Self-Care for Common Colds: The Pivotal Role of Vitamin D, Vitamin C, Zinc, and Echinacea in Three Main Immune Interactive Clusters (Physical Barriers, Innate and Adaptive Immunity) Involved during an Episode of Common Colds—Practical Advice on Dosages and on the Time to Take These Nutrients/Botanicals in order to Prevent or Treat Common Colds

Table 2

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

Authors	Type of study	Subjects	Dosage	Results	Type of immunity involved	Mechanism of action
Bergman et al.; 2015	A randomized, placebo-controlled, and double-blinded study	The per protocol population ( patients aged 18 to 75 years), who completed the study, consisted of vitamin D treated and placebo treated patients.	oral vitamin D3 (4000 IU/day for 1 year) treated and oil (Miglyol) placebo treated patients.; Follow-up: 12 months.	Vitamin D supplementation increased the probability of staying free of respiratory tract infections (RTI) during the study year (RR 0.64, 95% CI 0.43–0.94). Further, the total number of RTIs was also reduced in the vitamin D group (86 RTIs) versus placebo (120 RTIs; ). Finally, the time to the first RTI was significantly extended in the vitamin D group (HR 1.68, 95% CI 1.03–2.68, ).		The role of vitamin D in respiratory tract infections is still not clear, despite several large RCTs in the area. This can probably be explained by the large heterogeneity in these randomized controlled trials (RCTs).
Bock et al.; 2011	A double-blind, placebo-controlled trial	59 healthy adult subjects (49% females).	Subjects received oral vitD3 (140,000 IU oleovitD3, monthly) or placebo (almond oil) for a period of 3 months.	% regulatory T cells (Tregs) increased significantly only in the vit D group. A short time high-dose vitD3 supplementation significantly increased the frequency of Tregs, but did not further improve β-cell function in apparently healthy subjects.	Adaptive immunity: T cells and β cell function	The immunomodulatory potential of vit D might be an important mechanistic link for the association of vit D and T1D.
Goodall et al.; 2014	Double-blind clinical trial	600 participants (≥17 years), 471 (78.5%) completed all surveys while 43 (7.2%) completed none.	Participants were randomized to receive a container with eight capsules of either 10,000 IU of active vitamin D3 or identical placebo. Students are randomized into 4 treatment arms: (1) vitamin D3 and gargling, (2) placebo and gargling,; (3) vitamin D3 and no gargling, and (4) placebo and no gargling.	Of 600 participants, 471 (78.5%) completed all surveys while 43 (7.2%) completed none; 150 (25.0%) reported clinical URTI. Seventy participants (23.3%) randomized to vitamin D3 reported clinical URTI compared to 80 (26.7%) randomized to placebo (RR: 0.79, CI95: 0.61–1.03, ). Eighty-five participants (28.3%) randomized to gargling reported clinical upper respiratory tract infection (URTI) compared to 65 participants (21.7%) randomized to the no gargling arm (RR: 1.3, CI95: 0.92–1.57, ). Laboratory testing identified 70 infections (46.7 per 100 URTIs). Vitamin D3 treatment was associated with a significantly lower risk for laboratory confirmed URTI (RR: 0.54, CI95: 0.34–0.84, ) and with a significantly lower mean viral load measured as log10 viral copies/mL (mean difference: −0.89, CI95: −1.7, −0.06, ). Fewer students assigned to gargling experienced laboratory confirmed URTI; however this was not statistically significant (RR: 0.82, CI95: 0.53–1.26, ).		Vitamin D3 is a promising intervention for the prevention of URTI. Vitamin D3 significantly reduced the risk of laboratory confirmed URTI and may reduce the risk of clinical infections.
