Seminar

Ebola virus disease

Denis Malvy, Anita K McElroy, Hilde de Clerck, Stephan Günther, Johan van Griensven

Lancet 2019; 393: 936–48 Ebolaviruses are pathogenic agents associated with a severe, potentially fatal, systemic disease in man and great apes.
Published Online Four species of ebolaviruses have been identified in west or equatorial Africa. Once the more virulent forms enter the
February 15, 2019 human population, transmission occurs primarily through contact with infected body fluids and can result in major
http://dx.doi.org/10.1016/
epidemics in under-resourced settings. These viruses cause a disease characterised by systemic viral replication,
S0140-6736(18)33132-5
immune suppression, abnormal inflammatory responses, major fluid and electrolyte losses, and high mortality.
Department for Infectious and
Tropical Diseases, University Despite recent progress on vaccines, and with no licensed prophylaxis or treatment available, case management is
Hospital Centre of Bordeaux, essentially supportive with management of severe multiple organ failure resulting from immune-mediated cell
Bordeaux, France damage. The 2013–16 outbreak was classified by WHO as a Public Health Emergency of International Concern,
(Prof D Malvy MD);
which drew attention to the challenges of diseases caused by infections with ebolaviruses and questioned scientific,
INSERM 1219, University of
Bordeaux, Bordeaux, France clinical, and societal preparation to handle future epidemics.
(Prof D Malvy); Department of
Pediatrics, University of Introduction Seminar reviews available knowledge about the epidemi­
Pittsburgh School of Medicine,
Ebolaviruses are negative stranded RNA viruses that ology, disease manifestation, patho­ physiology, case
Pittsburgh, PA, USA
(A K McElroy PhD); Médecins belong to the Filoviridae family and are endemic to regions manage­ment, and community control of these diseases.
sans Frontières, Brussels, of west and equatorial Africa. These public health
Belgium (H de Clerck MD); pathogens are primarily transmitted by human-to-human Virology
Department of Virology,
Bernhard-Nocht-Institute for
contact with infected body fluids and corpses and causes Ebolaviruses belong to the genus Ebolavirus of the family
Tropical Medicine, Hamburg, severe and acute systemic disease with high mortality. Filoviridae in the order Mononegavirales, viruses whose
Germany (Prof S Günther MD); Ebola­viruses have substantial epidemic potential, as genome consists of a single strand of RNA with negative
and Institute of Tropical shown by the 2013–16 west African outbreak.1 This polarity. The genus Ebolavirus contains five species
Medicine, Antwerp, Belgium
(Prof J van Griensven MD)
outbreak was unprecedented in scale, with more than with the taxonomic designations: Bundibugyo ebolavirus
28 000 confirmed cases and 11 000 deaths.2 Its economic (Bundibugyo virus), Reston ebolavirus (Reston virus),
Correspondence to:
Prof Denis Malvy, Department impact on the west African region was crippling. This Sudan ebolavirus (Sudan virus), Taï Forest ebolavirus
for Infectious and Tropical outbreak also showed that, in a context of resource-poor (Taï Forest virus), and Zaire ebolavirus (Ebola virus).
Diseases, University Hospital public infrastructure, a rapid transition from primarily This taxonomy, revised in 2011, is emphasised because
Centre of Bordeaux,
affected rural villages to the urban areas of larger cities can nearly identical terms have different meanings:
F-33075 Bordeaux, France
[email protected] occur. With considerable efforts from the affected countries Ebolavirus and Zaire ebolavirus refer to taxonomic
and with international support, the outbreak was ultimately classifications, whereas Ebola virus is a virus.3 More
controlled. This outbreak was also unique in that it information about the properties of the virus can be
See Online for appendix triggered the initiation and implementation of com­pre­ found in the appendix.
hensive research programmes into ebolavirus-related Only Bundibugyo, Sudan, and Ebola viruses have been
pathology, which has led to major scientific advances. This associated with disease outbreaks in humans.4 These
outbreaks occurred mainly in South Sudan and Uganda
for Bundibugyo and Sudan viruses, and in the Democratic
Search strategy and selection criteria Republic of Congo, Republic of Congo, and Gabon for
We searched PubMed for publications with the terms “viral Ebola virus. Henceforward, the disease caused by
haemorrhagic fever”, “Ebola”, “Ebola virus”, “Ebola vaccine”, Bundibugyo virus is designated Bundibugyo virus disease,
“Ebola transmission”, “Ebola antibody”, “Ebola virus disease”, by Sudan virus as Sudan virus disease, and by Ebola virus
“Ebola pathogenesis”, “Ebola diagnosis”, and “Ebola as Ebola virus disease. The disease caused by any of these
treatment” in various combinations without any language ebola viruses is called Ebola disease. Between 1976 and
restrictions. The search covered the period from 1967, 2014, these three viruses had caused over 20 known
the year of the discovery of filoviruses, until Jan 14, 2018. outbreaks owing to human-to-human transmission, with a
Review articles were cited when appropriate. Research total of 2400 cases and 1600 deaths.4 Overall case fatality
published since the Lancet Seminar published on this topic in has been 25% for Bundibugyo virus disease, 50% for
2011, and since the 2013–16 west African outbreak was given Sudan virus disease, and 80% for Ebola virus disease.4
particular attention. We provide an overview of Ebola The largest ever-recorded outbreak of Ebola virus disease
focusing on updating the reader on recent advances and occurred in west Africa from 2013–16 following a single
controversies. We also included references that were Ebola virus introduction from the natural reservoir into
recommended by peer reviewers. Information from sources the human population.5,6 Virus genomes from more than
other than peer-reviewed journals has been evaluated but 5% of all recorded cases have been sequenced, which has
was not considered to add indispensable new information, so allowed the spread of the disease to be reconstructed
is not covered in this Seminar. across country borders and the molecular clock of
Ebola virus in the human host to be estimated at

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Guinea Burkino Faso

Chad Sudan
Benin
Sierra Nigeria
Leone Ethiopia
Côte d’Ivoire Ghana
South Sudan
Liberia Central African Republic
West Africa Cameroon
outbreak
(2014) Somalia
Taï Forest
(1984) Equatorial Guinea Uganda
Congo
First Ebola Kenya
(Brazzaville)
virus (Zaire) Gabon North Kivu
outbreak province First Sudan
Bundibugyo virus (1976) (2018) virus outbreak
Ebola virus Bundibugyo
Sudan virus (1976)
(2007)
Taï Forest virus DR Congo
Equator
1–19 cases identified
province Tanzania
20–49 cases identified
(2018)
50–99 cases identified
100–700 cases identified Angola

