Background and objectiveLack of consensus on diagnosis of ACO limits our understanding of the impact, management and outcomes of ACO. The present observational study aims to describe the prevalence, clinical characteristics and course of individuals with ACO based on various definitions used in clinical practice.MethodsWe included individuals with COPD from the prospective, multisite CanCOLD study and defined subjects with ACO using seven definitions commonly used in the literature.ResultsData including questionnaires, lung function and CT scans were analysed from 522 individuals with COPD who were randomly recruited from the population. Among them, 264 fulfilled at least one of the seven definitions of ACO. Prevalence of ACO varied from 3.8% to 31%. Regardless of the definition, individuals with ACO had worse outcomes (lung function and higher percentage of fast decliners, symptoms and exacerbations, health‐related quality of life and comorbidities) than the remaining patients with COPD. Conversely, patients with non‐ACO had higher emphysema and bronchiolitis scores. The three definitions that included atopy and/or physician diagnosis of asthma identified subjects who differed significantly from patients with COPD. The two ACO definitions with post‐bronchodilator reversibility were concordant with COPD and were the least stable, with less than 50% of the patients from each group maintaining reversibility over visits.ConclusionAtopy and physician‐diagnosed asthma are more distinguishing characteristics to identify ACO. This finding needs to be validated using measures of airway inflammation and other specific biomarkers.

The mechanisms linking reduced diffusing capacity of the lung for carbon monoxide (DlCO) to dyspnea and exercise intolerance across the chronic obstructive pulmonary disease (COPD) continuum are poorly understood. COPD progression generally involves both DlCO decline and worsening respiratory mechanics, and their relative contribution to dyspnea has not been determined. In a retrospective analysis of 300 COPD patients who completed symptom-limited incremental cardiopulmonary exercise tests, we tested the association between peak oxygen-uptake (V̇o2), DlCO, and other resting physiological measures. Then, we stratified the sample into tertiles of forced expiratory volume in 1 s (FEV1) and inspiratory capacity (IC) and compared dyspnea ratings, pulmonary gas exchange, and respiratory mechanics during exercise in groups with normal and low DlCO [i.e., <lower limit of normal (LLN)] using Global Lung Function Initiative reference values. DlCO was associated with peak V̇o2 ( P = 0.006), peak work-rate ( P = 0.005), and dyspnea/V̇o2 slope ( P < 0.001) after adjustment for other independent variables (airway obstruction and hyperinflation). Within FEV1 and IC tertiles, peak V̇o2 and work rate were lower ( P < 0.05) in low versus normal DlCO groups. Across all tertiles, low DlCO groups had higher dyspnea ratings, greater ventilatory inefficiency and arterial oxygen desaturation, and showed greater mechanical volume constraints at a lower ventilation during exercise than the normal DlCO group (all P < 0.05). After accounting for baseline resting respiratory mechanical abnormalities, DlCO<LLN was consistently associated with greater dyspnea and poorer exercise performance compared with preserved DlCO. The higher dyspnea ratings and earlier exercise termination in low DlCO groups were linked to significantly greater pulmonary gas exchange abnormalities, higher ventilatory demand, and associated accelerated dynamic mechanical constraints. NEW & NOTEWORTHY Our study demonstrated that chronic obstructive pulmonary disease patients with diffusing capacity of the lung for carbon monoxide (DlCO) less than the lower limit of normal had greater pulmonary gas exchange abnormalities, which resulted in higher ventilatory demand and greater dynamic mechanical constraints at lower ventilation during exercise. This, in turn, led to greater exertional dyspnea and exercise intolerance compared with patients with normal DlCO.

