JAK-inhibitor and type I interferon ability to produce favorable clinical outcomes in COVID-19 patients: a systematic review and meta-analysis
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Abstract
Background
The spread of a highly pathogenic, novel coronavirus (SARS-CoV-2) has emerged as a once-in-a-century pandemic, having already infected over 63 million people worldwide. Novel therapies are urgently needed. Janus kinase-inhibitors and Type I interferons have emerged as potential antiviral candidates for COVID-19 patients due to their proven efficacy against diseases with excessive cytokine release and their direct antiviral ability against viruses including coronaviruses, respectively.
Methods
A search of MEDLINE and MedRxiv was conducted by three investigators from inception until July 30th 2020 and included any study type that compared treatment outcomes of humans treated with Janus kinase-inhibitor or Type I interferon against controls. Inclusion necessitated data with clearly indicated risk estimates or those that permitted their back-calculation. Outcomes were synthesized using RevMan.
Results
Of 733 searched studies, we included four randomized and eleven non-randomized trials. Five of the studies were unpublished. Those who received Janus kinase-inhibitor had significantly reduced odds of mortality (OR, 0.12; 95% CI, 0.03–0.39, p < 0.001) and ICU admission (OR, 0.05; 95% CI, 0.01–0.26, p< 0.001), and had significantly increased odds of hospital discharge (OR, 22.76; 95% CI, 10.68–48.54, p < 0.00001) when compared to standard treatment group. Type I interferon recipients had significantly reduced odds of mortality (OR, 0.19; 95% CI, 0.04–0.85, p < 0.05), and increased odds of discharge bordering significance (OR, 1.89; 95% CI, 1.00–3.59, p =0.05).
Conclusions
Janus kinase-inhibitor treatment is significantly associated with positive clinical outcomes in terms of mortality, ICU admission, and discharge. Type I interferon treatment is associated with positive clinical outcomes in regard to mortality and discharge. While these data show promise, additional well-conducted RCTs are needed to further elucidate the relationship between clinical outcomes and Janus kinase-inhibitors and Type I interferons in COVID-19 patients.
Article activity feed
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SciScore for 10.1101/2020.08.10.20172189: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization Inclusion necessitated that the trial be a human study accessible in English, and could include pediatric or adult studies, observational studies, retrospective cohorts, randomized clinical trials, and case reports. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources 20] Search Strategy and Study Quality Assessment: MEDLINE (via PubMed) and MedRxiv were searched since inception throughout July 30th, 2020 by three investigators (LW, AC, JV). MEDLINEsuggested: (MEDLINE, RRID:SCR_002185)PubMedsuggested: (PubMed, RRID:SCR_004846)Results from OddPu…
SciScore for 10.1101/2020.08.10.20172189: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization Inclusion necessitated that the trial be a human study accessible in English, and could include pediatric or adult studies, observational studies, retrospective cohorts, randomized clinical trials, and case reports. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources 20] Search Strategy and Study Quality Assessment: MEDLINE (via PubMed) and MedRxiv were searched since inception throughout July 30th, 2020 by three investigators (LW, AC, JV). MEDLINEsuggested: (MEDLINE, RRID:SCR_002185)PubMedsuggested: (PubMed, RRID:SCR_004846)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:Another limitation of this study is the aspect of drug combination. Included studies varied in the drugs administered in the control arm and in addition to JAK-inhibitor or Type I interferon in the treatment group. Types and doses of JAK-inhibitors and Type I interferons also differed across studies. Moreover, publication bias may have been present in some of the analyses conducted (Supplemental Figure 1; Supplemental Figure 2). The low number of studies make it difficult to assess asymmetry in funnel plot analyses. However, we attempted to mitigate this bias with the inclusion of six unpublished articles. A further limitation of this study is the exclusion of a large number of studies that presented heterogenous data that precluded pooled analyses. Lastly, this meta-analysis included two studies consisting of similar study teams that examined the same association,[24, 25] enhancing the likelihood of bias in the same direction in analyses where both of these studies were included. In conclusion, this meta-analysis supports the value of JAK-inhibitor and Type I interferon therapy as antivirals in combating SARS-CoV-2 infection. This study consolidates existing data and reaffirms the conclusion that, within COVID-19 patients, JAK-inhibitor treatment is significantly associated with positive clinical outcomes in terms of mortality, ICU admission, and discharge, as well as Type I interferon treatment’s association with positive clinical outcomes in regard to mortality and dischar...
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.
- Thank you for including a protocol registration statement.
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SciScore for 10.1101/2020.08.10.20172189: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources 20] Search Strategy and Study Quality Assessment MEDLINE (via PubMed) and MedRxiv were searched since inception throughout July 30th, 2020 by three investigators (LW, AC, JV). PubMedsuggested: (PubMed, RRID:SCR_004846)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when …
SciScore for 10.1101/2020.08.10.20172189: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources 20] Search Strategy and Study Quality Assessment MEDLINE (via PubMed) and MedRxiv were searched since inception throughout July 30th, 2020 by three investigators (LW, AC, JV). PubMedsuggested: (PubMed, RRID:SCR_004846)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:
Another limitation of this study is the aspect of drug combination. Included studies varied in the drugs administered in the control arm and in addition to JAK-inhibitor or Type I interferon in the treatment group. Types and doses of JAKinhibitors and Type I interferons also differed across studies. Moreover, publication bias may have been present in some of the analyses conducted (Supplemental Figure 1; Supplemental Figure 2). The low number of studies make it difficult to assess asymmetry in funnel plot analyses. However, we attempted to mitigate this bias with the inclusion of six unpublished articles. A further limitation of this study is the exclusion of a large number of studies that presented heterogenous data that precluded pooled analyses. Lastly, this meta-analysis included two studies consisting of similar study teams that examined the same association,[24, 25] enhancing the likelihood of bias in the same direction in analyses where both of these studies were included. In conclusion, this meta-analysis supports the value of JAK-inhibitor and Type I interferon therapy as antivirals in combating SARS-CoV-2 infection. This study consolidates existing data and reaffirms the conclusion that, within COVID-19 patients, JAK-inhibitor treatment is significantly associated with positive clinical outcomes in terms of mortality, ICU admission, and discharge, as well as Type I interferon treatment’s association with positive clinical outcomes in regard to mortality and discharge. Although these findings should assist physicians deciding which antivirals to administer to SARS-CoV-2 infected patients, they also point to a clear need of additional well-designed RCTs examining the relationship of JAK-inhibitor and Type I interferon and clinical outcomes of COVID-19 patients. FUNDING Lokesh Sharma is supported by Parker B Francis Fellowship. Charles Dela Cruz is supported by Veterans affairs Merit Grant (BX004661), Department of Defense grant (PR181442), and a U19 supplement for this work (AI089992-09S2). CONTRIBUTORSHIP STATEMENT Lucas Walz (LW); conception of investigation, planning of investigation, data retrieval, article screening, data analysis, written reporting, data interpretation. Avi J. Cohen (AC); planning of investigation, data retrieval, article screening, data analysis, written reporting, data interpretation. Andre P. Rebaza, MD (AR); written reporting, data interpretation. James Vanchieri (JV): data retrieval, article screening. Martin D. Slade, MPH (MS): data analysis. Charles S. Dela Cruz, MD, PhD (CDC): planning of investigation, data retrieval, written reporting, data interpretation; supervision. Lokesh Sharma, PhD (LS): conception of investigation, planning of investigation, written reporting, data interpretation; supervision.
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.
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.
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