Salmeterol/fluticasone combination in the treatment of COPD

Clinical trials of a combination therapy of an inhaled corticosteroid, fluticasone propionate (FP), with a long-acting β₂-agonist, salmeterol (Sal), have demonstrated a greater improvement in lung function and in quality of life measures after the combination compared with either component of alone. In a subanalysis of the data of the TRISTAN study, Sal/FP reduced exacerbation rates in COPD patients with a baseline FEV₁<50% of predicted. A combination therapy of budesonide and formoterol improved quality of life and FEV₁, and reduced exacerbations better than either component alone. In studies of FP or of Sal/FP in COPD, there was a reduction in all-cause mortality by 25% relative to placebo. Sal/FP has anti-inflammatory effects in COPD airways. FP inhibits markers of systemic inflammation, and it is not known whether Sal/FP has an advantage over FP alone. While long-acting β₂-agonists such as Sal can be recommended for treatment of moderate COPD, addition of inhaled steroid therapy such as FP should be considered in more severe disease.     

Plasma homocysteine is elevated in COPD patients and is related to COPD severity

Background:

Although recent studies have found that total plasma homocysteine (tHCY) and chronic obstructive pulmonary disease (COPD) are both risk factors for cardiac disease, there have been few studies of plasma homocysteine levels in COPD patients. We tested the hypothesis that total plasma homocysteine (tHCY) would be elevated in patients diagnosed with COPD compared with controls.

Methods:

We studied 29 COPD outpatients and 25 asymptomatic subjects (controls) over age 55 years with measurement of forced expiratory volume in one second (FEV₁), forced vital capacity (FVC), St. Georges Respiratory Questionnaire (SGRQ) score, tHCY and serum C-reactive protein (sCRP).

Results:

There was no difference between controls vs. COPD patients in mean age or gender but mean (SD) FEV₁ was 2.25 (0.77) vs 1.43 (0.60) L; FEV₁% predicted 76.1 (17.2) vs 49.1 (16.3) p < 0.001 in both cases. Median (IQR) tHCY was 8.22 (6.63, 9.55) in controls vs 10.96 (7.56, 13.60) micromol/l for COPD, p = 0.006 and sCRP 0.89 (0.47, 2.55) vs 2.05 (0.86, 6.19) mg/l, p = 0.023. tHCY(log) was also higher in (r, p) smokers (0.448, 0.001), patients with low FEV₁% (−0.397, 0.003), males (0.475, <0.001), but high SGRQ Total score (0.289, 0.034), and high sCRP (0.316, 0.038). tHCY(log) was independently related to (regression coefficient, p) sCRP(log) (0.087, 0.024), male gender (0.345, <0.001) and presence of COPD (0.194, 0.031). Median (IQR) tHCY GOLD Stage I and II 8.05 (7.28, 11.04), GOLD Stage III and IV: 11.83(9.30, 18.30); p = 0.023.

Conclusions:

Plasma homocysteine is significantly elevated in COPD patients relative to age and sex-matched controls and is related to serum CRP and COPD severity.     

Functional results of unilateral lung volume reduction surgery in alpha1-antitrypsin deficient patients

Lung volume reduction surgery (LVRS) has been shown to improve lung function and exercise tolerance in patients with severe emphysema. Some predictors of poor outcome have been described but the role of alpha₁-antitrypsin (α₁-AT) deficiency is still not well known. The aim of this study was to analyze the results of unilateral LVRS in our center according to the α₁-AT status. The results of LVRS in 17 deficient patients and 35 nondeficient patients were analyzed at 3–6 months and 1 year after surgery. Compared with baseline, a significant improvement of FEV₁, partial pressure in arterial blood (PaO₂), dyspnea score and walking distance was observed in the two groups at 3–6 months after surgery and the studied parameters remained significantly improved at 1 year in the nondeficient group. By contrast, PaO₂ and walking distance returned towards baseline in the deficient group at 1 year whereas improvement of FEV₁ and dyspnea score was persistent. Mean values of FEV₁ at baseline, 3–6 months, and 1 year were 22 ± 6%, 29 ± 11%, and 26 ± 9% and 28 ± 12%, 38 ± 17%, and 40 ± 17% predicted in the deficient group and in the non-deficient group, respectively. In conclusion, the functional benefit is short-lasting in α₁-AT deficient patients after unilateral LVRS.     

