Practical guide to cardiopulmonary exercise testing in adults.

Unexplained exertional dyspnoea or fatigue can arise from a number of underlying disorders and shows only a weak correlation with resting functional or imaging tests. Noninvasive cardiopulmonary exercise testing (CPET) offers a unique, but still under-utilised and unrecognised, opportunity to study cardiopulmonary and metabolic changes simultaneously. CPET can distinguish between a normal and an abnormal exercise response and usually identifies which of multiple pathophysiological conditions alone or in combination is the leading cause of exercise intolerance. Therefore, it improves diagnostic accuracy and patient health care by directing more targeted diagnostics and facilitating treatment decisions. Consequently, CPET should be one of the early tests used to assess exercise intolerance. However, this test requires specific knowledge and there is still a major information gap for those physicians primarily interested in learning how to systematically analyse and interpret CPET findings. This article describes the underlying principles of exercise physiology and provides a practical guide to performing CPET and interpreting the results in adults.

Noninvasive Measurement of Pulmonary Function in Experimental Mouse Models of Airway Disease.

Mouse models have become an indispensable tool in translational research of human airway disease and have provided much of our understanding of the pathogenesis of airway disease such as asthma. In these models the ability to assess pulmonary function and particularly airway responsiveness is critically important. Existing methods for testing pulmonary function in mice in vivo include noninvasive and invasive technologies. Noninvasive head-out body plethysmography is a well-established and widely accepted technique which has been proven as a reliable method to measure lung function on repeated occasions in intact, conscious mice. We have performed several validation studies in allergic mice to compare the parameter midexpiratory flow (EF50) as a noninvasive marker of airflow limitation with invasively measured gold standard parameters of lung mechanics. The results of these studies showed a good agreement of EF50 with the invasive assessment of lung resistance and dynamic compliance with a somewhat lower sensitivity of EF50. The measurement of EF50 together with basic respiratory parameters is particularly appropriate for simple and repeatable screening of pulmonary function in large numbers of mice or if noninvasive measurement without use of anesthesia is required. Beyond known applications, head-out body plethysmography also provides a much-needed high-throughput screening tool to gain insights into the impact and kinetics of respiratory infections such as SARS-COV-2 on lung physiology in laboratory mice.

Tiotropium versus salmeterol for the prevention of exacerbations of COPD.

BACKGROUND: Treatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-to-very-severe chronic obstructive pulmonary disease (COPD) but do not specify whether a long-acting anticholinergic drug or a ß(2)-agonist is the preferred agent. We investigated whether the anticholinergic drug tiotropium is superior to the ß(2)-agonist salmeterol in preventing exacerbations of COPD. METHODS: In a 1-year, randomized, double-blind, double-dummy, parallel-group trial, we compared the effect of treatment with 18 µg of tiotropium once daily with that of 50 µg of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year. RESULTS: A total of 7376 patients were randomly assigned to and treated with tiotropium (3707 patients) or salmeterol (3669 patients). Tiotropium, as compared with salmeterol, increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P<0.001). Tiotropium also increased the time to the first severe exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001), reduced the annual number of moderate or severe exacerbations (0.64 vs. 0.72; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P=0.002), and reduced the annual number of severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P<0.001). Overall, the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups. There were 64 deaths (1.7%) in the tiotropium group and 78 (2.1%) in the salmeterol group. CONCLUSIONS: These results show that, in patients with moderate-to-very-severe COPD, tiotropium is more effective than salmeterol in preventing exacerbations. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov number, NCT00563381.).

Characterisation of exacerbation risk and exacerbator phenotypes in the POET-COPD trial.

