Identification of novel mechanistically distinct endotypes of pandemic influenza-associated acute respiratory failure
Identification of novel mechanistically distinct endotypes of pandemic influenza-associated acute respiratory failure
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鉴定大流行性流感相关急性呼吸衰竭的新的机制不同的内型
DOI：
10.1101/2020.07.12.20150474
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Samanta R
中科院分区：
文献类型：
--
作者：
Samanta R
呼吸道病毒大流行导致由单一病因引起的大量急性呼吸衰竭病例，从而减少了训诫侮辱的异质性，并使人们能够更好地了解宿主反应的变化。2009-2011年，发生了一场流感大流行，全球数百万人感染了H1N1。在这里，我们使用新的生物信息学方法结合临床、蛋白质生物标记物和来自流感相关急性呼吸衰竭患者的基因组数据来识别三种机械上分离的亚型，它们具有显著不同的临床结果。鉴定出的三种内型分别为“中性粒细胞驱动”(16.3%)、“适应性”(51.9%)和“内皮细胞渗漏”(31.7%)。中性粒细胞驱动的患者表现出先天免疫激活的证据，并伴随着相关的多器官功能障碍，并减少了30天的存活率。这些患者可以通过步态机制的改变而与适应性内型区分开来，步态机制是对干扰素-γ的一种晚期转录调节反应，通过减少铜蓝蛋白基因的翻译来抑制天然免疫。中性粒细胞驱动内型的患者干扰素-γ水平显着升高，但似乎无法抑制其先天免疫反应。通过Sit-Robo信号通路的改变，内皮细胞渗漏内型可以与中性粒细胞驱动和适应性内型区分开来，Sit-Robo信号通路是维持内皮屏障完整性的重要途径；尽管具有这种内型的患者需要机械通气，但他们不会像中性粒细胞驱动的内型患者那样发生多器官衰竭，临床结果显著改善。重要的是，所鉴定的内型在48小时内是稳定的，这为未来的分层干预性临床试验打开了可能性。一句话摘要我们已经鉴定了三种新的流感相关急性呼吸衰竭的机制不同的亚型，具有不同的临床结果。
Respiratory viral pandemics result in large numbers of cases of acute respiratory failure arising from a single etiology, thus reducing the heterogeneity of precepting insult and allowing improved insight into the variation of host responses. In 2009-2011, an influenza pandemic occurred, with pH1N1 infecting millions of people worldwide. Here, we have used novel bioinformatic methods to combine clinical, protein biomarker, and genomic data from patients with influenza-associated acute respiratory failure to identify three mechanistically discrete sub-types with significantly different clinical outcomes. The three endotypes identified can be described as “neutrophil-driven” (16.3%), “adaptive” (51.9%), and “endothelial leak” (31.7%). The neutrophil driven patients display evidence of innate immune activation with associated multi-organ dysfunction and reduced 30-day survival. These patients could be differentiated from the adaptive endotype by an alteration in the GAIT-mechanism, a late transcriptional regulatory response to IFN-γ that acts to suppress innate immunity by reducing caeruloplasmin mRNA translation. Patients with the neutrophil-driven endotype had significantly increased IFN-γ levels but appeared unable to suppress their innate immune response. The endothelial leak endotype could be distinguished from both the neutrophil driven and adaptive endotypes by alterations in Slit-Robo signalling, a pathway important in the maintenance of endothelial barrier integrity; Although patients with this endotype required mechanical ventilation, they did not develop multi-organ failure in the manner of the neutrophil-driven endotype patients, and had significantly better clinical outcomes. Importantly, the endotypes identified were stable over 48 hours opening up the possibility of stratified interventional clinical trials in the future.One Sentence SummaryWe have identified three new mechanistically distinct subtypes of influenza associated acute respiratory failure, with differential clinical outcomes.
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影响因子：
76.2
作者：
Calfee, Carolyn S.;Delucchi, Kevin;Parsons, Polly E.;Thompson, B. Taylor;Ware, Lorraine B.;Matthay, Michael A.
通讯作者：
Matthay, Michael A.
影响因子：
13.8
作者：
Mukhopadhyay, Rupak;Jia, Jie;Arif, Abul;Ray, Partho Sarothi;Fox, Paul L.
通讯作者：
Fox, Paul L.
DOI：
10.1152/ajplung.00380.2014
发表时间：
2015-06-01
影响因子：
4.9
作者：
Kangelaris, Kirsten Neudoerffer;Prakash, Arun;Calfee, Carolyn S.
通讯作者：
Calfee, Carolyn S.
DOI：
10.13294/j.aps.2016.0050
发表时间：
2016
期刊：
生理学报
影响因子：
--
作者：
徐华敏;王俊;宋宁;姜宏;谢俊霞
通讯作者：
谢俊霞
影响因子：
7.6
作者：
Gorbunova, Elena E.;Gavrilovskaya, Irina N.;Mackow, Erich R.
通讯作者：
Mackow, Erich R.