Camargo et al.; 2012	Double-blind clinical trial	744 Mongolian; children from 21 third- and fourth-grade classrooms (9-10 years old), but this analysis focused on a subset of 247 children who were assigned to daily ingestion of unfortified regular milk or milk fortified with 300 IU of vitamin D3.; 50% of children, who drank milk, were male.; 54% of children, who drank milk vitamin D fortified were male.	The Blue Sky Study examined 5 approaches to improve the vitamin D status of Mongolian schoolchildren: (1) 300 IU of vitamin D3 daily in Mongolian milk (); (2) 300 IU of vitamin D3 daily in US milk (); (3) 300 IU of vitamin D3 daily in a milk substitute (); (4) 300 IU of vitamin D3 in a daily pill (); and (5) a total of 13,700 IU of vitamin D3 in pills given over the first 7 days of study ().; Follow-up: winter (January–March).	At baseline, the median serum 25(OH)D level was 7 ng/mL (interquartile range: 5–10 ng/mL). At the end of the trial, follow-up was 99% (), and the median 25(OH)D levels of children in the control versus vitamin D groups were significantly different (7 versus 19 ng/mL; = 0.001). Compared with controls, children receiving vitamin D reported significantly fewer ARIs during the study period (mean: 0.80 versus 0.45; ), with a rate ratio of 0.52 (95% confidence interval: 0.31–0.89). Adjusting for age, gender, and history of wheezing, vitamin D continued to halve the risk of ARI (rate ratio: 0.50 [95% confidence interval: 0.28–0.88]). Similar results were found among children either below or above the median 25(OH)D level at baseline (rate ratio: 0.41 versus 0.57; p for interaction = .27).		Vitamin D supplementation significantly reduced the risk of ARIs in winter among Mongolian children with vitamin D deficiency.
Urashima et al.; 2010	A multicenter, randomized, double-blind, placebo-controlled, parallel-group trial	430 schoolchildren (56% were male) aged 6–15 y, with or without underlying diseases, were eligible and asked to participate in the study by the pediatricians in charge of the outpatient clinics.	The participants were asked to take 3 tablets twice daily, total: 1200 IU vitamin D3 (217 children) or placebo (213 children).; The accrual period was from December 1, 2008, to March 31, 2009.	Influenza A occurred in 18 of 167 (10.8%) children in the vitamin D3 group compared with 31 of 167 (18.6%) children in the placebo group [relative risk (RR), 0.58; 95% CI: 0.34, 0.99; ]. The reduction in influenza A was more prominent in children who had not been taking other vitamin D supplements (RR: 0.36; 95% CI: 0.17, 0.79; ) and who started nursery school after age 3 y (RR: 0.36; 95% CI: 0.17, 0.78; ). In children with a previous diagnosis of asthma, asthma attacks as a secondary outcome occurred in 2 children receiving vitamin D3 compared with 12 children receiving placebo (RR: 0.17; 95% CI: 0.04, 0.73; ).		Vitamin D3 supplementation during the winter may reduce the incidence of influenza A, especially in specific subgroups of schoolchildren.
Şişmanlar et al.; 2016	Clinical trial	Sixty-three children aged between six months and five years with lower respiratory infections and 59 age-matched children who had no history of respiratory symptoms in the last month and no accompanying chronic disease.	Follow-up: December 2010 and February 2011.; 25 (OH) vitamin D level of <20 ng/mL was considered vitamin D deficiency, a level of 20–30 ng/mL was considered vitamin D insufficiency, a level of >30 ng/mL was considered normal, and a level of >150–200 ng/mL was considered intoxication.	No significant correlation was found between vitamin D levels and lower respiratory tract infection in terms of disease and its severity. However, it was found that vitamin D deficiency/insufficiency was observed with a high rate in all children included in the study.		Although no correlation was found between vitamin D level and lower respiratory tract infection, it is recommended that vitamin D level should be measured in children with lower respiratory tract infection and vitamin D supplementation should be given to all children especially in winter months based on the fact that the level of vitamin D was lower than normal in approximately half of the children included in the study and considering the effects of vitamin D on infections, pulmonary functions, and immunity.
