Severe Coronavirus Disease 2019 (COVID-19) is Associated With Elevated Serum Immunoglobulin (Ig) A and Antiphospholipid IgA Antibodies

  1. Omar Hasan Ali
  2. David Bomze
  3. Lorenz Risch
  4. Silvio D Brugger
  5. Matthias Paprotny
  6. Myriam Weber
  7. Sarah Thiel
  8. Lukas Kern
  9. Werner C Albrich
  10. Philipp Kohler
  11. Christian R Kahlert
  12. Pietro Vernazza
  13. Philipp K Bühler
  14. Reto A Schüpbach
  15. Alejandro Gómez-Mejia
  16. Alexandra M Popa
  17. Andreas Bergthaler
  18. Josef M Penninger
  19. Lukas Flatz

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Abstract

Background

Severe coronavirus disease 2019 (COVID-19) frequently entails complications that bear similarities to autoimmune diseases. To date, there are little data on possible immunoglobulin (Ig) A–mediated autoimmune responses. Here, we aim to determine whether COVID-19 is associated with a vigorous total IgA response and whether IgA antibodies are associated with complications of severe illness. Since thrombotic events are frequent in severe COVID-19 and resemble hypercoagulation of antiphospholipid syndrome, our approach focused on antiphospholipid antibodies (aPL).

Methods

In this retrospective cohort study, clinical data and aPL from 64 patients with COVID-19 were compared from 3 independent tertiary hospitals (1 in Liechtenstein, 2 in Switzerland). Samples were collected from 9 April to 1 May 2020.

Results

Clinical records of 64 patients with COVID-19 were reviewed and divided into a cohort with mild illness (mCOVID; 41%), a discovery cohort with severe illness (sdCOVID; 22%) and a confirmation cohort with severe illness (scCOVID; 38%). Total IgA, IgG, and aPL were measured with clinical diagnostic kits. Severe illness was significantly associated with increased total IgA (sdCOVID, P = .01; scCOVID, P < .001), but not total IgG. Among aPL, both cohorts with severe illness significantly correlated with elevated anticardiolipin IgA (sdCOVID and scCOVID, P < .001), anticardiolipin IgM (sdCOVID, P = .003; scCOVID, P< .001), and anti–beta 2 glycoprotein-1 IgA (sdCOVID and scCOVID, P< .001). Systemic lupus erythematosus was excluded from all patients as a potential confounder.

Conclusions

Higher total IgA and IgA-aPL were consistently associated with severe illness. These novel data strongly suggest that a vigorous antiviral IgA response, possibly triggered in the bronchial mucosa, induces systemic autoimmunity.

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  1. Version published to 10.1093/cid/ciaa1496
  2. ScreenIT

    SciScore for 10.1101/2020.07.21.20159244: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The collection of patient data and blood samples were approved by the respective local ethics committees of the participating study centers (Project-IDs 2020-00676, 2020-00821, and 2020-00646).
    Consent: All participants agreed to the hospitals’ general consent policies allowing further use of clinical data and biologic material (LLS and KSSG) or signed an informed consent (USZ).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    SARS-CoV-2 antibodies were analyzed by two different antibody tests: a lateral flow immunochromatographic assay (LFIA, gold nanoparticle-based, SGIT flex Covid 19, Sugentech, South Korea) and an electro-chemiluminescence immunoassay (ECLIA, Elecsys Anti-SARS-CoV-2, Roche Diagnostics International Ltd, Switzerland).
    Anti-SARS-CoV-2
    suggested: None
    Coefficients of variations, as determined by commercially available control materials were 4.5% for total IgA, <2.0% for total IgG, 4.6% for aPL antibodies, and 3.7% for lupus-antibodies.
    total IgA
    suggested: None
    total IgG
    suggested: None
    aPL
    suggested: None
    Software and Algorithms
    SentencesResources
    All analyses were performed using R software, version 3.5.0 (R Project for Statistical Computing, Vienna, Austria).
    R Project for Statistical
    suggested: (R Project for Statistical Computing, RRID:SCR_001905)

    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:
    Potential limitations of the study are its cohort sizes and retrospective design. Nevertheless, the inclusion of a discovery and an independent confirmation cohort from different health care centers is as well as similar age among cohorts are major strengths of the study. These data contribute to our understanding of the potential role of autoimmunity in severe COVID-19. In conclusion, we present a novel significant association between severe COVID-19, elevated total IgA and IgA-aPL. These findings suggest that autoantibodies may be causally linked to COVID-19 severity and thrombosis. We hypothesize that COVID-19 is a potent inductor of autoimmunity and recommend further studies with larger cohorts and mechanistic exploration to validate these findings.

    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

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  3. Version published to 10.1101/2020.07.21.20159244v1 on medRxiv