BACKGROUND: Data examining the characteristics of patients with frequent exacerbations of chronic obstructive pulmonary disease (COPD) and associated hospitalisations and mortality are scarce. METHODS: Post-hoc analysis of the Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, targeting exacerbations as the primary endpoint. Patients were classified as non-, infrequent, and frequent exacerbators (0, 1, or ≥ 2 exacerbations during study treatment), irrespective of study treatment. A multivariate Cox regression model assessed the effect of covariates on time to first exacerbation. RESULTS: In total, 7376 patients were included in the analysis: 63.5% non-exacerbators, 22.9% infrequent, 13.6% frequent exacerbators. Factors significantly associated with exacerbation risk were age, sex, body mass index, COPD duration and severity, smoking history, baseline inhaled corticosteroid use, and preceding antibiotic or systemic corticosteroid courses. Frequent exacerbators had greater severity and duration of COPD, received more pulmonary medication, and ≥ 2 systemic corticosteroid or antibiotic courses in the preceding year, and were more likely to be female and ex-smokers. The small proportion of frequent exacerbators (13.6%) accounted for 56.6% of exacerbation-related hospitalisations, which, overall, were associated with a three-fold increase in mortality. CONCLUSION: The frequent exacerbator phenotype was closely associated with exacerbation-related hospitalisations, and exacerbation-related hospitalisations were associated with poorer survival. TRIAL REGISTRATION: NCT00563381; Study identifier: BI 205.389.

Detection of air trapping in chronic obstructive pulmonary disease by low frequency ultrasound.

BACKGROUND: Spirometry is regarded as the gold standard for the diagnosis of COPD, yet the condition is widely underdiagnosed. Therefore, additional screening methods that are easy to perform and to interpret are needed. Recently, we demonstrated that low frequency ultrasound (LFU) may be helpful for monitoring lung diseases. The objective of this study was to evaluate whether LFU can be used to detect air trapping in COPD. In addition, we evaluated the ability of LFU to detect the effects of short-acting bronchodilator medication. METHODS: Seventeen patients with COPD and 9 healthy subjects were examined by body plethysmography and LFU. Ultrasound frequencies ranging from 1 to 40 kHz were transmitted to the sternum and received at the back during inspiration and expiration. The high pass frequency was determined from the inspiratory and the expiratory signals and their difference termed ΔF. Measurements were repeated after inhalation of salbutamol. RESULTS: We found significant differences in ΔF between COPD subjects and healthy subjects. These differences were already significant at GOLD stage 1 and increased with the severity of COPD. Sensitivity for detection of GOLD stage 1 was 83% and for GOLD stages worse than 1 it was 91%. Bronchodilator effects could not be detected reliably. CONCLUSIONS: We conclude that low frequency ultrasound is cost-effective, easy to perform and suitable for detecting air trapping. It might be useful in screening for COPD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01080924.

Effects of inhaled corticosteroids in stable chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) has been described as a heterogeneous multifactorial disorder associated with an abnormal inflammatory response of the peripheral airways and with variable morphologic, physiologic and clinical phenotypes. This notion of the disease is actually poorly supported by data, and there are substantial discrepancies and a weak correlation between inflammation, structural damage, functional impairment and degree of clinical symptoms. This problem is compounded by a poor understanding of the complexity and intricacies on the inflammatory pathways in COPD. Despite the evidence for efficacy of inhaled corticosteroids (ICS) on selected clinical endpoints in COPD, we cannot assume that anti-inflammatory treatment with ICS alone or in combination with long-acting bronchodilators will necessarily improve the underlying inflammatory processes and patient relevant outcomes in COPD. Given the widespread use of inhaled corticosteroids (ICS) alone or in combination for the treatment of COPD across all severities, it is important to weigh their clinically proven benefits and shortcomings cautiously and critically. Reviewed is the current evidence-based role of ICS on inflammatory markers and patient relevant outcomes in COPD.

A practical guide to bioelectrical impedance analysis using the example of chronic obstructive pulmonary disease.

