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THE SURVEILLANCE OF VIRAL HAEMORRHAGIC FEVER IN ZAIRE

MUYEMBE-TAMFUM LINTAK
Université Nationale du Zaïre, Campus de Kinshasa, Faculté de Médecine, Service de Microbiologie, B.P. 834, Kinshasa XI, Zaïre Republic.

An outbreak of viral haemorrhagic fever occurred in Zaire in the Equateur Province, in September 1976.

The first case was recorded in Yambuku Mission hospital. More than 40 villages, located within a radius of 50 km from Yambuku were involved. A first epidemiological investigation was done in Yambuku by the local health authorities of the Equateur Province on September 15, whereas the central governsent two teams of physicians respectively on September 23 and October 4.

As a microbiologist, I visited the area together with Dr. Omombo, epidemiologist, on September 23.

Our mission was expected to last six days but we shortened it to 24 hours in order to speed the diagnostic procedure since the situation was very serious. We carried out some manipulations without special precautions, except the traditional hygiene of handwashing with soap and disinfection with iodinated alcohol after examination of patients or manipulation of fatal cases.

We collected :

- three liver autopsy specimens from persons who died a few hours before we arrived,

- five blood cultures from febrile patients,

- blood samples for routine serological reactions.

The liver specimens were fixed in formalin and sent to the Institut Pasteur in Dakar, which is one of the WHO Reference Centers for yellow fever. The blood cultures remained negative. The results of the Widal tests were difficult to interpret because the patients live in an area endemic for salmonellosis. Some weeks later, a junior pathologist of Zaire suggested the diagnosis of yellow fever.

Moreover, in order to precise the nature of the disease and to encourage the Mission members, it was decided to evacuate to Kinshasa the nurse missionary who became ill on September 23, and a priest who had travelled with the index case of the epidemic to Kota-Koli, two weeks before.

We travelled with our patients and samples by Land Rover to Bumba, and flew back 24 hours later to Kinshasa via Kisangani.

From N'djili airport the two patients took a taxi to a clinic in downtown Kinshasa.

The nurse's serum was sent to the Institute of Tropical Medicine in Antwerpen, where a new virus was isolated. Unfortunately, the nurse died on October 6. Her companion fell ill on October 8, and died on October 14. A ZaTrian nurse who cared for these two patients fell ill on October 13 and died on October 20. The priest was never infected and did not develop antibodies.

Haemorrhagic fevers are endemic in Africa. For some of them the mode of transmission is well known.

Yellow fever is transmitted from monkey to man by Aedes mosquitoes. Therefore mosquito control measures are partially effective in preventing and stopping the spread of epidemic yellow fever. Vaccination gives a longlasting protection.

In Lassa fever, the virus reservoir is the multimammate rat Mastomys natalensis. In the absence of vaccination against the disease, control measures based on a good knowledge of the ecology of these rats have been effective in the prevention of the spread of the disease.

In the accidental infections by Marburg fever the virus source was the vervet monkey Cercopithecus aethiops imported from Uganda for scientific purposes. In the natural infections, as in the Johannesburg outbreak in 1978, neither the reservoir nor the vector are known.

At present, the source of Ebola virus is also unknown.

Lassa, Marburg and Ebola viruses can be transmitted from man to man. These infections are very dangerous, particularly in Africa, where people live in such a promiscuity that person to person transmission is easily achieved. Surveillance of numerous primary and secondary contacts is difficult.

Therefore, in Zaire, before the nature of the disease was known, we decided

1: - to stop the circulation of patients and families between villages; soldiers guarded the main routes,

2: - to bury the corpses as quickly as possible after death in order to avoid prolonged contact with other members of the family. Because of the high risk of contamination among nurses and other hospital workers in Yambuku, we recommended :

1º - to wear gowns, masks and gloves,

2º - to avoid contact with blood, urine and other body fluids of patients.

The Department of Public Health sent relevant clinical and epidemiological information to most Zaïrian hospitals. Early in the epidemic, the signs and symptoms of the disease are similar to those of malaria or salmonellosis, the prime sign for alarm must be the high mortality rate among patients.

In Zaire, the surveillance of haemorrhagic fevers is presently included in the national public health program. A medical doctor is now present in most rural hospitals and is responsible for the surveillance of the surrounding villages. For the future, we hope to maintain contact with the doctors in the rural areas for permanent surveillance of fevers of unknown etiology.

The mobile teams of FONAMES and FOMETRO distributed all over the country, can also give information to the National Public Health authorities, if they suspect viral haemorrhagic fever. Most of the rural hospitals belong to the Missionaries and have radio contact twice a day with urban hospitals.

Since the outbreak in Yambuku, two micro-epidemics have been notified, but these were false alarms.

Nevertheless, we think that the possibility for new epidemics is real. It would be useful to have a stock of immune plasma in Zaire. Moreover, laboratory facilities for rapid diagnosis of the disease are essential. In the absence of these in Zaire, we depend on collaborative investigations with high security laboratories in foreign countries.


