Sex-differences in COPD: from biological mechanisms to therapeutic considerations.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous respiratory condition characterized by symptoms of dyspnea, cough, and sputum production. We review sex-differences in disease mechanisms, structure-function-symptom relationships, responses to therapies, and clinical outcomes in COPD with a specific focus on dyspnea. Females with COPD experience greater dyspnea and higher morbidity compared to males. Imaging studies using chest computed tomography scans have demonstrated that females with COPD tend to have smaller airways than males as well as a lower burden of emphysema. Sex-differences in lung and airway structure lead to critical respiratory mechanical constraints during exercise at a lower absolute ventilation in females compared to males, which is largely explained by sex differences in maximum ventilatory capacity. Females experience similar benefit with respect to inhaled COPD therapies, pulmonary rehabilitation, and smoking cessation compared to males. Ongoing re-assessment of potential sex-differences in COPD may offer insights into the evolution of patterns of care and clinical outcomes in COPD patients over time.

Physiological Factors Associated with Unsatisfied Inspiration at Peak Exercise in Healthy Adults.

INTRODUCTION: Contrary to common belief, a growing body of evidence suggests that unsatisfied inspiration (UI), an inherently uncomfortable quality of dyspnea, is experienced by ostensibly healthy adults during high-intensity exercise. Based on our understanding of the mechanisms of UI among people with chronic respiratory conditions, this analysis tested the hypothesis that the experience of UI at peak exercise in young, healthy adults reflects the combination of high ventilatory demand and critical inspiratory constraints. METHODS: In a retrospective analysis design, data included 321 healthy individuals (129 females) aged 25 ± 5 yrs. Data were collected during one visit to the laboratory, which included anthropometrics, spirometry, and an incremental cardiopulmonary cycling test to exhaustion. Metabolic and cardiorespiratory variables were measured at peak exercise, and qualitative descriptors of dyspnea at peak exercise were assessed using a list of 15 descriptor phrases. RESULTS: 34% of participants (n = 109) reported sensations of UI at peak exercise. Compared to the Non-UI group, the UI group achieved a significantly higher peak work rate (243 ± 77 vs. 235 ± 69 W, P = 0.016, d = 0.10), rate of O2 consumption (3.32 ± 1.02 vs. 3.27 ± 0.96 L·min-1, P = 0.018, d = 0.05), minute ventilation (120 ± 38 vs. 116 ± 35 L·min-1, P = 0.047, d = 0.11), and breathing frequency (50 ± 9 vs. 47 ± 9 breaths·min-1, P = 0.014, d = 0.33), while having a lower exercise-induced change (peak-baseline) in inspiratory capacity (0.07 ± 0.41 vs. 0.20 ± 0.49 L, P = 0.023, d = 0.29). The inspiratory reserve volume to minute ventilation ratio at peak exercise was also lower in the UI vs. Non-UI group. Dyspnea intensity and unpleasantness ratings were significantly higher in the UI vs. Non-UI group at peak exercise (both P < 0.001). CONCLUSIONS: Healthy individuals reporting UI at peak exercise have relatively greater inspiratory constraints compared to those who do not select UI.

Dysanapsis is not associated with exertional dyspnoea in healthy male and female never-smokers aged 40 years and older.

In healthy adults, airway-to-lung (i.e., dysanapsis) ratio is lower and dyspnoea during exercise at a given minute ventilation (V̇E) is higher in females than in males. We investigated the relationship between dysanapsis and sex on exertional dyspnoea in healthy adults. We hypothesized that females would have a smaller airway-to-lung ratio than males and that exertional dyspnoea would be associated with airway-to-lung ratio in males and females. We analyzed data from n = 100 healthy never-smokers aged ≥40 years enrolled in the Canadian Cohort Obstructive Lung Disease (CanCOLD) study who underwent pulmonary function testing, a chest computed tomography scan, and cardiopulmonary exercise testing. The luminal area of the trachea, right main bronchus, left main bronchus, right upper lobe, bronchus intermedius, left upper lobe, and left lower lobe were 22%-37% smaller (all p < 0.001) and the airway-to-lung ratio (i.e., average large conducting airway diameter relative to total lung capacity) was lower in females than in males (0.609 ± 0.070 vs. 0.674 ± 0.082; p < 0.001). During exercise, there was a significant effect of V̇E, sex, and their interaction on dyspnoea (all p < 0.05), indicating that dyspnoea increased as a function of V̇E to a greater extent in females than in males. However, after adjusting for age and total lung capacity, there were no significant associations between airway-to-lung ratio and measures of exertional dyspnoea, regardless of sex (all r < 0.34; all p > 0.05). Our findings suggest that sex differences in airway size do not contribute to sex differences in exertional dyspnoea.

