Search

Activity-related dyspnea in chronic lung disease is centrally related to dynamic ( dyn ) inspiratory constraints to tidal volume expansion. Lack of reference values for exertional inspiratory reserve (IR) has limited the yield of cardiopulmonary exercise testing in exposing the underpinnings of this disabling symptom. One hundred fifty apparently healthy subjects (82 males) aged 40-85 underwent incremental cycle ergometry. Based on exercise inspiratory capacity (IC dyn ), we generated centile-based reference values for the following metrics of IR as a function of absolute ventilation: IR dyn1 ([1-(tidal volume/IC dyn )] x 100) and IR dyn2 ([1-(end-inspiratory lung volume/total lung capacity] x 100). IR dyn1 and IR dyn2 standards were typically lower in females and older subjects (p<0.05 for sex and age versus ventilation interactions). Low IR dyn1 and IR dyn2 significantly predicted the burden of exertional dyspnea in both sexes (p<0.01). Using these sex and age-adjusted limits of reference, the clinician can adequately judge the presence and severity of abnormally low inspiratory reserves in dyspneic subjects undergoing cardiopulmonary exercise testing., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest relative to this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Exertional dyspnea, a key complaint of patients with chronic obstructive pulmonary disease (COPD), ultimately reflects an increased inspiratory neural drive to breathe. In non-hypoxemic patients with largely preserved lung mechanics - as those in the initial stages of the disease - the heightened inspiratory neural drive is strongly associated with an exaggerated ventilatory response to metabolic demand. Several lines of evidence indicate that the so-called excess ventilation (high ventilation-CO 2 output relationship) primarily reflects poor gas exchange efficiency, namely increased physiological dead space. Pulmonary function tests estimating the extension of the wasted ventilation and selected cardiopulmonary exercise testing variables can, therefore, shed unique light on the genesis of patients' out-of-proportion dyspnea. After a succinct overview of the basis of gas exchange efficiency in health and inefficiency in COPD, we discuss how wasted ventilation translates into exertional dyspnea in individual patients. We then outline what is currently known about the structural basis of wasted ventilation in "minor/trivial" COPD vis-à-vis the contribution of emphysema versus a potential impairment in lung perfusion across non-emphysematous lung. After summarizing some unanswered questions on the field, we propose that functional imaging be amalgamated with pulmonary function tests beyond spirometry to improve our understanding of this deeply neglected cause of exertional dyspnea. Advances in the field will depend on our ability to develop robust platforms for deeply phenotyping (structurally and functionally), the dyspneic patients showing unordinary high wasted ventilation despite relatively preserved FEV 1 .

Rationale: It is increasingly recognized that adults with preserved ratio impaired spirometry (PRISm) are prone to increased morbidity. However, the underlying pathophysiological mechanisms are unknown. Objectives: Evaluate the mechanisms of increased dyspnea and reduced exercise capacity in PRISm. Methods: We completed a cross-sectional analysis of the CanCOLD (Canadian Cohort Obstructive Lung Disease) population-based study. We compared physiological responses in 59 participants meeting PRISm spirometric criteria (post-bronchodilator FEV 1  < 80% predicted and FEV 1 /FVC ⩾ 0.7), 264 control participants, and 170 ever-smokers with chronic obstructive pulmonary disease (COPD), at rest and during cardiopulmonary exercise testing. Measurements and Main Results: Individuals with PRISm had lower total lung, vital, and inspiratory capacities than healthy controls (all P  < 0.05) and minimal small airway, pulmonary gas exchange, and radiographic parenchymal lung abnormalities. Compared with healthy controls, individuals with PRISm had higher dyspnea/[Formula: see text]o 2 ratio at peak exercise (4.0 ± 2.2 vs. 2.9 ± 1.9 Borg units/L/min; P  < 0.001) and lower [Formula: see text]o 2peak (74 ± 22% predicted vs. 96 ± 25% predicted; P  < 0.001). At standardized submaximal work rates, individuals with PRISm had greater Vt/inspiratory capacity (Vt%IC; P  < 0.001), reflecting inspiratory mechanical constraint. In contrast to participants with PRISm, those with COPD had characteristic small airways dysfunction, dynamic hyperinflation, and pulmonary gas exchange abnormalities. Despite these physiological differences among the three groups, the relationship between increasing dyspnea and Vt%IC during cardiopulmonary exercise testing was similar. Resting IC significantly correlated with [Formula: see text]o 2peak ( r  = 0.65; P  < 0.001) in the entire sample, even after adjusting for airflow limitation, gas trapping, and diffusing capacity. Conclusions: In individuals with PRISm, lower exercise capacity and higher exertional dyspnea than healthy controls were mainly explained by lower resting lung volumes and earlier onset of dynamic inspiratory mechanical constraints at relatively low work rates. Clinical trial registered with www.clinicaltrials.gov (NCT00920348).

