Aprepitant for Cough in Lung Cancer. A Randomized Placebo-controlled Trial and Mechanistic Insights.

Rationale: Effective cough treatments are a significant unmet need in patients with lung cancer. Aprepitant is a licensed treatment for nausea and vomiting, which blocks substance P activation of NK-1 (neurokinin 1) receptors, a mechanism also implicated in cough.Objectives: To assess aprepitant in patients with lung cancer with cough and evaluate mechanisms in vagal nerve tissue.Methods: Randomized double-blind crossover trial of patients with lung cancer and bothersome cough. They received 3 days of aprepitant or matched placebo; after a 3-day washout, patients crossed to the alternative treatment. The primary endpoint was awake cough frequency measured at screening and Day 3 of each treatment; secondary endpoints included patient-reported outcomes. In vitro, the depolarization of isolated guinea pig and human vagus nerve sections in grease-gap recording chambers, indicative of sensory nerve activation, was measured to evaluate the mechanism.Measurements and Main Results: Twenty patients with lung cancer enrolled, with a mean age 66 years (±7.7); 60% were female and 80% had non-small cell cancer, 50% had advanced stage, and 55% had World Health Organization performance status 1. Cough frequency improved with aprepitant, reducing by 22.2% (95% confidence interval [CI], 2.8-37.7%) over placebo while awake (P = 0.03), 30.3% (95% CI, 12.7-44.3) over 24 hours (P = 0.002), and 59.8% (95% CI, 15.1-86.0) during sleep (P = 0.081). Patient-reported outcomes all significantly improved. Substance P depolarized both guinea pig and human vagus nerve. Aprepitant significantly inhibited substance P-induced depolarization by 78% in guinea pig (P = 0.0145) and 94% in human vagus (P = 0.0145).Conclusions: Substance P activation of NK-1 receptors appears to be an important mechanism driving cough in lung cancer, and NK-1 antagonists show promise as antitussive therapies.

Effect of centrally and peripherally acting GABAB agonism on the healthy human cough reflex.

BACKGROUND: Currently there are no effective licensed anti-tussive therapies. Understanding how the neuronal mechanisms mediating the cough reflex in animal models translate to humans is important for the development of effective therapies. Pre-clinical studies suggest that the activation of GABAB receptors in both the peripheral and central nervous systems inhibit cough. OBJECTIVE: To compare the effect of central and peripherally acting GABAB agonists (lesogaberan and baclofen) on the cough reflex in healthy volunteers. METHODS: We performed a single center, double-blind, double-dummy, three-way crossover trial in healthy controls comparing single doses of lesogaberan (120 mg MR), with baclofen (40 mg) and placebos. Cough responses to inhaled capsaicin were assessed at screening and 2h post-dose on each study day. The primary endpoint was the maximum number of coughs evoked at any concentration of capsaicin (Emax) and the secondary endpoint was the concentration evoking 50% of the maximal response (ED50). RESULTS: Fifteen participants enrolled onto the study (median age 29 (IQR 25-44) years; 7 females, mean BMI 24.6(±3.0). Lesogaberan treatment produced a small, statistically significant increase in Emax compared with placebo [mean 13.4coughs (95%CI 10.1-17.9) vs. 11.8coughs (8.8-15.9), p = 0.04], but had no effect on ED50 [geometric mean 47.4 µM (95%CI 24.4-91.7) vs 37.6 µM (95%CI 19.2-73.5), p = 0.37]. In contrast, baclofen had no significant effect on Emax (11.1, 95%CI 8.1-15.4) (p = 0.23), but significantly increased ED50 compared with placebo (geometric mean 75.2 µM (95%CI 37.2-151.8), p = 0.002). CONCLUSION: This data suggests the anti-tussive actions of GABAB agonists, in healthy volunteers, occur in the central rather than the peripheral nervous system.

Allergen challenge increases capsaicin-evoked cough responses in patients with allergic asthma.

