Cytomegalovirus Infection in Pediatric Haploidentical Hematopoietic Stem Cell Transplantation at a Single Center

Introduction : Clinical aspects and risk factors of Cytomegalovirus (CMV) reactivation and diseases are an emerging interest in recent investigation fields of hematopoietic stem cell transplantation (HSCT). Several risk factors and clinical manifestations of CMV infection have been reported in numbers of previous reports. Monitoring of viral replication and timely given antiviral agents have resulted in a decreased incidence of CMV-related death recently. However, CMV in still a major cause of infectious complications after HSCT. Specially in haploidentical HSCT setting, clinical manifestations and associated risk factors have been rarely reported. This study is conducted to identify risk factors and clinical aspects of CMV reactivation and disease in pediatric haploidentical HSCT.

Methods : We retrospectively reviewed the medical records of 92 pediatric patients who underwent haploidentical HSCT using ex vivo T cell-depleted grafts at Asan Medical Center between December, 2004 and June, 2016. After haploidentical HSCT, all recipients were monitored for CMV infection by CMV pp65 antigen and/or CMV-PCR. Both recipient and donor were screened for CMV serology before the HSCT. During the study period, methodologic changes in ex vivo T cell depletion and CMV prophylaxis policy have been modulated with the course of time. During the 1^st study period (Group I, n=19), CD3⁺ T cell was depleted without CMV prophylaxis while ganciclovir for CMV prophylaxis was given with CD3⁺ T cell depletion during the 2^nd period (Group II, n=16). The T cells expressing alpha-beta T cell receptor (TCR_αβ) was depleted during the 3^rd period (Group III, n=57) with ganciclovir prophylaxis.

Results : Of the 92 patients, 49 (53.3%) developed CMV reactivation after haploidentical HSCT. CMV reactivation significantly reduced in group II and III compared to group I (84±8.4% vs 46±5.9%; p<0.001). Patients with chronic graft-versus-host-disease (GVHD) also experienced more reactivation (p=0.041). In the multivariate analysis, difference of study group was the only variable predicted the occurrence of CMV reactivation (Group I vs Group III; hazard ratio, 3.728; 95% confidence interval (CI), 1.910-7.278). CMV disease was developed in 16/92 (17.4%) patients during the study period (16/49, 32.7% among CMV reactivation patients). The peak CMV pp65 antigen level, peak CMV DNA-PCR level, and duration of CMV antigenemia were significantly higher in patients with CMV disease (p=0.024, p=0.009, p=0.046, respectively). In univariate analysis, the peak CMV pp65 antigen level (p=0.020), and duration of CMV antigenemia (p=0.05) were associated with increased occurrence of CMV disease. In multivariate analysis, CMV disease significantly increased in patients with high CMV pp65 antigenemia greater than 40/200,000 cells (hazard ratio, 3.568; 95% CI 1.062-12.594). CMV diseases included retinitis in 12 (75%), pneumonitis in 3 (25%), gastritis, colitis, and encephalitis in 1 (8.3%) each, respectively. Of the 16 patients, 3 patients (2 pneumonitis, 1 encephalitis) died of CMV disease.

Conclusions : Our study demonstrated that ganciclovir prophylaxis has effectively reduced the occurrence of CMV reactivation in ex vivo T cell depleted haploidentical HSCT. In addition, close monitoring of CMV pp65 antigen and timely preemptive management is important to prevent CMV related death.