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R ev i ew A r t i c l e

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
Ebola virus disease(EVD) is a zoonotic disease caused by an
RNA virus of the family Filoviridae and genus Ebola virus
leading to severe hemorrhagic fever and fulminant septic
shock.[1] In the 2014 outbreak though with the roots being
discovered in late 2013, events in West Africa changed
the perception of EVD from an exotic tropical disease to a
global health security and threat.[2] This review manuscript
describes the current update with regard to disease burden,
historical insight, agent, host, environment, reservoir, source,
routes of transmission, pathogenesis, clinical features,
laboratory diagnosis, and control and management of EVD.

Problem Statement
The first outbreak occurred in Zaire(Congo) in 1976
followed by several outbreaks within Africa(except one
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in the Philippines, Italy, and the USA). Figure1 depicts


the affected countries in Western Africa during the most
recent outbreak. On August 8, 2014, the World Health
Organization(WHO) declared the EVD outbreak in West
Africa as a Public Health Emergency of International
Concern, emphasizing the need for international focus and
cooperation to control the outbreak.[3] The imported EVD
case in Nigeria resulted in a small outbreak and similar
imported cases in USA and Spain, which at first appeared
to have been wellcontained eventually led to infection
among health care workers.[4] EVD has an average case
fatality rate of 50% while it was 76% in the 2014 outbreak
in Guinea, Liberia, and Sierra Leon but was found to be
Address for correspondence: Dr.Sandeep Sachdeva,
Department of Community Medicine, North DMC Medical College,
Hindu Rao Hospital, Delhi110007, India.
Email:sachdevadr@yahoo.in
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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, etal.: Ebola virus disease

slightly less(61%) in hospitalized patients.[5,6] Globally


there were a total of 28,639 reported confirmed, probable
and suspect cases of EVD in affected countries with 11,316
deaths (Feb 2016) with a similar proportion in males
and females. As per WHO notification, human to human
transmission ended in Sierra Leone (Nov 2015); Guinea
(Dec 2015) and Liberia (Jan 2016). These countries have
entered into a 90-days period of enhanced surveillance
adults aged 1544years are three to four times more
likely to be affected than children aged less than 14years.
Atotal of 874 confirmed health worker infections and 509
deaths were reported in the abovementioned countries.[7]

remained restricted to a limited area [Table 1]. The rising


trend of EVD outbreaks have occurred due to increased
movement of people into previously inaccessible areas
and increased consumption of bush meat.[9] Figure2
depicts Ebola outbreak(cases and death) in the African
continent according to the years. The roots of current
outbreak emanated some-where during December 2013
but it is not known with certainty how the index case
became infected. [10] Genetic similarities among the
samples of current outbreak suggest a single event of
virus transmission from the natural reservoir followed by
sustained humantohuman transmission.[11]

Historical Perspective

Agent Factors

The discovery of Ebola began in Yambuku village in


Zaire where a Belgian nun became ill, and a Belgian
doctor sent her blood sample for investigation.
Dr.Peter Piot, a clinical microbiologist, who saw this
spaghettishaped virions under the electron microscope
could not come to a conclusion. He mistook it to be
the Marburg virus and sent the photo to other experts
in the world; however, they confirmed that it was
not the Marburg virus. The nun died and several
villagers were affected by a similar illness and were
dying. Piot travelled to Yambuku to investigate the
epidemic through a detailed history and maps to make
connections and within 3months carried out extensive
isolation of cases and contacts. They thought of naming
the virus after the Yambuku village but realized that it
would stigmatize the village, so they named the virus
after the nearest river, the Ebola river.[8]

