Neurological Complications of Ebola Virus Infection
Neurological Complications of Ebola Virus Infection
Bridgette Jeanne Billioux 0
Bryan Smith 0
Avindra Nath 0
0 Section of Infections of the Nervous System, National Institute of Neurological Diseases and Stroke, National Institutes of Health , Bethesda, MD , USA
1 Avindra Nath
Ebola virus disease is one of the deadliest pathogens known to man, with a mortality rate between 25-90% depending on the species and outbreak of Ebola. Typically, it presents with fever, headache, voluminous vomiting and diarrhea, and can progress to a hemorrhagic illness; neurologic symptoms, including meningoencephalitis, seizures, and coma, can also occur. Recently, an outbreak occurred in West Africa, affecting > 28,000 people, and killing > 11,000. Owing to the magnitude of this outbreak, and the large number (>17,000) of Ebola survivors, the medical and scientific communities are learning much more about the acute manifestations and sequelae of Ebola. A number of neurologic complications can occur after Ebola, such as seizures, memory loss, headaches, cranial nerve abnormalities, and tremor. Ebola may also persist in some immunologically privileged sites, including the central nervous system, and can rarely lead to relapse in disease. Owing to these findings, it is important that survivors are evaluated and monitored for neurologic symptoms. Much is unknown about this disease, and treatment remains largely supportive; however, with ongoing clinical and basic science, the mechanisms of how Ebola affects the central nervous system and how it persists after acute disease will hopefully become more clear, and better treatments and clinical practices for Ebola patients will be developed.
Ebola; meningitis; encephalitis; microvascular disease; deafness; vertigo; insomnia; cognition; magnetic resonance imaging
Published online: 13 July 2016
# The American Society for Experimental NeuroTherapeutics, Inc. (outside the U.S.) 2016
Filoviruses have come to global attention recently with the
large outbreak of Ebola virus disease (EVD) originating in
Guinea in West Africa beginning in December 2013.
Filoviruses, which include the various Ebola species (Zaire,
Bundibugyo, Reston, Sudan, and Tai Forest) and Marburg
virus, are some of the most deadly pathogens known to infect
humans, with mortality rates ranging between 25% and 90%
]. They were first discovered in 1967, when researchers in
Germany and Yugoslavia developed hemorrhagic fever after
handling green monkey specimens; the virus that was
subsequently isolated from these cases was called Marburg virus,
after the city in Germany where most of the cases occurred .
A little less than a decade later, in 1976, Ebola virus was
identified as the cause of 2 outbreaks of highly fatal
hemorrhagic fever in northern Zaire [now Democratic Republic of
Congo (DRC)] and southern Sudan; the virus takes its name
from the Ebola River, which runs near the village of
Yambuku, where the first outbreak took place [
]. After these
initial outbreaks, subsequent outbreaks of Marburg virus and
Ebola virus occurred sporadically in different parts of Africa,
primarily central Africa, including Marburg virus outbreaks in
the DRC in 1999 and Angola in 2005, and Ebola virus
outbreaks in Kikwit (DRC), in 1995, Gulu (Uganda) in 2000, and
Bundibugyo (Uganda) in 2008. These various outbreaks
occurred largely in rural areas and were relatively small,
affecting between < 10 and 425 patients per outbreak . However,
in December 2013, an Ebola [Zaire ebolavirus (EBOV)]
outbreak occurred in Guinea in West Africa and rapidly spread to
other parts of West Africa, including areas of high population
density, primarily in Liberia and Sierra Leone; the outbreak
also included some imported but generally well-contained
cases in Nigeria, Spain, and the USA [
]. It has become the
largest outbreak in history, with 28,639 cases and 11,316
deaths due to EVD as of 17 February 2016 . With
thousands of EVD survivors, the medical and scientific
communities are learning more about the natural history of EVD than
ever before. In particular, sequelae of Ebola are becoming
more and more apparent, including ophthalmologic,
rheumatologic, and neurologic sequelae. The persistence of Ebola
virus and the potential for EVD relapse are also becoming
more evident. Further knowledge and education about these
fascinating emerging/re-emerging infectious diseases are
warranted to continue surveillance and potential treatment of
current survivors, as well as to prevent other outbreaks from
occurring or from spreading, given modern day trends in
Ebola virus is a negative-strand RNA virus that is 19 kb in
size. It has 7 structural proteins (NP, VP-24, 30, 35, and 40)
and 1 nonstructural protein (L5). The virus mainly infects
macrophages and endothelial cells and uses the C1 protein
associated with Niemann–Picks disease as a receptor. Thus,
cells derived from patients with Niemann–Pick disease are
resistant to infection by the virus. Several species of the virus
have been identified, which have been associated with
different outbreaks. The Zaire strain has a 70–90% mortality rate. In
comparison, the mortality rate for the Sudan virus is 50% and
the Bundibugyo virus is 25%.
