doi:10.1111/j.1440-1754.2007.01051.

ANNOTATION

Group A streptococcal infections in children

Andrew C Steer,1 Margaret H Danchin1 and Jonathan R Carapetis1,2
1
Centre for International Child Health, University of Melbourne, Department of Paediatrics, Murdoch Childrens Research Institute, Royal Childrens Hospital,
Melbourne, Victoria and 2Menzies School of Health Research, Darwin, Northern Territory, Australia

Abstract: The group A streptococcus causes the widest range of disease in humans of all bacterial pathogens. Group A streptococcal
diseases are more common in children than adults with diseases ranging from pharyngitis and impetigo to invasive infections and the post-
streptococcal sequelae acute rheumatic fever and acute post-streptococcal glomerulonephritis. The global burden of severe group A
streptococcal disease is concentrated largely in developing countries and Indigenous populations such as Aboriginal Australians. Control of
group A streptococcal disease is poor in these settings and the need for a vaccine has been argued. With an ever-increasing understanding of
the group A streptococcus at a molecular level, new and sophisticated vaccines are currently in human trials and the next decade holds exciting
prospects for curbing group A streptococcal diseases.

Key words: acute rheumatic fever; epidemiology; group A streptococcus; impetigo; pharyngitis; post-streptococcal glomerulonephritis.

The group A beta-haemolytic streptococcus (GAS) is a common
infective agent in children that causes the widest range of clini-
cal disease in humans of any bacterium. The spectrum of GAS
diseases can be divided into superficial, invasive, toxin-
mediated and post-infectious diseases (Table 1). The GAS has a
large armamentarium of virulence factors responsible for this
broad range of human disease. The most common infections
caused by GAS are pharyngitis and pyoderma, which occur
particularly in children. Invasive disease is less common but has
a high rate of mortality and long-term morbidity. Group A
streptococcal toxin-mediated diseases are scarlet fever and
streptococcal toxic shock syndrome (STSS), the latter of which
is usually found in association with invasive disease and has
a high case fatality rate. The post-infectious auto-immune
sequelae of GAS infection, acute rheumatic fever (ARF) and
acute post-streptococcal glomerulonephritis (APSGN), are the
Key Points
1 The group A streptococcus is a major bacterial pathogen affect-
ing children globally; the greatest burden of disease, particu-
larly invasive disease and post-streptococcal sequelae, is in
children in resource-poor areas.
2 Penicillin remains the treatment of choice for GAS disease;
intravenous immunoglobulin and clindamycin are important
adjuncts in treating invasive disease.
3 Vaccines against the GAS are in development, but an effective
and widely available vaccine is several years away; effective
treatment and control strategies against GAS disease are avail-
able to clinicians and public health specialists.
Correspondence: Professor Jonathan Carapetis, Menzies School of
Health Research, PO Box 41096, Casuarina, NT 0811, Australia. Fax:
+61 88922 8999; email: jonathan.carapetis@menzies.edu.au
Accepted for publication 19 April 2006.
major global causes of GAS-related morbidity and mortality, and
pose challenging questions about pathogenesis and control.
Around the world, an estimated 18 million people currently
suffer from a serious GAS disease with over 1.7 million new
cases per year and 500 000 deaths per year. In addition to
serious diseases, there are over 100 million prevalent cases of
pyoderma and over 600 million new cases of GAS pharyngitis
per year.3 Reports of outbreaks of ARF and an increasing inci-
dence of invasive disease in industrialised countries since the
1980s have highlighted GAS as a cause of disease in children in
these areas. However, the burden of severe GAS disease is
predominantly in developing countries and impoverished popu-
lations living in wealthy countries.
Microbiology and Pathogenesis
One hundred and twenty years after its discovery by Louis
Pasteur in 1879 the entire genome of an M1 strain of GAS was
sequenced in 2001,4 and a further eight strains sequenced
since.5 The GAS is a Gram-positive organism that is seen in
chains on Gram stain. On blood agar, GAS displays characteristic
beta-haemolysis due to the haemolysin streptolysin S. It is dif-
ferentiated from other streptococci by Lancefield grouping
based on serological specificity of cell wall group-specific
carbohydrates.6
The GAS has numerous surface and extracellular factors that
confer virulence (Fig. 1). With genetic sequencing more than
40 virulence associated genes have been revealed to date.4 The
cell surface M protein is the main antigenic determinant of
GAS.7 It aids in adherence but most importantly enables the
bacterium to evade phagocytosis which is the major defense
of the human host.7 Lipoteichoic acid, fibronectin binding
proteins and the hyaluronic acid capsule aid in adherence to
epithelial cells. M protein, capsule, streptokinase, the DNases,
hyaluronidase and SpeB are all responsible for the tissue

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Group A streptococcal infections in children AC Steer et al.

