Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
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CMV antigenemia following pediatric hematopoietic stem cell transplantation : risk factors and outcomes

소아 조혈모세포 이식 후 거대세포 바이러스 항원혈증 발생 : 위험인자와 임상 경과

  • Cho, Eun-Young (Department of Pediatrics, College of Medicine, The Catholic University of Korea) ;
  • Park, Young-Shil (Department of Pediatrics, College of Medicine, The Catholic University of Korea) ;
  • Lee, Dae-Hyung (Department of Pediatrics, College of Medicine, The Catholic University of Korea) ;
  • Park, Ji Kyoung (Depatment of Pediatrics, Pusan Paik Hospital, College of Medicine, Inje University) ;
  • Choi, Sangrhim (Department of Pediatrics, College of Medicine, The Catholic University of Korea) ;
  • Kim, Sun Young (Department of Pediatrics, College of Medicine, Chungnam National University) ;
  • Jang, Pil-Sang (Department of Pediatrics, College of Medicine, The Catholic University of Korea) ;
  • Lee, Dong-Gun (Department of Internal Medicine, College of Medicine, The Catholic University of Korea) ;
  • Chung, Nak-Gyun (Department of Pediatrics, College of Medicine, The Catholic University of Korea) ;
  • Kim, Jong-Hyun (Department of Pediatrics, College of Medicine, The Catholic University of Korea) ;
  • Jeong, Dae-Chul (Department of Pediatrics, College of Medicine, The Catholic University of Korea) ;
  • Cho, Bin (Department of Pediatrics, College of Medicine, The Catholic University of Korea) ;
  • Hur, Jae Gyun (Department of Pediatrics, College of Medicine, The Catholic University of Korea) ;
  • Kang, Jin Han (Department of Pediatrics, College of Medicine, The Catholic University of Korea) ;
  • Kim, Hack Ki (Department of Pediatrics, College of Medicine, The Catholic University of Korea)
  • 조은영 (가톨릭대학교 의과대학 소아과학교실) ;
  • 박영실 (가톨릭대학교 의과대학 소아과학교실) ;
  • 이대형 (가톨릭대학교 의과대학 소아과학교실) ;
  • 박지경 (인제대학교 의과대학 부산백병원 소아과) ;
  • 최상림 (가톨릭대학교 의과대학 소아과학교실) ;
  • 김선영 (충남대학교 의과대학 소아과학교실) ;
  • 장필상 (가톨릭대학교 의과대학 소아과학교실) ;
  • 이동건 (가톨릭대학교 의과대학 내과학교실) ;
  • 정낙균 (가톨릭대학교 의과대학 소아과학교실) ;
  • 김종현 (가톨릭대학교 의과대학 소아과학교실) ;
  • 정대철 (가톨릭대학교 의과대학 소아과학교실) ;
  • 조빈 (가톨릭대학교 의과대학 소아과학교실) ;
  • 허재균 (가톨릭대학교 의과대학 소아과학교실) ;
  • 강진한 (가톨릭대학교 의과대학 소아과학교실) ;
  • 김학기 (가톨릭대학교 의과대학 소아과학교실)
  • Received : 2005.09.06
  • Accepted : 2005.10.25
  • Published : 2006.02.15
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Abstract

