original article
The
new england journal
of
medicine
n engl j med 372;1 nejm.org january 1, 2015
40
Clinical Presentation of Patients with Ebola
Virus Disease in Conakry, Guinea
Elhadj Ibrahima Bah, M.D., Marie-Claire Lamah, M.D., Tom Fletcher, M.R.C.P.,
Shevin T. Jacob, M.D., M.P.H., David M. Brett-Major, M.D., M.P.H.,
Amadou Alpha Sall, Ph.D., Nahoko Shindo, M.D., Ph.D., William A. Fischer II, M.D.,
Francois Lamontagne, M.D., Sow Mamadou Saliou, M.D.,
Daniel G. Bausch, M.D., M.P.H.&T.M., Barry Moumié, M.D., Tim Jagatic, M.D.,
Armand Sprecher, M.D., James V. Lawler, M.D., M.P.H., Thierry Mayet, M.D.,
Frederique A. Jacquerioz, M.D., María F. Méndez Baggi, M.D.,
Constanza Vallenas, M.D., Christophe Clement, M.D., Simon Mardel, M.D.,
Ousmane Faye, Ph.D., Oumar Faye, Ph.D., Baré Soropogui, Pharm.D.,
Nfaly Magassouba, D.V.M., Ph.D., Lamine Koivogui, Pharm.D., Ph.D.,
Ruxandra Pinto, Ph.D., and Robert A. Fowler, M.D.C.M.
The authors’ affiliations are listed in the
Appendix. Address reprint requests to
Dr. Fowler at the Departments of Medi-
cine and Critical Care Medicine, Sunny-
brook Health Sciences Centre, University
of Toronto, 2075 Bayview Ave., Toronto,
ON M4N 3M5, Canada, or at rob.fowler@
sunnybrook.ca.
This article was published on November 5,
2014, at NEJM.org.
N Engl J Med 2015;372:40-7.
DOI: 10.1056/NEJMoa1411249
Copyright © 2014 Massachusetts Medical Society.
ABSTRACT
Background
In March 2014, the World Health Organization was notified of an outbreak of Zaire
ebolavirus in a remote area of Guinea. The outbreak then spread to the capital,
Conakry, and to neighboring countries and has subsequently become the largest
epidemic of Ebola virus disease (EVD) to date.
Methods
From March 25 to April 26, 2014, we performed a study of all patients with laboratory-
confirmed EVD in Conakry. Mortality was the primary outcome. Secondary out-
comes included patient characteristics, complications, treatments, and comparisons
between survivors and nonsurvivors.
Results
Of 80 patients who presented with symptoms, 37 had laboratory-confirmed EVD.
Among confirmed cases, the median age was 38 years (interquartile range, 28 to 46),
24 patients (65%) were men, and 14 (38%) were health care workers; among the
health care workers, nosocomial transmission was implicated in 12 patients (32%).
Patients with confirmed EVD presented to the hospital a median of 5 days (inter-
quartile range, 3 to 7) after the onset of symptoms, most commonly with fever (in
84% of the patients; mean temperature, 38.6°C), fatigue (in 65%), diarrhea (in 62%),
and tachycardia (mean heart rate, >93 beats per minute). Of these patients, 28 (76%)
were treated with intravenous fluids and 37 (100%) with antibiotics. Sixteen pa-
tients (43%) died, with a median time from symptom onset to death of 8 days (in-
terquartile range, 7 to 11). Patients who were 40 years of age or older, as compared
with those under the age of 40 years, had a relative risk of death of 3.49 (95%
confidence interval, 1.42 to 8.59; P = 0.007).
Conclusions
Patients with EVD presented with evidence of dehydration associated with vomiting
and severe diarrhea. Despite attempts at volume repletion, antimicrobial therapy, and
limited laboratory services, the rate of death was 43%.
Patients with Ebola Virus Disease in Conakry, Guinea
n engl j med 372;1 nejm.org january 1, 2015
41
E
bola virus is one of three members
of the Filoviridae family and comprises
five distinct species. Infection with Zaire
ebolavirus (EBOV) has historically resulted in the
highest case fatality rate — up to 90%.