invasive capacity of GAS. C5a peptidase limits recruitment of

Table 1 The spectrum of clinical disease caused by the group A strep- phagocytes.8 Streptococcal inhibitor of complement aids in
tococcus in children (adapted from Curtis1 with permission) evading complement mediated killing.9
Asymptomatic colonisation Streptococcal pyrogenic exotoxins are responsible for the
Throat clinical features of STSS and scarlet fever by acting as superan-
Skin (immediately preceding infection) tigens, which stimulate around 20% of the T-cell population by
Also vagina, anus, scalp binding directly to the T-cell receptor rather than having to be
Supercial infection presented in the MHC II binding groove. Rheumatic fever is the
Pharyngitis and pharyngotonsillitis result of an interaction between a GAS strain with certain unde-
Pyoderma fined features that confer an ability to cause ARF and a host
Invasive disease with inherited susceptibility. This interaction leads to an auto-
Bacteraemia/septicaemia immune response directed against cardiac, synovial, subcutane-
Skin/soft tissue suppurative disease ous, epidermal and neuronal tissues. Traditional teaching states
Erysipelas that ARF follows pharyngitis but not pyoderma, although this
Cellulitis (including perianal cellulitis)
has recently been questioned.10 An auto-immune response to
Wound infection
GAS infection is also responsible for APSGN, probably due to
Varicella superinfection
deposition of a streptococcal antigen directly in the glomerulus.7
Necrotising fasciitis
Group A streptococcal typing is mainly based on the M pro-
Pyomyositis
tein in the past, serotyping was used but in recent years
Puerperal sepsis
Neonatal omphalitis
genotyping of the amino-terminal portion of the M protein gene
Suppurative respiratory disease (emm sequence typing) has largely replaced serotyping. There
Peritonsillar abscess are currently around 180 emm sequence types and 800 emm
Retropharyngeal abscess subtypes described, but new types and subtypes are being iden-
Cervical lymphadenitis tified regularly.
Sinusitis
Otitis media
Pneumonia Supercial Infections
Empyema
Pharyngitis
Central nervous system
Meningitis Epidemiology
Brain abscess
Musculoskeletal The GAS is the main bacterial cause of pharyngitis and is
Osteomyelitis responsible for around 1530% of cases of acute pharyngitis in
Septic arthritis children.11 The incidence of GAS culture-positive pharyngitis in
Cardiac school-aged children ranges from 0.95 per child-year in an
Endocarditis urban slum area of northern12 India to 0.13 per child year in
Gastrointestinal urban Melbourne.13
Peritonitis
Hepatic
Liver abscess Clinical features
Genitourinary
The features suggestive of GAS pharyngitis include age 5
Urinary tract infection
12 years (although with the advent of day care, rates in children
Toxin-mediated disease
Scarlet fever
aged 25 years appear to be increasing), fever, tender and
Streptococcal toxic shock syndrome enlarged anterior cervical nodes and tonsillopharyngeal
Post-infectious sequelae erythema and exudate.11 However, they are not sufficient to
Rheumatic fever allow an accurate diagnosis to be made without microbiological
Acute post-streptococcal glomerulonephritis confirmation. Features suggestive of a viral aetiology include
Reactive arthritis absence of fever, conjunctivitis, coryza and diarrhoea.14
Erythema nodusum Attempts to combine these features into a clinical algorithm for
PANDAS the diagnosis of GAS pharyngitis have been unsuccessful with
a relatively low sensitivity and specificity compared with bacte-
PANDAS, Paediatric Autoimmune Neuropsychiatric Disorders Associ- riological diagnosis.15
ated with Streptococcal infections the existence of this syndrome as a
distinct entity has been questioned.2
Diagnosis
Inoculation of a throat swab onto sheep-blood agar remains the
gold standard for diagnosis, with a sensitivity of 9095%.16
Rapid antigen tests are now also highly sensitive and specific,17
but they are not used widely in Australia.

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AC Steer et al. Group A streptococcal infections in children

Cytoplasmic Fibronectin binding

membrane proteins protein F,
opacity factor and others

Cytoplasm

Other extracellular
virulence factors
Streptolysin S
Streptolysin O
DNase A-D
Fig. 1 The basic outer cell antigenic structure
Hyaluronidase
of the group A streptococcus. Dnase, deoxyribo- Streptokinase
nuclease; NADase, NAD glycohydrolase; Spe, NADase
streptococcal pyrogenic exotoxin; SSA, strepto- C5a peptidase
coccal superantigen; SMEZ, streptococcal mito- Spe-B (Streptococcal
proteinase)
genic exotoxin Z; SIC, streptococcal inhibitor of
Spe-A,C,G,H,J-M
complement; GRAB, a surface protein which SSA
binds the proteinase inhibitor 2-macroglobulin; Peptidoglycan
SMEZ and SMEZ-2
layer
SOD, superoxide dismutase; Mac, a homologue SIC
of human CD11b that inhibits opsonophagocyto- Group specific carbohydrate GRAB
sis; Sc1A and 1B, cell wall-attached proteins that SOD
Mac
aid in adherence to human cells; EndoS and IdeS, Hyaluronic acid capsule Sc1A and 1B
2 secreted enzymes that have specic effects on -helical M protein and EndoS and IdeS
IgG. M-related protein

