76
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
Unrecognized Diseases in Africa II. LASSA FEVER
The epidemiological pattern of Lassa fever has developed slowly and inexorably since the first case was discovered in a mission nurse in Lassa, Nigeria in 1969. A readable and factual account of developments through 1971 has appeared in book form (1) and much has happened since then. The 1969 outbreak was limited to the original case in Lassa, and two secondary cases, also in mission nurses, in Jos, Nigeria. The first two nurses died. The third, evacuated to the United States, recovered after prolonged and serious illness. The virus isolation and identification work was carried out in the Rockefeller Foundation supported Yale Arbovirus Research Unit in New Haven, Connecticut (2). In the course of these investigations, there were two laboratory acquired infections, with the death of one laboratory worker. A second outbreak of the disease was noted in Jos in January-February 1970, with 23 cases and 13 deaths. In March 1972, an outbreak was recorded in a mission hospital in Zorzor, Liberia, with 10 cases and four deaths. Later in 1972, a focus of disease activity was uncovered in the region of Panguma, Sierra Leone. A detailed epidemiological study (3) established that the disease had been active in the region for more than 24 months previously. A total of 64 probable cases was established on the basis of virus isolation, for some cases, and retrospective serological diagnosis for others, with an estimated 23 deaths. The next episode was recorded from a mission hospital in Onitsha, Nigeria, in January 1974, with two cases and one death. The 1975 season has started off with an outbreak near Zaria, Nigeria, with two cases and two deaths. The virus has been determined to belong to the arenavirus group (4). This group includes the wellknown and much studied lymphocytic choriomeningitis (LCM) virus, Junin virus (causing Argentinian haemorrhagic fever), Machupo virus (causing Bolivian haemorrhagic fever) and several other viruses, not associated with human disease, namely Tacaribe (Trinidad), Amapari (Brazil), Pichinde (Colombia), Tamiami (Florida), Parana (Paraguay) and Latino (Bolivia). Epidemiological studies on several of these viruses have established a pattern of infection in small rodents, leading often to long persisting infections, accompanied by virus excretion in the urine for prolonged periods of time.
Outbreaks of disease in human beings have been determined, in the cases of LCM, Junin and Machupo, to be rodent associated. Mortality rates in the latter two diseases are high, although not as high as in Lassa fever. AU of the Lassa fever outbreaks thus far uncovered have been hospital associated, with a high proportion of cases occurring in hospital staff, physicians, nurses and attendants. An 'index case' in an indigene of the region has been located in several instances and at least two of the hospital episodes have been associated with maternity wards. Serosurveys, particularly detailed in the Sierra Leone outbreaks, have demonstrated antibody rates as high as 13 per cent in the indigenous populations, the highest rates being seen in females of childbearing age. A clustering of seropositives in household groups associated with a case has been observed, in many instances with no history of illness. Seropositives have also been found in hospital staff members without recognized disease. Limited serosurveys in African populations not from known active foci have revealed no seropositives, or very low rates. The full extent of virus endemicity in West Africa is not known. Serological studies on mission hospital associated workers are in progress on a limited scale. Search for rodent reservoirs of virus have been carried out in Nigeria and Sierra Leone. The vims has been recovered from a common African rodent, Mastomys natalensis trapped in the Panguma region of Sierra Leone (5). Treatment with plasma from a recovered case has been tried in a small number of cases, and in all cases except one, when tried, has been followed by recovery. A very limited quantity of immune plasma has been stockpiled, and most of this is held in Nigeria. The clinical spectrum in Lassa fever (6, 7) extends from mild cases, to very serious and fatal illnesses. After an insidious onset, the patient may progress through a septicaemic-like phase to the appearance of serious effusions, haemorrhages, disturbed mental state, shock and death. Diagnosis may be by virus isolation (not lightly undertaken) or by complement-fixation test on sera of recovered cases. Virus has been isolated from serum, throat washings, urine, and pleural exudates. A satisfactory arid simple virus neutralization test has not yet been developed, and all work with live
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EDITORIALS
virus must be conducted with most stringent isolation precautions. The Center for Disease Control of the US Public Health Service, in Atlanta, Georgia, is the only facility where Lassa virus is knowingly handled. The virus could be unwittingly handled in any laboratory in Africa, or indeed in the world, to which materials from an ill patient or traveller might be referred. The World Health Organization has proposed a policy for Lassa fever management (7). An editorial in the Lancet (8) extends the discussion but implies that certain features such as the rodent reservoirs, the spectrum of disease and therapy are better understood than they really are. Recognition of Lassa fever depends primarily on a continuing high level of suspicion. This is obviously very difficult in regions with much malaria, endemic yellow fever, typhoid fever and rickettsioses, where patients ill from these or other diseases may be referred to hospitals with little or no accompanying history or epidemiological observations. The issue is complicated because of the present inevitable time lapse between suspicion and confirmation, plus the obvious dangers in handling a suspected virus isolation. Current restrictions on shipping dangerous pathogens by air add further complications. "\ Both in Africa, and in other continents, there is a reluctance to admit suspect Lassa fever patients to hospital. In outbreaks, such as the Onitsha outbreak of 1974, a hospital involved may actually be cleared of patients and closed. Panic is not an exaggeration of the reactions observed when Lassa fever is suspected.
