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Muroid Virus NephropathiesHAEMORRHAGIC fever is a term that first came into
general use during the Korean war when a disease newto Western medicine appeared among United Nationstroops. I It was designated initially epidemichaemorrhagic fever and subsequently Korean
haemorrhagic fever (KHF). While investigating thisnew illness, in which haemorrhage was often severe,Western physicians became aware that a whole groupof haemorrhagic fevers had been described in theSoviet Union during the previous decades usuallylabelled by geographic location-Crimean haemor-rhagic fever, Far Eastern haemorrhagic fever,Uzbekistan haemorrhagic fever, Omsk haemorrhagicfever, Central Asian haemorrhagic fever, Yaroslavhaemorrhagic fever, and so on. The Far Eastern varietywas also known as haemorrhagic nephrosonephritis orhaemorrhagic fever with renal syndrome (HFRS).Subsequent investigations established that these
designations encompass several distinct nosologicalentities, for each of which a virus aetiology has beenestablished. The agents are all RNA viruses of varioustaxonomic groups. Unfortunately, the alreadyambiguous designation haemorrhagic fever was laterapplied to other disease entities encountered in thePhilippine Islands, Thailand, Singapore, Argentina,Bolivia, and elsewhere. To confuse matters further, thename epidemic haemorrhagic fever, at first appliedspecifically to the Korean disease, has been used byIndex Medicus and other medical indices to embracevarious other infections caused by viruses belonging togroups very different from that causing the Koreandisease (e.g., flavivirus, arenavirus, nairovirus). Yellowfever, caused by a mosquito-borne flavivirus, and RiftValley fever virus, a mosquito-borne phlebovirus, canboth elicit haemorrhagic fevers.
In 1952-53 Gajdusek, reviewing the published workon haemorrhagic fevers, noted the close similarity ofthe Korean disease to the milder forms of "epidemic"and sporadic cases that had been reported in EuropeanRussia, and to the nephropathia epidemica of northernNorway, Sweden, and Finland. He conjectured that
1. Smadel JE. Epidemic hemorrhagic fever Am J Publ Health 1953; 43: 1327-302. Gajdusek DC. Acute infectious hemorrhagic fevers and mycotoxicoses in the Union of
Soviet Socialist Republics (U.S. Army Medical Service Graduate School, MedicalScience Publication No. 2).Washington, D.C.: Walter Reed Army Medical Center,1953.
the diseases were related and caused by the same orsimilar viruses.2.5 This has now been substantiated.The isolation by Lee and Lee of the virus causingKHF, now called Hantaan virus,7 from the lungs of thenatural reservoir, the striped field mouse Apodemusagrarius, launched a new era in the study of
haemorrhagic fevers with renal syndrome throughoutthe world. (One manifestation is an outbreak of corres-pondence in this issue of The Lancet.) As a result wenow know that the widespread HFRS of EasternSiberia and the epidemic haemorrhagic fever of 19provinces of the Republic of China are caused by thesame virus,s’13 and HFRS in European Russia andnephropathia epidemica in Scandinavia are caused byantigenically related viruses that are distinguishableserologically from the Hantaan virus.8-15 In addition,the antigen of nephropathia epidemica and HFRS hasbeen demonstrated in European Russia in the lungs ofthe natural reservoir voles, Clethrionomys glareolus andMicrotus Sp.17 Similarly, the HFRS of the Balkan
countries, recognised in Hungary, Czechoslovakia,Bulgaria, Romania, Yugoslavia, and Greece, has beenshown, in Yugoslavia and Greece thus far, to be causedby an agent antigenically resembling that of
nephropathia epidemica of Scandinavia.9, 16,18 (Theposition is summarised on p. 1406 by Dr Lee and co-workers.) Thus, HFRS viruses cause viral
nephropathy across much of the Eurasian landmass inthe form of a haemorrhagic disease of great clinicalseverity with 5% to over 20% mortality in East Asia, ina much milder form of non-haemorrhagic nephropathywith low mortality in Scandinavia, and probably in
3. Gajdusek DC. Hemorrhagic fevers in Asia. A problem in medical ecology. GeographicalRev 1956; 46: 20.
4. Gajdusek DC. Das epidemische hemorrhagische fieber. Klin Wschr 1956; 34: 769.5. Gajdusek DC. Virus hemorrhagic fevers Special reference to hemorrhagic fever with
renal syndrome (epidemic hemorrhagic fever). J Pediat 1962; 60: 141.6. Lee HW, Lee PW. Korean hemorrhagic fever II: Isolation of etiologic agent. Korean J
Virol 1977; 7: 19.7. Lee HW, French GR, Lee PW, Baek LJ, Tsuchiya K, Foulke RS. Observations on
natural and laboratory infection of rodents with the etiologic agent of Koreanhemorrhagic fever. Am J Trop Med Hyg 1981; 30: 477-82.