Management Presenting complaint with sore throat

Clinical examination
In populations with a low incidence of ARF the need to inves-
tigate and treat GAS pharyngitis has been questioned.18,19 Rea-
sons to treat GAS pharyngitis include prevention of ARF,
prevention of suppurative complications, reduction of the No features of Features suggest GAS pharyngitis:
severity or duration of symptoms and reduction of secondary GAS - Age 415 years
pharyngitis - Fever
transmission of GAS.19,20 Balanced against this are the side - Tonsillopharyngeal erythema or exudate
effects of antibiotic therapy, the risk of treatment failure - Tender or enlarged anterior cervical
lymph nodes
(around 1015% bacteriological failure using penicillin)21 and
- Absence of viral symptoms (cough,
promotion of antibiotic resistance. The reduction in duration of coryza, conjunctivitis)
illness using antibiotic treatment is said to be modest, although
this has been underestimated because very few studies have Throat swab and culture
been conducted in children with proven GAS pharyngitis or Penicillin V 250 mg children / 500 mg adults bd
those with severe symptoms, the group in whom the benefits (or IM benzathine penicillin G single dose*)

of antibiotic treatment may be greatest.19,22,23 A recent clinical

trial also found a high rate of quinsy in placebo-treated children,
raising the possibility that suppurative complications may
increase if antibiotic treatment of sore throat is abandoned.22
Until better data are available, we recommend antibiotic
treatment for sore throat of more than mild severity in patients
with features consistent with GAS pharyngitis, with the main
aim of symptomatic relief, and secondary aims of preventing
suppurative and non-suppurative sequelae and reducing trans-
mission of virulent strains (Fig. 2). All treated cases should have
a throat culture (or rapid antigen test) performed and antibiotics
should be discontinued if these tests are negative. Investigation
and antibiotic treatment are not indicated if the sore throat is
of mild severity and there are no or minimal concerns about
the other aims of treatment. Antibiotic treatment should not be
based on clinical features alone. These recommendations do not
relate to populations at high risk of ARF (e.g. Indigenous Aus-
tralians living in tropical and subtropical areas) as these patients
should always have antibiotic treatment,24 and ideally culture
confirmation if available.
Culture negative for Culture positive for
GAS GAS
No
investigations Cease antibiotics Continue antibiotics
No antibiotics for 10 days
Fig. 2 Recommendations for the management of acute pharyngitis in
populations at low risk of acute rheumatic fever (adapted from Danchin23
with permission). *Erythromycin may be used for proven penicillin-allergic
patients. GAS, group A streptococcus; IM, intramuscular.
Penicillin is the first-line agent most commonly recom-
mended for GAS pharyngitis.14,21,24 However, there is generally
a 20% to 25% higher eradication rate after the use of more
broad spectrum agents, such as cephalosporins25 and azithromy-
cin,26 compared with penicillin. A recent meta-analysis sug-
gested an increased likelihood of bacteriological and clinical
failure in adult patients with GAS pharyngitis treated with oral

