Cytokine Response Patterns in Severe Pandemic 2009 H1N1 and Seasonal Influenza among Hospitalized Adults

Background Studying cytokine/chemokine responses in severe influenza infections caused by different virus subtypes may improve understanding on pathogenesis. Methods Adults hospitalized for laboratory-confirmed seasonal and pandemic 2009 A/H1N1 (pH1N1) influenza were studied. Plasma concentrations of 13 cytokines/chemokines were measured at presentation and then serially, using cytometric-bead-array with flow-cytometry and ELISA. PBMCs from influenza patients were studied for cytokine/chemokine expression using ex-vivo culture (Whole Blood Assay,±PHA/LPS stimulation). Clinical variables were prospectively recorded and analyzed. Results 63 pH1N1 and 53 seasonal influenza patients were studied. pH1N1 patients were younger (mean±S.D. 42.8±19.2 vs 70.5±16.7 years), and fewer had comorbidities. Respiratory/cardiovascular complications were common in both groups (71.4% vs 81.1%), although severe pneumonia with hypoxemia (54.0% vs 28.3%) and ICU admissions (25.4% vs 1.9%) were more frequent with pH1N1. Hyperactivation of the proinflammatory cytokines IL-6, CXCL8/IL-8, CCL2/MCP-1 and sTNFR-1 was found in pH1N1 pneumonia (2–15 times normal) and in complicated seasonal influenza, but not in milder pH1N1 infections. The adaptive-immunity (Th1/Th17)-related CXCL10/IP-10, CXCL9/MIG and IL-17A however, were markedly suppressed in severe pH1N1 pneumonia (2–27 times lower than seasonal influenza; P−values<0.01). This pattern was further confirmed with serial measurements. Hypercytokinemia tended to be sustained in pH1N1 pneumonia, associated with a slower viral clearance [PCR-negativity: day 3–4, 55% vs 85%; day 6–7, 67% vs 100%]. Elevated proinflammatory cytokines, particularly IL-6, predicted ICU admission (adjusted OR 12.6, 95%CI 2.6–61.5, per log10unit increase; P = 0.002), and correlated with fever, tachypnoea, deoxygenation, and length-of-stay (Spearman's rho, P-values<0.01) in influenza infections. PBMCs in seasonal influenza patients were activated and expressed cytokines ex vivo (e.g. IL-6, CXCL8/IL-8, CCL2/MCP-1, CXCL10/IP-10, CXCL9/MIG); their ‘responsiveness’ to stimuli was shown to change dynamically during the illness course. Conclusions A hyperactivated proinflammatory, but suppressed adaptive-immunity (Th1/Th17)-related cytokine response pattern was found in severe pH1N1 pneumonia, different from seasonal influenza. Cytokine/immune-dysregulation may be important in its pathogenesis.

[1]  D. Hui,et al.  Dexamethasone in community-acquired pneumonia , 2011, The Lancet.

[2]  Zijian Feng,et al.  Early use of glucocorticoids was a risk factor for critical disease and death from pH1N1 infection. , 2011, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[3]  Hugh Rosen,et al.  Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus , 2011, Proceedings of the National Academy of Sciences.

[4]  D. Hui,et al.  Complications and outcomes of pandemic 2009 Influenza A (H1N1) virus infection in hospitalized adults: how do they differ from those in seasonal influenza? , 2011, The Journal of infectious diseases.

[5]  L. Brochard,et al.  Early corticosteroids in severe influenza A/H1N1 pneumonia and acute respiratory distress syndrome. , 2011, American journal of respiratory and critical care medicine.

[6]  J. Sung,et al.  Viral Clearance and Inflammatory Response Patterns in Adults Hospitalized for Pandemic 2009 Influenza A(H1N1) Virus Pneumonia , 2011, Antiviral therapy.

[7]  J. Alcorn,et al.  Influenza A Inhibits Th17-Mediated Host Defense against Bacterial Pneumonia in Mice , 2011, The Journal of Immunology.

[8]  Jindrich Cinatl,et al.  Comparison of pro-inflammatory cytokine expression and cellular signal transduction in human macrophages infected with different influenza A viruses , 2011, Medical Microbiology and Immunology.

[9]  C. Ciuce,et al.  Clinical aspects and cytokine response in severe H1N1 influenza A virus infection , 2010, Critical care.

[10]  M. Ison,et al.  Influenza 2010–2011: Lessons from the 2009 pandemic , 2010, Cleveland Clinic Journal of Medicine.

[11]  Yi Guan,et al.  Systems-level comparison of host responses induced by pandemic and seasonal influenza A H1N1 viruses in primary human type I-like alveolar epithelial cells in vitro , 2010, Respiratory research.

[12]  Jiyuan Zhang,et al.  Preferential loss of Th17 cells is associated with CD4 T cell activation in patients with 2009 pandemic H1N1 swine-origin influenza A infection , 2010, Clinical Immunology.

