Factors Associated with CMV Disease in Pediatric Hematopoietic Stem Cell Transplantation

Purpose.  Cytomegalovirus (CMV) infection remains a significant source of morbidity in pediatric hematopoietic stem cell transplantation (HSCT).  Current strategies for mitigating the effect of CMV on outcome include weekly measurement of CMV viral load in the blood through post-transplant day 100 and use of acyclovir prophylaxis in the peritransplant period in patients at risk for CMV infection (patients in which the HSCT donor or recipient had CMV IgG seropositivity indicative of latent infection).  Risk factors predicting CMV infection in pediatric HSCT are not well understood, and factors affecting recurrence of CMV viremia following an initial episode have not been reported.

Methods. We performed a retrospective review of consecutive cases at our institution between 2011 and 2014 where the recipient was at risk for CMV infection.  We calculated odds ratios (OR) and 95% confidence intervals (CI) of CMV reactivation as a function of HSCT characteristics.  This study was approved by the Institutional Review Board of the Dana-Farber Cancer Institute.

Results.  Out of a total of 91 at risk patients, 26 (29%) patients had CMV infection (defined as CMV viremia without target organ involvement) occurring at a median of 46 days following HSCT (range: 9-127).  One patient died from biopsy-proven CMV pneumonitis.  There was a trend towards recipients with underlying malignant conditions having increased risk of CMV infection compared to others (OR=2.3; 95% CI=0.9-6.0; p=0.08).  There was a significantly increased risk of CMV infection in recipients of an umbilical cord blood compared to other sources (OR=9.45; 95% CI=1.8-50.6; p=0.009). Patients with acute graft-versus-host disease (aGVHD) had a significantly increased risk of CMV infection (OR=3.6; 95% CI=1.1-12.1; p=0.04). All patients with viremia received a 14-day course of antiviral and immunoglobulin therapy.  Patients who failed to clear the virus completely from the blood at the end of 14 days of therapy had no increased risk of CMV recurrence (p=0.2).  A total of 6/26 (23%) HSCT recipients experienced CMV recurrence, at a median of 33 days (range 9-74) following initial CMV clearance.  In the subset of recipients who experienced a recurrence of CMV infection, there was a trend toward increased treatment-related mortality (TRM; OR=9.5; 95% CI = 0.7-132; p=0.09).  However, among all recipients at risk, CMV viremia was not associated with increased TRM (p=0.7).

Conclusions.  Pediatric patients seropositive for CMV who receive umbilical cord HSCTs have increased risk for CMV viremia in the post-HSCT period.  CMV infection is associated with aGVHD.  If treated with antivirals, recurrence of CMV can be prevented.  Multiple episodes of CMV viremia may be associated with increased TRM.  This study broadens understanding of CMV disease in pediatric HSCT, and is the first to analyze factors influencing recurrence of CMV infection.