Specific Cytokine Profiles Predict the Severity of Influenza A Pneumonia: A Prospectively Multicenter Pilot Study

Yu Xie, Yan Yu, Lili Zhao, Pu Ning, Qiongzhen Luo, Ying Zhang, Lu Yin, Yali Zheng, Zhancheng Gao, Yu Xie, Yan Yu, Lili Zhao, Pu Ning, Qiongzhen Luo, Ying Zhang, Lu Yin, Yali Zheng, Zhancheng Gao

Abstract

Purpose: Studying the cytokine profiles in influenza A pneumonia could be helpful to better understand the pathogenesis of the disease and predict its prognosis. Patients and Methods. Patients with influenza A pneumonia (including 2009H1N1, H1N1, H3N1, and H7N1) hospitalized in six hospitals from January 2017 to October 2018 were enrolled (ClinicalTrials.gov ID, NCT03093220). Sputum samples were collected within 24 hours after admission and subsequently analyzed for cytokine profiles using a Luminex assay.

Results: A total of 35 patients with influenza A pneumonia were included in the study. The levels of IL-6, IFN-γ, and IL-2 were increased in patients with severe influenza A pneumonia (n =10) (P = 0.002, 0.009, and 0.008, respectively), while those of IL-5, IL-25, IL-17A, and IL-22 were decreased compared to patients with nonsevere pneumonia (P = 0.0001, 0.009, 0.0001, and 0.006, respectively). The levels of IL-2 and IL-6 in the nonsurvivors (n = 5) were significantly higher than those in the survivors (P = 0.043 and 0.0001, respectively), while the levels of IL-5, IL-17A, and IL-22 were significantly lower (P = 0.001, 0.012, and 0.043, respectively). The IL-4/IL-17A ratio has the potential to be a good predictor (AUC = 0.94, P < 0.05, sensitivity = 88.89%, specificity = 92.31%) and an independent risk factor (OR, 95% CI: 3.772, 1.188-11.975; P < 0.05) for intermittent positive pressure ventilation (n = 9).

Conclusion: Significant dysregulation of cytokine profiles can be observed in patients with severe influenza A pneumonia.

Conflict of interest statement

The authors declare that there is no conflict of interest regarding the publication of this paper.

Copyright © 2021 Yu Xie et al.

Figures

Figure 1
Figure 1
Flow diagram of the study. Abbreviations: CAP: community-acquired pneumonia.
Figure 2
Figure 2
Levels of cytokines in different subgroups of patients with influenza A pneumonia. (a) Comparison of the levels of IFN-γ, IL-2, IL-5, IL-25, IL-6, IL-17A, and IL-22 in the NSP group (n = 25) and SP group (n = 10). (b) Comparison of the levels of IL-2, IL-5, IL-6, IL-17A, and IL-22 in the survival group (n = 30) and nonsurvival group (n = 5). ∗P < 0.05, ∗∗P < 0.01, ∗∗∗∗P < 0.0001. Abbreviations: SP: severe pneumonia; NSP: nonsevere pneumonia; IFN: interferon; IL: interleukin.
Figure 3
Figure 3
Overview of cytokine profiles in patients with influenza A pneumonia with different prognoses. (a) Patients were divided into the NSP group (n = 25, green) and SP group (n = 10, red). (b) Patients were divided into a survival group (n = 30, green) and a nonsurvival group (n = 5, red). Abbreviations: SP: severe pneumonia; NSP: nonsevere pneumonia; TNF: tumor necrosis factor; IL: interleukin; IFN: interferon.
Figure 4
Figure 4
ROC curve analysis of various indicators to predict IPPV in patients with influenza A pneumonia. Abbreviations: NLR: neutrophil/lymphocyte ratio; IL: interleukin; PSI: pneumonia severity index.

