Vitamin D for the management of asthma.

BACKGROUND: Since the previous Cochrane Review on this topic in 2016, debate has continued surrounding a potential role for vitamin D in reducing risk of asthma exacerbation and improving asthma control. We therefore conducted an updated meta-analysis to include data from new trials completed since this date. OBJECTIVES: To evaluate the effectiveness and safety of administration of vitamin D or its hydroxylated metabolites in reducing the risk of severe asthma exacerbations (defined as those requiring treatment with systemic corticosteroids) and improving asthma symptom control. SEARCH METHODS: We searched the Cochrane Airways Group Trial Register and reference lists of articles. We contacted the authors of studies in order to identify additional trials. Date of last search: 8 September 2022. SELECTION CRITERIA: We included double-blind, randomised, placebo-controlled trials of vitamin D in children and adults with asthma evaluating exacerbation risk or asthma symptom control, or both. DATA COLLECTION AND ANALYSIS: Four review authors independently applied study inclusion criteria, extracted the data, and assessed risk of bias. We obtained missing data from the authors where possible. We reported results with 95% confidence intervals (CIs). The primary outcome was the incidence of severe asthma exacerbations requiring treatment with systemic corticosteroids. Secondary outcomes included the incidence of asthma exacerbations precipitating an emergency department visit or requiring hospital admission, or both, end-study childhood Asthma Control Test (cACT) or Asthma Control Test (ACT) scores, and end-study % predicted forced expiratory volume in one second (FEV1). We performed subgroup analyses to determine whether the effect of vitamin D on risk of asthma exacerbation was modified by baseline vitamin D status, vitamin D dose, frequency of dosing regimen, form of vitamin D given, and age of participants. MAIN RESULTS: We included 20 studies in this review; 15 trials involving a total of 1155 children and five trials involving a total of 1070 adults contributed data to analyses. Participant ages ranged from 1 to 84 years, with two trials providing data specific to participants under five years (n = 69) and eight trials providing data specific to participants aged 5 to 16 (n = 766). Across the trials, 1245 participants were male and 1229 were female, with two studies not reporting sex distribution. Fifteen trials contributed to the primary outcome analysis of exacerbations requiring systemic corticosteroids. The duration of trials ranged from three to 40 months; all but two investigated effects of administering cholecalciferol (vitamin D3). As in the previous Cochrane Review, the majority of participants had mild to moderate asthma, and profound vitamin D deficiency (25-hydroxyvitamin D (25(OH)D) < 25 nmol/L) at baseline was rare. Administration of vitamin D or its hydroxylated metabolites did not reduce or increase the proportion of participants experiencing one or more asthma exacerbations treated with systemic corticosteroids (odds ratio (OR) 1.04, 95% CI 0.81 to 1.34; I2 = 0%; 14 studies, 1778 participants; high-quality evidence). This equates to an absolute risk of 226 per 1000 (95% CI 185 to 273) in the pooled vitamin D group, compared to a baseline risk of 219 participants per 1000 in the pooled placebo group. We also found no effect of vitamin D supplementation on the rate of exacerbations requiring systemic corticosteroids (rate ratio 0.86, 95% CI 0.62 to 1.19; I2 = 60%; 10 studies, 1599 participants; high-quality evidence), or the time to first exacerbation (hazard ratio 0.82, 95% CI 0.59 to 1.15; I2 = 22%; 3 studies, 850 participants; high-quality evidence). Subgroup analysis did not reveal any evidence of effect modification by baseline vitamin D status, vitamin D dose, frequency of dosing regimen, or age. A single trial investigating administration of calcidiol reported a benefit of the intervention for the primary outcome of asthma control. Vitamin D supplementation did not influence any secondary efficacy outcome meta-analysed, which were all based on moderate- or high-quality evidence. We observed no effect on the incidence of serious adverse events (OR 0.89, 95% CI 0.56 to 1.41; I2 = 0%; 12 studies, 1556 participants; high-quality evidence). The effect of vitamin D on fatal asthma exacerbations was not estimable, as no such events occurred in any trial. Six studies reported adverse reactions potentially attributable to vitamin D. These occurred across treatment and control arms and included hypercalciuria, hypervitaminosis D, kidney stones, gastrointestinal symptoms and mild itch. In one trial, we could not ascertain the total number of participants with hypercalciuria from the trial report. We assessed three trials as being at high risk of bias in at least one domain; none of these contributed data to the analysis of the outcomes reported above. Sensitivity analyses that excluded these trials from each outcome to which they contributed did not change the null findings. AUTHORS' CONCLUSIONS: In contrast to findings of our previous Cochrane Review on this topic, this updated review does not find evidence to support a role for vitamin D supplementation or its hydroxylated metabolites to reduce risk of asthma exacerbations or improve asthma control. Participants with severe asthma and those with baseline 25(OH)D concentrations < 25 nmol/L were poorly represented, so further research is warranted here. A single study investigating effects of calcidiol yielded positive results, so further studies investigating effects of this metabolite are needed.

