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 caused134 cases with 44 deaths. Probing the host factors contributingto 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 highconcentrations of (in particular) IL-6, IL-8, and macrophage inflammatory protein-10 were predictive of a less favorable or fatal outcome. Analysis of bronchoalveolar lavage samples showed up to1,000-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 diseaseprogression and were less likely to survive. Compared withpatients with the rs12252-T/T or rs12252-T/C genotype of IFITM3,patients with the C/C genotype had a shorter time from diseaseonset to the time point when they sought medical aid (hospitaladmission or antiviral therapy) and a shorter interval to development of the acute respiratory distress syndrome stage (reflected byshorter intervals between clinical onset and methylprednisolonetreatments and higher rates of mechanical ventilator use), as wellas experiencing elevated/prolonged lung virus titers and cytokineproduction and higher mortality. The present analysis providesreported data on the H7N9 influenza-induced "cytokine storm" atthe 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 forthe treatment and management of severe influenza pneumonia.