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Concept: Bronchodilator


Chronic obstructive pulmonary disease (COPD) is often misdiagnosed and inappropriately treated in many patients. COPD is a distinct disease from adult-onset asthma; however, some patients with COPD may present with several forms of airway disease described as asthma-COPD overlap (ACO). Bronchodilators and inhaled corticosteroids (ICS) both have a place in standard maintenance treatment of COPD and asthma; however, recommendations for use differ widely. In patients with COPD, long-acting bronchodilators are effective initial monotherapy treatment, while ICS monotherapy is recommended as initial treatment in patients with asthma. Clinicians need to be confident in their diagnosis to ensure that correct treatment is given, as misguided treatment decisions can result in significantly increased safety risks for patients. This review highlights the differences in diagnosis and treatment between COPD, asthma, and ACO and discusses the data supporting guideline recommendations for use of bronchodilators in COPD treatment in contrast to asthma or ACO.

Concepts: Asthma, Medical terms, Pneumonia, Chronic obstructive pulmonary disease, Spirometry, Obstructive lung disease, Bronchodilator


ABSTRACT BACKGROUND: Disease progression in chronic obstructive pulmonary disease (COPD) is associated with decline in exercise performance over time. We assessed whether tiotropium might mitigate this by determining its effect on treadmill endurance time (ET) over 2 years. METHODS: Randomized, double-blind, placebo-controlled trial of tiotropium 18 µg daily in patients with COPD (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 70%; postbronchodilator FEV1 < 65%). Primary endpoint: ET at 90% of baseline maximum work rate at 96 weeks. Secondary endpoints: ET at other visits, ET by smoking status, spirometry, St George Respiratory Questionnaire (SGRQ). RESULTS: 519 patients randomized (tiotropium 260, placebo 259), mean 65 years, 77% men, 34% continuing smokers, FEV1 1.25 L (44% predicted). Significantly more patients discontinued placebo: hazard ratio (95% CI) 0.61 (0.44, 0.83). Baseline ET was 301 s (improvement tiotropium/placebo: 13% overall, P = 0.009; 18% at 48 weeks, P = 0.004; 13% at 96 weeks, P = 0.106). In patients with baseline ET between 2-10 minutes (n = 404), improvement at 96 weeks was 19% (P = 0.04). Current smokers had higher ET with tiotropium vs placebo (P = 0.018). FEV1/FVC improved with tiotropium (P < 0.01). SGRQ total score at 96 weeks improved with tiotropium vs placebo by 4.03 units (P = 0.007). CONCLUSIONS: Treadmill ET was numerically greater over 2 years with tiotropium vs placebo. However, 96-week difference was not statistically significant. Spirometry and health status also improved with tiotropium over 2 years, attesting to the benefits of long-acting bronchodilator NCT00525512.

Concepts: Pulmonology, Asthma, Respiratory physiology, Chronic obstructive pulmonary disease, Spirometry, Tiotropium, Obstructive lung disease, Bronchodilator


OBJECTIVE: To estimate the cost-effectiveness of adding a selective phosphodiesterase-4 inhibitor, roflumilast, to a long-acting bronchodilator therapy (LABA) for the treatment of patients with severe-to-very severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis with a history of frequent exacerbations from the UK payer perspective. METHODS: A Markov model was developed to predict the lifetime cost and outcomes [exacerbations rates, life expectancy, and quality-adjusted life years (QALY)] in patients treated with roflumilast, which showed a reduction in the exacerbation rates and lung function improvement in a pooled analysis from two clinical trials, M2-124 and M2-125. Sensitivity analyses were conducted to explore the impact of uncertainties on the cost-effectiveness. RESULTS: The addition of roflumilast to concomitant LABA reduced the number of exacerbations from 15.6 to 12.7 [2.9 (95 % CI 0.88-4.92) exacerbations avoided] and increased QALYs from 5.45 to 5.61 [0.16 (95 % CI 0.02-0.31) QALYs gained], at an incremental cost of £3,197 (95 % CI £2,135-£4,253). Cost in LABA alone and LABA + roflumilast were £16,161 and £19,358 respectively. The incremental cost-effectiveness ratios in the base case were £19,505 (95 % CI £364-£38,646) per quality-adjusted life-year gained and 18,219 (95 % CI £12,697-£49,135) per life-year gained. Sensitivity analyses suggest that among the main determinants of cost-effectiveness are the reduction of exacerbations and the case fatality rate due to hospital-treated exacerbations. Probabilistic sensitivity analysis suggests that the probability of roflumilast being cost-effective is 82 % at willingness-to-pay £30,000 per QALY. CONCLUSIONS: The addition of roflumilast to LABA in the treatment of patients with severe-to-very severe COPD reduces the rate of exacerbations and can be cost-effective in the UK setting.

