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Ebola virus disease in the light of epidemiological

triad

Gurmeet Kaur, Sandeep Sachdeva, Diwakar Jha, Anika Sulania

Department of Community Medicine, North DMC Medical College, Hindu Rao Hospital, Delhi, India

Abstract
Ebola virus disease (EVD) is one of the most virulent pathogens among viral hemorrhagic fevers affecting economically deprived
countries of the world with reported case fatality rates of up to 90% due to multiorgan failure and severe bleeding complications.
The most recent outbreak of 2014 has set the alarm bell ringing across the globe for increased focus, funding, research, and
development toward the control and management of this emerging viral communicable disease that has a potential pandemic
threat. This manuscript review and update current knowledge with regard to epidemiology of EVD problem statement, historical
perspective, agent, host, environment, reservoir of infection, routes of transmission, pathogenesis, clinical features, laboratory
diagnosis, management, and control. The review was undertaken using the key words epidemiology, public health, outbreak control
of Ebola virus, EVD, emerging disease, and/or pandemic disease through medical search engines and abstracting databases
such as Pubmed, Google Scholar, and websites of international health agencies such as the World Health Organization (WHO)
and Centers for Disease Control and Prevention (CDC).
Keywords: Burial practices, communicable disease, emerging disease, environment, epidemiology, infection, public health, risk
exposure, surveillance, transmission

Introduction in the Philippines, Italy, and the USA). Figure 1 depicts


the affected countries in Western Africa during the most
Ebola virus disease (EVD) is a zoonotic disease caused by an recent outbreak. On August 8, 2014, the World Health
RNA virus of the family Filoviridae and genus Ebola virus Organization (WHO) declared the EVD outbreak in West
leading to severe hemorrhagic fever and fulminant septic Africa as a Public Health Emergency of International
shock.[1] In the 2014 outbreak though with the roots being Concern, emphasizing the need for international focus and
discovered in late 2013, events in West Africa changed cooperation to control the outbreak.[3] The imported EVD
the perception of EVD from an exotic tropical disease to a case in Nigeria resulted in a small outbreak and similar
global health security and threat.[2] This review manuscript imported cases in USA and Spain, which at first appeared
describes the current update with regard to disease burden, to have been wellcontained eventually led to infection
historical insight, agent, host, environment, reservoir, source, among health care workers.[4] EVD has an average case
routes of transmission, pathogenesis, clinical features, fatality rate of 50% while it was 76% in the 2014 outbreak
laboratory diagnosis, and control and management of EVD. in Guinea, Liberia, and Sierra Leon but was found to be

Problem Statement
The first outbreak occurred in Zaire (Congo) in 1976
followed by several outbreaks within Africa (except one

How to cite this article: Kaur G, Sachdeva S, Jha D, Sulania A.


Ebola virus disease in the light of epidemiological triad. Trop J Med
Res 2017;20:1-9.

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Kaur, et al.: Ebola virus disease

slightly less (61%) in hospitalized patients.[5,6] Globally remained restricted to a limited area [Table 1]. The rising
there were a total of 28,639 reported confirmed, probable trend of EVD outbreaks have occurred due to increased
and suspect cases of EVD in affected countries with 11,316 movement of people into previously inaccessible areas
deaths (Feb 2016) with a similar proportion in males and increased consumption of bush meat.[9] Figure 2
and females. As per WHO notification, human to human depicts Ebola outbreak (cases and death) in the African
transmission ended in Sierra Leone (Nov 2015); Guinea continent according to the years. The roots of current
(Dec 2015) and Liberia (Jan 2016). These countries have outbreak emanated somewhere during December 2013
entered into a 90days period of enhanced surveillance but it is not known with certainty how the index case
adults aged 1544 years are three to four times more became infected. [10] Genetic similarities among the
likely to be affected than children aged less than 14 years. samples of current outbreak suggest a single event of
A total of 874 confirmed health worker infections and 509 virus transmission from the natural reservoir followed by
deaths were reported in the abovementioned countries.[7] sustained humantohuman transmission.[11]

