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MARBURG VIRUS DISEASE

M. DIETRICH
Bernhard-Nocht Institute for Nautical and Tropical Diseases, Clinical Department, Bernhard-Nocht-Strasse 74, 2000 Hamburg 4, Germany.

INTRODUCTION

Marburg Virus Disease is a hemorrhagic fever first described in 1967 when laboratory workers became ill after contacts with monkeys imported from Uganda to Marburg, Germany. Therefore synonyma are also Green Monkey or Vervet Monkey disease. In Marburg and Frankfurt, Germany, and in Belgrade, Jugoslavia, 31 patients got infected, of whom 7 died. Six of all patients were secondary cases (1).


TABLE 1 MARBURG VIRUS DISEASE


1967


Marburg and Frankfort/GERMANY

Belgrade/YUGOSLAVIA

Infected 31; died 7


(secondary 6)


1975


Johannesburg/S.A.

Infected 3; died 1

(secondary 2)


In 1975 a patient died in Johannesburg, South Africa, from Marburg Virus disease that he acquired in Rhodesia, evidently while travelling. Two secondary 2 cases occurred, who recovered completely (2).

MORPHOLOGY AND TAXONOMIC STATUS

The virus particle size was measured 75 nm x 650 nm approximately It is a virus with high complex structure related to viruses of vesicular stomatitis and rabies. The taxonomic status is not clearly defined. It was proposed to include it to the rhabdo-virus group by morphological criteria. At the present time it is still unclassified (4).



Fig. 1. Marburg Virus from VERO cell culture medium,


Negative staining 50 000 x


Courtesy of W. Slenczka and D. Peters, 1977 Marburg and Hamburg.

TRANSMISSION

In Marburg, Frankfurt, and Belgrade it became clear that either contacts with blood or organs of infected monkeys (Cercopithecus aethiops) or contact with already infected patients led to infection.

TABLE 2
MARBURG VIRUS DISEASE


clinical symptoms:


fever, myalgia, vomiting, diarrhoea, maculopapular symptoms: rash, bleedinq tendency, conjunctivitis, other


laboratory:


leukopenia, morphol. changes, thrombocytopenia, elevated GOT, GPT, decreased protein, other


histology:


cell necroses (multiple organs), inclusion bodies


clinical diagnoses:


hepatitis, myocarditis, pancreatitis, bronchitis, diagnoses: kidney failure, hepatic failure, encephalitis, other


The case in Johannesburg raised the possibility of being infected by a sting as concluded from patient's history. This could not be proved yet. Therefore, transmissions by to date unknown vectors remain possible. The two other cases were secondary.

RESERVOIR

Though monkeys from Uganda were the first known animals to be infected, the natural reservoir is still unknown. Epidemiological studies in monkeys trapped in Uganda and in monkeys' trappers indicated possible infection being present in a natural reservoir in Uganda (5). Further studies on monkeys in South Africa could not support this conclusion (6). However, animal inoculation was possible in a number of species, e.g. in guinea pigs, suckling mice, monkeys of different species, suckling hamsters, as well as in Aedes aegypti.

CLINICAL FEATURES

Incubation time is 4 to 9 days. Evidently, the virus spreads rapidly to most organs of the body inducing major dysfunction.

TABLE 3
MARBURG VIRUS DISEASE

Agent:

virus particle size 75nm x 650nm

Taxonomic status:

rhabdo virus-like

Transmission:

1 organs, blood (or contaminated materials) from vervet monkeys
2 blood, contact from infected patients (nosocomial inf.)
3 tick bite ?

Incubation:

4-9 days

Virus association:

two months (sperms, eye fluid)

Mortality:

approximately 25%


Headache, myalgia and fever occur followed by vomiting, conjunctivitis, a maculo-papular rash, enanthema, and enlarged lymph nodes. Watery diarrhoea occurs most frequently. In case of recovery symptoms improve over a period of several weeks. Reconvalescence requires up to several months. In more severe cases hemorrhagic disorders occur. Most remarkable are hemorrhages from the gastro-intestinal tract connected with poor prognosis. Other symptoms are mental disturbances, hyperaesthesia, and myelitis. Considerable bradycardia may be one of the symptoms in the beginning except in fatal cases during agony, where tachycardia is prevailing. 25% of the patients observed up to date died. Thus, the mortality is comparable with the mortality from Lassa fever.

