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. 1994 Jun;144(6):1219–1225.

Epstein-Barr virus (EBV) infects T lymphocytes in childhood EBV-associated hemophagocytic syndrome in Taiwan.

I J Su 1, R L Chen 1, D T Lin 1, K S Lin 1, C C Chen 1
PMCID: PMC1887465  PMID: 8203462

Abstract

We have reported the prevalence of a fulminant hemophagocytic syndrome (HS) in previously healthy young children in Taiwan, most of which probably represent a lethal form of primary or active Epstein-Barr virus (EBV) infection. To further confirm their EBV association, in situ EBV hybridization (ISH) was performed on tissue biopsies from 15 pediatric HS patients (median age, 3 years and 4 months) using digoxigenin-labeled RNA probes EBER1. Double labeling immunostaining and ISH was then performed to define the immunophenotype of the lymphoid cells containing the EBV transcripts. Among the 13 patients who had serological evidence of acute or active EBV infection, 9 had demonstrable EBER1 transcripts in bone marrow, liver, and/or skin biopsies. EBER1-specific signal was not detectable in the two specimens from EBV-seronegative patients. The distribution of EBV-containing cells could be extensive or scattered. To our surprise, the EBER1 transcripts existed exclusively in T lymphoid cells in all nine cases examined rather than in B cells as previously believed in infectious mononucleosis. Considering the young affected age of the HS patients and the serological response to EBV, we suggest that EBV can infect T cells in primary EBV infection and the proliferation of these EBV-infected T cells may be responsible for the ominous outcome in childhood HS patients in Taiwan.

