Chronic Active Epstein-Barr Virus Infection
Epstein-Barr virus (EBV) is a ubiquitous virus and is related to various diseases. Primary EBV infection is usually asymptomatic, and it sometimes progresses to infectious mononucleosis, which resolves spontaneously after the emergence of EBV-specific immunity. But, in some apparently immunocompeten...
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| Published in | The Japanese Journal of Pediatric Hematology Vol. 20; no. 6; pp. 572 - 580 |
|---|---|
| Main Author | |
| Format | Journal Article |
| Language | Japanese |
| Published |
THE JAPANESE SOCIETY OF PEDIATRIC HEMATOLOGY/ONCOLOGY
2006
特定非営利活動法人 日本小児血液・がん学会 |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0913-8706 1884-4723 |
| DOI | 10.11412/jjph1987.20.572 |
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| Abstract | Epstein-Barr virus (EBV) is a ubiquitous virus and is related to various diseases. Primary EBV infection is usually asymptomatic, and it sometimes progresses to infectious mononucleosis, which resolves spontaneously after the emergence of EBV-specific immunity. But, in some apparently immunocompetent hosts, chronic infections can develop. Chronic active EBV infection (CAEBV) is characterized by chronic or recurrent infectious mononucleosis-like symptoms, such as fever, extensive lymphadenopathy, hepatosplenomegaly, and pancytopenia. Patients with CAEBV have high viral loads in their peripheral blood and/or an unusual pattern of EBV-related antibodies. This disease is rare but severe with high morbidity and mortality. Recent advances in technology have increased our understanding of CAEBV pathophysiology, indicating that the clonal expansion of EBV-infected T or natural killer (NK) cells plays a central role in the pathogenesis of CAEBV. However, it remains unclear whether CAEBV is truly a monoclonal lymphoproliferative disorder. In this review, I summarize the clinical feature of CAEBV and discuss our current understanding of the pathogenicity of the disease. |
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| AbstractList | Epstein-Barr virus (EBV) is a ubiquitous virus and is related to various diseases. Primary EBV infection is usually asymptomatic, and it sometimes progresses to infectious mononucleosis, which resolves spontaneously after the emergence of EBV-specific immunity. But, in some apparently immunocompetent hosts, chronic infections can develop. Chronic active EBV infection (CAEBV) is characterized by chronic or recurrent infectious mononucleosis-like symptoms, such as fever, extensive lymphadenopathy, hepatosplenomegaly, and pancytopenia. Patients with CAEBV have high viral loads in their peripheral blood and/or an unusual pattern of EBV-related antibodies. This disease is rare but severe with high morbidity and mortality. Recent advances in technology have increased our understanding of CAEBV pathophysiology, indicating that the clonal expansion of EBV-infected T or natural killer (NK) cells plays a central role in the pathogenesis of CAEBV. However, it remains unclear whether CAEBV is truly a monoclonal lymphoproliferative disorder. In this review, I summarize the clinical feature of CAEBV and discuss our current understanding of the pathogenicity of the disease. Epstein-Barr virus (EBV) is a ubiquitous virus and is related to various diseases. Primary EBV infection is usually asymptomatic, and it sometimes progresses to infectious mononucleosis, which resolves spontaneously after the emergence of EBV-specific immunity. But, in some apparently immunocompetent hosts, chronic infections can develop. Chronic active EBV infection (CAEBV) is characterized by chronic or recurrent infectious mononucleosis-like symptoms, such as fever, extensive lymphadenopathy, hepatosplenomegaly, and pancytopenia. Patients with CAEBV have