G for, 53 incubation period of, 97
treatment of, 53–54 tetracycline for, 98
Prevotella melaninogenica, 53, 54i, 55i treatment of, 98
Prevotella oralis, 53 Psoriasis, tinea capitis and, 622
Primary amebic meningoencephalitis (PAM), 13 Pubic lice (pediculosis pubis), 443
Primary effusion lymphoma, 271 clinical manifestations of, 443
Primary pneumonic plague, 457 diagnostic tests for, 443
Primary syphilis, 594, 602 epidemiology of, 443
Prion diseases (transmissible spongiform etiology of, 443
encephalopathies), 481–484, 484i incubation period of, 443
clinical manifestations of, 481 treatment of, 443
diagnostic tests for, 482–483 Puerperal sepsis from group A streptococcal infections,
epidemiology of, 482 568
etiology of, 481–482 Pulmonary abscesses from Pasteurella infections, 435
incubation period of, 482 Pulmonary coccidioidomycosis, 119i
treatment of, 483 Pulmonary disease from nontuberculous mycobacteria,
Proctitis from gonococcal infections, 190 667

ERRNVPHGLFRVRUJ
INDEX 765

Pulmonary edema from hantavirus pulmonary syndrome, Rashes


207 from African trypanosomiasis, 657
Pulmonary fibrosis from paragonimiasis, 413 from arboviruses, 24
Pulmonary histoplasmosis, 258 from Arcanobacterium haemolyticum infections, 33
Pulmonary hypertension from dengue, 145
from respiratory syncytial virus, 494 from Ehrlichia and Anaplasma infections, 154
from Schistosoma haematobium, 529 from endemic typhus, 698
Pulmonary infections from Epstein-Barr virus, 165
from blastomycosis, 64 from group A streptococcal infections, 568
from Burkholderia infections, 73 from human herpesvirus 6 and 7, 268
Pulmonary sporotrichosis, 545 from Kawasaki disease, 313i
Punch biopsy for leishmaniasis, 324 from leprosy, 330
Puncture aspiration, infusion of protoscolicidal agents, from leptospirosis, 335
and reaspiration (PAIR), 617 from Lyme disease, 351i–352i
Purpura from parvovirus B19, 430
from cytomegalovirus infection, 138 from Q fever, 485
of foot, 383i from rat-bite fever, 492
from meningococcal infections, 378 from Rocky Mountain spotted fever, 502
Purpura fulminans, 581i from rubella, 510
Purulent pericarditis from Haemophilus influenzae, 200 from schistosomiasis, 529
Pustules from nocardiosis, 401 from smallpox, 539
Puumala virus, 218 from syphilis, 594
Pyoderma from Toxoplasma gondii infections, 637
from nocardiosis, 401 from varicella-zoster infections, 702
from staphylococcal infections, 566i from West Nile virus, 718
Pyogenic arthritis Rat-bite fever, 492–493, 493i
from Lemierre disease, 183 clinical manifestations of, 492
from pneumococcal infections, 464 diagnostic tests for, 492
Pyomyositis doxycycline for, 492
from Yersinia enterocolitica, 723 epidemiology of, 492
from staphylococcal infections, 562i etiology of, 492
gentamicin for, 492
Q incubation period of, 492
penicillin G for, 492
Q fever, 485–487, 487i rash of, 493i
clinical manifestations of, 485 streptomycin for, 492
diagnostic tests for, 485–486 treatment of, 492
doxycycline for, 486 Rat bites, 407i, 408i
epidemiology of, 485 Rattus norvegicus, 699i
etiology of, 485 Rattus rattus, 462i
incubation period of, 485 Reactive arthritis
treatment, 486 as complication of viral Campylobacter infections, 76
trimethoprim-sulfamethoxazole for, 486 from Yersinia enterocolitica, 723
Quantification techniques for hookworm infections, 264 Rectal prolapse from trichuriasis, 655
Quantitative antimicrobial susceptibility testing for Rectal swab
staphylococcal infections, 553 for enterovirus infections, 161
QuickELISA Anthrax-PA Kit, 19 for gonococcal infections, 191
for Shigella infections, 535
R Recurrent arthritis from Lyme disease, 347
Rabies, 488–491, 489i Recurrent diarrhea from HIV infection, 276
clinical manifestations of, 488 Recurrent herpes simplex, 254i
diagnostic tests for, 488–489 Red blood cell aplasia from parvovirus B19, 430
epidemiology of, 488 Rehydration
etiology of, 488 for Campylobacter infections, 77
incubation period of, 488 Reiter syndrome
treatment of, 489 from Campylobacter infections, 76
Rabies encephalitis, 491i from Chlamydia trachomatis, 99
Raccoons as carriers of rabies virus, 490i Relapsing fever (Borrelia infections), 67–68, 69i
Radiographs for clostridial myonecrosis, 109. See also clinical manifestations of, 67
Chest radiographs diagnostic tests for, 68
Radiolucent bone disease from congenital rubella, 510 doxycycline for, 68
Radiometric broth techniques for nontuberculous epidemiology of, 67
mycobacteria, 688 erythromycin for, 68