Heightened sensation of leg effort contributes importantly to poor exercise tolerance in patient populations. We aim to provide a sex- and age-adjusted frame of reference to judge symptom's normalcy across progressively higher exercise intensities during incremental exercise. Two-hundred and seventy-five non-trained subjects (130 men) aged 19-85 prospectively underwent incremental cycle ergometry. After establishing centiles-based norms for Borg leg effort scores (0-10 category-ratio scale) versus work rate, exponential loss function identified the centile that best quantified the symptom's severity individually. Peak O 2 uptake and work rate (% predicted) were used to threshold gradually higher symptom intensity categories. Leg effort-work rate increased as a function of age; women typically reported higher scores at a given age, particularly in the younger groups (p < 0.05). For instance, "heavy" (5) scores at the 95th centile were reported at ~200 W (<40 years) and ~90 W (≥70 years) in men versus ~130 W and ~70 W in women, respectively. The following categories of leg effort severity were associated with progressively lower exercise capacity: ≤50th ("mild"), >50th to <75th ("moderate"), ≥75th to <95th ("severe"), and ≥ 95th ("very severe") (p < 0.05). Although most subjects reporting peak scores <5 were in "mild" range, higher scores were not predictive of the other categories (p > 0.05). This novel frame of reference for 0-10 Borg leg effort, which considers its cumulative burden across increasingly higher exercise intensities, might prove valuable to judging symptom's normalcy, quantifying its severity, and assessing the effects of interventions in clinical populations., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Reduced lung diffusing capacity for carbon monoxide (DL CO ) at rest and increased ventilation ( ⩒ E )-carbon dioxide output ( ⩒ CO 2 ) during exercise are frequent findings in dyspneic smokers with largely preserved FEV 1 . It remains unclear whether low DL CO and high ⩒ E are mere reflections of alveolar destruction (i.e. emphysema) or impaired pulmonary perfusion in non-emphysematous tissue contributes to these functional abnormalities. Sixty-four smokers (41 males, FEV ⩒ = 84 ± 13%predicted) underwent pulmonary function tests, an incremental exercise test, and quantitative chest computed tomography. Total pulmonary vascular volume (TPVV) was calculated for the entire segmented vascular tree (VIDA Vision™). Using the median % low attenuation area (-950 HU), participants were dichotomized into "Trace" or "Mild" emphysema (E), each group classified into preserved 2 are mere reflections of alveolar destruction (i.e. emphysema) or impaired pulmonary perfusion in non-emphysematous tissue contributes to these functional abnormalities. Sixty-four smokers (41 males, FEV 1 = 84 ± 13%predicted) underwent pulmonary function tests, an incremental exercise test, and quantitative chest computed tomography. Total pulmonary vascular volume (TPVV) was calculated for the entire segmented vascular tree (VIDA Vision™). Using the median % low attenuation area (-950 HU), participants were dichotomized into "Trace" or "Mild" emphysema (E), each group classified into preserved versus reduced DL CO . Within each emphysema subgroup, participants with abnormally low DL CO showed lower TPVV, higher ⩒ E - ⩒ CO 2 , and exertional dyspnea than those with preserved DL CO ( p  < 0.05). TPVV ( r  = 0.34; p after adjusting for age and height. Despite lower emphysema burden, Trace-E participants with reduced DL r had lower TPVV, higher dyspnea, and lower peak work rate than the Mild-E with preserved DL p  = 0.67), correlated with lower DL CO after adjusting for age and height. Despite lower emphysema burden, Trace-E participants with reduced DL CO had lower TPVV, higher dyspnea, and lower peak work rate than the Mild-E with preserved DL CO ( p  < 0.05). Interestingly, TPVV (but not emphysema) correlated inversely with both dyspnea-work rate ( r = -0.36, p  = 0.004) and dyspnea- ⩒ E slopes ( r = -0.40, p  = 0.001). Reduced pulmonary vascular volume adjusted by emphysema extent is associated with low DL CO and heightened exertional ventilation in dyspneic smokers with minor emphysema. Impaired perfusion of non-emphysematous regions of the lungs has greater functional and clinical consequences than hitherto assumed in these subjects.

Background: The precise mechanisms driving poor exercise tolerance in patients with fibrotic interstitial lung diseases (fibrotic ILDs) showing a severe impairment in single-breath lung diffusing capacity for carbon monoxide (D LCO < 40% predicted) are not fully understood. Rather than only reflecting impaired O 2 transfer, a severely impaired D LCO may signal deranged integrative physiologic adjustments to exercise that jointly increase the burden of exertional symptoms in fibrotic ILD., Methods: Sixty-seven subjects (46 with idiopathic pulmonary fibrosis, 24 showing D LCO < 40%) and 22 controls underwent pulmonary function tests and an incremental cardiopulmonary exercise test with serial measurements of operating lung volumes and 0-10 Borg dyspnea and leg discomfort scores., Results: Subjects from the D LCO < 40% group showed lower spirometric values, more severe restriction, and lower alveolar volume and transfer coefficient compared to controls and participants with less impaired D LCO ( P < .05). Peak work rate was ∼45% (vs controls) and ∼20% (vs D LCO > 40%) lower in the former group, being associated with lower (and flatter) O 2 pulse, an earlier lactate (anaerobic) threshold, heightened submaximal ventilation, and lower S pO 2 . Moreover, critically high inspiratory constrains were reached at lower exercise intensities in the D LCO < 40% group ( P < .05). In association with the greatest leg discomfort scores, they reported the highest dyspnea scores at a given work rate. Between-group differences lessened or disappeared when dyspnea intensity was related to indexes of increased demand-capacity imbalance, that is, decreasing submaximal, dynamic ventilatory reserve, and inspiratory reserve volume/total lung capacity ( P > .05)., Conclusions: A severely reduced D LCO in fibrotic ILD signals multiple interconnected derangements (cardiovascular impairment, an early shift to anaerobic metabolism, excess ventilation, inspiratory constraints, and hypoxemia) that ultimately lead to limiting respiratory (dyspnea) and peripheral (leg discomfort) symptoms. D LCO < 40%, therefore, might help in clinical decision-making to indicate the patient with fibrotic ILD who might derive particular benefit from pharmacologic and non-pharmacologic interventions aimed at lessening these systemic abnormalities., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2023 by Daedalus Enterprises.)

