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Meta-Analysis
. 2023 Feb 6;2(2):CD011511.
doi: 10.1002/14651858.CD011511.pub3.

Vitamin D for the management of asthma

Anne Williamson  1 , Adrian R Martineau  2 , Aziz Sheikh  3 , David Jolliffe  2 , Chris J Griffiths  4
Affiliations
Meta-Analysis

Vitamin D for the management of asthma

Anne Williamson et al. Cochrane Database Syst Rev. .

Abstract
in English, Spanish

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 (25‐hidroxivitamina 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.

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Conflict of interest statement

Anne Williamson: none known.

Aziz Sheikh: none known.

David Jolliffe: none known.

Adrian R Martineau (ARM) and Christopher J Griffiths (CJG) acted as investigators in one or more clinical trials contributing data to this review. The risk of bias assessment for the study authored by ARM was performed independently by AW and CJG (Camargo 2021). The risk of bias assessment for the study authored by ARM and CJG was performed independently by UN and CJC in the previous systematic review (Martineau 2015). For all other studies, AW and ARM independently assessed the risk of bias for each study.

ARM declares receipt of funding in the last 36 months to support vitamin D research from the following companies who manufacture or sell vitamin D supplements: Pharma Nord Ltd, DSM Nutritional Products Ltd, Thornton & Ross Ltd and Hyphens Pharma Ltd. ARM also declares support for attending meetings from the following companies who manufacture or sell vitamin D supplements: Pharma Nord Ltd and Abiogen Pharma Ltd. ARM also declares participation on the Data and Safety Monitoring Boards for the VITALITY trial (Vitamin D for Adolescents with HIV to reduce musculoskeletal morbidity and immunopathology, NCT01784029) and the Trial of Vitamin D and Zinc Supplementation for Improving Treatment Outcomes Among COVID‐19 Patients in India (NCT04641195). ARM also declares unpaid work as a Programme Committee member for the Vitamin D Workshop. ARM also declares receipt of vitamin D capsules for clinical trial use from Pharma Nord Ltd, Synergy Biologics Ltd and Cytoplan Ltd.

