The bottom line
Ebola virus disease is a severe, often fatal, zoonotic infection caused by a virus
of the Filoviridae family (genus Ebolavirus)
Human to human transmission occurs through contact with body fluids from infected
patients. The incubation period after infection is 1-21 days and patients are not
considered infectious until they develop symptoms
Initial stages of infection are non-specific, which makes the differential diagnosis
broad. A history of exposure and clinical suspicion of infection should prompt isolation
Management is currently focused on supportive care and infection control. Healthcare
workers should familiarise themselves with local guidance
Case fatality rates range from 30% to 90%
Because of the high likelihood of infected people travelling, all countries should
have tested and practised protocols ready for screening and managing patients
This clinical review has been developed for The BMJ in collaboration with BMJ Best
Practice, based on a regularly updated web/mobile topic that supports evidence-based
decision making at the point of care. To view the complete and current version, please
refer to the Ebola virus infection topic on the BMJ Best Practice website.
Ebola virus disease is a severe, often fatal, zoonotic filovirus infection (fig 1
). There are five species: Zaire ebolavirus, Sudan ebolavirus, Taï Forest ebolavirus,
Bundibugyo ebolavirus, and Reston ebolavirus.1
Fig 1 Infographic on Ebola virus disease
Zaire ebolavirus is responsible for the current outbreak in west Africa, the largest
outbreak since the virus was discovered in 1976 (fig 2
).
Fig 2 Map of Ebola virus outbreaks 1976-2014 (Centers for Disease Control and Prevention)
Transmission occurs by close contact with body fluids of infected patients. The incubation
period after infection is usually 5-9 days, with a range of 1-21 days in 95% or more
of patients,2
3 and patients are not considered infectious until they develop symptoms. The initial
presentation is non-specific, which makes early clinical diagnosis difficult. Human
infection carries a high case fatality rate depending on the species of Ebola virus
and quality of supportive care available.4
5
Ebola virus infection (formerly Ebola haemorrhagic fever) is part of a group of diseases
known as viral haemorrhagic fevers.6
What causes it?
The virus is thought to be initially acquired by exposure to body fluids or tissue
from infected animals, such as bats and non-human primates; however, the natural reservoir
and mode of transmission to humans has not been confirmed.7
8 Laboratory testing of reservoir competence shows that successful infection is possible
in bats and rodents, but not in plants or arthropods.9
10
11
12 Animal to human transmission may occur during hunting and consumption of the reservoir
species or infected non-human primates. The practice of butchering or eating bush
meat or food contaminated with bat faeces (three species of tree roosting bats have
been implicated as a reservoir) is also thought to contribute.
Human to human transmission occurs through contact with body fluids from infected
patients.13 In early epidemics, the re-use of non-sterile injections was responsible
for many healthcare associated transmissions.14 However, although this remains a risk,
most cases result from close physical contact or contact with body fluids (such as
sweat, blood, faeces, vomit, saliva, genital secretions, urine, and breast milk) of
infected patients. In a study of viral shedding in various body fluids, Ebola virus
was isolated from saliva, breast milk, stool, tears, and semen up to 40 days after
the onset of illness,15
16
17 confirming the possibility of delayed sexual transmission. Virus may be found in
urine during recovery, and the duration of this phenomenon needs further study.18
Infection through inhalation is possible in non-human primates, but there is no evidence
for airborne transmission in humans.19
Outside endemic areas, Ebola virus infection is rare and is usually imported.20 Travellers
from affected areas, and laboratory scientists and others working with potentially
infected materials and animals, are at high risk.
What is the pathophysiology of this infection
Although there have been major advances in elucidating the pathogenesis of Ebola virus
infection, most of the studies were performed in non-human primate and rodent models.8
This is because of the difficulties in conducting human studies in poorly resourced
settings where these infections naturally occur.
The virus genome consists of a single 19 kb strand of negative sense RNA with seven
viral genes that are transcribed by the viral RNA dependent RNA polymerase present
in the virion. The single strand of RNA is covered by helically arranged viral nucleoproteins
NP and VP30, which are linked by matrix proteins VP24 and VP4 to the lipid bilayer
that coats the virion.21
Tissue invasion occurs through infected fluid coming into contact with breaks in the
mucosa or skin. This can occur with animal to human or human to human transmission.
