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The effect of zinc on the outcome of patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials

Published:January 21, 2023DOI:https://doi.org/10.1016/j.jinf.2023.01.023
      Dear Editor
      We read with great interest the meta-analysis by Qian et al that investigated the clinical efficacy and safety in the treatment of patients with COVID-19.
      • Zheng Q
      • Ma P
      • Wang M
      • Cheng Y
      • Zhou M
      • Ye L
      • et al.
      Efficacy and safety of Paxlovid for COVID-19:a meta-analysis.
      Based on the analysis of seven studies, the authors demonstrated that the overall risk of death and hospitalization among COVID-19 patients was significantly lower in the nirmatrelvir plus ritonavir group than control group (odds ratio, 0.22; 95% CI, 0.11–0.45; I2 =93%).
      • Zheng Q
      • Ma P
      • Wang M
      • Cheng Y
      • Zhou M
      • Ye L
      • et al.
      Efficacy and safety of Paxlovid for COVID-19:a meta-analysis.
      In addition to nirmatrelvir plus ritonavir, many studies also evaluated whether other cost-effective agents, such as fluvoxamine,
      • Marcec R
      • Dodig VM
      • Likic R.
      A meta-analysis regarding fluvoxamine and hospitalization risk of COVID-19 patients: TOGETHER making a difference.
      ,
      • Cheema HA
      • Jafar U
      • Elrashedy AA
      • Shahid A
      • Awan RU
      • Ehsan M
      • et al.
      Efficacy and safety of fluvoxamine for the treatment of COVID-19 patients: A systematic review and meta-analysis.
      famotidine
      • Cheema HA
      • Shafiee A
      • Athar MMT
      • Shahid A
      • Awan RU
      • Afifi AM
      • et al.
      No evidence of clinical efficacy of famotidine for the treatment of COVID-19: a systematic review and meta-analysis.
      or zinc
      • Arora U
      • Priyadarshi M
      • Katiyar V
      • Soneja M
      • Garg P
      • Gupta I
      • et al.
      Risk factors for Coronavirus disease-associated mucormycosis.
      could be repurposed as potential agents for patients with COVID-19.
      Recently, one randomized controlled trial (RCT), which investigated the clinical efficacy of zinc supplement for patients with COVID-19.
      • Ben Abdallah S
      • Mhalla Y
      • Trabelsi I
      • Sekma A
      • Youssef R
      • Bel Haj Ali K
      • et al.
      Twice-Daily Oral Zinc in the Treatment of Patients With Coronavirus Disease 2019: A Randomized Double-Blind Controlled Trial.
      Ben Abdallash et al found that compared with placebo, treatment with oral zinc was associated with a lower 30-day mortality, ICU admission rate and shorter duration of symptoms and length of hospital stay.
      • Ben Abdallah S
      • Mhalla Y
      • Trabelsi I
      • Sekma A
      • Youssef R
      • Bel Haj Ali K
      • et al.
      Twice-Daily Oral Zinc in the Treatment of Patients With Coronavirus Disease 2019: A Randomized Double-Blind Controlled Trial.
      Overall, the findings of this RCT suggest the promising role of zinc in the treatment of patients with COVID-19.
      • Ben Abdallah S
      • Mhalla Y
      • Trabelsi I
      • Sekma A
      • Youssef R
      • Bel Haj Ali K
      • et al.
      Twice-Daily Oral Zinc in the Treatment of Patients With Coronavirus Disease 2019: A Randomized Double-Blind Controlled Trial.
      However, previous RCT by Thomas et al. reported that zinc could not significantly decrease the duration of symptoms and was early terminated for futility.
      • Thomas S
      • Patel D
      • Bittel B
      • Wolski K
      • Wang Q
      • Kumar A
      • et al.
      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.
      Similar, the RCT by Abd-Elsalam et al did not find the additional clinical benefit of zinc supplement.
      • Abd-Elsalam S
      • Soliman S
      • Esmail ES
      • Khalaf M
      • Mostafa EF
      • Medhat MA
      • et al.
      Do Zinc Supplements Enhance the Clinical Efficacy of Hydroxychloroquine?: a Randomized, Multicenter Trial.
      To solve this conflict, we conducted this meta-analysis of RCTs to assess the clinical efficacy of zinc for patients with COVID-19.