References

    1. Xu X. W., Wu X. X., Jiang X. G., et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ . 2020;368:p. m606. doi: 10.1136/bmj.m606.
    1. Yang X., Yu Y., Xu J., et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. The Lancet Respiratory Medicine . 2020;8(5):475–481. doi: 10.1016/S2213-2600(20)30079-5.
    1. Thompson W. W., Weintraub E., Dhankhar P., et al. Estimates of US influenza-associated deaths made using four different methods. Influenza and Other Respiratory Viruses . 2009;3(1):37–49. doi: 10.1111/j.1750-2659.2009.00073.x.
    1. Darwish I., Mubareka S., Liles W. C. Immunomodulatory therapy for severe influenza. Expert Review of Anti-Infective Therapy . 2011;9(7):807–822. doi: 10.1586/eri.11.56.
    1. To K. K., Hung I. F., Li I. W., et al. Delayed clearance of viral load and marked cytokine activation in severe cases of pandemic H1N1 2009 influenza virus infection. Clinical Infectious Diseases . 2010;50(6):850–859. doi: 10.1086/650581.
    1. Beigel J. H., Farrar J., Han A. M., Hayden F. G., Hyer R., de Jong M. D., et al. Avian influenza a (H5N1) infection in humans. The New England Journal of Medicine . 2005;353(13):1374–1385. doi: 10.1056/NEJMra052211.
    1. Liu Q., Zhou Y. H., Yang Z. Q. The cytokine storm of severe influenza and development of immunomodulatory therapy. Cellular & Molecular Immunology . 2016;13(1):3–10. doi: 10.1038/cmi.2015.74.
    1. Oldstone M. B., Rosen H. Cytokine storm plays a direct role in the morbidity and mortality from influenza virus infection and is chemically treatable with a single sphingosine-1-phosphate agonist molecule. Current Topics in Microbiology and Immunology . 2014;378:129–147. doi: 10.1007/978-3-319-05879-5_6.
    1. Tisoncik J. R., Korth M. J., Simmons C. P., Farrar J., Martin T. R., Katze M. G. Into the eye of the cytokine storm. Microbiology and Molecular Biology Reviews . 2012;76(1):16–32. doi: 10.1128/MMBR.05015-11.
    1. Teijaro J. R. The role of cytokine responses during influenza virus pathogenesis and potential therapeutic options. Current Topics in Microbiology and Immunology . 2014;386:3–22. doi: 10.1007/82_2014_411.
    1. Uchide N., Toyoda H. Antioxidant therapy as a potential approach to severe influenza-associated complications. Molecules . 2011;16(3):2032–2052. doi: 10.3390/molecules16032032.
    1. Hung I. F. N., To K. K. W., Lee C. K., et al. Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest . 2013;144(2):464–473. doi: 10.1378/chest.12-2907.
    1. Hui D. S., Lee N., Chan P. K., Beigel J. H. The role of adjuvant immunomodulatory agents for treatment of severe influenza. Antiviral Research . 2018;150:202–216. doi: 10.1016/j.antiviral.2018.01.002.
    1. Cao B., Gao H., Zhou B., et al. Adjuvant corticosteroid treatment in adults with influenza A (H7N9) viral pneumonia. Critical Care Medicine . 2016;44(6):e318–e328. doi: 10.1097/CCM.0000000000001616.
    1. on behalf of the GETGAG Study Group, Moreno G., Rodríguez A., et al. Corticosteroid treatment in critically ill patients with severe influenza pneumonia: a propensity score matching study. Intensive Care Medicine . 2018;44(9):1470–1482. doi: 10.1007/s00134-018-5332-4.
    1. Niederman M. S., Mandell L. A., Anzueto A., et al. Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention. American Journal of Respiratory and Critical Care Medicine . 2001;163(7):1730–1754. doi: 10.1164/ajrccm.163.7.at1010.
    1. Pavord I. D., Pizzichini M. M., Pizzichini E., Hargreave F. E. The use of induced sputum to investigate airway inflammation. Thorax . 1997;52(6):498–501. doi: 10.1136/thx.52.6.498.
    1. Kelly M. M., Keatings V., Leigh R., et al. Analysis of fluid-phase mediators. The European Respiratory Journal. Supplement . 2002;37:24s–39s.
    1. Yu Y., Zhao L., Xie Y., et al. Th1/Th17 cytokine profiles are associated with disease severity and exacerbation frequency in COPD patients. International Journal of Chronic Obstructive Pulmonary Disease . 2020;Volume 15:1287–1299. doi: 10.2147/COPD.S252097.
    1. Lubin J. H., Colt J. S., Camann D., et al. Epidemiologic evaluation of measurement data in the presence of detection limits. Environmental Health Perspectives . 2004;112(17):1691–1696. doi: 10.1289/ehp.7199.
