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Viral Infections

Lack of known hepatitis virus in hepatitis-associated aplastic anemia and outcome after bone marrow transplantation

Bone Marrow Transplantation volume 27, pages 183–190 (2001)Cite this article

Abstract

Viral infection has been shown to induce aplastic anemia, unidentified types of hepatitis being the most common cause for aplastic anemia-associated viral hepatitis. The survival rate for this group of patients after bone marrow transplantation with stem cells from an HLA-matched sibling is not well known. The aim of this study was to determine the prevalence of hepatitis G virus (HGV) and transfusion transmitted virus (TTV) infection in non-A, non-B, non-C hepatitis associated-aplastic anemia (HAAA) patients, and to define the role of bone marrow transplantation (BMT) as a therapeutic modality for this disease. Sixty-eight patients (43 males and 25 females) with aplastic anemia, underwent allogeneic BMT at the Hadassah University Hospital between 1981 and 1997. Onset of hepatitis was defined as jaundice and elevated alanine aminotransaminase (ALT) levels. Onset of aplastic anemia was defined as the first date on which varying degrees of pancytopenia occurred: hemoglobin level below 10 g/dl, WBC below 2 × 109/l and low platelet count 10 × 1010/l. Serial serum samples from HAAA patients were assayed for virological and/or serological markers of hepatitis A, B, C, D, E, G viruses, TTV and parvovirus B19. Seventeen of the 68 patients with aplastic anemia (25%) suffered from hepatitis, 12 males and five females, ages 5 to 36 years. The mean interval between onset of hepatitis and first indication of aplastic anemia was 62 days (range 14–225 days). The development of aplastic anemia was unrelated to age, sex or severity of hepatitis. Ten of the 17 patients (59%) achieved complete ALT recovery prior to the diagnosis of aplastic anemia. Serum samples were available for 15 patients; none had evidence of acute or active hepatitis A, B, C, D, E, G and TTV virus infection at the time of diagnosis. Parvovirus B19 DNA sequences were not detectable in 10 of 12 tested cases; two positive results were detected in serum samples obtained after blood transfusion, making the analysis of these positive results difficult. All 17 patients underwent BMT. The mean post-BMT follow-up period was 38 months (range 1 day–123 months), five patients (30%) died 1 to 160 days post BMT, and 12 (70%) are alive 31 to 123 months after BMT. Relapsing hepatitis was not observed in any of the patients. In conclusion, HAAA is a disease of the young and the etiologic agent associated with HAAA remains unknown. HGV, TTV and parvovirus B19 sequences were not detected in any of the HAAA cases. The survival rate after BMT with stem cells from an HLA-matched sibling is similar to that for patients with non-hepatitis-associated aplastic anemia. Bone Marrow Transplantation (2001) 27, 183–190.

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References

  1. International agranulocytosis and aplastic anemia study. Incidence of aplastic anemia: the relevance of diagnostic criteria Blood 1987 70: 1718–1721

  2. Bottiger LE, Westerholm B . Aplastic anemia. I. Incidence and aetiology Acta Med Scand 1972 192: 315–318

    Article  CAS  PubMed  Google Scholar 

  3. Chapuis B, Von Fliedner VE, Jeannet M et al. Increased frequency of DR2 in patients with aplastic anemia and increased DR sharing in their parents Br J Haematol 1986 63: 51–57

    Article  CAS  PubMed  Google Scholar 

  4. Odum N, Platz P, Morling N et al. Increased frequency of HLA-DPw3 in severe aplastic anemia (AA) Tissue Antigens 1987 20: 184–185

    Google Scholar 

  5. Appelbaum FR, Fefer A . The pathogenesis of aplastic anemia Semin Hematol 1981 18: 241–257

    CAS  PubMed  Google Scholar 

  6. Camitta BM, Storb R, Thomas ED . Aplastic anemia: pathogenesis, diagnosis, treatment and prognosis New Engl J Med 1982 306: 645, 712–718