Figures

1
1
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Forest plot of comparison: vitamin D versus placebo (all studies), outcome 1.1: proportion of participants experiencing one or more asthma exacerbations treated with systemic corticosteroids
4
4
Funnel plot of comparison 1: Vitamin D versus placebo (all studies), outcome 1.2 Rate ratio, exacerbation requiring corticosteroids
5
5
Funnel plot of comparison: Vitamin D versus placebo (all studies), outcome: 1.11 End‐study FEV1, % predicted
6
6
Funnel plot of comparison: 1 Vitamin D versus placebo (all studies), outcome: 1.9 People with one or more study‐defined exacerbations
1.1
1.1. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 1: Proportion of participants with one or more exacerbations treated with systemic corticosteroids
1.2
1.2. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 2: Rate of exacerbations treated with systemic corticosteroids
1.3
1.3. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 3: Time to first exacerbation treated with systemic corticosteroids
1.4
1.4. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 4: Proportion of participants with one or more exacerbations requiring systemic corticosteroids (stratified by baseline 25[OH]D)
1.5
1.5. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 5: Proportion of participants with one or more exacerbations requiring systemic corticosteroids (stratified by daily dose equivalent)
1.6
1.6. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 6: Rate ratio, exacerbations requiring systemic corticosteroids (stratified by vitamin D type)
1.7
1.7. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 7: Proportion of participants with one or more exacerbations treated with systemic corticosteroids (stratified by dosing regimen)
1.8
1.8. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 8: Proportion of participants with one or more exacerbations requiring systemic corticosteroids (stratified by age)
1.9
1.9. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 9: Proportion of participants with one or more exacerbations treated with systemic corticosteroids (excluding trials at unclear risk of bias)
1.10
1.10. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 10: Proportion of participants with one or more exacerbation as defined in primary trials (excluding trials at high risk of bias)
1.11
1.11. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 11: Proportion of participants with one or more exacerbations treated with systemic corticosteroids (risk difference)
1.12
1.12. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 12: Proportion of participants with one or more exacerbations requiring emergency department visit or hospitalisation, or both
1.13
1.13. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 13: End‐study C‐ACT/ACT score
1.14
1.14. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 14: End‐study FEV1, % predicted
1.15
1.15. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 15: Proportion of participants with one or more serious adverse events due to any cause
1.16
1.16. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 16: Proportion of participants with fatal asthma exacerbation
1.17
1.17. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 17: Proportion of participants with one or more exacerbation as defined in primary trials
1.18
1.18. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 18: % eosinophils, lower airway
1.19
1.19. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 19: End‐study log 10 total IgE, IU/ml
1.20
1.20. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 20: End‐study FVC, % predicted
1.21
1.21. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 21: End‐study PEFR (L/min)
1.22
1.22. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 22: Withdrawals from trial
1.23
1.23. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 23: Withdrawals from trial (excluding trials at high risk of bias)
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Aglipay 2019 {published and unpublished data}
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Camargo 2021 {published and unpublished data}
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Castro 2014 {published data only}
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    1. Denlinger LC, King TS, Cardet JC, Craig TJ, Holguin F, Kraft M, et al. Vitamin D supplementation and the risk of colds in patients with asthma. Journal of Allergy and Clinical Immunology 2015;135:AB109. - PMC - PubMed
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Ducharme 2019 {published and unpublished data}
    1. Ducharme FM, Jensen M, Mailhot G, Alos N, White J, Rousseau E, et al. Impact of two oral doses of 100,000 IU of vitamin D3 in preschoolers with viral induced asthma: a pilot randomised controlled trial. Trials 2019;20(1):138. [DOI: 10.1186/s13063-019-3184-z] - DOI - PMC - PubMed
