Low testosterone and high cytokine levels correlate with lethal H7N9 infections in men: a retrospective cohort study from 98 H7N9 patients

Abstract

SummaryBackgroundHuman infections with avian influenza A (H7N9) virus emerged in East China in March 2013. In contrast to seasonal influenza A viruses, H7N9 infections showed a strong sex bias. Over the five epidemic waves in China, ~70% of all H7N9 cases were observed in men. Thus, in this human cohort, we retrospectively analyzed sex hormones as well as inflammatory cytokine and chemokine levels in men and women infected with avian H7N9 influenza.MethodsWe systematically analyzed the underlying correlation based on established human cohorts of two age groups (18-49 years and ≥50 years) including laboratory-confirmed H7N9 cases as well as seasonal influenza cases, H7N9 close contacts and poultry workers as controls in dependency on sex. The level of testosterone, estradiol and cytokines/chemokines were measured in all study participants. We compared the levels of sex hormones, cytokines/chemokines by sex and disease outcome.FindingsWe included H7N9 cases (n=98), close contacts (n =71), poultry workers (n =108) and mild seasonal influenza cases (n =53) in this study. Samples were collected between 2014 and 2017. All control groups showed similar median age within H7N9 cases except for the seasonal influenza group with a younger median age. In H7N9 infected men, testosterone levels were strongly reduced compared to male H7N9 virus-negative close contacts or males with seasonal influenza. Low testosterone levels in H7N9 infected men correlated with high inflammatory cytokine levels, e.g. IL-6, and lethal outcome in those 18-49 years of age. No significant differences were detected in estradiol levels in H7N9 infected men. In H7N9 infected women (≥ 50 years), estradiol levels were significantly elevated compared to H7N9 virus-negative close contacts. However, increased estradiol levels did not significantly correlate with lethal outcome in women albeit a slight tendency towards poor outcome could be detected.InterpretationThis study provides evidence that low testosterone levels in H7N9 influenza infected men correlate with inflammatory cytokine/chemokine responses and lethal outcome. Thus, treatment of H7N9 influenza virus infected patients should consider sex-specific mitigation strategies.FundingThis study was supported by the National Key Research and Development Program of China (2016YFC1200200 to Y.L.S. and 2016YFD0500208 to D.Y.W), the Guangdong Province Science and Technology Innovation Strategy Special Fund (2018A030310337 to Y.K.C), the German Free and Hanseatic City of Hamburg (to HPI (G.G.)) as well as the German Federal Ministry of Health (to HPI (G.G.)).