Zinc for COVID-19: real-time analysis of all 81 studies

Zinc for COVID-19: real-time meta analysis of 43 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for mortality, ventilation, hospitalization, progression, and viral clearance. 13 studies from 13 independent teams in 7 different countries show statistically significant improvements in isolation (9 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 29% [16‑39%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, similar for peer-reviewed studies, and similar after excluding studies using combined treatment. Early treatment is more effective than late treatment.

• Sufficiency studies, analyzing outcomes based on serum levels, show 74% [60‑84%] improvement for patients with higher zinc levels (10 studies).

• Results are robust — in exclusion sensitivity analysis 12 of 33 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.

• 7 studies use combined treatments. When excluding those studies, the pooled improvement is 24% [11‑35%] compared to 29% [16‑39%].

• Early treatment results are dominated by [Thomas], however this study used a low dose and was conducted in a location with low levels of zinc deficiency.

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 9% of zinc studies show zero events in the treatment arm. Multiple treatments are typically used in combination, and other treatments are more effective.

• No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used. Denying the efficacy of treatments increases mortality, morbidity, collateral damage, and endemic risk.

• All data to reproduce this paper and sources are in the appendix.

[Tabatabaeizadeh] present another meta analysis for zinc, showing significant improvement for mortality.

Covid Analysis et al., 8/16/2022, preprint, 1 author.

Association of Trace Element Status in COVID-19 Patients with Disease Severity

Bego et al., Journal of Trace Elements in Medicine and Biology, doi:10.1016/j.jtemb.2022.127055

Analysis of 210 hospitalized patients in Bosnia and Herzegovina with serum levels measured on admission, showing significantly lower zinc and selenium levels in patients that died or had severe cases, compared to mild cases.

Bego et al., 8/4/2022, Bosnia and Herzegovina, peer-reviewed, 10 authors, study period January 2021 - July 2021.

Evaluating the efficacy and safety of a novel prophylactic nasal spray in the prevention of SARS-CoV-2 infection: A multi-centre, double blind, placebo-controlled, randomised trial.

Balmforth et al., Journal of Clinical Virology, doi:10.1016/j.jcv.2022.105248

648 patient RCT pHOXWELL nasal spray in India, showing significantly lower IgGS+ and significantly lower symptomatic cases with treatment.

pHOXWELL includes a combination of natural virucidal agents and is designed to mimic the fluid surrounding healthy cells. The spray included xylitol, zinc chloride, polyethylene glycol 400, poloxamer, disodium hydrogen phosphate, sodium chloride, hydroxypropyl methylcellulose, ginger oil, eucalyptus oil, basil oil, clove oil, sodium hydrogen carbonate, potassium dihydrogen phosphate, ethylenediaminetetraacetic acid, sodium hyaluronate, calcium chloride dihydrate, benzalkonium chloride, magnesium chloride hexahydrate, potassium chloride, and glycerol. The spray was administered up to three times per day (TID) 140 μl/nostril for 45 days, with a gap of 6-8 hours between doses.

risk of symptomatic case, 47.4% lower, RR 0.53, p < 0.001, treatment 57 of 275 (20.7%), control 112 of 281 (39.9%), NNT 5.2, OR converted to RR.

risk of IgG positive, 62.7% lower, RR 0.37, p < 0.001, treatment 36 of 275 (13.1%), control 97 of 281 (34.5%), NNT 4.7, adjusted, OR converted to RR, multivariable.

Excluded in meta analysis: combined treatments may contribute more to the effect seen.

Balmforth et al., 7/25/2022, Double Blind Randomized Controlled Trial, placebo-controlled, India, peer-reviewed, 15 authors, study period April 2021 - July 2021, this trial uses multiple treatments in the treatment arm (combined with multiple treatments) - results of individual treatments may vary, trial CTRI/2021/04/032989.

