Association between adenovirus viral load and mortality in pediatric allo-HCT recipients: the multinational AdVance study

Abstract

This multivariable analysis from the AdVance multicenter observational study assessed adenovirus (AdV) viremia peak, duration, and overall AdV viral burden-measured as time-averaged area under the viremia curve over 16 weeks (AAUC 0-16 ) -as predictors of all-cause mortality in pediatric allo-HCT recipients with AdV viremia. In the 6 months following allo-HCT, 241 patients had AdV viremia ≥ 1000 copies/ml. Among these, 18% (43/241) died within 6 months of first AdV ≥ 1000 copies/ml. Measures of AdV viral peak, duration, and overall burden of infection consistently correlate with all-cause mortality. In multivariable analyses, controlling for lymphocyte recovery, patients with AdV AAUC 0-16 in the highest quartile had a hazard ratio of 11.1 versus the lowest quartile (confidence interval 5.3-23.6); for peak AdV viremia, the hazard ratio was 2.2 for the highest versus lowest quartile. Both the peak level and duration of AdV viremia were correlated with short-term mortality, independent of other known risk factors for AdV-related mortality, such as lymphocyte recovery. AdV AAUC 0-16 , which assesses both peak and duration of AdV viremia, is highly correlated with mortality under the current standard of care. New therapeutic agents that decrease AdV AAUC 0-16 have the potential of reducing mortality in this at-risk patient population.

Adenovirus persistence, reactivation, and clinical management

“…Recent studies have addressed the prognostic role of diagnostic parameters including HAdV peak levels and the time-averaged area under the curve (AAUC) of virus copy numbers in PB [58,43]. The predictive value for patient outcome reflected by all-cause, non-relapse, or HAdV-related mortality was determined, and was significant for the parameters tested [58,43]. The predictive value for patient outcome reflected by all-cause, non-relapse, or HAdV-related mortality was determined, and was significant for the parameters tested [58,43].…”

“…Other commonly used antivirals, such as ribavirin, ganciclovir, or foscarnet, have either highly questionable or no efficacy against HAdV infections [1,47,51]. This drug, provided at a recommended dose of 2 mgÁkg À1 (and a maximum of 100 mg) twice weekly, permitted clearance of the virus in a substantial proportion of patients, even in the absence of immune reconstitution [61,43], with GI symptoms as the main toxic side effect. This drug, provided at a recommended dose of 2 mgÁkg À1 (and a maximum of 100 mg) twice weekly, permitted clearance of the virus in a substantial proportion of patients, even in the absence of immune reconstitution [61,43], with GI symptoms as the main toxic side effect.…”

“…The observation that patients can succumb to disseminated HAdV disease within a few days after presenting with symptoms of systemic infection highlights the need for careful diagnostic monitoring and early implementation of therapeutic measures [23]. Although lethal HAdV infections have been described both in adult and pediatric allogeneic SCT recipients, the reported frequency of invasive infections with severe clinical courses is considerably higher in children [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] (Table 2). Different groups have tried to define thresholds of HAdV levels in plasma as a trigger for the initiation of antiviral treatment [44][45][46], Table 1.…”

“…In this regard, the documentation of rising virus copy numbers may be a more universal parameter, which is rather independent of the particular methodological approach used, as long as a quantitative (at present predominantly molecular) technique is employed. Nevertheless, clinical experience in the pediatric setting has indicated that the initiation of treatment at the stage of invasive HAdV infection, as documented by the presence of viremia, may not prevent disseminated disease with lethal outcome in a number of instances [1,23,33,43]. These observations have stimulated the search for diagnostic options facilitating early assessment of the risk for systemic infections, and the gastrointestinal (GI) tract was demonstrated to represent the most important compartment for expansion of the virus prior to dissemination in pediatric SCT recipients [33].…”

“…The occurrence of HAdV reactivation in SCT recipients may be associated with life-threatening clinical manifestations. Although lethal HAdV infections have been described both in adult and pediatric allogeneic SCT recipients, the reported frequency of invasive infections with severe clinical courses is considerably higher in children [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] (Table 2). Invasive infection is defined by the presence of adenoviremia, and serial diagnostic monitoring of peripheral blood (PB) samples during the post-transplant course is therefore of paramount importance.…”