Associations Among 25-Hydroxyvitamin D Levels, Lung Function, and Exacerbation Outcomes in COPD

An Analysis of the SPIROMICS Cohort
Published:January 17, 2020DOI:


      The relationship between 25-hydroxyvitamin D (25-OH-vitamin D) and COPD outcomes remains unclear. Using the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), we determined associations among baseline 25-OH-vitamin D and cross-sectional and longitudinal lung function and COPD exacerbations.


      Serum 25-OH-vitamin D level was measured in stored samples from 1,609 SPIROMICS participants with COPD. 25-OH-vitamin D levels were modeled continuously and dichotomized as deficient (< 20 ng/mL) vs not deficient (≥ 20 ng/mL). Outcomes of interest included % predicted FEV1 (current and 1-year longitudinal decline) and COPD exacerbations (separately any and severe, occurring in prior year and first year of follow-up).


      Vitamin D deficiency was present in 21% of the cohort and was more prevalent in the younger, active smokers, and blacks. Vitamin D deficiency was independently associated with lower % predicted FEV1 (by 4.11%) at enrollment (95% CI, –6.90% to –1.34% predicted FEV1; P = .004), 1.27% predicted greater rate of FEV1 decline after 1 year (95% CI, –2.32% to –0.22% predicted/y; P = .02), and higher odds of any COPD exacerbation in the prior year (OR, 1.32; 95% CI, 1.00-1.74; P = .049). Each 10-ng/mL decrease in 25-OH-vitamin D was associated with lower baseline lung function (–1.04% predicted; 95% CI, –1.96% to –0.12% predicted; P = .03) and increased odds of any exacerbation in the year before enrollment (OR, 1.11; 95% CI, 1.01-1.22; P = .04).


      Vitamin D deficiency is associated with worse cross-sectional and longitudinal lung function and increased odds of prior COPD exacerbations. These findings identify 25-OH-vitamin D levels as a potentially useful marker of adverse COPD-related outcomes.

