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Background: In adults with serious respiratory illness, breathlessness is prevalent and associated with reduced health-related quality of life. The aim of this review was to assess the impact of breathing techniques on breathlessness in adults with serious respiratory illness., Methods: Electronic databases were searched to identify randomised controlled trials testing breathing techniques (techniques that aim to alter the respiratory pattern, excluding respiratory muscle training) in people with serious respiratory illness. The primary outcome was breathlessness and secondary outcomes were health-related quality of life and adverse events. Two authors independently screened for inclusion, evaluated risk of bias and extracted data., Results: 73 randomised controlled trials were included with 5479 participants, most with COPD or asthma. Breathing exercises (pursed lip and/or diaphragmatic breathing) reduced breathlessness measured by the modified Medical Research Council scale compared to usual care (mean difference (MD) -0.40 points, 95% CI -0.70- -0.11, eight studies, n=323), although the effect did not exceed the minimal important difference. Yoga breathing also improved modified Medical Research Council score compared to usual care (MD -1.05 points, 95% CI -2.45-0.35, three studies, n=175). Breathing techniques consistently improved health-related quality of life in people with COPD and asthma on multiple health-related quality of life measures in comparison to usual care, with effects that generally exceeded the minimal important difference. No adverse events related to breathing techniques were reported., Conclusion: Breathing techniques may improve breathlessness, and consistently improve health-related quality of life, in people with serious respiratory illness. These findings support the use of breathing exercises in the care of people with serious respiratory illness., Competing Interests: Conflicts of interest: L. Romero declares funding from the European Respiratory Society to design search strategies for this review. A.E. Holland declares authorship on one of the systematic reviews included in this study but no other conflicts of interest. All other authors declare no conflicts of interest., (Copyright ©The authors 2024.)

Background: People living with serious respiratory illness experience a high burden of symptoms. This review aimed to determine whether multicomponent services reduce symptoms in people with serious illness related to respiratory disease., Methods: Electronic databases were searched to identify randomised controlled trials (RCTs) evaluating multicomponent services that enrolled patients due to symptoms, rather than underlying disease, and provided at least one nonpharmacological intervention. The primary outcome was chronic breathlessness and secondary outcomes were health-related quality of life (HRQoL), cough, fatigue and adverse events. At least two authors independently screened studies, assessed risk of bias and extracted data., Results: Five RCTs, involving 439 patients, were included. In comparison to usual care, multicomponent services improved breathlessness mastery (Chronic Respiratory Questionnaire (CRQ) mastery scale, mean difference (MD) 0.43 points, 95% CI 0.20-0.67, three RCTs, 327 participants) and HRQoL (CRQ total score, MD 0.24 points, 95% CI 0.04-0.40, two RCTs, 237 participants). Fatigue did not improve with multicomponent services and no studies evaluated cough. No serious adverse events were reported. The one study evaluating mortality found increased survival in those accessing a multicomponent service. The certainty of evidence was very low, mainly due to detection and reporting bias., Conclusion: Multicomponent services improve breathlessness mastery and HRQoL, with minimal risk. These findings support the use of multicomponent symptom-directed services for people living with serious respiratory illness., Competing Interests: Conflict of interest: All authors have nothing to disclose., (Copyright ©The authors 2024.)

