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. 1995 Mar;146(3):552–579.

Hantavirus Pulmonary Syndrome

Pathogenesis of an Emerging Infectious Disease

Sherif R Zaki, Patricia w Greer, Lisa M Coffield, Cynthia S Goldsmith, Kurt B Nolte, Kathy Foucar, Richard M Feddersen, Ross E Zumwalt, Gayle L Miller, Ali S Khan, Pierre E Rollin, Thomas G Ksiazek, Stuart T Nichol, Brian WJ Mahy, Clarence J Peters
PMCID: PMC1869168  PMID: 7887439

Abstract

A recent outbreak of a severe pulmonary disease in the southwestern United States was etiologically linked to a previously unrecognized bantavirus. The virus has been isolated from its majorreservoir, the deer mouse, Peromyscus maniculatus,and recently named Sin Nombre virus. Clinically, the disease has become known as the bantavirus pulmonary syndrome (HPS). Since May 1993, 44 fatal cases of HPS have been identified through clinicopathological review and immunobistochemical(IHC) testing of tissues from 273 patients who died of an unexplained noncardiogenic pulmonary edema. In 158 cases for which suitable specimens were available, serologicaltesting and/or reverse transcription-polymerase chain reaction (RT-PCR) amplification of extracted RNA was also performed. IHC, serological, and PCR results were concordant for virtually all HPS and non-HPS patients when more than one assay was performed. The prodromal ilness of HPS is similar to that of many other viral diseases. Consistent bematological features include thrombocytopenia, bemoconcentration, neutropbilic leukocytosis with a left shift, and reactivel lymphocytes. Pulmonary bistopatbological features were similar in most of the fatal HPS cases (40/44) and consisted of an interstitial pneumonitis with a variable mononuclear cell infiltrate, edema, and focal byaline membranes. In four cases, bowever, pulmonary features were significantly different and included diffuse alveolar damage and variable degrees of severe air space disorganization. IHC analysis showed widespread presence of bantaviral antigens in endothelial cells of the microvasculature, particularly in the lung. Hantaviral antigens were also observed within follicular dendritic cells, macrophages, and lymphocytes. Hantaviral inclusions were observed in endothelial cells of lungs by thinsection electron microscopy, and their identity was verified by immunogold labeling. Virus-like particles were seen in pulmonary endothelial cells and macropbages. HPS is a newly recognized, often fatal disease, with a spectrum of microscopic morphological changes, which may be an important cause of severe and fatal illness presenting as adult respiratory distress syndrome.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Belloni P. N., Carney D. H., Nicolson G. L. Organ-derived microvessel endothelial cells exhibit differential responsiveness to thrombin and other growth factors. Microvasc Res. 1992 Jan;43(1):20–45. doi: 10.1016/0026-2862(92)90004-9. [DOI] [PubMed] [Google Scholar]
  2. Berman J. S., Beer D. J., Theodore A. C., Kornfeld H., Bernardo J., Center D. M. Lymphocyte recruitment to the lung. Am Rev Respir Dis. 1990 Jul;142(1):238–257. doi: 10.1164/ajrccm/142.1.238. [DOI] [PubMed] [Google Scholar]
  3. Bevilacqua M. P., Nelson R. M., Mannori G., Cecconi O. Endothelial-leukocyte adhesion molecules in human disease. Annu Rev Med. 1994;45:361–378. doi: 10.1146/annurev.med.45.1.361. [DOI] [PubMed] [Google Scholar]
