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Marburg agent disease: In man
295
(The previous number of these Transactions, Vol. 63, No. 2, was published on 11 April, 1969). ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, ORDINARY MEETING Manson House, Thursday, 20 February, 1969. SIR JOHN BOYD, O.B.E., M.D., F,R.C.P., F.~.S., in the Chair.
MARBURG AGENT DISEASE: IN MAN G. A. M A R T I N I Medizinische Universit~itsklinik, 3.55 Marburg/Lahn, Germany During recent years monkeys from tropical countries, especially green monkeys and macacques (Cereopithecus and Macaca), have been imported in large numbers into Europe. Until now only single cases of diseases transmitted by monkeys have been known, e.g. herpes simiae and rabies. The new disease observed in Marburg, Frankfurt and Belgrade was the first to occur as an epidemic.
The disease in man In August 1967, 3 patients with symptoms of an infectious disease were admitted to the medical department of the university of Marburg within 3 days. They had been working in a Marburg factory where vaccines and sera are produced. The three patients had had direct contact with the green monkeys or their organs. We soon became aware of 3 other patients in Frankfurt who apparently got the disease at the same time and who also had been handling material from the same group of monkeys from Uganda. Within a few days it became obvious that this disease, which was transmitted by monkeys, was absolutely new to us, and it was necessary to organize emergency public health measures to avoid any spread. This was very difficult because nothing was known of the infectious agent or its spread. In the course of the following 3 weeks 17 more patients were admitted to our hospital. 2 others, a doctor and a nurse, became infected in the hospital. Much later, on 13 November, another patient was admitted who had been infected by her husband. Thus we had 23 patients, and our survey of the clinical aspects, its different courses and the complications, is based on observations made on them. In all patients from the Marburg factory a direct contact with blood, parts of the organs or cell cultures could be proved. 10 patients had assisted in the killing or postmortem dissecting of the monkeys; 3 others had trephined their skulls. Another patient had to prepare the cell cultures of the kidneys. 5 patients had cleaned the receptacles which had contained the cukures. The doctor had hurt herself through the rubber glove with a hypodermic needle, with which she had taken blood from a patient. The nurse had been infected by exposure to the patients. One patient apparently iiffected his wife by sexual intercourse. It was proved by the antibody fluorescence method that his sperm contained the infectious material.
Incubation p e r i o d The incubation period can be determined in some patients who have only once been exposed to the infectious material (Fig. 1).
296
M A R B U R G A G E N T DISEASE: I N M A N 26 July "~1
F., Klaus
tT Aue. e
1;t
16
20
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29 yrs . . . .
K., Hch.
30 yrs.
H., Michael
40 yrs.
D.. Wol'fg.
20 yrs.
M., Peter
63 yrs.
A
H,, Josef
5~ yrs.
-
U./Ewald
39 yrs.
R., Joach.
39 yrs.
K.. Marga
19 yrs.
0., Bernh.
51 yrs.
P., Hch.
39 yrs.
C,, Peter
A A
~
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56 yrs.
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21
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t7
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A
~ A .
L. Renate
13
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39 yrs.
F,, Christa
9
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9.
13.
17.
21.
25.
39 yrs.
iz
iB. Nov.1967
Time of e x p o s u r e and d u r a t i o n of illness in 23 patients. 'Time of e x p o s u r e is t a k e n as the p e r i o d d u r i n g w h i d l FIe.1. with infectious material was possible.
The monkey-keeper Heinrich P. came back from his holiday on 13 August and did his job of killing monkeys from 14 to 23 August. The first symptoms appeared on 21 August. On 28 August the laboratory assistant Renate L. broke a test-tube which had conmined infected material; he fellJU on 4 September. The only contact of the laboratory assistant Maria K. with infected material took place on August 18 and 21. She fell ill on 26 August. The nurse'Anneliese K. began to work in the ward on 23 August and became ill on 30 August. Dr. Inga H. was infected by the prick of a needle on 22 August and showed the first symptoms 5 days later, on 27 August. Thus it can be accepted that the incubation period lasted from 5 to 7 days. Symptomatology The symptoms and signs were very similar in spke of the various degrees of the illness. After having seen the first patients we were able to make the clinical diagnosis; symptoms and signs were so characteristic that only one misdiagnosis, in many suspected cases, was made. As an example I give the history of a case which we think to be typical. Case history The laboratory assistant Marga K. had worked in the Marburg serum factory since March 1967. Her job was to fetch newly removed kidneys from the post-mortem room, to clean them, and to prepare them for further processing. The rule was that she had to wear gloves and mouth cover in order to avoid contamination of the cultures. Occasionally she helped with the fixation of the killed animals on the necropsy table.
