Hantaviruses: History and Overview

  • K. M. Johnson
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 256)


As early as 1913, Russian clinical records from far eastern Siberia describe the human viral disease now known as hemorrhagic fever with renal syndrome (HFRS) (Casals et al. 1970). Dr. Ho Wang Lee (1982) found a Chinese medical account of a similar disease dating to about A.D. 960. This is not surprising in view of its unique renal complication and the fact that the etiologic agent of HFRS proved to be a zoonotic virus that causes chronic infection with urinary excretion in the murid rodent, Apodemus agrarius. This mouse is the most common wild rodent over much of northern and eastern Asia and often invades cultivated fields, gardens, haystacks, and sometimes human dwellings. Human conflict during the lethal 20th century also played a prominent role in elucidation of the etiology, clinical evolution, epidemiology, and ecology of HFRS. “Field nephritis”, which occurred in both allied and German troops in Flanders during World War I, may well have been caused by a hantavirus now known to occur in western Europe and Scandinavia (Bradford 1916; Arnold 1944). Japanese military physicians encountered the disease in the mid 1930s after invading Manchuria (Kitano 1944), Finnish and German soldiers were affected during World War II (Stuhlfauth 1943; Hortung 1944), and UN troops first encountered the original hantavirus during the Korean Conflict in 1951 (Smadel 1953).


Hemorrhagic Fever Hemorrhagic Fever With Renal Syndrome Indian Health Service Lassa Fever Nephropathia Epidemica 
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  1. Arnold OH (1944) Die sogenannte Feldnephritis; klinische Studie zur Symptomologie, Pathologie und Artiologie einer akuten diffusion Gefasserkrankung infektioser Genese. Thieme, LeipzigGoogle Scholar
  2. Arthur RR, Lofts RS, Gomez J, Glass GE, LeDuc JW, Childs JE (1992) Grouping of hantaviruses by small (s) genome segment polymerase chain reaction and amplification of viral RNA from wild-caught rats. Am J Trop Med Hyg 47:210–224PubMedGoogle Scholar
  3. Avsic-Zupanc T, Xiao SY, Stojanovic R, Gligic A, van der Groen G, LeDuc JW (1992) Characterization of Dobrava virus: a hantavirus from Slovenia, Yugoslavia. J Med Virol 38:132–137PubMedCrossRefGoogle Scholar
  4. Bradford JR (1916) Nephritis in the British troops in Flanders Qland. J Med 9:445–459Google Scholar
  5. Brummer-Korvenkontio M, Vahari A, von Bonsdorff CH, Vuorimies J, Manni T, Penttinen K, Oker-Blom N, Laehdvirta J (1980) Nephropathia epidemica: detection of antigen in bank voles and serologic diagnosis of human infection. J Infect Dis 141:131–134PubMedCrossRefGoogle Scholar
  6. Casals J, Henderson BE, Hoogstraal H, Johnson KM, Shelokov A (1970) A review of Soviet viral hemorrhagic fevers, 1969. J Infect Dis 122:437–453PubMedCrossRefGoogle Scholar
  7. Childs JE, Korch GW, Glass GE, LeDuc JW, Shah KV (1987) Epizootiology of hantavirus infections in Baltimore: isolation of a virus from Norway rats, and characteristics of infected rat populations. Am J of Epi 126:55–68Google Scholar