DISCUSSION
S.R. Pattyn : False alarms were mentioned and I would like to ask what are the simplest clinical criteria to exclude haemorrhagic fever.
P. Piot : I don't think there is any single clinical symptom or sign which can exclude the diagnosis of Ebola virus or another haemorrhagic fever infection. Even if the patients are not bleeding, you cannot exclude any of the haemorrhagic feoers. There are only some signs or symptoms which are statistically valuable but not appLicable to individual patients.
O.W. Prozesky : We had two false alarms, this is due to informal surveillance we had organized in South Africa. We have arranged that in such cases the corpses be put in two plastic bags immediately and that a limited autopsy be performed and liver be obtained through the plastic. The liver is to be sent for investigation both in fixed and unfixed forms. In the first case the diagnosis of any Onyalai was made and the second was a case of tick-bite fever.
D.P. Francis : When called into these areas, I don't think there is going to be one isolated case. The individual case of haemorrhagic fever is no doubt very difficult to diagnose. The key at the larger outbreaks are clusters of human to human transmission most of which are in the hospital. The action from then on will be the same, that is to isolate the primary contacts and to get away from the patients.
A. Fabiyi : I am very interested in the five sera Dr. Smith told us about, from haemorragic patients. What were the sera tested against ? The reason why I am asking this is that we have shown that dengue virus is active in Africa, so that dengue shook syndrome could occur, although that would depend on the age of the patients involved. It would be nice to know what antigens were used in the testing of these sera ?
D. Smith : The five cases that I referred to were tested only against Ebola and Marburg. These were sporadic cases that had occurred while we were in the Sudan. It is from an area with very sporadic, usually family cases, three or five at a time, over the last six or seven years. Dr. Metselaar previously had investigated this area with Dr. Casals, they screened for substantially more possibilities.
J. Casals : I don't recall the exact antigens that were used for testing your sera but I believe there were included Chikungunya, Sindbis, West Nile, Banzi, Ntaya and Lassa. Those arboviruses were used because we depend on their cross-reactivity to pick any possible antibodies. Unfortunately, as far as I recall, the tests were not diagnostic. I want to add a comment. As a collaborating Center with WHO, we receive sera from all over the world. We can handle very easily arboviruses because we have the antigens. Sera coming from Africa will have to be tested for particular antigens like Lassa or Congo-Crimean viruses. As long as Drs. Johnson and Webb send us the antigens we can test for these. Marburg and Ebola however are entirely out of our hands since we cannot handle these antigens. Two other antigens pose problems as we are not allowed to handle them because of interdiction by the Department of Agriculture. These are Rift Valley Fever and Nairobi Sheep Disease. I don't know where the supply of antigens will come from. Finally, I want to ask Dr. Smith whether in his experience he has seen recently or within the last five years, many human cases of Rift Valley Fever in Kenya.
D. Smith : There has been a fairly substantial outbreak in a very remote part of Northern Kenya, part of the Rift Valley. Like all those things we got to know about it after it had happened. There were possibly between 500 and 700 acute cases of a short febrile illness with perhaps 50 or 75 deaths. A very small proportion had haemorrhagic features. We only found 8 or 9 people who were reputedly convalescent, whom we bled and we have the serum now in Nairobi. You highlighted some of the problems. It is a little difficult now, with this wide array of possibilities, to know quite what to do with these sera.
P. Brès : We should do what we did before in similar circumstances : we send these sera to Dr. Casals and, if necessary, he sends the sera further to other places. It takes time, but it is the only thing we can do.
M. Isaäcson : Rift Valley Fever diagnosis is a routine procedure in our National Institute of Virology and we would like to offer the services of that laboratory for Rift Valley diagnosis.
J.G. Breman : I think Dr. Pattyn's question was very critical as to what exactly do you do practically. I think Dr. Prozesky answered that in part. It is very important for everyone to have a clear idea as to what specimens to take because you really can't make the diagnosis clinically nor can you consider every febrile illness as a possible haemorrhagic fever in a rural hospital. Our recommendation was to do as Dr. Prozesky recommended actually, but not even taking fresh tissue as we considered it so lethal, but to put it in formalin. Dr. Muyembe raised an interesting point in that he got a report from Dakar, one of the best places in the world, saying that later on, this was diagnosed as yellow fever and Dr. Murphy showed us Councilman-like bodies which were very impressive. Is indeed the histopathologic picture very much like yellow fever ? We can't really put all these slides under electron microscopy immediately, certainly not in Dakar, Khartoum or Kinshasa. The second question is for Dr. Brès and Dr. Muyembe regarding staff available and specimens that have come in. I think after these epidemics, certainly in Zaire, we have a well-trained corps of national epidemiologists and qualified personnel. Dr. Miatudilla told me he has been designated to do the investigations in the future. I want to ask Dr. Muyembe if, since last year, any pathologic specimens have come in and what has been found.
O.W. Prozesky : we decided on liver because all these haemorrhagic virus diseases reflect in the liver. I don't think that the specimen need tell you whether it is yellow fever, Marburg, Ebola, Rift Valley, you do not have a chance really to diagnose that on histology, which you mostly do, but you can do electron microscopy on that same liver. We do negative staining on the liver juice expressed from it, to visualize the virus. In my limited experience the histology of yellow fever, Marburg, Ebola, is so similar that a specific diagnosis is impossible on one specimen. But a group diagnosis is possible and that is what is needed at that stage.