Li-ng et al.; 2009	A 3-month prospective, randomized, double-blind, placebo-controlled trial of vitamin D3 supplementation in ambulatory adults	162 adults (18–80 years old) were randomized.; Male: 17 active, 13 placebo.; Female: 61 active, 57 placebo.	84 patients received 50 μg/d vitamin D3 and 78 patients received placebo.; Follow-up: March–June 2007.	There were no significant differences between the active and placebo patients at baseline. The baseline 25-OHD levels ranged from 16 to 156 nmol/l with mean level of  nmol/l in the study population. At baseline, 23% of the active patients exceeded 75 nmol/l.
Bischoff-Ferrari et al.; 2012	Clinical trial	20 white postmenopausal women, 50 to 70 years of age, in general good health with an average 25(OH)D level of  ng/mL (mean ± SD) and a mean age of years were randomized to either 20 mg of HyD or 20 mg (800 IU) of vitamin D3 per day in a double-blind manner.	Participants attended one screening visit and 14 clinical visits during a 4-month trial period.; Women who passed eligibility criteria signed informed consent and were randomly assigned to one of four groups: 20 mg HyD daily, 20 mg (800 IU) vitamin D3 daily, 140 mg HyD weekly, or 140 mg (5600 IU) vitamin D3 weekly. All supplements were taken orally. We randomized five participants to each treatment group. The dose of vitamin D3 was chosen to compare to the current standard for vitamin D3 (20 mg800 IU/d).	Mean 25(OH)D levels increased to 69.5 ng/mL in the HyD group. This rise was immediate and sustained. Mean 25(OH)D levels increased to 31.0 ng/mL with a slow increase in the vitamin D3 group. Women on HyD compared with vitamin D3 had 2.8-fold increased odds of maintained or improved lower extremity function (odds ratio [OR]2.79; 95% confidence interval [CI], 1.18–6.58) and a 5.7-mmHg decrease in systolic blood pressure ( 0.0002). Both types of vitamin D contributed to a decrease in five out of seven markers of innate immunity, significantly more pronounced with HyD for eotaxin, IL-12, MCP-1, and MIP-1 b. There were no cases of hypercalcemia at any time point. Twenty micrograms (20 mg) of HyD per day resulted in a safe, immediate, and sustained increase in 25(OH)D serum levels in all participants, which may explain its significant benefit on lower extremity function, systolic blood pressure, and innate immune response compared with vitamin D3.	innate immune response	The study shows that 20 mg HyD is significantly more efficient and more rapid in shifting healthy postmenopausal women into a desirable 25(OH)D serum level of at least 30 ng/mL compared to 800 IU (20 mg) vitamin D3.
Charan et al.; 2012	A systematic review and meta-analysis	Humans; Adults (18–80 year, 18–28 men, and postmenopausal women) and children (1–3 year, 6–15 year).; The population number is not reported.	Dose of vitamin D used in these clinical trials ranged from 400 IU/day to 2000 IU/day. In one clinical trial single parenteral dose of vitamin D was given (100000 IU).	Events of respiratory tract infections were significantly lower in vitamin D group as compared to control group [odds ratio = 0.582 (0.417–0.812) ] according to random model. On separate analysis of clinical trials dealing with groups of children and adults, beneficial effect of vitamin D was observed in both, according to fixed model [odds ratio = 0.579 (0.416–0.805), and odd ratio = 0.653 (0.472–0.9040), resp.].	Innate and adaptive; immunity	It is believed that vitamin D increases the production of natural antibodies. Vitamin D is also known to strengthen the immunity by inducing monocyte differentiation and inhibiting lymphocyte proliferation. It is also postulated that vitamin D enhances the phagocytic activity of macrophages.
