Determinants of severity in patients with pandemic influenza

Abstract

Novel strains of influenza are a major threat to security, health and well-being, but their timing and impact on global health cannot be predicted. An influenza pandemic was declared in June 2009, caused by the novel influenza A(H1N1)pdm09 virus. Although illness was generally mild, the pandemic is thought to have caused more than 250,000 deaths worldwide. To learn more about the causes of severe influenza, the Mechanisms of Severe Acute Influenza Consortium (MOSAIC) was formed to conduct an integrated study of host, pathogen and co-pathogen factors that may affect disease severity. Two hundred and fifty-five patients with influenza-like illness (ILI), including 172 (67%) with confirmed influenza, were recruited during the second pandemic wave (winter 2009/10) and the third, post-pandemic wave (winter 2010/11). Sequential samples were obtained from the respiratory tract and blood throughout illness and recovery. Detailed clinical data were also collected to facilitate the interpretation of laboratory findings. Patients with ILI caused by other viral and bacterial pathogens were also recruited, along with asymptomatic healthy controls. Translation of the Consortium’s aims into an achievable clinical study was a significant undertaking in this body of work. The development of clinical protocols, the standardised sampling of patients and the collection of clinical and microbiological data were all essential tasks. Despite these challenges and a limited window of opportunity for recruitment, a large biobank and a database of detailed clinical data have been established. To address the contribution of differences in gene expression in pathogenesis, whole blood transcriptomics analysis was performed. Two major transcriptional profiles were seen in influenza patients at the first time point: a marked up-regulation of interferon-associated genes in those with illness that tended to be milder and of shorter duration, and up-regulation of neutrophil-associated and bacterial-response genes in those with more established, often critical illness. To supplement and enrich the gene expression findings, we measured cytokines and chemokines in serum/plasma and respiratory tract secretions. Exuberant immune mediator responses were observed in many patients, consistent with cytokine storm, but subgroups appear to have different response patterns. Findings are expected to help reveal the contribution of bacterial infections in severe influenza, in addition to demonstrating an association between severity of illness and changes in the immune response. The results have potential applications in the development of improved diagnostics and therapeutics, as well as broadening our understanding of influenza pathogenesis in humans.