Historical Perspective Agent Factors


The discovery of Ebola began in Yambuku village in Ebola virus contains singlestranded negative RNA linear
Zaire where a Belgian nun became ill, and a Belgian genome, about 1819 kb in size and encodes seven genes
doctor sent her blood sample for investigation. (NP, VP35, VP40, VP30, VP24, L, and GP). [12] Five
Dr. Peter Piot, a clinical microbiologist, who saw this genetically distinct Ebola virus species within the genus
spaghettishaped virions under the electron microscope Ebola virus are known [Zaire Ebola virus (ZEBOV), Sudan
could not come to a conclusion. He mistook it to be Ebola virus (SEBOV), Tai Forest Ebola virus, Bundibugyo
the Marburg virus and sent the photo to other experts Ebola virus (BEBOV), and Reston Ebola virus (REBOV)].
in the world; however, they confirmed that it was The genomes of the five different Ebola viruses (BEBOV,
not the Marburg virus. The nun died and several ZEBOV, REBOV, SEBOV, and Ta Forest Ebola virus) are
villagers were affected by a similar illness and were different in sequence, number, and location of gene
dying. Piot travelled to Yambuku to investigate the overlaps. However, REBOV species is reported to cause
epidemic through a detailed history and maps to make disease only in nonhuman primates; ZEBOV, SEBOV, and
connections and within 3 months carried out extensive BEBOV are responsible for most of the Ebola hemorrhagic
isolation of cases and contacts. They thought of naming fever (EHF) outbreaks but ZEBOV constitutes a particularly
the virus after the Yambuku village but realized that it serious threat to both human and animals in subSaharan
would stigmatize the village, so they named the virus Africa with case fatality rates as high as 90%.
after the nearest river, the Ebola river.[8]
Reservoir of Infection
Historically, EVD outbreaks often occurred in small
villages close to or located in tropical rainforests and Fruit bats of the Pteropodidae family are considered to
be the natural reservoirs of Ebola virus.[13]

Figure 1: Countries affected in the 2014 Ebola outbreak in


West Africa Figure 2: EBV outbreak by year

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Table 1: EBV major epidemics episode according to region and year


Incidences of epidemics Year Regions affected Description
First 1976 Central Africa, Democratic Republic First outbreak of Ebola. Hemorrhagic fever
of Congo (ZAIRE), and Sudan
Second 1989 South Africa Mysterious outbreak (initially diagnosed as Simian hemorrhagic
Reston, Virginia fever virus among a shipment of crabeating macaque monkeys
impor ted from the Philippines. Named Reston Ebola virus
Third 2014 West Africaaffecting Guinea, Sierra Largest outbreak to date
Leone, Liberia, and Nigeria
EBV=Ebola virus

