Gotoh M, Yoshizawa S, Katagiri S, Suguro T, Asano M, Kitahara T, Akahane D, Okabe S, Tauchi T, Ito Y, Ohyashiki K
First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.
Transpl Infect Dis. 2014 Jun;16(3):440-9. doi: 10.1111/tid.12229. Epub 2014 May 9.
Viral infections and their occult reactivation occasionally cause not only organ damage, but also exacerbation of acute graft-versus-host disease (aGVHD), which may increase transplantation-related mortality synergistically. To determine correlations between viral reactivation and transplantation-related complications, we performed various viral screening tests on the 30th day after allogeneic hematopoietic stem cell transplantation (HSCT), and assessed the clinical implications.
Between August 2007 and January 2013, 49 patients (37 men, 12 women) underwent HSCT in our hospital. The stem cell sources were bone marrow (n = 21), peripheral blood (n = 13), and cord blood (n = 15). The presence of cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpesvirus (HHV) 6, and HHV7 in plasma samples prospectively collected from HSCT recipients on day 30 after HSCT was assayed by quantitative polymerase chain reaction, and the correlations with transplantation-related complications were evaluated.
The positivities of CMV, EBV, HHV6, and HHV7 were 44.9%, 22.4%, 53.1%, and 18.3%, respectively. We analyzed transplantation-related complications, and a significant correlation was found only between HHV6 and grade 2-4 aGVHD from day 30 to day 100 (P < 0.001). Using a receiver operating characteristic curve, the area under the curve was calculated as 0.86 (95% confidence interval [CI], 0.74-0.98) between the viral load (VL) of HHV6 and grade 2-4 aGVHD. The sensitivity and specificity were 79% and 93%, respectively, when a cutoff value of 87 copies/mL was used. In multivariate analysis using the Fine and Gray proportional hazards model, the clinically determined high-risk patients (P = 0.004; hazard ratio [HR], 3.69; 95% CI, 1.52-9.00) and the positivity of HHV6 (P < 0.001; HR, 9.957; 95% CI, 2.68-37.06) were extracted as independent risk factors for the cumulative incidence of grade 2-4 aGVHD on or after post-HSCT day 30. The only risk factor extracted for the elevation of HHV6 VL >87 copies/mL was cord blood transplantation (P = 0.0032; odds ratio, 7.10; 95% CI, 1.98-30.00).
All of the risk factors previously reported to predict severe aGVHD were obtained only during, but not after, HSCT. Our study suggests that the reactivation of HHV6 (≥ 87 copies/mL) at 30 days after HSCT is a possible predictive marker for grade 2-4 aGVHD on or after post-HSCT day 30.
病毒感染及其隐匿性再激活不仅偶尔会导致器官损伤，还会使急性移植物抗宿主病（aGVHD）加重，这可能会协同增加移植相关死亡率。为了确定病毒再激活与移植相关并发症之间的相关性，我们在异基因造血干细胞移植（HSCT）后第30天进行了各种病毒筛查试验，并评估了其临床意义。
2007年8月至2013年1月期间，我院49例患者（37例男性，12例女性）接受了HSCT。干细胞来源为骨髓（n = 21）、外周血（n = 13）和脐带血（n = 15）。通过定量聚合酶链反应检测HSCT受者在HSCT后第30天前瞻性采集的血浆样本中巨细胞病毒（CMV）、爱泼斯坦-巴尔病毒（EBV）、疱疹病毒（HHV）6和HHV7的存在情况，并评估其与移植相关并发症的相关性。
CMV、EBV、HHV6和HHV7的阳性率分别为44.9%、22.4%、53.1%和18.3%。我们分析了移植相关并发症，发现仅在HSCT后第30天至第100天期间，HHV6与2-4级aGVHD之间存在显著相关性（P < 0.001）。使用受试者工作特征曲线，计算HHV6病毒载量（VL）与2-4级aGVHD之间的曲线下面积为0.86（95%置信区间[CI]，0.74-0.98）。当使用87拷贝/mL的临界值时，敏感性和特异性分别为79%和93%。在使用Fine和Gray比例风险模型的多变量分析中，临床确定的高危患者（P = 0.004；风险比[HR]，3.69；95% CI，1.52-9.00）和HHV6阳性（P < 0.001；HR，9.957；95% CI，2.68-37.06）被确定为HSCT后第30天及以后2-4级aGVHD累积发生率的独立风险因素。HHV6 VL >87拷贝/mL升高的唯一风险因素是脐带血移植（P = 0.0032；优势比，7.10；95% CI，1.98-30.00）。
所有先前报道的预测严重aGVHD的风险因素仅在HSCT期间而非之后获得。我们的研究表明，HSCT后30天HHV6（≥87拷贝/mL）的再激活可能是HSCT后第30天及以后2-4级aGVHD的预测标志物。