high viral loads in their peripheral blood and/or an unusual pattern of EBV-related antibodies. This disease is rare but severe with high morbidity and mortality. Recent advances in technology have increased our understanding of CAEBV pathophysiology, indicating that the clonal expansion of EBV-infected T or natural killer (NK) cells plays a central role in the pathogenesis of CAEBV. However, it remains unclear whether CAEBV is truly a monoclonal lymphoproliferative disorder. In this review, I summarize the clinical feature of CAEBV and discuss our current understanding of the pathogenicity of the disease. Epstein-Barr virus (EBV) は普遍的なウイルスであり, 初感染は無症候性のことが多いが, 時に伝染性単核球症となる.これらEBVの初感染は, ウイルス特異的免疫の出現により, 通常, 自然消退する.しかし, 一見免疫が正常と思われる個体にEBVの慢性感染が起こることがある.慢性活動性EBV感染症 (CAEBV) は発熱, リンパ節腫脹, 肝脾腫などの伝染性単核球症様症状が持続あるいは反復する疾患である.患者は末梢血中にEBV量の著明な増加を認め, EBV関連抗体価の異常を伴うことが多い.本疾患はまれではあるが, 非常に重篤かっ予後の悪い疾患である.近年, EBVに感染したTもしくはnatural killer (NK) 細胞の単クローン的な増殖がCAEBVの発症病理に大きく関わっていることが明らかとなっている.本稿ではCAEBVの臨床像についてまとめ, 本疾患の発症病理に関しても議論する. |
| Author | KIMURA, Hiroshi |
| Author_FL | 木村 宏 |
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| Publisher | THE JAPANESE SOCIETY OF PEDIATRIC HEMATOLOGY/ONCOLOGY 特定非営利活動法人 日本小児血液・がん学会 |
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| References | 10) Williams H, Crawford DH : Epstein-Barr virus : The impact of scientific advances on clinical practice. Blood 107 : 862-869, 2006 29) Sayos J, Wu C, Mona M, et al : The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395 : 462-469, 1998 40) Uehara T, Nakaseko C, Hara S, et al : Successful control of Epstein-Barr virus (EBV) -infected cells by allogeneic nonmyeloablative stem cell transplantation in a patient with the lethal form of chronic active EBV infection. Am J Hematol 76 : 368-372, 2004 32) Kawaguchi H, Miyashita T, Herbst H, et al : Epstein-Barr virus-infected T lymphocytes in Epstein-Barr virusassociated hemophagocytic syndrome. J Clin Invest 92 : 1444-1450, 1993 36) Savoldo B, Huls MH, Liu Z, et al : Autologous Epstein-Barr virus (EBV) -specific cytotoxic T cells for the treatment of persistent active EBV infection. Blood 100 : 4059-4066, 2002 27) Kimura H, Tsuge I, Imai S, et al : Intact antigen presentation for Epstein-Barr virus (EBV) -specific CTL by a lymphoblastoid cell line established from a patient with severe chronic active EBV infection. Med Microbiol Immunol 184 : 63-68, 1995 4) Jones JF, Ray CG, Minnich LL, et al : Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses : Elevated anti-early antigen antibodies. Ann Intern Med 102 : 1-7, 1985 18) Jones J, Shurin S, Abramowsky C, et al : T-cell lymphomas containing Epstein-Barr viral DNA in patients with chronic Epstein-Barr virus infections. N Engl J Med 318 : 733-741, 1988 21) Kasahara Y, Yachie A, Takei K, et al : Differential cellular targets of Epstein-Barr virus (EBV) infection between acute EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection. Blood 98 : 1882-1888, 2001 39) Yagita M, Iwakura H, Kishimoto T, et al : Successful allogeneic stem cell transplantation from an unrelated donor for aggressive Epstein-Barr virus-associated clonal T-cell proliferation with hemophagocytosis. Int J Hematol 74 : 451-454, 2001 8) Straus SE : The chronic mononucleosis syndrome. J Infect Dis 157 : 405-412, 1988 11) Kimura H, Hoshino Y, Kanegane H, et al : Clinical and virologic characteristics of chronic active Epstein-Barr virus infection. Blood 98 : 280-286, 2001 17) Okano M, Kawa K, Kimura H, et al : Proposed guidelinesfor diagnosing chronic active Epstein-Barr virus infection. Am J Hematol 80 : 64-69, 2005 24) Toyabe S, Harada W, Uchiyama M : Biclonal expansion of T cells infected with monoclonal Epstein-Barr virus (EBV) in a patient with chronic, active EBV infection. Clin Exp Immunol 134 : 92-97, 2003 15) Kikuta H, Taguchi