Chen et al.; 2016	Clinical trial	99 women with a history of two or more successive miscarriages.; A total of 35 patients constituted the vitamin D normal group (VDN) (age 33.6 y ± 3.9), and 51 patients were included in the vitamin D insufficiency group (VDI) (age 32.4 y ± 3.9), and 13 vitamin D deficiency patients in VDD (age 33.0 y ± 4.4).	Patients with recurrent miscarriage (RM) were supplemented with 0.5 μg/day of 1,25(OH)2D for 2 months and then peripheral blood cells.	The percentage of CD19+ B cells and NK cytotoxicity at an effector-to-target cell (E : T) ratio of 50 : 1, 25 : 1, and 12.5 : 1 were significantly higher in the vitamin D insufficiency group (VDI) than in the vitamin D normal group (VDN) ( each). The proportion of TNF-α-expressing Th cells was significantly higher in the vitamin D deficiency group (VDD) than in VDN (). However, there were no significant differences between VDI and VDD. This dysregulation was significantly reduced with 1,25(OH)2D supplementation.	Innate and adaptive immunity: cell-mediated immunity	It was found that the percentage of peripheral blood CD19+ B cells, the percentage of TNF-α- producing Th cells, and NK cytotoxicity at all E : T ratios were dramatically reduced under 1,25(OH)2D supplementation. it has been shown that 1,25(OH)2D could downregulate several genes associated with TNF-α, including proteins involved in the transcription of TNF-α, one of its primary receptors, and TNF-α itself. Vitamin D was also able to depolarize perforin expression in the cytoplasm, which reduced the NK cytotoxicity in RM patients.
Dankers et al.; 2017	Review			The review discussed the effect of vitamin D which is the modulation of the immune system.; The review discusses the current knowledge about the molecular mechanisms underlying the immunomodulatory effects of vitamin D and how these advances can be used in the treatment of autoimmune diseases.	Autoimmunity, innate and adaptive; immunity
De Gruijl and Pavel; 2012	Randomized clinical study	105 student volunteers (18–30 years of age) divide in 3 groups.	The participants were randomized to 3 groups: (A) subjected to 3 times a week sub-sunburn sunbed exposure (), (B) daily vitamin D supplementation, 1000 IU (), and (C) a control group without any intervention (). The mean serum level of 25-hydroxyvitamin D (25(OH)D) dropped from 62 to 55 nmol in group C, while these levels rose from 62 to 109 and from 58 to 93 nmol in groups A and B.	Although fewer colds occurred in the groups (A) and (B) compared with control group (C), the difference was not significant. The initial 25(OH)D levels in the volunteers that caught a cold () were not significantly different from those who did not (): mean of 61 (SD 21) versus 61 (SD 20) nmol (nor were the final levels different: mean of 86 (SD 31) versus 86 (SD 32) nmol ).	Innate immunity and skin barrier	The study shows sub-sunburn sunbed treatment to be effective in tanning and in increasing the 25(OH)D serum level, more so than oral vitamin D supplementation by 1000 IU per day. Despite earlier results suggesting a possible beneficial effect on colds, this 8-week mid-winter course of sunbed exposures has, however, no appreciable effect on colds.
de Sá Del Fiol et al.; 2015	Review	Humans.		This study aimed to review recent clinical and epidemiological studies conducted in adults and children and to evaluate the functional role of vitamin D in respiratory infections. The evaluated studies show an important immunomodulatory role of vitamin D, which reduces the incidence and risk of URTIs (upper respiratory tract infections), both in children and in adults. Combating URTIs can be done prophylactically, associating the use of vaccines against Streptococcus pneumoniae with strengthening the immune system through supplementation with vitamin D.	Innate and adaptive immune system	Vitamin D appears to combat infection via multiple mechanisms. It has a direct influence on the production of cathelicidin, which may lead to increased susceptibility to viruses and bacteria, and it influences cytokine profiles during infection via the innate and adaptive immune system.