Monocytes, macrophages, and dendritic cells are the preferred replication sites for
filoviruses on initial infection. Infected cells migrate to the regional lymph nodes,
liver, and spleen, thereby disseminating the infection. Ebola virus has a wide cell
tropism and can infect a variety of cell types.8
21 It also has the remarkable ability to modulate the expression of genes involved
in the host immune response, causing lymphocyte apoptosis and attenuation of the protective
effects of interferon.22
23
The host immune response is crucial and dictates the outcome of infection. Progression
to severe disease occurs when the virus triggers expression of a host of pro-inflammatory
cytokines, including interferons; interleukins (ILs) such as IL-2, IL- 6, IL-8, and
IL-10; interferon inducible protein; and tumour necrosis factor α (TNF-α).8
21
24 This causes endothelial activation and reduced vascular integrity, release of tissue
factor (with associated onset of coagulopathy), and increased nitric oxide levels
(with associated hypotension).25 Thrombocytopenia is most commonly caused by loss
of platelets from damaged tissue or more generalised virus induced disseminated intravascular
coagulation, where coagulation factors are depleted.26 Disseminated intravascular
coagulation, along with acute hepatic impairment, predisposes the patient to bleeding
complications. Other complications of severe disease include acute kidney injury,
hepatitis, and pancreatitis.21 An early antibody response, along with reduced lymphocyte
depletion, is associated with effective viral clearance and survival.16
The development of shock is still not well understood. Many factors may contribute,
including bacterial sepsis, possibly through gut translocation of bacteria; a direct
effect of the virus; disseminated intravascular coagulation; and haemorrhage.23
How are people at risk identified?
Ebola virus infection is transmitted mainly through close physical contact with infected
patients. There is no evidence of a risk of infection before symptoms develop, but
late diagnosis delays effective patient isolation, allowing for potential transmission
of the infection among contacts. Screening and active case finding are therefore essential
to avoid or stop an epidemic.
Early diagnosis hinges on identifying patients who are at risk. Case definitions developed
by WHO and the US Centers for Disease Control and Prevention (CDC) are based on a
history of exposure and clinical evidence of illness (for example, fever, headache,
and myalgia). In the current epidemic areas, history of exposure is now less useful.
Screening ensures the quick identification of potential cases that need immediate
isolation and investigation. People who are asymptomatic and have epidemiological
risk factors may need to be monitored (for example, twice daily temperature readings)
for the duration of the incubation period, depending on their risk of exposure. This
ensures rapid recognition of symptoms and immediate isolation.
Contacts
Contacts of infected patients (including healthcare workers and household contacts)
are at risk of infection if they were exposed to the patient’s body fluids without
protective equipment within the past 21 days.2
3 Brief interactions, such as walking past a person or moving through a hospital,
do not constitute close contact.
Epidemiological risk factors are divided into high risk, some risk, low (but not zero)
risk, and no identifiable risk categories.
A contact is defined by WHO as someone who has slept in the same household as a patient;
had direct physical contact with the patient during the illness or at the funeral;
touched the patient’s body fluids, clothes, or bed linens during the illness; or been
breast fed by the patient (babies).27
What infection prevention and control measures are used?
Boxes 1 and 2 list infection prevention and control measures for healthcare workers
and people living in affected areas. If infection is suspected on the basis of initial
screening, immediate isolation is warranted before any further investigations. This
is crucial to reduce contact with other patients and healthcare workers while the
patient is being investigated. Isolation measures should be continued until the patient
has tested negative.28
Box 1: Infection control measures for healthcare workers
Wear protective clothing
Practise proper infection control and sterilisation measures
Isolate suspected patients from each other (if possible), and patients with confirmed
disease from those with suspected disease
Avoid direct contact with bodies of people who have died from Ebola, or suspected
Ebola. During epidemics, avoid direct contact with any dead body
Notify health officials if you have direct contact with the body fluids of an infected
patient
Box 2: Infection control measures for people in affected areas
Practise careful hygiene (for example, wash hands with soap and water, alcohol based
hand sanitiser, or diluted chlorine)
Avoid contact with body fluids
Do not handle items that have come into contact with an infected person’s body fluids
(such as clothes, medical equipment, and needles)
Avoid funeral or burial rituals that require handling of the body of someone who has
died from proven or suspected Ebola
Avoid contact with non-human primates and bats, including body fluids or raw meat
prepared from these animals
Avoid hospitals in west Africa in which infected patients are being treated
Returning travellers, including healthcare workers, should follow national policy
for surveillance and should monitor their health for 21 days and seek medical attention
if symptoms develop, especially fever
Personal protective equipment
The highest risk facing healthcare workers when looking after infected patients is
inadvertently touching their own faces or neck under the face shield during patient
care, and removing (doffing) personal protective equipment (PPE; shown in fig 3
).
