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Lassa Fever and Marburg Virus Disease· T

Lassa Fever and Marburg Virus Disease· T

WHO Chronicle, 1974, 28, 212-219

Lassa and disease· T. P. Monath

In the light of progress in , it comes as a surprise to discover a disease, an disease moreover, caused by a "new "virus. This has happened twice in recent years. The diseases, disease and , are caused by unrelated that are highly pathogenic for man and both have been responsible for illness and among scientists and medical personnel. Both diseases are in the continent of and are known or suspected to have natural transmission cycles in nonhuman vertebrate hosts. This article, by the Director of the WHO Regional Reference Centre for , briefly describes the historical background, the epidemiology, and the clinical manifestations of these diseases, which are of interest to WHO because of their appearance among health personnel and because they can be mistaken for fever.

In 1967 a total of 30 cases of virus disease, Of two people who became contaminated in the 7 of them fatal, were reported at Marburg and laboratory while working on material from these , Federal Republic of , and at cases, one died. A hitherto unknown virus was , among employees of research institutes isolated. A year later the same virus was found to be who had handled organs of monkeys imported responsible for an outbreak in with a mor­ from Mrica. Four secondary cases occurred in tality rate of 52% in hospitalized cases. A medical personnel who attended those patients and who performed autopsies contracted the disease one resulted from a household contact. The out­ and died. Outbreaks appeared in other countries in break was so unexpected that when it occurred in the following years. This disease is WHO was requested to dispatch pathological sam­ now called " Lassa fever ". ples to in the network of International WHO has shown great interest in these two and Regional Reference Centres for Virus Diseases, " new " diseases because of their manifestation as and several countries offered the assistance of their and the appearance of secondary cases, maximum security laboratories. A very dangerous mainly among health service personnel, and " new " virus, now known as Marburg virus, was because in Africa they could be mistaken for out­ found to be the agent responsible for these cases. breaks of owing to the similarity of Curiously enough, no other case has been reported certain symptoms. since 1967, although many monkeys are still imported from Africa and strict precautions are not always taken in handling them. • Based on unpublished WHO document VIR/73 .11 . A limited number In 1969 a missionary nurse died in Mrica of an of copies of this document are available to officially or professionally undiagnosed infectious disease. A colleague who interested persons on request to Virus Diseases, World Health Organiza­ had attended her also contracted the disease and tion, 1211 Geneva 27, Switzerland. 1 Director, WHO Regional Reference Centre for Arboviruses, Center died. A third nurse recovered after a severe illness. for Disease Control, Fort Collins, Colo., USA.

