title: Randomized Trial of Vitamin D Supplementation and Risk of Acute Respiratory Infection in Mongolia Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. GRADE guidelines: 4. Rating the quality of evidence--study limitations (risk of bias). Lack of a relation between serum 25-hydroxyvitamin D concentrations and asthma in adolescents. Does vitamin D administered to children with asthma treated with inhaled glucocorticoids affect short-term growth or bone turnover? Effect of Vitamin D Supplementation on Moderate to Severe Bronchial Asthma GRADE guidelines: 5. Rating the quality of evidence--publication bias. GRADE guidelines: 3. Rating the quality of evidence. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial. Effect of vitamin D and inhaled corticosteroid treatment on lung function in children. Serum micronutrient concentrations and childhood asthma: the PIAMA birth cohort study. Prospective association of 25-hydroxyvitamin d3 and d2 with childhood lung function, asthma, wheezing, and flexural dermatitis.
abstract: 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 Asthma exacerbations , most often caused by respiratory tract infections , are the leading causes of asthma morbidity and comprise a significant proportion of asthma-related costs . Vitamin D status might play a role in preventing asthma exacerbations . OBJECTIVES We sought to assess the relationship between serum vitamin D levels and subsequent severe asthma exacerbations . METHODS We measured  25-hydroxyvitamin D levels in sera collected from 1024 children with mild-to-moderate persistent asthma at the time of enrollment in a multicenter clinical trial of children r and omized to receive budesonide , nedocromil , or placebo ( as-needed beta-agonists ) : the Childhood Asthma Management Program . Using multivariable modeling , we examined the relationship between baseline vitamin D levels and the odds of any hospitalization or emergency department visit over the 4 years of the trial . RESULTS Thirty-five percent of all subjects were  vitamin D insufficient , as defined by a level of 30 ng/mL or less 25-hydroxyvitamin D. Mean vitamin D levels were lowest in African American subjects and highest in white subjects . After adjusting for age , sex , body mass index , income , and treatment group , insufficient vitamin D status was associated with a higher odds of any hospitalization or emergency department visit ( odds ratio , 1.5 ; 95 % CI , 1.1 - 1.9 ; P = .01 ) . CONCLUSION Vitamin D insufficiency is common in this population of North American children with mild-to-moderate persistent asthma and is associated with higher odds of severe exacerbation over a 4-year period BACKGROUND To our knowledge , no rigorously design ed clinical trials have evaluated the relation between vitamin D and physician-diagnosed seasonal influenza . OBJECTIVE We investigated the effect of vitamin D supplements on the incidence of  seasonal influenza A in schoolchildren . DESIGN From December 2008 through March 2009 , we conducted a r and omized , double-blind , placebo-controlled trial comparing vitamin D(3 ) supplements ( 1200 IU/d ) with placebo  in schoolchildren . The primary outcome was the incidence of influenza A , diagnosed with influenza antigen testing with a nasopharyngeal swab specimen . RESULTS Influenza A occurred in 18 of 167 ( 10.8 % ) children in the vitamin D(3 ) group compared with 31 of 167 ( 18.6 % ) children in the  placebo  group [ relative risk ( RR ) , 0.58 ; 95 % CI : 0.34 , 0.99 ; P = 0.04 ] . 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 ; P = 0.006 ) and who started nursery school after age 3 y ( RR : 0.36 ; 95 % CI : 0.17 , 0.78 ; P = 0.005 ) . In children with a previous diagnosis of asthma , asthma attacks as a secondary outcome occurred in 2 children receiving vitamin D(3 ) compared with 12 children receiving placebo ( RR : 0.17 ; 95 % CI : 0.04 , 0.73 ; P = 0.006 ) . CONCLUSION This study suggests that vitamin D(3 ) supplementation during the winter may reduce the incidence of influenza A , especially in specific subgroups of schoolchildren . This trial was registered at https://center.umin.ac.jp as UMIN000001373 In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias . Well-established limitations of r and omized trials include failure to conceal allocation , failure to blind , loss to follow-up , and failure to appropriately consider the intention-to-treat principle . More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results . Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance . Risk of bias may vary across outcomes ( e.g. , loss to follow-up may be far less for all-cause mortality than for quality of life ) , a consideration that many systematic review s ignore . In deciding whether to rate down for risk of bias -- whether for r and omized trials or observational studies -- authors should not take an approach that averages across studies . Rather , for any individual outcome , when there are some studies with a high risk , and some with a low risk of bias , they should consider including only the studies with a lower risk of bias BACKGROUND Decreased 25-hydroxyvitamin D [ 25(OH)D ] concentrations have been associated with an increased prevalence and severity of asthma and a lower response to inhaled corticosteroids . OBJECTIVE The objective was to determine the association between serum 25(OH)D concentrations and asthma prevalence , severity , and response to asthma treatment . DESIGN Secondary analyses were conducted in 2 sample s of adolescents 12 - 20 y of age : 1 ) NHANES 2001 - 2006 ( n = 6487 ) , a cross-sectional nationally representative sample of the US population , and 2 ) a cohort of inner-city adolescents with asthma managed prospect ively for 46 wk with guidelines -based therapy in the Asthma Control Evaluation ( ACE ; n = 226 ) trial .  RESULTS Mean ( ±SD ) serum 25(OH)D concentrations in the NHANES and ACE sample s were lower in African Americans than in non-African Americans ( NHANES : 14.9 ± 6.5 compared with 23.0 ± 8.4 ng/mL , P < 0.0001 ; ACE : 11.2 ± 6.9 compared with 15.8 ± 7.1 ng/mL , P < 0.0001 ) . In the NHANES sample , mean concentrations did not differ between participants without and with asthma ( African Americans : 14.9 ± 6.4 compared with 15.0 ± 6.6 ng/mL , respectively , P = 0.87 ; non-African Americans : 23.0 ± 8.5 compared with 23.6 ± 8.2 ng/mL , respectively , P = 0.16 ) . In the ACE models that used either a predefined cutoff ( < 20 ng/mL ) or linear regression , 25(OH)D concentrations showed either no relation or minor contradictory correlations with indicators of asthma severity , treatment requirements , spirometry , or atopy/inflammation . CONCLUSION In 2 sample s of adolescents , overall serum 25(OH)D concentrations were low and were not consistently associated with the presence of asthma , multiple asthma characteristics , asthma morbidity , or response to treatment . The ACE trial was registered at clinical trials.gov as NCT0011441 Our objective was to assess whether administration of 25-OH-vitamin D to children with asthma treated with inhaled dry-powder budesonide 400 microg daily affects short-term growth or markers of bone turnover . We utilized a r and omized , double-blind , two-period crossover trial with run-in and washout periods of 2 weeks and treatment periods of 4 weeks duration . The setting was an Outpatient clinic in a secondary referral center . Subjects included 14 boys and 3 girls with a mean age of 11.7 ( range , 6.1 - 14.4 ) years . Interventions included 15 microg ( 600 IU ) 25-OH-vitamin D ( cholecalciferol ) in one tablet ABCDin(R ) once daily in the morning . Primary outcome measures were : lower leg growth rate , serum osteocalcin , and serum markers of type I collagen turnover , i.e. , the amino terminal propeptide of type I procollagen ( PINP ) , the carboxy terminal propeptide of type I procollagen ( PICP ) ( formation markers ) , and the carboxy terminal pyridinoline cross-linked telopeptide of type I collagen ( ICTP ) ( degradation markers ) . Secondary outcome measures were parameters of asthma control and serum 25-OH-vitamin D. Lower leg growth rate was 0.22 mm/week during vitamin D and 0.25 mm/week during placebo treatment ( NS ) . Osteocalcin was 59.9 and 57.8 microg/l during vitamin D and placebo treatment , respectively , PINP 574 and 565 microg/l , PICP 381 and 382 microg/l , and ICTP 11.5 and 11.1 microg/l , respectively ( NS ) . Serum 25-OH-vitamin D was 76.3 nmol/l and 48.2 nmol/l , respectively ( P < 0.001 ) . There were no statistically significant differences in measures of pulmonary function . In conclusion , administration of 25-OH-vitamin D does not affect short-term growth or markers of bone turnover in children with asthma treated with inhaled dry-powder budesonide 400 microg daily Objective To define the therapeutic role of vitamin D in children with moderate to severe bronchial asthma as an adjunct to st and ard treatment . Methods Hundred asthmatic children of either sex , attending the respiratory and asthma clinic were enroled in the study . Diagnosis was made on the basis of history and clinical examination . R and omization was done using sealed opaque envelop method . In addition to the treatment as per GINA guidelines , one group received oral vitamin D3 ( Cholecalciferol ) 60,000 IU per month for 6 mo and the other group received placebo powder in the form of glucose sachet with a double blinded design . Monthly follow up of every patient was done and during every visit change in severity , level of control , Peak expiratory flow rate ( PEFR ) , steroid dosage , number of exacerbations and number of emergency visits were assessed . Results Monthly doses of 60,000 IU vitamin D significantly reduced the number of exacerbations as compared to placebo ( p = 0.011 ) . PEFR significantly increased in the treatment group ( p = 0.000 ) . Monthly doses of vitamin D significantly reduced the requirement of steroids ( p = 0.013 ) and emergency visits ( p = 0.015 ) . Control of asthma was achieved earlier in patients who received monthly vitamin D. Vitamin D significantly reduced the level of severity of asthma patients over 6 mo of treatment ( p = 0.016 ) . Conclusions Vitamin D has a definite role in the management of moderate to severe persistent bronchial