Concepts: Health economics, Asthma, Lung, Costs, Chronic obstructive pulmonary disease, Cost-utility analysis, Bronchodilator, Cost-Effectiveness Analysis Registry


The basic features of bronchial asthma are dyspnea with wheezing and objectively confirmed obstructive respiratory disorder reversible after inhalation of bronchodilators. In stable intermittent bronchial asthma, these features are not present; therefore confirmation of asthma consists of the presence of bronchial hyperresponsiveness (BHR). In the present study, there were 902 bronchoprovocation tests performed for the verification of BHR. A significant criterium for BHR is a decrease of FEV(1) of 20% from the baseline level. Every test either positive or negative was finished with inhalation of four doses of salbutamol through a spacer. We obtained 675 bronchoprovocation tests negative and 227 positive. Among the 675 subjects with a negative test there were 49 subjects who after inhalation of salbutamol had an increase in FEV(1) of ≥20% above baseline. The bronchodilatatory response of these 49 subjects, makes one think about the so-called latent bronchospasm present already at baseline, limiting further constriction during bronchoprovocation tests. The detection of such latent bronchospasm in BHR increases the number of patients with an objectively confirmed bronchial asthma from 25.0% to 30.5%. Our results suggest that bronchodilation test be performed in all patients with suspected bronchial asthma to allow detecting latent bronchospasm as an initial stage of the disease.

Concepts: Asthma, Respiratory system, Obstructive lung disease, Bronchiole, Bronchodilator, Bronchial hyperresponsiveness, Bronchiolitis, Bronchospasm


This article focuses on recent data which highlight the clinical settings in which exhaled nitric oxide (F(E)NO) is potentially helpful, or not, as a clinical tool. It is becoming clearer that, selectively applied, F(E)NO measurements can provide reliable clinical guidance, particularly when values are low. Such values are associated with high negative predictive values (>90%). Increased F(E)NO levels are associated with much more modest positive predictive values (75%-85%) and these are less reliable. These general principles apply when diagnosing steroid responsiveness in relation to asthma, chronic cough, and COPD. Although randomised trials do not support routine use of exhaled NO measurements in uncomplicated bronchial asthma, there is evidence that in patients with difficult asthma, or asthma associated with pregnancy, F(E)NO enhances overall management, and the decision to commence or increase inhaled steroid therapy (yes/no) may be made more accurately. Exhaled NO is potentially relevant in the assessment of occupational asthma (serial measurements) and also in diagnosing bronchiolitis obliterans in lung transplant patients.

Concepts: Asthma, Cough, Chronic obstructive pulmonary disease, Nitric oxide, Bronchiole, Bronchiolitis obliterans, Exhaled nitric oxide, Bronchodilator


Asthma-COPD overlap syndrome (ACOS) or asthma-COPD overlap captures the subset of patients with airways disease who have features of both asthma and chronic obstructive pulmonary disease (COPD). Although definitions of ACOS vary, it is generally thought to encompass persistent airflow limitation in a patient older than 40 years of age with either a history of asthma or large bronchodilator reversibility. ACOS affects about a quarter of patients with COPD and almost a third of patients who previously had asthma. Compared with their counterparts with asthma or COPD alone, patients with ACOS have significantly worse respiratory symptoms, poorer quality of life, and increased risk of exacerbations and hospital admissions. Whether this condition emerges after gradual shifts in airway remodelling and inflammation in a patient with COPD, as the result of noxious exposures in a patient with asthma, or even as a de novo disease with its own pathology is yet to be determined. Nevertheless, using treatments developed for asthma or COPD that target eosinophilic, neutrophilic, or paucigranulocytic airway inflammation may be a helpful approach to these patients until further clinical trials can be performed.

Concepts: Medicine, Asthma, Pneumonia, Hospital, Chronic obstructive pulmonary disease, Respiratory system, Obstructive lung disease, Bronchodilator


INTRODUCTION: Unexplained respiratory symptoms reported by athletes are often incorrectly considered secondary to exercise-induced asthma. We hypothesised that this may be related to exercise induced laryngeal obstruction (EILO). This study evaluates the prevalence of EILO in an unselected cohort of athletes. METHODS: We retrospectively reviewed the prevalence of EILO in a cohort of athletes (n=91) referred consecutively during a two-year period for asthma work-up including continuous laryngoscopy during exercise (CLE) testing. We compared clinical characteristics and bronchial hyper-reactivity between athletes with and without EILO. RESULTS: Of 88 athletes who completed a full work-up, 31 (35.2%) had EILO and 38 (43.2%) had a positive bronchoprovocation or bronchodilator reversibility test. The presence of inspiratory symptoms did not differentiate athletes with and without EILO. Sixty-one percent of athletes with EILO and negative bronchoprovocation and bronchodilator reversibility tests used regular asthma medication at referral. CONCLUSION: In athletes with unexplained respiratory symptoms, EILO is an important differential diagnosis not discerned from other aetiologies by clinical features. These findings have important implications for the assessment and management of athletes presenting with persistent respiratory symptoms despite asthma therapy.