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Group A streptococcal infections in children
penicillin compared with oral cephalosporins,27 although this
claim has been strongly refuted.28,29 Given its record of success
over several decades for both treatment of GAS pharyngitis and
primary prevention of ARF, and that there has never been a
clinical isolate of GAS resistant to it, we recommend that pen-
icillin remains the antibiotic of choice for this indication.
Pyoderma
Epidemiology
Pyoderma refers to localised purulent infection of the skin. It
is an umbrella term for non-bullous impetigo, bullous impe-
tigo and folliculitis.30 Non-bullous impetigo is the most com-
mon form of pyoderma and is usually due to GAS, whereas
bullous impetigo and folliculitis are usually due to Staphylococ-
cus aureus. The aetiology of pyoderma differs between develop-
ing and industrialised nations. In tropical developing countries
and other impoverished populations such as the Aboriginal
population in Australia, GAS is the major pathogen, while
S. aureus appears to predominate in temperate, industrialised
countries.31
Pyoderma is endemic in children in many developing coun-
tries with prevalence rates averaging 7%.3 The exception is that
in Aboriginal Australians and in Pacific nations prevalence rates
of pyoderma are often over 50%.3,32 Infestation by the scabies
mite is commonly an underlying cause in these populations.33
Clinical features
Clinically, GAS non-bullous impetigo is usually indistinguish-
able from non-bullous impetigo caused by S. aureus. The infec-
tion commonly presents as a small pimple which evolves to a
purulent lesion covered by a honey-coloured crust. Lesions are
most commonly found on the arms or legs, at the sites of minor
trauma that are invariably needed for the organism to establish
an infection.34 The organism is highly transmissible, so affected
children may develop lesions elsewhere on their body, and
multiple cases within the same household or classroom are
quite common (hence the term school sores).
Management
In industrialised countries where superficial bacterial skin dis-
ease is less common, where the causative organism is often
S. aureus, and where local complications and post-streptococcal
sequelae are less common, most mild cases will respond to
topical treatment with mupirocin. Moderate cases can be
treated successfully with oral anti-staphylococcal antibiotics
such as flucloxacillin or cephalexin. A recent Cochrane review
of 57 trials suggested that topical mupirocin or fusidic acid is at
least as effective as oral anti-staphylococcal antibiotics.35
However, the results of the Cochrane review are not easily
applicable to developing countries and populations such as
remote Aboriginal people. The trials included in the review did
not come from these settings, where streptococcal impetigo is
most common and often severe, outbreaks of APSGN due to
virulent skin strains of GAS may occur, and invasive GAS dis-
ease occurs at high rates, often as a result of skin infection.36,37
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AC Steer et al.
In addition, the possible but unproven link between GAS skin
disease and ARF10 increases the importance of adequate treat-
ment. In remote Aboriginal communities, widespread use of
mupirocin for impetigo resulted in rapid emergence of methi-
cillin-resistant S. aureus.38 Intramuscular benzathine penicillin G
is currently the treatment of choice for streptococcal impetigo,39
although oral antibiotics such as flucloxacillin or cephalexin are
good alternatives when adherence can be assured. The effec-
tiveness of benzathine penicillin G may be reduced if S. aureus
emerges as a major cause of impetigo in developing countries
and Indigenous populations. It is important to ensure that
underlying scabies is appropriately treated, and that family
members and other close contacts are also examined and treated
for pyoderma and scabies. In populations with high rates of
scabies-related pyoderma, community treatment with scabi-
cides alone has been shown to reduce rates of pyoderma.40
Invasive Disease and Toxin-
Mediated Disease
Invasive GAS disease occurs when the bacterium infects a nor-
mally sterile site (Table 1). STSS occurs when an infecting GAS
strain produces toxins that lead to a characteristic set of clinical
features.
Epidemiology
From the 1980s onwards, severe GAS diseases were reported to
increase in incidence and severity North America, Europe and
Australia.4143 This change in epidemiology may relate to the
emergence of virulent strains of GAS. The incidence of invasive
GAS disease in most industrialised countries is between 2.5 and
3 per 100 000 and mortality rates vary between 10% and 20%.3
Recent data suggest that invasive GAS infections occur at
increased rates in developing countries. It is estimated that more
than 660 000 cases of invasive disease resulting in more than
160 000 deaths occur globally each year, most in developing
countries.3 The peak incidence of these infections occurs in
infants and elderly adults. Data from developing countries sug-
gest that GAS is the most common cause of invasive bacterial
disease in young infants aged 759 days.44 A Kenyan study found
that the incidence of GAS bacteraemia in children <15 years was
13 per 100 000 with a comparatively high mortality rate of
25%.3,45 Aboriginal Australians are at particularly high risk of
invasive infections with crude hospital-based incidence rates
of invasive GAS disease in the Northern Territory of 23.8 per
100 00037 and in north Queensland 82.5 per 100 000.46
Invasive GAS infections are more common in adults with
other comorbidities although many cases (and almost all in
children) occur in otherwise healthy individuals. Varicella infec-
tion is the most commonly identified precipitating factor in
children. There also may be an association between the use of
non-steroidal anti-inflammatory drugs and necrotising fasciitis
or STSS.47
Clinical features
The GAS causes a wide range of focal invasive infections includ-
ing soft tissue infections (in approximately 60% of cases),
