Ebola Virus Disease

Epidemiology, Clinical Features, Management,

and Prevention

Emanuele Nicastri, PhD, MDa, Gary Kobinger, PhD, MDb,

Francesco Vairo, MDa, Chiara Montaldo, MDa,
Leonard E.G. Mboera, PhD, BVMc, Rashid Ansunama, PhDd,
Alimuddin Zumla, MBChB, MSc, PhD, MD, FRCP(Lond), FRCP(Edin), FRCPath(UK), FAASe,
Giuseppe Ippolito, MD, FRCPa,*

KEYWORDS
 Ebola  Ebola virus diseases  Ebola hemorrhagic fever  Epidemiology  Diagnosis
 Treatment  Prevention  Vaccines

KEY POINTS
 Ebola virus disease (EVD) is a severe zoonotic disease caused by the Ebola virus
(EBOV), first discovered in 1976 near the Ebola River in the Democratic Republic
of Congo.
 Bats are the most likely host reservoir of EBOV. Humans acquire infection through direct
or indirect contact with blood, body fluids, and tissues.
 Human-to-human transmission of EBOV occurs via direct contact with an infected per-
son. Sexual transmission has been described.
 Initial symptoms are nonspecific often misdiagnosed as influenza or malaria. Suspicion of
EVD should prompt isolation and infection control measures.
 Outbreak control requires a multidisciplinary team effort applying case management,
infection prevention and control practices, surveillance and contact tracing, good labora-
tory service, safe and dignified burials, social and community mobilization.

Conflicts of interest: All of the authors have an interest in global public health and emerging
and reemerging infections. The authors have no other conflict of interest to declare.
a
National Institute for Infectious Diseases, Lazzaro Spallanzani, IRCCS, Via Portuense, 292,
Rome 00149, Italy; b Centre de Recherche en Infectiologie, Centre Hospitalier Universitaire de
Québec, Université Laval, 2705, Boulevard Laurier, RC-709, Québec, Québec G1V 4G2, Canada;
c
SACIDS Foundation for One Health, Sokoine University of Agriculture, PO Box 3297, Chuo
Kikuu, Morogoro, Tanzania; d Mercy Hospital Research Laboratory, School of Community
Health Sciences, Njala University, Bo Campus, Kulanda Town, Bo, Sierra Leone; e Center for
Clinical Microbiology, University College London, Royal Free Campus 2nd Floor, Rowland Hill
Street, London NW3 2PF, UK
* Corresponding author.
E-mail address: giuseppe.ippolito@inmi.it

Infect Dis Clin N Am 33 (2019) 953–976

https://doi.org/10.1016/j.idc.2019.08.005 id.theclinics.com
0891-5520/19/ª 2019 Elsevier Inc. All rights reserved.
954 Nicastri et al

INTRODUCTION

Ebola virus disease (EVD), also known as Ebola hemorrhagic fever or Ebola, is caused
by the Ebola virus (EBOV). EBOV is a linear, nonsegmented, single negative-stranded
RNA virus and is a member of the Filoviridae virus family, of which 6 species have been
identified named after the region of discovery: Zaire EBOV, Bundibugyo EBOV, Sudan
EBOV, Reston EBOV, Tai Forest EBOV, and Bombali EBOV. The Bundibugyo, Zaire,
and Sudan EBOVs are the cause of the large outbreaks in Africa. The Zaire EBOV
caused the 2014 to 2016 West African epidemic.1 The high case fatality rates have
endowed Ebola a reputation as one of the most deadly viral zoonotic diseases of
humans. Fig 1 shows the geographic distribution of Ebola in Africa.
The first human case of EVD was described in 1976 near the Ebola River in the
Democratic Republic of Congo (DRC). The first outbreak of EBOV affected 284
people, with a mortality of 53%. This outbreak was followed a few months later
by the second outbreak of EBOV in Yambuku, Zaire (now DRC). Until 2013,
EBOV outbreaks consisted of small numbers of cases that were contained by
basic public health and containment measures. The largest EVD epidemic
occurred in West Africa between 2013 and 2016, and detection of EVD cases in
the United Kingdom, Sardinia, Spain, and the United States focused global atten-
tion on the epidemic.

Fig. 1. Geographic distribution of Ebola in Africa.

 Ebola Virus Disease 955

On August 1, 2018, the Ministry of Health of the DRC declared a new outbreak of EVD
in North Kivu Province. As of March 17, 2019, there have been a total of 867 confirmed
cases, with 587 deaths.1 The DRC outbreak shows that public health and surveillance
efforts remain inadequate2 and EVD remains an important public health threat to global
health security. This article highlights the epidemiology, clinical features, diagnosis,
management, and prevention of EVD. It also reviews emerging field-friendly and
easy-to-use point-of-care rapid diagnostic technologies, viral characterization, geospa-
tial mapping of EVD transmission in urban and rural areas, World Health Organization
(WHO) standard-of-care and advanced clinical management of patients with EVD,
use of investigational new drugs and vaccines within compassionate use or phase II
and III clinical trials, and a WHO draft Ebola/Marburg research and development
(R&D) roadmap to prioritize the development of countermeasures (diagnostics, thera-
peutics, and vaccines) that are most needed by EVD-affected countries.3

