Zinc for COVID-19: real-time analysis of all 53 studies

A Case-Control Study for the Effectiveness of Oral Zinc in the Prevention and Mitigation of COVID-19

Gordon et al., Frontiers in Medicine, doi:10.3389/fmed.2021.756707 (Peer Reviewed)

Prospective study of zinc supplementation with 104 patients randomized to receive 10mg, 25mg, or 50mg of zinc picolinate daily, and a matched sample of 96 control patients from the adjacent clinic that did not routinely recommend/use zinc, showing significantly lower symptomatic COVID-19 with treatment.

risk of death, 67.6% lower, RR 0.32, p = 0.48, treatment 0 of 104 (0.0%), control 1 of 96 (1.0%), NNT 96, relative risk is not 0 because of continuity correction due to zero events.

risk of symptomatic case, 85.3% lower, RR 0.15, p = 0.02, treatment 2 of 104 (1.9%), control 9 of 96 (9.4%), NNT 13, adjusted, OR converted to RR.

Gordon et al., 12/13/2021, prospective, USA, North America, peer-reviewed, 2 authors.

Effect of a Nutritional Support System to Increase Survival and Reduce Mortality in Patients with COVID-19 in Stage III and Comorbidities: A Blinded Randomized Controlled Clinical Trial

Leal et al., SSRN, doi:10.2139/ssrn.3949424 (Preprint)

80 patient RCT with 40 patients treated with a comprehensive regimen of nutritional support, showing significantly lower mortality with treatment.

Treatment contained cholecalciferol, vitamin C, zinc, spirulina maxima, folic acid, glutamine, vegetable protein, selenium, resveratrol, omega-3 fatty acids, l-arginine, magnesium, probiotics, and B-complex IV. Adherence was strictly monitored. NCT04507867.

risk of death, 85.7% lower, RR 0.14, p = 0.03, treatment 1 of 40 (2.5%), control 7 of 40 (17.5%), NNT 6.7.

risk of mechanical ventilation, 57.1% lower, RR 0.43, p = 0.31, treatment 3 of 40 (7.5%), control 7 of 40 (17.5%), NNT 10.0.

Excluded in after exclusion results of meta analysis: combined treatments may contribute more to the effect seen.

Leal et al., 10/25/2021, Randomized Controlled Trial, Mexico, North America, preprint, 7 authors, 1 September, 2020 - 28 February, 2021, this trial uses multiple treatments in the treatment arm (combined with comprehensive nutritional support) - results of individual treatments may vary.

Low mortality from COVID-19 at a nursing facility in France following a combined preventive and active treatment protocol

Worcel et al., Annals of Palliative Medicine, doi:10.21037/apm-21-1707 (Peer Reviewed)

Report on the relatively low mortality and relatively mild COVID-19 symptoms at a French nursing facility that has adopted several treatments including vitamin D, zinc, anticoagulants, corticosteroids, and a multivitamin.

Worcel et al., 10/12/2021, peer-reviewed, 5 authors.

A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of a Nutritional Supplement (ImmuActive) for COVID-19 Patients

Majeed et al., Evidence-Based Complementary and Alternative Medicine, doi:10.1155/2021/8447545 (Peer Reviewed)

RCT 100 patients in India, 50 treated with ImmuActive (curcumin, andrographolides, resveratrol, zinc, selenium, and piperine), showing improved recovery with treatment.

risk of mechanical ventilation, 66.2% lower, RR 0.34, p = 1.00, treatment 0 of 45 (0.0%), control 1 of 47 (2.1%), NNT 47, relative risk is not 0 because of continuity correction due to zero events.

risk of hospitalization, 79.7% lower, RR 0.20, p = 0.49, treatment 0 of 45 (0.0%), control 2 of 47 (4.3%), NNT 24, relative risk is not 0 because of continuity correction due to zero events.

relative ordinal scale, 43.0% better, RR 0.57, p = 0.004, treatment 45, control 47, day 28.

relative time to improve one unit on ordinal scale, 30.1% lower, relative time 0.70, treatment 45, control 47.

risk of no recovery, 24.6% lower, RR 0.75, p = 0.08, treatment 26 of 45 (57.8%), control 36 of 47 (76.6%), NNT 5.3, day 28.

time to viral-, 5.8% lower, relative time 0.94, p = 0.47, treatment 45, control 47.

Majeed et al., 10/11/2021, Double Blind Randomized Controlled Trial, India, South Asia, peer-reviewed, 4 authors, this trial uses multiple treatments in the treatment arm (combined with curcumin, andrographolides, resveratrol, selenium, and piperine) - results of individual treatments may vary.

Resveratrol and Zinc in the Treatment of Outpatients With COVID-19 – The Reszinate Study - A Phase 1/2 Randomized Clinical Trial Utilizing Home Patient-Obtained Nasal and Saliva Viral Sampling

Kaplan et al., SSRN, 10.2139/ssrn.3934228 (Preprint)

Small RCT of zinc plus resveratrol in COVID-19+ outpatients, not showing significant differences in viral clearance or symptoms. There was a non- statistically significant trend toward more rapid decrease in symptoms in the treatment group. Although the treatment group was older (46.3 vs. 38.5) and had more severe baseline symptoms, they had similar symptomatic recovery by the second week.

risk of mechanical ventilation, 14.3% higher, RR 1.14, p = 1.00, treatment 1 of 14 (7.1%), control 1 of 16 (6.2%).

risk of ICU admission, 14.3% higher, RR 1.14, p = 1.00, treatment 1 of 14 (7.1%), control 1 of 16 (6.2%).

risk of hospitalization, 14.3% higher, RR 1.14, p = 1.00, treatment 1 of 14 (7.1%), control 1 of 16 (6.2%).

Kaplan et al., 10/1/2021, Randomized Controlled Trial, USA, North America, preprint, 12 authors, 21 September, 2020 - 22 January, 2021, this trial uses multiple treatments in the treatment arm (combined with resveratrol) - results of individual treatments may vary.

