Table 1.

Studies on zinc, immunity, and common cold presented in the narrative review.

Authors	Type of study	Subjects	Dosage	Results	Type of immunity Involved	Mechanism of action
Turner; 2001	Clinical study, randomized	Ninety-one volunteers	41 treated with active medication (consisted of 33 mM zinc gluconate) and 50 treated with placebo for 3 days were inoculated with rhinovirus and then were treated with study medication for an additional 6 days, single nasal spray of 120 mL per nostril, at ∼4-h intervals, 5 times each day	Zinc treatment had no effect on total symptom score, rhinorrhea, nasal obstruction, or the proportion of infected volunteers who developed clinical colds
Mahalanabis et al.; 2004	Randomized, double-blind, placebo-controlled clinical trial	153 children aged 2–24	Four treatment: (1) zinc acetate (10 mg elemental Zn twice daily for 5 d) plus a placebo for vitamin A, (2) vitamin A as retinyl palmitate [10,000 μg retinol equivalents (RE) twice daily for 4 d] plus a placebo for zinc, (3) zinc plus vitamin A according to the above schedule, or (4) placebo for zinc and for vitamin A	Zinc treatment significantly reduces duration of fever and very ill status in boys, but not in girls, with severe acute lower respiratory infection (ALRI)		Zinc as a micronutrient plays a key role at the catalytic sites of a wide range of enzymes and is critical to human growth, metabolism, and immune function. The diets of children in many developing countries are often deficient in zinc and a high phytate : zinc ratio in their diet reduces zinc bioavailability
Barnett et al.; 2016	A randomized double-blind, placebo-controlled trial	53 nursing home elderly (aged ≥65 y)	Supplementation with 30 mg Zn/d for 3 mo	The increase in serum zinc concentration is associated with the enhancement of T cell function	Adaptive immunity	Mainly because of an increase in the number of T cells and Zn improves T cell-mediated function by increasing the number of functional T cells in the periphery
Prasad et al.; 2007	Randomized, double-blind, placebo-controlled trial	Fifty healthy subjects of both sexes aged 55–87 y	Each day for 12 mo, subjects in the zinc-supplemented group received 1 capsule of zinc gluconate (15 mg elemental zinc) orally	The mean incidence of infections per subject in 12 mo was significantly lower in the zinc-supplemented group than in the placebo group. A significantly lower incidence of fever and a nonsignificant trend toward a lower incidence of the common cold were observed in the zinc-supplemented group than in the placebo group	Innate immunity	Zinc supplementation decreased not only the production of inflammatory cytokines but also that of oxidative stress marker: the increase of IL-2 production in zinc-deficient elderly subjects by increasing the gene expression of IL-2 and by a decrease in IL-10 production
Pinna et al.; 2002	Clinical study	8 healthy men	The subjects were given a controlled 3-d rotating diet that contained 4.6 mg Zn/d. Zn intakes were adjusted by giving Zn gluconate supplements. During baseline periods and repletion periods, subjects' Zn intakes totaled 13.7 mg/d. During restriction period, the subjects consumed 4.6 mg of highly available Zn	Changes in lymphocyte proliferation and IL-2R expression may be early markers of mild zinc deficiency	Innate immunity	Zinc restriction reduced peripheral blood mononuclear cells (PBMNC) proliferation at all mitogen concentrations tested except 10 mg/L. Dietary zinc restriction reduced IL-2R secretion by PBMNC stimulated at a suboptimal PHA concentration. The secretion of IFN-γ and TNF-α was unchanged throughout the study
Maggini et al.; 2012	Data from two preliminary, double-blind, randomized, placebo-controlled trials, parallel-group	Study 1 included 30 patients: 13 males and 17 females Study 2 enrolled 64 patients: 25 males and 39 females	1000 mg vitamin C plus 10 mg zinc	Supplementation with vitamin C and zinc may represent an efficacious measure
Prasad et al.; 2008	Randomized, double-blind, placebo-controlled trial	Fifty ambulatory volunteers were recruited within 24 h of developing symptoms of the common cold	1 lozenge containing 13.3 mg of zinc (as zinc acetate) or placebo every 2-3 h while being awake	Mean durations of cold symptoms, cough, nasal discharge, and muscle ache were significantly decreased in the zinc group compared with the placebo group thanks to its anti-inflammatory and antioxidant properties	Innate immunity	The decrease in sIL-1ra and sTNF-R1 levels in the zinc group only suggests that zinc decreased the oxidative stress, resulting in decreased activation of monocytes and macrophages Zinc decreases ICAM-1 levels and induces the zinc-dependent transcription factor A20 in monocytes and macrophages, which inhibits NF-kB activation via the TNF-R-associated factor pathway Zinc is an inhibitor of NADPH oxidase, an enzyme that initiates the generation of free radicals; it is essential for superoxide dismutase and for generation of metallothionein, reduced the concentration of the oxidative stress markers, and inhibited the ex vivo induction of TNF-α and IL-1β mRNA in mononuclear cells; and it provided protection against TNF-α-induced NF-kB activation in isolated peripheral blood mononuclear cells
