Zaire,: Ebola Haemorrhagic Fever in 1976
Zaire,: Ebola Haemorrhagic Fever in 1976
Zaire,: Ebola Haemorrhagic Fever in 1976
Between 1 September and 24 October 1976, 318 cases ofacute viral haemorrhagic fever
occurred in northern Zaire. The outbreak was centred in the Bumba Zone of the Equateur
Region and most of the cases were recorded within a radius of 70 km of Yambuku,
although a few patients sought medical attention in Bumba, Abumombazi, and the capital
city of Kinshasa, where individual secondary and tertiary cases occurred. There were
280 deaths, and only 38 serologically confirmed survivors.
The index case in this outbreak had onset of symptoms on I September 1976, five days
after receiving an injection of chloroquine for presumptive malaria at the outpatient clinic at
Yambuku Mission Hospital (YMH). He had a clinical remission of his malaria symptoms.
Within one week several other persons who had received injections at YMH also suffered
from Ebola haemorrhagic fever, and almost all subsequent cases hadeither received injections
at the hospital or had had close contact with another case. Most of these occurred during the
first four weeks of the epidemic, after which time the hospital was closed, 11 of the 17 staff
members having died of the disease. All ages and both sexes were affected, but women 15-
29 years of age had the highest incidence of disease, a phenomenon strongly related to
attendance at prenatal and outpatient clinics at the hospital where they received injections.
The overall secondary attack rate was about 5 %, although it ranged to 20% among close
relatives such as spouses, parent or child, and brother or sister.
Active surveillance disclosed that cases occurred in 55 of some 550 villages which were
examined house-by-house. The disease was hitherto unknown to the people of the affected
region. Intensive search for cases in the area of north-eastern Zaire between the Bumba
Zone and the Sudan frontier near Nzara and Maridi failed to detect definite evidence of a
link between an epidemic of the disease in that country and the outbreak near Bumba.
Nevertheless it was established that people can and do make the trip between Nzara and
Bumba in not more than four days: thus it was regarded as quite possible that an infected
person had travelled from Sudan to Yambuku and transferred the virus to a needle of the
hospital while receiving an injection at the outpatient clinic.
Both the incubation period, and the duration of the clinical disease averaged about one
week. After 3-4 days of non-specific symptoms and signs, patients typically experienced
progressively severe sore throat, developed a maculopapular rash, had intractable abdominal
pain, and began to bleedfrom multiple sites, principally the gastrointestinal tract. Although
laboratory determinations were limited and not conclusive, it was concluded that patho-
genesis of the disease included non-icteric hepatitis andpossibly acute pancreatitis as well as
disseminated intravascular coagulation.
This syndrome was caused by a virus morphologically similar to Marburg virus, but
immunologically distinct. It was named Ebola virus. The agent was isolated from the blood
of 8 of 10 suspected cases using Vero cell cultures. Titrations of serial specimens obtained
from one patient disclosed persistent viraemia of 106.5-104.5 infectious units from the third
day of illness until death on the eighth day. Ebola virus particles were found in formalin-
IThe members of the International Commission are listed in Annex 1, page 293. Requests for reprints should be
addressed to Dr K. M. Johnson, Chief, Special Pathogens Branch, Virology Division, Bureau of Laboratories, Center for
Disease Control, Atlanta, GA 30333, USA; or to Dr J. G. Breman, Smallpox Eradication, World Health Organization,
1211 Geneva 27, Switzerland.
3690 - 271-
272 REPORT OF AN INTERNATIONAL COMMISSION
fixed liver specimens from three cases. Survivors of infection were found to have indirect
fluorescent antibodies to Ebola virus in titres of 1: 64-1: 256 within three weeks after onset
ofdisease and these serum titres persisted with only slight decrease for a period of 4 months.
,4 total of 201 units (200-300 ml each) of plasma containing Ebola virus antibodies in
titres of at least 1: 64 were obtained and frozen. Two of these units were used to treat a
laboratory worker infected with Ebola virus. This person recovered, which suggests that the
antibodies may have helped therapeutically.
Virus transmission was interrupted by stopping injections and by isolation ofpatients in
their villages. Use of protective clothing and respirators, strict isolation of patients, and
careful disposal of potentially contaminated excreta and fomites will almost certainly
prevent future major outbreaks. The virus is probably rarely transmitted by intfectious
aerosols, although infection via large droplets remains a possibility.
Only limited ecological investigations were made, since the epidemiology of the outbreak
strongly suggested that the virus had been imported into Bumba Zone. Ebola virus was not
recovered from representative samples of bedbugs or of rodents (Rattus rattus and
Mastomys spp.) having more or less close contact with humans. Ebola virus antibodies were
found, however, in five persons who were not ill and had not had contact with the " infected "
villages or the Yambuku hospital during the epidemic. If these findings can be confirmed by
an independent method of testing, they would suggest that the virus is in fact endemic to the
region and should lead to further effort to uncover a viral reservoir in Zaire.
This paper describes the work of an International investigate the cause, the clinical manifestations, and
Commission formed in Kinshasa, Zaire, on 18 Octo- the epidemiology of a newly recognized disease,
ber 1976 and directed by the Minister of Health of termed Ebola haemorrhagic fever, and to advise and
that country, Dr Nguete Kikhela. Its mission was to assist the Ministry with measures for controlling it.
THE OUTBREAK
KINSHASA-YAMBUKU z I 100 KM
YAMBUKU-MARIDI = 825 KM
Fig. 1. Locations of the principal centres of the outbreaks of Ebola haemorrhagic fever, Sudan-Zaire, 1976.