Course and Survival of COVID-19 Patients with Comorbidities in Relation to the Trace Element Status at Hospital Admission

Laing et al., Nutrients, doi:10.3390/nu13103304 (Peer Reviewed)

Retrospective 79 hospitalized patients in Belgium, showing mortality associated with zinc and selenium deficiency.

risk of death, 79.0% lower, RR 0.21, p = 0.01, high zinc levels 3 of 49 (6.1%), low zinc levels 7 of 24 (29.2%), NNT 4.3.

Laing et al., 9/22/2021, retrospective, Belgium, Europe, peer-reviewed, 11 authors.

Nutritional Immunity, Zinc Sufficiency, and COVID-19 Mortality in Socially Similar European Populations

Singh et al., Frontiers in Immunology, doi:10.3389/fimmu.2021.699389 (Peer Reviewed)

Analysis of zinc sufficiency showing a positive correlation between sufficiency and COVID-19 within European countries.

Unmeasured confounders are likely to be significant, for example the higher sufficiency countries also have significantly higher tourism and international travel on average. This confounder is not mentioned and could more than account for the observation.

Sufficiency levels were relatively high in all countries. Zinc sufficiency estimates were from 2005.

Higher sufficiency countries: Iceland France Ireland Finland UK Switzerland Netherlands Spain Italy Sweden Norway Denmark
Lower sufficiency countries: Portugal Belgium Lithuania Hungary Germany Poland Estonia Czechia Ukraine Bulgaria Slovakia

Singh et al., 9/17/2021, peer-reviewed, 4 authors.

The correlation between serum selenium, zinc, and COVID-19 severity: an observational study

Jahromi et al., BMC Infectious Diseases, doi:10.1186/s12879-021-06617-3 (Peer Reviewed)

Prospective analysis of 84 patients in Iran, showing higher selenium and zinc levels associated with a decrease in serum CRP level. There was no statistically significant association between selenium/zinc levels and disease severity.

Jahromi et al., 9/3/2021, peer-reviewed, 14 authors.

Supplement Usage Pattern in a Group of COVID- 19 Patients in Tehran

Bagheri et al., Journal of Family & Reproductive Health, doi:10.18502/jfrh.v14i3.4668 (Peer Reviewed)

Retrospective 510 patients in Iran, showing lower risk of severity with vitamin D (statistically significant) and zinc (not statistically significant) supplementation. IR.TUMS.VCR.REC.1398.1063.

risk of progression, 60.4% lower, RR 0.40, p = 0.41, treatment 33, control 477, adjusted, multinomial logistic regression, RR approximated with OR.

risk of being in the hospitalized vs. outpatient group, 41.0% lower, RR 0.59, p = 0.37, treatment 4 of 33 (12.1%), control 167 of 477 (35.0%), NNT 4.4, adjusted, OR converted to RR, binary logistic regression.

Bagheri et al., 9/1/2021, retrospective, Iran, Middle East, peer-reviewed, 6 authors.

Serum zinc and copper in people with COVID-19 and zinc supplementation in parenteral nutrition

Arrieta et al., Nutrition, doi:10.1016/j.nut.2021.111467 (Peer Reviewed)

Retrospective 35 COVID-19 patients on parenteral nutrition on Spain, showing serum zinc levels inversely associated with length of hospital stay. There was no signficant association between zinc and mortality (p>0.1, actual results are not provided).

Arrieta et al., 8/31/2021, peer-reviewed, 13 authors.

COVID-19 related treatment and outcomes among COVID-19 ICU patients: A retrospective cohort study

Assiri et al., Journal of Infection and Public Health, doi:10.1016/j.jiph.2021.08.030 (Peer Reviewed)

Retrospective 118 ICU patients in Saudi Arabia showing no significant differences in unadjusted results with zinc, vitamin D, and favipiravir treatment.

risk of death, 80.8% higher, RR 1.81, p = 0.44, treatment 10 of 60 (16.7%), control 4 of 58 (6.9%), OR converted to RR.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Assiri et al., 8/28/2021, retrospective, Saudi Arabia, Middle East, peer-reviewed, 8 authors.

The Association between Vitamin D and Zinc Status and the Progression of Clinical Symptoms among Outpatients Infected with SARS-CoV-2 and Potentially Non-Infected Participants: A Cross-Sectional Study

Golabi et al., Nutrients, doi:10.3390/nu13103368 (preprint 8/26/2021) (Peer Reviewed)

Analysis of vitamin D and zinc levels in 53 PCR+ outpatients and 53 matched controls, showing lower zinc levels in COVID-19 patients, and increased risk of cases and symptoms with vitamin D deficiency. There was no significant difference in the use of supplements between cases and controls. IR.ABADANUMS.REC.1399.073.

Golabi et al., 8/26/2021, peer-reviewed, 10 authors.

Serum trace elements levels and clinical outcomes among Iranian COVID‐19 patients

Pour et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.08.053 (Peer Reviewed)

Prospective analysis of 114 ICU patients and 112 matched non-ICU patients in Iran, showing mortality associated with lower zinc levels. There was no significant difference in zinc levels between ICU and non-ICU patients. IR.TBZMED.REC.1399.711.

Pour et al., 8/25/2021, prospective, Iran, Middle East, peer-reviewed, 7 authors.

Evaluation of the relationship between serum levels of zinc, vitamin B12, vitamin D, and clinical outcomes in patients with COVID-19

Shakeri et al., Journal of Medical Virology, doi:10.1002/jmv.27277 (Peer Reviewed)

Retrospective 293 hospitalized patients in Iran showing lower levels of zinc, vitamin B12, and vitamin D in patients that died, with statistical significance reached only for zinc.

Shakeri et al., 8/18/2021, Iran, Middle East, peer-reviewed, 7 authors.

