True or False: Zinc is beneficial against common colds, COVID-19, and monkeypox

Zinc (Zn2+) is the second-most abundant trace metal in the human body after iron and an essential element of protein structure and function (1). This mineral supports fetal growth and development, intracellular signaling, enzyme activity, gustatory and olfactory functions, as well as reproductive, skeletal, neuronal, cardiovascular, and wound healing functions. It plays an integral role during an immune response, and its homeostasis is crucial to maintaining proper immune function (1). Zinc-deficient populations tend to be the most prone to viral infections since zinc levels play an essential role in influencing antiviral immunity (2). Zinc modulates proinflammatory responses, partly by targeting a protein called Nuclear Factor Kappa B (NF-B), a transcription factor, which is important in regulating oxidative stress and inflammation (2).

Cold-fighting mechanism of zinc

Approximately 16% of all deep respiratory infections are associated with zinc deficiency (3). As part of the immune response, there are two main mechanisms; innate (fast, non-antigen specific) and adaptive immunity (slower, antigen-specific), and zinc significantly influences both mechanisms (4). Zinc regulates the proteins that form tight junctions (the intercellular barrier between epithelial cells), which are essential for preserving the integrity of mucosal membranes. On the other hand, viral inflammation appears to be aggravated by a reduction of this mucosal integrity and loss of tight junction cohesion. Additionally, zinc has demonstrated antiviral effects by disrupting viral replication by altering the proteolytic processing of RNA-dependent RNA polymerase in Hepatitis C virus, Influenza viruses, and Rhinoviruses (5). Most common colds are caused by human rhinoviruses that possess intracellular adhesion molecule-1 (ICAM-1) receptors (which play a role in inflammation). Taking zinc within 24 hours of symptoms is recommended as it is a competitive inhibitor of ICAM-1 on both rhinovirus particles and nasal epithelium.

There are multiple steps in viral replication that can be inhibited by zinc (6). A summary is in the figure below.

Figure from The Role of Zinc in Antiviral Immunity. Adv. Nutr. 2019 Jul; 10(4): 696–710.

Step 1: Viral uncoating Step 2: Viral genome transcription Step 3: Translation of viral proteins and polyproteins Step 4: Genome replication and assembly Step 5: Viral protein synthesis and release

CV, Cytomegalovirus; EMCV, Encephalomyocarditis virus; FMDV, Foot-and-mouth disease virus; HIV, Human immunodeficiency virus; HCV, Hepatitis C virus; HRV, Human rhinovirus; HSV, Herpes simplex virus; HPV, human papillomavirus; PV, Pasteur Virus; SARS, Severe acute respiratory syndrome; SFV, Semliki Forest virus; SV, Respiratory syncytial virus; VZV, Varicella-zoster virus.

• In 1984, Eby et al published the first study on the efficacy of zinc gluconate lozenges for the treatment of the common cold (7).

• Several studies have suggested zinc ions inhibit the replication of diverse viruses in vitro by inhibiting viral polypeptide cleavage (8).

• Among these viruses are eight of nine rhinoviruses tested and herpes simplex viruses are known for causing common colds (9,10).

• A meta-analysis (analysis of many previous studies combined) of individual patient data conducted in 2017 concluded that patients taking zinc lozenges recovered faster by a rate ratio of 3.1. 70% of zinc patients recovered on the fifth day compared with 27% of placebo patients (11).

• According to a Cochrane review conducted in 2013, (14 studies, 1,656 participants), zinc administered within 24 hours of symptom onset was found to be effective in reducing the duration of cold symptoms (12).

A meta-analysis of seven trials recently reported that zinc lozenges (>75 mg/day of elemental zinc) reduced cold symptoms by 33% (13).

• The zinc in a slow-release tablet binds to the receptors in mucus membranes of the upper respiratory tract, reducing the number of rhinoviruses that invade cells and establishing an infection. In this regard, it is probably effective in reducing the spread of colds.

What form and dose of zinc are best for colds?