Comparing the reliability of muscle oxygen saturation with common performance and physiological markers across cycling exercise intensity.

Introduction: Wearable near-infrared spectroscopy (NIRS) measurements of muscle oxygen saturation (SmO2) demonstrated good test-retest reliability at rest. We hypothesized SmO2 measured with the Moxy monitor at the vastus lateralis (VL) would demonstrate good reliability across intensities. For relative reliability, SmO2 will be lower than volume of oxygen consumption (V̇O2) and heart rate (HR), higher than concentration of blood lactate accumulation ([BLa]) and rating of perceived exertion (RPE). We aimed to estimate the reliability of SmO2 and common physiological measures across exercise intensities, as well as to quantify within-participant agreement between sessions. Methods: Twenty-one trained cyclists completed two trials of an incremental multi-stage cycling test with 5 min constant workload steps starting at 1.0 watt per kg bodyweight (W·kg-1) and increasing by 0.5 W kg-1 per step, separated by 1 min passive recovery intervals until maximal task tolerance. SmO2, HR, V̇O2, [BLa], and RPE were recorded for each stage. Continuous measures were averaged over the final 60 s of each stage. Relative reliability at the lowest, median, and highest work stages was quantified as intraclass correlation coefficient (ICC). Absolute reliability and within-subject agreement were quantified as standard error of the measurement (SEM) and minimum detectable change (MDC). Results: Comparisons between trials showed no significant differences within each exercise intensity for all outcome variables. ICC for SmO2 was 0.81-0.90 across exercise intensity. ICC for HR, V̇O2, [BLa], and RPE were 0.87-0.92, 0.73-0.97, 0.44-0.74, 0.29-0.70, respectively. SEM (95% CI) for SmO2 was 5 (3-7), 6 (4-9), and 7 (5-10)%, and MDC was 12%, 16%, and 18%. Discussion: Our results demonstrate good-to-excellent test-retest reliability for SmO2 across intensity during an incremental multi-stage cycling test. V̇O2 and HR had excellent reliability, higher than SmO2. [BLa] and RPE had lower reliability than SmO2. Muscle oxygen saturation measured by wearable NIRS was found to have similar reliability to V̇O2 and HR, and higher than [BLa] and RPE across exercise intensity, suggesting that it is appropriate for everyday use as a non-invasive method of monitoring internal load alongside other metrics.

Exercise responses and mental health symptoms in COVID-19 survivors with dyspnoea.

Objectives: Dyspnoea is a common persistent symptom post-coronavirus disease 2019 (COVID-19) illness. However, the mechanisms underlying dyspnoea in the post-COVID-19 syndrome remain unclear. The aim of our study was to examine dyspnoea quality and intensity, burden of mental health symptoms, and differences in exercise responses in people with and without persistent dyspnoea following COVID-19. Methods: 49 participants with mild-to-critical COVID-19 were included in this cross-sectional study 4 months after acute illness. Between-group comparisons were made in those with and without persistent dyspnoea (defined as modified Medical Research Council dyspnoea score ≥1). Participants completed standardised dyspnoea and mental health symptom questionnaires, pulmonary function tests, and incremental cardiopulmonary exercise testing. Results: Exertional dyspnoea intensity and unpleasantness were increased in the dyspnoea group. The dyspnoea group described dyspnoea qualities of suffocating and tightness at peak exercise (p<0.05). Ventilatory equivalent for carbon dioxide (V'E/V'CO2) nadir was higher (32±5 versus 28±3, p<0.001) and anaerobic threshold was lower (41±12 versus 49±11% predicted maximum oxygen uptake, p=0.04) in the dyspnoea group, indicating ventilatory inefficiency and deconditioning in this group. The dyspnoea group experienced greater symptoms of anxiety, depression and post-traumatic stress (all p<0.05). A subset of participants demonstrated gas-exchange and breathing pattern abnormalities suggestive of dysfunctional breathing. Conclusions: People with persistent dyspnoea following COVID-19 experience a specific dyspnoea quality phenotype. Dyspnoea post-COVID-19 is related to abnormal pulmonary gas exchange and deconditioning and is linked to increased symptoms of anxiety, depression and post-traumatic stress.