Forno 2020 {published and unpublished data}
    1. Forno E, Bacharier LB, Phipatanakul W, Guilbert TW, Cabana MD, Ross K, et al. Effect of vitamin D3 supplementation on severe asthma exacerbations in children with asthma and low vitamin D levels: The VDKA Randomized Clinical Trial. JAMA 2020;324(8):752-60. - PMC - PubMed
    1. Han YY, Forno E, Bacharier LB, Phipatanakul W, Guilbert TW, Cabana MD, et al. Vitamin D supplementation, lung function and asthma control in children with asthma and low vitamin D levels. European Respiratory Journal 2021;58(4):2100989. [DOI: 10.1183/13993003.00989-2021] - DOI - PMC - PubMed
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Jat 2020 {published and unpublished data}
    1. Jat KR, Goel N, Gupta N, Chandra PG, Sudip D, Rakesh L, et al. Efficacy of vitamin D supplementation in asthmatic childrenwith vitamin D deficiency: a randomized controlled trial(ESDAC trial). Pediatric Allergy and Immunology 2021;32(3):479– 88. [DOI: 10.1111/pai.13415] - DOI - PubMed
Jensen 2016 {unpublished data only}
    1. Jensen M, Mailhot G, Alos N, Rousseau E, White J, Khamessan A, et al. Vitamin D intervention in preschoolers with viral-induced asthma (DIVA): a pilot randomised controlled trial. American Journal of Respiratory and Critical Care Medicine 2015;191:A3360. - PMC - PubMed
    1. Jensen ME, Mailhot G, Alos N, Rousseau E, White J, Khamessan A, et al. Vitamin D intervention in preschoolers with viral-induced asthma (DIVA): a pilot randomised controlled trial. Trials 2016;17:353. [DOI: 10.1186/s13063-016-1483-1] - DOI - PMC - PubMed
Jerzynska 2016 {published and unpublished data}
    1. Jerzynska J, Stelmach W, Rychlik B, Lechańska J, Podlecka D, Stelmach I. The clinical effect of vitamin D supplementation combined with grass-specific sublingual immunotherapy in children with allergic rhinitis. Allergy and Asthma Proceedings 2016;37(2):105-14. [DOI: 10.2500/aap.2016.37.3921] - DOI - PubMed
Jiang 2017 {published data only}
    1. Jiang C, Yi R, Na H, Lin S. A randomized controlled study of Vitamin D3 supplementation on childhood asthma control. Chongqing Medicine 2017;46(32):4505-7. [DOI: 10.3969/j.issn.1671-8348.2017.32.011] - DOI
Kerley 2016 {published and unpublished data}
    1. Kerley CP, Hutchinson K, Cormican L, Faul J, Greally P, Coghlan D, et al. Vitamin D3 for uncontrolled childhood asthma: A pilot study. Paediatric Allergy and Immunology 2016;27:404-12. [PMID: 10.1111/pai.12547] - DOI - PubMed
Lewis 2012 {published data only}
    1. Lewis E, Fernandez C, Nella A, Hopp R, Gallagher JC, Casale TB. Relationship of 25-hydroxyvitamin D and asthma control in children. Annals of Allergy, Asthma and Immunology 2012;108(4):281-2. - PubMed
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Majak 2009 {published and unpublished data}
    1. Majak P, Jerzyiska J, Smejda K, Stelmach I, Timler D, Stelmach W. Correlation of vitamin D with Foxp3 induction and steroid-sparing effect of immunotherapy in asthmatic children. Annals of Allergy, Asthma and Immunology 2012;109(5):329-35. - PubMed
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Majak 2011 {published data only}
    1. Majak P, Olszowiec-Chlebna M, Smejda K, Stelmach I. Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. Journal of Allergy and Clinical Immunology 2011;127(5):1294-6. - PubMed
Martineau 2015 {published data only}
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Ramos‐Martínez 2018 {published data only}
    1. Ramos-Martínez E, López-Vancell MR, Fernández de Córdova-Aguirre JC, Rojas-Serrano J, Chavarría A, Velasco-Medina A, et al. Reduction of respiratory infections in asthma patients supplemented with vitamin D is related to increased serum IL-10 and IFNγ levels and cathelicidin expression. Cytokine 2018;108:239–46. - PubMed
Tachimoto 2016 {published and unpublished data}
    1. Tachimoto H, Mezawa H, Segawa T, Akiyama N, Ida H, Urashima M. Improved control of childhood asthma with low-dose, short-term vitamin D supplementation: a randomized, double-blind, placebo-controlled trial. Allergy 2016;71(7):1001-9. - PubMed
Thakur 2021 {published and unpublished data}
    1. Thakur C, Kumar J, Kumar P, Goyal JP, Singh K, Gupta A. Vitamin‐D supplementation as an adjunct to standard treatmentof asthma in children: a randomized controlled trial (ViDASTA Trial). Pediatric Pulmonology 2021;56:1427–33. [DOI: 10.1002/ppul.25287] - DOI - PubMed
Urashima 2010 {published data only}
    1. Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in school children. American Journal of Clinical Nutrition 2010;91(5):1255-60. - PubMed
Yadav 2014 {published data only}
    1. Yadav M, Mittal K. Effect of vitamin D supplementation on moderate to severe bronchial asthma. Indian Journal of Pediatrics 2014;81(7):650-4. - PubMed

