Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Low Serum 25-Hydroxyvitamin D Level and Risk of Upper Respiratory Tract Infection in Children and Adolescents Vitamin D3 supplementation and upper respiratory tract infections in a randomized, controlled trial. Prevention of urinary tract infections with vitamin D supplementation 20,000 IU per week for five years. Results from an RCT including 511 subjects Vitamin D supplementation and upper respiratory tract infections in adolescent swimmers: a randomized controlled trial. A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections. Vitamin D status has a linear association with seasonal infections and lung function in British adults. Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial. Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): a multicentre, double-blind, randomised controlled trial. Cord Blood Vitamin D Deficiency Is Associated With Respiratory Syncytial Virus Bronchiolitis Randomized Trial of Vitamin D Supplementation and Risk of Acute Respiratory Infection in Mongolia High Doses of Vitamin D to Reduce Exacerbations in Chronic Obstructive Pulmonary Disease Vitamin D3 and gargling for the prevention of upper respiratory tract infections: a randomized controlled trial Effect of High-Dose vs Standard-Dose Wintertime Vitamin D Supplementation on Viral Upper Respiratory Tract Infections in Young Healthy Children Zinc combined with vitamin A reduces upper respiratory tract infection morbidity in a randomised trial in preschool children in Indonesia. Serum 25-Hydroxyvitamin D and the Incidence of Acute Viral Respiratory Tract Infections in Healthy Adults
Background Low serum levels of 25-hydroxyvitamin D3 are associated with an increased risk of respiratory tract infections ( RTIs ) . Clinical trials with vitamin D3 against various infections have been carried out but data are so far not conclusive . Thus , there is a need for additional r and omised controlled trials of effects of vitamin D3 on infections . Objective To investigate if supplementation with vitamin D3 could reduce infectious symptoms and antibiotic consumption among patients with antibody deficiency or frequent RTIs . Design A double-blind r and omised controlled trial . Setting Karolinska University Hospital , Huddinge . Participants 140 patients with antibody deficiency ( selective IgA subclass deficiency , IgG subclass deficiency , common variable immune disorder ) and patients with increased susceptibility to RTIs ( > 4 bacterial RTIs/year ) but without immunological diagnosis . Intervention Vitamin D3 ( 4000 IU ) or placebo was given daily for 1 year . Primary and secondary outcome measures The primary endpoint was an infectious score based on five parameters : symptoms from respiratory tract , ears and sinuses , malaise and antibiotic consumption . Secondary endpoints were serum levels of 25-hydroxyvitamin D3 , microbiological findings and levels of antimicrobial peptides ( LL-37 , HNP1–3 ) in nasal fluid . Results The overall infectious score was significantly reduced for patients allocated to the vitamin D group ( 202 points ) compared with the placebo group ( 249 points ; adjusted relative score 0.771 , 95 % CI 0.604 to 0.985 , p=0.04 ) . Limitations A single study centre , small sample size and a selected group of patients . The sample size calculation was performed using p=0.02 as the significance level whereas the primary and secondary endpoints were analysed using the conventional p=0.05 as the significance level . Conclusions Supplementation with vitamin D3 may reduce disease burden in patients with frequent RTIs BACKGROUND Recent studies suggest a role for vitamin D in innate immunity , including the prevention of respiratory tract infections ( RTIs ) . We hypothesize that serum 25-hydroxyvitamin D ( 25[OH]D ) levels are inversely associated with self-reported recent upper RTI ( URTI ) . METHODS We performed a secondary analysis of the Third National Health and Nutrition Examination Survey , a probability survey of the US population conducted between 1988 and 1994 . We examined the association between 25(OH)D level  and  recent URTI in 18 883 participants 12 years and older . The analysis adjusted for demographics and clinical factors ( season , body mass index , smoking history , asthma , and chronic obstructive pulmonary disease ) . RESULTS The median serum 25(OH)D level was 29 ng/mL ( to convert to nanomoles per liter , multiply by 2.496 ) ( interquartile range , 21 - 37 ng/mL ) , and 19 % ( 95 % confidence interval [ CI ] , 18%-20 % ) of participants reported a recent URTI . Recent URTI was reported by 24 % of participants with 25(OH)D levels less than 10 ng/mL , by 20 % with levels of 10 to less than 30 ng/mL , and by 17 % with levels of 30 ng/mL or more ( P < .001 ) . Even after adjusting for demographic and clinical characteristics , lower 25(OH)D levels were independently associated with recent URTI ( compared with 25[OH]D levels of > or = 30 ng/mL : odds ratio [ OR ] , 1.36 ; 95 % CI , 1.01 - 1.84 for < 10 ng/mL and 1.24 ; 1.07 - 1.43 for 10 to < 30 ng/mL ) . The association between 25(OH)D level and URTI seemed to be stronger in individuals with asthma and chronic obstructive pulmonary disease ( OR , 5.67 and 2.26 , respectively ) . CONCLUSIONS Serum 25(OH)D levels are inversely associated with recent URTI . This association may be stronger in those with respiratory tract diseases . R and omized controlled trials are warranted to explore the effects of vitamin D supplementation on RTI Respiratory tract infections ( RTIs ) are very common worldwide . We prospect ively demonstrate an association between low serum 25-hydroxyvitamin D level and increased risk of laboratory-confirmed viral upper RTI  in children . Future studies should evaluate the role of supplementation to reduce RTIs BACKGROUND R and omized controlled trials testing the association between vitamin D status and upper respiratory tract infection ( URTI ) have given mixed results . During a multicenter , r and omized controlled trial of colorectal adenoma chemoprevention , we tested whether 1000 IU/day vitamin D(3 ) supplementation reduced winter episodes and duration of URTI and its composite syndromes , influenza-like illness ( ILI ; fever and ≥2 of sore throat , cough , muscle ache , or headache ) and colds ( no fever , and ≥2 of runny nose , nasal congestion , sneezing , sore throat , cough , swollen or tender neck gl and s ) . METHODS The 2259 trial participants were aged 45 - 75 , in good health , had a history of colorectal adenoma , and had a serum 25-hydroxyvitamin D level ≥12 ng/mL. They were r and omized to vitamin D(3 ) ( 1000 IU/day ) , calcium ( 1200 mg/day ) , both , or placebo . Of these , 759 participants completed daily symptom diaries . Secondary data included semiannual surveys of all participants . RESULTS Among those who completed symptom diaries , supplementation did not significantly reduce winter episodes of URTI ( rate ratio [ RR ] , 0.93 ; 95 % confidence interval [ CI ] , .79 - 1.09 ) including colds ( RR , 0.93 ; 95 % CI , .78 - 1.10 ) or ILI ( RR , 0.95 ; 95 % CI , .62 - 1.46 ) , nor did it reduce winter days of illness ( RR , 1.13 ; 95 % CI , .90 - 1.43 ) . There was no significant benefit according to adherence , influenza vaccination , body mass index , or baseline vitamin D status . Semiannual surveys of all participants ( N = 2228 ) identified no benefit of supplementation on ILI ( odds ratio [ OR ] , 1.14 ; 95 % CI , .84 - 1.54 ) or colds ( OR , 1.03 ; 95 % CI , .87 - 1.23 ) . CONCLUSIONS Supplementation with 1000 IU/day vitamin D(3 ) did not significantly reduce the incidence or duration of URTI in adults with a baseline serum 25-hydroxyvitamin D level ≥12 Abstract Background : In observational studies vitamin D deficiency is associated with increased risk of infections , whereas the effect of vitamin D supplementation in r and omized controlled trials is non-conclusive . Methods : Five hundred and eleven subjects with prediabetes were r and omized to vitamin D3 ( 20,000 IU per week ) versus placebo for five years . Every sixth month , a question naire on respiratory tract infections ( RTI ) ( common cold , bronchitis , influenza ) and urinary tract infection ( UTI ) was filled in . Results : Mean baseline serum 25-hydroxyvitamin D ( 25(OH)D ) level was 60 nmol/L. 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 . Eighteen subjects in the vitamin D group and 34 subjects in the placebo group reported UTI during the study ( p < 0.02 ) , whereas no significant differences were seen for 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 . Conclusion : Supplementation with vitamin D might prevent UTI , but confirmatory studies are needed Observational studies identified associations between vitamin D insufficiency ( serum 25(OH)D < 30ng·ml-1 ) and risk of upper respiratory infection ( URI ) .  