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

Objective 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

Rapid review protocol : zinc for the prevention or treatment of COVID-19 and other coronavirus-related respiratory tract infections

Background: The global COVID-19 pandemic has prompted an urgent search for effective interventions. SARS-CoV-2 mortality/morbidity risk increases with age and for those chronic disease co-morbidities, both of which are associated with lower zinc status, as is the risk of infection. Methods: Rapid review methods will be applied to a systematic review of zinc for the prevention or treatment of SARS-CoV-2 and viral respiratory tract infections in humans. Included are published studies reporting randomised and quasi-randomised controlled trials that compare zinc intervention to placebo and/or other comparator interventions. English and Chinese language databases will be searched for primary studies of viral respiratory tract infections and clinical trial registries for SARS-CoV-2 infections. Due to concerns about indirectness, studies evaluating non-SARS-CoV-2 coronavirus infections will be rated down by one level, and non-specific or confirmed non-coronavirus viral infections will be rated down by two levels. Review constraints include (1) using Google translate when screening articles published in languages other than English or Chinese and limited translation (2) following calibration, only one reviewer will screen articles, extract data, appraise quality and conduct the analysis, (3) prioritising data extraction and meta-analyses of SARS-CoV-2 studies and critical outcomes of other viral infections, followed by high risk groups and (4) reporting important preliminary findings prior to peer review if necessary. Discussion: The application of these rapid review methods and broadening the inclusion criteria to include other coronavirus-related viral respiratory tract infections aims to enable a timely evidence appraisal of priority research questions and dissemination of results. Study registration: PROSPERO CRD42020182044

Choose your shortcuts wisely : COVID-19 rapid reviews of traditional, complementary and integrative medicine

Background: The COVID-19 pandemic has led to an explosion of rapid reviews geared towards providing time sensitive answers for clinical and policy decision-makers. Rapid reviews (RRs) strike a balance between rigour and rapidity to minimise bias and optimise transparency within specified constraints. Methods: This review article appraised the methods and reporting standards of a convenience sample of RR protocols and RRs of COVID-19 clinical management questions, published in the first six-months of 2020. Inclusion criteria were all RR protocols evaluating traditional, complementary, and integrative medicine (TCIM) registered on PROSPERO, and all RRs indexed on PubMed or published on the Oxford COVID-19 Evidence Service. A purpose-specific 9-item reporting checklist reflecting recommended minimum requirements for RRs was applied. Findings were synthesised and narrated in the context of methodological considerations for conducting and reporting RRs of TCIM. Results: Included studies were five RR protocols of TCIM and 16 RRs, of which five considered TCIM. Wide variations in RR methods were proposed or applied, as were the reporting standards. All five RRs that evaluated TCIM had the lowest reporting standards that limited reproducibility and transparency. Despite accepted recommendations, most RRs did not publish a protocol. Conclusions: We propose that specific research disciplines, such as TCIM, have a uniqueness that may lead to unacceptable outputs if minimum methodological standards are not applied. The recommended minimum requirements will optimise the credibility of rapid reviews of TCIM and limit the risk of prematurely disregarding a potentially effective intervention

Zinc for the prevention and treatment of SARS-CoV-2 and other acute viral respiratory infections : a rapid review