Characterization of Critically Ill COVID-19 Patients at a Brooklyn Safety-Net Hospital

Capone et al., Cureus, doi:10.7759/cureus.9809 (Peer Reviewed)

Retrospective 102 ICU patients in the USA, 73 receiving vitamin C and zinc, showing a negative correlation of treatment with mortality, but not reaching statistical significance (p = 0.31).

Capone et al., 8/17/2021, USA, North America, peer-reviewed, 11 authors.

Clinical features, demography and predictors of outcomes of SARS-CoV-2 infection in a tertiary care hospital in India - a cohort study

Elavarasi et al., medRxiv, doi:10.1101/2021.08.10.21261855 (Preprint)

Retrospective 2017 hospitalized patients in India, showing lower mortality with zinc treatment.

risk of death, 65.1% lower, RR 0.35, p < 0.001, treatment 486, control 1,201, adjusted, OR converted to RR, model 4, multivariate logistic regression, control prevalence approximated with overall prevalence.

Elavarasi et al., 8/12/2021, retrospective, India, South Asia, preprint, 26 authors.

Identification of drugs associated with reduced severity of COVID-19: A case-control study in a large population

Israel et al., Epidemiology and Global Health Microbiology and Infectious Disease, doi:10.7554/eLife.68165 (Peer Reviewed)

Case control study examining medication usage with a healthcare database in Israel, showing lower risk of hospitalization with calcium + zinc supplements (defined as being picked up within 35 days prior to PCR+), however only 10 patients took the supplements. Other patients may have acquired supplements outside of the healthcare system.

risk of hospitalization, >99.9% lower, RR <0.001, p = 0.04, treatment 0 of 10 (0.0%), control 6,953 of 20,849 (33.3%), NNT 3.0, OR converted to RR, relative risk is not 0 because of continuity correction due to zero events, PCR+, cohort 2.

Excluded in after exclusion results of meta analysis: treatment or control group size extremely small.

Israel et al., 7/27/2021, retrospective, Israel, Middle East, peer-reviewed, 10 authors, this trial uses multiple treatments in the treatment arm (combined with calcium) - results of individual treatments may vary.

Nutritional and lifestyle changes required for minimizing the recovery period in home quarantined COVID-19 patients of Punjab, Pakistan

Rabail et al., Food Science & Nutrition, doi:10.1002/fsn3.2458 (Peer Reviewed)

Survey of 80 recovered COVID-19 patients in Pakistan, showing faster recovery with vitamin C, vitamin D, and zinc supplementation.

Rabail et al., 7/9/2021, peer-reviewed, 11 authors.

20-Week Study of Clinical Outcomes of Over-the-Counter COVID-19 Prophylaxis and Treatment

Margolin et al., Journal of Evidence-Based Integrative Medicine, doi:10.1177/2515690X211026193 (Peer Reviewed)

Retrospective 113 outpatients, 53 (patient choice) treated with zinc, quercetin, vitamin C/D/E, l-lysine, and Quina, showing lower cases with treatment. Results are subject to selection bias and limited information on the groups is provided. See [1].

[1] journals.sagepub.com/doi/full/10.1177/2515690X211058417

risk of case, 94.4% lower, RR 0.06, p = 0.003, treatment 0 of 53 (0.0%), control 9 of 60 (15.0%), NNT 6.7, relative risk is not 0 because of continuity correction due to zero events.

risk of COVID-19 or flu-like illness, 81.1% lower, RR 0.19, p = 0.01, treatment 2 of 53 (3.8%), control 12 of 60 (20.0%), NNT 6.2.

Margolin et al., 7/6/2021, retrospective, USA, North America, peer-reviewed, 5 authors, this trial uses multiple treatments in the treatment arm (combined with quercetin, vitamin C/D/E, l-lysine, and Quina) - results of individual treatments may vary.

The association between serum levels of micronutrients and the severity of disease in patients with COVID-19

Beigmohammadi et al., Nutrition, doi:10.1016/j.nut.2021.111400 (Peer Reviewed)

Retrospective 60 ICU patients in Iran, showing that lower levels of vitamin D, magnesium, and zinc were significantly associated with higher APACHE scores (P = 0.001, 0.028, and <0.001, respectively) and higher lung involvement (P = 0.002, 0.045, and <0.001, respectively).

Beigmohammadi et al., 6/24/2021, retrospective, Iran, Middle East, peer-reviewed, 8 authors.

Clinical Significance of Micronutrient Supplementation in Critically Ill COVID-19 Patients with Severe ARDS

Notz et al., Nutrients, doi:10.3390/nu13062113 (Peer Reviewed)

Retrospective 22 ICU patients, showing most patients had low selenium status biomarkers and low zinc levels, and reporting on treatment with nutrient supplementation including selenium and zinc. Authors conclude that sufficient selenium and zinc levels may be important for an adequate immune response in critically ill patients with severe COVID-19 ARDS.

Notz et al., 6/20/2021, retrospective, Germany, Europe, peer-reviewed, 13 authors.

Zinc2+ ion inhibits SARS-CoV-2 main protease and viral replication in vitro

Panchariya et al., Chemical Communications, doi:10.1039/D1CC03563K (Peer Reviewed) (In Vitro)

In Silico and In Vitro study showing that ionic zinc inhibits SARS-CoV-2 main protease (M^pro) and inhibits viral replication.

Zinc acetate inhibited viral replication in Vero E6 cells, while zinc glycinate and zinc gluconate did not at non-toxic concentrations. The combination of zinc acetate with zinc ionophore quercetin significantly improved inhibition at low concentrations.

Panchariya et al., 6/15/2021, peer-reviewed, 18 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Plasma zinc status and hyperinflammatory syndrome in hospitalized COVID-19 patients: an observational study

Verschelden et al., medRxiv, doi:10.1101/2021.06.09.21258271 (Preprint)

Prospective study of 139 hospitalized COVID-19 patients, showing 96% had zinc deficiency. Higher zinc levels were associated with a shorter length of hospitalization. Mortality and ventilation was lower with higher zinc levels, but not reaching statistical significance.