212 Lassa fever over a long period, with a peak incidence during the rainy months of 1972. Lassa fever was recognized for the first time in 1969. The four epidemics that occurred in widely Epidemiology separated foci in West Africa between 1969 and 1973 involved more than 100 cases. The public In the nosocomial outbreaks in Jos, Nigeria health importance of the disease in West Africa is (1970) and Zorzor, (1972), the virus was emphasized by the high case fatality ratio (36-67 %) introduced into the hospitals by African patients and the fact that transmission may occur from admitted with undiagnosed febrile illnesses. Secon­ person to person, especially in the hospital envi­ dary, occurred among hospital staff and ronment. Up to the present, 20 medical workers, patients. These epidemics were short-lived and few including a physician and 14 nurses and midwives, tertiary infections occurred. The reasons for the have acquired Lassa fever and 9 have died. interruption of the outbreaks after the generation of secondary cases are not clear but it appears that, The infectious agent although the primary index cases were highly infec­ tious, the secondary cases were not. Lassa virus contains ribonucleic acid (RNA). Epidemiological investigations revealed that very Under the , the viral particles mild or even subclinical infections were not un­ are seen to vary in size (70-150 mfL) and shape and common; the high case fatality rates reflect the have characteristic surface projections and internal severity of among the patients hospitalized electron-dense particles. The virus is related both with the disease. In addition, it appears that morphologically and serologically to lymphocytic intimate contact with an index case was associated choriomeningitis (LCM) virus and to viruses in with a high risk of infection. Relatives or medical the Tacaribe complex (including the causative attendants providing direct personal or agents of Argentinian and Bolivian haemorrhagic care (bathing, disposing of , feeding, changing ). A new taxonomic designation encom­ maternity pads and linens, etc.) were most likely passing all these agents has been proposed: the to contract the disease. However, cases also oc­ " ". curred among patients or hospital visitors who had Lassa virus has a cytopathogenic effect on Vero no direct contact with the index cases, as far as is cell cultures within 4-5 days of infection. When known. adult mice are inoculated intracerebrally with the The epidemic in Panguma-Tongo, , virus, some succumb. Newborn mice generally differed from the previous nosocomial outbreaks survive the infection but may continue to excrete in several important respects. Cases occurred over Lassa virus in the urine for long periods. a period of more than a year and, in most instances, the infection appeared to have originated outside Occurrence the hospital. The results of epidemiological and Lassa fever appears to be limited to West Africa. serological studies favour (but do not prove) the Epidemics have occurred in circumscribed localities hypothesis that the virus was spread within certain in Liberia, Nigeria, and Sierra Leone. Retrospective affected households by person-to-person trans­ serological surveys have indicated a wide distribu­ mission. Neither in this outbreak nor in previous tion of the virus in northern and central Nigeria. outbreaks could the source of infection for the The affected areas in Liberia and Sierra Leone are primary (index) cases responsible for introducing nearly contiguous, and a serological survey has Lassa virus into the affected household or hospital demonstrated Lassa in a number of be identified. However, the demonstration of localities in the eastern and southern provinces of antibodies among persons with no history of illness Sierra Leone. Serological evidence indicates that suggests that individuals with unrecognized or mild the virus was present in the Republic of as infections might act as " silent " sources of the long ago as 1952 and in eastern Senegal very virus. recently. It is likely that the virus is in fact widely Certain related arenaviruses have a natural cycle distributed in West Africa, but, even if this is not of transmission in cricetine . It has therefore so, the risk of the disease being spread or imported been postulated that Lassa fever is also a , from affected to unaffected areas is appreciable. but until recently no confirmatory data were Epidemics have affected both Guinean savanna available. Lassa virus has recently been repeatedly and rainforest zones. The hospital outbreaks in isolated from the tissues of rodents collected in Nigeria and Liberia occurred during the long dry Sierra Leone. All isolations have been from a single season. In Sierra Leone, however, cases appeared species, the multimammate Mastomys natal-

213 ensis,2 which is a common commensal in Tab~e 1.. Lassa fever: frequency of symptoms and physical findmgs m an outbreak at Jos, Nigeria West ~fric~. Rodents of other species commonly found m villages of the epidemic zone in Sierra Frequen- Frequen- Symptom Sign !-eone (Mus musculus and Rattus rattus) were not cy ( %)a cy ( %) a mfected. The relative importance of rodent-man virus transmission has not been established but 83 83 it is probably great and may explain both the cough 78 abdominal tender- appearance of sporadic cases and the epidemic ness 57 sore throat 70 coated tongue 39 spread of the disease in situations such as existed 65 cervicallymphaden- in Sierra Leone. opathy 39 The means by which the virus is spread from 44 30 person to person or rodent to man has not been diarrhoea 39 swollen neck or face 30 39 muscle tenderness 26 elucidated. Parenteral of the virus 22 rales 17 through breaks in the skin caused by accidental chest pain 22 petechiae 9 injuries with needles and sharp instruments, etc. deafness 17 leucopenia 3 has accounted for a few infections. Since the (< 4000 mm ) 26 virus has been repeatedly isolated from the pharynx dizziness 13 albuminuria (> 2+) 65 b and urine, respiratory and urine droplet transmis­ tinnitus 4 sion is a likely mode of person-to-person infection. The likelihood. of parenteral inoculation through a Among 23 cases. b Among 20 cases. cuts and abrasiOns and of infection via the naso­ pharynx or would increase with the intimacy of contact with an infected indi­ and others had low-grade fevers of 37.2-38.3°C. vidual, and this would be true also of the size of Fever may also briefly recur during the early the in.fective dose. Indirect spread of the virus by convalescent period. the airborne route and mechanical transmission The convalescent phase begins in the second to by bedpans, contaminated hands utensils or fourth weeks with return of the temperature to is also possible but unpro~ed. Airborne normal and a rapid improvement in the patients' spread was postulated to account for the epidemic condition, though they may complain of fatigue in Jos in 1970. The presence of severe pulmonary for several weeks. Alopecia developed in some involvement in some patients with Lassa fever patients, and there may be irreversible . favours the hypothesis of this mode of transmission. Clinical laboratory findings Rodents may excrete virus in their urine and saliva The leucocyte count is characteristically low and thus contaminate air, food, or drinking-. 3 ( < 4000/mm ) during the acute phase of the Clinical features infection. In some patients a shift to the left in the The symptomatology of Lassa fever is quite granulocyte series and a relative lymphopenia have nonspecific, especially early in the disease, and been noted, but in others the differential count has the diagnosis is rarely entertained until a number not been remarkable. Elevations of the leucocyte of similar cases have occurred. Because of the risk count in the second or third week of illness have of nosocomial spread, all practising in been described, but may be related to bacterial West Africa and medical authorities elsewhere who superinfection. When measured, the platelet count receive febrile patients from possible endemic areas has been normal, but serial studies on individual should remain alert to the possibility of Lassa patients are lacking. The prothrombin time may be fever. prolonged. The urine may contain albumin and an The is probably within the abnormal sediment with, in particular, granular range of 3-16 days (10 days was recorded for one casts. case with a known exposure). The onset is insidious Very few elaborate laboratory examinations have with fever, , malaise, headache, and myalgia: been conducted. The urea nitrogen level may By the third to sixth day, the symptoms (Table 1) be elevated, possibly on account of , are intense and the patient seeks medical attention. , gastrointestinal bleeding, or renal The febrile stage lasts from 7 to 21 days. The damage; creatinine clearances have not been fever itself is variable. Some patients had fevers mea~ured. Elevated levels of enzymes, in­ that spiked daily to 40.0--40.6°C in the afternoon cludmg aspartate aminotransferase, lactate dehydro- or evening; some, especially those with severe or 2 Aiso sometimes referred to as Mastomys coucha Rattus coucha fatal infections, had persistently high temperatures; R . natalensis, or Traomys natalensis. ' '

