The mineral zinc is known to play a key role in the immune system, and people who are deficient in zinc experience an increased incidence in different pathologies.

Several aspects of the immune system are affected by this mineral—from the dermis barrier to the regulation of genes within lymphocytes.

Macrophages, a monocyte variant with an important immunological function, is adversely affected by zinc deficiency that can deregulate cytokine production in the intracellular media.

Apoptosis is a programmed cell death mechanism that can be enhanced by the presence of zinc. Zinc also acts as a factor in the endogenous antioxidant system with the potential to stabilize cell membranes.

Zinc deficiency can interfere with human health and be the cause of several pathological changes and alterations such as hypogonadism, cognitive changes, decreased activity of the immune system, diarrhea, delayed healing processes, oligospermia, and loss of muscle mass; and it can affect the activity of auxiliary T cells.

Many biological structures such as proteins, tissue and organs are protected against diseases involving the immune system which can be of two types:

• Innate immune system, which is a non-specific defense mechanism that acts immediately after the antigen appears in the body.
• Acquired immunology system, also known as adaptive immunity, identified as a specific antigen immunity.

The most important cell in our body that protects it from disease is the leukocyte.

Zinc deficiency can negatively influence immune function, leading to infection of the different systems in the body.

All infections develop because inflammatory cytokines, such as IL6, IL2, IL-β, decrease within the plasma due to zinc deficiency; and this mineral in turn allows normal functioning of neutrophils and natural killer cells.

When there is a zinc deficiency, it can affect the development of acquired immunity that is modulated by T lymphocytes in B lymphocytes by activating cytokine production by TH1.^1-4

The recommended daily doses (RDA) for zinc are 11 mg/day for men and 8 mg/day for women. In general the isolated use of zinc is recommended for short periods of time to be later associated with copper maintaining a physiological ratio not greater than 16:1.

Zinc: Clinical Review

A study carried out on 15 patients with an average of 70 years of age administering 200 mg of zinc sulphate 2x per day for one month when compared to the 15 control patients, relating age and sex, found a significant improvement in the following immunological parameters in the treated group:

• Number of circulating T lymphocytes
• A delay in cutaneous hypersensitivity to antigens such as PPD, candidine, and streptokinase-streptodornase.
• Response by IgG antibodies to tetanus vaccine, showing the effectiveness of zinc administration in the elderly to improve immune function.⁵

Chemical and biochemical aspects of moderate to severe zinc deficiency for humans is well defined, but recognizing mild zinc deficiencies is still very difficult. To study this, a group of human volunteers developed mild zinc deficiency using an experimental semi-synthetic diet.^6-8

In this model, immunological deficiency was clearly established mainly on lymphocyte and thymic activity, with decreased killer cell activity, decreased IL-2, decreased testosterone, oligospermia, and altered ammonia metabolism.^6-8

A meta-analysis was conducted of placebo-controlled studies using chewable zinc tablets to treat acquired flu with a daily dose of 75 gr; seven studies were included, three using zinc acetate and four using zinc gluconate. All studies were double blind, and a statistically significant reduction in the total duration of the cold was found in both the gluconate and acetate groups; but zinc acetate seemed more effective.⁹

In another randomized double-blind placebo-controlled study, participants who suffered from common colds received zinc gluconate with 23 mg elemental zinc, initially two at a time and then 2 every two hours, not exceeding 12 tablets for adults and 9 tablets for young people. Children under 27 kg received half the dose not exceeding six tablets a day. This treatment was continued for seven days. This analysis was restricted to 65 patients who reported being ill for three days or less before starting the study and who continued treatment throughout the survey. The zinc group had a significantly faster recovery speed to becoming asymptomatic and more had recovered at the end of 7 days. The prevalence and severity of symptoms were significantly lower in the zinc group. More adverse effects were found in the zinc group with oral irritation, alteration of taste, nausea, and mainly the tablets are not palatable.¹⁰

In another randomized double-blind placebo-controlled study, 100 patients with influenza that persisted for 24 hours or less received a placebo or tablet containing 13.3 mg of elemental zinc from zinc gluconate, administered every 2 hours until the subject was asymptomatic. There was a statistically notable reduction in the duration of the flu with a reduction in nasal and throat symptoms, cough, headache, runny nose, rhinorrhea. Among the side effects, they were higher in the zinc group associated with nausea and halitosis.¹¹

A randomized double-blind placebo-controlled study of 50 patients with a common cold received 12.8 elemental zinc from zinc acetate and were instructed to take one tablet every 2 to 3 hours as long as they were awake and for as long as needed to reverse their symptoms. This study found a significant reduction in the symptoms of influenza in the zinc group. Also, after 12 days the severity of the condition was significantly less in the medicated group. There are no differences in inflammatory markers of cytokines.¹²

In two randomized placebo-controlled studies, 273 patients who were experimentally induced with rhino virus type 39 and 281 patients who acquired a cold in the natural form were asked to take 13.3 mg of elemental zinc in the form of zinc gluconate or 5 mg or 11.5 mg of zinc acetate every 2 or 3 hours while awake—maximum 6 tablets per day for 14 days. The results showed a statistically significant reduction in the duration of colds in the experimental infection using zinc gluconate, but not in the acetate group. None of the groups showed a reduction in severity compared with placebo during the three days that were tested. For a cold of natural origin, there was no significant reduction.¹³

