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

  1. José Alberto Choreño-Parra
  2. Luis Armando Jiménez-Álvarez
  3. Alfredo Cruz-Lagunas
  4. Tatiana Sofía Rodríguez-Reyna
  5. Gustavo Ramírez-Martínez
  6. Montserrat Sandoval-Vega
  7. Diana Lizzeth Hernández-García
  8. Eduardo M. Choreño-Parra
  9. Yalbi I. Balderas-Martínez
  10. Mariana Esther Martinez-Sánchez
  11. Eduardo Márquez-García
  12. Edda Sciutto
  13. José Moreno-Rodríguez
  14. José Omar Barreto-Rodríguez
  15. Hazel Vázquez-Rojas
  16. Gustavo Iván Centeno-Sáenz
  17. Néstor Alvarado-Peña
  18. Citlaltepetl Salinas-Lara
  19. Carlos Sánchez-Garibay
  20. David Galeana-Cadena
  21. Gabriela Hernández
  22. Criselda Mendoza-Milla
  23. Andrea Domínguez
  24. Julio Granados
  25. Lula Mena-Hernández
  26. Luis Ángel Pérez-Buenfil
  27. Guillermo Domínguez-Cheritt
  28. Carlos Cabello-Gutiérrez
  29. Cesar Luna-Rivero
  30. Jorge Salas-Hernández
  31. Patricio Santillán-Doherty
  32. Justino Regalado
  33. Angélica Hernández-Martínez
  34. Lorena Orozco
  35. Federico Ávila-Moreno
  36. Ethel A. García-Latorre
  37. Carmen M. Hernández-Cárdenas
  38. Shabaana A. Khader
  39. Albert Zlotnik
  40. Joaquín Zúñiga

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Abstract

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.

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  1. Version published to 10.3389/fimmu.2021.593595
  2. ScreenIT

    SciScore for 10.1101/2020.08.10.20170761: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: Study approval: The Institutional Review Boards of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
    Consent: All participants or their legal guardians provided written informed consent in accordance with the Declaration of Helsinki for Human Research.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Sections were incubated overnight at room temperature with optimal dilutions (1:100) of the following antibodies: anti-IFN-γ (Anti-Interferon gamma antibody, ab9657, Abcam, UK)
    anti-IFN-γ
    suggested: (Abcam Cat# ab9657, RRID:AB_2123314)
    Anti-Interferon gamma antibody ,
    suggested: (Abcam Cat# ab9657, RRID:AB_2123314)
    anti-IL-1β (IL-1β Antibody (H-153): sc-7884, Santa Cruz Biotechnology Inc., Santa Cruz, CA), anti-IL-4 (IL-4 Antibody (OX81): sc-53084, Santa Cruz Biotechnology Inc., Santa Cruz, CA), and anti-IL-17A (Anti-IL-17 antibody (ab91649), Abcam, UK)
    anti-IL-1β
    suggested: None
    IL-4
    suggested: (Santa Cruz Biotechnology Cat# sc-53084, RRID:AB_629791)
    anti-IL-17A
    suggested: None
    Anti-IL-17
    suggested: None
    Software and Algorithms
    SentencesResources
    Data retrieval: Microsoft Excel (MS Excel 365) was used for data collection of the epidemiological and clinical information.
    Microsoft Excel
    suggested: (Microsoft Excel, RRID:SCR_016137)
    Serum levels of different cytokines, chemokines, growth factors, and other immune mediators were determined by Luminex assays using the Luminex platform Bio-Plex Multiplex 200 (Bio-Rad Laboratories, Inc., Hercules, CA, USA)
    Bio-Rad Laboratories
    suggested: (Bio-Rad Laboratories, RRID:SCR_008426)
    All analyses were conducted using GraphPad Prism 8 (La Jolla, CA), R Statistical Software (Foundation for Statistical Computing, Vienna, Austria
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    ) packages Factoextra and MASS, and Python packages pandas v0.23.4 and seaborn v0.10.1.
    Python
    suggested: (IPython, RRID:SCR_001658)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Limitations: A limitation of our study is that we did not recruit patients infected with seasonal influenza virus subtypes. Thus, our observations are only useful to distinguish between influenza A(H1N1) pdm09 and SARS-CoV-2 infection. The clinical and immunological characteristics of SARS-CoV-2 and seasonal influenza have been compared in a recent study by Mudd et al., which is under review (67). In such a study, researchers found that COVID-19, as compared to seasonal influenza, is characterized by lower mean cytokine levels in serum. Conversely, we found that cytokine levels were higher in COVID-19 patients than in individuals with pandemic influenza A(H1N1). These discrepancies are probably related to variations in the virulence and capacity to induce inflammatory immune responses of seasonal and pandemic influenza virus subtypes. Finally, another limitation of our study is that we did not measure cytokine levels in serial serum/plasma samples from our two cohorts of influenza and COVID-19 patients. Thus, future investigations should compare differences in the kinetics of immune responses against both diseases. Despite this, our study provides important insights into the differences between the two most important respiratory pathogens that have caused pandemics of international concern in recent years.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2020.08.10.20170761v1 on medRxiv