214 Table 2. of Lassa fever disturbances of some organs-the brain and the kidneys, in particular-are produced directly by Clinical Differential diagnosis a viral damage or indirectly by factors such as hypo­ symptoms Phase More tension, hypoxaemia, acidosis, and and signs likely Less likely imbalance. The pathogenesis of the pulmonary oedema or heart failure described in some patients fever is similarly in question. chills headache yellow fever Differential diagnosis myalgia dengue, chikun­ chest, abdominal gunya T:;tble 2 shows the common and less common pains diseases that must be distinguished from Lassa enterovirus, fever. most closely resembles Lassa vomiting adenovirus fever and is the primary diagnosis considered by diarrhoea typhoid infections l early physicians in the tropics when a patient has a pro­ relative brady- { acute fever cardia Lassa longed febrile illness with insidious onset, brady­ dehydration fever meningococcaemia cardia, gastrointestinal symptoms, cough, bleeding, cough epidemic conjunctivitis scarlet fever , and leucopenia. exudative or ulcera- louse-borne relaps- tive pharyngitis ing fever Definitive diagnosis lymphadenopathy Lassa fever may be diagnosed by the isolation rash leucopenia of the virus from the blood, serum, throat washings, urine, pleural fluid, or viscera obtained at necropsy. abnormal bleeding At present, only the laboratory at the Virology facial, cervical Branch, Center for Disease Control, Atlanta, Ga., oedema rales Lass a USA, is equipped to attempt isolation of the virus effusions, ascites fever safely. Since the virus does not withstand prolonged malaria petechiae late typhoid bacteraemia shipment at ambient temperatures, the collection deafness acute fever of specimens for virus isolation is generally not hypotension yellow epidemic typhus oliguria fever feasible in Africa. If special circumstances make it CNS disturbances necessary to attempt the shipment of specimens, freshly frozen or refrigerated samples should be sent death to the Center for Disease Control by air on dry or wet ice. When such a shipment is planned, it a The italics indicate entities for which specific treatment would be advisable for the senders to seek the is available. assistance of the local Ministry of Health, the local WHO representative, or a regional virus laboratory genase, and creatinine phosphokinase, have been in making suitable arrangements. Before specimens noted in some, but not all, cases. There are in­ are shipped, the Center for Disease Control should sufficient data to judge whether these tests could be notified of the airline, flight number, and cargo be used diagnostically. Consistent changes in the waybill number. Cables should be addressed to the have not been demonstrated. Chief, Virology Branch, Center for Disease Control. Electrocardiographic alterations have been reported Diagnosis may also be made by serological tests but are nonspecific. The chest X-ray may show on paired serum samples collected during the acute pulmonary infiltrates and/or pleural effusions. and convalescent stages of illness. The complement fixation (CF) test is used to detect specific anti­ Pathology and pathophysiology bodies to Lassa virus. At present, little information From the clinical description it is evident that is available on the time of appearance the illness is characterized by the dysfunction of after infection. From a small number of observa­ many organs and tissues, including the heart, lungs, tions, it appears that CF antibodies are first pleura, intestine, , skeletal muscle, lympho­ detectable (often at a low titre) in the third week reticular system, brain, skin, and kidney. In most after the onset of the disease. For serological patients, the systemic manifestations predominate, diagnosis 2-5 ml of serum is obtained during the rather than effects referable to specific organ sys­ first 2 weeks of illness and again 4-8 weeks after tems. The mechanisms responsible for the physio­ the onset. The sera should be handled with care logical changes producing the systemic toxaemia since they may contain live virus. When sera are are not understood. It is also not clear whether the separated and stored, a meticulous aseptic tech-