Inflammation associated with lung function abnormalities in COVID-19 survivors.

BACKGROUND: Activation of inflammatory pathways promotes organ dysfunction in COVID-19. Currently, there are reports describing lung function abnormalities in COVID-19 survivors; however, the biological mechanisms remain unknown. The aim of this study was to analyze the association between serum biomarkers collected during and following hospitalization and pulmonary function in COVID-19 survivors. METHODS: Patients recovering from severe COVID-19 were prospectively evaluated. Serum biomarkers were analyzed from admission to hospital, peak during hospitalization, and at the time of discharge. Pulmonary function was measured approximately 6 weeks after discharge. RESULTS: 100 patients (63% male) were included (age 48 years, SD ± 14) with 85% having at least one comorbidity. Patients with a restrictive spirometry pattern (n = 46) had greater inflammatory biomarkers compared to those with normal spirometry (n = 54) including peak Neutrophil-to-Lymphocyte ratio (NLR) value [9.3 (10.1) vs. 6.5 (6.6), median (IQR), p = 0.027] and NLR at hospital discharge [4.6 (2.9) vs. 3.2 (2.9) p = 0.005] and baseline C-reactive protein value [164.0 (147.0) vs. 106.5 (139.0) mg/dL, p = 0.083). Patients with an abnormal diffusing capacity (n = 35) had increased peak NLR [8.9 (5.9) vs. 5.6 (5.7) mg/L, p = 0.029]; baseline NLR [10.0 (19.0) vs. 4.0 (3.0) pg/ml, p = 0.002] and peak Troponin-T [10.0 (20.0) vs. 5.0 (5.0) pg/ml, p = 0.011] compared to patients with normal diffusing capacity (n = 42). Multivariable linear regression analysis identified predictors of restrictive spirometry and low diffusing capacity, but only accounted for a low degree of variance in pulmonary function outcome. CONCLUSION: Overexpression of inflammatory biomarkers is associated with subsequent lung function abnormalities in patients recovered from severe COVID-19.

The effect of severe intensity bouts on muscle oxygen saturation responses in trained cyclists.

Near-infrared spectroscopy (NIRS) quantifies muscle oxygenation (SmO2) during exercise. Muscle oxygenation response to self-paced, severe-intensity cycling remains unclear. Observing SmO2 can provide cycling professionals with the ability to assess muscular response, helping optimize decision-making. We aimed to describe the effect of self-paced severe intensity bouts on SmO2, measured noninvasively by a wearable NIRS sensor on the vastus lateralis (VL) muscle, and examine its reliability. We hypothesized a greater desaturation response with each bout, whereas, between trials, good reliability would be observed. Fourteen recreationally trained, and trained cyclists completed a ramp test to determine the power output (PO) at the respiratory compensation point (RCP). Athletes completed two subsequent visits of 50-minute sessions that included four severe-intensity bouts done at 5% above RCP PO. Muscle oxygenation in the VL was monitored using a wearable NIRS device. Measures included mean PO, heart-rate (HR), cadence, and SmO2 at bout onset, during work (work SmO2), and ΔSmO2. The bouts were compared using a one-way repeated measures ANOVA. For significant differences, a Fisher's least square difference post-hoc analysis was used. A two-way repeated measures ANOVA was used using trial and bout as main factors. Intraclass correlations (ICC) were used to quantify relative reliability for mean work, and standard error of the measurement (SEM) was used to quantify absolute agreement of mean work SmO2. Both PO and cadence showed no effect of bout or trial. Heart-rate at bout 2 (168 ± 8 bpm) and 4 (170 ± 7 bpm) were higher than bout 1 (160 ± 6 bpm). Onset SmO2 (%) response significantly increased in the final two bouts of the session. Mean work SmO2 increased across bouts, with the highest value displayed in bout 4 (36 ± 22%). ΔSmO2 showed a smaller desaturation response during bout 4 (27 ± 10%) compared to bout 3 (31 ± 10%). Mean work SmO2 ICC showed good reliability (ICC = 0.87), and SEM was 12% (CI 9-15%). We concluded that a non-invasive, affordable, wearable NIRS sensor demonstrated the heterogeneous muscle oxygenation response during severe intensity cycling bouts with good reliability in trained cyclists.