Fig 3 Healthcare worker in personal protective equipment at an Ebola treatment centre
in Sierra Leone, 2014 (with permission from Chris Lane, Public Health England/WHO)
Healthcare workers should understand the following basic principles of using PPE:
Donning—PPE must be donned correctly in the proper order before entering the patient
care area. Because PPE cannot be adjusted while in the patient care area, care should
be taken to ensure it is as comfortable as possible before entering and that no skin
is exposed. Donning activities must be directly observed by a trained observer and
a final check performed before entering the patient care area
During patient care—PPE must remain in place and be worn correctly for the duration
of exposure to potentially contaminated areas. PPE should not be adjusted during patient
care. Healthcare workers should regularly disinfect gloved hands using an alcohol
based hand rub or chlorinated water, particularly after handling body fluids. If there
is a partial or total breach in PPE (such as gloves separating from sleeves to leave
exposed skin, a tear in an outer glove, or a needlestick) during patient care, the
healthcare worker must move immediately to the doffing area to assess the exposure
and implement the facility exposure plan, if indicated
Doffing—Removal of used PPE is a high risk process that requires a structured procedure,
a trained observer, and a designated area for removal to ensure protection. PPE must
be removed slowly and deliberately in the correct sequence to reduce the possibility
of self contamination or other exposure. A stepwise process should be developed and
used during training and daily practice.29
The importance of a “buddy” when inside the patient care area, and during donning
and doffing, to ensure safe practice cannot be overstated, together with guidance
from independent monitors if available.
What other measures are needed if Ebola virus disease is suspected?
If infection is suspected, the patient should be isolated and all healthcare workers
in contact with the patient should wear personal protective equipment.
Contact tracing (family, friends, and work colleagues) is essential. People who have
been exposed to Ebola virus within the past 21 days and who are asymptomatic need
to be monitored for the duration of the incubation period with twice daily temperature
readings to ensure rapid recognition of symptoms. If symptoms are detected immediate
isolation is essential.30
Healthcare workers suspected of being infected should be isolated and treated in the
same way as any other patient until a negative diagnosis is confirmed.31 If exposure
to body fluids from a patient with suspected infection has occurred, the person should
immediately wash affected skin surfaces with soap and water and irrigate mucous membranes
with copious amounts of water.
The patient’s home and any personal belongings that might have been contaminated (such
as clothes, linens, eating utensils, and medical material) should be disinfected or
disposed of (usually by incineration). In epidemic areas, the patient’s home is sprayed
with 0.5% chorine solution.
What are the clinical features?
The case definition for Ebola virus infection is very broad and includes a long list
of possible differential diagnoses (fig 4
).
Fig 4 Differential diagnosis. Confirmatory tests should be performed before, or in
tandem with, differentiating tests if Ebola virus infection is suspected
History
The initial assessment of a patient with suspected Ebola hinges on two main factors:
epidemiological risk (for example, living or working in, or arrival from, an endemic
area such as west Africa in the past 21 days) and presence or history of a fever in
the past 24 hours. Apart from healthcare workers, people who work with primates or
bats from endemic areas or with high risk clinical samples are also at high risk.
A detailed history helps to clarify the level of risk for infection and to assess
the possibility of other causes of an acute febrile syndrome (fig 5
). Because malaria is still the most common cause of febrile illness in returning
travellers, the presence of risk factors for acquiring malaria should be assessed
(for example, living or working in, or arriving from, an endemic area; inadequate
or absent chemoprophylaxis; not using insecticides or bed nets).36 Infection control
risk should be assessed. Having determined that a patient may be infected, the doctor
needs to determine how infectious the patient currently is. For example, the absence
of vomiting or diarrhoea reduces the risk of transmission, whereas uncontrolled diarrhoea
greatly increases the risk.
Precautionary isolation procedures and use of PPE are mandated in symptomatic patients
who may be at risk of infection until the infection is confirmed or excluded. It is
extremely important to minimise the risk of transmission while investigating patients
(see later).28
37
Fig 5 Diagnostic pathway for the investigation of suspected Ebola virus infection
(produced by the BMJ Evidence Centre)
Symptoms
There are typically three phases of illness, starting with a few days of non-specific
fever, headache, and myalgia, followed by a gastrointestinal phase in which diarrhoea
and vomiting, abdominal symptoms, and dehydration are prominent. In the second week,
the patient may recover or deteriorate, with a third phase of illness including collapse,
neurological manifestations, and bleeding, which is often fatal.38
The most common symptoms reported between symptom onset and case detection in the
2014 outbreak were fever (87.1%), fatigue (76.4%), loss of appetite (64.5%), vomiting
(67.6%), diarrhoea (65.6%), headache (53.4%), abdominal pain (44.3%), and unexplained
bleeding (18%) (box 3).3 The high frequency of vomiting and diarrhoea means that patients
are often dehydrated and hypovolaemic, particularly if they present late.
Box 3: Typical symptoms of Ebola virus disease4
Fever ≥37.5°C*
Fatigue
Nausea or vomiting
Diarrhoea
Headache
Abdominal pain
Myalgia
Prostration
Sore throat
Unexplained bleeding or bruising
Spontaneous abortion or miscarriage
Hiccups
Rash
*The temperature threshold for “fever” level varies between different guidelines.39
Children present with similar symptoms to adults; however, younger children are reported
to have more respiratory (such as cough and dyspnoea) and gastrointestinal symptoms,
but less bleeding and neurological signs, than adults.40
41 Anecdotally, children under 4 years present initially with more subtle symptoms
before developing a fever and are often diagnosed late.