28 610 cases identified

Zambia

Figure 1: Outbreaks of Ebola disease in sub-Saharan Africa

1·2 × 10−³ substitutions per site per year.5–7 This evolutionary a transit hub located at the Congo River. Fortunately,
rate overlaps with that of other RNA viruses. Few adaptive the outbreak was controlled relatively quickly, with a
mutations, notably an alanine to valine exchange at GP total of 54 cases, of whom 33 died. Control of the
position 82, have been selected in the outbreak strain outbreak in North-Kivu is hampered by sustained
because they enhance virus entry into human cells.8,9 In violent conflict in the region.
addition, polymorphism in residue 544 has been identified To our knowledge, Ebola virus disease outbreaks have
as enhancing infection in other outbreaks.10 However, no been restricted to African countries, with some dissemin­
evidence has shown that the presence of these mutations ation between neighbouring countries.7 Nonetheless, the
or the accumulation of neutral substitutions measurably disease can spread due to the ease of international
changed the clinical presentations, disease severity, or travel,15,16 and indeed secondary infection from patients
transmissibility of the virus (appendix).11 that travelled from African countries has been reported in
Spain and in USA.17–19 In addition, unfamiliarity with
Epidemiology Ebola virus disease outside of the endemic area has led to
Since ebolaviruses were first identified in 1976 delayed diagnosis of imported cases.18,19
(appendix), over 20 known outbreaks of Ebola disease Ebola virus disease is considered to be zoonotic, with
have been identified in sub-Saharan Africa, mostly in occasional spillovers to humans, apes, and possibly
Sudan, Uganda, Democratic Republic of Congo, and other animals. Fruit bats belonging to the Pteropodidae
Gabon, and mainly due to the Ebola and Sudan viruses family are thought to be the natural hosts of the Ebola
(figure 1). Most of these outbreaks have occurred in virus, although the virus has not been isolated yet from
isolated rural areas, but the outbreak in Gulu in 2000 bats in natural conditions. Humans are likely infected
was in a semi-urban area of Uganda. However, it is either by handling sick or dead infected forest animals,
possible that small outbreaks, might not have been or by direct or indirect contact with infected bats.20
identified as such. The largest outbreak to date, due to Secondary human-to-human transmission can occur via
the Ebola virus, occurred in 2013–16 in west Africa, direct contact with blood, secretions, or other body
predominantly affecting Guinea, Sierra Leone, and fluids from infected humans. Caring for the sick or
Liberia.1,12 It included multiple countries, both rural and handling dead bodies (eg, during traditional funerals)
urban areas, and had very high incidence and mortality is associated with a particularly high risk, which
(>28 000 cases with >11 000 deaths).2 However, because also explains why nosocomial transmission occurs
of under-reporting, the true burden might have been frequently before the outbreak is identified. Sexual
considerably higher.2 In this outbreak, the overall mean transmission by survivors of Ebola virus disease has
case fatality in confirmed cases with recorded clinical also been reported.21,22 Seroprevalence surveys suggest
outcomes was 62·9% (95% CI 61·9%–64·0%).2 The that asymptomatic infections can occur.23
latest outbreaks were declared in May, 2018, in a remote Beyond the direct morbidity and mortality attributable
area in the Equateur province and in August, 2018, in to Ebola virus disease, the disease has indirect effects on
the North Kivu province in the Democratic Republic of population health because resources are diverted from
Congo.13,14 The situation became of concern in May, 2018, programmes aimed at controlling other diseases of major
when the outbreak reached Mbandaka, a large city and importance—such as HIV infections,24–27 malaria,24,25,28,29

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methods for detection of filoviruses have been virus

A
isolation in cell culture (appendix). When patients with
Ebola virus disease present at a hospital, typically 3–6 days
EBOV RNA in blood of patients who die after the onset of the symptoms, the viral load is already
EBOV RNA in blood of patients who survive
EBOV RNA in seminal fluid of male patients
high and detectable in the patient’s blood by RT-PCR in the
who survive (after discharge) vast majority of cases.35–38 However, a single negative RT-
EBOV-specific IgM PCR finding early after onset does not exclude Ebola virus
EBOV-specific IgG
EBOV RNA in various body fluids (saliva, tears, disease and, therefore, testing should be repeated several
sweat, breastmilk, urine, cerebrospinal fluid, times over a period of 72 h if clinical suspicion persists.39
Concentration

ocular fluid, amniotic fluid, vaginal fluid)