Swimmers are highly prone to URIs , which might hinder their performance . The aim of this study was to examine if vitamin D3 supplementation reduces URI burden in vitamin D-insufficient swimmers . Fifty-five competitive adolescent swimmers with vitamin D insufficiency were r and omized to receive vitamin D3 ( 2,000IU·d-1 ) or placebo for 12 winter weeks . A URI symptom question naire was completed weekly . Serum 25(OH)D concentrations were measured by radio-immunoassay before and after supplementation . We used linear regression to examine the relation between the change in 25(OH)D concentrations during the trial , and the duration and severity of URIs . There were no between-group differences in the frequency , severity , or duration of URIs . Exploratory analyses revealed that in the placebo group only , the change in 25(OH)D concentrations during the trial was highly associated with the duration of URIs ( r = -0.90,p < .001 ) , and moderately associated with the severity of URIs ( r = -0.65,p = .043 ) . The between-group differences for duration  were highly significant . Vitamin D3 supplementation in adolescent swimmers with vitamin D insufficiency did not reduce URI burden . However , larger decreases in serum 25(OH)D concentrations were associated with significantly longer and more severe URI episodes Vitamin D has been shown to be an important immune system regulator . Vitamin D insufficiency during winter may cause increased susceptibility to upper respiratory tract infections ( URIs ) . To determine whether vitamin D supplementation during the winter season prevents or decreases URI symptoms , 162 adults were r and omized to receive 50 microg vitamin D3 ( 2000 IU ) daily or matching placebo for 12 weeks . A bi-weekly question naire was used to record the incidence and severity of URI symptoms . There was no difference in the incidence of URIs between the vitamin D and placebo groups ( 48 URIs vs. 50 URIs , respectively , P=0.57 ) . There was no difference in the duration or severity of URI symptoms between the vitamin D and placebo groups [ 5.4+/-4.8 days vs. 5.3+/-3.1 days , respectively , P=0.86 ( 95 % CI for the difference in duration -1.8 to 2.1 ) ] . The mean 25-hydroxyvitamin D level at baseline was similar in both groups ( 64.3+/-25.4 nmol/l in the vitamin D group ; 63.0+/-25.8 nmol/l in the placebo group ; n.s . ) . After 12 weeks , 25-hydroxyvitamin D levels increased significantly to 88.5+/-23.2 nmol/l in the vitamin D group , whereas there was no change in vitamin D levels in the placebo group . There was no benefit of vitamin D3 supplementation in decreasing the incidence or severity of symptomatic URIs during winter . Further studies are needed to determine the role of vitamin D in infection Higher vitamin D concentrations have been proposed as a protective ' seasonal stimulus ' against influenza , and there are suggestions for associations with other aspects of respiratory health . The aim of the present study was to investigate the relationship of current vitamin D status ( measured by 25-hydroxyvitamin D , 25(OH)D ) with  respiratory infections and lung function .  We used cross-sectional data from 6789 participants in the nationwide 1958 British birth cohort who had measurements of 25(OH)D , lung function ( forced expiratory volume in 1 s ( FEV1 ) and forced vital capacity ( FVC ) ) and respiratory infections available from the age of 45 years . In this population , the prevalence of respiratory infections had a strong seasonal pattern in the opposite direction to the pattern for 25(OH)D concentrations . Each 10 nmol/l increase in 25(OH)D was associated with a 7 % lower risk of infection ( 95 % CI 3 , 11 % ) after adjustment for adiposity , lifestyle and socio-economic factors . For FEV1 and FVC , each 10 nmol/l increase in 25(OH)D was associated with 8 ( 95 % CI 3 , 13 ) ml and 13 ( 95 % CI 7 , 20 ) ml higher volume , respectively , after controlling for covariates . Associations of 25(OH)D with FEV1 and FVC were only slightly attenuated after further adjustment for infection and other respiratory illness . In conclusion , vitamin D status had a linear relationship with respiratory infections and lung function . R and omised controlled trials are warranted to investigate the role of vitamin D supplementation on respiratory health and to establish the underlying mechanisms CONTEXT Observational studies have reported an inverse association between serum 25-hydroxyvitamin D ( 25-OHD ) levels and incidence of upper respiratory tract infections ( URTIs ) . However , results of clinical trials of vitamin D supplementation have been inconclusive . OBJECTIVE To determine the effect of vitamin D supplementation on incidence and severity of URTIs in healthy adults . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , placebo-controlled trial conducted among 322 healthy adults between February 2010 and November 2011 in Christchurch , New Zeal and . INTERVENTION Participants were r and omly 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 ( n = 161 ) , or placebo administered in an identical dosing regimen ( n = 161 ) , for a total of 18 months . MAIN OUTCOME MEASURES The primary end point was number of URTI episodes . Secondary end points were duration of URTI episodes , severity of URTI episodes , and number of days of missed work due to URTI episodes . RESULTS The mean baseline 25-OHD level of participants was 29 ( SD , 9 ) ng/mL. Vitamin D supplementation result ed in an increase in serum 25-OHD levels that was maintained at greater than 48 ng/mL throughout the study . There were 593 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 . These findings remained unchanged when the analysis was repeated by season and by baseline 25-OHD levels . CONCLUSION In this trial , monthly administration of 100,000 IU of vitamin D did not reduce the incidence or severity of URTIs in healthy adults . TRIAL REGISTRATION anzctr.org.au Identifier : ACTRN12609000486224 BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) often have vitamin D deficiency , which is associated with increased susceptibility to upper respiratory infection-a major precipitant of exacerbation . Multicentre trials of vitamin D supplementation for prevention of exacerbation and upper respiratory infection in patients with COPD are lacking . We therefore investigated whether vitamin D3 ( colecalciferol ) supplementation would reduce the incidence of moderate or severe COPD exacerbations and upper respiratory infections . METHODS We did a r and omised , double-blind , placebo-controlled trial of vitamin D3 supplementation in adults with COPD in 60 general practice s and four Acute National Health Service Trust clinics in London , UK . Patients were allocated to receive six 2-monthly oral doses of 3 mg vitamin D3 or placebo over 1 year in a 1:1 ratio using computer-generated permuted block r and omisation . Participants and study staff were masked to treatment assignment . Co primary outcomes were time to first moderate or severe exacerbation and first upper respiratory infection . Analysis was by intention to treat . A prespecified subgroup analysis was done to assess whether effects of the intervention on the co primary outcomes were modified by baseline vitamin D status . This trial is registered with Clinical Trials.gov , number NCT00977873 . FINDINGS 240 patients were r and omly allocated to the vitamin D3 group ( n=122 ) and placebo group ( n=118 ) . Vitamin D3 compared with placebo did not affect time to first moderate or severe exacerbation ( adjusted hazard ratio 0·86 , 95 % CI 0·60 - 1·24 , p=0·42 ) or time to first upper respiratory infection ( 0·95 , 0·69 - 1·31 , p=0·75 ) . Prespecified subgroup analysis showed that vitamin D3 was protective against moderate or severe exacerbation in participants with baseline serum 25-hydroxyvitamin D concentrations of less than 50 nmol/L ( 0·57 , 0·35 - 0·92 , p=0·021 ) , but not in those with baseline 25-hydroxyvitamin D levels of at least 50 nmol/L ( 1·45 , 0·81 - 2·62 , p=0·21 ; p=0·021 for interaction between allocation and baseline serum 25-hydroxyvitamin D status ) . Baseline vitamin D status did not modify the effect of the intervention on risk of upper respiratory infection ( pinteraction=0·41 ) . INTERPRETATION Vitamin D3 supplementation protected against moderate or severe exacerbation , but not upper respiratory infection , in patients with COPD with baseline 25-hydroxyvitamin D levels of less than 50 nmol/L. Our findings suggest that correction of vitamin D deficiency in patients with COPD reduces the risk of moderate or severe exacerbation . FUNDING UK National Institute for Health Research BACKGROUND : Respiratory syncytial virus ( RSV ) is the most important pathogen causing severe lower respiratory tract infection ( LRTI ) in infants . Epidemiologic and basic studies suggest that vitamin D may protect against RSV LRTI . OBJECTIVE : To determine the association between plasma vitamin D concentrations at birth and the subsequent risk of RSV LRTI . DESIGN : A prospect i ve birth cohort study was performed in healthy term neonates . Concentrations of 