The role of combination therapy with corticosteroids and long-acting ��2-agonists in the prevention of exacerbations in COPD

Acute exacerbations of COPD can complicate the course of the disease in patients with severe airway obstruction. Reduction of exacerbations is an important clinical outcome in evaluating new therapies in COPD. Combination therapies with long-acting β-agonists and inhaled corticosteroids have now been approved for use. Three 1-year randomized clinical trials, which studied the effect of combining a long-acting β₂-agonist with an inhaled corticosteroid in COPD, documented that exacerbation frequency was lower with therapy than placebo. Combination therapy had a similar effect to its monocomponents in the trial evaluating salmeterol/fluticasone combination. However, when patients with more severe COPD were studied using a combination of budesonide and formoterol, a clear improvement was seen in the overall exacerbation rates compared with the use of a long-acting β₂-agonist alone.     

Formoterol in the management of chronic obstructive pulmonary disease

Bronchodilators represent the hallmark of symptomatic treatment of Chronic Obstructive Pulmonary Disease (COPD). There are four categories of bronchodilators: anticholinergics, methylxanthines, short-acting β₂-agonists, and long-acting β₂-agonists such as formoterol. Significant research has been performed to investigate the efficacy, safety and tolerability of formoterol in the therapeutic field of COPD. Formoterol exhibits a rapid onset of bronchodilation similar to that observed with salbutamol, yet its long bronchodilatory duration is comparable to salmeterol. In addition, formoterol presents with a clear superiority in lung function improvement compared with either ipratropium bromide or oral theophylline, while its efficacy improves when administered in combination with ipratropium. Formoterol has been shown to better reduce dynamic hyperinflation, which is responsible for exercise intolerance and dyspnea in COPD patients, compared with other bronchodilators, whereas it exerts synergistic effect with tiotropium. Moreover, formoterol reduces exacerbations, increases days free of use of rescue medication and improves patients’ quality of life and disease symptoms. Formoterol has a favorable safety profile and is better tolerated than theophylline. Collectively, data extracted from multicenter clinical trials support formoterol as a valid therapeutic option in the treatment of COPD.     

Efficacy and Safety of Umeclidinium Added to Fluticasone Propionate/Salmeterol in Patients with COPD: Results of Two Randomized, ­Double-Blind Studies

Combinations of drugs with distinct and complementary mechanisms of action may offer improved efficacy in the treatment of chronic obstructive pulmonary disease (COPD). In two 12-week, double-blind, parallel-group studies, patients with COPD were randomized 1:1:1 to once-daily umeclidinium (UMEC; 62.5 μg and 125 μg) or placebo (PBO), added to twice-daily fluticasone propionate/salmeterol (FP/SAL; 250/50 μg). In both studies, the primary efficacy measure was trough forced expiratory volume in 1 second (FEV₁) at Day 85. Secondary endpoints were weighted-mean (WM) FEV₁ over 0–6 hours post-dose (Day 84) and rescue albuterol use. Health-related quality of life outcomes (St. George's Respiratory Questionnaire [SGRQ] and COPD assessment test [CAT]) were also examined. Safety was assessed throughout. Both UMEC+FP/SAL doses provided statistically significant improvements in trough FEV₁ (Day 85: 0.127–0.148 L) versus PBO+FP/SAL. Similarly, both UMEC+FP/SAL doses provided statistically-significant improvements in 0–6 hours post-dose WM FEV₁ versus PBO+FP/SAL (Day 84: 0.144–0.165 L). Rescue use over Weeks 1–12 decreased with UMEC+FP/SAL in both studies versus PBO+FP/SAL (Study 1, 0.3 puffs/day [both doses]; Study 2, 0.5 puffs/day [UMEC 125+FP/SAL]). Decreases from baseline in CAT score were generally larger for both doses of UMEC+FP/SAL versus PBO+FP/SAL (except for Day 84 Study 2). In Study 1, no differences in SGRQ score were observed between UMEC+FP/SAL and PBO+FP/SAL; however, in Study 2, statistically significant improvements were observed with UMEC 62.5+FP/SAL (Day 28) and UMEC 125+FP/SAL (Days 28 and 84) versus PBO+FP/SAL. The incidence of on-treatment adverse events across all treatment groups was 37–41% in Study 1 and 36–38% in Study 2. Overall, these data indicate that the combination of UMEC+FP/SAL can provide additional benefits over FP/SAL alone in patients with COPD.     