8. Tkachenko EA, Donets MA, Rezapkin GV, et al. Serotypes of HFRS (haemorrhagicfever with renal syndrome) virus in East European and Far Eastern U.S S.R. Lancet1982; i: 863.
9. Lee PW, Svedmyr A, Gajdusek DC, Gibbs CJ, Jr, Nystrom K. Antigenic differencebetween European and East Asian viruses causing haemorrhagic fever with renalsyndrome. Lancet 1981; i: 256-57.
10. Svedmyr A, Lee PW, Gibbs CJ, Jr, Gajdusek DC Virus hemorrhagic fever with renalsyndrome: immunological evidence of strain differences in various geographic foci.V Int Congr Virol 1981; 202.
11. Lee PW, Gajdusek DC, Gibbs CJ, Jr, Xu ZY. Aetiological relation between Koreanhaemorrhagic fever and epidemic haemorrhagic fever with renal syndrome in thePeople’s Republic of China. Lancet 1980; i: 819-20.
12. Lee PW, Gibbs CJ, Jr, Gajdusek DC, Hsiang CM, Hsiung GD. Identification ofepidemic haemorrhagic fever with renal syndrome in China with Korean
haemorrhagic fever. Lancet 1980, i: 1025-26.13. Cohen MS, Casals J, Hsiung GD, et al Epidemic hemorrhagic fever in Hubei
Province, the People’s Republic of China: a clinical and serological study. Yale JBiol Med 1981; 54: 41-55.
14. Svedmyr A, Lee HW, Berglund A, Hoorn B, Nystrom K, Gajdusek DC Epidemicnephropathy in Scandinavia is related to Korean haemorrhagic fever Lancet 1979; i:100.
15. Lee HW, Lee PW, Lahevirta J, Brummer-Korvenkontio M. Aetiological relationbetween Korean haemorrhagic fever and nephropathia epidemica. Lancet 1979; i:186-87.
16. Svedmyr A, Lee PW, Gajdusek DC, Gibbs CJ, Jr, Nystrom K Antigenicdifferentiation of the viruses causing Korean haemorrhagic fever and epidemic(endemic) nephropathy of Scandinavia. Lancet 1980; ii: 315-16.
17. Chumakov MP, Gavrilovskaya IN. Are there two serotypes of the agent of
haemorrhagic fever with renal syndrome? Lancet 1980; ii: 690-91.18. Lee HW, Antoniadis A Serological evidence for Korean haemorrhagic fever in Greece.
Lancet 1981; i: 832.
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both forms in the Balkan countries and EuropeanRussia.]9 Dr Tkachenko and co-workers (p. 1407)suggest also that infection may be silent or atypical.On the evidence of serological tests for both Hantaan
virus and nephropathia epidemica virus this newlydefined group of rodent viruses, morphologically andbiochemically resembling the Bunyaviridae, existsworldwide. Urban forms of the disease have been
identified-firstly, a form transmitted to man, mainlylaboratory personnel, by infected laboratory rats inJ apan20 and Belgium21 where the laboratory-bred whiterats (Rattus norvegicus) are silently infected carriers;and, secondly, a form carried to man by persistentlyinfected urban rats in Japan and Korea, which appearsas a mild non-haemorrhagic acute febrile nephropathyin city dwellers.22,23 The virus has been detected inseaport and other urban rats over- a wide geographicdistribution, in a form antigenically resembling theKHF virus.24.27 Furthermore, serologically differentbut antigenically related viruses have beendemonstrated in wild murine rodents in the Americas
(see p. 1405). The antigen related to the Hantaan virusfound in the lungs of seropositive Microtus
pennsylvanicus on Prospect Hill, Frederick, Marylandreacts slightly better with nephropathia epidemicathan with KHF antisera, although the sera of theseProspect Hill rodents react only with the KHF antigenand homologous Prospect Hill antigen but not withnephropathia epidemica antigen. Laboratory rats andseronegative M. pennsylvanicus inoculated with
antigen-positive lung from Prospect HillM. pennsylvanicus have acquired specific antibodies tothe homologous antigen and specific antigen in theirlungs. Antibody to Hantaan virus has been foundoccasionally in human sera in the United States
(Alaska, Maryland) and in Bolivia and India.28,29 On p.