Limit of detection of RT-PCR or serology
Viral load peaks 3–7 days after the onset of symptoms. In
fatal cases, viraemia is usually 10–100 fold higher then in
survivors.35–38 In survivors, viraemia will decrease to under
the limit of RT-PCR detection (approximately 1000 virus
RNA copies per mL of blood) around 2–3 weeks after
disease onset (figure 2). IgG and IgM develop in survivors,
but not in all fatal cases,36,40,41 thus, diagnosing of Ebola
virus disease using serology is only possible in a fraction
of symptomatic patients and, for an unambiguous diag­
nosis, requires seroconversion or a substantial increase in
0 5 15 30 60 180 360 antibody titre in paired serum samples. However, serology
Time since onset of disease (days) is the method of choice to diagnose pauci­symptomatic or
asymptomatic Ebola virus infec­tions, which are charac­
B terised by ex­tremely low viraemia and development of IgG
Individual-level post-exposure prophylaxis Treatment approach: antibody therapy, Treatment approach: antiviral and IgM about 3 weeks after infection.42,43 Diagnosis of
antiviral
post-mortem Ebola virus disease (eg, people who did not
attend a hospital and died in the community) is best done
by RT-PCR on an oral swab.44,45 Another, although rarely
Day 0 Day 6 Day 21 Day 0 Day 14 Months 3–12
used, post-mortem technique, is antigen detection by
Contagium Symptom onset immunohistochemistry on a skin biopsy. 46
During the acute phase of the disease and convalescence,
Exposure to high risk of transmission Acute phase, fatal disease*, or clinical Convalescent phase, possible viral
(via direct contact; within the community) recovery persistence in reservoirs
viral RNA can be detected by RT-PCR in other bodily
fluids, such as saliva, tears, sweat, breast milk, urine, CSF,
Viral recrudescence from sanctuary sites ocular fluid, amniotic fluid, vaginal fluid, and seminal
(CNS, eye); relapse
(meningoencephalitis, uveitis) fluid. Viral RNA can remain detectable in these fluids after
the RT-PCR on blood becomes negative.21,47–59 Irrespective
High risk of transmission (sexual); Asymptomatic carriage of replicative virus
individual, and community risk, (male genital tract)
of the severity of the acute disease, Ebola virus tends to
post-epidemic resurgence persist, specifically in so-called immunologically privileged
sites (such as the eye, central nervous system, and testis)
Late-onset sequelae of Ebola virus
disease; possible post-Ebola syndrome?† where antiviral immune response are less effective against
the virus. Persistence is associated with clinical sequelae,
Figure 2: Time sequence of the evolution of the Ebola virus infection and disease disease reactivation,19 long-term virus shedding, and virus
(A) Time-course of presence of Ebola virus (EBOV) in body compartments. (B) Time-course of clinical manifestations transmission (figure 2). Male survivors’ seminal fluid can
of Ebola virus disease. Depending upon the specific sign or symptom and the timing after infection, sequelae could be remain positive to RT-PCR testing for months to years
the result of residual dysfunction from direct viral cytopathic effects or immune cell damage during acute disease,
after discharge of Ebola treatment centre (after resolution
post-infective or reactive injury, molecular mimicry, autoimmune disease, or immune complex deposition, individually
or in combination. *Fatal disease: viral septic shock (tissue breakdown), multisystem organ failure, and immune of acute disease) with a 4-fold reduction of virus RNA
paralysis. †Ebola virus disease associated sequelae and late-onset complications (musculoskeletal disorders, diffuse concentrations per month. The virus found in the seminal
pain syndrome, chronic fatigue syndrome; neurocognitive disorders, sensory impairments; ocular-visual impairment, fluid can still be infectious and sexually transmitted for
secondary cataract), and mental health disorders with the backdrop of psychosocial distress.
more than a year after disease onset.21,22,48,56–58 Cases of
women transmitting the virus via breastfeeding have been
tuberculosis,24,25,30 and human African trypanosomiasis31— reported, although the duration of infectivity by this route
from programmes improving maternal and infant is unknown.60 Reports suggest that other reservoirs and
health32,33 and from primary care.34 other human-to-human transmission routes of persisting
virus in humans could still be uncovered.61
Diagnosis
Real-time RT-PCR tests were the cornerstone of the Acute clinical manifestations
laboratory response during the 2013–16 west African Ebola The tropism of Ebola virus provides some indication
virus disease outbreak, although, for many years, the main regarding the pathogenic mechanisms of Ebola virus

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disease (appendix), some of which are summarised in clinical prediction tools for Ebola virus disease, integrating
figure 3. discriminatory symptoms or signs.66–68 However, their
After an incubation period of 2–21 days, Ebola virus overall diagnostic accuracy was gener­ally too low to be
disease typically starts as a non-specific viral syndrome of meaningfully integrated in clinical triage systems.
abrupt onset. The most common symptoms are high fever, Laboratory features include variable degrees of anaemia
malaise, fatigue, and body aches. These symptoms are and thrombocytopenia. Changes in number and type of
usually followed after a few days by gastrointestinal white blood cells are more variable. Renal dysfunction
symptoms, which include nausea, vomiting, and diarrhoea. (with or without proteinuria) (up to 50% in the 2013–2016
This phase can range from mild-to-severe, with fluid loss outbreak), and substantial increases in liver enzymes
of up to 5–10 L/day. Other, rarer, symptoms and signs are (particularly aspartate aminotransferase) are common.65
cough and dyspnoea, conjunctival injection, hiccups, or Creatine phosphokinase and amylase concentrations
localised pain (chest, abdomen, muscles, or joints).62 (with or without clinical pancreatitis) can be increased.
Although some patients will start recovering at this Electrolyte abnormalities are common, especially hypo­
stage (sometimes after a relatively mild disease), others kalaemia, hyponatraemia, and hypocalcaemia.64,69 Clotting
will go into shock, possibly due to hypovolaemia and a tests can indicate a varying degree of intravascular
systemic inflammatory response. Around this time,
patients can present with haemorrhagic events, which
include conjunctival bleeding, petechiae, gastrointestinal Lymph node Liver
bleeding, mucosal haemorrhage, and continued oozing APC Macrophage Hepatocytes
after venepuncture (table 1).62,63 However, haemorrhage
was an uncommon symptom in the 2013–16 west African
outbreak. Neurological events are rare and include
B cell CD4 or CD8
confusion, delirium, and convulsions. Some cases of TLR4
Ebola virus disease-related encephalitis have been signalling
reported.65 Other late symptoms include dysphagia, throat
pain, and oral ulcers. Exceptionally, sudden death can B cell and CD4 or CD8 Macrophage Development of
occur in recovering patients, possibly due to cardiac T cell activation activation and viral inclusion
arrhythmias. A maculopapular rash has been described, cytokine bodies; necrosis
elaboration
but it is often only discretely visible on patients with dark
skin. If patients survive the stage of shock, gradual
recovery can occur. Several studies have aimed to define Blood

APC Monocyte CD4 or CD8 NK

Figure 3: Ebola virus tropism TIM 1

The tropism of Ebola virus gives some clues as to pathogenic mechanisms. signalling
Early targets include antigen presenting cells (APCs) in lymphoid tissues but,
over time, many different cell types are infected, including, but not limited to,
hepatocytes, and endothelial cells, resulting in several consequences. Infection of
APCs in the lymph node stimulates B cell and CD4 or CD8 T cell activation, but
lymphocytes also undergo apoptosis during Ebola virus disease. Ebola virus directly Monocyte subset loss T cell activation and NK cell subset loss
infects both hepatocytes and hepatic macrophages, but no clinical studies have and possibly cytokine proliferation and
investigated the mechanisms involved after infection. Interactions between Ebola elaboration cytokine elaboration
virus glycoprotein and Toll-like receptor 4 (TLR4) on hepatic macrophages could
further activate macrophages and potentiate cytokine elaboration. Infection of
blood APCs or monocytes could potentiate cytokine elaboration, and loss of Endothelium Sanctuary sites: brain,
subsets of monocytes are noted in infected individuals. Whether monocytes are eyes, and epididymis
lost from blood because they are infected or because they are recruited to sites of
inflammation is unclear. Furthermore, interactions between T-cell Macrophage
immunoglobulin and mucin domain1 (TIM1) on T cells might promote
non-specific immune activation and potentiation of the cytokine and chemokine
WBC
cascade. Natural killer (NK) cell subset loss also occurs during infection, although
the reason for this event is not known (NK cells are not directly infected by Ebola
virus). Endothelial cells can become infected late in the infection phase, but early
during the disease, the endothelium is activated via cytokine and chemokine
stimulation. An activated endothelium has increased permeability and is Increased permeability by activation via
chemoattractive to white blood cells, which extravasate into sites of inflammation. cytokines and chemokines; chemoattractive
Tissue factor release from activated endothelial cells could lead to activation of to WBCs
coagulation. Simultaneously, the activated endothelium up-regulates
thrombomodulin which inhibits coagulation via activation of protein C. Elevated Tissue factor release→coagulation activation
levels of D-dimer noted in patients are indicative of ongoing fibrinolysis. Activation Thrombomodulin→coagulation inhibition
of these opposing pathways are indicative of the coagulopathy that is seen during D-dimer→Fibrinolysis
Ebola virus disease. It has also been shown that macrophages in the chambers of
Virion
the eye, brain, and epididymis are sites of viral persistence (sanctuary sites).