Background: Infections are considered as leading causes of acute exacerbations of chronic obstructive pulmonary disease (COPD). Non-infectious risk factors such as short-term air pollution exposure may play a clinically important role. We sought to estimate the relationship between short-term air pollutant exposure and exacerbations in Canadian adults living with mild to moderate COPD., Methods: In this case-crossover study, exacerbations ('symptom based': ≥48 hours of dyspnoea/sputum volume/purulence; 'event based': 'symptom based' plus requiring antibiotics/corticosteroids or healthcare use) were collected prospectively from 449 participants with spirometry-confirmed COPD within the Canadian Cohort Obstructive Lung Disease. Daily nitrogen dioxide (NO 2 ), fine particulate matter (PM 2.5 ), ground-level ozone (O 3 ), composite of NO 2 and O 3 (O x ), mean temperature and relative humidity estimates were obtained from national databases. Time-stratified sampling of hazard and control periods on day '0' (day-of-event) and Lags ('-1' to '-6') were compared by fitting generalised estimating equation models. All data were dichotomised into 'warm' (May-October) and 'cool' (November-April) seasons. ORs and 95% CIs were estimated per IQR increase in pollutant concentrations., Results: Increased warm season ambient concentration of NO 2 was associated with symptom-based exacerbations on Lag-3 (1.14 (1.01 to 1.29), per IQR), and increased cool season ambient PM 2.5 was associated with symptom-based exacerbations on Lag-1 (1.11 (1.03 to 1.20), per IQR). There was a negative association between warm season ambient O 3 and symptom-based events on Lag-3 (0.73 (0.52 to 1.00), per IQR)., Conclusions: Short-term ambient NO 2 and PM 2.5 exposure were associated with increased odds of exacerbations in Canadians with mild to moderate COPD, further heightening the awareness of non-infectious triggers of COPD exacerbations., Competing Interests: Competing interests: BAR reports grants/contracts from the Canadian Institutes of Health Research (CIHR), Réseau de Recherche en Santé Respiratoire du Québec (RSRQ), Research Institute of the MUHC (RI MUHC), Ministère de l'Économie et de l'Innovation (MEI) Québec, McGill University Health Centre (MUHC) Foundation Grant, Fonds de Recherche Santé Québec (FRSQ), and CHEST Foundation Grant; and payments/honoraria from the Canadian Thoracic Society (CTS), CHEST/ACCP, Respiplus (non-profit), Alberta Kinesiology Association (AKA), and McGill University Continuing Professional Development (CPD). SDA reports payments/honoraria from AstraZeneca, GSK; and participation on Data Safety Monitoring/Advisory Board for AstraZeneca, GSK, and Sanofi. PH reports grants/contracts from Boehringer Ingelheim, Cyclomedica, Grifols, Vertex; consulting fees from Acceleron, AstraZeneca, Boehringer Ingelheim, Covis, GlaxoSmithKline, Janssen, Novartis, Sanofi, Teva, Takeda, Valeo; and leadership/fiduciary role in the Canadian Thoracic Society. FM reports grants/contracts from GlaxoSmithKline, AstraZeneca, Sanofi, Novartis, Boehringer Ingelheim, Grifols; consulting fees from AstraZeneca; payment/honoraria from GlaxoSmithKline, Boehringer Ingelheim, Grifols, Novartis; and stock/stock options from Oxynov. DM reports grants/contracts from AstraZeneca, Boehringer Ingelheim, Canadian Institute of Health Research, GlaxoSmithKline, Grifols, Lung Association—Saskatchewan, Novartis, Sanofi, Saskatchewan Health Research Foundation, Schering-Plough; consulting fees from Alberta Health Services, Canadian Foundation for Healthcare Improvement, Health Canada, Lung Association—Saskatchewan, Ontario Ministry of Health and Long-Term Care, Saskatchewan Health Authority, Yukon Health and Social Services; payment/honoraria from the Lung Association—Saskatchewan, American College of Chest Physicians; leadership/fiduciary role in the CHEST journal, Canadian Thoracic Society, American Thoracic Society and AARC; and is an employee of the University of Saskatchewan. DE O’D reports grants/contracts from AstraZeneca, Lung Health Foundation and Boehringer Ingelheim Canada; and payment/honoraria from GSK and Viajes Pacifico. BLW reports payment/honoraria from AstraZeneca, GSK, Sanofi; and Data Safety Monitoring/Advisory Board participation for AstraZeneca, GSK, and Sanofi. JB reports grants/contracts from the Canadian Institute of Health Research (CIHR), Réseau en santé respiratoire du FRQS, McGill University, McGill University Health Centre Foundation, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GSK, Grifols, Novartis, Sanofil, Trudell Canada Ltd; and payment/honoraria from AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GSK, Pfizer Canada Ltd, and Trudell Canada Ltd., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Ventilatory demand-capacity imbalance, as inferred based on a low ventilatory reserve, is currently assessed only at peak cardiopulmonary exercise testing (CPET). Peak ventilatory reserve, however, is poorly sensitive to the submaximal, dynamic mechanical ventilatory abnormalities that are key to dyspnea genesis and exercise intolerance. Objectives: After establishing sex- and age-corrected norms for dynamic ventilatory reserve at progressively higher work rates, we compared peak and dynamic ventilatory reserve for their ability to expose increased exertional dyspnea and poor exercise tolerance in mild to very severe chronic obstructive pulmonary disease (COPD). Methods: We analyzed resting functional and incremental CPET data from 275 controls (130 men, aged 19-85 yr) and 359 Global Initiative for Chronic Obstructive Lung Disease patients with stage 1-4 obstruction (203 men) who were prospectively recruited for previous ethically approved studies in three research centers. In addition to peak and dynamic ventilatory reserve (1 - [ventilation / estimated maximal voluntary ventilation] × 100), operating lung volumes and dyspnea scores (0-10 on the Borg scale) were obtained. Results: Dynamic ventilatory reserve was asymmetrically distributed in controls; thus, we calculated its centile distribution at every 20 W. The lower limit of normal (lower than the fifth centile) was consistently lower in women and older subjects. Peak and dynamic ventilatory reserve disagreed significantly in indicating an abnormally low test result in patients: whereas approximately 50% of those with a normal peak ventilatory reserve showed a reduced dynamic ventilatory reserve, the opposite was found in approximately 15% ( P  < 0.001). Irrespective of peak ventilatory reserve and COPD severity, patients who had a dynamic ventilatory reserve below the lower limit of normal at an isowork rate of 40 W had greater ventilatory requirements, prompting earlier attainment of critically low inspiratory reserve. Consequently, they reported higher dyspnea scores, showing poorer exercise tolerance compared with those with preserved dynamic ventilatory reserve. Conversely, patients with preserved dynamic ventilatory reserve but reduced peak ventilatory reserve reported the lowest dyspnea scores, showing the best exercise tolerance. Conclusions: Reduced submaximal dynamic ventilatory reserve, even in the setting of preserved peak ventilatory reserve, is a powerful predictor of exertional dyspnea and exercise intolerance in COPD. This new parameter of ventilatory demand-capacity mismatch may enhance the yield of clinical CPET in the investigation of activity-related breathlessness in individual patients with COPD and other prevalent cardiopulmonary diseases.