Denlinger et al.; 2016	A clinical trial: the AsthmaNet VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness) trial	408 adult patients.	Patients are randomized to receive placebo or cholecalciferol (100,000 IU load plus 4,000 IU/d) for 28 weeks as add-on therapy.	A total of 203 participants experienced at least one cold. Despite achieving 25-hydroxyvitamin D levels of 41.9 ng/ml (95% confidence interval [CI], 40.1–43.7 ng/ml) by 12 weeks, vitamin D supplementation had no effect on the primary outcome: the average peak WURSS-21 scores (62.0 [95% CI, 55.1–68.9; placebo] and 58.7 [95% CI, 52.4–65.0; vitamin D]; ). The rate of colds did not differ between groups (rate ratio [RR], 1.2; 95% CI, 0.9–1.5); however, among African Americans, those receiving vitamin D versus placebo had an increased rate of colds (RR, 1.7; 95% CI, 1.1–2.7; ). This was also observed in a responder analysis of all subjects achieving vitamin D sufficiency, regardless of treatment assignment (RR, 1.4; 95% CI, 1.1–1.7; ).	Epithelium innate immunity	The authors hypothesized but did not observe that achieving vitamin D sufficiency would allow for enhanced responsiveness to ICS (the daily dose of inhaled corticosteroid) with respect to lung function owing to the ability of vitamin D to influence steroid metabolism. Conversely, it is also possible that the change in ICS doses during the protocol influenced vitamin D metabolism and/or the expression of the vitamin D receptor and binding protein, so it is possible that we did not give enough vitamin D and that 25(OH)D levels in the serum do not reflect the changes relevant to airway epithelium innate immunity.
Erickson et al.; 2000	Review			Micronutrients such as zinc, selenium, iron, copper, b-carotene, vitamins A, C, and E, and folic acid can influence several components of innate immunity. Selected micronutrients play an important role in alteration of oxidant-mediated tissue injury, and phagocytic cells produce reactive oxidants as part of the defense against infectious agents.	Innate immunity	Deficiencies in zinc and vitamins A and D may reduce natural killer cell function, whereas supplemental zinc or vitamin C may enhance their activity.
Hewison; 2012	Overview			It is now clear that cells from the immune system contain all the machinery needed to convert 25-hydroxyvitamin D to active 1,25- dihydroxyvitamin D, and for subsequent responses to 1,25-dihydroxyvitamin D. Such mechanisms are important for promoting antimicrobial responses to pathogens in macrophages and for regulating the maturation of antigen-presenting dendritic cells. The latter may be a key pathway by which vitamin D controls T lymphocyte (T cell) function. However, T cells also exhibit direct responses to 1,25-dihydroxyvitamin D, notably the development of suppressor regulatory T cells.	Innate and adaptive; immunity	Vitamin D is a key factor linking innate and adaptive immunity, and both of these functions may be compromised under conditions of vitamin D insufficiency.
Gupta et al.; 2016	A randomized control trial	38 adults with vitamin D deficiency and untreated pre- or early stage I hypertension were included.	Participants are randomized to either low- (400 IU daily) or high- (4000 IU daily) dose oral vitamin D3 for 6 months.	Treatment with 4000 IU of vitamin D3 decreased intracellular CD4+ ATP release by 95.5 ng/ml (interquartile range, −219.5 to 105.8). In contrast, 400 IU of vitamin D3 decreased intracellular CD4+ ATP release by 0.5 ng/ml (interquartile range, −69.2 to 148.5). In a proportional odds model, high-dose vitamin D3 was more likely than low-dose vitamin D3 to decrease CD4+ ATP release (odds ratio, 3.43; 95% confidence interval, 1.06–1.11).	Adaptive immunity: cell-mediated immunity	Treatment with high-dose vitamin D3 reduces CD4 T cell activation, providing direct human data that vitamin D may influence cell-mediated immunity (CMI). These findings offer a mechanistic correlation for the potential influence of vitamin D on the course of immune-mediated disorders.
