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Postgrad Med J: first published as 10.1136/pgmj.49.574.542 on 1 August 1973. Downloaded from Postgraduate Medical Journal (August 1973) 49, 542-546.

Marburg virus disease

G. A. MARTINI M.D.

University of , West

Summary Within a few hours the fever increased to 390C In the late summer of 1967 an epidemic in thirty-one without rigors and reached a maximum on the 3rd patients in Germany and of a disease trans- and 4th days; the temperature fell gradually after- mitted from African green monkeys occurred; seven wards with a second peak between the 12th and 20th patients died. The was from 4 to 7 days. days. The clinical features were headache, high Relative bradycardia occurred, especially in the fever, diarrhoea, a very characteristic , severe early days, whereas tachycardia was only found in tendency and involvement of the central ner- the fatal cases. Many patients complained from the vous system. Nearly all organs were involved and beginning about nausea and suffered from frequent, showed severe cell necroses. The aetiological agent and occasionally uncontrollable, vomiting. Watery was identified as an RNS-virus and was named diarrhoea with or mucus occurred up to tenby copyright. . It was detected in the blood, urine, times daily with symptoms and signs of severe throat-washing and seminal fluid. and acute renal failure. All patients developed a characteristic maculo- papular rash on the 5th to 8th IN August 1967 a hitherto unknown severe infectious days. It began on the face and on the then disease with features of haemorrhagic fever was buttocks, progressed to observed simultaneously in Germany and Yugo- the trunk and extremities. Most characteristic were slavia which could be traced to imported monkeys dark red pinhead papules round the hair follicles. (Cercopithecus aethiops) from After 1 or 2 days it developed into a sharply de- . lineated Until then only single cases of diseases trans- maculo-papular lesion which coalesced into mitted by monkeys were known (e.g. herpes simiae, a more diffuse and dark red erythema. Cutaneous http://pmj.bmj.com/ , ). The new disease was the first to was rare. The rash was in many patients occur as an epidemic. accompanied by scrotal dermatitis or erythema of the greater labia. About the end of the second week Incidence all patients peeled, especially on the palms and soles. The external rash was in most cases accompanied Altogether thirty-one persons (twenty males, by an enanthem with dark red colouring of the eleven females) contracted the disease: at Marburg soft palate and tapioca-like transparent lesions. twenty-three, at six, and at two A and photophobia developed in on October 2, 2021 by guest. Protected persons. Out of these thirty-one patients seven died. half of the patients. Swelling of the lymph nodes was The epidemic appeared in August and ended in observed in the nuchal, cervical, and axillary regions November 1967. Before and afterwards no more between the 3rd and 6th days of illness. The lymph cases were seen. nodes were soft and sensitive to pressure. The spleen was palpable in only one patient, the liver Clinical picture (Figs. 1 and 2) was tender but not enlarged. The central nervous The incubation period could be determined in system was affected in different ways. Nearly all some patients who had only once been exposed to patients showed a sullen, slightly aggressive, and the infectious material; it varied from 3 to 9 days. negativistic behaviour. Those who died became The prodromal phase was very short. The disease restless, confused, unconscious, and died in deep began rather abruptly with extreme malaise, pains . Two had severe . Some patients in the limbs, and severe frontal and temporal complained of paraesthesia and restless legs. One headache. patient developed a severe post-infectious myelitis Postgrad Med J: first published as 10.1136/pgmj.49.574.542 on 1 August 1973. Downloaded from 543

Headache (n =23)

Drowsiness (n=18)

Myalgia (n = 10) Vomiting (n = 21) Diarrhoea_ I(n=19)

Lymphadenopathy (n =I0)

Enanthem (n=17) Rash (n= 23) 2 4 6 8 10 12 14 16 18

39L 140 by copyright.

D 38 120

E 37 100oo

2 4 6 8 10 12 14 16 18 ESR (mm) 6/16 8/18 12/23 38/72 47/67 (n C) Fa) 03^~~~~~~)

o, , (Ooo0 http://pmj.bmj.com/ u) E C o 0 O 0 x OO o O 0o~ ~ ~ 0 0 u)E 0000o E000, 00 000.0

. 0o*o o0o o o )* o 0 D C) 2 4 6 8 10 12 6 IaysolcnIss on October 2, 2021 by guest. Protected Days of illness ,1 2 4 6 8 10 12 14 16 18 FIG. 1. Incidence and duration of main . Height of curves in top part is determined by the number of patients with listed symptom on a given day. For SGOT, WBC and platelet counts, the figure indicates how many patients had reached maximal or minimal levels on the stated day. (Courtesy ofthe Editor, Deutsche medizinische Wochenschrift.) with a Landry-type of paralysis with albumino- from the nose, gingiva and gastro-intestinal tract, cellular dissociation in the cerebrospinal fluid and haematuria. The women had genital bleeding. (Guillain-Barre syndrome). One patient became At the sites of injections and needle punctures severe psychotic several weeks after the acute illness. bleeding occurred. About half of the patients exhibited marked The pancreas was affected in several patients as haemorrhagic diathesis with spontaneous bleeding shown by the increased amylase values. Postgrad Med J: first published as 10.1136/pgmj.49.574.542 on 1 August 1973. Downloaded from 544 G. A. Martini