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Adequate prevention or correction of fluid losses, by

Time since Clinical features Typical patient
symptom onset providing oral or parenteral fluids, is standard practice in
the critically ill, even if there is little evidence supporting
Early febrile or 0–3 days Non-specific features: fever, Ambulatory, able to compensate
mild stage weakness, lethargy, and myalgia for fluid losses; no indication for its clinical utility in the case of Ebola virus disease.75,85
intravenous fluid administration Intravenous fluids are required when oral fluid intake is
Gastrointestinal 3–10 days Same as early stage plus diarrhoea, Unable to compensate for fluid not possible, for example if the patient is too weak,71 or
involvement vomiting, or both, or abdominal pain losses because of emesis or large in case of ileus,52 drowsiness, or coma.84 Administration
volume losses; indication for
intravenous fluid administration
of crystalloid fluids in sufficient quan­ tities to achieve
haemodynamic stability is the recom­mended standard
Complicated 7–12 days Same as gastrointestinal involvement Critically ill, usually
stage stage plus haemorrhage, shock, organ hypovolaemic, often with of care when intravenous fluids are required;77,85 how
failure, and neurological complications confusion or seizures aggressive this fluid correction needs to be has yet to be
determined. Whatever the case, caution might be
Adapted from Chertow and colleagues63 and Hunt and colleagues.64
required in a disease in which vascular leakage86 or renal
Table 1: Ebola virus disease presentation by stage impairment can occur,69,71 particularly in settings in which
Ebola virus disease outbreaks occur, where resources
coagulation. Metabolic acidosis can occur, particularly in required to follow up fluid resuscitation and deal with
cases of shock and renal failure. possible complications—such as skilled staff, oxygen
A wide range of prognostic factors have been identified supplementation, mechanical ventilation, or kidney
for Ebola virus disease fatality. High viral loads, replacement therapy—might be insufficient.62,69,75
combined with severe muscle breakdown and renal Since renal impairment is associated with increased
impairment, have consistently been predictive of fatal outcomes in Ebola virus disease, addressing
death,70,71 whereas associations with specific symptoms kidney impairment is relevant.69 Impairment of prerenal
and signs (eg, hiccups and conjunctivitis) have not been origin requires more aggressive intervention, whereas
consistent across studies.64 Differences in severity of impairment of renal origin can be managed more
clinical events and outcome might exist between young conservatively by careful fluid replacement.69 However, as
children, young adults, and older people, but this has renal impair­ment can also be an indicator of more severe
not been shown unequivocally in all outbreaks.64,72 disease, whether renal replacement strategies yield any
Pregnant women face high mortality and a high risk of survival benefit remains to be determined.
miscarriage and still­ birth.73 The clinical presentation In recent outbreaks, the installation of point of care
and severity has also been used to stratify patient biochemistry testing has facilitated the correction of
manage­ment.64 electrolyte imbalances,62,69 although the exact effect of
Clinical presentation can further be compounded by those interventions has yet to be determined.69 Close
concurrent comorbidities and infections, such as malaria follow-up of biochemical parameters might be a challenge
and bacterial sepsis. Clinical signs and symptoms have in resource-limited settings, where the safe installation
also varied across the different outbreaks. Although this and operation of a quality clinical laboratory might not
variation is likely to be related to the specific outbreak always be feasible.62,75 Ideally, renal function, haemoglobin
context and the ebolavirus species involved, unreliable or haematocrit values, electrolyte concentrations, anion
data collection could also contribute to the discrepancies. gap, blood glucose, and lactate should be determined
For example, haemorrhagic events were highly prevalent systematically at the bedside.87
in 1976 outbreak in Yambuku, but less so in many other Patients treated in intensive care settings appear to have
outbreaks, including the west African one.65 Importantly, lower mortality than those treated in field settings,
during the west African outbreak, fever was absent in although there have been very few cases to confirm this
at least 10% of the cases. This presentation questions observation.88 Among potential reasons for this decreased
WHO’s case definition for Ebola virus disease, which mortality might be access to organ replacement strategies
lists fever as a key symptom.65,74 (haemodialysis, artificial venti­lation, or haemodynamic
support). However, the added value and feasibility of such
Management technology in resource-constrained settings requires
Supportive care further study. Nonetheless, the fact that high-level opti­
Without a specific treatment, management of patients mised care appears to improve outcome needs to be
with Ebola virus disease consists of the provision of promoted to overcome perceptions that Ebola virus
supportive and, as required and when possible, critical disease is fatal and that patients cannot be cured.
care, on the basis of the pathophysiological similarities
between, on the one hand, Ebola virus disease and, on Therapeutics
the other hand, septic and possible hypovolaemic shock Most investigational therapies for Ebola virus disease are
(appendix).75–77 In addition, symptomatic and empirical aimed at rapidly reducing viral replication to limit the
treatment for concurrent infections is provided, tailored inflammatory storm triggered by viral expansion by
to the needs of individual patients (table 2). allowing effective innate and adaptive immune responses

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Recommended care Comments

Concomitant infections Broad spectrum antibiotics;62 empirical systematic Patients might be at higher risk of concomitant infections due to translocation of bacteria in the
malaria treatment in malaria-endemic areas78 gastrointestinal tract62,79
Hypoxaemia Oxygen therapy62 Supplemental oxygen should be used with caution, and conservative (target Sp02 <94%) regimens should
be preferred because of a potentially elevated mortality risk with more intensive administration75,80
Nausea or vomiting Antiemetic drugs (metoclopramide or ··
ondansetron,71,75 or potentially haloperidol)81,82
Mild-to-moderate pain Paracetamol83 Paracetamol is preferred over non-steroidal anti-inflammatory drugs because of their potential bleeding risk63
Severe pain Opiates ··
Encephalitis or encephalopathy Opiates for symptomatic management84 ··
Critically ill patients Oral feeding wherever possible, otherwise enteral Both local food and ready-to-use therapeutic food might be used;75 providing local food has the advantage
feeding85 that patients know it and like its taste and might be more motivated to eat it
Palliative care Opiates75 ··

SpO2=oxygen partial saturation pressure.