Background: People living with serious respiratory illness experience a high burden of distressing symptoms. Although opioids are prescribed for symptom management, they generate adverse events, and their benefits are unclear., Methods: We examined the efficacy and safety of opioids for symptom management in people with serious respiratory illness. Embase, MEDLINE and the Cochrane Central Register of Controlled Trials were searched up to 11 July 2022. Reports of randomised controlled trials administering opioids to treat symptoms in people with serious respiratory illness were included. Key exclusion criteria included <80% of participants having a nonmalignant lung disease. Data were extracted regarding study characteristics, outcomes of breathlessness, cough, health-related quality of life (HRQoL) and adverse events. Treatment effects were pooled using a generic inverse variance model with random effects. Risk of bias was assessed using the Cochrane Risk of Bias tool version 1., Results: Out of 17 included trials, six were laboratory-based exercise trials (n=70), 10 were home studies measuring breathlessness in daily life (n=788) and one (n=18) was conducted in both settings. Overall certainty of evidence was "very low" to "low". Opioids reduced breathlessness intensity during laboratory exercise testing (standardised mean difference (SMD) -0.37, 95% CI -0.67- -0.07), but not breathlessness measured in daily life (SMD -0.10, 95% CI -0.64-0.44). No effects on HRQoL (SMD -0.42, 95% CI -0.98-0.13) or cough (SMD -1.42, 95% CI -3.99-1.16) were detected. In at-home studies, opioids led to increased frequency of nausea/vomiting (OR 3.32, 95% CI 1.70-6.51), constipation (OR 3.08, 95% CI 1.69-5.61) and drowsiness (OR 1.37, 95% CI 1.01-1.86), with serious adverse events including hospitalisation and death identified., Conclusions: Opioids improved exertional breathlessness in laboratory exercise studies, but did not improve breathlessness, cough or HRQoL measured in daily life at home. There were significant adverse events, which may outweigh any benefits., Competing Interests: Conflict of interest: N.E. Smallwood reports grants from NHMRC, MRFF, Cancer Council Australia, Fisher & Paykel Healthcare (FPH), Windermere Foundation, Lung Foundation Australia, Lord Mayor's Foundation Melbourne and Bethlehem Griffiths Foundation, consulting fees from The Limbic and Orchard Consulting, lecture honoraria from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, FPH and Health Ed, travel support from Chiesi and Boehringer Ingelheim, leadership roles as Board Director and past state president of the Thoracic Society of Australia and New Zealand, Board Director of Victorian Doctors’ Program and co-chair of the guidelines committee for European Respiratory Society; and receipt of equipment from FPH, outside the submitted work. M. Wijsenbeek reports grants from The Netherlands Organisation for Health Research and Development, The Dutch Lung Foundation, The Dutch Pulmonary Fibrosis organization, Sarcoidosis.nl, Boehringer Ingelheim, Hoffman la Roche and AstraZeneca-Daiichi, consulting fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Galapagos, Galecto, GSK, Hoffman la Roche, Horizon therapeutics, Kinevant Sciences, Molecure, Nerre Therapeutics, Novartis, PureTech Health, Thyron, Trevi and Vicore, lecture honoraria from Boehringer Ingelheim, CSL Behring, Hoffman la Roche and Novartis, travel support from Boehringer Ingelheim, GSK, Hoffman la Roche and Galapagos, advisory board participation with Galapagos, and leadership roles as Chair of the Idiopathic Interstitial Pneumonia group of the European Respiratory Society, Member of the board of the Netherlands Respiratory Society, Member of the scientific advisory board of the European Idiopathic Pulmonary Fibrosis and related disorders federation, Chair of the educational committee of the European Reference Network for rare Lung Diseases, and membership of the advisory board of the Dutch Lungfibrosis and Sarcoidosis patient associations, outside the submitted work. A-M. Russell reports consulting fees from Boehringer Ingelheim, and lecture honoraria from Boehringer Ingelheim, Hoffman La Roche and the Irish Lung Fibrosis Association, outside the submitted work. A.E. Holland is President of Thoracic Society of Australia and New Zealand, an unpaid position unrelated to the present work. All other authors have nothing to disclose., (Copyright ©The authors 2024.)