25-hydroxyvitamin D ( 25-OHD ) in cord blood plasma were related to RSV LRTI in the first year of life , defined as parent-reported LRTI symptoms in a daily log and simultaneous presence of RSV RNA in a nose-throat specimen . RESULTS : The study population included 156 neonates . Eighteen ( 12 % ) developed RSV LRTI . The mean plasma 25-OHD concentration was 82 nmol/L. Overall , 27 % of neonates had 25-OHD concentrations < 50 nmol/L , 27 % had 50 - 74 nmol/L and only 46 % had 25-OHD 75 nmol/L. Cord blood 25-OHD concentrations were strongly associated with maternal vitamin D3 supplementation during pregnancy . Concentrations of 25-OHD were lower in neonates who subsequently developed RSV LRTI compared with those who did not ( 65 nmol/L versus 84 nmol/L , P = .009 ) . Neonates born with 25-OHD concentrations < 50 nmol/L had a sixfold ( 95 % confidence interval : 1.6 - 24.9 ; P = .01 ) increased risk of RSV LRTI in the first year of life compared with those with 25-OHD concentrations ≥75 nmol/L. CONCLUSIONS : Vitamin D deficiency in healthy neonates is associated with increased risk of RSV LRTI in the first year of life . Intensified routine vitamin D supplementation during pregnancy may be a useful strategy to prevent RSV LRTI during infancy OBJECTIVE : Observational studies suggest that serum levels of 25-hydroxyvitamin D ( 25[OH]D ) are inversely associated with acute respiratory infections ( ARIs ) . We hypothesized that vitamin D supplementation of children with vitamin D deficiency would lower the risk of ARIs . METHODS : By using cluster r and omization , classrooms of 744 Mongolian schoolchildren were r and omly assigned to different treatments in winter ( January – March ) . This analysis focused on a subset of 247 children who were assigned to daily ingestion of unfortified regular milk ( control ; n = 104 ) or milk fortified with 300 IU of vitamin D3 ( n = 143 ) . This comparison was double-blinded . The primary outcome was the number of parent-reported ARIs over the past 3 months . RESULTS : 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 % ( n = 244 ) , and the median 25(OH)D levels of children in the control versus vitamin D groups was significantly different ( 7 vs 19 ng/mL ; P < .001 ) . Compared with controls , children receiving vitamin D reported significantly fewer ARIs during the study period ( mean : 0.80 vs 0.45 ; P = .047 ) , 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 vs 0.57 ; Pinteraction = .27 ) . CONCLUSIONS : Vitamin D supplementation significantly reduced the risk of ARIs in winter among Mongolian children with vitamin D deficiency BACKGROUND Low serum 25-hydroxyvitamin D ( 25-[OH]D ) levels have been associated with lower FEV(1 ) , impaired immunologic control , and increased airway inflammation . Because many patients with chronic obstructive pulmonary disease ( COPD ) have vitamin D deficiency , effects of vitamin D supplementation may extend beyond preventing osteoporosis . OBJECTIVE To explore whether supplementation with high doses of vitamin D could reduce the incidence of COPD exacerbations . DESIGN R and omized , single-center , double-blind , placebo-controlled trial . ( Clinical Trials.gov registration number : NCT00666367 ) SETTING University Hospitals Leuven , Leuven , Belgium . PATIENTS 182 patients with moderate to very severe COPD and a history of recent exacerbations . INTERVENTION 100,000 IU of vitamin D supplementation or placebo every 4 weeks for 1 year . MEASUREMENTS The primary outcome was time to first exacerbation . Secondary outcomes were exacerbation rate , time to first hospitalization , time to second exacerbation , FEV(1 ) , quality of life , and death . RESULTS Mean serum 25-(OH)D levels increased significantly in the vitamin D group compared with the placebo group ( mean between-group difference , 30 ng/mL [ 95 % CI , 27 to 33 ng/mL ] ; P < 0.001 ) . The median time to first exacerbation did not significantly differ between the groups ( hazard ratio , 1.1 [ CI , 0.82 to 1.56 ] ; P = 0.41 ) , nor did exacerbation rates , FEV(1 ) , hospitalization , quality of life , and death . However , a post hoc analysis in 30 participants with severe vitamin D deficiency ( serum 25-[OH]D levels < 10 ng/mL ) at baseline showed a significant reduction in exacerbations in the vitamin D group ( rate ratio , 0.57 [ CI , 0.33 to 0.98 ] ; P = 0.042 ) . LIMITATION This was a single-center study with a small sample size . CONCLUSION High-dose vitamin D supplementation in a sample of patients