19. Gajdusek DC. Hemorrhagic fever with renal syndrome (Korean hemorrhagic fever,epidemic hemorrhagic fever, nephropathia epidemica), a newly recognised zoonoticplague of the Eurasian landmass with the possibility of related muroid virusnephropathies on other continents. In: Mackenzie JS, ed. Viral diseases in South-East Asia and the Western Pacific Sydney: Academic Press, 1982: 576-94
20. Hayashi TTA, Kikuchi K, Urasawa S, Suzuki A, Yachi A, Nakao T, Nagai H.Comprehensive reports of epidemic hemorrhagic fever (Korean hemorrhagic fever)observed in Sapporo Medical College in 1981 Sapporo Med J 1981; 51: suppl.K1-K41
21. Desmyter J. Laboratory rat Hantaan virus infection in Europe (presented by Johnson,KN). Fourth International Conference on Comparative Virology, Banff, Canada,October, 1982
22. Umenai T, Watanabe M, Sekino H, et al Korean hemorrhagic fever among ruralresidents in Japan J Infect Dis 1982; 44: 460-63.
23. Lee HW Korean hemorrhagic fever. In: Melnick JL, ed. Progress in medical virology,vol. 28 Basel Karger, 1982: 96-113
24. Gajdusek DC, Gibbs CJ, Jr, Lee HW. Virus hemorrhagic fever with renal syndrome(HFRS). a sylvatic zoonosis of the Eurasian continent. I. Evidence for straindifferences: differing rodent reservoirs, virulence for man, and patterns of seasonaloccurrence in various foci. Abstracts of Tenth International Congress on TropicalMedicine and Malaria, Manila, 1980 61.
25. Lee PW, Yanagihara R, Franko MC, Amyx HL, Gibbs CJ, Jr, Gajdusek DC, Traub R.Preliminary evidence that Hantaan or a closely related virus is enzootic in domesticrodents. N Engl J Med 1982; 307: 624-25.
26. LeDuc JW, Smith GA, Hasty SE, Johnson KM. Preliminary evidence that Hantaan ora closely related virus is enzootic in domestic animals. N Engl J Med 1982; 307: 624.
27. Tsai TF, Bauer SP, Sasso DR, et al Preliminary evidence that Hantaan or a closelyrelated virus is enzootic in domestic rodents. N Engl J Med 1982; 307: 623-24.
28. Gibbs CJ, Jr, Lee PW, Gajdusek DC Virus hemorrhagic fever with renal syndrome.IV. Serological evidence of the presence of a virus of the hemorrhagic fever withrenal syndrome group in North and South America and in India. Abstracts of TenthInternational Congress on Tropical Medicine and Malaria, Manila, 1980: 42.
29. Lee PW, Gibbs CJ, Jr, Gajdusek DC, Svedmyr A. Antibody to Korean haemorrhagicfever virus in man in parts of the world where haemorrhagic fever with renalsyndrome is not known. Lancet 1981; ii: 256.