Assessment of dyspnoea severity during incremental cardiopulmonary exercise testing (CPET) has long been hampered by the lack of reference ranges as a function of work rate (WR) and ventilation (V̇E). This is particularly relevant to cycling, a testing modality which overtaxes the leg muscles leading to a heightened sensation of leg discomfort.Reference ranges based on dyspnoea percentiles (0–10 Borg scale) at standardised WRs and V̇E were established in 275 apparently healthy subjects aged 20–85 (131 men). They were compared with values recorded in a randomly selected “validation” sample (N=451, 224 men). Their usefulness in properly uncovering the severity of exertional dyspnoea were tested in 167 subjects under investigation for chronic dyspnoea (“testing sample”) who terminated CPET due to leg discomfort (86 men).Iso-WR and, to a lesser extent, iso-V̇E reference ranges (5th–25th, 25th–50th, 50–75th and 75th–95th percentiles) increased as a function of age, being systematically higher in women (p<0.01). There was no significant differences in percentiles distribution between “reference” and “validation” samples (p>0.05). Submaximal dyspnoea-WR scores lied within the 75th–95th or >95th percentiles in 108/118 (91.5%) subjects of the “testing” sample who showed physiological abnormalities known to elicit exertional dyspnoea i.e., ventilatory inefficiency and/or critical inspiratory constraints. In contrast, dyspnoea scores typically lied in the 5th–50th range in subjects without those abnormalities (p<0.001).This frame of reference might prove useful to uncover the severity of exertional dyspnoea in subjects who otherwise would be labeled as “non-dyspneic” while providing mechanistic insights into the genesis of this distressing symptom.

The prevailing view is that exertional dyspnoea in patients with combined idiopathic pulmonary fibrosis (IPF) and emphysema (CPFE) can be largely explained by severe hypoxaemia. However, there is little evidence to support these assumptions.We prospectively contrasted the sensory and physiological responses to exercise in 42 CPFE and 16 IPF patients matched by the severity of exertional hypoxaemia. Emphysema and pulmonary fibrosis were quantified using computed tomography. Inspiratory constraints were assessed in a constant work rate test: capillary blood gases were obtained in a subset of patients.CPFE patients had lower exercise capacity despite less extensive fibrosis compared to IPF (p=0.004 and 0.02, respectively). Exertional dyspnoea was the key limiting symptom in 24 CPFE patients who showed significantly lower transfer factor, arterial carbon dioxide tension and ventilatory efficiency (higher minute ventilation (V′E)/carbon dioxide output (V′CO2) ratio) compared to those with less dyspnoea. However, there were no between-group differences in the likelihood of pulmonary hypertension by echocardiography (p=0.44). High dead space/tidal volume ratio, low capillary carbon dioxide tension emphysema severity (including admixed emphysema) and traction bronchiectasis were related to a high V′E/V′CO2 ratio in the more dyspnoeic group. V′E/V′CO2 nadir >50 (OR 9.43, 95% CI 5.28–13.6; p=0.0001) and total emphysema extent >15% (2.25, 1.28–3.54; p=0.01) predicted a high dyspnoea burden associated with severely reduced exercise capacity in CPFEContrary to current understanding, hypoxaemia per se is not the main determinant of exertional dyspnoea in CPFE. Poor ventilatory efficiency due to increased “wasted” ventilation in emphysematous areas and hyperventilation holds a key mechanistic role that deserves therapeutic attention.

Many patients with severe chronic obstructive pulmonary disease (COPD) report unpleasant respiratory sensation at rest, further amplified by adoption of supine position (orthopnoea). The mechanisms of this acute symptomatic deterioration are poorly understood.16 patients with advanced COPD and history of orthopnoea and 16 age- and sex-matched healthy controls (CTRL) underwent pulmonary function tests and detailed sensory-mechanical measurements including inspiratory neural drive (IND, diaphragm electromyography), oesophageal and gastric pressures in sitting and supine positions.Patients had severe airflow obstruction (FEV1: 40±18%predicted) and lung hyperinflation. Regardless of the position, patients had lower inspiratory capacity (IC) and higher IND for a given tidal volume (i.e. greater neuromechanical dissociation (NMD)), higher intensity of breathing discomfort, minute ventilation (⩒E) and breathing frequency (Fb) compared with CTRL (all p<0.05). In supine position in CTRL (versus sitting erect): IC increased (by 0.48L) with a small drop in ⩒E mainly due to reduced Fb (all p<0.05). By contrast, patients’ IC remained unaltered, but dynamic lung compliance decreased (p<0.05) in the supine position. Breathing discomfort, inspiratory work of breathing, inspiratory effort, IND, NMD and neuro-ventilatory uncoupling all increased in COPD in the supine position (p<0.05), but not in CTRL. Orthopnoea was associated with acute changes in IND (r=0.65, p=0.01), neuro-ventilatory uncoupling (r=0.76, p=0.001) and NMD (r=0.73, p=0.002).In COPD, onset of orthopnoea coincided with an abrupt increase in elastic loading of the inspiratory muscles in recumbency in association with increased IND and greater neuromechanical dissociation of the respiratory system.