Question: Dyspnoea persisting despite treatments of underlying causes requires symptomatic approaches. Medical hypnosis could provide relief without the untoward effects of pharmacological approaches. We addressed this question through experimentally induced dyspnoea in healthy humans (inspiratory threshold loading (excessive inspiratory effort) and carbon dioxide stimulation (air hunger))., Material and Methods: 20 volunteers (10 women, aged 21-40 years) were studied on four separate days. The order of the visits was randomised in two steps: firstly, the "inspiratory threshold loading first" versus "carbon dioxide first" group (n=10 in each group); secondly, the "medical hypnosis first" versus "visual distraction first" subgroup (n=5 in each subgroup). Each visit comprised three 5-min periods (reference, intervention, washout) during which participants used visual analogue scales (VAS) to rate the sensory and affective dimensions of dyspnoea, and after which they completed the Multidimensional Dyspnea Profile., Results: Medical hypnosis reduced both dimensions of dyspnoea significantly more than visual distraction (inspiratory threshold loading: sensory reduction after 5 min 34% of full VAS versus 8% (p=0.0042), affective reduction 17.6% versus 2.4% (p=0.044); carbon dioxide: sensory reduction after 5 min 36.9% versus 3% (p=0.0015), affective reduction 29.1% versus 8.7% (p=0.0023)). The Multidimensional Dyspnea Profile showed more marked sensory effects during inspiratory threshold loading and more marked affective effects during carbon dioxide stimulation., Answer to the Question: Medical hypnosis was more effective than visual distraction at attenuating the sensory and affective dimensions of experimentally induced dyspnoea. This provides a strong rationale for clinical studies of hypnosis in persistent dyspnoea patients., Competing Interests: Conflict of interest: C. Morélot-Panzini reports grants from Fondation du Souffle and lecture honoraria from Chiesi, outside the submitted work.Conflict of interest: L. Serresse reports lecture honoraria from Chiesi and travel support from SOS Oxygene, outside the submitted work.Conflict of interest: T. Similowski reports consulting fees from AstraZeneca, Chiesi, KPL Consulting, Lungpacer Inc. and OSO-AI; lecture honoraria from Chiesi and Vitalaire; stock or stock options from AUSTRAL Dx and HEPHAI; and the following patents: WO2008006963A3, WO2012004534A1, WO2013164462A1; outside the submitted work.Conflict of interest: The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Introduction: Pathophysiology changes associated with pleural effusion, its drainage and factors governing symptom response are poorly understood. Our objective was to determine: 1) the effect of pleural effusion (and its drainage) on cardiorespiratory, functional and diaphragmatic parameters; and 2) the proportion as well as characteristics of patients with breathlessness relief post-drainage., Methods: Prospectively enrolled patients with symptomatic pleural effusions were assessed at both pre-therapeutic drainage and at 24-36 h post-therapeutic drainage., Results: 145 participants completed pre-drainage and post-drainage tests; 93% had effusions ≥25% of hemithorax. The median volume drained was 1.68 L. Breathlessness scores improved post-drainage (mean visual analogue scale (VAS) score by 28.0±24 mm; dyspnoea-12 (D12) score by 10.5±8.8; resting Borg score before 6-min walk test (6-MWT) by 0.6±1.7; all p<0.0001). The 6-min walk distance (6-MWD) increased by 29.7±73.5 m, p<0.0001. Improvements in vital signs and spirometry were modest (forced expiratory volume in 1 s (FEV 1 ) by 0.22 L, 95% CI 0.18-0.27; forced vital capacity (FVC) by 0.30 L, 95% CI 0.24-0.37). The ipsilateral hemi-diaphragm was flattened/everted in 50% of participants pre-drainage and 48% of participants exhibited paradoxical or no diaphragmatic movement. Post-drainage, hemi-diaphragm shape and movement were normal in 94% and 73% of participants, respectively. Drainage provided meaningful breathlessness relief (VAS score improved ≥14 mm) in 73% of participants irrespective of whether the lung expanded (mean difference 0.14, 95% CI 10.02-0.29; p=0.13). Multivariate analyses found that breathlessness relief was associated with significant breathlessness pre-drainage (odds ratio (OR) 5.83 per standard deviation (sd) decrease), baseline abnormal/paralyzed/paradoxical diaphragm movement (OR 4.37), benign aetiology (OR 3.39), higher pleural pH (OR per sd increase 1.92) and higher serum albumin level (OR per sd increase 1.73)., Conclusions: Breathlessness and exercise tolerance improved in most patients with only a small mean improvement in spirometry and no change in oxygenation. Breathlessness improvement was similar in participants with and without trapped lung. Abnormal hemi-diaphragm shape and movement were independently associated with relief of breathlessness post-drainage., Competing Interests: Conflict of interest: S. Muruganandan has nothing to disclose. Conflict of interest: M. Azzopardi has nothing to disclose. Conflict of interest: R. Thomas has nothing to disclose. Conflict of interest: D.B Fitzgerald has nothing to disclose. Conflict of interest: Y.J. Kuok has nothing to disclose. Conflict of interest: H.M. Cheah has nothing to disclose. Conflict of interest: C.A. Read has nothing to disclose. Conflict of interest: C.A. Budgeon has nothing to disclose. Conflict of interest: P.R. Eastwood has nothing to disclose. Conflict of interest: S. Jenkins has nothing to disclose. Conflict of interest: B. Singh has nothing to disclose. Conflict of interest: K. Murray has nothing to disclose. Conflict of interest: Y.C.G. Lee has served on the advisory board of CareFusion/BD Ltd and has previously led clinical trials for which Rocket Medical plc (UK) provided the drainage kits for study participants without charge, as well as providing an unrestricted educational grant to assist the running of the trial., (Copyright ©ERS 2020.)