215 nique must be used to avoid contamination. such patients and efforts made to eliminate it as Specimens are labelled with the patient's name, a cause of shock. the date of the onset of illness, and the date the Specific measures. Convalescent plasma from serum was obtained. An insulated container with recovered patients has been used in the of wet ice or canned refrigerant should preferably be acute Lassa fever. To date, 4 patients have been used for shipment. However, bacteriologically treated in this way and 3 have responded with sterile sera may be shipped at ambient temperatures defervescence, the resolution of pleural effusions, for a week or longer without any loss of antibody. 3 and rapid symptomatic improvement. The fourth Other means of diagnosis have received little died within 48 hours of receiving plasma; it was attention. The virus has been seen by electron considered possible that in this patient renal microscopy in liver tissue obtained by needle failure was precipitated by the transfusion. Even from a patient immediately after death. It is possible though no controlled studies have been conducted that the electron microscopic examination of and the administration of antibodies is usually serum or biopsy material could provide a rapid ineffective against viral infections once the disease means of diagnosis in some cases. Fluorescent is established, the experience of the author and of antibody techniques have not yet been employed in others is that serotherapy alters the course of Lassa the study of Lassa fever. fever favourably. It is desirable, but often not possible, to ascertain beforehand that Lassa virus Treatment and management antibodies are present in the donor's plasma. If it is General measures. Treatment is largely sympto­ necessary to select donors solely on the basis of matic and supportive. Patients should be placed in recovery from clinically diagnosed Lassa fever bed in quiet surroundings, moved as little as they should have been convalescent for at least possible, and, if necessary, given sedation. Sedatives 2 months to allow for the development of anti­ and anti-emetics having marked hypotensive side bodies and the clearance of viraemia. In practice, effects should be avoided. Vital signs are measured 1 or 2 units (250 ml each) of convalescent plasma, at frequent intervals, and the fluid intake and output matched if possible to the recipient's major blood are recorded. grouping, are transfused over 30-90 minutes. Lassa Patients with vomiting, diarrhoea, and dysphagia fever patients may excrete virus from the pharynx who have signs of dehydration should receive or in the urine for up to 3 weeks following trans­ judicious fluid replacement by the intravenous fusion, and must still be considered potentially route. It may be necessary to supplement intra­ infectious. venous solutions with potassium chloride. Evidence At present immune plasma is not generally of widespread capillary leakage, pulmonary oedema, available. Small amounts have been collected from hydrothorax, or cardiac failure will modify the survivors and are stored at hospitals in Jos, Nigeria, programme of fluid and electrolyte administration, and Panguma, Sierra Leone, and at the Center for and salt and water may have to be restricted in such Disease Control, Atlanta, Ga., USA. cases since fluids will be rapidly lost from the vascular bed. Fever should be controlled with oral Control or rectal salicylates and by sponge baths with Because no methods of or of tepid water. specific treatment are known, is at During the first days in the hospital, present the only effective means of reducing the and antimalarials have been routinely administered risk of person-to-person transmission of Lassa to patients suspected of having Lassa fever. fever virus. Obviously, the degree to which quaran­ Although there is good evidence that antibiotics do tine is effective will depend upon the efficiency with not alter the course of Lassa fever, their use is which cases are recognized and diagnosed. In the justified as a diagnostic measure, especially when hospital, routine but strictly enforced isolation of typhoid fever is suspected. It is best to administer patients appears to be effective in limiting transmis­ antibiotics in moderately high doses by the par­ sion of the virus to other patients and hospital staff. enteral route; chloramphenicol or ampicillin have Patients suspected of having the disease should be been employed most often. If a clinical response is removed to an isolation ward where their activities not observed after 4-5 days, the antibiotics may be and those of visitors can be controlled. Attending discontinued. staff and relatives providing medical and personal In most hospitals in Africa, the management of 1 Laboratories able to perform CF tests for Lassa fever antibodies at patients developing signs of shock severely taxes the the present time are : Institut Pasteur, Dakar, Senegal; Virus Research available resources of personnel, equipment, and Laboratory, University College Hospital, Ibadan, Nigeria; Yale Research Unit, 60 College Street, New Haven, Conn., 06510, USA: supplies. Silent haemorrhage should be suspected in Center for Disease Control, Atlanta, Ga., USA.