    1. Hornung R. W., Reed L. D. Estimation of average concentration in the presence of nondetectable values. Applied Occupational and Environmental Hygiene . 1990;5(1):46–51. doi: 10.1080/1047322X.1990.10389587.
    1. Bradley-Stewart A., Jolly L., Adamson W., et al. Cytokine responses in patients with mild or severe influenza a(H1N1)pdm09. Journal of Clinical Virology . 2013;58(1):100–107. doi: 10.1016/j.jcv.2013.05.011.
    1. Martinez-Ocaña J., Olivo-Diaz A., Salazar-Dominguez T., et al. Plasma cytokine levels and cytokine gene polymorphisms in Mexican patients during the influenza pandemic a(H1N1)pdm09. Journal of Clinical Virology . 2013;58(1):108–113. doi: 10.1016/j.jcv.2013.05.013.
    1. Zúñiga J., Torres M., Romo J., et al. Inflammatory profiles in severe pneumonia associated with the pandemic influenza A/H1N1 virus isolated in Mexico City. Autoimmunity . 2011;44(7):562–570. doi: 10.3109/08916934.2011.592885.
    1. Hagau N., Slavcovici A., Gonganau D. N., et al. Clinical aspects and cytokine response in severe H1N1 influenza A virus infection. Critical Care . 2010;14(6):p. R203. doi: 10.1186/cc9324.
    1. Matsumoto Y., Kawamura Y., Nakai H., et al. Cytokine and chemokine responses in pediatric patients with severe pneumonia associated with pandemic A/H1N1/2009 influenza virus. Microbiology and Immunology . 2012;56(9):651–655. doi: 10.1111/j.1348-0421.2012.00489.x.
    1. Bermejo-Martin J. F., de Lejarazu R. O., Pumarola T., et al. Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza. Critical Care . 2009;13(6):p. R201. doi: 10.1186/cc8208.
    1. L’Huillier A. G., Ferreira V. H., Hirzel C., et al. Cytokine profiles and severity of influenza infection in transplant recipients. The Journal of Infectious Diseases . 2019;219(4):535–539. doi: 10.1093/infdis/jiy535.
    1. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annual Review of Immunology . 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045.
    1. Paul W. E., Seder R. A. Lymphocyte responses and cytokines. Cell . 1994;76(2):241–251. doi: 10.1016/0092-8674(94)90332-8.
    1. Weaver C. T., Harrington L. E., Mangan P. R., Gavrieli M., Murphy K. M. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity . 2006;24(6):677–688. doi: 10.1016/j.immuni.2006.06.002.
    1. Yamada Y. K., Meager A., Yamada A., Ennis F. A. Human interferon alpha and gamma production by lymphocytes during the generation of influenza virus-specific cytotoxic T lymphocytes. The Journal of General Virology . 1986;67(11):2325–2334. doi: 10.1099/0022-1317-67-11-2325.
    1. Mbawuike I. N., Fujihashi K., DiFabio S., et al. Human interleukin-12 enhances interferon-gamma-producing influenza-specific memory CD8+ cytotoxic T lymphocytes. The Journal of Infectious Diseases . 1999;180(5):1477–1486. doi: 10.1086/315090.
    1. McMichael A. J., Gotch F. M., Noble G. R., Beare P. A. Cytotoxic T-cell immunity to influenza. The New England Journal of Medicine . 1983;309(1):13–17. doi: 10.1056/NEJM198307073090103.
    1. Kaiser L., Fritz R. S., Straus S. E., Gubareva L., Hayden F. G. Symptom pathogenesis during acute influenza: interleukin-6 and other cytokine responses. Journal of Medical Virology . 2001;64(3):262–268. doi: 10.1002/jmv.1045.
    1. Lv J., Wang D., Hua Y. H., et al. Pulmonary immune responses to 2009 pandemic influenza A (H1N1) virus in mice. BMC Infectious Diseases . 2014;14(1):p. 197. doi: 10.1186/1471-2334-14-197.
    1. Suzuki H., Kundig T. M., Furlonger C., et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science . 1995;268(5216):1472–1476. doi: 10.1126/science.7770771.
    1. Setoguchi R., Hori S., Takahashi T., Sakaguchi S. Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. The Journal of Experimental Medicine . 2005;201(5):723–735. doi: 10.1084/jem.20041982.
    1. Abbas A. K., Trotta E., R Simeonov D., Marson A., Bluestone J. A. Revisiting IL-2: Biology and therapeutic prospects. Sci Immunol . 2018;3(25) doi: 10.1126/sciimmunol.aat1482.
    1. McKinstry K. K., Alam F., Flores-Malavet V., et al. Memory CD4 T cell-derived IL-2 synergizes with viral infection to exacerbate lung inflammation. PLoS Pathogens . 2019;15(8, article e1007989) doi: 10.1371/journal.ppat.1007989.