G. A. MARTINI
297
On 18 August 1967 she had malaise and myalgia. On the following day she developed fever up to 30°C. On 20 August, the third day, for the first time, she vomited, one day later there was burning and reddening of the conjunctiva; the temperature now rose to 40°C. On the fifth day she was admitted to our infectious diseases ward. At this time a maculo-papular rash appeared on the face, the trunk and the proximal parts Headache n = 23 Drowsiness n 18 My~lgia n = 10 Vomiting n ~- 21 Diarrhoea n=lg
¢
Lymphadenopathy n=10
Enanthem n~17 Raah n =. 23
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of the limbs, with a red enanthema of the soft palate that reached to the hard palate, and a non-itching erythema of the labia majora. There were enlarged lymph nodes in the
298
MARBURG AGENT 'DISEASE: IN MAN
the neck, along the line of the sterno-mastoid, and in the axillae. The liver was not enlarged, the spleen not palpable. There was leucopenia with a shift to the left of the granu!ocytes, and thrombocytopenia. Transaminase was only slightly elevated. Fig. 2 gives a summary of the most important findings. On the 6th day the conjunctivitis decreased. On the face, trunk and extremities a maculo-papular rash developed. Vomiting continued and she had a watery, not mucous or bloody, diarrhoea, which made an intravenous infusion of fluid and electrolytes necessary. On the 8th day a diffuse cutaneous erythema developed over the whole body. Diarrhoea continued, but vomiting stopped. On the 9th day there was a significant improvement; diarrhoea decreased. On the 27th day the skin began to peel, especially on the face, palms and lower legs. On the 36th day the patient left hospital. She did not show any further clinical signs, but convalescence was delayed and she remained debilitated for several weeks.
Summary of the clinical features In the beginning there was an abrupt feeling of prostration by which the first day of the illness was clearly to be fixed. At the same time there was severe headache, mainly in the frontal and temporal area (Fig. 3). Some patients also remarked that their Headache Malaise PyrexJa Exanthem Vomiting Diarrhoea Drowsiness Enal,them Conjuctivitis ECG dhanges Dry mouth Lymphadenopathy Haemorrhagic diathests Scrotat or labial erythema CNS involvement Bronchitis Paraesthesia Herpes Ulckrs on the side oF the tongue Orchitis Pericarditis Pleurisy
D
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of patients 20 2'3
No.
ib
FIG. :3. Incidence of s u b j e c t i v e symptoms and 0 b j e c t i v e signs of tile disease in 23 patients. eyes were sensitive to pressure. Most had pain and feeling of tenseness in the muscles of the trunk, especially in the lumbar region. These muscle aches were difficult to distinguish from true meningism, which was seen in two cases only. On lumbar puncture in both patients the cell count was normal. In one the l~rotein content was normal whereas in the other it was slightly increased (68 mg.% ). In the early days the rise in temperature was accompanied by frequent severe nausea and vomiting, especially after food, but also independent of'it. One or two days later watery diarrhoea occurred with blood or mucus, up to 10 evacuations a day, but whereas vomiting stopped in most
G. A. MARTINI
299
cases when the temperature became normal, diarrhoea continued for several days. The more severe the aspect of the disease, the greater the tendency to diarrhoea. In some patients vomiting and diarrhoea followed a period of constipation; 2 patients, however, had chronic constipation the whole time. Many patients complained of a dry mouth which sometimes occurred even before the beginning of vomiting and diarrhoea. The most reliable diagnostic sign was a characteristic rash. It began on days 5-7 on the buttocks, trunk and the outer sides of both upper arms, as distinctly marked, pinhead dark red papules around the hair follicles. This stage lasted up to 24 hours and developed into a maculo-papular, sharply delineated lesion which later coalesced into a more diffuse rash. Especially in the severe cases a diffuse dark livid erythema developed on the face, the trunk and the limbs, which disappeared within several days. During the erythema period some patients had marked cyanosis. One patient had herpes labialis before the appearance of the erythema, another had several watery herpes-like lesions on the abdomen and the big toe, when the rash was disappearing. After the 16th day all patients peeled, especially on the palms, soles of the feet and the extremities. This lasted from a few days to 2 weeks. The rash was often accompanied by scrotal dermatitis or erythema of the labia majora. About half the patients had conjunctivitis at the beginning or later, but the fundus did not show any pathological changes, especially no haemorrhage. Nearly all patients who were in the hospital during the decisive period showed a deep dark red colouring of the soft palate, which also spread to the hard palate. This enanthema was much more intense than the non-specific reddening of the throat often found in febrile infectious diseases. In some patients it was already visible one day before the rash developed and disappeared at the same time as the skin changes. Besides the enanthema there were often fine tapioca-like transparent lesions. In 4 patients a swelling and reddening of the tonsils with pinhead, yellowish, non-confluent membranes was seen. In some there were glandular swellings already before the rash. In 4 of the fatal cases the patients were very restless, becoming confused and comatose at the end. Many patients did not remember the most severe period of their illness; in one the phase of confusion and impairment of consciousness lasted for 10 days and was followed by a mood of anxiety or depression. These mental disturbances disappeared later. Most patients showed a sullen, slightly aggressive or negativistic behaviour. 2 had paraesthesia with a feeling as i f they were lying on crumbs. Others had acroparaesthesia, especially tingling in the big toe. 2 patients had restless legs for several days. During the crisis many suffered from hyperaesthesia. One patient developed myelitis after the acute phase of the disease was over. Initially there was a rise in temperature to over 39°C. During the first 6 days the temperature rose to 40°C., and then fell gradually, with a second peak between the 12th and 14th days (Fig. 2). Relative bradycardia occurred especially in the early days. Tachycardia corresponding to the height of temperature was only found in the fatal cases.