Purpose : Cytomegalovirus(CMV) infection still remains as a major cause of morbidity and mortality after stem cell transplantation. In this study, we analyzed the results of antigenemia-guided preemptive therapy among children with allogeneic hematopoietic stem cell transplantation to determine the incidence and risk factors associated with CMV antigenemia, and evaluated the efficacy of the CMV antigenemia based preemptive therapy. Methods : We enrolled 213 pediatric patients following allogeneic hematopoietic stem cell transplantation(HSCT), at the Catholic HSCT center between October 1998 and December 2003. Pre-emptive ganciclovir was started when more than 5 CMV Ag-positive cells were detected in matched sibling HSCT, and when any Ag-positive cells were seen in unrelated allogenic HSCT. Results : CMV antigenemia was observed in 88(41.3 percent) of 213 patients on median day 28(day 11-99). In univariated analysis, use of unrelated donors(other than siblings), age of recipient(more than 5 years at transplant) at transplantation, the presence of recipient CMV-IgG before transplantation, TBI-based conditioning regimen and the presence of acute GvHD(grade ${\geq}II$) were the risk factors for positive CMV antigenemia. In multivariate analysis, unrelated bone marrow transplantation, positive recipient CMV serology and acute GvHD(grade ${\geq}II$) were the independent risk factors for positive CMV antigenemia. Conclusion : Risk factors of CMV infection in children were CMV serostatus of the recipient, the source of stem cells, and acute graft-versus-host disease. The pre-emptive therapy based on CMV antigenemia was effective in the prevention of CMV disease.

목 적 : CMV 감염은 여전히 조혈모세포 이식 후 가장 중요한 감염 중 하나로 이환율과 사망률의 주요 원인이다. 조혈모세포 이식 후 CMV 감염 발생에 대한 위험인자의 분석 및 CMV pp65 항원혈증에 입각한 선제치료의 효과와 질환의 경과를 평가하고자 본 연구를 시행하였다. 방 법 : 1998년 10월부터 2003년 12월까지 가톨릭대학교 성모병원 소아과에서 이식을 시행받은 환아를 대상으로 하였다. pp66항원을 이용한 항원혈증검사를 토대로 혈연간 이식 환아의 경우 CMV 항원 양성세포가 5개 이상 발견된 경우, 비혈연간 이식 환아의 경우는 CMV 항원 양성세포가 하나라도 발견된 경우 ganciclovir 선제치료를 시작하였다. 결 과 : CMV 항원혈증은 대상 환아 213명 중 88명(41.3%)에서 관찰되었고, 각각 비혈연간 골수이식(62.5%), 비혈연간 제대혈이식(36.8%), HLA-일치 혈연간 이식(25.3%)이었다. 이식유형에 따른 CMV 항원혈증 발생확률은 비혈연간 골수이식($62.5{\pm}5.4%$)이 비혈연간 제대혈이식($36.8{\pm}7.8%$) 또는 HLA-일치 혈연간 이식($25.3{\pm}4.5%$)보다 통계적으로 유의하게 높았다. 단변량 분석에 의하면 비혈연간 이식, 이식 시 환자 연령(5세 이상), 이식 전 환자의 CMV-IgG, 전처치로 전신방사선조사의 사용 및 2도 이상의 급성 이식편대 숙주병의 발생이 CMV 항원혈증 발생의 위험인자이었다. 다변량분석에 의하면 비혈연간 이식, 이식전 환자의 CMV-IgG 양성상태 및 2도 이상의 급성 이식편대 숙주병의 발생이 독립적인 위험인자이었다. 이식환자 213명 중 7례(3.3%)에서 CMV 질환이 발생하였다(고항원혈증에서 6례 발생). 결 론 : 소아 조혈모세포 이식에 있어서 CMV 감염의 위험인자는 이식 전 환자의 CMV 혈청학적 상태, 조혈모세포 공급원, 급성 이식편대 숙주병이었으며, CMV 항원혈증에 입각한 ganciclovir 선제치료는 CMV 질환의 발생을 예방하는데 효과적이었다.