The best form of zinc is the ionic form, as it has consistently shown the best results. Ionic zinc lozenges are available in several forms, including ​gluconate,​ ​sulfate​, and ​acetate​. Depending on the type, absorption, tolerability, and bioavailability may differ. The best way to get ionic form is from Zinc acetate (which releases 100% of ionic zinc). 14 At the time of the first dose of zinc, its antiviral properties are not apparent. A typical adult requires between 8 and 13 milligrams (mg) of zinc each day, but high doses of zinc - about 75 mg/day - are required to produce these antiviral effects. 12 Although taking zinc lozenges every two to three hours while awake will result in daily zinc intakes well above the tolerable upper intake level of 40 mg/day for adults (according to NIH), zinc taken at a dose of 50 to 180 mg per day for one to two weeks has not caused serious side effects (15).

Side effects

Zinc toxicity is very rare, with symptoms of zinc toxicity including nausea, vomiting, epigastric pain, and fatigue when you consume more than 200 to 400 mg of zinc in 24 hours. It has been shown that oral zinc is taken long-term and in high doses can lead to copper deficiency, which might result in neurological effects such as numbness and weakness in the arms and legs (16). It should be noted that several case reports have been published about individuals experiencing a loss of sense of smell (anosmia) following the use of intranasal zinc as a cold remedy (17). The FDA warns consumers about the risk of anosmia associated with the use of intranasal products.

Drug interactions

According to the Mayo Clinic, some medications that zinc may interact with include:

• Penicillamine - used to treat symptoms of rheumatoid arthritis.

• Thiazide diuretics - In people with zinc deficiencies, thiazide diuretics may need higher doses because they lose more zinc through urination.

• Quinolone or tetracycline antibiotics - zinc can interfere with their ability to fight bacteria. When taking antibiotics, take the supplement four to six hours prior to or two hours after the antibiotic.

Zinc against coronavirus disease 2019 (COVID-19)

Zinc can be an important adjuvant when treating COVID-19 because it decreases lung inflammation, improves mucociliary clearance, prevents ventilation-associated lung injury, and modulates immune recall, especially in the elderly.5 Through its spike proteins, SARS-CoV-2 (the virus that causes COVID-19) binds to angiotensin-converting enzyme 2 (ACE2) on the surface of cells to initiate viral replication. The expression of ACE-2 is regulated by another protein, Sirtuin 1 (SIRT1), and zinc reduces SIRT-1-mediated expression of ACE2.18 There was a retrospective analysis of the impact of zinc on the mortality of COVID-19 patients admitted to a hospital in Spain. The investigators found a significantly lower plasma level of zinc in COVID-19 patients who died (43 lg/dl) than the patients who survived (63.1 lg/dl). Each unit increase of plasma zinc during hospitalization resulted in a 7% reduction in in-hospital mortality after adjusting for different variables. 19 In another study, however, using zinc with or without vitamin C did not affect the severity of mild covid (20). Hence, zinc may be useful as an adjuvant, but there is not enough clinical evidence to recommend it as a treatment for Covid-19.

Zinc against monkeypox

Zinc is an excellent antioxidant, an anti-inflammatory, an immunomodulator, and a powerful antiviral. It protects cells and tissues from a viral infection, oxidative damage, and dysfunction, possibly because of its ability to inhibit the RNA-dependent RNA polymerase. Currently, there is no evidence that zinc supplementation can improve symptoms or be effective against the monkeypox virus. Clinical studies, however, indicate that the topical use of Zinc Oxide suspension on the affected skin manifestations offers multiple benefits to infected monkeypox patients (21). Besides drying out the pox, zinc reduces itching and prevents superinfection by bacteria. It is essential to conduct further experimental and clinical studies to learn if zinc has antiviral activity against monkeypox.

Conclusion

Research strongly supports that zinc is beneficial for reducing cold symptoms. The preliminary data available suggests that zinc may not be as beneficial for COVID-19 symptoms as it is for the common cold, but more research is needed. Overall, zinc seems to be beneficial for reducing the symptoms of many viral infections. Little is known about the role/benefits of zinc for monkeypox. However, zinc seems to be beneficial for treating monkeypox spots. Due to the possibility of side effects of zinc for some individuals, it is recommended that > 100 mg of zinc per day be avoided. It is also recommended that you talk to your healthcare professional before taking any zinc supplements.

Written by Nida Mariyam, a fourth-year medical student, and edited by Aldrin V. Gomes, PhD

References

1) Ana F. Vinha et al. Ijsrm. Human, 2019; 13 (3): 57-80.

2) Gammoh NZ, Rink L. Zinc in Infection and Inflammation. Nutrients. 2017; 17;9(6):624.