References to studies excluded from this review

Alansari 2015 {published data only}
    1. Alansari K, Alattar M, Ibrahim KY, Davidson BL, Elnair MB, Mohamed AN. A randomized trial of vitamin D to reduce pediatric asthma exacerbations. American Journal of Respiratory and Critical Care Medicine 2015;191:A2621.
Arshi 2014 {published data only}
    1. Arshi S, Fallahpour M, Nabavi M, Bemanian MH, Javad-Mousavi SA, Nojomi M, et al. The effects of vitamin D supplementation on airway functions in mild to moderate persistent asthma. Annals of Allergy, Asthma and Immunology 2014;113(4):404-9. - PubMed
Babar 2017 {published data only}
    1. Babar MZ, Hussain M, Majeed SA. Vitamin D supplementation improves FEV1 in patients of Bronchial Asthma. Pakistan Journal of Medical Sciences 2017;33(5):1144-7. [DOI: 10.12669/pjms.335.12990] - DOI - PMC - PubMed
Bantz 2015 {published data only}
    1. Bantz SK, Dy T, Herzog R. Vitamin D deficiency in a young, atopic pediatric population. Journal of Allergy and Clinical Immunology 2015;135((2 Suppl 1)):AB148.
Baris 2014 {published data only}
    1. Baris S, Kiykim A, Ozen A, Tulunay A, Karakoc-Aydiner E, Barlan IB. Vitamin D as an adjunct to subcutaneous allergen immunotherapy in asthmatic children sensitized to house dust mite. Allergy 2014;69(2):246-53. - PubMed
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Bar Yoseph 2015 {published data only}
    1. Bar-Yoseph R, Livnat G, Schnapp Z, Dabbah H, Goldbart A, Bentur LPY. The effect of vitamin D therapy on airway reactivity and airway inflammation in asthmatic children. In: European Respiratory Society Annual Congress; 2013 Sept 7-11; Barcelona. Vol. 42, Suppl 57. 2013:1159.
    1. Bar Yoseph R, Livnat G, Schnapp Z, Hakim F, Dabbah H, Goldbart A. The effect of vitamin D on airway reactivity and inflammation in asthmatic children: a double-blind placebo-controlled trial. Pediatric Pulmonology 2015;50(8):747-53. [DOI: 10.1002/ppul.23076] - DOI - PubMed
Breitenbuecher 2012 {published data only}
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Darabi 2013 {published data only}
    1. Darabi B, Moin M, Pourpak Z. The effect of vitamin D supplementation over asthma outcome. In: 2nd International Congress of Immunology; 2013 Feb 19-21; Tehran. 2013.
De Groot 2015 {published data only}
    1. Groot JC, Roon EN, Storm H, Bel EH, ten Brinke A. The effect of a single high dose vitamin D3 on neutrophilic airway inflammation in nonatopic asthma. European Respiratory Journal 2012;40(Suppl 56):P1790.
    1. De Groot JC, Van Roon EN, Storm H, Veeger NJ, Bel EH, Ten Brinke A. The effect of vitamin D on airway inflammation in non-atopic asthma. American Journal of Respiratory and Critical Care Medicine 2014;189:A1390.
    1. De Groot JC, Roon EN, Storm H, Veeger NJ, Zwinderman AH, Hiemstra PS, et al. Vitamin D reduces eosinophilic airway inflammation in non-atopic asthma. Journal of Allergy and Clinical Immunology 2015;135(3):670-5. - PubMed
Dodamani 2019 {published data only}
    1. Dodamani MH, Muthu V, Thakur R, Pal A, Sehgal IS, Dhooria S, et al. A randomised trial of vitamin D in acute-stage allergic bronchopulmonary aspergillosis complicating asthma. Mycoses 2019;62:4. [DOI: 10.1111/myc.12879] - DOI - PubMed
Emami Ardestani 2020 {published data only}
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EUCTR2016‐004827‐22‐NL {published and unpublished data}