CASE DEFINITION OF EBOLA VIRUS DISEASE

In 1999 the WHO proposed the use of a case definition for hemorrhagic fever using the
following clinical criteria: body temperature greater than or equal to 38.3 C (101 F) for
less than 3 weeks’; severe illness and no predisposing factors for hemorrhagic man-
ifestations; and at least 2 of the following: hemorrhagic symptoms of hemorrhagic or
purple rash, epistaxis, hematemesis, hemoptysis, blood in stools, or other hemorrhag-
ic signs; and no established alternative diagnosis.4
In 2009, a systematic review reported that only 58% of patients with EVD in the liter-
ature met the 2009 WHO case definition.5 During the 2013 to 2016 West African
outbreak, fever was absent in at least 10% of the cases with no major hemorrhagic
manifestations.6 This clinical presentation questions previous EVD case definitions,
which, including fever and hemorrhagic manifestations, make it too specific, and
not sensitive enough for case detection. Thus substantial changes have been pro-
posed in the eleventh revision of the International Classification of Diseases (ICD-
11), with an innovative EVD case definition that links epidemiologic and clinical
perspective, including the presence of a severe disease with high case fatality and
unusual prolonged disease manifestations.7,8
A confirmed case of EVD is now defined as a suspected case (patient with fever
and no response to treatment of usual causes of fever in the area, with at least 1 of
the following signs: bloody diarrhea, bleeding from gums, bleeding into skin [pur-
pura], bleeding into eyes and urine) with laboratory EBOV confirmation (positive
immunoglobulin M antibody, positive polymerase chain reaction [PCR] or viral
isolation).

EPIDEMIOLOGY OF EBOLA VIRUS DISEASE

Historical
EVD was first recognized in 1976, when 2 separate outbreaks were identified in the
DRC (then Zaire) and in South Sudan (then Sudan).9 At that time, it was assumed
that these outbreaks were a single event associated with an infected person traveling
between the 2 regions. However, further investigations revealed that there were 2
genetically distinct viruses: Zaire EBOV and Sudan EBOV, which came from 2 different
sources and spread independently in each of the affected areas.
The first case was reported on August 22, 1976. The patient was a 42-year-old
headmaster of the Yambuku Mission School, Équateur Region, returned from a
2-week driving excursion to northern Zaire; along the route, he purchased antelope
and smoked monkey meat. He presented on August 26 to the outpatient clinic of
956 Nicastri et al

the 120-bed Yambuku Mission Hospital with chills and fever and was treated for ma-
laria with apparent relief. One week later, he returned with severe headache, muscle
pain, nausea, abdominal complaints, and intestinal bleeding. He died on September
6, after the occurrence of a severe hemorrhagic syndrome of unknown cause. The
EBOV was first isolated in 1976 (isolate E718) from the blood sample of a 42-year-
old Belgian nursing sister who was working at the Yambuku Mission Hospital,
DRC.10 Karl Johnson, the International Commission scientific director, suggested
the name Ebola virus. Ebola is a river part of the Congo River network, about 60 km
from the first EVD-affected area. It was chosen to ensure that the Yambuku commu-
nity was not stigmatized. The name is a distortion of the local Ngbandi name Legbala,
meaning white water or pure water.10

Ebola Virus Host Reservoir

The specific host reservoir for EBOV remains unknown. After the first discovery of
EBOV, studies to find the host reservoir focused on animals, insects, and plants. Ebola
seems to be introduced into the human population through close contact with the
blood, secretions, meat, organs, or other bodily fluids of infected animals, such as
bats, chimpanzees, gorillas, monkeys, forest antelope, and porcupines in rain forest.
Although nonhuman primates and other mammals were implicated in the first cases of
EVD, and the host reservoir is not yet confirmed, the candidate reservoir seems most
likely to be African fruit bats.

Ebola Virus Disease Outbreaks in Africa Since 1976

Table 1 summarizes all EVD outbreaks recorded since the first discovery. Until the
2013 to 2016 EVD epidemic in West Africa, EVD outbreaks occurred in fairly isolated
remote areas and were contained quickly. In contrast, the 2013 to 2016 EVD epidemic
also involved major urban areas,1 with a total of 28,646 suspected cases and 11,310
deaths (39.5% mortality). Approximately 20% of EVD cases occurred in children less
than 15 years of age. A substantial portion of EBOV transmission events might have
been undetected, particularly in the first phase of the 2013 to 2016 outbreak because
there were cases of mild illness with minimal symptoms recorded.11 These data bring
new insight into the transmission dynamics and risk factors that underpin EBOV spill-
over events.
During the ninth EVD outbreak in the first 2018 semester in Équateur Province in
DRC, there was a total of 54 cases with 33 deaths (case fatality ratio [CFR], 61%). A
vaccination strategy was successfully applied between May and June 2018, with a to-
tal of 3481 people vaccinated, targeting frontline health care workers (HCWs) as pri-
ority categories, and EVD primary and secondary contacts.12
Later, on August 1, 2018, the DRC Ministry of Health declared an outbreak of Zaire
EBOV in the North Kivu province, the country’s 10th outbreak since the discovery of
EVD in 1976.13 Since then, the EBOV epidemic has spread in the Ituri provinces. As
of March 28, 2019, a total of 1044 cases (978 confirmed and 66 probable cases)
and 652 deaths (586 confirmed and 66 probable) have been reported (Fig 2)
(https://mailchi.mp/sante.gouv.cd/ebola_kivu_28mar19?e52ee85af345).

