Impact of vitamin D on spirometry findings and quality of life in patients with chronic obstructive pulmonary disease: a randomized, double-blinded, placebo-controlled clinical trial

Introduction

COPD is a chronic inflammatory disorder with irreversible and progressive limitation of expiratory airflow, mainly affecting the small airways, that is associated with systemic inflammation and multiorgan involvement.¹ It was estimated that COPD had caused 3.2 million deaths worldwide in 2015.² In Europe, 40 million people have different stages of COPD, of which 60% suffer from significantly impaired lung function.³

Different risk factors have been suggested for COPD development, including genetic and environmental factors; however, cigarette smoking is known to be the most damaging factor.⁴ Other risk factors include passive smoking, hyperreactivity of airways, occupational exposure, air pollution, male sex, advanced age, respiratory infection, and low socioeconomic status.^2,5–7

There is a significant correlation between vitamin D₃ deficiency and COPD severity. Vitamin D₃ plays an important role in COPD pathogenesis.⁸ It has a variety of effects on human bodyfunction, including reduced cell proliferation,⁹ increased apoptosis, and¹⁰ enhanced differentiation. Vitamin D₃ is also a potent regulator of such biological phenomena as angiogenesis, extracellular matrix production, and immunoresponse.¹¹ Vitamin D₃ supplementation decreases the risk of acute respiratory infections and exacerbations of asthma.² Jolliffe et al showed beneficial effects of vitamin D₃ in patients with COPD who had suffered vitamin D₃ deficiency (<10 ng/mL).² They also confirmed that vitamin D₃ metabolites play a key role in inducing anti-infection effector mechanisms and decrease inflammatory responses.² There have been fewer studies done on the role of vitamin D₃ in patients with COPD. Vitamin D₃ may affect quality of life, lung function, and number of exacerbations in patients with COPD.^6,7,12 Han et al investigated the effects of vitamin D₃ in rat models of COPD.¹² They showed that vitamin D₃ was able significantly to reduce inflammation and improve lung function. They believed that vitamin D₃ could be a novel clinical approach to treat patients with COPD.¹²

There have not been any randomized, double blinded, placebo-controlled clinical trials done on the effectiveness of vitamin D₃ supplementation in patients with COPD. This study was designed to evaluate the effectiveness of vitamin D₃ on quality of life، lung function, and number of exacerbations in patients with COPD.

Methods

A randomized, double-blinded, placebo-controlled clinical trial was conducted on patients who had been referred to the respiratory clinic of Razi Hospital between August and December 2015 (Figure 1). This was a pilot study, and the sample size was set at 30 patients in both the control and intervention groups. Levels of vitamin D₃ were measured in eligible patients before intervention. Sampling was performed in the same season, with the same daily activity and the same sunlight exposure.

Figure 1 Study flowchart (CONSORT format).

Patients who were included had 10–30 ng/mL vitamin D₃ as per GOLD guidelines.¹³ Cell counts, liver-function tests, ischemic electrocardiographic changes, calcium, phosphorus, andalkaline phosphatase of eligible patients were normal. Patients with COPD were stable in terms of physical and clinical health.

Patients not included had congestive heart failure, osteoporosis, acute myocardial infarction, glomerular filtration rate ≤45 mL/min/1.73 m^2,14 hypercalcemia (~>10.3), malignancy, and sarcoidosis. In addition, patients who had used long-term azithromycin, with very low levels of vitamin D₃ (<10 ng/mL), and who took antiepileptic drugs were excluded.

Clinical symptoms of eligible patients included shortness of breath, especially during physical activities, wheezing, chest tightness, clearing the throat first thing in the morning, and a chronic cough with mucus (sputum).

Primary outcomes of the study were quality of life measured by COPD Assessment Test (CAT) score and lung function evaluated by spirometry of patients with COPD. It is important to say that chest X-rays were not used for patients with COPD.

Study valuables comprised age, sex, body-mass index, cigarette smoking, FEV₁, FEV₁/FVC, number of exacerbations, CAT score, COPD severity, and vitamin D₃ in blood.

Patients with COPD received 0.5–1 mg steroid per kilogram of body weight when exacerbating for 7–14 days. Both patients and questioners did not have any information from the study groups. Subsequently, placebo (gelatin) and vitamin D₃ were placed in two separate envelopes, then classified according to random blocks. We used stored plasma samples to measure circulating vitamin D₃metabolites, which is the accepted biomarker for vitamin D₃.¹⁵ In the next stage, radioimmunoassays wereconducted to measure vitamin D₃ levels.¹⁶

Finally, 63 patients remained: 32 for intervention and 31 as controls. The study received ethics approval from the Committee on Publication Ethics of Guilan University of Medical Sciences, and patients filed written informed consent. General health questionnaires were used to enroll patients with symptoms of COPD. The CAT questionnairewas first translated into Persian and then back into English.

Patients placed in the intervention group took 50,000 IU vitamin D₃, and those in the control group received placebo once a week for 8 weeks, then once a month for 4 months. After 6 months, the same questionnaire was used. Double-blinding was applied on both patients and care providers during the study.