Heodoche immunoblasts and so-called pyronino- Molaise plasma cells, Pyrex ia phil blast cells, up to 15 % of the total count. Bone Exonthem Vomiting marrow puncture showed an elevated number of Diarrhoea Drowsiness immature megakariocytes. All patients developed Enonthem Conjuctivitis severe thrombocytopenia with sometimes less than ECG changes Dry mouth 10,000/mm3. At the same time the thrombin time was LymphOdenopothy Hoemorrhogic diathesis prolonged, indicating consumptive . Scrotol or lobal0 erythema CNS involvement In none of ten patients in whom the prothrombin Bronchitis Paroesthesia time, partial thromboplastin time and fibrinogen Herpes Ulcers on the side of the tongue were measured did the alterations and plasma Orchi tis Pericorditis factors explain the severe haemorrhagic Pleurisy diathesis. 5 10 15 20 23 The extreme increase of serum transaminases and No of patients the severe FIG. 2. Incidence of symptoms and signs. (Courtesy of other liver enzymes reflected hepato- the Editor, Deutsche medizinische Wochenschrift.) cellular damage. In four of the five patients who died the transaminases increased up to 3000-6000 U/1. The relation between SGOT and SGPT was 7: 1. Nearly all patients had signs of severe hepato- The maximum increase was between the 7th and cellular damage with an extreme increase of the 8th days, with a second peak around the 35th day transaminase levels. Neither jaundice nor true in three patients. The bilirubin was only slightly hepatic failure developed. In the electrocardiogram increased in some patients with anuria. The creatinin alterations compatible with diffuse myocarditis and and urea were elevated in those patients who died disturbances of cardiac rhythm were seen. In many with renal failure. The total serum decreased patients cardiac failure developed. Nearly all of markedly in several patients. the patients who died had severe kidney involvement The other complications included broncho-

with acute renal failure. Those who survived had pneumonia (five cases), leg oedema (five cases),by copyright. longer periods of polyuria. The haemopoetic system (three cases), post-infectious myelitis (one was severely damaged in nearly all patients as could case), and (one case). be recognized by marked leukopenia and severe thrombocytopenia. Pathology Course of the disease In nearly all organs areas of focal without The illness lasted 15-20 days. In some cases much inflammatory reaction were seen. They were there was a relapse. Five patients showed a further particularly obvious in the liver, in the lymphatic increase of serum transaminase at this time system, in the spleen, in the testicles and ovaries, with an increased temperature. The convalescent and in the pancreas. In addition the lymphatic period was very drawn out. There were disturbances tissue showed plasmacellular, monocytoidal trans-http://pmj.bmj.com/ ofthe autonomic nervous system with exhaustion and formation. Together with the areas of necrosis so- increased perspiration. Some of the patients had a called basophilic bodies were noticed near the necrotic considerable loss of hair and complained of tender- cells or as inclusion bodies in parenchymal cells. ness of the liver and alcohol intolerance. Unilateral Those patients who died showed glial nodule en- testicular atrophy was observed in five patients. cephalitis in all areas of the brain and serious Some had reduced libido and potency and oligo- parenchymal damage of the kidneys with definite

spermia; the ketosteroid levels were normal. Three signs of tubular insufficiency and haemorrhagic on October 2, 2021 by guest. Protected women were delivered of four healthy babies with diathesis in all organs. no signs of disease. findings Diagnosis The erythrocyte sedimentation rate rarely exceeded Laboratory methods included the direct isolation the upper normal range. The haematologic changes of the agent in the blood, organ tissues, throat apart from leukopenia and thrombocytopenia were washings, urine and semen (Fig. 3). Virus antigen characterised by a shift to in the granulo- was made visible by means of immuno-fluorescence. cytes with up to 40% stab cells, promyelo-, meta- Direct electron microscopic demonstration of the myelo- and myelocytes. This shift to the left was virus was possible after centrifugation of serum on to accompanied by the appearance of so-called de- carrier films. generative granulocytes and Pelger-like cells. There The morphology of the Marburg virus is most was a marked increase of atypical lymphocytes, unusual. It differs in size and shape from most known Postgrad Med J: first published as 10.1136/pgmj.49.574.542 on 1 August 1973. Downloaded from Marburg virus disease 545

* a a Marburg * * * * *E 0 -lNo 0 * o

Frankfurt a * * 0 0 Belgrade * O 1______l1 ll l1 1 111 ll ll 1 11ll11 ll lll 8 10 12 14 16 18 2022 2426 28 30 3 5 7 9 11 3 5 7 9 11 Aug 1967 Sept 1967 Oct 1967 Nov 1967

* Group from monkey blood or organs. O Group 2 Infection from monkey kidney cell cultures.