Effects of hypoxia on exercise-induced diaphragm fatigue in healthy males and females.

Following high-intensity, normoxic exercise there is evidence to show that healthy females, on average, exhibit less fatigue of the diaphragm relative to males. In the present study, we combined hypoxia with exercise to test the hypothesis that males and females would develop a similar degree of diaphragm fatigue following cycle exercise at the same relative exercise intensity. Healthy young participants (n = 10 male; n = 10 female) with a high aerobic capacity (120% predicted) performed two time-to-exhaustion (TTE; ~85% maximum) cycle tests on separate days breathing either a normoxic or hypoxic (FiO2  = 0.15) gas mixture. Fatigue of the diaphragm was assessed in response to cervical magnetic stimulation prior to, immediately post-exercise, 10-, 30-, and 60-min post-exercise. Males and females had similar TTE durations in normoxia (males: 690 ± 181 s; females: 852 ± 401 s) and hypoxia (males: 381 ± 160 s; females: 400 ± 176 s) (p > 0.05). Cycling time was significantly shorter in hypoxia versus normoxia in both males and females (p < 0.05) and did not differ on the basis of sex (p > 0.05). Following the hypoxic TTE tests, males and females experienced a similar degree of diaphragm fatigue compared to normoxia as shown by 20%-25% reductions in transdiaphragmatic twitch pressure. This occurred despite the fact that exercise time in hypoxia was substantially shorter relative to normoxia and the cumulative diaphragm work was lower. We also observed that females did not fully recover from diaphragm fatigue in hypoxia, whereas males did (p < 0.05). Sex differences in the rate of diaphragm contractility recovery following exercise in hypoxia might relate to sex-based differences in substrate utilization or diaphragm blood flow.

Voluntary activation of the diaphragm after inspiratory pressure threshold loading.

After a bout of isolated inspiratory work, such as inspiratory pressure threshold loading (IPTL), the human diaphragm can exhibit a reversible loss in contractile function, as evidenced by a decrease in transdiaphragmatic twitch pressure (PDI,TW ). Whether or not diaphragm fatigability after IPTL is affected by neural mechanisms, measured through voluntary activation of the diaphragm (D-VA) in addition to contractile mechanisms, is unknown. It is also unknown if changes in D-VA are similar between sexes given observed differences in diaphragm fatigability between males and females. We sought to determine whether D-VA decreases after IPTL and whether this was different between sexes. Healthy females (n = 11) and males (n = 10) completed an IPTL task with an inspired duty cycle of 0.7 and targeting an intensity of 60% maximal transdiaphragmatic pressure until task failure. PDI,TW and D-VA were measured using cervical magnetic stimulation of the phrenic nerves in combination with maximal inspiratory pressure maneuvers. At task failure, PDI,TW decreased to a lesser degree in females vs. males (87 ± 15 vs. 73 ± 12% baseline, respectively, p = 0.016). D-VA decreased after IPTL but was not different between females and males (91 ± 8 vs. 88 ± 10% baseline, respectively, p = 0.432). When all participants were pooled together, the decrease in PDI,TW correlated with both the total cumulative diaphragm pressure generation (R2  = 0.43; p = 0.021) and the time to task failure (TTF, R2 = 0.40; p = 0.30) whereas the decrease in D-VA correlated only with TTF (R2  = 0.24; p = 0.041). Our results suggest that neural mechanisms can contribute to diaphragm fatigability, and this contribution is similar between females and males following IPTL.