Physical examination
A full physical examination should be undertaken with precautionary isolation procedures
and use of PPE. The aim of examination is to exclude a focus for sepsis while looking
for signs of viral haemorrhagic fever (such as conjunctival injection, purpuric rash,
or other signs of bleeding).
Vital signs should be taken:
Fever (≥37.5°C)—Fever is the presenting symptom in about 90% of patients,3
39
42 and its presence is enough to raise concern in the appropriate epidemiological
context. Wide variations in body temperature are seen during the course of illness,
with normothermia or hypothermia occurring in the later stages of fatal infection.40
43
44 Some patients initially have a low grade fever with no other symptoms
Blood pressure—Hypotension is a feature of preterminal disease and shock. It is underdocumented
in field studies, owing to a lack of measuring equipment in endemic areas43
Pulse rate—Bradycardia may be present in the initial stages of illness, whereas tachycardia
may be seen in the later stages of fatal infections43
Respiratory rate—Tachypnoea, along with tachycardia, correlates with a more severe
or advanced infection. It is more likely to be caused by respiratory compensation
of a metabolic acidosis than respiratory involvement.43
Other possible findings include a maculopapular rash, bleeding, hiccups, hepatomegaly,
lymphadenopathy, and neurological signs (box 4).43
Box 4: Physical examination findings
Maculopapular rash
Develops early in the course of illness in 25-52% of patients,43 although its occurrence
has been much lower (5%) in the 2014 outbreak3
Often described as non-pruritic, erythematous, and maculopapular
May begin focally then become diffuse, generalised, and confluent. Some have described
it as morbilliform
May become purpuric or petechial later on in the infection in patients with coagulopathy
May be difficult to discern in dark skinned patients
Bleeding
Bleeding manifestations (such as epistaxis, bleeding gums, haemoptysis, easy bruising,
conjunctival bleeding, haematuria, and oozing from injection or venipuncture sites)
were present in 30-36% of infected patients in previous outbreaks,8
43
44
45
46 but they have been reported in only 18% of patients in the 2014 outbreak3
5
38
47
Hiccups
A sign of advanced infection, typically seen in the last 2-3 days of fatal infections
Hepatomegaly or epigastric tenderness
Tender hepatomegaly, with the edge of the liver palpable below the rib cage, has been
reported but is rare
Lymphadenopathy
Enlarged lymph nodes have been reported but are rare
Neurological signs
Confusion, depressed consciousness, encephalopathy, and seizures are rare but their
presence indicates advanced infection
Multi-organ dysfunction is common in advanced infection and includes acute kidney
injury, pancreatitis, adrenal failure, and liver damage. Hepatitis is common, with
aspartate aminotransferase (AST) higher than alanine aminotransferase (ALT), although
jaundice is rare.23 Renal dysfunction is common in advanced disease but can be reversed
with adequate fluid resuscitation in the initial stages.23 In early disease it may
be caused by dehydration, but in later stages it may be a consequence of disseminated
intravascular coagulation or direct damage to the kidneys by the Ebola virus.23
43 Massive bleeding, typically in the gastrointestinal tract (for example, bloody
diarrhoea or melaena), is usually seen only in fatal cases.43 Internal bleeding may
be missed if there are no external signs.
Signs that indicate severe or advanced infection include hiccups, hypotension, tachycardia,
hepatomegaly, splenomegaly, confusion, and seizures.
How is it investigated?
All specimens should be collected according to strict protocols.
Initial investigations
The main confirmatory test for Ebola virus infection is a positive Ebola RT-PCR.48
This test should be ordered in all patients with suspected Ebola infection while the
patient is isolated. The results of RT-PCR are available 24-48 hours before those
of enzyme linked immunosorbent assay (ELISA) testing. In Western settings, Ebola RT-PCR
may be available only in regional or national reference laboratories that have a high
level of biosafety precautions (category 4 facilities).8 In epidemic settings and
some European countries, category 4 laboratories are set up locally, and RT-PCR is
available four hours after the sample has arrived. Viral RNA can be detected in the
patient’s blood by RT-PCR from day 3 to days 6-17 of symptoms. A positive result implies
that the patient is potentially infectious, particularly if there is active diarrhoea,
vomiting, or bleeding. If negative, the test should be repeated within 48 hours because
viral load can be low and undetectable early in the illness. Negative tests should
also be repeated to rule out the diagnosis (or confirm resolution of infection) if
there is a strong suspicion of Ebola.31 Higher viral load correlates with adverse
outcome.5
24
38
47
49
The choice of whether to test for Ebola depends on the patient’s history and the risk
of infection (fig 5).