Table 2: Major interventional components for symptomatic care of Ebola virus disease in resource-constrained settings

to clear the infection. Some of these investigational primates, with a good safety profile in phase 1 studies.98
treatments were tested during the 2013–16 Ebola outbreak It is being evaluated with the aim of blocking persistent
in west Africa, but these clinical trials could not show Ebola virus shedding in the semen of male survivors of
unequivocal efficacy of any treatment (table 3). Nevertheless, Ebola virus disease (NCT 02818582). ZMapp, a
promising experimental inter­ventions were identified and combination of three human­ ised recombinant mAbs
the rapid implementation of these trials emerged as a key has been shown to have anti-Ebola virus activity in vitro
component of the response to the global outbreak.89 In and in non-human primates studies.92 Zmapp efficacy
September, 2014, WHO inventoried a list of potential drug against Ebola virus disease assessed in a randomised,
candidates developed or repurposed to Ebola virus disease controlled trial92 could not be determined as the trial did
with shown antiviral efficacy in vitro or in animal models not reach the target sample size as the incidence of
(table 3). These therapeutics are nucleoside and nucleotide Ebola infection decreased in the 2013–16 Ebola virus
analogues,72,90 nucleic acid-based drugs,93 and immuno­ outbreak in west Africa. In consequence, a statistically
therapeutics,91,92,94,95 including blood-derived products from significant difference in mortality between study groups
convalescent individuals.91,94 Outside of the remit of a clinical could not be observed (table 2). Moreover, crucial
trials, it was determined by WHO that these investigational challenges were identified, including the need for a so-
therapeutics could be offered on an emergency or com­ called cold chain and the major resource commitment
passionate use basis. How­ever emergency or compassionate required to administer the product.89,92 Since then,
use would not allow sufficient evidence about safety and results from a co-formulated cocktail of three human
efficacy to be col­lected.19,88,96,97 Therapeutics with encouraging mAbs (REGN3470-3471-3479) targeting three non-
preliminary efficacy or safety profiles requires further overlapping epitopes of Ebola virus look promising,
investigation to determine efficacy in humans (eg, rem­ justifying further clinical development as a single-dose
desivir), appropriate dosage (eg, favipiravir), and treatment therapy for Ebola virus disease.99 Other approaches offer
combinations for targeting distinct pathways in the viral protection with a single mAb (as opposed to a cocktail),
lifecycle.72,92,98 In addition, effective drugs that pass the potentially simpli­ fying manu­ facturing processes and
blood–brain barrier are needed for the management of reducing costs (eg, mAb114),100 and could also provide
clinical recurrence of Ebola virus disease and to penetrate cross-species protection of relevance against other ebola­
immunologically and anatomically preserved sites and viruses.101 In the outbreak in the North Kivu province
reservoirs in survivors beyond the acute phase of the of the Democratic Republic of Congo (declared in
disease. August, 2018), mAb114, REGN3470-3471-3479, ZMapp,
To date, no medical therapeutic has been clinically and remdesivir are the investigational treatments to be
proven to be successful (ie, effective in decreasing used under an expan­ded access protocol. A randomised
mortality) in the specific treatment of Ebola virus in­ controlled trial (NCT03719586) is in progress to assess
fections. Promising data on investigational therapeutics the four therapeutic agents in this outbreak.
exist for small molecules with direct antiviral activity72,98
and candidate monoclonal antibodies (mAbs), some of Long-term sequelae
which act by preventing the binding of the glycoprotein The pathogenesis and the biological events leading to
of Ebola virus (EboGP) to its cellular receptor.92,99,100 sequelae of Ebola virus disease are only partly understood,
Notably, the nucleoside analogue remdesivir adminis­ and the relationship between the severity of acute disease
tered by the intravenous route was found to be highly or exposure to experimental therapies, on the one hand,
effective against Ebola virus disease in non-human and frequency or severity of complications, risk of viral

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Company and Treatment approach In-vivo non-human Clinical trial registration Trial design, Formulation, dosing Result Comments, issues, and
country description primate anti-Ebola number (deadline status compatison, and regimen, and concerns
Seminar

