Incidence, patterns, and outcomes of adenovirus infections in patients following allogeneic hematopoietic cell transplantation

Abstract

Abstract Background: Adenovirus (AdV) infection is a recognized complication following allogeneic hematopoietic cell transplantation (allo-HCT), with incidence rates that can vary significantly depending on the patient population, being more common in pediatric patients than adults. The risk is highest in the first 3 to 4 months post-transplant, especially in T-cell-depleted graft recipients, patients with severe lymphopenia, and in the setting of acute on chronic graft-versus-host disease (GVHD). This study aims to evaluate the incidence, clinical patterns, and outcomes associated with adenovirus infections in patients following allogeneic hematopoietic stem cell transplantation (alloHCT). Methods: A systematic review was conducted of PubMed, ClinicalTrials.gov, and Cochrane CENTRAL databases to identify studies in which the incidence, clinical manifestations, and outcomes of adenovirus infection were reported for patients who had undergone allo-HCT and developed post-transplant AdV infection. The incidence of AdV infection was established as the primary outcome. AdV infection rates across different treatment groups, AdV infection-related mortality, overall survival, and cumulative incidence of AdV-related events were included as secondary outcomes. Pooled proportions with 95% confidence intervals (CIs) were calculated using R version 4.4.3 (R Foundation for Statistical Computing, Vienna, Austria). Results: A systematic review and meta-analysis included 23 studies with 6,053 patients. The median age ranged from 12.8 to 60 years, with 57.4% male (n=3,473). Median follow-up was 2.5–57 months. Underlying diagnoses were acute myeloid leukemia (27.6%, n=2,569), myelodysplastic syndrome (11%, n=970), acute lymphoblastic leukemia (11%, n=946), Hodgkin/non-Hodgkin lymphoma (5%, n=465), chronic myeloid leukemia (3%, n=292), multiple myeloma (5%, n=492), chronic lymphocytic leukemia (2.6%, n=202), aplastic anemia (0.7%, n=57), and other unspecified diagnoses. Conditioning regimens included myeloablative (49%, n=4,325), non-myeloablative (14.5%, n=923), and reduced-intensity (16.5%, n=1,281). The pooled AdV infection rate was 32.0% (95% CI: 9.0%–67.0%, I²=94.0%, p<0.001). Cidofovir monotherapy was used in 292 patients (31.7% of those treated), while 2,032 (37.7%) received cidofovir with other agents, and 2,541 (99.6%) received alternative regimens, including preemptive therapy, Cytovir-ADV, rituximab, third-party cytotoxic T lymphocytes, or surgical interventions. Subgroup analyses showed infection rates of 43.0% (95% CI: 13.0%–79.0%, I²=95.6%, p<0.001) for cidofovir monotherapy, 31.0% (95% CI: 10.0%–65.0%, I²=93.2%, p<0.001) for combination therapy, and 14.0% (95% CI: 12.0%–15.0%, I²=0.0%, p=0.84) for alternative regimens. AdV-related mortality was 6.0% (95% CI: 3.0%–13.0%, I²=91.3%, p<0.001). Overall survival, reported in few studies, ranged from 40% to 65% at 2.5–24 months. Cumulative AdV infection incidence, reported in 9 studies, included 6.0% at 6 months (Sedlacek et al.), 8.5% viremia and 3.2% disease at day 100 (Lee et al.), 10.0% at day 100 and 23.0% at 1 year (Chaekal et al.), and 165 cases by day 180 (Abidi et al.). Common assessment points were day 100, day 180, and 1 year post-transplant. Antiviral therapy uptake, reported in studies (e.g., Chandorkar et al., Oltolini et al., Hill et al.), ranged from 10% to over 60%. Conclusion: In patients who underwent allogeneic hematopoietic cell transplantation (allo-HCT), a high pooled incidence of adenovirus infection was observed. No significant differences in infection rates were identified across treatment groups, including cidofovir monotherapy, combination regimens, and alternative therapies. These findings underscore the significant burden of AdV infection and its associated mortality in this patient population. Future research should focus on optimizing antiviral strategies and exploring novel therapies to reduce AdV incidence and improve outcomes.