Verschelden et al., 6/12/2021, preprint, 8 authors.

Evaluation of Zinc Sulfate as an Adjunctive Therapy in COVID-19 Critically Ill Patients: a Two Center Propensity-score Matched Study

Al Sulaiman et al., Critical Care, doi:10.1186/s13054-021-03785-1 (preprint 6/7/2021) (Peer Reviewed)

Retrospective 266 ICU patients showing lower mortality with zinc treatment (very close to statistical significance), and higher odds of acute kidney injury. NRC21R/287/07.

risk of death, 36.0% lower, RR 0.64, p = 0.11, treatment 23 of 82 (28.0%), control 32 of 82 (39.0%), NNT 9.1, adjusted, in-hospital, PSM, multivariable Cox proportional hazards.

risk of death, 48.0% lower, RR 0.52, p = 0.03, treatment 19 of 82 (23.2%), control 31 of 82 (37.8%), NNT 6.8, adjusted, 30 day, PSM, multivariable Cox proportional hazards.

ICU time, 25.0% higher, relative time 1.25, p = 0.28, treatment 82, control 82.

hospitalization time, 6.2% higher, relative time 1.06, p = 0.61, treatment 82, control 82.

Al Sulaiman et al., 6/7/2021, retrospective, propensity score matching, Saudi Arabia, Middle East, peer-reviewed, 10 authors, 1 March, 2020 - 31 March, 2021.

Selenium, zinc, and vitamin D supplementation affect the clinical course of COVID-19 infection in Hashimoto’s thyroiditis

Asimi et al., Endocrine Abstracts, doi:10.1530/endoabs.73.PEP14.2 (Preprint)

Retrospective 356 Hashimoto's thyroiditis outpatients, 270 taking vitamin D, zinc, and selenium, showing significantly lower hospitalization with treatment. Authors adjust for age, gender, BMI, and smoking status, reporting statistically significant associations with p<0.001 for hospitalization and mechanical ventilation, however they do not report the adjusted risks.

risk of mechanical ventilation, 97.4% lower, RR 0.03, p < 0.001, treatment 0 of 270 (0.0%), control 9 of 86 (10.5%), NNT 9.6, relative risk is not 0 because of continuity correction due to zero events, unadjusted.

risk of hospitalization, 99.0% lower, RR 0.010, p < 0.001, treatment 0 of 270 (0.0%), control 24 of 86 (27.9%), NNT 3.6, relative risk is not 0 because of continuity correction due to zero events, unadjusted.

risk of severe case, 99.5% lower, RR 0.005, p < 0.001, treatment 0 of 270 (0.0%), control 51 of 86 (59.3%), NNT 1.7, relative risk is not 0 because of continuity correction due to zero events, unadjusted.

Excluded in after exclusion results of meta analysis: excessive unadjusted differences between groups.

Asimi et al., 5/22/2021, retrospective, Bosnia and Herzegovina, Europe, preprint, 3 authors, this trial uses multiple treatments in the treatment arm (combined with vitamin D and selenium) - results of individual treatments may vary.

Hypozincemia in the early stage of COVID-19 is associated with an increased risk of severe COVID-19

Fromonot et al., Clinical Nutrition, doi:10.1016/j.clnu.2021.04.042 (Peer Reviewed)

Analysis of 240 consecutive patients in France, showing significantly higher zinc deficiency in COVID-19 patients, and significantly greater risk of hospitalization for COVID-19 patients with zinc deficiency. 2020PI087.

risk of hospitalization, 89.2% lower, RR 0.11, p = 0.002, high zinc levels 6 of 110 (5.5%), low zinc levels 7 of 42 (16.7%), NNT 8.9, OR converted to RR, within COVID-19 patients.

risk of case, 27.6% lower, RR 0.72, p = 0.003, high zinc levels 110 of 188 (58.5%), low zinc levels 42 of 52 (80.8%), NNT 4.5.

Fromonot et al., 5/3/2021, prospective, France, Europe, peer-reviewed, 6 authors.

Serum vitamin D, calcium, and zinc levels in patients with COVID-19

Elham et al., Clinical Nutrition ESPEN, doi:10.1016/j.clnesp.2021.03.040 (Peer Reviewed)

Case control study with 93 hospitalized patients in Iran and 186 control patients, showing significantly lower vitamin D, zinc, and calcium levels in cases. IR.SHOUSHTAR.REC.1399.017.

Elham et al., 4/18/2021, retrospective, case control, Iran, Middle East, peer-reviewed, 6 authors.

Serum Zinc, Copper, and Other Biometals Are Associated with COVID-19 Severity Markers

Skalny et al., Metabolites, doi:10.3390/metabo11040244 (Peer Reviewed)

Analysis of serum metal levels in 150 COVID-19 patients and 44 controls, finding that COVID-19 severity was associated with lower serum Ca, Fe, Se, Zn levels when compared to controls.

Skalny et al., 4/15/2021, peer-reviewed, 14 authors.

Positive impact of oral hydroxychloroquine and povidone-iodine throat spray for COVID-19 prophylaxis: an open-label randomized trial

Seet et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.04.035 (Peer Reviewed)

Prophylaxis RCT in Singapore with 3,037 low risk patients, showing lower serious cases, lower symptomatic cases, and lower confirmed cases of COVID-19 with all treatments (ivermectin, HCQ, PVP-I, and Zinc + vitamin C) compared to vitamin C.

Meta-analysis of vitamin C in 6 previous trials shows a benefit of 16%, so the actual benefit of ivermectin, HCQ, and PVP-I may be higher. Cluster RCT with 40 clusters.

There were no hospitalizations and no deaths. NCT04446104.

risk of severe case, 49.7% lower, RR 0.50, p = 0.03, treatment 33 of 634 (5.2%), control 64 of 619 (10.3%), NNT 19.

risk of case, 26.9% lower, RR 0.73, p = 0.03, treatment 300 of 634 (47.3%), control 433 of 619 (70.0%), NNT 4.4, adjusted, OR converted to RR, model 6.