CLINICAL FEATURES OF EBOLA VIRUS DISEASE

The clinical features of EVD are detailed in Table 2. The incubation period is between 5
and 9 days, with a range from 1 to 21 days. A range of clinical manifestations of EVD
occur, from mild to the rapidly fulminant. Early symptoms of EVD may be similar to
those of other causes of fever, such as malaria, dengue, Lassa fever, Marburg,
Table 1
Occurrence and distribution of Ebola virus disease outbreaks since 1976

Cases Deaths
Date Country Virus (N) (N) CFR (%) Description Reference
1 Jun–Nov 1976 Sudan SUDV 284 151 53 First outbreak in Sudan: index cases were WHO,71 1978
workers in a cotton factory: 37%
infected workers. Many medical care
personnel infected
2 Aug 1976 Zaire EBOV 318 280 88 First outbreak in DRC, ex Zaire, in WHO,9 1976
Équateur province in Yambuku and
surrounding areas: 38% serologically
confirmed survivors
3 Jun 1977 Zaire EBOV 1 1 100 Second outbreak in DRC, ex Zaire, with no Heymann et al,72
known connection with the 1976 1980
outbreak
4 Aug–Sep 1979 Sudan SUDV 34 22 65 Second outbreak at the same site as the Baron et al,73
1976 Sudan epidemic 1983
5 1989 Philippine Reston 3 0 0 High mortality in the cynomolgus Miranda et al,74
macaques with 3 asymptomatic 1991
infected individuals
6 1990 United States Reston 4 0 0 Linked to monkeys imported from CDC,75 1990
Philippines with 4 asymptomatic
infected individuals
7 1994 Cote d’Ivoire Tai Forest 4 0 0 High mortality in the chimpanzee Le Guenno et al,76
population in the Tai Forest, with 1 1995

Ebola Virus Disease

recovered scientist in Switzerland
8 Dec 1994 to Gabon EBOV 52 31 60 First outbreak in Gabon in Makoku in Georges et al,77
Feb 1995 gold-mining camps in the rain forest 1999
along the Ivindo River, initially thought
to be yellow fever

(continued on next page)

957
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Nicastri et al
Table 1
(continued )
Cases Deaths
Date Country Virus (N) (N) CFR (%) Description Reference
9 May–Jul 1995 Zaire EBOV 315 250 79 Third outbreak in DRC, ex Zaire, in Kikwit. Khan et al,78 1999
Transmission was halted once PPE and
other measures were used
10 Jan–Apr 1996 Gabon EBOV 60 45 75 Second outbreak in Gabon in the village Georges et al,77
of Mayibout and neighboring areas 1999
after eating a chimpanzee found dead
11 Jul 1996 to Gabon EBOV 37 21 57 Third outbreak in Gabon in the Booué Georges et al,77
Mar 1997 area with transport of patients to 1999
Libreville. The index patient was a
hunter in a forest timber camp
12 Oct 2000 to Uganda SUDV 425 224 53 First outbreak in Uganda, in the Gulu, Okware et al,79 2002
Jan 2001 Masindi, and Mbarara districts. Three
main risk factors: attending funerals,
having contact with affected patients,
and providing medical care without
PPE
13 Oct 2001 to Gabon, Republic EBOV 124 96 77 Occurred on both sides of the border WHO et al,80 2003
Jul 2002 of Congo between Gabon (fourth outbreak) and
the RC; first outbreak). Abnormal
number of animals found dead in
Gabon
14 Dec 2002 to Republic of EBOV 143 128 90 Second outbreak in RC in of Mbomo and Formenty et al,81 2003
Apr 2003 Congo Kéllé districts in the Cuvette Ouest
Department
15 Nov–Dec 2003 Republic of EBOV 35 29 83 Third outbreak in RC in Mbomo villages WHO,82 2004
Congo
16 Apr–Jun 2004 Sudan SUDV 17 7 41 Third outbreak in Yambio county WHO,83 2005
concurrent with an outbreak of
measles
17 April 2005 Republic of EBOV 12 10 83 Fourth outbreak in RC in Etoumbi medical —
Congo centers: most cases among hunters,
caregivers, or funeral attendees
18 Aug–Nov 2007 DRC EBOV 264 187 71 Fourth outbreak in DRC in the WHO,84 2007
Kasai-Occidental province
19 Dec 2007 to Uganda BDBV 149 37 25 Second outbreak in Uganda in the MacNeil et al,85 2011
Jan 2008 Bundibungyo district; this was the first
identification of the BDBV
20 Dec 2008 to DRC EBOV 32 15 47 Fifth outbreak in DRC in the Mweka and WHO,86 2009
Feb 2009 Luebo health zones in the
Kasai-Occidental province
21 May 2011 Uganda SUDV 1 1 100 Third outbreak in Uganda in the Luwero Shoemaker et al,87
district 2012
22 Jun–Aug 2012 Uganda SUDV 17 7 41 Fourth and fifth outbreaks in Uganda in 2 Albarino et al,87 2013
sites: Luwero, Jinja, and Nakasongola
districts, and Orientale province

(continued on next page)

Ebola Virus Disease

959
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Nicastri et al
Table 1
(continued )
Cases Deaths
Date Country Virus (N) (N) CFR (%) Description Reference
23 Jun–Nov 2012 DRC BDBV 35 13 36 Sixth outbreak in DRC in the Orientale Albarino et al,88 2013
province. No epidemiologic link with
2012 outbreak in Uganda
24 Dec 2013 to West Africa, EBOV 28,616 11,310 39 The largest Ebola outbreak in terms of Baize et al.89 2014
Jan 2016 mainly Liberia, human patients, fatalities, and
Sierra Leone, multiple-site involvement in different
and Guinea countries in both urban and rural
Conakry settings. It began in Guéckédou,
Guinea, in December 2013
25 Aug–Nov 2014 DRC EBOV 66 49 74 Seventh outbreak in DRC in Équateur Maganga et al,90
province 2014
26 May 2017 DRC EBOV 8 4 50 Eighth outbreak in DRC in the Likati Nsio et al,99 2019
health zone in Bas-Uélé province close
to central African Republic
27 May–Jul 2018 DRC EBOV 54 33 61 Ninth outbreak in DRC in the Ebola outbreak
north-western towns of Bikoro and team,91 2018
Mbandaka in Équateur province.
VSV-ZEBOV vaccine has been used to
contain the outbreak
28 August 2018 DRC EBOV 3099 2074 66.9 ongoing 10th outbreak in DRC started on August WHO, 2019100
to present 1, 2018: the second largest outbreak in
North Kivu and, as of March 1, 2019, it
is still ongoing