Prostaglandin F2α elevates blood pressure and promotes atherosclerosis

Little is known about prostaglandin F_2α in cardiovascular homeostasis. Prostaglandin F_2α dose-dependently elevates blood pressure in WT mice via activation of the F prostanoid (FP) receptor. The FP is expressed in preglomerular arterioles, renal collecting ducts, and the hypothalamus. Deletion of the FP reduces blood pressure, coincident with a reduction in plasma renin concentration, angiotensin, and aldosterone, despite a compensatory up-regulation of AT1 receptors and an augmented hypertensive response to infused angiotensin II. Plasma and urinary osmolality are decreased in FP KOs that exhibit mild polyuria and polydipsia. Atherogenesis is retarded by deletion of the FP, despite the absence of detectable receptor expression in aorta or in atherosclerotic lesions in Ldlr KOs. Although vascular TNF_α, inducible nitric oxide enzyme and TGF_β are reduced and lesional macrophages are depleted in the FP/Ldlr double KOs, this result reflects the reduction in lesion burden, as the FP is not expressed on macrophages and its deletion does not alter macrophage cytokine generation. Blockade of the FP offers an approach to the treatment of hypertension and its attendant systemic vascular disease.     

Minimal Clinically Important Differences in COPD Lung Function

The FEV₁ is widely used by physicians in the diagnosis, staging, treatment, monitoring and establishing prognosis for patients with COPD. The MCID is the smallest difference which patients perceive as beneficial and which would mandate a change in patient management. A precise MCID for FEV₁ has not been established.

In attempt to establish a MCID for predose or trough FEV₁, several limitations need to be addressed. There are issues such as reproducibility, repeatability, acceptability, variability, placebo effect, and equipment effects. Patient factors, such as baseline level of FEV₁, albuterol reversibility, diurnal variation, influence the results.

Nonetheless, using anchoring techniques, a change in pre dose FEV₁ of about 100 mL can be perceived by patients, correlates with fewer relapses following exacerbations and is in the range usually achieved with bronchodilators approved for COPD.

In the future, consistent reporting of spirometric variables, such as a predose FEV₁ and other outcomes, can be incorporated into a more quantitative effort to establish the MCID. Also distributional/statistical methods may be useful in determining the MCID FEV₁.     

Once-daily fluticasone furoate/vilanterol versus twice-daily fluticasone propionate/salmeterol in patients with asthma well controlled on ICS/LABA

Objective: We aimed to demonstrate non-inferiority of once-daily fluticasone furoate/vilanterol 100/25 µg (FF/VI) to twice-daily fluticasone propionate/salmeterol 250/50 µg (FP/SAL) in adults/adolescents with asthma well controlled on inhaled corticosteroid/long-acting β₂ agonist (ICS/LABA). Methods: This was a randomized, double-blind, double-dummy, parallel-group, 24-week study (NCT02301975/GSK study 201378). Patients whose asthma met study-defined criteria for control were randomized 1:1:1 to receive FF/VI, FP/SAL or twice-daily FP 250 µg for 24 weeks. Primary endpoint was change from baseline in evening trough forced expiratory volume in 1 second (FEV₁). Secondary endpoints included rescue-/symptom-free 24-hour periods. Safety was also assessed. Results: The intent-to-treat (ITT) population included 1504 randomized and treated patients (504 FF/VI; 501 FP/SAL; 499 FP); mean age 43.5 years, 64% female. FF/VI demonstrated non-inferiority (using a margin of ?100 mL) to FP/SAL for evening trough FEV₁ at Week 24 (ITT: 19 mL [95% confidence interval (CI) ?11 to 49]; per protocol population [N = 1336]: 6 mL [95% CI ?27 to 40]). Improvement in evening trough FEV₁ at Week 24 for both FF/VI (123 mL; p < 0.001) and FP/SAL (104 mL; p < 0.001) was greater than FP. FF/VI increased rescue-/symptom-free 24-hour periods by 1.2%/1.2% compared with FP/SAL. All treatments were well tolerated. On-treatment adverse event (AE) rates were 43% to 45% across arms; there were no drug-related serious AEs. Conclusions: FF/VI was non-inferior to FP/SAL for evening trough FEV₁ at 24 weeks. These data suggest that patients well controlled on FP/SAL could step across to FF/VI without loss of control.     

