Henk A. Thiadens

Effect of Fluticasone With and Without Salmeterol on Pulmonary Outcomes in Chronic Obstructive Pulmonary Disease: 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 microg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 microg twice daily, and salmeterol, 50 microg 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 FEV(1) 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 FEV(1) 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. .

Identifying asthma and chronic obstructive pulmonary disease in patients with persistent cough presenting to general practitioners: descriptive study

Abstract Objective: To determine the prevalence of asthma and chronic obstructive pulmonary disease in patients not known to have these disorders, who present in general practice with persistent cough, and to ascertain criteria to help general practitioners in diagnosis. Design: Descriptive study. Setting: Primary healthcare centre in the Netherlands. Subjects: 192 patients aged 18-75 years, not known to have asthma or chronic obstructive pulmonary disease, attending their general practitioner with cough persisting for at least 2 weeks. Methods: A diagnosis of asthma or chronic obstructive pulmonary disease was based on the recurrence of airway symptoms in the past year accompanied by spirometric measurements (including bronchodilator testing) and methacholine provocation tests. A scoring formula to estimate the probability of asthma or chronic obstructive pulmonary disease, based on history and physical examination, was generated by means of logistic regression. Results: 74 patients (39%) were classified as having asthma, 14 (7%) as having chronic obstructive pulmonary disease. The best formula for predicting asthma or chronic obstructive pulmonary disease used scores for three symptoms: (reported) wheeze,(reported) dyspnoea, and allergen induced symptoms, together with prolonged expiration, pack years of smoking, and female sex. Variables were scored 1 when present and 0 when absent, except for allergen induced symptoms (1.5) and number of pack years of smoking (n/25). With a cut off value of 3 on the scoring formula, 76% of the patients could be classified correctly. Conclusions: About half of patients with persistent cough who present to a general practitioner have asthma or chronic obstructive pulmonary disease. With a simple formula based on three symptoms and prolonged expiration, pack years of smoking, and female sex, most patients may be identified correctly in general practice. Key messages Nearly half the patients attending a general practitioner with persistent cough show features of asthma or chronic obstructive pulmonary disease (significant bronchodilator response, airway obstruction, or hyperresponsiveness) Most cases can be identified through history taking and physical examination only The key variables to predict which patients are likely to have asthma or chronic obstructive pulmonary disease are: current wheeze and dyspnoea, symptoms elicited by allergens, prolonged expiration, cumulative smoking, and female sex The scoring formula composed of the key variables may help to determine when it is necessary to perform pulmonary function testing to confirm or reject a diagnosis of asthma or chronic obstructive pulmonary disease

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

BackgroundChronic 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.MethodsIn 114 COPD patients (99 male, age: 62 ± 8 yr, 41 [31–55] pack-years, no inhaled or oral corticosteroids, postbronchodilator FEV1: 63 ± 9% pred, FEV1/IVC: 48 ± 9%) we obtained induced sputum and measured health status (St. Georges respiratory questionnaire (SGRQ)), postbronchodilator FEV1, hyperinflation (RV/TLC), and airway hyperresponsiveness to methacholine (PC20). Sputum was induced by hypertonic saline and differential cell counts were obtained in 102 patients.ResultsUnivariate 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 PC20 (B = -9.3, p = 0.024). Current smoking and FEV1 were not significantly associated with health status in the multiple regression analysis.ConclusionWe 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.

Value of measuring diurnal peak flow variability in the recognition of asthma: a study in general practice

In this study we analysed the value of measuring diurnal peak flow variability (DPV) in general practice for diagnosing asthma or chronic obstructive pulmonary disease (COPD). One hundred and eighty-two subjects, aged 18-75 yrs, with undiagnosed asthma or COPD, presenting with a persistent cough recorded a peak flow diary twice daily for 2 weeks. A diagnosis of asthma or COPD was based on the recurrence of airway symptoms in the past year accompanied by spirometric measurements and a provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second. DPV was expressed as amplitude percentage highest of the day. Cut-off values of 15% and 20% (DPV15%, DPV20%) were employed and the number of days that these values were reached, was assessed. The influence of age, sex and pack-years smoking on DPV was analysed by logistic regression. The a priori probability to have asthma (n=69) or COPD (n=12) was 45% (81/182) and increased to >70% with a DPV20% for at least 3, and a DPV15% for at least 4 days. Scoring formulas for asthma (DPV15% (number of days present) + 4 (if female sex)) and for asthma and COPD combined (8x DPV15% (number of days present) + 24 (if female sex) + pack-years smoking) predicted which subjects were at risk for having asthma (or COPD). Simple formulas based on the number of days with diurnal peak flow variability at 15%, female sex and pack-years can predict which patients with persistent cough are likely to have asthma or chronic obstructive pulmonary 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