Seet et al., 4/14/2021, Cluster Randomized Controlled Trial, Singapore, Asia, peer-reviewed, 15 authors, this trial compares with another treatment - results may be better when compared to placebo.

COVID-19 severity in relation to sociodemographics and vitamin D use

Abdulateef et al., Open Medicine, doi:10.1515/med-2021-0273 (Peer Reviewed)

Survey of 428 recovered COVID-19 patients in Iraq, showing fewer hospital visits for patients on prophylactic vitamin C or D. Hospitalization was lower for those on vitamin C, D, or zinc, without statistical significance.

risk of hospitalization, 13.1% lower, RR 0.87, p = 0.83, treatment 7 of 111 (6.3%), control 23 of 317 (7.3%), NNT 105, unadjusted.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Abdulateef et al., 4/8/2021, retrospective, Iraq, Middle East, peer-reviewed, 7 authors, July 2020 - August 2020.

Clinical characteristics of hospitalised patients with COVID-19 and the impact on mortality: a single-network, retrospective cohort study from Pennsylvania state

Gadhiya et al., BMJ Open, doi:10.1136/bmjopen-2020-042549 (Peer Reviewed)

Retrospective 283 patients in the USA showing higher mortality with all treatments (not statistically significant). Confounding by indication is likely. In the supplementary appendix, authors note that the treatments were usually given for patients that required oxygen therapy. Oxygen therapy and ICU admission (possibly, the paper includes ICU admission for model 2 in some places but not others) were the only variables indicating severity used in adjustments.

risk of death, 40.9% higher, RR 1.41, p = 0.33, treatment 21 of 54 (38.9%), control 34 of 229 (14.8%), adjusted, OR converted to RR, multivariate logistic regression.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely.

Gadhiya et al., 4/8/2021, retrospective, USA, North America, peer-reviewed, 4 authors.

3219 hospitalised patients with COVID-19 in Southeast Michigan: a retrospective case cohort study

Mulhem et al., BMJ Open, doi:10.1136/bmjopen-2020-042042 (Peer Reviewed)

Retrospective database analysis of 3,219 hospitalized patients in the USA. Very different results in the time period analysis (Table S2), and results significantly different to other studies for the same medications (e.g., heparin OR 3.06 [2.44-3.83]) suggest significant confounding by indication and confounding by time.

risk of death, 45.6% lower, RR 0.54, p < 0.001, treatment 256 of 1,596 (16.0%), control 260 of 1,623 (16.0%), adjusted, OR converted to RR, logistic regression.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely, substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.

Mulhem et al., 4/7/2021, retrospective, database analysis, USA, North America, peer-reviewed, 3 authors.

Risk factors for developing COVID-19: a population-based longitudinal study (COVIDENCE UK)

Holt et al., medRxiv, doi:10.1101/2021.03.27.21254452 (Preprint)

Prospective survey-based study with 15,227 people in the UK, showing lower risk of COVID-19 cases with vitamin A, vitamin D, zinc, selenium, probiotics, and inhaled corticosteroids; and higher risk with metformin and vitamin C. Statistical significance was not reached for any of these. Results are subject to confounding, with only the vitamin D result fully adjusted. NCT04330599. COVIDENCE UK.

risk of case, 6.8% lower, RR 0.93, p = 0.77, treatment 21 of 750 (2.8%), control 425 of 14,477 (2.9%), NNT 737, adjusted, OR converted to RR, minimally adjusted, group sizes approximated.

Excluded in after exclusion results of meta analysis: significant unadjusted confounding possible.

Holt et al., 3/30/2021, prospective, United Kingdom, Europe, preprint, 31 authors, 1 May, 2020 - 5 February, 2021.

Low blood zinc concentrations in patients with poor clinical outcome during SARS-CoV-2 infection: is there a need to supplement with Zinc COVID-19 patients?

Dubourg et al., Journal of Microbiology, Immunology and Infection, doi:10.1016/j.jmii.2021.01.012 (Peer Reviewed)

Retrospective 275 patients showing zinc levels significantly lower in patients with poor outcomes, 840 vs. 970 µg/L, p< 0.0001.

Dubourg et al., 2/13/2021, peer-reviewed, 8 authors.

Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection: The COVID A to Z Randomized Clinical Trial

Thomas et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2021.0369 (Peer Reviewed)

Small 214 low-risk outpatient RCT showing non-statistically significant faster recovery with zinc and with vitamin C. Study performed in the USA where zinc deficiency is relatively uncommon. The zinc dosage is relatively low, 50mg zinc glcuonate (7mg elemental zinc), one tenth of that shown to reduce the duration of colds in other studies [1]. NCT04342728.

[1] patrickholford.com/blog/vitamin-c-speeds-up-covid-recovery

risk of hospitalization, 43.7% higher, RR 1.44, p = 0.72, treatment 5 of 58 (8.6%), control 3 of 50 (6.0%).

recovery time, 11.9% lower, relative time 0.88, p = 0.38, treatment 58, control 50, mean time to a 50% reduction in symptoms.

Thomas et al., 2/12/2021, Randomized Controlled Trial, USA, North America, peer-reviewed, 11 authors.

Deficiency of antioxidants and increased oxidative stress in COVID-19 patients: A cross-sectional comparative study in Jigawa, Northwestern Nigeria

Muhammad et al., SAGE Open Medicine, doi:10.1177/2050312121991246 (Peer Reviewed)

Case control study with 50 symptomatic COVID-19 patients and 21 healthy controls in Nigeria, showing that COVID-19 patients had significantly lower levels of selenium and zinc, and vitamins A, C, and E. Control patients were younger than COVID-19 patients. The p value for zinc in Table 2 appears to be a typo.

Muhammad et al., 2/1/2021, Nigeria, Africa, peer-reviewed, 8 authors.