Abbreviations: BDBV, Bundibungyo virus; CDC, US Centers for Disease Control and Prevention; CFR, case fatality ratio; PPE, personal protective equipment; RC,
Republic of the Congo; SUDV, Sudan EBOV; VSV-ZEBOV, vesicular stomatitis virus–Zaire EBOV.
 Ebola Virus Disease 961

Fig. 2. Distribution of EVD cases by place of residence in the 2019 Ebola DRC outbreak.
(Courtesy of the World Health Organization, Geneva, Switzerland, https://www.who.int/
csr/don/08-august-2019-ebola-drc/en/ ; with permission.)

Crimean Congo hemorrhagic fever, typhoid, shigellosis, rickettsial diseases, borrelio-

sis, leptospirosis, and viral hepatitis.
The clinical presentations of patients in the Zaire and Sudan EVD outbreaks in 1976
were similar and were characterized by initial unspecific febrile syndrome followed by
vomiting, diarrhea, impaired kidney and liver functions, and internal and external
bleeding.9,10 The main differences involved the case fatality rates, with values of
88% (280 deaths from 318 cases) in Zaire and 53% (151 deaths from 284 cases) in
Sudan, and the high frequency of chest pain (83%) and cough (49%) in Sudan.1,9,10
In the 2013 to 2016 EVD outbreak in West Africa, severe presentations of EVD included
severe gastroenteritis with dehydration,14 severe sepsis, multiple organ failure (kid-
neys, liver, respiratory and coagulation systems),15–18 and shock19,20 (see Table 2).
Bleeding was not commonly reported. EBOV viral load is an important prognostic fac-
tor. Patients who did not survive had 10-fold to 100-fold higher viral loads at the time of
hospital admission compared with survivors.21,22 Patients who survive seem to have
lower average peak viremia levels, and show faster decay in viremia than those who
did not survive.6 In survivors, viremia decreases to less than the limit of reverse tran-
scription (RT) PCR detection around 2 to 3 weeks after symptom’s onset. The host im-
mune response seems important in influencing the outcome of EVD. Early antibody
responses to EBOV, and reduced lymphocyte depletion, are associated with effective
EBOV viral clearance and survival.

CLINICAL MANAGEMENT OF EBOLA VIRUS DISEASE

There is no specific antiviral treatment of EVD, and recovery depends on supportive

clinical care and treatment of complications (see Table 2). Management guidelines23
from previous EVD outbreaks in 2013 were primarily focused on HCW safety and deliv-
ering treatment and care in rural areas with limited access to medical care. The man-
agement of patients with EVD was based on supportive therapy with oral hydration
 962
Table 2
Clinical characteristics of Ebola virus disease

Nicastri et al
Clinical Disease
Phase of EVD Duration Progression Symptoms Clinical Features Treatment
Prodromal 1–3 d, following Nonspecific Sudden onset of fever, tiredness, Feverish (<38 C) or remittent fever, Antipyretics, oral hydration
phase an incubation febrile headaches, sore throat, muscular lethargy, myalgia
period of 5–9 d syndrome pain, weakness, loss of appetite,
(range: 1–21 d) skin rash, cough
Systemic 3–10 d Gastrointestinal, Persistent fever, tiredness, High temperature with pulse- Early detection of systemic
involvement liver, adrenal, abdominal pain, nausea, temperature dissociation (relative involvement and isolation
pancreatic, vomiting, profuse watery bradycardia), progressive with strict infection control
and kidney diarrhea, bruising and bleeding drowsiness, partial response to measures. Use of PPE
involvement from gums simple orders Instituting best supportive
Agitation and irritability Patients unable to take care of care measures
themselves and may require Antipyretics, oral and aggressive
intensive care intravenous hydration,
Bleeding from gums and stools antimalarials, antibiotics
Hepatomegaly, splenomegaly EBOV-specific therapy:
Hematuria, proteinuria Zmapp or REGN-1EB3 or
Low white cell count (lymphopenia), mAb11
low platelet count, and abnormal
liver and renal function tests. Both
ALT and AST levels are increased
(AST increases more than ALT)
Urgent tests: malaria, Ebola RT-PCR,
full blood count, serum creatinine
and urea, liver function tests,
arterial blood gases, coagulation
studies, blood cultures
— Neurologic Persistent high temperature with Deep prostration, mood alterations, Antipyretics, aggressive
involvement confusion, panic, seizures, rarely seizures, coma intravenous hydration,
hallucinations, agitation, and Completely dependent on antimalarials, antibiotics
irritability caregivers in the community and with good CNS penetration
Reduced or no response to simple acute/critical care setting in EBOV-specific therapy:
orders with advancing disease hospitals Zmapp or REGN-1EB3 or
mAb11 plus remdesivir
 Multiorgan 7–16 d Systemic Nonresponsive and comatose, no Hypovolemic, severe sepsis or septic Intensive care with circulatory/
failure involvement response to simple orders. shock, acute renal insufficiency hemodynamic and ventilatory
(25%–90% Bleeding from all mucous support, renal dialysis,
mortality) membranes and all orifices transfusions
Hiccups (sign of terminal illness) EBOV-specific therapy:
Zmapp or REGN-1EB3 or
mAb11 plus remdesivir
Adult respiratory Shortness and rapid breathing, Severe dyspnea at rest, central and All previous therapy plus
distress cough, chest pain, and bluish skin peripheral cyanosis, drowsiness, noninvasive or invasive
syndrome coloration jaundice mechanical ventilation

See Table 3 for details on specific treatment of Ebola viral disease.

Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; RT-PCR, reverse transcription polymerase chain reaction; CNS, central nervous system.

Ebola Virus Disease

963
964 Nicastri et al

and on the strict application of infection control measures to prevent transmission to

HCWs, other patients and relatives, and to the community. High-level isolation and
containment procedures hampered the implementation of standard clinical interven-
tions for critically ill patients infected with other life-threatening pathogens in high-
resources countries.24
Management of EVD is more challenging in both urban and rural settings. Manage-
ment of EVD outbreaks requires strict and early implementation of infection prevention
and control measures, assembly of multidisciplinary teams of trained staff, biocontain-
ment units, and engagement of community leaders and community HCWs. Treating
patients with EVD requires understanding of risk exposure of acquiring EBOV, training
in infection prevention and control measures, and ability to work in difficult field con-
ditions of extreme heat and humidity while wearing complete personal protective
equipment (PPE).19,24–26
In the 2013 to 2016 West African EVD outbreak, aggressive supportive care and
antiviral therapy improved patient outcomes. It is therefore likely that the dramatic
decrease of CFR from around 75% in the first 2014 months to less than 40% at the
end of the outbreak reflected both care enhancement and less severe case mix at pre-
sentation.27–34 This lower CFR could gradually approximate the 18.5% CFR reported
among HCWs evacuated to medical facilities in the United States and Europe.30 How-
ever, despite the use of new high-level deployable infectious disease units, highly
aggressive therapeutic strategies, and innovative antivirals and vaccines in first-line
HCWs and EVD contacts in the 10th EVD outbreak in DRC, the CFR still reaches un-
acceptable levels (as high as 64%).

ADVANCED LEVELS OF CARE SETTING IN RESOURCE-LIMITED COUNTRIES

In 2014, many EVD care groups operating in the field27,28 endorsed the need for more
aggressive symptomatic treatment, early identification of severe cases, and prompt
treatment of dehydration and related electrolyte imbalances and organ-supporting
care. Human resources and funding, combined with experience from EVD treatment
of patients transported to North America and Europe, strengthened the idea of critical
care provision in resource-constrained settings.30 The Italian nongovernmental orga-
nization EMERGENCY delivered care sequentially at 2 Ebola treatment centers (ETCs)
in Sierra Leone: the first at Lakka, where general hospital medical care was provided to
patients with EVD based on fluids, symptomatic drugs, antibiotics, and antimalarial
treatment. In Goderich, a well-equipped intensive care unit (ICU), capable of providing
24-hour nursing and medical assessment and support, mechanical ventilation, intra-
venous vasoactive medications, and renal replacement therapy, was constructed to
implement the first ever, dedicated ICU-ETC in Africa.31 An ETC-ICU was set up in
a very short time with limited resources and highly trained and skilled personnel. Inten-
sive supportive treatment resulted in shorter time to discharge in survivors and survival
advantage in patients with intermediate-severe EVD.31 High-level optimized care
seems to improve outcomes and needs to be promoted to overcome perceptions
that EVD is always fatal. The added value and the feasibility of hemodialysis, artificial
ventilation, or hemodynamic support in low-resource settings require further studies.6

EBOLA VIRUS–SPECIFIC TREATMENTS

The 2013 to 2016 EVD outbreak gave an opportunity to evaluate specific antiviral
drugs, although the clinical trials evaluating favipiravir32 and Zmapp33 started too
late in the outbreak to give any meaningful results. Most of the patients evacuated
to Europe or to North America for medical treatment received investigational therapies
 Ebola Virus Disease 965

and two-thirds of them received at least 2 experimental drugs under compassionate

protocol.30
During the current 10th DRC EVD outbreak, DRC health regulatory authorities
established a committee to review and recommend investigational use of therapeutics
in individual patient’s care under expanded access or compassionate use, based on
the WHO ethical framework (monitored emergency use of unregistered and experi-
mental interventions [MEURI], WHO 2016) until approved protocols for clinical trials
are available (Table 3).
At present, 5 agents for compassionate use in the treatment of patients diagnosed
with EVD have been approved. The monoclonal antibody MAb114 was the first agent
to be approved for use, then additional biologics (REGN-EB3 and ZMapp) and the an-
tivirals remdesivir and favipiravir completed the approval processes.34–36 For most of
these agents, efficacy studies involving EBOV challenges in nonhuman primates have
been supportive. Very few data are available on the use of investigational new drugs
during the 10th DRC EVD outbreak. At the end of 2018, a WHO situation report stated
that investigational agents had been administered to 38 patients: MAb114 (22 pa-
tients), remdesivir (9 patients), and ZMapp (7 patients). Nineteen of these patients
had been discharged, 12 had died, and 7 had remained hospitalized; those who
died were in advanced stages of disease when treatment was initiated (WHO. Ebola
situation reports: DRC; http://www.who.int/ebola/situation-reports/drc-2018/en/).

HIGH-LEVEL DEPLOYABLE INFECTIOUS DISEASE UNITS

The main function of the high-level infectious disease unit is to keep high-risk patients
in 1 strictly selected and dedicated area. There are numerous challenges with implica-
tions for both staff safety and patient care in the plastic tents commonly used as high-
level infectious disease units: daytime temperatures typically are high, with profuse
sweating even before donning PPE to enter the high-risk zone; dehydration of staff
is a constant concern; putting on PPE takes up to half an hour and each team member
has to be carefully checked to ensure that there are no exposed skin areas at risk for
infection. Every activity within the high-risk zone is performed according to written
procedures and is strictly monitored. Different solutions to address these challenges
have been proposed. Particularly, during the 10th DRC outbreak, a recent advance in
patient care and management was the use by the Alliance for International Medical Ac-
tion (ALIMA) of individual air-conditioned biosecure cubicles, Cube (manufactured by
Securotec in France, http://www.securotec.fr/), in ETCs.37 With such cubicles, HCWs
can provide intravenous fluids and therapeutics through specialized ports and are thus
free from the burdensome PPE used during the 2013 to 2016 West African outbreak
and able to spend more time with their patients.37 However, the role of the cubicle
strategy is mostly recognized in the early phase of an EVD outbreak or in patients
with EVD without severe clinical presentations.