Ebola virus contains singlestranded negative RNA linear


genome, about 1819kb in size and encodes seven
genes(NP, VP35, VP40, VP30, VP24, L, and GP).[12] Five
genetically distinct Ebola virus species within the genus
Ebola virus are known[Zaire Ebola virus(ZEBOV), Sudan
Ebola virus(SEBOV), Tai Forest Ebola virus, Bundibugyo
Ebola virus(BEBOV), and Reston Ebola virus(REBOV)].
The genomes of the five different Ebola viruses(BEBOV,
ZEBOV, REBOV, SEBOV, and Ta Forest Ebola virus) are
different in sequence, number, and location of gene
overlaps. However, REBOV species is reported to cause
disease only in nonhuman primates; ZEBOV, SEBOV, and
BEBOV are responsible for most of the Ebola hemorrhagic
fever(EHF) outbreaks but ZEBOV constitutes a particularly
serious threat to both human and animals in subSaharan
Africa with case fatality rates as high as 90%.

Historically, EVD outbreaks often occurred in small


villages close to or located in tropical rainforests and

Figure 1: Countries affected in the 2014 Ebola outbreak in


West Africa
2

Reservoir of Infection
Fruit bats of the Pteropodidae family are considered to
be the natural reservoirs of Ebola virus.[13]

Figure 2: EBV outbreak by year

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Table1: EBV major epidemics episode according to region and year


Incidences of epidemics
First

Year
1976

Second

1989

Third

2014

Regions affected
Central Africa, Democratic Republic
of Congo(ZAIRE), and Sudan
South Africa
Reston, Virginia
West Africa-affecting Guinea, Sierra
Leone, Liberia, and Nigeria

Description
First outbreak of Ebola. Hemorrhagic fever
Mysterious outbreak(initially diagnosed as Simian hemorrhagic
fever virus among a shipment of crabeating macaque monkeys
imported from the Philippines. Named Reston Ebola virus
Largest outbreak to date

EBV=Ebola virus

Source of Infection
The virus is transmitted from wildlife to people through
contact with infected fruit bats and through intermediate
hosts such as monkeys, apes, or pigs that become infected
through contact with bat saliva or feces. Ebola virus
can infect humans by direct contact with the blood and
body fluids of infected animals such as apes, gorillas,
and monkeys.[1416] No evidences show that pet cat/
dogs, mosquitoes, or other insects can transmit Ebola
virus. Humantohuman transmission occurs through
direct contact with organs, blood, secretions of the
body and other fluids(such as urine, feces, semen,
breast milk, mucus, vomit) of an infected person and
materials contaminated with these fluids.[17,18] Infected
syringes and needles are other ways by which the virus
can be transmitted while air or water does not spread
EVD. Breaches in the control of infections and universal
precautions have resulted in frequent infections among
health workers. Direct contact with the body of a deceased
person during burial ceremonies is another classic way
by which Ebola can be transmitted.[19]

IMMUNITYEbola infection interferes with proper


functioning of theinnate immune system.EBOV proteins
blunt the human immune response to viral infections by
interfering with the cells ability to produce and respond
to interferon proteins such asinterferonalpha,beta, and
gamma. By inhibiting these immune responses, EBOV
quickly spreads throughout the body.[2224]

Environment

The incubation period of Ebola virus is 2-21days and


therefore, it is recommended that infected individuals be
isolated for at least 21days. Latest studies have shown
that Ebola transmission occurs when there is a high viral
load in body fluids.[20] The person remains infectious as
long as the virus is present in the blood and body fluids
while those who have completely recovered from EBV
cannot spread it further. Ebola virus has been detected
in the semen of recovered patients and such patients are
advised to abstain from sex or use condoms for three
months after being cured. There is no evidence yet on
when women recovering from the Ebola virus can resume
breastfeeding.[21]