    Google Scholar 

  7. Marmont AM, Bacigalupo A . Aplastic anemia: pathogenesis and treatment Haematologica 1988 73: 133–144

    CAS  PubMed  Google Scholar 

  8. Nissen-Druey C . Pathophysiology of aplastic anemia Baillières Clin Haematol 1989 2: 37–49

    Article  CAS  PubMed  Google Scholar 

  9. Nissen C . The pathophysiology of aplastic anemia Semin Hematol 1991 28: 313–318

    CAS  PubMed  Google Scholar 

  10. Zoumbos NC, Gascon P, Djeu JY et al. Circulating activated suppressor T lymphocytes in aplastic anemia New Engl J Med 1985 312: 257–265

    Article  CAS  PubMed  Google Scholar 

  11. Linet MS, Markovitz JA, Sensenbrenner LL et al. A case–control study of aplastic anemia Leukemia Res 1989 13: 3–11

    Article  CAS  Google Scholar 

  12. Issaragrasil S, Issaragrasil S, Chieh CW, Takaku F . Aplastic anemia in the Orient Br J Haematol 1986 62: 1–6

    Article  PubMed  Google Scholar 

  13. Issaragrasil S, Sriratanasatavon C, Piankijagum A et al. Incidence of aplastic anemia in Bangkok Blood 1991 77: 2166–2168

    Google Scholar 

  14. Liang TJ, Jeffers L, Reddy RK et al. Fulminant or subfulminant non-A, non-B viral hepatitis: the role of hepatitis C and E viruses Gastroenterology 1993 104: 556–562

    Article  CAS  PubMed  Google Scholar 

  15. Ajlouni K, Doeblin TD . The syndrome of hepatitis and aplastic anemia Br J Haematol 1974 27: 345–355

    Article  CAS  PubMed  Google Scholar 

  16. Hagler L, Pastore RA, Bergin JJ . Aplastic anemia following viral hepatitis: report of 2 fatal cases and literature review Medicine (Baltimore) 1975 54: 139–164

    Article  CAS  Google Scholar 

  17. Pol S, Driss F, Devergie A et al. Is hepatitis C virus involved in hepatitis-associated aplastic anemia? Ann Intern Med 1990 113: 435–437

    Article  CAS  PubMed  Google Scholar 

  18. Hibbs JR, Frickhofen N, Rosenfeld SJ et al. Aplastic anemia and viral hepatitis Non-A, non-B, non-C? JAMA 1992 267: 2051–2054

    Article  CAS  PubMed  Google Scholar 

  19. Storb R, Longton G, Anasetti C et al. Changing trends in marrow transplantation for aplastic anemia Bone Marrow Transplant 1992 10: (Suppl. 1) 45–52

    PubMed  Google Scholar 

  20. Bacigalupo A . Treatment of severe aplastic anemia Baillières Clin Haematol 1989 2: 19–35

    Article  CAS  PubMed  Google Scholar 

  21. Schlueter V, Schmolke S, Stark K et al. Reverse transcription-PCR detection of hepatitis G virus J Clin Microbiol 1996 34: 2660–2664

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Musiani M, Azzi A, Zerbini M et al. Nested polymerase chain reaction assay for the detection of B19 parvovirus DNA in human immunodeficiency virus patients J Med Virol 1993 40: 157–160

    Article  CAS  PubMed  Google Scholar 

  23. Perrillo RP, Pohl DA, Roodman ST, Tsai CC . Acute non-A, non-B hepatitis with serum sickness-like syndrome and aplastic anemia JAMA 1981 245: 494–496

    Article  CAS  PubMed  Google Scholar 

  24. Brown KE, Tisdale J, Dunbar CE et al. Hepatitis-associated aplastic anemia New Engl J Med 1997 336: 1059–1064

    Article  CAS  PubMed  Google Scholar 

  25. Zaidi Y, Chapman CS, Myint S . Aplastic anemia after HGV infection Lancet 1996 348: 471–472

    Article  CAS  PubMed  Google Scholar 

  26. Hibbs JR, Issaragrisl S, Young NS . High prevalence of hepatitis C viremia among aplastic anemia patients and controls Thailand Am J Trop Med Hyg 1992 46: 564–570