Laboratory findings Leucopenia, already obvious on the first day, was characteristic. On days 4-5 in some cases the leucocyte count was as low as,lO00 per c.mm., in all cases with a shift to the left in the differential count from the beginning. In some patients we could also see single myelocytes and promyelocytes. In many cases the granulocytes were changed in a characteristic way, sometimes like pseudo-Pelgar cells or degenerated
300
MARBURG AGENT DISEASE: I N M A N
cells Between the 4th and 19th days peculiar forms of lymphocytes were found in all patients, which are not seen in the normal peripheral blood. These were plasmacellular and monocytoid lymphocytes plasma cells plasmoblasts, pyroninophil blast cells or immuniblasts. These plasma cells and similar forms were the most characteristic morphological finding in the peripheral blood; their total numbers never exceeded 15%. A sternal puncture was performed in 3 patients between the 15th and 17th days; there was normal erythropoiesis and many younger forms of granulocytes. In two patients there was an increase of the plasma ceils up to 30~/o and significant increase of immature megakaryocytes. All patients developed severe thrombocytopenia; the lowest counts being found between the 6th and 12th days. Single observations show that the decrease of the thrombocytes began at the onset of the disease. In 2 patients who died the thrombocytes decreased to less than 10,000 per c.mm. In several patients we saw remarkable sludging of the thrombocytes. During the thrombocytopenia phase, 7 patients had a severe haemorrhagic diathesis, leading to haemorrhage from the gums and nose and from puncture lesions, and into the gastro-intestinal tract with haematemesis and melaena. It was remarkable that the rash never became hemorrhagic; only 2 patients had purpura. At different times in 10 patients the prothrombin time (Quick), partial thromboplastin time, plasma thrombin time and fibrinogen were measured. In none of the patients were the plasma coagulation factors altered enough to explain the severe haemorrhagic diathesis; 6 of 13 fibrinogen examinations even showed slightly increased levels. Total plasma protein decreased significantly in all patients during the illness, in an extreme cases to 4.3%. There was no considerable proteinuria. Hypoproteinaemia was also found in patients who had no diarrhoea. All plasma fractions were changed nearly to the same extent, and electrophoresis therefore showed no characteristic changes. In all patients there was an increase Of S G O T and SGPT, and glutamated dehydrase, sorbitol dehydrogenase and glutamyl transpeptidase were increased in all cases where these enzymes were examined. The maximum increase of the hepato-specific enzymes was between the 7th and 8th days. In 4 of the 5 patients who died, S G O T increased to 2500 E/1. and even up to 5900 E/1. As a rule the increase of S G P T was lower than that of SGOT. The relation between S G O T and S G P T was 7 : 1 in the extreme case. In some patients a second increase of transaminases was seen. This second peak was around the 35th day in 3 patients. It was interesting that in the final phase only in one case were the increased transaminases accompanied by an increase of serum bilirubin. Serum alkaline phosphatase was always normal. Creatinine phosphokinase was examined only in some severe cases; it was always normal. In some cases the amylase was significantly increased. Regular tests could not be performed because of the danger to the laboratory workers, and the beginning and duration of the amylase increase could therefore not be determined. One patient had an increase of amylase from the 6th to the 24th day with maximum levels up to 700 Somogyi units. In 50~/o we could prove a hypokalaemia with levels up to 2.3 mval/1. Hypokalaemia in most cases occurred at the same time as vomiting and diarrhoea. In 3 cases hypokalaemia could not be related to enteral loss of potassium.