Malaria is still the most common cause of fever in people who live or work in, or
travellers who have returned from, an endemic area and should be ruled out.36 If a
malaria rapid diagnostic test is positive, malaria should be treated while keeping
in mind the possibility of a dual infection. Ebola virus infection should be considered
in a patient who does not respond to antimalarial therapy.
It is recommended that confirmatory tests for Ebola virus infection are performed
before, or in tandem with, differentiating tests for other suspected conditions if
Ebola virus infection is suspected.
Other investigations
In the past, only a malaria screen and RT-PCR were recommended because of the risk
to laboratory workers. However, it is now recognised that other investigations can
be done safely according to recommended guidelines, as long as the laboratory is informed
of the sample in advance, and the samples are correctly packaged and retained at the
end in case the results are positive.28
42 Local protocols should be clear about safe transport of samples to the local and
referral laboratories and safe handling on receipt in the local laboratory.
Box 5 outlines additional investigations that may add valuable information to help
guide further management, and that should be ordered if possible.
Box 5: Other useful investigations when diagnosing Ebola virus disease
Antigen capture enzyme linked immunosorbent assay (ELISA) testing
A useful diagnostic test with high specificity, although it is not universally available
Most likely to give a positive result on days 3-6 of symptoms and can give widely
variable results from days 7-1617
Can be used to confirm the diagnosis along with a positive reverse transcriptase-polymerase
chain reaction result
Full blood count
Decreasing platelet count with marked lymphopenia can be seen in the initial stages
of infection but is not diagnostic. This is often followed by neutrophil leucocytosis
in the later stages in patients who eventually recover, along with normalisation of
thrombocytopenia. Leucocytosis may persist and show immature forms
Patients with severe disease may show a progressive decline in platelet count as a
manifestation of disseminated intravascular coagulation (DIC)
Haemoglobin may be low in patients with bleeding manifestations43
Coagulation studies
Prolonged prothrombin time or activated partial thromboplastin time is associated
with more severe infection and bleeding manifestations such as DIC
D-dimer values are four times higher on days 6-8 of infection in patients who die
than in those who survive50
Renal function and serum electrolytes
Raised serum creatinine or urea and abnormal electrolytes may indicate acute kidney
injury; this may be seen at the end of the first week of infection51
Some studies found hypokalaemia (associated with vomiting and diarrhoea) in about
half of cases
Hypocalcaemia has been associated with fatal infection
Haematuria and proteinuria may also be seen in severe disease
Oliguria that does not respond to fluid resuscitation is a poor prognostic sign43
Arterial blood gases
Arterial or venous blood lactate, pH, and bicarbonate can help identify the degree
of systemic hypoperfusion and guide fluid resuscitation in acutely ill patients with
signs of sepsis52
Raised lactate is a marker of tissue hypoperfusion and is an indicator of shock.
Liver function tests
Both ALT and AST are usually raised; most studies show that AST rises more than ALT—this
is more suggestive of systemic tissue damage rather than hepatocellular injury
The AST:ALT ratio peaked at 15:1 on days 6-8 of infection in fatal cases compared
with days 5:1 in non-fatal cases43
45
50
Bilirubin, γ-glutamyl transferase, and alkaline phosphatase are often slightly raised.
Greatly raised ALT and severe jaundice suggests an alternative diagnosis (such as
viral hepatitis)
Serum amylase
High concentrations have been reported in several studies and indicate the presence
of pancreatitis, an indicator of severe infection43
Blood cultures
Negative blood cultures are helpful because they rule out other non-viral infectious
causes (such as sepsis or enteric fever)
Ebola specific IgM and IgG antibodies
Useful in later stages of infection
IgM antibodies can appear in serum as early as day 2 after infection but results are
variable up to day 9. They become negative between 30 and 168 days after symptom onset
An IgG response develops between days 6 and 18 and can persist for several years
A positive IgM or a rising IgG titre is strong evidence of recent Ebola virus infection17
Chest radiography
Useful in patients with respiratory symptoms
Pulmonary infiltrates are not typical of infection and suggest an alternative (or
comorbid) diagnosis
May be difficult to arrange in an isolation unit and should be ordered judiciously
to avoid contamination53
How is it managed?
The mainstay of treatment is early recognition of infection, coupled with effective
isolation and best available supportive care in a hospital setting.