BACKGROUND: Cough is a common and troublesome symptom in asthmatic patients, but little is known about the neuronal pathways that trigger cough. The mechanisms by which airway inflammation, airway hyperresponsiveness, and variable airflow obstruction cause cough are unclear. OBJECTIVE: We sought to investigate the effects of allergen exposure on cough reflex sensitivity. METHODS: We performed a 9-visit, randomized, single-blind, placebo-controlled, 2-way crossover study comparing cough responses to inhaled capsaicin in patients with mild atopic asthma after allergen challenge compared with diluent control. Full-dose capsaicin challenge was performed at screening to determine the capsaicin dose inducing a half-maximal response, which was subsequently administered at 30 minutes and 24 hours after inhaled allergen/diluent challenge. Spontaneous coughing was measured for 24 hours after allergen/diluent. Methacholine challenge and sputum induction were performed before and after allergen/diluent challenge. RESULTS: Twelve steroid-naive subjects completed the study (6 female subjects; mean age, 34.8 years). Allergen inhalation caused both an early (mean ± SD, 38.2% ± 13.0%) and late (mean ± SD, 23.7% ± 13.2%) decrease in FEV1 and an increase in sputum eosinophil counts 24 hours later (after diluent: median, 1.9% [interquartile range, 0.8% to 5.8%]; after allergen: median, 14.9% [interquartile range, 8.9% to 37.3%]; P = .005). There was also an increase in capsaicin-evoked coughs after allergen exposure compared with diluent at both 30 minutes (geometric mean coughs, 21.9 [95% CI, 16.5-29.20] vs 12.1 [95% CI, 8.3-17.7]; P < .001) and 24 hours (geometric mean coughs, 16.1 [95% CI, 11.3-23.0] vs 9.8 [95% CI, 6.1-15.8]; P = .001). Allergen exposure was also associated with an increase in spontaneous coughs over 24 hours. CONCLUSION: Allergen-induced bronchoconstriction and airway eosinophilia result in increased cough reflex sensitivity to capsaicin associated with an increase in 24-hour spontaneous coughing.

Neurophenotypes in Airway Diseases. Insights from Translational Cough Studies.

RATIONALE: Most airway diseases, including chronic obstructive pulmonary disease (COPD), are associated with excessive coughing. The extent to which this may be a consequence of increased activation of vagal afferents by pathology in the airways (e.g., inflammatory mediators, excessive mucus) or an altered neuronal phenotype is unknown. Understanding whether respiratory diseases are associated with dysfunction of airway sensory nerves has the potential to identify novel therapeutic targets. OBJECTIVES: To assess the changes in cough responses to a range of inhaled irritants in COPD and model these in animals to investigate the underlying mechanisms. METHODS: Cough responses to inhaled stimuli in patients with COPD, healthy smokers, refractory chronic cough, asthma, and healthy volunteers were assessed and compared with vagus/airway nerve and cough responses in a cigarette smoke (CS) exposure guinea pig model. MEASUREMENTS AND MAIN RESULTS: Patients with COPD had heightened cough responses to capsaicin but reduced responses to prostaglandin E2 compared with healthy volunteers. Furthermore, the different patient groups all exhibited different patterns of modulation of cough responses. Consistent with these findings, capsaicin caused a greater number of coughs in CS-exposed guinea pigs than in control animals; similar increased responses were observed in ex vivo vagus nerve and neuron cell bodies in the vagal ganglia. However, responses to prostaglandin E2 were decreased by CS exposure. CONCLUSIONS: CS exposure is capable of inducing responses consistent with phenotypic switching in airway sensory nerves comparable with the cough responses observed in patients with COPD. Moreover, the differing profiles of cough responses support the concept of disease-specific neurophenotypes in airway disease. Clinical trial registered with www.clinicaltrials.gov (NCT 01297790).

P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study.