1407 Dr Gibbs and his co-workers report positivefindings in 2 renal patients and 1 hospital employee.The Hantaan virus was isolated from the lungs of naturally
infected wild-caught Apodemus agrarius, collected in the
endemic areas of Korea, by serial passage - of lung tissueto uninfected A. agrarius mice. The indirect immuno-
fluorescence test showed development of anti-KHFantibodies in sera and specific KHF virus antigen in the lungsof recipient mice. Subsequently, the virus was adapted togrowth in Fisher and Wistar laboratory rats, 30 in nude
mice,31 and in Vero E-6 (a clone of African green monkeykidney)3-’ and A-549 (human lung carcinoma) continuous celllines.33 Virus-infected lung and kidney cell lines provideexcellent sources of antigen for immunofluorescence tests.Virions resembling those of known Bunyaviridae have beenfound in KHF-infected cells by electron microscopy;32,34theputative virions are spherical to oval particles with unitmembranes and subunit surface structures with an averagediameter of about 95 nm and a buoyant density of 1’ 15 -1 18g/ml. Lately, the tripartite RNA genome of the Bunyavirusgroup has been demonstrated for Hantaan virus. 35 Althoughaggregates of virions were observed by immune electronmicroscopy after reaction with human and rabbit anti-KHFantibodies, no such reaction has been observed withantibodies to other viruses of the Bunyamwera supergroup. 34An enzyme immunoassay test has been developed for the76-118 strain of the Hantaan virus by means of A-549 andVero E-6 infected cells, and on p. 1405 Dr Lee and co-workers show how blocking antibody tests are providing newsensitive methods for antibody estimation and evidence ofantigenic variations among different strains of the virus.The virus causing nephropathia epidemica of Scandinavia
has been demonstrated in the lungs ofC7n’oMo?My/<2?’go/Mvoles trapped in the endemic regions, and on passage intoseronegative C. glareolus has resulted in development ofnephropathia-epidemica-specific antibody and the appear-ance of viral antigen in their lungs.36 However, the virus hasnot yet been maintained in serial passage in vivo nor has itbeen adapted to growth in vitro. Until lately, none of therodents susceptible to KHF or nephropathia epidemicaviruses became obviously ill, so there was no laboratorymodel for assessing virulence of different strains. Tsai reportsthat intracerebral inoculation of the E-6 adapted Hantaanvirus into 2-4-day-old suckling mice results in pantropicinfection, with increasing virulence for mice with successivepassages. 37Since bleeding is seldom a feature either of urban
cases of HFRS acquired from contact with urban rats inKorea and Japan or of nephropathia epidemica
30. Lee PW, Amyx HL, Gibbs CJ, Jr, Gajdusek DC, Lee HW Propagation of Koreanhemorrhagic fever virus in laboratory rats. Infect Immun 1981, 31: 334-38
31. Lee PW, Amyx HL, Gajdusek DC. The susceptibility of nude mice to Hantaan virus.Proc Soc Exp Biol Med (in press)
32. McCormick JB, Palmer EL, Sasso DR, Kiley MP Morphological identification of theagent of Korean haemorrhagic fever (Hantaan virus) as a member of the
Bunyaviridae. Lancet 1982; i: 765-6833. French GR, Foulke RS, Brand OA, Eddy GA, Lee HW, Lee PW. Korean hemorrhagic
fever: propagation ofthe etiologic agent m a cell line ofhuman origin. Science 1981,211: 1046-48.
34. White JD, Shirey FG, French GR, Huggins JW, Brand OM, Lee HW Hantaan virus,aetiological agent of Korean hemorrhagic fever, has Bunyaviridae-like morphologyLancet 1982, i: 768-71.
35. Dalrymple J, Hestys S, Harrison S, Schmaljohn C. Partial characterisation of Hantaanvirus. Abstracts of Fourth International Conference on Comparative Virology,Banff, Canada, October, 1982: 117.
36. Brummer-Korvenkonito M, Vaheri A, von Bonsdorff CH, et al Nephropathiaepidemica: detection of antigen in bank voles and serologic diagnosis of humaninfection. J Infect Dis 1980; 141: 131-34
37. Tsai TF, Bauer S, McCormick JB, Kurata T Intracerebral inoculation of sucklingmice with Hantaan virus. Lancet 1982; ii: 503-04.