Mob ay
E singa T"i"9 7/ 8
6
Bongolu /
YA?MUKU 6
A eti
aan
tYaloseaba / /Yamisolo Yanoanda
10 Yal
Lisalama
Fig. 2A R tflw tB unba
Fig. 2. Routes followed by the surveillance teams. The numbers identify the teams.
haemorrhagic fever in Yambuku was admitted to addition to about 14 staff members, 37 primary
Ngaliema hospital on 25 September 1976, the third contacts of the third case were quarantined for three
day after onset of symptoms. Her primary care was weeks. Serum specimens obtained from 25 persons at
given by a colleague who had accompanied her from the end of quarantine were tested for Ebola IFA
Yambuku. This patient died on 30 September. The antibodies and were all negative.
second nursing sister, who had not used protective
clothing, became ill on 8 October and died 6 days Surveillance in the epidemic area
later. Thus the incubation period was estimated to The first special surveillance teams began work on
be 8-14 days. A third nurse had helped with the first 9 November 1976 and by 16 November all teams
case from 27 September, but not the second. She was were functioning. Although an average of about
on leave in Kinshasa during the second week of 5-10 possible cases were seen per week, none had
October and had onset of headache and low grade Ebola haemorrhagic fever. At the end of November
fever on 13 October; so the incubation period in her it was clear that the last probable case had died on
case was 13-16 days. Prior to her admission on 15 5 November in the village of Bongulu II, some 30 km
October, she had exposed personnel at the Ministry east of Yambuku. During their work the surveillance
of Foreign Affairs, where she made arrangements for teams visited 550 villages, interviewed more than
an overseas study visit, at two other hospital emer- 34 000 families with an average of about 7 members,
gency rooms in Kinshasa, and various members of that is, approximately 238 000 persons. A total of
her family. This patient, who died on 20 October, 231 probable cases were identified during active
was cared for by her sister who was a nurse. surveillance, but this figure did not include persons
Although careful barrier nursing had been practised from the village of Yambuku itself. Also, many
and emergency arrangements made for disposal of possible convalescent persons were identified and
all potentially contaminated articles, the possibility bled. The results of this work are given in the
that further cases would occur was considered highly following section.
likely and it was deemed imperative to stop the chain The teams completed second and third visits to
of transmission in Kinshasa. To this end a portable villages as planned, and teams 1, 5, 6, and 7 made a
negative-pressure bed isolator was obtained from fourth village check in late December. Based on
Canada and installed in a room in the pavilion these data the International Commission advised
where the three cases were managed. Quarantined lifting quarantine in Bumba Zone on 16 December
medical staff were trained in operation of this equip- 1976, which was six weeks after the last death from
ment. Fortunately, no further cases occurred. In Ebola haemorrhagic fever.
EPIDEMIOLOGICAL INVESTIGATIONS
Fig. 3. Location of epidemic area and the noninfected villages surveyed serologically.
from resting sites in homes. Cimicid bugs were teral injection on 26 August. His fever resolved
picked from bamboo beds and clothing. Wild rapidly and he was afebrile until 1 September when
rodents were hand caught by village youths and a he again had fever to 39.20C. Other symptoms and
few other mammals were shot by local hunters. Mist signs ensued and he was admitted to YMH on
nets were employed to capture bats emerging from 5 September with gastrointestinal bleeding. He died
houses at dusk. on 8 September.
RESULTS At least 9 other cases occurred during the first
week of September, all among persons who had
Origin and course of the epidemic received treatment for other diseases at the out-
The first known case, a 44-year-old male instruc- patient clinic at YMH. Names of persons treated at
tor at the Mission School, presented himself to the the outpatient clinic and specific diagnoses were not
outpatient clinic at Yambuku Mission Hospital recorded. Thus, it was impossible to determine
(YMH) on 26 August 1976 with a febrile illness whether persons with fever had visited YMH in late
thought to be malaria. This man had toured the August. It was of interest, however, that a man
Mobaye-Bongo zone in the northern Equateur about 30 years of age had been admitted to the
Region by automobile from 10 to 22 August with medical ward on 28 August suffering from " dysen-
6 other Mission workers. The group visited some of tery and epistaxis ", a diagnosis not otherwise listed
the larger towns (Abumombazi, Yakoma, Katokoli, in the preceding eight months. This man, listed as
Wapinda) along the road from Yambuku to Bado- resident in Yandongi, the capital village of the
lit6, but never arrived at that village because a bridge collectivity some 7 km from Yambuku, was taken
had been washed away a few kilometres east of the from the hospital two days later. He turned out to be
town. On 22 August, fresh and smoked antelope and a person completely unknown to the residents and
monkey meat were purchased on the road about authorities of Yandongi.
50 km north of Yambuku. The patient and his Case histories quickly suggested that YMH was a
family ate stewed antelope on his return, but not the major source of dissemination of Ebola haemor-
monkey meat. He was given chloroquine by paren- rhagic fever. It was learned that parenteral injection
EBOLA HAEMORRHAGIC FEVER IN ZAIRE, 1976 279
Table 2. Distribution of numbers of cases in villages attack rates of greater than 2 per 1000. Sixty-four
percent of cases occurred in villages having 1-5 cases
Number Number % Cumulative and only 3 villages had more than 20 cases (Table 2).
of cases of villages of villages %
The epidemic spread relatively slowly. During the
1 17 30.9 30.9 first two weeks all cases were restricted to a radius of
2-5 18 32.7 63.6 30 km from Yambuku. Nearly two more weeks
6-9 12 21.8 85.4 passed before a patient was evacuated to Kinshasa.
10-14
Cases were introduced in early October into Abu-
4 7.3 92.7
mombazi and Bumba, the two large towns limiting
15-19 1 1.8 94.5 the north-south extension of the outbreak. The
20-29 1 1.8 96.3 mean duration of the epidemic in the villages was
> 30 2 3.7 100.0 25.6 days.
Thirteen of 17 staff members at YMH acquired
Total 55 the disease and 11 of these died, with the result that
the hospital closed on 3 October. Although all staff
members had contact with patients, their families,
was the principal mode of administration of nearly and instruments used in treatment, one male nurse
all medicines. and three female midwives escaped infection.
