Adenovirus Infections in Patients Undergoing Umbilical Cord Blood Hematopoietic Stem Cell Transplantation.

Adenovirus infections are an important source of morbidity and mortality among stem cell transplant (SCT) recipients, with infections occurring in 5-21% of patients, with an associated mortality of up to 50%. Little is known about the clinical features and incidence of adenovirus infection after cord blood SCT (CB-SCT) in adults.

The DFCI/BWH umbilical CB-SCT cohort transplanted from 2003-2008 was analyzed. Adenovirus infection was diagnosed by blood PCR, culture, immunofluorescence, or immunohistochemistry. Baseline covariates included age, sex, malignancy being treated, conditioning, graft versus host disease (GVHD) prophylaxis, incident GVHD and its severity. Data was censored on 7/1/2009.

92 patients underwent CB-SCT during the period; 89 were double cord recipients. 68 underwent reduced-intensity conditioning consisting of fludarabine (180mg/m2), melphalan (100 mg/m2), and ATG (Thymoglobulin® 6 mg/kg). GVHD prophylaxis with sirolimus and tacrolimus was used in 57 patients, cyclosporine and mycophenolate mofetil in 17, and other combinations in the rest of the cohort. Median follow up was 363 days (range, 1-1848 days). Adenovirus testing was routinely done for persistent febrile illness, respiratory, gastrointestinal and hepatic syndromes. Adenovirus infection was diagnosed in 6/92 for a cumulative incidence of 6.5%. Three were female, median age was 51 years (range, 37-62). Underlying disease was MDS in 1, NHL in 2, AML in 2 and HD in 1. Median time to diagnosis was 152 days (range, 23-768) from CB-SCT. Three patients were diagnosed within 100 days post CB-SCT: all had diarrhea and fever. The other 3 patients were diagnosed between 8 months to 2 years after transplant: one patient each had respiratory, urinary and gastrointestinal infection. Three of the six patients developed concomitant CMV reactivation with their adenovirus infection: 2 of these occurred within 100 days of transplant, and one occurred 1 year after HSCT. Three of the 6 patients with adenovirus infection also developed grade II-IV acute GVHD and 2 developed chronic GHVD. The onset of acute GVHD was closely associated in time with the development of adenovirus infection; this was not the case of chronic GVHD. Two patients had blood adenovirus loads > 1 million copies/mL, and were treated with cidofovir with improvement in symptoms and decline in virus loads. Of the 6 patients, 3 died of relapsed disease, none died of complications attributable to adenovirus infection.

Since recipients of T-cell depleted transplants are at higher risk for viral infections compared to those receiving unmanipulated grafts, we hypothesized that umbilical cord recipients would be at an increased risk for adenovirus infection due to the limited number of immunocompetent T-cells in cord blood grafts. Surprisingly, we detected adenovirus infection in only 6.5% of patients in this cohort, and none died as a consequence of adenovirus infection. Further study of the immunity to adenoviruses in CB-SCT adult recipients is warranted.

Off Label Use: cidofovir for treatment of adenovirus infection.