Source of Infection IMMUNITYEbola infection interferes with proper


functioning of the innate immune system. EBOV proteins
The virus is transmitted from wildlife to people through blunt the human immune response to viral infections by
contact with infected fruit bats and through intermediate interfering with the cells ability to produce and respond
hosts such as monkeys, apes, or pigs that become infected to interferon proteins such as interferonalpha, beta, and
through contact with bat saliva or feces. Ebola virus gamma. By inhibiting these immune responses, EBOV
can infect humans by direct contact with the blood and quickly spreads throughout the body.[2224]
body fluids of infected animals such as apes, gorillas,
and monkeys.[1416] No evidences show that pet cat/ Environment
dogs, mosquitoes, or other insects can transmit Ebola
virus. Humantohuman transmission occurs through SEASONHuman EVD outbreaks in Africa suggest that
direct contact with organs, blood, secretions of the the onset of these outbreaks was associated with conditions
body and other fluids (such as urine, feces, semen, with high absolute humidity and low temperature.
breast milk, mucus, vomit) of an infected person and Previous outbreaks in humans have been observed in both
materials contaminated with these fluids.[17,18] Infected dry and wet seasons.[25,26] Seasonal migration of fruit bats
syringes and needles are other ways by which the virus may result in increased contact with humans and other
can be transmitted while air or water does not spread animals. Bats naturally host many viruses that are highly
EVD. Breaches in the control of infections and universal pathogenic to other mammals. It has been hypothesized
precautions have resulted in frequent infections among that the flight activities of bats maintain a high body
health workers. Direct contact with the body of a deceased temperature and metabolic rate, which mimic the effect
person during burial ceremonies is another classic way of febrile immune response in limiting the virulence of a
by which Ebola can be transmitted.[19] virus that may otherwise be highly pathogenic. Seasonal
and behavioral factors such as long migratory flight may
Period of Infectivity influence body temperature and metabolic rate in bats.
This may result in altered susceptibility to and severity of
The incubation period of Ebola virus is 221 days and Ebola infection. Reduction in susceptibility and severity
therefore, it is recommended that infected individuals be may have bidirectional effects on Ebola transmission
isolated for at least 21 days. Latest studies have shown dynamics. While less severe infections may allow infected
that Ebola transmission occurs when there is a high viral bats to remain active in transmitting the virus, reduction
load in body fluids.[20] The person remains infectious as in susceptibility may reduce the overall infection rate
long as the virus is present in the blood and body fluids among the bat population.[2631] Peaks in mortality due
while those who have completely recovered from EBV to EVD in chimpanzees, gorillas, and duikers (a type
cannot spread it further. Ebola virus has been detected of antelope) were observed to coincide with some of
in the semen of recovered patients and such patients are the previous human outbreaks. [32] EVD outbreaks in
advised to abstain from sex or use condoms for three nonhuman primates have mostly been reported to occur
months after being cured. There is no evidence yet on at the end of rainy seasons.[33] However, it has been
when women recovering from the Ebola virus can resume unclear whether this was due to earlier humid conditions
breastfeeding.[21] or current dry conditions.

Host Factors Mode of Transmission


AGE AND SEXAll ages and both sexes show an equal EVD is a zoonotic disease and each outbreak in the human
preponderance for the disease. population is initiated by a (single) introduction from an

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Kaur, et al.: Ebola virus disease

animal reservoir. Ebola viruses enter the human body via convert the virus from the enzootic cycle to the epizootic
mucosal surfaces, abrasions, and injuries in the skin or by cycle of transmission [Figure 3].
direct parental transmission. It is likely that for the index
case, infection occurs after human contact with primates, for Clinical Features
example, due to hunting or consumption of infected animals
while other mammals such as antelopes and rodents have The symptoms of EVD begin with fever, headache, fatigue,
also been mentioned as potential reservoirs.[34] Due to the sore throat, and muscle pain, which later progress to anorexia,
high viral loads seen in the body fluids of EVD patients, nausea, diarrhea, vomiting, rash, abdominal pain, cough,
humantohuman transmission can easily occur. This shortness of breath, postural hypotension, edema, headache,
transmission seems to take place through body fluid contact
confusion, and coma. In certain cases, a maculopapular rash
and not by airborne transmission (e.g., infective aerosols).
develops after 57 days of the symptoms.[37,38] Hemorrhagic
When hygiene and personal protective measures are not
complications such as mucosal hemorrhages, nose bleeding,
adequate, the risk is considerable.[35] Furthermore, cultural
vomiting/coughing up of blood, blood in the stool, petechiae,
aspects such as local funeral ceremonies with potential
ecchymoses, and uncontrollable bleeding from venipuncture
contact with body fluids from patients who have died from
sites are seen in severe cases, along with other features such
EVD contributed to the magnitude of this outbreak.[36]
as severe metabolic disturbances, convulsion, shock, and
Sylvatic Ebola fever multiple organ failure. These complications are the most
In the tropical rainforests, Ebola occurs in monkeys and common causes of death in EBVinfected patients.[39] Figure 4
chimpanzees that consume halfeaten fruits left over by depicts the usual progression of EBV in humans.
fruit bats. These infected monkeys then pass the virus to
other monkeys by coming in contact of the body fluids Laboratory Diagnosis
of infected monkeys, chimpanzees, or pigs, etc. Humans
entering the forest come in contact with these infected Pathogenesis
monkeys or pigs due to hunting, bush meat preparation, Ebola after enters the body at the cellular level docks
and logging of woods; thus, humans enter the cycle and with the cell membrane and then viral RNA is released

