Role of Adenovirus Reactivation on Blood and Stool Samples in Pediatric Hematopoietic Stem Cell Transplantation

One of the major challenges in pediatric hematopoietic stem cell transplantation (HSCT) is the susceptibility to viral infections and reactivations, which can lead to potentially life-threatening complications and increase the transplant-related mortality (TRM). Adenovirus (AdV) infection is associated to severe complications in HSCT recipients, including gastrointestinal disease, pneumonia, and hepatitis. Treatment options for AdV infection are limited and there is no accepted standard of care for AdV prevention and treatment. The aim of our prospective study was to analyze the incidence of AdV reactivation on stool and plasma samples of pediatric patients undergoing HSCT for both malignant and non-malignant disease at a single pediatric Hematology-Oncology unit. Endpoints were the cumulative incidence of AdV reactivation, measured on blood and stool samples, in the first 100 days after HSCT, and correlation between AdV DNAemia, on stool samples and transplant-related mortality after HSCT. A total of 140 patients were analyzed. Twenty-five (18%) patients were positive for AdV only on stool samples, 2 (2%) only on blood samples and 23 (16%) patients were positive on both blood and stool samples. In our pediatric cohort, cumulative incidence of AdV reactivation on stool samples was 36% (95% confidence interval, CI, 28-46), on blood samples 21% (95% CI, 15-30) (p-value<0.05). Cumulative incidence of AdV reactivation was higher on stool samples, due to the modality of AdV distribution (intestinal lymphocytes represents the main reservoir for AdV). AdV positivity on stool samples was a frequent event after and before HSCT (9 patients were positive on stool before HSCT), while AdV DNAemia was observed less frequently, and showed a close correlation with stool positivity; cumulative incidence of AdV DNAemia for patients with a previous positivity on stool samples, was 49% (95% CI, 36-65) (p-value<0.01). In our cohort, stool positivity anticipated AdV DNAemia by a median of 10 days (range, 1-66).

Cumulative incidence of AdV reactivation on both stool and blood samples was higher in haploidentical HSCT (46% and 32% respectively), than in matched unrelated donors (MUD) (32% and 5%) and in HSCT from matched familiar donors (17% and 9%). In our pediatric cohort, type of donor and age at the time of HSCT represented the best predictors of both blood and stool DNA positivity for AdV. Furthermore, in our cohort, positivity for AdV on blood and/or stool increases the risk of transplant-related mortality, although this result was not statistically significant.

Based on our data, we now perform screening of AdV on stool samples before HSCT and weekly surveillance of AdV viral load on stool and blood samples in transplant recipients with a previous positivity on stool and/or blood, and with specific risk factors (type of donor, severity of immunosuppression). Due to the limited treatment options for AdV infections, identification of patients at increased risk of AdV reactivation and early diagnosis of viral complications are crucial for successful HSCT outcome.

Tambaro:Jazz Pharma: Membership on an entity's Board of Directors or advisory committees, Other: travel expense; Amgen: Other: travel expense, Speakers Bureau; Novartis: Other: travel support; Neovii: Other: travel support ; Gilead: Membership on an entity's Board of Directors or advisory committees; Medac: Other: travel support , Speakers Bureau.