ERRNVPHGLFRVRUJ
766 INDEX

Relapsing fever (Borrelia infections), continued Reverse-sequence screening for syphilis, 597
etiology of, 67 Reverse transcriptase-PCR
incubation period of, 68 for astrovirus infections, 43
penicillin for, 68 for hemorrhagic fever, 216
tetracycline for, 68 for hepatitis E, 244
treatment of, 68 for human calicivirus infections, 404
Renal disease from group B streptococcal infections, 582 for human metapneumovirus, 385
Renal failure for mumps, 392
from clostridial myonecrosis, 109 for norovirus, 404
from Ehrlichia and Anaplasma infections, 154 Reye syndrome from varicella-zoster infections, 703, 706
from epidemic typhus, 700 Rhabdomyolysis from Q fever, 485
from malaria, 361 Rhadinovirus, 271
from plague, 457 Rhagades, 594
Renal tuberculosis, 664 from syphilis, 594
Reoviridae, 25 Rheumatic fever
Residual paralytic disease from poliovirus infections, 476 acute, 571
Respiratory distress from group B streptococcal from group A streptococcal infections, 568
infections, 582 Rhinitis
Respiratory failure from malaria, 361 from group A streptococcal infections, 568
Respiratory muscle paralysis from West Nile virus, 718 from influenza, 294
Respiratory papillomas, 407 Rhinorrhea
Respiratory papillomatosis, 408–409 from human bocavirus, 66
Respiratory syncytial virus (RSV), 494–497 from human coronaviruses, 122
α- and β-adrenergic agents for, 496 Rhipicephalus sanguineus, 503, 505i
antimicrobial therapy for, 496 Rhodococcus equi, 401
clinical manifestations of, 494 Rib fractures from pertussis, 445
corticosteroid therapy for, 496 Rice-water stool, 715i
diagnostic tests for, 495 Rickettsia, 498
electron micrograph of, 496i Rickettsia akari, 500
epidemiology of, 494–495 Rickettsia felis, 698
etiology of, 494 Rickettsia parkeri, 498
incubation period of, 495 Rickettsia phillipi, 498
ribavirin for, 495 Rickettsia typhi, 698
treatment of, 495–496 Rickettsial diseases
Respiratory syncytial virus (RSV) bronchiolitis, clinical manifestations of, 498
pneumonia and, 497i diagnostic tests for, 498
Respiratory tract infections doxycycline, 499
from adenovirus infections, 4 epidemiology of, 498
from Arcanobacterium haemolyticum infections, 33 etiology of, 498
from Chlamydophila pneumoniae, 95 incubation period of, 498
from hemorrhagic fever, 215 treatment of, 499
from human metapneumovirus, 385 Rickettsialpox, 500–501
from non–group A or B streptococcal and chloramphenicol for, 500
enterococcal infections, 586 clinical manifestations of, 500
from parainfluenza viral infections, 416 diagnostic tests for, 500
from Pasteurella infections, 435 chloramphenicol for, 500
from pertussis, 445 doxycycline for, 500
Respiratory tract symptoms from lymphocytic epidemiology of, 500
choriomeningitis, 359 etiology of, 500
Retinal granulomas from toxocariasis, 634 fluoroquinolones for, 500
Retinal lesions from candidiasis, 79 incubation period of, 500
Retinitis papulovesicular lesions of, 501i
from cytomegalovirus infection, 138 patient with, 501i
from Rift Valley fever, 218 treatment of, 500
Retro-orbital headache from lymphocytic Rickettsia prowazekii, 700
choriomeningitis, 359 Rickettsia rickettsii, 500, 502
Retro-orbital pain from dengue, 145 Rift Valley fever, 218–219, 220i
Retropharyngeal abscesses from group A streptococcal Rigors
infections, 568 from influenza, 294
Retropharyngeal space infection from malaria, 361
from Bacteroides infection, 53 Rimantadine for influenza, 297
from Prevotella infection, 53

ERRNVPHGLFRVRUJ
INDEX 767

Ringworm, 624i incubation period of, 503


black dot, 622 rashes from, 505i, 506i, 507i
of the body (tinea corporis), 626–628, 627i, 628i treatment of, 503
butenafine for, 626 Romaña sign from American trypanosomiasis, 660
ciclopirox for, 626 Roseola, 268–270
clinical manifestations of, 626 clinical manifestations of, 268
clotrimazole for, 626 diagnostic tests for, 269
diagnosis of, 626 epidemiology of, 268–269
econazole for, 626 etiology of, 268
epidemiology of, 626 from human herpesvirus 6 and 7, 268
etiology of, 626 incubation period of, 269
fluconazole for, 626 treatment of, 269
griseofulvin for, 626 Roseola infantum, 227i
incubation period of, 626 Rotavirus infections, 508–509, 509i
ketoconazole for, 626 clinical manifestations of, 508
miconazole for, 626 diagnostic tests for, 508–509
naftifine for, 626 epidemiology of, 508
oxiconazole for, 626 etiology of, 508
sulconazole for, 626 incubation period of, 508
terbinafine for, 626 treatment of, 509
tolnaftate for, 626 Rubella, 510–515
treatment of, 626 clinical manifestations of, 510
of the feet (tinea unguium), 631–633, 633i diagnostic tests for, 511
clinical manifestations of, 631 epidemiology of, 510–511
clotrimazole for, 631 etiology of, 510
diagnosis of, 631 incubation period of, 511
econazole for, 631 maternal, 510
epidemiology of, 631 postauricular lymphadenopathy in, 514i
etiology of, 631 postnatal, 510
fluconazole for, 631 rash caused by, 513i, 514i
itraconazole for, 631 treatment of, 511
miconazole for, 631 Rubivirus, 510
terbinafine for, 631–632
treatment of, 631–632 S
of the scalp (tinea capitis), 622–625, 624i, 625i
clinical manifestations of, 622 Sabia virus, 215
diagnostic tests for, 622–623 Saddle nose from syphilis, 594
epidemiology of, 622 Salmonella enterica, 516, 519i
etiology of, 622 Salmonella infections, 169, 516–523
fluconazole for, 623 amoxicillin for, 518
griseofulvin for, 623–624 ampicillin for, 518
incubation period of, 622 antimicrobial therapy for, 517–518
treatment of, 623 azithromycin for, 518
Risus sardonicus, 620i ceftriaxone for, 518
Ritter disease, 548 ciprofloxacin for, 519
River blindness (onchocerciasis), 405–406, 406i clinical manifestations of, 516
clinical manifestations of, 405 corticosteroid therapy for, 519
diagnostic tests for, 405 diagnostic tests for, 518
epidemiology of, 405 epidemiology of, 516–517
etiology of, 405 etiology of, 516
incubation period of, 405 fluoroquinolones for, 518
treatment of, 405–406 incubation period of, 518
RNA PCR assay for HIV, 277 treatment of, 518–519
Rocky Mountain spotted fever (RMSF), 500, 502–507, trimethoprim-sulfamethoxazole for, 518
505i, 506i, 507i Salmonella meningitis, 522i
antimicrobial therapy for, 503 Salmonella pneumonia, 523i
chloramphenicol for, 503 Salmonella sepsis with dactylitis, 521i
clinical manifestations of, 502 Salmonella septicemia, 523i
diagnostic tests for, 503 Salmonellosis
doxycycline for, 503 food poisoning from, 114
epidemiology of, 502–503 shigellosis and, 520i, 537i
etiology of, 502