[13]  R. P. Arya,et al.  Role of Host Immune Response and Viral Load in the Differential Outcome of Pandemic H1N1 (2009) Influenza Virus Infection in Indian Patients , 2010, PloS one.

[14]  J. Rello,et al.  Pandemic Influenza , 2018, Emergency Medicine.

[15]  C. Agrati,et al.  Association of profoundly impaired immune competence in H1N1v-infected patients with a severe or fatal clinical course. , 2010, The Journal of infectious diseases.

[16]  D. Banner,et al.  Modeling host responses in ferrets during A/California/07/2009 influenza infection. , 2010, Virology.

[17]  Michael Shaw,et al.  Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. , 2010, The New England journal of medicine.

[18]  Y. Guan,et al.  Immunopathology and Infectious Diseases Tropism and Innate Host Responses of the 2009 Pandemic H 1 N 1 Influenza Virus in ex Vivo and in Vitro Cultures of Human Conjunctiva and Respiratory Tract , 2010 .

[19]  Ron A M Fouchier,et al.  Severity of Pneumonia Due to New H1N1 Influenza Virus in Ferrets Is Intermediate between That Due to Seasonal H1N1 Virus and Highly Pathogenic Avian Influenza H5N1 Virus , 2010, The Journal of infectious diseases.

[20]  D. Hui,et al.  Clinical Management of Pandemic 2009 Influenza A(H1N1) Infection , 2010, Chest.

[21]  Samson S. Y. Wong,et al.  Delayed Clearance of Viral Load and Marked Cytokine Activation in Severe Cases of Pandemic H1N1 2009 Influenza Virus Infection , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[22]  Wenxin Wu,et al.  Innate immune response to H3N2 and H1N1 influenza virus infection in a human lung organ culture model. , 2010, Virology.

[23]  J. Rello,et al.  Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza , 2009, Critical care.

[24]  V. Kuchroo,et al.  Interleukin-17 and type 17 helper T cells. , 2009, The New England journal of medicine.

[25]  Lyn Finelli,et al.  Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009. , 2009, The New England journal of medicine.

[26]  J. Peiris,et al.  Innate immune responses to influenza A H5N1: friend or foe? , 2009, Trends in immunology.

[27]  P. Österlund,et al.  Pandemic H1N1 2009 Influenza A Virus Induces Weak Cytokine Responses in Human Macrophages and Dendritic Cells and Is Highly Sensitive to the Antiviral Actions of Interferons , 2009, Journal of Virology.

[28]  A. Antonopoulou,et al.  Effect of the novel influenza A (H1N1) virus in the human immune system , 2009, Critical Care.

[29]  Robert Schechter,et al.  Factors associated with death or hospitalization due to pandemic 2009 influenza A(H1N1) infection in California. , 2009, JAMA.

[30]  J. Alcorn,et al.  Critical Role of IL-17RA in Immunopathology of Influenza Infection , 2009, The Journal of Immunology.

[31]  K. Legge,et al.  Innate immune control and regulation of influenza virus infections , 2009, Journal of leukocyte biology.

[32]  J. Sung,et al.  Viral Loads and Duration of Viral Shedding in Adult Patients Hospitalized with Influenza , 2009, The Journal of infectious diseases.

[33]  M. Hosoya,et al.  Differences in serum cytokine levels between influenza virus A and B infections in children. , 2009, Cytokine.

[34]  T. Strutt,et al.  Tc17, a Unique Subset of CD8 T Cells That Can Protect against Lethal Influenza Challenge1 , 2009, The Journal of Immunology.

[35]  Carole R. Baskin,et al.  Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus , 2009, Proceedings of the National Academy of Sciences.

[36]  J. Farrar,et al.  Insights into inflammation and influenza. , 2008, The New England journal of medicine.

[37]  Penny A. Rudd,et al.  Severe seasonal influenza in ferrets correlates with reduced interferon and increased IL-6 induction. , 2008, Virology.

[38]  Simon A. Jones,et al.  Interleukin-6 Is Crucial for Recall of Influenza-Specific Memory CD4+ T Cells , 2008, PLoS pathogens.

[39]  J. Sung,et al.  Hypercytokinemia and hyperactivation of phospho-p38 mitogen-activated protein kinase in severe human influenza A virus infection. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[40]  Yi Guan,et al.  Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia , 2006, Nature Medicine.

[41]  C. Lam,et al.  Raised plasma concentration and ex vivo production of inflammatory chemokines in patients with systemic lupus erythematosus , 2005, Annals of the rheumatic diseases.

[42]  R. Salomão,et al.  Impaired Production of Interferon-&ggr; and Tumor Necrosis Factor-&agr; but not of Interleukin 10 in Whole Blood of Patients with Sepsis , 2003, Shock.

[43]  H. Dockrell,et al.  Cytokine profiles using whole-blood assays can discriminate between tuberculosis patients and healthy endemic controls in a BCG-vaccinated population. , 2002, Journal of immunological methods.