BACKGROUND: Preclinical studies suggest that P2X3 receptors are expressed by airway vagal afferent nerves and contribute to the hypersensitisation of sensory neurons. P2X3 receptors could mediate sensitisation of the cough reflex, leading to chronic cough. We aimed to investigate the efficacy of a first-in-class oral P2X3 antagonist, AF-219, to reduce cough frequency in patients with refractory chronic cough. METHODS: We did a double-blind, placebo-controlled, two-period, crossover study at one UK centre. With a computer-generated sequence, we randomly assigned patients with refractory chronic cough to AF-219, 600 mg twice a day, or to placebo (1:1), and then, after a 2 week washout, assigned patients to receive the other treatment. Patients, health-care providers, and investigators were masked to sequence assignment. We assessed daytime cough frequency (primary endpoint) at baseline and after 2 weeks of treatment using 24 h ambulatory cough recordings. The primary analysis used a mixed effects model with the intention-to-treat population. This study was registered at ClinicalTrials.gov, number NCT01432730. FINDINGS: Of 34 individuals assessed between Sept 22, 2011, and Nov 29, 2012, we randomly assigned 24 patients (mean age 54·5 years; SD 11·1). In the observed case analysis, cough frequency was reduced by 75% when patients were allocated to AF-219 compared when allocated to placebo (p=0·0003). Daytime cough frequency fell from a mean 37 coughs per h (SD 32) to 11 (8) coughs per h after AF-219 treatment versus 65 (163) coughs per h to 44 (51) coughs per h after placebo. Six patients withdrew before the end of the study because of taste disturbances, which were reported by all patients taking AF-219. INTERPRETATION: P2X3 receptors seem to have a key role in mediation of cough neuronal hypersensitivity. Antagonists of P2X3 receptors such as AF-219 are a promising new group of antitussives. FUNDING: Afferent Pharmaceuticals.

Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: a double-blind randomized controlled trial.

BACKGROUND: Inhalation of capsaicin, the extract of hot chili peppers, induces coughing in both animals and human subjects through activation of transient receptor potential vanilloid 1 (TRPV1) on airway sensory nerves. Therefore the TRPV1 receptor is an attractive target for the development of antitussive agents. OBJECTIVE: We sought to assess the antitussive effect of TRPV1 antagonism in patients with refractory chronic cough. METHODS: Twenty-one subjects with refractory chronic cough (>8 weeks) attending a specialist clinic were recruited to a randomized, double-blind, placebo-controlled crossover trial assessing a TRPV1 antagonist (SB-705498). Cough reflex sensitivity to capsaicin (concentration of capsaicin inducing at least 5 coughs) and 24-hour cough frequency were coprimary end points assessed after a single dose of SB-705498 (600 mg) and matched placebo. Cough severity and urge to cough were reported on visual analog scales, and cough-specific quality of life data were also collected. RESULTS: Treatment with SB-705498 produced a significant improvement in cough reflex sensitivity to capsaicin at 2 hours and a borderline significant improvement at 24 hours compared with placebo (adjusted mean difference of +1.3 doubling doses at 2 hours [95% CI, +0.3 to +2.2; P = .0049] and +0.7 doubling doses at 24 hours [95% CI, +0.0 to +1.5; P = .0259]). However, 24-hour objective cough frequency was not improved compared with placebo. Patient-reported cough severity, urge to cough, and cough-specific quality of life similarly suggested no effect of SB-705498. CONCLUSION: This study raises important questions about both the role of TRVP1-mediated mechanisms in patients with refractory chronic cough and also the predictive value of capsaicin challenge testing in the assessment of novel antitussive agents.

Predictors of objective cough frequency in chronic obstructive pulmonary disease.

RATIONALE: Cough is one of the principal symptoms of chronic obstructive pulmonary disease (COPD) but the potential drivers of cough are likely to be multifactorial and poorly understood. OBJECTIVES: To quantify cough frequency in an unselected group of subjects with COPD and investigate the relationships between cough, reported sputum production, smoking, pulmonary function, and cellular airway inflammation. METHODS: We studied 68 subjects with COPD (mean age, 65.6 ± 6.7 yr; 67.6% male; 23 smokers; 45 ex-smokers) and 24 healthy volunteers (mean age, 57.5 ± 8.9 yr; 37.5% male; 12 smokers; 12 nonsmokers). Subjects reported cough severity, cough-specific quality of life, and sputum expectoration and performed spirometry, sputum induction, cough reflex sensitivity to capsaicin, and 24-hour ambulatory cough monitoring. MEASUREMENTS AND MAIN RESULTS: COPD current smokers had the highest cough rates (median, 9 coughs/h [interquartile range, 4.3-15.6 coughs/h]), almost double that of COPD ex-smokers (4.9 [2.3-8.7] coughs/h; P = 0.018) and healthy smokers (5.3 [1.2-8.3] coughs/h; P = 0.03), whereas healthy volunteers coughed the least (0.7 [0.2-1.4] coughs/h). Cough frequency was not influenced by age or sex and only weakly correlated with cough reflex sensitivity to capsaicin (log C5 r = -0.36; P = 0.004). Reported sputum production, smoking history, and current cigarette consumption strongly predicted cough frequency, explaining 45.1% variance in a general linear model (P < 0.001). In subjects producing a sputum sample, cough frequency was related to current cigarette consumption and percentage of sputum neutrophils (P = 0.002). CONCLUSIONS: Ambulatory objective monitoring provides novel insights into the determinants of cough in COPD, suggesting sputum production, smoking, and airway inflammation may be more important than sensitivity of the cough reflex.