ERRNVPHGLFRVRUJ
768 INDEX

Salpingitis Secondary pneumonic plague, 457


from Chlamydia trachomatis, 99 Secondary syphilis, 594, 602, 609i, 610i
from gonococcal infections, 190 Sedimentation rate, increased for Kawasaki disease, 309
from pinworm infection, 452 Segmental (nodular) pneumonia, 469i
Sanguinopurulent exudate, 91i Seizures
Sapovirus, 404 from amebic keratitis, 13
Sarcoptes scabiei, 524, 525i from amebic meningoencephalitis, 13
SARS. See Severe acute respiratory syndrome (SARS) from American trypanosomiasis, 660
Scabies, 524–528 from cysticercosis, 611
antihistamines for, 525 from hemorrhagic fever, 215
antimicrobial therapy for, 525 from human herpesvirus 6 and 7, 268
clinical manifestations of, 524 from pertussis, 445
corticosteroids for, 525 from smallpox, 539
crotamiton for, 525 from tapeworm diseases, 611
diagnostic tests for, 524–525 from Toxoplasma gondii infections, 637
epidemiology of, 524 SEM disease from herpes simplex infections, 246
etiology of, 524 Sennetsu fever, 156t
incubation period of, 524 Sensorineural hearing loss (SNHL) from cytomegalovirus
ivermectin for, 525 infection, 138
lindane for, 525 Seoul virus, 218
linear papulovesicular burrows of, 525i Sepsis from plague, 457
Norwegian, 524 Sepsis syndrome
permethrin for, 525 from herpes simplex, 246
treatment of, 525 from Lemierre disease, 183
Scalded skin syndrome from staphylococcal infections, Septic arthritis
548 from group A streptococcal infections, 568
Scaling from tinea corporis, 626 from group B streptococcal infections, 582
Scalp abscesses from Haemophilus influenzae, 200
from gonococcal infections, 193 from melioidosis from Burkholderia pseudomallei, 73
from staphylococcal infections, 548 from Pasteurella infections, 435
from tinea capitis, 622 Septicemia, 171i
Scalp lesions from tinea capitis, 622 from Arcanobacterium haemolyticum infections, 33
Scaly lesions from Burkholderia infections, 73
from tinea pedis, 631 clinical signs of, 169
from tinea unguium, 631 from Escherichia coli, 169
Scarlatiniform exanthem from Arcanobacterium from Listeria monocytogenes infections, 339
haemolyticum infections, 33 from Pasteurella infections, 435
Scarlatiniform rash from Yersinia pseudotuberculosis from Strongyloides, 591
infection, 723 treatment for, 518
Scarlet fever, 579i, 580i from Vibrio infections, 716
from group A streptococcal infections, 568 from Yersinia pseudotuberculosis infection, 723
Schistosoma haematobium, 529, 534i Septicemic plague, 457
Schistosoma intercalatum, 529 Serodiagnosis for strongyloidiasis, 591
Schistosoma japonicum, 529 Serologic antibody tests for Epstein-Barr virus, 166–167
Schistosoma mansoni, 529 Serologic assays
Schistosoma mekongi, 529 for Baylisascaris infections, 58
Schistosoma species eggs, 533i for enterovirus infections, 161
Schistosome dermatitis from schistosomiasis, 529, 533i for human herpesvirus 8, 269
Schistosomiasis, 529–534 for mumps, 393
clinical manifestations of, 529 for Toxoplasma gondii, 639
diagnostic tests for, 530 Serologic enzyme immunoassay tests for lymphatic
epidemiology of, 529–530 filariasis, 355
etiology of, 529 Serologic tests
with hepatosplenomegaly, 533i for American trypanosomiasis, 661
incubation period of, 530 for Chlamydophila pneumoniae, 95
oxamniquine for, 530 for Chlamydophila psittaci, 97
praziquantel for, 530 for hepatitis A, 227
treatment of, 530 for hepatitis B virus, 232
Scrapie prion protein, 481 for herpes simplex virus, 248
Scrotal lymphangitis, from lymphatic filariasis, 357i for leishmaniasis, 324
Seborrheic dermatitis for Lyme disease, 345
pityriasis versicolor and, 455 for malaria, 363
from tinea capitis, 622 for measles, 373

ERRNVPHGLFRVRUJ
INDEX 769

for nocardiosis, 401 Short-limb syndrome, 707i


for pertussis, 446 Shoulder myalgia from hantavirus pulmonary syndrome,
for schistosomiasis, 530 207
for Toxoplasma gondii, 639 Sickle cell dactylitis, 521i
for trichinellosis, 647 Sickle cell disease, Mycoplasma pneumoniae infections
for tularemia, 693 and, 396
Serratia marcescens, 169, 170 Sigmodon hispidus (cotton rat), 207, 210i
Serum antibody assay for tapeworm diseases, 612 Sigmoidoscopy for Balantidium coli infection, 56
Serum concentrations for rubella, 511 Sin Nombre virus (SNV), 207, 208i, 218
Serum C-reactive protein concentration for Kawasaki Sinusitis, 467
disease, 309 allergic, 38
Serum IgG antibody test for parvovirus B19, 431 from Arcanobacterium haemolyticum infections, 33
Serum specimens from Chlamydophila pneumoniae, 95
for epidemic typhus, 700 from group A streptococcal infections, 473
for plague, 457 from Haemophilus influenzae, 200
for severe acute respiratory syndrome, 123 from Mycoplasma pneumoniae infections, 396
for Vibrio cholerae infections, 713 from pneumococcal infections, 464
Serum varicella IgG antibody test for varicella-zoster Skeletal muscle biopsy specimen for trichinellosis, 647
infections, 706 Skin biopsies for leprosy, 331
Severe acute respiratory syndrome (SARS), 122–125, 124i Skin lesions, 164i
clinical manifestations of, 122 from blastomycosis, 64
diagnostic tests for, 123–124 from Burkholderia infections, 74
epidemiology of, 123 from leprosy, 331–332
etiology of, 122 from syphilis, 594
incubation period of, 123 from tinea cruris, 629
treatment of, 124 from varicella-zoster infections, 703
Sexual abuse from Vibrio infections, 716
acquired syphilis, 595 Skin scrapings
gonococcal infections, 191–192 for pityriasis versicolor, 455
Shiga toxin-producing E coli (STEC), 174, 174t, 175, 178i for tinea cruris, 629
Shigella boydii, 535 for tinea pedis and tinea unguium, 631
Shigella dysenteriae, 535 Skin warts, 407
Shigella flexneri, 535 Skunks as carriers of rabies virus, 490i
Shigella infections, 535–538 “Slapped cheek” appearance, in parvovirus B19 infections,
amoxicillin for, 536 430, 432i
ampicillin for, 536 Slate-colored macules from pediculosis pubis, 443
antimicrobial therapy for, 536 Sleep disturbance from pertussis, 445
azithromycin for, 536 Slit lamp examination for onchocerciasis, 405
ceftriaxone for, 536 Slit-smears for leprosy, 331
cephalosporins for, 536 Smallpox (variola), 539–543, 541i, 542i
ciprofloxacin for, 536 cidofovir for, 540
clinical manifestations of, 535 clinical manifestations of, 539–540
diagnostic tests for, 535–536 diagnostic tests for, 540
epidemiology of, 535 epidemiology of, 540
etiology of, 535 etiology of, 540
fluoroquinolone for, 536 incubation period of, 540
incubation period of, 535 lesions from, 541i, 542i, 543i
treatment of, 536 pustules, 542i
trimethoprim-sulfamethoxazole for, 536 treatment of, 540
Shigella sonnei, 535, 536i, 537i Sneezing from human coronaviruses, 122
Shigella species from bacterial vaginosis, 51 Snowstorm of acute histoplasmosis, 262i
Shigellosis Snuffles from syphilis, 594
bloody mucoid stool of, 538i Soft tissue infection from pneumococcal infections, 464
food poisoning from, 114 Somnolence from African trypanosomiasis, 657
Shingles from varicella-zoster infections, 703 Sore throat
Shock from babesiosis, 405
from dengue, 145 from Chlamydophila pneumoniae, 95
from group B streptococcal infections, 582 from human coronaviruses, 122
from hemorrhagic fever, 215 from influenza, 294
from hemorrhagic fever with renal syndrome, 218 from Lemierre disease, 183
from meningococcal infections, 378 from poliovirus infections, 476
from Rift Valley fever, 218 from Toxoplasma gondii infections, 637