Olfactory Disturbances as Presenting Manifestation Among Egyptian Patients with COVID-19: Possible Role of Zinc

Abdelmaksoud et al., Biological Trace Element Research, doi:10.1007/s12011-020-02546-5 (Peer Reviewed)

134 COVID-19 patients, 49 treated with zinc, showing faster recovery of olfactory function in patients treated with zinc (median 7 vs. 18 days). There was no difference in overall recovery time. There were 4 deaths but authors do not indicate zinc treatment status. There was no significant difference in zinc levels based on severity. SVU-MED-MBC004-2020-04.

Abdelmaksoud et al., 1/7/2021, peer-reviewed, 9 authors, 1 May, 2020 - 31 August, 2020.

Potential Role of Zinc in the COVID-19 Disease Process and its Probable Impact on Reproduction

Sethuram et al., Reproductive Sciences, doi:10.1007/s43032-020-00400-6 (Review) (Peer Reviewed)

Review of zinc deficiency and supplementation for COVID-19, including potential impacts on reproductive health.

Sethuram et al., 1/7/2021, peer-reviewed, 3 authors.

Zinc against COVID-19? Symptom surveillance and deficiency risk groups

Joachimiak et al., PLOS Neglected Tropical Diseases, doi:10.1371/journal.pntd.0008895 (Review) (Peer Reviewed)

Literature review concluding that zinc should be included as part of preventative supplementation for COVID-19, in general for support of immune health, and should also be considered in the context of zinc deficiency acquired during a viral infection and host immune response.

Joachimiak et al., 1/4/2021, peer-reviewed, 1 author.

Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19)

McCullough et al., Reviews in Cardiovascular Medicine, doi:10.31083/j.rcm.2020.04.264 (Review) (Peer Reviewed)

Review urging early treatment of COVID-19 with sequential multidrug treatment that has been shown to be safe and effective. Proposed treatment includes zinc, vitamin D & C, quercetin, and depending on age, comorbidities, and symptoms may include >=2 of HCQ, ivermectin, favipiravir; AZM/DOXY; corticosteroids; colchicine; bamlanivimab; aspirin; LMWH; and supplemental oxygen.

McCullough et al., 12/30/2020, peer-reviewed, 58 authors.

Association Between Low Zinc Levels and Severity of Acute Respiratory Distress Syndrome by New Coronavirus SARS-CoV-2

Gonçalves et al., Nutrition in Clinical Practice, doi:10.1002/ncp.10612 (Peer Reviewed)

Retrospective 169 ICU patients in Brazil, 214 with low zinc levels, showing an association between low zinc levels and severe ARDS. CAAE 30608,020.9.0000.8114.

risk of severe case, 82.3% lower, RR 0.18, p < 0.001, high zinc levels 7 of 55 (12.7%), low zinc levels 145 of 214 (67.8%), NNT 1.8, adjusted, OR converted to RR, ≥70 μg/dL, logistic regression.

Gonçalves et al., 12/23/2020, retrospective, Brazil, South America, peer-reviewed, 9 authors.

Efficacy of High Dose Vitamin C, Melatonin and Zinc in Iranian Patients with Acute Respiratory Syndrome due to Coronavirus Infection: A Pilot Randomized Trial

Darban et al., Journal of Cellular & Molecular Anesthesia, doi:10.22037/jcma.v6i2.32182 (Peer Reviewed)

Small RCT in Iran with 20 ICU patients, 10 treated with high-dose vitamin C, melatonin, and zinc, not showing significant differences. IRCT20151228025732N52.

risk of progression, 33.3% lower, RR 0.67, p = 1.00, treatment 2 of 10 (20.0%), control 3 of 10 (30.0%), NNT 10.

ICU time, 6.0% lower, relative time 0.94, p = 0.30, treatment 10, control 10.

Darban et al., 12/15/2020, Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 8 authors, this trial uses multiple treatments in the treatment arm (combined with melatonin and vitamin C) - results of individual treatments may vary.

Modest effects of dietary supplements during the COVID-19 pandemic: insights from 445 850 users of the COVID-19 Symptom Study app

Louca et al., BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2021-000250 (preprint 11/30/20) (Peer Reviewed)

Survey analysis of dietary supplements showing no significant difference in PCR+ cases with zinc usage. These results are for PCR+ cases only, they do not reflect potential benefits for reducing the severity of cases. A number of biases could affect the results, for example users of the app may not be representative of the general population, and people experiencing symptoms may be more likely to install and use the app.

risk of case, 0.9% lower, RR 0.99, p = 0.80, OR converted to RR, United Kingdom, all adjustment model.

Louca et al., 11/30/2020, retrospective, United Kingdom, Europe, peer-reviewed, 26 authors.

Do Zinc Supplements Enhance the Clinical Efficacy of Hydroxychloroquine?: a Randomized, Multicenter Trial

Abd-Elsalam et al., Biological Trace Element Research, doi:10.1007/s12011-020-02512-1 (Peer Reviewed)

191 patient RCT in Egypt comparing the addition of zinc to HCQ, not showing a significant difference.

Clinical recovery at 28 days was 79.2% in the zinc group and 77.9% control, p = 0.969.

Mechanical ventilation was used with 4 patients in the zinc group and 6 control. There were 5 deaths in each group.

No information on baseline zinc values was recorded. We note that Egypt has a low rate of zinc deficiency so supplementation is less likely to be helpful in Egypt [1, 2]

[1] ncbi.nlm.nih.gov/pmc/articles/PMC3510072/

[2] ncbi.nlm.nih.gov/pmc/articles/PMC3510072/bin/pone.0050568.s003.xls

risk of death, 1.0% lower, RR 0.99, p = 0.99, treatment 5 of 96 (5.2%), control 5 of 95 (5.3%), NNT 1824.

risk of mechanical ventilation, 34.0% lower, RR 0.66, p = 0.54, treatment 4 of 96 (4.2%), control 6 of 95 (6.3%), NNT 47.

risk of no recovery, 5.8% lower, RR 0.94, p = 0.97, treatment 20 of 96 (20.8%), control 21 of 95 (22.1%), NNT 79.

hospitalization time, 3.6% lower, relative time 0.96, p = 0.55, treatment 96, control 95.