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Selected References

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  1. Ambruso D. R., Hays T., Zwartjes W. J., Tubergen D. G., Favara B. E. Successful treatment of lymphohistiocytic reticulosis with phagocytosis with epipodophyllotoxin VP 16-213. Cancer. 1980 May 15;45(10):2516–2520. doi: 10.1002/1097-0142(19800515)45:10<2516::aid-cncr2820451008>3.0.co;2-v. [DOI] [PubMed] [Google Scholar]
  2. Chen R. L., Su I. J., Lin K. H., Lee S. H., Lin D. T., Chuu W. M., Lin K. S., Huang L. M., Lee C. Y. Fulminant childhood hemophagocytic syndrome mimicking histiocytic medullary reticulosis. An atypical form of Epstein-Barr virus infection. Am J Clin Pathol. 1991 Aug;96(2):171–176. doi: 10.1093/ajcp/96.2.171. [DOI] [PubMed] [Google Scholar]
  3. Cheng A. L., Su I. J., Chen Y. C., Uen W. C., Wang C. H. Characteristic clinicopathologic features of Epstein-Barr virus-associated peripheral T-cell lymphoma. Cancer. 1993 Aug 1;72(3):909–916. doi: 10.1002/1097-0142(19930801)72:3<909::aid-cncr2820720341>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
  4. Cohen R. A., Hutter J. J., Jr, Boxer M. A., Goldman D. S. Histiocytic medullary reticulosis associated with acute Epstein-Barr (EB) virus infection. Am J Pediatr Hematol Oncol. 1980 Fall;2(3):245–248. [PubMed] [Google Scholar]
  5. Craig F. E., Clare C. N., Sklar J. L., Banks P. M. T-cell lymphoma and the virus-associated hemophagocytic syndrome. Am J Clin Pathol. 1992 Feb;97(2):189–194. doi: 10.1093/ajcp/97.2.189. [DOI] [PubMed] [Google Scholar]
  6. Feingold K. R., Soued M., Staprans I., Gavin L. A., Donahue M. E., Huang B. J., Moser A. H., Gulli R., Grunfeld C. Effect of tumor necrosis factor (TNF) on lipid metabolism in the diabetic rat. Evidence that inhibition of adipose tissue lipoprotein lipase activity is not required for TNF-induced hyperlipidemia. J Clin Invest. 1989 Apr;83(4):1116–1121. doi: 10.1172/JCI113991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fujiwara F., Hibi S., Imashuku S. Hypercytokinemia in hemophagocytic syndrome. Am J Pediatr Hematol Oncol. 1993 Feb;15(1):92–98. doi: 10.1097/00043426-199302000-00012. [DOI] [PubMed] [Google Scholar]
  8. Gaffey M. J., Frierson H. F., Jr, Medeiros L. J., Weiss L. M. The relationship of Epstein-Barr virus to infection-related (sporadic) and familial hemophagocytic syndrome and secondary (lymphoma-related) hemophagocytosis: an in situ hybridization study. Hum Pathol. 1993 Jun;24(6):657–667. doi: 10.1016/0046-8177(93)90247-e. [DOI] [PubMed] [Google Scholar]
  9. Goulder P., Seward D., Hatton C. Intravenous immunoglobulin in virus associated haemophagocytic syndrome. Arch Dis Child. 1990 Nov;65(11):1275–1277. doi: 10.1136/adc.65.11.1275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Henle G., Henle W. Observations on childhood infections with the Epstein-Barr virus. J Infect Dis. 1970 Mar;121(3):303–310. doi: 10.1093/infdis/121.3.303. [DOI] [PubMed] [Google Scholar]
  11. Henter J. I., Elinder G., Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991 Feb;18(1):29–33. [PubMed] [Google Scholar]
  12. Henter J. I., Elinder G., Söder O., Hansson M., Andersson B., Andersson U. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood. 1991 Dec 1;78(11):2918–2922. [PubMed] [Google Scholar]
  13. Hsu S. M., Raine L., Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 1981 Apr;29(4):577–580. doi: 10.1177/29.4.6166661. [DOI] [PubMed] [Google Scholar]
  14. Huang L. M., Lee C. Y., Lin K. H., Chuu W. M., Lee P. I., Chen R. L., Chen J. M., Lin D. T. Human herpesvirus-6 associated with fatal haemophagocytic syndrome. Lancet. 1990 Jul 7;336(8706):60–61. doi: 10.1016/0140-6736(90)91580-4. [DOI] [PubMed] [Google Scholar]
  15. Ishihara S., Tawa A., Yumura-Yagi K., Murata M., Hara J., Yabuuchi H., Hirai K., Kawa-Ha K. Clonal T-cell lymphoproliferation containing Epstein-Barr (EB) virus DNA in a patient with chronic active EB virus infection. Jpn J Cancer Res. 1989 Feb;80(2):99–101. doi: 10.1111/j.1349-7006.1989.tb02273.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jones J. F., Shurin S., Abramowsky C., Tubbs R. R., Sciotto C. G., Wahl R., Sands J., Gottman D., Katz B. Z., Sklar J. T-cell lymphomas containing Epstein-Barr viral DNA in patients with chronic Epstein-Barr virus infections. N Engl J Med. 1988 Mar 24;318(12):733–741. doi: 10.1056/NEJM198803243181203. [DOI] [PubMed] [Google Scholar]
  17. Korbjuhn P., Anagnostopoulos I., Hummel M., Tiemann M., Dallenbach F., Parwaresch M. R., Stein H. Frequent latent Epstein-Barr virus infection of neoplastic T cells and bystander B cells in human immunodeficiency virus-negative European peripheral pleomorphic T-cell lymphomas. Blood. 1993 Jul 1;82(1):217–223. [PubMed] [Google Scholar]
  18. Lin K. H., Chiang C. H., Yang C. S. Age distribution of Epstein-Barr virus, cytomegalovirus and rubella virus antibodies. Taiwan Yi Xue Hui Za Zhi. 1987 Dec;86(12):1316–1319. [PubMed] [Google Scholar]