216 care should wear gowns, gloves, and masks when in control may be used as an emergency measure in the isolation ward. Utensils and instruments should community-based outbreaks or a preventive measure be soaked in a suitable such as a 10% in areas where antibody surveys or sporadic clinical solution of chlorine bleach after use and before cases suggest that the virus is enzootic-endemic. being removed from the ward for sterilization. Research is needed for the better definition of the After making examinations or providing nursing zoology and population dynamics of the natural care, hospital personnel should change before , M. natalensis, so that a useful control pro­ proceeding to the next patient. Great ingenuity is gramme can be formulated. required in devising effective but practicable methods The evacuation of persons suspected of having for the disposal of excreta and other waste materials Lass'a fever to other medical centres presents and for the sterilization of linen. The isolation special problems. The clinician wiii find it unde­ rooms should probably be screened against insects. sirable to subject a patient to the stresses of travel; In the hospital laboratory, potentially infectious on the other hand, it is advantageous to have specimens of blood and urine from isolated patients facilities for modern intensive care. Whenever pos­ should be handled with the utmost care. In general, sible, evacuation should take place before the measures similar to those applied to cases of seventh day of iiiness. At present, Lassa fever is not smallpox may be used. The physician in charge a quarantinable disease under international regul­ should personally supervise the quarantine pro­ ations; commercial airliners have therefore been cedures, apply common sense, and allay the super­ used to evacuate patients suspected of having the stitions and fears of patients and staff until the disease. Since a laboratory diagnosis could not be procedures become routine practice. made prior to their evacuation, these patients have Under certain circumstances (e.g., after usually been described as suffering from "fever of probably attributable to Lassa fever have occurred unknown origin". Stringent precautions must be in the community or patients suspected of having observed throughout the evacuation, and if possible Lassa fever have been admitted to hospital) it may be the area of the plane containing the evacuee should desirable to isolate patients with fever of unknown be cordoned off. Under these circumstances, the origin as a matter of routine until a working risk to other passengers would appear to be small. diagnosis is established, perhaps after a therapeutic Of greater concern than the transport of possibly trial with antimalarials and antibiotics. The question infectious patients across international boundaries of discharging a patient with Lassa fever is difficult. under controlled conditions is the risk that the Although evidence accumulated during the recent virus may be unwittingly brought in by a traveller outbreak in Sierra Leone suggests that most patients in the incubation or early acute phase of the no longer shed virus after the 14th day, virus disease. To provide a rational basis for quarantine excretion has been shown to continue for a month measures, further surveys are needed to determine or more after the onset of illness. In practice, it is the regions where Lassa fever virus is active, and a rarely possible to keep a patient in hospital after he programme of surveillance must be instituted both has regained his strength and wellbeing, or to prove in West Africa and in the developed countries. by laboratory tests that he is free from virus. Lassa fever patients released within a month of the onset Marburg (" green monkey ") virus disease of iiiness should probably be advised to sleep in separate quarters at home, not to share eating is an acute febrile infection utensils, and to dispose of urine and faeces properly. first recognized in 1967 during an epidemic among The control of the disease in a community-based laboratory workers exposed to the infected tissues outbreak with person-to-person transmission, such of imported African green monkeys (Cercopithecus as that in Panguma-Tongo, Sierra Leone, may not aethiops) in Germany and . Person-to­ be possible. To some extent transmission can be person nosocomial secondary transmission occurred limited by surveillance, identification, hospital­ from the hospitalized primary cases to medical ization, and isolation of patients, since potentially attendants. No further epidemics or sporadic cases infectious individuals are thereby removed from have appeared among persons potentially exposed general circulation. The quarantine of households to nonhuman in America or Europe. containing patients or of the affected town itself are Nevertheless, serological surveys have indicated measures to be considered by the that the virus is present in East Africa ( and authorities. ) and causes infections in monkeys and man. Since a rodent has been implicated as a probable Since these retrospective studies have not associated natural host, the reduction of the rodent population serological evidence of infection with or may be considered as a control measure. Rodent animal illness, Marburg virus disease is at present