Exhaled volatile organic compounds for phenotyping chronic obstructive pulmonary disease: a cross-sectional study.

BACKGROUND: Non-invasive phenotyping of chronic respiratory diseases would be highly beneficial in the personalised medicine of the future. Volatile organic compounds can be measured in the exhaled breath and may be produced or altered by disease processes. We investigated whether distinct patterns of these compounds were present in chronic obstructive pulmonary disease (COPD) and clinically relevant disease phenotypes. METHODS: Breath samples from 39 COPD subjects and 32 healthy controls were collected and analysed using gas chromatography time-of-flight mass spectrometry. Subjects with COPD also underwent sputum induction. Discriminatory compounds were identified by univariate logistic regression followed by multivariate analysis: 1. principal component analysis; 2. multivariate logistic regression; 3. receiver operating characteristic (ROC) analysis. RESULTS: Comparing COPD versus healthy controls, principal component analysis clustered the 20 best-discriminating compounds into four components explaining 71% of the variance. Multivariate logistic regression constructed an optimised model using two components with an accuracy of 69%. The model had 85% sensitivity, 50% specificity and ROC area under the curve of 0.74. Analysis of COPD subgroups showed the method could classify COPD subjects with far greater accuracy. Models were constructed which classified subjects with ≥2% sputum eosinophilia with ROC area under the curve of 0.94 and those having frequent exacerbations 0.95. Potential biomarkers correlated to clinical variables were identified in each subgroup. CONCLUSION: The exhaled breath volatile organic compound profile discriminated between COPD and healthy controls and identified clinically relevant COPD subgroups. If these findings are validated in prospective cohorts, they may have diagnostic and management value in this disease.

A double-blind randomised placebo-controlled trial investigating the effects of lesogaberan on the objective cough frequency and capsaicin-evoked coughs in patients with refractory chronic cough.

Objective: Baclofen is a centrally acting γ-aminobutyric acid type B (GABAB) receptor agonist which reduces gastro-oesophageal reflux and suppresses the cough reflex; however, central nervous system side-effects limit its use. Lesogaberan is a novel peripherally acting GABAB agonist, but its effects on refractory chronic cough are unknown. Design: We performed a single-centre, placebo-controlled, double-blind randomised crossover study in patients with chronic cough, refractory to the treatment of underlying conditions. Patients were randomised to treatment with lesogaberan 120 mg modified release twice daily or matched placebo for 2 weeks and then crossed over to the alternative therapy after a 2-week washout. The primary end-point was 24-h cough frequency measured with an acoustic monitoring system. In addition, cough responses to capsaicin were measured, and gastro-oesophageal reflux assessed by 24-h pH/impedance at screening. Results: 22 patients were randomised to receive lesogaberan/placebo or placebo/lesogaberan (female (73%); mean±sd age 63.7±7.2 years; median (interquartile range) cough duration 10.5 (5.8-17.0) years; mean (95% CI) 45 (29-67) reflux events in 24 h; two patients had abnormal oesophageal acid exposure times). Although lesogaberan reduced cough counts by 26% over placebo, this did not reach statistical significance (p=0.12). However, lesogaberan did significantly improve cough responses to capsaicin (p=0.04) and the number of cough bouts (p=0.04) compared with placebo. Lesogaberan was well tolerated in this study. Conclusions: Lesogaberan improved cough hypersensitivity and the number of bouts of coughing, but not coughs per hour. This implies a possible role for peripheral GABAB receptors in refractory chronic cough.

Biomarkers of systemic inflammation and depression and fatigue in moderate clinically stable COPD.