  8. Childs JE, Ksiazek TG, Spiropoulou CF, Krebs JW, Morzunov S, Maupin GO, Gage KL, Rollin PE, Sarisky J, Enscore RE, Frey JK, Peters CJ, Nichol ST (1994) Serologic and genetic identification of Peromyscus maniculatus as the primary rodent reservoir for a new hantavirus in the southwestern United States. J Infect Dis 169:1271–1280PubMedCrossRefGoogle Scholar
  9. Cho HW, Howard CR (1999) Antibody responses in humans to an inactivated hantavirus vaccine (Hantavax). Vaccine 17:2569–2575PubMedCrossRefGoogle Scholar
  10. Chu Y-K, Jennings G, Schmaljohn A, Elgh F, Hjelle B, Lee H-W, Jenison S, Ksiazek T, Peters CJ, Rollin P, Schmaljohn C (1995) Cross-neutralization of hantaviruses with immune sera from experimentally infected animals and from hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome patients. J Infect Dis 172:1581–1584PubMedCrossRefGoogle Scholar
  11. Crowley MR, Katz RW, Kessler R, Simpson SQ, Levy H, Hallin GW, Cappon J, Krahling JB, Wernly J (1998) Successful treatment of adults with severe hantavirus pulmonary syndrome with extracorporeal membrane oxygenation. Crit Care Med F 26:409–414CrossRefGoogle Scholar
  12. Desmyter J, Johnson KM, Deckers C, LeDuc JW, Brasseur F, van Ypersele de Strihou C (1983) Laboratory rat associated outbreak of haemorrhagic fever with renal syndrome due to Hantaan-like virus in Belgium. Lancet ii: 1445–1448CrossRefGoogle Scholar
  13. Earle DP (1954) Symposium on epidemic hemorrhagic fever. Am J Med 16:617–709CrossRefGoogle Scholar
  14. Earley EM, Johnson KM (1988) The lineage of the vero, vero 76 and its clone C1008 in the United States. In: Simizu B, Terasima T (eds) Vero cells - origin, properties and biomedical applications. Department of Microbiology, School of Medicine, Chiba University, JapanGoogle Scholar
  15. Engelthaler DM, Mosley DG, Cheek JE, Levy CE, Komatsu KK, Ettestad P, Davis T, Tanda DT, Miller L, Frampton JW, Porter R, Bryan RT (1999) Climatic and environmental patterns associated with hantavirus pulmonary syndrome, Four Corners region, United States. Emerg Infect Dis 5:87–94PubMedCrossRefGoogle Scholar
  16. Ennis FA, Cruz J, Spiropoulou CF, Waite D, Peters CJ, Nichol ST, Kariwa H, Koster FT (1997) Hantavirus pulmonary syndrome: CD8+ and CD4+ cytotoxic T lymphocytes to epitopes on Sin Nombre virus nucleocapsid protein isolated during acute illness. Virology 238:380–390PubMedCrossRefGoogle Scholar
  17. Feldmann H, Sanchez A, Morzunov S, Spiropoulou CF, Rollin PE, Ksiazek TG, Peters CJ, Nichol ST (1993) Utilization of autopsy RNA for the synthesis of the nucleocapsid antigen of a newly recognized virus associated with hantavirus pulmonary syndrome. Virus Res 30:351–367PubMedCrossRefGoogle Scholar
  18. Ferrer JF, Jonsson CB, Esteban E, Galligan D, Basombrio MA, Peralta-Ramos M, Bharadwaj M, Torrez-Martinez N, Callahan J, Segovia A, Hjelle B (1998) High prevalence of hantavirus infection in Indian communities of the Paraguayan and Argentinean Gran Chaco. Am J Trop Med Hyg 59:438–444PubMedGoogle Scholar
  19. Frampton JW, Lanser S, Nichols CR (1995) Sin Nombre virus infection in 1959. Lancet 346:781–782PubMedCrossRefGoogle Scholar
  20. French GR, Foulke RS, Brand OA, Eddy GA, Lee HW, Lee PW (1981) Propagation of etiologic agent of Korean hemorrhagic fever in a cultured continuous cell line of human origin. Science 211:1046–1048PubMedCrossRefGoogle Scholar
