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• Improving the quality of life in asthmatic patients supplemented with vitamin D: variability in the studies and discrepancy in the results.
  Rubén Andújar-Espinosa, Lourdes Salinero-González
  Published on: 28 December 2020
• Does vitamin D supplementation in patients with vitamin D deficiency improve quality of life?
  Nobuyuki Horita, Takeshi Kaneko
  Published on: 13 November 2020

• Published on: 28 December 2020

  Improving the quality of life in asthmatic patients supplemented with vitamin D: variability in the studies and discrepancy in the results.

  • Rubén Andújar-Espinosa, Pulmonology / Associate Professor in Health Sciences Hospital Clínico Universitario Virgen de la Arrixaca. Murcia. Spain / University of Murcia
  • Other Contributors:
    • Lourdes Salinero-González, Endocrinology and Nutrition

  Vitamin D could have potentiating effects on the innate and adaptive immune system (1). This would explain a potential defense effect against respiratory infections. Based on this, this vitamin has been linked to respiratory diseases such as COPD, asthma, respiratory infections and even lung cancer (2). In November 2020, our work team published the ACVID randomized clinical trial, and we have received a letter from Dr. Nobuyuki Horita asking us two questions about our results. In the first place, he lists a series of studies that show a great discrepancy in the results on quality of life, requesting our opinion on this discrepancy. Second, he asks for our opinion on the results of our work in terms of improving quality of life without an increase in lung function.
  The authors continue to maintain that “some beneficial association was observed in the group of patients receiving vitamin D compared to the placebo group” in the studies analyzed in our article. In fact, in the VIDA research (3) the authors describe a small but significant association with the decrease in the dose of ciclesonide required to maintain asthma control in the vitamin D group. It is true that in this study the quality improvement Life is better in the control group, but this is a secondary objective. In the ViDiAs study (4) the authors found no significant differences in the reduction of asthma attacks or upper airway infections (coprimary outcomes), but, although they did not find clinical impr...

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  Vitamin D could have potentiating effects on the innate and adaptive immune system (1). This would explain a potential defense effect against respiratory infections. Based on this, this vitamin has been linked to respiratory diseases such as COPD, asthma, respiratory infections and even lung cancer (2). In November 2020, our work team published the ACVID randomized clinical trial, and we have received a letter from Dr. Nobuyuki Horita asking us two questions about our results. In the first place, he lists a series of studies that show a great discrepancy in the results on quality of life, requesting our opinion on this discrepancy. Second, he asks for our opinion on the results of our work in terms of improving quality of life without an increase in lung function.
  The authors continue to maintain that “some beneficial association was observed in the group of patients receiving vitamin D compared to the placebo group” in the studies analyzed in our article. In fact, in the VIDA research (3) the authors describe a small but significant association with the decrease in the dose of ciclesonide required to maintain asthma control in the vitamin D group. It is true that in this study the quality improvement Life is better in the control group, but this is a secondary objective. In the ViDiAs study (4) the authors found no significant differences in the reduction of asthma attacks or upper airway infections (coprimary outcomes), but, although they did not find clinical improvement in quality of life, they did find a statistically significant difference between the arms. Quality of life was also a secondary objective of the ViDiAs study and discrepancies were found in the control of asthma measured with ACT that was worse in the group treated with vitamin D. In the study by Arshi et al (5) they observed an increase in pulmonary function tests (primary ednpoint). In the work of De Groot (6), a reduction in the percentage of eosinophils in induced sputum was found in patients with higher eosinophilic proportions in the sputum, as their primary objective. No changes in quality of life were observed. As Dr. Nobuyuki Horita indicates, there are discrepancies in different studies regarding the results on quality of life, as in the works of Rajanandh (7), Kerley (8) and Majak (9, 10). The ACVID study (11) was designed to investigate improvement in asthma control measured with ACT as a primary endpoint and quality of life measured with Mini-AQLQ was a secondary endpoint. A clinically and statistically significant improvement in asthma control was observed and, in addition, a statistically significant improvement in quality of life was found in patients receiving vitamin D versus placebo. We believe that the existing discrepancy in the results regarding vitamin D and asthma is due to the high variability in the design of the different studies with respect to the inclusion and exclusion criteria and the primary objectives of the studies. It would be necessary to standardize the design of the studies with clear primary objectives that later allow quality meta-analyzes to be carried out, with strong and credible results, to draw reliable and consistent conclusions that allow the asthma management guidelines to be changed.
  Regarding the second question, in the ACVID study, the improvement in quality of life measured with MiniAQLQ was a secondary objective of the study, so the results must be analyzed with caution. A statistically significant improvement was observed in the group that received calcifediol supplementation compared to the group that received placebo with a difference of 0.70 (95% CI: 0.63 - 1.64; p = 0.01). The mean variation between the total initial and final scores in the Mini-AQLQ was 1.05 in the intervention group and -0.09 in the control group, p <0.001. However, no significant differences were observed in FEV1 between groups, nor in the initial and final difference in each group. We do not know for sure why this improvement in the quality of life of patients supplemented with vitamin D is due, but it is probably due to the different mechanisms by which this vitamin could influence asthma. Vitamin D could cause the modulation of different pro-inflammatory cytokines and would increase the production of antimicrobial peptides, such as cathelicidin and beta-defensin 2 (12). This vitamin has direct effects on T cells, reduces the production of IgE and increases the synthesis of IL-10 (13). Furthermore, vitamin D can reduce IL-17 responses in severe asthma, reducing bronchial hyperresponsiveness, remodeling, steroid resistance, and the synthesis of pro-inflammatory cytokines (14). In asthma, unlike COPD, lung function is variable and is usually preserved in patients in a stable phase, for this reason the patients in the ACVID study maintain their lung function unchanged during the study period. The improvement in quality of life could be due to the effects of vitamin D in reducing bronchial hyperresponsiveness, the synthesis of pro-inflammatory cytokines and resistance to steroids, which resulted in an improvement in asthma control and, therefore, therefore, in an improvement in the quality of life of asthmatic patients.
  We thank Dr. Nobuyuki Horita for his interest in the ACVID study and hope we have responded to his concerns.

