Zinc for the prevention or treatment of acute viral respiratory tract infections in adults: a rapid systematic review and meta-analysis of randomised controlled trials
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Abstract
To evaluate the benefits and risks of zinc formulations compared with controls for prevention or treatment of acute viral respiratory tract infections (RTIs) in adults.
Method
Seventeen English and Chinese databases were searched in April/May 2020 for randomised controlled trials (RCTs), and from April/May 2020 to August 2020 for SARS-CoV-2 RCTs. Cochrane rapid review methods were applied. Quality appraisals used the Risk of Bias 2.0 and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.
Results
Twenty-eight RCTs with 5446 participants were identified. None were specific to SARS-CoV-2. Compared with placebo, oral or intranasal zinc prevented 5 RTIs per 100 person-months (95% CI 1 to 8, numbers needed to treat (NNT)=20, moderate-certainty/quality). Sublingual zinc did not prevent clinical colds following human rhinovirus inoculations (relative risk, RR 0.96, 95% CI 0.77 to 1.21, moderate-certainty/quality). On average, symptoms resolved 2 days earlier with sublingual or intranasal zinc compared with placebo (95% CI 0.61 to 3.50, very low-certainty/quality) and 19 more adults per 100 were likely to remain symptomatic on day 7 without zinc (95% CI 2 to 38, NNT=5, low-certainty/quality). There were clinically significant reductions in day 3 symptom severity scores (mean difference, MD −1.20 points, 95% CI −0.66 to −1.74, low-certainty/quality), but not average daily symptom severity scores (standardised MD −0.15, 95% CI −0.43 to 0.13, low-certainty/quality). Non-serious adverse events (AEs) (eg, nausea, mouth/nasal irritation) were higher (RR 1.41, 95% CI 1.17 to 1.69, NNHarm=7, moderate-certainty/quality). Compared with active controls, there were no differences in illness duration or AEs (low-certainty/quality). No serious AEs were reported in the 25 RCTs that monitored them (low-certainty/quality).
Conclusions
In adult populations unlikely to be zinc deficient, there was some evidence suggesting zinc might prevent RTIs symptoms and shorten duration. Non-serious AEs may limit tolerability for some. The comparative efficacy/effectiveness of different zinc formulations and doses were unclear. The GRADE-certainty/quality of the evidence was limited by a high risk of bias, small sample sizes and/or heterogeneity. Further research, including SARS-CoV-2 clinical trials is warranted.
PROSPERO registration number
CRD42020182044.
Article activity feed
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SciScore for 10.1101/2020.11.02.20220038: (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 Post-protocol input from consumer/patient advocate representatives who were blinded to the results, led to minor changes to the outcomes and the rating of their importance (Table 1). Power Analysis When rating imprecision, the optimal information size of effect estimates was based on single-study sample size calculations of included studies, or a conventional 2-sided or equivalence sample size calculation, with an 80% power and a type 1 error rate of 5%. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources RevMan 5.4,61 R … SciScore for 10.1101/2020.11.02.20220038: (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 Post-protocol input from consumer/patient advocate representatives who were blinded to the results, led to minor changes to the outcomes and the rating of their importance (Table 1). Power Analysis When rating imprecision, the optimal information size of effect estimates was based on single-study sample size calculations of included studies, or a conventional 2-sided or equivalence sample size calculation, with an 80% power and a type 1 error rate of 5%. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources RevMan 5.4,61 R software,62 Microsoft Excel, and GRADEpro GDT63 were used for the statistical analyses. GRADEpro GDT63suggested: NoneSoftware and Algorithms Sentences Resources Protocol: This rapid review (RR) conforms with the Interim Guidance from the Cochrane Rapid Reviews Methods Group,2 the Cochrane Handbook,49 and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)50. Cochrane Rapid Reviewssuggested: NoneCochranesuggested: (Cochrane Library, RRID:SCR_013000)The following databases were searched with no limits on language nor date: PubMed, Embase PubMedsuggested: (PubMed, RRID:SCR_004846)Embasesuggested: (EMBASE, RRID:SCR_001650), Cochrane CENTRAL, Academic Search Complete, Allied and Complementary Medicine Database, Alt Health Watch Cochrane CENTRALsuggested: (Cochrane Central Register of Controlled Trials, RRID:SCR_006576)CINAHL Plus with Full Text, Health Source, PsycINFO, China Knowledge Resource Integrated Database (CNKI), medRxiv, bioRxiv, U.S. National Library of Medicine Register of Clinical Trials (ClinicalTrials.gov), PsycINFOsuggested: (PsycINFO, RRID:SCR_014799)bioRxivsuggested: (bioRxiv, RRID:SCR_003933)Data from graphical reports were extracted with WebPlotDigitizer Version 4.257 with any rounding of decimal places and whole person estimates favouring the null hypothesis. WebPlotDigitizersuggested: (WebPlotDigitizer, RRID:SCR_013996)RevMan 5.4,61 R software,62 Microsoft Excel, and GRADEpro GDT63 were used for the statistical analyses. Microsoft Excelsuggested: (Microsoft Excel, RRID:SCR_016137)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 of this review: Consultation with consumer advocates helped focus this review on issues that matter to patients and affirmed the relevance of indirect evidence. Notwithstanding, the indirectness to SARS-CoV-2 is a major limitation that constrained the overall certainty of the evidence. The only direct evidence that we are aware of comes from non-randomised studies of interventions.8,16-19 However, including these studied would not have changed the conclusions. The certainty of the evidence would have remained very low for all outcomes. Other limitations to the certainty of the evidence included serious concerns about the inconsistency of the estimates of effect for duration. Wide variations in the methodology, zinc interventions, demographics of the study participants, and changes in the seasonal epidemiology of viral RTIs are all likely to have contributed to this heterogeneity. We were more cautious than previous reviewers,45,46 and downgraded the certainty of the evidence by two levels for inconsistency. A high risk of bias for most of the RCT outcomes was another concern. Except for adverse effects, many RCT outcomes has at least some concerns. Reassuringly, the estimates of effects for all critical outcomes were robust following removal of RCTs with a high risk of bias. Nevertheless, were more cautious than previous reviewers,42-46 and downgraded the certainty of the evidence due to risk of bias by one level for all prevention, duration and seve...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04342728 Completed Coronavirus 2019 (COVID-19)- Using Ascorbic Acid and Zinc Su… NCT04377646 Not yet recruiting A Study of Hydroxychloroquine and Zinc in the Prevention of … NCT04447534 Recruiting Zinc With Chloroquine/Hydroxychloroquine in Treatment of COV… 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.
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