  4. Brown Z., Gerritsen M. E., Carley W. W., Strieter R. M., Kunkel S. L., Westwick J. Chemokine gene expression and secretion by cytokine-activated human microvascular endothelial cells. Differential regulation of monocyte chemoattractant protein-1 and interleukin-8 in response to interferon-gamma. Am J Pathol. 1994 Oct;145(4):913–921. [PMC free article] [PubMed] [Google Scholar]
  5. Chakrabarti L., Isola P., Cumont M. C., Claessens-Maire M. A., Hurtrel M., Montagnier L., Hurtrel B. Early stages of simian immunodeficiency virus infection in lymph nodes. Evidence for high viral load and successive populations of target cells. Am J Pathol. 1994 Jun;144(6):1226–1237. [PMC free article] [PubMed] [Google Scholar]
  6. Chapman L. E., Khabbaz R. F. Etiology and epidemiology of the Four Corners hantavirus outbreak. Infect Agents Dis. 1994 Oct;3(5):234–244. [PubMed] [Google Scholar]
  7. Chen L. B., Yang W. S. Abnormalities of T cell immunoregulation in hemorrhagic fever with renal syndrome. J Infect Dis. 1990 May;161(5):1016–1019. doi: 10.1093/infdis/161.5.1016. [DOI] [PubMed] [Google Scholar]
  8. Childs J. E., Ksiazek T. G., Spiropoulou C. F., Krebs J. W., Morzunov S., Maupin G. O., Gage K. L., Rollin P. E., Sarisky J., Enscore R. E. Serologic and genetic identification of Peromyscus maniculatus as the primary rodent reservoir for a new hantavirus in the southwestern United States. J Infect Dis. 1994 Jun;169(6):1271–1280. doi: 10.1093/infdis/169.6.1271. [DOI] [PubMed] [Google Scholar]
  9. Chu Y. K., Rossi C., Leduc J. W., Lee H. W., Schmaljohn C. S., Dalrymple J. M. Serological relationships among viruses in the Hantavirus genus, family Bunyaviridae. Virology. 1994 Jan;198(1):196–204. doi: 10.1006/viro.1994.1022. [DOI] [PubMed] [Google Scholar]
  10. Cosgriff T. M. Mechanisms of disease in Hantavirus infection: pathophysiology of hemorrhagic fever with renal syndrome. Rev Infect Dis. 1991 Jan-Feb;13(1):97–107. doi: 10.1093/clinids/13.1.97. [DOI] [PubMed] [Google Scholar]
  11. Duchin J. S., Koster F. T., Peters C. J., Simpson G. L., Tempest B., Zaki S. R., Ksiazek T. G., Rollin P. E., Nichol S., Umland E. T. Hantavirus pulmonary syndrome: a clinical description of 17 patients with a newly recognized disease. The Hantavirus Study Group. N Engl J Med. 1994 Apr 7;330(14):949–955. doi: 10.1056/NEJM199404073301401. [DOI] [PubMed] [Google Scholar]
  12. ENTWISLE G., HALE E. Hemodynamic alterations in hemorrhagic fever. Circulation. 1957 Mar;15(3):414–425. doi: 10.1161/01.cir.15.3.414. [DOI] [PubMed] [Google Scholar]
  13. Elliott L. H., Ksiazek T. G., Rollin P. E., Spiropoulou C. F., Morzunov S., Monroe M., Goldsmith C. S., Humphrey C. D., Zaki S. R., Krebs J. W. Isolation of the causative agent of hantavirus pulmonary syndrome. Am J Trop Med Hyg. 1994 Jul;51(1):102–108. doi: 10.4269/ajtmh.1994.51.102. [DOI] [PubMed] [Google Scholar]
  14. Feldmann H., Sanchez A., Morzunov S., Spiropoulou C. F., Rollin P. E., Ksiazek T. G., Peters C. J., Nichol S. T. Utilization of autopsy RNA for the synthesis of the nucleocapsid antigen of a newly recognized virus associated with hantavirus pulmonary syndrome. Virus Res. 1993 Dec;30(3):351–367. doi: 10.1016/0168-1702(93)90101-r. [DOI] [PubMed] [Google Scholar]