      We identified RCTs, which investigated the clinical efficacy and safety of zinc in the treatment of patients with COVID-19 from PubMed, Cochrane Library, EMBASE, Clinicaltrial.gov and Google Scholar without language restrictions from inception to December 13, 2022. The search strategy used a combination of controlled vocabulary and free-text words. The outcomes of interest included 28-day mortality rate, hospitalization rate, length of hospital stay, the duration of symptom, symptom recover rate, and the risk of adverse events (AEs). Data were synthesized using the random-effects model. Pooled estimates of the risk difference (RD) and mean difference (MD) with a 95% confidence interval (CI) for dichotomous and continuous data, respectively, were calculated using Review Manager Version 5.4.1.
      Four RCTs
      • Ben Abdallah S
      • Mhalla Y
      • Trabelsi I
      • Sekma A
      • Youssef R
      • Bel Haj Ali K
      • et al.
      Twice-Daily Oral Zinc in the Treatment of Patients With Coronavirus Disease 2019: A Randomized Double-Blind Controlled Trial.
      • Thomas S
      • Patel D
      • Bittel B
      • Wolski K
      • Wang Q
      • Kumar A
      • et al.
      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.
      • Abd-Elsalam S
      • Soliman S
      • Esmail ES
      • Khalaf M
      • Mostafa EF
      • Medhat MA
      • et al.
      Do Zinc Supplements Enhance the Clinical Efficacy of Hydroxychloroquine?: a Randomized, Multicenter Trial.
      • Patel O
      • Chinni V
      • El-Khoury J
      • Perera M
      • Neto AS
      • McDonald C
      • et al.
      A pilot double-blind safety and feasibility randomized controlled trial of high-dose intravenous zinc in hospitalized COVID-19 patients.
      were identified (Table 1). Except one was a single-center phase 2 study,
      • Patel O
      • Chinni V
      • El-Khoury J
      • Perera M
      • Neto AS
      • McDonald C
      • et al.
      A pilot double-blind safety and feasibility randomized controlled trial of high-dose intravenous zinc in hospitalized COVID-19 patients.
      all the other three were multicenter trials.
      • Ben Abdallah S
      • Mhalla Y
      • Trabelsi I
      • Sekma A
      • Youssef R
      • Bel Haj Ali K
      • et al.
      Twice-Daily Oral Zinc in the Treatment of Patients With Coronavirus Disease 2019: A Randomized Double-Blind Controlled Trial.
      • Thomas S
      • Patel D
      • Bittel B
      • Wolski K
      • Wang Q
      • Kumar A
      • et al.
      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.
      • Abd-Elsalam S
      • Soliman S
      • Esmail ES
      • Khalaf M
      • Mostafa EF
      • Medhat MA
      • et al.
      Do Zinc Supplements Enhance the Clinical Efficacy of Hydroxychloroquine?: a Randomized, Multicenter Trial.
      In Abd-Elsalam et al's study, the intervention and the comparator was zinc plus hydroxychloroquine (HCQ) and HCQ only, respectively.
      • Abd-Elsalam S
      • Soliman S
      • Esmail ES
      • Khalaf M
      • Mostafa EF
      • Medhat MA
      • et al.
      Do Zinc Supplements Enhance the Clinical Efficacy of Hydroxychloroquine?: a Randomized, Multicenter Trial.
      In other three RCTs, the intervention and the comparator was zinc and placebo or standard of care, respectively.
      • Ben Abdallah S
      • Mhalla Y
      • Trabelsi I
      • Sekma A
      • Youssef R
      • Bel Haj Ali K
      • et al.
      Twice-Daily Oral Zinc in the Treatment of Patients With Coronavirus Disease 2019: A Randomized Double-Blind Controlled Trial.
      ,
      • Thomas S
      • Patel D
      • Bittel B
      • Wolski K
      • Wang Q
      • Kumar A
      • et al.
      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.
      ,
      • Patel O
      • Chinni V
      • El-Khoury J
      • Perera M
      • Neto AS
      • McDonald C
      • et al.
      A pilot double-blind safety and feasibility randomized controlled trial of high-dose intravenous zinc in hospitalized COVID-19 patients.
      The treatment duration ranged from 7 days to 15 days.