High case fatality rates may be related to the supportive care available in resource
poor rural settings where outbreaks have occurred They reflect the difficulties that
patients in these settings have in accessing basic medical care in a healthcare structure
that is overwhelmed.3
5
During the 2014 outbreak, comprehensive supportive care—including organ support in
intensive care units—was available to cases imported to developed countries such as
Spain, Italy, Switzerland, Germany, France, Norway, the UK, and the US.18
54
55 Despite this, deaths still occurred because of the lack of specific effective treatments.
There is active debate about the suitability of moving patients with advanced disease
and a poor prognosis to intensive care, where the risk for nosocomial infection may
be high.52
56
57 However, failure to provide full supportive care to those with suspected (not confirmed)
infection may result in substandard care for these patients, who may later be shown
to have a treatable disease such as malaria. Local hospital protocols should consider
how this situation should be handled for patients with suspected infection before
possible transfer to the intensive care unit, and for those who have already been
transferred there.52
56
57
Isolation and infection control
Patients identified as being at risk of infection should immediately be isolated in
a room with private bathroom facilities.
All attending healthcare personnel must wear PPE that conforms with published protocols
(fig 3).29
58 All contaminated materials (such as clothes and bed linens) should be treated as
potentially infectious.
Specimens for laboratory investigations (such as Ebola RT-PCR, full blood count, serum
creatinine and urea, liver function tests, arterial blood gases, coagulation studies,
blood cultures, and investigations for other conditions such as malaria) should be
collected and sent off according to local and national protocols. Judicious selection
of investigations is needed to reduce the risk of transmission to laboratory workers
and other healthcare personnel. Early placement of a central line (if possible) allows
blood to be taken and fluids to be given while minimising the risk of needlestick
injuries.
Fluid and electrolyte replacement
Vomiting and diarrhoea are common, so patients are often dehydrated and hypovolaemic,
particularly if they present late. This is probably the cause of the high case fatality
rates because essential clinical monitoring (temperature, respiratory rate, pulse
rate, blood pressure, and fluid input and output) is often difficult in resource poor
settings.
Oral rehydration solutions can be used for patients who can tolerate oral administration
and who are not severely dehydrated.
The volume of intravenous fluids needed should be assessed on the basis of the clinical
examination (level of dehydration, signs of shock) and fluid losses (volume of diarrhoea
or vomitus, or both). Large volumes of fluid replacement (>10 L/day) may be needed
in febrile patients with diarrhoea.18
Access to point of care tests in the isolation facility means that the patient’s biochemical
status can be monitored more efficiently and reduces the risks associated with specimen
transport.5
52 Electrolyte monitoring should be performed daily. More frequent monitoring can
be considered if large volumes of intravenous fluids are being given or if severe
biochemical abnormalities are present. High blood lactate values are a reliable measure
of hypoperfusion and can help guide fluid resuscitation.52 In patients with anuria
who do not respond to fluid resuscitation, renal replacement therapy has been used,18
55
59 although there are no trial data to support its effectiveness.
Major bleeding is uncommon, but is seen in advanced infection that is usually fatal.
When available, platelet and plasma transfusions should be given according to local
protocols.60
Symptomatic management
The following management strategies are recommended:
Fever and pain—Fever and pain should be treated with paracetamol first. Opioid analgesics
(such as morphine) are preferable for more severe pain. Non-steroidal anti-inflammatory
drugs (including aspirin) should be avoided because of the associated increased risk
of bleeding and potential for nephrotoxicity31
Nausea and vomiting—Oral or intravenous antiemetics (such as ondansetron and metoclopramide)
are recommended31
Heartburn, dysphagia, and upper abdominal pain—An antacid or proton pump inhibitor
(such as omeprazole) may be beneficial31
Seizures—Although uncommon, seizures can be seen in advanced disease and pose a risk
to healthcare workers because they increase the risk of contact with the patient’s
body fluids. Contributing factors (such as high temperature, hypoperfusion, and electrolyte
disturbances) must be recognised and corrected. A benzodiazepine can be used to abort
the seizure and can be given intramuscularly or rectally if intravenous access is
unavailable. An anticonvulsant (such as phenobarbital) can be given for repeated seizures31
Agitation—Although uncommon, agitation can occur in advanced disease. It may be associated
with encephalopathy or may be a direct effect of the virus on the brain. Judicious
use of a sedative (such as haloperidol or a benzodiazepine) will help to keep the
patient calm and prevent needlestick injuries in healthcare workers31
Sepsis and septic shock—Management follows the same principles as for bacterial sepsis.61
It should include broad spectrum antibiotics (such as ceftriaxone, piperacillin-tazobactam,
or meropenem) in the first hour after sending blood cultures, rapid intravenous fluid
resuscitation with assessment of response, appropriate airway management and oxygen
administration, and monitoring of urine output preferably by urethral catheterisation.
Broad spectrum antibiotics in these patients are used to target the presumed translocation
of gut organisms. This is not backed by any evidence. Blood cultures are difficult
to perform safely in infected patients.
In the absence of a response to initial management, inotropic support should be considered,
preferably through a central venous catheter in an intensive care unit where invasive
monitoring enables more aggressive correction of fluids, electrolytes, and acid-base
balance.52
54
Malaria should be tested for and treated with appropriate antimalarial therapy. In
endemic settings all patients in Ebola treatment centres are treated for malaria routinely.5
38
47
Are there any emerging treatments?