Bioelectrical impedance analysis (BIA) is a simple, inexpensive, quick and non-invasive technique for measuring body composition. The clinical benefit of BIA can be further enhanced by combining it with bioelectrical impedance vector analysis (BIVA). However, there is a substantial lack of information on the practical aspects of BIA/BIVA for those primarily interested in learning how to use and interpret this method in practice. The purpose of this article is to provide some guidance on the use of BIA/BIVA with special attention to practical considerations.This report reflects the authors' practical experience with the use of single-frequency BIA in combination with BIVA, particularly in COPD patients. First, the method and principles of BIA/BIVA are briefly described. Then, a practice-oriented approach to the interpretation and analysis of characteristic examples of altered nutritional and fluid status as seen with BIA/BIVA in COPD patients (e.g. malnutrition in obese and underweight patients with COPD, water retention) is presented.As our examples show BIA/BIVA is an attractive and easy-to-learn tool for quick nutritional assessment and is therefore of great clinical benefit in daily practice.

[Specialist examination: Is the current format still up-to-date?] / Die mündliche Facharztprüfung: Ist das aktuelle Format noch zeitgemäß?

The non-standardized oral specialist examination is the final step of the specialist medical training in Germany. The debate on its current format has long been at the centre of discussions on further training policies. The purpose of this article is to draw attention to relevant structural deficits of the German specialist examination - also in comparison to German-speaking neighboring countries and pan-European developments - and to provide possible approaches to a more structured oral examination.

Outcome measures in chronic obstructive pulmonary disease (COPD): strengths and limitations.

Current methods for assessing clinical outcomes in COPD mainly rely on physiological tests combined with the use of questionnaires. The present review considers commonly used outcome measures such as lung function, health status, exercise capacity and physical activity, dyspnoea, exacerbations, the multi-dimensional BODE score, and mortality. Based on current published data, we provide a concise overview of the principles, strengths and weaknesses, and discuss open questions related to each methodology. Reviewed is the current set of markers for measuring clinically relevant outcomes with particular emphasis on their limitations and opportunities that should be recognized when assessing and interpreting their use in clinical trials of COPD.

Is there a role for antiinflammatory treatment in COPD?

By definition, chronic obstructive pulmonary disease (COPD) is associated with an abnormal inflammatory response of affected lungs. Therefore, the search for an effective anti-inflammatory therapy for this debilitating disease is intense. However, to date, there is no such anti-inflammatory treatment for COPD. While there are some modest effects of inhaled corticosteroids on selected clinical endpoints in COPD, it remains to be proven that the observed effects are due to changes in the underlying inflammation, in particular since relevant clinical endpoints of COPD can be significantly improved by treatments not targeting inflammation. Therefore, it appears justified to reconsider the present knowledge about any linkage of local and systemic inflammation and clinical features of COPD, including lung function, exacerbations, disease progression, and mortality. Any such link needs to be carefully established before future anti-inflammatory therapies for COPD are developed and investigated in clinical trials, in particular since proof-of-concept trials aiming merely at inflammatory markers in COPD may not be predictive of clinical success or failure. The present review summarizes current knowledge about the role of inflammation in COPD, and critically analyzes results from clinical trials with inhaled corticosteroids and phosphodiesterase-4 inhibitors in COPD, the two classes of putative antiinflammatory agents with the richest body of evidence from controlled studies.

Invasive and noninvasive methods for studying pulmonary function in mice.

The widespread use of genetically altered mouse models of experimental asthma has stimulated the development of lung function techniques in vivo to characterize the functional results of genetic manipulations. Here, we describe various classical and recent methods of measuring airway responsiveness in vivo including both invasive methodologies in anesthetized, intubated mice (repetitive/non-repetitive assessment of pulmonary resistance (RL) and dynamic compliance (Cdyn); measurement of low-frequency forced oscillations (LFOT)) and noninvasive technologies in conscious animals (head-out body plethysmography; barometric whole-body plethysmography). Outlined are the technical principles, validation and applications as well as the strengths and weaknesses of each methodology. Reviewed is the current set of invasive and noninvasive methods of measuring murine pulmonary function, with particular emphasis on practical considerations that should be considered when applying them for phenotyping in the laboratory mouse.

[Pathomechanisms in chronic obstructive pulmonary disease (COPD)]. / Pathomechanismen der chronisch-obstruktiven Lungenerkrankung (COPD).