Factors Associated with Length of Hospital Stay among COVID-19 Patients in Saudi Arabia: A Retrospective Study during the First Pandemic Wave

Alahmari et al., Healthcare, doi:10.3390/healthcare10071201

Retrospective 977 hospitalized patients in Saudi Arabia, showing significantly shorter hospitalization with zinc treatment.

hospitalization time, 30.2% lower, relative time 0.70, p < 0.001, treatment mean 6.39 (±0.76) n=130, control mean 9.15 (±0.27) n=847.

Alahmari et al., 6/27/2022, retrospective, Saudi Arabia, peer-reviewed, 7 authors, study period 1 May, 2020 - 30 July, 2020.

COVID-19 prophylaxis with Doxycycline and Zinc in Health Care Workers: A prospective randomized double-blind clinical tria

Stambouli et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2022.06.016

Prophylaxis RCT with 59 zinc + doxycycline, 56 doxycycline, and 57 placebo healthcare workers, showing lower symptomatic cases and significantly improved Ct values with the addition of zinc to doxycycline treatment. Doxycycline 100mg/day and zinc 15 mg/day.

risk of symptomatic case, 68.4% lower, RR 0.32, p = 0.36, treatment 1 of 59 (1.7%), control 3 of 56 (5.4%), NNT 27, zinc + doxycycline vs. doxycycline.

risk of case, 5.1% lower, RR 0.95, p = 1.00, treatment 5 of 59 (8.5%), control 5 of 56 (8.9%), NNT 220, zinc + doxycycline vs. doxycycline.

relative Ct values, 21.4% better, RR 0.79, p < 0.001, treatment mean 29.0 (±1.3) n=59, control mean 22.8 (±4.0) n=56, zinc + doxycycline vs. doxycycline.

Stambouli et al., 6/17/2022, Double Blind Randomized Controlled Trial, placebo-controlled, Tunisia, peer-reviewed, 22 authors, study period 12 November, 2020 - 10 February, 2021, trial NCT04584567 (history).

Efficacy and Safety of Aspirin, Promethazine, and Micronutrients for Rapid Clinical Recovery in Mild to Moderate COVID-19 Patients: A Randomized Controlled Clinical Trial

Kumar et al., Cureus, doi:10.7759/cureus.25467

RCT 260 patients in India, 130 treated with aspirin, promethazine, vitamin C, D, B3, zinc, and selenium, showing faster recovery with treatment. There was no hospitalization, ICU admission, or supplemental oxygen requirements in either group.

risk of no recovery, 89.2% lower, RR 0.11, p = 0.05, treatment 0 of 99 (0.0%), control 4 of 93 (4.3%), NNT 23, relative risk is not 0 because of continuity correction due to zero events, day 10, dyspnea.

risk of no recovery, 95.4% lower, RR 0.05, p < 0.001, treatment 0 of 99 (0.0%), control 10 of 93 (10.8%), NNT 9.3, relative risk is not 0 because of continuity correction due to zero events, day 10, anosmia.

risk of no recovery, 94.3% lower, RR 0.06, p = 0.003, treatment 0 of 99 (0.0%), control 8 of 93 (8.6%), NNT 12, relative risk is not 0 because of continuity correction due to zero events, day 10, fatigue.

risk of no recovery, 387.9% higher, RR 4.88, p = 0.50, treatment 2 of 99 (2.0%), control 0 of 93 (0.0%), continuity correction due to zero event, day 10, myalgia.

risk of no recovery, 193.9% higher, RR 2.94, p = 1.00, treatment 1 of 99 (1.0%), control 0 of 93 (0.0%), continuity correction due to zero event, day 10, headache.

risk of no recovery, 8.5% lower, RR 0.91, p = 0.66, treatment 37 of 99 (37.4%), control 38 of 93 (40.9%), NNT 29, day 10, cough.

Kumar et al., 5/30/2022, Randomized Controlled Trial, India, peer-reviewed, mean age 36.0, 8 authors, study period December 2021 - February 2022, this trial uses multiple treatments in the treatment arm (combined with aspirin, promethazine, vitamin C, D, B3, and selenium) - results of individual treatments may vary, trial CTRI/2021/06/034254.

