Vitamin D supplementation in chronic obstructive pulmonary disease patients with low serum vitamin D: a randomized controlled trial

Rachida Rafiq, Floor E Aleva, Jasmijn A Schrumpf, Johannes M Daniels, Pierre M Bet, Wim G Boersma, Paul Bresser, Michiel Spanbroek, Paul Lips, Tim J van den Broek, Bart J F Keijser, André J A M van der Ven, Pieter S Hiemstra, Martin den Heijer, Renate T de Jongh, PRECOVID-study group, Martin den Heijer, Renate T de Jongh, Paul Lips, Rachida Rafiq, Floor E Aleva, André van der Ven, Pieter S Hiemstra, Jasmijn A Schrumpf, Annelies M Slats, Johannes M A Daniëls, Pierre M Bet, Wim G Boersma, Paul Bresser, Michiel Spanbroek, Petra Huisman, Serge A van Wolferen, Marielle E A C Broeders, Peter van Hengel, Gert-Jan Braunstahl, Rachida Rafiq, Floor E Aleva, Jasmijn A Schrumpf, Johannes M Daniels, Pierre M Bet, Wim G Boersma, Paul Bresser, Michiel Spanbroek, Paul Lips, Tim J van den Broek, Bart J F Keijser, André J A M van der Ven, Pieter S Hiemstra, Martin den Heijer, Renate T de Jongh, PRECOVID-study group, Martin den Heijer, Renate T de Jongh, Paul Lips, Rachida Rafiq, Floor E Aleva, André van der Ven, Pieter S Hiemstra, Jasmijn A Schrumpf, Annelies M Slats, Johannes M A Daniëls, Pierre M Bet, Wim G Boersma, Paul Bresser, Michiel Spanbroek, Petra Huisman, Serge A van Wolferen, Marielle E A C Broeders, Peter van Hengel, Gert-Jan Braunstahl

Abstract

Background: Vitamin D deficiency is frequently found in patients with chronic obstructive pulmonary disease (COPD). Vitamin D has antimicrobial, anti-inflammatory, and immunomodulatory effects. Therefore, supplementation may prevent COPD exacerbations, particularly in deficient patients.

Objectives: We aimed to assess the effect of vitamin D supplementation on exacerbation rate in vitamin D-deficient patients with COPD.

Methods: We performed a multicenter, double-blind, randomized controlled trial. COPD patients with ≥1 exacerbations in the preceding year and a vitamin D deficiency (15-50 nmol/L) were randomly allocated in a 1:1 ratio to receive either 16,800 International Units (IU) vitamin D3 or placebo once a week during 1 y. Primary outcome of the study was exacerbation rate. Secondary outcomes included time to first and second exacerbations, time to first and second hospitalizations, use of antibiotics and corticosteroids, pulmonary function, maximal respiratory mouth pressure, physical performance, skeletal muscle strength, systemic inflammatory markers, nasal microbiota composition, and quality of life.

Results: The intention-to-treat population consisted of 155 participants. Mean ± SD serum 25-hydroxyvitamin D [25(OH)D] concentration after 1 y was 112 ± 34 nmol/L in the vitamin D group, compared with 42 ± 17 nmol/L in the placebo group. Vitamin D supplementation did not affect exacerbation rate [incidence rate ratio (IRR): 0.90; 95% CI: 0.67, 1.21]. In a prespecified subgroup analysis in participants with 25(OH)D concentrations of 15-25 nmol/L (n = 31), no effect of vitamin D supplementation was found (IRR: 0.91; 95% CI: 0.43, 1.93). No relevant differences were found between the intervention and placebo groups in terms of secondary outcomes.

Conclusions: Vitamin D supplementation did not reduce exacerbation rate in COPD patients with a vitamin D deficiency.This trial was registered at clinicaltrials.gov as NCT02122627.

Keywords: chronic obstructive pulmonary disease; exacerbation rate; muscle strength; physical function; pulmonary function; vitamin D.

© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

FIGURE 1
FIGURE 1
Flow diagram of study participants. This flow diagram depicts the screening and randomization of participants for the study. The numbers of participants excluded because of supplement use or high vitamin D concentrations are not generalizable, because a large part was already prescreened by their physicians at the outpatient clinic or during hospital admission. COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s; ITT, intention-to-treat; IU, International Unit; 25(OH)D, 25-hydroxyvitamin D.
FIGURE 2
FIGURE 2
Bray–Curtis distance multidimensional scaling plot showing the nasal microbiota before and after the vitamin D or placebo treatment. Statistical analysis was performed on 88 placebo samples (n = 44, baseline; n = 44, 12-mo) and 88 vitamin D samples (n = 44, baseline; n = 44, 12-mo). No effect of active treatment was observed when taking both sampling points into account (PERMANOVA: R2 = 0.006036, P = 0.837433), nor when only considering the samples collected at the last study visit (PERMANOVA: R2 = 0.0212145, P = 0.538). MDS1: dimension 1, representing 7.4% of total variation; MDS2: dimension 2, representing 7.1% of total variation. PERMANOVA, permutational multivariate ANOVA.

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