      Key Words


      25-OH-vitamin D (25-hydroxyvitamin D), AECOPD (acute exacerbation of COPD), FSAD (functional small-airway disease), GOLD (Global Initiative for Chronic Obstructive Lung Disease), Pi10 (standardized airway wall thickness at an internal perimeter of 10 mm), SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), VDD (vitamin D deficiency)
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        • Horadagoda C.
        • Dinihan T.
        • Roberts M.
        • Kairaitis K.
        Body composition and micronutrient deficiencies in patients with an acute exacerbation of chronic obstructive pulmonary disease.
        Intern Med J. 2017; 47: 1057-1063
        • Rawal G.
        • Yadav S.
        Nutrition in chronic obstructive pulmonary disease: a review.
        J Transl Intern Med. 2015; 3: 151-154
        • Persson L.J.
        • Aanerud M.
        • Hiemstra P.S.
        • Hardie J.A.
        • Bakke P.S.
        • Eagan T.M.
        Chronic obstructive pulmonary disease is associated with low levels of vitamin D.
        PLoS One. 2012; 7e38934
        • Zhu M.
        • Wang T.
        • Wang C.
        • Ji Y.
        The association between vitamin D and COPD risk, severity, and exacerbation: an updated systematic review and meta-analysis.
        Int J Chron Obstruct Pulmon Dis. 2016; 11: 2597-2607
        • Holick M.F.
        • Binkley N.C.
        • Bischoff-Ferrari H.A.
        • et al.
        Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.
        J Clin Endocrinol Metab. 2011; 96: 1911-1930
        • Herr C.
        • Greulich T.
        • Koczulla R.A.
        • et al.
        The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer.
        Respir Res. 2011; 12: 31
        • Zosky G.R.
        • Berry L.J.
        • Elliot J.G.
        • James A.L.
        • Gorman S.
        • Hart P.H.
        Vitamin D deficiency causes deficits in lung function and alters lung structure.
        Am J Respir Crit Care Med. 2011; 183: 1336-1343
        • Black P.N.
        • Scragg R.
        Relationship between serum 25-hydroxyvitamin D and pulmonary function in the third national health and nutrition examination survey.
        Chest. 2005; 128: 3792-3798
        • Tsiligianni I.G.
        • van der Molen T.
        A systematic review of the role of vitamin insufficiencies and supplementation in COPD.
        Respir Res. 2010; 11 (171-171)
        • Janssens W.
        • Lehouck A.
        • Carremans C.
        • Bouillon R.
        • Mathieu C.
        • Decramer M.
        Vitamin D beyond bones in chronic obstructive pulmonary disease: time to act.
        Am J Respir Crit Care Med. 2009; 179: 630-636
        • Skaaby T.
        • Husemoen L.L.
        • Thuesen B.H.
        • et al.
        Vitamin D status and chronic obstructive pulmonary disease: a prospective general population study.
        PLoS One. 2014; 9e90654
        • Sanket S.
        • Madireddi J.
        • Stanley W.
        • Sura P.
        • Prabhu M.
        Relation between vitamin D deficiency and severity of chronic obstructive pulmonary disease: a case control study.
        J Clin Diagn Res. 2016; 10: OC16-OC19
        • Mendy A.
        • Forno E.
        • Niyonsenga T.
        • Gasana J.
        Blood biomarkers as predictors of long-term mortality in COPD.
        Clin Respir J. 2018; 12: 1891-1899
        • Persson L.J.
        • Aanerud M.
        • Hiemstra P.S.
        • et al.
        Vitamin D, vitamin D binding protein, and longitudinal outcomes in COPD.
        PLoS One. 2015; 10e0121622
        • Zhao G.
        • Ford E.S.
        • Tsai J.
        • Li C.
        • Croft J.B.
        Low concentrations of serum 25-hydroxyvitamin D associated with increased risk for chronic bronchitis among US adults.
        Br J Nutr. 2012; 107: 1386-1392
        • Vestbo J.
        • Edwards L.D.
        • Scanlon P.D.
        • et al.
        Changes in forced expiratory volume in 1 second over time in COPD.
        N Engl J Med. 2011; 365: 1184-1192
        • Kunisaki K.M.
        • Niewoehner D.E.
        • Singh R.J.
        • Connett J.E.
        Vitamin D status and longitudinal lung function decline in the Lung Health Study.
        Eur Respir J. 2011; 37: 238-243
        • Lange N.E.
        • Sparrow D.
        • Vokonas P.
        • Litonjua A.A.
        Vitamin D deficiency, smoking, and lung function in the Normative Aging Study.
        Am J Respir Crit Care Med. 2012; 186: 616-621
        • Lehouck A.
        • Mathieu C.
        • Carremans C.
        • et al.
        High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial.
        Ann Intern Med. 2012; 156: 105-114
        • Martineau A.R.
        • James W.Y.
        • Hooper R.L.
        • et al.
        Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): a multicentre, double-blind, randomised controlled trial.
        Lancet Respir Med. 2015; 3: 120-130
        • Rafiq R.
        • Prins H.J.
        • Boersma W.G.
        • et al.
        Effects of daily vitamin D supplementation on respiratory muscle strength and physical performance in vitamin D-deficient COPD patients: a pilot trial.
        Int J Chron Obstruct Pulmon Dis. 2017; 12: 2583-2592
        • Malinovschi A.
        • Masoero M.
        • Bellocchia M.
        • et al.
        Severe vitamin D deficiency is associated with frequent exacerbations and hospitalization in COPD patients.
        Respir Res. 2014; 15: 131
        • Jolliffe D.A.
        • Greenberg L.
        • Hooper R.L.
        • 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: 337-345
        • Couper D.
        • LaVange L.M.
        • Han M.
        • et al.
        Design of the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS).
        Thorax. 2014; 69: 491-494
        • Woodruff P.G.
        • Barr R.G.
        • Bleecker E.
        • et al.
        Clinical significance of symptoms in smokers with preserved pulmonary function.
        N Engl J Med. 2016; 374: 1811-1821
        • Han M.K.
        • Quibrera P.M.
        • Carretta E.E.
        • et al.
        Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort.
        Lancet Respir Med. 2017; 5: 619-626
        • Paulin L.M.
        • Smith B.M.
        • Koch A.
        • et al.
        Occupational exposures and computed tomographic imaging characteristics in the SPIROMICS cohort.
        Ann Am Thorac Soc. 2018; 15: 1411-1419
        • Sieren J.P.
        • Newell Jr., J.D.
        • Barr R.G.
        • et al.
        SPIROMICS protocol for multicenter quantitative computed tomography to phenotype the lungs.
        Am J Respir Crit Care Med. 2016; 194: 794-806
        • Smith B.M.
        • Hoffman E.A.
        • Rabinowitz D.
        • et al.
        Comparison of spatially matched airways reveals thinner airway walls in COPD: the Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study and the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS).
        Thorax. 2014; 69: 987-996
        • Lederer D.J.
        • Bell S.C.
        • Branson R.D.
        • et al.
        Control of confounding and reporting of results in causal inference studies: guidance for authors from editors of respiratory, sleep, and critical care journals.
        Ann Am Thorac Soc. 2019; 16: 22-28
        • Janssens W.
        • Bouillon R.
        • Claes B.
        • et al.
        Vitamin D deficiency is highly prevalent in COPD and correlates with variants in the vitamin D-binding gene.
        Thorax. 2010; 65: 215-220
        • Afzal S.
        • Lange P.
        • Bojesen S.E.
        • Freiberg J.J.
        • Nordestgaard B.G.
        Plasma 25-hydroxyvitamin D, lung function and risk of chronic obstructive pulmonary disease.
        Thorax. 2014; 69: 24-31
        • Gombart A.F.
        The vitamin D-antimicrobial peptide pathway and its role in protection against infection.
        Future Microbiol. 2009; 4: 1151-1165
        • Zhang Y.
        • Leung D.Y.
        • Richers B.N.
        • et al.
        Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1.
        J Immunol. 2012; 188: 2127-2135
        • Cantorna M.T.
        • Yu S.
        • Bruce D.
        The paradoxical effects of vitamin D on type 1 mediated immunity.
        Mol Aspects Med. 2008; 29: 369-375
        • Szekely J.I.
        • Pataki A.
        Effects of vitamin D on immune disorders with special regard to asthma, COPD and autoimmune diseases: a short review.
        Expert Rev Respir Med. 2012; 6: 683-704
        • Jolliffe D.A.
        • James W.Y.
        • Hooper R.L.
        • et al.
        Prevalence, determinants and clinical correlates of vitamin D deficiency in patients with chronic obstructive pulmonary disease in London, UK.
        J Steroid Biochem Mol Biol. 2018; 175: 138-145
        • Holmgaard D.B.
        • Mygind L.H.
        • Titlestad I.L.
        • et al.
        Serum vitamin D in patients with chronic obstructive lung disease does not correlate with mortality: results from a 10-year prospective cohort study.
        PLoS One. 2013; 8e53670
        • Moosavi S.A.J.
        • Shoushtari M.H.
        The effects of vitamin D supplementation on pulmonary function of chronic obstructive pulmonary disease patients, before and after clinical trial.
        Diseases. 2015; 3: 253-259
        •, U.S. National Library of Medicine
        Cathelicidin and Vitamin D: Impact on Populations At-Risk and With COPD.