ANTECEDENTES: Desde la revisión Cochrane anterior sobre este tema en 2016, ha continuado el debate en torno a una posible función de la vitamina D en la reducción del riesgo de exacerbación del asma y la mejora de su control. Por lo tanto, se realizó un metanálisis actualizado para incluir los datos de los nuevos ensayos completados desde esta fecha. OBJETIVOS: Evaluar la eficacia y seguridad de la administración de vitamina D o sus metabolitos hidroxilados para reducir el riesgo de exacerbaciones graves del asma (definidas como aquellas que requieren tratamiento con corticosteroides sistémicos) y mejorar el control de sus síntomas. MÉTODOS DE BÚSQUEDA: Se buscó en el registro de ensayos del Grupo Cochrane de Vías respiratorias (Cochrane Airways Group) y en las listas de referencias de los artículos. Se estableció contacto con los autores de los estudios para identificar ensayos adicionales. Fecha de la última búsqueda: 8 de septiembre de 2022. CRITERIOS DE SELECCIÓN: Se incluyeron los ensayos doble ciego, aleatorizados, controlados con placebo de vitamina D en niños y adultos con asma que evaluaron el riesgo de exacerbación o el control de los síntomas del asma, o ambos. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Cuatro autores de la revisión aplicaron de forma independiente los criterios de inclusión de los estudios, extrajeron los datos y evaluaron el riesgo de sesgo. Cuando fue posible, se obtuvieron los datos faltantes a través de los autores de los estudios. Los resultados se informaron con intervalos de confianza (IC) del 95%. El desenlace principal fue la incidencia de exacerbaciones graves del asma que requirieron tratamiento con corticosteroides sistémicos. Los desenlaces secundarios incluyeron la incidencia de exacerbaciones del asma que precipitaron acudir al servicio de urgencias o requirieron ingreso hospitalario, o ambas, las puntuaciones de la childhood Asthma Control Test (cACT) o la Asthma Control Test (ACT) al final del estudio, y el % previsto de volumen espiratorio forzado en un segundo (VEF1) al final del estudio. Se realizaron análisis de subgrupos para determinar si el efecto de la vitamina D sobre el riesgo de exacerbación del asma se veía modificado por el estado inicial de vitamina D, la dosis de vitamina D, la frecuencia de la posología, la formulación de la vitamina D administrada y la edad de los participantes. RESULTADOS PRINCIPALES: En esta revisión se incluyeron 20 estudios; 15 ensayos con un total de 1155 niños y cinco ensayos con un total de 1070 adultos aportaron datos para los análisis. Las edades de los participantes variaron entre 1 y 84 años, con dos ensayos que proporcionaron datos específicos de participantes menores de 5 años (n = 69) y ocho ensayos que proporcionaron datos específicos de participantes de 5 a 16 años (n = 766). En todos los ensayos, 1245 participantes eran hombres y 1229 mujeres, y dos estudios no informaron acerca de la distribución por sexos. Quince ensayos contribuyeron al análisis del desenlace principal: exacerbaciones que requirieron corticosteroides sistémicos. La duración de los ensayos fue de entre 3 y 40 meses; todos menos dos investigaron los efectos de la administración de colecalciferol (vitamina D3). Al igual que en la revisión Cochrane anterior, la mayoría de los participantes presentaban asma de leve a moderada y la deficiencia importante de vitamina D (25­hidroxivitamina