Suboptimal Consumption of Relevant Immune System Micronutrients Is Associated with a Worse Impact of COVID-19 in Spanish Populations

Galmés et al., Nutrients, doi:10.3390/nu14112254

Ecological study in Spain, showing lower intake of vitamin D, A, B9, and zinc in regions with the highest COVID-19 incidence and mortality.

Vitamin D intake was associated with lower prevalence, incidence, and a combined incidence+mortality index. Vitamin A intake was correlated with lower incidence, ∆incidence, and combined incidence+mortality, while not reaching statistical significance (p = 0.09, 0.07, 0.06). Vitamin B9, B12, and zinc were associated with lower ∆incidence.

Authors analyze 10 vitamins and minerals endorsed by the European Food Safety Authority (EFSA) as having sufficient evidence for a causal relationship between intake and optimal immune system function: vitamins D, A, C, B6, B9, B12, zinc, copper, iron, and selenium.

The intake of all 10 showed an inverse correlation with ∆incidence and combined incidence+mortality (statistically significant only as shown).

Galmés et al., 5/27/2022, Spain, peer-reviewed, 3 authors.

Zinc supplementation and COVID-19 mortality: a meta-analysis

Tabatabaeizadeh, S., European Journal of Medical Research, doi:10.1186/s40001-022-00694-z

Meta analysis of five zinc treatment studies for COVID-19, showing significantly lower mortality.

risk of death, 43.0% lower, OR 0.57, p < 0.001, RR approximated with OR.

Tabatabaeizadeh et al., 5/23/2022, peer-reviewed, 1 author.

Survival analysis based on body mass index in patients with Covid-19 admitted to the intensive care unit of Amir Al-Momenin Hospital in Arak – 2021

Zangeneh et al., Obesity Medicine, doi:10.1016/j.obmed.2022.100420

Retrospective 193 ICU patients in Iran, showing no significant difference with zinc treatment.

risk of death, 21.0% higher, HR 1.21, p = 0.66, Cox proportional hazards.

Zangeneh et al., 5/13/2022, retrospective, Iran, peer-reviewed, 3 authors.

Prevalence of Micronutrient Deficiencies in Patients Hospitalized with COVID-19: An Observational Cohort Study

Voelkle et al., Nutrients, doi:10.3390/nu14091862

Prospective study of 57 consecutive hospitalized COVID-19 patients in Switzerland, showing higher risk of mortality/ICU admission with vitamin A, vitamin D, and zinc deficiency, with statistical significance only for vitamin A and zinc. Adjustments only considered age.

risk of death/ICU, 77.1% lower, RR 0.23, p = 0.007, high zinc levels 5 of 35 (14.3%), low zinc levels 10 of 22 (45.5%), NNT 3.2, adjusted, inverted to make RR<1 favor high zinc levels, OR converted to RR.

Voelkle et al., 4/30/2022, prospective, Switzerland, peer-reviewed, median age 67.0, 9 authors, study period 17 March, 2020 - 30 April, 2020.

Risk factors for Coronavirus disease-associated mucormycosis

Arora et al., Journal of Infection, doi:10.1016/j.jinf.2021.12.039

Retrospective 152 COVID-associated mucormycosis cases and 200 controls, showing lower risk of COVID-associated mucormycosis with zinc treatment.

risk of progression, 95.0% lower, OR 0.05, p < 0.001, case control OR.

Arora et al., 3/31/2022, retrospective, India, peer-reviewed, 34 authors.

Calcium, Magnesium, and Zinc Supplementation during Pregnancy: The Additive Value of Micronutrients on Maternal Immune Response after SARS-CoV-2 Infection

Citu et al., Nutrients, doi:10.3390/nu14071445

Retrospective 448 pregnant women with COVID-19. Patients with calcium, zinc, and magnesium supplementation, or magnesium only, had a significantly higher titer of SARS-CoV-2 anti-RBD antibodies. There was no statistically significant difference in severe cases based on supplementation.

risk of severe case, 17.6% lower, RR 0.82, p = 1.00, treatment 2 of 74 (2.7%), control 2 of 61 (3.3%), NNT 174, Ca+Mg+Zn vs. Mg.