217 only of potential public health importance in region of Uganda (the source of the monkeys Africa. implicated in the outbreak) revealed no evidence of an epizootic or of clinical illness among monkey The infectious agent trappers. However, complement-fixing antibodies Marburg virus has been the subject of intensive to Marburg virus were detected in up to 30% of the laboratory studies. It has been isolated in guinea pigs animals sampled between 15 August and 27 October a nd various cell-culture systems. The virus particle 1967. An increasing prevalence of antibody was probably contains lipid and RNA and has an found during this period. The evidence suggested elongated cylindrical or filamentous shape when that the virus had recently spread through the viewed with the electron microscope. Although monkey population without causing many deaths. this appearance and the cytoplasmic inclusions Antibody was also detected in 3 monkey trappers. observed in infected cells by light microscopy super­ No subclinical infections occurred in the European ficially resemble those of and related viruses, epidemic. the basic morphological structure of the Marburg Antibody to Marburg virus has been detected in virus is distinctive and it shares no antigenic pro­ baboons bled in Kenya. The geographical range of perties with rhabdoviruses or with any other known Marburg virus thus includes Uganda and Kenya, viruses. Marburg virus is not at present included in but it cannot be extended with certainty without a ny existing taxonomic group. further studies. The natural cycle of transmission at The virus is not pathogenic for mice but when present is believed to involve only nonhuman adapted produces illness in guineapigs and ham­ primates although studies of other vertebrate sters. Monkeys of various . species including C. species are incomplete. The natural means of aethiops have been experimentally inoculated with transmission from monkey to monkey is uncertain, Marburg virus. These animals developed a uni­ but several modes are possible or likely. Monkeys formly fatal infection which pathologically re­ have been experimentally infected by , and sembled the disease in man. Death occurred on the infected animals may excrete the virus in the urine seventh or eighth day after inoculation. and saliva. The apparent latent persistence of virus in tissues and semen for long periods suggests other Epidemiology possible modes of natural transmission. The pos­ Green monkeys were exported from East Africa sibility that haematophagous play a in large numbers for use in laboratories in the USA role in the transmission of Marburg virus has been a nd other countries, with no untoward results investigated in the laboratory. aegypti until 1967. During August and September of that were successfully infected by intra­ year, 25 laboratory workers in Marburg, Frankfurt, thoracic inoculation, but their capacity to transmit and Belgrade developed an acute illness. All had the virus has not been shown. been exposed to the tissues of green monkeys shipped from Entebbe, Uganda, 2-3 weeks prior Clinical manifestations to the epidemic. Primary cases resulted from The illness characteristically begins with the exposure to the virus during autopsies, surgical sudden onset of fever, malaise, headache, and nephrectomies, and the preparation of cell cultures myalgia, especially in the lumbosacral region. The from infected monkeys. The route of infection was headache and myalgia generally subside by the not definitely elucidated, although the respiratory fourth to seventh days. Gastrointestinal symptoms, t ract or conjunctivae may have been involved in including nausea, vomiting, and watery diarrhoea, some cases. Secondary cases occurred in 2 phys­ may appear within the first 24 hours, but are more icians, 2 nurses, and a pathology assistant, all of frequent by the third or fourth day. Diarrhoea may whom were exposed to the primary case. The route persist for several days after defervescence. Dehy­ of infection in these cases was probably parenteral, dration is common. via accidental needle pricks or skin abrasions. A Evidence for hepatic injury was present in most sixth secondary case was venereally acquired from a cases during the second week of illness but clinical patient 83 days after the onset of illness. Marburg was not observed. Renal damage mani­ virus was demonstrated in the patient's semen fested by , oliguria, and rising blood despite the presence of circulating antibodies in urea nitrogen levels appeared in some patients, t he serum. especially the severely ill. The incubation period ranged between 4 and 9 The duration of the acute febrile illness is days. The was 29% for the primary approximately 2 weeks. Death has occurred as cases but none of the 6 secondary cases proved fatal. early as the 8th and as late as the 17th day. A Epidemiological studies in the Lake Kyoga relative bradycardia was frequently noted during