A dose-ranging study of tiotropium delivered via Respimat? Soft MistTM Inhaler or HandiHaler? in COPD patients

This was a multicenter, randomized, double-blind within device, parallel-group, dose-ranging study. COPD patients (n = 202; 86% male; mean age: 61 years) were randomized to receive tiotropium 1.25 μg, 2.5 μg, 5 μg, 10 μg, or 20 μg Respimat^® SMI (a novel, propellant-free device); tiotropium 18 μg HandiHaler^®; placebo Respimat^®; or placebo HandiHaler^® for 3 weeks. The primary endpoint was trough FEV₁ on Day 21. Other assessments included FVC, PEFR, rescue medication use, safety, and pharmacokinetics. In general, all active treatments improved the primary and secondary endpoints on Day 21 (steady state) compared with placebo. Tiotropium 5 μg Respimat^®, 20 μg Respimat^®, and tiotropium 18 μg HandiHaler^® were statistically significantly higher than placebo for the primary endpoint (mean change in trough FEV₁ was 150 mL (both Respimat^® doses) versus 20 mL (placebo Respimat^®); p < 0.05; and 230 mL (HandiHaler^®) versus −90 mL (placebo HandiHaler^®); p ≤ 0.001). The urinary excretion (up to 2 hours post-dose) of tiotropium 5–10 μg Respimat^® was comparable with tiotropium 18 μg HandiHaler^®; the overall incidence of adverse events was comparable across treatment groups. Tiotropium 5 and 10 μg Respimat^® improve lung function in COPD patients and appear to be comparable with tiotropium 18 μg HandiHaler^®.     

Comparison and optimal use of fixed combinations in the management of COPD

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Indications for the use of long-acting β₂-agonists (LABAs) and inhaled corticosteroids (ICS) in patients with COPD are described in the various international guidelines, but no special recommendations are made concerning the use of combination inhalers containing a LABA as well as an ICS. To determine the place of combination inhalers in the treatment of COPD we reviewed recent literature concerning this subject. On molecular level ICS/LABA combination therapy has anti-inflammatory properties which cannot be attributed to ICS alone. All clinical studies indicate that the two available combinations (salmeterol/fluticasone and formoterol/budesonide) significantly reduce exacerbation rate of moderate/severe exacerbations when compared with placebo. Some studies also showed a significant reduction in exacerbation rate compared with LABA monotherapy, but not compared with ICS monotherapy. From the patient’s perspective, ICS/LABA combination inhalers are the first choice when both need to be prescribed, possibly improving patient compliance for ICS. Currently little evidence is available to predict if flexible treatment with LABA/ICS combination inhalers will improve disease control in COPD. Further studies are needed to elucidate the clinical benefit of combination inhalers versus the individual components in different inhalers, and to investigate the clinical benefit of flexible dosing of combination inhalers in patients with COPD.     

Aggregation of mononuclear and red blood cells through an ��4��1-Lu/basal cell adhesion molecule interaction in sickle cell disease

Background

Abnormal interactions between red blood cells, leukocytes and endothelial cells play a critical role in the occurrence of the painful vaso-occlusive crises associated with sickle cell disease. We investigated the interaction between circulating leukocytes and red blood cells which could lead to aggregate formation, enhancing the incidence of vaso-occlusive crises.

Design and Methods

Blood samples from patients with sickle cell disease (n=25) and healthy subjects (n=5) were analyzed by imaging and classical flow cytometry after density gradient separation. The identity of the cells in the peripheral blood mononuclear cell layer was determined using antibodies directed specifically against white (anti-CD45) or red (anti-glycophorin A) blood cells.

Results

Aggregates between red blood cells and peripheral blood mononuclear cells were visualized in whole blood from patients with sickle cell disease. The aggregation rate was 10-fold higher in these patients than in control subjects. Both mature red blood cells and reticulocytes were involved in these aggregates through their interaction with mononuclear cells, mainly with monocytes. The size of the aggregates was variable, with one mononuclear cell binding to one, two or several red blood cells. Erythroid Lu/basal cell adhesion molecule and α₄β₁ integrin were involved in aggregate formation. The aggregation rate was lower in patients treated with hydroxycarbamide than in untreated patients.