Citu et al., 3/30/2022, retrospective, Romania, peer-reviewed, survey, 14 authors, study period 14 April, 2020 - 14 February, 2022, this trial uses multiple treatments in the treatment arm (combined with calcium) - results of individual treatments may vary.

Free Zinc as a Predictive Marker for COVID-19 Mortality Risk

Maares et al., Nutrients, doi:10.3390/nu14071407

Analysis of 33 COVID-19 patients and 86 control patients in Germany, showing lower free serum zinc levels associated with COVID-19 and mortality.

Maares et al., 3/28/2022, retrospective, Germany, peer-reviewed, 9 authors.

Low serum levels of zinc and 25-hydroxyvitmain D as potential risk factors for COVID-19 susceptibility: a pilot case-control study

Ghanei et al., European Journal of Clinical Nutrition, doi:10.1038/s41430-022-01095-5

Case control study with 90 COVID-19 cases and 95 matched controls in Iran, showing significantly lower zinc levels for cases.

Ghanei et al., 3/23/2022, prospective, Iran, peer-reviewed, 6 authors, study period 20 March, 2020 - 20 January, 2021.

Micronutrient Improvement of Epithelial Barrier Function in Various Disease States: A Case for Adjuvant Therapy

DiGuilio et al., International Journal of Molecular Sciences, doi:10.3390/ijms23062995 (Review)

Review of epithelial and endothelial barrier compromise and associated disease risk including COVID-19, and the potential benefits of vitamin A, vitamin D, and zinc for improving barrier function.

DiGuilio et al., 3/10/2022, peer-reviewed, 8 authors.

Immune-boosting effect of natural remedies and supplements on progress of, and recovery from COVID-19 infection

Shehab et al., Tropical Journal of Pharmaceutical Research, doi:10.4314/tjpr.v21i2.13

Retrospective survey-based analysis of 349 COVID-19 patients, showing a lower risk of severe cases with vitamin D, zinc, turmeric, and honey prophylaxis in unadjusted analysis, without statistical significance. REC/UG/2020/03.

risk of severe case, 47.4% lower, RR 0.53, p = 0.24, treatment 4 of 65 (6.2%), control 22 of 188 (11.7%), NNT 18, unadjusted, severe vs. mild cases.

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

Shehab et al., 2/28/2022, retrospective, multiple countries, peer-reviewed, survey, 7 authors, study period September 2020 - March 2021.

The impact of vitamin and mineral supplements usage prior to COVID-19 infection on disease severity and hospitalization

Nimer et al., Bosnian Journal of Basic Medical Sciences, doi:10.17305/bjbms.2021.7009

Retrospective survey based analysis of 2,148 COVID-19 recovered patients in Jordan, showing no significant differences in the risk of severity and hospitalization with zinc prophylaxis.

risk of hospitalization, 25.4% higher, RR 1.25, p = 0.21, treatment 41 of 326 (12.6%), control 178 of 1,822 (9.8%), adjusted, OR converted to RR, multivariable.

risk of severe case, 13.0% higher, RR 1.13, p = 0.46, treatment 46 of 326 (14.1%), control 214 of 1,822 (11.7%), adjusted, OR converted to RR, multivariable.

Nimer et al., 2/28/2022, retrospective, Jordan, peer-reviewed, survey, 4 authors, study period March 2021 - July 2021.

In Vitro Determination of Inhibitory Effects of Humic Substances Complexing Zn and Se on SARS-CoV-2 Virus Replication

Hajdrik et al., Foods, doi:10.3390/foods11050694 (In Vitro)

In Vitro study of a humic substance containing vitamin C, selemium ions, and zinc ions, showing 50% SARS-CoV-2 inhibition at picomolar concentrations.

Hajdrik et al., 2/26/2022, peer-reviewed, 11 authors.

