Host immunological response and factors associated with clinical outcome in patients with the novel influenza A H7N9 infection

Abstract

In March 2013, an influenza outbreak caused by the novel avian-origin H7N9 influenza A virus emerged in eastern China and had caused 43 fatalities by 31 July 2013, although the basis for disease pathogenesis still remains unclear. To assess the immunological and viral factors associated with disease severity, viral RNA and inflammatory cytokines were quantified for 18 H7N9 patients in Shanghai, China. Detailed clinical information was collected and clinical laboratory investigations were performed for all patients. H7N9 infection is characterized by high pharyngeal virus load and frequent detection of viral RNA in blood. High pharyngeal virus load persisted through the first 10 days of antiviral therapy in fatal cases. Genetic characterization of the H7N9 virus revealed an Arg292Lys mutation in the neuraminidase gene associated with oseltamivir-resistance. Pronounced lymphopenia and high chemokine and cytokine levels were observed in H7N9-infected patients, particularly in those where disease was fatal. Serum levels of interleukin-6 (IL-6), IL-8 and macrophage inflammatory protein-1β in our subjects also correlated positively with pharyngeal virus load. Lymphocyte counts <0.5 × 109 cells/L, and serum IL-6 >97 pg/mL, IL-8 >40 pg/mL and C-reactive protein >90 mg/L were identified as being connected with adverse clinical outcome through univariate logistic analysis. Significant survival differences were also observed between patients with serum C-reactive protein <90 mg/L or creatinine <90 µmol/L and those with higher levels. Our data demonstrated that high viral load, and the resulting intense inflammatory responses, played an important role in H7N9 pathogenesis. Though immunomodulatory treatment has potential benefits, the focus of clinical management should be on preventing the intense cytokine response by early diagnosis and effective antiviral treatment.