Abd-Elsalam et al., 11/29/2020, Randomized Controlled Trial, Egypt, Africa, peer-reviewed, 10 authors.

Zinc and SARS‑CoV‑2: A molecular modeling study of Zn interactions with RNA‑dependent RNA‑polymerase and 3C‑like proteinase enzymes

Pormohammad et al., International Journal of Molecular Medicine, doi:10.3892/ijmm.2020.4790 (Peer Reviewed)

In Silico analysis supporting the hypothesis that Zn would bind and regulate the enzymatic activities of 3CL^pro and RdRp of SARS‑CoV-2 and therefore inhibit viral replication. Since Zn has established immune health benefits, is readily available, inexpensive and safe, the authors propose that Zn could help ameliorate COVID-19.

Pormohammad et al., 11/18/2020, peer-reviewed, 3 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Treatment with Zinc is Associated with Reduced In-Hospital Mortality Among COVID-19 Patients: A Multi-Center Cohort Study

Frontera et al., Research Square, doi:10.21203/rs.3.rs-94509/v1 (Preprint)

Retrospective 3,473 hospitalized patients showing 37% lower mortality with HCQ+zinc.

PSM aHR 0.63, p=0.015
regression aHR 0.76, p = 0.023

risk of death, 37.0% lower, RR 0.63, p = 0.01, treatment 121 of 1,006 (12.0%), control 424 of 2,467 (17.2%), NNT 19, adjusted, PSM.

risk of death, 24.0% lower, RR 0.76, p = 0.02, treatment 121 of 1,006 (12.0%), control 424 of 2,467 (17.2%), NNT 19, adjusted, regression.

Frontera et al., 10/26/2020, retrospective, propensity score matching, USA, North America, preprint, median age 64.0, 14 authors, this trial uses multiple treatments in the treatment arm (combined with HCQ) - results of individual treatments may vary.

Low Levels of Few Micronutrients May Impact COVID-19 Disease Progression: An Observational Study on the First Wave

Tomasa-Irriguible et al., Metabolites, doi:10.3390/metabo11090565 (preprint 10/26/2020) (Peer Reviewed)

Retrospective 120 hospitalized patients in Spain showing zinc deficiency associated with higher ICU admission.

risk of mechanical ventilation, 49.3% lower, RR 0.51, p = 0.06, high zinc levels 7 of 31 (22.6%), low zinc levels 49 of 89 (55.1%), NNT 3.1, adjusted, OR converted to RR, ≥84 mcg/dL, multivariate logistic regression.

risk of ICU admission, 52.0% lower, RR 0.48, p = 0.02, high zinc levels 9 of 31 (29.0%), low zinc levels 55 of 89 (61.8%), NNT 3.1, adjusted, OR converted to RR, ≥84 mcg/dL, multivariate logistic regression, final model.

Tomasa-Irriguible et al., 10/26/2020, retrospective, Spain, Europe, peer-reviewed, 7 authors.

Prediction of Survival Odds in COVID-19 by Zinc, Age and Selenoprotein P as Composite Biomarker

Heller et al., Redox Biology, doi:10.1016/j.redox.2020.101764 (Peer Reviewed)

Analysis of 35 COVID-19 patients showing a significant correlation for serum zinc levels between COVID-19 patients and controls, and between COVID-19 survivors and non-survivors.

Heller et al., 10/20/2020, peer-reviewed, 14 authors.

Low Zinc Levels at Admission Associates with Poor Clinical Outcomes in SARS-CoV-2 Infection

Vogel-González et al., Nutrients, doi:10.3390/nu13020562 (preprint 10/11/2020) (Peer Reviewed)

Retrospective 249 PCR+ hospitalized patients in Spain, 58 with zinc levels on admission <50 μg/dL, showing higher mortality and ICU admission, and slower recovery with low zinc levels.

risk of death, 77.2% lower, RR 0.23, p < 0.001, high zinc levels 9 of 191 (4.7%), low zinc levels 12 of 58 (20.7%), NNT 6.3, ≥50 μg/dL.

risk of ICU admission, 71.3% lower, RR 0.29, p < 0.001, high zinc levels 34 of 191 (17.8%), low zinc levels 36 of 58 (62.1%), NNT 2.3, ≥50 μg/dL.

recovery time, 68.0% lower, relative time 0.32, p < 0.001, high zinc levels 191, low zinc levels 58, ≥50 μg/dL.

Vogel-González et al., 10/11/2020, retrospective, Spain, Europe, peer-reviewed, 16 authors.

COVID-19: Poor outcomes in patients with zinc deficiency

Jothimani (Peer Reviewed)

Prospective study of zinc levels in 47 hospitalized COVID-19 patients and 45 healthy controls. COVID-19 patients had significantly lower zinc levels (74.5 vs. 105.8 median μg/dl, p < 0.001). 57.4% of COVID-19 patients were zinc deficient, and they had higher rates of complications, ARDS, prolonged hospital stay, and increased mortality.

risk of death, 89.7% lower, RR 0.10, p = 0.06, high zinc levels 0 of 20 (0.0%), low zinc levels 5 of 27 (18.5%), NNT 5.4, relative risk is not 0 because of continuity correction due to zero events.

risk of ICU admission, 92.4% lower, RR 0.08, p = 0.02, high zinc levels 0 of 20 (0.0%), low zinc levels 7 of 27 (25.9%), NNT 3.9, relative risk is not 0 because of continuity correction due to zero events.

Jothimani et al., 9/10/2020, prospective, India, South Asia, peer-reviewed, 11 authors.

