LASSA FEVER : HISTORICAL OVERVIEW AND CONTEMPORARY INVESTIGATION
J.B. MCCORMICK and K.M. JOHNSON
U.S. Public Health Service, Center for Disease Control, Atlanta, Georgia 30333, U.S.A.
Science is a tapestry woven from remnants by workers linked by principle and the disparate ways of interhuman communication. The grand design is hidden from each weaver until chance and the accumulated fabric reveals itself in dramatic form. In 1934 and 1935 a new virus was recovered from monkeys, humans, and mice (1,2,3). It was named lymphocytic choriomeningitis virus of mice (LCM). For more than three decades this virus remained a morphological and biological orphan, albeit a profound model for much of modern immunological theory in the field of immune tolerance (4), until Dalton et al. revealed its unique configuration marked by the virionic incorporation of variable numbers of host-cell ribosomes in 1968 (5). Meantime the virus of Argentine hemorrhagic fever (AHF) named Junin was isolated in 1958 (6), and found to be immunologically related to another virus called Tacaribe which had been recovered from bats in Trinidad by workers of the Rockefeller Foundation perusing studies on the ecology of vector-borne viruses of the tropics (7).
In 1963 workers from the U.S. National Institutes of Health based in Panama isolated the causative agent of Bolivian hemorrhagic fever, a disease indistinguishable from AHF, and found that it shared antigens with Junin and Tacaribe viruses (8). Machupo virus induced chronic tolerant infection in its natural rodent reservoir host Calomys callosus (9) which was similar to the pattern of infection from LCM in Mus musculus elucidated by Traub in the 1930's (10,11).
Within months of the report of the morphological characteristics of LCM in 1968, Murphy et al. (12) demonstrated that Machupo virus shared these unique structural properties. Thus was born the family of viruses known as arenaviridae (arenosus = sandy, to mark the unique ribosomal entrapment in varions) (13).
In the 1960's Frame at Columbia University sought and received the collaboration of Rockefeller Foundation personnel, by now integrated into the facultY of Yale University School of Medicine, in screening the families of medical missionaries in Africa for indigenous viral infections. This cooperation resulted in the isolation of Lassa virus in 1969. The original virus strain was obtained from the blood of a missionary nurse from Jos, Nigeria.
She was the fourth patient in a nosocomial transmission chain originating from an obstetrical patient residing in Lassa, Nigeria, who sought treatment in Jos for a septic abortion 14,15). When the virions of Lassa virus were found to be indistinguishable from LCM, Machupo, Junin, and other arenaviruses, it was evident that Lassa fever was likely to prove to be rodent-transmitted.
In 1970 another Lassa outbreak occurred in the hospital at Jos. There were 28 cases and 13 deaths. Ratttus Ratttus and Mus musculus were found in and near houses of patients but none yielded Lassa virus, and retrospective analysis of this epidemic revealed that transmission of infection had occurred directly in the hospital (16). Although gastro-intestinal hemorrhage similar to that characteristic of the South American arenaviral hemorrhagic fevers (SAHF) was observed in some patients, unique complications such as pleural effusion, deafness and acute "nephritis" were recorded (17).
In 1972 Lassa fever hospital "outbreaks" were recognized in Liberia and Sierra Leone (18,19). During investigation of the latter, several Lassa virus isolates were made from mastomys natalensis, a rodent found in man-disturbed biotopes and human dwellings throughout most of sub-saharan Africa (20). The general rule of arenavirus biology was confirmed. Mortality rates in these "epidemics" were high (36-38%), but village sero-surveys done in Sierra Leone using a complement fixation test revealed that six percent of the population had experienced Lassa virus infection (19). A similar study in the region of Jos, Nigeria, employing a neutralization test which has not proven to be reproducible, showed that 13 percent of persons had Lassa virus antibodies (21).
More recently a fluorescent antibody method has been employed to measure anti-Lassa antibodies (22). By this technique, Lassa virus has been documented to occur in humans in most of West Africa including Ivory Coast, Ghana, Senegal, Guinea, Gambia, Upper Volta, Mali and the Central African Empire (23,24).
But Mastomys rodents are present in much of Africa. Why is Lassa fever a West African disease ? Although nature's pattern is unclear, there are clues. A virus antigenically related, but probably not identical, to Lassa has been isolated from mastomys in Mozambique (25). Elucidation of its pathogenetic properties and geographic distribution may help unravel the mystery. In addition Mastomys natalensis rodents bearing three distinct numbers of chromosomes have been reported from Africa (26). West African animals have 32 and 38 chromosomes (26), while those in southern Africa have 32 or 36 chromosomes. The latter forms have been documented to be distinct biological species (27). Time and work will tell us whether these clues are relevant.
Simple biological and virological parameters, however, suggest that the pathogenesis of Lassa virus infection in man is distinct from that of Junin and Machupo viruses. The South American diseases are characterized by a bleeding diathesis, low and intermittent viremia and a long interval between onset of symptoms and appearance of humoral antibodies (9). Virus is rarely detectable in urine and other clinical complications are unusual. Lassa fever, in contrast, is marked by prolonged viremia, a variety of major clinical manifestations and the simultaneous presence of both virus and specific antibodies in the blood during the second week of illness (28,29). Available data suggest that severe Lassa fever may have an immunopathological etiology. Finally, Junin and Machupo viruses have rarely been transmitted directly from person to person (9), whereas Lassa virus has produced several notable outbreaks based on this mode of transmission (16,18).