Concepts: Asthma, Medical terms, Medical diagnosis, Differential diagnosis, Bronchiole, REFER, Bronchodilator, Bronchiolitis


Background Tracking longitudinal measurements of growth and decline in lung function in patients with persistent childhood asthma may reveal links between asthma and subsequent chronic airflow obstruction. Methods We classified children with asthma according to four characteristic patterns of lung-function growth and decline on the basis of graphs showing forced expiratory volume in 1 second (FEV1), representing spirometric measurements performed from childhood into adulthood. Risk factors associated with abnormal patterns were also examined. To define normal values, we used FEV1 values from participants in the National Health and Nutrition Examination Survey who did not have asthma. Results Of the 684 study participants, 170 (25%) had a normal pattern of lung-function growth without early decline, and 514 (75%) had abnormal patterns: 176 (26%) had reduced growth and an early decline, 160 (23%) had reduced growth only, and 178 (26%) had normal growth and an early decline. Lower baseline values for FEV1, smaller bronchodilator response, airway hyperresponsiveness at baseline, and male sex were associated with reduced growth (P<0.001 for all comparisons). At the last spirometric measurement (mean [±SD] age, 26.0±1.8 years), 73 participants (11%) met Global Initiative for Chronic Obstructive Lung Disease spirometric criteria for lung-function impairment that was consistent with chronic obstructive pulmonary disease (COPD); these participants were more likely to have a reduced pattern of growth than a normal pattern (18% vs. 3%, P<0.001). Conclusions Childhood impairment of lung function and male sex were the most significant predictors of abnormal longitudinal patterns of lung-function growth and decline. Children with persistent asthma and reduced growth of lung function are at increased risk for fixed airflow obstruction and possibly COPD in early adulthood. (Funded by the Parker B. Francis Foundation and others; number, NCT00000575 .).

Concepts: Pulmonology, Asthma, Lung, Chronic obstructive pulmonary disease, Emphysema, Spirometry, Obstructive lung disease, Bronchodilator


The current Global initiative for chronic Obstructive Lung Disease (GOLD) treatment strategy recommends the use of one or more bronchodilators according to the patient’s airflow limitation, their history of exacerbations, and symptoms. The LANTERN study evaluated the effect of the long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) dual bronchodilator, QVA149 (indacaterol/glycopyrronium), as compared with the LABA/inhaled corticosteroid, salmeterol/fluticasone (SFC), in patients with moderate-to-severe COPD with a history of ≤1 exacerbation in the previous year.

Concepts: Asthma, Medical terms, Patient, Chronic obstructive pulmonary disease, Patience, Obstructive lung disease, Bronchodilator, Respiratory diseases


β2-adrenoceptor agonists are the mainstay therapy for patients with asthma but their effectiveness in cigarette smoke (CS)-induced lung disease such as chronic obstructive pulmonary disease (COPD) is limited. In addition, bronchodilator efficacy of β2-adrenoceptor agonists is decreased during acute exacerbations of COPD (AECOPD), caused by respiratory viruses including influenza A. Therefore, the aim of the present study was to assess the effects of the β2-adrenoceptor agonist salbutamol (SALB) on small airway reactivity using mouse precision cut lung slices (PCLS) prepared from CS-exposed mice and from CS-exposed mice treated with influenza A virus (Mem71, H3N1). CS exposure alone reduced SALB potency and efficacy associated with decreased β2-adrenoceptor mRNA expression, and increased tumour necrosis factor α (TNFα) and interleukin-1β (IL-1β) expression. This impaired relaxation was restored by day 12 in the absence of further CS exposure. In PCLS prepared after Mem71 infection alone, responses to SALB were transient and were not well maintained. CS exposure prior to Mem71 infection almost completely abolished relaxation, although β2-adrenoceptor and TNFα and IL-1β expression were unaltered. The present study has shown decreased sensitivity to SALB after CS or a combination of CS and Mem71 occurs by different mechanisms. In addition, the PCLS technique and our models of CS and influenza infection provide a novel setting for assessment of alternative bronchodilators.

Concepts: Pulmonology, Asthma, Virus, Pneumonia, Tobacco smoking, Chronic obstructive pulmonary disease, Obstructive lung disease, Bronchodilator