Prevalence, determinants and clinical correlates of vitamin D deficiency in patients with Chronic Obstructive Pulmonary Disease in London, UK.

Vitamin D deficiency is common in patients with chronic obstructive pulmonary disease (COPD), yet a comprehensive analysis of environmental and genetic determinants of serum 25-hydroxyvitamin D (25[OH]D) concentration in patients with this condition is lacking. We conducted a multi-centre cross-sectional study in 278 COPD patients aged 41-92 years in London, UK. Details of potential environmental determinants of vitamin D status and COPD symptom control and severity were collected by questionnaire, and blood samples were taken for analysis of serum 25(OH)D concentration and DNA extraction. All participants performed spirometry and underwent measurement of weight and height. Quadriceps muscle strength (QS) was measured in 134 participants, and sputum induction with enumeration of lower airway eosinophil and neutrophil counts was performed for 44 participants. Thirty-seven single nucleotide polymorphisms (SNP) in 11 genes in the vitamin D pathway (DBP, DHCR7, CYP2R1, CYP27B1, CYP24A1, CYP27A1, CYP3A4, LRP2, CUBN, RXRA, and VDR) were typed using Taqman allelic discrimination assays. Linear regression was used to identify environmental and genetic factors independently associated with serum 25(OH)D concentration and to determine whether vitamin D status or genetic factors independently associated with % predicted forced expiratory volume in one second (FEV1), % predicted forced vital capacity (FVC), the ratio of FEV1 to FVC (FEV1:FVC), daily inhaled corticosteroid (ICS) dose, respiratory quality of life (QoL), QS, and the percentage of eosinophils and neutrophils in induced sputum. Mean serum 25(OH)D concentration was 45.4nmol/L (SD 25.3); 171/278 (61.5%) participants were vitamin D deficient (serum 25[OH]D concentration <50nmol/L). Lower vitamin D status was independently associated with higher body mass index (P=0.001), lower socio-economic position (P=0.037), lack of vitamin D supplement consumption (P<0.001), sampling in Winter or Spring (P for trend=0.006) and lack of a recent sunny holiday (P=0.002). Vitamin D deficiency associated with reduced % predicted FEV1 (P for trend=0.060) and % predicted FVC (P for trend=0.003), but it did not associate with FEV1:FVC, ICS dose, QoL, QS, or the percentage of eosinophils or neutrophils in induced sputum. After correction for multiple comparisons testing, genetic variation in the vitamin D pathway was not found to associate with serum 25(OH)D concentration or clinical correlates of COPD severity. Vitamin D deficiency was common in this group of COPD patients in the UK, and it associated independently with reduced % predicted FEV1 and FVC. However, genetic variation in the vitamin D pathway was not associated with vitamin D status or severity of COPD.

Prevalence, determinants and clinical correlates of vitamin D deficiency in adults with inhaled corticosteroid-treated asthma in London, UK.

Vitamin D deficiency is common in children with asthma, and it associates with poor asthma control, reduced forced expiratory volume in one second (FEV1) and increased requirement for inhaled corticosteroids (ICS). Cross-sectional studies investigating the prevalence, determinants and clinical correlates of vitamin D deficiency in adults with asthma are lacking. We conducted a multi-centre cross-sectional study in 297 adults with a medical record diagnosis of ICS-treated asthma living in London, UK. Details of potential environmental determinants of vitamin D status, asthma control and medication use were collected by questionnaire; blood samples were taken for analysis of serum 25(OH)D concentration and DNA extraction, and participants underwent measurement of weight, height and fractional exhaled nitric oxide concentration (FeNO), spirometry and sputum induction for determination of lower airway eosinophil counts (n=35 sub-group). Thirty-five single nucleotide polymorphisms (SNP) in 11 vitamin D pathway genes (DBP, DHCR7, RXRA, CYP2R1, CYP27B1, CYP24A1, CYP3A4 CYP27A1, LRP2, CUBN, VDR) were typed using Taqman allelic discrimination assays. Linear regression was used to identify environmental and genetic factors independently associated with serum 25(OH)D concentration, and to determine whether vitamin D status was independently associated with Asthma Control Test (ACT) score, ICS dose, FeNO, forced vital capacity (FVC), FEV1 or lower airway eosinophilia. Mean serum 25(OH)D concentration was 50.6nmol/L (SD 24.9); 162/297 (54.5%) participants were vitamin D deficient (serum 25(OH)D concentration <50nmol/L). Lower vitamin D status was associated with higher body mass index (P=0.014), non-White ethnicity (P=0.036), unemployment (P for trend=0.012), lack of vitamin D supplement use (P<0.001), sampling in Winter or Spring (P for trend <0.001) and lack of a recent sunny holiday abroad (P=0.030), but not with potential genetic determinants. Vitamin D status was not found to associate with any marker of asthma control investigated. Vitamin D deficiency is common among UK adults with ICS-treated asthma, and classical environmental determinants of serum 25(OH)D operate in this population. However, in contrast to studies conducted in children, we found no association between vitamin D status and markers of asthma severity or control.

Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs).

RATIONALE: Asthma exacerbations are commonly precipitated by viral upper respiratory infections (URIs). Vitamin D insufficiency associates with susceptibility to URI in patients with asthma. Trials of vitamin D in adults with asthma with incidence of exacerbation and URI as primary outcome are lacking. OBJECTIVE: To conduct a randomised controlled trial of vitamin D3 supplementation for the prevention of asthma exacerbation and URI (coprimary outcomes). MEASUREMENTS AND METHODS: 250 adults with asthma in London, UK were allocated to receive six 2-monthly oral doses of 3 mg vitamin D3 (n=125) or placebo (n=125) over 1 year. Secondary outcomes included asthma control test and St George's Respiratory Questionnaire scores, fractional exhaled nitric oxide and concentrations of inflammatory markers in induced sputum. Subgroup analyses were performed to determine whether effects of supplementation were modified by baseline vitamin D status or genotype for 34 single nucleotide polymorphisms in 11 vitamin D pathway genes. MAIN RESULTS: 206/250 participants (82%) were vitamin D insufficient at baseline. Vitamin D3 did not influence time to first severe exacerbation (adjusted HR 1.02, 95% CI 0.69 to 1.53, p=0.91) or first URI (adjusted HR 0.87, 95% CI 0.64 to 1.16, p=0.34). No clinically important effect of vitamin D3 was seen on any of the secondary outcomes listed above. The influence of vitamin D3 on coprimary outcomes was not modified by baseline vitamin D status or genotype. CONCLUSIONS: Bolus-dose vitamin D3 supplementation did not influence time to exacerbation or URI in a population of adults with asthma with a high prevalence of baseline vitamin D insufficiency. TRIAL REGISTRATION NUMBER: NCT00978315 (ClinicalTrials.gov).

Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) often have vitamin D deficiency, which is associated with increased susceptibility to upper respiratory infection-a major precipitant of exacerbation. Multicentre trials of vitamin D supplementation for prevention of exacerbation and upper respiratory infection in patients with COPD are lacking. We therefore investigated whether vitamin D3 (colecalciferol) supplementation would reduce the incidence of moderate or severe COPD exacerbations and upper respiratory infections. METHODS: We did a randomised, double-blind, placebo-controlled trial of vitamin D3 supplementation in adults with COPD in 60 general practices and four Acute National Health Service Trust clinics in London, UK. Patients were allocated to receive six 2-monthly oral doses of 3 mg vitamin D3 or placebo over 1 year in a 1:1 ratio using computer-generated permuted block randomisation. Participants and study staff were masked to treatment assignment. Coprimary outcomes were time to first moderate or severe exacerbation and first upper respiratory infection. Analysis was by intention to treat. A prespecified subgroup analysis was done to assess whether effects of the intervention on the coprimary outcomes were modified by baseline vitamin D status. This trial is registered with ClinicalTrials.gov, number NCT00977873. FINDINGS: 240 patients were randomly allocated to the vitamin D3 group (n=122) and placebo group (n=118). Vitamin D3 compared with placebo did not affect time to first moderate or severe exacerbation (adjusted hazard ratio 0·86, 95% CI 0·60-1·24, p=0·42) or time to first upper respiratory infection (0·95, 0·69-1·31, p=0·75). Prespecified subgroup analysis showed that vitamin D3 was protective against moderate or severe exacerbation in participants with baseline serum 25-hydroxyvitamin D concentrations of less than 50 nmol/L (0·57, 0·35-0·92, p=0·021), but not in those with baseline 25-hydroxyvitamin D levels of at least 50 nmol/L (1·45, 0·81-2·62, p=0·21; p=0·021 for interaction between allocation and baseline serum 25-hydroxyvitamin D status). Baseline vitamin D status did not modify the effect of the intervention on risk of upper respiratory infection (pinteraction=0·41). INTERPRETATION: Vitamin D3 supplementation protected against moderate or severe exacerbation, but not upper respiratory infection, in patients with COPD with baseline 25-hydroxyvitamin D levels of less than 50 nmol/L. Our findings suggest that correction of vitamin D deficiency in patients with COPD reduces the risk of moderate or severe exacerbation. FUNDING: UK National Institute for Health Research.

