Inhaled treatment of COPD: a Delphi consensus statement.

BACKGROUND: Global Initiative for Chronic Obstructive Lung Disease (GOLD) global strategy (2015) provides guidance for the treatment of chronic obstructive pulmonary disease (COPD) with different first-choice options per GOLD category without specification. OBJECTIVES: To evaluate the level of medical experts' consensus on their preferred first-choice treatment within different COPD categories. METHODS: A two-round Delphi Panel consisting of 15 questions was completed by Belgian pulmonologists (n=31) and European (n=10) COPD experts. RESULTS: Good consensus was reached by both expert groups for long-acting bronchodilators instead of short-acting bronchodilators as first-choice treatment in GOLD A. Single bronchodilation with long-acting muscarinic antagonist (LAMA) was preferred over long-acting ß2-agonist (LABA) and LABA/LAMA as first-choice treatment in GOLD B and GOLD C. For GOLD D patients based on the forced expiratory volume in 1 second (FEV1)<50%, a very good consensus was reached for LAMA/LABA as first-choice treatment. For GOLD D patients based on frequent or severe exacerbations, there was a good consensus for LABA/LAMA/inhaled corticosteroids (ICS) as first choice in the Belgian group. According to the European experts, both LABA/LAMA and LABA/LAMA/ICS could be the first choice for these patients. CONCLUSION: Belgian and European experts recommend long-acting bronchodilators as first-choice treatment. Treatment containing ICS was found only appropriate in patients with FEV1<50% and ≥2 moderate exacerbations or 1 severe exacerbation/year.

Vitamin D supplementation during rehabilitation in COPD: a secondary analysis of a randomized trial.

RATIONALE: Pulmonary rehabilitation is an important treatment for patients with Chronic Obstructive Pulmonary Disease, who are often vitamin D deficient. As vitamin D status is linked to skeletal muscle function, we aimed to explore if high dose vitamin D supplementation can improve the outcomes of rehabilitation in Chronic Obstructive Pulmonary Disease. MATERIAL AND METHODS: This study is a post-hoc subgroup analysis of a larger randomized trial comparing a monthly dose of 100.000 IU of vitamin D with placebo to reduce exacerbations. 50 Subjects who followed a rehabilitation program during the trial are included in this analysis. We report changes from baseline in muscle strength and exercise performance between both study arms after 3 months of rehabilitation. RESULTS: Vitamin D intervention resulted in significantly higher median vitamin D levels compared to placebo (51 [44-62] ng/ml vs 15 [13-30] ng/ml; p < 0.001). Patients receiving vitamin D had significantly larger improvements in inspiratory muscle strength (-11±12 cmH2O vs 0±14 cmH2O; p = 0.004) and maximal oxygen uptake (110±211 ml/min vs -20±187 ml/min; p = 0.029). Improvements in quadriceps strength (15±16 Nm) or six minutes walking distance (40±55 meter) were not significantly different from the effects in the placebo group (7±19 Nm and 11±74 meter; p>0.050). CONCLUSION: High dose vitamin D supplementation during rehabilitation may have mild additional benefits to training.

Antielastin B-cell and T-cell immunity in patients with chronic obstructive pulmonary disease.

RATIONALE: Antielastin autoimmunity has been hypothesised to drive disease progression in chronic obstructive pulmonary disease (COPD). The proposed mechanism is currently disputed by conflicting data. The authors aimed to explore antibody responses against elastin in a large and extensively characterised COPD population and to assess elastin-specific peripheral T-cell reactivity in a representative subgroup. METHODS: Antielastin antibodies were analysed with indirect ELISA on the plasma of 320 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease 1-4) and 143 smoking controls. In a second group of 40 patients with COPD and smoking controls, T-cell responses against extracellular matrix (elastin, collagen I and collagen V) were determined with enzyme-linked immunosorbent spot (EliSpot) (interferon γ (IFNγ) and interleukin-2) on peripheral blood mononuclear cells and compared with the responses of 11 never-smoking controls. RESULTS: Antielastin antibody titres were not elevated in patients with COPD compared with smoking controls and even decreased significantly with increasing severity of COPD (p<0.001). Lower antielastin antibody titres were also found in a subgroup of patients with CT-proven emphysema. Elastin-specific INFγ-mediated T helper 1 responses could not be revealed in smoking subjects with and without COPD. Collagen I-mediated T-cell responses were also absent, which contrasted with a significant increased anticollagen V response in the smoking controls and patients with COPD compared with the never smokers (p=0.008). Collagen V-mediated T-cell responses could not discriminate between patients with COPD and smoking controls. CONCLUSION: A systemic immune response against elastin could not be identified in patients with COPD. By contrast, collagen V-mediated autoimmunity was increased in the subgroup of smokers and may potentially contribute to the pathogenesis of COPD.