Complications On the 12th day after the acute symptoms had disappeared one patient suddenly developed bronch6pneumonia with exudative pleuritis, with an increase of temperature,
G. A. MARTINI
301
chest pain, yellowish-bloody sputum, and extensive pleural effusion on the left side, From the sputum Staphylococcus aureus and Escherichia coli were grown. After intensive treatment with antibiotics and 2 pleural punctures with drainage of 800 ml. the patient recovered within 6 weeks. This patient and 2 others developed marked oedema of the lower parts of the legs between the 8th and 16th days after the total serum protein had decreased below 6 g.%. The oedema disappeared within a fortnight after administration of human albumin and digitalis. A 19-year-old patient, who was only slightly ill and had already left hospital, developed orchitis on the 36th day after the beginning of the disease; the temperature rose to 38°C., the general condition was nearly normal. Laboratory tests did not show any new changes. The orchitis disappeared 5 days later after treatment with prednisone. When the patient was examined 3 weeks later the left testis was significantly smaller than the right one. On the 31st day one patient showed a new increase of the transaminase up to 113 E/1. without any new complaints. A woman who had been dismissed already and stayed in a convalescent home, had again to be admitted to the hospital 73 days after the beginning of the illness because of a new increase of the SGOT up to 200 Eft. The SGPT was 175 E/1.; bromsulphthalein retention was 21% after 45 minutes; alkaline phosphatase was 25 E/1. The psychological behaviour of this patient had been very remarkable from the beginning; she now developed an acute psychosis and had to be transferred to a mental hospital. She later recovered completely. Treatment
In all patients antibiotic treatment was tried. Tetracycline, chloramphenicol, penicillin, cephalothin and streptomycin, singly or in combination, did not influence the course of the disease. In order to avoid secondary infection, the treatment was finally restricted to cephalothin, but temperatures did not fall, diarrhoea did not stop and the severe conditions did not improve. Symptoms were treated according to the usual rules. The greatest problem was the treatment of the haemorrhagic tendency, and as thrombocytes and plasma dotting factors decreased, a combined treatment was given, with transfusion of fresh blood, concentrations of thrombocytes, fibrinogen, epsilon-aminocaproic-acid and vitamin K. Of great value was the French preparation PPSB from the Centre National de Transfusion Sanguine, Paris, which contains a concentration of the dotting factors prothrombin, proconvertin, Stuart factor, and antihaemophil globulin B. The severe haemorrhagic tendency could be influenced at least for some hours. Another difficulty was the balancing of the fluid and electrolytes. In nearly all cases electrolytes had to be given, especially potassium, and because of the hypoproteinaemia some patients were given large amounts of human albumin, up to 30 g. daffy. But even then the plasma protein level could sometimes only be kept at 4 g.%. In most pauents urine was passed without any special measures; some were given mannitol (Osmofundin). In one anuric patient peritoneal dialysis was performed. Strophanthin and digitalis were given. Two patients were given high doses of prednisone in the terminal period, but without any effect. Of great value was the treatment with antipyretics, especially Novalgin (dipyrone); in most patients temperatures came down and general conditions improved. Further course
Of the 23 patients 5 (aged 19-39) died between the 8th and 16th days. Of the 18 surviving patients 2 were kept in hospital: one with a psychosis and another one with
302
MARBURG AGETN DISEASE: I N MAN
myelitis. All patients were regularly examined after they had left the hospital, and all Complained of increased exhaustion, sweats, and loss of hair. Some continued to lose weight in spite of good appetite and sufficient intake of calories. Most had tender livers, and in 12 liver biopsy was performed during the convalescent period, 4-31 days after the temperature had become normal. 2 patients at this time still had slightly increased transaminase levels; liver biopsy showed single cell necrosis, moderate fatty degeneration, slight mesenchymal reaction and focal increases of the Kupffer cells. Other patients showed no characteristic changes, or a normal morphological picture. In further examinations electrocardiogram, the X-ray picture of the thorax, total serum protein, electrophoresis, SGOT, SGPT, serum electrolytes, blood picture and thrombocytes were normal in nearly all patients. An older patient with evidence of right bundle branch block in the electrocardiogram developed oedema of the lower legs after having left the hospital and needed continuous treatment with digitoxin and frusemide (Lasix). Total protein and electrophoresis were normal.
(The previous number of these Transactions, Vol. 63, No. 2, was published on 11 April, 1969). ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, ORDINARY MEETING Manson House, Thursday, 20 February, 1969. SIR JOHN BOYD, O.B.E., M.D., F,R.C.P., F.~.S., in the Chair.