Between 1 September and 24 October, 318 pro-
bable and confirmed cases/infections of Ebola Attack rates, incubation period, and mode of trans-
haemorrhagic fever occurred with 280 deaths, an mission
infection fatality rate of 88 %. The epidemic reached All ages and both sexes were affected (Table 3) but
a peak during the fourth week, at which time the females slightly predominated. Age/sex attack rates,
YMH was closed, then it receded over the next four using the Yandongi collectivity as the population
weeks. denominator, showed that adult females had the
Fifty-five of about 250 villages in the epidemic highest attack rate. Much of this excess illness was
area recorded cases. All but one of these were in associated with receipt of parenteral injections at
Bumba Zone, the exceptions being to the north. All YMH or one of its clinics. The distribution of
affected villages were within 120 km of Yambuku, disease by age group and type of transmission was
and the majority were along roads running east and essentially equal for both sexes except for injection-
west of the mission (Fig. 3). These roads had more associated illness among persons 15-29 years old.
villages per kilometre than roads running north and Females comprised 22 of 24 such cases in the 21-
south of the epicentre. Forty-three of 73 villages in village study.
Yandongi collectivity had cases and the attack rate The single common risk factor in comparison with
for this area was 8.0 per 1000 persons. None of the matched family and village controls for 85 of 288
other 6 collectivities in the epidemic region had cases where the means of transmission was deter-
50
45
40
35.
30 H PERSON TO PERSON
E BOTH
* SYRINGE
25-
c
20-
Fig. 4. Number of cases of Ebola haemorrhagic fever in the Equateur Region, by day of onset and by probable type
of transmission.
mined, was receipt of one or more injections at Most of the cases related to injection occurred
YMH. Injections received away from YMH were during the first 4 weeks of the epidemic (Fig. 4).
very unusual. Other factors such as previous case- Indeed, it seems likely that closure of YMH was the
contact, exposure to food, water, hospital buildings, single event of greatest importance in the eventual
domestic and wild animals, or travel within three termination of the outbreak.
months prior to onset, were not associated with this Several parameters were compared for persons
type of transmission. An additional 149 persons acquiring infection by contact and injection, respec-
acquired the disease following contact with patients, tively. Although no statistically significant differ-
usually in their home villages, and 43 cases had a ences were found in terms of duration of symptoms
history of both patient contact and receipt of injec- and signs of illness (Table 4), no person whose
tion within three weeks prior to onset of illness. contact was exclusively parenteral injection survived
Seventeen persons who lived outside Yambuku had the disease. All 20 survivors with symptoms and
contact at YMH and may have received injections signs had documented contact with at least one other
there without reporting this fact to their family. patient, although in 4 instances the survivor had also
EBOLA HAEMORRHAGIC FEVER IN ZAIRE, 1976 281
Table 4. Mean duration (in days) of symptoms and signs presenting in patients a
by type of transmission
Fatal Cases
Convalescents
Injection Person-to-person
Duration i SE Duration i SE Duration ± SE
Symptoms
Fever 7.3 (0.53) 7.1 (0.43) 6.4 (1.63)
Headache 7.2 (0.52) 7.4 (0.46) 4.8 (0.86)
Sore throat 6.3 (0.49) 6.5 (0.49) 10.7 (2.57)
Abdominal pain 5.5 (0.53) 6.2 (0.46) 8.3 (2.28)
Myalgia 7.3 (0.55) 6.9 (0.43) 5.7 (1.01)
Nausea 5.0 (0.61) 5.4 (0.63) 4.8 (2.37)
Arthritis 6.3 (0.48) 7.0 (0.47) 9.9 (2.08)
Other b 7.2 (2.10) 3.3 (0.61) 4.4 (0.76)
Signs
Bleeding 3.1 (0.30) 4.0 (0.33) 9.3 (2.95)
Diarrhoea 4.8 (0.47) 4.9 (0.36) 7.5 (1.75)
Oral/throat lesions 5.1 (0.60) 5.7 (0.50) 5.3 (0.64)
Vomiting 3.7 (0.40) 4.3 (0.44) 3.9 (1.17)
Conjunctivitis 4.8 (0.78) 5.1 (0.60) 6.2 (1.80)
Cough 7.5 (1.08) 6.9 (0.87) 10.0 (3.98)
Abortion 2.3 (0.98) 1.0 (0) 7.0 (0)
Oedema 2.5 (1.48) 2.0 (0) 0 -
received an injection. The mean incubation period for than one patient before becoming ill, particularly
cases acquired by injection was 6.3 days. In 17 cases medical staff at YMH. However, in one case of the
where only one or two days of patient contact disease, the only possible source of infection was
occurred, the mean incubation period was also contact with a probable case 48 hours before the
6.3 days. latter developed symptoms.
Persons acquiring the disease by contact had a Five consecutive generations of transmission of
variety of close associations with cases as indicated Ebola haemorrhagic fever were documented in one
in Table 5. No statistically significant differences instance. No sporadic, apparently spontaneous,
occurred among cases or family or village control probable cases were recorded. When " family " was
groups, except that cases were more likely than defined as all persons living in contiguous housing
controls to have aided at childbirth of another and sharing common eating facilities, secondary
patient. Contact cases had a mean of 9.5 days of attack rates never exceeded 8 % (Table 6). However,
contact with active cases before becoming ill (range when 92 families affected in the 21 villages surveyed
1 to 21 days). Several persons had contact with more along an east-west axis close to Yambuku were
282 REPORT OF AN INTERNATIONAL COMMISSION
Table 5. Factors associated with person-to-person spread for cases, family controls;
and village controls
Person-to-person Family controls Village controls
Risk factor cases
No. % Yes No. % Yes No. % Yes
examined, contact attack rates were 16.7, 3.6, and holds prior to the epidemic. Between 4 September
9.0 % in three successive generations of transmission. and 18 October 1976, 24 persons became probable or
Moreover, there were marked differences in second- confirmed cases of the disease. The first case was a
ary contact transmissions related both to sex of the man 27 years old who received an injection at the
primary case and to blood and marital relationships YMH outpatient clinic on 29 August. Within 6 days,
within households. The secondary attack rate was 4 more persons with a history of injection at YMH
27.3 % among spouses, brothers, sisters, parents, and became ill. During this same period 2 nurses, a
children but only 8.0% among all other relatives. medical assistant and a catechist contracted the
Among the high-risk relatives, 10 of 60 contacts disease. These persons had all been in frequent
became ill when the primary case was male, and 27 of contact with patients at the hospital, but had not
75 when the primary case was female. Although the received injections. By mid-October, 15 additional
precise factors involved were impossible to determine, villagers had become ill, 12 of them following close
direct care of cases and intimate family contact, contact with patients in this or other villages. Seven
including sexual intercourse, were possibly the of these contacts occurred in the homes of neigh-
important variables. bours, and 3 were contacts with sick relatives in
other villages. Information on 3 cases was lacking.