  21. Gajdusek DC (1962) Viral hemorrhagic fevers. J Ped 60:841–857CrossRefGoogle Scholar
  22. Hallin GW, Simpson SQ, Crowell RE, James DS, Koster FT, Mertz GJ, Levy H (1996) Cardiopulmonary manifestations of hantavirus pulmonary syndrome. Crit Care Med 24:252–258PubMedCrossRefGoogle Scholar
  23. Hortling H (1944) Leptospiro sista muistuttava epidemia Lapissa Sotilaslaak Aikak 19:8–19Google Scholar
  24. Huggins JW, Kim GR, Brand OM, McKee KT Jr (1986) Ribavirin therapy for Hantaan virus infection in suckling mice. J Infect Dis 153:489–497PubMedCrossRefGoogle Scholar
  25. Huggins JW, Hsiang CM, Cosgriff TM, Guang MY, Smith JI, Wu ZO, LeDuc JW, Zheng ZM, Meegan JM, Wang QN, Oland DD, Gui XE, Gibbs PH, Yuan GH, Zhang TM (1991) Prospective, double-blind,concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome. J Infect Dis 164:1119–1127PubMedCrossRefGoogle Scholar
  26. Ishii S (1942) Studies on Song-go fever. Jap Army Med J 355:1755–1758Google Scholar
  27. Johnson KM, Mackenzie RB, Webb PA, Kuns ML (1965a) Chronic infection of rodents by Machupo virus. Science 150:1618–1619PubMedCrossRefGoogle Scholar
  28. Johnson KM, Wiebenga NH, Mackenzie RB, Kuns ML, Tauraso NM, Shelokov A, Webb PA, Justines G, Beye HK (1965b) Virus isolations from human cases of hemorrhagic fever in Bolivia. Proc Soc Exp Biol Med 118:113–118PubMedGoogle Scholar
  29. Kanerva M, Vaheri A, Mustonen J, Partanen J (1998) High-producer allele of tumour necrosis factoralpha is part of the susceptibility MHC haplotype in severe Puumala virus-induced nephropathia epidemica. Scand J Infect Dis 30:532–534PubMedCrossRefGoogle Scholar
  30. Khan AS, Khabbaz RF, Armstrong LR, Holman RC, Bauer SP, Graber J, Strine T, Miller G, Reef S, Tappero J, Rollin PE, Nichol ST, Zaki SR, Bryan RT, Chapman LE, Peters CJ, Ksiazek TG (1996) Hantavirus pulmonary syndrome: the first 100 US cases. J Infect Dis 173:1297–1303PubMedCrossRefGoogle Scholar
  31. Kitano M (1944) A study of epidemic hemorrhagic fever. J Manchou Med 19:191–209Google Scholar
  32. Kulagin SM, Fedorova NI, Ketiladze ES (1962) Laboratory outbreak of hemorrhagic fever with renal syndrome (Russian). J Micro Epidemiol Immunol 33:121–126Google Scholar
  33. Kuns ML (1965) Symposium on some aspects of hemorrhagic fevers in the Americas. Epidemiology of Machupo virus infection. II. Ecological and control studies of hemorrhagic fever. Amer J Trop Med Hyg 14:813–816Google Scholar
  34. Lahdevirta J (1971) Nephropathia epidemica in Finland. Ann Clin Res (Finland) 3:1154Google Scholar
  35. Lahdevirta J, Savola J, Brummer-Korvenkontio M, Berndt R, Illikainen R, Vaheri A (1984) Clinical and serological diagnosis of nephropathia epidemica, the mild type of haemorrhagic fever with renal syndrome. J Infect 9:230–238PubMedCrossRefGoogle Scholar
  36. LeDuc JW, Smith GA, Johnson KM (1984) Hantaan-like viruses from domestic rats captured in the United States. Am J Trop Med Hyg 33:992–998PubMedGoogle Scholar
  37. LeDuc JW, Smith GA, Pinheiro FP, Vasconcelos PFC, Rosa EST, Maiztequi J (1985) Isolation of a Hantaan-related virus from Brazilian rats and serologic evidence of its widespread distribution in South America. J Trop Med Hyg 34:810–815Google Scholar
