title: Early hypercytokinemia is associated with interferon-induced transmembrane protein-3 dysfunction and predictive of fatal H7N9 infection.
abstract: A unique avian-origin A/H7N9 influenza virus has so far caused 134 cases with 44 deaths. Probing the host factors contributing to disease severity, we found that lower levels of plasma inflammatory cytokines on hospital admission correlated with faster recovery in 18 patients with A/H7N9 influenza virus, whereas high concentrations of (in particular) IL-6, IL-8, and macrophage inflammatory protein-1β were predictive of a less favorable or fatal outcome. Analysis of bronchoalveolar lavage samples showed up to 1,000-fold greater cytokine/chemokine levels relative to plasma. Furthermore, patients with the rs12252-C/C IFN-induced transmembrane protein-3 (IFITM3) genotype had more rapid disease progression and were less likely to survive. Compared with patients with the rs12252-T/T or rs12252-T/C genotype of IFITM3, patients with the C/C genotype had a shorter time from disease onset to the time point when they sought medical aid (hospital admission or antiviral therapy) and a shorter interval to development of the acute respiratory distress syndrome stage (reflected by shorter intervals between clinical onset and methylprednisolone treatments and higher rates of mechanical ventilator use), as well as experiencing elevated/prolonged lung virus titers and cytokine production and higher mortality. The present analysis provides reported data on the H7N9 influenza-induced "cytokine storm" at the site of infection in humans and identifies the rs12252-C genotype that compromises IFITM3 function as a primary genetic correlate of severe H7N9 pneumonia. Together with rs12252 sequencing, early monitoring of plasma cytokines is thus of prognostic value for the treatment and management of severe influenza pneumonia.
authors.affiliation: Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Medical College, Fudan University, Shanghai, 201508, China.
authors.forename: Zhongfang
authors.initials: Z
authors.lastname: Wang
authors.forename: Anli
authors.initials: A
authors.lastname: Zhang
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Wan
authors.forename: Xinian
authors.initials: X
authors.lastname: Liu
authors.forename: Chao
authors.initials: C
authors.lastname: Qiu
authors.forename: Xiuhong
authors.initials: X
authors.lastname: Xi
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Ren
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Dong
authors.forename: Meijuan
authors.initials: M
authors.lastname: Bao
authors.forename: Liangzhu
authors.initials: L
authors.lastname: Li
authors.forename: Mingzhe
authors.initials: M
authors.lastname: Zhou
authors.forename: Songhua
authors.initials: S
authors.lastname: Yuan
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
authors.forename: Zhaoqin
authors.initials: Z
authors.lastname: Zhu
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Li
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.forename: Shuihua
authors.initials: S
authors.lastname: Lu
authors.forename: Peter C
authors.initials: PC
authors.lastname: Doherty
authors.forename: Katherine
authors.initials: K
authors.lastname: Kedzierska
authors.forename: Jianqing
authors.initials: J
authors.lastname: Xu
mesh_terms: D001483:Base Sequence; D002681:China / Q000453:epidemiology; D016207:Cytokines / Q000097:blood / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D004196:Disease Outbreaks / Q000266:history*; D005838:Genotype; D049674:History, 21st Century; D006801:Humans; D064766:Influenza A Virus, H7N9 Subtype; D007251:Influenza, Human / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology*; D008168:Lung / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D011379:Prognosis; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D018709:Statistics, Nonparametric
chemical_list: D016207:Cytokines; D017931:DNA Primers; C080082:IFITM3 protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins
keywords: avian influenza; clinical outcome