Airway inflammation contributes to health status in COPD:a cross-sectional study

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow limitation and airway inflammation, accompanied by decreased health status. It is still unknown which factors are responsible for the impaired health status in COPD. We postulated that airway inflammation negatively contributes to health status in COPD. METHODS: In 114 COPD patients (99 male, age: 62 ± 8 yr, 41 [31–55] pack-years, no inhaled or oral corticosteroids, postbronchodilator FEV(1): 63 ± 9% pred, FEV(1)/IVC: 48 ± 9%) we obtained induced sputum and measured health status (St. George's respiratory questionnaire (SGRQ)), postbronchodilator FEV(1), hyperinflation (RV/TLC), and airway hyperresponsiveness to methacholine (PC(20)). Sputum was induced by hypertonic saline and differential cell counts were obtained in 102 patients. RESULTS: Univariate analysis showed that SGRQ total and symptom score were positively associated with % sputum macrophages (r = 0.20, p = 0.05; and r = 0.20, p = 0.04, respectively). Multiple regression analysis confirmed these relationships, providing significant contributions of % sputum macrophages (B = 0.25, p = 0.021) and RV/TLC (B = 0.60, p = 0.002) to SGRQ total score. Furthermore, SGRQ symptom score was associated with % sputum macrophages (B = 0.30, p = 0.03) and RV/TLC (B = 0.48, p = 0.044), whilst SGRQ activity score was associated with % sputum macrophages (B = 0.46, p = 0.002), RV/TLC (B = 0.61, p = 0.015), and PC(20 )(B = -9.3, p = 0.024). Current smoking and FEV(1 )were not significantly associated with health status in the multiple regression analysis. CONCLUSION: We conclude that worse health status in COPD patients is associated with higher inflammatory cell counts in induced sputum. Our findings suggest that airway inflammation and hyperinflation independently contribute to impaired health status in COPD. This may provide a rationale for anti-inflammatory therapy in this disease

Prediction of Long-Term Benefits of Inhaled Steroids by Phenotypic Markers in Moderate-to-Severe COPD:A Randomized Controlled Trial

BACKGROUND:The decline in lung function can be reduced by long-term inhaled corticosteroid (ICS) treatment in subsets of patients with chronic obstructive pulmonary disease (COPD). We aimed to identify which clinical, physiological and non-invasive inflammatory characteristics predict the benefits of ICS on lung function decline in COPD. METHODS:Analysis was performed in 50 steroid-naive compliant patients with moderate to severe COPD (postbronchodilator forced expiratory volume in one second (FEV1), 30-80% of predicted, compatible with GOLD stages II-III), age 45-75 years, >10 packyears smoking and without asthma. Patients were treated with fluticasone propionate (500 μg bid) or placebo for 2.5 years. Postbronchodilator FEV1, dyspnea and health status were measured every 3 months; lung volumes, airway hyperresponsiveness (PC20), and induced sputum at 0, 6 and 30 months. A linear mixed effect model was used for analysis of this hypothesis generating study. RESULTS:Significant predictors of attenuated FEV1-decline by fluticasone treatment compared to placebo were: fewer packyears smoking, preserved diffusion capacity, limited hyperinflation and lower inflammatory cell counts in induced sputum (p<0.04). CONCLUSIONS:Long-term benefits of ICS on lung function decline in patients with moderate-to-severe COPD are most pronounced in patients with fewer packyears, and less severe emphysema and inflammation. These data generate novel hypotheses on phenotype-driven therapy in COPD. TRIAL REGISTRATION:ClinicalTrials.gov NCT00158847

Predictors of attenuation of long-term FEV₁ decline by fluticasone treatment.

<p>Definition of abbreviations: postbr. = postbronchodilator; FEV₁ = forced expiratory volume in one second; % pred = percentage of predicted value; PC₂₀ methacholine = the provocative concentration of methacholine that causes a decrease in FEV₁ of 20%; RV/TLC = residual volume/total lung capacity; TLCO = diffusion capacity of the lung for carbon monoxide.</p><p>^#Index category is defined relative to median value, and represents the more favourable outcome by fluticasone. Reference category is complementary. The interaction term (treatment*stratum*time) reflects the additional effect of predictor variables to the effect of treatment with inhaled fluticasone compared to placebo on longitudinal changes in FEV₁. The corresponding P values for predictor variables are reported in Table 4. A favourable effect on decline in FEV₁ would be a decrease in decline caused by inhaled corticosteroids.</p><p>Predictors of attenuation of long-term FEV₁ decline by fluticasone treatment.</p

A priori defined predictors.

<p>Definition of abbreviations: FEV₁ = forced expiratory volume in one second; % pred = percentage of predicted value; PC₂₀ methacholine = the provocative concentration of methacholine that causes a decrease in FEV₁ of 20%; RV/TLC = residual volume/total lung capacity; TLC = total lung capacity; TLCO = diffusion capacity of the lung for carbon monoxide.</p><p>5 Domains of potential predictors are listed in the table: (1) packyears; (2) presence of chronic bronchitis; (3) lung function (4) TLCO; and (5) absolute and differential cell counts in induced sputum.</p

Patient characteristics at baseline.

<p>^║PC₂₀ methacholine is expressed as geometric mean (standard deviation in doubling dose (DD)).</p><p>^‡range 1 to 5 (higher scores indicate more dyspnea);</p><p>^†range 0 (best) to 100 (worst score);</p><p>^§range 0 (best) to 6 (worst score).</p><p>Definition of abbreviations: postbr. = postbronchodilator; FEV₁ = forced expiratory volume in one second; % pred = percentage of predicted value; PC₂₀ methacholine = the provocative concentration of methacholine that causes a decrease in FEV₁ of 20%; RV/TLC = residual volume/total lung capacity; TLCO = diffusion capacity of the lung for carbon monoxide.</p><p>Characteristics of the study population per treatment group at baseline. Data represent mean (SD).</p

Mean values of predictors per stratum per treatment.