Analysis of the predictive factors for a critical illness of COVID-19 during treatment － relationship between serum zinc level and critical illness of COVID-19

Yasui et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.09.008 (Peer Reviewed)

Retrospective 62 hospitalized patients, 29 with serum zinc data, showing significantly lower serum zinc levels for severe COVID-19 cases (intubation) compared with mild and moderate cases, p = 0.005. Authors recommend zinc supplementation.

risk of mechanical ventilation, 92.5% lower, RR 0.08, p = 0.001, high zinc levels 1 of 20 (5.0%), low zinc levels 6 of 9 (66.7%), NNT 1.6, zinc >= 70μg/dL.

Yasui et al., 9/7/2020, retrospective, Japan, Asia, peer-reviewed, 10 authors.

The Minimal Effect of Zinc on the Survival of Hospitalized Patients With COVID-19

Yao et al., Chest, doi:10.1016/j.chest.2020.06.082 (Peer Reviewed)

Retrospective 242 hospitalized patients in the USA showing adjusted hazard ratio for zinc treatment, aHR 0.66 [0.41-1.07]. [1] notes that the study would be more informative if baseline serum zinc levels were known.

[1] ncbi.nlm.nih.gov/pmc/articles/PMC7836617/

risk of death, 34.0% lower, RR 0.66, p = 0.09, treatment 73 of 196 (37.2%), control 21 of 46 (45.7%), NNT 12, adjusted, multivariate Cox regression.

Yao et al., 7/22/2020, retrospective, USA, North America, peer-reviewed, 9 authors.

Clinical comorbidities, characteristics, and outcomes of mechanically ventilated patients in the State of Michigan with SARS-CoV-2 pneumonia

Krishnan et al., J Clin Anesth., doi:10.1016/j.jclinane.2020.110005 (Peer Reviewed)

Retrospective 152 mechanically ventilated patients in the USA showing unadjusted lower mortality with vitamin C, vitamin D, HCQ, and zinc treatment, statistically significant only for vitamin C.

risk of death, 17.6% lower, RR 0.82, p = 0.18, treatment 31 of 58 (53.4%), control 61 of 94 (64.9%), NNT 8.7.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Krishnan et al., 7/20/2020, retrospective, USA, North America, peer-reviewed, 13 authors.

COVID-19 Outpatients – Early Risk-Stratified Treatment with Zinc Plus Low Dose Hydroxychloroquine and Azithromycin: A Retrospective Case Series Study

Derwand et al., International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2020.106214 (preprint 7/3) (Peer Reviewed)

79% lower mortality and 82% lower hospitalization with early HCQ+AZ+Z. Retrospective 518 patients (141 treated, 377 control).

risk of death, 79.4% lower, RR 0.21, p = 0.12, treatment 1 of 141 (0.7%), control 13 of 377 (3.4%), NNT 37, OR converted to RR.

risk of hospitalization, 81.6% lower, RR 0.18, p < 0.001, treatment 4 of 141 (2.8%), control 58 of 377 (15.4%), NNT 8.0, OR converted to RR.

Derwand et al., 7/3/2020, retrospective, USA, North America, peer-reviewed, 3 authors, this trial uses multiple treatments in the treatment arm (combined with HCQ and azithromycin) - results of individual treatments may vary.

Treatment of SARS-CoV-2 with high dose oral zinc salts: A report on four patients

Finzi et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.06.006 (Peer Reviewed)

Case report on 4 patients treated with high dose zinc. All patients experienced significant improvement after one day.

Finzi et al., 6/6/2020, peer-reviewed, 1 author.

Zinc sulfate in combination with a zinc ionophore may improve outcomes in hospitalized COVID-19 patients

Carlucci et al., J. Med. Microbiol., Sep 15, 2020, doi: 10.1099/jmm.0.001250 (preprint 5/8) (Peer Reviewed)

Retrospective 932 patients showing that the addition of zinc to HCQ+AZ reduced mortality / transfer to hospice, ICU admission, and the need for ventilation.

risk of death/hospice, 37.7% lower, RR 0.62, p = 0.002, treatment 54 of 411 (13.1%), control 119 of 521 (22.8%), NNT 10, adjusted, OR converted to RR, multivariate logistic regression.

risk of mechanical ventilation, 18.0% lower, RR 0.82, p = 0.40, treatment 29 of 411 (7.1%), control 62 of 521 (11.9%), NNT 21, adjusted, OR converted to RR, multivariate logistic regression.

risk of ICU admission, 23.5% lower, RR 0.77, p = 0.17, treatment 38 of 411 (9.2%), control 82 of 521 (15.7%), NNT 15, adjusted, OR converted to RR, multivariate logistic regression.

Carlucci et al., 5/8/2020, retrospective, USA, North America, peer-reviewed, 6 authors.

Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture

te Velthuis et al., PLOS Pathogens 2010, 6:11, doi:10.1371/journal.ppat.1001176 (Peer Reviewed) (In Vitro)

Shows that the combination of Zn2+ and a zinc ionophore (pyrithione) at low concentrations inhibits the replication of SARS-CoV and equine arteritis virus (EAV) in cell culture. Recommends further study of the use of zinc-ionophores as antiviral compounds.

te Velthuis et al., 1/1/2010, peer-reviewed, 6 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Antiandrogens	(meta)	Metformin	(meta)
Aspirin	(meta)	Molnupiravir	(meta)
Bamlanivimab	(meta)	Nigella Sativa	(meta)
Bromhexine	(meta)	Nitazoxanide	(meta)
Budesonide	(meta)	Paxlovid	(meta)
Casirivimab/i..	(meta)	Povidone-Iod..	(meta)
Colchicine	(meta)	Probiotics	(meta)
Conv. Plasma	(meta)	Proxalutamide	(meta)
Curcumin	(meta)	Quercetin	(meta)
Favipiravir	(meta)	Remdesivir	(meta)
Fluvoxamine	(meta)	Sotrovimab	(meta)
Hydroxychlor..	(meta)	Vitamin A	(meta)
Iota-carragee..	(meta)	Vitamin C	(meta)
Ivermectin	(meta)	Vitamin D	(meta)
Melatonin	(meta)	Zinc	(meta)

Other Treatments		Global Adoption