asthma as an adjunct to st and ard treatment In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if a body of evidence is associated with a high risk of publication bias . Even when individual studies included in best- evidence summaries have a low risk of bias , publication bias can result in substantial overestimates of effect . Authors should suspect publication bias when available evidence comes from a number of small studies , most of which have been commercially funded . A number of approaches based on examination of the pattern of data are available to help assess publication bias . The most popular of these is the funnel plot ; all , however , have substantial limitations . Publication bias is likely frequent , and caution in the face of early results , particularly with small sample size and number of events , is warranted This article introduces the approach of GRADE to rating  quality of evidence .  GRADE specifies four categories-high , moderate , low , and very low-that are applied to a body of evidence , not to individual studies . In the context of a systematic review , quality reflects our confidence that the estimates of the effect are correct . In the context of recommendations , quality reflects our confidence that the effect estimates are adequate to support a particular recommendation . R and omized trials begin as high- quality evidence , observational studies as low quality . " Quality " as used in GRADE means more than risk of bias and so may also be compromised by imprecision , inconsistency , indirectness of study results , and publication bias . In addition , several factors can increase our confidence in an estimate of effect . GRADE provides a systematic approach for considering and reporting each of these factors . GRADE separates the process of assessing quality of evidence from the process of making recommendations . Judgments about the strength of a recommendation depend on more than just the quality of evidence IMPORTANCE In asthma and other diseases , vitamin D insufficiency is associated with adverse outcomes . It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency . OBJECTIVE To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels . DESIGN , SETTING , AND PARTICIPANTS The VIDA ( Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma ) r and omized , double-blind , parallel , placebo-controlled trial study ing adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart , Lung , and Blood Institute 's AsthmaNet network , with enrollment starting in April 2011 and follow-up complete by January 2014 . After a run-in period that included treatment with an inhaled corticosteroid , 408 patients were r and omized . INTERVENTIONS Oral vitamin D3 ( 100,000 IU once , then 4000 IU/d for 28 weeks ; n = 201 ) or placebo ( n = 207 ) was added to inhaled ciclesonide ( 320 µg/d ) . If asthma control was achieved after 12 weeks , ciclesonide was tapered to 160 µg/d for 8 weeks , then to 80 µg/d for 8 weeks if asthma control was maintained . MAIN OUTCOMES AND MEASURES The primary outcome was time to first asthma treatment failure ( a composite outcome of decline in lung function and increases in use of β-agonists , systemic corticosteroids , and health care ) . RESULTS Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks ( 28 % [ 95 % CI , 21%-34 % ] with vitamin D3 vs 29 % [ 95 % CI , 23%-35 % ] with placebo ; adjusted hazard ratio , 0.9 [ 95 % CI , 0.6 - 1.3 ] ) . Of 14 prespecified secondary outcomes , 9 were analyzed , including asthma exacerbation ; of those 9 , the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control ( 111.3 µg/d [ 95 % CI , 102.2 - 120.4 µg/d ] in the vitamin D3 group vs 126.2 µg/d [ 95 % CI , 117.2 - 135.3 µg/d ] in the placebo group ; difference of 14.9 µg/d [ 95 % CI , 2.1 - 27.7 µg/d ] ) . CONCLUSIONS AND RELEVANCE Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency . These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01248065 RATIONALE Low vitamin D levels are associated with asthma and decreased airway responsiveness . Treatment with inhaled corticosteroids improves airway responsiveness and asthma control . OBJECTIVES To assess the effect of vitamin D levels on prebronchodilator FEV(1 ) , bronchodilator response , and responsiveness to methacholine ( PC(20 ) , provocative concentration of methacholine producing a 20 % decline in FEV(1 ) ) in patients with asthma treated with inhaled corticosteroids . METHODS We measured  25-hydroxyvitamin D levels  in the serum of children with persistent asthma at the time of enrollment in the Childhood Asthma Management Program . We divided subjects into the vitamin D sufficiency ( > 30 ng/ml ) , insufficiency ( 20 - 30 ng/ml ) , and deficiency ( < 20 ng/ml ) groups . Covariates included age , treatment , sex , body mass index , race , history of emergency department visits , hospitalizations , and season that vitamin D specimen was drawn . Our main outcome measures were change in prebronchodilator FEV(1 ) , bronchodilator response , and PC(20 ) from enrollment to 8 - 12 months . MEASUREMENTS AND MAIN RESULTS Of the 1,024 subjects , 663 ( 65 % ) were vitamin D sufficient , 260 ( 25 % ) were insufficient , and 101 ( 10 % ) were deficient . Vitamin D-deficient subjects were more likely to be older , African American , and have a higher body mass index compared with the vitamin D-sufficient and insufficient subjects . In the inhaled corticosteroid treatment group , prebronchodilator FEV(1 ) increased from r and omization to 12 months by 140 ml in the vitamin D-deficient group and prebronchodilator FEV(1 ) increased by 330 ml in the vitamin D insufficiency group and by 290 ml in the vitamin D sufficiency group ( P = 0.0072 ) , in adjusted models . CONCLUSIONS In children with asthma treated with inhaled corticosteroids , vitamin D deficiency is associated with poorer lung function than in children with vitamin D insufficiency or sufficiency BACKGROUND Research suggests an influence of micronutrients on  childhood asthma .  So far , evidence mainly originates from cross-sectional studies using nutrient intake data , which is not an accurate measure of nutrient status . This study aim ed to investigate the cross-sectional and prospect i ve associations between serum concentrations of magnesium , vitamin D , selenium , and zinc and prevalence of ( severe ) asthma , atopy , and bronchial hyperresponsiveness ( BHR ) in childhood . METHODS In the Prevention and Incidence of Asthma and Mite Allergy birth cohort study , serum nutrient concentrations were available for a 4-yr-old subgroup ( n = 372 ) and for a different 8-yr-old subgroup ( n = 328 ) . Yearly question naires inquired about asthma prevalence until 8 yr of age . Allergic sensitization was measured at 4 and 8 yr of age ; BHR was measured at 8 yr of age . Data were analyzed with logistic regression and generalized estimating equations models . RESULTS There was a consistent ( non-significant ) inverse association between serum magnesium concentrations and asthma prevalence . Serum vitamin D concentrations measured at age 4 were inversely associated with asthma at ages 4 - 8 [ e.g. , cross-sectional association between vitamin D tertile 3 vs. 1 and severe asthma : odds ratio ( OR ) : 0.49 , 95 % confidence interval ( CI ) : 0.25 - 0.95 ] , whereas vitamin D measured at age 8 was positively associated with asthma at age 8 ( e.g. , cross-sectional association between vitamin D tertile 3 vs. 1 and severe asthma : OR : 2.14 , 95 % CI : 0.67 - 6.82 ) . CONCLUSIONS Our study contributes to the evidence that children with higher serum magnesium concentrations are less likely to have asthma . The associations between serum vitamin D concentrations and asthma were age-dependent BACKGROUND Higher serum total 25-hydroxyvitamin D ( 25(OH)D ) concentrations have been associated with better lung function and lower risk of allergic disease . 25(OH)D3 constitutes the majority of total 25(OH)D and has been suggested to be more potent than 25(OH)D2 . We studied the prospect i ve associations of 25(OH)D2 and 25(OH)D3 with asthma , wheezing , flexural dermatitis , and lung function in children who participated in the Avon Longitudinal Study of Parents and Children-a population -based contemporary birth cohort of children born in 1991 - 1992 from South West Engl and . METHODS Serum 25(OH)D2 and 25(OH)D3 concentrations , measured at a mean age of 9.8 years , were related to incident cases of wheezing ( study sample : n = 3,323 , 141 cases ; 4 % ) , asthma ( n = 3,323 , 464 cases ; 14 % ) , and flexural dermatitis ( n = 3,748 , 300 cases ; 8 % ) , as well as lung function ( forced expiratory volume in 1 second [ FEV1 ] , forced vital capacity [ FVC ] , and mid-forced expiratory flow assessed at a mean age of 15.5 years : n = 2,259 ) . RESULTS 25(OH)D2 was inversely associated with flexural dermatitis ( adjusted odds ratio per doubling of exposure = 0.83 [ 95 % confidence interval = 0.72 - 0.94 ] ) and wheezing ( 0.83 [ 0.68 - 1.00 ] ) , and 25(OH)D3 was positively associated with flexural dermatitis ( 1.09 [ 1.00 - 1.18 ] ) and wheezing ( 1.14 [ 1.03 - 1.28 ] ) . 25(OH)D2 was weakly positively associated with FEV1 , and FVC . 25(OH)D3 was not associated with lung function . CONCLUSIONS These results suggest that higher 25(OH)D3 concentrations are associated with increased risk of wheezing and flexural dermatitis . Despite being one of the few prospect i ve studies and being able to adjust for confounders , these findings need replication . Our results do not provide strong evidence that lower concentrations of vitamin D are detrimental to  respiratory and allergic health in children
target: There was no significant effect for asthma symptom scores and lung function .
  Conclusions and Relevance R and omized controlled trials provide some low- quality evidence to support vitamin D supplementation for the reduction of asthma exacerbations .
background: Importance There is growing evidence that vitamin D plays a role in the pathogenesis of asthma but it is unclear whether supplementation during childhood may improve asthma outcomes .
  Objectives The objective of this systematic review and meta- analysis was to evaluate the efficacy and safety of vitamin D supplementation as a treatment or adjunct treatment for asthma .