      Table 1Characteristics of included studies
      Study designStudy siteStudy periodPatientsInterventionComparator
      Abd-Elsalam et al, 2020
      • Abd-Elsalam S
      • Soliman S
      • Esmail ES
      • Khalaf M
      • Mostafa EF
      • Medhat MA
      • et al.
      Do Zinc Supplements Enhance the Clinical Efficacy of Hydroxychloroquine?: a Randomized, Multicenter Trial.
      Randomized controlled trialMulticenter in EgyptFrom June 23, 2020 to August 23, 2020Patient with COVID-1950 mg of elemental zinc twice daily and hydroxychloroquine for 15 daysHydroxychloroquine
      Ben Abdallah et al, 2022
      • Ben Abdallah S
      • Mhalla Y
      • Trabelsi I
      • Sekma A
      • Youssef R
      • Bel Haj Ali K
      • et al.
      Twice-Daily Oral Zinc in the Treatment of Patients With Coronavirus Disease 2019: A Randomized Double-Blind Controlled Trial.
      randomized, double-blind, placebo-controlled trialMulticenter in Tunisiafrom February 15, 2022 to May 4, 2022Adult patients with COVID-1925 mg of elemental zinc twice daily for 15 daysPlacebo
      Patel et al, 2021
      • Patel O
      • Chinni V
      • El-Khoury J
      • Perera M
      • Neto AS
      • McDonald C
      • et al.
      A pilot double-blind safety and feasibility randomized controlled trial of high-dose intravenous zinc in hospitalized COVID-19 patients.
      Phase 2a double‐blind, randomized controlled trialSingle center in AustraliaFrom September 3, 2021 to November 9, 2021Hospitalized adults with COVID-190.24 mg/kg/day of elemental zinc for a maximum of 7 daysPlacebo
      Thomas et al, 2021
      • Thomas S
      • Patel D
      • Bittel B
      • Wolski K
      • Wang Q
      • Kumar A
      • et al.
      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.
      randomized clinical open-label trialMulticenter in USfrom April 27, 2020, to October 14, 2020Adult patients with COVID-1950 mg of zinc at

      Bedtime for 10 days
      Standard of care
      Figure 1
      Figure 1
      Figure 1Forest plot of 28-day mortality between zinc and comparator
      Overall, the mortality of the study group receiving zinc was 5.5% (22/400), which was numerically lower than that of the control group (7.3% [30/412]). The difference did not reach statistical significance (RD, -0.01; 95% CI, -0.03 to 0.02, p = 0.55, supplemental figure 1) and no heterogeneity was detected (I2 = 0%, p = 0.68). This result remained unchanged using leave-one-out sensitivity test, which assessed the influence of individual studies by performing a series of meta-analyses that leave out one of the studies in the original meta-analysis. Similarly, there were no significant differences between zinc and comparator in terms of hospitalization rate (RD, -0.01; 95% CI, -0.06 to 0.03; p = 0.55; I2 = 17%), length of hospital stay (MD, -2.41 days; 95% CI, -4.99 to 0.70; p = 0.14; I2 = 90%), symptom recovery (RD, 0.01; 95% CI, -0.08 to 0.09; p = 0.87; I2 = 0%), duration of symptom (MD, -1.22 days; 95% CI, -5.23 to 2.80; p = 0.55; I2 = 89%) and risk of AE (RD, 0.07; 95% CI, -0.14 to 0.29; p = 0.52; I2 = 93%).
      Based on our findings, although zinc supplement was safe in the treatment of patients with COVID-19, it did not help improve the clinical outcomes. These findings were supported by the following evidence. There was no significant difference in terms of mortality, the risk of hospitalization, length of study, clinical recovery and the duration of symptoms between the study group receiving zinc supplement and the control group. Therefore, it did not support the routine use of zinc supplement for COVID-19 patients.
      However, our findings should be interpreted cautiously due to the following limitations. First, the number of RCTs was limited, and most analyses of outcomes were based on small patient numbers. Second, some findings of the present meta-analyses regarding secondary outcome were associated with high heterogeneity.
      In conclusion, zinc supplement did not provide additional benefit for patients with COVID-19. However, further large scale RCT is warranted to clarify the usefulness of zinc for COVID-19.

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