MARBURG AGENT DISEASE: IN MAN G. A. M A R T I N I Medizinische Universit~itsklinik, 3.55 Marburg/Lahn, Germany During recent years monkeys from tropical countries, especially green monkeys and macacques (Cereopithecus and Macaca), have been imported in large numbers into Europe. Until now only single cases of diseases transmitted by monkeys have been known, e.g. herpes simiae and rabies. The new disease observed in Marburg, Frankfurt and Belgrade was the first to occur as an epidemic.
The disease in man In August 1967, 3 patients with symptoms of an infectious disease were admitted to the medical department of the university of Marburg within 3 days. They had been working in a Marburg factory where vaccines and sera are produced. The three patients had had direct contact with the green monkeys or their organs. We soon became aware of 3 other patients in Frankfurt who apparently got the disease at the same time and who also had been handling material from the same group of monkeys from Uganda. Within a few days it became obvious that this disease, which was transmitted by monkeys, was absolutely new to us, and it was necessary to organize emergency public health measures to avoid any spread. This was very difficult because nothing was known of the infectious agent or its spread. In the course of the following 3 weeks 17 more patients were admitted to our hospital. 2 others, a doctor and a nurse, became infected in the hospital. Much later, on 13 November, another patient was admitted who had been infected by her husband. Thus we had 23 patients, and our survey of the clinical aspects, its different courses and the complications, is based on observations made on them. In all patients from the Marburg factory a direct contact with blood, parts of the organs or cell cultures could be proved. 10 patients had assisted in the killing or postmortem dissecting of the monkeys; 3 others had trephined their skulls. Another patient had to prepare the cell cultures of the kidneys. 5 patients had cleaned the receptacles which had contained the cukures. The doctor had hurt herself through the rubber glove with a hypodermic needle, with which she had taken blood from a patient. The nurse had been infected by exposure to the patients. One patient apparently iiffected his wife by sexual intercourse. It was proved by the antibody fluorescence method that his sperm contained the infectious material.
Incubation p e r i o d The incubation period can be determined in some patients who have only once been exposed to the infectious material (Fig. 1).
296
M A R B U R G A G E N T DISEASE: I N M A N 26 July "~1
F., Klaus
tT Aue. e
1;t
16
20
2~
A
K . Adolf
29 yrs . . . .
K., Hch.
30 yrs.
H., Michael
40 yrs.
D.. Wol'fg.
20 yrs.
M., Peter
63 yrs.
A
H,, Josef
5~ yrs.
-
U./Ewald
39 yrs.
R., Joach.
39 yrs.
K.. Marga
19 yrs.
0., Bernh.
51 yrs.
P., Hch.
39 yrs.
C,, Peter
A A
~
~]~
r=~-__ A~ ~A
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56 yrs.
-
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t7
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A
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__
39 yrs.
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9
A
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tsept 5
A
29 yrs. =
R., Marga
2e
+
27 yrs.
28.
1. 5. SEPT.
9.
13.
17.
21.
25.
39 yrs.
iz
iB. Nov.1967
Time of e x p o s u r e and d u r a t i o n of illness in 23 patients. 'Time of e x p o s u r e is t a k e n as the p e r i o d d u r i n g w h i d l FIe.1. with infectious material was possible.
The monkey-keeper Heinrich P. came back from his holiday on 13 August and did his job of killing monkeys from 14 to 23 August. The first symptoms appeared on 21 August. On 28 August the laboratory assistant Renate L. broke a test-tube which had conmined infected material; he fellJU on 4 September. The only contact of the laboratory assistant Maria K. with infected material took place on August 18 and 21. She fell ill on 26 August. The nurse'Anneliese K. began to work in the ward on 23 August and became ill on 30 August. Dr. Inga H. was infected by the prick of a needle on 22 August and showed the first symptoms 5 days later, on 27 August. Thus it can be accepted that the incubation period lasted from 5 to 7 days. Symptomatology The symptoms and signs were very similar in spke of the various degrees of the illness. After having seen the first patients we were able to make the clinical diagnosis; symptoms and signs were so characteristic that only one misdiagnosis, in many suspected cases, was made. As an example I give the history of a case which we think to be typical. Case history The laboratory assistant Marga K. had worked in the Marburg serum factory since March 1967. Her job was to fetch newly removed kidneys from the post-mortem room, to clean them, and to prepare them for further processing. The rule was that she had to wear gloves and mouth cover in order to avoid contamination of the cultures. Occasionally she helped with the fixation of the killed animals on the necropsy table.