    Article  CAS  PubMed  Google Scholar 

  27. Kurtzman G, Young N . Viruses and bone marrow failure Baillières Clin Haematol 1989 2: 51–67

    Article  CAS  PubMed  Google Scholar 

  28. Byrnes JJ, Banks AT, Piatack M, Kim JP . Hepatitis G associated aplastic anemia Lancet 1996 348: 472

    Article  CAS  PubMed  Google Scholar 

  29. Charlton M, Adjei P, Poterucha J et al. TT-virus infection in North American blood donors, patients with fulminant hepatic failure, and cryptogenic cirrhosis Hepatology 1998 28: 839–842

    Article  CAS  PubMed  Google Scholar 

  30. Naoumov NV, Petrova EP, Thomas MG, Williams R . Presence of a newly described human DNA virus (TTV) in patients with liver disease Lancet 1998 352: 195–197

    Article  CAS  PubMed  Google Scholar 

  31. Simmonds P, Davidson F, Lycett C et al. Detection of a novel DNA virus (TTV) in blood donors and blood products Lancet 1998 352: 191–195

    Article  CAS  PubMed  Google Scholar 

  32. Young N . Hematologic and hematopoietic consequences of B-19 parvovirus infection Semin Hematol 1988 25: 159–172

    CAS  PubMed  Google Scholar 

  33. Sokal EM, Melchior M, Cornu C et al. Acute parvovirus B19 infection associated with fulminant hepatitis of favorable prognosis in young children Lancet 1998 352: 1739–1741

    Article  CAS  PubMed  Google Scholar 

  34. Vinters HV, Mah V, Mohrbann R, Wiley CA . Evidence for human immunodeficiency virus (HIV) infection of the brain in a patient with aplastic anemia Acta Neuropathol 1988 76: 321–324

    Article  CAS  PubMed  Google Scholar 

  35. Morales CE, Sriram I, Baumann MA . Myelodysplastic syndrome occurring as possible first manifestation of human immunodeficiency virus infection with subsequent progression to aplastic anemia Int J STD AIDS 1990 1: 55–57

    Article  CAS  PubMed  Google Scholar 

  36. Issaragrasil S, Kaufman DW, Anderson TE et al. An association of aplastic anemia in Thailand with low socioeconomic status Br J Haematol 1995 91: 80–84

    Article  Google Scholar 

  37. Issaragrasil S, Chansung K, Kaufman D et al. Aplastic anemia in rural Thailand: it's association with grain farming and agricultural pesticide exposure Am J Public Health 1997 87: 1551–1554

    Article  Google Scholar 

  38. Issaragrasil S, Kaufman DW, Young NS . The epidemiology of acquired aplastic anemia (AA) in Thailand Blood 1995 86: (Suppl. 1) 478a (Abstr.)

    Google Scholar 

  39. Kagan WA, Ascensao J, Pahwa R et al. Aplastic anemia: presence in human bone marrow of cells that suppress myelopoiesis Proc Natl Acad Sci USA 1976 73: 2890–2894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mangan KF, D'Alessandro L, Mullaney MT . Action of anti thymocyte globulin on normal human erythroid progenitor cell proliferation in vitro: erythropoietic growth enhancing factors are released from marrow accessory cells J Lab Clin Med 1986 107: 353–364

    CAS  PubMed  Google Scholar 

  41. Kawano T, Nissen C, Gratwohl A, Speck B . Immunostimulatory effects of different antilymphocyte globulin preparations: a possible clue to their clinical effect Br J Haematol 1988 68: 115–119

    Article  CAS  PubMed  Google Scholar 

  42. Speck B, Gluckman E, Haak HL, van-Rood JJ . Treatment of aplastic anaemia by antilymphocyte globulin with and without allogeneic bone-marrow infusion Lancet 1977 2: 1145–1148

    Article  CAS  PubMed  Google Scholar 

  43. Champlin RE, Ho W, Gale RP . Antilymphocyte globulin treatment in patients with aplastic anemia New Engl J Med 1983 308: 113–118

    Article  CAS  PubMed  Google Scholar 

  44. Camitta B, O'Reilly RJ, Sensenbrenner L et al. Antithoracic duct lymphocyte globulin therapy of severe aplastic anemia Blood 1983 62: 883–888

