From Influenza-Induced Acute Lung Injury to Multiorgan Failure

  • B. M. TangEmail author
  • T. Cootes
  • A. S. McLean
Part of the Annual Update in Intensive Care and Emergency Medicine book series (AUICEM)


Influenza viruses are among the most common causes of human respiratory infection, causing high morbidity and mortality. In the United States, influenza results in approximately 200,000 hospitalizations and 36,000 deaths during a seasonal epidemic [1]. During a pandemic, up to 50% of the population can be infected by influenza, increasing the number of deaths [2]. In 1918, the worst influenza pandemic recorded in history caused up to 50 million deaths worldwide, with elderly, infants, and people with underlying illness having the highest risk of fatality [3].


  1. 1.
    Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289:179–86.CrossRefGoogle Scholar
  2. 2.
    Simonsen L. The global impact of influenza on morbidity and mortality. Vaccine. 1999;17(Suppl 1):S3–10.CrossRefGoogle Scholar
  3. 3.
    Taubenberger JK, Morens DM. The pathology of influenza virus infections. Annu Rev Pathol Mech Dis. 2008;3:499–522.CrossRefGoogle Scholar
  4. 4.
    Tripathi S, White MR, Hartshorn KL. The amazing innate immune response to influenza A virus infection. Innate Immun. 2015;21:73–98.CrossRefGoogle Scholar
  5. 5.
    Camp JV, Jonsson CB. A role for neutrophils in viral respiratory disease. Front Immunol. 2017;8:11.CrossRefGoogle Scholar
  6. 6.
    Iwasaki A, Pillai PS. Innate immunity to influenza virus infection. Nature. 2014;14:315–28.Google Scholar
  7. 7.
    Brandes M, Klauschen F, Kuchen S, Germain RN. A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection. Cell. 2013;154:197–212.CrossRefGoogle Scholar
  8. 8.
    Narasaraju T, Yang E, Samy RP, et al. Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis. Am J Pathol. 2011;179:199–210.CrossRefGoogle Scholar
  9. 9.
    Fujisawa H. Inhibitory role of neutrophils on influenza virus multiplication in the lungs of mice. Microbiol Immunol. 2001;45:679–88.CrossRefGoogle Scholar
  10. 10.
    Tate MD, Brooks AG, Reading PC, Mintern JD. Neutrophils sustain effective CD8(+) T-cell responses in the respiratory tract following influenza infection. Immunol Cell Biol. 2012;90:197–205.CrossRefGoogle Scholar
  11. 11.
    Kim HM, Lee YW, Lee KJ, et al. Alveolar macrophages are indispensable for controlling influenza viruses in lungs of pigs. J Virol. 2008;82:4265–74.CrossRefGoogle Scholar
  12. 12.
    Herold S, von Wulffen W, Steinmueller M, et al. Alveolar epithelial cells direct monocyte transepithelial migration upon influenza virus infection: impact of chemokines and adhesion molecules. J Immunol. 2006;177:1817–24.CrossRefGoogle Scholar
  13. 13.
    Cole SL, Ho LP. Contribution of innate immune cells to pathogenesis of severe influenza virus infection. Clin Sci. 2017;131:269–83.CrossRefGoogle Scholar
  14. 14.
    Auffray C, Sieweke MH, Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol. 2009;27:669–92.CrossRefGoogle Scholar
  15. 15.
    Jost S, Altfeld M. Control of human viral infections by natural killer cells. Annu Rev Immunol. 2013;31:163–94.CrossRefGoogle Scholar
  16. 16.
    Schultz-Cherry S. Role of NK cells in influenza infection. Curr Top Microbiol Immunol. 2015;386:109–20.PubMedGoogle Scholar
  17. 17.
    Grayson MH, Holtzman MJ. Emerging role of dendritic cells in respiratory viral infection. J Mol Med. 2007;85:1057–68.CrossRefGoogle Scholar
  18. 18.