LABORATORY FINDINGS

Laboratory parameters indicate the multiple organ damage. Leukopenia followed by leukocytosis is an almost typical feature, usable for diagnosis. Differential blood count demonstrates shift to the left of the granulocytes, as well as pseudo-Pelger cells, and atypical lymphocytes with activated nuclei, plasma cells or lymphoblasts (7). Considerable thrombocytopenia may cause bleeding tendency. In some cases laboratory parameters may suggest dissiminated intravascular coagulation with subsequent kidney failure (8). Elevated GOT and GPT levels indicate severe liver damage. ECG changes are comparable with myocarditis or other damage of the myocardium.

An interesting fact is that the association with active virus material can be observed for a long time. In one case, who recovered, virus particles could be detected in sperma. In this case there was evidence that the patient infected his wife by sexual intercourse . A secondary case showed that even two months after the disease was observed, virus particles could be isolated on the eye-chamber fluid (2)

PATHOLOGY

Postmortem sections showed that almost in all organs of corpses with Marburg virus focal necrosis could be detected by routine histology. Damage of the parenchyma of the kidneys suggested tubular deficiency. Hemorrhagic diathesis and plasma cellular infiltration could be observed in various tissues. Cerebral damage as described in panencephalitis with glial nodules may be present.

DIAGNOSIS

Diagnosis of Marburg virus disease may be difficult in a single case, but less difficult in an epidemic outbreak. Patient's history as well as typical rash and other clinical symptoms, especially hemorrhages, may lead to suspect Marburg virus disease. Furthermore, morphology of peripheral blood smears and other hematological parameters including platelet count may assist the diagnosis.

TABLE 4
MARBURG VIRUS DISEASE

diagnosis:

history, source of infection, clinical symptoms, antibody formation (IF), characteristic changes peripheral blood cells, direct virus morphology blood; organ biopsy, inoculation guinea-pig; VERO cell culture

treatment:

symptomatic, life support questionable: interferon, convalescent serum


Rapid confirmation may be possible by immune fluorescence methods. Direct examination of blood or organ biopsies can be done by electron microscopy. Cytopathic effect in Vero cell culture or the detection of virus from guineapigs inoculated with blood from a diseased patient will give evidence of the diagnosis.

TREATMENT

Symptomatic care of these patients is necessary. This includes balance of fluids and electrolytes, as well as treatment of hemorrhagic disorder which, of course, must be defined by laboratory parameters exactly. It is questionable whether convalescent plasma will prevent severe disease or, in any way, improve the status of the patients. The use of interferon seems to be experimental at the time being.

PREVENTION

To prevent the occurrence of Marburg virus disease cases is impossible, because it is not known where the natural reservoir is located. However, in case of a suspected case of Marburg virus disease, preventive measures have to be taken in order to protect attending personnel from infection. It seems that routine isolation procedures may be sufficient. However, the occurrence of secondary cases in the Marburg virus infection in Johannesburg in 1975

teaches us that secondary infection may occur despite these measures. More strict isolation facilities have been used for reverse isolation of patients with susceptibility to infection, e.g. in the case of bone-marrow transplantation. Plastic isolation systems have been used (10). Therefore, also in isolation of cases with hemorrhagic fever the use of plastic isolation systems with negative pressure and completely tied plastic bag should be safer, and will avoid any quarantine procedures for attending hospital staff". Materials from the patients have to be processed with specific care! Therefore, any laboratory investigations including the definite diagnosis has to be done under strict regulations of safety. Consequently, only few institutions all over the world can deal with such cases under optimal conditions.

SUMMARY

Marburg virus disease is a hemorrhagic fever, up to date unclassified. Mortality of the disease is 25% approximately. Despite the fact that the first outbreak was caused by contact with monkeys, the natural reservoir is still unknown. Transmission may occur by contacts with infected patients. Animal experiments showed that even Aedes aegypti could be a transmitter. Important to know that association with the virus or virus particle may last for several months.