There is no reason to doubt that Lassa fever will recur in Africa. There is a compelling call for more extended studies on the disease. The full geographic distribution needs to be known and better and safer diagnostic tests devised. The pattern of endemicity in animal reservoirs needs much more study. The existence of strains with different levels of pathogenicity for human beings has been noted (6) and calls for further exploration. The factors contributing to epidemic outbreaks in human populations need to be identified. The diagnostic features and pathogenesis in man need much more study. Present therapy needs careful evaluation. Finally, a vaccine is needed. None of these needs are going to be met in the near future unless further high containment laboratory facilities are established, at least one of which should be in Africa. REFERENCES
(1) Fuller, J. G.: Fever. E. P. Dutton, 1974. (2) Buckley, S. M. et al.: Amer. J. Trop. Med. & Hyg. 19: 680, 1970. (3) Frascr, D. W. et al.: Amer. J. Trop. Med. & Hyg. 23: 1131, 1974. (4) Rowe, W. P. et al.: / . Virology 5: 651, 1970. (5) Monath, T. P. et al.: Science 185: 263,1974. (6) Monath, T. P. et al.: Amer. J. Trop. Med. & Hyg. 23: 1140, 1974. (7) World Health Organization: WHO Weekly Epid. Record 49: 341, 1974. (8) Editorial: Lancet 1, 376, 1975. This is the second in a series of three editorials on Unrecognized Diseases in Africa. Thefirst(March 1975, 7-8) was incorrectly headed Undiagnosed Diseases in Africa.
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
Unrecognized Diseases in Africa II. LASSA FEVER
The epidemiological pattern of Lassa fever has developed slowly and inexorably since the first case was discovered in a mission nurse in Lassa, Nigeria in 1969. A readable and factual account of developments through 1971 has appeared in book form (1) and much has happened since then. The 1969 outbreak was limited to the original case in Lassa, and two secondary cases, also in mission nurses, in Jos, Nigeria. The first two nurses died. The third, evacuated to the United States, recovered after prolonged and serious illness. The virus isolation and identification work was carried out in the Rockefeller Foundation supported Yale Arbovirus Research Unit in New Haven, Connecticut (2). In the course of these investigations, there were two laboratory acquired infections, with the death of one laboratory worker. A second outbreak of the disease was noted in Jos in January-February 1970, with 23 cases and 13 deaths. In March 1972, an outbreak was recorded in a mission hospital in Zorzor, Liberia, with 10 cases and four deaths. Later in 1972, a focus of disease activity was uncovered in the region of Panguma, Sierra Leone. A detailed epidemiological study (3) established that the disease had been active in the region for more than 24 months previously. A total of 64 probable cases was established on the basis of virus isolation, for some cases, and retrospective serological diagnosis for others, with an estimated 23 deaths. The next episode was recorded from a mission hospital in Onitsha, Nigeria, in January 1974, with two cases and one death. The 1975 season has started off with an outbreak near Zaria, Nigeria, with two cases and two deaths. The virus has been determined to belong to the arenavirus group (4). This group includes the wellknown and much studied lymphocytic choriomeningitis (LCM) virus, Junin virus (causing Argentinian haemorrhagic fever), Machupo virus (causing Bolivian haemorrhagic fever) and several other viruses, not associated with human disease, namely Tacaribe (Trinidad), Amapari (Brazil), Pichinde (Colombia), Tamiami (Florida), Parana (Paraguay) and Latino (Bolivia). Epidemiological studies on several of these viruses have established a pattern of infection in small rodents, leading often to long persisting infections, accompanied by virus excretion in the urine for prolonged periods of time.