Epidemic in the village of Yamolembia I Ten cases were among males, 14 among females.
This village, located 5 km from Yambuku, was Adults of 15-45 years of age were most commonly
chosen for detailed analysis of disease transmission. affected. Only 2 persons survived, both contact
The town was mapped and a door-to-door census infections. Cases occurred in 15 households with 98
revealed that 415 persons were resident in 71 house- members; four households had secondary cases, and
one other had more than one case but it could not be
Table 6. Attack rate in family contacts by generation documented sufficiently to arrive at a conclusion as
of transmission to the mode of transmission. There were 6 secondary
and 3 tertiary cases, giving transmission rates of 7.2
Generation
No. of
families
No. of
family
No. of
subsequent
Attack and 4.0%, respectively. Households with cases were
with cases exposures cases
rate (%) scattered through the village and no pattern of
transmission other than very close patient contact
1 61 498 38 7.6 was established.
2 62 459 20 4.4 In December 1976 and January 1977, sera were
3 18 117 3 2.6 solicited from as many people as possible; a total of
4 5 29 1 3.4 236 were obtained. Three persons, 2 of them in
clinically noninfected households, who had not had
Total 146 1103 62 5.6 symptoms during or since the epidemic, were found
to have Ebola virus IFA titres of at least 1: 64. All
EBOLA HAEMORRHAGIC FEVER IN ZAIRE, 1976 283
Table 7. Ebola virus IFA antibodies among residents of the epidemic area by age group, sex, and exposure status
Age group (years)
Category Sex _ Unknown Total
1-9 10-19 20-29 30-39 40-49 >50
ll M 2 5 15 (2) 16 (2) 7 10 (1) 55 (5)
F 2(2)a 11 (2) 14(3) 16(6) 11 (2) 12 66(15)
Total 146 (3) 165 (3) 174 (7) 162(9) 130 (4) 196 (8) 11 984 (38) b
a Numbers in parentheses indicate the number of persons with Ebola virus IFA titres of at least 1: 64.
b Includes the 4 positive titres with unknown history.
3 had experienced contact with fatal cases. Extra- In a further effort to document either concurrent
polating to the entire population, 2 more silent asymptomatic infection or possible past infection
infections might be expected. Thus it appeared that with Ebola virus, 442 persons were bled in 4 neigh-
29 people (7%) in the village had been infected, bouring villages that had had no fatal cases of the
clinical illness ensued in 83% with an infection- disease. Sera from 5 persons 8-48 years old contained
mortality rate of 76 %. IFA antibodies in titres of 1: 64. None of these
people were sick, had had contact with persons in
Serological and ecological studies other villages, or had visited YMH during the
Serum specimens were obtained in November and epidemic.
December 1976 and January 1977 from 984 persons Sera from 58 persons in various exposure cate-
resident in 48 of the 55 towns and villages reporting gories had anti-Ebola IFA titres of 1: 4-1 : 32. The
probable cases of the disease. These individuals were specificity of these reactions was doubted when it
classed as clinically ill, not ill but in contact with a was found that samples from 4 of 200 San Blas
case, or neither ill nor in contact. More than half of Indians from Panama also had such " antibodies "
the subjects were resident in 8 villages, each having for Ebola but not Marburg virus. Final interpreta-
more than 5 probable cases. These persons were bled tion of these data awaits development of another
during rapid survey excursions, taking the entire method for measurement of type-specific antibodies
family as the unit of study. The composition of these to these agents.
groups by age, sex, and epidemiological characteris- Suspensions of 818 bedbugs, Cimex hemipterus F.,
tic is given in Table 7 together with the number and formed into 21 pools, were inoculated into Vero cell
category of persons having Ebola virus IFA titres of cultures. No virus was recovered. Negative results
at least 1: 64. Data from Yamolembia I are in- also were obtained from the following: 8 Culex
cluded. Thirty-eight positives were found. Twenty cinereus Theo., 2 Culex pipiens fatigans Wied. and
(16.5%) of 121 ill persons were confirmed as having 5 Mansonia africana Theo. mosquitos; sera from 10
had Ebola haemorrhagic fever, and 10 (2.5%) of domestic pigs and one cow; viscera (usually spleen,
404 persons in contact with cases also had such anti- liver, kidney, and heart) from 7 unidentified bats,
bodies. There were 4 antibody-positive persons who 123 rodents including 69 Mastomys (= Praomys)
admitted neither illness nor contact with patients. (among which P. tullbergi minor (Hatt.) predomi-
These people were questioned a second time and bled nated) and 30 Rattus rattus, 8 squirrels, 6 Cercopi-
again, and confirmed to have Ebola IFA antibodies. thecus monkeys (not aethiops) and 2 small duikers
Antibodies were found also in sera of 4 people (Cephalophus monticola Thunberg). Rattus rattus,
whose history was not clear and who could not be bats, bedbugs and mosquitos were captured in
found a second time for confirmatory study. infected villages; other wild species were captured or
284 REPORT OF AN INTERNATIONAL COMMISSION
shot in the nearby forest. Rattus rattus were found in as were the Aedes aegypti indices (Yandongi village,
village dwellings but Mastomys were not. 5 November 1976, Breteau index 3.6; container
The mosquito man-biting-rate was low in villages, index 2.3).