    1. EUCTR2016‐004827‐22‐NL. Study to determine the safety/tolerability of the simultaneous treatment of BM41-vaccine and vitamin D 3 in patients with birch pollen allergy [A randomized, double‐blind, placebo‐controlled, double‐dummy study to determine the safety/tolerability of a simultaneous subcutaneous treatment of BM41 and vitamin D 3 in patients with moderate to severe allergic rhinitis/ rhinoconjunctivitis caused by birch pollen ‐ BM41ViD]. www.clinicaltrialsregister.eu/ctr-search/search?query=2016-004827-22 (first received 25 July 2017). [CENTRAL: CN-01884690]
Ganmaa 2020 {published data only}
    1. Ganmaa D, Gantsetseg G, Khulan D, Ariunzaya S, Delgereh B, Sumiya E, et al. G582 Phase 3 randomised controlled trial of vitamin D supplementation in 8,851 Mongolian schoolchildren. Archives of Disease in Childhood 2020;105:A209. [DOI: 10.1136/archdischild-2020-rcpch.499] - DOI
Goldring 2013 {published data only}
    1. Goldring ST, Griffiths CJ, Martineau AR, Robinson S, Yu C, Poulton S, et al. Prenatal vitamin D supplementation and child respiratory health: a randomised controlled trial. PLOS One 2013;8(6):e66627. - PMC - PubMed
Huo 2019 {published data only}
    1. Huo BB, Huang H. Effect of vitamin D combined with salbutamol on children with bronchial asthma. Drug Evaluation Research 2019;42(1):125-8.
Lakatos 2000 {published data only}
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Litonjua 2014 {published data only}
    1. Litonjua AA, Lange NE, Carey VJ, Brown S, Laranjo N, Harshfield BJ, et al. The Vitamin D Antenatal Asthma Reduction Trial (VDAART): rationale, design, and methods of a randomized, controlled trial of vitamin D supplementation in pregnancy for the primary prevention of asthma and allergies in children. Contemporary Clinical Trials 2014;38(1):37-50. - PMC - PubMed
Liu 2018 {published data only}
    1. Liu WJ, Wang YT, Bi LX, Liang L. Adjuvant therapy of vitamin D3 was associated with decreased serum TLR4 and S100 beta proteins and delayed recurrence of severe asthma among children. Chinese Journal of Immunology 2018;34:1382‐6. [CENTRAL: CN-02174146]
Mansuroglu 2017 {published data only}
    1. Mansuroglu U, Ntas DUA, Dogruel D. The relationship between Vitamin D deficiency and wheezing in young children; a randomized study. Asthma Allergy Immunology / astim allerji immunoloji 2017;15(2):93-102. [DOI: 10.21911/aai.350] - DOI
McDonald 2006 {published data only}
    1. McDonald CF, Matthews S, Seeman E. A two year double blind placebo controlled prospective study of the effects of calcitriol on bone mineral density (BMD) in patients with asthma. In: Proceedings of the Thoracic Society of Australia & New Zealand, Annual Scientific Meeting; 2003 April 4-9; Adelaide. 2003:P022.
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Menon 2014 {published data only}
    1. Menon B, Nima G, Dogra V, Mittal A, Kaur C, Mittal U. Evaluation of vitamin D in bronchial asthma and the effect of vitamin D supplementation on asthma severity and control: A randomised control trial. European Respiratory Journal 2014;44(Suppl 58):P4049.
Miraglia del Giudice 2016 {published data only}
    1. Miraglia del Giudice M, Maiello N, Allegorico A, Iavarazzo L, Capasso M, Capristo C, et al. Lactobacillus reuteri DSM 17938 plus vitamin D3 as ancillary treatment in allergic children with asthma. Annals of Allergy, Asthma and Immunology 2016;117(6):710-12. [DOI: 10.1016/j.anai.2016.09.004] - DOI - PubMed
Nanzer 2014 {published data only}