SEASONHuman EVD outbreaks in Africa suggest that


the onset of these outbreaks was associated with conditions
with high absolute humidity and low temperature.
Previous outbreaks in humans have been observed in both
dry and wet seasons.[25,26] Seasonal migration of fruit bats
may result in increased contact with humans and other
animals. Bats naturally host many viruses that are highly
pathogenic to other mammals. It has been hypothesized
that the flight activities of bats maintain a high body
temperature and metabolic rate, which mimic the effect
of febrile immune response in limiting the virulence of a
virus that may otherwise be highly pathogenic. Seasonal
and behavioral factors such as long migratory flight may
influence body temperature and metabolic rate in bats.
This may result in altered susceptibility to and severity of
Ebola infection. Reduction in susceptibility and severity
may have bidirectional effects on Ebola transmission
dynamics. While less severe infections may allow infected
bats to remain active in transmitting the virus, reduction
in susceptibility may reduce the overall infection rate
among the bat population.[2631] Peaks in mortality due
to EVD in chimpanzees, gorillas, and duikers(a type
of antelope) were observed to coincide with some of
the previous human outbreaks.[32] EVD outbreaks in
nonhuman primates have mostly been reported to occur
at the end of rainy seasons.[33] However, it has been
unclear whether this was due to earlier humid conditions
or current dry conditions.

Host Factors

Mode of Transmission

AGE AND SEXAll ages and both sexes show an equal


preponderance for the disease.

EVD is a zoonotic disease and each outbreak in the human


population is initiated by a(single) introduction from an

Period of Infectivity

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animal reservoir. Ebola viruses enter the human body via


mucosal surfaces, abrasions, and injuries in the skin or by
direct parental transmission. It is likely that for the index
case, infection occurs after human contact with primates, for
example, due to hunting or consumption of infected animals
while other mammals such as antelopes and rodents have
also been mentioned as potential reservoirs.[34] Due to the
high viral loads seen in the body fluids of EVD patients,
humantohuman transmission can easily occur. This
transmission seems to take place through body fluid contact
and not by airborne transmission(e.g.,infective aerosols).
When hygiene and personal protective measures are not
adequate, the risk is considerable.[35] Furthermore, cultural
aspects such as local funeral ceremonies with potential
contact with body fluids from patients who have died from
EVD contributed to the magnitude of this outbreak.[36]
Sylvatic Ebola fever
In the tropical rainforests, Ebola occurs in monkeys and
chimpanzees that consume halfeaten fruits left over by
fruit bats. These infected monkeys then pass the virus to
other monkeys by coming in contact of the body fluids
of infected monkeys, chimpanzees, or pigs, etc. Humans
entering the forest come in contact with these infected
monkeys or pigs due to hunting, bush meat preparation,
and logging of woods; thus, humans enter the cycle and

convert the virus from the enzootic cycle to the epizootic


cycle of transmission[Figure3].

Clinical Features
The symptoms of EVD begin with fever, headache, fatigue,
sore throat, and muscle pain, which later progress to anorexia,
nausea, diarrhea, vomiting, rash, abdominal pain, cough,
shortness of breath, postural hypotension, edema, headache,
confusion, and coma. In certain cases, a maculopapular rash
develops after 5-7days of the symptoms.[37,38] Hemorrhagic
complications such as mucosal hemorrhages, nose bleeding,
vomiting/coughing up of blood, blood in the stool, petechiae,
ecchymoses, and uncontrollable bleeding from venipuncture
sites are seen in severe cases, along with other features such
as severe metabolic disturbances, convulsion, shock, and
multiple organ failure. These complications are the most
common causes of death in EBVinfected patients.[39] Figure4
depicts the usual progression of EBV in humans.

Laboratory Diagnosis
Pathogenesis
Ebola after enters the body at the cellular level docks
with the cell membrane and then viral RNA is released

Figure 3: Transmission of Ebola virus disease


4

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into the cytoplasm leading to the production of new viral


proteins. New viral genomes rapidly coated in protein
create cores, viral cores, stack up in cell, migrate to the
cell surface and produce transmembrane proteins, then
push through cell surface and become enveloped by cell
membrane ssRNA genome mutations, which are capable
of rapid mutation, very adaptable in evading host
defenses and environmental change, can cause direct
infection of tissues, immune dysregulation, hypovolemia,
vascular collapse, electrolyte abnormalities, multiorgan
failure, septic shock, disseminated intravascular
coagulation(DIC), and coagulopathy.