Figure 3: Transmission of Ebola virus disease

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Kaur, et al.: Ebola virus disease

into the cytoplasm leading to the production of new viral After 3 days of the symptoms, the Ebola virus usually
proteins. New viral genomes rapidly coated in protein reaches detectable levels in blood and cannot be ruled
create cores, viral cores, stack up in cell, migrate to the out earlier than 3 days by any test. Even during the
cell surface and produce transmembrane proteins, then convalescent stage, the virus can be isolated from the
push through cell surface and become enveloped by cell blood, semen, tears, urine, feces, vaginal secretions,
membrane ssRNA genome mutations, which are capable and milk [Figure 5]. IgM enzymelinked ELISA,
of rapid mutation, very adaptable in evading host antigencapture ELISA, PCR, and virus isolation are the
defenses and environmental change, can cause direct diagnostic tests available and IgM and IgG antibodies
infection of tissues, immune dysregulation, hypovolemia, are used later in the disease course for the diagnosis of
vascular collapse, electrolyte abnormalities, multiorgan Ebola [Table 2].
failure, septic shock, disseminated intravascular
coagulation (DIC), and coagulopathy. Laboratory findings in EVD include coagulation
derangements such as prothrombin time (PT) and
Virus isolation and serology prolonged prothrombin time (PTT) prolonged,
It is difficult to diagnose Ebola virus in the early stages due a nd l e u k o p e ni a f o l l ow e d by n e u t r o p h i l i a ,
to nonspecific symptoms, which coexist in patients who thrombocytopenia (50,000100,000/mL range), and
are suffering from common diseases such as malaria and elevated liver enzyme: Elevation serum aspartate
typhoid fever. Seroconversion of the EVD can be detected aminotransferase (AST) > alanine transferase (ALT)
in the blood only when patient symptoms suggest a high and renal defects that include proteinuria and increased
level of virus load inside the body. This requires 3 days creatinine. Early and wellregulated inflammatory
in order to reach for viral detectable levels. Laboratory response with elevated interlukin (IL)6 concentration
test conducted in diagnosis such as antigencapture and IL1beta presence in a symptomatic patient is
enzymelinked immunosorbent assay (ELISA) testing, indicative of a good outcome while a defective innate
immunoglobin M (IgM) ELISA, and polymerase chain immune reaction with excessive macrophage/monocyte
reaction (PCR) using specific primers are used within a few activation with release of interleukin10, absent antibody
days of the onset of symptoms.[40] Immunohistochemistry response and elevated concentration of interleukin1RA,
testing, PCR, and virus isolation could be tested [Table 2]. and neopterin after a few days of the onset of disease
A team of international scientists under Cambridge are associated with a fatal outcome.[42] According to a
University released a dataset in 2015 that allows the study, lymphoid depletion and lymphopenia associated
global scientific community to monitor the pathogens with Zaire Ebola virus was most likely due to lymphocyte
evolution on a realtime basis. Sequencing the genome of apoptosis via Fas/Fas ligand (FasL) interaction. The
a virus tells us how it spreads and changes while passing excessive macrophage/monocyte activation leads to a
from one person to another. Rapid sequencing (in a matter cytokine storm triggering disseminated intravascular
of days) enables epidemiologists to decipher the source coagulation, hypotension, and vascular dysfunction,
of individual strains and helps to eliminate the need to resulting in multiple organ failure, vascular collapse,
rely upon Ebola patients to detail their travel history as and shock. [43] According to a recent study, elevated
different strains can be tracked without difficulty.[41] thrombomodulin and ferritin levels have been associated
with the death and hemorrhage in Ebola virusinfected
patients.[44]

