Potentially effective drugs for the treatment of COVID-19 or MIS-C in children: a systematic review

  1. Zijun Wang
  2. Siya Zhao
  3. Yuyi Tang
  4. Zhili Wang
  5. Qianling Shi
  6. Xiangyang Dang
  7. Lidan Gan
  8. Shuai Peng
  9. Weiguo Li
  10. Qi Zhou
  11. Qinyuan Li
  12. Joy James Mafiana
  13. Rafael González Cortés
  14. Zhengxiu Luo
  15. Enmei Liu
  16. Yaolong Chen

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Abstract

The purpose of this systematic review is to evaluate the efficacy and safety of using potential drugs: remdesivir and glucocorticoid in treating children and adolescents with COVID-19 and intravenous immunoglobulin (IVIG) in treating MIS-C. We searched seven databases, three preprint platform, ClinicalTrials.gov, and Google from December 1, 2019, to August 5, 2021, to collect evidence of remdesivir, glucocorticoid, and IVIG which were used in children and adolescents with COVID-19 or MIS-C. A total of nine cohort studies and one case series study were included in this systematic review. In terms of remdesivir, the meta-analysis of single-arm cohort studies have shown that after the treatment, 54.7% (95%CI, 10.3 to 99.1%) experienced adverse events, 5.6% (95%CI, 1.2 to 10.1%) died, and 27.0% (95%CI, 0 to 73.0%) needed extracorporeal membrane oxygenation or invasive mechanical ventilation. As for glucocorticoids, the results of the meta-analysis showed that the fixed-effect summary odds ratio for the association with mortality was 2.79 (95%CI, 0.13 to 60.87), and the mechanical ventilation rate was 3.12 (95%CI, 0.80 to 12.08) for glucocorticoids compared with the control group. In terms of IVIG, most of the included cohort studies showed that for MIS-C patients with more severe clinical symptoms, IVIG combined with methylprednisolone could achieve better clinical efficacy than IVIG alone.

Conclusions : Overall, the current evidence in the included studies is insignificant and of low quality. It is recommended to conduct high-quality randomized controlled trials of remdesivir, glucocorticoids, and IVIG in children and adolescents with COVID-19 or MIS-C to provide substantial evidence for the development of guidelines.

What is Known: • The efficacy and safety of using potential drugs such as remdesivir, glucocorticoid, and intravenous immunoglobulin (IVIG) in treating children and adolescents with COVID-19/MIS-C are unclear.
What is New: • Overall, the current evidence cannot adequately demonstrate the effectiveness and safety of using remdesivir, glucocorticoids, and IVIG in treating children and adolescents with COVID-19 or MIS-C. • We are calling for the publication of high-quality clinical trials and provide substantial evidence for the development of guidelines.

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  1. Version published to 10.1007/s00431-022-04388-w
  2. Version published to 10.21203/rs.3.rs-851844/v1 on Research Square
  3. ScreenIT

    SciScore for 10.1101/2021.07.20.21260827: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    RandomizationBefore the formal screening process, researchers in each group randomly selected 50 studies to undertake a pilot study selection and ensure consistency in understanding the inclusion and exclusion criteria.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Search strategy: Two researchers in each group independently searched for literature using MEDLINE (via PubMed), Web of Science, the Cochrane library, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), Wanfang Data, and WHO COVID-19 database (https://search.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/), ClinicalTrials.gov (https://clinicaltrials.gov/), MedRxiv (https://www.medrxiv.org/), BioRxiv (https://www.biorxiv.org/), SSRN (https://www.ssrn.com/index.cfm/en/), and Google.
    MEDLINE
    suggested: (MEDLINE, RRID:SCR_002185)
    PubMed
    suggested: (PubMed, RRID:SCR_004846)
    Cochrane library
    suggested: (Cochrane Library, RRID:SCR_013000)
    BioRxiv
    suggested: (bioRxiv, RRID:SCR_003933)
    Google
    suggested: (Google, RRID:SCR_017097)
    Study selection: Two researchers in each group independently screened literature using the EndNote citation management software, and any disagreements were resolved by discussion.
    EndNote
    suggested: (EndNote, RRID:SCR_014001)
    The risk of bias of the included randomized controlled trials was assessed using Cochrane’s risk of bias tool [21].
    Cochrane’s
    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:
    Strengths and limitations: This study is the first systematic review accessing the remdesivir, glucocorticoids and IVIG in treating children and adolescents with COVID-19. The study highlights the current status of evidence, identifies research gaps and proffer recommendations for developing clinical practice guidelines in treating children and adolescents with COVID-19. However, there are also some limitations: 1) All the studies using remdesivir in treating children with were low-quality single-arm cohort studies; thus, its efficacy and safety could not be clearly ascertained. 2) Due to the small sample size in the studies using glucocorticoids as treatment included in the study, the results of meta-analysis may be biased to some extent, and 3) Quantitative analysis of studies on the treatment of MIS-C by IVIG was not feasible due to the heterogeneity of their outcome indicators. 4.3. Further suggestions: Based on the results of this systematic review, we recommend 1) high-quality randomized controlled trials of potentially effective drugs for children with COVID-19; 2) develop better guidelines based on substantial current evidence, provide a timely guide for clinical workers, and update them in real-time according to the evidence situation.

    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 10.1101/2021.07.20.21260827v2 on medRxiv
  5. Version published to 10.1101/2021.07.20.21260827v1 on medRxiv