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CLINICAL ASPECTS OF EBOLA VIRUS INFECTION IN YAMBUKU AREA, ZAIRE, 1976.

P.PIOT(1), P. BUREAU(2), G. BREMAN (3), D. HEYMANN(3), V. KINTOKI(4), M. MASAMBA(4), M.MBUYI(4), M. MIATUDILA(6), F. RUPPOL(7), S. VAN NIEUWENHOVE(1,7), M.K. WHITE(3),G. VAN DER GROEN(1), P. WEBB(3), H. WULFF (3), K.M. JOHNSON(3)
1) Instituut voor Tropische Geneeskunde, Laboratory of Bacteriology, Nationalestraat 155, 2000 Antwerpen, Belgium.
2) Institut Pasteur, Teheran, Iran.
3) Center for Disease Control, Atlanta, U.S.A.
4) Cliniques Universitaires UNAZA, Kinshasa, Zaire.
5) Lisala, Zaire.
6) FOMECO, Kinshasa, Zaire.
7) FOMETRO, Kinshasa, Zaire.
SUMMARY

Observations of six active cases and of a retrospective survey on 265 probable or serologically confirmed cases of Ebola virus infection in Zaire,1976, area are presented. Predominant symptoms of the disease included profound prostration, fever, headache, myalgia, arthralgia, abdominal pain and sore throat.

The most frequent signs were diarrhea, vomiting, oropharyngeal lesions, cough and conjunctivitis. Bleeding occurred in 70 percent of all cases, mainly from the gastrointestinal tract. Proteinuria was uniformly present. Skin rash was seldom reported among black skinned patients. Central nervous involvement was evident in some cases. Abortion occurred among 23 percent of 82 pregnant women who had the disease. Ten cases of possible neonatal Ebola virus infection occurred, but were not definitely elucidated.

The first accurate clinical description of Ebola virus infection (EVI) is found in the report of Dr. Ngoy Mushola from Bumba, who stayed at Yambuku hospital from September 1976, 15th to 19th : "the illness is characterized with a high temperature of about 39°C, hematemesis, diarrhea with blood, retrosternal abdominal pain, prostration with "heavy" articulations, and rapid evolution death after a mean of 3 days".

Subsequent observations of acute cases and of a retrospective survey on more than 250 probable and serologically confirmed cases are presented in this paper.

METHODS

Six patients were questioned and examined briefly during the acute stage in villages by survey team physicians during preliminary investigations at the end of October 1976. Information on other cases was obtained in villages of the affected region by six physician-led teams working with local nurse interpreters. Data were obtained as part of a retrospective epidemiological study in NovemberDecember 1977 using standardized forms. Family members provided information on fatal cases. Case and infection criteria were as described under surveillance and containment(1).

One International Medical Commission (ICM) member documented independently 136 fatal cases between November 1st and 9th, 1976. Concordance of findings in these two surveys was excellent.

RESULTS

Interviews were completed on 231 probable cases, and 34 individuals who were found to have Ebola virus antibodies by immunofluorescence. The frequency of symptoms and signs in these groups is shown in tables 1 and 2 respectively.

TABLE 1
PERCENTAGE OF SYMPTOMS PRESENTING IN PERSONS(1) WITH EBOLA INFECTION AND CONTROLS IN ZAIRE, 1976,


Symptom


Death


Probable cases


Positive Titer

 

N


%


n


%


Fever


231


98.1


34


58.8


Headache


210


96.2


34


58.8


Abdominal Pain


201


81.1


34


50.0


Sore Throat


207


79.2


34


32.4


Myalgia


206


79.1


34


47.1


Nausea


178


66.3


30


33.3


Arthritis


193


53.4


34


38.2


Other (2)


42


50.0


23


26.1


(1) Age I or >.

(2) Anorexia, chest pain-pleuritis, chills, tinnitus, vertigo.

n = Total respondents.

% = Positive yes/respondents.

TABLE 2
PERCENTAGE OF SIGNS PRESENTING IN PERSONS(1) WITH EBOLA VIRUS INFECTION IN ZAIRE, 1976.


Symptom


Death (Probable Cases)


Positive Titer



N


%


N


%


Bleeding


223


77.6


34


17.6


Diarrhea


228


78.5


34


44.1


Oral-Throat Lesions


208


73.6


34


26.5


Vomiting


225


64.9


34


35.3


Conjunctivitis


208


58.2


34


35.3


Cough


208


35.6


34


17.6


Abortion


73


24.7


9


11.1


Edema


193


4.1


34


0


Jaundice


191


5.2


34


0


Other (2)


141


3.5


33


3.0


(1) > 1 year only.

(2) Amennorhea, dark urine, paralysis, polyuria, rash, dysarthria, hiccoughs, hyperhidrosis, lymphadenitis, paralysis, polyuria, rash.

The onset of illness was often sudden with progressively more severe frontal headache soon spreading occipitally. Fever was almost invariably present from the beginning as was weakness. Myalgia appeared very early, often from the first day of illness. It was reported as cervical and low back pain radiating into the legs. Arthralgia of the large joints was also very common from the beginning. Severe generalized disease became very soon apparent. Patients presented a typical lethargic, expressionless face with deep set eyes. There was often a complete loss of appetite and a rapid weight loss subsisting for a long time in those who recovered from the disease.