Bhandari et al.; 2002	Double masked, randomized placebo-controlled trial	2482 children aged 6 to 30 months	Daily elemental zinc, 10 mg to infants and 20 mg to older children or placebo for four months. Zinc gluconate	Zinc supplementation substantially reduced the incidence of pneumonia in children who had received vitamin A	Skin Innate immunity and adaptive immunity	Supplementation improves immune functions, including delayed cutaneous hypersensitivity, and increases the number of CD4 (helper) lymphocytes In experimental models zinc deficiency has been shown to impair cellular and humoral immune function
Bogden et al.; 1990	Double-blind partial crossover design	63 subjects (age 60–89)	3–6 month supply of placebo, 15 mg of Zn, or 100 mg Zn-capsules	Zinc had positive effects on one measure of cellular immune function but at the same time had an adverse effect on another measure of cellular immunity	Innate immunity	NK cell activity was enhanced, but, except for this cellular immune functions, were not significantly improved Delayed dermal hypersensitivity (DDH) increased in the study in placebo group and the suppression of the increase in DDH by zinc persisted
Mc Donald et al.; 2015	A randomized, double-blind, placebo-controlled clinical trial	2400 infants who were 6 wk of age and born to HIV-negative mothers in a low-malaria setting, Tanzania	Oral supplementation of MVs (vitamin B complex and vitamins C and E), zinc, zinc + MVs, or placebo for 18 mo. From the time of randomization to 6 mo of age, infants received 1 capsule/d, and from 7 mo of age to the end of follow-up, 2 capsules were provided daily The capsule contained 5 mg of zinc	Acute upper respiratory infections were significantly lower for infants supplemented with zinc than for those who did not receive zinc	Adaptive immunity	Mean CD4 T cell percentage was slightly but significantly higher among children who received zinc and MVs in comparison with placebo
Isbaniah et al.; 2010	Double-blind, randomized, placebo-controlled trial	Chronic obstructive pulmonary disease (COPD) patients with acute upper respiratory tract infection (URTI)—108 mostly male patients (age 40–81)	Treatment: EP (Echinacea purpurea) or EP + zinc, selenium, and ascorbic acid or placebo zinc = 10 mg	The combination of EP—zinc, selenium, and ascorbic acid—alleviates exacerbation symptoms caused by URTI in COPD	Innate and adaptive response	It seems that both selenium and zinc act on T lymphocytes, through modulating IL-2 secretion, its receptor expression, and sensitivity, as well as the thymulin activity which is required for the differentiation of CD4+ T cells. Zinc is included in the biosynthesis of leukotriene B4. Finally, the transcriptional repressor Gfi1, a zinger finger protein, was identified as a regulator of the innate immune response and to be essential for the development of macrophages-dependent cytokine production and granulocytes
Field et al.; 1987	Clinical study	15 female patients	Zinc supplements (50, 100, 150 mg)	Evidence in plasma and leucocyte zinc concentrations in an elderly population	Innate immunity	Decrease in granulocyte with high zinc doses probably thanks to the diminished phagocytic and chemotactic activity of polymorphonuclear cells
Wintergerst et al.; 2005	Review: a large number of randomized controlled intervention trials	Human	Daily intakes of 10–30 mg of zinc for children with infectious diseases	The authors explain that zinc and vitamin C play an important role in immune system: adequate intakes ameliorate symptoms and shorten the duration of respiratory tract infection, including the common cold, but there are discrepancies in trials that have been considered	Innate and adaptive immunity	Zinc is essential for the intracellular binding of tyrosine kinase to T cell receptors, which are required for T lymphocyte development and activation—lowered zinc status impairs cellular mediators of innate immunity such as phagocytosis by macrophages and neutrophils, natural killer cell activity, generation of the oxidative burst, and complement activity
Sanchez et al.; 2014	Randomized triple-blind community trial	301 children, 2–5 years of age	Children were distributed in three groups receiving zinc amino acid chelate, zinc sulfate, and placebo five days a week for 16 weeks 7 mg of zinc for children with 2-3 years and 9,45 mg of zinc for children with 4-5 years	Zinc amino acid chelate had a better effect on reducing the incidence of acute respiratory infection in children	Innate immunity	Probably thanks to the production of interferon and the modulation of inflammatory cytokines
