Severe influenza infection has no effective treatment available. One of the key barriers to developing host-directed therapy is a lack of reliable prognostic factors needed to guide such therapy. Here, we use a network analysis approach to identify host factors associated with severe influenza and fatal outcome. In influenza patients with moderate-to-severe diseases, we uncover a complex landscape of immunological pathways, with the main changes occurring in pathways related to circulating neutrophils. Patients with severe disease display excessive neutrophil extracellular traps formation, neutrophil-inflammation and delayed apoptosis, all of which have been associated with fatal outcome in animal models. Excessive neutrophil activation correlates with worsening oxygenation impairment and predicted fatal outcome (AUROC 0.817-0.898). These findings provide new evidence that neutrophil-dominated host response is associated with poor outcomes. Measuring neutrophil-related changes may improve risk stratification and patient selection, a critical first step in developing host-directed immune therapy.

Biomedical Centre Medical Faculty Plzen Charles University Prague Staré Město Czech Republic

Centre for Immunology and Allergy Research The Westmead Institute for Medical Research Sydney Australia

Department of Chemistry and Biochemistry Laurentian University Laurentian Canada

Department of Chemistry and Biological Chemistry Harvard University Cambridge MA USA

Department of Emergency Medicine Royal North Shore Hospital Sydney Australia

Department of Emergency Medicine St Vincent Hospital Sydney Australia

Department of Emergency Medicine Westmead Hospital Sydney Australia

Department of Infection Genetics Helmholtz Centre for Infection Research Braunschweig Germany

Department of Intensive Care Medicine Nepean Hospital Sydney Australia

Department of Internal Medicine Medical Faculty Plzen Charles University Prague Staré Město Czech Republic

Department of Internal Medicine Medical Microbiology and Community Health Sciences University of Manitoba Winnipeg Canada

Department of Microbiology Immunology and Biochemistry University of Tennessee Health Science Centre Memphis TN USA

Department of Preventive Medicine University of Tennessee Health Science Centre Memphis TN USA

Genome Analytics Helmholtz Centre for Infection Research Braunschweig Germany

National HIV and Retrovirology Laboratories JC Wilt Infectious Disease Research Centre Public Health Agency of Canada Department of Medical Microbiology and Infectious Disease University of Manitoba Winnipeg Canada

Otto von Guerike University of Magdeburg Clinic of Pneumology Magdeburg Germany

Respiratory Tract Infection Research Node Marie Bashir Institute for Infectious Diseases and Biosecurity Sydney Australia

Section of Critical Care Medicine and Section of Infectious Diseases Departments of Medicine Medical Microbiology and Pharmacology University of Manitoba Winnipeg Canada

Sydney Informatic Hub The University of Sydney Sydney Australia

Townsville Hospital Townsville Queensland Australia

University of Veterinary Medicine Hannover Germany

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