virus activity declared as of July, 2018) outcome intervention

Favipiravir Toyama Chemical, Small-molecule Established at high JIKI trial started in Open label, single arm Oral administration; 99 adult participants; No significant difference in
(T-705) Fujifilm group direct-acting antiviral doses; reference December, 2014, in trial; with historical loading dose of 2400 mg, mortality of 20% (95% CI mortality with the predefined
(Tokyo, Japan) drug; nucleobase treatment window Guinea, for acute Ebola controls; sequential 2400 mg, and 1200 mg of 11·6–32·4) in patients with a target value of 30% for
6-fluoro-3-hydroxy-2- of 0–3 days virus disease, number analyses; primary favipiravir every 8 h on mild viral load and 91% treated patients with mild
pyrazinecarboxamide; NCT02329054 endpoint: day 14 treatment day 1, followed (95% CI 78·8–91·1) in patients viral load and of 85% for those
licensed anti-influenza (completed) survival by a maintenance dose of with a very high viral load; with high to very high viral
drug (Avigan) in Japan 1200 mg twice a day to low residual values during load values; no proven
in March, 2014 ; viral total of 10 doses maintenance dose survival benefit in treatment
RNA polymerase (L) administration of Ebola virus disease as a
inhibitor; established monotherapy in patients with
anti-Ebola virus a very high viral load; higher
activity in vitro doses that those used in this
trial to be evaluated for safety
and suitable dosing72
Convalescent Not applicable Antibody therapy Convalescent whole Ébola-Tx started in Open label, single arm Intravenous infusion of 84 participants; mortality No survival benefit91
plasma ABO-compatible blood and February, 2015, in Guinea, trial; with historical 400–500 mL of between day 3 and day 16 of
plasma form hyper-immune for acute Ebola virus controls; primary convalescent plasma from 31% in the intervention group
convalescent donors, serum (purified and disease, number endpoint: day 14 two donors, administered and 38% in the control group;
unverified levels of concentrated IgG NCT02342171 survival as two consecutive odds ratio adjusted for viral
neutralising antibodies and species-matched (completed) (200–250 mL each) load and age of 0·88 (95% CI
convalescent IgG) transfusions; start point of 0·51–1·51)
evaluated treatment within 48 h of
confirmation of Ebola virus
disease
ZMapp MappBio Antibody therapy; Promising PREVAIL II started in Open label, Intravenous infusion of Target enrolment not reached Suggestive but not statistically
(San Diego, specific monoclonal effectiveness data February, 2015, for acute multicentre 50 mg/kg of ZMapp by (72 participants for conclusive effectiveness data
CA, USA) antibody combination; from treatment Ebola virus disease, randomised safety and slow intravenous infusion 200 targeted); mortality at day for treatment of individuals
cocktail of three studies; reference number NCT02363322 efficacy controlled trial within 12–24 h of 28 of 22% in the intervention with Ebola virus disease;
chimerised antibodies treatment window (ongoing but not with adaptive trial randomisation, every group and 37% in the control relatively complex
(c13C6, 2G4 and 4G7) of 5 days recruiting) design; control group 3 days; total of three doses group; in participants with a administration (2–12 h per
selected from MB-003 with optimised care very high viral load (Ct ≤22) at infusion); raised concerns
and ZMab antibody alone, including inclusion, mortality of 47% about systemic side-effects;
cocktails; target favipiravir in Guinea; (7 of 45 patients) in the staffing resource
established as distinct primary endpoint: day intervention group and of 60% commitment; requires cold
epitopes on the viral 28 survival (9 of 15 patients) in the control chain; specific for Ebola virus92
glycoprotein group; 91% posterior
probability to be superior to
optimised care alone, but did
not reach the 98% probability
required to establish superiority
TKM-130803 Arbutus Nucleic acid-based Evaluated; reference RAPIDE-TKM started in Open-label, single arm Intravenous infusion of 12 participants, mortality at No overall survival benefit;
(TKM) Biopharma, therapeutic; small treatment window February, 2015, trial, component of a 0·3 mg/kg of day 14 of 25%, after exclusion systemic side-effects
formerly Tekmira RNA-lipid nanoparticle of 3 days in Sierra Leone, for acute multistage approach; TKM-130803, once daily; of 2 early fatal cases (within the concerns (acute cytokine
Pharmaceuticals product; targets Ebola virus disease, with historical and total of seven doses first 48 h following inclusion); release syndrome) evidenced
(Burnaby, Canada) established as the number concurrent controls; trial discontinued after futility in healthy human
mRNA of the viral RNA PACTR201501000997429 primary endpoint: day analysis (survival at day 14 volunteers93
polymerase (L) and the (completed) 14 survival ≤55%)
viral protein 35 (VP35)

Only approaches that have shown efficacy in vivo have been listed. In addition, only clinical trials that enrolled more than ten participants are listed. All of the medical countermeasures listed are investigational drugs for treatment of infected individuals
and require regulatory approval for emergency use outside clinical research or approved protocols. When a dose is reported, it corresponds to the stated adult dose. Refer to trial protocols for weight adjustment. Ct=cycle threshold. VP=viral protein.

Table 3: Overview of investigational therapeutics evaluated in clinical trials in Ebola virus disease during the 2013–16 west African outbreak

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Leading company or institution and Vector Administration Ebola component and Comments
country of origin glycoprotein*
Recombinant Merck (USA) VSV Single dose Ebola virus, Kikwit Replication competent vaccine
VSV-ZEBOV strain (1995)
ChAd3-EBO-Z with or GlaxoSmithKline (UK) and, for Chimpanzee adenoviral Single dose or heterologous Ebola virus, Mayinga ··
without MVA-BN-Filo MVA-BN-Filo, Bavarian Nordic (Denmark) serotype 3 or MVA prime-boost regimen strain (1976)
Ad26.ZEBOV with Johnson & Johnson (USA), and Human adenoviral Heterologous prime-boost Ebola virus, Mayinga MVA-BN-Filo encodes Ebola virus, Sudan
MVA-BN-Filo MVA-BN-Filo from Bavarian Nordic serotype 26 or MVA regimen strain (1976) virus, and Marburg virus glycoproteins,
(Denmark) and Taï Forest virus nucleoprotein
Ad5-ZEBOV Academy of Military Medical Sciences and Human adenoviral Single dose or homologous Ebola virus, Makona Freeze-dried powder, stable for more than
CanSino Biologics (China) serotype 5 prime-boost regimen strain (2014) 2 weeks even if kept at a temperature
of 37°C; licensed in China
GamEvac-Combi Gamalei Scientific Research Institute of VSV and Ad5-vectored Heterologous prime-boost Ebola virus, Makona Licensed in Russia
Epidemiology and Microbiology (Russia) vaccine regimen strain (2014)

VSV=vesicular stomatitis Indiana virus. MVA=modified vaccinia Ankara virus. Ad5=human adenoviral serotype 5. *The year the strain (from which the glycoprotein was derived) was isolated is given in brackets.

Table 4: Overview of the main vaccines with accelerated clinical development during the 2013–16 Ebola virus disease outbreak

persistence, or disease recrudescence, on the other hand, Vaccines and prevention

remains unclear. Although a wide range of vaccines had been developed
It is increasingly recognised that Ebola virus might over the previous decades, clinical development was
persist for weeks or months in selected immunologically impressively accelerated, under intense media attention,
privileged body sites of survivors, suggesting delayed during the 2013–16 west-African Ebola virus disease
viral clearance and an increased risk of renewed outbreak (table 4).108,109
transmission in locations where the original outbreak A single dose of a recombinant vesicular stomatitis
has been controlled (figure 2). The origin of a resurgence Indiana virus vectored vaccine (rVSV-ZEBOV) containing
of Ebola virus disease in the forest region of Guinea, for EboGP was found to be immunogenic in phase 1 trials.110
example, was traced to sexual transmission from a male Arthritis was frequently described in vaccinated patients
survivor 16 months after clinical recovery.22 The central in Switzerland, but this adverse event was not confirmed
nervous system might also be a reservoir for Ebola virus, in African populations. rVSV-ZEBOV was evaluated in
as described in the case of a patient who developed a phase 3 trial in Guinea using a protocol of ring-
meningoencephalitis 9 months after initial recovery vaccination, the principle of which relies on the vacci­
from acute Ebola virus disease.19 nation of both confirmed patients with Ebola virus
Experience with Ebola virus disease survivors has disease’s direct contacts and of those contact’s direct
provided new insights into individual patient needs contacts.111 The vaccine was reported highly effective
and into the need to control disease transmission during (efficacy 100% [95% CI 68·9–100], p=0·0045), although
relapse or through sexual transmission. With the out­ uncertainty remains about the magnitude of its efficacy.
break of Ebola virus disease in west Africa, it became The study also showed the feasibility of a ring-vaccination
clear that thousands of Ebola virus disease survivors can approach during an outbreak of Ebola virus disease,
have sequelae,102–104 some of which might be incapacitating including in response to a post-epidemic recrudescent
or severe, such as persistent arthral­gia, arthritis,105 and cluster that emerged in Guinea.112 Ring vaccination with
vision-threatening uveitis.53,106 The mental health effects this vaccine was also implemented during the 2018
of Ebola virus disease on survivors and family and outbreaks in the Democratic Republic of the Congo as
community members are also considerable.107 part of WHO’s Expanded Access Framework. Over
Clinical management after survival of Ebola virus 60 000 individuals were vaccinated until Jan 15, 2019, and
disease is based on comprehensive follow-up care, vaccination is still ongoing. An important aspect of the
including monitoring of rheumatological, auditory, and 2018 vaccination campaign in the Democratic Republic
ocular function, with particular focus on the identification of the Congo was that, in addition to the vaccination of
of visual acuity deficits or raised intraocular pressure.106 contacts and first-line health-care workers, individuals in
Mental health screening examinations need to be offered the community who might come into contact with sick
with provision of continued psychological and social people such as traditional healers, religious leaders, and
support as app­ropriate.104,106 Male survivors and their sexual motorcyclists (who might transport sick patients), were
partners should receive individual advice, including also vaccinated.
counselling on safer sex until their seminal fluid is free of Systematic vaccination with rVSV-ZEBOV vaccine re­
viral RNA, although this approach requires facilities able quires prior confirmation that Ebola virus is responsible
to screen the semen of survivors, which might not be the for the outbreak using gene sequencing13 to ensure that the
case in every country affected by Ebola virus disease. vaccine will be effective. Outstanding questions remain