After 3days of the symptoms, the Ebola virus usually


reaches detectable levels in blood and cannot be ruled
out earlier than 3days by any test. Even during the
convalescent stage, the virus can be isolated from the
blood, semen, tears, urine, feces, vaginal secretions,
and milk[Figure5]. IgM enzymelinked ELISA,
antigencapture ELISA, PCR, and virus isolation are the
diagnostic tests available and IgM and IgG antibodies
are used later in the disease course for the diagnosis of
Ebola[Table2].

Virus isolation and serology


It is difficult to diagnose Ebola virus in the early stages due
to nonspecific symptoms, which coexist in patients who
are suffering from common diseases such as malaria and
typhoid fever. Seroconversion of the EVD can be detected
in the blood only when patient symptoms suggest a high
level of virus load inside the body. This requires 3days
in order to reach for viral detectable levels. Laboratory
test conducted in diagnosis such as antigencapture
enzymelinked immunosorbent assay(ELISA) testing,
immunoglobin M(IgM) ELISA, and polymerase chain
reaction(PCR) using specific primers are used within a few
days of the onset of symptoms.[40] Immunohistochemistry
testing, PCR, and virus isolation could be tested[Table2].
Ateam of international scientists under Cambridge
University released a dataset in 2015 that allows the
global scientific community to monitor the pathogens
evolution on a realtime basis. Sequencing the genome of
a virus tells us how it spreads and changes while passing
from one person to another. Rapid sequencing(in a matter
of days) enables epidemiologists to decipher the source
of individual strains and helps to eliminate the need to
rely upon Ebola patients to detail their travel history as
different strains can be tracked without difficulty.[41]

Laboratory findings in EVD include coagulation


derangements such as prothrombin time(PT) and
prolonged prothrombin time(PTT) prolonged,
and leukopenia followed by neutrophilia,
thrombocytopenia(50,000100,000/mL range), and
elevated liver enzyme: Elevation serum aspartate
aminotransferase(AST) > alanine transferase(ALT)
and renal defects that include proteinuria and increased
creatinine. Early and wellregulated inflammatory
response with elevated interlukin(IL)6 concentration
and IL1beta presence in a symptomatic patient is
indicative of a good outcome while a defective innate
immune reaction with excessive macrophage/monocyte
activation with release of interleukin10, absent antibody
response and elevated concentration of interleukin1RA,
and neopterin after a few days of the onset of disease
are associated with a fatal outcome.[42] According to a
study, lymphoid depletion and lymphopenia associated
with Zaire Ebola virus was most likely due to lymphocyte
apoptosis via Fas/Fas ligand(FasL) interaction. The
excessive macrophage/monocyte activation leads to a
cytokine storm triggering disseminated intravascular
coagulation, hypotension, and vascular dysfunction,
resulting in multiple organ failure, vascular collapse,
and shock.[43] According to a recent study, elevated
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


2014 outbreak

Figure 5: Detection of virus from different body fluids during


the acute and convalescent phases

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Table2: Lab diagnosis of EBV


Timeline of infection
Within a few days after
the symptoms begin
Later in the course of the
disease or after recovery
Retrospectively in
deceased patients

Diagnostic tests available


ELISA
IgM ELISA
PCR
Virus isolation
IgM and IgG# antibodies
Immunohistochemistry testing
PCR
Virus isolation

