ORIGINAL ARTICLE
Risk Factors for Human Herpesvirus 6 Reactivation and its Relationship With Syndrome of Inappropriate Antidiuretic Hormone Secretion After Stem Cell Transplantation in Pediatric Patients Naohisa Toriumi, MD,* Ryoji Kobayashi, MD, PhD,w Makoto Yoshida, MD, PhD,* Akihiro Iguchi, MD, PhD,z Takeo Sarashina, MD,* Hitoshi Okubo, MD,* Daisuke Suzuki, MD, PhD,w Hirozumi Sano, MD,z Masao Ogata, MD, PhD,y and Hiroshi Azuma, MD, PhD*
Summary: There have been several reports on the reactivation of human herpesvirus 6 (HHV6) after stem cell transplantation (SCT) in adults, which sometimes induces severe illness. Few reports exist on pediatric patients; therefore, we retrospectively examined HHV6 reactivation after SCT in children. We reviewed 80 patients with a median age of 6 years. We analyzed HHV6 DNA serum samples from the patients before SCT and at 20 and 40 days after SCT using polymerase chain reaction. We also analyzed the relationship between HHV6 reactivation and the syndrome of inappropriate antidiuretic hormone secretion (SIADH). At 20 days after SCT, 35.0% of serum samples were positive for HHV6 DNA. The median viral load was 3.1 104 copies/mL serum. Multivariate analysis showed cord blood transplantation as the only risk factor for HHV6 reactivation. HHV6 reactivation occurs in 59.4% of 32 patients who underwent cord blood transplantation and in 18.8% of 48 patients who underwent SCT from other sources. Among the 14 patients with SIADH, 78.6% experienced HHV6 reactivation. Among the 66 patients without SIADH, only 25.8% had HHV6 reactivation. This result was statistically significant (P < 0.001). This analysis revealed that HHV6 reactivation occurs in many children. In addition, HHV6 reactivation plus SIADH should prompt evaluation for central nervous system disease. Key Words: human herpesvirus 6, stem cell transplantation, children, syndrome of inappropriate antidiuretic hormone secretion
clinical complications including hepatitis,3 pneumonitis,4 myelosuppression,3,5 and encephalitis.3,6 However, there are few reports on HHV6 reactivation after SCT in children.7 We previously reported that syndrome of inappropriate antidiuretic hormone secretion (SIADH) also seems to be one of the complications of SCT.8,9 In that study, 16 of 140 pediatric patients who had undergone SCT were later diagnosed with SIADH. Multivariable analysis revealed that an age below 4 years and transplantation from an HLA-mismatched donor were particularly the risk factors for SIADH.8 In addition, we indicated that patients who had undergone cord blood transplantation (CBT) had an earlier onset of SIADH with more severe symptoms compared with patients who had undergone bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT). In addition, neurological sequelae were more frequent after SCT in survivors with SIADH than in those without SIADH.9 In this study, we investigated the incidence of HHV6 reactivation after SCT in pediatric patients and have evaluated its association with SIADH after SCT.
MATERIALS AND METHODS
(J Pediatr Hematol Oncol 2014;36:379–383)
Patients
P
rimary human herpesvirus 6 (HHV6) infection is a common occurrence during early childhood. Almost all children are exposed to HHV6 and have the antibody against the virus by the latter half of their first year of life.1 After primary infection, HHV6 remains latent except during the periods of immune suppression. HHV6 has been shown to reactivate in 40% to 50% of hematopoietic stem cell transplantation (SCT) recipients.2 Many studies in adult SCT recipients have suggested that HHV6 can cause Received for publication January 22, 2013; accepted June 15, 2013. From the *Department of Pediatrics, Asahikawa Medical University; wDepartment of Pediatrics, Sapporo Hokuyu Hospital; zDepartment of Pediatrics, Hokkaido University Graduate School of Medicine, Hokkaido; and yDepartment of Hematology, Oita University Faculty of Medicine, Oita, Japan. The authors declare no conflict of interest. Reprints: Naohisa Toriumi, MD, Department of Paediatrics, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan (e-mail:
[email protected]). Copyright r 2013 by Lippincott Williams & Wilkins
J Pediatr Hematol Oncol
Volume 36, Number 5, July 2014
This study was performed retrospectively at Hokkaido University Hospital, Asahikawa Medical University Hospital, or Sapporo Hokuyu Hospital using repository samples. In these 3 hospitals, a total of 306 pediatric patients underwent SCT for malignant or nonmalignant disease between February 1988 and May 2011. Our study included 80 patients for whom frozen samples were available. Among the patients, 48 were boys and 32 were girls. The median age was 6 years (range, 0 to 18 y). Forty-nine patients had hematological malignancy: among them, 24 had acute lymphoblastic leukemia, 16 suffered from acute myelogenous leukemia, 4 had chronic myelogenous leukemia, 3 had juvenile myelomonocytic leukemia, and 2 suffered from non-Hodgkin lymphoma. Thirty-one patients had other diseases: 14 had solid tumors, 8 had bone marrow failure, 5 had immune deficiencies, 3 had metabolic disorders, and 1 had chronic active Epstein-Barr virus infection. The SCT types were as follows: BMT in 43 patients, PBSCT in 4 patients, BMT and PBSCT in 1 patient, and www.jpho-online.com |
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CBT in 32 patients. The transplant donors comprised 18 HLA-matched siblings, 3 one-antigen–mismatched siblings, 3 HLA-matched or HLA-mismatched parents, 22 HLA-matched unrelated donors, 24 HLA one-antigen– mismatched unrelated donors, 3 two-antigen–mismatched unrelated donors, and 7 autotransplantations. The characteristics of the study patients are shown in Table 1. In most patients, conditioning regimens comprised standard myeloablation using a combination of cyclophosphamide (Cy) and etoposide (VP) with either total body irradiation (“TBI/Cy/VP”; n = 21) or busulfan (Bu; “Bu/Cy/VP”; n = 8). There were 13 patients using antithymocyte globulin or antilymphocyte globulin. Acyclovir was routinely prescribed for all patients from 7 days before SCT to 35 days after SCT.
Evaluation of Hyponatremia Serum sodium levels were measured for all patients using a routine automated analyzer every morning until 40 days after SCT and 2 to 3 times weekly thereafter. We defined hyponatremia as a serum sodium level