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con­cerning the long-term safety and immunogenicity of coordination, including the Coalition for Epidemic
the vaccine. Studies aimed at defining immune correlates Preparedness Innovations.120
of protection will be crucial for accelerating approval of
vaccines against Ebola virus disease. Logistical challenges Disease control
have also appeared, notably the requirement to store the To control Ebola disease outbreaks, it is essential to stop
vaccines at –80°C, which is demanding and might not be transmission and interrupt spread of disease in the most
practical in the field. However, in cases where transporting affected populations. To date, this control has been
the frozen vaccine to remote locations is impractical, achieved through a multidisciplinary, holistic approach
vaccine can be transported at 2–8°C, although, in such including early case identification, rapid isolation, and
cases, the quality of the vaccine should always be evaluated clinical management of patients with Ebola virus disease;
by visual inspection (ie, check for precipitates) before use. safe and dignified burial practices; health promotion and
The chimpanzee adenovirus serotype 3 vectored vaccine community engagement; support to health structures;
(ChAd3-EBO-Z), administered as a single shot, was and transversal coordination.121–123
found to be safe and immunogenic in phase 1 trials.113 Early case identification is important to prevent
Boosting with a Modified vaccinia Ankara virus (MVA)- outbreaks spreading, which would require reinforcement
based vaccine enhanced long-term immunity. The ChAd3- of surveillance systems for early identification of suspect
EBO-Z and rVSV-ZEBOV vaccines were assessed in parallel cases in at-risk areas. These surveillance systems should
in a phase 3 trial with a phase 2 subtrial to assess be complemented with the establishment of national
safety and immunogenicity of the vaccines (PREVAIL I); laboratory capacity able to rapidly and reliably detect
the phase 2 component of the trial was expanded, but ebolaviruses and other haemorrhagic fever viruses using
the phase 3 component was discontinued because of the state-of-the-art technologies. The usefulness of such
declining case load in Liberia at the time. The data obtained approach is exemplified by the positive effect of Uganda’s
supported the safety and immunogenicity (up to 12 months) viral haemorrhagic fever surveillance system on morbidity
of both vaccines.114 A human adenovirus vectored vaccine and mortality in this country (ie, resulted in earlier
(Ad26.ZEBOV) boosted with the MVA vaccine was also identification of cases and lower numbers of total cases
found to be safe and immunogenic in phase 1 trials.115 The per outbreak).124
PREVAC trial116 (NCT02876328) will evaluate this Ad26 Rapid isolation of Ebola disease cases is crucial in order
vectored vaccine (with or without an MVA booster) and the to achieve outbreak control.121,125,126 One of the most
rVSV vectored vaccine (single shot or boosted) in Guinea, effective ways to achieve rapid isolation of the disease is
Sierra Leone, Liberia, and Mali, with the aim of providing through provision of care in appropriate settings, such as
data on long-term safety and immunogenicity. Ebola Treatment Centres (ETCs, appendix). Isolation and
Vaccines based on the circulating strain of the 2013–16 high quality care need to be provided with dignity,
Ebola virus disease outbreak were also developed rapidly respect, and compassion to be accepted by affected
in Russia and China. A heterologous prime-boost vaccine communities.123,127 As long as their safety is guaranteed,
using rVSV and Ad5 vectored vaccines expressing the affected families should be informed about and, as much
envelope protein of the Makona variant of the Ebola virus as possible, involved in the care of their close ones, and
strain that caused the west African outbreak has been visits by family members should be encouraged.123,127
licensed in Russia.117 In China, a lyophilised Ad5-based ETCs should be close to the affected communities and
vaccine based on the Makona variant has been licensed operate with a transparent polic (including open com­
for emergency use, following phase 1 studies in China munication with the affected communities about medical
and a phase 2 trial in Sierra Leone.118,119 Many other activities that occur in the ETC and possibility for families
vaccines are under develop­ment and likely to undergo to visit their affected family members in the ETC;
further clinical evaluation. Most deploy different types of appendix).122,123,127 Survivors can be crucial witnesses to
viral vectors, but viral-like particles are also being increase community acceptability, eg, by testifying about
evaluated.108,109 the care given in ETCs.123,126 Since high case fatality has
It is to be expected that several licenced vaccines will discouraged people from seeking care, the availability of
become available over the next decade, with different dedicated ETCs close to the affected regions might help
advantages and presenting different limitations with to increase acceptance. Recently, individual treat­ ment
respect to their safety profiles, the duration of immunity, units (such as biosecure emergency rooms) have been
monovalent versus polyvalent, and to logistical issues developed during the 2018 epidemics in the Democratic
such as storage conditions, cost, and availability. Republic of Congo, with the aim of amelio­ rating
Therefore, a wide range of options will be available to be adaptability and facilitating access for medical staff and
used in different contexts including ring-vaccination, families (appendix).
vaccination of health-care professionals during an Anecdotal evidence suggests that isolation and
outbreak, and vaccination in high-risk areas before an elementary care of Ebola disease patients within their
outbreak.108,109 Several initiatives have been undertaken to homes or communities could be an alternative to care in
ensure sustained funding mechanisms and international ETCs, notably when isolation is not accepted by the

