Critically ill COVID-19 patients with neutralizing autoantibodies against type I interferons have increased risk of herpesvirus disease

  1. Idoia Busnadiego
  2. Irene A. Abela
  3. Pascal M. Frey
  4. Daniel A. Hofmaenner
  5. Thomas C. Scheier
  6. Reto A. Schuepbach
  7. Philipp K. Buehler
  8. Silvio D. Brugger
  9. Benjamin G. Hale

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Abstract

Autoantibodies neutralizing the antiviral action of type I interferons (IFNs) have been associated with predisposition to severe Coronavirus Disease 2019 (COVID-19). Here, we screened for such autoantibodies in 103 critically ill COVID-19 patients in a tertiary intensive care unit (ICU) in Switzerland. Eleven patients (10.7%), but no healthy donors, had neutralizing anti-IFNα or anti-IFNα/anti-IFNω IgG in plasma/serum, but anti-IFN IgM or IgA was rare. One patient had non-neutralizing anti-IFNα IgG. Strikingly, all patients with plasma anti-IFNα IgG also had anti-IFNα IgG in tracheobronchial secretions, identifying these autoantibodies at anatomical sites relevant for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Longitudinal analyses revealed patient heterogeneity in terms of increasing, decreasing, or stable anti-IFN IgG levels throughout the length of hospitalization. Notably, presence of anti-IFN autoantibodies in this critically ill COVID-19 cohort appeared to predict herpesvirus disease (caused by herpes simplex viruses types 1 and 2 (HSV-1/-2) and/or cytomegalovirus (CMV)), which has been linked to worse clinical outcomes. Indeed, all 7 tested COVID-19 patients with anti-IFN IgG in our cohort (100%) suffered from one or more herpesviruses, and analysis revealed that these patients were more likely to experience CMV than COVID-19 patients without anti-IFN autoantibodies, even when adjusting for age, gender, and systemic steroid treatment (odds ratio (OR) 7.28, 95% confidence interval (CI) 1.14 to 46.31, p = 0.036). As the IFN system deficiency caused by neutralizing anti-IFN autoantibodies likely directly and indirectly exacerbates the likelihood of latent herpesvirus reactivations in critically ill patients, early diagnosis of anti-IFN IgG could be rapidly used to inform risk-group stratification and treatment options.

Trial Registration: ClinicalTrials.gov Identifier: NCT04410263 .

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  1. Version published to 10.1371/journal.pbio.3001709
  2. ScreenIT

    SciScore for 10.1101/2022.03.19.22272532: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: The study was approved by the Local Ethics Committee of the Canton of Zurich, Switzerland (Kantonale Ethikkommission Zurich BASEC ID 2020-00646) in accordance with the provisions of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonisation.
    Field Sample Permit: Sample Collection, Processing and Testing (Virus Diagnostics): SARS-CoV-2 was detected by real-time RT-PCR as previously described [15].
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Bead coating was assessed using mouse monoclonal antibodies against IFNα2, IFNβ or IFNω (anti-IFNα2: Novusbio
    anti-IFNα2
    suggested: None
    Sample Processing and Testing (IFN-Neutralizing Antibodies): 2.4 × 104 human embryonic kidney HEK293T cells (ATCC CRL-3216) per well in 96-well plates were reverse-transfected with 30ng of a plasmid containing the firefly luciferase (FF-Luc) gene under control of the IFN-inducible mouse Mx1 promoter (pGL3-Mx1P-FFluc) (kindly provided by Georg Kochs), together with 4ng of a control plasmid expressing Renilla luciferase (Ren-Luc) under a constitutively active promoter (pRL-TK-Renilla).
    IFN-Neutralizing
    suggested: None
    Antibodies)
    suggested: (BioVision Cat# 3754-100, RRID:AB_2192485)
    Mx1 promoter ( pGL3-Mx1P-FFluc )
    suggested: None
    Statistical Analyses: The association of anti-IFN autoantibodies and herpesvirus reactivations, with the additional analyses of only CMV or HSV-1/2 reactivation, was examined using logistic regression models.
    anti-IFN
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Sample Processing and Testing (IFN-Neutralizing Antibodies): 2.4 × 104 human embryonic kidney HEK293T cells (ATCC CRL-3216) per well in 96-well plates were reverse-transfected with 30ng of a plasmid containing the firefly luciferase (FF-Luc) gene under control of the IFN-inducible mouse Mx1 promoter (pGL3-Mx1P-FFluc) (kindly provided by Georg Kochs), together with 4ng of a control plasmid expressing Renilla luciferase (Ren-Luc) under a constitutively active promoter (pRL-TK-Renilla).
    HEK293T
    suggested: None
    Recombinant DNA
    SentencesResources
    Sample Processing and Testing (IFN-Neutralizing Antibodies): 2.4 × 104 human embryonic kidney HEK293T cells (ATCC CRL-3216) per well in 96-well plates were reverse-transfected with 30ng of a plasmid containing the firefly luciferase (FF-Luc) gene under control of the IFN-inducible mouse Mx1 promoter (pGL3-Mx1P-FFluc) (kindly provided by Georg Kochs), together with 4ng of a control plasmid expressing Renilla luciferase (Ren-Luc) under a constitutively active promoter (pRL-TK-Renilla).
    pGL3-Mx1P-FFluc
    suggested: None
    pRL-TK-Renilla
    suggested: RRID:Addgene_123656)
    Software and Algorithms
    SentencesResources
    Data Collection and Covariates: Clinical and laboratory data were obtained as previously described [15].
    Covariates
    suggested: None
    SPSS Science, Chicago, IL, USA) and Stata 16 (
    SPSS
    suggested: (SPSS, RRID:SCR_002865)

    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:
    A clear limitation of our study is the low patient sample size in our cohort and single-center study design, that did not provide us with sufficient statistical power to allow detection of small differences in clinical outcomes. This could be improved in future studies with higher participant numbers, and in studies with a pre-defined systematic sampling procedure for the detection of herpesvirus reactivations. Moreover, studies should perhaps investigate associations between the amount of reactivated herpesvirus load, the magnitude of IFN system suppression by anti-IFN autoantibodies, immunomodulation induced by clinicians, and multiple relevant patient outcomes (e.g. length of stay in ICU, length of stay in hospital, duration of mechanical ventilation, duration of ARDS, and mortality). We also acknowledge that our study is limited by the inability to assess levels of anti-IFN autoantibodies in patients prior to SARS-CoV-2 infection. Thus, we can currently only speculate that an immunodeficient state was pre-existing in certain patients and exacerbated COVID-19 severity and the likelihood of herpesvirus reactivations. In conclusion, detection of anti-IFN autoantibodies that bind and neutralize the antiviral type I IFNs can be performed relatively easily and rapidly, and could be used in future diagnostic efforts to understand the underlying causes of severe disease in both COVID-19 and other infectious disease manifestations [32]. While there are currently no specific therap...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04410263RecruitingMicrobiota in COVID-19 Patients for Future Therapeutic and P…

    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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  3. Version published to 10.1101/2022.03.19.22272532v1 on medRxiv