Conclusions

Our study gives visual evidence of the existence of circulating red blood cell-peripheral blood mononuclear cell aggregates in patients with sickle cell disease and shows that these aggregates are decreased during hydroxycarbamide treatment. Our results strongly suggest that erythroid Lu/basal cell adhesion molecule proteins are implicated in these aggregates through their interaction with α₄β₁ integrin on peripheral blood mononuclear cells.     

Nocturnal Oxygen Desaturation Index is Inversely Correlated with Airflow Limitation in Patients with Chronic Obstructive Pulmonary Disease

The concurrent diagnosis of chronic obstructive pulmonary disease (COPD) and sleep apnoea–hypopnoea syndrome (SAHS) (overlap syndrome), can contribute to worsening respiratory symptoms, but whether the severity of COPD is associated with co-morbid SAHS is unknown. We investigated whether the severity of COPD is associated with the complication of SAHS by examination of nocturnal oximetry as an alternative to polysomnography. Patients with COPD concurrently completed nocturnal oximetry, pulmonary function tests, a COPD assessment test, an Epworth sleepiness scale and a hospital anxiety and depression scale to evaluate the severity of COPD and possible concurrent presence of SAHS. We retrospectively analysed the data to assess correlation between the oxygen desaturation index (ODI) and each clinical variables and evaluated the predictors of ODI ≥ 15. This study included 103 patients (91 males, 88%) with a mean age of 72 ± 8 years and body mass index of 22 ± 3 kg/m². ODI was positively correlated with FEV₁, FEV₁/FVC and FEV₁% predicted, which meant that ODI was inversely correlated with airflow limitation. Univariate logistic regression analysis revealed that FEV₁% predicted and FEV₁/FVC were predictors of ODI ≥ 15. ODI is inversely correlated with airflow limitation and milder COPD patients may have co-morbid SAHS.     

Comparison of Mometasone Furoate Dry Powder Inhaler and Fluticasone Propionate Dry Powder Inhaler in Patients with Moderate to Severe Persistent Asthma Requiring High-Dose Inhaled Corticosteroid Therapy: Findings from a Noninferiority Trial

Background. Inhaled corticosteroids (ICSs) are one of the suggested first-line therapies for patients with persistent asthma of moderate severity. Methods: The efficacy and safety of mometasone furoate (MF) 400 μg twice daily (BID) and fluticasone propionate (FP) 500 μ g BID administered for 12 weeks via dry powder inhaler (DPI) were compared in a noninferiority trial, in adults with moderate-to-severe persistent asthma. The primary variable was the change from baseline in am peak expiratory flow rate (PEFR). pm PEFR, forced expiratory volume in 1 second (FEV₁), asthma symptoms, rescue medication use, response to therapy, exacerbation rates, and adverse events were also assessed. Results. The lower bound of 95% CIs for treatment differences in the primary variable ranged from 2.6% to 5.6% throughout the 12-week study and were within the prespecified noninferiority range. No significant between-group differences were observed in lung function, rescue medication use, response to therapy, exacerbation rates, or adverse events. At most of the weeks assessed, there were no between-group differences in asthma symptoms. Most adverse events were mild-to-moderate. Conclusion. MF-DPI 400 μ g BID was therapeutically equivalent to FP-DPI 500 μ g BID in patients with moderate-to-severe persistent asthma.     

Postoperative outcome after coronary artery bypass grafting in chronic obstructive pulmonary disease

BACKGROUND:

It is uncertain if the presence and severity of airflow obstruction in chronic obstructive pulmonary disease (COPD) is predictive of surgical morbidity and mortality after coronary artery bypass grafting (CABG).

METHODS:

Retrospective study of patients who underwent CABG between 1998 and 2003 in a university-affiliated hospital for whom a preoperative spirometry was available. COPD was diagnosed in smokers or ex-smokers 50 years of age or older in the presence of irreversible airflow obstruction. Patients were divided into three groups depending on the spirometry: controls (forced expiratory volume in 1 s [FEV₁] 80% or more, FEV₁/forced vital capacity [FVC] greater than 0.7), mild to moderate COPD (FEV₁ 50% or more and FEV₁/FVC 0.7 or less) and severe COPD (FEV₁ less than 50% and FEV₁/FVC 0.7 or less).