Bats are thought to be the major reservoir of the virus. They
can either directly infect humans or the bats may infect wild
animals that may then serve as an intermediary host.
Humanto-human transmission is the major cause of the spread of the
infection . The virus is shed in all bodily fluids, including
saliva, tears, sweat, urine, semen, and even ear wax.
Human-to-human transmission of Ebola virus usually occurs
through direct contact between infectious body fluids of a
patient with symptomatic EVD and mucous membranes and/
or broken skin of an uninfected individual . During acute
illness, Ebola virus can be detected in many body fluids,
including blood, excrement, vomitus, sweat, breast milk,
vaginal secretions, and semen . However, at different stages of
the disease, these body fluids have varying levels of
infectivity. The incubation period, which is the period of time
between infection with Ebola virus and first symptom onset, is
usually 4 to 10 days, but may be as brief as 2 days or as long as
21 days; during this time, risk of transmission of the virus is
essentially zero [8, 9]. During the first few days of
symptomatic disease, transmission seems to remain low; however, as
the disease progresses, infectivity and potential for
transmission increases significantly. During this period, viral loads in
various bodily fluids increase exponentially, with viral loads
reaching as high as billions of copies per milliliter of blood
late in the disease . Infected patients also produce large
quantities of infectious bodily fluids, as explosive diarrhea
and vomiting become more common as the infection
As Ebola virus can remain viable in liquid or dried material
for many days, transmission can occur from dead patients with
EVD or from improper handling of waste materials from
patients with EVD . Given these factors, people at highest
risk for contracting EVD tend to be the people who are
actively taking care of patients with EVD such as healthcare workers
or other caretakers, people who are in close contact with
patients with EVD in later stages of infection, and people who
come into direct contact with dead patients with EVD, through
burial or funeral practices [2, 13]. Although seemingly rare,
Ebola can also be transmitted through sexual contact, even in
the convalescent phase, as Ebola virus can persist in semen for
months after recovery from the illness . A case of Ebola
occurred in a woman in March 2015 whose only known Ebola
contact was via unprotected sex with an EVD survivor; after
genetic analysis it was confirmed that survivor’s and the
patient’s Ebola virus genomes were identical and that the
transmission likely occurred from sexual contact . Butchering
and handling of bushmeat, including nonhuman primates and
bats, have also previously been associated with outbreaks of
Ebola . Aerosolized transmission of Ebola has not been
established as a cause of disease in humans, although this
mode of transmission has been described in monkeys .
In most cases, prevention of transmission is achieved by
appropriate barrier precautions and disinfection when dealing
with patients with EVD and their waste. See Table 1 for a
summary of epidemiological risk factors for EVD.
Clinical Manifestations of Acute Infection: Symptoms and Signs
Early EVD symptoms are relatively nonspecific and typically
include a high fever, malaise, fatigue, headache, and
generalized body aches. Symptoms may begin abruptly and progress
over a few days to include abdominal pain, nausea, and
highvolume vomiting and diarrhea. Other associated signs and
symptoms include conjunctival injection, chest pain,
arthralgias, myalgias, asthenia, and hiccoughs [7, 18]. Early in the
disease course, symptoms may be mistaken for other tropical
Percutaneous or mucous membrane exposure to body fluids of a patient with EVD
Exposure to body fluids of a patient with EVD without appropriate PPE
Processing body fluids of a patient with EVD without PPE or standard biosafety
Direct contact without appropriate PPE with a dead body in a country with widespread
Having lived in the same house and provided care to a symptomatic patient with EVD
Direct contact with a symptomatic patient with EVD while using appropriate PPE in a
country with widespread EBOV
Close contact with a symptomatic patient with EVD in households, healthcare
facilities, or community settings
Having been in a country with widespread EVD transmission within the past 21 days
without a known exposure
Having brief direct contact (shaking hands, etc.) while not wearing PPE with a patient
with EVD while they are in the early stages of disease
Being in close proximity with a symptomatic patient with EVD for a brief period of
Direct contact with a patient with EVD while using appropriate PPE in a country
without widespread EBOV
Having traveled on an aircraft with a symptomatic patient with EVD
Contact with an asymptomatic person who had contact with a patient with EVD
Contact with an asymptomatic person who had contact with a symptomatic patient
Having been in a country with widespread EBOV transmission > than 21 days ago
Having been in a country without widespread EBOV transmission but without any
exposures defined above
diseases, such as malaria, dengue, or cholera . A recent
account of an Ebola treatment unit (ETU) in Monrovia,
Liberia, describes the typical output from a patient with
EVD as an estimate of 5 liters or more of watery diarrhea
per day, lasting for up to 7 days and sometimes longer .