Y, Tomizawa K, et al : Epstein-Barr virus genome-positive T lymphocytes in a boy with chronic active EBV infection associated with Kawasakilike disease. Nature 333 : 455-457, 1988 25) Shibata Y, Hoshino Y, Hara S, et al : Clonality analysis by sequence variation of the latent membrane protein 1 gene in patients with chronic active Epstein-Barr virus infection. J Med Virol 78 : 770-779, 2006 35) Kuzushima K, Yamamoto M, Kimura H, et al : Establishment of anti-Epstein-Barr virus (EBV) cellular immunity by adoptive transfer of virus-specific cytotoxic T lymphocytes from an HLA-matched sibling to a patient with severe chronic active EBV infection. Clin Exp Immunol 103 : 192-198, 1996 26) 脇口宏, 藤枝幹也, 松本健治, 他 : 慢性活動性Epstein-Barr (EB) ウイルス感染症児の免疫学的研究 (1) 特異的キラーT細胞とNK細胞活性低下にっいて.日児誌90 : 1572-1579, 1986 34) 木村宏, 河敬世, 大石勉, 他 : 慢性活動性EBV感染症の長期予後にっいて.日児誌, 印刷中 3) Tobi M, Morag A, Ravid Z, et al : Prolonged atypical illness associated with serological evidence of persistent Epstein-Barr virus infection. Lancet 1 : 61-64, 1982 31) Katano H, Ali MA, Patera AC, et al : Chronic active Epstein-Barr virus infection associated with mutations in perforin that impair its maturation. Blood 103 : 1244-1252, 2004 7) Rickinson AB : Chronic, symptomatic Epstein-Barr virus infection. Immunology Today 7 : 13-14, 1986 20) Kimura H, Hoshino Y, Hara S, et al : Differences between T cell-type and natural killer cell-type chronic active Epstein-Barr virus infection. J Infect Dis 191 : 531-539, 2005 13) Kimura H, Morishima T, Kanegane H, et al : Prognostic factors for chronic active Epstein-Barr virus infection. J Infect Dis 187 : 527-533, 2003 9) Okano M, Matsumoto S, Osato T, et al : Severe chronic active Epstein-Barr virus infection syndrome. Clin Microbiol Rev 4 : 129-135, 1991 38) Fujii N, Takenaka K, Hiraki A, et al : Allogeneic peripheral blood stem cell transplantation for the treatment of chronic active Epstein-Barr virus infection. Bone Marrow Transplant 26 : 805-808, 2000 14) Ishihara S, Okada S, Wakiguchi H, et al : Clonal lymphoproliferation following chronic active EpsteinBarr virus infection and hypersensitivity to mosquito bites. Am J Hematol 54 : 276-281, 1997 37) Okamura T, Hatsukawa Y, Arai H, et al : Blood stem-cell transplantation for chronic active Epstein-Barr virus with lymphoproliferation. Lancet 356 : 223-224, 2000 30) Sumazaki R, Kanegane H, Osaki M, et al : SH2D1A mutations in Japanese males with severe Epstein-Barr virus associated illness. Blood 98 : 1268-1270, 2001 2) Virelizier JL, Lenoir G, Griscelli C : Persistent Epstein-Barr virus infection in a child with hypergamma-globulinaemia and immunoblastic proliferation associated with a selective defect in immune interferon secretion. Lancet 2 : 231-234, 1978 19) Kawa-Ha K, Ishihara S, Ninomiya T, et al : CD3-negative lymphoproliferative disease of granular lym-phocytes containing Epstein-Barr viral DNA. J Clin Invest 84 : 51-55, 1989 1) Cohen JI : Epstein-Barr virus infection. N Engl J Med 343 : 481-492, 2000 33) Lay JD, Tsao CJ, Chen JY, et al : Upregulation of tumor necrosis factor-alpha gene by Epstein-Barr virus and ac-tivation of macrophages in Epstein-Barr virus-infected T cells in the pathogenesis of hemophagocytic syndrome. J Clin Invest 100 : 1969-1967, 1997 12) 石原重彦, 多和昭雄, 岡田伸太郎, 他 : 本邦における.慢性活動性EBV感染症の特徴.1.臨床像および疫学的検討.日児誌95 : 80-90, 1991 5) Straus SE, Tosato G, Armstrong G, et al : Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med 102 : 7-16, 1985 16) Kimura H, Morita M, Yabuta Y, et al : Quantitative analysis of Epstein-Barr virus load by using a real-time PCR assay. J Clin Microbiol 37 : 132-136, 1999 28) Sugaya N, Kimura H, Hara S, et al : Quantitative analysis of Epstein-Barr virus (EBV) -specific CD8+ T cells in patients with chronic active EBV infection. J Infect Dis 190 : 985-988, 2004 6) Straus SE, Cohen JI, Tosato G, et al : NIH conference. Epstein-Barr virus infections : Biology, pathogenesis, and management. Ann Intern Med 118 : 45-58, 1993 23) 脇口宏 : 慢性活動性EBV感染症はEBV関連リンパ腫/白血病か?日児誌107 : 2-9, 2003 22) Kawa K, Okamura T, Yagi K, et al : Mosquito allergy and Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disease. Blood 98 : 3173-3174, 2001 |