  19. McClain K., Gehrz R., Grierson H., Purtilo D., Filipovich A. Virus-associated histiocytic proliferations in children. Frequent association with Epstein-Barr virus and congenital or acquired immunodeficiencies. Am J Pediatr Hematol Oncol. 1988 Fall;10(3):196–205. [PubMed] [Google Scholar]
  20. Mroczek E. C., Weisenburger D. D., Grierson H. L., Markin R., Purtilo D. T. Fatal infectious mononucleosis and virus-associated hemophagocytic syndrome. Arch Pathol Lab Med. 1987 Jun;111(6):530–535. [PubMed] [Google Scholar]
  21. Nydegger U. E. Intravenous immunoglobulin in combination with other prophylactic and therapeutic measures. Transfusion. 1992 Jan;32(1):72–82. doi: 10.1046/j.1537-2995.1992.32192116438.x. [DOI] [PubMed] [Google Scholar]
  22. Ohga S., Matsuzaki A., Nishizaki M., Nagashima T., Kai T., Suda M., Ueda K. Inflammatory cytokines in virus-associated hemophagocytic syndrome. Interferon-gamma as a sensitive indicator of disease activity. Am J Pediatr Hematol Oncol. 1993 Aug;15(3):291–298. [PubMed] [Google Scholar]
  23. Reedman B. M., Klein G. Cellular localization of an Epstein-Barr virus (EBV)-associated complement-fixing antigen in producer and non-producer lymphoblastoid cell lines. Int J Cancer. 1973 May;11(3):499–520. doi: 10.1002/ijc.2910110302. [DOI] [PubMed] [Google Scholar]
  24. Reisman R. P., Greco M. A. Virus-associated hemophagocytic syndrome due to Epstein-Barr virus. Hum Pathol. 1984 Mar;15(3):290–293. doi: 10.1016/s0046-8177(84)80194-x. [DOI] [PubMed] [Google Scholar]
  25. Risdall R. J., McKenna R. W., Nesbit M. E., Krivit W., Balfour H. H., Jr, Simmons R. L., Brunning R. D. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer. 1979 Sep;44(3):993–1002. doi: 10.1002/1097-0142(197909)44:3<993::aid-cncr2820440329>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  26. Starkie C. M., Kenny M. W., Mann J. R., Cameron A. H., Hill F. G. Histiocytic medullary reticulosis following acute lymphoblastic leukemia. Cancer. 1981 Feb 1;47(3):537–544. doi: 10.1002/1097-0142(19810201)47:3<537::aid-cncr2820470319>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  27. Su I. J., Hsieh H. C., Lin K. H., Uen W. C., Kao C. L., Chen C. J., Cheng A. L., Kadin M. E., Chen J. Y. Aggressive peripheral T-cell lymphomas containing Epstein-Barr viral DNA: a clinicopathologic and molecular analysis. Blood. 1991 Feb 15;77(4):799–808. [PubMed] [Google Scholar]
  28. Su I. J., Hsieh H. J., Lee C. Y. Histiocytic medullary reticulosis: a lethal form of primary EBV infection in young children in Taiwan. Lancet. 1989 Feb 18;1(8634):389–389. doi: 10.1016/s0140-6736(89)91768-6. [DOI] [PubMed] [Google Scholar]
  29. Sullivan J. L., Woda B. A., Herrod H. G., Koh G., Rivara F. P., Mulder C. Epstein-Barr virus-associated hemophagocytic syndrome: virological and immunopathological studies. Blood. 1985 May;65(5):1097–1104. [PubMed] [Google Scholar]
  30. Svedmyr E., Jondal M. Cytotoxic effector cells specific for B Cell lines transformed by Epstein-Barr virus are present in patients with infectious mononucleosis. Proc Natl Acad Sci U S A. 1975 Apr;72(4):1622–1626. doi: 10.1073/pnas.72.4.1622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Tchernia G., Mirica C., Delfraissy J. F. Histiocytic medullary reticulosis, a lethal form of primary EBV infection. Lancet. 1989 Jun 3;1(8649):1265–1266. doi: 10.1016/s0140-6736(89)92359-3. [DOI] [PubMed] [Google Scholar]
  32. Thorley-Lawson D. A. Immunological responses to Epstein-Barr virus infection and the pathogenesis of EBV-induced diseases. Biochim Biophys Acta. 1989 Feb;948(3):263–286. doi: 10.1016/0304-419x(89)90002-4. [DOI] [PubMed] [Google Scholar]
  33. Thorley-Lawson D. A. Immunological responses to Epstein-Barr virus infection and the pathogenesis of EBV-induced diseases. Biochim Biophys Acta. 1989 Feb;948(3):263–286. doi: 10.1016/0304-419x(89)90002-4. [DOI] [PubMed] [Google Scholar]
  34. Weiss L. M., Jaffe E. S., Liu X. F., Chen Y. Y., Shibata D., Medeiros L. J. Detection and localization of Epstein-Barr viral genomes in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy-like lymphoma. Blood. 1992 Apr 1;79(7):1789–1795. [PubMed] [Google Scholar]
  35. Wilson M. S., Weiss L. M., Gatter K. C., Mason D. Y., Dorfman R. F., Warnke R. A. Malignant histiocytosis. A reassessment of cases previously reported in 1975 based on paraffin section immunophenotyping studies. Cancer. 1990 Aug 1;66(3):530–536. doi: 10.1002/1097-0142(19900801)66:3<530::aid-cncr2820660321>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  36. Yoneda N., Tatsumi E., Kawanishi M., Teshigawara K., Masuda S., Yamamura Y., Inui A., Yoshino G., Oimomi M., Baba S. Detection of Epstein-Barr virus genome in benign polyclonal proliferative T cells of a young male patient. Blood. 1990 Jul 1;76(1):172–177. [PubMed] [Google Scholar]

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