Abstract
Despite recent progress in the diagnostic risk assessment of human adenovirus (HAdV) infections in immunocompromised patients, clinical complications mediated by these viruses continue contributing to significant morbidity and mortality, particularly in the pediatric hematopoietic allogeneic stem cell transplant (HSCT) setting. Current data highlight the importance of monitoring stool samples to assess the risk of invasive HAdV infections in children undergoing HSCT. The advent of novel, more effective antiviral treatment options might permit successful virus control even at the stage of systemic infection, thus increasing the interest in optimized HAdV monitoring in peripheral blood (PB). We have screened over 300 pediatric HCST recipients by serial monitoring of stool and PB specimens, and identified 31 cases of invasive HAdV infection by quantitative pan-adenovirus RQ-PCR analysis of consecutive PB specimens. The diagnostic parameters assessed included HAdV peak levels (PL) and the time-averaged area under the curve (AAUC) of virus copy numbers. The predictive value for patient outcome reflected by non-relapse and HAdV-related mortality was determined. The patients were assigned to quartiles based on their PL and AAUC, and the readouts were highly correlated (p < 0.0001). Non-relapse mortality in patients by AAUC quartile (lowest to highest) was 26, 50, 75, and 86%, respectively, and AAUC was strongly correlated with non-relapse mortality (p < 0.0001), while the association between PL and non-relapse mortality was less pronounced (p = 0.013). HAdV-related mortality was absent or very low in patients within the two lower quartiles of both PL and AAUC, and increased to ≥70% in the upper two quartiles. Despite the significant correlation of PL and AAUC with patient outcome, it is necessary to consider that the risk of non-relapse mortality even within the lowest quartile was still relatively high, and it might be difficult therefore to translate the results into differential treatment approaches. By contrast, the correlation with HAdV-related mortality might permit the identification of a low-risk patient subset. Nevertheless, the well-established correlation of HAdV shedding into the stool and intestinal expansion of the virus with the risk of invasive infection will expectedly remain an essential diagnostic parameter in the pediatric HSCT setting.
Highlights
The incidence and severity of invasive human adenovirus (HAdV) infections in allogeneic hematopoietic allogeneic stem cell transplant (HSCT) recipients correlate with different factors including the level of immune system impairment, mediated in part by the conditioning regimen and the employment of strongly T-cell depleting strategies (Saif et al, 2015; Rustia et al, 2016)
The distribution of HAdV species detected in peripheral blood (PB), displaying predominance of species C and A, corresponded to that detected in children with intestinal persistence of the virus (Kosulin et al, 2016c) (Table 2)
Novel treatment options including the antiviral agent brincidofovir, which has documented efficacy in patients with invasive HAdV infection (Florescu et al, 2012; Grimley et al, 2017; Hiwarkar et al, 2017; Ramsay et al, 2017; Lopez et al, 2018), highlight the need for additional PB-based diagnostic parameters permitting the assessment of viral response to treatment and prediction of outcome
Summary
The incidence and severity of invasive HAdV infections in allogeneic HSCT recipients correlate with different factors including the level of immune system impairment, mediated in part by the conditioning regimen and the employment of strongly T-cell depleting strategies (Saif et al, 2015; Rustia et al, 2016). The ability to control the infection by current therapeutic modalities, including adoptive transfer of HAdV-specific T-cells, has been suggested to depend on timely onset of treatment (Lion et al, 2003; Feuchtinger et al, 2006; Geyeregger et al, 2014; Lion, 2014; Feucht et al, 2015) This notion has sparked the search for diagnostic parameters permitting early risk assessment of impending invasive infection and disseminated disease. Employment of the novel antiviral agent brincidofovir was shown in clinical studies to permit efficient HAdV elimination even in patients displaying viremia, and the efficacy of this drug was independent from immune reconstitution, in contrast to treatment with cidofovir (Florescu et al, 2012; Grimley et al, 2017; Hiwarkar et al, 2017) These clinical observations highlighted the need to establish improved diagnostic parameters based on the screening of peripheral blood samples. In line with previously published definitions (Lion et al, 2010), disseminated HAdV disease was diagnosed by the detection of multiple organ involvement (e.g., hepatitis, encephalitis, retinitis) in the presence of two or more HAdV-positive PCR assays in peripheral blood and other sites tested
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