ELISA=Enzymelinked immunosorbent assay, IgM=Immunoglobin M, PCR=Polymerase


chain reaction, #IgG=Immunoglobin G, EBV=Ebola virus

Prevention of Ebola
Various case definitions and risk assessment as advocated
for EBV for priority attention include:[45]
Person under investigation
A person who has both consistent symptoms and risk
factors as follows:
Clinical criteriaFever(>38.6C or 101.5F) and
additional symptoms such as severe headache,
muscle pain, vomiting, diarrhoea, abdominal pain,
or unexplained haemorrhage; and epidemiologic
risk factors within the past 21days before the onset
of symptoms such as contact with blood or other
body fluids or human remains of a patient known
to have or suspected to have EVD; residence in or
travel to an area where EVD transmission is active;
or direct handling of bats or nonhuman primates
from diseaseendemic areas
Suspected case: Any person, alive or dead, suffering
or having suffered from a sudden onset of high fever
and having had contact with: A suspected, probable,
or confirmed Ebola or Marburg case; a dead or sick
animal(for Ebola) or any person with the sudden
onset of high fever and at least three of the following
symptoms, i.e., headache, vomiting, anorexia/loss of
appetite, diarrhoea, lethargy, stomach pain, aching
muscles or joints, difficulty swallowing, breathing
difficulties, and hiccup or any person with inexplicable
bleeding or any sudden, inexplicable death
Probable case: Any suspected case evaluated by a
clinician or any deceased suspected case(where it
was not possible to collect specimens for laboratory
confirmation) having an epidemiological link with
a confirmed case
Confirmed case: Acase with laboratoryconfirmed
diagnostic evidence of Ebola virus infection
Laboratory confirmed case: Any suspected or
probable cases with a positive laboratory result.
Laboratoryconfirmed cases must test positive for
the virus antigen, either by the detection of virus

RNA by reverse transcriptasepolymerase chain


reaction(RTPCR) or by detection of IgM antibodies
directed against Marburg or Ebola
Noncase: Any suspected or probable case with a
negative laboratory result. Noncase showed no
specific antibodies, RNA, or specific detectable
antigens.

Evd Risk Assessment


Highrisk exposure
Percutaneous(e.g.,needle stick) or mucous membrane
exposure to blood or body fluids of a person with Ebola
while the person was symptomatic or exposure to the
blood or body fluids(including but not limited to feces,
saliva, sweat, urine, vomit, and semen) of a person
with Ebola while the person was symptomatic without
appropriate personal protective equipment(PPE)
or processing blood or body fluids from an Ebola
patient without appropriate PPE or standard biosafety
precautions or direct contact with a dead body
without appropriate PPE in a country with widespread
transmission or cases in urban areas with uncertain
control measures or having lived in the immediate
household and provided direct care to a person with
Ebola while the person was symptomatic.
Some risk exposure
In countries with widespread transmission or cases in
urban areas with uncertain control measures: Direct
contact while using appropriate PPE with a person with
Ebola while the person was symptomatic or with the
persons body fluids, any direct patient care in other
health care settings or close contact in households, health
care facilities, or community settings with a person with
Ebola while the person was symptomatic.Close contact
is defined as being present at a close proximity for a
prolonged period of time while not wearing appropriate
PPE within approximately 3 feet(1 meter) of a person
with Ebola while the person was symptomatic. Public
health action and supervision of the movement of persons
infected with EVD is shown in Table3 according to risk
exposure.[46]

Control Measures
The health system capacity of developing countries
involved in EVD outbreak is very low and requires both
shortand longterm control measures. The international
community gave an overwhelming, decisive but delayed
response. Some of the generic and specific viral control
measures include:[4752]

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Plans for emergency care including adequate


quarantine facilities
Prompt diagnosis and isolation of the suspected
patient
Symptomatic management
Adequate laboratory facilities and support
Proper surveillance, case management, and contact
tracing
Health education and removal of stigma/myth/
misconception
Restriction of the movement of people suffering from
EBV
Training of health care providers
Universal precaution including provision and
availability of logistics/equipment
Safe burial practices
Personal and safe hand hygiene
Dedicated transport facilities for a person infected
with EBV
Change in dietary practices, especially of tribal
natives
Promotion of sanitary environmental conditions
Homeprotective kits
Recording, reporting, and incident management
system
Development and strengthening of communication
channels
Overall socioeconomic and infrastructure
development
International commitment, research, and funding.