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

“MATH+” Multi-Modal Hospital Treatment Protocol for COVID-19 Infection: Clinical and Scientific Rationale

Kory et al., Journal of Clinical Medicine Research, doi:10.14740/jocmr4658 (Review)

Review of the data supporting the MATH+ hospital treatment protocol for COVID-19.

Kory et al., 2/24/2022, peer-reviewed, 6 authors.

Role of Zinc and Clinicopathological Factors for COVID-19-Associated Mucormycosis (CAM) in a Rural Hospital of Central India: A Case-Control Study

Kumar et al., Cureus, doi:10.7759/cureus.22528

Case control study of 105 COVID-19 patients in India, 55 with mucormycosis and 50 without, showing zinc prophylaxis and diabetes both associated with mucormycosis in unadjusted results. This is likely confounded because zinc supplementation is commonly used with diabetes [academic.oup.com], and Arora et al. show lower risk of mucormycosis with zinc prophylaxis, aOR 0.05 [0.01–0.19] [Arora]. There was no significant difference in mortality based on zinc prophylaxis in unadjusted results.

1. academic.oup.com, https://academic.oup.com/ajcn/article/110/1/76/5510583.

2. Arora et al., Journal of Infection, doi:10.1016/j.jinf.2021.12.039, Risk factors for Coronavirus disease-associated mucormycosis, https://www.journalofinfection.com..cle/S0163-4453(21)00654-X/fulltext.

risk of death, 20.0% lower, RR 0.80, p = 0.71, treatment 6 of 75 (8.0%), control 3 of 30 (10.0%), NNT 50, unadjusted.

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

Kumar et al., 2/23/2022, retrospective, India, peer-reviewed, 10 authors, study period June 2021 - August 2021.

Evaluation of zinc, copper, and Cu:Zn ratio in serum, and their implications in the course of COVID-19

Ivanova et al., Journal of Trace Elements in Medicine and Biology, doi:10.1016/j.jtemb.2022.126944

Retrospective 75 COVID-19 hospitalized patients and 68 healthy controls in Bulgaria, showing mortality associated with lower zinc levels.

Ivanova et al., 2/8/2022, retrospective, Bulgaria, peer-reviewed, 7 authors, study period January 2021 - April 2021.

Geographical distribution of trace elements (selenium, zinc, iron, copper) and case fatality rate of COVID-19: a national analysis across conterminous USA

Chen et al., Environmental Geochemistry and Health, doi:10.1007/s10653-022-01204-0

Analysis of the geographical association between concentrations of selenium, zinc, iron, and copper in surface soils and COVID-19 case fatality rates, showing low zinc levels associated with higher case fatality rates.

Chen et al., 1/30/2022, retrospective, USA, peer-reviewed, 6 authors, study period 8 October, 2020 - 25 March, 2021.

The difference in the dietary inflammatory index, functional food, and antioxidants intake between COVID -19 patients and healthy persons

Mohajeri et al., Mediterranean Journal of Nutrition and Metabolism, doi:10.3233/MNM-211521

Retrospective dietary survey analysis of 500 COVID-19 patients and 500 healthy matched controls in Iran, showing that COVID-19 patients had lower daily consumption of vitamin C, vitamin D, vitamin E, zinc, and selenium. IR.ARUMS.REC.1400.008.

Mohajeri et al., 1/29/2022, retrospective, Iran, peer-reviewed, 4 authors.

Comparative Analysis of Serum Zinc, Copper and Magnesium Level and Their Relations in Association with Severity and Mortality in SARS-CoV-2 Patients

PVSN et al., Biological Trace Element Research, doi:10.1007/s12011-022-03124-7

Analysis of 150 COVID+ hospitalized patients in India, showing lower zinc levels associated with higher severity.

PVSN et al., 1/22/2022, India, peer-reviewed, 14 authors.