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acquired from voles in Scandinavia, the termhaemorrhagic fever for these entities is misleading.Although occasionally the illness may be so mild as tomake the diagnosis difficult, all patients have
proteinuria and azotaemia and some show petechiae,haemoconcentration, hypotension, and renal failure.Only about one-fifth have severe features such as shock,major haemorrhage, and gross fluid and electrolyteimbalance. Illness of moderate severity is conveniently,if rather arbitrarily, divided into five phases-febrile,hypotensive (shock), oliguric, diuretic, andconvalescent.I,5,19,22 Except in those who have hadcentral nervous system haemorrhages, completerecovery is usual, with apparent immunity to
reinfection. 13,19The antibody patterns reported by Dr Lee and his co-
workers suggest the possibility of at least a third virusantigenic type in addition to Hantaan and
nephropathia epidemica, and also the possiblepresence of the East Asian type of virus in Europe. Thevirus is carried to man by excretions and aerosols fromhealthy rodent carriers which excrete the virus indroplets from their lungs and in saliva and urine. Sinceall of these rodent carriers apparently belong to thesuprafamily Muroidae and the genera Apodemus,Clethrionomys, Microtus, and Rattus, and because allpatients have some degree of renal involvement whilemany have no haemorrhages, Gajdusek has suggestedthe name "muroid virus nephropathies" to replaceHFRS.19 He and his co-workers have prepared a
comprehensive bibliography-of the published work onHFRS.38
Malaria and the Red Cell
As pointed out in a recent volume of the BritishMedical Bulletin, the world health threat posed bymalaria is almost as frightening as it was 30 years ago.The achievements and failures of the global malariaeradication programme are still hotly debated. The factremains that the parasite reservoir throughout theworld is still immense, and according to W.H.O.estimates some 1620 million people inhabit areas inwhich exposure to malaria infection is moderate to
high.2 In 1978, 13’7 million cases of malaria werenotified to W.H.O.; almost certainly this is a consider-able underestimate of the real incidence of the disease.The genome of the parasite (and its vector) seems to befar more cunning than the pharmaceutical andchemical industries, and there is a genuine fear that,unless new approaches to prevention or therapy aredeveloped, matters may get worse.In summarising the current state of research in
38. Gajdusek DC, Goldgaber D, Millard E, Ono S. Bibliography of hemorrhagic fever withrenal syndrome (muroid virus nephropathies). Bethesda, Maryland: NationalInstitutes of Health, 1982.
1. Cohen S, ed. Malaria. Br Med Bull 1982; 38: 115-218.2. Bruce-Chwatt LJ. Imported malaria an uninvited guest Br Med Bill 1982; 38:
malaria vaccines Cohen3 draws attention to a curious
paradox. While in man the slow development andincomplete nature of naturally acquired immunity tomalaria does not encourage hopes of vaccination
against this disease, experimental vaccination againstrodent, simian, and human plasmodia frequentlyinduces a greater immunity than that engendered bythe corresponding natural infection. Although stage-specific immunity to sporozoites, merozoites, andgametocytes has been achieved in various experimentalsystems, culture techniques cannot supply these formsof plasmodia in sufficient quantity for a vaccinationprogramme. Hence, attention has focused lately on theisolation and characterisation of stage-specificantigens-an approach much helped by the advent ofhybridoma and recombinant DNA technology. Manyantigens from sporozoites, merozoites, or gametes arenow being analysed as possible candidates for a role invaccine development. For success, this type ofmolecular fishing expedition requires a great amountof luck, particularly in view of the parasite’s constantlychanging genome. In this context it might be veryhelpful to know which parasite proteins are of criticalimportance in interactions with the host; presumablymolecules of this type would be less likely to undergomutational modification.The main target cell of the malarial parasite is the
erythrocyte. Because of the high specificity of par-ticular parasites for erythrocytes of different species,the identification of putative receptors on these cellsmight offer the possibility of identifying parasiteantigens which interact with them and hence whichmight be of particular functional importance. Oneapproach is to study the interaction of malarial
parasites with red cells which have well-defined
genetically determined differences of their membranestructure. This notion was pioneered by Miller and hiscolleagues4 who showed that human erythrocyteslacking the Duffy blood group are refractory to
invasion by merozoites of Plasmodium knowlesi.
However, further work on this system has underlinedthe complexity of the invasion mechanism. For
example, although Duffy-negative human red cells arenot invaded by P. knowlesi, merozoites recognise andbecome attached to them;5 invasion must therefore be amulti-step process. Pasvol and Wilson have employeda similar approach to study the interaction betweenP. falciparum and human red cells. A few years ago itwas noticed that, although human red cells lackingmany individual blood-group antigens includingDuffy are susceptible to P. falciparum, cells fromindividuals with the rare En(a-) variant might be
3. Cohen S. Progress in malaria vaccine development. Br Med Bull 1982; 38: 161-664. Miller LH, Mason SJ. Dvorak JA. McGinniss MH, Rothman IK. Erythrocyte
receptors for (Plasmodium knowlesi) malaria Duffy blood group determinants.Science 1975, 189: 561-63.
5. Miller LH, Alkawa M Johnson JG, Shiroishi T. Interaction between cytochalasinB-treated malarial parasites and erythrocytes Attachment and junction formation JExp Med 1979, 149: 172-84
6. Pasvol G, Wilson RJM. The interaction of malaria parasites with red blood cells BrMed Bull 1982; 38: 133-40.
