Disseminated Adenovirus Infections after Allogeneic Hematopoietic Stem Cell Transplantation: High Rate of Associated Co-Morbidity and Mortality.
Authors: Robin Marie , Marque-Juillet Stéphanie , Scieux Catherine , de Latour Régis Peffault , Ferry Christèle , Rocha Vanderson , Devergie Agnès , Gluckman Eliane , Ribaud Patricia , Socié Gérard 
Published: October 2019

Abstract
Adenovirus (ADV) infection is associated with significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this study was to determine the cumulative incidence, the evolution and the risk factors of disseminated ADV infection defined as a real time ADV PCR positive in blood and 1 or more additional sites. Between January 2000 and April 2006, 38 patients with disseminated ADV were identified. Median age at diagnosis was 15 years (4 – 48). Primary diseases were leukemia (n=16), Fanconi anemia (n=10) or others (n=2). All but one patient received an unrelated HSCT. The graft consisted in peripheral blood (n=3), bone marrow (n=10) and cord blood (n=15). Plasma ADV PCR was positive at a median of 79 days after HSCT (range: 12 – 460). Involved organs were: liver (n=12), respiratory tract (n=15), gut (n=21), cystitis (n=12) and 19 patients had fever. Twenty-one patients had grade II-IV GVHD. The majority of the patients had other concomitant infections: invasive fungal infection (n=15), 1 to 4 other virus (CMV, EBV, RSV, parainfluenzae, BK virus) (n=21) and bacteremia (n=12). Risk factors for disseminated ADV were analyzed among patients who received an unrelated HSCT, and separately in adults and in children. 265 patients received an unrelated HSCT during the same period. Cumulative incidence (with death as a competing event) of disseminated ADV was 9% (95%CI: 4–3) in adults and 18% (95%CI: 10-27) in children. In adults, grade II–IV GVHD [time dependant covariate, Hazard Ratio (HR): 3.47, 95%CI: 1.14–10.6, p = 0.029] and cord blood as source of stem cell [HR: 7.10, 95%CI: 2.41-20.9, p = 0.0038] were associated with disseminated ADV infection. In children, grade II-IV GVHD [HR: 3.94, 95%CI: 1.15–13.5, p = 0.029] and Fanconi as primary disease [HR: 5.28, 95%CI: 1.69-16.6, p = 0.0043] were associated with disseminated ADV infection. Twenty-three patients were treated by cidofovir. Four patients had complete response (CR) [negative ADV PCR], 2 patients had primary CR followed by relapse and 2 patients had stable disease 90 and 67 days after treatment initiation. Fifteen patients were refractory to treatment. Main differences between responders and non-responders were ADV DNA load at onset of treatment (1343 versus 71 674 copies/ml), median time from HSCT to ADV diagnosis (98 versus 53 days), dosage of corticosteroids at time of treatment (0.75mg/kg/d versus 1.5 mg/kg/d), neutrophil (2× 109/L versus 1.5 × 109/L) and lymphocyte count (0.135 × 109/L and 0.070 × 109/L). An increase in the plasma viral load of ≥ 4 log10 in the 30 days after the first cidofovir dose was always followed by a fatal issue (n=9). Four-month infectious-related mortality and 1-year survival after diagnosis was 72% (95% confidence interval: 55–90) and 23% (95%CI:10–51). The only survivors were among the sustained responders in whom 1-year survival was 33% (95%CI: 7–100). In spite of earlier diagnosis and cidofovir treatment, disseminated ADV disease after HSCT leads to a high mortality rate, mainly related to multiple infections for all patients, reflecting a profound underlying immune defect.