Background: Individuals with COPD and preserved ratio impaired spirometry (PRISm) findings in clinical settings have an increased risk of cardiovascular disease (CVD)., Research Question: Do individuals with mild to moderate or worse COPD and PRISm findings in community settings have a higher prevalence and incidence of CVD compared with individuals with normal spirometry findings? Can CVD risk scores be improved when impaired spirometry is added?, Study Design and Methods: The analysis was embedded in the Canadian Cohort Obstructive Lung Disease (CanCOLD). Prevalence of CVD (ischemic heart disease [IHD] and heart failure [HF]) and their incidence over 6.3 years were compared between groups with impaired and normal spirometry findings using logistic regression and Cox models, respectively, adjusting for covariables. Discrimination of the pooled cohort equations (PCE) and Framingham risk score (FRS) in predicting CVD were assessed with and without impaired spirometry., Results: Participants (n = 1,561) included 726 people with normal spirometry findings and 835 people with impaired spirometry findings (COPD Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 1 disease, n = 408; GOLD stage ≥ 2, n = 331; PRISm findings, n = 96). Rates of undiagnosed COPD were 84% in GOLD stage 1 and 58% in GOLD stage ≥ 2 groups. Prevalence of CVD (IHD or HF) was significantly higher among individuals with impaired spirometry findings and COPD compared with those with normal spirometry findings, with ORs of 1.66 (95% CI, 1.13-2.43; P = .01∗) (∗ indicates statistical significane with P < .05) and 1.55 (95% CI, 1.04-2.31; P = .033∗), respectively. Prevalence of CVD was significantly higher in participants having PRISm findings and COPD GOLD stage ≥ 2, but not GOLD stage 1. CVD incidence was significantly higher, with hazard ratios of 2.07 (95% CI, 1.10-3.91; P = .024∗) for the impaired spirometry group and 2.09 (95% CI, 1.10-3.98; P = .024∗) for the COPD group compared to individuals with normal spirometry findings. The difference was significantly higher among individuals with COPD GOLD stage ≥ 2, but not GOLD stage 1. The discrimination for predicting CVD was low and limited when impaired spirometry findings were added to either risk score., Interpretation: Individuals with impaired spirometry findings, especially those with moderate or worse COPD and PRISm findings, have increased comorbid CVD compared with their peers with normal spirometry findings, and having COPD increases the risk of CVD developing., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

The functional disturbances driving "out-of-proportion" dyspnoea in patients with fibrosing interstitial lung disease (f-ILD) showing only mild restrictive abnormalities remain poorly understood. Eighteen patients (10 with idiopathic pulmonary fibrosis) showing preserved spirometry and mildly reduced total lung capacity (≥70% predicted) and 18 controls underwent an incremental cardiopulmonary exercise test with measurements of operating lung volumes and Borg dyspnoea scores. Patients' lower exercise tolerance was associated with higher ventilation (V̇ E )/carbon dioxide (V̇CO 2 ) compared with controls (V̇ E /V̇CO 2 nadir=35 ± 3 versus 29 ± 2; p < 0.001). Patients showed higher tidal volume/inspiratory capacity and lower inspiratory reserve volume at a given exercise intensity, reporting higher dyspnoea scores as a function of both work rate and V̇ E . Steeper dyspnoea-work rate slopes were associated with lower lung diffusing capacity, higher V̇ E /V̇CO 2 , and lower peak O 2 uptake (p < 0.05). Heightened ventilatory demands in the setting of progressively lower capacity for tidal volume expansion on exertion largely explain higher-than-expected dyspnoea in f-ILD patients with largely preserved dynamic and "static" lung volumes at rest., (Copyright © 2023. Published by Elsevier B.V.)

Following pulmonary embolism (PE), a third of patients develop persistent dyspnea, which is commonly termed the post-PE syndrome. The neurophysiological underpinnings of exertional dyspnea in patients with post-PE syndrome without pulmonary hypertension (PH) are unclear. Thus, the current study determined if abnormally high inspiratory neural drive (IND) due, in part, to residual pulmonary gas-exchange abnormalities, was linked to heightened exertional dyspnea and exercise limitation, in such patients. Fourteen participants with post-PE syndrome (without resting PH) and 14 age-, sex-, and body mass index-matched healthy controls undertook pulmonary function testing and a symptom-limited cycle cardiopulmonary exercise test with measurements of IND (diaphragmatic electromyography), ventilatory requirements for CO 2 (V̇e/V̇co 2 ), and perceived dyspnea intensity (modified Borg 0-10 scale). Post-PE (vs. control) had a reduced resting transfer coefficient for carbon monoxide ( K CO : 84 ± 15 vs. 104 ± 14%pred, P < 0.001) and peak oxygen uptake (V̇o 2peak ) (76 ± 14 vs. 124 ± 28%pred, P < 0.001). IND and V̇e/V̇co 2 were higher in post-PE than controls at standardized submaximal work rates ( P < 0.05). Dyspnea increased similarly in both groups as a function of increasing IND but was higher in post-PE at standardized submaximal work rates ( P < 0.05). High IND was associated with low K CO ( r = -0.484, P < 0.001), high V̇e/V̇co 2 nadir ( r = 0.453, P < 0.001), and low V̇o 2peak ( r = -0.523, P < 0.001). In patients with post-PE syndrome, exercise IND was higher than controls and was associated with greater dyspnea intensity. The heightened IND and dyspnea in post-PE, in turn, were strongly associated with low resting K CO and high exercise V̇e/V̇co 2 , which suggest important pulmonary gas-exchange abnormalities in this patient population. NEW & NOTEWORTHY This study is the first to show that increased exertional dyspnea in patients with post-pulmonary embolism (PE) syndrome, without overt pulmonary hypertension, was strongly associated with elevated inspiratory neural drive (IND) to the diaphragm during exercise, compared with healthy controls. The greater IND was associated with impairments in pulmonary gas exchange and significant deconditioning. Our results help to explain why many patients with post-PE syndrome report significant dyspnea at relatively low levels of physical activity.