CLINICAL MANIFESTATIONS
seconds, respectively. Fibrin degradation products, Table 8. Virological findings in a patient treated at
measured with a commercial kit (Burroughs-Well- Ngaliema Hospital, Kinshasa, October 1976
come) were recorded as 1 + and 2+ on days 7 and 8.
The first case was treated with aspirin, antibiotics, Day of Viraemia IFA antibodies to:
disease (logia/mi) Ebola virus Marburg virus
corticosteroids, blood transfusion, and intravenous
fluids. The second patient received aspirin, hydro-
cortisone, immunoglobulin, intravenous fluids, and 3 5.5
an experimental drug, moroxydine. Enterovioform
4a 5.5 <2 <2
was given to control diarrhoea but without success.
The third patient was treated for unconfirmed ma- 5 5.5 <2 <2
laria during the first 2 days of illness. When the 5.5 <2 <2
etiological agent of the epidemic was shown to be a 4.5
Marburg-like virus, she was given, on day 4, 500 ml
of Marburg human plasma obtained from a recov- 6 4.5
ered patient in South Africa. This plasma had an 5.0
IFA titre of 1: 32. In anticipation of disseminated 7 6.5
intravascular coagulation (DIC), she was given
16 000 units of heparin on day 6 and 30 000 units 4.5
daily thereafter. Although anticoagulation was un- 8b 45
satisfactory, as shown by the normal PTT on days 7
and 8, she had less clinical bleeding than the other
two patients. On the day prior to death she com- a Patient received 500 ml of anti-Marburg plasma.
b Patient died.
plained of substernal chest pain and had a tachy-
cardia of 136 with a gallop rhythm. Digitalization
slowed this rate only slightly. Marked oedema of the legs. Sore throat was often reported in association
face and upper limbs was present. with a sensation of a " ball " in the throat. Chest pain
Although no autopsies were performed, it ap- and pleuritis were uncommon. Of persons with anti-
peared clinically that these patients died of hypo- bodies, 59 % had one or more symptoms, the most
volaemic shock. Evidence for DIC was fragmentary, prominent being fever, headache, abdominal pain,
but this syndrome may well have precipitated the and arthralgia. Many more persons who had been in
bleeding and shock in all cases. Postmortem liver contact with fatal cases reported symptoms but had
biopsy in the first case revealed marked focal he- no Ebola virus antibodies. Illness in antibody-posi-
patic-cell necrosis with large intracytoplasmic eosi- tive individuals was, in general, marked by profound
nophilic inclusions. Marburg virus-like particles prostration, weight loss, and a convalescent period
were visualized with an electron microscope (2). of 1-3 weeks.
Ebola virus was recovered on day 6 from blood The signs observed among the three study groups
specimens from patient 1 and on days 3 and 6 from are also depicted in Table 9. Diarrhoea (3 or more
patient 2. Quantitative virus assays on blood from liquid stools for 1 or more days), bleeding, and
the third patient are shown in Table 8. No IFA oral/throat lesions were more common in fatal cases
antibodies against Ebola or Marburg viruses were than among survivors. History of symptoms and
present. signs for the control group covered the interval from
1 September to 15 November 1976 and were much
Retrospective field studies less frequent.
Questionnaire forms were completed on 231 pro- The gastrointestinal tract was the most common
bable cases 1 year of age or older, 34 individuals who site of bleeding, and haemorrhage occurred more
were found to have Ebola virus IFA antibodies, and often among fatal than nonfatal infections
198 controls. The numbers of responses obtained for (Table 10). Bleeding varied from melaena and slow
each symptom and the percentages responding oozing from gums to brisk haemorrhage from mul-
positively in these groups are shown in Table 9. Fever tiple sites in fulminating cases. Oral lesions, which
and headache were almost invariably present. The were observed in a few patients, were typically
headache often radiated to the cervical spine and was herpetic, although a greyish patchy exudate was
associated with low-back pain radiating into the noted on the soft palate and oropharynx in one
286 REPORT OF AN INTERNATIONAL COMMISSION
Symptoms
Fever 231 98 34 59 198 11
Headache 210 96 34 59 196 14
Abdominal pain 201 81 34 50 186 9
Sore throat 207 79 34 32 192 2
Myalgia 206 79 34 47 195 7
Nausea 178 66 30 33 187 2
Arthritis 193 53 34 38 188 8
Other c 42 5 23 26 115 5
Signs
Diarrhoea 228 79 34 44 194 6
Bleeding 223 78 34 18 196 1
Oral/throat lesions 208 74 34 27 195 2
Vomiting 225 65 34 35 193 2
Conjunctivitis 208 58 34 35 195 4
Cough 208 36 34 18 192 4
Abortion 73 25 9 11 56 0
Jaundice 191 5 34 0 190 0
Oedema 193 4 34 0 194 0
Lymphadenitis 141 4 33 3 192 1
Other d 166 2 32 3 183 0
instance. Conjunctivitis was nonpurulent, and cough turn within 19 days. These cases of possible neonatal
appeared to be associated with oral/throat lesions Ebola haemorrhagic fever had few signs and symp-
rather than with lower respiratory tract pathology. toms. Seven were said to have had fever but bleeding
One patient observed in a village on two successive was infrequent. In the absence of virological and
days was leaning forward, restless, and complained pathological data it was not possible to decide
of severe epigastric pain radiating to the back. He whether these deaths represented actual cases of
vomited frequently and had intractable singultus. neonatal infection or resulted from the many other
Abortion occurred among 25 % of 73 pregnant causes of high infant mortality in this area.
women who died. One of 9 pregnant survivors also The duration of symptoms and signs among per-
aborted. sons with and without haemorrhagic fever is given in
Eleven live infants were born to mothers who died Table 11. Data for the " convalescent " group were
of haemorrhagic fever. All of these children died in by far the most reliable. Nonspecific symptoms
EBOLA HAEMORRHAGIC FEVER IN ZARE, 1976 287
among the small number of controls reporting illness Table 10. Bleeding manifestations in patientsa with
lasted as long as in haemorrhagic fever patients. Ebola haemorrhagic fever
Serum samples were obtained from 63 of the con- Fatal cases Cases with
trols and none was positive for Ebola virus anti- Type of bleeding (probable cases) b positive IFA b
bodies. Illness among fatal cases ranged from 1 to 15 No. % No. %
days with a strong unimodal peak at 6-8 days.