Chronic obstructive pulmonary disease (COPD) is one of the most common chronic diseases worldwide, and its morbidity and mortality are still increasing. Thus, it is expected that, globally, COPD will be the third most common cause of death by 2020. Moreover, COPD leads to enormous health-economic costs (i. e., outpatient and inpatient treatment, inability to work). Nevertheless, the prevalence of COPD is underestimated also in Germany. This is partly because often, the disease is symptomatic only in its advanced stages and as a result it is not diagnosed until late. In addition, the therapeutic effects on the long-term course and the progression of the disease are limited. Therefore, a much deeper understanding of the manifold and complex pathomechanisms of this pathomorphologically varied disease is needed before new therapeutic strategies can be developed. The aim of this review is to discuss current concepts of the pathophysiology of COPD and their scientific bases. The authors will concentrate mainly on a differentiated description of the pathomechanisms which cause chronic obstructive bronchiolitis and obstructive pulmonary emphysema.

Asthma control in patients treated with inhaled corticosteroids and long-acting beta agonists: A population-based analysis in Germany.

BACKGROUND: The prevalence and the characteristics of poor asthma control among adults treated with combinations of inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA) are not completely understood. METHODS: Data from adult patients in Germany with self-reported asthma treated with an ICS-LABA combination in the National Health and Wellness Survey (NHWS) were analysed. Patients with well-controlled and not well-controlled asthma according to the Asthma Control Test (ACT) score were compared, with respect to socio-demographic characteristics, attitudes, adherence and outcomes. RESULTS: Among the German patients with self-reported asthma (5.2% of the respondents), 16.2% (382 patients) were treated with an ICS-LABA combination and did not report concomitant chronic obstructive pulmonary disease, chronic bronchitis or emphysema. In this subgroup, 55.8% had not well-controlled asthma (ACT < 20). ICS-LABA treated patients with not well-controlled asthma were more likely to report emergency visits (16.4% vs. 8.9%), missed more time from work (absenteeism: 12.9% vs. 4.3%), were more impaired while at work (presenteeism: 29.0% vs. 14.9%) and were more likely to be women (69.0% vs. 57.4%), compared with well-controlled patients. There were no significant differences in age, body mass index, smoking, income, education or self-reported adherence between the two groups, but different attitudes regarding the patient-physician relationship. CONCLUSIONS: A substantial proportion of patients treated with ICS and LABA had not well-controlled asthma. These patients did not differ from well-controlled patients in terms of education or self-reported adherence, but in terms of their attitudes regarding the patient-physician relationship.

Impact of tiotropium + olodaterol on physical functioning in COPD: results of an open-label observational study.

BACKGROUND: Maintaining and improving physical functioning is key to mitigating the cycle of deconditioning associated with chronic obstructive pulmonary disease (COPD). We evaluated the impact of free combination of the long-acting anticholinergic tiotropium plus the long-acting ß2-agonist olodaterol on physical functioning in a real-world clinical setting. METHODS: In this open-label noninterventional study, Global initiative for chronic Obstructive Lung Disease (GOLD) B-D patients with COPD aged ≥40 years were treated for 4-6 weeks with either tiotropium 5 µg + olodaterol 5 µg (both via Respimat(®) inhaler) or tiotropium 18 µg (HandiHaler(®)) + olodaterol 5 µg (Respimat(®)) once daily. Physical functioning was assessed by the self-reported 10-item Physical Functioning Questionnaire (PF-10). The primary end point was the percentage of patients achieving therapeutic success, defined as a 10-point increase in the PF-10 between baseline (visit 1) and weeks 4-6 (visit 2). Secondary end points included absolute PF-10 scores, Physicians' Global Evaluation, satisfaction with Respimat(®) and adverse events. RESULTS: A total of 1,858 patients were treated: 1,298 (69.9%) with tiotropium 5 µg + olodaterol 5 µg and 560 (30.1%) with tiotropium 18 µg + olodaterol 5 µg. At study end, 1,683 (92.6%) and 1,556 patients (85.6%) continued using tiotropium and olodaterol, respectively; 48.9% (95% confidence interval: 46.5, 51.3) achieved the primary end point. Therapeutic success rates were significantly higher for maintenance-naïve patients compared to those who had received prior therapy (59.1% vs 44.5%; P<0.0001), largely driven by maintenance-treatment-naïve GOLD B (59.8%) and C (63.0%) patients. Absolute physical functioning scores increased from an average baseline of 44.0 (standard deviation: 25.2) to 54.2 (standard deviation: 26.9) at visit 2. Patients' general condition improved from baseline to visit 2, and patients were largely satisfied with the Respimat(®) inhaler. Adverse events were reported by 7.5% of patients; the most common were respiratory in nature. CONCLUSION: Tiotropium + olodaterol improved physical functioning within 4-6 weeks in patients with moderate-to-very severe COPD. GOLD B and C patients with no prior maintenance treatment demonstrated the greatest benefit.