Background: Reduced exercise capacity has been reported previously in patients with OSA hypopnea syndrome (OSAHS), although the underlying mechanisms are unclear., Research Question: What are the underlying mechanisms of reduced exercise capacity in untreated patients with OSAHS? Is there a role for systemic or pulmonary vascular abnormalities?, Study Design and Methods: This was a cross-sectional observational study in which 14 patients with moderate to severe OSAHS and 10 control participants (matched for age, BMI, smoking history, and FEV 1 ) underwent spirometry, incremental cycle cardiopulmonary exercise test (CPET) with arterial line, resting echocardiography, and assessment of arterial stiffness (pulse wave velocity [PWV] and augmentation index [AIx])., Results: Patients (age, 50 ± 11 years; BMI, 30.5 ± 2.7 kg/m 2 ; smoking history, 2.4 ± 4.0 pack-years; FEV 1 to FVC ratio, 0.78 ± 0.04; FEV 1 , 85 ± 14% predicted, mean ± SD for all) had mean ± SD apnea hypopnea index of 43 ± 19/h. At rest, PWV, AIx, and mean pulmonary artery pressure (PAP) were higher in patients vs control participants (P < .05). During CPET, patients showed lower peak work rate (WR) and oxygen uptake and greater dyspnea ratings compared with control participants (P < .05 for all). Minute ventilation (V· E ), ventilatory equivalent for CO 2 output (V· E /V·CO 2 ), and dead space volume (V D ) to tidal volume (V T ) ratio were greater in patients vs control participants during exercise (P < .05 for all). Reduction in V D to V T ratio from rest to peak exercise was greater in control participants compared with patients (0.24 ± 0.08 vs 0.04 ± 0.14, respectively; P = .001). Dyspnea intensity at the highest equivalent WR correlated with corresponding values of V· E /V·CO 2 (r = 0.65; P = .002), and dead space ventilation (r = 0.70; P = .001). Age, PWV, and mean PAP explained approximately 70% of the variance in peak WR, whereas predictors of dyspnea during CPET were rest-to-peak change in V D to V T ratio and PWV (R 2  = 0.50; P < .001)., Interpretation: Patients with OSAHS showed evidence of pulmonary gas exchange abnormalities during exercise (in the form of increased dead space) and resting systemic vascular dysfunction that may explain reduced exercise capacity and increased exertional dyspnea intensity., (Copyright © 2022 American College of Chest Physicians. All rights reserved.)

Increased ventilation relative to metabolic demands, indicating alveolar hyperventilation and/or increased physiological dead space (excess ventilation), is a key cause of exertional dyspnoea. Excess ventilation has assumed a prominent role in the functional assessment of patients with heart failure (HF) with reduced (HFrEF) or preserved (HFpEF) ejection fraction, pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). We herein provide the key pieces of information to the caring physician to 1) gain unique insights into the seeds of patients' shortness of breath and 2) develop a rationale for therapeutically lessening excess ventilation to mitigate this distressing symptom. Reduced bulk oxygen transfer induced by cardiac output limitation and/or right ventricle-pulmonary arterial uncoupling increase neurochemical afferent stimulation and (largely chemo-) receptor sensitivity, leading to alveolar hyperventilation in HFrEF, PAH and small-vessel, distal CTEPH. As such, interventions geared to improve central haemodynamics and/or reduce chemosensitivity have been particularly effective in lessening their excess ventilation. In contrast, 1) high filling pressures in HFpEF and 2) impaired lung perfusion leading to ventilation/perfusion mismatch in proximal CTEPH conspire to increase physiological dead space. Accordingly, 1) decreasing pulmonary capillary pressures and 2) mechanically unclogging larger pulmonary vessels (pulmonary endarterectomy and balloon pulmonary angioplasty) have been associated with larger decrements in excess ventilation. Exercise training has a strong beneficial effect across diseases. Addressing some major unanswered questions on the link of excess ventilation with exertional dyspnoea under the modulating influence of pharmacological and nonpharmacological interventions might prove instrumental to alleviate the devastating consequences of these prevalent diseases., Competing Interests: Conflict of interest: None declared., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

In people with COPD, pulmonary gas-exchange efficiency may be impaired because of abnormal alveolar ventilation (V˙A), capillary perfusion (Q˙c), or both. Both have been reported in early and mild stages of the disease. Such derangements often accompany significant clinical consequences such as activity-related dyspnea and exercise intolerance. Although much attention has been paid to pharmacologic treatment of mechanical abnormalities in COPD (eg, bronchodilators to deflate the lungs), increasing neurochemical afferent activity, secondary to gas-exchange inefficiency, has remained elusive as a therapeutic target. Hence, in this invited review, we first summarize how dyspnea, leading to poor exercise tolerance in COPD, may be explained by an increased venous admixture resulting from low V˙A/Q˙c, or wasted ventilation related to high V˙A/Q˙c, or both. We review the conflicting evidence supporting current treatments for gas-exchange inefficiency and exercise tolerance that act primarily on V˙A (bronchodilators, antiinflammatory medications) or Q˙c (oral and inhaled vasodilators, almitrine, and supplemental oxygen). Finally, to address the current knowledge and health care gaps, we propose two independent clinical research foci that may lead to a better understanding of the role of pulmonary gas-exchange inefficiency and activity-related dyspnea in COPD: (1) enhanced and deeper phenotyping of patients with COPD with V˙A/Q˙c abnormalities and (2) evaluation of existing and novel pharmacologic treatments to improve gas-exchange inefficiency, exertional dyspnea, and exercise tolerance across the spectrum of COPD severity., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Low resting inspiratory capacity (IC) and low maximal inspiratory pressure (MIP) have previously been linked to exertional dyspnea, exercise limitation, and poor survival in chronic obstructive pulmonary disease (COPD). The interaction and relative contributions of these two related variables to important clinical outcomes are unknown. The objective of the current study was to examine the interaction between resting IC and MIP (both % predicted), exertional dyspnea, exercise capacity, and long-term survival in patients with COPD. Two hundred and eighty-five patients with mild to advanced COPD completed standard lung function testing and a cycle cardiopulmonary exercise test. Multiple regression determined predictors of the exertional dyspnea-ventilation slope and peak oxygen uptake (V̇o 2peak ). Cox regression determined predictors of 10-year mortality. IC was associated with the dyspnea-ventilation slope (standardized β = -0.42, P < 0.001), whereas MIP was excluded from the regression model ( P = 0.918). IC and MIP were included in the final model to predict V̇o 2peak . However, the standardized β was greater for IC (0.43) than MIP (0.22). After adjusting for age, sex, body mass index, cardiovascular risk, airflow obstruction, and diffusing capacity, resting IC was independently associated with 10-year all-cause mortality (hazard ratio = 1.25, confidence interval 5%-95% = 1.16-1.34, P < 0.001), whereas MIP was excluded from the final model (all P = 0.829). Low resting IC was consistently linked to heightened dyspnea intensity, low V̇o 2peak , and worse survival in COPD even after accounting for airway obstruction, inspiratory muscle strength, and diffusing capacity. These results support the use of resting IC as an important physiological biomarker closely linked to key clinical outcomes in COPD. NEW & NOTEWORTHY To our knowledge, this study is the first to show an independent association between low resting inspiratory capacity (IC) and, severe exertional dyspnea, exercise limitation, and increased mortality risk, after accounting for the severity of airway obstruction, inspiratory muscle strength, and diffusing capacity. These results support the use of resting IC as an important independent physiological biomarker closely linked to key clinical outcomes in COPD.