1
Out-
breaks typically originate with introduction of
the virus into humans from a wild animal reser-
voir, with subsequent human-to-human trans-
mission, often fueled by nosocomial amplifica-
tion in resource-poor settings. Aside from a single
infection with Tai Forest ebolavirus, West Africa has
never had an outbreak of Ebola virus disease
(EVD).
2,3
The Republic of Guinea, on the west coast of
Africa, has a population of approximately 11 mil-
lion persons, a life expectancy at birth of 58 years,
and an annual gross national income of 970 inter-
national dollars, with an expenditure on health
care of 67 international dollars per capita per
year.
4
Conakry, the capital and largest city, with
an approximate population of 2 million persons,
is served by a number of large hospitals, including
Donka Hospital (the major public and university-
affiliated medical center), Ignace Deen Hospital,
and the Hôpital de l’Amitié Sino-Guinéenne, in
addition to a number of privately funded health
clinics.
On March 21, 2014, the World Health Orga-
nization (WHO) was formally notified of a rap-
idly evolving outbreak of EVD centered in the
prefecture of Guéckédou, in the forested region
of southeastern Guinea, with potential spread
to border areas in Liberia and Sierra Leone.
5
Infected travelers from Guéckédou subsequent-
ly initiated chains of transmission of EVD in
Conakry, more than 600 km away, marking the
world’s largest urban EVD outbreak and herald-
ing the largest ever EVD epidemic, involving
Guinea, Sierra Leone, Liberia, Nigeria, Senegal,
and Mali.
6
A concurrent but epidemiologically
unrelated outbreak has also been recognized in
the Democratic Republic of Congo.
6
The care of patients with EVD in Conakry
initially occurred at two sites: the Hôpital de
l’Amitié Sino-Guinéenne, which mainly focused
on a large nosocomial outbreak affecting health
care workers, and a stand-alone EVD treatment
unit established on the grounds of Donka Hos-
pital by the Ministry of Health, supported by
Médecins sans Frontières and the WHO. As of
October 31, 2014, the Guinea Ministry of Health
had reported a cumulative total of 1667 clinical
cases of EVD (with 1018 deaths), including 244
cases (and 98 deaths) in Conakry; a total of
13,562 cases (and 4950 deaths) were reported
throughout West Africa.
7
Here we describe de-
mographic and clinical characteristics of the
patients at presentation, the clinical course of
EVD, and outcomes of all patients admitted for
care in Conakry during a 1-month period at the
onset of the outbreak.
Methods
Study Design
We conducted a retrospective, observational
study of all patients with suspected or confirmed
EVD who were admitted for care in Conakry
from March 25 to April 26, 2014 (Fig. S1 in the
Supplementary Appendix, available with the full
text of this article at NEJM.org). We used a stan-
dard case definition that was established by the
WHO and the Guinea Ministry of Health (Table
S1 in the Supplementary Appendix). Laboratory
confirmation of EVD was made on the basis of
results on quantitative reverse-transcriptase–
polymerase-chain-reaction (RT-PCR) assay in a
laboratory established at Donka Hospital by the
Institute Pasteur in Dakar, Senegal. Laboratory
staff members used rapid Taqman RT-PCR assays
for the detection of EBOV using 5-FAM and
3-TAMRA tagged probes and a portable Smart-
Cycler TD. EBOV RNA in patient samples was
measured according to the standard described by
Weidmann et al.,
8
in which the sample is diluted
to a range of 1 copy to 1 million copies and is
then tested in quadruplicate to construct a stan-
dard curve for estimating the number of genome
copies. Follow-up testing for antibodies against
EBOV by means of enzyme-linked immunosor-
bent assay (ELISA) was performed as needed. Pa-
tients were treated in accordance with protocols
established for viral hemorrhagic fever by Méde-
cins sans Frontières and WHO urgent interim
guidance for case management, endorsed by the
Ministry of Health.