EBOLA VIRUS VACCINES

As of December 31, 2018, 58 clinical trials on Ebola vaccine are registered on

ClinicalTrials.gov: of them, 40 trials are completed, 7 are active and not recruiting,
and 7 are recruiting.38 However, clinical efficacy data are only reported in the Ebola
Ça Suffit vaccination trial in Guinea.39 This trial evaluated vaccine effectiveness in
EVD contacts, randomized for immediate or delayed vaccination with the recombi-
nant, replication-competent, vesicular stomatitis virus–based vaccine expressing
the glycoprotein of a Zaire EBOV (rVSV-ZEBOV). Investigators estimated a 100% vac-
cine efficacy in individuals vaccinated in the immediate group compared with those
 966
Table 3
Newer treatments for Ebola virus disease

EVD
Ebola Clinical
Treatment Mode of Action Protection Human Use Phase Drug Company Web Site Bibliography
Convale Human serum obtained from Ebola NtAb titer Used since the Phase III NA http://www.who.int/bloodproducts/brn/ Van Griensven
-scence EVD survivors increases in KiKwit outbreak brn_positionpaperconvplasmafiloviruses_ et al,92,93 2016
sera survivors but no efficacy finalweb14august2014.pdf
compared with in 2016 clinical
deceased trial
patients; also
in vitro data
Zmappa Human/mouse chimeric triple Postexposure It seems beneficial Phase II Mapp www.mappbio.com Qiu et al,94 2014;
monoclonal antibody protection in but no significant Biopharma- PREVAIL II
mixture (c13C6, h-13F6, NHP up to efficacy in ceuticals Writing Group;
and c6D8) produced on day 5 PREVAIL trial Multi-National
cellular lines obtained from PREVAIL II Study
tobacco plants Team,33 2016
REGN-1EB3 Specific anti- EBOV triple Postexposure Anecdotal use Phase I–II Regeneron https://www.regeneron.com/perspectives/ Pascal et al,95 2018
antibody mixture by protection making-ebola-drug
immunizing VelocImmune by IV single
mice dose in NHP
up to day 5
 mAb114 Single human monoclonal Postexposure Anecdotal use. Phase I Ridgeback http://www.ridgebackcap.com Corti et al,36 2016;
antibody identified from a protection by Safe and well Biothera- Gaudinski
survivor of the 1995 Kikwit IV single dose tolerated in peutics et al,96 2019
outbreak, approximately in NHP humans by US NIAID
11 y after infection license
Remdesivir, A monophosphoramidate Postexposure Anecdotal use and Phase II Gilead Sciences www.gilead.com/science-and-medicine/ Warren et al,97
GS-5734, prodrug of adenosine protection by use in survivors pipeline 2016; Jacobs
analogues, inhibits EBOV IV infusion in with viral et al,51 2016
RNA-dependent RNA all NHP persistence
polymerase at day 3–15 in semen
Favipiravir, Influenza viral RNA Postexposure Stockpile available, Phase III MediVector http://www.medivector.com/ Furuta et al,98
T-705 polymerase inhibitor, could protection in limited efficacy in per Fujifilm 2013; Sissoko
share antiviral activity laboratory low to moderate et al,32 2016
against other RNA viruses mouse viremia, well
such as Ebola up to day 6 tolerated

Abbreviations: IV, intravenous; NA, not available; NHP, non-human primate; NIAID, National Institute of Allergy and Infectious Diseases; NtAb, neutralizing antibody.
a
In a few anecdotal cases, ZMab (a murine monoclonal Ab mixture) and Mil 77 (a monoclonal antibody produced by MabWorks in China) was used in the 2013 to 2016 outbreak.
The preliminary data of the WHO/NIAID/INRB multi-drug randomized control trial (PALM study) to evaluate the safety and efficacy of four drugs (ZMapp, remdesivir, mAb114 and
REGN-EB3) used for treatment of Ebola patients in the Democratic Republic of the Congo (DRC) have been released on August 12, 2019. The data and safety monitoring board
(DSMB) recommended that the study be stopped and that all future patients be randomized to receive either REGN-EB3 or mAb114 in what is being considered an extension phase
of the study. This recommendation was based on the fact that an early stopping criterion in the protocol had been met by one of the products, REGN-EB3. The preliminary results in
499 study participants indicated that individuals receiving REGN-EB3 or mAb114 had a greater chance of survival compared to participants in the other two arms.101
The reported mortality was 49% in patients receiving ZMapp, 53% in those who received remdesivir, 34%, in the group that received mAb114, 29% in those on REGN-EB3. In the
patients who sought treatment early after infection and had lower viremia the mortality was 6% in the Regeneron antibody group and 11% with mAb114, versus 24% and 33% in
patients treated with ZMapp and remdesivir respectively.102