Martinez- Estevez et al.; 2016	12-month randomized controlled trial, triple-blind	355 children underwent randomization, with 174 assigned to the zinc supplementation group and 181 to the control group	Children in the active supplementation group received 5 mg of zinc oxide plus 525 mg of calcium carbonate plus 70 UI of vitamin D3 (Kid Cal), and children in the nonsupplemented control group received 525 mg of calcium carbonate plus 70 UI of vitamin D3	Decreased the incidence of URTI	Innate immunity	Among the various mechanisms involved in the antiviral effects of zinc, the ICAM-1 receptor blocking has been considered as one of the most important actions
Brooks et al.; 2004	Double-blind placebo-controlled trial	270 children (age 2–23 months)	Elemental zinc, 20 mg per day, or placebo	Zinc accelerates recovery from severe pneumonia in children and could help reduce antimicrobial resistance by decreasing multiple antibiotic exposures and lessen complications and deaths where second line drugs are unavailable	Innate immunity	Zinc has role in the acute phase response mediated by cytokines during acute infection, helping to boost the body's immune response through a defense cascade, beginning with mobilization and sequestration of zinc to metallothionein-rich tissue, rapid upregulation of immune defense specific protein synthesis, activation of immune defense activity such as macrophages, lymphocytes, and NK cells and antibody-dependent cytotoxicity
Sazawal et al.; 1997	A double-blind, randomized controlled trial	Children (zinc 38, control 48)	Zinc gluconate to provide elemental zinc 10 mg daily and 20 mg during diarrhea	Zinc supplementation improves cellular immune status: regarding cell-mediated immunity (CMI), the percentage of anergic or hypoergic children (using induration score) decreased from 67% to 47% in the zinc group. The zinc group had a significantly higher rise in the geometric means of CD3, CD4, and CD4/CD8 ratio with no difference in CD8 and CD20. The rise in CD4 was significantly higher in the zinc as compared to the control group	Adaptive immunity	The observation of an increase in the number of circulating T lymphocytes, especially CD4 cells, after zinc supplementation may be explained by direct effect of zinc ion on the lymphocyte membrane affecting maturation and differentiation of T lymphocytes or by a stimulation of thymus endocrine function. Once T lymphocytes leave the thymus their differentiation and maturation are thought to be regulated by zinc-thymulin and deficiency of zinc-thymulin has been associated with secondary cellular immune deficiency and with immune senescence. Thus terminal deoxynucleotidyl transferase or zinc-thymulin has been suggested as possible mechanism by which zinc may be affecting T cell development and function
Sempertegui et al.; 1996	A randomized double-blind placebo-controlled trial	50 children (age 12–59 months old)	10 mg of zinc sulfate or placebo	After treatment (on day 60), the cutaneous delayed-type hypersensitivity (DTH) was higher in treated group; the incidence of fever, cough, and upper respiratory tracts secretions was lower in S group, but after 120 days the incidence of fever and upper respiratory tracts secretions was the same in both groups, but the incidence of cough was higher in S group	Innate immunity	The mechanism is not clear, probably improving cellular immunity
Bogden et al.; 1988	Clinical study	103 elderly subjects (age 60–89 years)	Three treatments: placebo, or 15 mg zinc/day or 100 mg/day for 3 months	In a subgroup (34,3%), Zn administration enhanced delayed dermal hypersensitivity (DDH)	Skin, innate immunity	cellular immunity will not be enhanced by Zn supplementation, but they argued that cellular immunity in subgroups of elderly people will be improved by Zn supplementation
Fortes et al.; 1998	A double-blind, randomized, controlled trial	178 elderly patients	4 treatments: (1) vit. A (800 μg retinol palmitate), (2) zinc (25 mg as zinc sulfate), (3) zinc + vit. A (800 μg retinol palmitate and 25 mg of zinc sulfate), (4) placebo	Zinc supplementation improves cell-mediated immune response, because it increases the number of CD4+DR+T cells and cytotoxic T lymphocytes	Immune and adaptive response	Effect on thymulin levels that promotes T cells functions, including suppressor function and interleukin-2 production. Zn prevents the negativity effects of vit. A on immunity
Turk et al.; 1998	Clinical study	26 patients in hemodialysis and 11 healthy patients (HP) were vaccinated with multivalent influenza vaccine (MIV)	Supplementation with 120 mg of ZnSO4	Zn supplementation could not restore the immune parameters and enhance antibody response to MIV in HP