This profuse vomiting and diarrhea can quickly lead to
intravascular volume depletion, electrolyte disorders,
hypoperfusion, and shock . Although Ebola has been traditionally
known as a hemorrhagic fever, hemorrhagic manifestations
are a late complication, and may be seen in only a minority
of patients . These symptoms include petechiae,
ecchymosis, oozing from venipuncture sites, mucosal hemorrhage,
hematemesis, or melena . Women who are pregnant may
have spontaneous abortions associated with significant
Acute Neurologic Manifestations
In the acute phase, patients with EVD may present with a
number of neurologic signs and symptoms, although serious
neurologic manifestations are relatively infrequent. Most
commonly, patients will complain of a nonspecific headache,
which often presents as an early symptom. Altered mental
status, from mild confusion to delirium with hallucinations,
may also occur, but may be secondary to a host of variables,
including electrolyte abnormalities and shock. In severe cases,
coma may occur . Meningitis and encephalitis related to
EVD have also been reported in the recent outbreak, as well as
in prior outbreaks, although the incidence is not well
documented [22–24]. During acute EVD, seizures have also been
reported, although these are not well characterized .
Detailed neurological evaluations and investigations have
been hard to perform on acutely ill patients in endemic
regions. However, 1 patient admitted to the National Institutes
of Health (NIH) was studied extensively. He developed
profound muscle weakness in the first week of the illness,
requiring intubation and ventilatory support. This was followed by
meningoencephalitis as manifested by classical meningeal
signs, delirium, eye movement abnormalities, and frontal
release signs. He also had conjunctivitis (Fig. 1). When the
meningeal signs gradually resolved and the patient was
extubated, he was noted to have decreased short-term
memory, hypomania, hyperphagia and insomnia, mild cerebellar
signs, and mild weakness of the lower limbs. Over the next
few days and weeks most of the symptoms gradually resolved.
Three weeks after the onset of symptoms he had uveitis,
which resolved with topical corticosteroids. Magnetic
resonance imaging of the brain showed multiple punctate
microvascular lesions in the white matter (Fig. 2). When seen 7
months later, he had chronic fatigue and decreased executive
function . Assessment of severity of neurological
symptoms necessitates the use of a numerical scale; however,
existing scales do not take into account symptoms such as
meningitis, hypomania, and hyperphagia. Hence, we have
developed an Ebola scale that used the NIH’s stroke scale and
added another 16 points for the additional signs (Table 2).
Neurologic assessment of patients in an acute setting poses
multiple challenges. The patient needs to be admitted to an
isolation unit with intensive care facilities. The physician
needs to be trained in biosafety procedures and how to dress
and wear multiple layers of protective clothing (Fig. 3). The
process of changing clothes can take nearly 30 min. Only
limited neurologic assessment is possible. For example,
sensory examination and fundoscopy cannot be performed owing
to the face shield. Ultimately, we were able to conduct an
indirect ophthalmoscopy using an innovative technique .
Physicians who examined the patients were required to
monitor and report their own temperature for 21 days and travel
restrictions were imposed upon them.
Confirmation of Ebola diagnosis is done by detection of
Ebola RNA via reverse transcriptase polymerase chain
reaction (RT-PCR) or through detection of viral antigens by
enzyme-linked immunosorbent assay. RT-PCR is usually able
to detect Ebola RNA within 3 days of symptom onset, but this
may need to be repeated in PCR-negative patients who are
suspected to have the disease, particularly early after
symptom onset [
]. In the patient seen at the NIH, the viral load
in the blood paralleled the severity of the neurological
symptoms (Fig. 4) .
