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Zinc Supplementation and COVID-19

Last Updated: July 17, 2020

Recommendations

  • There are insufficient data to recommend either for or against the use of zinc for the treatment of COVID-19.
  • The COVID-19 Treatment Guidelines Panel (the Panel) recommends against using zinc supplementation above the recommended dietary allowance for the prevention of COVID-19, except in a clinical trial (BIII).

Rationale

Increased intracellular zinc concentrations efficiently impair replication in a number of RNA viruses.1 Zinc has been shown to enhance cytotoxicity and induce apoptosis when used in vitro with a zinc ionophore (e.g., chloroquine). Chloroquine has also been shown to enhance intracellular zinc uptake in vitro.2 The relationship between zinc and COVID-19, including how zinc deficiency affects the severity of COVID-19 and whether zinc supplements can improve clinical outcomes, is currently under investigation.3 Zinc levels are difficult to measure accurately, as zinc is distributed as a component of various proteins and nucleic acids.4

Zinc supplementation alone or in combination with hydroxychloroquine for prevention and treatment of COVID-19 is currently being evaluated in clinical trials. The optimal dose of zinc for the treatment of COVID-19 is not established. The recommended dietary allowance for elemental zinc is 11 mg daily for men and 8 mg for nonpregnant women.5 The doses used in registered clinical trials for COVID-19 vary between studies, with a maximum dose of zinc sulfate 220 mg (50 mg of elemental zinc) twice daily.

Long-term zinc supplementation can cause copper deficiency with subsequent reversible hematologic defects (i.e., anemia, leukopenia) and potentially irreversible neurologic manifestations (i.e., myelopathy, paresthesia, ataxia, spasticity).6,7 Zinc supplementation for a duration as short as 10 months has been associated with copper deficiency.8 In addition, oral zinc can decrease the absorption of medications that bind with polyvalent cations.5 Because zinc has not been shown to have clinical benefit and may be harmful, the Panel recommends against using zinc supplementation above the recommended dietary allowance for the prevention of COVID-19, except in a clinical trial (BIII).

Clinical Data

Retrospective Study of Hydroxychloroquine and Azithromycin With or Without Zinc

This study has not been peer-reviewed.

A retrospective observational study compared zinc supplementation to no zinc supplementation in hospitalized patients with COVID-19 who received hydroxychloroquine and azithromycin from March 2 to April 5, 2020. On March 25, the institution’s standard of care was updated to include supplementation with zinc sulfate 220 mg orally twice daily. Patients who received any other investigational therapies were excluded. Only patients who were discharged from the hospital, transferred to hospice, or died were included in the analysis. Outcome measures included duration of hospital stay, duration of mechanical ventilation, maximum oxygen flow rate, average oxygen flow rate, average FiO2, maximum FiO2, admission to the intensive care unit (ICU), duration of ICU stay, death or transfer to hospice, need for intubation, and discharge destination.9

Results

  • A total of 932 patients were included in this analysis; 411 patients received zinc, and 521 did not.
  • The two groups had similar demographic characteristics.
  • Patients who received zinc had higher absolute lymphocyte count and lower troponin and procalcitonin levels at baseline than those who did not receive zinc.
  • In univariate analysis, no differences were observed between the two groups in duration of hospital stay, duration of mechanical ventilation, maximum oxygen flow rate, average oxygen flow rate, or average FiO2.
  • In bivariate logistic regression analysis, zinc supplementation was associated with a decreased mortality rate or rate of transfer to hospice; however, the association with a decreased mortality rate was no longer significant when analysis was limited to patients who were treated in the ICU.

Limitations

  • This is a retrospective review; patients were not randomized to receive zinc therapy or to receive no zinc. The statistical methods used do not account for confounding variables or patient differences between those who were treated with zinc sulfate and those who were not, with one exception: the authors attempted to account for the change in the institution’s treatment standards by using a logistic regression analysis for patients admitted after March 25.
  • The preprint did not include specific details on the timing of zinc initiation, and the patients’ clinical statuses at the start of therapy were not reported.
  • The preprint also did not specify how many patients did or did not receive zinc before and after the institution’s treatment standards changed to include zinc sulfate on March 25. The authors used a logistic regression analysis to account for this, as discussed above.
  • Only patients who died or who were transferred to hospice or discharged are included in the analyses. The exclusion of those who were still hospitalized as of April 5 makes it difficult to compare the clinical outcomes for those who received or did not receive zinc sulfate.

Given the nature of the study design and its limitations, the authors do not recommend using this study to guide clinical practice.

References

  1. te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ. Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 2010;6(11):e1001176. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21079686.
  2. Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding WQ. Chloroquine is a zinc ionophore. PLoS One. 2014;9(10):e109180. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25271834.
  3. Calder PC, Carr AC, Gombart AF, Eggersdorfer M. Optimal nutritional status for a well-functioning immune system is an important factor to protect against viral infections. Nutrients. 2020;12(4). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32340216.
  4. Hambridge K. The management of lipohypertrophy in diabetes care. Br J Nurs. 2007;16(9):520-524. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17551441.
  5. National Institutes of Health. Office of Dietary Supplements. Zinc fact sheet for health professionals. 2020. Available at: https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/. Accessed June 26, 2020.
  6. Myint ZW, Oo TH, Thein KZ, Tun AM, Saeed H. Copper deficiency anemia: review article. Ann Hematol. 2018;97(9):1527-1534. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29959467.
  7. Kumar N. Copper deficiency myelopathy (human swayback). Mayo Clin Proc. 2006;81(10):1371-1384. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17036563.
  8. Hoffman HN, 2nd, Phyliky RL, Fleming CR. Zinc-induced copper deficiency. Gastroenterology. 1988;94(2):508-512. Available at: https://www.ncbi.nlm.nih.gov/pubmed/3335323.
  9. Carlucci P, Ahuja T, Petrilli CM, Rajagopalan H, Jones S, Rahimian J. Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.05.02.20080036v1.