The effect of proportional assist ventilation on the electrical activity of the human diaphragm during exercise.

NEW FINDINGS: What is the central question of this study? What is the effect of lowering the normally occurring work of breathing on the electrical activity and pressure generated by the diaphragm during submaximal exercise in healthy humans? What is the main finding and its importance? Ventilatory assist during exercise elicits a proportional lowering of both the work performed by the diaphragm and diaphragm electrical activity. These findings have implications for exercise training studies using proportional assist ventilation to reduce diaphragm work in patients with cardiopulmonary disease. ABSTRACT: We hypothesized that when a proportional assist ventilator (PAV) is applied in order to reduce the pressure generated by the diaphragm, there would be a corresponding reduction in electrical activity of the diaphragm. Healthy participants (five male and four female) completed an incremental cycle exercise test to exhaustion in order to calculate workloads for subsequent trials. On the experimental day, participants performed submaximal cycling, and three levels of assisted ventilation were applied (low, medium and high). Ventilatory parameters, pulmonary pressures and EMG of the diaphragm (EMGdi ) were obtained. To compare the PAV conditions with spontaneous breathing intervals, ANOVA procedures were used, and significant effects were evaluated with a Tukey-Kramer test. Significance was set at P < 0.05. The work of breathing was not different between the lowest level of unloading and spontaneous breathing (P = 0.151) but was significantly lower during medium (25%, P = 0.02) and high (36%, P < 0.001) levels of PAV. The pressure-time product of the diaphragm (PTPdi ) was lower across PAV unloading conditions (P < 0.05). The EMGdi was significantly lower in medium and high PAV conditions (P = 0.035 and P < 0.001, respectively). The mean reductions of EMGdi with PAV unloading were 14, 22 and 39%, respectively. The change in EMGdi for a given lowering of PTPdi with the PAV was significantly correlated (r = 0.61, P = 0.01). Ventilatory assist during exercise elicits a reduction in the electrical activity of the diaphragm, and there is a proportional lowering of the work of breathing. Our findings have implications for exercise training studies using assisted ventilation to reduce diaphragm work in patients with cardiopulmonary disease.

Effects of Face Masks on the Multiple Dimensions and Neurophysiological Mechanisms of Exertional Dyspnea.

INTRODUCTION: During the coronavirus disease 2019 pandemic, public health officials widely adopted the use of face masks (FM) to minimize infections. Despite consistent evidence that FMs increase dyspnea, no studies have examined the multidimensional components of dyspnea or their underlying physiological mechanisms. METHODS: In a randomized crossover design, 16 healthy individuals ( n = 9 women, 25 ± 3 yr) completed incremental cycling tests over three visits, where visits 2 and 3 were randomized to either surgical FM or no mask control. Dyspnea intensity and unpleasantness were assessed throughout exercise (0-10 Borg scale), and the Multidimensional Dyspnea Profile was administered immediately after exercise. Crural diaphragmatic EMG and esophageal pressure were measured using a catheter to estimate neural respiratory drive and respiratory muscle effort, respectively. RESULTS: Dyspnea unpleasantness was significantly greater with the FM at the highest equivalent submaximal work rate achieved by a given participant in both conditions (iso-work; 5.9 ± 1.7 vs 3.9 ± 2.9 Borg 0-10 units, P = 0.007) and at peak exercise (7.8 ± 2.1 vs 5.9 ± 3.4 Borg 0-10 units, P = 0.01) with no differences in dyspnea intensity ratings throughout exercise compared with control. There were significant increases in the sensory quality of "smothering/air hunger" ( P = 0.01) and the emotional response of "anxiousness" ( P = 0.04) in the FM condition. There were significant increases in diaphragmatic EMG and esophageal pressure at select submaximal work rates, but no differences in heart rate, pulse oximetry-derived arterial oxygen saturation, or breathing frequency throughout exercise with FMs compared with control. FMs significantly reduced peak work rate and exercise duration (both P = 0.02). CONCLUSIONS: FMs negatively impact the affective domain of dyspnea and increase neural respiratory drive and respiratory muscle effort during exercise, although the impact on other cardiorespiratory responses are minimal.