Background and objective: The combination of both reduced resting diffusing capacity of the lung for carbon monoxide (DL CO ) and ventilatory efficiency (increased ventilatory requirement for CO 2 clearance [ _ V E / _ VCO 2 ]) has been linked to exertional dyspnoea and exercise intolerance in chronic obstructive pulmonary disease (COPD) but the underlying mechanisms are poorly understood. The current study examined if low resting DL CO and higher exercise ventilatory requirements were associated with earlier critical dynamic mechanical constraints, dyspnoea and exercise limitation in patients with mild COPD. Methods: In this retrospective analysis, we compared _ V E / _ VCO 2 , dynamic inspiratory reserve volume (IRV), dyspnoea and exercise capacity in groups of patients with Global Initiative for Chronic Obstructive Lung Disease stage 1 COPD with (1) a resting DL CO at or greater than the lower limit of normal (≥LLN; Global Lung Function Initiative reference equations [n = 44]) or (2) below the

Activity-related dyspnoea is a key cause of physical impairment in cardiovascular and respiratory diseases [1]. Despite remarkable diagnostic advances in the past decades, discriminating "the heart" versus "the lungs" as a cause of exertional dyspnoea remains a challenge for cardiologists and pulmonologists. This state of affairs is not surprising if one considers that the respiratory neural drive, a key correlate of exertional dyspnoea, is characteristically increased in heart and lung diseases [2]. The differentiating feature, however, is the relative contribution of lung mechanical abnormalities as they are, by definition, more pronounced in the respiratory than in the cardiac patient [3]. Cardiopulmonary exercise testing (CPET) has long been advocated as the test of choice to determine the primary source of exercise limitation in these patients. In real life, however, there is substantial overlap in the physiological abnormalities underlying cardiovascular and respiratory diseases. It follows that CPET remains largely underused to untangle such a complex conundrum [4]. This scenario is partially explained by the fact that the interpretation of CPET in dyspnoeic patients remains heavily focused on physiological constructs. Although those physiological variables are important to objectively determine the biological basis of dyspnoea, it is surprising that little attention, if any, has been given to the symptom per se as an auxiliary diagnostic tool.In this context, the burden of exertional dyspnoea can be readily quantified by expressing its severity (e.g. 0-10 Borg category-ratio scale) as a function of work rate (WR). The relationship between dyspnoea and ventilation (V′ E ), however, is more complex and may present with some discriminating features. Thus, if the ventilatory pump is free of major mechanical constraints (e.g. cardiocirculatory diseases), the increased drive to breathe can be largely translated into an equally high V′ E [5]. In other words, the intensity and trajectory of dyspnoea as a function of V′ E may not differ substantially from the pattern observed in normal subjects. Conversely, if the mechanical constraints typical of respiratory diseases preclude the ventilatory pump to "respond" to an increased drive, dyspnoea is expected to increase at a faster rate than V′ E [6]. Owing to the fact that such constraints further increase beyond a certain critical intensity [7], it is conceivable that they could be identified by a sudden upward inflection of dyspnoea against V′ E . To the authors' knowledge, such theoretical constructs have not yet been put under scrutiny with the specific objective of discriminating cardiovascular versus respiratory disease as a cause of exertional dyspnoea.In a proof-of-concept study, we enrolled two groups of patients: those in whom the cardiocirculatory derangements dominate over the lung mechanical abnormalities (chronic heart failure (CHF) with reduced left ventricular ejection fraction, n=14) and vice versa (COPD, n=14). The control group consisted of 10 age-a...

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