with COPD did not reduce the incidence of exacerbations . In participants with severe vitamin D deficiency at baseline , supplementation may reduce exacerbations . PRIMARY FUNDING SOURCE Applied Biomedical Research Program , Agency for Innovation by Science and Technology ( IWT-TBM ) Background We undertook a 2X2 factorial , r and omized controlled trial ( RCT ) to assess whether vitamin D3 supplementation ( 10,000 international units per week ) versus placebo and gargling versus no gargling could prevent  viral  ,  clinical upper respiratory tract infection ( URTI ) in university students . Methods We r and omized 600 students 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 . Students completed weekly electronic surveys and su bmi tted self-collected mid-turbinate nasal flocked swabs during September and October in 2010 or 2011 . Symptomatic students also completed an electronic symptom diary . The primary and secondary outcomes were the occurrence of symptomatic clinical URTI and laboratory confirmed URTI respectively . Results 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 % ) r and omized to vitamin D3 reported clinical URTI compared to 80 ( 26.7 % ) r and omized to placebo ( RR:0.79 , CI95:0.61 - 1.03 , p = 0.09 ) . Eighty-five participants ( 28.3 % ) r and omized to gargling reported clinical URTI compared to 65 participants ( 21.7 % ) r and omized to the no gargling arm ( RR:1.3 , CI95:0.92 - 1.57 , p = 0.19 ) . 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 , p = 0.007 ) and with a significantly lower mean viral load measured as log10 viral copies/mL ( mean difference : -0.89 , CI95 : -1.7 , -0.06 , p = 0.04 ) . Fewer students assigned to gargling experienced laboratory confirmed URTI , however this was not statistically significant ( RR:0.82 , CI95:0.53 - 1.26 , p = 0.36 ) . Conclusions These results suggest that 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 . Trial registration Clinical Trials Registration : NCT01158560 Importance Epidemiological studies support a link between low 25-hydroxyvitamin D levels and a higher risk of viral upper respiratory tract infections . However , whether winter supplementation of vitamin D reduces the risk among children is unknown . Objective To determine whether high-dose vs st and ard-dose vitamin D supplementation reduces the incidence of wintertime upper respiratory tract infections in young children . Design , Setting , and Participants A r and omized clinical trial was conducted during the winter months between September 13 , 2011 , and June 30 , 2015 , among children aged 1 through 5 years enrolled in TARGet Kids ! , a multisite primary care practice –based research network in Toronto , Ontario , Canada . Interventions Three hundred forty-nine participants were r and omized to receive 2000 IU/d of vitamin D oral supplementation ( high-dose group ) vs 354 participants who were r and omized to receive 400 IU/d ( st and ard-dose group ) for a minimum of 4 months between September and May. Main Outcome Measures The primary outcome was the number of laboratory-confirmed viral upper respiratory tract infections based on parent-collected nasal swabs over the winter months . Secondary outcomes included the number of influenza infections , noninfluenza infections , parent-reported upper respiratory tract illnesses , time to first upper respiratory tract infection , and serum 25-hydroxyvitamin D levels at study termination . Results Among 703 participants who were r and omized ( mean age , 2.7 years , 57.7 % boys ) , 699 ( 99.4 % ) completed the trial . The mean number of laboratory-confirmed upper respiratory tract infections per child was 1.05 ( 95 % CI , 0.91 - 1.19 ) for the high-dose group and 1.03 ( 95 % CI , 0.90 - 1.16 ) for the st and ard-dose group , for a between-group difference of 0.02 ( 95 % CI , −0.17 to 0.21 ) per child . There was no statistically significant difference in number of laboratory-confirmed infections between groups ( incidence rate ratio [ RR ] , 0.97 ; 95 % CI , 0.80 - 1.16 ) . There was also no significant difference in the median time to the first laboratory-confirmed infection : 3.95 months ( 95 % CI , 3.02 - 5.95 months ) for the high-dose group vs 3.29 months ( 95 % CI , 2.66 - 4.14 months ) for the st and ard-dose group , or number of parent-reported upper respiratory tract illnesses between groups ( 625 for high-dose vs 600 for st and ard-dose groups , incidence RR , 1.01 ; 95 % CI , 0.88 - 1.16 ) . At study termination , serum 