Laboratory abnormalities seem to be somewhat variable
but may include leukopenia or leukocytosis (with leukopenia
typically early in the disease and leukocytosis later on), and
thrombocytopenia. Transaminase testing often reveals
abnormalities, usually with a greater elevation in aspartate
transaminase than alanine transaminase . With the marked
volume loss common in the recent outbreak, electrolyte
derangements such as hypo- and hypernatremia, hypocalcemia,
hypokalemia, and hypomagnesemia have often been reported
. Renal insufficiency and lactic acidosis may also be
commonly seen. Coagulation abnormalities such as prolongation
of international normalized ratio and partial thromboplastin
time may also occur, although these laboratory abnormalities
were not as prominent in this outbreak compared with others
. In cases of multiorgan failure, all of the above may be
seen, often at markedly deranged values . There are very
few reports of cerebrospinal fluid (CSF) analysis during acute
EVD. However, in 2 different cases of encephalitis related to
EVD, CSF analysis revealed Ebola virus present in the CSF.
In the first case, a lumbar puncture was performed early in the
course of disease, revealing a viral load of 1 × 106 viral
copies/ml and a normal cell count and glucose in the CSF
. In the second case, a lumbar puncture was performed at
day 41 after EVD onset; Ebola virus was detected at a cycle
threshold (CT) value of 37.6, but further CSF analysis was
not available . Although not typical laboratory analyses,
cytokine analyses on patients with Ebola have in the past
revealed a Bcytokine storm^, with increased proinflammatory
cytokine and chemokine production in patients with Ebola,
particularly in those with more severe disease .
Fig. 2 Magnetic resonance imaging scan of patient with Ebola
meningoencephalitis: fluid-attenuated inversion recovery images were
taken 3 weeks after onset of symptoms and after resolution of clinical
signs of meningitis. Punctate high signal intensity lesions represent
microvascular disease. There is also some associated cortical atrophy
Owing to biosafety concerns, autopsies have not been
performed on patients who have died of acute Ebola infection.
However, microglial nodules and perivascular infiltrates
involving both gray and white matter were noted in 2 cases of
Marburg disease manifested as subacute encephalitis [29, 30].
Nonhuman primate studies of EVD show glial nodules or
meningoencephalitis were observed in 5 of 6 animals
surviving 3 weeks following infection. Glial nodules stained positive
for viral antigen, suggesting microglial cells as a possible
reservoir for virus in the brain .
Ebola is one of the most highly fatal infectious diseases
known to humans. In prior outbreaks, fatality has ranged from
25% with the Bundibugyo outbreak in Uganda in 2007 up to
89% with the Zaire strain outbreak in the Republic of Congo
in 2001 . Generally, mortality rates are higher in outbreaks
due to the Zaire strain (70-90% historically), with about 40%
mortality seen in Bundibugyo, and about 50% mortality in
Sudan species of Ebola . This current outbreak is caused
by the Makona variant of the Zaire species of Ebola; however,
a lower case fatality rate has been noted during this outbreak
. As of 17 February 2016, there have been 28,639 cases
with 11,316 deaths during the recent outbreak, with a case
fatality rate of about 40% . This decreased mortality rate
is of unclear significance as yet but is potentially due to a trend
towards overall earlier access to treatment and more
comprehensive supportive treatment, or in differences in the virulence
of the current strain.
The long-term outcomes of Ebola survivors has been of
significant recent interest. There have only been brief reports of
these outcomes from prior Ebola outbreaks, including a study
of 70 survivors from a 2007 outbreak in Uganda. These
survivors, evaluated at approximately 29 months after
infection, most commonly reported memory loss, retro-orbital pain,
hearing loss, and arthralgias . A longitudinal study
followed a smaller group of survivors from the 1995 outbreak in
what was then Zaire found primarily arthralgia and myalgia
to be persistent problems in more than half of the cohort of 29
survivors when compared with uninfected household contacts
. Tellingly, the survivors reported a functional decline
when compared with before the EVD outbreak. In comparison
with the household contacts, the survivors were more likely to
report a decline in both overall health (70% vs 18%) and
ability to work (70% vs 7%) .