Examination of hospital records in eastern Sierra Leone between 1972 and 1975 revealed that clinical Lassa fever was almost certainly endemic to this region (30). Indeed, hospital records and the published literature (31,32) strongly suggested that Lassa fever had been described clinically from this area as far back as 1956. These considerations led to the organization of a multinational prospective study of Lassa fever in Sierra Leone which was initiated in February 1977, to address a variety of questions:
1. What is the spectrum of human response to Lassa virus infection ?
2. What is the true mortality rate of Lassa virus infection ?
3. What are the clinical consequences of Lassa virus infection in Children ?
4. How contagious is Lassa fever in an endemic setting ?
5. How can Lassa fever be diagnosed in less than 24 hours ?
6. Do Lassa fever patients have circulating antigen-antibody complexes ?
7. Is Lassa fever an immunosuppressive disease ?
8. Do passive anti-Lassa anti bodies have a role in treatment of Lassa fever ? Experimental work in monkeys with Machupo virus suggests that antibodies may be life-saving (33). Trials among Lassa patients are inconclusive (34).
9. What are the infection-competition dynamics among Mastamys and other "peridomestic" rodents which lead to human infection ?
10. What is the relation of mastomys chromosome type to chronic Lassa virus infection and excretion ?
A field laboratory has been established in Kenema for immunological work and for processing materials for virus assay at the Center for Disease Control in Atlanta. To date work has focused on febrile patients admitted to three hospitals near Kenema, although village-based studies of both human and rodent populations are planned.
From February through July 1977 we examined 263 hospitalized adults with fever. Lassa fever occurred continuously and 143 of these patients were deemed to have the disease based on virus isolation, a four-fold or greater increase in antibodies to the virus, or an initial titer of at least 1:1024 by the indirect fluorescent technique (IFAT). Males and females were equally affected and the mortality rate was about 20% although further laboratory work is required before the numbers are made precise.
No single symptom or sign was significantly correlated with laboratory-diagnosed Lassa fever. Combinations of findings such as pharyngitis, conjunctivitis and bleeding, however, were definitely predictive in the minority of patients in whom they occurred. Major complications, none of which were seen in more than 5% of Lassa fever cases, included deafness, abortion, pleural effusion, pericarditis, orchitis and iridocyclitis.
A search for Lassa fever among hospitalized children was begun in October. To date, nine cases have been confirmed, although it is already clear that this diagnosis accounts for a much smaller fraction of serious febrile disease in children than among adults.
Human serosurveys in villages of eastern Sierra Leone are in progress. Early returns suggest that prevalence of anti-Lassa antibodies varies widely but may reach 40 percent. At least one instance of asymptomatic Lassa infection has been documented. Despite the high prevalence of infection in hospitals we have observed only a single case of the disease which appeared to have been acquired through contact with a Lassa patient.
Promising preliminary results have been obtained in rapid diagnosis of Lassa infection among patients admitted prior to the appearance of specific antibodies. Epithelial cells are obtained from the conjunctiva using a curette, placed in a small amount of buffered saline, and acetone fixed in wells of teflon-templated microscope slides. Lassa-specific antigen has been found in a minority of such cells from several independently confirmed cases using the IFAT. We regard the ability to make early rapid diagnosis as crucial to scientific assessment of the value of passive antibody or any other method in the treatment of Lassa fever, in addition we are evaluating specific IgM antibody in the diagnosis of Lassa fever.
Lassa fever is clearly the most significant arenavirus disease of man in terms of morbidity, mortality, and its potential for person to person transmission. Unlike the arenaviral hemorrhagic fevers of South America, an array of serious clinical complications occurs which, together with the early appearance of antibodies in the presence of viremia, suggests that an immunopathological mechanism may be important in Lassa fever.
Accumulating evidence strongly suggests that Lassa virus infection may lead to a complete spectrum of host response in man, and that in fact this disease is neither as lethal nor as contagious as originally thought. Until much more is known, however, prudence requires that Lassa fever or even suspected cases of it be managed with maximum attention or containment and protection for medical and paramedical personnel.
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A.W. Woodruff : Since we had the first patient some six years ago that indicated that there was this focus of Lassa fever in Sierra Leone, we naturally kept an eye open for other cases of Lassa fever from that area and for other viral infections that might present as pyrexias among people coming from West Africa. We have not found any Lassa antibodies, nor Ebola or Marburg, but a fascinating array of other virus infections have turned up in these people. We have in addition to 5 cases of Dengue and 2 of Chikungunya, 4 in which there was only O'nyong-nyong antibody present. These came from Nigeria, Ghana, possibly Sierra Leone. This is, I think, the first evidence of this infection in Nigeria. Ntaya has turned up four times and is of some interest, there has not previously been any clinical record of symptoms associated with it. The involvement of the central nervous system, in at least two of these patients, raises the possibility that it my have neurotrophic propensities. Although Zinga has only been recovered from the Central African Empire, it seems possible to acquire it in Southeastern Nigeria. Perhaps the most fascinating was a Le Dantec virus antibody which appeared not in a person who had come from Africa but who had been bitten by an insect when unloading a cargo in Britain and had developed encephalitis and later Parkinson's disease which would be related to that infection.
P. Brès : O'nyong-nyong was an epidemic virus which appeared some fifteen years ago in East-Africa and then disappeared. But Chikungunya was very widespread, and it is mostly very difficult to make a difference between 0'nyongnyong and Chikungunya. So if the diagnosis of O'nyong-nyong is certain, I think this is worth being published.