25-hydroxyvitamin D levels were 48.7 ng/mL ( 95 % CI , 46.9 - 50.5 ng/mL ) in the high-dose group and 36.8 ng/mL ( 95 % CI , 35.4 - 38.2 ng/mL ) in the st and ard-dose group . Conclusions and Relevance Among healthy children aged 1 to 5 years , daily administration of 2000 IU compared with 400 IU of vitamin D supplementation did not reduce overall wintertime upper respiratory tract infections . These findings do not support the routine use of high-dose vitamin D supplementation in children for the prevention of viral upper respiratory tract infections . Trial Registration clinical trials.gov Identifier : Zn supplementation has shown inconsistent effects on  respiratory morbidity in young children in developing countries . Few studies have focused on upper respiratory tract infection ( URTI ) , a frequent cause of morbidity in this group , and potential benefit from Zn supplementation or factors that influence its efficacy . We investigated the effects of Zn supplementation on URTI before and after vitamin A supplementation . This r and omised double-blinded controlled Zn supplementation study was conducted on 826 children aged 2 - 5 years .  Placebo or Zn ( 10 mg/d ) was given in syrup daily for 4 months , with 200 000 IU vitamin A ( 60 mg retinol ) given to all children at 2 months . Health workers visited children every 3 d for compliance and morbidity information . We found that 84 % of children experienced URTI during the study . Zn supplementation reduced the percentage of days with URTI ( 12 % reduction ; P = 0·09 ) , with greater impact following vitamin A supplementation ( 20 % reduction ; P = 0·01 ) . Vitamin A supplementation was associated with a decreased number but an increased duration of URTI episodes . We conclude that Zn combined with vitamin A supplementation significantly reduced the percentage of days with URTI in a population of preschool Indonesian children with marginal nutritional status . The results suggest that vitamin A status modifies the efficacy of Zn supplementation  on URTI Background Declining serum concentrations of 25-hydroxyvitamin D seen in the fall and winter as distance increases from the equator may be a factor in the seasonal increased prevalence of influenza and other viral infections . This study was done to determine if serum 25-hydroxyvitamin D concentrations correlated with the incidence of acute viral respiratory tract infections . Methodology / Findings In this prospect i ve cohort study serial monthly concentrations of 25-hydroxyvitamin D were measured over the fall and winter 2009–2010 in 198 healthy adults , blinded to the nature of the substance being measured . The participants were evaluated for the development of any acute respiratory tract infections by investigators blinded to the 25-hydroxyvitamin D concentrations . The incidence of infection in participants with different concentrations of vitamin D was determined . One hundred ninety-five ( 98.5 % ) of the enrolled participants completed the study . Light skin pigmentation , lean body mass , and supplementation with vitamin D were found to correlate with higher concentrations of 25-hydroxyvitamin D. Concentrations of 38 ng/ml or more were associated with a significant ( p<0.0001 ) two-fold reduction in the risk of developing acute respiratory tract infections and with a marked reduction in the percentages of days ill . Conclusions / Significance Maintenance of a 25-hydroxyvitamin D serum concentration of 38 ng/ml or higher should significantly reduce the incidence of acute viral respiratory tract infections and the burden of illness caused thereby , at least during the fall and winter in temperate zones . The findings of the present study provide direction for and call for future interventional studies examining the efficacy of vitamin D supplementation in reducing the incidence and severity of specific viral infections , including influenza , in the general population and in sub population s with lower 25-hydroxyvitamin D concentrations , such as pregnant women , dark skinned individuals , and the obese
INTERPRETATION Results indicate that vitamin D has a protective effect against RTI , and dosing once-daily seems most effective .
BACKGROUND Low levels of 25-OH vitamin D are associated with  respiratory tract infection ( RTI ) .
However , results from r and omized controlled trials are inconclusive .
Therefore , we performed a systematic review and meta- analysis to assess the preventive effect of vitamin D supplementation on RTI .