Invasive versus noninvasive measurement of allergic and cholinergic airway responsiveness in mice.

BACKGROUND: This study seeks to compare the ability of repeatable invasive and noninvasive lung function methods to assess allergen-specific and cholinergic airway responsiveness (AR) in intact, spontaneously breathing BALB/c mice. METHODS: Using noninvasive head-out body plethysmography and the decrease in tidal midexpiratory flow (EF50), we determined early AR (EAR) to inhaled Aspergillus fumigatus antigens in conscious mice. These measurements were paralleled by invasive determination of pulmonary conductance (GL), dynamic compliance (Cdyn) and EF50 in another group of anesthetized, orotracheally intubated mice. RESULTS: With both methods, allergic mice, sensitized and boosted with A. fumigatus, elicited allergen-specific EAR to A. fumigatus (p < 0.05 versus controls). Dose-response studies to aerosolized methacholine (MCh) were performed in the same animals 48 h later, showing that allergic mice relative to controls were distinctly more responsive (p < 0.05) and revealed acute airway inflammation as evidenced from increased eosinophils and lymphocytes in bronchoalveolar lavage. CONCLUSION: We conclude that invasive and noninvasive pulmonary function tests are capable of detecting both allergen-specific and cholinergic AR in intact, allergic mice. The invasive determination of GL and Cdyn is superior in sensitivity, whereas the noninvasive EF50 method is particularly appropriate for quick and repeatable screening of respiratory function in large numbers of conscious mice.

Brain-derived neurotrophic factor (BDNF) contributes to neuronal dysfunction in a model of allergic airway inflammation.

Brain-derived neurotrophic factor (BDNF) is a candidate molecule for mediating functional neuronal changes in allergic bronchial asthma. Recently, enhanced production of BDNF during allergic airway inflammation caused by infiltrating T-cells and macrophages as well as by resident airway epithelial cells has been described. It was the aim of this study to investigate the effect of enhanced BDNF levels on lung function and airway inflammation in a mouse model of allergic inflammation. Ovalbumin-sensitised BALB/c mice were challenged in two consecutive allergen challenges. Prior to the challenge, the mice were treated with either anti-BDNF antibodies or isotype-matched control antibodies. Airway responsiveness to methacholine, capsaicin and electric field stimulation, as well as airway inflammation and chronic airway obstruction 1 week after the last allergen challenge were assessed. Anti-BDNF blocked enhanced reactivity in response to capsaicin, but not airway smooth muscle hyper-reactivity in vivo. Furthermore, persistent airway obstruction, as observed 1 week after the last allergen challenge, was to a large extent prevented by anti-BDNF treatment. In vitro, BDNF and anti-BDNF treatment had a profound effect on local neuronal hyper-reactivity, as shown by electric field stimulation experiments. In contrast, neither BDNF nor anti-BDNF treatment affected airway inflammation. Our data indicate that development of allergen-induced neuronal hyper-reactivity in mice is partially mediated by BDNF. British Journal of Pharmacology (2004) 141, 431-440. doi:10.1038/sj.bjp.0705638

Repetitive measurements of pulmonary mechanics to inhaled cholinergic challenge in spontaneously breathing mice.