    CAS  PubMed  Google Scholar 

  45. Young N, Griffith P, Brittain E et al. A multi-center trial of antithymocyte globulin in aplastic anemia and related diseases Blood 1988 72: 1861–1869

    CAS  PubMed  Google Scholar 

  46. Camitta BM, Doney K . Immunosuppressive therapy for aplastic anemia: indications, agents, mechanisms, and results Am J Pediatr Hematol Oncol 1990 12: 411–424

    Article  CAS  PubMed  Google Scholar 

  47. Bacigalupo A, VanLint MT, Cerri R et al. Treatment of severe aplastic anemia with bolus 6-methylprednisolone and antilymphocyte globulin Blut 1980 41: 168

    Google Scholar 

  48. Issaragrisil S, Tangnai-Trisorana Y, Siriseriwan T et al. Methylprednisolone therapy in aplastic anemia: correlation of in vitro tests and lymphocyte subsets with clinical response Eur J Haematol 1988 40: 343–349

    Article  CAS  PubMed  Google Scholar 

  49. Lazzarino M, Morra E, Canevari A et al. Cyclosporine in the treatment of aplastic anemia and pure red cell aplasia Bone Marrow Transplant 1989 4: (Suppl. 4) 165–167

    PubMed  Google Scholar 

  50. Hinterberger Fiscer M, Hocker P, Lechner K et al. Oral cyclosporine-A is effective treatment for untreated and also for previously immunosuppressed patients with severe bone marrow failure Eur J Haematol 1989 43: 136–142

    Article  Google Scholar 

  51. Totterman TH, Hoglund M, Bengtsson M et al. Treatment of pure red-cell aplasia and aplastic anemia with cyclosporine: long-term clinical effects Eur J Haematol 1989 42: 126–133

    Article  CAS  PubMed  Google Scholar 

  52. Camitta BM, Thomas ED, Nathan DG et al. A prospective study of androgens and bone marrow transplantation for treatment of severe aplastic anemia Blood 1979 53: 504–514

    CAS  PubMed  Google Scholar 

  53. Champlin RE, Ho WG, Feig SA et al. Do androgens enhance the response to antithymocyte globulin in patients with aplastic anemia? Prospective randomized trial Blood 1985 66: 184–188

    CAS  PubMed  Google Scholar 

  54. Kaltwasser JP, Dix U, Schalk KP, Vogt H . Effect of androgens on the response to antithymocyte globulin in patients withaplastic anemia Eur J Haematol 1988 40: 111–118

    Article  CAS  PubMed  Google Scholar 

  55. Antin JH, Smith BR, Holmes W, Rosenthal DS . Phase I/II study of recombinant human granulocyte–macrophage colony-stimulating factor in aplastic anemia and myelodysplastic syndrome Blood 1988 72: 705–713

    CAS  PubMed  Google Scholar 

  56. Vadhan-Raj S, Buescher S, Broxmeyer HE et al. Stimulation of myelopoiesis in patients with aplastic anemia by recombinant human granulocyte–macrophage colony-stimulating factor New Engl J Med 1988 319: 1628–1634

    Article  CAS  PubMed  Google Scholar 

  57. Guinan EC, Sieff CA, Oette DH, Nathan DG . A phase I/II trial of recombinant granulocyte–macrophage colony-stimulating factor for children with aplastic anemia Blood 1990 76: 1077–1082

    CAS  PubMed  Google Scholar 

  58. Kapoor N, Hvizdala E, Good RA . High-dose intravenous gamma globulin as an approach to treatment of antibody mediated pancytopenia Br J Haematol 1988 59: 98–99

    Article  Google Scholar 

  59. Sadowitz PD, Dubowy RL . Intravenous immunoglobulin in treatment of aplastic anemia Am J Pediatr Hematol Oncol 1990 12: 198–200

    Article  CAS  PubMed  Google Scholar 

  60. Bodenstein H . Successful treatment of aplastic anemia with high-dose immunoglobulin New Engl J Med 1991 324: 1368–1369

