Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance
Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance
复制标题
新型甲型 H7N9 流感病毒引起的人类疾病不良临床结果与持续病毒脱落和抗病毒耐药性出现之间的关联
DOI：
10.1016/s0140-6736(13)61125-3
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发表时间：
2013-06-29
期刊：
影响因子：
168.9
通讯作者：
Yuan, Zhenghong
中科院分区：
文献类型：
--
作者：
Hu, Yunwen;Lu, Shuihua;Yuan, Zhenghong
背景3月30日，中国东部地区在严重呼吸系统疾病患者中检出一种新型甲型流感亚型H7N9病毒（a /H7N9）。与该病毒不良临床结果相关的病毒学因素尚不清楚。我们量化了A/H7N9患者标本中的病毒载量并分析了抗病毒耐药性突变。方法对2013年4月4日至4月20日在上海市公共卫生临床中心（SPHCC）收治的14例甲型H7N9禽流感患者进行研究，这些患者在入院前接受抗病毒治疗（奥司他韦或帕拉米韦）少于2天。我们依次调查了这些患者咽喉、粪便、血清和尿液标本中的病毒载量。我们还对这些标本中的病毒RNA进行了测序，以研究与神经氨酸酶抑制剂耐药性相关的突变及其与疾病结局的关系。结果所有患者均出现肺炎，其中7例需要机械通气，3例进一步恶化依赖体外膜氧合（ECMO）， 2例死亡。抗病毒治疗与11名幸存患者咽拭子标本中病毒载量的减少有关。3例患者持续高病毒载量在喉咙，尽管抗病毒治疗成为ECMO依赖。已知病毒神经氨酸酶（NA）基因发生Arg292Lys突变，导致对扎那米韦和奥司他韦产生耐药性，其中两名患者也接受了皮质类固醇治疗。其中，野生型序列Arg292在抗病毒治疗开始2天后出现，耐药突变体Lys292在治疗开始9天后占主导地位。解释抗病毒治疗后病毒载量的降低与预后的改善相关。两名同时接受皮质类固醇治疗的患者出现NA Arg292Lys突变，导致治疗失败和临床结果不佳。甲型H7N9病毒出现抗病毒药物耐药性，特别是在接受皮质类固醇治疗的患者中，令人担忧，需要密切监测，并在大流行防范规划中予以考虑。
Background On March 30, a novel influenza A subtype H7N9 virus (A/H7N9) was detected in patients with severe respiratory disease in eastern China. Virological factors associated with a poor clinical outcome for this virus remain unclear. We quantified the viral load and analysed antiviral resistance mutations in specimens from patients with A/H7N9.Methods We studied 14 patients with A/H7N9 disease admitted to the Shanghai Public Health Clinical Centre (SPHCC), China, between April 4, and April 20, 2013, who were given antiviral treatment (oseltamivir or peramivir) for less than 2 days before admission. We investigated the viral load in throat, stool, serum, and urine specimens obtained sequentially from these patients. We also sequenced viral RNA from these specimens to study the mutations associated with resistance to neuraminidase inhibitors and their association with disease outcome.Findings All patients developed pneumonia, seven of them required mechanical ventilation, and three of them further deteriorated to become dependent on extracorporeal membrane oxygenation (ECMO), two of whom died. Antiviral treatment was associated with a reduction of viral load in throat swab specimens in 11 surviving patients. Three patients with persistently high viral load in the throat in spite of antiviral therapy became ECMO dependent. An Arg292Lys mutation in the virus neuraminidase (NA) gene known to confer resistance to both zanamivir and oseltamivir was identified in two of these patients, both also received corticosteroid treatment. In one of them, wild-type sequence Arg292 was noted 2 days after start of antiviral treatment, and the resistant mutant Lys292 dominated 9 days after start of treatment.Interpretation Reduction of viral load following antiviral treatment correlated with improved outcome. Emergence of NA Arg292Lys mutation in two patients who also received corticosteroid treatment led to treatment failure and a poor clinical outcome. The emergence of antiviral resistance in A/H7N9 viruses, especially in patients receiving corticosteroid therapy, is concerning, needs to be closely monitored, and considered in pandemic preparedness planning.