Serum zinc levels in pediatric patients with COVID-19

Ekemen Keleş et al., European Journal of Pediatrics, doi:10.1007/s00431-021-04348-w

Prospective study of 100 COVID+ pediatric patients in Turkey, showing significantly increased risk of hospitalization for patients with zinc deficiency.

risk of hospitalization, 75.3% lower, RR 0.25, p = 0.01, high zinc levels (≥70μg/dL) 10 of 89 (11.2%), low zinc levels (<70μg/dL) 5 of 11 (45.5%), NNT 2.9.

Ekemen Keleş et al., 1/22/2022, prospective, Turkey, peer-reviewed, 7 authors, study period 3 August, 2020 - 15 November, 2020.

Zinc use is associated with improved outcomes in COVID-19: results from the CRUSH-COVID registry

Mayberry et al., Critical Care Medicine, doi:10.1097/01.ccm.0000807104.82650.d6

Retrospective 2,028 COVID patients in the USA, showing significantly lower mortality, ventilation, ICU admission, and progression to ARDS with zinc use, defined as at least one dose from one week prior to admission to 48 hours after admission.

risk of death, 53.5% lower, OR 0.47, p < 0.001, treatment 938, control 1,090, adjusted, multivariable, RR approximated with OR.

risk of mechanical ventilation, 64.2% lower, OR 0.36, p < 0.001, treatment 938, control 1,090, adjusted, multivariable, RR approximated with OR.

risk of ICU admission, 60.0% lower, OR 0.40, p < 0.001, treatment 938, control 1,090, adjusted, multivariable, RR approximated with OR.

death/ventilation/ICU, 57.8% lower, OR 0.42, p < 0.001, treatment 938, control 1,090, adjusted, multivariable, primary outcome, RR approximated with OR.

progression to ARDS, 85.4% lower, OR 0.15, p < 0.001, treatment 938, control 1,090, adjusted, multivariable, RR approximated with OR.

Mayberry et al., 12/16/2021, retrospective, USA, peer-reviewed, 14 authors, study period March 2020 - April 2021.

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

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, inverted to make RR<1 favor treatment, OR converted to RR.

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

Vitamin D, Zinc and Iron in Adult Patients with Covid-19 and Their Action in the Immune Response as Biomarkers

Ramos et al., Global Journal of Health Science, doi:10.5539/gjhs.v14n1p1

Retrospective 13 COVID-19 patients and 7 controls in Brazil, showing no significant difference in zinc deficiency.

risk of case, 23.6% lower, RR 0.76, p = 0.64, high zinc levels (≥70μg/dL) 5 of 9 (55.6%), low zinc levels (<70μg/dL) 8 of 11 (72.7%), NNT 5.8.

Ramos et al., 11/15/2021, retrospective, Brazil, peer-reviewed, 11 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-Martínez et al., International Journal of Environmental Research and Public Health, doi:10.3390/ijerph19031172 (preprint 10/25/2021)

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-Martínez et al., 10/25/2021, Randomized Controlled Trial, Mexico, peer-reviewed, 7 authors, study period 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, trial NCT04507867 (history).

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

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

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, 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, showing no significant differences in viral clearance or symptoms. 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, preprint, 12 authors, study period 21 September, 2020 - 22 January, 2021, average treatment delay 5.9 days, 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

Du Laing et al., Nutrients, doi:10.3390/nu13103304

Retrospective 73 hospitalized COVID-19 patients in Belgium, showing higher risk of mortality with selenium deficiency and zinc deficiency.

risk of death, 79.0% lower, RR 0.21, p = 0.01, high zinc levels (≥660µg/L) 3 of 49 (6.1%), low zinc levels (<660µg/L) 7 of 24 (29.2%), NNT 4.3.

risk of death, 78.4% lower, RR 0.22, p = 0.03, high zinc levels (≥660µg/L) 2 of 17 (11.8%), low zinc levels (<660µg/L) 6 of 11 (54.5%), NNT 2.3, >65 years.

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

Du Laing et al., 9/22/2021, retrospective, Belgium, 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

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

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

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, OR 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, inverted to make RR<1 favor treatment, OR converted to RR, binary logistic regression.

