Zinc and selenium supplementation in COVID-19 prevention and treatment: a systematic review of the experimental studies

Background and aim: The COVID-19 pandemic has severely affected the world's population in the last two years. Along with non-pharmacological public health interventions, major efforts have also been made to identify effective drugs or active substances for COVID-19 prevention and treatment. These include, among many others, the trace elements zinc and selenium, based on laboratory studies and some observational human studies. However, both of these study designs are not adequate to identify and approve treatments in human medicine, and experimental studies in the form of randomized controlled trials are needed to demonstrate the effectiveness and the safety of any interventions. Methods: We undertook a systematic review in which we searched for published and unpublished clinical trials using zinc or selenium supplementation to treat or prevent COVID-19 in the Pubmed, Scopus and ClinicalTrials databases up to 10 January 2022. Results: Amongst the published studies, we did not find any trial with selenium, whereas we retrieved four eligible randomized clinical trials using zinc supplementation, only one of which was double-blind. One of these trials looked at the effect of the intervention on the rate of new SARS-CoV-2 infections, and three at the COVID-19 clinical outcome in already infected individuals. The study populations of the four trials were very heterogeneous, ranging from uninfected individuals to those hospitalized for COVID-19. Only two studies investigated zinc alone in the intervention arm with no differences in the endpoints. The other two studies examined zinc in association with one or more drugs and supplements in the intervention arm, therefore making it impossible to disentangle any specific effects of the element. In addition, we identified 22 unpublished ongoing clinical trials, 19 on zinc, one on selenium and two on both elements. Conclusion: No trials investigated the effect of selenium supplementation on COVID-19, while the very few studies on the effects of zinc supplementation did not confirm efficacy. Therefore, preventive or therapeutic interventions against COVID-19 based on zinc or selenium supplementation are currently unjustified, although when the results of the on-going studies are published, this may change our conclusion