High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial.

BACKGROUND: Low serum 25-hydroxyvitamin D (25-[OH]D) levels have been associated with lower FEV(1), impaired immunologic control, and increased airway inflammation. Because many patients with chronic obstructive pulmonary disease (COPD) have vitamin D deficiency, effects of vitamin D supplementation may extend beyond preventing osteoporosis. OBJECTIVE: To explore whether supplementation with high doses of vitamin D could reduce the incidence of COPD exacerbations. DESIGN: Randomized, single-center, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00666367) SETTING: University Hospitals Leuven, Leuven, Belgium. PATIENTS: 182 patients with moderate to very severe COPD and a history of recent exacerbations. INTERVENTION: 100,000 IU of vitamin D supplementation or placebo every 4 weeks for 1 year. MEASUREMENTS: The primary outcome was time to first exacerbation. Secondary outcomes were exacerbation rate, time to first hospitalization, time to second exacerbation, FEV(1), quality of life, and death. RESULTS: Mean serum 25-(OH)D levels increased significantly in the vitamin D group compared with the placebo group (mean between-group difference, 30 ng/mL [95% CI, 27 to 33 ng/mL]; P < 0.001). The median time to first exacerbation did not significantly differ between the groups (hazard ratio, 1.1 [CI, 0.82 to 1.56]; P = 0.41), nor did exacerbation rates, FEV(1), hospitalization, quality of life, and death. However, a post hoc analysis in 30 participants with severe vitamin D deficiency (serum 25-[OH]D levels <10 ng/mL) at baseline showed a significant reduction in exacerbations in the vitamin D group (rate ratio, 0.57 [CI, 0.33 to 0.98]; P = 0.042). LIMITATION: This was a single-center study with a small sample size. CONCLUSION: High-dose vitamin D supplementation in a sample of patients with COPD did not reduce the incidence of exacerbations. In participants with severe vitamin D deficiency at baseline, supplementation may reduce exacerbations. PRIMARY FUNDING SOURCE: Applied Biomedical Research Program, Agency for Innovation by Science and Technology (IWT-TBM).

COPD, bone metabolism, and osteoporosis.

COPD and osteoporosis are strongly associated because of common risk factors such as age, smoking, and inactivity. In addition, COPD-related systemic inflammation, vitamin D deficiency, and the use of systemic corticosteroids enhance ongoing bone destruction. Osteoporosis, in turn, may cause fragility fractures, which further impair mobility and increase morbidity and mortality. Vertebral compression fractures and rib cage fractures in patients with COPD may also reduce pulmonary function or enhance exacerbations. Early prevention and treatment of osteoporosis in COPD is, therefore, important and should be based on integrated risk assessment tools such as FRAX, which take bone mineral density, history of fragility fractures, and population-specific clinical factors into account. As long as intervention studies focusing on the bone in COPD are lacking, a more rigorous application of existing treatment guidelines of osteoporosis in general is mandatory.

Alveolar and bronchial exhaled nitric oxide in chronic obstructive pulmonary disease.