  15. Gu X. S., Wang D. Q., Yang S. H., Yan D. Y. Activation of the alternative complement pathway in patients with epidemic hemorrhagic fever. Chin Med J (Engl) 1984 Apr;97(4):283–290. [PubMed] [Google Scholar]
  16. Hill J. D., Ratliff J. L., Parrott J. C., Lamy M., Fallat R. J., Koeniger E., Yaeger E. M., Whitmer G. Pulmonary pathology in acute respiratory insufficiency: lung biopsy as a diagnostic tool. J Thorac Cardiovasc Surg. 1976 Jan;71(1):64–71. [PubMed] [Google Scholar]
  17. Hjelle B., Chavez-Giles F., Torrez-Martinez N., Yates T., Sarisky J., Webb J., Ascher M. Genetic identification of a novel hantavirus of the harvest mouse Reithrodontomys megalotis. J Virol. 1994 Oct;68(10):6751–6754. doi: 10.1128/jvi.68.10.6751-6754.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hjelle B., Jenison S., Torrez-Martinez N., Yamada T., Nolte K., Zumwalt R., MacInnes K., Myers G. A novel hantavirus associated with an outbreak of fatal respiratory disease in the southwestern United States: evolutionary relationships to known hantaviruses. J Virol. 1994 Feb;68(2):592–596. doi: 10.1128/jvi.68.2.592-596.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hughes J. M., Peters C. J., Cohen M. L., Mahy B. W. Hantavirus pulmonary syndrome: an emerging infectious disease. Science. 1993 Nov 5;262(5135):850–851. doi: 10.1126/science.8235607. [DOI] [PubMed] [Google Scholar]
  20. Hung T., Chou Z. Y., Zhao T. X., Xia S. M., Hang C. S. Morphology and morphogenesis of viruses of hemorrhagic fever with renal syndrome (HFRS). I. Some peculiar aspects of the morphogenesis of various strains of HFRS virus. Intervirology. 1985;23(2):97–108. doi: 10.1159/000149591. [DOI] [PubMed] [Google Scholar]
  21. Hung T., Zhou J. Y., Tang Y. M., Zhao T. X., Baek L. J., Lee H. W. Identification of Hantaan virus-related structures in kidneys of cadavers with haemorrhagic fever with renal syndrome. Arch Virol. 1992;122(1-2):187–199. doi: 10.1007/BF01321127. [DOI] [PubMed] [Google Scholar]
  22. Huynh H. K., Dorovini-Zis K. Effects of interferon-gamma on primary cultures of human brain microvessel endothelial cells. Am J Pathol. 1993 Apr;142(4):1265–1278. [PMC free article] [PubMed] [Google Scholar]
  23. Jones M., Hoover R., Meyrick B. Endotoxin enhancement of lymphocyte adherence to cultured sheep lung microvascular endothelial cells. Am J Respir Cell Mol Biol. 1992 Jul;7(1):81–89. doi: 10.1165/ajrcmb/7.1.81. [DOI] [PubMed] [Google Scholar]
  24. KIM D. CLINICAL ANALYSIS OF 111 FATAL CASES OF EPIDEMIC HEMORRHAGIC FEVER. Am J Med. 1965 Aug;39:218–220. doi: 10.1016/0002-9343(65)90044-6. [DOI] [PubMed] [Google Scholar]
  25. Kim S., Kang E. T., Kim Y. G., Han J. S., Lee J. S., Kim Y. I., Hall W. C., Dalrymple J. M., Peters C. J. Localization of Hantaan viral envelope glycoproteins by monoclonal antibodies in renal tissues from patients with Korean hemorrhagic fever H. Am J Clin Pathol. 1993 Oct;100(4):398–403. doi: 10.1093/ajcp/100.4.398. [DOI] [PubMed] [Google Scholar]
  26. Kurata T., Tsai T. F., Bauer S. P., McCormick J. B. Immunofluorescence studies of disseminated Hantaan virus infection of suckling mice. Infect Immun. 1983 Jul;41(1):391–398. doi: 10.1128/iai.41.1.391-398.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. LUKES R. J. The pathology of thirty-nine fatal cases of epidemic hemorrhagic fever. Am J Med. 1954 May;16(5):639–650. doi: 10.1016/0002-9343(54)90270-3. [DOI] [PubMed] [Google Scholar]