  1. Garcia de Tena J, El Hachem Debek A, Hernandez Gutierrez C, Izquierdo Alonso JL. The role of vitamin D in chronic obstructive pulmonary disease, asthma and other respiratory diseases. Arch Bronconeumol. 2014;50(5):179-84.
  2. Herr C, Greulich T, Koczulla RA, Meyer S, Zakharkina T, Branscheidt M, et al. The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer. Respir Res. 2011;12:31.
  3. Castro M, King TS, Kunselman SJ, Cabana MD, Denlinger L, Holguin F, et al. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial. JAMA. 2014;311(20):2083-91.
  4. Martineau AR, MacLaughlin BD, Hooper RL, Barnes NC, Jolliffe DA, Greiller CL, et al. Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs). Thorax. 2015;70(5):451-7.
  5. 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. Ann Allergy Asthma Immunol. 2014;113(4):404-9.
  6. de Groot JC, van Roon EN, Storm H, Veeger NJ, Zwinderman AH, Hiemstra PS, et al. Vitamin D reduces eosinophilic airway inflammation in nonatopic asthma. J Allergy Clin Immunol. 2015;135(3):670-5 e3.
  7. Rajanandh MG, Nageswari AD, Prathiksha G. Effectiveness of vitamin D3 in severe persistent asthmatic patients: A double blind, randomized, clinical study. J Pharmacol Pharmacother. 2015;6(3):142-6.
  8. Kerley CP, Hutchinson K, Cormican L, Faul J, Greally P, Coghlan D, et al. Vitamin D3 for uncontrolled childhood asthma: A pilot study. Pediatr Allergy Immunol. 2016;27(4):404-12.
  9. Majak P, Olszowiec-Chlebna M, Smejda K, Stelmach I. Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. J Allergy Clin Immunol. 2011;127(5):1294-6.
  10. Majak P, Rychlik B, Stelmach I. The effect of oral steroids with and without vitamin D3 on early efficacy of immunotherapy in asthmatic children. Clin Exp Allergy. 2009;39(12):1830-41.
  11. Andujar-Espinosa R, Salinero-Gonzalez L, Illan-Gomez F, Castilla-Martinez M, Hu-Yang C, Ruiz-Lopez FJ. Effect of vitamin D supplementation on asthma control in patients with vitamin D deficiency: the ACVID randomised clinical trial. Thorax. 2020.
  12. Hansdottir S, Monick MM, Lovan N, Powers L, Gerke A, Hunninghake GW. Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state. J Immunol. 2010;184(2):965-74.
  13. Hartmann B, Heine G, Babina M, Steinmeyer A, Zugel U, Radbruch A, et al. Targeting the vitamin D receptor inhibits the B cell-dependent allergic immune response. Allergy. 2011;66(4):540-8.
  14. Nanzer AM, Chambers ES, Ryanna K, Richards DF, Black C, Timms PM, et al. Enhanced production of IL-17A in patients with severe asthma is inhibited by 1alpha,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion. J Allergy Clin Immunol. 2013;132(2):297-304 e3.

