title: Prospective, comprehensive, and effective viral monitoring in children undergoing allogeneic hematopoietic stem cell transplantation.
abstract: Major advances in the monitoring and treatment of viral infections after hematopoietic stem cell transplantation (HSCT) have been achieved over the last decade. The appropriate extent of viral monitoring and antiviral therapy remains controversial, and reports in pediatric patients receiving allogeneic unmanipulated hematopoietic stem cells (HSCs) are sparse. A total of 40 pediatric patients who underwent HSCT with either peripheral blood stem cells (PBSCs, n = 30) or bone marrow (BM; n = 10) were prospectively monitored every week for viral DNAemia (VDNA) by simultaneous detection of cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV6), human adenovirus (ADV), and polyoma BK virus (BKV) using real-time TaqMan polymerase chain reaction (PCR). All patients received prophylactic acyclovir and preemptive ganciclovir (GCV) when 500 copies/microg DNA (EBV/HHV6) or >1 copy/microg DNA (CMV) were detected on 2 consecutive measurements. VDNA occurred in 25 of 40 recipients (CMV, 11/40 patients [28%]; EBV, 19/40 [48%]; HHV6, 2/40 [5%]; ADV/BKV, 1/40) and was found exclusively after neutrophil engraftment and in most cases up to day +100. Recurrent VDNA (P = .028) and (readily treatable) viral disease (P = .003) were observed predominantly in patients suffering from nonmalignant diseases, a cohort characterized by delayed lymphocyte engraftment. VDNA occurred more frequently in HLA-mismatched HSCT and in the 24 of 40 patients receiving antithymocyte globulin (ATG). The incidence of EBV, but not that of CMV, was increased in the ATG group. Yet, in these patients, viral loads of both EBV and CMV were higher, but with prompt initiation of preemptive GCV, no posttransplantation lymphoproliferative disorder or other life-threatening morbidities occurred. HHV6 was typically detected at low viral loads (<10(2) copies/microg DNA), with only 5% of HSC recipients fulfilling our HHV6 criteria for triggering GCV treatment. In multivariate analysis, ATG treatment, HLA mismatch, recipient CMV seropositivity, and stem cell source, but not severe acute graft-versus-host disease were identified as independent risk factors for VDNA. This comprehensive viral monitoring program with defined thresholds for initiation of preemptive GCV effectively prevents the development of critical viral disease, even in high-risk patients receiving ATG.
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Heinrich-Heine-University, Düsseldorf, Germany. schoenberger@med.uni-duesseldorf.de
authors.forename: S
authors.initials: S
authors.lastname: Schönberger
authors.forename: R
authors.initials: R
authors.lastname: Meisel
authors.forename: O
authors.initials: O
authors.lastname: Adams
authors.forename: Y
authors.initials: Y
authors.lastname: Pufal
authors.forename: H J
authors.initials: HJ
authors.lastname: Laws
authors.forename: J
authors.initials: J
authors.lastname: Enczmann
authors.forename: D
authors.initials: D
authors.lastname: Dilloo
mesh_terms: D000257:Adenoviridae Infections / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology / Q000517:prevention & control; D000293:Adolescent; D000961:Antilymphocyte Serum; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001739:BK Virus / Q000302:isolation & purification; D016026:Bone Marrow Transplantation / Q000706:statistics & numerical data; D002648:Child; D002675:Child, Preschool; D004279:DNA, Viral / Q000097:blood; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use; D006086:Graft vs Host Disease / Q000150:complications; D019337:Hematologic Neoplasms / Q000601:surgery; D018380:Hematopoietic Stem Cell Transplantation / Q000706:statistics & numerical data; D006566:Herpesviridae Infections / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology / Q000517:prevention & control; D006801:Humans; D007223:Infant; D008297:Male; D036102:Peripheral Blood Stem Cell Transplantation / Q000706:statistics & numerical data; D027601:Polyomavirus Infections / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology / Q000517:prevention & control; D011183:Postoperative Complications / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology* / Q000517:prevention & control; D011292:Premedication; D011446:Prospective Studies; D014184:Transplantation, Homologous; D014766:Viremia / Q000175:diagnosis / Q000453:epidemiology; D014777:Virus Diseases / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology* / Q000517:prevention & control; D055815:Young Adult
chemical_list: D000961:Antilymphocyte Serum; D000998:Antiviral Agents; D004279:DNA, Viral; D015774:Ganciclovir