  28. LeDuc J. W. Epidemiology of Hantaan and related viruses. Lab Anim Sci. 1987 Aug;37(4):413–418. [PubMed] [Google Scholar]
  29. LeDuc J. W., Ksiazek T. G., Rossi C. A., Dalrymple J. M. A retrospective analysis of sera collected by the Hemorrhagic Fever Commission during the Korean Conflict. J Infect Dis. 1990 Nov;162(5):1182–1184. doi: 10.1093/infdis/162.5.1182. [DOI] [PubMed] [Google Scholar]
  30. Lee M., Kim B. K., Kim S., Park S., Han J. S., Kim S. T., Lee J. S. Coagulopathy in hemorrhagic fever with renal syndrome (Korean hemorrhagic fever). Rev Infect Dis. 1989 May-Jun;11 (Suppl 4):S877–S883. [PubMed] [Google Scholar]
  31. Levy H., Simpson S. Q. Hantavirus pulmonary syndrome. Am J Respir Crit Care Med. 1994 Jun;149(6):1710–1713. doi: 10.1164/ajrccm.149.6.8004332. [DOI] [PubMed] [Google Scholar]
  32. Linderholm M., Billström A., Settergren B., Tärnvik A. Pulmonary involvement in nephropathia epidemica as demonstrated by computed tomography. Infection. 1992 Sep-Oct;20(5):263–266. doi: 10.1007/BF01710791. [DOI] [PubMed] [Google Scholar]
  33. Lähdevirta J. Clinical features of HFRS in Scandinavia as compared with East Asia. Scand J Infect Dis Suppl. 1982;36:93–95. [PubMed] [Google Scholar]
  34. Lähdevirta J. The minor problem of hemostatic impairment in nephropathia epidemica, the mild Scandinavian form of hemorrhagic fever with renal syndrome. Rev Infect Dis. 1989 May-Jun;11 (Suppl 4):S860–S863. doi: 10.1093/clinids/11.supplement_4.s860. [DOI] [PubMed] [Google Scholar]
  35. MacLennan I. C. Germinal centers. Annu Rev Immunol. 1994;12:117–139. doi: 10.1146/annurev.iy.12.040194.001001. [DOI] [PubMed] [Google Scholar]
  36. Mantovani A., Bussolino F., Dejana E. Cytokine regulation of endothelial cell function. FASEB J. 1992 May;6(8):2591–2599. doi: 10.1096/fasebj.6.8.1592209. [DOI] [PubMed] [Google Scholar]
  37. Munro J. M., Pober J. S., Cotran R. S. Tumor necrosis factor and interferon-gamma induce distinct patterns of endothelial activation and associated leukocyte accumulation in skin of Papio anubis. Am J Pathol. 1989 Jul;135(1):121–133. [PMC free article] [PubMed] [Google Scholar]
  38. Murphy F. A., Winn W. C., Jr, Walker D. H., Flemister M. R., Whitfield S. G. Early lymphoreticular viral tropism and antigen persistence. Tamiami virus infection in the cotton rat. Lab Invest. 1976 Feb;34(2):125–140. [PubMed] [Google Scholar]
  39. Nash G., Blennerhassett J. B., Pontoppidan H. Pulmonary lesions associated with oxygen therapy and artifical ventilation. N Engl J Med. 1967 Feb 16;276(7):368–374. doi: 10.1056/NEJM196702162760702. [DOI] [PubMed] [Google Scholar]
  40. Nichol S. T., Spiropoulou C. F., Morzunov S., Rollin P. E., Ksiazek T. G., Feldmann H., Sanchez A., Childs J., Zaki S., Peters C. J. Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness. Science. 1993 Nov 5;262(5135):914–917. doi: 10.1126/science.8235615. [DOI] [PubMed] [Google Scholar]
  41. Nolte K. B., Feddersen R. M., Foucar K., Zaki S. R., Koster F. T., Madar D., Merlin T. L., McFeeley P. J., Umland E. T., Zumwalt R. E. Hantavirus pulmonary syndrome in the United States: a pathological description of a disease caused by a new agent. Hum Pathol. 1995 Jan;26(1):110–120. doi: 10.1016/0046-8177(95)90123-x. [DOI] [PubMed] [Google Scholar]