Bagheri et al., 9/1/2021, retrospective, Iran, 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

Retrospective 35 COVID-19 patients on parenteral nutrition on Spain, showing serum zinc levels inversely associated with length of hospital stay. There was no significant 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

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%), inverted to make RR<1 favor treatment, 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, 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)

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

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, 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

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, 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

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, 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, 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

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, >99.99% lower, OR <0.001, p = 0.04, treatment 0 of 6,953 (0.0%) cases, 10 of 13,906 (0.1%) controls, NNT 3.0, case control OR, 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, 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

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, Pakistan, peer-reviewed, survey, 11 authors, study period November 2020 - February 2021.

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

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 [journals.sagepub.com].

1. journals.sagepub.com, https://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, 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

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, 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

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, 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 (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)

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, HR 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, HR 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, peer-reviewed, 10 authors, study period 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, 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

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, inverted to make RR<1 favor high zinc levels, 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, 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

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, 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

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

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 symptomatic case, 49.7% lower, RR 0.50, p < 0.001, 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, peer-reviewed, 15 authors, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04446104 (history).

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

Abdulateef et al., Open Medicine, doi:10.1515/med-2021-0273

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, peer-reviewed, 7 authors, study period 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

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, 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

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 confounding by time 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, peer-reviewed, 3 authors.

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

Holt et al., Thorax, doi:10.1136/thoraxjnl-2021-217487

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. Except for vitamin D, the results for treatments we follow were only adjusted for age, sex, duration of participation, and test frequency. 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, peer-reviewed, 34 authors, study period 1 May, 2020 - 5 February, 2021, trial NCT04330599 (history) (COVIDENCE UK).

A pilot double‐blind safety and feasibility randomized controlled trial of high‐dose intravenous zinc in hospitalized COVID‐19 patients

Patel et al., Journal of Medical Virology, doi:10.1002/jmv.26895

Small early terminated RCT with 33 hospitalized patients in Australia, 15 treated with zinc, showing no significant difference in clinical outcomes. Treatment increased zinc levels above the deficiency cutoff. Intravenous zinc 0.5mg/kg/day (elemental zinc concentration 0.24mg/kg/day) for up to 7 days. ACTRN12620000454976.

risk of death, 20.0% lower, RR 0.80, p = 1.00, treatment 2 of 15 (13.3%), control 3 of 18 (16.7%), NNT 30.

Patel et al., 2/25/2021, Double Blind Randomized Controlled Trial, Australia, peer-reviewed, 12 authors.

Seroprevalence of IgG against SARS-CoV-2 and its determinants among healthcare workers of a COVID-19 dedicated hospital of India

Mahto et al., American Journal of Blood Research, 11:1

Retrospective 689 healthcare workers in India, showing no significant difference in IgG positivity with zinc prophylaxis.

risk of IgG positive, 36.8% lower, RR 0.63, p = 0.35, treatment 10 of 38 (26.3%), control 83 of 651 (12.7%), adjusted, OR converted to RR, multivariable.

Mahto et al., 2/15/2021, retrospective, India, peer-reviewed, 6 authors.

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

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

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 gluconate (7mg elemental zinc), one tenth of that shown to reduce the duration of colds in other studies [patrickholford.com]. NCT04342728.

1. patrickholford.com, https://www.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 mean 5.9 (±4.9) n=58, control mean 6.7 (±4.4) n=50, mean time to a 50% reduction in symptoms, primary outcome.

Thomas et al., 2/12/2021, Randomized Controlled Trial, USA, peer-reviewed, 11 authors, trial NCT04342728 (history).

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

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, 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

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, study period 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)

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)

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)

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

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, inverted to make RR<1 favor high zinc levels, OR converted to RR, ≥70 μg/dL, logistic regression.

Gonçalves et al., 12/23/2020, retrospective, Brazil, 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

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, 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.

