Recovered and dead outcome patients caused by influenza A (H7N9) virus infection show different pro-inflammatory cytokine dynamics during disease progress and its application in real-time prognosis

The persistent circulation of influenza A(H7N9) virus within poultry markets and human society leads to sporadic epidemics of influenza infections. Severe pneumonia and acute respiratory distress syndrome (ARDS) caused by the virus lead to high morbidity and mortality rates in patients. Hyper induction of pro-inflammatory cytokines, which is known as “cytokine storm”, is closely related to the process of viral infection. However, systemic analyses of H7N9 induced cytokine storm and its relationship with disease progress need further illuminated. In our study we collected 75 samples from 24 clinically confirmed H7N9-infected patients at different time points after hospitalization. Those samples were divided into three groups, which were mild, severe and fatal groups, according to disease severity and final outcome. Human cytokine antibody array was performed to demonstrate the dynamic profile of 80 cytokines and chemokines. By comparison among different prognosis groups and time series, we provide a more comprehensive insight into the hypercytokinemia caused by H7N9 influenza virus infection. Different dynamic changes of cytokines/chemokines were observed in H7N9 infected patients with different severity. Further, 33 cytokines or chemokines were found to be correlated with disease development and 11 of them were identified as potential therapeutic targets. Immuno-modulate the cytokine levels of IL-8, IL-10, BLC, MIP-3a, MCP-1, HGF, OPG, OPN, ENA-78, MDC and TGF-β 3 are supposed to be beneficial in curing H7N9 infected patients. Apart from the identification of 35 independent predictors for H7N9 prognosis, we further established a real-time prediction model with multi-cytokine factors for the first time based on maximal relevance minimal redundancy method, and this model was proved to be powerful in predicting whether the H7N9 infection was severe or fatal. It exhibited promising application in prognosing the outcome of a H7N9 infected patients and thus help doctors take effective treatment strategies accordingly.

[1]  G. Gao,et al.  Epidemiology, Evolution, and Pathogenesis of H7N9 Influenza Viruses in Five Epidemic Waves since 2013 in China. , 2017, Trends in microbiology.

[2]  K. To,et al.  Avian influenza virus A H7N9 infects multiple mononuclear cell types in peripheral blood and induces dysregulated cytokine responses and apoptosis in infected monocytes. , 2017, The Journal of general virology.

[3]  Li Wang,et al.  Corrigendum: The Serum Profile of Hypercytokinemia Factors Identified in H7N9-Infected Patients can Predict Fatal Outcomes , 2016, Scientific reports.

[4]  K. Zen,et al.  Pro-inflammatory cytokine dysregulation is associated with novel avian influenza A (H7N9) virus in primary human macrophages. , 2016, The Journal of general virology.

[5]  Zhan-Qiu Yang,et al.  The cytokine storm of severe influenza and development of immunomodulatory therapy , 2015, Cellular and Molecular Immunology.

[6]  K. To,et al.  Suboptimal Humoral Immune Response against Influenza A(H7N9) Virus Is Related to Its Internal Genes , 2015, Clinical and Vaccine Immunology.

[7]  Shigui Yang,et al.  The Serum Profile of Hypercytokinemia Factors Identified in H7N9-Infected Patients can Predict Fatal Outcomes , 2015, Scientific Reports.

[8]  J. Peiris,et al.  Clinical, Virological and Immunological Features from Patients Infected with Re-Emergent Avian-Origin Human H7N9 Influenza Disease of Varying Severity in Guangdong Province , 2015, PloS one.

[9]  T. Tumpey,et al.  A(H7N9) Virus Results in Early Induction of Proinflammatory Cytokine Responses in both Human Lung Epithelial and Endothelial Cells and Shows Increased Human Adaptation Compared with Avian H5N1 Virus , 2015, Journal of Virology.

[10]  K. To,et al.  Avian Influenza A H7N9 Virus Induces Severe Pneumonia in Mice without Prior Adaptation and Responds to a Combination of Zanamivir and COX-2 Inhibitor , 2014, PloS one.

[11]  Z. Chen,et al.  Host immunological response and factors associated with clinical outcome in patients with the novel influenza A H7N9 infection. , 2014, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[12]  Yong Liu,et al.  Profiles of Acute Cytokine and Antibody Responses in Patients Infected with Avian Influenza A H7N9 , 2014, PloS one.