  42. POWELL G. M. Hemorrhagic fever: a study of 300 cases. Medicine (Baltimore) 1954 May;33(2):97–153. [PubMed] [Google Scholar]
  43. Parmentier H. K., van Wichen D., Sie-Go D. M., Goudsmit J., Borleffs J. C., Schuurman H. J. HIV-1 infection and virus production in follicular dendritic cells in lymph nodes. A case report, with analysis of isolated follicular dendritic cells. Am J Pathol. 1990 Aug;137(2):247–251. [PMC free article] [PubMed] [Google Scholar]
  44. Pensiero M. N., Sharefkin J. B., Dieffenbach C. W., Hay J. Hantaan virus infection of human endothelial cells. J Virol. 1992 Oct;66(10):5929–5936. doi: 10.1128/jvi.66.10.5929-5936.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Pilewski J. M., Albelda S. M. Adhesion molecules in the lung. An overview. Am Rev Respir Dis. 1993 Dec;148(6 Pt 2):S31–S37. doi: 10.1164/ajrccm/148.6_Pt_2.S31. [DOI] [PubMed] [Google Scholar]
  46. Pober J. S. Warner-Lambert/Parke-Davis award lecture. Cytokine-mediated activation of vascular endothelium. Physiology and pathology. Am J Pathol. 1988 Dec;133(3):426–433. [PMC free article] [PubMed] [Google Scholar]
  47. Radzun H. J., Hansmann M. L., Heidebrecht H. J., Bödewadt-Radzun S., Wacker H. H., Kreipe H., Lumbeck H., Hernandez C., Kuhn C., Parwaresch M. R. Detection of a monocyte/macrophage differentiation antigen in routinely processed paraffin-embedded tissues by monoclonal antibody Ki-M1P. Lab Invest. 1991 Sep;65(3):306–315. [PubMed] [Google Scholar]
  48. Ringler D. J., Wyand M. S., Walsh D. G., MacKey J. J., Chalifoux L. V., Popovic M., Minassian A. A., Sehgal P. K., Daniel M. D., Desrosiers R. C. Cellular localization of simian immunodeficiency virus in lymphoid tissues. I. Immunohistochemistry and electron microscopy. Am J Pathol. 1989 Feb;134(2):373–383. [PMC free article] [PubMed] [Google Scholar]
  49. Ruo S. L., Sanchez A., Elliott L. H., Brammer L. S., McCormick J. B., Fisher-Hoch S. P. Monoclonal antibodies to three strains of hantaviruses: Hantaan, R22, and Puumala. Arch Virol. 1991;119(1-2):1–11. doi: 10.1007/BF01314318. [DOI] [PubMed] [Google Scholar]
  50. STEER A. Pathology of hemorrhagic fever: a comparison of the findings; 1951 and 1952. Am J Pathol. 1955 Mar-Apr;31(2):201–221. [PMC free article] [PubMed] [Google Scholar]
  51. SWIFT W. E., Jr Clinical aspects of the renal phase of epidemic hemorrhagic fever. Ann Intern Med. 1953 Jan;38(1):102–105. doi: 10.7326/0003-4819-38-1-102. [DOI] [PubMed] [Google Scholar]
  52. Schmaljohn C. S., Dalrymple J. M. Analysis of Hantaan virus RNA: evidence for a new genus of bunyaviridae. Virology. 1983 Dec;131(2):482–491. doi: 10.1016/0042-6822(83)90514-7. [DOI] [PubMed] [Google Scholar]
  53. Schmaljohn C. S. Nucleotide sequence of the L genome segment of Hantaan virus. Nucleic Acids Res. 1990 Nov 25;18(22):6728–6728. doi: 10.1093/nar/18.22.6728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Schriever F., Nadler L. M. The central role of follicular dendritic cells in lymphoid tissues. Adv Immunol. 1992;51:243–284. doi: 10.1016/s0065-2776(08)60489-7. [DOI] [PubMed] [Google Scholar]
  55. Schuurman H. J., Krone W. J., Broekhuizen R., Goudsmit J. Expression of RNA and antigens of human immunodeficiency virus type-1 (HIV-1) in lymph nodes from HIV-1 infected individuals. Am J Pathol. 1988 Dec;133(3):516–524. [PMC free article] [PubMed] [Google Scholar]