Treatment is supportive only, because specific treatment is not known. Special attention has to be given to strict isolation procedures as necessary in patient care and for diagnostic laboratory investigations.

REFERENCES
1. Martini, G.A., Knauff, H.G., Schmidt, H.A. et a]. (1968) Ober eine bisher unbekannte, von Affen eingeschleppte Infektionskrankheit: Marburg Virus-krankheit, Dtsch. med. Wschr., 53, 559.
2. Gear, i.S.S., Cassel, G.A., Gear, A.J. et al. (1975) Outbreak of Marburg virus disease in Johannesburg, Brit. med. J., 4, 489-493.
3. Peters, D., Muller, G., Slenczka, W. (1971) Morphology, Development, and Classification of the Marburg Virus, in Marburg Virus Disease, Eds.: G.A. Martini and R. Siegert, Berlin-Heidelberg-New York, Springer, 68-83.
4. Wulff, H., Lyle Conrad, J. (1977) Marburg Virus Disease, in Comparative Diagnosis of Viral Diseases, Vol. 11, Human and related viruses, Part B, p. 3, Eds.: E. Kurstak and C. Kurstak, New York, Academic Press.
5. Henderson, B.E., Kissling, R.E., Williams, M.C. et al. (1971) Epidemiological Studies in Uganda Relating to the "Marburg" Agent, in Marburg Virus Disease, Eds.: G.A. Martini and R. Siegert, Berlin-Heidelberg-New York, Springer, 166-176.
6. Strickland-Cholmley, M., and Malherbe, H. (1971) Examination of South African Primates for the Presence of Marburg Virus, in Marburg Virus Disease, Eds.: G.A. Martini and R. Siegert, Berlin-Heidelberg-New York, Springer, 195-202.
7. Havemann, K., Schmidt, H.A. (1971) Haematological Findings in Marburg Virus Disease: Evidence for Involvement of the Immunological System, in Marburg Virus Disease, Eds.: G.A. Martini and R. Siegert, BerlinHeidelberg-New York, Springer, 34-40.
8. Egbring, R., Slenczka, W., Baltzer, G. (1971) Clinical Manifestations and Mechanism of the Haemorrhagic Diathesis in Marburg Virus Disease, in Marburg Virus Disease, Eds.: G.A. Martini and R. Siegert, Berlin-HeidelbergNew York, Springer, 41-49.
9. Gedigk, P., Bechtelsheimer, H., Korb, G. (1968) Die pathologische Anatomie der Marburg Viruserkrankung, Dt. med. Wschr., 93, 572.
10. Dietrick, M., Abt, C., Pflieger, H. (1975) Experiences with a new isolated bed system in the treatment of acute leukemia, Med. Progr. Technol., 3, 85-89.
11. Emond, R.T.D., Evans, B., Bowen, E.T.W., Lloyd, G.(1977) A case of Ebola virus infection, Brit. med. J., 2, 541544.
DISCUSSION
M. lsaäcson : The Johannesburg-Marburg index case is of course the only Marburg case known that has been acquired in nature. The patient complained of some kind of sting or bite that he acquired one week prior to onset of illness. This was a very painful lesion. We did a rather thorough epidemiological investigation, and we in fact were able to identify the tree on the roadside under which the patient sat when he was stung or bitten by an unidentified agent. We proceeded to tear the roadside bank apart literally. The only sign of life we found from the entomological point of view was hundreds of spiders. We collected all the spiders we could find and took these to the laboratory. About half of these have now been investigated at the CDC in Atlanta as well as in our Laboratory in Johannesburg and have yielded no results. I think that these are the only comments I want to make on this particular case.
T.E. Woodward : Does the fact that we heard nothing about changes in the blood vessels mean that there is no vasculitis present ? Do you have any clue from findings in the gastro-intestinal tract why there is diarrhoea and intestinal bleeding ?
M. Dietrich : Around the vessels there were, as far as I remember, some cellular infiltrates, no pure vasculitis as such. The same holds true for the GI tract.

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