ERRNVPHGLFRVRUJ
770 INDEX

South American blastomycosis (paracoccidioidomycosis), Staphylococcus aureus infections, 183, 294, 524, 548–567
411–412 abscesses, 562i
amphotericin B for, 411 chronic osteomyelitis of, 563i
clinical manifestations of, 411 colonization and disease, 550–551
diagnostic tests for, 411 health care–associated methicillin-resistant, 551
epidemiology of, 411 from influenza, 294, 303i
etiology of, 411 parenteral antimicrobial agents for treatment of,
incubation period of, 411 555t–556t
itraconazole for, 411 pyoderma caused by, 566i
treatment of, 411 transmission of, in hospitals, 550
Specific IgM antibody tests for parvovirus B19, 431 Staphylococcus epidermidis, 549, 560i
Spinal fluid specimens for mumps, 392 Staphylococcus haemolyticus, 549
Spirillum minus, 492, 493i Staphylococcus lugdunensis, 550
Spleen abscesses from Yersinia enterocolitica, 723 Staphylococcus saprophyticus, 549
Spleen lesions from candidiasis, 79–80 Staphylococcus schleiferi, 550
Splenic rupture from Epstein-Barr virus, 165 Stillbirth from syphilis, 594
Splenomegaly St. Louis encephalitis virus, disease caused by arboviruses
from Epstein-Barr virus, 167 in Western hemisphere, 26t
from human immunodeficiency virus infection, 276 Stocking glove purpura, 434
from tularemia, 693 Stoll egg counting techniques for hookworm infections,
Splinter hemorrhages, 649i 264
Spontaneous hemorrhage from Ehrlichia and Anaplasma Stomatitis from enterovirus infections, 160
infections, 154 Stool antigen test for Helicobacter pylori infections, 213
Sporadic insomnia, 481 Stool cultures
Sporothrix brasiliensis, 545 for Balantidium coli infection, 56
Sporothrix globosa, 545 for Giardia intestinalis infections, 186
Sporothrix Mexicana, 545 for Salmonella infections, 518
Sporothrix schenckii, 545, 546i, 547i for strongyloidiasis, 591
Sporotrichosis, 545–547 for Yersinia enterocolitica infections, 723
amphotericin B for, 546 for Yersinia pseudotuberculosis infections, 723
clinical manifestations of, 545 Stool specimens
diagnostic tests for, 545 for Blastocystis hominis infections, 62
disseminated, 545 for Clostridium perfringens food poisoning, 114
epidemiology of, 545 for cryptosporidiosis, 129
etiology of, 545 for cyclosporiasis, 136
extracutaneous, 545 for cystoisosporiasis, 306
fixed cutaneous, 545 for hookworm infections, 264
fluconazole for, 545 for isosporiasis, 306
incubation period of, 545 for poliovirus infections, 476
itraconazole for, 545 for schistosomiasis, 529
potassium iodide for, 545 for severe acute respiratory syndrome, 123
pulmonary, 545 Strand-displacement assays for gonococcal infections, 191
treatment of, 545–546 Strawberry cervix, 651, 653i
Spotted fever rickettsiosis, 504 Strawberry tongue of scarlet fever, 579i
Staphylococcal infections, 548–567 Streptobacillary fever, 492
cefazolin for, 554 Streptobacillus moniliformis, 492, 493i
clinical manifestations of, 548–549 Streptococcal impetigo, 570
diagnostic tests for, 552–554 Streptococcal infections, non–group A or B, 586–590
epidemiology of, 550–552 ampicillin for, 587
etiology of, 550 clinical manifestations of, 586
incubation period of, 552 diagnostic tests for, 587
nafcillin for, 554 epidemiology of, 586
oxacillin for, 554, 556 etiology of, 586
treatment of, 554 gentamicin for, 587
vancomycin for, 554 incubation period of, 587
Staphylococcal pneumonia, 565i penicillin G for, 587
Staphylococcal scalded skin syndrome (SSSS), 548, 564i treatment of, 587
Staphylococcal toxic shock syndrome, 548, 549, 558 vancomycin for, 587
Staphylococcus aureus enterotoxins, 114 Streptococcal pharyngitis, 569
Streptococcal skin infections from group A streptococcal
infections, 568
Streptococcal toxic shock syndrome, 568, 569
treatment of, 574, 575