INTRODUCTION: COPD is an inflammatory disease with major co-morbidities. It has recently been suggested that depression may be the result of systemic inflammation. We aimed to explore the association between systemic inflammation and symptoms of depression and fatigue in patients with mainly moderate and clinically stable COPD using a range of inflammatory biomarkers, 2 depression and 2 fatigue scales. METHOD: We assessed 120 patients with moderate COPD (FEV1% 52, men 62%, age 66). Depression was assessed using the BASDEC and CES-D scales. Fatigue was assessed using the Manchester COPD-fatigue scale (MCFS) and the Borg scale before and after 6MWT. We measured systemic TNF-α, CRP, TNF-α-R1, TNF-α-R2 and IL-6. RESULTS: A multivariate linear model of all biomarkers showed that TNF-α only had a positive correlation with BASDEC depression score (p = 0.007). TNF-α remained positively correlated with depression (p = 0.024) after further adjusting for TNF-α-R1, TNF-α-R2, 6MWD, FEV1%, and pack-years. Even after adding the MCFS score, body mass and body composition to the model TNF-α was still associated with the BASDEC score (p = 0.044). Furthermore, patients with higher TNF-α level (> 3 pg/ml, n = 7) had higher mean CES-D depression score than the rest of the sample (p = 0.03). Borg fatigue score at baseline were weakly correlated with TNF-α and CRP, and with TNF-α only after 6MWT. Patients with higher TNF-α had more fatigue after 6MWD (p = 0.054). CONCLUSION: This study indicates a possible association between TNF-α and two frequent and major co-morbidities in COPD; i.e., depression and fatigue.

Chronic cough is associated with increased reporting of autonomic symptoms.

BACKGROUND: Patients with some neuronal hypersensitivity syndromes experience increased autonomic symptoms. Chronic cough is thought to be a neuronal hypersensitivity disorder and, therefore, may be associated with increased autonomic symptoms. METHODS: 96 chronic cough subjects were recruited from the tertiary cough clinic based at Wythenshawe Hospital, Manchester, UK; 76 healthy controls were also recruited. Subjects were aged >18 years. Those with significant respiratory disease, significant smoking history or taking medication known to affect cough or autonomic function were excluded. Subjects completed the Composite Autonomic Symptom Score (COMPASS) 31 autonomic symptom questionnaire, the Cough Quality of Life Questionnaire (CQLQ) and a cough severity visual analogue scale (VAS). RESULTS: 96 chronic cough subjects and 76 healthy volunteers were included in the final analysis. Mann-Whitney U-tests comparing COMPASS 31 scores in both groups showed that the total COMPASS 31 score was significantly higher in the patient group (median 18.4, interquartile range (IQR) 7.5-32.0) than the control group (median 3.6, IQR 1.1-9.5; p<0.001). The chronic cough subjects had significantly higher symptom scores than the healthy volunteer groups in all domains (p≤0.001) except vasomotor symptoms (p=0.770). There was a positive association between COMPASS 31 and CQLQ in the patient group (p<0.001, r=0.432) but not COMPASS 31 and VAS (p=0.227). INTERPRETATION: Chronic cough patients do indeed report more frequent and severe autonomic symptoms than healthy volunteers, indicating that this population may suffer from dysautonomia. At present, it remains unclear whether this occurs as a result of the cough or whether both the cough and dysfunction are part of some wider vagal pathology.

An open-label study of the tolerability and potential efficacy of memantine for treating refractory chronic cough.

Blocking NMDA receptors with memantine in refractory chronic cough patients is poorly tolerated and demonstrates no improvement in cough https://bit.ly/3kgx2g1.

A Randomized Controlled Trial to Assess the Effect of Lidocaine Administered via Throat Spray and Nebulization in Patients with Refractory Chronic Cough.