D [25(OH)D] < 25 nmol/l) al inicio del estudio fue poco frecuente. La administración de vitamina D o sus metabolitos hidroxilados no redujo ni aumentó la proporción de participantes que presentaron una o más exacerbaciones del asma tratada con corticosteroides sistémicos (odds ratio [OR] 1,04; IC del 95%: 0,81 a 1,34; I2 = 0%; 14 estudios, 1778 participantes; evidencia de calidad alta). Esto equivale a un riesgo absoluto de 226 por cada 1000 (IC del 95%: 185 a 273) en el grupo de vitamina D agrupado, en comparación con un riesgo inicial de 219 participantes por cada 1000 en el grupo placebo agrupado. Tampoco se encontraron efectos de la administración de suplementos de vitamina D sobre la tasa de exacerbaciones que requirieron corticosteroides sistémicos (cociente de tasas 0,86; IC del 95%: 0,62 a 1,19; I2 = 60%; 10 estudios, 1599 participantes; evidencia de calidad alta) ni sobre el tiempo transcurrido hasta la primera exacerbación (cociente de riesgos instantáneos 0,82; IC del 95%: 0,59 a 1,15; I2 = 22%; tres estudios, 850 participantes; evidencia de calidad alta). El análisis de subgrupos no reveló una evidencia de modificación del efecto en función del estado inicial de vitamina D, la dosis de vitamina D, la frecuencia de la posología ni la edad. Un único ensayo que investigó la administración de calcidiol informó sobre un efecto beneficioso de la intervención en el desenlace principal de control del asma. La administración de suplementos de vitamina D no influyó en ninguno de los desenlaces secundarios de eficacia metanalizados, todos ellos basados en evidencia de calidad moderada o alta. No se observaron efectos sobre la incidencia de eventos adversos graves (OR 0,89; IC del 95%: 0,56 a 1,41; I2 = 0%; 12 estudios, 1556 participantes; evidencia de calidad alta). No fue posible determinar el efecto de la vitamina D sobre las exacerbaciones mortales del asma ya que no se produjeron tales eventos en ningún ensayo. Seis estudios informaron sobre la presencia de reacciones adversas potencialmente atribuibles a la vitamina D. Estas se dieron en los grupos de tratamiento y control e incluyeron hipercalciuria, hipervitaminosis D, cálculos renales, síntomas gastrointestinales y prurito leve. En un ensayo, no fue posible determinar el número total de participantes con hipercalciuria a partir del informe del ensayo. Tres ensayos se consideraron con alto riesgo de sesgo en al menos un dominio; ninguno de ellos aportó datos al análisis de los desenlaces informados anteriormente. Los análisis de sensibilidad que excluyeron estos ensayos de cada desenlace al que contribuyeron no cambiaron los hallazgos nulos. CONCLUSIONES DE LOS AUTORES: En contraposición con los hallazgos de la revisión Cochrane anterior sobre este tema, esta revisión actualizada no encuentra evidencia que respalde una función de los suplementos de vitamina D o sus metabolitos hidroxilados en la reducción del riesgo de exacerbaciones del asma o la mejoría del control del asma. Los participantes con asma grave y aquellos con concentraciones iniciales de 25(OH)D < 25 nmol/l estuvieron escasamente representados, por lo que se justifica la realización de más estudios de investigación. Un único estudio que investigó los efectos del calcidiol proporcionó resultados positivos, por lo que se necesitan más estudios que investiguen los efectos de este metabolito.

Vitamin D for the management of asthma.