    Belz GT, Wilson NS, Kupresanin F, Mount AM, Smith CM. Shaping naive and memory CD8+ T cell responses in pathogen infections through antigen presentation. Adv Exp Med Biol. 2007;590:31–42.CrossRefGoogle Scholar
  19. 19.
    Sealy R, Surman S, Hurwitz JL, Coleclough C. Antibody response to influenza infection of mice: different patterns for glycoprotein and nucleocapsid antigens. Immunology. 2003;108:431–9.CrossRefGoogle Scholar
  20. 20.
    Sangster MY, Riberdy JM, Gonzalez M, Topham DJ, Baumgarth N, Doherty PC. An early CD4 +T cell–dependent immunoglobulin A response to influenza infection in the absence of key cognate T–B interactions. J Exp Med. 2003;198:1011–21.CrossRefGoogle Scholar
  21. 21.
    Braciale TJ, Sun J, Kim TS. Regulating the adaptive immune response to respiratory virus infection. Nat Rev Immunol. 2012;12:295–305.CrossRefGoogle Scholar
  22. 22.
    Sridhar S, Begom S, Bermingham A, et al. Cellular immune correlates of protection against symptomatic pandemic influenza. Nat Med. 2013;19:1305–12.CrossRefGoogle Scholar
  23. 23.
    Dunning J, Blankley S, Hoang LT, et al. Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza. Nat Immunol. 2018;19:625–35.CrossRefGoogle Scholar
  24. 24.
    Guan W, Yang Z, Wu NC, et al. Clinical correlations of transcriptional profile in patients infected with avian influenza H7N9 virus. J Infect Dis. 2018;368:1888–11.Google Scholar
  25. 25.
    Korteweg C, Gu J. Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. Am J Pathol. 2008;172:1155–69.CrossRefGoogle Scholar
  26. 26.
    Likos AM, Kelvin DJ, Cameron CM, et al. Influenza viremia and the potential for blood-borne transmission. Transfusion. 2007;47:1080–8.CrossRefGoogle Scholar
  27. 27.
    Choi SM, Xie H, Campbell AP, et al. Influenza viral RNA detection in blood as a marker to predict disease severity in hematopoietic cell transplant recipients. J Infect Dis. 2012;206:1872–7.CrossRefGoogle Scholar
  28. 28.
    Short KR, Brooks AG, Reading PC, Londrigan SL. The fate of influenza A virus after infection of human macrophages and dendritic cells. J Gen Virol. 2012;93:2315–25.CrossRefGoogle Scholar
  29. 29.
    Hou W, Gibbs JS, Lu X, et al. Viral infection triggers rapid differentiation of human blood monocytes into dendritic cells. Blood. 2012;119:3128–31.CrossRefGoogle Scholar
  30. 30.
    Hoeve MA, Nash AA, Jackson D, Randall RE, Dransfield I. Influenza virus A infection of human monocyte and macrophage subpopulations reveals increased susceptibility associated with cell differentiation. PLoS One. 2012;7:e29443.CrossRefGoogle Scholar
  31. 31.
    Steuerman Y, Cohen M, Peshes-Yaloz N, et al. Dissection of influenza infection vivo by single-cell RNA sequencing. Cell Syst. 2018;7:1–13.CrossRefGoogle Scholar
  32. 32.
    Fislova T, Gocnik M, Sladkova T, et al. Multiorgan distribution of human influenza A virus strains observed in a mouse model. Arch Virol. 2009;154:409–19.CrossRefGoogle Scholar
  33. 33.
    Zhang Z, Huang T, Yu F, et al. Infectious progeny of 2009 A (H1N1) influenza virus replicated in and released from human neutrophils. Sci Rep. 2015;5:1–11.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Intensive Care MedicineNepean HospitalKingswoodAustralia
  2. 2.Centre for Immunology and Allergy ResearchWestmead Institute for Medical ResearchWestmeadAustralia
  3. 3.Department of Infectious Diseases and Immunology, Central Clinical SchoolUniversity of SydneyDarlingtonAustralia

Personalised recommendations