| References_xml | – reference: 9) Okano M, Matsumoto S, Osato T, et al : Severe chronic active Epstein-Barr virus infection syndrome. Clin Microbiol Rev 4 : 129-135, 1991 – reference: 2) Virelizier JL, Lenoir G, Griscelli C : Persistent Epstein-Barr virus infection in a child with hypergamma-globulinaemia and immunoblastic proliferation associated with a selective defect in immune interferon secretion. Lancet 2 : 231-234, 1978 – reference: 1) Cohen JI : Epstein-Barr virus infection. N Engl J Med 343 : 481-492, 2000 – reference: 31) Katano H, Ali MA, Patera AC, et al : Chronic active Epstein-Barr virus infection associated with mutations in perforin that impair its maturation. Blood 103 : 1244-1252, 2004 – reference: 21) Kasahara Y, Yachie A, Takei K, et al : Differential cellular targets of Epstein-Barr virus (EBV) infection between acute EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection. Blood 98 : 1882-1888, 2001 – reference: 25) Shibata Y, Hoshino Y, Hara S, et al : Clonality analysis by sequence variation of the latent membrane protein 1 gene in patients with chronic active Epstein-Barr virus infection. J Med Virol 78 : 770-779, 2006 – reference: 3) Tobi M, Morag A, Ravid Z, et al : Prolonged atypical illness associated with serological evidence of persistent Epstein-Barr virus infection. Lancet 1 : 61-64, 1982 – reference: 20) Kimura H, Hoshino Y, Hara S, et al : Differences between T cell-type and natural killer cell-type chronic active Epstein-Barr virus infection. J Infect Dis 191 : 531-539, 2005 – reference: 33) Lay JD, Tsao CJ, Chen JY, et al : Upregulation of tumor necrosis factor-alpha gene by Epstein-Barr virus and ac-tivation of macrophages in Epstein-Barr virus-infected T cells in the pathogenesis of hemophagocytic syndrome. J Clin Invest 100 : 1969-1967, 1997 – reference: 4) Jones JF, Ray CG, Minnich LL, et al : Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses : Elevated anti-early antigen antibodies. Ann Intern Med 102 : 1-7, 1985 – reference: 13) Kimura H, Morishima T, Kanegane H, et al : Prognostic factors for chronic active Epstein-Barr virus infection. J Infect Dis 187 : 527-533, 2003 – reference: 12) 石原重彦, 多和昭雄, 岡田伸太郎, 他 : 本邦における.慢性活動性EBV感染症の特徴.1.臨床像および疫学的検討.日児誌95 : 80-90, 1991 – reference: 17) Okano M, Kawa K, Kimura H, et al : Proposed guidelinesfor diagnosing chronic active Epstein-Barr virus infection. Am J Hematol 80 : 64-69, 2005 – reference: 24) Toyabe S, Harada W, Uchiyama M : Biclonal expansion of T cells infected with monoclonal Epstein-Barr virus (EBV) in a patient with chronic, active EBV infection. Clin Exp Immunol 134 : 92-97, 2003 – reference: 8) Straus SE : The chronic mononucleosis syndrome. J Infect Dis 157 : 405-412, 1988 – reference: 26) 脇口宏, 藤枝幹也, 松本健治, 他 : 慢性活動性Epstein-Barr (EB) ウイルス感染症児の免疫学的研究 (1) 特異的キラーT細胞とNK細胞活性低下にっいて.日児誌90 : 1572-1579, 1986 – reference: 39) Yagita M, Iwakura H, Kishimoto T, et al : Successful allogeneic stem cell transplantation from an unrelated donor for aggressive Epstein-Barr virus-associated clonal T-cell proliferation with hemophagocytosis. Int J Hematol 74 : 451-454, 2001 – reference: 34) 木村宏, 河敬世, 大石勉, 他 : 慢性活動性EBV感染症の長期予後にっいて.