ERRNVPHGLFRVRUJ
INDEX 771

Streptococcus agalactiae, 582, 584i, 586 primary, 594


Streptococcus anginosus, 586 secondary, 594, 610i
Streptococcus constellatus, 586 tertiary, 594
Streptococcus dysgalactiae subsp equisimilis, 586 tetracycline for, 599
Streptococcus intermedius, 586 treatment of, 598–602, 600t
Streptococcus pneumoniae, 378, 464, 468i, 469i, 470i, 586 Systemic febrile illness from arboviruses, 24
from influenza, 294 Systemic toxicity from Clostridium difficile, 111
Streptococcus pyogenes, 524, 568, 576i, 586
Streptococcus pyogenes pneumonia, 580i T
Streptococcus viridans subacute bacterial endocarditis, 588i
Strongyloides stercoralis (strongyloidiasis), 591–593, 592i Tachycardia from clostridial myonecrosis, 109
albendazole for, 592 Tachypnea from Pneumocystis jiroveci infections, 472
clinical manifestations of, 591 Taenia saginata, 611, 613i
diagnostic tests for, 591 Taenia saginata asiatica, 611
epidemiology of, 591 Taeniasis (tapeworm diseases), 611–615
etiology of, 591 albendazole for, 612
incubation period of, 591 anticonvulsants for, 612
ivermectin for, 592 clinical manifestations of, 611
larvae, 592i corticosteroid therapy for, 612
life cycle for, 593i diagnosis of, 611–612
treatment of, 592 epidemiology of, 611
Strongyloidiasis (Strongyloides stercoralis), 591–593, 592i etiology of, 611
albendazole for, 592 incubation period of, 611
clinical manifestations of, 591 niclosamide for, 612
diagnostic tests for, 591 ocular, 612
epidemiology of, 591 praziquantel for, 612
etiology of, 591 treatment of, 612
incubation period of, 591 Taenia solium, 611, 613i, 614i
ivermectin for, 592 Tapeworm diseases (taeniasis and cysticercosis), 611–615
treatment of, 592 albendazole for, 612
Subacute sclerosing panencephalitis (SSPE), 372 anticonvulsants for, 612
Subdural bleeding, in whooping cough neonate, 445 clinical manifestations of, 611
Submucosal hemorrhage of human anthrax, 22i corticosteroid therapy for, 612
Subungual hemorrhage from trichinellosis, 647 diagnosis of, 611–612
Suppurative cervical adenitis from group A streptococcal epidemiology of, 611
infections, 568 etiology of, 611
Surgical excision for warts, 409 incubation period of, 611
Surgical wound infection from group A streptococcal niclosamide for, 612
infections, 568 ocular, 612
Susceptibility testing for pneumococcal infections, 465 praziquantel for, 612
Sweats treatment of, 612
from babesiosis, 45 Tau protein for Creutzfeldt-Jakob disease, 482
from malaria, 361 Temperature instability from Escherichia coli, 169
Swimmer’s itch, 530, 533i Tenesmus
from schistosomiasis, 529 from Shigella infections, 535
Sylvatic typhus, 700 from trichuriasis, 655
Syncope from pertussis, 455 Tenosynovitis
Synergistic bacterial gangrene from gonococcal infections, 190
from Bacteroides infection, 53 from Pasteurella infections, 435
from Prevotella infection, 53 Terminal ileitis from Yersinia pseudotuberculosis infection,
Syphilis, 594–610 723
acquired, 594, 595 Tertiary syphilis, 594, 598
chancroid and, 93 Tetanus (lockjaw), 619–621, 620i
clinical manifestations of, 594 cephalic, 619
congenital, 594, 598–599, 606i, 607i, 608i clinical manifestations of, 619
diagnostic tests for, 595–598 diagnostic tests for, 619
doxycycline for, 599 epidemiology of, 619
epidemiology of, 595 etiology of, 619
etiology of, 595 generalized, 619
incubation period of, 595 incubation period of, 619
latent, 594 infant with, 620i
penicillin G for, 598 local, 619
with penile chancre, 609i metronidazole for, 620
neonatal, 619, 620i

ERRNVPHGLFRVRUJ
772 INDEX

Tetanus (lockjaw), continued Thyroiditis from mumps, 392


penicillin G for, 620 Tick bite rash, in Lyme disease, 352i
tetanus immune globulin for, 619–620 Tick-borne encephalitis virus, disease caused by
treatment of, 619–620 arboviruses in Western hemisphere, 26t
Thalassemia from parvovirus B19, 430 Timorian filariasis, 355–358
Thigh myalgia from hantavirus pulmonary syndrome, 207 Tinea capitis (ringworm of the scalp), 622–625, 624i, 625i
Thoracic disease from actinomycosis, 1 ciclopirox for, 623
Threadlike warts, 407 clinical manifestations of, 622
Throat specimens diagnostic tests for, 622–623
for enterovirus infections, 161 epidemiology of, 622
for poliovirus infections, 476 etiology of, 622
Throat washing for mumps, 392 fluconazole for, 623
Thrombocytic anaplasmosis, 156t griseofulvin for, 623–624
Thrombocytopenia incubation period of, 622
from African trypanosomiasis, 657 ketoconazole for, 623
from Argentine hemorrhagic fever, 215 selenium sulfide for, 623
from Bolivian hemorrhagic fever, 215 terbinafine for, 623
from Borrelia infections, 67 treatment of, 623
from congenital rubella, 510 Tinea corporis (ringworm of the body), 626–628, 627i,
from Ehrlichia and Anaplasma infections, 154 628i
from Epstein-Barr virus, 165 butenafine for, 626
from hepatitis B, 230 ciclopirox for, 626
from malaria, 361 clinical manifestations of, 626
from mumps, 392 clotrimazole for, 626
from Rocky Mountain spotted fever, 502 diagnosis of, 626
from rubella, 510 econazole for, 626
from syphilis, 594 epidemiology of, 626
from Toxoplasma gondii infections, 637 etiology of, 626
from varicella-zoster infections, 703 fluconazole for, 626
from Venezuelan hemorrhagic fever, 215 griseofulvin for, 626
Thrombocytopenic purpura from cat-scratch disease, 88 incubation period of, 626
Thrombophlebitis ketoconazole for, 626
from Chlamydophila psittaci, 97 miconazole for, 626
from psittacosis, 97 naftifine for, 626
Thrombosis, 38 oxiconazole for, 626
Thrush, 79–87 sulconazole for, 626
amphotericin B for, 80–81 terbinafine for, 626
anidulafungin for, 81 tolnaftate for, 624
from candidiasis, 79 treatment of, 626
caspofungin for, 81 Tinea cruris (jock itch), 629
chronic, 87i butenafine for, 629
ciclopirox for, 80 ciclopirox for, 629
clinical manifestations of, 79 clinical manifestations of, 629
clotrimazole for, 80 clotrimazole for, 629
congenital, 84i, 85i diagnostic tests for, 629
diagnostic tests for, 79–80 econazole for, 629
disseminated, 79 epidemiology of, 629
econazole for, 80 etiology of, 629
epidemiology of, 79 griseofulvin for, 630
etiology of, 79 incubation period of, 629
fluconazole for, 80, 81 ketoconazole for, 629
incubation period of, 79 miconazole for, 629
invasive, 80–81 naftifine for, 629
ketoconazole for, 80 oxiconazole for, 629
micafungin for, 81 sulconazole for, 629
miconazole for, 80 terbinafine for, 629
mucocutaneous, 79, 80, 86i tolnaftate for, 629
naftifine for, 80 treatment of, 629–630
nystatin for, 80 Tinea lesion, 624i
oral, 79, 85i Tinea pedis (athlete’s foot), 631–633, 632i, 633i
oral nystatin suspension for, 80 clinical manifestations of, 631
treatment of, 80–82 clotrimazole for, 631
vaginal, 79 diagnosis of, 631