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AC Steer et al.
pneumonia, meningitis and others (Table 1). Bacteremia with-
out focus occurs in approximately 15% of cases of invasive GAS
disease. Usually there is little to distinguish GAS from other
bacterial causes of focal invasive disease, except that GAS infec-
tions are usually severe, more likely to cause complications, and
often slower to respond to treatment than other bacteria.
Necrotising fasciitis is a severe infection of muscle fascia,
subcutaneous fat and epidermis that rapidly leads to necrosis of
muscle fascia usually progressing to limb and life-threatening
disease within 24 h.48 In children, 90% of deaths occur in the
first 48 h after presentation.49 The recognition of infection beyond
the dermis is critical in diagnosing necrotising fasciitis severe
pain and tenderness disproportionate to the physical findings as
well as skin bullae and blistering are the clinical hallmarks that
differentiate necrotising fasciitis from more superficial infec-
tion.48 Survivors frequently require amputation or reconstructive
surgery, and many are left with permanent disability.
Pneumonia comprises around 10% of invasive GAS disease.50
Pneumonia due to GAS is often severe and empyema is very
common in one earlier series 100% of children with GAS
pneumonia had empyema.51 The exudate is often thick, persists
for several days and patients invariably require re-drainage or
surgical decortication. Children usually require 3 weeks or
more of antibiotics and persistence of fever for up to 10 days is
common.
In the 1930s GAS was the second most common cause of
meningitis after pneumococcus.52 Today, GAS meningitis is
uncommon in industrialised countries, but it remains common
in children in developing countries, particularly in young
infants and neonates.44,53 In children, approximately 50% of
patients have a distant primary focus of infection, usually
pharyngotonsillitis. Rates of neurological sequelae after GAS
meningitis are between 36% and 46%, the highest among the
major bacterial causes of meningitis.53,54
Streptococcal toxic shock syndrome
Streptococcal toxic shock syndrome occurs when the infecting
strain of GAS produces superantigens. The clinical features of
STSS include fever and rash with rapid progression to shock and
multiorgan failure (Table 255). Most patients have fever and
50% have hypotension at presentation; the other 50% will
develop hypotension within 4 h.47 The typical sunburn type
rash in STSS is widespread, erythematous, macular and blanch-
ing. Characteristically, there is subsequent desquamation about
2 weeks after the initial illness. Scarlet fever shares these clinical
features of erythematous rash and desquamation scarlet fever
and STSS are at extreme ends of the spectrum of streptococcal
toxin-mediated diseases. Scarlet fever was widely feared in the
nineteenth and early twentieth centuries with cyclic pandemics
of severe disease with high mortality. Although STSS was first
described in the mid 1980s,56 it almost certainly existed before
this time and it is likely that these early descriptions of severe
or septic scarlet fever were in fact cases of STSS.57
Streptococcal toxic shock syndrome has been described in
association with numerous foci of infection but soft tissue infec-
tion, usually necrotising fasciitis, is the most common focus
(approximately 60% of STSS cases).58 The GAS is isolated in
blood cultures in approximately 6080% of cases of STSS.41 In
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Group A streptococcal infections in children
Table 2 Diagnostic criteria for streptococcal toxic shock syndrome55
Streptococcal toxic shock syndrome case denition
1 Isolation of the group A streptococcus
A From a sterile site (denite case)
B From a non-sterile site (probable case)
2 Clinical signs of severity
A Hypotension
B Two or more of the following clinical and laboratory
abnormalities:
a Fever (>38.5C)
b Rash (diffuse macular erythema with subsequent
desquamation)
c Renal impairment
d Coagulopathy (platelets <100 or disseminated intravascular
coagulation)
e Liver abnormalities
f Adult respiratory distress syndrome
g Extensive tissue necrosis (including necrotising fasciitis)
contrast, in staphylococcal toxic shock syndrome, S. aureus is
cultured from the blood in only 3% of patients.59 The case
fatality rate of STSS is approximately 50%,41 although recent
data suggest that this is substantially lower in Australia (J
Carapetis, unpubl. data, 2005).
Management of invasive group A streptococcal
disease and STSS
The absence of sufficient features to fulfil the formal diagnostic
criteria should not deter early provisional diagnostic and
empiric treatment of STSS. Factors to consider in the manage-
ment of severe GAS disease are (i) aggressive supportive care;
(ii) early surgical debridement of necrotic tissue; (iii) correct use
of antibiotics; and (iv) intravenous immunoglobulin (IVIG).
Aggressive supportive care is the most important aspect of
management of severe GAS disease, particularly in STSS.
Patients often require massive fluid resuscitation due to the
capillary leak syndrome.
Wide surgical debridement of non-viable tissue in necrotising
fasciitis has been shown to improve outcome.60 However, if the
diagnosis is made before extensive tissue destruction or shock
has occurred, correct use of antibiotics and early administration
of IVIG may reduce the need for, or extent of, debridement.61
Penicillin is the antibiotic of choice for all GAS infections,
including severe invasive disease. There has never been a clini-
cal isolate of GAS resistant to penicillin. In the early stages of
severe invasive disease, particularly in impending or established
STSS or necrotising fasciitis, clindamycin should be added to
penicillin. Clindamycin has the theoretical benefits of circum-
venting the Eagle effect, reducing GAS toxin production, poten-
tiating phagocytosis, possessing superior tissue penetration and
having a longer post-antibiotic effect.6264 However, clindamycin
should not be used alone because of the possibility of resistance,