  38. LeDuc JW, Ksiazek TG, Rossi CA, Dalrymple JM (1990) A retrospective analysis of sera collected by the hemorrhagic fever commission during the Korean conflict. J Infect Dis 162:1182–1184PubMedCrossRefGoogle Scholar
  39. Lee HW (1982) Korean hemorrhagic fever. Prog Med Virol 28:96–113PubMedGoogle Scholar
  40. Lee HW, Lee PW (1976) Korean hemorrhagic fever. I. Demonstration of causative antigen and antibodies. Korean J Int Med 19:371–384Google Scholar
  41. Lee HW, Lee PW, Johnson KM (1978) Isolation of the etiologic agent of Korean hemorrhagic fever. J Infect Dis 137:298–308PubMedCrossRefGoogle Scholar
  42. Lee HW, Lee PW, Lahdevirta J, Brummer-Korvenkontio M (1979a) Aetiological relation between Korean haemorrhagic fever and nephropathia epidemica. Lancet 1:186–187PubMedGoogle Scholar
  43. Lee HW, Lee PW, Tamura M, Tamura T, Okuno Y (1979b) Etiological relation between Korean hemorrhagic fever and epidemic hemorrhagic fever in Japan. Biken J 22:41–45PubMedGoogle Scholar
  44. Lee HW, Lee PW, Baek LJ, Song CK, Seong IW (1981) Intraspecific transmission of Hantaan virus, etiologic agent of Korean hemorrhagic fever, in the rodent Apodemus agrarius. Am J Trop Med Hyg 30:1106–1112PubMedGoogle Scholar
  45. Lee HW, Baek LJ, Johnson KM (1982) Isolation of hantaan virus, the etiologic agent of Korean hemorrhagic fever, from wild urban rats. J Infect Dis 146:638–644PubMedCrossRefGoogle Scholar
  46. Lee PW, Amyx HL, Yanagihara R, Gajdusek DC, Goldgarber D, Gibbs CJ Jr (1985) Partial characterization of Prospect Hill virus isolated from meadow voles in the United States. J Infect Dis 152:826–829PubMedCrossRefGoogle Scholar
  47. Levis S, Rowe JE, Morzunov S, Enria DA, St Jeor S (1997) New hantaviruses causing hantavirus pulmonary syndrome in central Argentina. Lancet 349:998–999PubMedCrossRefGoogle Scholar
  48. Lloyd G, Jones N (1986) Infection of laboratory workers with hantavirus acquired from immunocytomas propagated in laboratory rats. J Infect 12:117–125PubMedCrossRefGoogle Scholar
  49. Matsumoto Y, Nishino K, Yagura T (1964) A case report of suspicious epidemic hemorrhagic fever. Biken J 7:95–106PubMedGoogle Scholar
  50. McCormick JB, Sasso DR, Palmer EL, Kiley MP (1982) Morphological identification of the agent of Korean haemorrhagic fever (Hantaan virus) as a member of the bunyaviridae. Lancet .1:765–768PubMedCrossRefGoogle Scholar
  51. Mills JN, Yates TL, Ksiazek TG, Peters CJ, Childs JE (1999) Long-term studies of hantavirus reservoir populations in the southwestern United States: rationale, potential, and methods. Emerg Infect Dis 5:95–101PubMedCrossRefGoogle Scholar
  52. MMWR Morb Mortal Wkly Rep (1993a) Outbreak of acute illness - Southwestern United States, 1993. 42:421–424Google Scholar
  53. MMWR Morb Mortal Wkly Rep (1993b) Update: outbreak of hantavirus infection - Southwestern United States, 1993. 42:441–443Google Scholar
  54. Mori M, Rothman AL, Kurane I, Montoya JM, Nolte KB, Norman JE, Waite DC, Koster FT, Ennis FA (1999) High levels of cytokine-producing cells in the lung tissues of patients with fatal hantavirus pulmonary syndrome. J Infect Dis 179:295–302PubMedCrossRefGoogle Scholar