[13]  Prognosis of 18 H7N9 Avian Influenza Patients in Shanghai , 2014, PloS one.

[14]  Weizhong Yang,et al.  Epidemiology of human infections with avian influenza A(H7N9) virus in China. , 2014, The New England journal of medicine.

[15]  P. Doherty,et al.  Early hypercytokinemia is associated with interferon-induced transmembrane protein-3 dysfunction and predictive of fatal H7N9 infection , 2013, Proceedings of the National Academy of Sciences.

[16]  Zheng Xing,et al.  Cytokine and chemokine levels in patients infected with the novel avian influenza A (H7N9) virus in China. , 2013, The Journal of infectious diseases.

[17]  Dayan Wang,et al.  Monitoring Avian Influenza A(H7N9) Virus through National Influenza-like Illness Surveillance, China , 2013, Emerging infectious diseases.

[18]  Y. Guan,et al.  Tropism and innate host responses of a novel avian influenza A H7N9 virus: an analysis of ex-vivo and in-vitro cultures of the human respiratory tract , 2013, The Lancet Respiratory Medicine.

[19]  Weizhong Yang,et al.  Biological features of novel avian influenza A (H7N9) virus , 2013, Nature.

[20]  R. Baxter.  Insulin-like growth factor binding protein-3 (IGFBP-3): Novel ligands mediate unexpected functions , 2013, Journal of Cell Communication and Signaling.

[21]  The fight against bird flu , 2013, Nature.

[22]  M. Katze,et al.  Integrated Clinical, Pathologic, Virologic, and Transcriptomic Analysis of H5N1 Influenza Virus-Induced Viral Pneumonia in the Rhesus Macaque , 2012, Journal of Virology.

[23]  S. Suner,et al.  Correlation of C-reactive protein to severity of symptoms in acute influenza A infection , 2012, Journal of emergencies, trauma, and shock.

[24]  J. Golmard,et al.  Excess winter mortality in France: influence of temperature, influenza like illness, and residential care status. , 2012, Journal of the American Medical Directors Association.

[25]  L. Kong,et al.  Serum D-dimer changes and prognostic implication in 2009 novel influenza A(H1N1). , 2011, Thrombosis research.

[26]  T. Inglis,et al.  Procalcitonin and C-reactive protein in severe 2009 H1N1 influenza infection , 2010, Intensive Care Medicine.

[27]  P. Doherty,et al.  A question of self‐preservation: immunopathology in influenza virus infection , 2007, Immunology and cell biology.

[28]  D. Groneberg,et al.  Monocytes of allergics and non-allergics produce, store and release the neurotrophins NGF, BDNF and NT-3 , 2005, Regulatory Peptides.

[29]  Fuhui Long,et al.  Feature selection based on mutual information criteria of max-dependency, max-relevance, and min-redundancy , 2003, IEEE Transactions on Pattern Analysis and Machine Intelligence.

[30]  R. Baxter,et al.  The role of the acid-labile subunit in regulating insulin-like growth factor transport across human umbilical vein endothelial cell monolayers. , 2004, The Journal of clinical endocrinology and metabolism.

[31]  J. Cyster,et al.  CXCL13 is required for B1 cell homing, natural antibody production, and body cavity immunity. , 2002, Immunity.

[32]  P. Patterson,et al.  Leukemia Inhibitory Factor, Interleukin 6, and Other Cytokines Using the GP130 Transducing Receptor: Roles in Inflammation and Injury , 1999, Stem cells.

[33]  C. Woolf,et al.  Leukemia Inhibitory Factor Is an Anti-Inflammatory and Analgesic Cytokine , 1998, The Journal of Neuroscience.

[34]  P. Proost,et al.  Human monocyte chemotactic proteins‐2 and ‐3: structural and functional comparison with MCP‐1 , 1996, Journal of leukocyte biology.

[35]  B. Dewald,et al.  Actions of the chemotactic cytokines MCP‐1, MCP‐2, MCP‐3, RANTES, MIP‐1α and MIP‐1β on human monocytes , 1995 .