Background: The global COVID-19 pandemic has prompted an urgent search for interventions to prevent and treat SARS-CoV-2. Higher risk of infection and adverse outcomes coincide with populations with chronic diseases and elderly who are at risk of zinc deficiency. Through several mechanisms zinc may prevent, reduce severity and duration of symptoms. Method: An a priori protocol was registered with PROSPERO on 27th April 2020 (CRD42020182044). Eight databases (one Chinese) and four clinical trial registries (one Chinese) were searched for randomised and quasi-randomised controlled trials (RCTs), evaluating single or adjunct zinc against placebo or active controls, for prevention and/or treatment of SARS-CoV-2, other coronaviruses or related infections. RR constraints included not searching bibliographies or contacting authors, single reviewers with calibration and second reviewer checking, meta-analyses and quality appraisal of critical and study primary outcomes only and reporting results as they became available. Results: 118 publications of 1,627 records met the inclusion criteria (35 Chinese and 83 English publications), 32 for prevention, 78 for treatment and 8 for both. Four RCTs specific to SARS-CoV-2 are ongoing; two are investigating zinc for prevention and two for treatment. As of 7 July 2020, no results were available. A wide range of zinc forms, including nasal spray/gel, lozenges, liquid, tablets and intramuscular were investigated. Conclusion: Currently, indirect evidence suggests zinc may potentially reduce the risk, duration and severity of SARS-CoV-2 infections, particularly for populations at risk of zinc deficiency including people with chronic disease co-morbidities and older adults. Direct evidence to determine if zinc is effective for either prevention or treatment of SARS-CoV-2 is pending. In the interim, assessing zinc status of people with chronic diseases and older adults, as part of a SARS-CoV-2 clinical work-up, is reasonable as both groups have a higher risk of zinc deficiency/insufficiency and poorer outcomes from SARS-CoV-2

Efficacy and safety of low and very low carbohydrate diets for type 2 diabetes remission : systematic review and meta-analysis of published and unpublished randomized trial data

OBJECTIVE: To determine the efficacy and safety of low carbohydrate diets (LCDs) and very low carbohydrate diets (VLCDs) for people with type 2 diabetes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Searches of CENTRAL, Medline, Embase, CINAHL, CAB, and grey literature sources from inception to 25 August 2020. STUDY SELECTION: Randomized clinical trials evaluating LCDs (<130 g/day or <26% of a 2000 kcal/day diet) and VLCDs (<10% calories from carbohydrates) for at least 12 weeks in adults with type 2 diabetes were eligible. DATA EXTRACTION: Primary outcomes were remission of diabetes (HbA1c <6.5% or fasting glucose <7.0 mmol/L, with or without the use of diabetes medication), weight loss, HbA1c, fasting glucose, and adverse events. Secondary outcomes included health related quality of life and biochemical laboratory data. All articles and outcomes were independently screened, extracted, and assessed for risk of bias and GRADE certainty of evidence at six and 12 month follow-up. Risk estimates and 95% confidence intervals were calculated using random effects meta-analysis. Outcomes were assessed according to a priori determined minimal important differences to determine clinical importance, and heterogeneity was investigated on the basis of risk of bias and seven a priori subgroups. Any subgroup effects with a statistically significant test of interaction were subjected to a five point credibility checklist. RESULTS: Searches identified 14 759 citations yielding 23 trials (1357 participants), and 40.6% of outcomes were judged to be at low risk of bias. At six months, compared with control diets, LCDs achieved higher rates of diabetes remission (defined as HbA1c <6.5%) (76/133 (57%) v 41/131 (31%); risk difference 0.32, 95% confidence interval 0.17 to 0.47; 8 studies, n=264, I2=58%). Conversely, smaller, non-significant effect sizes occurred when a remission definition of HbA1c <6.5% without medication was used. Subgroup assessments determined as meeting credibility criteria indicated that remission with LCDs markedly decreased in studies that included patients using insulin. At 12 months, data on remission were sparse, ranging from a small effect to a trivial increased risk of diabetes. Large clinically important improvements were seen in weight loss, triglycerides, and insulin sensitivity at six months, which diminished at 12 months. On the basis of subgroup assessments deemed credible, VLCDs were less effective than less restrictive LCDs for weight loss at six months. However, this effect was explained by diet adherence. That is, among highly adherent patients on VLCDs, a clinically important reduction in weight was seen compared with studies with less adherent patients on VLCDs. Participants experienced no significant difference in quality of life at six months but did experience clinically important, but not statistically significant, worsening of quality of life and low density lipoprotein cholesterol at 12 months. Otherwise, no significant or clinically important between group differences were found in terms of adverse events or blood lipids at six and 12 months. CONCLUSIONS: On the basis of moderate to low certainty evidence, patients adhering to an LCD for six months may experience remission of diabetes without adverse consequences. Limitations include continued debate around what constitutes remission of diabetes, as well as the efficacy, safety, and dietary satisfaction of longer term LCDs. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020161795