Wieringa et al.; 2010	Randomized, double-blind, controlled trial	229 pregnant women with a gestational age <20 weeks, and infants and women were followed up monthly until the infants were 6 months old	In addition to iron (30 mg as ferrous fumarate) and folic acid (0,4 mg), one group of women received β- carotene (4,5 mg), one group zinc (30 mg as zinc sulfate), and one group β- carotene plus zinc (4,5 and 30 mg, resp.)	Maternal supplementation with zinc and β-carotene affected the newborn's immune development, but only zinc supplementation affects morbidity in the infants	Innate immunity	Zinc gives higher interleukin-6 production
Erickson et al.; 2000	Review	Humans	Supplementation such as zinc, selenium, iron, copper, b-carotene, vitamins A, C, and E, and folic acid	Micronutrients have an important role in immunity	Innate immunity	Zinc enhances natural killer cell functions; zinc supplementation directly induced cytokine production, predominantly IL-1, IL-6, and TNF-a, by mononuclear cells in vitro
Maggini et al.; 2007	Review	Humans		Inadequate intake and status of vitamins and trace elements may lead to suppressed immunity, which predisposes to infections and aggravates undernutrition. Therefore, supplementation with these selected micronutrients (including zinc) can support the body's natural defense system by enhancing all three levels of immunity	Skin innate and adaptive immunity	It is involved in the cytosolic defense against oxidative stress (superoxide dismutase activity) and is an essential cofactor for thymulin which modulates cytokine release and induces proliferation. It helps to maintain skin and mucosal membrane integrity and increases cellular components of innate immunity (e.g., phagocytosis by macrophages and neutrophils, NK cell activity, generation of oxidative burst, DTH activity), antibody responses, and the numbers of cytotoxic CD8þT cells (Th1 response)
Calder and Kew; 2002	Review			Increasing intakes of some nutrients above habitual and recommended levels can enhance some aspects of immune function; low plasma Zn levels predicted the subsequent development of lower respiratory tract infections	Skin innate and adaptive immunity	In patients with Zn deficiency related to sickle cell disease, natural killer cell activity is decreased. Zinc supplementation increases thymus size, and topical application of Zn improves the DTH response in the area of skin on which the application was made Zn administration to preterm-low-birth-weight infants increases the number of circulating T lymphocytes and their proliferation and a 5 mg Zn/d increases measures of cell-mediated immune function
Singh and Das; 2013	Review	Humans	There is a significant reduction in the duration of cold at a dose of ≥75 mg/day	Zinc administered within 24 hours of onset of symptoms reduces the duration of common cold symptoms in healthy people	Enhancement of innate as well as acquired immunity	Not clear
Hojyo and Fukada; 2016	Review			Zn has role in dendritic cells (that are important to present the peptide-MHC-II complex on their cell surface to antigen-specific CD4+ helper T (Th) cells to initiate immune responses) because a reduction in Zn is required for proper antigen presentation via MHC-II to elicit adaptive immune responses Zn deficiency is characterized by immunodeficiency with thymic atrophy and lymphopenia Zn controls antibody-mediated humoral immune responses and ZIP10-Zn has a role in early B-cell development and the maintenance of mature B cells ZIP10-Zn signaling may control fate decisions in lymphocyte progenitors under physiological conditions and exacerbate malignancy under pathological conditions, according to the highly regulated pattern of ZIP10 expression	Innate and adaptive immunity	Zn facilitates the endocytosis of MHC-II but inhibits the trafficking of MHC-II from the lysosome/endosome compartments to the plasma membrane the ZnD-induced thymic atrophy could result from the combination of increased glucocorticoid levels, an impairment of thymulin activity, and impaired cell-intrinsic survival function ZIP10-Zn signaling regulates the expression of CD45R while simultaneously (and indirectly) enhancing the CD45R PTPase activity through a Zn-dependent process rather than by a direct effect on PTPase activity The effect on development could be explained by glucocorticoids and ZIP10 maintains mature B cells through a LYN-independent mechanism ZIP10-Zn signaling inhibits the apoptosis induced by activated caspases and promotes pro-B-cell survival in a cell-autonomous manner Cytokine stimulation (the first signal) activates the JAK-STAT pathway (the second signal), which further induces ZIP10 expression and eventually generates ZIP10-Zn signals (the third signal)