From the current outbreak, there has been a growing
interest in identifying the clinical outcomes of Ebola survivors. An
ongoing cohort study from Sierra Leone of 277 survivors seen
at a median of 121 days after ETU discharge specifically
examined ocular, auditory, and musculoskeletal outcomes.
Arthralgias were the most commonly reported symptom,
present in 76% of the cohort. New ocular symptoms were reported
in 60%, and 18% had uveitis on slit-lamp and dilated fundus
examinations. Furthermore, 24% reported tinnitus, aural
fullness, or hearing loss .
Neurologic sequelae are, unfortunately, less well
characterized than systemic and ophthalmic outcomes. One recent
study of Guinean survivors from the recent outbreak used a
questionnaire administered either in person or over the
telephone to collect data on a variety of persistent or new
symptoms, and many of the questions focused on neurologic and
psychiatric impairments since discharge from the ETU .
While the study was limited by the questionnaire design and
the lack of neurologic examinations, neurologic symptoms
were reported in a substantial number of participants during
the subacute convalescent period (defined as 91–210 days)
and included difficulty with concentration (37.5%) or memory
(21.3%), headache (29.2%), or dizziness (6.3%).
A larger, longitudinal study is currently ongoing
specifically to evaluate the neurologic outcomes in survivors of EVD
from the recent outbreak in Liberia . Approximately 150
survivors and 100 close contacts are being followed by a team
of neurologists with serial 6-month follow-up visits. Of the 87
survivors initially examined by the team, weakness, headache,
memory loss, depressed mood, and myalgia were the most
common symptoms. On neurologic examination, most
participants had some degree of objective abnormality. The
most common findings were impairments of either pursuits or
saccades (nearly two-thirds of the cohort); tremor, abnormal
reflexes or abnormal sensory findings in a third; and frontal
release signs in a sixth. The cohort is enrolling survivors and
contacts without selecting for neurologic symptoms;
however, there have been other survivors seen by the team of
neurologists with more overt neurologic manifestations. Focal
deficits consistent with stroke have been seen in several
survivors, including those with homonymous hemianopias,
hemiparesis, and cranial nerve palsies. Similarly, some
participants have a parkinsonian syndrome with rigidity,
shuffling gait, and retropulsion on examination. It is evident from
these detailed neurologic evaluations that a subset of
survivors have more severe neurologic manifestations that persist
after acute EVD infection.
It is important to note that most studies of Ebola
survivors to date have been cross-sectional so it is unknown
how persistent these findings will remain years after the
acute infection. Longitudinal cohort studies, including the
cohort study specifically addressing neurologic
complications, are ongoing.
As this current outbreak of Ebola virus is the largest in history,
there are many more survivors in whom to evaluate the
various sequelae of EVD. Some of the most startling findings
have been regarding the viral persistence of Ebola, which
may sometimes be harbored in immune-privileged areas of
the body such as the testes, placenta, eye, or central nervous
system. In prior outbreaks, viral persistence in certain body
fluids had been reported during the convalescent period. Ebola
virus was isolated in breast milk and semen 15 days and 82
days, respectively, after disease onset during the convalescent
phase, and Ebola RNA was detected in urine, feces, tears, and
from vaginal fluid 23, 29, 22, and 33 days after disease onset
[6, 38]. It was also known that ocular manifestations could
develop during convalescence, although these findings were
only found in a small number of patients and relatively little
was known about the nature of these ocular issues .
However, during the 2014 outbreak several systematic studies
(some ongoing) and a number of cases of Ebola relapse in
various parts of the body have alerted the community to the
significance of viral persistence of this pathogen.
Since these initial studies of Ebola virus persistence in
bodily fluids, several studies conducted during the recent
outbreak support the findings of persistent Ebola in bodily fluids.
Ebola viral RNA has recently been detected in convalescent
patients’ urine and sweat [40, 41]. However, one of the most
striking findings is the persistence of Ebola RNA in the semen
for prolonged periods of time. A study of 93 male survivors
found viral RNA in survivors up to 284 days after onset of
Fig. 4 (A) A gradual and
progressive decline in viral load
was noted in the blood and urine.