Figure 4: Clinical feature of EBV in humans as observed in Figure 5: Detection of virus from different body fluids during
2014 outbreak the acute and convalescent phases

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Table 2: Lab diagnosis of EBV RNA by reverse transcriptasepolymerase chain


Timeline of infection Diagnostic tests available reaction (RTPCR) or by detection of IgM antibodies
Within a few days after ELISA directed against Marburg or Ebola
the symptoms begin IgM ELISA Noncase: Any suspected or probable case with a
PCR negative laboratory result. Noncase showed no
Virus isolation specific antibodies, RNA, or specific detectable
Later in the course of the IgM and IgG# antibodies antigens.
disease or after recovery
Retrospectively in Immunohistochemistry testing
deceased patients PCR Evd Risk Assessment
Virus isolation

ELISA=Enzymelinked immunosorbent assay, IgM=Immunoglobin M, PCR=Polymerase Highrisk exposure
chain reaction, #IgG=Immunoglobin G, EBV=Ebola virus Percutaneous (e.g., needle stick) or mucous membrane
exposure to blood or body fluids of a person with Ebola
Prevention of Ebola while the person was symptomatic or exposure to the
blood or body fluids (including but not limited to feces,
Various case definitions and risk assessment as advocated saliva, sweat, urine, vomit, and semen) of a person
for EBV for priority attention include: [45] with Ebola while the person was symptomatic without
appropriate personal protective equipment (PPE)
Person under investigation or processing blood or body fluids from an Ebola
A person who has both consistent symptoms and risk patient without appropriate PPE or standard biosafety
factors as follows: precautions or direct contact with a dead body
Clinical criteriaFever (>38.6C or 101.5F) and without appropriate PPE in a country with widespread
additional symptoms such as severe headache, transmission or cases in urban areas with uncertain
muscle pain, vomiting, diarrhoea, abdominal pain, control measures or having lived in the immediate
or unexplained haemorrhage; and epidemiologic household and provided direct care to a person with
risk factors within the past 21 days before the onset Ebola while the person was symptomatic.
of symptoms such as contact with blood or other
body fluids or human remains of a patient known
Some risk exposure
to have or suspected to have EVD; residence in or
In countries with widespread transmission or cases in
travel to an area where EVD transmission is active;
urban areas with uncertain control measures: Direct
or direct handling of bats or nonhuman primates
from diseaseendemic areas contact while using appropriate PPE with a person with
Suspected case: Any person, alive or dead, suffering Ebola while the person was symptomatic or with the
or having suffered from a sudden onset of high fever persons body fluids, any direct patient care in other
and having had contact with: A suspected, probable, health care settings or close contact in households, health
or confirmed Ebola or Marburg case; a dead or sick care facilities, or community settings with a person with
animal (for Ebola) or any person with the sudden Ebola while the person was symptomatic. Close contact
onset of high fever and at least three of the following is defined as being present at a close proximity for a
symptoms, i.e., headache, vomiting, anorexia/loss of prolonged period of time while not wearing appropriate
appetite, diarrhoea, lethargy, stomach pain, aching PPE within approximately 3 feet (1 meter) of a person
muscles or joints, difficulty swallowing, breathing with Ebola while the person was symptomatic. Public
difficulties, and hiccup or any person with inexplicable health action and supervision of the movement of persons
bleeding or any sudden, inexplicable death infected with EVD is shown in Table 3 according to risk
Probable case: Any suspected case evaluated by a
exposure.[46]
clinician or any deceased suspected case (where it
was not possible to collect specimens for laboratory
confirmation) having an epidemiological link with Control Measures
a confirmed case
Confirmed case: A case with laboratoryconfirmed The health system capacity of developing countries
diagnostic evidence of Ebola virus infection involved in EVD outbreak is very low and requires both
Laboratory confirmed case: Any suspected or short and longterm control measures. The international
probable cases with a positive laboratory result. community gave an overwhelming, decisive but delayed
Laboratoryconfirmed cases must test positive for response. Some of the generic and specific viral control
the virus antigen, either by the detection of virus measures include: [4752]

