Persistent Autoimmune Activation and Proinflammatory State in Post-Coronavirus Disease 2019 Syndrome

  1. Yeny Acosta-Ampudia
  2. Diana M Monsalve
  3. Manuel Rojas
  4. Yhojan Rodríguez
  5. Elizabeth Zapata
  6. Carolina Ramírez-Santana
  7. Juan-Manuel Anaya

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Abstract

Background

The immunopathological pathways enabling post-coronavirus disease 2019 (COVID-19) syndrome (PCS) development are not entirely known. We underwent a longitudinal analysis of patients with COVID-19 who developed PCS aiming to evaluate the autoimmune and immunological status associated with this condition.

Methods

Thirty-three patients were included for longitudinal clinical and autoantibody analyses, 12 of whom were assessed for cytokines and lymphocyte populations. Patients were followed for 7–11 months after acute COVID-19. Autoimmune profile and immunological statuses were evaluated mainly by enzyme-linked-immunosorbent assays and flow cytometry.

Results

Latent autoimmunity and overt autoimmunity persisted over time. A proinflammatory state was observed in patients with PCS characterized by up-regulated interferon-α, tumor necrosis factor-α, granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-17A, IL-6, IL-1β, and IL-13, whereas interferon-γ-induced protein 10 (IP-10) was decreased. In addition, PCS was characterized by increased levels of Th9, CD8+ effector T cells, naive B cells, and CD4+ effector memory T cells. Total levels of immunoglobulin G S1-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies remained elevated over time.

Conclusions

The clinical manifestations of PCS are associated with the persistence of a proinflammatory and effector phenotype induced by SARS-CoV-2 infection. This long-term persistent immune activation may contribute to the development of latent and overt autoimmunity. Results suggest the need to evaluate the role of immunomodulation in the treatment of PCS.

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  1. Version published to 10.1093/infdis/jiac017
  2. ScreenIT

    SciScore for 10.1101/2021.11.17.21266457: (What is this?)

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

    Table 1: Rigor

    EthicsField Sample Permit: This study was done in compliance with Act 008430/1993 of the Ministry of Health of the Republic of Colombia, which classified it as minimal-risk research.
    Consent: All the patients were asked for their consent and were informed about the Colombian data protection law (1581 of 2012).
    IRB: The institutional review board of the CES University approved the study design.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Autoantibodies: Detection of IgM rheumatoid factor (RF), IgG anti-cyclic citrullinated peptide third generation (CCP3), IgM and IgG anti-cardiolipin antibodies (ACAs), IgM and IgG anti-β2 glycoprotein-1 (β2GP1) antibodies, IgG anti-double-stranded DNA (dsDNA) antibodies, IgG anti-thyroglobulin (Tg) antibodies and anti-thyroid peroxidase (TPO) antibodies were all quantified by enzyme-linked-immunosorbent assay (ELISA).
    IgM rheumatoid factor (RF), IgG
    suggested: (MyBioSource Cat# MBS531193, RRID:AB_2080461)
    anti-cardiolipin
    suggested: None
    anti-β2 glycoprotein-1 (β2GP1) antibodies, IgG
    suggested: None
    dsDNA) antibodies, IgG anti-thyroglobulin (Tg)
    suggested: None
    anti-thyroid peroxidase (TPO)
    suggested: None
    In addition, antinuclear antibodies (ANAs) were evaluated by using an indirect immunofluorescence assay.
    antinuclear
    suggested: None
    In case of ANAs positivity, anti-SSA/Ro, anti-SSB/La, anti-ribonucleoprotein (RNP) and anti-smith (Sm) antibodies were further evaluated by a commercial ELISA.
    anti-SSA/Ro
    suggested: (MyBioSource Cat# MBS705358, RRID:AB_10888702)
    anti-SSB/La
    suggested: None
    anti-smith (Sm)
    suggested: None
    Assessment of anti-IFN-α antibodies was done by ELISA (Thermo Fisher Scientific, Waltham, MA) following manufacturer’s specifications.
    anti-IFN-α
    suggested: None
    Anti-SARS-CoV-2 Antibodies: The Euroimmun anti-SARS-CoV-2 ELISA (Euroimmun, Luebeck, Germany) was used for serological detection of human IgG and IgA antibodies against the SARS-CoV-2 S1 structural protein, in accordance with the manufacturer’s instructions, as previously described [2].
    Anti-SARS-CoV-2
    suggested: None
    anti-SARS-CoV-2 ELISA
    suggested: None
    Initially, generalized linear models were used to evaluate longitudinal changes in IgA and IgG SARS-CoV-2 antibodies ratios, cytokines, and lymphocyte populations, as previously described [8].
    IgG SARS-CoV-2
    suggested: None
    Software and Algorithms
    SentencesResources
    A minimum of 100,000 lymphocytes per sample were acquired on a FACSCanto II™ flow cytometer (BD Biosciences™) and data was analyzed with FlowJo software version 9 (BD Biosciences™) as reported elsewhere [8].
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    BD Biosciences™
    suggested: (BD Biosciences, RRID:SCR_013311)

    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:
    Study limitations are acknowledged. A broader panel of B and T cells, as well as their functional analyses was not possible. Genetic analysis was not done. Another potential shortcoming of the present study is that the observed results might be due to chance alone or to the moderate sample size. However, this is unlikely because of the highly significant results observed after adjustments and corrections as well as their consistent direction and magnitude within the different analyses.

    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

    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 10.1101/2021.11.17.21266457v1 on medRxiv