(B) The neurological symptoms
were present at the time of onset
of infection but deteriorated
rapidly; however, most symptoms
resolved with supportive care CT
= cycle threshold; PCR =
polymerase chain reaction; NIH,
National Institutes of Health;
MMSE = Mini-Mental Status
symptoms, although at decreasing rates over time (with all
survivors who were tested at 2–3 months after onset having
EBOV RNA-positive semen, 65% of survivors positive at 4–6
months after onset, and 26% positive at 7–9 months after
onset) . These findings are of further interest given the
potential for sexual transmission of EVD, as in the previously
mentioned March 2015 case in Liberia . Owing to risk of
sexual transmission during convalescence, Ebola survivors
are now recommended to practice safe sex with barrier
protection for at least 12 months after recovery from EVD .
Although little is known about viral persistence in pregnant
or lactating women, a recent case revealed some interesting
findings. A pregnant woman treated at a Medecins Sans
Frontières ETU in Guinea was described by Baggi et al.
. This 7-months-pregnant woman was treated for EVD
and was EBOV negative by RT-PCR in the blood on day 8
after symptom onset and remained negative on day 10. Fetal
movement and heartbeat were lost on day 11, labor was
induced on day 15, and a stillborn baby was delivered. Despite
the mother’s negative EBOV results, high levels of EBOV
RNA were found in the fetal blood, placenta, amniotic fluid,
and meconium of the infant . This case illustrates the
potential need for special precautions and infection control
during delivery of EVD survivors, particularly when
temporally proximal to acute EVD.
The previous cases and studies illustrate the asymptomatic
persistence of Ebola virus, with the potential of transmission of
the disease to uninfected people. Another concern about viral
persistence that has arisen since the recent outbreak is relapse or
recurrence of EVD in a recovered survivor. A recent report
details a 43-year-old American physician who had clinically
recovered from EVD 9 weeks prior to developing severe
unilateral uveitis. Aqueous humor was obtained from the affected
eye, in which viable Ebola virus was detected . While
ocular manifestations including uveitis are known to occur in
EVD survivors during the convalescent phase, these findings
have been thought to be related to delayed immunological
factors. This case suggests that viral recurrence may be a
potential cause of uveitis, warranting further study.
More recently, a Scottish nurse was reported to have
developed neurological symptoms consistent with
meningoencephalitis 9 months after recovery from EVD. She was found to be
PCR-positive for Ebola virus in both CSF and serum, and she
was treated with an experimental therapy . While there are
very few reports to date consistent with Ebola recrudescence,
it is possible that these cases are under-reported, as the
majority of survivors live in West Africa with less access to
healthcare. Nevertheless, an additional concern from these
EVD relapse cases is the potential for EVD transmission
during viral recurrence (although, at least regarding the 2 cases
above, casual contact with either aqueous or CSF does not
typically occur). While further study of Ebola virus
persistence is needed in humans, and is ongoing in some natural
history studies, we can supplement some of this knowledge
with findings in nonhuman primate studies. Alves et al. 
reported a rhesus macaque infected with Ebola virus which
then recovered from infection without treatment; however, the
animal subsequently developed conjunctivitis and clinical
worsening, prompting sacrifice. At necropsy, lesions were
found in the eye which stained strongly for Ebola virus
antigen on immunohistochemistry; moreover, the brain, stomach,
and pancreas also showed evidence of Ebola virus antigen
. Although studies with Ebola in nonhuman primates are
typically ended before late complications occur in the animals,
these animal models could provide some meaningful insight
into viral persistence of Ebola.
Treatment of EVD requires not only a skilled and
knowledgeable team able to monitor and care for the acutely ill patient
with EVD, but also to protect the healthcare staff from
infection. Personal protective equipment (PPE) is required of every
person with the potential to come into contact with infectious
fluids. In the acute phase, when the potential for transmission
is exceedingly high, full barrier PPE is needed. Proper
donning and doffing of the PPE is vital, and various public health
organizations have published detailed guidelines that should
be followed during the care of every patient with known or
suspected acute EVD.
Treatment of Acute EVD
Despite vast differences in available resources in the different
countries where acute EVD has been treated, the fundamental
principles of care are the same: isolation, monitoring, and
supportive care. Isolating patients suspected of and confirmed
as having EVD is critical to prevent transmission. In
resourcelimited settings, the ETUs largely consisted of facilities often
far removed from the city center. Patients were assessed and
triaged based on volume status, evidence of organ failure, and
ability for self-care . Those with hypovolemia, not in
organ failure, and able to care for themselves were the focus of
management because they were most likely to improve in the
setting where intravenous fluid management was limited.