G. A. MARTINI
297
On 18 August 1967 she had malaise and myalgia. On the following day she developed fever up to 30°C. On 20 August, the third day, for the first time, she vomited, one day later there was burning and reddening of the conjunctiva; the temperature now rose to 40°C. On the fifth day she was admitted to our infectious diseases ward. At this time a maculo-papular rash appeared on the face, the trunk and the proximal parts Headache n = 23 Drowsiness n 18 My~lgia n = 10 Vomiting n ~- 21 Diarrhoea n=lg
¢
Lymphadenopathy n=10
Enanthem n~17 Raah n =. 23
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120-
37-
100•
,
ESR mm O
SGOT
•
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•
6/16
8/18
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16.
lb.
FIG. 2. Incidence and duration of main signs and symptoms: H e i ght of c u r v e s iu top p;~rt is d e t e r m i n e d b y t h e number of patients with t h e l i s t e d symptom on a g iven day. For SGOT, WBC and platelet counts, t h e f i g u r e i n d i c a t e s how m a n y patient.,; h a d r e a c h e d maximal or minimal levels on t h e s t a t e d da'i.
of the limbs, with a red enanthema of the soft palate that reached to the hard palate, and a non-itching erythema of the labia majora. There were enlarged lymph nodes in the
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MARBURG AGENT 'DISEASE: IN MAN
the neck, along the line of the sterno-mastoid, and in the axillae. The liver was not enlarged, the spleen not palpable. There was leucopenia with a shift to the left of the granu!ocytes, and thrombocytopenia. Transaminase was only slightly elevated. Fig. 2 gives a summary of the most important findings. On the 6th day the conjunctivitis decreased. On the face, trunk and extremities a maculo-papular rash developed. Vomiting continued and she had a watery, not mucous or bloody, diarrhoea, which made an intravenous infusion of fluid and electrolytes necessary. On the 8th day a diffuse cutaneous erythema developed over the whole body. Diarrhoea continued, but vomiting stopped. On the 9th day there was a significant improvement; diarrhoea decreased. On the 27th day the skin began to peel, especially on the face, palms and lower legs. On the 36th day the patient left hospital. She did not show any further clinical signs, but convalescence was delayed and she remained debilitated for several weeks.
Summary of the clinical features In the beginning there was an abrupt feeling of prostration by which the first day of the illness was clearly to be fixed. At the same time there was severe headache, mainly in the frontal and temporal area (Fig. 3). Some patients also remarked that their Headache Malaise PyrexJa Exanthem Vomiting Diarrhoea Drowsiness Enal,them Conjuctivitis ECG dhanges Dry mouth Lymphadenopathy Haemorrhagic diathests Scrotat or labial erythema CNS involvement Bronchitis Paraesthesia Herpes Ulckrs on the side oF the tongue Orchitis Pericarditis Pleurisy
D
m
of patients 20 2'3
No.
ib
FIG. :3. Incidence of s u b j e c t i v e symptoms and 0 b j e c t i v e signs of tile disease in 23 patients. eyes were sensitive to pressure. Most had pain and feeling of tenseness in the muscles of the trunk, especially in the lumbar region. These muscle aches were difficult to distinguish from true meningism, which was seen in two cases only. On lumbar puncture in both patients the cell count was normal. In one the l~rotein content was normal whereas in the other it was slightly increased (68 mg.% ). In the early days the rise in temperature was accompanied by frequent severe nausea and vomiting, especially after food, but also independent of'it. One or two days later watery diarrhoea occurred with blood or mucus, up to 10 evacuations a day, but whereas vomiting stopped in most
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cases when the temperature became normal, diarrhoea continued for several days. The more severe the aspect of the disease, the greater the tendency to diarrhoea. In some patients vomiting and diarrhoea followed a period of constipation; 2 patients, however, had chronic constipation the whole time. Many patients complained of a dry mouth which sometimes occurred even before the beginning of vomiting and diarrhoea. The most reliable diagnostic sign was a characteristic rash. It began on days 5-7 on the buttocks, trunk and the outer sides of both upper arms, as distinctly marked, pinhead dark red papules around the hair follicles. This stage lasted up to 24 hours and developed into a maculo-papular, sharply delineated lesion which later coalesced into a more diffuse rash. Especially in the severe cases a diffuse dark livid erythema developed on the face, the trunk and the limbs, which disappeared within several days. During the erythema period some patients had marked cyanosis. One patient had herpes labialis before the appearance of the erythema, another had several watery herpes-like lesions on the abdomen and the big toe, when the rash was disappearing. After the 16th day all patients peeled, especially on the palms, soles of the feet and the extremities. This lasted from a few days to 2 weeks. The rash was often accompanied by scrotal dermatitis or erythema of the labia majora. About half the patients had conjunctivitis at the beginning or later, but the fundus did not show any pathological changes, especially no haemorrhage. Nearly all patients who were in the hospital during the decisive period showed a deep dark red colouring of the soft palate, which also spread to the hard palate. This enanthema was much