Keywords

References

  1. Meyers JD, Flournoy N, Thomas ED. Nonbacterial pneumonia after allogenic marrow transplantation : a review of ten years' experience. Rev Infect Dis 1982;4:1119-32 https://doi.org/10.1093/clinids/4.6.1119
  2. Meyers JD, Flournoy N, Thomas ED. Risk factors for cytomegalovirus infection after human marrow transplantation. J Infect Dis 1986;153:478-88 https://doi.org/10.1093/infdis/153.3.478
  3. Ljungman P, Reusser P, de la Camara R, Einsele H, Engelhard D, Ribaud P, et al.; European Group for Blood and Marrow Transplantation. Management of CMV infections : recommendations from the infectious diseases working party of the EBMT. Bone Marrow Transplant 2004;33:1075-81 https://doi.org/10.1038/sj.bmt.1704505
  4. Bonon SH, Menoni SM, Rossi CL, De Souza CA, Vigorito AC, Costa DB, et al. Surveillance of cytomegalovirus infection in haematopoietic stem cell transplantation patients. J Infect 2005;50:130-7 https://doi.org/10.1016/j.jinf.2003.11.010
  5. Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis 2002;34:1094-7 https://doi.org/10.1086/339329
  6. Meyers JD. Prevention and treatment of cytomegalovirus infection after marrow transplantation. Bone Marrow Transplant 1988;3:95-104
  7. Miller W, Flynn P, McCullough J, Balfour HH Jr, Goldman A, Haake R, et al. Cytomegalovirus infection after bone marrow transplantation : an association with acute graftv- host disease. Blood 1986;67:1162-7
  8. Boeckh MJ, Ljungman P. Cytomegalovirus infection after hemopoietic stem cell transplantation. In : Bowden RA, Ljungman P, Paya CV, editors. Transplant infections. Second ed. Philadelphia : Lippincott Williams & Wilkins, 2003: 277-97
  9. Kim YK, Kim DW. Seroepidemiology of human cytomegalovirus in healthy adults measured by means of the anticomplement immunofluorescence technique. Korean J Infect Dis 1992;24:87-92
  10. Hahn JS, Lee SJ, Park WK, Ko YW, Kim HO, Lee SY. A survey on the cytomegalovirus antibodies in blood donors and the diseased. Korean J Blood Transfus 1990;1:21-34
  11. Grob JP, Grundy JE, Prentice HG, Griffiths PD, Hoffbrand AV, Hughes MD, et al. Immune donors can protect marrow- transplant recipients from severe cytomegalovirus infections. Lancet 1987;1:774-6
  12. Kollman C, Howe CW, Anasetti C, Antin JH, Davies SM, Filipovich AH, et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors : the effect of donor age. Blood 2001;98: 2043-51 https://doi.org/10.1182/blood.V98.7.2043
  13. Einsele H, Hebart H, Kauffmann-Schneider C, Sinzger C, Jahn G, Bader P, et al. Risk factors for treatment failure in patients receiving PCR-based preemptive therapy for CMV infection. Bone Marrow Transplant 2000;25:757-63 https://doi.org/10.1038/sj.bmt.1702226
  14. Emanuel D, Cunningham I, Jules-Elysee K, Brochstein JA, Kernan NA, Laver J, et al. Cytomegalovirus pneumonia after bone marrow transplantation successfully treated with the combination of ganciclovir and high-dose intravenous immune globulin. Ann Intern Med 1988;109:777-82 https://doi.org/10.7326/0003-4819-109-10-777
  15. Reed EC, Bowden RA, Dandliker PS, Lilleby KE, Meyers JD. Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants. Ann Intern Med 1988;109:783-8 https://doi.org/10.7326/0003-4819-109-10-783
  16. Bowden RA, Slichter SJ, Sayers MH, Mori M, Cays MJ, Meyers JD. Use of leukocyte-depleted platelets and cytomegalovirus- seronegative red blood cells for prevention of primary cytomegalovirus infection after marrow transplant. Blood 1991;78:246-50
  17. de Gast GC, Boland GJ, Vlieger AM, de Weger RA, Verdonck LF, Zwaan FE, et al. Abortive human cytomegalovirus infection in patients after allogeneic bone marrow transplantation. Bone Marrow Transplant 1992;9:221-5
