Kosulin Karin, Pichler Herbert, Lawitschka Anita, Geyeregger René, Lion Thomas
Molecular Microbiology, Children's Cancer Research Institute, Vienna, Austria.
Stem Cell Transplant Unit, St. Anna Children's Hospital, Vienna, Austria.
Front Microbiol. 2019 Feb 22;10:414. doi: 10.3389/fmicb.2019.00414. eCollection 2019.
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 ( < 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 ( < 0.0001), while the association between PL and non-relapse mortality was less pronounced ( = 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.
尽管在免疫功能低下患者的人腺病毒（HAdV）感染诊断风险评估方面取得了进展，但这些病毒介导的临床并发症仍然导致了显著的发病率和死亡率，尤其是在儿科异基因造血干细胞移植（HSCT）患者中。目前的数据强调了监测粪便样本以评估接受HSCT儿童侵袭性HAdV感染风险的重要性。新型、更有效的抗病毒治疗方案的出现可能使即使在全身感染阶段也能成功控制病毒，从而增加了对外周血（PB）中优化HAdV监测的兴趣。我们通过对粪便和PB样本进行连续监测，对300多名儿科HSCT受者进行了筛查，并通过对连续PB样本进行定量泛腺病毒RQ-PCR分析，确定了31例侵袭性HAdV感染病例。评估的诊断参数包括HAdV峰值水平（PL）和病毒拷贝数的时间平均曲线下面积（AAUC）。确定了非复发和HAdV相关死亡率所反映的患者预后的预测价值。根据患者的PL和AAUC将患者分为四分位数，结果高度相关（<0.0001）。按AAUC四分位数（从最低到最高）划分的患者非复发死亡率分别为26%、50%、75%和86%，AAUC与非复发死亡率密切相关（<0.0001），而PL与非复发死亡率之间的关联则不太明显（=0.013）。在PL和AAUC的两个较低四分位数范围内的患者中，HAdV相关死亡率不存在或非常低，而在较高的两个四分位数中则增加到≥70%。尽管PL和AAUC与患者预后有显著相关性，但必须考虑到即使在最低四分位数范围内，非复发死亡率的风险仍然相对较高，因此可能难以将结果转化为不同的治疗方法。相比之下，与HAdV相关死亡率的相关性可能有助于识别低风险患者亚组。然而，HAdV粪便排出以及病毒在肠道内扩散与侵袭性感染风险之间已确立的相关性，预计仍将是儿科HSCT环境中的一个重要诊断参数。