and only needs to be used for the first days of management until
the patient is stabilised.
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Group A streptococcal infections in children
Neutralising antibodies to GAS and streptococcal toxins have
been found in IVIG and humoral immunity is known to be
important in protecting against GAS disease.65 A randomised
controlled trial of the use of IVIG in STSS was stopped prema-
turely before statistically significant results were obtained
because of slow patient recruitment.66 However, the limited
data from this trial and a historically controlled observational
study67 suggest benefit in the use of IVIG in STSS. With this in
mind most experts recommend the use of IVIG in severe GAS
disease. It should be given early after presentation. There are a
number of dosing regimens but we recommend 2 g/kg as a
single infusion.
Post-streptococcal Diseases
The process by which GAS causes post-streptococcal disease is
poorly understood. Post-streptococcal diseases include ARF and
rheumatic heart disease (RHD), APSGN, erythema nodosum
and post-streptococcal reactive arthritis (PSRA). Post-strepto-
coccal reactive arthritis does not fulfil the Jones Criteria for the
diagnosis of ARF, and patients are said not to be at risk of cardiac
valvular damage. However, because some patients with this
diagnosis have later developed confirmed episodes of ARF, the
clinician should be very cautious about making a diagnosis of
PSRA. In populations with a high incidence of ARF, the diag-
nosis of PSRA should rarely, if ever, be made. Even in popula-
tions with low rates of ARF, it is recommended that penicillin
prophylaxis be administered for 1 year and then discontinued
if there is no evidence of valvular disease.68
Acute rheumatic fever and rheumatic heart disease
Epidemiology
Coinciding with the apparent resurgence of invasive GAS dis-
ease in the developed world, ARF also re-appeared in middle
class areas of the USA.69 This change in epidemiology has been
attributed to changes in the virulence of circulating strains of
GAS and possibly susceptibility in the host. In addition, chang-
ing patterns of antibiotic use, in particular the movement away
from using antibiotics for treating GAS pharyngitis in countries
with low rates of ARF, may also have affected the epidemiology
of GAS diseases.
The major burden of ARF and RHD is in developing countries
and in populations of Indigenous people living in poverty in
industrialised countries.3,70 More than 2.4 million children aged
514 years have RHD world-wide and 94% of these are in
developing countries.3 There are over 330 000 new cases of ARF
each year in children aged 514 years world-wide.3
In Australia, Indigenous people bear almost the entire brunt
of ARF and RHD, and have among the highest documented
rates in the world. The incidence of ARF in Northern Territory
Aboriginal children aged 514 years ranges from 250 to 350 per
100 000. The prevalence of RHD in Aboriginal people of all ages
in the same region is 1317 per 1000.71 Recent data from the
Top End of the Northern Territory suggest that the prevalence
in Aboriginal people is almost 20 per 1000.72
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AC Steer et al.
Clinical features
Acute rheumatic fever begins approximately 3 weeks after a
GAS infection (range 15 weeks), which is often asymptomatic.
The clinical features of ARF are outlined in the Jones Criteria
which were most recently updated in 1992.72 A World Health
Organization (WHO) expert advisory group has recently sug-
gested how the Jones Criteria should be applied to first and
recurrent episodes (Table 3).73 In particular, the WHO criteria
note that recurrent ARF can be diagnosed in a patient with RHD
based only on minor criteria, provided other more likely diag-
noses have been excluded. A diagnosis of ARF can be made
without other manifestations or evidence of recent streptococcal
infection in cases of isolated chorea or subacute carditis. In
addition, the WHO revisions have also allowed special consid-
eration to be given to patients in high incidence areas who
present with polyarthralgia or monoarthritis, fever and elevated
acute phase reactants to be considered as probable rheumatic
fever and be commenced on secondary prophylaxis. Recently
published guidelines on the diagnosis and management of ARF
and RHD in Australia recommend that polyarthralgia or
monoarthritis be considered as major criteria in high-risk popu-
lations such as Aboriginal Australians.74
In experienced hands, echocardiography can help to identify
and characterise rheumatic valvular disease, including subclin-
ical valve lesions.75,76 The significance of these findings is not
certain and as such the American Heart Association and the
WHO decided not to include echocardiographic evidence of
rheumatic valvular disease in their versions of the ARF diagnos-
tic criteria. However, clinicians serving populations with high
rates of ARF and RHD commonly use echocardiographically
diagnosed rheumatic valvular disease as a major manifestation
in interpreting the Jones criteria. The recently published Aus-
tralian ARF and RHD guidelines recommend that all patients
with suspected ARF should have an echocardiogram and that
subclinical carditis, based upon standard criteria, be considered
as a major criterion in high-risk populations such as Aboriginal
Australians.74
Rheumatic heart disease
Rheumatic heart disease is the chronic valvular pathology that
can follow ARF. Chronic valvular damage is most likely when
the first attack of ARF is severe and in the young patient, and
when there are recurrent attacks of ARF.77 The mitral valve is
involved in more than 90% of cases with mitral incompetence
the predominant lesion in young people and mitral stenosis
occurring in around 25% of patients in adolescence or adult-
hood.78 The aortic valve may also be affected damage to the
tricuspid or pulmonary valves in RHD is always due to increased
pressures from mitral or aortic valvular disease, not because of
direct rheumatic inflammation to the right-sided heart valves.
Management
Management of ARF primarily involves confirming the diagno-