    Article  CAS  PubMed  Google Scholar 

  61. Sadowitz PD, Dubowy RL . Intravenous immunoglobulin in the treatment of aplastic anemia Am J Pediatr Hematol Oncol 1990 12: 198–200

    Article  CAS  PubMed  Google Scholar 

  62. Lewis SM . Course and prognosis in aplastic anemia Br Med J 1965 1: 1027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lynch RE, Williams DM, Reading JC, Cartwright GE . The prognosis in aplastic anemia Blood 1975 45: 517–528

    CAS  PubMed  Google Scholar 

  64. de-Planque MM, Kluin-Nelemans HC, Van Krieken HJ et al. Evolution of acquired severe aplastic anemia to myelodysplasia and subsequent leukemia in adults Br J Haematol 1988 70: 55–62

    Article  CAS  PubMed  Google Scholar 

  65. Najean Y, Pecking A . Prognostic factors in acquired aplastic anemia. A study of 352 cases Am J Med 1979 67: 564–571

    Article  CAS  PubMed  Google Scholar 

  66. Kiem HP, McDonald GB, Myerson D et al. Marrow transplantation for hepatitis-associated aplastic anemia: a follow-up of long-term survivors Biol Blood Marrow Transplant 1996 2: 93–99

    CAS  PubMed  Google Scholar 

  67. Dugan MJ, Rouch DA, Akard LP et al. Successful allogeneic bone marrow transplantation in an adult with aplastic anemia following orthotopic liver transplantation for non-A, non-B, non-C hepatitis Bone Marrow Transplant 1993 12: 417–419

    CAS  PubMed  Google Scholar 

  68. Kawahara K, Storb R, Sanders J, Petersen FB . Successful allogeneic bone marrow transplantation in a 6.5-year-old male for severe aplastic anemia complicating orthotopic liver transplantation for fulminant non-A-non-B hepatitis Blood 1991 78: 1140–1143

    CAS  PubMed  Google Scholar 

  69. Shibuya A, Shinozawa T, Danya N, Maeda K . Successful bone marrow transplant and re-growth of hair in a patient with posthepatic aplastic anemia complicated by alopecia totalis Acta Paediatr Jpn 1990 32: 552–554

    Article  CAS  PubMed  Google Scholar 

  70. Tohda S, Suzuki T, Nagata K et al. Successful treatment of a patient with posthepatitic severe aplastic anemia with bolus methylprednisolone Jpn J Med 1990 29: 191–194

    Article  CAS  PubMed  Google Scholar 

  71. Kojima S, Matsuyama K, Kodera Y . Bone marrow transplantation for hepatitis-associated aplastic anemia Acta Haematol 1988 79: 7–11

    Article  CAS  PubMed  Google Scholar 

  72. Witherspoon RP, Storb R, Shulman H et al. Marrow transplantation in hepatitis-associated aplastic anemia Am J Hematol 1984 17: 269–278

    Article  CAS  PubMed  Google Scholar 

  73. Locasciulli A, van't-Veer L, Bacigalupo A et al. Treatment with marrow transplantation or immunosuppression of childhood acquired severe aplastic anemia: a report from the EBMT SAA Working Party Bone Marrow Transplant 1990 6: 211–217

    CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank all staff members of the Department of Bone Marrow Transplantation, and the Liver Unit, for the support in this study, in particular Nili Daudi, Ruth Adler, Rima Barsak, Ludmela Rivkin and Simcha Samuel for their valuable assistance.

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  1. Division of Medicine, Liver Unit, Hadassah University Hospital, Jerusalem, Israel

    R Safadi, Y Ilan, A Klein, M Ketzinel-Gilaad, K Ergunay, D Danon, D Shouval & E Galun

  2. Bone Marrow Transplantation Unit, Hadassah University Hospital, Jerusalem, Israel

    R Or, E Naparstek & A Nagler

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Safadi, R., Or, R., Ilan, Y. et al. Lack of known hepatitis virus in hepatitis-associated aplastic anemia and outcome after bone marrow transplantation. Bone Marrow Transplant 27, 183–190 (2001). https://doi.org/10.1038/sj.bmt.1702749

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