    1. Kang S., Narazaki M., Metwally H., Kishimoto T. Historical overview of the interleukin-6 family cytokine. The Journal of Experimental Medicine . 2020;217(5) doi: 10.1084/jem.20190347.
    1. Fajgenbaum D. C., June C. H. Cytokine Storm. The New England Journal of Medicine . 2020;383(23):2255–2273. doi: 10.1056/NEJMra2026131.
    1. Zhang S., Li L., Shen A., Chen Y., Qi Z. Rational use of tocilizumab in the treatment of novel coronavirus pneumonia. Clinical Drug Investigation . 2020;40(6):511–518. doi: 10.1007/s40261-020-00917-3.
    1. Taniguchi K., Karin M. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Seminars in Immunology . 2014;26(1):54–74. doi: 10.1016/j.smim.2014.01.001.
    1. Tanaka T., Narazaki M., Kishimoto T. Interleukin (IL-6) immunotherapy. Cold Spring Harbor Perspectives in Biology . 2018;10(8) doi: 10.1101/cshperspect.a028456.
    1. Xu X., Han M., Li T., et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proceedings of the National Academy of Sciences of the United States of America . 2020;117(20):10970–10975. doi: 10.1073/pnas.2005615117.
    1. Califano D., Furuya Y., Roberts S., Avram D., McKenzie A. N. J., Metzger D. W. IFN-gamma increases susceptibility to influenza A infection through suppression of group II innate lymphoid cells. Mucosal Immunology . 2018;11(1):209–219. doi: 10.1038/mi.2017.41.
    1. Zhu J., Paul W. E. CD4 T cells: fates, functions, and faults. Blood . 2008;112(5):1557–1569. doi: 10.1182/blood-2008-05-078154.
    1. Li C., Yang P., Sun Y., et al. IL-17 response mediates acute lung injury induced by the 2009 pandemic influenza A (H1N1) virus. Cell Research . 2012;22(3):528–538. doi: 10.1038/cr.2011.165.
    1. Chen T., Qiu H., Zhao M. M., et al. IL-17A contributes to HSV1 infection-induced acute lung injury in a mouse model of pulmonary fibrosis. Journal of Cellular and Molecular Medicine . 2019;23(2):908–919. doi: 10.1111/jcmm.13992.
    1. Ivanov S., Renneson J., Fontaine J., et al. Interleukin-22 reduces lung inflammation during influenza A virus infection and protects against secondary bacterial infection. Journal of Virology . 2013;87(12):6911–6924. doi: 10.1128/JVI.02943-12.
    1. Barthelemy A., Sencio V., Soulard D., et al. Interleukin-22 immunotherapy during severe influenza enhances lung tissue integrity and reduces secondary bacterial systemic invasion. Infection and Immunity . 2018;86(7) doi: 10.1128/IAI.00706-17.
    1. Jiang T. J., Zhang J. Y., Li W. G., 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. Clinical Immunology . 2010;137(3):303–310. doi: 10.1016/j.clim.2010.07.010.
    1. Moser E. K., Sun J., Kim T. S., Braciale T. J. IL-21R signaling suppresses IL-17+ gamma delta T cell responses and production of IL-17 related cytokines in the lung at steady state and after Influenza A virus infection. PLoS One . 2015;10(4, article e0120169) doi: 10.1371/journal.pone.0120169.
    1. Gurczynski S. J., Nathani N., Warheit-Niemi H. I., et al. CCR2 mediates increased susceptibility to post-H1N1 bacterial pneumonia by limiting dendritic cell induction of IL-17. Mucosal Immunology . 2019;12(2):518–530. doi: 10.1038/s41385-018-0106-4.
    1. Stein M., Keshav S., Harris N., Gordon S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. The Journal of Experimental Medicine . 1992;176(1):287–292. doi: 10.1084/jem.176.1.287.
    1. Minutti C. M., Knipper J. A., Allen J. E., Zaiss D. M. Tissue-specific contribution of macrophages to wound healing. Seminars in Cell & Developmental Biology . 2017;61:3–11. doi: 10.1016/j.semcdb.2016.08.006.
    1. Van Dyken S. J., Locksley R. M. Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease. Annual Review of Immunology . 2013;31:317–343. doi: 10.1146/annurev-immunol-032712-095906.
    1. Rogers K. J., Brunton B., Mallinger L., et al. IL-4/IL-13 polarization of macrophages enhances Ebola virus glycoprotein-dependent infection. PLoS Neglected Tropical Diseases . 2019;13(12, article e0007819) doi: 10.1371/journal.pntd.0007819.
    1. Bot A., Holz A., Christen U., et al. Local IL-4 expression in the lung reduces pulmonary influenza-virus-specific secondary cytotoxic T cell responses. Virology . 2000;269(1):66–77. doi: 10.1006/viro.2000.0187.

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