  55. Mustonen J, Partanen J, Kanerva M, Pietila K, Vapalahti O, Pasternack A, Vaheri A (1998) Association of HLA B27 with benign clinical course of nephropathia epidemica caused by Puumala hantavirus. Scand J Immunol 47:277–279PubMedCrossRefGoogle Scholar
  56. Mustonen J, Partanen J, Kanerva M, Pietila K, Vapalahti O, Pasternack A, Vaheri A (1996) Genetic susceptibility to severe course of nephropathia epidemica caused by Puumala hantavirus. Kidney Int 49:217–221PubMedCrossRefGoogle Scholar
  57. Myhrman G (1951) Nephropathia epidemica: a new infectious disease in Northern Scandanavia. Acta Med Scand 140:52–56PubMedCrossRefGoogle Scholar
  58. Nichol ST, Spiropoulou CF, Morzunov S, Rollin PE, Ksiazek TG, Feldmann H, Sanchez A, Childs J, Zaki S, Peters CJ (1993) Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness. Science 262:914–917PubMedCrossRefGoogle Scholar
  59. Nolte KB, Feddersen RM, Foucar K, Zaki SR, Koster FT, Madar D, Merlin TL, McFeeley PJ, Umland ET, Zumwalt RE (1995) Hantavirus pulmonary syndrome in the United States: a pathological description of a disease caused by a new agent. Hum Pathol 26:110–120PubMedCrossRefGoogle Scholar
  60. Nystom K (1982) Epidemiology of HFRS (endemic benign nephropathy - EBN) in Sweden. Scand J Infect Dis Suppl 36:92Google Scholar
  61. Padula PJ, Edelstein A, Miguel SD, Lopez NM, Rossi CM, Rabinovich RD (1998) Hantavirus pulmonary syndrome outbreak in Argentina: molecular evidence for person-to-person transmission of Andes virus. Virology 241:323–30PubMedCrossRefGoogle Scholar
  62. Parmenter RR, Brunt JW, Moore DI, Ernest S (1993) The hantavirus epidemic in the Southwest: rodent population dynamics and the implications for transmission of hantavirus-associated adult respiratory distress syndrome (HARDS) in the four corners region. Sevilleta LTER publication no. 41. Albuquerque, University of New Mexico, New MexicoGoogle Scholar
  63. Peters CJ, Simpson GL, Levy H (1999) Spectrum of Hantavirus infection: Hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Annu Rev Med 50:531–545PubMedCrossRefGoogle Scholar
  64. Puthavathana P, Lee HW, Kang CY (1992) Typing of hantaviruses from five continents by polymerase chain reaction. Virus Res 26:1–14PubMedCrossRefGoogle Scholar
  65. Schmaljohn CS, Dalrymple JM (1983) Analysis of Hantaan virus RNA: evidence for a new genus of Bunyaviridae. Virology 131:482–491PubMedCrossRefGoogle Scholar
  66. Schmaljohn CS, Hasty SE, Dalrymple JM, LeDuc JW, Lee HW, von Bonsdorff CH, Brummer-Korvenkontio M, Vaheri A, Tsai TF, Regnery HL, Goldgaber D, Lee PW (1985) Antigenic and genetic properties of viruses linked to hemorrhagic fever with renal syndrome. Science 227:1041–1044PubMedCrossRefGoogle Scholar
  67. Smadel JE (1953) Epidemic hemorrhagic fever. Am J Pub Hlth 43:1327–1330CrossRefGoogle Scholar
  68. Smorodintsev AA, Chudakov VG, Churilov AV (1959) Haemorrhagic nephroso-nephritis. In: Chapter 3: epidemiology. Pergamon Press, New YorkGoogle Scholar
  69. Stuhlfauth K (1943) Bericht uber ein neues schlammfieberahnliches krankheitsbild bei Deutschen truppen in Lappland. Dtsch Med Wochenschr 69:439–443CrossRefGoogle Scholar
  70. Svedmyr A, Lee PW, Goldgaber D, Yanagihara R, Gajdusek DC, Gibbs CJ, Nystrom K (1982) Antigenic differences between European and East Asian strains of HFRS virus. Scand J Infect Dis Suppl 36:86–87PubMedGoogle Scholar