<p>^#Index category is defined relative to median value, and represents the more favourable outcome by fluticasone. For example: decline of FEV₁ by fluticasone is diminished (= favourable outcome) in patients with a lower number of packyears (= index category).</p><p>^⊥Reference category is complementary to the index category.</p><p>Values are mean (standard deviation (SD)), unless stated otherwise.</p><p>^║PC₂₀ methacholine is expressed as geometric mean (standard deviation in doubling dose (DD)),</p><p>^‡sputum cells as Geometric mean (GSD).</p><p>Definition of abbreviations: postbr. = postbronchodilator; FEV₁ = forced expiratory volume in one second; % pred = percentage of predicted value; PC₂₀ methacholine = the provocative concentration of methacholine that causes a decrease in FEV₁ of 20%; RV/TLC = residual volume/total lung capacity; TLCO = diffusion capacity of the lung for carbon monoxide.</p><p>Mean values of predictors per stratum per treatment.</p

Effect of Fluticasone With and Without Salmeterol on Pulmonary Outcomes in Chronic Obstructive Pulmonary Disease A Randomized Trial: a randomized trial

Background: Inhaled corticosteroids (ICSs) and long-acting beta(2)-agonists (LABAs) are used to treat moderate to severe chronic obstructive pulmonary disease (COPD). Objective: To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD. Design: Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847) Setting: 2 university medical centers in The Netherlands. Patients: 114 steroid-naive current or former smokers with moderate to severe COPD. Measurements: Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months. Intervention: Random assignment by minimization method to receive fluticasone propionate, 500 mu g twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 mu g twice daily, and salmeterol, 50 mu g twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29). Results: 101 patients were greater than 70% adherent to therapy. Fluticasone therapy decreased counts of mucosal CD3(+) cells (-55% [95% CI, -74% to -22%]; P = 0.004), CD4(+) cells (-78% [CI, -88% to 60%]; P <0.001), CD8(+) cells (-57% [CI, -77% to -18%]; P = 0.010), and mast cells (-38% [CI, -60% to -2%]; P = 0.039) and reduced hyperresponsiveness (P = 0.036) versus placebo at 6 months, with effects maintained after 30 months. Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium, with accompanying reductions in sputum neutrophil, macrophage, and lymphocyte counts and improvements in FEV1 decline, dyspnea, and quality of life. Reductions in inflammatory cells correlated with clinical improvements. Discontinuing fluticasone therapy at 6 months increased counts of CD3(+) cells (120% [CI, 24% to 289%]; P = 0.007), mast cells (218% [CI, 99% to 407%]; P <0.001), and plasma cells (118% [CI, 9% to 336%]; P = 0.028) and worsened clinical outcome. Adding salmeterol improved FEV1 level. Limitations: The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months. Conclusion: ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD. Adding LABAs does not enhance these effects

Long-term predictors of FEV₁ decline by fluticasone treatment.

<p>(A) Prediction by packyears smoking of the decline of FEV₁ by 2.5 year fluticasone treatment (ml) and placebo, stratified by median values of the predictor by 30 months treatment with fluticasone compared to placebo. ^#Index category (Idx) is defined relative to median value, and represents the more favourable outcome by fluticasone. Reference category (Ref) is complementary. The group numbers of the patients are mentioned in each graph. For example: Fig 2A shows the decline in FEV₁ in ml/yr on the Y axis for patients with many pack years and patients with few pack years with fluticasone or placebo treatment, respectively, on the X axis. All P values are based on the results of the linear mixed effects model. The treatment*time interaction term corresponding to the difference in decline in FEV₁ between fluticasone and placebo in the low pack year stratum had a P value of 0.037. The interaction term (treatment*stratum*time) reflects the additional effect of pack years smoking stratum to the effect of treatment with inhaled fluticasone compared to placebo on longitudinal changes in FEV₁. The corresponding P value for pack years smoking is 0.023. A favourable effect on decline in FEV₁ would be a decrease in decline caused by inhaled corticosteroids. The figure shows that a lower number of packyears (= index category) decreases the decline in FEV₁ significantly. (B) Prediction by baseline FEV₁ of the decline of FEV₁ by 2.5 year fluticasone treatment (ml) and placebo, stratified by median values of the predictor by 30 months treatment with fluticasone compared to placebo. (C) Prediction by RV/TLC of the decline of FEV₁ by 2.5 year fluticasone treatment (ml) and placebo, stratified by median values of the predictor by 30 months treatment with fluticasone compared to placebo. (D) Prediction by TLCO of the decline of FEV₁ by 2.5 year fluticasone treatment (ml) and placebo, stratified by median values of the predictor by 30 months treatment with fluticasone compared to placebo. (E) Prediction by total number of cell counts in induced sputum of the decline of FEV₁ by 2.5 year fluticasone treatment (ml) and placebo, stratified by median values of the predictor by 30 months treatment with fluticasone compared to placebo. (F) Prediction by PC₂₀ methacholine of the decline of FEV₁ by 2.5 year fluticasone treatment (ml) and placebo, stratified by median values of the predictor by 30 months treatment with fluticasone compared to placebo. (G) Prediction by percentage of eosinophils in sputum of the decline of FEV₁ by 2.5 year fluticasone treatment (ml) and placebo, stratified by median values of the predictor by 30 months treatment with fluticasone compared to placebo.</p