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  Conflict of Interest:
  None declared.

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• Published on: 13 November 2020

  Does vitamin D supplementation in patients with vitamin D deficiency improve quality of life?

  • Nobuyuki Horita, Pulmonologist Yokohama City University Graduate School of Medicine
  • Other Contributors:
    • Takeshi Kaneko, Pulmonogist

  Asthma and chronic obstructive pulmonary disease (COPD) are two major obstructive lung diseases. Many epidemiological and genetic research including ours suggested possible association between vitamin D (VitD) and these diseases.[1 2] A meta-analysis by Jolliffe in 2019 demonstrated that VitD supplementation surely reduced the frequency of exacerbations in COPD patients who had VitD deficiency.[3] Vitamin D is an attractive option especially in developing countries because some of currently used medications such as bronchodilators and biologics are pricy. Given such background, VitD supplementation has been expected to be a new strategy for asthmatic patients with VitD deficiency. Thus, we read a report by Dr. Andújar-Espinosa et al. with a great interest.[4] The ACVID trial, a well-designed triple-blind randomized controlled trial (RCT), indicated greater improvement of quality of life (QOL) measured by Asthma Control Test (ACT) score as the primary endpoint, in the calcifediol arm compared to the placebo arm. Nonetheless, we have two concerns for this trial.
  First, there was a considerable discrepancy about the efficacy with previous reports. Inconsistency is a reason to degrade the quality of evidence.[5] Authors mentioned that "some beneficial association was observed in the group of patients receiving VitD compared with the placebo group" in all previous studies.[4] However, very limited data support the QOL improvement observed in ACVID trial. Dr. And...