more intense than the non-specific reddening of the throat often found in febrile infectious diseases. In some patients it was already visible one day before the rash developed and disappeared at the same time as the skin changes. Besides the enanthema there were often fine tapioca-like transparent lesions. In 4 patients a swelling and reddening of the tonsils with pinhead, yellowish, non-confluent membranes was seen. In some there were glandular swellings already before the rash. In 4 of the fatal cases the patients were very restless, becoming confused and comatose at the end. Many patients did not remember the most severe period of their illness; in one the phase of confusion and impairment of consciousness lasted for 10 days and was followed by a mood of anxiety or depression. These mental disturbances disappeared later. Most patients showed a sullen, slightly aggressive or negativistic behaviour. 2 had paraesthesia with a feeling as i f they were lying on crumbs. Others had acroparaesthesia, especially tingling in the big toe. 2 patients had restless legs for several days. During the crisis many suffered from hyperaesthesia. One patient developed myelitis after the acute phase of the disease was over. Initially there was a rise in temperature to over 39°C. During the first 6 days the temperature rose to 40°C., and then fell gradually, with a second peak between the 12th and 14th days (Fig. 2). Relative bradycardia occurred especially in the early days. Tachycardia corresponding to the height of temperature was only found in the fatal cases.
Laboratory findings Leucopenia, already obvious on the first day, was characteristic. On days 4-5 in some cases the leucocyte count was as low as,lO00 per c.mm., in all cases with a shift to the left in the differential count from the beginning. In some patients we could also see single myelocytes and promyelocytes. In many cases the granulocytes were changed in a characteristic way, sometimes like pseudo-Pelgar cells or degenerated
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MARBURG AGENT DISEASE: I N M A N
cells Between the 4th and 19th days peculiar forms of lymphocytes were found in all patients, which are not seen in the normal peripheral blood. These were plasmacellular and monocytoid lymphocytes plasma cells plasmoblasts, pyroninophil blast cells or immuniblasts. These plasma cells and similar forms were the most characteristic morphological finding in the peripheral blood; their total numbers never exceeded 15%. A sternal puncture was performed in 3 patients between the 15th and 17th days; there was normal erythropoiesis and many younger forms of granulocytes. In two patients there was an increase of the plasma ceils up to 30~/o and significant increase of immature megakaryocytes. All patients developed severe thrombocytopenia; the lowest counts being found between the 6th and 12th days. Single observations show that the decrease of the thrombocytes began at the onset of the disease. In 2 patients who died the thrombocytes decreased to less than 10,000 per c.mm. In several patients we saw remarkable sludging of the thrombocytes. During the thrombocytopenia phase, 7 patients had a severe haemorrhagic diathesis, leading to haemorrhage from the gums and nose and from puncture lesions, and into the gastro-intestinal tract with haematemesis and melaena. It was remarkable that the rash never became hemorrhagic; only 2 patients had purpura. At different times in 10 patients the prothrombin time (Quick), partial thromboplastin time, plasma thrombin time and fibrinogen were measured. In none of the patients were the plasma coagulation factors altered enough to explain the severe haemorrhagic diathesis; 6 of 13 fibrinogen examinations even showed slightly increased levels. Total plasma protein decreased significantly in all patients during the illness, in an extreme cases to 4.3%. There was no considerable proteinuria. Hypoproteinaemia was also found in patients who had no diarrhoea. All plasma fractions were changed nearly to the same extent, and electrophoresis therefore showed no characteristic changes. In all patients there was an increase Of S G O T and SGPT, and glutamated dehydrase, sorbitol dehydrogenase and glutamyl transpeptidase were increased in all cases where these enzymes were examined. The maximum increase of the hepato-specific enzymes was between the 7th and 8th days. In 4 of the 5 patients who died, S G O T increased to 2500 E/1. and even up to 5900 E/1. As a rule the increase of S G P T was lower than that of SGOT. The relation between S G O T and S G P T was 7 : 1 in the extreme case. In some patients a second increase of transaminases was seen. This second peak was around the 35th day in 3 patients. It was interesting that in the final phase only in one case were the increased transaminases accompanied by an increase of serum bilirubin. Serum alkaline phosphatase was always normal. Creatinine phosphokinase was examined only in some severe cases; it was always normal. In some cases the amylase was significantly increased. Regular tests could not be performed because of the danger to the laboratory workers, and the beginning and duration of the amylase increase could therefore not be determined. One patient had an increase of amylase from the 6th to the 24th day with maximum levels up to 700 Somogyi units. In 50~/o we could prove a hypokalaemia with levels up to 2.3 mval/1. Hypokalaemia in most cases occurred at the same time as vomiting and diarrhoea. In 3 cases hypokalaemia could not be related to enteral loss of potassium.