9,10
Data Collection
Data-collection forms encompassed epidemio-
logic and demographic data, exposure history,
occupation and recent travel, symptoms, onset
date, vital signs at admission, and medical his-
tory. Also recorded were daily symptoms, vital
signs, complications, treatments, laboratory test
results when available, and outcomes. The clini-
cal care team collected data from patients who
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were admitted to EVD treatment units. Admis-
sion data were reviewed daily by clinicians. Ap-
proval and a waiver from the need to provide
written informed consent were obtained from
the ethics review committees for the Guinean
government and the WHO.
Statistical Analysis
We used Student’s t-test, Fisher’s exact test, or
the Wilcoxon rank-sum test, as appropriate, to
determine the association between mortality and
the clinically informed variables of age, sex, oc-
cupation, the presence of gastrointestinal hem-
orrhage, the number of days between symptom
onset and presentation, and viral load at presen-
tation. We used Kaplan–Meier methods and log-
rank tests to determine survival curves for vari-
ous groups of patients, using the interval from
the onset of symptoms to death for those who
died within 28 days, with data censored at 28
days for survivors. We explored associations be-
tween the above-mentioned variables and death
in univariate analyses.
We used a multivariate Poisson regression
analysis with robust standard errors to investi-
gate our three primary clinically informed hy-
potheses: that mortality was associated with
older age, an increased interval from symptom
onset until presentation to a treatment facility,
and an increased viral load.
11,12
We examined
survival according to age using a scatter plot and
5-year age bins to determine the most appropri-
ate dichotomous age comparisons. We log-
transformed viral loads for primary compari-
sons among survivors and nonsurvivors and
performed sensitivity analyses dichotomizing
viral loads using two sets of values (less than the
sample median vs. greater than or equal to the
sample median and <100,000 copies per millili-
ter vs. ≥100,000 copies per milliliter). All statis-
tical tests were two-tailed, with a P value of less
than 0.05 considered to indicate statistical sig-
nificance. All analyses were performed with the
use of SAS software, version 9.3 (SAS Institute),
and R software, version 2.15.1.
Results
Study Patients
Eighty patients who had symptoms meeting the
definition of suspected EVD were admitted to the
two treatment facilities in Conakry. Among these
patients, 37 (46%) were confirmed to have EVD,
36 (97%) by means of RT-PCR and 1 who had
negative results on RT-PCR assay but had positive
results for IgG antibodies on ELISA (Table 1).
The latter patient had a clinical syndrome com-
patible with EVD and was a close contact of an-
other patient with confirmed disease.
The median age of the confirmed cases was
38 years (range, 19 to 61), and 24 (65%) were
men. The most common mechanism of contact
was through household clusters, which account-
ed for 23 cases (62%). Fourteen patients (38%)
Table 1. Characteristics, Symptoms, Vital Signs, and Time Course of Clinical
Progression of 37 Patients with Confirmed Ebola Virus Disease (EVD).*
Variable Value
Median age (IQR) — yr 38 (28–46)
Male sex — no. (%) 24 (65)
Health care worker — no. (%)
Yes 14 (38)
No 23 (62)
Known mechanism of contact — no./total no. (%)†
Health care 12/34 (35)
Household 23/37 (62)
Funeral 6/37 (16)
Known coexisting medical condition — no. (%)
Hypertension 2 (5)
Human immunodeficiency virus 2 (5)
Diabetes 1 (3)
Renal insufficiency 1 (3)
Tuberculosis 1 (3)
Malaria at presentation — no. (%) 4 (11)
Symptoms — no./total no. (%)
Fever 31/37 (84)
Fatigue 24/37 (65)
Diarrhea 23/37 (62)
Headache 12/21 (57)
Vomiting 21/37 (57)
Anorexia 16/37 (43)
Vital signs at admission
Temperature — °C 38.6±1
Heart rate — beats/min 93±14
Systolic blood pressure — mm Hg 125±25
Median interval from onset of symptoms (IQR) — days
To hospital admission 5 (3–7)
To death 8 (7–11)
* Plus–minus values are means ±SD. IQR denotes interquartile range.
† Some patients had more than one exposure.