Rationale: Impaired exercise ventilatory efficiency (high ventilatory requirements for CO 2 [[Formula: see text]e/[Formula: see text]co 2 ]) provides an indication of pulmonary gas exchange abnormalities in chronic obstructive pulmonary disease (COPD). Objectives: To determine 1 ) the association between high [Formula: see text]e/[Formula: see text]co 2 and clinical outcomes (dyspnea and exercise capacity) and its relationship to lung function and structural radiographic abnormalities; and 2 ) its prevalence in a large population-based cohort. Methods: Participants were recruited randomly from the population and underwent clinical evaluation, pulmonary function, cardiopulmonary exercise testing, and chest computed tomography. Impaired exercise ventilatory efficiency was defined by a nadir [Formula: see text]e/[Formula: see text]co 2 above the upper limit of normal (ULN), using population-based normative values. Measurements and Main Results: Participants included 445 never-smokers, 381 ever-smokers without airflow obstruction, 224 with Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 COPD, and 200 with GOLD 2-4 COPD. Participants with [Formula: see text]e/[Formula: see text]co 2 above the ULN were more likely to have activity-related dyspnea (Medical Research Council dyspnea scale ⩾ 2; odds ratio [5-95% confidence intervals], 1.77 [1.31 to 2.39]) and abnormally low peak [Formula: see text]o 2 ([Formula: see text]o 2peak below the lower limit of normal; odds ratio, 4.58 [3.06 to 6.86]). The Kco had a stronger correlation with nadir [Formula: see text]e/[Formula: see text]co 2 ( r  = -0.38; P  < 0.001) than other relevant lung function and computed tomography metrics. The prevalence of [Formula: see text]e/[Formula: see text]co 2 above the ULN was 24% in COPD (similar in GOLD 1 and 2 through 4), which was greater than in never-smokers (13%) and ever-smokers (12%). Conclusions: [Formula: see text]e/[Formula: see text]co 2 above the ULN was associated with greater dyspnea and low [Formula: see text]o 2peak and was present in 24% of all participants with COPD, regardless of GOLD stage. The results show the importance of recognizing impaired exercise ventilatory efficiency as a potential contributor to dyspnea and exercise limitation, even in mild COPD.

A cardiopulmonary exercise test (CPET) is ideally suited to quantify exercise tolerance and evaluate the pathophysiological mechanism(s) of dyspnea and exercise limitation in people with chronic respiratory disease. Although there are several statements on CPET and many outstanding resources detailing the cardiorespiratory and perceptual responses to exercise, limited information is available to support the health care provider in conducting a practical CPET evaluation. This article provides the health care provider with practical and timely information on how to use CPET data to understand dyspnea and exercise intolerance in people with chronic respiratory diseases. Information on CPET protocol, as well as how to evaluate maximal patient effort, peak rate of oxygen consumption, ventilatory demand, pulmonary gas exchange, ventilatory reserve, operating lung volumes, and exertional dyspnea, is presented. Two case examples are also described to highlight how these parameters are evaluated to provide a clinical interpretation of CPET data., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To assess whether night-time increases in mechanical loading negatively impact respiratory muscle function in COPD and whether compensatory increases in inspiratory neural drive (IND) are adequate to stabilize ventilatory output and arterial oxygen saturation, especially during sleep when wakefulness drive is withdrawn., Methods: 21 patients with moderate-to-severe COPD and 20 age-/sex-matched healthy controls (CTRL) participated in a prospective, cross-sectional, one-night study to assess the impact of COPD on serial awake, supine inspiratory capacity (IC) measurements and continuous dynamic respiratory muscle function (esophageal manometry) and IND (diaphragm electromyography, EMGdi) in supine sleep., Results: Supine inspiratory effort and EMGdi were consistently twice as high in COPD versus CTRL (p < 0.05). Despite overnight increases in awake total airways resistance and dynamic lung hyperinflation in COPD (p < 0.05; not in CTRL), elevated awake EMGdi and respiratory effort were unaltered in COPD overnight. At sleep onset (non-rapid eye movement sleep, N2), EMGdi was decreased versus wakefulness in COPD (- 43 ± 36%; p < 0.05) while unaffected in CTRL (p = 0.11); however, respiratory effort and arterial oxygen saturation (SpO 2 ) were unchanged. Similarly, in rapid eye movement (stage R), sleep EMGdi was decreased (- 38 ± 32%, p < 0.05) versus wakefulness in COPD, with preserved respiratory effort and minor (2%) reduction in SpO 2 ., Conclusions: Despite progressive mechanical loading overnight and marked decreases in wakefulness drive, inspiratory effort and SpO 2 were well maintained during sleep in COPD. Preserved high inspiratory effort during sleep, despite reduced EMGdi, suggests continued (or increased) efferent activation of extra-diaphragmatic muscles, even in stage R sleep., Clinical Trial Information: The COPD data reported herein were secondary data (Placebo arm only) obtained through the following Clinical Trial: "Effect of Aclidinium/Formoterol on Nighttime Lung Function and Morning Symptoms in Chronic Obstructive Pulmonary Disease" ( https://clinicaltrials.gov/ct2/show/NCT02429765 ; NCT02429765)., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In health, the near-eucapnic, highly efficient hyperpnea during mild-to-moderate intensity exercise is driven by three obligatory contributions, namely, feedforward central command from supra-medullary locomotor centers, feedback from limb muscle afferents, and respiratory CO 2 exchange (V̇CO 2 ). Inhibiting each of these stimuli during exercise elicits a reduction in hyperpnea even in the continuing presence of the other major stimuli. However, the relative contribution of each stimulus to the hyperpnea remains unknown as does the means by which V̇CO2 is sensed. Mediation of the hyperventilatory response to exercise in health is attributed to the multiple feedback and feedforward stimuli resulting from muscle fatigue. In patients with COPD, diaphragm EMG amplitude and its relation to ventilatory output are used to decipher mechanisms underlying the patients' abnormal ventilatory responses, dynamic lung hyperinflation and dyspnea during exercise. Key contributions to these exercise-limiting responses across the spectrum of COPD severity include high dead space ventilation, an excessive neural drive to breathe and highly fatigable limb muscles, together with mechanical constraints on ventilation. Major controversies concerning control of exercise hyperpnea are discussed along with the need for innovative research to uncover the link of metabolism to breathing in health and disease., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Evaluation of the intensity and quality of activity-related dyspnea is potentially useful in people with chronic obstructive pulmonary disease (COPD). The present study sought to examine associations between qualitative dyspnea descriptors, dyspnea intensity ratings, dynamic respiratory mechanics, and exercise capacity during cardiopulmonary exercise testing (CPET) in COPD and healthy controls., Methods: In this cross-sectional study, 261 patients with mild-to-very severe COPD (forced expiratory volume in 1 s, 62 ± 25%pred) and 94 age-matched controls (forced expiratory volume in 1 s, 114 ± 14%pred) completed an incremental cycle CPET to determine peak oxygen uptake (V˙O2peak). Throughout exercise, expired gases, operating lung volumes, and dyspnea intensity were assessed. At peak exercise, dyspnea quality was assessed using a modified 15-item questionnaire., Results: Logistic regression analysis revealed that among 15 dyspnea descriptors, only those alluding to the cluster "unsatisfied inspiration" were consistently associated with an increased likelihood for both critical inspiratory mechanical constraint (end-inspiratory lung volume/total lung capacity ratio ≥0.9) during exercise and reduced exercise capacity (V˙O2peak < lower limit of normal) in COPD (odds ratio (95% confidence interval), 3.26 (1.40-7.60) and 3.04 (1.24-7.45), respectively; both, P < 0.05). Thus, patients reporting "unsatisfied inspiration" (n = 177 (68%)) had an increased relative frequency of critical inspiratory mechanical constraint and low exercise capacity compared with those who did not select this descriptor, regardless of COPD severity or peak dyspnea intensity scores., Conclusions: In patients with COPD, regardless of disease severity, reporting descriptors in the unsatisfied inspiration cluster complemented traditional assessments of dyspnea during CPET and helped identify patients with critical mechanical abnormalities germane to exercise intolerance., (Copyright © 2021 by the American College of Sports Medicine.)