BACKGROUND: Several clinical trials of vitamin D to prevent asthma exacerbation and improve asthma control have been conducted in children and adults, but a meta-analysis restricted to double-blind, randomised, placebo-controlled trials of this intervention is lacking. OBJECTIVES: To evaluate the efficacy of administration of vitamin D and its hydroxylated metabolites in reducing the risk of severe asthma exacerbations (defined as those requiring treatment with systemic corticosteroids) and improving asthma symptom control. SEARCH METHODS: We searched the Cochrane Airways Group Trial Register and reference lists of articles. We contacted the authors of studies in order to identify additional trials. Date of last search: January 2016. SELECTION CRITERIA: Double-blind, randomised, placebo-controlled trials of vitamin D in children and adults with asthma evaluating exacerbation risk or asthma symptom control or both. DATA COLLECTION AND ANALYSIS: Two review authors independently applied study inclusion criteria, extracted the data, and assessed risk of bias. We obtained missing data from the authors where possible. We reported results with 95% confidence intervals (CIs). MAIN RESULTS: We included seven trials involving a total of 435 children and two trials involving a total of 658 adults in the primary analysis. Of these, one trial involving 22 children and two trials involving 658 adults contributed to the analysis of the rate of exacerbations requiring systemic corticosteroids. Duration of trials ranged from four to 12 months, and the majority of participants had mild to moderate asthma. Administration of vitamin D reduced the rate of exacerbations requiring systemic corticosteroids (rate ratio 0.63, 95% CI 0.45 to 0.88; 680 participants; 3 studies; high-quality evidence), and decreased the risk of having at least one exacerbation requiring an emergency department visit or hospitalisation or both (odds ratio (OR) 0.39, 95% CI 0.19 to 0.78; number needed to treat for an additional beneficial outcome, 27; 963 participants; 7 studies; high-quality evidence). There was no effect of vitamin D on % predicted forced expiratory volume in one second (mean difference (MD) 0.48, 95% CI -0.93 to 1.89; 387 participants; 4 studies; high-quality evidence) or Asthma Control Test scores (MD -0.08, 95% CI -0.70 to 0.54; 713 participants; 3 studies; high-quality evidence). Administration of vitamin D did not influence the risk of serious adverse events (OR 1.01, 95% CI 0.54 to 1.89; 879 participants; 5 studies; moderate-quality evidence). One trial comparing low-dose versus high-dose vitamin D reported two episodes of hypercalciuria, one in each study arm. No other study reported any adverse event potentially attributable to administration of vitamin D. No participant in any included trial suffered a fatal asthma exacerbation. We did not perform a subgroup analysis to determine whether the effect of vitamin D on risk of severe exacerbation was modified by baseline vitamin D status, due to unavailability of suitably disaggregated data. We assessed two trials as being at high risk of bias in at least one domain; neither trial contributed data to the analysis of the outcomes reported above. AUTHORS' CONCLUSIONS: Meta-analysis of a modest number of trials in people with predominantly mild to moderate asthma suggests that vitamin D is likely to reduce both the risk of severe asthma exacerbation and healthcare use. It is as yet unclear whether these effects are confined to people with lower baseline vitamin D status; further research, including individual patient data meta-analysis of existing datasets, is needed to clarify this issue. Children and people with frequent severe asthma exacerbations were under-represented; additional primary trials are needed to establish whether vitamin D can reduce the risk of severe asthma exacerbation in these groups.

Prenatal vitamin d supplementation and child respiratory health: a randomised controlled trial.

BACKGROUND: Observational studies suggest high prenatal vitamin D intake may be associated with reduced childhood wheezing. We examined the effect of prenatal vitamin D on childhood wheezing in an interventional study. METHODS: We randomised 180 pregnant women at 27 weeks gestation to either no vitamin D, 800 IU ergocalciferol daily until delivery or single oral bolus of 200,000 IU cholecalciferol, in an ethnically stratified, randomised controlled trial. Supplementation improved but did not optimise vitamin D status. Researchers blind to allocation assessed offspring at 3 years. Primary outcome was any history of wheeze assessed by validated questionnaire. Secondary outcomes included atopy, respiratory infection, impulse oscillometry and exhaled nitric oxide. Primary analyses used logistic and linear regression. RESULTS: We evaluated 158 of 180 (88%) offspring at age 3 years for the primary outcome. Atopy was assessed by skin test for 95 children (53%), serum IgE for 86 (48%), exhaled nitric oxide for 62 (34%) and impulse oscillometry of acceptable quality for 51 (28%). We found no difference between supplemented and control groups in risk of wheeze [no vitamin D: 14/50 (28%); any vitamin D: 26/108 (24%) (risk ratio 0.86; 95% confidence interval 0.49, 1.50; P = 0.69)]. There was no significant difference in atopy, eczema risk, lung function or exhaled nitric oxide between supplemented groups and controls. CONCLUSION: Prenatal vitamin D supplementation in late pregnancy that had a modest effect on cord blood vitamin D level, was not associated with decreased wheezing in offspring at age three years. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN68645785.