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  Asthma and chronic obstructive pulmonary disease (COPD) are two major obstructive lung diseases. Many epidemiological and genetic research including ours suggested possible association between vitamin D (VitD) and these diseases.[1 2] A meta-analysis by Jolliffe in 2019 demonstrated that VitD supplementation surely reduced the frequency of exacerbations in COPD patients who had VitD deficiency.[3] Vitamin D is an attractive option especially in developing countries because some of currently used medications such as bronchodilators and biologics are pricy. Given such background, VitD supplementation has been expected to be a new strategy for asthmatic patients with VitD deficiency. Thus, we read a report by Dr. Andújar-Espinosa et al. with a great interest.[4] The ACVID trial, a well-designed triple-blind randomized controlled trial (RCT), indicated greater improvement of quality of life (QOL) measured by Asthma Control Test (ACT) score as the primary endpoint, in the calcifediol arm compared to the placebo arm. Nonetheless, we have two concerns for this trial.
  First, there was a considerable discrepancy about the efficacy with previous reports. Inconsistency is a reason to degrade the quality of evidence.[5] Authors mentioned that "some beneficial association was observed in the group of patients receiving VitD compared with the placebo group" in all previous studies.[4] However, very limited data support the QOL improvement observed in ACVID trial. Dr. Andújar-Espinosa et al. misleadingly mentioned that ViDiAs researchers "found a significant association in improving quality of life, measured with the St George Respiratory Questionnaire (SGRQ).4" In fact, ViDiAs researchers wrote "of 16 secondary outcomes investigated, only one, respiratory QOL, as measured by the SGRQ, showed a statistically significant difference between arms, but this was just less than the 4-point minimum clinically important difference for this instrument.6" In the same trial, VitD supplementation led to 0.3 points poorer improvement of ACT score than placebo.[6] The QOL change from the baseline in the other previous studies are below. The largest RCT, VIDA, with 408 patients with baseline VitD < 30 ng/mL showed slightly better change of QOL in control arm.[7] Another large trial with 161 cases by Rajanandh revealed 3.1 points greater improvement of SGRQ total score in placebo group.8 Groot et al. randomized and analyzed 44 asthmatic patients with serum VitD below 100 ng/mL and detected no difference of QOL change.[9] Kerley et al. evaluated 39 children without requesting specific VitD level for inclusion and found placebo-favored QOL improvement in whole cohort and low VitD ( <50 ng/mL) cohort.[10] Majak et al. published two reports comparing steroid alone versus steroid plus VitD3 for patients with any serum VitD level.[11 12] These reports showed insignificant trends toward opposite directions with each other.[11 12] In short, although ACVID trial revealed drastic improvement of ACT score, no other studies achieved substantial benefit in QOL. Rather, many trials showed non-significant trend toward worse QOL in VitD arm. We would like to know what causes this discrepancy.
  The second is the lack of improvement of forced expiratory volume in one second (FEV1), the key measurement in asthma trials. Table 3 of the report by Dr. Andújar-Espinosa et al. implied that patients who were treated with calcifediol had 203 mL larger FEV1.4 However, this difference would disappear after adjusting baseline difference, 208 mL better in calcifediol arm.4 To our understanding, medical therapy improves QOL of patients with asthma mainly by resolving bronchial obstruction assessable by FEV1. We would like to ask Dr. Andújar-Espinosa how VitD improved the QOL without better FEV1 improvement.[4]
  Regardless of our concerns, we are grateful for the authors because they provided the most up-to-date information for VitD supplementation in asthmatic patients.[4]
  References
  1. Herr C, Greulich T, Koczulla RA, et al. The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer. Respiratory Research 2011;12.
  2. Horita N, Miyazawa N, Tomaru K, et al. Vitamin D binding protein genotype variants and risk of chronic obstructive pulmonary disease: a meta-analysis. Respirology (Carlton, Vic) 2015;20(2):219-25.
  3. Jolliffe DA, Greenberg L, Hooper RL, et al. Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials. Thorax 2019;74(4):337-45.
  4. Andújar-Espinosa R, Salinero-González L, Illán-Gómez F, et al. Effect of vitamin D supplementation on asthma control in patients with vitamin D deficiency: the ACVID randomised clinical trial. Thorax 2020.
  5. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 7. Rating the quality of evidence--inconsistency. Journal of clinical epidemiology 2011;64(12):1294-302.
  6. Martineau AR, MacLaughlin BD, Hooper RL, et al. Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs). Thorax 2015;70(5):451-7.
  7. Castro M, King TS, Kunselman SJ, et al. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial. Jama 2014;311(20):2083-91.
  8. Rajanandh MG, Nageswari AD, Prathiksha G. Effectiveness of vitamin D3 in severe persistent asthmatic patients: A double blind, randomized, clinical study. Journal of pharmacology & pharmacotherapeutics 2015;6(3):142-6.
  9. de Groot JC, van Roon EN, Storm H, et al. Vitamin D reduces eosinophilic airway inflammation in nonatopic asthma. The Journal of allergy and clinical immunology 2015;135(3):670-5.e3.
  10. Kerley CP, Hutchinson K, Cormican L, et al. Vitamin D3 for uncontrolled childhood asthma: A pilot study. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology 2016;27(4):404-12.
  11. Majak P, Olszowiec-Chlebna M, Smejda K, et al. Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. The Journal of allergy and clinical immunology 2011;127(5):1294-6.
  12. Majak P, Rychlik B, Stelmach I. The effect of oral steroids with and without vitamin D3 on early efficacy of immunotherapy in asthmatic children. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 2009;39(12):1830-41.

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  Conflict of Interest:
  None declared.

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