After 2 to 3 days of increasing severity of illness, gastrointestinal symptoms developed in most patients. Abdominal pain, including cramping, usually preceeded diarrhea (three or more liquid stools for one or more days) and/or vomiting and persisted nearly always until death. The stools were initially watery and clear, but turned black or contained red blood in 66.2% of all cases with bleeding history. Vomiting was somewhat less common than diarrhea, usually starting after the diarrhea had begun. Hematemesis with red blood or "vomito negro" were reported in 42.8% of those with bleeding history.

Sore throat occurred in most patients and was often reported in association with a sensation of a "ball" in the throat. Severe dysphagia was reported in some cases, and is probably due to pharyngeal or swollen tissues in the throat. Oral-throat lessions were a typical feature of the disease, especially in fatal cases. They were present as fissures and open sores, especially on the lips, and appeared after 3 to 4 days of illness. Typical herpetic oral lesions were observed in a few patients by one physician. A grayish patchy exudate was noted on the soft palate and oropharynx in one instance. About a quarter of the fatal cases had oropharyngeal hemorrhage, mainly gingival bleeding. The cough was dry and appeared to be associated with oral-throat lesions rather than with lower respiratory tract pathology. Chest pain was rarely reported by both relatives of fatal cases and convalescents. Conjunctivitis was present in more than half of the patients, was non-purulent and sometimes complicated with subconjunctival bleeding.

Bleeding manifestations are listed in table 3. The gastrointestinal tract was the most common site of bleeding, and hemorrhage occurred more often among fatal than non-fatal infections. Bleeding started on days 3-5, and varied from melena and slow oozing from gums to brisk hemorrhage from multiple sites in fulminant cases. Hematuria was not reported.

TABLE 3
BLEEDING MANIFESTATION OF PERSONS (1) WITH EBOLA VIRUS INFECTION, ZAIRE, 1976.


Manifestation


Death (Probable Cases)


Positive IFA



n


%


n


%


Melena


210


66.2


33


15.2


Hematemesis


222


42.8


33


6.1


Mouth-Gingival


215


25.6


33


0


Vaginal


108


20.4


24


4.2


Epistaxis


216


16.7


33


0


Injection Sites Scarification


197


6.6


33


3.0


(1) : > 1 year only.

Skin rash or desquamation were rarely mentioned by relatives of fatal cases or by survivors in this black skinned population, and were seldom observed by IMC-physicians in the field. Other less common or rare symptoms include edema, jaundice, tunnitus, vertigo, amenorrhea, dark urine, oliguria, polyuria, dysarthria, hiccoughs, hyperhidrosis and lymphadenitis. In some cases central nervous system involvement was observed, including terminal hemiplegia and psychobehavior.

The only clinical laboratory test done on patients admitted to Yambuku Hospital was urinary protein. This was reported as uniformly positive and was used as a major diagnostic criterion by the nursing sisters early in the epidemic.

The duration of symptoms and signs among persons with hemorrhagic fever is given in table 4. Data for the "convalescent" group were by far the most reliable. Illness among fatal cases ranged from 1 to 15 days with a strong unimodal peak of 6 to 8 days.

Fifty nine percent of persons with antibodies had one or more symptoms, the most prominent being fever, headache, abdominal pain, myalgia, diarrhea and athralgia Many more persons who had been in contact with fatal cases reported symptoms but had no Ebola virus antibodies. Bleeding and oral-throat lesions particularly were more common in fatal cases than among survivors. The convalescent period took 1 to 3 weeks in most cases, but in some survivors recovery Was very slow and could last up to 5 weeks. Convalescent patients were marked by profound prostration and weight loss. Non-specific symptoms such as headache and weakness only slowly disappeared. In at least two survivors psychotic behaviour was observed up to two months after recovery from the disease. They both showed character changes with confusion, anxiety, restlessness and aggressive behaviour.

TABLE 4
DURATION OF SYMPTOMS AND SIGNS OF PERSONS (1) WITH EBOLA VIRUS INFECTION


Symptom & Sign


Deaths Probable Case Mean Duration + SE


Convalescents Mean Duration + SE


Fever


7.2


(.28)


6.8


(1.48)


Headache


7.3


(.29)


5.5


(1.04)


Sore Throat


6.5


(.31)


10.7


(2.57)


Abdominal Pain


5.9


(.30)


7.9


(2.11)


Myalgia


7.1


(.30)


5.7


(1.01)


Arthralgia


6.5


(.32)


9.9


(2.08)


Bleeding


3.5


(.20)


9.3


(2.95)


Diarrhea


4.9


(.24)


7.5


(1.75)


Oral Throat Lesions


5.5


(.32)


5.3


( .64)


Vomiting


4.0


(.25)


3.9


(1.17)


Conjunctivitis


5.1


(.40)


6.3


(1.51)


Cough


6.9


(.57)


10.0


(3.98)


( 1) > 1 year of age.