Precise and repeatable measurements of pulmonary function in intact mice are becoming increasingly important for experimental investigations on various respiratory disorders including asthma. Here, we present validation of a novel in vivo method that, for the first time, combines direct and repetitive recordings of standard pulmonary mechanics with cholinergic aerosol challenges in anesthetized, orotracheally intubated, spontaneously breathing mice. We demonstrate that, in several groups of nonsensitized BALB/c mice, dose-related increases in pulmonary resistance and dynamic compliance to aerosolized methacholine are reproducible over short and extended intervals without causing detectable cytological alterations in the bronchoalveolar lavage or relevant histological changes in the proximal trachea and larynx regardless of the number of orotracheal intubations. Moreover, as further validation, we confirm that allergic mice, sensitized and challenged with Aspergillus fumigatus, were significantly more responsive to cholinergic challenge (P < 0.01) and exhibited marked eosinophilia and lymphocytosis in bronchoalveolar lavage fluids as well as significant pathological alterations in laryngotracheal histology compared with nonsensitized mice. We suggest that this approach will provide useful and necessary information on pulmonary mechanics in studies of various respiratory disorders in mice, including experimental models of asthma and chronic obstructive pulmonary disorder, investigations of pulmonary pharmacology, or more general investigations of the genetic determinants of lung function.

Noninvasive measurement of midexpiratory flow indicates bronchoconstriction in allergic rats.

This study was designed to evaluate the value and applicability of tidal breathing pattern analysis to assess bronchoconstriction in conscious rats. Using noninvasive, head-out body plethysmography and the decrease in tidal midexpiratory flow (EF(50)), we measured airway responsiveness (AR) to inhaled acetylcholine and allergen in conscious Brown-Norway rats, followed by invasive determination of pulmonary conductance (GL) and EF(50) in anesthetized rats. Dose-response studies to acetylcholine showed that noninvasively recorded EF(50) closely reflected the dose-dependent decreases observed with the invasive monitoring of simultaneously measured GL and EF(50). After sensitization and intratracheal boost to ovalbumin or saline, rats were assessed for early and late AR to aerosolized ovalbumin. Ovalbumin aerosol challenge resulted in early and late AR in allergen-sensitized rats, whereas controls were unresponsive. The allergen-specific AR, as measured noninvasively by EF(50), was similar in degree compared with invasively recorded EF(50) and GL and was associated with enhanced IgE and airway inflammation. We conclude that EF(50) is a noninvasive and physiologically valid index of bronchoconstriction in a rat model of asthma.

Effect of ADRB2 polymorphisms on the efficacy of salmeterol and tiotropium in preventing COPD exacerbations: a prespecified substudy of the POET-COPD trial.