Patients with mild chronic obstructive pulmonary disease (COPD) and lower resting diffusing capacity for carbon monoxide (DL CO ) often report troublesome dyspnea during exercise although the mechanisms are not clear. We postulated that in such individuals, exertional dyspnea is linked to relatively high inspiratory neural drive (IND) due, in part, to the effects of reduced ventilatory efficiency. This cross-sectional study included 28 patients with GOLD I COPD stratified into two groups with ( n  = 15) and without ( n  = 13) DL CO less than the lower limit of normal (2 ( V̇ E / V̇ CO 2 ), and respiratory mechanics during incremental cycle exercise in the three groups. Spirometry and resting lung volumes were similar between COPD groups. During exercise, dyspnea, IND and V̇ E / V̇ CO 2 were higher at equivalent work rates (WR) in the DL CO CO CO CO E / V̇ CO 2 at a given work rate. Higher ventilatory requirements in the DL CO

There is well established evidence that the minute ventilation ( V ' E )/carbon dioxide output ( V ' CO 2 ) relationship is relevant to a number of patient-related outcomes in COPD. In most circumstances, an increased V ' E / V ' CO 2 reflects an enlarged physiological dead space ("wasted" ventilation), although alveolar hyperventilation (largely due to increased chemosensitivity) may play an adjunct role, particularly in patients with coexistent cardiovascular disease. The V ' E / V ' CO 2 nadir, in particular, has been found to be an important predictor of dyspnoea and poor exercise tolerance, even in patients with largely preserved forced expiratory volume in 1 s. As the disease progresses, a high nadir might help to unravel the cause of disproportionate breathlessness. When analysed in association with measurements of dynamic inspiratory constraints, a high V ' E / V ' CO 2 is valuable to ascertain a role for the "lungs" in limiting dyspnoeic patients. Regardless of disease severity, cardiocirculatory (heart failure and pulmonary hypertension) and respiratory (lung fibrosis) comorbidities can further increase V ' E / V ' CO 2 A high V ' E / V ' CO 2 is a predictor of poor outcome in lung resection surgery, adding value to resting lung hyperinflation in predicting all-cause and respiratory mortality across the spectrum of disease severity. Considering its potential usefulness, the V ' E / V ' CO 2 should be valued in the clinical management of patients with COPD., Competing Interests: Conflict of interest: J.A. Neder has nothing to disclose. Conflict of interest: D.C. Berton has nothing to disclose. Conflict of interest: D.B. Philips has nothing to disclose. Conflict of interest: D.E. O'Donnell has nothing to disclose., (Copyright ©ERS 2021.)

Background: The Global Initiative for Obstructive Lung Disease (GOLD) does not promote diffusing capacity for carbon monoxide (Dlco) values in the evaluation of COPD. In GOLD spirometric stage I COPD patients, the clinical and prognostic impact of a low Dlco has not been explored., Research Question: Could a Dlco threshold help define an increased risk of death and a different clinical presentation in these patients?, Study Design and Methods: GOLD stage I COPD patients (n = 360) were enrolled and followed over 109 ± 50 months. Age, sex, pack-years' history, BMI, dyspnea, lung function measurements, exercise capacity, BODE index, and history of exacerbations were recorded. A cutoff value for Dlco was identified for all-cause mortality and the clinical and physiological characteristics of patients above and below the threshold compared. Cox regression analysis explored the predictive power of that cutoff value for all-cause mortality., Results: A Dlco cutoff value of <60% predicted was associated with all-cause mortality (Dlco ≥ 60%: 9% vs Dlco < 60%: 23%, P = .01). At a same FEV 1 % predicted and Charlson score, patients with Dlco < 60% had lower BMI, more dyspnea, lower inspiratory capacity (IC)/total lung capacity (TLC) ratio, lower 6-min walk distance (6MWD), and higher BODE. Cox multiple regression analysis confirmed that after adjusting for age, sex, pack-years history, smoking status, and BMI, a Dlco < 60% is associated with all-cause mortality (hazard ratio [HR], 95% CI = 3.37, 1.35-8.39; P = .009) INTERPRETATION: In GOLD I COPD patients, a Dlco < 60% predicted is associated with increased risk of death and worse clinical presentation. What the cause(s) of this association are and whether they can be treated need to be determined., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

