Clinical and Immunological Factors That Distinguish COVID-19 From Pandemic Influenza A(H1N1)

Front Immunol. 2021 Apr 21;12:593595. doi: 10.3389/fimmu.2021.593595. eCollection 2021.


The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is a global health threat with the potential to cause severe disease manifestations in the lungs. Although COVID-19 has been extensively characterized clinically, the factors distinguishing SARS-CoV-2 from other respiratory viruses are unknown. Here, we compared the clinical, histopathological, and immunological characteristics of patients with COVID-19 and pandemic influenza A(H1N1). We observed a higher frequency of respiratory symptoms, increased tissue injury markers, and a histological pattern of alveolar pneumonia in pandemic influenza A(H1N1) patients. Conversely, dry cough, gastrointestinal symptoms and interstitial lung pathology were observed in COVID-19 cases. Pandemic influenza A(H1N1) was characterized by higher levels of IL-1RA, TNF-α, CCL3, G-CSF, APRIL, sTNF-R1, sTNF-R2, sCD30, and sCD163. Meanwhile, COVID-19 displayed an immune profile distinguished by increased Th1 (IL-12, IFN-γ) and Th2 (IL-4, IL-5, IL-10, IL-13) cytokine levels, along with IL-1β, IL-6, CCL11, VEGF, TWEAK, TSLP, MMP-1, and MMP-3. Our data suggest that SARS-CoV-2 induces a dysbalanced polyfunctional inflammatory response that is different from the immune response against pandemic influenza A(H1N1). Furthermore, we demonstrated the diagnostic potential of some clinical and immune factors to differentiate both diseases. These findings might be relevant for the ongoing and future influenza seasons in the Northern Hemisphere, which are historically unique due to their convergence with the COVID-19 pandemic.

Keywords: COVID-19; Influenza A(H1N1) pdm09; SARS-CoV-2; acute respiratory distress syndrome; pandemic influenza.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • COVID-19* / blood
  • COVID-19* / epidemiology
  • COVID-19* / immunology
  • Cytokines* / blood
  • Cytokines* / immunology
  • Female
  • Humans
  • Influenza A Virus, H1N1 Subtype* / immunology
  • Influenza A Virus, H1N1 Subtype* / metabolism
  • Influenza, Human* / blood
  • Influenza, Human* / epidemiology
  • Influenza, Human* / immunology
  • Male
  • Matrix Metalloproteinase 1* / blood
  • Matrix Metalloproteinase 1* / immunology
  • Matrix Metalloproteinase 3* / blood
  • Matrix Metalloproteinase 3* / immunology
  • Middle Aged
  • Prospective Studies
  • Receptors, Immunologic* / blood
  • Receptors, Immunologic* / immunology
  • Th1 Cells / immunology
  • Th2 Cells / immunology


  • Cytokines
  • Receptors, Immunologic
  • MMP3 protein, human
  • Matrix Metalloproteinase 3
  • MMP1 protein, human
  • Matrix Metalloproteinase 1