日児誌, 印刷中 – reference: 6) Straus SE, Cohen JI, Tosato G, et al : NIH conference. Epstein-Barr virus infections : Biology, pathogenesis, and management. Ann Intern Med 118 : 45-58, 1993 – reference: 14) Ishihara S, Okada S, Wakiguchi H, et al : Clonal lymphoproliferation following chronic active EpsteinBarr virus infection and hypersensitivity to mosquito bites. Am J Hematol 54 : 276-281, 1997 – reference: 38) Fujii N, Takenaka K, Hiraki A, et al : Allogeneic peripheral blood stem cell transplantation for the treatment of chronic active Epstein-Barr virus infection. Bone Marrow Transplant 26 : 805-808, 2000 – reference: 7) Rickinson AB : Chronic, symptomatic Epstein-Barr virus infection. Immunology Today 7 : 13-14, 1986 – reference: 37) Okamura T, Hatsukawa Y, Arai H, et al : Blood stem-cell transplantation for chronic active Epstein-Barr virus with lymphoproliferation. Lancet 356 : 223-224, 2000 – reference: 15) Kikuta H, Taguchi Y, Tomizawa K, et al : Epstein-Barr virus genome-positive T lymphocytes in a boy with chronic active EBV infection associated with Kawasakilike disease. Nature 333 : 455-457, 1988 – reference: 23) 脇口宏 : 慢性活動性EBV感染症はEBV関連リンパ腫/白血病か?日児誌107 : 2-9, 2003 – reference: 32) Kawaguchi H, Miyashita T, Herbst H, et al : Epstein-Barr virus-infected T lymphocytes in Epstein-Barr virusassociated hemophagocytic syndrome. J Clin Invest 92 : 1444-1450, 1993 – reference: 28) Sugaya N, Kimura H, Hara S, et al : Quantitative analysis of Epstein-Barr virus (EBV) -specific CD8+ T cells in patients with chronic active EBV infection. J Infect Dis 190 : 985-988, 2004 – reference: 29) Sayos J, Wu C, Mona M, et al : The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395 : 462-469, 1998 – reference: 40) Uehara T, Nakaseko C, Hara S, et al : Successful control of Epstein-Barr virus (EBV) -infected cells by allogeneic nonmyeloablative stem cell transplantation in a patient with the lethal form of chronic active EBV infection. Am J Hematol 76 : 368-372, 2004 – reference: 16) Kimura H, Morita M, Yabuta Y, et al : Quantitative analysis of Epstein-Barr virus load by using a real-time PCR assay. J Clin Microbiol 37 : 132-136, 1999 – reference: 35) Kuzushima K, Yamamoto M, Kimura H, et al : Establishment of anti-Epstein-Barr virus (EBV) cellular immunity by adoptive transfer of virus-specific cytotoxic T lymphocytes from an HLA-matched sibling to a patient with severe chronic active EBV infection. Clin Exp Immunol 103 : 192-198, 1996 – reference: 5) Straus SE, Tosato G, Armstrong G, et al : Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med 102 : 7-16, 1985 – reference: 19) Kawa-Ha K, Ishihara S, Ninomiya T, et al : CD3-negative lymphoproliferative disease of granular lym-phocytes containing Epstein-Barr viral DNA. J Clin Invest 84 : 51-55, 1989 – reference: 11) Kimura H, Hoshino Y, Kanegane H, et al : Clinical and virologic characteristics of chronic active Epstein-Barr virus infection. Blood 98 : 280-286, 2001 – reference: 36) Savoldo B, Huls MH, Liu Z, et al : Autologous Epstein-Barr virus (EBV) -specific cytotoxic T cells for the treatment of persistent active EBV infection. Blood 100 : 4059-4066, 2002 – reference: 22) Kawa K, Okamura T, Yagi K, et al : Mosquito allergy and Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disease. Blood 98 : 3173-3174, 2001 – reference: 18) Jones J, Shurin S, Abramowsky C, et al : T-cell lymphomas containing Epstein-Barr viral DNA in patients with chronic Epstein-Barr virus infections. N Engl J Med 318 : 733-741, 1988 – reference: 10) Williams H, Crawford DH : Epstein-Barr virus : The impact of scientific advances on clinical practice. Blood 107 : 862-869, 2006 – reference: 30) Sumazaki R, Kanegane H, Osaki M, et al : SH2D1A mutations in Japanese males with severe Epstein-Barr virus associated illness. Blood 98 : 1268-1270, 2001 – reference: 27) Kimura H, Tsuge I, Imai S, et al : Intact antigen presentation for Epstein-Barr virus (EBV) -specific CTL by a lymphoblastoid cell line established from a patient with severe chronic active EBV infection. Med Microbiol Immunol 184 : 63-68, 1995 |
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