Assessment of specific immunotherapy efficacy using a novel placebo score-based method.

BACKGROUND: In trials of allergen immunotherapy, allergen exposure is typically assessed by pollen counts, but these may misrepresent exposure if performed remotely from multiple study centers. OBJECTIVE: To assess whether symptomatology in placebo-treated patients is a better measure of local allergen burden at individual centers in such trials. METHODS: Data from a multicenter, placebo-controlled trial of preseasonal grass pollen immunotherapy were reanalyzed to identify the 4 weeks at each center in which the placebo-treated subjects had the highest combined symptom/medication scores (CSMS). The difference in CSMS between active and placebo groups was compared during the 4 peak placebo score weeks (PlSW) and the 4 peak pollen count weeks (PoCW). RESULTS: The benefit of immunotherapy over placebo in the PlSW analysis (18.5%) was greater than in the PoCW analysis (13.6%), with increased statistical significance (P = .0001, .0038, respectively). Similar improved discrimination was observed when analyzing benefits in subgroups of patients with severe symptoms, a high disease burden, and in different geographical locations. CONCLUSION: This novel PlSW analysis results in better discrimination of the effects of allergen immunotherapy compared with placebo and may be widely applicable in similar studies, both prospectively and retrospectively.

Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis.

BACKGROUND: Specific immunotherapy is widely used to treat allergic rhinitis, but few large-scale clinical trials have been performed. OBJECTIVE: We sought to assess the efficacy and safety of specific immunotherapy with 2 doses of Alutard grass pollen in patients with moderately severe seasonal allergic rhinitis inadequately controlled with standard drug therapy. METHODS: We performed a double-blind, randomized, placebo-controlled study of 410 subjects (203 randomized to 100,000 standardized quality units [SQ-U] maintenance, 104 to 10,000 SQ-U, and 103 to placebo). Three hundred forty-seven (85%) completed treatment. Groups were well matched for demographics and symptoms. RESULTS: Across the whole pollen season, mean symptom and medication scores were 29% and 32% lower, respectively, in the 100,000-SQ-U group compared with those in the placebo group (both P < .001). Over the peak pollen season, mean symptom and medication scores were 32% and 41% lower, respectively, than those in the placebo group. The 10,000-SQ-U group had 22% less symptoms than the placebo group over the whole season (P < .01), but medication scores reduced by only 16% (P = .16). Quality-of-life measures confirmed the superiority of both doses to placebo. Local and delayed side effects were common but generally mild. Clinically significant early and delayed systemic side effects were confined to the 100,000-SQ-U group, but no life-threatening reactions occurred. CONCLUSIONS: One season of immunotherapy with Alutard grass pollen reduced symptoms and medication use and improved the quality of life of subjects with moderately severe hay fever. The 100,000-SQ-U regimen was more effective, but the 10,000-SQ-U regimen caused fewer side effects.

Glucocorticoid-resistant asthma.

Glucocorticoids are currently the most effective anti-inflammatory therapy for asthma. However, a small subset of asthma sufferers do not respond to clinically relevant doses of glucocorticoids and are termed "glucocorticoid resistant." These patients are characterized by increased bronchial hyperreactivity, lower morning peak expiratory flow rates, and a longer total duration of symptoms. The definition of glucocorticoid resistance is arbitrary, and a dosage and duration of oral glucocorticoid therapy that represent a completely adequate therapeutic trial have yet to be established. For research purposes, glucocorticoid-resistant asthma is defined on the basis of a lack of improvement in airway obstruction (FEV1) following a 2-week course of oral glucocorticoid therapy. Glucocorticoid resistance is associated with in vivo and in vitro alterations in cellular responses to exogenous glucocorticoids. We have implicated abnormal regulation of the activator protein I in the molecular mechanism of glucocorticoid resistance, a phenomenon that may be confined to T cells and monocytes. The identification of an alternatively spliced isoform of the glucocorticoid receptor (GR beta) has sparked interest in the functional role of this isoform and its potential involvement in the pathology of glucocorticoid resistance. Alternative therapies for this condition will have to await a better understanding of the mechanisms of glucocorticoid action.