O Group 3 Infection from patients.

o Group 4 Infection from virus carrier FIG. 3. Onset of Marburg virus disease in thirty-one patients. (Courtesy of Professor Siegert, Marburg, and Springer Verlag, .)

viruses. The mean length is about 665 nm. It shares Exposure in the household and family surroundings certain similarities with other viruses (plant viruses, remained without consequences. In one woman a Rabies, Egtred virus of rainbow trout). venereal way of transmission was the most probable, A complement fixing test using a cell since her husband was found to excrete the Marburg by copyright. culture antigen from infected Vero carrier cells is virus in his semen. highly specific. The simultaneous outbreak of the disease in Mar- burg, Frankfurt and Belgrade was traced to common Epidemiology imported monkeys of the species Cercopithecus There were four groups of infection (Fig. 4). The aethiops from Uganda. These monkeys were flown first and largest group consisted of persons who had because of the Near East crisis, to Germany and direct contact with blood and organs of monkeys Yugoslavia via London, where they were kept at the imported from Uganda. The second group consisted airport together with other animals. Seroepidemio- of laboratory workers who had contact with simian logic studies using a complement-fixing antibody organs or material. The third group con- test seemed to suggest a high percentage of positive tracted the infection from other patients' blood. reactions in monkeys from Uganda and from other http://pmj.bmj.com/ areas. These results could not be confirmed by other authors using a more specific method. The reservoir IHR + + and method of distribution of the Marburg virus are + still U unknown. Intrathoracic multiplication of the + + + Blood virus was possible in Aedes aegypti. ES + FR HO ++

KL +++

Treatment on October 2, 2021 by guest. Protected HI 0 0 Urine was H + The symptomatic. were HI + used prophylactically against secondary bacterial HO 0 + + Uie . Acute renal failure was treated according 0 to standard rules including peritoneal dialysis. Low KO 0 sodium human albumin was infused in patients with MA+0 + uoStood hypoproteinaemia, and and fluid supple- mented. The most difficult problem was the treat- HA ++ cases Liver biopsy ment of the haemorrhagic diathesis. Fresh blood 2 3 4 5 6 7 8 9 1011 121314151617 thrombocyte concentrates, fibrinogen, e-amino- Days of disease caproic acid, vitamin K and the French preparation FIG. 4. Isolation of the virus from blood, urine, throat PPSB (Prothrombin, Proconvertin, Stuart-factor washing and liver biopsy material. (Courtesy ofProfessor and antihaemophilicglobin B) were given. The Siegert, Marburg.) latter proved to be the most efficient. Postgrad Med J: first published as 10.1136/pgmj.49.574.542 on 1 August 1973. Downloaded from 546 G. A. Martini Course and prognosis MARTINI, G.A., KNAUFF, H., SCHMIDT, H., MAYER, G. & BALTZER, G. (1968) A hitherto unknown infectious disease The disease varied greatly in severity. There were contracted from monkeys. German Medical Monthly, 13, some mild cases but most of the patients were 457. Deutsche medizinische Wochinschrift, 93, 559. critically ill. The fatality rate was 22%. Complete recovery was the rule, but most patients even now MARTINI, G.A. & SCHMIDT, H.A. (1968) Spermatogene after 5 years complain about easy fatiguability, (Ybertragung des Marburg Virus. Klinische Wochenschrift, inability to concentrate, loss of libido, etc. It is 46, 391. very difficult to decide what complaints have a real background or which symptoms are due to the MARTINI, G.A. & SIEGERT, R. (Eds.) (1972) Marburg Virus unique situation, as all infections were acknowledged Disease. Springer Verlag, , Heidelberg, New York. as occupational hazards and the pension scheme makes it necessary that follow-up studies are SIEGERT, R. (1972) Marburg Virus. Virology Monographs, required every year. So a kind of post-Marburg vol. I1, pp. 97-154. Springer Verlag, Berlin. virus disease neurosis might play a role. STILLE, W., BOHLE, E., HELM, E., VAN REY, W. & SIEDE, W. References (1968) An infectious disease transmitted by Cercopithecus GORDON-SMITH, C.E. (1971) Lessons from Marburg disease. aethiops (Green Monkey disease). German Medical In: The Scientific Basis of Medicine. Annual Review (Ed. Monthly, 13, 470. Deutsche medizinische Wochenschrift, by Ian Gilliland and J. Francis). Athlone Press, London. 93, 572. by copyright. http://pmj.bmj.com/ on October 2, 2021 by guest. Protected