Patients with Ebola Virus Disease in Conakry, Guinea
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43
were health care workers, in whom nosocomial
transmission was implicated in 12 of 34 patients
(35%). Participation in funeral ceremonies of
confirmed cases was an additional risk factor
for 6 of these patients (16%).
Clinical features at presentation were nonspe-
cific and included fever in 31 patients (84%;
mean temperature, 38.6°C), fatigue in 24 patients
(65%), gastrointestinal symptoms (in 23 patients
with diarrhea [62%] and 21 with vomiting
[57%]), headache in 12 of 21 patients who were
evaluated (57%), and anorexia in 16 patients
(43%) (
Table 1
). At admission, patients had mild
tachycardia (mean [±SD], 93±14 beats per min-
ute) with a mean systolic blood pressure of
125±25 mm Hg. Hiccups occurred in 28% of
patients during the period of hospitalization.
The median time from symptom onset to pre-
sentation was 5 days (interquartile range, 3 to 7),
and the median time from symptom onset to
death was 8 days (interquartile range, 7 to 11).
Oral rehydration solution was given to 36 pa-
tients (97%), and 28 patients (76%) received ad-
ditional intravenous fluid resuscitation (
Table 2
).
A median of 1 liter of intravenous crystalloids
was administered during the first 24 hours after
admission. Antibiotics were administered empiri-
cally in 37 patients (100%) with gastrointestinal
symptoms, and artemisinin-based combination
therapy was administered in 7 patients (19%), of
whom 4 had confirmed Plasmodium falciparum
infection on rapid diagnostic testing. One pa-
tient (3%) received supplemental oxygen therapy
for hypoxemia.
For the first 3 weeks of the outbreak, no rou-
tine clinical laboratory testing was available. For
approximately 1 week, we used an i-STAT System
point-of-care device with CHEM8+ and CG4+
cartridges (Abbott Point of Care) to perform lim-
ited diagnostic testing in 3 patients with clinical
symptoms in the treatment center. In 1 patient,
we found severe prerenal kidney dysfunction
(creatinine, 13.9 mg per deciliter [1229 μmol per
liter]; and blood urea nitrogen, >140 mg per deci-
liter [>50.0 mmol per liter]) and accompanying
metabolic acidosis (pH, 7.21; and lactate, 7.4 mmol
per liter), results that improved after the admin-
istration of approximately 5 liters of intravenous
crystalloid fluids per day for 3 days (creatinine,
2.4 mg per deciliter [212 μmol per liter]; blood
urea nitrogen, 40 mg per deciliter [14.3 mmol
per liter]; pH, 7.46; and lactate, 1.1 mmol per
liter). Similar findings were noted in a second
patient (creatinine, 4.9 mg per deciliter [433 μmol
per liter]; and blood urea nitrogen, 73 mg per
deciliter [26.1 mmol per liter]), findings that
were probably caused by profound diarrhea
(potassium, 2.4 mmol per liter; and bicarbonate,
15 mmol per liter), which also resolved after the
administration of approximately 4 liters of intra-
venous crystalloid fluids per day for 3 days
along with potassium. Among 3 patients in whom
anemia was suspected, including 1 patient with
clinical evidence of lower gastrointestinal bleed-
ing, hematocrit levels were not profoundly low
(mean, 31.2±3.4).
Among the 16 patients (43%) who died, the
median duration of hospital stay was 5 days, as
compared with 9 days (interquartile range, 6 to
11) among survivors. The most common clinical
complication was hemorrhage, which was report-
ed in 19 patients (51%), most frequently gastro-
intestinal bleeding (in 9 patients), of whom 8 pa-
tients had melena and 1 patient each had
hematemesis and hematochezia (
Table 3
).
In univariate analyses, the viral load appeared
to be higher among patients who died than in
survivors (
Table 4
), but this finding was influ-
enced by the deaths of all 4 patients who had a
viral load of more than 100,000 copies per mil-
liliter on admission, and viral load was not signifi-
cantly associated with death on nonparametric
testing. Mortality was not significantly higher
among the few patients who had coexisting con-
ditions than in those without such conditions
(57.1% vs. 40.0%, P = 0.44). However, an older
Table 2. Therapies Received by 37 Patients Hospitalized for EVD.