  71. Tamura M (1964) Occurrence of epidemic hemorrhagic fever in Osaka City: first cases found in Japan with characteristic feature of marked proteinuria. Biken J 7:79–94PubMedGoogle Scholar
  72. Toro J, Vega JD, Khan AS, Mills JN, Padula P, Terry W, Yadon Z, Valderrama R, Ellis BA, Pavletic C, Cerda R, Zaki S, Shieh WJ, Meyer R, Tapia M, Mansilla C, Baro M, Vergara JA, Concha M, Calderon G, Enria D, Peters CJ, Ksiazek TG (1998) An outbreak of hantavirus pulmonary syndrome, Chile, 1997. Emerg Infect Dis 4:687–694PubMedCrossRefGoogle Scholar
  73. Traub R, Hertig M, Lawrence WH, Harriss TT (1954) Potential vectors and reservoirs of hemorrhagic fever in Korea. Am J Hyg 59:291–305PubMedGoogle Scholar
  74. Trencseni T, Keleti B (1971) Clinical aspects and epidemiology of haemorrhagic fever with renal syndrome. Akademiai Kiado, BudapestGoogle Scholar
  75. Tsai TF, Bauer SP, Sasso DR, Whitfield SG, McCormick JB, Caraway TC, McFarland L, Bradford H, Kurata T (1985) Serological and virological evidence of a Hantaan virus-related enzootic in the United States. J Infect Dis 152:126–144PubMedCrossRefGoogle Scholar
  76. Umenai T, Lee PW, Toyoda T, Yoshinaga K, Horiuchi T, Lee HW, Saito T, Hongo M, Nobunaga T, Ishida N (1979) Korean haemorrhagic fever in staff in an animal laboratory. Lancet 1:1314–1316PubMedCrossRefGoogle Scholar
  77. White JD, Shirey FG, French GR, Huggins JW, Brand OM, Lee HW (1982) Hantaan virus, aetiological agent of Korean haemorrhagic fever, has bunyaviridae-like morphology. Lancet 1:768–771PubMedCrossRefGoogle Scholar
  78. Xiao S-Y, Chu Y-K, Knauert FIK, Lofts R, Dalrymple JM, LeDuc JW (1992) Comparison of hantavirus isolates using a genus reactive primer pair polymerase chain reaction. J Gen Virol 73:567–573PubMedCrossRefGoogle Scholar
  79. Yankovski AK, Povalishina TP (1967) Hemorrhagic fever with a renal syndrome caused by aerial contamination. Mil Med J (Russian) 7:66–69Google Scholar
  80. Zaki SR, Greer PW, Coffield LM, Goldsmith CS, Nolte KB, Foucar K, Feddersen RM, Zum walt RE, Miller GL, Khan AS, et al. (1995) Hantavirus pulmonary syndrome. Pathogenesis of an emerging infectious disease. Am J Pathol 146:552–579PubMedGoogle Scholar
  81. Zaki SR, Khan AS, Goodman RA, Armstrong LR, Greer PW, Coffield LM, Ksiazek TG, Rollin PE, Peters CJ, Khabbaz RF (1996) Retrospective diagnosis of hantavirus pulmonary syndrome, 1978–1993: implications for emerging infectious diseases. Arch Pathol Lab Med 120:134–139PubMedGoogle Scholar
  82. Zeller HG, Karabatsos N, Calisher CH, Digoutte J-P, Cropp CB, Murphy FA, Shope RE (1989) Electron microscopic and antigenic studies of uncharacterized viruses. II. Evidence suggesting the placement of viruses in the family Bunyaviridae. Arch Virol 108:211–227PubMedCrossRefGoogle Scholar
  83. Zhu ZY, Tang HY, Li YJ, Weng JQ, Yu YX, Zeng RF (1994) Investigation on inactivated epidemic hemorrhagic fever tissue culture vaccine in humans. Chin Med J 107:167–170PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2001

Authors and Affiliations

  • K. M. Johnson
    • 1
  1. 1.Departments of Biology and MedicineUniversity of New MexicoPlacitasUSA

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