Chronic obstructive pulmonary disease (COPD) is a chronic illness that can be periodically punctuated by exacerbations, characterised by acute worsening of symptoms, including increased dyspnoea, cough, sputum production and sputum purulence. COPD exacerbations are common and have important clinical and economic consequences, including lost work productivity, increased utilisation of healthcare resources, temporary or permanent reductions in lung function and exercise capacity, hospitalisation, and sometimes death. Over the past two decades, clinicians and researchers have broadened their treatment goals for COPD to extend beyond improving lung function and symptoms, and have begun to address the importance of preventing and reducing exacerbations. However, despite the best efforts of clinicians and guideline committees, current definitions of COPD exacerbations are imperfect and fraught with problems. The cardinal symptoms of a COPD exacerbation are nonspecific and can result from acute cardiorespiratory illnesses other than COPD. A proposed definition, which may be more specific than current definitions, suggests that COPD exacerbation be defined as an acute or subacute worsening of dyspnoea (≥5 on a visual analogue scale that ranges from 0 to 10) sometimes but not necessarily accompanied by increased cough, sputum volume and/or sputum purulence. Necessary laboratory criteria for an exacerbation include oxygen desaturation ≤4% below that of stable state, elevated levels of circulating blood neutrophils or eosinophils (≥9000 neutrophils·mm -3 or ≥2% blood eosinophils) and elevated C-reactive protein (≥3 mg·L -1 ), without evidence of pneumonia or pulmonary oedema on chest radiography and with negative laboratory test results for other aetiologies. Herein, we discuss the current state of the art with respect to how we define COPD exacerbations, associated pitfalls and challenges, and opportunities for improvement., Competing Interests: Conflict of interest: V. Kim has nothing to disclose. Conflict of interest: S.D. Aaron has nothing to disclose., (Copyright ©ERS 2018.)

The vicious circle of dyspnoea-inactivity has been proposed, but never validated empirically, to explain the clinical course of chronic obstructive pulmonary disease (COPD). We aimed to develop and validate externally a comprehensive vicious circle model.We utilised two methods. 1) Identification and validation of all published vicious circle models by a systematic literature search and fitting structural equation models to longitudinal data from the Spanish PAC-COPD (Phenotype and Course of COPD) cohort (n=210, mean age 68 years, mean forced expiratory volume in 1 s (FEV 1 ) 54% predicted), testing both the hypothesised relationships between variables in the model ("paths") and model fit. 2) Development of a new model and external validation using longitudinal data from the Swiss and Dutch ICE COLD ERIC (International Collaborative Effort on Chronic Obstructive Lung Disease: Exacerbation Risk Index Cohorts) cohort (n=226, mean age 66 years, mean FEV 1 57% predicted).We identified nine vicious circle models for which structural equation models confirmed most hypothesised paths but showed inappropriate fit. In the new model, airflow limitation, hyperinflation, dyspnoea, physical activity, exercise capacity and COPD exacerbations remained related to other variables and model fit was appropriate. Fitting it to ICE COLD ERIC, all paths were replicated and model fit was appropriate.Previously published vicious circle models do not fully explain the vicious circle concept. We developed and externally validated a new comprehensive model that gives a more relevant role to exercise capacity and COPD exacerbations., Competing Interests: Conflict of interest: A. Agustí reports receiving grants and personal fees from AstraZeneca, GSK and Menarini, grants from MSD, and personal fees from Novartis, Teva and Chiesi, outside the submitted work. Conflict of interest: R. Rodriguez-Roisin reports receiving grants from Almirall and Menarini, personal fees for service on an advisory board from Boehringer Ingelheim, Pearl Therapeutics and Teva, and lecture fees from Novartis and Takeda, during the conduct of the study, all related to COPD. Conflict of interest: J. Garcia-Aymerich reports payments to her institution for consulting and lecturing from AstraZeneca, and receiving lecture fees from Esteve and Chiesi, outside the submitted work., (Copyright ©ERS 2018.)

Dyspnoea is usually caused by diagnosable cardiorespiratory mechanisms. However, frequently dyspnoea relates only weakly or not at all to cardiorespiratory functioning, suggesting that additional neuropsychosocial processes contribute to its experience. We tested whether the mere observation of dyspnoea in others constitutes such a process and would elicit dyspnoea, negative affect and increased brain responses in the observer.In three studies, series of pictures and videos were presented, which either depicted persons suffering from dyspnoea or nondyspnoeic control stimuli. Self-reports of dyspnoea and affective state were obtained in all studies. Additionally, respiratory variables and brain responses during picture viewing (late positive potentials in electroencephalograms) were measured in one study.In all studies, dyspnoea-related pictures and videos elicited mild-to-moderate dyspnoea and increased negative affect compared to control stimuli. This was paralleled by increased late positive potentials for dyspnoea-related pictures while respiratory variables did not change. Moreover, increased dyspnoea correlated modestly with higher levels of empathy in observers.The present results demonstrate that observing dyspnoea in others elicits mild-to-moderate dyspnoea, negative affect, and increased brain responses in the absence of respiratory changes. This vicarious dyspnoea has clinical relevance, as it might increase suffering in the family and medical caregivers of dyspnoeic patients., Competing Interests: Conflict of interest: T. Similowski reports personal fees from AstraZeneca, Boerhinger Ingelheim France, GSK, Lungpacer Inc., TEVA, Chiesi, Pierre Fabre and Invacare, and personal fees and non-financial support from Novartis, outside the submitted work. Conflict of interest: A. von Leupoldt received research grants STRT/13/002 and DBOF/14/021 from Research Fund KU Leuven, Belgium, research infrastructure grant AKUL/13/07 from Herculesstichting, Belgium, and long-term structural research funding Methusalem grant METH/15/011 from the Flemish Government, Belgium, during the conduct of the study., (Copyright ©ERS 2018.)