Statistical analysis

The χ² test was performed to compare qualitative variables between two groups. Normal parameter distribution was checked by Kolmogorov–Smirnov test. Student's t-test and paired t-test were used for variables distributed normally. Mann–Whitney U and Wilcoxon tests were performed on variables that did not have normal distribution. Two-tailed P<0.05 was considered significant.

Results

In this study, 30 men (93.8%) and two women (6.3%) were in the intervention group and 30 men (96.8%) and a woman (3.2%) in the placebo group. The mean age of those in the intervention group was 67.9±7.9 years and in the placebo 68.4±7.8 years.

At the beginning of the study, FEV₁, FEV₁/FVC, and CAT scores, number of exacerbations, and percentage of severity did not show significant differences between the intervention and control groups (P>0.05, Table 1). Neither FEV1 nor FEV1/FVC showed significant differences between the intervention and control groups (Table 2). There were significant differences in serum levels of vitamin D₃ between the intervention and control groups (51.83 vs 19.43 ng/mL) within 2–6 months from baseline (P<0.001, Table 2). There were no statistical differences in exacerbations between the groups after 2 months, within 2–6 months, or after 6 months from baseline. In addition, the qualitative analysis showed that exacerbations had not worsened after 6 months in the intervention group (Table 3). CAT scores showed statistical differences between the groups at 2 months from baseline in quality of life at every stage in the intervention group (Table 3).

Table 1 Studied variables before intervention in both control and vitamin D groups

Table 2 Studied variables at 2 and 6 months after intervention in both control and vitamin D groups

Table 3 Mean differences in studied variables in both control and vitamin D groups

Discussion

The current study reported a randomized, double-blinded, placebo-controlled clinical trial on the effect of vitamin D₃ supplementation on lung function and quality of life in patients with COPD. Janssens et alshow that serum levels of vitamin D₃ had significant correlations with the severity of COPDand exacerbations.¹⁷ They also observed that vitamin D₃ consumption improved pulmonary function and quality of life in COPD patients in six months. Patients were controlled with different doses of vitamin D₃. Serum vitamin D₃ in the intervention group increased from 19.33 to 51.83 ng/mL. Subsequently, quality of life and pulmonary function began to recover and exacerbations in patients with COPD were reduced. Furthermore, Lehouck et alreported that vitamin D₃ may reduce acute exacerbations of COPD symptoms in those with initially deficient levels.¹⁸ On the other hand, Hornikx et al showed prescribing 3 mg vitamin D₃ every 2 months over 1 year also maintain moderate or acute exacerbations, but not for upper respiratory tract infections (<50 nmol/L or 20 ngr/mL).¹⁹ They demonstrated that consuming 100.000 IU vitamin D₃ 3 months significantly improved inspiratory muscle strength and maximal oxygen uptake.¹⁹ In other words, deficient vitamin D₃ can also reduce actin and troponin, impair calcium uptake in the sarcoplasmic reticulum, adjust protein synthesis, and increase apoptosis.²⁰ Banerjee et al demonstrated that vitamin D₃ stimulated the airway smooth-muscle cells to express vitamin D₃ receptors and regulated inflammation, contraction, and remodeling in other cell types.²¹

Other studies found higher levels of vitamin D₃–binding protein in patients with COPD, which involved neutrophil chemotaxis and macrophage activation (which has an important role in COPD pathogenesis). Vitamin D₃-binding protein has a significant correlation with serum levels of vitamin D; therefore, increasing vitamin D₃ levels will increase those of vitamin D₃–binding protein.^22,23

However, Jolliffe et al found no effect of vitamin D₃ supplementation on the rate of exacerbations among patients with COPD, but that vitamin D₃ supplementation has protective effects on patients with low vitamin D₃ (<25 nmol/L).²

The findings of this study have some limitations. Firstly, this study was single-centered; therefore, the results require further investigation. Secondly, liver function, electrocardiography, calcium, and albumin of COPD patients were not measured. Thirdly, the sample was small and there was low power to detect an effect from vitamin D₃. There has not been a study done on lung function, number of exacerbations, and quality of life in patients with COPD. Further studies seem to be required in this field.

As believed, consumption of vitamin D₃ improves quality of life in COPD patients.

According to the evidence, getting 10,000 IU/day in patients with deficienct levels of vitamin D₃ (1,500–2,000 IU/day) would not be toxic.²² Undoubtedly, vitamin D₃ therapy cheap, which and could be one of its important advantages.²³ Finally, vitamin D₃ therapy could be a useful and safe optionsimultaneously with other procedures.

Conclusion

Vitamin D₃ (50,000 IU) supplementation can improve quality of life in patients with COPD. In fact, COPD might be controlled by different levels of vitamin D₃ in serum. We found that consuming 50,000 IU vitamin D₃ increased quality of life in COPD. In addition, we found that exacerbations had not worsened after 6 months.