BACKGROUND: The effect of ß2-adrenergic receptor (ADRB2) polymorphisms on the treatment response to longacting bronchodilators in chronic obstructive pulmonary disease (COPD) is unclear. We aimed to establish whether ADRB2 polymorphisms differentially affected COPD exacerbation outcomes in response to tiotropium versus salmeterol. METHODS: We did a prespecified analysis of the ADRB2 polymorphisms Arg16Gly and Gln27Glu within the 1 year randomised, double-blind, double-dummy, parallel-group Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, comparing the effects of treatment with tiotropium or salmeterol on exacerbations in 7376 patients with COPD. One blood sample was collected for pharmacogenetic testing from each patient who elected to participate in the substudy. Random assignment of patients to treatment groups was not stratified according to genotypes. Genomic DNA was extracted from whole-blood specimens and samples were genotyped for the two SNPs, rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu). All assays were done in technical duplicates and 10% of samples that were randomly chosen were repeated as technical duplicates in a second independent genotyping process. Our primary endpoint was the risk of a first exacerbation of COPD based on time to first exacerbation data. An exacerbation of COPD was defined as the increase or new onset of more than one symptom of COPD (cough, sputum, wheezing, dyspnoea, or chest tightness), with at least one of the symptoms lasting for 3 days or more and needing treatment with antibiotics or systemic glucocorticoids (moderate exacerbations), or admission to hospital (severe exacerbations). POET-COPD is registered with ClinicalTrials.gov, number NCT00563381. FINDINGS: 5125 patients gave informed consent for genotyping. The distributions of ADRB2 genotypes were well matched among groups. Polymorphisms at aminoacid 27 did not affect exacerbation outcomes. In the salmeterol group, patients with Arg16Arg genotype had a significantly reduced exacerbation risk compared with patients with Arg16Gly (p=0·0130) and Gly16Gly (p=0·0018) genotypes (proportion of patients with at least one exacerbation was 32·3% in Arg16Arg, 39·8% in Arg16Gly, and 42·1% in Gly16Gly). By contrast, exacerbation risk was not modified by polymorphisms at aminoacid 16 in the tiotropium group. The effect of the Arg16Gly polymorphism on treatment response to salmeterol was dependent on the use of inhaled corticosteroids (ICS). In patients untreated with ICS at baseline, Arg16Gly and Arg16Arg genotypes were associated with significantly prolonged time to first exacerbation compared with Gly16Gly (vs Arg16Gly p=0·0164; Arg16Arg p=0·0316; proportion of patients with at least one exacerbation was 28·3% in Arg16Arg, 31·6% in Arg16Gly, and 39·2% in Gly16Gly), whereas in patients on ICS at baseline, only the Arg16Arg genotype was associated with significantly prolonged time to first exacerbation compared with Gly16Gly (p=0·0198; not Arg16Gly p=0·64; proportion of patients with at least one exacerbation was 35·9% in Arg16Arg, 46·7% in Arg16Gly, and 44·8% in Gly16Gly). The respiratory disorders, in particular worsening of COPD, were the most common serious adverse events. INTERPRETATION: Patients with the Arg16Arg genotype had better exacerbation outcomes in response to salmeterol than Gly16Gly and Arg16Gly genotypes, suggesting a potential differential Arg16Gly genotype effect on treatment response to longacting ß-agonists (LABAs). However, the use of ADRB2 polymorphisms for predicting LABA treatment response is still limited and further prospective validation will be needed to advance the mechanistic understanding of ß-adrenergic polymorphisms and their association with clinical features of COPD. FUNDING: Boehringer Ingelheim and Pfizer.

Effect of tiotropium vs. salmeterol on exacerbations: GOLD II and maintenance therapy naïve patients.

The objective of this study was to investigate the effect of tiotropium compared with salmeterol on exacerbations in patients with moderate (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage II) chronic obstructive pulmonary disease (COPD) and those naïve to maintenance respiratory therapy in the 1-year Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD(®)) trial (NCT00563381). Time to first exacerbation (primary endpoint) and rates of exacerbations were analyzed using exploratory Cox and Poisson regression (adjusting for time on treatment). Of 7376 randomized patients, 3614 were GOLD stage II (tiotropium n = 1781; salmeterol n = 1833) and 1343 were maintenance therapy naïve (tiotropium n = 672; salmeterol n = 671). Tiotropium significantly increased time to first exacerbation vs. salmeterol in GOLD stage II patients (hazard ratio [HR], 0.88; 95% confidence interval [CI]: 0.79-0.99; p = 0.028) and maintenance therapy naïve patients (HR, 0.79; 95% CI, 0.65-0.97; p = 0.028). Annual exacerbation rates were also significantly lower with tiotropium in the maintenance naïve subgroup compared with salmeterol (rate ratio [RR], 0.77; 95% CI, 0.63-0.94; p = 0.012). In the GOLD stage II subgroup, the rate of hospitalized exacerbations per year was significantly lower with tiotropium than with salmeterol (RR, 0.70; 95% CI, 0.57-0.85; p < 0.001); tiotropium also significantly prolonged time to first hospitalized exacerbation versus salmeterol in this subgroup (HR, 0.66; 95% CI, 0.48-0.91; p = 0.012). In conclusion, results from this prespecified subgroup analysis support the selection of tiotropium as first-choice maintenance therapy for patients with GOLD stage II COPD.