    1. Chambers ES, Nanzer AM, Pfeffer PE, Richards DF, Martineau AR, Griffiths CJ, et al. Calcitriol restores glucocorticoid responsiveness in steroid resistant asthmatics through reduction of IL-17A. Immunology 2014;143:50.
    1. Chambers ES, Nanzer AM, Pfeffer PE, Richards DF, Timms PM, Martineau AR, et al. Distinct endotypes of steroid-resistant asthma characterized by IL-17A (high) and IFN-gamma (high) immunophenotypes: Potential benefits of calcitriol. Journal of Allergy and Clinical Immunology 2015;136(3):628-37. - PMC - PubMed
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Ozkars 2017 {published data only}
    1. Ozkars MY, Keskin O, Kucukosmanoglu E, Ulusal H, Orkme M. Effects of vitamin D use on asthma control. Zeynep Kamil Medical Journal 2017;48(4):142-5. [DOI: 10.16948/zktipb.320095] - DOI
Price 2015 {published data only}
    1. Price OJ, Hull JH, Howatson G, Robson-Ansley P, Ansley L. Vitamin D and omega-3 polyunsaturated fatty acid supplementation in athletes with exercise-induced bronchoconstriction: a pilot study. Expert Review of Respiratory Medicine 2015;9(3):369-78. - PubMed
Rajanandh 2015 {published data only}
    1. Nageswari AD, Rajanandh MG, Priyanka RK, Rajasekhar P. Effect of vitamin D3 on mild to moderate persistent asthmatic patients: a randomized controlled pilot study. Perspectives in Clinical Research 2014;5(4):167-71. - PMC - PubMed
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Salas 2018 {published data only}
    1. Salas AA, Woodfin T, Phillips V, Peralta-Carcelen M, Carlo WA, Ambalavanan N. Dose-response effects of early vitamin d supplementation on neurodevelopmental and respiratory outcomes of extremely preterm infants at 2 years of age: a randomized trial. Neonatology 2018;113(3):256-62. [DOI: 10.1159/000484399] - DOI - PMC - PubMed
Schou 2003 {published data only}
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Swangtrakul 2022 {published and unpublished data}
    1. Swangtrakul N, Manuyakorn W, Mahachoklertwattana P, Kiewngam P, Sasisakulporn C, Jotikasthirapa W, et al. Effect of vitamin D on lung function assessed by forced oscillation technique in asthmatic children with vitamin D deficiency: a randomized double-blind placebo-controlled trial. Asian Pacific Journal of Allergy and Immunology 2022;40(1):22-30. [DOI: 10.12932/AP-010519-0553] - DOI - PubMed
Thijs 2011 {published data only}
    1. Thijs W, Janssen K, Verhoosel RM, Papapoulos SE, Le Cessie S, Middeldorp S, et al. Effect of vitamin D treatment on antimicrobial peptides in asthma patients and healthy controls. European Respiratory Journal 2011;38(55):4888.
Torres 2013 {published data only}
    1. Torres J, Martinez M, Chavez E, Garcia D, Fabiano F, Hernandez J. Vitamin D levels in peripheral blood in patients with mild to moderate bronchial asthma. In: European Academy of Allergy and Clinical Immunology and World Allergy Organization World Allergy and Asthma Congress; 2013 June 22-26; Milan. 2013:68.
Utz 1976 {published data only}
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Yemelyanov 2001 {published data only}
    1. Yemelyanov A, Shevelev S, Murzin B, Shubin S. Efficacy and safety of calcium and vitamin D in treatment of steroid osteoporosis in asthmatic patients. European Respiratory Journal 2001;18:S33.
Zhu 2022 {published data only (unpublished sought but not used)}
    1. Zhu H, Zhang H, Chen H, Wu H. Effects of vitamin D combined with salmeterol/fluticasone on airway remodeling in children with bronchial asthma. Drug Biotechnology 2022;29(02):no pagination. [DOI: 10.19526/j.cnki.1005-8915.20220212] - DOI