Therapy Value
Oral rehydration solution — no. (%) 36 (97)
Intravenous fluids — no. (%) 28 (76)
Median volume of crystalloid solution administered in first
24 hr (IQR) — liters
1 (1–1)
Antibiotic treatment — no. (%)
Any 37 (100)
Ciprofloxacin 20 (54)
Ceftriaxone 13 (35)
Cefixime 5 (14)
Amoxicillin–clavulanic acid 1 (3)
Antimalarial treatment — no. (%) 7 (19)
Supplemental oxygen therapy — no. (%) 1 (3)
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age was associated with an increased risk of
death, with a median age of 29 years in survivors
as compared with 45 years in those who died
(P = 0.005) (Fig. 1). In a multivariable Poisson
regression analysis that was adjusted for age,
viral load, and time from symptom onset to
presentation, patients who were 40 years of age
or older had a relative risk of death of 3.49 (95%
confidence interval [CI], 1.42 to 8.59), as com-
pared with those under the age of 40 years
(P = 0.007). There were no significant differences
between survivors and nonsurvivors in the num-
ber of days between symptom onset and admis-
sion (relative risk in survivors, 0.94; 95% CI, 0.86
to 1.04; P = 0.22) and viral load on admission
(relative risk, 0.98; 95% CI, 0.91 to 1.07; P = 0.72).
Discussion
Patients, on average, presented 5 days after
symptom onset, and the most common manifes-
tations of EVD during hospitalization were fever,
vomiting, diarrhea, and related volume depletion
requiring the administration of intravenous flu-
ids and electrolyte therapy. Overall mortality
among patients presenting for treatment was
43%, and only the age of the patient was a sig-
nificant predictor of outcome. In contrast to pre-
vious Ebola virus outbreaks in which an older age
was also associated with a worse outcome, the
mean age of nonsurvivors in our study was
low.
13,14
The association between an older age
and a worse outcome among patients with viral
infections is often attributed to an increased
number of coexisting conditions. However, in
our study, the relative absence of known coexist-
ing conditions suggests that an older age may
have an independent association with mortality.
We also found that patients who presented for
care with the highest viral loads were the least
likely to survive, as has been shown for other
strains of Ebola virus.
15
After adjustment for dif-
Table 3. Clinical Complications and Outcomes for 37 Patients with EVD.
Variable Value
Hospital mortality — no. (%) 16 (43)
Median length of stay in hospital (IQR) — days 8 (6–11)
Known complications in hospital — no. (%)
Hemorrhage
Any 19 (51)
Gastrointestinal 9 (24)
Subconjunctival 4 (11)
Intravenous catheter site 4 (11)
Nasorespiratory tract 2 (5)
Renal failure* 2 (5)
Seizure 2 (5)
Oral candidiasis 1 (3)
Hypoxemia 1 (3)
* Renal failure was defined as a serum creatinine level of more than 4 mg per
deciliter (350 μmol per liter).
Table 4. Characteristics of Survivors and Nonsurvivors.
Characteristic
Survivors
(N = 21)
Nonsurvivors
(N = 16) P Value
Median age (IQR) — yr 29 (26–37) 45 (40–47) 0.005
Male:female ratio 14:7 10:6 1.00
Viral load at admission
Mean ±SD — copies/ml 8207±17,189 68,361±111,340 0.02
Median (IQR) — copies/ml 1079 (148–5059) 1915 (141–12,998) 0.47
>100,000 copies/ml — no. (%) 0 4 (25) 0.02
Health care worker — no. (%) 6 (29) 8 (50) 0.31
Clinical features
Hemorrhage — no. (%)
Any visible 8 (38) 11 (69) 0.1
Gastrointestinal 4 (19) 6 (38) 1.0
Interval from symptom onset to presentation (IQR) —
days
5 (4–8) 5 (2–7) 0.49