Comparing the Respiratory Compensation Point With Muscle Oxygen Saturation in Locomotor and Non-locomotor Muscles Using Wearable NIRS Spectroscopy During Whole-Body Exercise.

The relationship between the muscle deoxygenation breakpoint (Deoxy-BP) measured with near-infrared spectroscopy (NIRS), and the respiratory compensation point (RCP) has been well established. This relationship has also been reported using wearable NIRS, however not in locomotor and non-locomotor muscles simultaneously during whole-body cycling exercise. Our aim was to measure muscle oxygen saturation (SmO2) using wearable NIRS sensors, and to compare the Deoxy-BPs at each muscle with RCP during a ramp cycling exercise test. Twenty-two trained female and male cyclists completed a ramp exercise test to task intolerance on a cycling ergometer, at a ramp rate of 1 W every 2 s (30 W/min). SmO2 was recorded at the subjects' right vastus lateralis (VL) and right lateral deltoid. SmO2 and the Deoxy-BPs were assessed using a piecewise double-linear regression model. Ventilation (V̇E) and gas exchange were recorded, and RCP was determined from V̇E and gas exchange using a V-slope method and confirmed by two physiologists. The SmO2 profiles of both muscles and gas exchange responses are reported as V̇O2, power output (W), and time of occurrence (TO). SmO2 profiles at both muscles displayed a near-plateau or breakpoint response near the RCP. No differences were detected between the mean RCP and mean Deoxy-BP from either the locomotor or non-locomotor muscles; however, a high degree of individual variability was observed in the timing and order of occurrence of the specific breakpoints. These findings add insight into the relationships between ventilatory, locomotor, and non-locomotor muscle physiological breakpoints. While identifying a similar relationship between these breakpoints, individual variability was high; hence, caution is advised when using wearable NIRS to estimate RCP in an incremental ramp test.

Cardiorespiratory physiology, exertional symptoms, and psychological burden in post-COVID-19 fatigue.

Fatigue is a common, debilitating, and poorly understood symptom post-COVID-19. We sought to better characterize differences in those with and without post-COVID-19 fatigue using cardiopulmonary exercise testing. Despite elevated dyspnoea intensity ratings, V̇O2peak (ml/kg/min) was the only significant difference in the physiological responses to exercise (19.9 ± 7.1 fatigue vs. 24.4 ± 6.7 ml/kg/min non-fatigue, p = 0.04). Consistent with previous findings, we also observed a higher psychological burden in those with fatigue in the context of similar resting cardiopulmonary function. Our findings suggest that lower cardiorespiratory fitness and/or psychological factors may contribute to post-COVID-19 fatigue symptomology. Further research is needed for rehabilitation and symptom management following SARS-CoV-2 infection.

Predictors of Expiratory Flow Limitation during Exercise in Healthy Males and Females.

RATIONALE: It is unclear whether the frequency and mechanisms of expiratory flow limitation (EFL) during exercise differ between males and females. PURPOSE: This study aimed to determine which factors predispose individuals to EFL during exercise and whether these factors differ based on sex. We hypothesized that i) EFL frequency would be similar in males and females and ii) in females, EFL would be associated with indices of low ventilatory capacity, whereas in males, EFL would be associated with indices of high ventilatory demand. METHODS: Data from n = 126 healthy adults (20-45 y, n = 60 males, n = 66 females) with a wide range of cardiorespiratory fitness (81%-182% predicted maximal oxygen uptake) were included in the study. Participants performed spirometry and an incremental cycle exercise test to exhaustion. Standard cardiorespiratory variables were assessed throughout exercise. The tidal flow-volume overlap method was used to assess EFL based on a minimum threshold of 5% overlap between the tidal and the maximum expiratory flow-volume curves. Predictors of EFL during exercise were determined via multiple logistical regression using anthropometric, pulmonary function, and peak exercise data. RESULTS: During exercise, EFL occurred in 49% of participants and was similar between the sexes (females = 45%, males = 53%; P = 0.48). In males, low forced expired flow between 25% and 75% of forced vital capacity and high slope ratio as well as low end-expiratory lung volume, high breathing frequency, and high relative tidal volume at peak exercise were associated with EFL ( P < 0.001; Nagelkerke R2 = 0.73). In females, high slope ratio, high breathing frequency, and tidal volume at peak exercise were associated with EFL ( P < 0.001; Nagelkerke R2 = 0.61). CONCLUSIONS: Despite sex differences in respiratory system morphology, the frequency and the predictors of EFL during exercise do not substantially differ between the sexes.