Although experimental treatments for Ebola virus infection are under development,
they have not yet been fully tested for safety or effectiveness.62
63
Convalescent whole blood or plasma
There is limited evidence from past outbreaks that transfusion of blood from convalescent
patients might be beneficial in the acute phase of infection and may reduce mortality.46
63Trials are planned.62
64
ZMapp
The best known emerging treatment so far, ZMapp, is a combination of three humanised
monoclonal antibodies targeted at three Ebola virus glycoprotein epitopes and is engineered
for expression in tobacco plants.62
63
65
66 Before the current 2014 outbreak, ZMapp had proved protective when given to non-human
primates 24-48 hours after infection. Another study showed that the drug could rescue
non-human primates when treatment was started up to five days after infection.67 It
has not yet been tested in humans for safety or efficacy; however, very limited stock
(seven doses) was made available to infected patients during the current outbreak,
and only one patient died. Despite its potential, numbers are too small to make any
conclusions about the drug’s safety and efficacy. More doses are not currently available
to conduct larger trials, but development is being accelerated with support from the
US government.68
TKM-Ebola
TKM-Ebola consists of a combination of small interfering RNAs that target Ebola virus
RNA polymerase L, formulated with lipid nanoparticle technology. It has been shown
to be protective in non-human primates and is effective against Marburg virus in guinea
pigs and monkeys.62
63
66
69
70
71 The US Food and Drug Administration has granted expanded access to this drug under
an Investigational New Drug application. Under emergency protocols, it has been given
to a small number of patients.
Brincidofovir
Formerly known as CMX-001, brincidofovir is currently undergoing phase III trials
for the treatment of cytomegalovirus and adenovirus. It also shows activity against
Ebola virus in vitro. The drug has been used in patients with Ebola virus infection
in the US under Emergency Investigational New Drug applications approved by the FDA.
Trials are planned in the near future in west Africa.62
63
64
Favipiravir
Formerly known as T-705, favipiravir selectively inhibits viral RNA dependent RNA
polymerase. It is active against influenza viruses, West Nile virus, yellow fever
virus, foot and mouth disease virus, as well as other flaviviruses, arenaviruses,
bunyaviruses, and alphaviruses. The drug is approved in Japan for influenza pandemics
and is effective against Ebola virus in mouse models.62
63
72 Human trials are due to start in west Africa.64
BCX-4430
BCX-4430 is an adenosine analogue that is active against Ebola virus in rodents. It
is thought to act through the inhibition of viral RNA dependent RNA polymerase. It
is active against flaviviruses, bunyaviruses, arenaviruses, and paramyxoviruses. The
drug has been shown to be protective in non-human primates and rodents, even when
given 48 hours after infection with filoviruses63
73; however, no human studies have been performed.
AVI-7537
AVI-7537 consists of antisense phosphorodiamidate morpholino oligomers (PMOs) that
target the Ebola virus VP24 gene. It confers a survival benefit to Ebola virus infected
non-human primates.63
74 AVI-6002 consists of two PMOs (AV-7537 and AV-7539, which targets the VP35 gene).
AV-6002 has undergone phase I clinical studies.
Other agents
Interferons have been used in the past, with uncertain benefit.16
63 Therapeutic agents used for other diseases, such as amiodarone, clomiphene, and
chloroquine, inhibit Ebola virus interactions with human cells in models, and amiodarone
will shortly be trialled in west Africa.62
75
Vaccines
Two experimental vaccines are currently undergoing trials.62
63 cAd3-ZEBOV is a chimpanzee derived adenovirus vector with an Ebola virus gene inserted.76
Trials are under way in the United Kingdom, United States, Switzerland, and some African
countries. rVSV-ZEBOV is an attenuated vesicular stomatitis virus with one of its
genes replaced by an Ebola virus gene. Human trials have started in the US.
What is the prognosis?