3) Oyagbemi, A. A., Ajibade, T. O., Aboua, Y. G., Gbadamosi, I. T., Adedapo, A., Aro, A. O., Adejumobi, O. A., Thamahane-Katengua, E., Omobowale, T. O., Falayi, O. O., Oyagbemi, T. O., Ogunpolu, B. S., Hassan, F. O., Ogunmiluyi, I. O., Ola-Davies, O. E., Saba, A. B., Adedapo, A. A., Nkadimeng, S. M., McGaw, L. J., Kayoka-Kabongo, P. N., et al. (2021). Potential health benefits of zinc supplementation for the management of COVID-19 pandemic. Journal of food biochemistry, 2021; 45(2), e13604.

4) Dardenne M. Zinc and immune function. European journal of clinical nutrition, 2002; 56 Suppl 3, S20–S23.

5) Skalny, A. V., Rink, L., Ajsuvakova, O. P., Aschner, M., Gritsenko, V. A., Alekseenko, S. I., Svistunov, A. A., Petrakis, D., Spandidos, D. A., Aaseth, J., Tsatsakis, A., & Tinkov, A. A.. Zinc and respiratory tract infections: Perspectives for COVID‑19 (Review). International journal of molecular medicine, 2020; 46(1), 17–26.

6) Read, S. A., Obeid, S., Ahlenstiel, C., & Ahlenstiel, G. The Role of Zinc in Antiviral Immunity. Advances in nutrition (Bethesda, Md.), 2019; 10(4), 696–710.

7) Eby GA, Davis DR, Halcomb WW. Reduction in duration of common colds by zinc gluconate lozenges in a double blind study. Antimicrobial Agents and Chemotherapy 1984;25:20‐4.

8) Butterworth, B. E., and B. D. Korant. Characterization of the large picornaviral polypeptides produced in the presence of zinc ion. J. Virol. 1974;14:282-291.

9) Korant, B. D., & Butterworth, B. E. Inhibition by zinc of rhinovirus protein cleavage: interaction of zinc with capsid polypeptides. Journal of virology, 1976; 18(1), 298–306.

10) Korant, B. D., Kauer, J. C., & Butterworth, B. E. Zinc ions inhibit replication of rhinoviruses. Nature, 1974; 248(449), 588–590.

11) Hemilä, H., Fitzgerald, J. T., Petrus, E. J., & Prasad, A. Zinc Acetate Lozenges May Improve the Recovery Rate of Common Cold Patients: An Individual Patient Data Meta-Analysis. Open forum infectious diseases, 2017; 4(2), ofx059.

12) Singh, M., & Das, R. R. Zinc for the common cold. The Cochrane database of systematic reviews, 2013; (6), CD001364.

13) Hemilä H. Zinc lozenges and the common cold: a meta-analysis comparing zinc acetate and zinc gluconate, and the role of zinc dosage. JRSM open, 2017; 8(5), 2054270417694291.

14) Eby GA, 3rd. Zinc lozenges as cure for the common cold--a review and hypothesis. Med Hypotheses. 2010;74(3):482-92

15) Science M, Johnstone J, Roth DE, Guyatt G, Loeb M. Zinc for the treatment of the common cold: a systematic review and meta-analysis of randomized controlled trials. 2012;184(10): E551–E561.

16) https://www.mayoclinic.org/drugs-supplements-zinc/art-20366112

17) DeCook CA, Hirsch AR. Anosmia due to inhalational zinc: a case report. Chem Senses. 2000;25(5):659.

18) Zhang, H., Penninger, J. M., Li, Y., Zhong, N., & Slutsky, A. S. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive care medicine, 2020; 46(4), 586–590.

19) Khan, Abas & Mir, Mohammad. (2021). Zinc supplementation and COVID-19. Journal of Medical Case Reports and Reviews2021; 4:06.

20) Thomas, S., Patel, D., Bittel, B., Wolski, K., Wang, Q., Kumar, A., Il'Giovine, Z. J., Mehra, R., McWilliams, C., Nissen, S. E., & Desai, M. Y. (2021). 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. JAMA network open, 4(2), e210369.

21) Noe, S., Zange, S., Seilmaier, M. et al. Clinical and virological features of first human monkeypox cases in Germany. Infection (2022).