  56. Spiegel H., Herbst H., Niedobitek G., Foss H. D., Stein H. Follicular dendritic cells are a major reservoir for human immunodeficiency virus type 1 in lymphoid tissues facilitating infection of CD4+ T-helper cells. Am J Pathol. 1992 Jan;140(1):15–22. [PMC free article] [PubMed] [Google Scholar]
  57. Spiropoulou C. F., Morzunov S., Feldmann H., Sanchez A., Peters C. J., Nichol S. T. Genome structure and variability of a virus causing hantavirus pulmonary syndrome. Virology. 1994 May 1;200(2):715–723. doi: 10.1006/viro.1994.1235. [DOI] [PubMed] [Google Scholar]
  58. Tabrizchi H., Hansmann M. L., Parwaresch M. R., Lennert K. Distribution pattern of follicular dendritic cells in low grade B-cell lymphomas of the gastrointestinal tract immunostained by Ki-FDC1p: a new paraffin-resistant monoclonal antibody. Mod Pathol. 1990 Jul;3(4):470–478. [PubMed] [Google Scholar]
  59. Tang Y. M., Yang W. S., Zhang W. B., Bai X. F. Localization and changes of hemorrhagic fever with renal syndrome virus in lymphocyte subpopulation. Chin Med J (Engl) 1991 Aug;104(8):673–678. [PubMed] [Google Scholar]
  60. Tao H., Xia S. M., Chan Z. Y., Song G., Yanagihara R. Morphology and morphogenesis of viruses of hemorrhagic fever with renal syndrome. II. Inclusion bodies--ultrastructural markers of hantavirus-infected cells. Intervirology. 1987;27(1):45–52. doi: 10.1159/000149714. [DOI] [PubMed] [Google Scholar]
  61. Tenner-Racz K., Racz P., Bofill M., Schulz-Meyer A., Dietrich M., Kern P., Weber J., Pinching A. J., Veronese-Dimarzo F., Popovic M. HTLV-III/LAV viral antigens in lymph nodes of homosexual men with persistent generalized lymphadenopathy and AIDS. Am J Pathol. 1986 Apr;123(1):9–15. [PMC free article] [PubMed] [Google Scholar]
  62. Wang J. R., Yang P. Z., Wu Q., Sun T., Xu Z. Y., Dai Z. Y. The role of tissue immune complex, complement activation and its immunopathologic injury in the pathogenesis of the epidemic hemorrhagic fever. Chin Med J (Engl) 1986 Jan;99(1):21–26. [PubMed] [Google Scholar]
  63. Xiao S. Y., Leduc J. W., Chu Y. K., Schmaljohn C. S. Phylogenetic analyses of virus isolates in the genus Hantavirus, family Bunyaviridae. Virology. 1994 Jan;198(1):205–217. doi: 10.1006/viro.1994.1023. [DOI] [PubMed] [Google Scholar]
  64. Yan D., Gu X., Wang D., Yang S. Studies on immunopathogenesis in epidemic hemorrhagic fever: sequential observations on activation of the first complement component in sera from patients with epidemic hemorrhagic fever. J Immunol. 1981 Sep;127(3):1064–1067. [PubMed] [Google Scholar]
  65. Yanagihara R., Silverman D. J. Experimental infection of human vascular endothelial cells by pathogenic and nonpathogenic hantaviruses. Arch Virol. 1990;111(3-4):281–286. doi: 10.1007/BF01311063. [DOI] [PubMed] [Google Scholar]
  66. Zaki S. R., Albers R. C., Greer P. W., Coffield L. M., Armstrong L. R., Khan A. S., Khabbaz R., Peters C. J. Retrospective diagnosis of a 1983 case of fatal hantavirus pulmonary syndrome. Lancet. 1994 Apr 23;343(8904):1037–1038. doi: 10.1016/s0140-6736(94)90156-2. [DOI] [PubMed] [Google Scholar]
  67. Zhu P., Yang W. S. Effects of Hantaan virus on human endothelial cells and their significance in pathogenesis of hemorrhagic fever with renal syndrome. Chin Med J (Engl) 1991 Nov;104(11):924–929. [PubMed] [Google Scholar]

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