The only clinical laboratory test done on patients Melaena 210 66 33 15
admitted to Yambuku Hospital was urinary protein.
This was reported as uniformly positive and was Haematemesis 222 43 33 6
used as a major diagnostic criterion by the nursing Mouth/gingival 215 26 33 0
sisters early in the epidemic. Vaginal 108 20 24 4
Virological studies were limited. Ebola virus was Epistaxis 216 17 33 0
isolated in African green monkey kidney cells (Vero) Injection sites/
from blood specimens in 8 of 10 cases attempted. scarification 197 7 33 3
These specimens were taken 2-13 days after onset of
symptoms. Of interest was the simultaneous detec-
tion of virus and IFA Ebola antibodies to a titre of a Persons A 1 year of age.
b No. = no. of cases for whom there was a response to this
1: 32 in one patient. This man was in the 13th and question; % = percentage of cases for whom this type of bleeding
penultimate day of his illness. Ebola virus particles was reported.
were also visualized in 3 of 4 postmortem liver
qiopsies obtained from clinically suspect cases.
Table 11. Mean duration (days) of symptoms and signs in patient a who died probably
from Ebola haemorrahgic fever, convalescents with positive IFA titres, and controls
Fatal cases Convalescents Controls
Symptoms and signs (probable cases)
Duration ± SE Duration ± SE Duration ± SE
PLASMAPHERESIS OF CONVALESCENTS
DISCUSSION
No more dramatic or potentially explosive epi- disease surveillance and the prompt solicitation of
demic of a new acute viral disease has occurred in international assistance, nor of the need for the
the world in the past 30 years. The case mortality development of international resources, comprising
rate of Ebola haemorrhagic fever in Zaire of 88 % is personnel, equipment, transport, communication,
the highest on record except for rabies infection. In and finance, that can be made available in a very few
the circumstances it was not surprising that much days to cope with such emergencies.
desired information was never obtained. Delays in Although laboratory data were virtually non-
recognition, notification to international health existent, the clinical picture seen in this outbreak
agencies, and specific diagnosis of the disease con- resembled illness produced by the related Marburg
tributed greatly to this outcome. No better example virus. If anything, the evolution of Ebola haemor-
comes to mind to illustrate the need for national rhagic fever appeared to be more inexorable and less
EBOLA HAEMORRHAGIC FEVER IN ZAIRE, 1976 299
variable than Marburg virus infection. Though far The Zaire epidemic had all the attributes of a
from proven, we suspect that acute defibrination common source outbreak, together with a fortunate-
syndrome and pancreatitis were major features of ly low rate of secondary person-to-person transmis-
the syndrome and severe liver disease was evident. sion. The means by which the virus was introduced
At the time of its formation on 18 October 1976, into Yambuku Mission Hospital will probably never
the International Commission knew that the epi- be precisely known, but it seems possible that it was
demic was of at least 7 weeks duration, that the brought directly from the Sudan by man. Dissemina-
Yambuku mission hospital was nonfunctional be- tion of the agent into the villages of the region was
cause many of the personnel had died of the disease principally through contaminated equipment used
and that transmission was occurring in Kinshasa. for parenteral injections. The epidemic waned when
We suspected, but did not know, that the fatality the hospital was closed for want of medical staff.
rate of the disease was very high. There was no That careful disposal of contaminated excreta and
information concerning secondary infection rates fomites, as well as strict barrier nursing using res-
and it was impossible to foretell that the last case pirators, could break the chain of transmission was
during this epidemic would die within 3 weeks. demonstrated during the small outbreak in Kinshasa.
In contrast to observations made simultaneously Still simpler isolation precautions and a change in
in Sudan, the illness in Zaire had fewer respiratory the cultural customs at funerals appears to have con-
symptoms, a shorter clinical course, and a higher tributed to the dying out of infection in the villages.
fatality rate (4). Whether this was due to differences Although the data were not always statistically
in the virulence of the virus per se or to host and convincing, we had the strong impression that Ebola
ecological variables such as climate (relative humid- haemorrhagic fever acquired by injection differed
ity) is not known. At the present time the agents from that due to contact with another case. The
recovered from Sudan and Zaire are thought to be mortality was higher. In one study, secondary trans-
identical, although definitive neutralization tests mission rates also were higher from index cases that
have not yet been done. were parenterally induced. It may be that increased
Viraemia appears to be a constant feature of virus replication and excretion following parenteral
Ebola virus infection in man. The virus persisted in infection accounts for all or most of these differ-
large amounts in the blood in the single, well studied ences, but other causes were by no means excluded.
case. The finding of both virus and antibodies in the The observed " neonatal " cases of the disease
blood of another agonal case 13 days after onset of were not definitively elucidated. One wishes to know
symptoms raises the possibility, regarded as unlikely, whether Ebola virus can pass through the placenta
that antigen-antibody complexes may contribute to and infect the fetus, and whether virus is present in
the pathology of infection. This and a number of human milk and is infectious if ingested.
other important virological questions can only be Finally, a better method for measuring Ebola
pursued for the moment through studies using mon- virus antibodies is needed in order to interpret the
keys. One of the most pressing is the need for a way serological findings reported here. That less than
to make rapid diagnosis in suspected cases of the 20% of persons gave a history of acute illness
disease by searching for cells containing viral anti- following contact with a fatal case was no surprise.