Risk Factors Associated With In-Hospital Mortality in a US National Sample of Patients With COVID-19

Rosenthal et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2020.29058

Retrospective database analysis of 64,781 hospitalized patients in the USA, showing lower mortality with vitamin C or vitamin D (authors do not distinguish between the two), and higher mortality with zinc and HCQ, statistically significant for zinc. Authors excluded hospital-based outpatient visits, without explanation. Confounding by indication is likely, adjustments do not appear to include any information on COVID-19 severity at baseline.

risk of death, 16.0% higher, OR 1.16, p = 0.003, adjusted, multivariable, RR approximated with OR.

Excluded in after exclusion results of meta analysis: confounding by indication is likely and adjustments do not consider COVID-19 severity at baseline.

Rosenthal et al., 12/10/2020, retrospective, database analysis, USA, peer-reviewed, 5 authors.

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)

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, 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

191 patient RCT in Egypt comparing the addition of zinc to HCQ, not showing a significant difference. 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 [ncbi.nlm.nih.gov, ncbi.nlm.nih.gov (B)].

1. ncbi.nlm.nih.gov, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510072/.

2. ncbi.nlm.nih.gov (B), https://www.ncbi.nlm.nih.gov/pmc/a..C3510072/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, 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

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, HR 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, HR 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, 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)

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, inverted to make RR<1 favor high zinc levels, 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, inverted to make RR<1 favor high zinc levels, OR converted to RR, ≥84 mcg/dL, multivariate logistic regression, final model.

Tomasa-Irriguible et al., 10/26/2020, retrospective, Spain, 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

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)

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, peer-reviewed, 16 authors.

COVID-19: Poor outcomes in patients with zinc deficiency

Jothimani

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, peer-reviewed, 11 authors.

Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework

Galmés et al., Nutrients, doi:10.3390/nu12092738

Ecological study of European countries analyzing 10 vitamins and minerals endorsed by the European Food Safety Authority as having sufficient evidence for a causal relationship between intake and optimal immune system function: vitamins D, A, C, B6, B9, B12, zinc, copper, iron, and selenium.

Intake levels of all 10 showed an inverse correlation with the relative mortality rate, while all except vitamin B6 and selenium showed an inverse correlation with incidence and mortality. Most individual correlations did not reach statistical significance. Authors note greater association in populations genetically predisposed towards lower micronutrient status.

Galmés et al., 9/8/2020, retrospective, peer-reviewed, 3 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

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, 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

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

1. ncbi.nlm.nih.gov, https://www.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%), adjusted, multivariate Cox regression.

Yao et al., 7/22/2020, retrospective, USA, 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

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, 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)

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, 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

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)

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%), 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%), adjusted, OR converted to RR, multivariate logistic regression.

Carlucci et al., 5/8/2020, retrospective, USA, 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 (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)	Melatonin	(meta)
Aspirin	(meta)	Metformin	(meta)
Bamlaniv../e..	(meta)	Molnupiravir	(meta)
Bebtelovimab	(meta)	N-acetylcys..	(meta)
Bromhexine	(meta)	Nigella Sativa	(meta)
Budesonide	(meta)	Nitazoxanide	(meta)
Cannabidiol	(meta)	Nitric Oxide	(meta)
Casirivimab/i..	(meta)	Paxlovid	(meta)
Colchicine	(meta)	Peg.. Lambda	(meta)
Conv. Plasma	(meta)	Povidone-Iod..	(meta)
Curcumin	(meta)	Probiotics	(meta)
Diet	(meta)	Proxalutamide	(meta)
Ensitrelvir	(meta)	Quercetin	(meta)
Ensovibep	(meta)	Remdesivir	(meta)
Exercise	(meta)	Sleep	(meta)
Famotidine	(meta)	Sotrovimab	(meta)
Favipiravir	(meta)	Tixagev../c..	(meta)
Fluvoxamine	(meta)	Vitamin A	(meta)
Hydroxychlor..	(meta)	Vitamin C	(meta)
Iota-carragee..	(meta)	Vitamin D	(meta)
Ivermectin	(meta)	Zinc	(meta)
Lactoferrin	(meta)

Other Treatments		Global Adoption