967
968 Nicastri et al

eligible and randomized to the delayed group. However, on days 0 to 9, incident cases
occurred in vaccine recipients at a similar rate to that in controls. The magnitude of this
efficacy has been widely debated, but a likely substantial protection to immediate re-
cipients seems to be warranted.40 Vaccination-related adverse events are a major
concern for rVSV-ZEBOV recipients. In a Swiss cohort study, despite a significant
dose vaccine reduction strategy, 10 (19%) of 53 vaccine recipients experienced
arthritis.41 Female gender (odds ratio [OR], 2.2, 95% confidence interval [CI], 1.1–
4.1) and a medical history of arthritis (OR, 2.8; 95% CI, 1.3–6.2) were independent
risk factors for the development of arthritis after vaccination.41 Soon after the
announcement of the 10th EVD outbreak in DRC, vaccination with rVSV-ZEBOV
began on August 8, 2018, implementing a ring protocol strategy. A cumulative total
of 92,502 people have been vaccinated as of March 18, 2019 (Ministère de la Santé,
DRC; see https://mailchi.mp/sante.gouv.cd/ebola_kivu_28mar19?e52ee85af345).

CLINICAL SEQUELAE AND EBOLA VIRUS PERSISTENCE IN SURVIVORS

In EVD survivors, clinical sequelae such as uveitis, arthralgia, and fatigue are common
and can affect up to the two-thirds of survivors.42 All studies from the 2013 to 2016
outbreak are consistently finding no association with EBOV viral load in plasma during
the acute phase. However in a single longitudinal study in Port Loko, a higher EBOV viral
load at presentation was independently associated with uveitis (adjusted OR [aOR], 3.33;
95% CI, 1.87–5.91) and with new ocular symptoms or ocular diagnoses (aOR, 3.04; 95%
CI, 1.87–4.94).43 However, this finding was not confirmed in subsequent studies,44 and
EBOV was not identified by RT-PCR in ocular fluid or conjunctivae in 50 EVD survivors
with ocular disease.45 Clinical and laboratory evidence suggests that pathogenesis of
eye disease involves blood-ocular barrier breakdown and the potential for EBOV to
persist in monocytes, macrophages, and retinal pigment epithelium.46

PERSISTENCE OF EBOLA VIRUS IN SURVIVORS

The EBOV can persist in selected body compartments of EVD survivors, most notably in
semen. EBOV has been isolated from the semen of an EVD survivor on day 83 after symp-
tom onset,47 and EBOV RNA has been detected in the semen of 4 of 38 (11%) survivors up
to month 15, and in 1 of 25 survivors (4%) up to month 18.48 Although the potential contri-
bution of sexual transmission to the scale of the epidemic is largely unknown, a case
report has been published on EBOV sexual transmission about 470 days after symptoms
onset in a survivor from Guinea with EBOV persistence in semen up to day 531.49 In addi-
tion, of 5 male-to-female events associated with EBOV transmission from survivors, 1 of
them, with at least 4 generations of secondary cases, was reported.50 Understanding the
duration of EBOV shedding in EVD survivors and preventing further transmission is
essential for promoting infection control public health measures and for controlling the
Ebola epidemic. In addition, the central nervous system might also be a reservoir for
EBOV, as described in the case of a patient who developed meningoencephalitis with
EBOV detection 9 months after initial recovery from acute EVD.51

POSTEXPOSURE PROPHYLAXIS

The most effective method of protecting HCWs and laboratory workers from acquiring
EBOV when managing patients with EVD is the implementation of strict infection con-
trol measures with the use of appropriate PPE. However, even when optimal measures
are taken, accidental exposures to EBOV have occurred.52 In these cases, postexpo-
sure prophylaxis has been considered.
 Ebola Virus Disease 969

Antiviral Drugs
In the antiviral portfolio, favipiravir is reported to have a weak antiviral activity against
EBOV at low viral load.32 This result can preclude its efficacy as a therapeutic agent
but not as postexposure prophylaxis characterized by presumed low viremia settings.
Favipiravir was used as postexposure prophylaxis in few HCWs during the 2013 to
2016 West Africa outbreak, with no secondary cases.53 Two of them received addi-
tional monoclonal antibody therapy. Other small-molecule inhibitors are under devel-
opment, including the nucleoside analogue BCX4430 and the nucleotide analogue
GS-5734, but, although promising, only in vivo data are available.

Prophylactic Vaccines
Development of the rVSV-ZEBOV vaccine offered the first opportunity for use of EVD
postexposure prophylaxis. It has been used in 8 HCWs with different EBOV
exposures, 7 of them during the West African outbreak.52 However, there are a few
concerns about the use of vaccines as postexposure prophylaxis. First, when consid-
ering the 7-day to 10-day EBOV incubation period, vaccine-induced immunity could
be insufficiently rapid to prevent the disease, and might only attenuate or delay the
symptom onset. Second, current vaccines are specific for Zaire EBOV and might offer
less or no protection against other species.