In another double-blind randomized placebo-controlled study, 100 healthy children, aged 8 to 13 years, received 15 mg of zinc in the form of chelated bis-glycine, 1 per day or placebo for three months. The idea was to research the presence of any cold symptoms at any time for three months. Statistically fewer coughs and runny noses were found, but there was more fever in the zinc group although the differences were not significant.¹⁴

Children with zinc deficiency in developing countries have increased risk of various types of infectious diseases; a published study shows that improving zinc deficiency in Thai children can reduce the duration of dengue fever as well as limit hospitalization in addition to other advantages that the authors cite in relation to normal levels of zinc over the general health of children.¹⁵

In a randomized double-blind study with placebo control, 32 patients who were exposed to rhinovirus 39 were given 23 mg of elemental zinc gluconate or placebo every 2 hours for a total of eight days, starting on the second day of exposure. Both groups had a very similar infection, but the statistically significant reduction was only found in the group that took zinc. In another study, 45 patients were exposed to rhinovirus 13 and took the same dose and the same proportion of zinc, but no statistically significant difference was found.¹⁶

A study published in 2016 shows that zinc-deficient patients could be associated with increased chronic inflammation in HIV positive patients, showing that zinc could function as an anti-inflammatory agent in patients with zinc deficiency.¹⁷

Using 46 mg of elemental zinc in gluconate format daily in healthy elderly patients for six months, an association was found with the reduction of the body’s inflammatory status.¹⁸

A study carried out on nine male patients for a duration of six months found that the normalization of zinc deficiency had the ability to restore the concentration of TNF-α and IL-1 leptin, although it did not influence the fat mass or other hormones circulating.¹⁹

Conclusion

This systematic review shows us clearly that patients who are clinically deficient in zinc and patients who are administered zinc in the initial phase of viral exposure respond with a faster regression of symptoms and an improvement in clinical response. Regarding inflammation markers, studies are controversial; and it is still necessary to carry out expanded multicenter studies. Although it is recommended to use the zinc mentioned above, it is important to review the concepts of the association of zinc with other nutrients that act in parallel pathways of the immune response.

References

1. Khanam S. Impact of Zinc in Immune Response. Immunology. Curr Res. 2018,2:1
2. Kumar P, et al. KUMAR and Clark Clinic Medicine 8^th Edinburgh: Elsevier/Saunders
3. Lasis, et al. Zinc Supplementation for the Prevention of Pneumonia in Children age 2 Months to 59 Months. Cochrane database syst rev 12: CD005978.
4. Foste M, et al. Zinc and Regulation of Inflammatory Cytokines: Implications for Cardiometabolic Disease. Nutrients. 2012;4: 676-694
5. Duchateaus J, et al. Beneficial Effects of Oral Zinc Supplementation on the Immune Response of Old People. The American Journal of Medicine. May 1981; vol 70; 1001-1004
6. Prasad AS, et. al. Serum Thymulin in Human Zinc Deficiency. J Clin. 1988; 82:1202-10.
7. Beck FW, et al. Changes in Cytokines Production and T Cell Subpopulation in Experimentally. Induced Zinc Deficient Humans. Am J. Physiol Endocrional Metb. 1997; 272: 1002-7
8. Prasad AS, et al. Experimental Zinc Deficiency. Ann Intern Med. 1978; 89:483-90.
9. Hemila H, et al. Zinc Lozenges and the Common Cold: A Meta-Analysis Comparing Zinc Acetate and Zinc Gluconate, and the Role of Zinc Dosage. Journal of the Royal Society of Medicine Open. 2017 May 2;8(5)
10. EBY GA, et al. Reduction in Duration of Common Colds by Zinc Gluconate Lozenges in a Double-Blind Study. Antimicrob Agent Chemotherapy. 1984. Jan; 25 (1)
11. Mossad SB, et al. Zinc Gluconate Lozenges for Treating the Common Cold. A Randomized, Double-Blind, Placebo-Controlled Study. Ann of Internal Medicine. 1996. Jul 15; 125(2): 81-8
12. Ananda S, et. al. Duration of Symptoms and Plasma Cytokine Levels in Patients with the Common Cold Treated with Zinc Acetate. The Journal of Infectious Disease. 15 August 2000.
13. Turner RB, et. al. Effect of Treatment with Zinc Gluconate or Zinc Acetate on Experimental and Natural Colds. Clinical Infectious Disease. November 15, 2000; 13 (5): 1202-1208.
14. Weismann K, et al. Zinc Gluconate Lozenges for Common Cold. A Double-Blind Clinical Trial. Danish Medical Bulletin. 1990 Jun; 37 (3): 279-81.
15. Weismann K, et al. A Randomized Controlled Trial of Zinc Supplementation as Adjuvant Therapy for Dengue Viral Infection in Thai Children. Pediatrics. October 16, 1098
16. Farr MB, et al. Two Randomized Controlled Trials of Zinc Gluconate Lozenge Therapy of Experimentally Induced Rhinovirus Colds. Antimicrobial Agents and Chemotherapy. August 1987; 31 (8): 1183-7.
17. University of Massachusetts at Amherst. Zinc Deficiency May Contribute to Increased Inflammation Among HIV-Positive Individuals. Science News. April 22, 2016.
18. Bao Bin, et al. Zinc Decreases C-reactive Protein, Lipid Peroxidation, and Inflammatory Cytokines in Elderly Subjects: a Potential Implication of Zinc as an Atheroprotective agent. Am J. Clin Nutr. 2010 June 9; 9(16): 1634-41.
19. Mantzoros CS. Zinc May Regulate Serum Leptin Concentrations in Humans. Journal of the American College of Nutrition. 1998 Jun; 17(3);270-5.