Antiemetics, antidiarrheals, and oral rehydration solutions
are all staples of countering the gastrointestinal losses
associated with acute EVD [11, 20].
Beyond monitoring and supportive care, Ebola-specific
therapeutics have been evaluated during this recent outbreak.
Plasma or whole blood from survivors of severe infections
have been successfully used for other emerging outbreaks,
most notably for influenza . The utility of this
convalescent plasma or whole blood is not fully known currently. A
study from Guinea of 99 patients with confirmed EVD who
each received, within 2 days of diagnosis, 2 consecutive doses
of convalescent plasma from 2 different EVD survivors found
a nonsignificant decrease in the risk of death with a risk
difference of –3% when compared with historic controls from the
same outbreak and when adjusted for age and the PCR CT
ZMapp (Mapp Biopharmaceutical, San Diego, CA, USA),
a triple monoclonal antibody cocktail that has shown promise
based on nonhuman primate data, was studied during the
recent outbreak. A randomized, placebo-controlled trial enrolled
72 patients with EVD and the drug was given at a mean of 4.2
days after symptom onset. Thirty-seven percent of patients
who were randomized to receive standard of care died versus
22% of those who receives standard of care + Zmapp. The
results were not statistically significant; however, the study
did not meet its enrollment target of 200 patients by the time
the outbreak ended .
The antiviral drug favipiravir was studied in Guinea in 80
patients with EVD; however, there was no placebo control
group to assess efficacy. The mortality rate of 54% in those
who received favipiravir was not statistically different than the
mortality rate of 58% among Bhistoric^ controls from the same
outbreak and area that the authors used for analysis . The
authors suggest that those who received favipiravir and had a
higher pretreatment CT value had a lower mortality than
historic controls; however, they also note that the study was not
adequately powered or designed to detect such an effect.
A number of vaccines against Ebola have undergone
preclinical studies and subsequent clinical trials in humans. The
vaccine CAd3-EBOV, which uses an attenuated version of
a chimpanzee adenovirus, underwent phase I trials in the
USA and UK, and a phase II trial in Mali and showed strong
immunogenicity and there were no significant adverse effects
in the early trials . Similarly, a vesicular stomatitis virus
that has been modified to express an EBOV glycoprotein,
rVSV-EBOV, underwent phase I studies in multiple countries
followed by a phase II trial in Guinea. Subsequently, phase
III trials have been underway in Guinea (rVSV-EBOV),
Sierra Leone (rVSV-EBOV), and Liberia (rVSV-EBOV and
cAD3-EBOV as separate arms) [53, 54]. All results have
been promising; however, measuring efficacy of these
vaccines has been limited by the declining number of new Ebola
cases in West Africa.
Conclusion: Goals and Challenges
There are a number of unique challenges associated with
Ebola. Given its high consequences and biosafety level 4
status, it is a difficult pathogen to study. Although some
potential therapies are in development, treatment is largely
supportive at this point, and mortality remains very high. The
most important interventions in an outbreak remain public
health initiatives such as containment, hygiene, and
prevention of transmission. However, this recent outbreak was
considerably challenging to contain, as it occurred in highly and
densely populated areas with poor health infrastructure.
Moreover, many of the populations in the affected areas were
characterized by cultures rich in tribal ritual, as well as a
strong sense of community; these aspects initially led to local
distrust and skepticism of outside-led public health initiatives,
hindering the relief response and attempts of containment.
However, with improved community-based initiatives taking
cultural traditions and beliefs into account and incorporating
community leaders, this outbreak was eventually controlled,
albeit after 2 years, tens of thousands of cases, and > 11,000
deaths from the virus .
The magnitude of this outbreak has brought to light many
aspects of this virus which were previously either unknown or
vague, such as acute, as well as persistent, neurologic issues
and virologic persistence in various areas of the body,
including the central nervous system. These issues require
considerable further research; however, with further longitudinal study
and close follow-up of Ebola survivors, in combination with
in vitro and animal model studies of Ebola, more answers will
hopefully be found in regard to this fascinating and deadly
pathogen in the near future.
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