ERRNVPHGLFRVRUJ
INDEX 773

econazole for, 631 incubation period of, 639


epidemiology of, 631 leucovorin for, 642
etiology of, 631 pyrimethamine for, 642
fluconazole for, 631 reactivation of chronic infection, 637–638
itraconazole for, 631 spiramycin for, 643
miconazole for, 631 sulfadiazine for, 642
terbinafine for, 631–632 treatment of, 642–643
treatment of, 631–632 trimethoprim-sulfamethoxazole for, 642
Tinea unguium (ringworm of the feet), 631–633, 633i Toxoplasma gondii retinitis, 645i
clinical manifestations of, 631 Toxoplasma gondii–specific IgA and IgE antibody test for
clotrimazole for, 631 toxoplasma, 639
diagnosis of, 631 Toxoplasmic encephalitis, 637–638, 641
econazole for, 631 Toxoplasmosis (Toxoplasma gondii), 637–646, 643i–646i
epidemiology of, 631 clindamycin for, 642
etiology of, 631 clinical manifestations of, 637–638
fluconazole for, 631 congenital, 637, 639
itraconazole for, 631 diagnostic tests for, 639–641
miconazole for, 631 epidemiology of, 638–639
terbinafine for, 631–632 etiology of, 638
treatment of, 631–632 from human immunodeficiency virus infection, 276
Tinea versicolor (pityriasis versicolor), 455–456, 456i incubation period of, 639
clinical manifestations of, 455 leucovorin for, 642
diagnosis of, 455 pyrimethamine for, 642
epidemiology of, 455 spiramycin for, 643
etiology of, 455 sulfadiazine for, 642
incubation period of, 455 treatment of, 642–643
treatment of, 455 trimethoprim-sulfamethoxazole for, 642
Tissue biopsy Trachipleistophora, 386
for candidiasis, 80 Trachoma, 99
for paracoccidioidomycosis, 411 azithromycin for, 101
Togaviridae, 25 from Chlamydia trachomatis, 99
Tonsillitis doxycycline for, 101
from adenovirus infections, 4 erythromycin for, 101
from Fusobacterium infections, 183 treatment of, 101
from tularemia, 693 Transbronchial biopsy for Pneumocystis jiroveci
Tonsillopharyngeal infection from gonococcal infections, infections, 473
190 Transcription-mediated amplification for gonococcal
Tonsillopharyngitis, 33 infections, 191
Tonsil swabbing for group A streptococcal infections, 570 Transient aplastic crisis from parvovirus B19, 430
Toxic shock syndrome Transient pneumonitis, acute, from Ascaris lumbricoides
from staphylococcal infections, 548, 549 infections, 35
treatment of, 574 Transmissible spongiform encephalopathies (prion
Toxocara canis, 413, 634, 635i, 635i diseases), 481–484, 484i
Toxocara cati, 634 clinical manifestations of, 481
Toxocariasis (visceral larva migrans, ocular larva diagnostic tests for, 482–483
migrans), 634–636 epidemiology of, 482
albendazole for, 634 etiology of, 481–482
clinical manifestations of, 634 incubation period of, 482
corticosteroid therapy for, 634 treatment of, 483
diagnostic tests for, 634 Transverse myelitis
epidemiology of, 634 from Epstein-Barr virus, 165
etiology of, 634 from mumps, 392
incubation period of, 634 from Mycoplasma pneumoniae infections, 396
treatment of, 634 from tapeworm diseases, 611
Toxoplasma gondii infections (toxoplasmosis), 637–646, Tremors from American trypanosomiasis, 660
643i–646i Treponemal tests for syphilis, 596
clindamycin for, 642 Treponema pallidum, 68, 594, 604i
clinical manifestations of, 637–638 Treponema pallidum particle agglutination (TP-PA) for
diagnostic tests for, 639–641 syphilis, 594
epidemiology of, 638–639 Triatomine bug, 662i
etiology of, 638 Trichinella spiralis, 647
from human immunodeficiency virus infection, 276,
290i

ERRNVPHGLFRVRUJ
774 INDEX

Trichinellosis (Trichinella spiralis), 647–650, 648i–650i ethionamide for, 674


albendazole for, 647 etiology of, 664–666
clinical manifestations of, 647 fluoroquinolones for, 674
corticosteroid therapy for, 647 incubation period of, 666
diagnostic tests for, 647 isoniazid for, 671
epidemiology of, 647 miliary, 683i
etiology of, 647 mycobacterial, 690i
incubation period of, 647 pyrazinamide for, 673–674, 676
mebendazole for, 647 renal, 664
treatment of, 647 rifampin for, 673, 676
Trichomonas vaginalis infections (trichomoniasis), from sporotrichosis, 545
651–654, 652i, 653i streptomycin for, 674
from bacterial vaginosis, 51 treatment of, 671–680, 672t
clinical manifestations of, 651 Tuberculosis disease, 664
diagnostic tests for, 651–652 drug resistance, 676
epidemiology of, 651 human immunodeficiency virus infection and, 289i
etiology of, 651 treatment of, 675–676
incubation period of, 651 Tularemia, 693–697, 695i
metronidazole for, 652 ciprofloxacin for, 694
tinidazole for, 652 clinical manifestations of, 693
treatment of, 652 diagnostic tests for, 693–694
Trichophyton interdigitale, 629 doxycycline for, 694
Trichophyton mentagrophytes, 626, 629, 631 epidemiology of, 693
Trichophyton rubrum, 626, 629, 631 etiology of, 693
Trichophyton schoenleinii, 622 gentamicin for, 694
Trichophyton tonsurans, 622, 626, 629 incubation period of, 693
Trichophyton verrucosum, 629 pneumonic, 693
Trichosporonosis, 180t treatment of, 694
Trichotillomania, tinea capitis and, 622 Tularemia pneumonia, 697i
Trichuriasis Tularemic ulcer, 697i
albendazole for, 655 Tympanocentesis for otitis media, 467
mebendazole for, 655 Typhoidal tularemia, 693
Trichuriasis (whipworm infection), 655 Typhoid fever from Salmonella infections, 520i, 522i
clinical manifestations of, 655 Typhus
diagnostic tests for, 655 endemic, 698–699
epidemiology of, 655 clinical manifestations of, 698
etiology of, 655 diagnostic tests for, 698
incubation period of, 655 doxycycline for, 698
treatment of, 655 epidemiology of, 698
Trichuris trichiura, 655 etiology of, 698
Trichuris trichiura colitis, 655 incubation period of, 698
Trigeminal neuralgia from herpes simplex virus, 247 treatment of, 698
Trismus epidemic, 700–701
from Lemierre disease, 183 chloramphenicol for, 701
from tetanus, 619, 620i clinical manifestations of, 700
Trypanosoma brucei gambiense infection, 657, 658i diagnostic tests for, 700–701
Trypanosoma brucei rhodesiense infection, 657 doxycycline for, 701
Trypanosoma cruzi, 660, 661i, 662i epidemiology of, 700
Trypanosomiasis etiology of, 700
African, 657–659 incubation period of, 700
American, 660–663 pediculicides for, 701
Tube agglutination for tularemia, 693 treatment of, 701
Tuberculin skin test (TST), 683i Tzanck test, 249, 252i, 253i
results from, 668–671
for tuberculosis, 664, 668 U
Tuberculosis, 664–685
clinical manifestations of, 664 Ulcer(s)
congenital, 664 from amebiasis, 7
corticosteroids for, 677 from Balantidium coli infection, 56
definitions of, 666–671 chancroid, 93
diagnostic tests for, 666–671 duodenal, from Helicobacter pylori infections, 213
epidemiology of, 666 gastric, from Helicobacter pylori infections, 213
ethambutol for, 674 genital, from chancroid, 93