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 /V˙CO 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 /V˙CO 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 E /V˙CO 2 (nadir and slope) was consistently higher in the DL CO  < LLN compared with the other groups (all p < 0.05). The DL CO  < LLN group had lower IRV and greater dyspnoea intensity at standardized submaximal work rates and lower peak work rate and oxygen uptake than the other two groups (all p < 0.05)., Conclusion: Reduced exercise capacity in patients with DL CO  < LLN was related to higher ventilatory requirements, a faster rate of decline in dynamic IRV and greater dyspnoea during exercise. These simple measurements should be considered for the clinical evaluation of unexplained exercise intolerance in individuals with ostensibly mild COPD., (© 2021 Asian Pacific Society of Respirology.)

Objective: Impaired respiratory mechanics and gas exchange may contribute to sleep disturbance in patients with COPD. We aimed to assess putative associations of different domains of lung function (airflow limitation, lung volumes, and gas exchange efficiency) with polysomnography (PSG)-derived parameters of sleep quality and architecture in COPD., Methods: We retrospectively assessed data from COPD 181 patients ≥ 40 years of age who underwent spirometry, plethysmography, and overnight PSG. Univariate and multivariate linear regression models predicted sleep efficiency (total sleep time/total recording time) and other PSG-derived parameters that reflect sleep quality., Results: The severity of COPD was widely distributed in the sample (post-bronchodilator FEV1 ranging from 25% to 128% of predicted): mild COPD (40.3%), moderate COPD (43.1%), and severe-very severe COPD (16.6%). PSG unveiled a high proportion of obstructive sleep apnea (64.1%) and significant nocturnal desaturation (mean pulse oximetry nadir = 82.2% ± 6.9%). After controlling for age, sex, BMI, apnea-hypopnea index, nocturnal desaturation, comorbidities, and psychotropic drug prescription, FEV1/FVC was associated with sleep efficiency (β = 25.366; R2 = 14%; p < 0.001), whereas DLCO predicted sleep onset latency (β = -0.314; R2 = 13%; p < 0.001) and rapid eye movement sleep time/total sleep time in % (β = 0.085; R2 = 15%; p = 0.001)., Conclusions: Pulmonary function variables reflecting severity of airflow and gas exchange impairment, adjusted for some potential confounders, were weakly related to PSG outcomes in COPD patients. The direct contribution of the pathophysiological hallmarks of COPD to objectively measured parameters of sleep quality seems to be less important than it was previously assumed.

Background: Exercise-induced hypoxaemia is a hallmark of chronic fibrotic interstitial lung disease ( f -ILD). It remains unclear whether patients' severe hypoxaemia may exaggerate locomotor muscle fatigue and, if so, to what extent oxygen (O 2 ) supplementation can ameliorate these abnormalities., Methods: Fifteen patients (12 males, 9 with idiopathic pulmonary fibrosis) performed a constant-load (60% peak work rate) cycle test to symptom limitation (Tlim) while breathing medical air. Fifteen age-matched and sex-matched controls cycled up to patients' Tlim. Patients repeated the exercise test on supplemental O 2 (42%±7%) for the same duration. Near-infrared spectroscopy assessed vastus lateralis oxyhaemoglobin concentration ((HbO 2 )). Pre-exercise to postexercise variation in twitch force (∆Tw) induced by femoral nerve magnetic stimulation quantified muscle fatigue., Results: Patients showed severe hypoxaemia (lowest O 2 saturation by pulse oximetry=80.0%±7.6%) which was associated with a blunted increase in muscle (HbO 2) during exercise vs controls (+1.3±0.3 µmol vs +4.4±0.4 µmol, respectively; p<0.001). Despite exercising at work rates ∼ one-third lower than controls (42±13 W vs 66±13 W), ∆Tw was greater in patients (∆Tw/external work performed by the leg muscles=-0.59±0.21 %/kJ vs -0.25±0.19 %/kJ; p<0.001). Reversal of exertional hypoxaemia with supplemental O 2 was associated with a significant increase in muscle (HbO 2) , leading to a reduced decrease in ∆Tw in patients (-0.33±0.19 %/kJ; p<0.001 vs air). Supplemental O 2 significantly improved leg discomfort (p=0.005)., Conclusion: O 2 supplementation during exercise improves leg muscle oxygenation and fatigue in f -ILD. Lessening peripheral muscle fatigue to enhance exercise tolerance is a neglected therapeutic target that deserves clinical attention in this patient population., Competing Interests: Competing interests: MM was funded by a European Respiratory Society’s Long Term Fellowship and the John Alexander Stuart Fellowship, Queen’s University. JAN has been funded by the New Clinician Scientist Program from the Southeastern Ontario Academic Medical Association (SEAMO), Canada. His laboratory was established owing to the Canadian Foundation for Innovation’s John R. Evans Leaders Fund, Canada., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

There is growing recognition that a sizable fraction of COPD patients with forced expiratory volume in one second (FEV 1 )/forced vital capacity ratio below the lower limit of normal but preserved FEV 1 reports out-of-proportion dyspnea relative to the severity of airflow limitation. Most physicians, however, assume that patients' breathlessness is unlikely to reflect the negative physiological consequences of COPD vis-à-vis FEV 1 normalcy. This concise review integrates the findings of recent studies which uncovered the key pathophysiological features shared by these patients: poor pulmonary gas exchange efficiency (increased "wasted" ventilation) and gas trapping. These abnormalities are associated with two well-known causes of exertional dyspnea: heightened ventilation relative to metabolic demand and critically low inspiratory reserves, respectively. From a clinical standpoint, a low diffusion capacity associated with increased residual volume (RV) and/or RV/total lung capacity ratio might uncover these disturbances, identifying the subset of patients in whom exertional dyspnea is causally related to "mild" COPD.