Laaksi et al.; 2010	A placebo-controlled double-blinded study	164 voluntary young Finnish men (18–28 years of age).	The subjects were randomly assigned to the intervention group, which received 400 IU (10 mg) vitamin D3 daily, or the control group, which received placebo for 6 months.	After daily supplementation, the mean serum 25(OH)D concentrations (±SD) were  nmol/L () in the intervention group and  nmol/L () in the placebo group (). The number of days of absence from duty due to respiratory tract infection did not differ between groups. Mean number of absence days (±SD) was days in the intervention group and days in the placebo group (). There was an effect during the first 6 weeks of the study, with a mean (±SD) of absence days in the intervention group and absence days in the placebo group ().	Innate immunity
Maggini et al.; 2007	Review			The vitamins A, B6, B12, C, D, and E; folic acid; and the trace elements iron, zinc, copper, and selenium work in synergy to support the protective activities of the immune cells. Finally, all these micronutrients, with the exception of vitamin C and iron, are essential for antibody production. Overall, inadequate intake and status of these vitamins and trace elements may lead to suppressed immunity, which predisposes one to infections and aggravates malnutrition.	Innate, adaptive immunity and autoimmunity	Vitamin D and especially its biologically active metabolite 1,25-dihydroxycholecalciferol (1,25(OH)2D3) act as powerful immunoregulators. The discovery of significant quantities of vitamin D receptors in monocytes, macrophages, and thymus tissue suggests a specific role of vitamin D and its metabolites in the immune system. Most cells of the immune system except B cells express vitamin D receptors.
Martineau et al.; 2017	Systematic review and meta-analysis of individual participant data (IPD) from randomized controlled trials	Total 11321 participants, aged 0 to 95 years.	Benefit was greater in those receiving daily or weekly vitamin D without additional bolus doses (NNT = 20), and the protective effects against acute respiratory tract infection in this group were strongest in those with profound vitamin D deficiency at baseline (NNT = 4).	Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; for heterogeneity < 0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; for interaction = 0.05). Among those receiving daily or weekly vitamin D; protective effects were stronger in those with baseline 25-hydroxyvitamin D levels < 25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥ 25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; for interaction = 0.006).
Mayan et al.; 2015	Clinical trial	82 adolescent swimmers for serum 25(OH)D and TREC (T cell receptor excision circles) concentrations; it was found that 55 had vitamin D insufficiency.	Fifty-five participants (67%) had vitamin D insufficiency and comprised an interventional study group, where subjects were randomized to receive supplementation of either vitamin D3 (2000 IU/day) in liquid drops or a placebo. Subjects who were vitamin D sufficient did not receive any supplementation or treatment. Randomized supplementation of either vitamin D3 or placebo was given for 12 winter weeks.	TREC concentrations decreased with the participants’ age (, ), with no significant between-gender difference. TREC concentrations did not materially differ among subjects with normal, insufficient, or deficient vitamin D status and were not affected by vitamin D supplementation. No significant correlations were found between TREC levels, or their changes during the study period, and mean upper respiratory infections (URI) severity or duration.	Adaptive immunity	The authors found no significant correlation between vitamin D and TREC levels, either before or after supplementation, suggesting that the immunomodulatory effects of vitamin D are not exerted directly on the thymus gland. Indeed, several other mechanisms by which vitamin D may influence T cell function have been proposed, including direct endocrine effects on T cells mediated via systemic calcitriol, direct intracrine conversion of 25(OH)D to calcitriol by T cells, direct paracrine effects of calcitriol on T cells following conversion of 25(OH)D to calcitriol by monocytes or dendritic cells, and indirect effects on antigen presentation to T cells mediated via localized antigen-presenting cells affected by calcitriol.
Schwalfenberg; 2011	Review			This review looks at the critical role of vitamin D in improving barrier function, production of antimicrobial peptides including cathelicidin and some defensins, and immune modulation. The function of vitamin D in the innate immune system and in the epithelial cells of the oral cavity, lung, gastrointestinal system, genitourinary system, skin, and surface of the eye is discussed.	Epithelial barrier and innate immunity
Murdoch et al.; 2012	Double-blind, placebo-controlled trial	322 healthy adults.	Participants were randomly assigned to receive an initial dose of 200,000 IU oral vitamin D3, then 200,000 IU 1 month later, then 100,000 IU monthly (), or placebo administered in an identical dosing regimen (), for a total of 18 months.	The mean baseline 25-OHD level of participants was 29 (SD, 9) ng/mL. Vitamin D supplementation resulted in an increase in serum 25-OHD levels that was maintained at greater than 48 ng/mL throughout the study. There were 593 upper respiratory tract infections (URTI) episodes in the vitamin D group and 611 in the placebo group, with no statistically significant differences in the number of URTIs per participant (mean, 3.7 per person in the vitamin D group and 3.8 per person in the placebo group; risk ratio, 0.97; 95% CI, 0.85–1.11), number of days of missed work as a result of URTIs (mean, 0.76 days in each group; risk ratio, 1.03; 95% CI, 0.81–1.30), duration of symptoms per episode (mean, 12 days in each group; risk ratio, 0.96; 95% CI, 0.73–1.25), or severity of URTI episodes.