ERRNVPHGLFRVRUJ
INDEX 775

skin, from leishmaniasis, 328i metronidazole for, 52


tularemia, 697i treatment of, 52
Ulcerative chancroid lesions, 94i Valvular heart disease from non–group A or B
Ulcerative enanthem from herpes simplex, 246 streptococcal and enterococcal infections, 586
Ulceroglandular syndrome from tularemia, 693 Vancomycin-intermediate Staphylococcus aureus (VISA),
Umbilical hernia from pertussis, 450i 552, 557
Undifferentiated B- or T-lymphocyte lymphomas from Vancomycin-resistant Staphylococcus aureus (VRSA), 552
Epstein-Barr virus, 165 Variant Creutzfeldt-Jakob disease, 481, 483i
Unilateral inguinal suppurative adenitis from chancroid, Varicella (chickenpox), 539, 707i
93 Varicella embryopathy, 707i
Upper respiratory tract culture for pneumococcal Varicella fasciitis, 710i
infections, 464 Varicella from HIV infection, 293i
Upper respiratory tract illness Varicella lesions, 708i, 709i
from human coronaviruses, 122 Varicella pneumonia, 710i
from respiratory syncytial virus, 494 Varicella-zoster virus (VZV) infections, 703–706
Urease testing for Helicobacter pylori infections, 213 acyclovir for, 706
Urethral obstruction from granuloma inguinale, 198 antiviral therapy for, 706
Urethritis clinical manifestations of, 703–704
from Campylobacter infections, 76 diagnostic tests for, 705–706, 705t
from Chlamydia trachomatis, 99 epidemiology of, 704–705
from gonococcal infections, 190 etiology of, 704
from Kawasaki disease, 309 famciclovir for, 706
from pinworm infection, 452 incubation period of, 705
from Trichomonas vaginalis infections, 651 treatment of, 706
Urgency from Schistosoma haematobium, 529 valacyclovir for, 706
Urinary tract infections Varicellovirus, 704
from Burkholderia infections, 73 Variola major, 539
from group B streptococcal infections, 582 Variola minor, 539, 541i
from non–group A or B streptococcal and Variola (smallpox), 539–543, 541i, 542i
enterococcal infections, 586 cidofovir for, 540
from Schistosoma haematobium, 529 clinical manifestations of, 539–540
from staphylococcal infections, 549 diagnostic tests for, 540
Urine specimens for gonococcal infections, 191 epidemiology of, 540
Urticarial rash from trichinellosis, 647 etiology of, 540
Uveitis from leptospirosis, 309 incubation period of, 540
lesions from, 541i, 542i, 543i
V pustules, 542i
treatment of, 540
Vaccine-associated paralytic poliomyelitis (VAPP), 476 Vascular collapse and shock from malaria, 361
Vaccines Vasculitis from Rocky Mountain spotted fever, 506i
for children with human immunodeficiency virus Venereal Disease Research Laboratory (VDRL) slide test
infection, 284–285 for syphilis, 596
for diphtheria, 149–150 Venezuelan equine encephalitis virus, 24
oral poliovirus, 476–477 disease caused by arboviruses in Western hemisphere,
Vaccinia, 540, 543i 26t
Vaginal candidiasis, 79 Venezuelan hemorrhagic fever, 215
Vaginal discharge Vertebral osteomyelitis, 563i
from chancroid, 93 Vesicular fluid for varicella-zoster infections, 705
from Trichomonas vaginalis infections, 651 Vesicular tularemia, 693
Vaginal swabs for gonococcal infections, 191 Vesivirus, 404
Vaginitis Vibrio alginolyticus, 716
from bacterial vaginosis, 51 Vibrio cholerae infections (cholera), 712–713, 713i, 714i
from Chlamydia trachomatis, 99 antimicrobial therapy for, 713
from gonococcal infections, 190 clinical manifestations of, 712
from group A streptococcal infections, 568 diagnostic tests for, 712–713
from pinworm infection, 452 epidemiology of, 712
Vaginosis, bacterial, 51–52 etiology of, 712
clindamycin for, 52 incubation period of, 712
clinical manifestations of, 51 parenteral rehydration for, 713
diagnostic tests for, 51–52 treatment of, 713
epidemiology of, 51 Vibriocidal antibody titers for Vibrio cholerae infections,
etiology of, 51 713
incubation period of, 51