Complications On the 12th day after the acute symptoms had disappeared one patient suddenly developed bronch6pneumonia with exudative pleuritis, with an increase of temperature,
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chest pain, yellowish-bloody sputum, and extensive pleural effusion on the left side, From the sputum Staphylococcus aureus and Escherichia coli were grown. After intensive treatment with antibiotics and 2 pleural punctures with drainage of 800 ml. the patient recovered within 6 weeks. This patient and 2 others developed marked oedema of the lower parts of the legs between the 8th and 16th days after the total serum protein had decreased below 6 g.%. The oedema disappeared within a fortnight after administration of human albumin and digitalis. A 19-year-old patient, who was only slightly ill and had already left hospital, developed orchitis on the 36th day after the beginning of the disease; the temperature rose to 38°C., the general condition was nearly normal. Laboratory tests did not show any new changes. The orchitis disappeared 5 days later after treatment with prednisone. When the patient was examined 3 weeks later the left testis was significantly smaller than the right one. On the 31st day one patient showed a new increase of the transaminase up to 113 E/1. without any new complaints. A woman who had been dismissed already and stayed in a convalescent home, had again to be admitted to the hospital 73 days after the beginning of the illness because of a new increase of the SGOT up to 200 Eft. The SGPT was 175 E/1.; bromsulphthalein retention was 21% after 45 minutes; alkaline phosphatase was 25 E/1. The psychological behaviour of this patient had been very remarkable from the beginning; she now developed an acute psychosis and had to be transferred to a mental hospital. She later recovered completely. Treatment
In all patients antibiotic treatment was tried. Tetracycline, chloramphenicol, penicillin, cephalothin and streptomycin, singly or in combination, did not influence the course of the disease. In order to avoid secondary infection, the treatment was finally restricted to cephalothin, but temperatures did not fall, diarrhoea did not stop and the severe conditions did not improve. Symptoms were treated according to the usual rules. The greatest problem was the treatment of the haemorrhagic tendency, and as thrombocytes and plasma dotting factors decreased, a combined treatment was given, with transfusion of fresh blood, concentrations of thrombocytes, fibrinogen, epsilon-aminocaproic-acid and vitamin K. Of great value was the French preparation PPSB from the Centre National de Transfusion Sanguine, Paris, which contains a concentration of the dotting factors prothrombin, proconvertin, Stuart factor, and antihaemophil globulin B. The severe haemorrhagic tendency could be influenced at least for some hours. Another difficulty was the balancing of the fluid and electrolytes. In nearly all cases electrolytes had to be given, especially potassium, and because of the hypoproteinaemia some patients were given large amounts of human albumin, up to 30 g. daffy. But even then the plasma protein level could sometimes only be kept at 4 g.%. In most pauents urine was passed without any special measures; some were given mannitol (Osmofundin). In one anuric patient peritoneal dialysis was performed. Strophanthin and digitalis were given. Two patients were given high doses of prednisone in the terminal period, but without any effect. Of great value was the treatment with antipyretics, especially Novalgin (dipyrone); in most patients temperatures came down and general conditions improved. Further course
Of the 23 patients 5 (aged 19-39) died between the 8th and 16th days. Of the 18 surviving patients 2 were kept in hospital: one with a psychosis and another one with
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myelitis. All patients were regularly examined after they had left the hospital, and all Complained of increased exhaustion, sweats, and loss of hair. Some continued to lose weight in spite of good appetite and sufficient intake of calories. Most had tender livers, and in 12 liver biopsy was performed during the convalescent period, 4-31 days after the temperature had become normal. 2 patients at this time still had slightly increased transaminase levels; liver biopsy showed single cell necrosis, moderate fatty degeneration, slight mesenchymal reaction and focal increases of the Kupffer cells. Other patients showed no characteristic changes, or a normal morphological picture. In further examinations electrocardiogram, the X-ray picture of the thorax, total serum protein, electrophoresis, SGOT, SGPT, serum electrolytes, blood picture and thrombocytes were normal in nearly all patients. An older patient with evidence of right bundle branch block in the electrocardiogram developed oedema of the lower legs after having left the hospital and needed continuous treatment with digitoxin and frusemide (Lasix). Total protein and electrophoresis were normal.