Ebola Vaccine and Drugs


The disease always had an epicenter in African countries.
Since 1976, no attempt were made to create the vaccine
against the deadly disease until at present, when the
localized problem has surmounted to become a global
threat. Currently, there are no effective and target
vaccines or treatments which are approved for human use.
Tables4 and 5 describes the potential Ebola vaccine and
drugs in different stages of research and development.[40]
Is India safe from EBV?
The current situation is unlikely to favor establishment
of EBV in India because of the following:
Bats: Absence of Pteropiridae family bats in India;
febrile immune response of bats resulting in
attenuation of viral load; and localized flight range
of bats in the African subcontinent
Environment: Absence of high absolute humidity
and low temperature, along with rains for the
breeding of Ebola virus

Virus: Absence of virus in the Indian subcontinent.
Surveillance at major international airports,
especially during the risk period.

Table3: Public health monitoring and movement/restriction


of people with EBV according to risk exposure
Risk
level

Public health action


Monitoring
Restricted
public activities
High risk Direct active monitoring Yes
Some
Direct active monitoring Casebycase
risk
assessment
Low risk Active monitoring for
No
some; direct active
monitoring for others
No risk No
No

Restricted
travel
Yes
Casebycase
assessment
No
No

EBV=Ebola virus

Table4: List of EBV vaccine that is actively being developed


for clinical use
Vaccine
cAd3
ZEBOV
VSVG
ZEBOV
MVABN

Status
Phage I
Phage I

Feature
Attenuated
adenovirus
Attenuated VSV

2015a)

Company
GSK and NIAID
NewLink Genetics
and PHAC
Bavarian Nordic

Attenuated
vaccinia virus
AdVac
2015a)
Attenuated
Crucell
adenovirus
SynCon
Preclinical Polyvalent vaccine Inovio
VesiculoVax Preclinical Attenuated VSV
ProfectusBioSciences
VSV=Vesicular stomatitis virus, EBV=Ebola virus, MVA-BN=Modified vaccinia
ankara-bavarian nordic, GSK=Glaxo smith kline, NIAID=National institute of allergy and
infectious diseases, PHAC=Public Health Agency of Canada

Table5: List of EBV drug that is actively being developed


for clinical use
Drug
ZMapp

Status
Phage I

Favipiravir
TKMEbola
Brincidofovir
BCX4430

Approved
for IAV
Phage I
Phage III
Preclinical

AVI7537

Phage I

Feature
Three chimeric
monoclonal antibodies
Inhibition of viral RNA
dependent RNA
siRNA
Oral nucleotide analog
Inhibition of viral RNA
polymerase
Binding Ebola RNA

Company
LeafBio,
Inc.
Fujifilm
Tekmira
Chimerix
BioCryst
Sarepta

siRNA=Synthetic RNA, EBV=Ebola virus, TKM=Tekimira, IAV=Influenza A virus

But this does not rule out India to be safe from Ebola as
it can be imported through any case/incubating Ebola
traveler visiting India. The Government of India has issued
standard operating guidelines for the surveillance, control,
and management of EBV disease in accordance with the
WHO protocols. India has health organization quarantine
centers at 24 airports with all international airports and
sea ports to be equipped with thermal scanners in the
near future. The government has identified about 10
laboratories in the country that will handle testing if a
case is reported and in NewDelhi, Dr.Ram Manohar
Lohia Hospital has been designated as nodal hospital

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Kaur, etal.: Ebola virus disease

and National Centre for Disease Control(NCDC) as a


nodal surveillance institution for EVD outbreak. Since
we are still not clear about the epidemiology of Ebola, all
international health regulations need to be followed for
prevention of a viral outbreak. While urgent steps have
been taken by India and other countries to enhance their
preparedness and response capacities, the international
focus must be on containment of outbreak at the source.
Acknowledgements
The Dean, North Delhi Municipal Corporation(DMC)
Medical College and Hindu Rao Hospital, Delhi110007
for constant encouragement, advice, and guidance.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.

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