Table 5 summarizes the findings in six active cases observed in villages around Yambuku during a preliminary survey in October 1976 by ICM physicians. Four of these were virologically or serologically confirmed cases. All the patients were in their seventh to nineth day of illness. They all exhibited a typical appearance of the disease with expressionless face and profound prostration. A relative bradycardia was found in patient n°1. Patient n°2 complained of severe epigastric pain radiating to the back suggesting pancreatic involvement, vomited and had intractable hiccoughs. He had enenthema on the hard and soft palate. Half of the patients suffered from chest pain and gingival bleeding. The only survivor was seen at the nineth day of her illness and showed a less severe course of the disease. She was a serologically confirmed case.

Abortion occurred among 25 percent of 73 pregnant women who died. Two of nine pregnant survivors also aborted. Ten infants were born to mothers who died of EVI. All of these children died in turn within 19 days. These cases of possible neonatal Ebola virus infection had few symptoms. Seven were said to have had fever but bleeding was infrequent. In the absence of virological and pathological data it was not possible to decide whether these represented actual cases of neonatal infection.

DISCUSSION

The clinical features of Ebola virus infection as seen in this outbreak are virtually indistinguishable from those seen in the related Marburg virus infection (2,3).

If anything, the evolution of EVI appeared to be more inexorable and less variable than hemorrhagic fever due to the Marburg agent. Skin rash appeared to be less common than in Marburg disease, but was uniformly present among white patients (4,5) and was frequent during the EVI outbreak in Sudan6. This difference may be due to the use of mainly retrospective data. Oropharyngeal lesions and sore throat were far less frequent in Marburg disease.

In contrast to observations made simultaneously in Sudan, the Zaire illness had less respiratory symptoms, a shorter clinical course and a higher fatality rate. Whether this was due to differences in virus virulence per se, route of infection (injection or person-to-person), or to host and ecological variables such as climate (relative humidity) is not known.

TABLE 5
SYMPTOMS AND SIGNS OF 6 CONFIRMED OR PROBABLE CASES OF EBOLA VIRUS INFECTION AS OBSERVED BETWEEN THE 7TH AND 9TH DAY OF ILLNESS IN YAMBUKU AREA,ZAIRE, 1976.


Case


Sex


Age


Outcome (1)


Fever


Headache


Nausea


Abdomial pain


Myalgia


Anorexia


Sore throat


Chest pain


Arhtralgia


Diarrhea


Bleeding


Oral-throat lesions


Gingival bleeding


Vomiting


Conjuvitis


1


M


25


+


+


+


+


+


+


+

 

+


+


+


+

   

+


+


2


M


32


+


+


+


+


+


+


+


+


+

 

+


+


+


+

   

3


F


36


+


+


+


+


+


+


+


+

 

+


+


+


+


+


+

 

4


F


40


+


+


+


+


+


+


+


+

 

+


+


+


+


+


+

 

5


M


30


+


+


+


+


+


+


+


+

           

+


+


6


F


30


+


+


+


+

   

+

 

+

 

+

         

Other symptoms:

1: Bradycardia

2: Enanthema-Hiccoughs-Dyspnoea

5: Dark urine

6: Cough, Weight loss

Though far from proven, we suspect that consumptive coagulopathy (disseminated intravascular coagulation) and pancreatitis were major features of the syndrome. Death appeared to be preceeded by shock.

Early in the disease symptomatology is non-specific making diagnosis very difficult until more similar cases appear and the severe hemorrhagic syndrome becomes apparent. Even then, differential diagnosis with other hemorrhagic fevers such as Lassa fever can be clinically impossible, although bleeding occurs 7 less frequently in Lassa fever

There is a need for prospective clinical studies with appropriate controls (patients admitted with fever) and thorough investigations on the virology, haematology and biochemistry of EVI. This could give clues for diagnosis and management of the illness, Rapid diagnostic methods would be of invaluable help to control outbreaks.

REFERENCES
1. Sureau, P., et al. (1978) Containment and surveillance of an epidemic of Ebola virus infection in Yambuku area, Zaire, 1976, in Ebola Virus Hemorrhagic Fever, ed., Pattyn, S.R., Antwerpen, Belgium.
2. Gear, J.S.S., et al. (1975) Outbreak of Marburg virus disease in Johannesburg. Brit. Med. J., 4, 489-493.
3. Martini, G.A. (1971) Marburg virus disease. Clinical syndrome. in Martini, G.A. & Siegert, R. ed., Marburg Virus Disease. Springer-Verlag, Berlin, pp. 1-9.
4. Emond, R.T.D., et al. (1977) A case of Ebola virus infection. Brit.Med. J., 2, 541-544.
5. Isaacson, M. (1978) An outbreak of African Hemorrhagic fever caused by Ebola virus at the Ngaliema Hospital, Kinshasa, Zaire. in Ebola Virus Hemorrhagic Fever, ed., Pattyn, S.R., Antwerpen, Belgium.
6. W.H.O. team (1976) Report on Viral Hemorrhagic Fever in Sudan, 1976.
7. Monath, T.P. & Casals, J. (1975) Diagnosis of Lassa fever and the isolation and management of patients. Bull. Wld. Hlth. Org., 52, 707-715.

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