Impaired Ventilatory Efficiency, Dyspnea, and Exercise Intolerance in Chronic Obstructive Pulmonary Disease: Results from the CanCOLD Study.

Rationale: Impaired exercise ventilatory efficiency (high ventilatory requirements for CO2 [[Formula: see text]e/[Formula: see text]co2]) 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]co2 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]co2 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]co2 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]o2 ([Formula: see text]o2peak 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]co2 (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]co2 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]co2 above the ULN was associated with greater dyspnea and low [Formula: see text]o2peak 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.

Association of BMI with pulmonary function, functional capacity, symptoms, and quality of life in ILD.

Obesity is a health epidemic associated with greater morbidity and mortality in the general population. Mass loading of the thorax from obesity leads to a restrictive pulmonary defect that reduces lung capacity in obese individuals without pulmonary disease, and may exacerbate the restrictive pulmonary physiology that is characteristic of interstitial lung disease (ILD). The purpose of this study was to test the association of body mass index (BMI) with pulmonary function, functional capacity, and patient-reported outcomes (dyspnea and quality of life) in patients with ILD. We analyzed 3169 patients with fibrotic ILD from the Canadian Registry for Pulmonary Fibrosis. Patients were subcategorized as underweight (BMI<18.5 kg/m2), normal weight (18.5≤BMI<25), overweight (25≤BMI<30), obese I (30≤BMI<35), obese II (35≤BMI<40), and obese III (BMI>40). Analysis was performed using a linear regression with adjustment for common prognostic variables. Overweight and obese BMI categories were associated with worse pulmonary function, functional capacity, dyspnea, and quality of life compared to normal weight. This is likely a result of mass loading on the thorax, and we speculate that intentional weight-loss may improve lung function and functional capacity in obese patients with fibrotic ILD. The underweight BMI category was also associated with worse functional capacity compared to normal weight, which may reflect greater disease severity or the presence of other comorbidities. Future work should explore the clinical utility of BMI to improve patient outcomes.

Sex Differences in Diaphragm Voluntary Activation after Exercise.

INTRODUCTION: The female diaphragm develops less fatigue after high-intensity exercise compared with males. Diaphragm fatigability is typically defined as a decrease in transdiaphragmatic twitch pressure (Pdi,TW) and represents the contractile function of the muscle. However, it is unclear whether this sex difference persists when examining changes in voluntary activation, which represents a neural mechanism contributing to fatigability. PURPOSE: This study aimed to determine if high-intensity cycling results in a decrease in diaphragm voluntary activation (D-VA) and to explore if the decrease in D-VA is different between sexes. METHODS: Twenty-five participants (15 females) completed a single bout of high-intensity constant load cycling. D-VA and Pdi,TW were measured before and after exercise using cervical magnetic stimulation of the phrenic nerves to assess diaphragm fatigability. RESULTS: Participants were of similar aerobic fitness when expressed relative to predicted values (females: 114% ± 25% predicted, males: 111% ± 11% predicted; P = 0.769). Pdi,TW decreased relative to baseline to 85.2% ± 16.7% and 70.3% ± 12.4% baseline (P = 0.012) in females and males, respectively, immediately after exercise. D-VA also decreased in both females and males immediately after exercise. The decrease in D-VA was less in females compared with males (95.4% ± 4.9% baseline vs 87.4% ± 10.8% baseline, respectively; P = 0.018). CONCLUSIONS: D-VA decreases after whole-body exercise in both females and males, although the magnitude of the decrease is not as large in females compared with males. The findings of this study suggest that the female diaphragm is more resistant to both contractile and neural mechanisms of fatigability after whole-body exercise.

Using Cardiopulmonary Exercise Testing to Understand Dyspnea and Exercise Intolerance in Respiratory Disease.

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.