Drug treatments affecting ACE2 in COVID-19 infection: a systematic review protocol

  1. Hajira Dambha-Miller
  2. Ali Albasri
  3. Sam Hodgson
  4. Christopher Wilcox
  5. Nazrul Islam
  6. Shareen Khan
  7. Paul Little
  8. Simon Griffin

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Abstract

The SARS-CoV-2 virus causing COVID-19 binds human angiotensin-converting enzyme 2 (ACE2) receptors in human tissues. ACE2 expression may be associated with COVID-19 infection and mortality rates. Routinely prescribed drugs that up- or down-regulate ACE2 expression are, therefore, of critical research interest as agents that might promote or reduce risk of COVID-19 infection in a susceptible population.

Aim

To collate evidence on routinely prescribed drug treatments in the UK that could up- or down-regulate ACE2, and thus potentially affect COVID-19 infection.

Design & setting

Systematic review of studies published in MEDLINE, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature), the Cochrane Library, and Web of Science from inception to 1 April 2020.

Method

A systematic review will be conducted in line with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Inclusion criteria will be: (1) assesses the effect of drug exposure on ACE2 level of expression or activity; (2) the drug is included in the British National Formulary ( BNF ) and, therefore, available to prescribe in the UK; and (3) a control, placebo, or sham group is included as comparator. Exclusion criteria will be: (1) ACE2 measurement in utero; (2) ACE2 measurement in children aged <18 years; (3) drug not in the BNF ; and (4) review article. Quality will be assessed using the Cochrane risk of bias tool for human studies, and the SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) risk of bias tool for animal studies.

Results

Data will be reported in summary tables and narrative synthesis.

Conclusion

This systematic review will identify drug therapies that may increase or decrease ACE2 expression. This might identify medications increasing risk of COVID-19 transmission, or as targets for intervention in mitigating transmission.

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  1. Version published to 10.3399/bjgpopen20x101115
  2. ScreenIT

    SciScore for 10.1101/2020.05.25.20100438: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Search Strategy: Systematic searches will be conducted from inception until 1/4/2020 in the following databases: MEDLINE, EMBASE, CINAHL, the Cochrane Library, and Web of Science.
    MEDLINE
    suggested: (MEDLINE, RRID:SCR_002185)
    EMBASE
    suggested: (EMBASE, RRID:SCR_001650)
    Cochrane Library
    suggested: (Cochrane Library, RRID:SCR_013000)

    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:
    Strengths and limitations: The strengths of this review protocol include its broad search strategy; inclusion of both human and animal studies; inclusion of studies from all languages; and the intention to rapidly assess and synthesise the evidence to meet the pressing research needs of the COVID-19 pandemic. Weaknesses include anticipated heterogeneity across animal and human models which may complicate result interpretation. Furthermore, we do not intend to contact authors of papers to obtain missing data due to the need to urgently report findings amidst the current pandemic. Comparison to existing literature: We believe this to be the first systematic review assessing associations between drug exposure and ACE2 expression for drugs routinely prescribed in the UK. Implications for practice: Identification of the best evidence on these drugs might, for example, inform clinicians considering whether patients should be advised to stop ACE inhibitors21. Conversely, drugs which are associated with ACE2 downregulation might represent a therapeutic strategy to reduce viral transmission and disease spread.

    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.

    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 10.1101/2020.05.25.20100438v1 on medRxiv