Benefits and risks of zinc for adults during covid-19: rapid systematic review and meta-analysis of randomised controlled trials

Objective To evaluate the benefits and risks of any type of zinc intervention to prevent or treat SARS-CoV-2. Design A living, systematic review and meta-analysis, incorporating rapid review methods. Data sources 17 English and Chinese databases and clinical trial registries were searched in April/May 2020, with additional covid-19 focused searches in June and August 2020. Eligibilitycriteria and analysis Randomized control trials (RCTs) published in any language comparing zinc to a control to prevent or treat SARS-CoV-2. Other viral respiratory tract infections (RTIs) were included, but the certainty of evidence downgraded twice for indirectness. Screening, data extraction, risk of bias appraisal (RoB-2 tool) and verification was performed by calibrated, single reviewers. RCTs with adult populations were prioritised for analysis. Results 123 RCTs were identified. None were specific to SARS-CoV-2 nor other coronaviruses. 28 RCTs evaluated oral (15-45mg daily), sublingual (45-300mg daily), or topical nasal (0.09-2.6 mg daily) zinc to prevent or treat nonspecific viral RTIs in 3,597 adults without zinc deficiency. Compared to placebo, zinc prevented 5 mild to moderate RTIs per 100 person-months, including in older adults (95% confidence interval 1 to 9) (number needed to treat (NTT)=20). There was no significant difference in the rates of non-serious adverse events (AE). For RTI treatment, a clinically important reduction in peak symptom severity scores was found for zinc compared to placebo (mean difference 1.2 points, 0.7 to 1.7), but not average daily symptom severity (standardised mean difference 0.2, 0.1 to 0.4). 19 fewer per 100 adults were at risk of remaining symptomatic over the first 7 days (2 to 38, NNT=5) and the mean duration of symptoms was 2 days shorter (0.2 to 3.5), however, there was substantial heterogeneity (I 2 = 82% and 97%). 14 more per 100 experienced a non-serious AE (4 to 16, NNT=7) such as nausea, or mouth or nasal irritation. No differences in illness duration nor AE were found when zinc was compared to active controls. No serious AE, including copper deficiency, were reported by any RCT. Quality of life outcomes were not assessed. Confidence in these findings for SARS-CoV-2 is very low due to serious indirectness and some concerns about bias for most outcomes. Conclusions Zinc is a potential therapeutic candidate for preventing and treating SARS-CoV-2, including older adults and adults without zinc deficiency (very low certainty). Zinc may also help to prevent other viral RTIs during the pandemic (moderate certainty) and reduce the severity and duration of symptoms (very low certainty). The pending results from seven RCTs evaluating zinc for SARS-CoV-2 will be tracked. Systematic review registration PROSPERO CRD42020182044