A.W. Woodruff : In Africa, 90% of fevers will be malaria, to take the blood film under secure conditions wearing gloves with more caution than perhaps has been exercised in most places in the past, remains the central and most important examination. Then comes the clinical decision : is the condition consistent with the presence of malaria, is it wholly explained by the presence of malaria parasites ? Here I think the clinical training of those who go to Africa comes into very forcibly. Physicians should be trained in the recognition of the most likely clinical syndromes that they are going to be confronted with and in particular malaria.
F.A. Murphy : Wouldn't it be practicable if only one specimen would be collected ? One of the problems is that when everything has to be divided and some o'f it is fixed and some is not. frozen material and fixed material cannot be shipped in the same box and everything multiplies. So I think there are great advantages in sending only one piece of liver in the frozen state, this provides material on which a lot of things can be done. it offers the advantage of ultimately arriving at an etiologic diagnosis rather than the frustration of an array of presumptives and not confirmatory hard evidence.
K.M. Johnson : I think I'll have to disagree with my colleague. He is right in terms of the single specimen and what kind it ought to be to obtain the maximum information. My own concern at the moment, in view of the probable sporadic occurrence of these diseases, would be to find the simplest, cheapest way to get any kind of specimen conveniently to some place where something could be learned. If I had to do it, I think I would return to the suggestion and the methods fundamentally used so beautifully for so long in the tropics by -the Rockefeller Foundation and that is ; put a piece of Liver in a fixative and mail it. You are quite right that it may not be able always to show exactly which virus is involved, but we could even begin to fill in a geographic map of Africa. Latin America, Asia, in terms of the distribution of these kinds of diseases. We would then be in a much better position for future investigations and to really focus on places where we know we want something frozen from, but I understand this means a lot of work to the pathologist.
C.E. Gordon Smith : I think we are building up a beautiful sort of castle in the air. My experience of collecting things from people in tropical countries is that they are not, on the whole, very keen on people rushing around cutting pieces out of them. It is extraordinarily difficult getting post-mortem examinations of even the simplest sort in many countries. The situation you referred to was that of a service working in a highly disciplined situation in South America which would probably never be acceptable in Africa. I would like to hear from the Africans about the realism of the suggestions that have been made, remembering that the situation is quite different during a Large epidemic where everyone is frightened to death and really very draconian measures are possible. But we are talking about the first cases in a place where there never had been any previously.
K.S. Daoud : I agree with Dr. Gordon Smith. The people do not allow any post-mortem especially if it is a first case of disease occurring in that region. Secondly, I don't think it is advisable to take a liver biopsy during life when the liver is very friable and bleeding.
T. Muyembe : Autopsies are avoided because of lack of protective material. Furthermore, autopsies are not allowed. We did not receive any material for diagnosis since the end of 1976.
J.G. Breman : Dr. Gordon Smith's cement is very pertinent, I have had some experience in getting specimens from another area of Africa for cholera, smallpox and yellow fever. We developed a special simple kit with basic material and distributed this in one country of 5.000.000 people, having meetings with 15 of the regional doctors responsible for public health activities. This was after the big epidemics of yellow fever in 1965 and 1971. From '71 to '75 not one specimen had come in to the regional health organization. After this kit was distributed 18 liver specimens were obtained in one year and several series of serum specimens specifically from people with jaundice. The liver specimens were not taken with the menacing-looking viscerotome, but with a thin liver biopsy needle which does not require a major incision. This was generally accepted and the people were motivated. Of course the results were communicated properly to the doctors and we were surprised to see so many specimens.
J. Casals : We assume here that febrile illness that presents haemorrhages in the skin is necessarily Ebola, Marburg or Yellow fever but there are many other such febrile illnesses in Africa and elsewhere and a liver specimen is not going to help much in making a diagnosis. What about dengue haemorrhagic fever ? What about Chikungunya, which in the surveys that we conducted in Nigeria and now in Liberia resembles very much a mild form of Lassa ? Evidently the first thing that one has to do to have a rapid diagnosis is to find the antigen, but this is often missed entirely and we have to depend on serological diagnosis. The serum can be tested in many different laboratories. Dr. Isaäcson can do the Rift Valley fever, perhaps in Kenya they can do the Nairobi Sheep Disease, we ourselves and C.D.C. can do other viruses but are specimens to be sent in five different directions ? What I would like to see is that it could be done all under one roof and be given an answer.
P. Brès : I think the best method is to do what has been done before that is to make contact with the Virus Diseases Unit in Geneva and according to the problem which may be different from one place to the other, you will presumably get some advice where to send the material to. I think that is the best thing I can propose now.
D.P. Francis : We did out first two post-mortems in the Sudan approximately four and seven hours after death. we put the specimens in Ziquid nitrogen within half an hour but no virus was obtained. Therefore I would return to Dr.Johnson's suggestion and mail fix tissues together with sera, as suggested by Dr. Casals.

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