218 the first 5 or 6 days of illness. Complications been noted in the kidneys. Cerebral oedema, pan­ attributed to the disease included bacterial pneu­ encephalitis, and glial nodules associated with peri­ monia, , testicular atrophy, chemical hepatic vascular lymphocytic infiltrates have been observed. dysfunction or (possibly from blood trans­ Increased numbers of plasma cells were found in the fusions), acute , and myelitis. Virus was lymph nodes, , and gastric mucosa. Also demonstrated in the liver of one patient with described are basophilic inclusions in the hepatitis during late convalescence. Convalescence of cells in many organs. was prolonged for 3-4 weeks in most cases; lethargy, fatigue, and loss of hair were frequent symptoms. The management of cases As in Lassa fever, is a Laboratory diagnosis cardinal feature in the management of Marburg Clinical laboratory studies show evidence of virus disease. Antipyretics, the maintenance of the leucopenia on the first day of illness; minimal counts fluid, acid-base, and electrolyte balances, and the were found on days 4-9. A shift to the left in the maintenance of the blood volume without producing granulocyte series and the appearance of abnormal a circulatory overload are required. Renal tubular granulocytes (pseudo-Pelger's cells) were also noted. damage and renal failure appear to be of greater Atypical lymphocytes and circulating plasma cells clinical significance in this disease than in Lassa and plasmoblasts were characteristic findings. fever. Severe haemorrhage occurred in 30% of the Elevations of serum aspartate aminotransferase cases studied. Transfusion of convalescent plasma and alanine aminotransferase levels were consist­ has been associated with clinical improvement. ently observed, sometimes to a very high degree, with peaks between the seventh and twelfth days. The control of Marburg virus disease An increase in serum amylase was observed in some The prevention of epidemics of Marburg virus cases. disease in laboratory workers and others exposed to Hypoprotdnaemia was present in many patients monkeys exported from Africa has received much and was associated with the appearance of oedema attention. Persons handling monkeys, and especially in some of them. A rapid definitive diagnosis has monkey tissues, in Africa should take similar been made by the direct examination of blood or precautions, including the quarantine of animals, liver biopsy material with the electron microscope the use of protective gloves and masks, and the or a fluorescent antibody technique. Viraemia coin­ proper disposal of contaminated carcasses and cides with the febrile stage (approximately 2 weeks). instruments. The sensitivity of these techniques applied to The disease has not yet been recognized in a primary isolation material is uncertain. sporadic form in Africa, but this may be due to a Virus isolation may also be attempted by inocul­ low level of surveillance, misdiagnosis, and the ating cell cultures and guineapigs but, because of unavailability of medical resources in remote areas. the relative heat lability of Marburg virus and The clinical syndrome of Marburg virus disease is the problems inherent in collecting and shipping distinctive enough, at least in its full-blown form , specimens from African hospitals for specialized to arouse the suspicion of the physician. In East virological studies, serological diagnosis (by the Africa, disease entities that might be confused with CF test) seems a more practicable alternative. The Marburg virus disease include yellow fever, epid­ suggestions in the section on Lassa fever (page 215) emic typhus, typhoid fever, spirillosis, leptospirosis, referring to the collection and shipment of sera are and possibly Congo virus infection. It is not known applicable to Marburg virus also. CF antibodies whether mild atypical syndromes are associated appear in the sera of infected individuals during the with Marburg virus infection. Patients with un­ second or third weeks after the onset of illness. diagnosed febrile illness, especially those with haemorrhage or other clinical features resembling Pathology Marburg virus disease, should be questioned care­ Marburg virus is pantropic: it produces lesions fully about possible exposure to monkeys or in most of the organs studied. Focal is monkey meat. Suspected cases should be isolated most striking in the liver, lymphocytic tissue, in the hospital and special care taken to prevent ovaries, and testes. Small haemorrhagic areas are the exposure of medical attendants to the patients• widespread in many tissues. Tubular necrosis has blood, saliva, and urine.

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