Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID

  1. Matthew C. Woodruff
  2. Kevin S. Bonham
  3. Fabliha A. Anam
  4. Tiffany A. Walker
  5. Caterina E. Faliti
  6. Yusho Ishii
  7. Candice Y. Kaminski
  8. Martin C. Ruunstrom
  9. Kelly Rose Cooper
  10. Alexander D. Truong
  11. Adviteeya N. Dixit
  12. Jenny E. Han
  13. Richard P. Ramonell
  14. Natalie S. Haddad
  15. Mark E. Rudolph
  16. Srilakshmi Yalavarthi
  17. Viktoria Betin
  18. Ted Natoli
  19. Sherwin Navaz
  20. Scott A. Jenks
  21. Yu Zuo
  22. Jason S. Knight
  23. Arezou Khosroshahi
  24. F. Eun-Hyung Lee
  25. Ignacio Sanz

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Abstract

While immunologic correlates of COVID-19 have been widely reported, their associations with post-acute sequelae of COVID-19 (PASC) remain less clear. Due to the wide array of PASC presentations, understanding if specific disease features associate with discrete immune processes and therapeutic opportunities is important. Here we profile patients in the recovery phase of COVID-19 via proteomics screening and machine learning to find signatures of ongoing antiviral B cell development, immune-mediated fibrosis, and markers of cell death in PASC patients but not in controls with uncomplicated recovery. Plasma and immune cell profiling further allow the stratification of PASC into inflammatory and non-inflammatory types. Inflammatory PASC, identifiable through a refined set of 12 blood markers, displays evidence of ongoing neutrophil activity, B cell memory alterations, and building autoreactivity more than a year post COVID-19. Our work thus helps refine PASC categorization to aid in both therapeutic targeting and epidemiological investigation of PASC.

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  1. Version published to 10.1038/s41467-023-40012-7
  2. Version published to 10.1101/2021.09.21.21263845v2 on medRxiv
  3. ScreenIT

    SciScore for 10.1101/2021.09.21.21263845: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Human Participants: All research was approved by the Emory University Institutional Review Board (Emory IRB nos.
    Consent: Informed consent was obtained from all participants or, if they were unable to provide informed consent, from designated healthcare surrogates
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Adults aged ≥18 years with documented SARS-CoV-2 antigen or anti-nucleocapsid antibody (64%), or those meeting the CDC COVID-19 clinical case definition who were experiencing new or worsening symptoms and were >14 days from COVID-19 onset (36%) were eligible.
    anti-nucleocapsid
    suggested: None
    Thawed plasma was aliquoted and distributed for the following tests: anti-nuclear antibodies (ANA) were measured using enzyme-linked immunosorbent assays (ELISA) (QUANTA Lite; Inova Diagnostics) and indirect immunofluorescence (IFA) (NOVA Lite; Inova
    anti-nuclear
    suggested: None
    a Diagnostics); anti-double-stranded DNA (dsDNA) antibodies were also measured by ELISA and were confirmed by IFA with Crithidia luciliae; extractable nuclear antigen autoantibodies (anti-Sm, anti-SS-B/La IgG, anti-Scl-70 IgG, anti-U1RNP IgG, anti-RNP70 IgG, anti-CENP IgG, anti-Jo-1 IgG, and anti-CCP IgG) as well as Rheumatoid Factor (RF) IgA and IgM were measured using the EliA test on the Phadia 250 platform (ThermoFisher Scientific); IgG, IgM, and IgA isotypes of anti-cardiolipin and anti-β2-glycoprotein, as well as anti-Ro52, anti-Ro60, anti-GBM, anti-PR3, and anti-MPO were measured using a chemiluminescence immunoassay (BIO-FLASH; Inova Diagnostics); anti-CarP, anti-RNA-pol-III, and the IgG and IgM isotypes of anti-PS/PT were measured by ELISA (QUANTA Lite; Inova Diagnostics), while C- and P-ANCA were measured by IFA (NOVA Lite; Inova Diagnostics).
    anti-double-stranded DNA
    suggested: None
    dsDNA
    suggested: (GenWay Biotech Inc. Cat# 18-511-244499-2 ml, RRID:AB_1021324)
    anti-Sm, anti-SS-B/La IgG
    suggested: None
    anti-Scl-70 IgG
    suggested: None
    anti-U1RNP IgG
    suggested: None
    anti-RNP70 IgG
    suggested: None
    anti-CENP IgG
    suggested: None
    anti-Jo-1 IgG
    suggested: None
    anti-CCP IgG
    suggested: None
    anti-cardiolipin
    suggested: None
    anti-β2-glycoprotein
    suggested: None
    anti-Ro52
    suggested: (Antibodies-Online Cat# ABIN284731, RRID:AB_10773266)
    anti-Ro60
    suggested: None
    anti-GBM
    suggested: None
    anti-PR3
    suggested: None
    anti-MPO
    suggested: None
    anti-CarP, anti-RNA-pol-III,
    suggested: None
    anti-PS/PT
    suggested: None
    Software and Algorithms
    SentencesResources
    PASC Participants: Patients with PASC (n=95) were referred by primary care providers or by self-referral to Emory University Midtown, Emory University Executive Park, and Grady Memorial Hospital PASC Clinics
    PASC
    suggested: (PASC , RRID:SCR_016642)
    All Participants: Peripheral blood was collected in either heparin sodium tubes (PBMCs) or serum tubes (serum; both BD Diagnostic Systems).
    BD Diagnostic Systems
    suggested: None
    Study data were collected and managed using REDCap electronic data capture tools hosted at Emory University.
    REDCap
    suggested: (REDCap, RRID:SCR_003445)
    a Diagnostics); anti-double-stranded DNA (dsDNA) antibodies were also measured by ELISA and were confirmed by IFA with Crithidia luciliae; extractable nuclear antigen autoantibodies (anti-Sm, anti-SS-B/La IgG, anti-Scl-70 IgG, anti-U1RNP IgG, anti-RNP70 IgG, anti-CENP IgG, anti-Jo-1 IgG, and anti-CCP IgG) as well as Rheumatoid Factor (RF) IgA and IgM were measured using the EliA test on the Phadia 250 platform (ThermoFisher Scientific); IgG, IgM, and IgA isotypes of anti-cardiolipin and anti-β2-glycoprotein, as well as anti-Ro52, anti-Ro60, anti-GBM, anti-PR3, and anti-MPO were measured using a chemiluminescence immunoassay (BIO-FLASH; Inova Diagnostics); anti-CarP, anti-RNA-pol-III, and the IgG and IgM isotypes of anti-PS/PT were measured by ELISA (QUANTA Lite; Inova Diagnostics), while C- and P-ANCA were measured by IFA (NOVA Lite; Inova Diagnostics).
    ThermoFisher Scientific)
    suggested: None

    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    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.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  4. Version published to 10.1101/2021.09.21.21263845v1 on medRxiv