Significance of pathogenic detection by next-generation sequencing in bronchoalveolar lavage fluid on anti-infective treatment of patients with hematological malignancies
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摘要: 目的 血液肿瘤患者化疗后常伴发各种感染，而临床上对于病原不明确的持续或反复发热患者处理困难。本研究针对此类患者，探索进行支气管肺泡灌洗液(BALF)二代测序(NGS)病原学检测的时机及其对抗感染治疗结果的影响。方法 选取2020年7月至2021年9月血液科住院的10例血液肿瘤化疗后感染性发热的患者为研究对象，该类患者虽采取经验性抗感染治疗，但仍有反复或持续发热，并且病原微生物经传统病原检测无法确定。胸部影像检查发现有肺部病灶进展，行纤维支气管镜下肺泡灌洗术(BAL)并获取BALF，同时进行NGS和传统病原学检查。根据病原学结果调整抗菌药物治疗，并评价治疗效果。结果 10例患者在进行BAL检查前，中位发热时间8(2~19) d，中位最高体温39.6(38.8~40.7)℃，中位使用抗菌药物种类3(1~5)种，5例患者在未吸氧情况下血氧饱和度 < 0.90，9例有咳嗽、咳痰症状，4例有胸水表现，且10例患者血液、痰液标本的常规病原学检测均未发现明确的病原菌。在随诊胸部影像学检查中，新发肺部影像改变显示9例累及双侧，4例为结节样或片状实变。BALF标本的NGS病原学检查显示9例患者有明确的病原菌检出，其中5例检出细菌，5例检出真菌，1例为病毒，1例为分枝杆菌，并有3例病原为混合性; 而BALF标本的传统病原学检查仅有1例阳性病原结果。对9例NGS阳性病原的患者，根据病原结果调整抗菌药物，调整后3例患者抗菌药物总数减少，7例患者抗菌药物类别变化，调整抗菌药物治疗后，8例患者体温正常，且咳嗽、咳痰等症状消失。结论 血液肿瘤患者化疗后出现持续或反复发热，且在常规经验性抗感染治疗效果不佳时，需要密切随诊胸部影像学检查。如出现肺部影像学改变，可在纤维支气管镜下取BALF进行NGS检测，根据病原结果调整抗菌策略。Abstract: Objective The management of persistent/recurrent febrile infection in patients with hematological malignancies is challenging, especially for those with unidentified pathogen. In this study, we explore the clinical setting and timing of incorporating of metagenomics next generation sequencing(NGS) to detect possible pathogen.Methods From July 2020 to September 2021, ten patients had febrile episodes post chemotherapy. Even with at least two lines of empirical anti-microbial treatment, all patients were still had persistent/recurrent fever. When a progression on thoracic CT or X-rays was noted during a routine follow-up, bronchoalveolar lavage fluid(BALF) was obtained for NGS and convention assays for possible pathogens.Results All ten patients had persistent/recurrent fever when included in this study. At the time of BALF collection, the median time of fever was 8(2-19) days, median highest temperature recorded was 39.6(38.8-40.7) ℃, median number of anti-microbial agents was 3(1-5), Five of patients had some degree of hypoxia, 9 of patients had complaints of cough, 10 patients had plural effusion. Nine patients had positive pathogenic finding by NGS assay, while only one patient had positive finding by conventional assays. The classification of NGS findings included bacteria(5/9), fungi(5/9), virus(1/9) and Mycobacterium(1/9). Besides 3/9 cases had a mixed pathogenic finding by NGS assay. Anti-microbial agents were employed according to the pathogenic findings for the nine patients with positive NGS results, and all patients had alteration of anti-microbial agents. Nine patients had a resolved fever as a result of more targeted anti-microbial management.Conclusion In the setting of patients with hematological malignancies, our results suggested that a close monitoring of thoracic imaging may be necessary for those persistent/recurrent febrile patients who were treated empirically. A metagenomics NGS assay was highly effective in the detection of the possible pathogen of the pulmonary infection, especially when BALF was sampled at the time of a progression was noted at the thoracic imaging.
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表 1 患者治疗后肺部影像学变化比较
序号 BALF前影像学表现 治疗后复查影像学表现 病例1 双侧多发浸润影 左侧病灶基本吸收，右侧病灶面积吸收1/2以上 病例2 右侧单发空洞影 右侧病灶面积吸收1/2以上 病例3 左侧单发浸润伴部分实变影 实变影基本吸收，左侧病灶面积吸收1/2以上 病例4 双侧多发结节样影 双侧病灶面积均吸收1/2以上 病例5 双侧多发浸润影 双侧病灶面积均吸收1/2以上 病例6 双侧多发结节样伴左侧部分实变影 未复查 病例7 双侧多发浸润影 右侧病灶面积吸收1/2以上，左侧病灶基本吸收 病例8 双侧多发浸润伴部分磨玻璃样影 双侧病灶基本吸收，磨玻璃样影明显变淡 病例9 双侧多发浸润伴左侧部分实变影 实变影基本吸收，双侧病灶面积均吸收1/2以上 病例10 双侧多发浸润伴右侧部分实变影 实变影基本吸收，双侧病灶面积均吸收1/2以上 
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