RESULTS:

Among the 411 files studied, 322 (249 men, 68±8 years of age) were retained (controls, n=101; mild to moderate COPD, n=153; severe COPD, n=68). The mortality rate (3.0%, 2.6% and 0%, respectively) was comparable among the three groups. Patients with severe COPD had a slightly longer hospital stay than controls (mean difference 0.7±1.4 days, P<0.05). Pulmonary infections were more frequent in severe COPD (26.5%) compared with mild to moderate COPD (12.4%) and controls (12.9%), P<0.05. Atrial fibrillation tended to be more frequent in severe COPD than in the other two groups.

CONCLUSION:

Mortality rate associated with CABG surgery is not influenced by the presence and severity of airflow obstruction in patients with COPD. The incidence of pulmonary infections and length of hospital stay were increased in patients with severe COPD.     

Advanced glycation end products in the skin are enhanced in COPD

Background

Cigarette smoking is the main cause of chronic obstructive pulmonary disease (COPD) inducing oxidative stress and local tissue injury, resulting in pulmonary inflammation. Advanced glycation end products (AGEs) are produced by glycation and oxidation processes and their formation is accelerated in inflammatory conditions. In this study we assessed whether AGE accumulation in the skin is elevated in COPD and associates with disease severity.

Methods

202 mild-to-very-severe COPD patients and 83 old (40–75 years) and 110 young (18–40 years) healthy smokers and never-smokers were included. AGEs were measured by skin autofluorescence (SAF). Demographic variables, smoking habits, co-morbidities and lung function values were obtained.

Results

COPD patients (FEV₁ = 55% predicted) had significantly higher SAF values than old and young healthy controls: 2.5 vs. 1.8 and 1.2 (arbitrary units, p < 0.05). No differences in SAF values were found between GOLD stages I-IV (2.4, 2.3, 2.5, 2.5 respectively). Lower function (FEV₁/FVC, MEF₅₀/FVC, RV/TLC) and higher number of packyears were significantly associated with SAF (p < 0.05).

Conclusions

SAF is increased in mild-to-very severe COPD patients compared with healthy controls. Interestingly, SAF was not associated with disease severity as values were comparable between different GOLD stages (stage I-IV) of COPD. This may suggest that AGEs play a role in the induction phase of COPD in susceptible smokers. Future studies should further investigate the mechanisms underlying AGEs formation and accumulation in COPD.     

Is Exhaled Nitric Oxide a Useful Adjunctive Test for Assessing Asthma?

Rationale. To determine the general utility of clinical (Asthma Control Test) and physiologic (forced expiratory volume in the first second of exhalation [FEV₁] and fractionated exhaled nitric oxide level [FeNO]) parameters for characterizing asthma patients. Methods. Two cross-sectional independent studies simultaneously enrolled 100 patients in the US and 109 patients in Spain ≥ 18 years of age with a physician-diagnosis of asthma and confirmed by a ≥ 12% improvement in FEV₁ after bronchodilators or the presence of airway hyperresponsiveness, a central feature of asthma, as measured by methacholine challenge (PC₂₀ < 10 mg/mL). There was no restriction on asthma severity or treatment. Patients were excluded if they had a diagnosis of chronic obstructive pulmonary disease and/or were current cigarette smokers. Statistical analyses were performed to compare ACT, FeNO, and spirometry within and between sites. Results. Population characteristics revealed significant differences in distributions of age, percent-predicted FEV₁ (%FEV₁), FeNO, inhaled corticosteroid usage, and atopy between the two populations. The Spain site enrolled younger patients with milder asthma, based on higher %FEV₁ values and less frequent treatment with inhaled corticosteroids. At each site, mean FeNO levels decreased as asthma control categories increased, and means were lower in the US. There was a negative correlation between ACT and FeNO that was statistically significant for Spain patients not treated with inhaled corticosteroids. Conclusions. The results of this study support the use of FeNO as an adjunctive tool for assessing asthma primarily in mild inhaled corticosteroid (ICS)-naïve asthma patients. The lack of correlation of ACT with FeNO in this and other studies across the entire population appears to reflect the heterogeneity of asthma patients who have an admixture of asthma severity and treatment regimens making it very difficult to appreciate the nuances of sensitive tests like FeNO.     

