Abstract

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.

Details

Title
Neutrophils-related host factors associated with severe disease and fatality in patients with influenza infection
Author
Tang, Benjamin M 1   VIAFID ORCID Logo  ; Shojaei, Maryam 2 ; Teoh, Sally 3 ; Meyers, Adrienne 4 ; Ho, John 4 ; T Blake Ball 4 ; Keynan, Yoav 5 ; Amarnath Pisipati 6 ; Kumar, Aseem 7 ; Eisen, Damon P 8 ; Lai, Kevin 9 ; Gillett, Mark 10 ; Santram, Rahul 11 ; Geffers, Robert 12   VIAFID ORCID Logo  ; Schreiber, Jens 13 ; Mozhui, Khyobeni 14 ; Huang, Stephen 3 ; Parnell, Grant P 15 ; Nalos, Marek 16 ; Holubova, Monika 17   VIAFID ORCID Logo  ; Chew, Tracy 18   VIAFID ORCID Logo  ; Booth, David 15 ; Kumar, Anand 19 ; McLean, Anthony 3 ; Schughart, Klaus 20 

1  Department of Intensive Care Medicine, Nepean Hospital, Sydney, Australia; Centre for Immunology and Allergy Research, The Westmead Institute for Medical Research, Sydney, Australia; Respiratory Tract Infection Research Node, Marie Bashir Institute for Infectious Diseases and Biosecurity, Sydney, Australia 
2  Department of Intensive Care Medicine, Nepean Hospital, Sydney, Australia; Centre for Immunology and Allergy Research, The Westmead Institute for Medical Research, Sydney, Australia 
3  Department of Intensive Care Medicine, Nepean Hospital, Sydney, Australia 
4  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 
5  Department of Internal Medicine, Medical Microbiology and Community Health Sciences, University of Manitoba, Winnipeg, Canada 
6  Department of Chemistry and Biological Chemistry, Harvard University, Cambridge, MA, USA 
7  Department of Chemistry and Biochemistry, Laurentian University, Laurentian, Canada 
8  Townsville Hospital, Townsville, Queensland, Australia 
9  Department of Emergency Medicine, Westmead Hospital, Sydney, Australia 
10  Department of Emergency Medicine, Royal North Shore Hospital, Sydney, Australia 
11  Department of Emergency Medicine, St. Vincent Hospital, Sydney, Australia 
12  Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany 
13  Otto-von-Guerike University of Magdeburg, Clinic of Pneumology, Magdeburg, Germany 
14  Department of Preventive Medicine, University of Tennessee Health Science Centre, Memphis, TN, USA 
15  Centre for Immunology and Allergy Research, The Westmead Institute for Medical Research, Sydney, Australia 
16  Department of Intensive Care Medicine, Nepean Hospital, Sydney, Australia; Department of Internal Medicine, Medical Faculty Plzen, Charles University Prague, Staré Město, Czech Republic 
17  Biomedical Centre, Medical Faculty Plzen, Charles University Prague, Staré Město, Czech Republic 
18  Sydney Informatic Hub, The University of Sydney, Sydney, Australia 
19  Section of Critical Care Medicine and Section of Infectious Diseases, Departments of Medicine, Medical Microbiology and Pharmacology, University of Manitoba, Winnipeg, Canada 
20  Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany; University of Veterinary Medicine, Hannover, Germany; Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Centre, Memphis, TN, USA 
Pages
1-13
Publication year
2019
Publication date
Jul 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-11249-y
ProQuest document ID
2267391683
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.