背景:弥漫性肺泡出血(DAH)是一种危及生命的肺毒性,可在造血细胞移植(HCT)后出现。由于分布在多个中心的病例很少,风险因素和结果没有得到很好的理解。
目的:本流行病学研究的目的是表征发病率,结果,与HCT后DAH相关的移植相关危险因素和共病重症监护诊断。
方法:对6,995名年龄≤21岁的患者的多中心队列进行了回顾性分析,这些患者在2008-2014年期间通过国际血液和骨髓移植研究中心注册并与虚拟儿科系统数据库交叉匹配,以获得重症监护特征。多变量Cox比例风险模型用于确定DAH的危险因素。使用Logistic回归模型来确定与DAH相关的重症监护诊断。使用具有里程碑意义的方法和以DAH作为时变协变量的Cox回归分析生存结果。
结果:81例患者在HCT后中位54天(IQR23-160天)发生DAH,移植后1年累积发生率为1.0%(95%CI0.81~1.3%),在所有PICU患者中,有7.6%的患者出现这种情况.危险因素包括非恶性血液病的移植(参考:恶性血液病,HR=1.98,95%CI1.22-3.22,p=0.006),使用钙调磷酸酶抑制剂加霉酚酸酯(CNIMMF)作为GvHD预防,(参考:钙调神经磷酸酶抑制剂加甲氨蝶呤,HR=1.89,95%CI1.07-3.34,p=0.029),和III-IV级急性GvHD(HR=2.67,95%CI1.53-4.66,p<0.001)。重症监护住院的DAH患者的全身性高血压发生率明显较高,肺动脉高压,心包疾病,肾功能衰竭,和细菌/病毒/真菌感染(p<0.05)比没有DAH。从DAH时代开始,中位生存期为2.2个月,1年总生存期为26%(95%CI17-36%).在所有HCT患者中,考虑时,DAH的发展与未经校正的全因HCT后死亡率增加7倍相关(HR6.96,95%CI5.42-8.94,p<0.001).在HCT后2个月存活的患者的标志性分析中,发生DAH的患者1年总生存率为33%(95%CI18~49%),而未发生DAH的患者1年总生存率为82%(95%CI81~83%)(p<0.001).
结论:尽管DAH很少见,与HCT后高死亡率相关.我们的数据表明,在非恶性血液学移植适应症的背景下,临床医生应该对肺部症状的患者增加DAH的怀疑指数。使用CNI+MMF作为GvHD预防和严重急性GvHD。如果结果不佳,则需要进一步调查和验证可修改的风险因素。
BACKGROUND: Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary toxicity that can arise after hematopoietic cell transplantation (HCT). Risk-factors and outcomes are not well-understood due to a sparsity of cases spread across multiple centers.
OBJECTIVE: The objectives of this epidemiologic study were to characterize the incidence, outcomes, transplant-related risk factors and co-morbid critical care diagnoses associated with post-HCT DAH.
METHODS: Retrospective analysis was performed on a multi-center cohort of 6,995 patients ≤21 years old who underwent allogeneic HCT between 2008-2014 identified through the Center for International Blood and Marrow Transplant Research registry and cross-matched with the Virtual Pediatric Systems database to obtain critical care characteristics. A multivariable Cox-proportional hazard model was used to determine risk factors for DAH. Logistic regression models were used to determine critical care diagnoses associated with DAH. Survival outcomes were analyzed using both a landmark approach and Cox-regression with DAH as a time-varying covariate.
RESULTS: DAH occurred in 81 patients at a median 54 days post-HCT (IQR 23-160 days), with a 1-year post-transplant cumulative incidence probability of 1.0% (95% CI 0.81-1.3%) and was noted in 7.6% of all PICU patients. Risk factors included transplant for non-malignant hematologic disease (Referent: malignant hematologic disease, HR=1.98, 95% CI 1.22-3.22, p=0.006), use of calcineurin inhibitor plus mycophenolate mofetil (CNI + MMF) as GvHD prophylaxis, (Referent: calcineurin inhibitor plus methotrexate, HR=1.89, 95% CI 1.07-3.34, p=0.029), and grade III-IV acute GvHD (HR=2.67, 95% CI 1.53-4.66, p<0.001). Critical care admitted patients with DAH had significantly higher rates of systemic hypertension, pulmonary hypertension, pericardial disease, renal failure, and bacterial/viral/fungal infections (p<0.05) than those without DAH. From the time of DAH, median survival was 2.2 months and one-year overall survival was 26% (95% CI 17-36%). Among all HCT patients, the development of DAH when considered was associated with a seven-fold increase in unadjusted all-cause post-HCT mortality (HR 6.96, 95% CI 5.42-8.94, p<0.001). In a landmark analysis of patients alive 2 months post-HCT, patients who developed DAH had a one-year overall survival of 33% (95% CI 18-49%) versus 82% (95% CI 81-83%) for patients without DAH (p<0.001).
CONCLUSIONS: Although DAH is rare, it is associated with high mortality in the post-HCT setting. Our data suggest that clinicians should have a heightened index of suspicion of DAH in patients with pulmonary symptoms in the context of non-malignant hematologic transplant indication, use of CNI + MMF as GvHD prophylaxis and severe acute GvHD. Further investigations and validation of modifiable risk factors are warranted given poor outcomes.