ERRNVPHGLFRVRUJ
776 INDEX

Vibrio infections, 716 from smallpox, 539


aminoglycosides for, 716 from Strongyloides, 591
antimicrobial therapy for, 716 from trichinellosis, 647
cephalosporins for, 716 Vulvitis from bacterial vaginosis, 51
clinical manifestations of, 716 Vulvovaginal burning from Trichomonas vaginalis
diagnostic tests for, 716 infections, 651
doxycycline for, 716 Vulvovaginal candidiasis, treatment for, 80
epidemiology of, 716 Vulvovaginal infections
etiology of, 716 from Bacteroides infection, 53
incubation period of, 716 from Prevotella infection, 53
treatment of, 716 Vulvovaginal pruritus from Trichomonas vaginalis
trimethoprim-sulfamethoxazole for, 716 infections, 651
Vibrio parahaemolyticus, 716
Vibrio vulnificus, 716 W
Vincent stomatitis, 184i
Viral antigen Warts, 407
in nasopharyngeal specimens for respiratory syncytial anogenital, 407
virus, 495 cutaneous, 407
for parainfluenza virus infections, 385 cutaneous nongenital, 407
Viral cultures for West Nile virus, 719 filiform, 407
Viral gastroenteritis from Campylobacter infections, 76 flat, 407
Viral meningitis from poliovirus infections, 476 nongenital, 408
Viral nucleic acid plantar, 407
for hemorrhagic fever, 216 skin, 407
for human papillomaviruses, 408 threadlike, 407
Viral shedding tretinoin for, 409
from influenza, 295 Washerwoman’s hand, 715i
in respiratory syncytial virus, 494 Water contamination as cause of Escherichia coli diarrhea,
Viridans streptococci from non–group A or B 175
streptococcal and enterococcal infections, 586 Wayson stain for plague, 457
Visceral leishmaniasis (kala-azar), 323, 324, 328i Weakness
Visceral toxocariasis, 635i from brucellosis, 70
Visual impairment from tapeworm diseases, 611 from Q fever, 485
Vitamin A supplementation for measles, 373 from West Nile virus, 718
Vitamin B12 deficiency from tapeworm infections, 616 Weight loss
Vitiligo, pityriasis versicolor and, 373 from African trypanosomiasis, 657
Vittaforma, 312 from babesiosis, 45
Vomiting. See also Nausea from brucellosis, 70
from anthrax, 18 from cryptosporidiosis, 129
from astrovirus infections, 43 from cyclosporiasis, 136
from babesiosis, 45 from cystoisosporiasis, 306
from Bacillus cereus, 49 from histoplasmosis, 258
from Balantidium coli infection, 56 from isosporiasis, 306
from Clostridium perfringens food poisoning, 114 from leishmaniasis, 323
from cryptosporidiosis, 129 from nontuberculous mycobacteria, 686
from cyclosporiasis, 136 from paracoccidioidomycosis, 411
from cystoisosporiasis, 306 from tuberculosis, 664
from dengue, 145 Weil syndrome from leptospirosis, 335
from Ehrlichia and Anaplasma infections, 154 West African sleeping sickness, 657
from Escherichia coli, 169 Western blot assays
from hantavirus pulmonary syndrome, 207 for hantavirus pulmonary syndrome, 208
from Helicobacter pylori infections, 213 for human herpesvirus 8, 272
from hookworm infections, 264 Western blot serologic antibody test for paragonimiasis,
from influenza, 294 414
from isosporiasis, 306 Western equine encephalitis virus, disease caused by
from leptospirosis, 335 arboviruses in Western hemisphere, 26t
from malaria, 361 West Nile encephalitis virus, 26t
from pertussis, 445 West Nile virus (WNV), 718–722
from Q fever, 485 antigen for, 722i
from rat-bite fever, 492 clinical manifestations of, 718
from rickettsialpox, 500 diagnostic tests for, 719
from Rocky Mountain spotted fever, 502 epidemiology of, 718–719
from rotavirus infections, 508 etiology of, 718

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INDEX 777

histopathologic features of, 722i Y


incubation period of, 719
Yeast-phase antigen for Histoplasma capsulatum, 259
treatment of, 719
Yellow fever virus, 25, 29i, 30i
Wet-mount preparation of vaginal discharge for
disease caused by arboviruses in Western hemisphere,
Trichomonas vaginalis infection, 651
26t
Wheezing
vaccine recommendations, 29i, 30i
from human bocavirus, 66
Yersinia enterocolitica infections (enteritis and other
from respiratory syncytial virus, 494
illnesses), 723–725
from toxocariasis, 634
aminoglycosides for, 724
Whipworm infection (trichuriasis), 655
antimicrobial therapy for, 724
clinical manifestations of, 655
cephalosporin for, 724
diagnostic tests for, 655
chloramphenicol for, 724
epidemiology of, 655
clinical manifestations of, 723
etiology of, 655
diagnostic tests for, 724
incubation period of, 655
doxycycline for, 724
treatment of, 655
epidemiology of, 723–724
White blood cell count for pertussis, 446
etiology of, 723
Whooping cough (pertussis), 445–451
fluoroquinolones for, 724
antimicrobial therapy for, 446
incubation period of, 724
azithromycin for, 446
treatment of, 724
clinical manifestations of, 445
trimethoprim-sulfamethoxazole for, 724
diagnostic tests for, 445–446
Yersinia kristensenii, 725i
epidemiology of, 445
Yersinia pestis, 436i, 457, 458i, 459i, 463i
erythromycin for, 446
Yersinia pseudotuberculosis infections (enteritis and other
etiology of, 445
illnesses), 723–725
incubation period of, 445
aminoglycosides for, 724
treatment of, 446
antimicrobial therapy for, 724
trimethoprim-sulfamethoxazole for, 446
cephalosporin for, 724
Winterbottom sign, 657
chloramphenicol for, 724
Wood light examination for pityriasis versicolor, 455
clinical manifestations of, 723
World Health Organization (WHO), oral rehydration
diagnostic tests for, 724
solution (ORS), 713
doxycycline for, 724
Wound botulism, 104, 108i
epidemiology of, 723–724
Wound infections
etiology of, 723
from Arcanobacterium haemolyticum infections, 33
fluoroquinolones for, 724
from Bacillus cereus, 49
incubation period of, 724
from Burkholderia infections, 73
treatment of, 724
from staphylococcal infections, 548
trimethoprim-sulfamethoxazole for, 724
from Vibrio infections, 712
Wright-stained smear
for molluscum contagiosum, 389 Z
in Yersinia pestis, 459i Zygomycosis. See Mucormycosis
Wuchereria bancrofti, 355, 357i

X
Xenopsylla cheopis, 698
X-linked lymphoproliferative syndrome from Epstein-
Barr virus, 165

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Red Book ® ATLAS of pediatric infectious diseases   
Red Book ® Red Book ®

ATLAS
of pediatric infectious diseases
3rd Edition
Editor: Carol J. Baker, MD, FAAP
ATLAS
of pediatric infectious diseases

3rd Edition
Incorporating key content from the AAP Red Book®, this newly updated
edition provides must-know information for diagnosing, evaluating, and Editor: Carol J. Baker, MD, FAAP
treating more than 100 pediatric conditions.
A peerless pictorial resource Includes
More than 1,200 finely detailed clinical photos and
1,200+
radiographs illustrate disease features. Succinct
captions illuminate crucial aspects of patient images — 
presentation and disease processes and offer valuable with 400+
new! Now with

1c,o2lo 00+
insights for differential diagnosis.
A super-efficient quick reference and learning tool
Concise text descriptions step you through diagnosis, evaluation,
and management essentials for each condition. r photos
•  Clinical manifestations •  Incubation period
• Etiology • Diagnostic tests
• Epidemiology • Treatment
For other pediatric infectious disease resources, visit the
American Academy of Pediatrics at shop.aap.org.
BAKER

ERRNVPHGLFRVRUJ

AAP

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