The natural clinical course of Ebola virus infection varies markedly between the different
viral species and according to the level of supportive medical care available. The
most lethal species is Zaire ebolavirus, which has a reported case fatality rate of
up to 90%. The rate in the current 2014 outbreak is less than this and is estimated
at 60-70%, although accurate data are biased by poor record keeping and registration.3
Most epidemics have occurred in resource poor settings with little supportive care,
and the case fatality rate in high income settings could be less than 40%.52 Mortality
is higher in younger children (<5 years) and adults over 40 years than in adolescents
and young adults.3
5
38
40
41
47
51 An observational study during an outbreak in 1995 showed a marked decrease in the
case fatality rate from 93% to 69% between the initial and final phases of the outbreak.77
This suggests that later cases were recognised earlier and possibly received higher
quality care. Pregnant women have a high incidence of miscarriage and the infection
is almost always fatal in these women.38
78
79
80
Infection course
Patients who die tend to develop clinical signs early on in the infection, with death,
usually attributed to shock and multi-organ failure, typically occurring between days
6 and 16 (median 9 days) from symptom onset.19
81
82 Patients who eventually recover exhibit isolated fever for several days with improvement
typically around days 6-11. A high viral load at presentation is correlated with mortality.5
24
38
47
49 Biomarkers as prognostic indicators require further study.51
81
Recovery and convalescence
Patients who live through the second week of infection have more than a 75% chance
of surviving.43 Patients are usually discharged from the isolation facility when they
are ambulant, able to self care, have no serious symptoms (such as diarrhoea, vomiting,
or bleeding), and have two negative Ebola RT-PCR results taken 48 hours apart.47
Patients who survive usually have a protracted recovery characterised by asthenia,
weight loss, and migratory arthralgia. Skin desquamation and transient hair loss are
also common. Late manifestations during convalescence are uncommon but include uveitis,
orchitis, myelitis, parotitis, pancreatitis, hepatitis, psychosis, hearing loss and
tinnitus.44 The cause of these manifestations is unclear but they might be related
to immune complex phenomena.
Survivors of infection probably have lifetime immunity to the same strain of Ebola
virus. Such patients have therefore been invaluable in caring for those with active
infections.
What advice should patients be given during recovery?
Patients should be educated about the likely course of convalescence and the possibility
of long term complications. There are no specific requirements for monitoring after
discharge; however, eligible patients may be asked to donate blood from 28 days after
discharge to be used in the treatment of patients with active infection.
Male patients should be reminded about the importance of using condoms to prevent
sexual transmission in the three months after resolution of infection.15
16
17 Women should be advised not to breast feed during infection.15
Survivors and orphans of those who died from the disease face stigma and ostracism
in many communities. This—along with substantial associated psychological disturbance—was
reported after previous outbreaks,83
84 and it is an increasing problem in the 2014 outbreak.
Additional educational resources
Resources for healthcare professionals
WHO. Infection control. Aide-memoire for infection prevention and control in a healthcare
facility (www.who.int/injection_safety/toolbox/docs/en/AideMemoireInfectionControl.pdf?ua=1)
Centers for Disease Control and Prevention (CDC). Infection control for viral haemorrhagic
fevers in the African healthcare setting (www.cdc.gov/vhf/abroad/vhf-manual.html)
WHO. Infection prevention and control guidance summary (www.who.int/csr/resources/publications/ebola/evd-guidance-summary/en/)
CDC. What is contact tracing? (www.cdc.gov/vhf/ebola/pdf/contact-tracing.pdf)
CDC. Epidemiologic risk factors to consider when evaluating a person for exposure
to Ebola virus (www.cdc.gov/vhf/ebola/exposure/risk-factors-when-evaluating-person-for-exposure.html)
WHO. Steps to put on personal protective equipment (PPE) (www.who.int/csr/disease/ebola/put_on_ppequipment.pdf?ua=1)
WHO. Steps to remove PPE (www.who.int/csr/disease/ebola/remove_ppequipment.pdf?ua=1)
UK Government. Gateway to UK government and Public Health England guidelines (https://www.gov.uk/government/topical-events/ebola-virus-government-response)
Health Protection Scotland guidelines gateway (www.hps.scot.nhs.uk/travel/viralhaemorrhagicfever.aspx)
European Centre for Disease Control and Prevention (ECDC) gateway to European guidelines
and epidemiological updates (http://ecdc.europa.eu/en/healthtopics/ebola_marburg_fevers/Pages/index.aspx)
Ebola Response Anthropology Platform (www.ebola-anthropology.net/)—This platform engages
with crucial sociocultural and political dimensions of the Ebola outbreak and build
locally appropriate interventions
Resources for travellers and people in affected areas
WHO. Ebola virus disease fact sheet (www.who.int/mediacentre/factsheets/fs103/en/)
CDC. Questions and answers on Ebola (www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/qa.html)
CDC. Bushmeat from Africa should not be imported into other countries (www.cdc.gov/vhf/ebola/pdf/bushmeat-and-ebola.pdf)
WHO produce guidance for travellers. Travel and transport risk assessment (www.who.int/csr/resources/publications/ebola/travel-guidance/en)
CDC. Ebola—travel notices (wwwnc.cdc.gov/travel/diseases/ebola)—As of 31 October 2014,
the CDC recommend avoiding non-essential travel to Liberia, Guinea, and Sierra Leone,
and practising enhanced precautions in Democratic Republic of the Congo
ECDC. Travel advisories (http://www.ecdc.europa.eu/en/healthtopics/ebola_marburg_fevers/information-travellers/Pages/information-travellers.aspx)