Longitudinal analysis reveals elevation then sustained higher expression of autoantibodies for six months after SARS-CoV-2 infection

  1. Nahid Bhadelia
  2. Alex Olson
  3. Erika Smith
  4. Katherine Riefler
  5. Jacob Cabrejas
  6. Maria-Jose Ayuso
  7. Katherine Clarke
  8. Rachel R. Yuen
  9. Nina H. Lin
  10. Zachary J. Manickas-Hill
  11. Ian Rifkin
  12. Andreea Bujor
  13. Manish Sagar
  14. Anna C. Belkina
  15. Jennifer E. Snyder-Cappione

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Abstract

High autoantibody levels are found in individuals hospitalized for COVID-19. The temporal trajectories and levels of these autoantibodies months into convalescence after SARS-CoV-2 infection are unclear. It is also unknown if the composite autoantibody signatures of convalescent SARS-CoV-2-infected individuals resemble those with diagnosed autoimmune diseases. We measured the circulating levels of 17 autoantibodies associated with autoimmune connective tissue diseases from SARS-CoV-2 hospitalized and outpatient participants, as well as from individuals with scleroderma (SSc), systemic lupus erythematosus (SLE), and uninfected pre-pandemic controls. Seven of the 17 autoantibodies measured were higher in hospitalized and/or outpatient SARS-CoV-2 individuals an average of six months after symptom onset compared with controls, with multivariate analyses revealing links between SARS-CoV-2 infection and positivity of SSB-La, Sm, Proteinase 3, Myleoperoxidase, Jo-1, and Ku reactive IgG six months post-symptom onset. Autoantibody levels from SARS-CoV-2 infected individuals were followed over time from initial symptom onset for an average of six months, and different temporal autoantibody trajectories were classified. A ‘negative, then positive’ expression pattern was found for at least one autoantibody in 18% of the outpatient and 53% of the hospitalized participants, indicating initiation and durable expression of self-reactive immune responses post-infection, particularly with severe acute illness. Analysis of individual participant autoantibody expression patterns revealed similar patterns between pre-pandemic and convalescent SARS-CoV-2 infected groups that are distinct from participants with both the SSc and SLE. As autoantibody positivity can occur years prior to autoimmune disease onset, the possibility that SARS-CoV-2-associated autoantibodies are a herald of future autoimmune disorders requires further investigation.

One Sentence Summary

Autoantibody levels rise after acute SARS-CoV-2 infection and remain elevated for at least six months after symptom onset in participants with mild or severe COVID-19.

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  1. ScreenIT

    SciScore for 10.1101/2022.05.04.22274681: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Systemic lupus erythematosus samples were previously biobanked and were obtained under the following protocols: Autoimmune Kidney Research Studies and Patient Registry and the Autoimmune Kidney Research Repository approved by the Boston University Medical Center Institutional Review Board.
    Consent: Inclusion criteria for participants with lupus included the following: (1) participants must be >18 years of age, (2) participants with a diagnosis of autoimmune disease with or without kidney disease, and (3) participants must be able to read and understand the consent form.
    Sex as a biological variablenot detected.
    RandomizationModel confidence was calculated by randomly permuting Y 100 times and rebuilding the model to form a distribution of error for these randomly generated models, then comparing the model to this distribution with the Mann–Whitney U-test to determine the significance of the model.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Other statistical analyses were carried out using GraphPad version 9 or Matlab.
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Matlab
    suggested: (MATLAB, RRID:SCR_001622)

    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:
    There are additional limitations to our study. We sought to understand the immunologic trajectories noted in patients with this novel pathogen over longer periods post exposure. However, our study is not linked to clinical outcomes of interest during convalescence but rather is providing a broad background understanding of autoantibody dynamics in SARS-CoV-2 convalescent individuals. We also only examine a limited number of autoantibodies generally linked to autoimmune connective tissue disorders, the symptoms of which have been suggested to be consistent with PASC. To date, one of the issues to linking clinical outcomes such as PASC to immunological phenomenon has been the lack of a unifying clinical case criteria and understanding of the diverse phenotypes for this condition. The National Institutes of Health recently funded a large prospective cohort with the goal of understanding post-acute sequalae of SARS-CoV-2, entitled Researching COVID to Enhance Recovery (RECOVER), which may make such investigations possible in near future (https://recovercovid.org). Additionally, as mentioned above, our study does not have similar longitudinal samples from other viral infections, or for pre-pandemic controls (particularly those that might be hospitalized with severe illness). These types of controls should be included in future prospective cohorts of SARS-CoV-2 infection. We also do not have pre-infection samples for the SARS-CoV-2 cases, which would enable discerning early induced...

    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.

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  2. Version published to 10.1101/2022.05.04.22274681v1 on medRxiv