Budesonide�Cformoterol (inhalation powder) in the treatment of COPD

The budesonide–formoterol dry powder inhaler (Symbicort^® Turbuhaler^® 160/4.5–640/18 μg/day) contains the long-acting β₂-adrenoreceptor agonist formoterol and the inhaled corticosteroid budesonide. Two large, 12-month trials examined the effect of budesonide–formoterol 160/4.5 μg twice daily in COPD patients who met these criteria. The studies were identical, except one in which the patients had received oral prednisolone 30 mg/day and had inhaled formoterol 4.5 μg twice daily for 2 weeks before randomization. In terms of the FEV₁, budesonide–formoterol produced an effect greater than that of both budesonide alone and formoterol alone reported in previous studies. The combination was generally more effective than either of the components in terms of peak expiratory flow, symptoms, and exacerbations. These advantages of the combination over those of either budesonide alone or formoterol alone were quite consistent. Improving lung function and decreasing symptoms significantly, budesonide–formoterol combination therapy provides significant clinical improvements in COPD, despite the limited reversibility of impaired lung function in the disease.     

Association of serum vitamin D levels with disease severity,systemic inflammation,prior lung function loss and exacerbations in a cohort of patients with chronic obstructive pulmonary disease (COPD)

BackgroundVitamin D deficiency has been associated with chronic disorders including chronic obstructive pulmonary disease (COPD) but the relationships with inflammation, exacerbations and disease progression remain unclear.MethodsIn this monocentric cross-sectional observational study we analyzed the disease status, systemic inflammation, prior exacerbation frequency and loss in lung function in relation to serum 25-hydroxyvitamin D (25-OHD) levels in a cohort of 94 patients with COPD. Serum 25-OHD, C-reactive protein, interleukin-6 and tumor necrosis factor-α were quantified. Exacerbation frequencies and sunlight exposure were assessed. These parameters were analyzed in correlation to the current forced expiratory volume in 1 s (FEV₁), the individual average 3-year FEV₁ decline and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage.ResultsWe observed fair correlation between serum 25-OHD and the current FEV₁ (r=0.38, P<0.001). Furthermore, mean serum 25-OHD was significantly altered between patients of GOLD stages I–IV (P=0.013). There was weak negative correlation of 25-OHD and the average annual change of the FEV₁ (r=−0.26, P<0.05). Furthermore, we observed fair negative correlation between 25-OHD and C-reactive protein (r=−0.32, P<0.01) as well as weak negative correlation with interleukin-6 (r=−0.23, P<0.05). While the exacerbation frequency significantly differed between GOLD stages (P=0.04), there was no direct association between exacerbations and 25-OHD levels.ConclusionOur data confirm frequent vitamin D deficiency in COPD and point out correlations between 25-OHD levels, systemic inflammation, disease severity and progression.     

Systemic inflammation after inspiratory loading in chronic obstructive pulmonary disease

Objective

Patients with chronic obstructive pulmonary disease (COPD) present systemic inflammation. Strenuous resistive breathing induces systemic inflammation in healthy subjects. We hypothesized that the increased respiratory load that characterizes COPD can contribute to systemic inflammation in these patients.

Patients and methods

To test this hypothesis, we compared leukocyte numbers and levels of circulating cytokines (tumor necrosis factor alpha [TNFα], interleukin-1β [IL-1β], IL-6, IL-8, and IL-10), before and 1 hour after maximal incremental inspiratory loading in 13 patients with stable COPD (forced expiratory volume in one second [FEV₁] 29 ± 2.5% ref) and in 8 healthy sedentary subjects (FEV₁ 98 ± 5% ref).

Results

We found that: (1) at baseline, patients with COPD showed higher leukocyte counts and IL-8 levels than controls (p < 0.01); and, (2) one hour after maximal inspiratory loading these values were unchanged, except for IL-10, which increased in controls (p < 0.05) but not in patients with COPD.

Conclusions

This study confirms the presence of systemic inflammation in COPD, shows that maximal inspiratory loading does not increase the levels of pro-inflammatory cytokines (IL-1β, IL-8) in COPD patients or controls, but suggests that the former may be unable to mount an appropriate systemic anti-inflammatory response to exercise.