gen. Retrospective specific diagnosis of fatal cases by Most of these persons had mild, self-limiting dis-
electron microscopic examination of formalin-fixed eases, these being highly endemic in the area. But if
liver biopsies appears quite promising and should be the IFA data are correct, at least 2.5 % of persons in
attempted in all cases of acute febrile haemorrhagic contact with fatal cases experienced subclinical infec-
disease in Africa. tion. In addition, the finding of antibodies in a few
No evidence was obtained for persistent viral individuals in the absence of any known contact with
carriage in the Zaire cases of Ebola infection, a Ebola virus during the epidemic raises the possibility
phenomenon documented on two occasions for that the agent is in fact endemic in the Yambuku
Marburg virus (5, 6). But it should be remembered area and is occasionally transmitted to man. A
that the number of appropriate, immunosequestered definitive answer is essential to further ecological
sites sampled was very small. However, semen from exploration of what is now a very mysterious agent.
one patient infected with a Zaire strain of Ebola As in the case of Marburg virus, the source of Ebola
virus in the United Kingdom contained virus for virus is completely unknown beyond the simple fact
more than 2 months after onset of symptoms (3). that it is African in origin.
290 REPORT OF AN INTERNATIONAL COMMISSION
RECOMMENDATIONS
The International Commission was disbanded on 4. Maintain a list of experienced Zairian person-
29 January 1977. At that time it made the following nel so that appropriate action can be taken without
recommendations to the Government of the Repub- delay in the event of a new epidemic.
lic of Zaire:
1. Maintain active national surveillance for acute 5. Maintain a stock of basic medical supplies and
haemorrhagic disease. Require regular positive and protective clothing for use in future suspected out-
negative reporting. Investigate all suspected cases breaks.
and take appropriate action including collection of 6. Keep plasma from immune donors in readi-
diagnostic specimens, the institution of clinical isola- ness. Make standardized clinical observations and
tion procedures, and the use of protective clothing obtain serial serum specimens following use of
for medical personnel. plasma in the treatment of suspected cases of Ebola
2. Distribute pertinent information to medical haemorrhagic fever in order to obtain further infor-
and other personnel participating in surveillance and mation concerning the effectiveness of this treat-
update this material by appropriate documents. ment.
3. Organize a national campaign to inform health
personnel of the proper methods for sterilizing Commission members also participated in a con-
syringes and needles in order to ensure that patients sultation sponsored by WHO in January 1977.
are not infected with diseases from other patients as Detailed recommendations were made for dealing
a result of poor technique. Reconsider the need for with future outbreaks wherever they may occur, as
parenteral injections when patients can take well as for continued investigations of the biology of
medicines by mouth. Prohibit or strictly regulate the Ebola virus. These suggestions have been pub-
activities of itinerant nurses who treat all diseases by lished (7), and are wholeheartedly endorsed by this
injection. Commission.
ACKNOWLEDGEMENTS
The detailed contributions of governments, agencies, work of the Commission could not have been per-
and individuals are too lengthy to enumerate here. The formed: Mrs G. Allen, Mr L. Armour, Father L. Claes.
government of Zaire made a continuous, concerted effort Mr. G. Cook, Father G. A. Slegers, Mr J. Jansens, Mr T.
to provide leadership, personnel, transport, and supplies. Lindland, Mr J. Masters, Father C. Rommel, Father
Belgium, Canada, France, South Africa, the United G. Six, and Ms L. Welch.
Kingdom, the United States of America, and the World Nongovernmental agencies, without whom the work
Health Organization (WHO) all sent materials and sup- of the Commission could not have proceeded, included
plies. Critical administrative and logistic roles were Oxfam (UK) which loaned three vehicles; the Baptist
assumed in Kinshasa and Bumba Zone by personnel of Mission Hospitals (USA) at Karawa and Tandala which
FOMECO (Fonds Medical de Coordination), FOMETRO provided physicians, nurses, drivers, and vehicles for
(Fonds Medical Tropical, Belgium), Mission Medicale disease surveillance; the Protestant Mission Aviation
Franqaise, the US Agency for International Develop- Fellowship (USA) which provided radio equipment,
ment, and WHO. Mr N. Staehling and Mrs E. Duckett of radio time, and air transportation of supplies and equip-
the Center for Disease Control, Atlanta, kindly provided ment; and the Catholic Church (Belgium) which donated
statistical assistance. We wish to thank particularly the radio and communications equipment to the Commis-
following individuals who performed vital roles in main- sion.
taining communications and supplies, without which the
EBOLA HAEMORRHAGIC FEVER IN ZAIRE, 1976 291
RESUMIt
FItVRE HtMORRAGIQUE EBOLA AU ZAIRE, 1976
Entre le ler septembre et le 24 octobre 1976, 318 cas de non specifiques, les malades ont eu progressivement
fievre h6morragique virale aigue se sont produits dans le de fortes douleurs a la gorge, des eruptions maculopapu-
Zaire septentrional. La poussee avait son centre dans la leuses et de douleurs abdominales irreductibles, et com-
Zone de Bumba, R6gion de l'Equateur, et la plupart des mence A presenter des saignements a des sieges mul-
cas ont 6te observ6s dans un rayon de 70 km autour de tiples, principalement dans le tractus gastro-intestinal.
Yambuku; quelques malades cependant se sont fait Bien que les analyses de laboratoire qui ont ete faites aient
soigner a Bumba, a Abumombazi et A Kinshasa, la ete limit6es, ne permettant pas de conclusion, on a estime
capitale, oiu on a enregistre des cas isoles secondaires que la pathogenese de la maladie comprenait une hepatite
et tertiaires. II y a eu 280 deces, et seulement 38 survivants non icterique et eventuellement une pancreatite aigue
dont l'infection a 6te confirm6e s6rologiquement. ainsi qu'une coagulation intravasculaire diffuse.