EBOLA VIRUS DIAGNOSTIC TESTS

During an outbreak, empiric EVD diagnosis is usually made based on unspecific febrile
syndrome. It is the most frequently used clinical diagnostic tool used in low-resource
settings and is not discriminatory in areas with a high incidence of malaria, Lassa fever
virus, yellow fever, and other arbovirus infections.
Laboratory diagnosis of EBOV infection plays a critical role in patent management and
outbreak response efforts. However, establishing safe testing strategies for this high-
biosafety-level pathogen in resource-poor environments remains extremely challenging.
Over the past decade, 3 basic methods for diagnosing EBOV infection have been
developed: (1) serologic tests that detect anti-EBOV antibodies, (2) antigen tests that
detect EBOV viral proteins, and (3) molecular tests that detect viral RNA sequences.
There are 2 types of diagnostic test for Ebola. Rapid diagnostic tests detect a viral
protein54 and those based on PCR identify the virus’s genomic material.55
Serologic testing for antiviral antibodies is generally not used because antibodies
can persist for many months after recovery, and antibody responses during acute
illness are variable. However, EBOV antigen detection and molecular tests have
proved very effective for acute diagnosis, because virus levels in the blood typically
increase to high levels within the first few days of infection. Some antigen diagnostic
tests are designed to broadly detect EBOV infection, whereas others distinguish
among the 5 known EBOV species. No tests have yet shown the ability to detect Ebola
antigen before the onset of symptoms.
During recent EVD outbreaks, the WHO approved an in vitro RT-PCR diagnostic
product, RealStar Filovirus Screen RT-PCR Kit 1.0 (Altona Diagnostics GmbH), which
was assessed under an emergency quality assessment mechanism established by the
WHO to address the lack of Ebola tests, and to fast track countries’ access to reliable
testing options.
This product was successfully used to diagnose EBOV infections. However, its
deployment and clinical impact were limited because of the infrastructure and
training required to accurately run the assay. Capillary blood samples could serve
as an alternative to venous blood samples for EBOV diagnosis by RT-PCR even in
970 Nicastri et al

cases in which venipuncture is difficult to perform; for example, with newborns and
infants or when adult patients reject venipuncture for cultural or religious reasons.56
These limitations highlight the need for portable diagnostics with ambient
temperature–stable reagents that can be deployed in low-resource settings. To
bridge this gap, several diagnostic platforms and assays compatible with austere en-
vironments have been designed and approved as Emergency Use Assessment and
Listing procedures by the WHO.57
At present, 14 tests for EBOV are under development and evaluation as point-of-
care portable and fully automated tests. HCWs and public health groups have not
been able to access them quickly because of high costs and it takes staff at labora-
tories or health centers 2 to 8 weeks to obtain the tests. The recently developed
DPP Ebola Antigen System (Chembio Diagnostic Systems Inc.) is used with blood
specimens, including capillary fingerstick whole blood, and has been approved by
the US Food and Drug Administration.55

PREVENTION, SURVEILLANCE, AND CONTROL

Early Case Detection and Isolation
Early case diagnosis and isolation of patients with EVD during outbreaks is impor-
tant.58 A surveillance system is essential in guiding the control measures required to
reduce morbidity and mortality caused by EVD.59 Control strategies during an Ebola
outbreak include proactive case detection, contact tracing and management, safe
and dignified burials, and prevention of new infections.60,61. Successful contact
tracing requires skills in the assessment of EVD symptoms, interviewing techniques,
and counseling. Persons who conduct contact tracing should have investigative skills
to find and track all potential contacts and the ability to analyze the evidence,62 and
their success is determined by the level of trust between the community and the public
health system and the quality of the diagnostic and treatment services.63

Community Engagement and Education

Control strategy efforts might be improved with data on the knowledge, attitudes, and
practices in EVD-affected populations.64 Health communication and social mobilization
efforts to improve the public’s knowledge, attitudes, and practices regarding EVD were
important in controlling the 2013 to 2016 outbreak.65 The 2018 to 2019 outbreak in
eastern DRC differed from the 2013 to 2016 outbreak in several ways, including multiple
previous EVD outbreaks in the country, long-standing violent conflict, large numbers of
internally displaced persons living in temporary camps, and availability of the new rVSV-
ZEBOV vaccine.64 Despite the knowledge that transmission via infected corpses was
high, 8% of Congolese people involved in the survey would wash or touch the body if
a family member died of suspected EVD. It suggests that an important minority of Con-
golese people might also engage in high-risk burial practices.64
During an EVD epidemic, prevention and control measures include mandatory
prompt and safe burial of the dead. The burial team refer to guidelines for dignified
burial of Muslim and Christian patients. A safe burial can be accomplished by a trained
burial team using appropriate PPE, placing the body in a puncture-resistant and leak-
resistant plastic body bag and burying the body in a grave. Ideally, used burial team
PPE should be incinerated.66

Preventing Infection in Health Care Workers

HCWs can be exposed to health care–related EBOV infection when caring for patients
with EVD. During the 2014 EVD outbreak in DRC, all 8 HCWs died, whereas during the
 Ebola Virus Disease 971

2013 to 2016 West African epidemic more than 890 HCWs were infected, with a case
fatality rate of 57%.67 Before working with patients with EVD, all HCWs involved in the
care of patients with EVD must receive training and show competency in performing all
Ebola-related infection control practices and procedures, specifically in proper don-
ning and doffing PPE.68 PPE should include double gloves; gown or coverall and
apron; facemask (N95 mask) or powered, air-purifying respirator (PAPR); eye protec-
tion (goggles or face shield); head cover; and boots. PAPR may be preferable to the
N95 mask during procedures that generate aerosols of body fluids. Use of PAPR,
compared with the N95 mask, is more comfortable for the HCWs, but it could increase
the contamination risk.69,70

ACKNOWLEDGMENTS

This study was supported by the Italian Ministry of Health. E. Nicastri, F. Vairo, C.
Montaldo, and G. Ippolito acknowledge support from the Italian Ministry of Health,
grants to Ricerca Corrente linea 1 to National Institute for Infectious Diseases Lazzaro
Spallanzani, IRCCS. L. Mboera, R. Ansumana, F. Vairo, C. Montaldo, A. Zumla, and G.
Ippolito acknowledge support from the PANDORA-ID-NET Consortium, which is
funded by the European and Developing Countries Clinical Trials Partnership
(EDCTP2) programme (EDCTP Grant RIA2016E-1609), which is supported under Ho-
rizon 2020, the European Union’s Framework Programme for Research and Innova-
tion. E. Nicastri, F. Vairo, and G. Ippolito are Professors at Saint Camillus
International University of Health and Medical Sciences in Rome.

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