sis, relieving the pain of arthritis, and managing cardiac failure
with medication or, rarely, surgery. All patients with ARF
should receive a dose of intramuscular benzathine penicillin G
Journal of Paediatrics and Child Health 43 (2007) 203213
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AC Steer et al.
Table 3 20022003 World Health Organization criteria for the diagnosis of rheumatic fever and rheumatic heart disease73
The Jones Criteria (1992 Update):
Major manifestations
Minor manifestations
Evidence of antecedent
GAS infection
Diagnostic categories:
Primary episode of ARF
Recurrent attack of ARF in a patient without established RHD
Recurrent attack of ARF in a patient with established RHD
Rheumatic chorea Insidious onset rheumatic carditis
Chronic valve lesions of RHD (patients presenting for the rst
time with pure mitral stenosis or mixed mitral valve disease
and/oraortic valve disease)
ARF, acute rheumatic fever; GAS, group A streptococcus; RHD, rheumatic heart disease.
or 10 days of oral penicillin V, although there is little empirical
evidence to suggest that this affects the outcome.79 Salicylates
or non-steroidal anti-inflammatory drugs are used only for
symptomatic relief of joint inflammation and fever; they have
no role in the treatment of carditis.80 Corticosteroids are some-
times used for the treatment of severe cardiac failure, although
there is no evidence that they affect the likelihood of develop-
ing, or the severity of, subsequent RHD.81 Most cases of Syden-
hams chorea can be treated without medication; more severe
cases should be treated with either carbamazepine or valproic
acid.82
Management of RHD primarily involves close follow-up,
ensuring adherence to secondary prophylaxis, and medical or
surgical treatment of cardiac failure if it develops. In recent
years, there has been a trend toward operating earlier in the
natural history of disease, when valvular tissue is not severely
scarred and calcified.83 This may allow the surgeon to repair
rather than replace the valve leaflets, which in turn provides a
good functional result without the need for long-term anti-
coagulation.84 The prognosis after mechanical valve replace-
ment in remote Aboriginal people is particularly poor, with only
52% of patients remaining alive without a major complication
5 years after surgery.85
Journal of Paediatrics and Child Health 43 (2007) 203213
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Journal compilation 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
Group A streptococcal infections in children
Carditis
Polyarthritis
Chorea
Erythema marginatum
Subcutaneous nodules
Clinical: Arthralgia
Fever
Laboratory: Elevated acute phase reactants (erythrocyte sedimentation rate,
leukocyte count)
ECG: Prolonged PR interval
Elevated or rising streptococcal antibody titres (anti-streptolysin-O or anti-DNase B titre)
Positive throat culture or rapid streptococcal antigen test
Recent scarlet fever
Criteria (using above Jones Criteria):
Two major manifestations, or
One major and two minor manifestations
Plus
Evidence of antecedent GAS infection
Two minor manifestations
Plus
Evidence of antecedent GAS infection
Two major manifestations, or
One major and two minor manifestations
Plus
Evidence of antecedent GAS infection
Other major manifestations or evidence of antecedent
GAS infection not required
Do not require any other criteria to be diagnosed as having RHD
There are two recognised methods of control of ARF and RHD
primary and secondary prophylaxis. Primary prophylaxis is
the prompt and accurate diagnosis of GAS pharyngitis and treat-
ment with 10 days of oral penicillin V or a single dose of intra-
muscular benzathine penicillin G. This method can prevent
ARF.19,86 However, in practice it has had little impact on ARF
incidence in developing countries, because of difficulties in pro-
viding diagnostic services, the poor performance of clinical diag-
nostic algorithms for GAS pharyngitis, problems with the
availability and quality of antibiotics, different health-seeking
behaviour for sore throats, and the fact that only one-third of
people with ARF report a previous sore throat severe enough
for them to seek medical care, even in industrialised countries.87
Secondary prophylaxis involves regular administration of pen-
icillin (usually 4-weekly benzathine penicillin G) for many years.
This strategy prevents recurrent ARF, avoids further damage to
heart valves, and has been demonstrated to lead to regression
of existing heart valve lesions and reduce RHD mortality.88 This
is the only intervention that has proven to be practical and cost-
effective in all settings, and should be the mainstay of efforts to
control RHD.73 Secondary prophylaxis and other aspects of RHD
care and control are most effectively delivered as part of a
coordinated, register-based RHD control programme.
209
Group A streptococcal infections in children
Acute post-streptococcal glomerulonephritis
Epidemiology
There are over 470 000 cases of APSGN that occur annually
leading to approximately 5000 deaths, with 97% of these cases
in less developed countries.3 APSGN, unlike ARF, tends to occur
in outbreaks that are associated with virulent skin strains of
GAS.89 Several outbreaks have been described in Aboriginal
children in northern Australia associated with GAS pyoderma.90
Clinical features
The symptoms and signs of APSGN appear 13 weeks after GAS
pharyngitis and 36 weeks after GAS pyoderma. Whereas ARF
rarely occurs in children aged less than 4 years, APSGN may
occur in younger children, sometimes in the first 2 years of life.
The most common presentation of APSGN is dark urine and
facial oedema (Table 4). Hypertension occurs in around 60
70% of cases, primarily as a result of water and salt retention,
although in some cases a nephrotic syndrome may occur.
With the activation of the alternative pathway of the comple-
ment system, C3 levels are almost always diminished early in
the disease this is an important diagnostic test in APSGN.92
Other causes of nephritis including systemic lupus erythemato-