References to ongoing studies

Chiewchalermsri 2020 {published and unpublished data}
    1. Chiewchalermsri C, Sangkanjanavanich S, Pradubpongsa P, Mitthamsiri W, Jaisupa N, Sangasapaviliya A, et al. Adjunctive vitamin D2 supplement in patient with allergen-specific immunotherapy randomized, double blind, placebo-controlled trial. Journal of Allergy and Clinical Immunology 2020;145(2):AB60. [DOI: 10.1016/j.jaci.2019.12.712] - DOI
Gold 2016 {published and unpublished data}
    1. Gold DR, Litonjua AA, Carey VJ, Manson JE, Buring JE, Lee IM, et al. Lung VITAL: rationale, design, and baseline characteristics of an ancillary study evaluating the effects of vitamin D and/or marine omega-3 fatty acid supplements on acute exacerbations of chronic respiratory disease, asthma control, pneumonia and lung function in adults. Contemporary Clinical Trials 2016;47:185-95. [DOI: 10.1016/j.cct.2016.01.003] - DOI - PMC - PubMed
IRCT20190721044288N1 {published data only}
    1. IRCT20190721044288N1. The effect of vitamin D on pulmonary function and serum level of interleukin 10 and antioxidant activity in patient with moderate to severe asthma. trialsearch.who.int/Trial2.aspx?TrialID=IRCT20190721044288N1 (first received 27 October 2020).
Jensen 2019 {published and unpublished data}
    1. Ducharme F. Vitamin D In the Prevention of Viral-induced Asthma in Preschoolers (DIVA). clinicaltrials.gov/ct2/show/NCT03365687 (first received 7 December 2017). [URL: clinicaltrials.gov/ct2/show/NCT03365687]
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Lee 2018 {published and unpublished data}
    1. Lee MT, Kattan M, Fennoy I, Arpadi SM, Miller RL, Cremers S, et al. Randomized phase 2 trial of monthly Vitamin D to prevent respiratory complications in children with sickle cell disease. Blood Advances 2018;2(9):969-78. [DOI: 10.1182/bloodadvances.2017013979] - DOI - PMC - PubMed
NCT02424552 {published data only}
    1. NCT02424552. Effect of vitamin D as add-on therapy for vitamin D insufficient patients with severe asthma (EVITA) [EVITA Trial: Effect of vitamin D as add-on therapy for vitamin D insufficient patients with severe asthma: a randomized, double-blind, placebo-controlled trial]. clinicaltrials.gov/ct2/show/NCT02424552 (first received 23 April 2015).
NCT04117581 {published data only}
    1. NCT04117581. A study to investigate the effect of vitamin d3 supplementation on asthma symptoms in adults with asthma (VITDAS) (VITDAS) [A daily 5000 IU vitamin D supplement for the improvement of lung function and asthma control in adults with asthma: a randomised controlled trial]. clinicaltrials.gov/ct2/show/NCT04117581 (first received 7 October 2019). [CLINICALTRIALS.GOV: NCT04117581]
NCT05043116 {published data only}
    1. NCT05043116. High-dose vitamin D supplement for the prevention of acute asthma-like symptoms in preschool children (COPSACvitd) [High-dose vitamin D supplement for the prevention of acute asthma-like symptoms in preschool children - a double-blind, randomized, controlled trial]. clinicaltrials.gov/ct2/show/NCT05043116 (first received 14 September 2021). [CLINICALTRIALS.GOV: NCT05043116]
Patella 2013 {published data only}
    1. Florio G, Rubano A, Patella V. Effect of sublingual specific immunotherapy associated to vitamin D3 and lactobacillus reuteri in asthmatic teens. American Journal of Respiratory and Critical Care Medicine 2015;191:A4269.
    1. Patella V, Florio G, Palmieri M. Vitamin D3 associated to lactobacillus reuteri improves effects of allergen immunotherapy in asthmatic children. In: European Respiratory Society 23rd Annual Congress; 2013 Sep 7-11; Barcelona. 2013.
TCTR20210129003 {published data only}
    1. TCTR20210129003. Adjunctive vitamin A and vitamin D3 (Cholecalciferol) for enhancing efficacy of allergen-specific immunotherapy in allergic rhinitis, a randomized, double-blind, placebo-controlled trial. www.thaiclinicaltrials.org/show/TCTR20210129003 (first received 26 January 2021). [TCTR: TCTR20210129003]
UMIN000004160 {published data only}
    1. UMIN000004160. A randomized, double blind, comparative study of vitamin D3 versus placebo in small children with asthma to prevent asthma attack. center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000004995 (first received 1 October 2010).

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