Le cas initial avait ressenti les premiers symptomes le Le syndrome en question etait du a un virus mor-
ler septembre 1976, cinq jours apres une injection de phologiquement analogue au virus Marburg, mais
chioroquine pour paludisme presume faite au service de immunologiquement distinct de celui-ci, virus qu'on a
consultation externe de l'H6pital de la Mission de appele Ebola. Cet agent a ete isol6 dans le sang de huit cas,
Yambuku et suivie de r6mission clinique des symptomes sur un total de dix cas suspects, en cultures de cellules
de paludisme. Dans l'espace d'une semaine, plusieurs Vero. Les titrages de specimens successifs preleves
autres personnes A qui des injections avaient ete admi- sur un malade ont revel6 une viremie persistante de
nistrees, au meme h6pital, ont et6 egalement atteintes 10 6,5 a 10 "56 unites infectantes a partir du troisieme jour
de fievre hemorragique d'Ebola, et presque tous les cas de la maladie et jusqu'au deces, survenu au huitieme
ult6rieurement observes ou bien avaient recu des injec- jour. Des particules de virus Ebola ont ete trouvees
tions A l'hopital, ou bien avaient et en contact etroit dans des specimens hepatiques fix6s au formol, pro-
avec un autre malade. La plupart de ces cas se sont pro- venant de trois cas. On a constat6 par l'epreuve de la
duits au cours des quatre premieres semaines de l'epi- fluorescence indirecte que les survivants pr6sentaient des
d6mie, apres quoi l'h6pital a e ferme, 11 des 17 membres titres d'anticorps anti-virus Ebola de 1: 64 a 1: 256 dans
de son personnel ayant succombe a la maladie. Des sujets les trois semaines suivant le debut de la maladie, et ces
de tout age et des deux sexes ont e affect6s, mais l'inci- titres persistaient, avec seulement une faible diminution,
dence la plus 6lev6e a ete observee chez les femmes de 15 pendant une periode de quatre mois.
A 29 ans, et on a de fortes raisons d'associer ce fait a la Au total on a obtenu et congele 201 unit6s (de 200-
frequentation des consultations prenatales et des consul- 300 ml chacune) de plasma contenant des anticorps
tations externes de l'hbpital, o'u ces femmes avaient requ anti-virus Ebola au titre d'au moins 1: 64. Deux de ces
des injections. Le taux general d'atteinte secondaire a unites ont servi A traiter un travailleur de laboratoire
ete d'environ 5 %, mais il s'elevait a 20% parmi les per- infecte par le virus Ebola. Le sujet a gueri, ce qui fait
sonnes etroitement apparentees au malade, telles que penser que les anticorps peuvent avoir joue un role
conjoint, parents, enfants, freres ou sceurs. therapeutique.
La surveillance active a permis de constater que des On a pu interrompre la transmission du virus en cessant
cas s'etaient produits dans 55 villages sur un total d'envi- les injections et en isolant les malades dans leurs villages.
ron 550 qui ont e examin6s maison par maison. La L'utilisation de vetements protecteurs et de masques
maladie en cause etait jusqu'alors inconnue de la popula- respiratoires, un strict isolement des malades et une
tion de la region affectee. La recherche intensive des cas soigneuse elimination des excreta et des objets eventuelle-
dans la region du nord-est du Zaire situee entre la Zone ment contamines devraient presque certainement per-
de Bumba et la frontiere du Soudan, pres de Nzara et mettre d'eviter de nouvelles grandes poussees de la
de Maridi, n'a pas permis d'etablir la preuve certaine maladie. II est probable que le virus est rarement transmis
d'un lien entre une epidemie de la meme maladie dans par des aerosols contamin6s, mais l'eventualite d'une
ce pays et la poussee qui s'est produite autour de Bumba. infection par des gouttelettes de grande taille ne peut pas
On a toutefois etabli que les gens peuvent faire, et font etre ecartee.
effectivement, le voyage entre Nzara et Bumba en quatre On n'a fait que des enquetes ecologiques limitees,
jours: il parait donc tout a fait possible qu'une personne puisque l'epidemiologie de la poussee fait fortement
infect6e se soit rendue du Soudan a Yambuku et qu'elle penser que dans la Zone de Bumba, le virus avait ete
ait contamin6 par le virus une aiguille de seringue lors importe. Le virus Ebola a et mis en evidence dans des
d'une injection subie a la consultation externe de l'hopital. echantillons representatifs de punaises de lit ou de ron-
La duree de la periode d'incubation comme celle de la geurs (Rattus rattus et Mastomys spp.) ayant des contacts
maladie clinique ont e en moyenne d'une semaine. Apres plus ou moins etroits avec I'homme. Mais on a aussi
avoir pr6sente pendant 3-4 jours des symptomes et signes mis en evidence des anticorps anti-virus Ebola chez cinq
292 REPORT OF AN INTERNATIONAL COMMISSION
personnes qui n'avaient pas ete malades et n'avaient pas vations pourraient indiquer qu'en fait le virus existe 'a
eu de contact avec les villages e infectes # ou l'hopital de 1'etat enddmique dans la region, ce qui devrait inciter A
Yambuku au cours de l'6pid6mie. Si elles pouvaient etre entreprendre de nouveaux efforts pour decouvrir un
confirmees par une autre methode d'epreuve, ces obser- reservoir de virus au Zaire.
REFERENCES
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the diagnosis of Lassa fever infection. Bulletin of the of the World Health Organization, 56: 247-269 (1978).
World Health Organization, 52: 429-436 (1975). 5. MARTIm, G. A. & SCHMIDT, H. Spermatogene fiber-
tragung des Marburg virus. Klinische Wochenschrift,
2. JOHNSON, K. M. ET AL. Isolation and partial charac- 46: 391 (1968).
terization of a new virus causing acute iaemorrhagic
fever in Zaire. Lancet, 1: 569-571 (1977). 6. GEAR, J. S. S. ET AL. Outbreak of Marburg virus
disease in Johannesburg. British medical journal, 4:
3. EMOND, R. T. S. ET AL. A case of Ebola virus 489-493 (1975).
infection. British medical journal, 2: 541-544 (1977). 7. Weekly epidemiological record, 52: 185-192 (1977).
EBOLA HAEMORRHAGIC FEVER IN ZAIRE, 1976 293
Annex 1