Bartley; 2010	Review			Vitamin D is involved in the production of defensins and cathelicidin-antimicrobial peptides that provide a natural defense against potential microbiological pathogens. Vitamin D supplementation increases cathelicidin production. Low vitamin D levels are associated with an increased incidence of upper respiratory tract infections.	Innate immunity
Jorde et al.; 2016	Randomized controlled trial	Five hundred and eleven subjects with prediabetes.	Participants are randomized to vitamin D3 (20,000 IU per week) versus placebo for five years. Two hundred and fifty-six subjects received vitamin D and 255 placebo. One hundred and sixteen subjects in the vitamin D and 111 in the placebo group completed the five-year study.	Mean baseline serum 25-hydroxyvitamin D (25(OH)D) level was 60 nmol/. Eighteen subjects in the vitamin D group and 34 subjects in the placebo group reported urinary tract infections (UTI) during the study (), whereas no significant differences were seen for respiratory tract infections (RTI). The effect on UTI was most pronounced in males. The effect of vitamin D on UTI was unrelated to baseline serum 25(OH)D level.
Kamen and Tangpricha; 2010	Review			The importance of vitamin D in the regulation of cells of the immune system has gained increased appreciation over the past decade with the discovery of the vitamin D receptor (VDR) and key vitamin D metabolizing enzymes expressed by cells of the immune system.	Innate and adaptive immunity	The hormonal form of vitamin D upregulates antimicrobial peptides, namely, cathelicidin, to enhance clearance of bacteria at various barrier sites and in immune cells. Vitamin D modulates the adaptive immune system by direct effects on T cell activation and on the phenotype and function of antigen-presenting cells (APCs), particularly of DCs. The purpose of this manuscript is to review the molecular and clinical evidence for vitamin D as a modulator of the innate and adaptive immune system.
Bolland et al.; 2017	Editorial		Authors consider that current evidence does not support the use of vitamin D supplementation to prevent disease, except for those at high risk of osteomalacia, currently defined as 25-hydroxyvitamin D levels less than 25 nmol/L.	In absolute terms, the primary result is a reduction from 42% to 40% in the proportion of participants experiencing at least one acute respiratory tract infection. It seems unlikely that the general population would consider a 2% absolute risk reduction sufficient justification to take supplements. Furthermore, the definition of acute respiratory tract infection varied between studies, consisting of a mixture of diverse conditions such as acute otitis media, laboratory confirmed influenza, self-reported colds, parent reported colds or chest infections, or radiograph confirmed pneumonia.
Khakshour et al.; 2015	Cross-sectional study	90 children below 5 years of age suffering from respiratory infections.		In the group of children with respiratory disorders, 9 (42.9%) exhibited vitamin D deficiency. Vitamin D deficiency showed no meaningful statistical relation with acute respiratory infections ().		It is assumed that the lack of significant differences in vitamin D is due to the gestational age and other factors except that vitamin D deficiency plays crucial roles in respiratory system infections.
Zittermann et al.; 2016	Review			Regarding acute respiratory tract infection, RCTs indicate a significant risk reduction by vitamin D supplements [OR = 0.65; 95% confidence interval (CI) 0.50–0.85]. There is evidence that daily administration is more effective than high-dose bolus administration [OR = 0.48 (95% CI 0.30–0.77) versus OR = 0.87 (95% CI 0.67–1.14)] and that individuals with deficient or insufficient (30–50 nmol/l) circulating 25-hydroxyvitamin D levels benefit most.	Innate and adaptive; immunity