Outbreaks of disease in human beings have been determined, in the cases of LCM, Junin and Machupo, to be rodent associated. Mortality rates in the latter two diseases are high, although not as high as in Lassa fever. AU of the Lassa fever outbreaks thus far uncovered have been hospital associated, with a high proportion of cases occurring in hospital staff, physicians, nurses and attendants. An 'index case' in an indigene of the region has been located in several instances and at least two of the hospital episodes have been associated with maternity wards. Serosurveys, particularly detailed in the Sierra Leone outbreaks, have demonstrated antibody rates as high as 13 per cent in the indigenous populations, the highest rates being seen in females of childbearing age. A clustering of seropositives in household groups associated with a case has been observed, in many instances with no history of illness. Seropositives have also been found in hospital staff members without recognized disease. Limited serosurveys in African populations not from known active foci have revealed no seropositives, or very low rates. The full extent of virus endemicity in West Africa is not known. Serological studies on mission hospital associated workers are in progress on a limited scale. Search for rodent reservoirs of virus have been carried out in Nigeria and Sierra Leone. The vims has been recovered from a common African rodent, Mastomys natalensis trapped in the Panguma region of Sierra Leone (5). Treatment with plasma from a recovered case has been tried in a small number of cases, and in all cases except one, when tried, has been followed by recovery. A very limited quantity of immune plasma has been stockpiled, and most of this is held in Nigeria. The clinical spectrum in Lassa fever (6, 7) extends from mild cases, to very serious and fatal illnesses. After an insidious onset, the patient may progress through a septicaemic-like phase to the appearance of serious effusions, haemorrhages, disturbed mental state, shock and death. Diagnosis may be by virus isolation (not lightly undertaken) or by complement-fixation test on sera of recovered cases. Virus has been isolated from serum, throat washings, urine, and pleural exudates. A satisfactory arid simple virus neutralization test has not yet been developed, and all work with live
77
EDITORIALS
virus must be conducted with most stringent isolation precautions. The Center for Disease Control of the US Public Health Service, in Atlanta, Georgia, is the only facility where Lassa virus is knowingly handled. The virus could be unwittingly handled in any laboratory in Africa, or indeed in the world, to which materials from an ill patient or traveller might be referred. The World Health Organization has proposed a policy for Lassa fever management (7). An editorial in the Lancet (8) extends the discussion but implies that certain features such as the rodent reservoirs, the spectrum of disease and therapy are better understood than they really are. Recognition of Lassa fever depends primarily on a continuing high level of suspicion. This is obviously very difficult in regions with much malaria, endemic yellow fever, typhoid fever and rickettsioses, where patients ill from these or other diseases may be referred to hospitals with little or no accompanying history or epidemiological observations. The issue is complicated because of the present inevitable time lapse between suspicion and confirmation, plus the obvious dangers in handling a suspected virus isolation. Current restrictions on shipping dangerous pathogens by air add further complications. "\ Both in Africa, and in other continents, there is a reluctance to admit suspect Lassa fever patients to hospital. In outbreaks, such as the Onitsha outbreak of 1974, a hospital involved may actually be cleared of patients and closed. Panic is not an exaggeration of the reactions observed when Lassa fever is suspected.
There is no reason to doubt that Lassa fever will recur in Africa. There is a compelling call for more extended studies on the disease. The full geographic distribution needs to be known and better and safer diagnostic tests devised. The pattern of endemicity in animal reservoirs needs much more study. The existence of strains with different levels of pathogenicity for human beings has been noted (6) and calls for further exploration. The factors contributing to epidemic outbreaks in human populations need to be identified. The diagnostic features and pathogenesis in man need much more study. Present therapy needs careful evaluation. Finally, a vaccine is needed. None of these needs are going to be met in the near future unless further high containment laboratory facilities are established, at least one of which should be in Africa. REFERENCES
(1) Fuller, J. G.: Fever. E. P. Dutton, 1974. (2) Buckley, S. M. et al.: Amer. J. Trop. Med. & Hyg. 19: 680, 1970. (3) Frascr, D. W. et al.: Amer. J. Trop. Med. & Hyg. 23: 1131, 1974. (4) Rowe, W. P. et al.: / . Virology 5: 651, 1970. (5) Monath, T. P. et al.: Science 185: 263,1974. (6) Monath, T. P. et al.: Amer. J. Trop. Med. & Hyg. 23: 1140, 1974. (7) World Health Organization: WHO Weekly Epid. Record 49: 341, 1974. (8) Editorial: Lancet 1, 376, 1975. This is the second in a series of three editorials on Unrecognized Diseases in Africa. Thefirst(March 1975, 7-8) was incorrectly headed Undiagnosed Diseases in Africa.
