Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation

  1. Florence WJ Chioh
  2. Siew-Wai Fong
  3. Barnaby E Young
  4. Kan-Xing Wu
  5. Anthony Siau
  6. Shuba Krishnan
  7. Yi-Hao Chan
  8. Guillaume Carissimo
  9. Louis LY Teo
  10. Fei Gao
  11. Ru San Tan
  12. Liang Zhong
  13. Angela S Koh
  14. Seow-Yen Tan
  15. Paul A Tambyah
  16. Laurent Renia
  17. Lisa FP Ng
  18. David C Lye
  19. Christine Cheung

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Abstract

Numerous reports of vascular events after an initial recovery from COVID-19 form our impetus to investigate the impact of COVID-19 on vascular health of recovered patients. We found elevated levels of circulating endothelial cells (CECs), a biomarker of vascular injury, in COVID-19 convalescents compared to healthy controls. In particular, those with pre-existing conditions (e.g., hypertension, diabetes) had more pronounced endothelial activation hallmarks than non-COVID-19 patients with matched cardiovascular risk. Several proinflammatory and activated T lymphocyte-associated cytokines sustained from acute infection to recovery phase, which correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Notably, we found higher frequency of effector T cells in our COVID-19 convalescents compared to healthy controls. The activation markers detected on CECs mapped to counter receptors found primarily on cytotoxic CD8 + T cells, raising the possibility of cytotoxic effector cells targeting activated endothelial cells. Clinical trials in preventive therapy for post-COVID-19 vascular complications may be needed.

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  1. Version published to 10.7554/elife.64909 on eLife
  2. ScreenIT

    SciScore for 10.1101/2020.11.16.20232835: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Antibodies
    SentencesResources
    Optimal compensation was achieved using compensation control beads (Anti-Mouse Ig, κ/Negative Control Compensation Particles Set, 552843) together with corresponding conjugated antibodies.
    Anti-Mouse Ig ,
    suggested: None
    Software and Algorithms
    SentencesResources
    Study design, participants and clinical data collection of convalescent COVID-19 patients: Convalescent COVID-19 individuals were recalled from the PROTECT study which is a prospective observational cohort study at three public hospitals in Singapore (the National Centre for Infectious Diseases, National University Hospital and Changi General Hospital)
    PROTECT
    suggested: (ProTECT, RRID:SCR_004531)
    Study protocols were approved by ethics committees of the National Healthcare Group (2012/00917)
    National Healthcare
    suggested: None
    Flow cytometry was performed using BD LSRFortessa X-20 (BD Biosciences) and data acquisition was performed on FACSDiva software, version 8.0.1 (BD Biosciences)
    FACSDiva
    suggested: (BD FACSDiva Software, RRID:SCR_001456)
    Acquired data were analyzed using FlowJo software, version 10.7.1.
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    Data analysis was done with Bio-Plex Manager 6.1.1 software.
    Bio-Plex Manager
    suggested: None
    Protein-protein interaction networks of the CEC associated cytokines were predicted and illustrated with Search Tool for the Retrieval of Interacting Genes/Proteins database (STRING) (version 11.0; available at: https://string-db.org).
    STRING
    suggested: (STRING, RRID:SCR_005223)
    Statistical analyses for this correlative study were performed using GraphPad Prism software, version 8.3.1.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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:
    We are mindful of the limitations with this current study. First, we noted the major determinants of cardiovascular risks in convalescent COVID-19 and non-COVID-19 patients, but there might have been unmeasured confounding conditions that could contribute to some heterogeneity in our CEC and cytokine profiling. Second, convalescent blood samples were collected at various time points due to logistical constraints in recalling recovered patients on the same day post-infection. Finally, to understand post-COVID-19 complications, long-term phenotyping of vascular functions and immune profiles of convalescent patients is still lacking due to short term horizons from when these individuals were first infected. There is a critical need to monitor prospective cohorts of recovered individuals in order to establish the full spectrum of clinical courses of complications. Global efforts in this aspect are evident and are underway. Hematologic assessment (i.e. thrombin generation, platelet activation studies, von Willebrand factor) is commonly performed to help manage convalescent patients who have been re-admitted for acute thrombosis. It would be valuable to risk stratify convalescent patients before adverse events happen. Our profiling of CECs may serve as a form of vascular surveillance to complement hematologic assessment in identifying early molecular and endothelial changes in high-risk individuals. Analysis of CECs may detect subclinical changes in the vasculatures and be able to ...

    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: Please consider improving the rainbow (“jet”) colormap(s) used on page 10. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    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.

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  3. Version published to 10.1101/2020.11.16.20232835v1 on medRxiv