  18. van Prooijen HC, Visser JJ, van Oostendorp WR, de Gast GC, Verdonck LF. Prevention of primary transfusion-associated cytomegalovirus infection in bone marrow transplant recipients by the removal of white cells from blood components with high-affinity filters. Br J Haematol 1994;87: 144-7 https://doi.org/10.1111/j.1365-2141.1994.tb04884.x
  19. Verdonck LF, de Graan-Hentzen YC, Dekker AW, Mudde GC, de Gast GC. Cytomegalovirus seronegative platelets and leukocyte-poor red blood cells from random donors can prevent primary cytomegalovirus infection after bone marrow transplantation. Bone Marrow Transplant 1987;2:73-8
  20. Li CR, Greenberg PD, Gilbert MJ, Goodrich JM, Riddle SR. Recovery of HLA-restricted cytomegalovirus(CMV)-specific T-cell responses after allogeneic bone marrow transplant : correlation with CMV disease and effect of ganciclovir prophylaxis. Blood 1994;83:1971-9
  21. Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation : a randomized double-blind study. Blood 1996;88:4063-71
  22. Schmidt GM, Horak DA, Niland JC, Duncan SR, Forman SJ, Zaia JA. A randomized, controlled trial of prophylactic ganciclovir for cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow transplants; The City of Hope-Stanford-Syntex CMV Study Group. N Engl J Med 1991;324:1005-11 https://doi.org/10.1056/NEJM199104113241501
  23. van der Bij W, Torensma R, van Son WJ, Anema J, Schirm J, Tegzess AM, et al. Rapid immunodiagnosis of active cytomegalovirus infection by monoclonal antibody staining of blood leucocytes. J Med Virol 1988;25:179-88 https://doi.org/10.1002/jmv.1890250208
  24. Mori T, Okamoto S, Matsuoka S, Yajima T, Wakui M, Watanabe R, et al. Risk-adapted pre-emptive therapy for cytomegalovirus disease in patients undergoing allogeneic bone marrow transplantation. Bone Marrow Transplant 2000;25:765-9 https://doi.org/10.1038/sj.bmt.1702227
  25. Choi SM, Lee DG, Choi JH, Yoo JH, Kim YJ, Park SH, et al. Risk-adapted preemptive therapy for cytomegalovirus disease after allogeneic stem cell transplantation : a singlecenter experience in Korea. Int J Hematol 2005;81:69-74 https://doi.org/10.1532/IJH97.A30402
  26. Kanda Y, Mineishi S, Saito T, Seo S, Saito A, Suenaga K, et al. Pre-emptive therapy against cytomegalovirus(CMV) disease guided by CMV antigenemia assay after allogeneic hematopoietic stem cell transplantation : a single-center experience in Japan. Bone Marrow Transplant 2001;27:437-44 https://doi.org/10.1038/sj.bmt.1702805
  27. Small TN, Papadopoulos EP, Boulad F, Kiehn T, Stiles J, Sepkowitz K, et al. Outcome of pre-emptive or prophylactic anti-viral therapy to prevent CMV disease following T cell depleted related or unrelated BMT. Blood 2001;98:S394a (Abstract 1659)
  28. Manteiga R, Martino R, Sureda A, Labeaga R, Brunet S, Sierra J, et al. Cytomegalovirus pp65 antigenemia-guided pre-emptive treatment with ganciclovir after allogeneic stem transplantation: a single-center experience. Bone Marrow Transplant 1998;22:899-904 https://doi.org/10.1038/sj.bmt.1701439
  29. Humar A, Lipton J, Welsh S, Moussa G, Messner H, Mazzulli T. A randomized trial comparing cytomegalovirus antigenemia assay vs screening bronchoscopy for the early detection and prevention of disease in allogeneic bone marrow and peripheral blood stem cell transplant recipients. Bone Marrow Transplant 2001;28:485-90 https://doi.org/10.1038/sj.bmt.1703178
  30. Meijer E, Boland GJ, Verdonck LF. Prevention of cytomegalovirus disease in recipients of allogeneic stem cell transplants. Clin Microbiol Rev 2003;16:647-57 https://doi.org/10.1128/CMR.16.4.647-657.2003