sus which can present with similar clinical features and low
serum complement levels. In APSGN the depression of C3 is
transient and should return to normal at 68 weeks.93 The C3
level should therefore be re-checked at 68 weeks and if it
remains depressed then other diagnoses including systemic
lupus erythematosus must be considered.
Renal biopsy is generally not required if the diagnosis is clear
indications for biopsy may include the development of acute
renal failure, nephrotic syndrome, insufficient evidence of ante-
cedent streptococcal infection and a persistently low serum C3
level. In most cases of APSGN the clinical course is benign, but
overwhelming acute renal failure with crescent formation does
occur.93 Acute mortality is low in settings where high quality
medical care is available. Management of oedema and hyper-
tension is important and is usually able to be controlled with
Table 4 The diagnostic criteria for acute post-streptococcal
glomerulonephritis91
The presence of two or more of the following:
1 Macroscopic or microscopic haematuria (>10 red blood cells/mm3 on
urine microscopy or 2+ on urine dipstick)
2 Oedema (any of denite facial pufness, pitting peripheral oedema,
ascites, or other clear evidence of oedema)
3 Hypertension (diastolic blood pressure >90 mmHg in children
13 years and older or >80 mmHg in children <13 years)
And
Reduced serum C3 level
And
Evidence of antecedent streptococcal infection (Elevated or rising anti-
streptolysin-O titre or anti-DNase B titre or isolation of GAS from throat
or skin sore culture or positive rapid antigen test from throat swab)
210
Journal compilation 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
AC Steer et al.
fluid restriction and frusemide. Serum potassium should be
monitored as patients may present with hyperkalemia. Angio-
tensin-converting enzyme inhibitors such as captopril can be
considered as second line agents.
There is no evidence that primary prophylaxis (i.e. treatment
of a person already infected with a nephritogenic strain to
prevent the development of APSGN) is effective. However, on
a public health level mass benzathine penicillin administration
in the setting of an outbreak may contain further cases partic-
ularly by targeting treatment of children with skin sores and
household contacts of cases.94 There are now a number of
reports in northern Australia documenting the success of mass
benzathine penicillin administration in the setting of an epi-
demic, including one program that focused on treating those
with pyoderma only.90,91
Epidemic APSGN in children has a very favourable outcome
with a 10-year renal survival rate of 92% and minimal risk of
hypertension.95,96 However, the coexistence in Aboriginal Aus-
tralians in the Northern Territory of endemic pyoderma, high
rates of APSGN and high rates of end-stage renal failure have
raised the question of whether childhood APSGN could be a risk
factor for chronic renal failure later in life.97
Vaccine Development
Group A streptococcal vaccine development has fallen into two
groups focused on either M protein antigens or non-M protein
antigens. Among the non-M protein antigens being investigated
are GAS carbohydrate, C5a peptidase and fibronectin binding
proteins; none of these has progressed to clinical trials.
M protein vaccines are either based upon the variable ami-
noterminus region these vaccines are multivalent and type-
specific or the C-terminal conserved region these antigens
are thought to be common to most or all GAS strains (Fig. 3).
The most advanced vaccine candidate is one based upon the
aminoterminus region. An N-terminal vaccine based on 26 emm
types has undergone phase I and II clinical trials in adults, with
good evidence of safety and immunogenicity.99 It is estimated
Variable
Aminoterminus between
strains
A repeat region
B repeat region
Conserved
C repeat region between
strains
D repeat region or
transmembrane region
Fig. 3 Schematic drawing of the M protein (adapted from Good98).
Journal of Paediatrics and Child Health 43 (2007) 203213
2007 The Authors
AC Steer et al.
that this 26 valent vaccine will provide protection against 80
90% of invasive GAS isolates in North America.100 However,
there are many circulating emm types of GAS, and the dominant
strains can change rapidly, even in affluent communities.101 The
diversity of emm types in developing countries is even greater,
and new emm types emerge frequently.102 Therefore, while type-
specific vaccines hold promise in affluent communities, they
may prove to have limited effectiveness in developing countries
and other settings with high rates of GAS diseases.
Vaccines based on the conserved region of the M protein may
potentially provide protection against all GAS strains. Research-
ers in Australia have identified a peptide in the conserved C
repeat region that induces antibodies that are opsonic and pro-
tective in mice.103 Clinical trials of this candidate are currently
in preparation.
Any GAS vaccine will be required to undergo strict safety
evaluation because of the possibility that the vaccine itself could
induce autoimmunity. This concern arose after a crude M-
protein-based vaccine appeared to be associated with cases of
ARF when administered to siblings of ARF patients in the
1970s.104 Although this study provided no conclusive proof that
the vaccine was dangerous, and numerous other GAS vaccine
trials have not been associated with any cases of ARF, the US
Food and Drug Administration disallowed the administration of
GAS vaccines to humans. GAS vaccine development is now
proceeding following review of this legislation. However, a GAS
vaccine remains at least several years away, and a vaccine that
is effective and affordable in developing countries is an even
more distant possibility. Therefore, there is an urgent need to
institute effective public health control measures, particularly
in developing countries.
Acknowledgement
The authors would like to thank Dr Michael Batzloff, Queen-
sland Institute of Medical Research, Brisbane, Australia, for his
kind assistance in developing Figure 1.
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