BACKGROUND: Fractional exhaled NO (Fe,NO) has yielded inconsistent results in COPD. Measuring exhaled NO at multiple flow rates however, allows to dissect exhaled NO in an alveolar (CAlv,NO) and bronchial (J'aw,NO) fraction, which are claimed to better reflect the bronchial and alveolar inflammation in COPD. We examined whether the use of Fe,NO, CAlv,NO and J'aw,NO may contribute to the clinical diagnosis of COPD. METHODS: One hundred and fifty one patients were included in this case-control design: 28 healthy nonsmokers, 39 healthy smokers, 55 COPD nonsmokers and 29 COPD smokers. Prior to spirometry, exhaled NO was measured at three different flow rates (50, 100 and 200 ml/s; NIOX-FLEX) from which Fe,NO, CAlv,NO and J'aw,NO were calculated. RESULTS: Mean Fe,NO, mean CAlv,NO and mean J'aw,NO of healthy individuals were not significantly different from COPD patients and none of these variables correlated with FEV(1). In both healthy and COPD patients, current smoking significantly reduced Fe,NO, J'aw,NO and CAlv,NO. Multivariate analysis demonstrated that in contrast to gender, age, BMI, GOLD stage and the use of inhaled corticosteroids, current smoking was the only variable affecting CAlv,NO. (p=0.0115) CONCLUSION: We conclude that similar to single breath exhaled NO, exhaled NO at different flow rates does not contribute to the diagnosis of COPD in standard respiratory practice.

Vitamin D deficiency is highly prevalent in COPD and correlates with variants in the vitamin D-binding gene.

INTRODUCTION: Vitamin D deficiency has been associated with many chronic illnesses, but little is known about its relationship with chronic obstructive pulmonary disease (COPD). OBJECTIVES: Serum 25-hydroxyvitamin D (25-OHD) levels were measured in 414 (ex)-smokers older than 50 years and the link between vitamin D status and presence of COPD was assessed. The rs7041 and rs4588 variants in the vitamin D-binding gene (GC) were genotyped and their effects on 25-OHD levels were tested. RESULTS: In patients with COPD, 25-OHD levels correlated significantly with forced expiratory volume in 1 s (FEV(1)) (r=0.28, p<0.0001). Compared with 31% of the smokers with normal lung function, as many as 60% and 77% of patients with GOLD (Global Initiative for Obstructive Lung Disease) stage 3 and 4 exhibited deficient 25-OHD levels <20 ng/ml (p<0.0001). Additionally, 25-OHD levels were reduced by 25% in homozygous carriers of the rs7041 at-risk T allele (p<0.0001). This correlation was found to be independent of COPD severity, smoking history, age, gender, body mass index, corticosteroid intake, seasonal variation and rs4588 (p<0.0001). Notably, 76% and 100% of patients with GOLD stage 3 and 4 homozygous for the rs7041 T allele exhibited 25-OHD levels <20 ng/ml. Logistic regression corrected for age, gender and smoking history further revealed that homozygous carriers of the rs7041 T allele exhibited an increased risk for COPD (OR 2.11; 95% CI 1.20 to 3.71; p=0.009). CONCLUSION: Vitamin D deficiency occurs frequently in COPD and correlates with severity of COPD. The data warrant vitamin D supplementation in patients with severe COPD, especially in those carrying at-risk rs7041 variants.

Vitamin D beyond bones in chronic obstructive pulmonary disease: time to act.

The discovery that the vitamin D endocrine system regulates a very large number of genes and their associated biological processes improves our insight into the fundamental role of vitamin D and sun exposure for human health. Accumulating epidemiological data are linking a low vitamin D nutritional status to highly prevalent diseases such as cancer, autoimmune diseases, and chronic infections. Approximately half of the world's elderly, and to a lesser extent the adult population, have insufficient to deficient 25-hydroxyvitamin D (25-OHD) serum levels, and several intervention studies are being undertaken to study the impact of adequate vitamin D supplementation in chronic diseases. In this perspective we claim that chronic obstructive pulmonary disease (COPD) is a candidate disease for which vitamin D supplementation might be beneficial. Epidemiological studies revealed a dose-dependent association between serum 25-OHD levels and pulmonary function so that adequate vitamin D supplementation may extend beyond its protection against osteoporotic fractures. In line with the novel insights on its immune function, it is tempting to speculate that vitamin D may down-regulate the inflammatory immune response in the airways while boosting innate immune defense against different microorganisms. Apart from its affects on osteoporosis, vitamin D may also interfere with other comorbidities of COPD such as skeletal muscle weakness, cardiovascular disease, and cancer. Because respiratory treatments in COPD fail to reverse disease progression, interventional trials that may exploit the broader potential of vitamin D are warranted. A further challenge of such studies is to define optimal serum 25-OHD levels for such noncalcemic endpoints.