Inflammasome-related Markers upon ICU Admission do not Correlate with Outcome in Critically Ill COVID-19 Patients

  1. Barbara Adamik
  2. Magdalena Ambrożek-Latecka
  3. Barbara Dragan
  4. Aldona Jeznach
  5. Jakub Śmiechowicz
  6. Waldemar Gożdzik
  7. Tomasz Skirecki

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Abstract

Purpose:

The development of targeted biological therapies for coronavirus disease 2019 (COVID-19) requires reliable biomarkers that could help indicate how patients are responding. The hyperactivation of inflammasomes by the SARS-CoV2 virus is hypothesized to contribute to a more severe course of the COVID-19 disease. Therefore, we aimed to evaluate the prognostic value of several inflammasome-related cytokines and proteins upon admission to the intensive care unit (ICU).

Patients and Methods:

We performed a prospective cohort study. Plasma samples were obtained from 45 critically ill COVID-19 patients and 10 patients without any signs of infection (traumatic brain injury [TBI]) on admission to the ICU. Concentrations of IL-1 a , IL-1 β , IL-18, IL-1RA, galectin-1, apoptosis-associated speck-like proteins, LDH, ferritin, and gasdermin D were analyzed. A cell-free caspase-1 plasma assay was done by inhibitor-based immunoprecipitation followed by a Western Blot. Demographic and clinical characteristics were recorded.

Results:

Inhospital mortality in COVID-19 patients was 62%. Galectin-1 was 1.8-fold lower in COVID-19 than in TBI patients (17101.84 pg/mL vs. 30764.20 pg/mL, P  = 0.007), but other inflammasome-related biomarkers had similar concentrations. Patients with a Sequential Organ Failure Assessment (SOFA) score of > 9 on admission who were at high risk of death had significantly higher galectin-1 but lower IL-1RA in comparison with low-risk patients (25551.3 pg/mL vs. 16302.7 pg/mL, P  = 0.014; 14.5 pg/mL vs. 39.4pg/mL, P  = 0.04, respectively). Statistically significant correlations were observed between: IL-1 a and platelets (r = –0.37), IL-1 β and platelets (r = –0.36), ferritin and INR (r = 0.39). Activated caspase-1 p35, whose presence was related to higher fibrinogen and lower D-dimers, was detected in 12 out of 22 COVID-19 patients and in none of the TBI patients. Moreover, densitometric analysis showed a significantly higher amount of p35 in patients with a SOFA score > 9.

Conclusion:

We found that the systemic markers of activation of inflammasomes in critically ill COVID-19 patients were not directly related to outcome. Therefore, potential interventions aimed at the inflammasome pathway in this group of patients may be of limited effectiveness and should be biomarker-guided.

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  1. Version published to 10.1097/shk.0000000000001923
  2. Version published to 10.1101/2021.10.30.21265662v2 on medRxiv
  3. ScreenIT

    SciScore for 10.1101/2021.10.30.21265662: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Consents from the critically ill COVID-19 patients were waived due to the state of unconsciousness in these patients which was accepted by the Wroclaw Medical University Bioethics Committee (consent No. 394/2021).
    Consent: Consents from the critically ill COVID-19 patients were waived due to the state of unconsciousness in these patients which was accepted by the Wroclaw Medical University Bioethics Committee (consent No. 394/2021).
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Densitometric analysis was done by GelAnalyzer 19.1.
    GelAnalyzer
    suggested: None

    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:
    This study has several limitations related with small patients’ group and lack of mechanistic investigations. Noteworthy, our study group is well-defined and limited to the ARDS and sepsis forms of COVID-19. Although we analyzed several proteins related with activation of the inflammasome we did not measure other relevant mediators that can interact with this pathway (e.g. interferons). The present study would also benefit from the flow cytometry data of the inflammasome activation in circulating blood cells. Moreover, we analyzed only plasma proteins and it should be noted that they may not fully reflect the tissue response. Finally, we were not able to explain the heterogenic pattern of the inflammasome activity in these patients.

    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.

  4. Version published to 10.1101/2021.10.30.21265662v1 on medRxiv