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patient or the community.122 The effectiveness and safety Nonetheless, this response only was implemented after
of such alternative forms of isolation and care have yet to several thousands of deaths had already occurred. The
be evaluated and will probably be dependent on the delay in the response negatively affected local perceptions
resources available. of the reactivity of the international community. However,
Findings from studies suggest that contact tracing this delay also increased awareness in organisations such
(identification, listing, and following up of contacts of as the WHO of the public health consequences of Ebola
patients with Ebola disease) contributes to the control of disease, which enabled a more prompt response in the
outbreaks, although people’s dignity and privacy need to 2018 outbreaks in the Democratic Republic of Congo.
be respected.122,128,129 An audit of contact tracing in Liberia This response led to substantial advances along the road
during 2014–15 showed that contact tracing was successful towards case management of the disease, notably with
in 26·7% of all Ebola virus disease cases and detected respect to life-saving conservative treatments and to the
3·6% of new cases.130 Prerequisites for effective contact systematic control of transmission routes, including
tracing include the availability of sufficient skilled human infection during patient care and funerals.
resources and logistical support, including mobile Importantly, knowledge of the ecological activity of
telephones and motorbikes or cars,122 which might be ebolaviruses in wildlife is still needed. Better under­
challenging in the low-resource settings in which Ebola standing of the pathogenesis of Ebola virus disease has
disease outbreaks occur.128,129 However, effective co­ been an important achievement, but key questions
ordination and community involvement might allow remain about the potentially paradoxical host responses,
effective contact tracing even when resources are restricted. about the subtypes of antigen presenting cells that are
Safe burial practices also contribute to effective control activated by Ebola virus and, importantly, about how
of Ebola disease outbreaks (appendix).125 Permitting at­ the virus accesses immune sanctuary sites and the
tendance and allowing time for traditional ceremonies, factors that facilitate its reactivation. Studies looking at
while taking all necessary safety precautions, can greatly Ebola virus disease survivors who could have long-
increase the community’s acceptance and compliance term immunity against Ebola virus might enable the
with safe burial activities.123 development of new approaches for treatment options.
Cultural practices and beliefs might create barriers to the Research on optimising diagnosis and on the development
perception and management of patients with symptoms of of treatment paradigms and prophylaxis options is cru­
Ebola disease, resulting in delayed referral of infected cial during rare epidemics of Ebola virus disease, and the
individuals for care. In many places where Ebola disease associated ethical challenges need to be met. Despite the
occurs, the disease remains unknown and can often be constraints associated with low-resource regions and
seen as a consequence of witchcraft. Health promotion the unpredictability of disease outbreaks, candidate
activities are crucial to obtain the acceptance of the therapies must undergo rigorous clinical trials.
different intervention control activities by the communities. In addition to its direct health consequences, Ebola virus
These health promotion activities should preferably be disease also has indirect health consequences, because it
done by people who had been exposed to Ebola disease127 diverts much needed resources from other major health-
and be based on a dialogue with the community, rather care services. Also, the 2013–16 West Africa Ebola outbreak
than an exercise in top-down information They should aim has exposed the limits of our ability to deal with epidemic
to address the concerns and experiences of the affected health emergencies and the challenge for national and
communities (app­endix).123 The communities, represented international health security that these emergencies
by local trusted leaders should be encouraged to get represent. Many valuable lessons have been learned, from
involved in the different outbreak control interventions the challenge and psychology of quarantine procedures to
(eg, through participation in outbreak intervention teams, the effective provision of care. Nonetheless, several social,
such as local religious leaders being part of burial geopolitical, and economic barriers remain to be tackled to
teams).122,127 Traditional healers and religious leaders should accelerate response to an outbreak, including the paucity
have a central role in vaccination programmes, not just for of human resources and specialised infrastructures for
their own safety, but also to set an example within their treatment and diagnosis; the delayed referral of infected
communities, and should receive health education to individuals for care due to cultural or physical constraints;
enhance their potential to recognise cases of Ebola disease and the delay in the engagement and empowerment of
and react appropriately. affected com­ munities. Awareness of these issues and
A high level of coordination is required, since many addressing them adequately will be crucial for the
resources need to be mobilised and multiple people will management of future epidemics in underprivileged and
potentially have to cooperate.122 remote areas where Ebola disease and other deadly
infectious diseases could typically re-emerge.
Conclusion Contributors
An unprecedented international response finally enabled DM oversaw the preparation of this Review. All authors contributed to
the Ebola virus disease epidemic that ravaged countries the writing of different sections of the manuscript and approved its final
version.
in west Africa from 2013 to 2016 to be overcome.

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Declaration of interests 20 Emanuel J, Marzi A, Feldmann H. Filoviruses: ecology, molecular

DM has participated in the International Ebola Advisory Board biology, and evolution. Adv Virus Res 2018; 100: 189–221.
organised by Gilead Sciences, for which he received no fees. AKM, HdC, 21 Mate SE, Kugelman JR, Nyenswah TG, et al. Molecular evidence of
SG, and JvG declare no competing interests. sexual transmission of Ebola virus. N Engl J Med 2015; 373: 2448–54.
22 Diallo B, Sissoko D, Loman NJ, et al. Resurgence of Ebola virus
Acknowledgments disease in Guinea linked to a survivor with virus persistence in
The authors would like to thank Cynthia Goldsmith and Pierre Rollin seminal fluid for more than 500 days. Clin Infect Dis 2016; 63: 1353–56.
(Centers for Disease Control, Atlanta, USA), Sylvain Cherkaoui 23 Bower H, Glynn JR. A systematic review and meta-analysis of
(Cosmos, Paris), Caroline Thirion (ALIMA, Dakar), seroprevalence surveys of Ebola virus infection. Sci Data 2017;
Bernard-Alex Gauzère (Tropical and Humanitarian Medicine, 4: 160133.
University of Bordeaux, France), and Nicolas Beaumont (French Red 24 Hira S, Piot P. The counter effects of the Ebola epidemic on control
Cross, Paris) for their contributions to the figures; and to Adam Doble and treatment of HIV/AIDS, tuberculosis, and malaria in
and Isabelle Gauthier (Foxymed, Paris) for editorial support with west Africa. AIDS 2016; 30: 2555–59.
finalising the manuscript from its constituent parts. 25 Parpia AS, Ndeffo-Mbah ML, Wenzel NS, Galvani AP. Effects of
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