The tryptophan catabolite or kynurenine pathway in COVID-19 and critical COVID-19: a systematic review and meta-analysis

  1. Abbas F. Almulla
  2. Thitiporn Supasitthumrong
  3. Chavit Tunvirachaisakul
  4. Ali Abbas Abo Algon
  5. Hussein K. Al-Hakeim
  6. Michael Maes

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Abstract

Background

Coronavirus disease 2019 (COVID-19) is accompanied by activated immune-inflammatory pathways and oxidative stress, which both induce indoleamine-2,3-dioxygenase (IDO), a key enzyme of the tryptophan (TRP) catabolite (TRYCAT) pathway. The aim of this study was to systematically review and meta-analyze the status of the TRYCAT pathway, including the levels of TRP and kynurenine (KYN) and the activity of IDO, as measured by the ratio of KYN/TRP.

Methods

This systematic review searched PubMed, Google Scholar, and Web of Sciences and included 14 articles that compared TRP and tryptophan catabolites (TRYCATs) in COVID-19 patients versus non-COVID-19 controls, as well as severe/critical versus mild/moderate COVID-19. The analysis was done on a total of 1269 people, including 794 COVID-19 patients and 475 controls.

Results

The results show a significant (p < 0.0001) increase in the KYN/TRP ratio (standardized mean difference, SMD = 1.099, 95% confidence interval, CI: 0.714; 1.484) and KYN (SMD = 1.123, 95% CI: 0.730; 1.516) and significantly lower TRP (SMD = − 1.002, 95%CI: − 1.738; − 0.266) in COVID-19 versus controls. The KYN/TRP ratio (SMD = 0.945, 95%CI: 0.629; 1.262) and KYN (SMD = 0.806, 95%CI: 0.462; 1.149) were also significantly (p < 0.0001) higher and TRP lower (SMD = − 0.909, 95% CI: − 1.569; − 0.249) in severe/critical versus mild/moderate COVID-19. No significant difference was detected in kynurenic acid (KA) and the KA/KYN ratio between COVID-19 patients and controls.

Conclusions

Our results indicate increased activity of the IDO enzyme in COVID-19 and severe/critical patients. The TRYCAT pathway is implicated in the pathophysiology and progression of COVID-19 and may signal a worsening outcome of the disease.

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  1. Version published to 10.1186/s12879-022-07582-1
  2. ScreenIT

    SciScore for 10.1101/2022.02.01.22270268: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variableAll required data extracted from the articles were entered in a predefined excel spreadsheet file made for this project, including researcher’s names, publication date, quantitative data of TRP and TRYCATs, the number of the participants either as a COVID-19 or control groups, demographic data such as age (expressed as mean ±SD), male/female count, type of sample, serum or plasma, severity level, country latitude in which the study was conducted, and quality scores of the studies (see below).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The current meta-analysis was in compliance with the standards of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 (Page, McKenzie et al. 2021), the guidelines of the Cochrane Handbook for Systematic Reviews and Interventions (
    Cochrane Handbook
    suggested: None
    We entered specific mesh terms and keywords in electronic databases to find related articles in PubMed/MEDLINE, Google Scholar, and Web of Science.
    PubMed/MEDLINE
    suggested: None
    Google Scholar
    suggested: (Google Scholar, RRID:SCR_008878)

    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:
    Some limitations of the current systematic review and meta-analysis should be discussed. Not all studies clearly described the types of medications, the treatment protocol, the relevant comorbidities, and even the vaccination status of the patients. Moreover, non survivors following COVID-19 were sometimes lumped together with survivors. Due the small sample sizes and paucity of data on some TRYCATs, we were unable to estimate KMO and KYNU activity. Therefore, serum TRP and a more complete panel of serum TRYCATs should be determined in well-powered studies in the different stages of COVID-19 (i.e., mild, moderate, severe, critical, non-survival).

    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 10.1101/2022.02.01.22270268 on medRxiv