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Plans for emergency care including adequate Table 3: Public health monitoring and movement/restriction
quarantine facilities of people with EBV according to risk exposure
Prompt diagnosis and isolation of the suspected Risk Public health action
patient level Monitoring Restricted Restricted
Symptomatic management public activities travel
Adequate laboratory facilities and support High risk Direct active monitoring Yes Yes
Proper surveillance, case management, and contact Some Direct active monitoring Casebycase Casebycase
tracing risk assessment assessment
Health education and removal of stigma/myth/ Low risk Active monitoring for No No
misconception some; direct active
Restriction of the movement of people suffering from monitoring for others
EBV No risk No No No
Training of health care providers EBV=Ebola virus

Universal precaution including provision and


availability of logistics/equipment Table 4: List of EBV vaccine that is actively being developed
Safe burial practices for clinical use
Personal and safe hand hygiene Vaccine StatusFeature Company
Dedicated transport facilities for a person infected cAd3 Phage I
Attenuated GSK and NIAID
with EBV ZEBOV adenovirus
Change in dietary practices, especially of tribal VSVG Phage I Attenuated VSV NewLink Genetics
natives ZEBOV and PHAC
MVABN 2015a) Attenuated Bavarian Nordic
Promotion of sanitary environmental conditions vaccinia virus
Homeprotective kits AdVac 2015a) Attenuated Crucell
Recording, reporting, and incident management adenovirus
system SynCon Preclinical Polyvalent vaccine Inovio
Development and strengthening of communication VesiculoVax Preclinical Attenuated VSV ProfectusBioSciences
channels
VSV=Vesicular stomatitis virus, EBV=Ebola virus, MVABN=Modified vaccinia
Overall socioeconomic and infrastructure ankarabavarian nordic, GSK=Glaxo smith kline, NIAID=National institute of allergy and
infectious diseases, PHAC=Public Health Agency of Canada
development
International commitment, research, and funding.
Table 5: List of EBV drug that is actively being developed
for clinical use
Ebola Vaccine and Drugs Drug Status Feature Company
ZMapp Phage I Three chimeric LeafBio,
The disease always had an epicenter in African countries. monoclonal antibodies Inc.
Since 1976, no attempt were made to create the vaccine Favipiravir Approved Inhibition of viral RNA Fujifilm
against the deadly disease until at present, when the for IAV dependent RNA
localized problem has surmounted to become a global TKMEbola Phage I siRNA Tekmira
threat. Currently, there are no effective and target Brincidofovir Phage III Oral nucleotide analog Chimerix
BCX4430 Preclinical Inhibition of viral RNA BioCryst
vaccines or treatments which are approved for human use. polymerase
Tables 4 and 5 describes the potential Ebola vaccine and AVI7537 Phage I Binding Ebola RNA Sarepta
drugs in different stages of research and development.[40]
siRNA=Synthetic RNA, EBV=Ebola virus, TKM=Tekimira, IAV=Influenza A virus

Is India safe from EBV? But this does not rule out India to be safe from Ebola as
The current situation is unlikely to favor establishment it can be imported through any case/incubating Ebola
of EBV in India because of the following: traveler visiting India. The Government of India has issued
Bats: Absence of Pteropiridae family bats in India;
standard operating guidelines for the surveillance, control,
febrile immune response of bats resulting in
and management of EBV disease in accordance with the
attenuation of viral load; and localized flight range
of bats in the African subcontinent WHO protocols. India has health organization quarantine
Environment: Absence of high absolute humidity centers at 24 airports with all international airports and
and low temperature, along with rains for the sea ports to be equipped with thermal scanners in the
breeding of Ebola virus near future. The government has identified about 10
Virus: Absence of virus in the Indian subcontinent. laboratories in the country that will handle testing if a
Surveillance at major international airports, case is reported and in New Delhi, Dr. Ram Manohar
especially during the risk period. Lohia Hospital has been designated as nodal hospital

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