BACKGROUND: Refractory chronic cough (RCC) is a debilitating condition for which there are no licensed treatments. Lidocaine is a nonselective inhibitor of voltage-gated sodium channels with potential antitussive effects, but randomized placebo-controlled studies evaluating its efficacy in RCC are lacking. OBJECTIVE: To investigate the efficacy of nebulized lidocaine and lidocaine throat spray versus matched placebos in RCC. METHODS: This was a randomized, double-blind, double-dummy, placebo-controlled, 3-way crossover study, comparing the effect of single doses of nebulized lidocaine with lidocaine delivered by a throat spray and matched placebo. The primary end point was cough frequency over the 10 hours following treatment. Secondary end points were visual analog scale scores for urge-to-cough and cough severity; an exploratory analysis evaluated hourly cough rates up to 5 hours after treatment. RESULTS: Twenty-six subjects with RCC were recruited (22 females; mean age, 53.5 ± 12.1 years; FEV1 %predicted, 105.2 ± 16.8 L; forced vital capacity %predicted, 112.4 ± 18 L). Lidocaine throat spray, but not nebulized lidocaine, significantly reduced 10-hour cough frequency as compared with placebo (throat spray, 22.6 coughs/h; nebulization, 26.9 coughs/h; and placebos, 27.6 coughs/h; P = .04,). Lidocaine throat spray showed the greatest effect on cough compared with placebo in the first hour after administration (31.7 coughs/h vs 74.2 coughs/h; P = .004). Both nebulizer and spray treatments significantly alleviated urge-to-cough and cough severity visual analog scale scores compared with placebo (P < .05). There were no serious adverse events associated with lidocaine therapy. CONCLUSIONS: Lidocaine throat spray was effective in reducing cough frequency in patients with RCC. Voltage-gated sodium channel inhibitors applied to pharynx have potential as therapies for RCC.

Cough in Patients With Lung Cancer: A Longitudinal Observational Study of Characterization and Clinical Associations.

BACKGROUND: Cough is common in patients with lung cancer, and current antitussive treatments are suboptimal. There are little published data describing cough in patients with lung cancer or work assessing clinical associations. The aim of this study is to fill that gap. METHODS: This was a longitudinal prospective observational single-cohort study over 60 days. Patients were assessed through self-reported validated scales and, in a subsample, ambulatory cough monitoring at study entry (day 0), day 30, and day 60. RESULTS: At study entry, 177 patients were included and 153 provided data at day 60. The median duration of cough was 52 weeks (interquartile range, 8.5-260). Cough was described as severe enough to warrant treatment in 62% of the patients. Depending on the scale used, performance status was associated with both cough severity and cough impact (P < .001) at study entry, whereas higher cough severity at study entry was associated with female sex (P = .02), asthma (P = .035), and reflux disease (P < .001). Cough impact at study entry was additionally associated with experiencing nausea (P = .018). Cancer characteristics (ie, cancer stage, histology) were not associated with cough severity nor cough impact; neither was smoking or COPD. CONCLUSIONS: This is the first study to describe characteristics of cough in patients with lung cancer and to identify clinical associations that may be relevant for its treatment. Our data suggest that cough is a frequent and distressing symptom and an unmet clinical need. Its association with gastrointestinal symptoms in this study may improve our understanding of pathophysiology and therapeutic options for cough occurring in patients with lung cancer.

Depression and its relationship with poor exercise capacity, BODE index and muscle wasting in COPD.

BACKGROUND: The prevalence of depression in stable COPD patients varies markedly, possibly because of use of different scales. We aimed to assess depression using 2 different depression scales and to examine the association between depression and poor exercise performance, BODE index and muscle wasting in clinically stable COPD patients. METHODS: 122 stable COPD patients were assessed with the Centre for Epidemiologic Studies Depression Scale (CES-D) and the Brief Assessment Schedule Depression Cards (BASDEC). We also assessed patients with spirometry, bioelectrical impedance analysis, 6-minute walk distance (6MWD), St George's Respiratory Questionnaire (SGRQ) and MRC dyspnoea and Borg scales. RESULTS: The CES-D and BASDEC scales detected almost similar prevalence rates of depression (21% vs 17%) with a Kappa coefficient of 0.68, p<0.0001. The BASDEC scale detected more depression in women and was more closely associated with dyspnoea than the CES-D. COPD severity was associated with depression when using BODE scores but not when GOLD categories were used. Each of the CES-D and BASDEC depression scores were associated with 6MWD after adjusting for FEV1% predicted, gender, age and pack-years (p = <0.0001 and 0.001, respectively). Also, patients with a 6MWD<350 scored significantly higher on both depression scales. Wasted patients appeared to have higher depression scores, but the difference was statistically insignificant. CONCLUSION: The administration of different depression scales may affect some of the characteristics of depressed patients rather than the prevalence rate of depression. Depression was associated with poor exercise performance and BODE index in COPD.