What is the experience of people living with breathlessness due to medical conditions, those caring for them and those treating them, with regard to quality of life and the nature of clinical interactions?Electronic databases (Ovid MEDLINE, Embase, CINAHL Plus and PsycINFO) were searched (January 1987 to October 2017; English language), for qualitative studies exploring the experience of chronic breathlessness (patients, carers and clinicians). Two independent reviewers screened titles, abstracts and papers retrieved against inclusion criteria. Disagreements were resolved with a third reviewer. Primary qualitative data were extracted and synthesised using thematic synthesis.Inclusion and synthesis of 101 out of 2303 international papers produced four descriptive themes: 1) widespread effects of breathlessness; 2) coping; 3) help-seeking behaviour; and 4) clinicians' responsiveness to the symptom of breathlessness. The themes were combined to form the concept of "breathing space", to show how engaged coping and appropriate help-seeking (patient) and attention to symptom (clinician) helps maximise the patient's quality of living with breathlessness.Breathlessness has widespread impact on both patient and carer and affects breathing space. The degree of breathing space is influenced by interaction between the patient's coping style, their help-seeking behaviour and their clinician's responsiveness to breathlessness itself, in addition to managing the underlying disease., Competing Interests: Conflict of interest: None declared., (Copyright ©ERS 2018.)

Mortality and symptom burden from chronic obstructive pulmonary disease (COPD) and lung cancer are similar but there is thought to be an inequality in palliative care support (PCS) between diseases. This nationally representative study assessed PCS for COPD patients within primary care in the UK.This was a cohort study using electronic healthcare records (2004-2015). Factors associated with receiving PCS were assessed using logistic regression for the whole cohort and deceased patients.There were 92 365 eligible COPD patients, of which 26 135 died. Only 7.8% of the whole cohort and 21.4% of deceased patients received PCS. Lung cancer had a strong association with PCS compared with other patient characteristics, including Global Initiative for Chronic Obstructive Lung Disease stage and Medical Research Council Dyspnoea score (whole cohort, lung cancer: OR 14.1, 95% CI 13.1-15; deceased patients, lung cancer: OR 6.5, 95% CI 6-7). Only 16.7% of deceased COPD patients without lung cancer received PCS compared with 56.5% of deceased patients with lung cancer. In patients that received PCS, lung cancer co-diagnosis significantly increased the chances of receiving PCS before the last month of life (1-6 versus ≤1 month pre-death: risk ratio 1.4, 95% CI 1.3-1.7).Provision of PCS for COPD patients in the UK is inadequate. Lung cancer, not COPD, was the dominant driver for COPD patients to receive PCS., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2018.)

The benefit of inspiratory muscle training (IMT) combined with a pulmonary rehabilitation programme (PRP) is uncertain. We aimed to demonstrate that, in severe and very severe chronic obstructive pulmonary disease (COPD) patients, IMT performed during a PRP is associated with an improvement of dyspnoea.In a single-blind randomised controlled trial, 150 severe or very severe COPD patients were allocated to follow PRP+IMT versus PRP alone. The evaluations were performed at inclusion and after 4 weeks. The primary outcome was the change in dyspnoea using the Multidimensional Dyspnoea Profile questionnaire at the end of a 6-min walk test (6MWT) at 4 weeks. Secondary outcomes were changes in dyspnoea using the Borg (end of the 6MWT) and modified Medical Research Council scales and in functional parameters (maximal inspiratory pressure ( P Imax ), inspiratory capacity, 6MWT and quality of life). All analyses were performed on an intention-to-treat basis.Dyspnoea decreased significantly in both groups; however, the improvement of dyspnoea was not statistically different between the two groups. We only found a statistically significant greater increase of P Imax after IMT+PRP than after PRP alone.In this trial including severe or very severe COPD patients, we did not find a significant benefit of IMT during PRP+IMT as compared to PRP alone on dyspnoea, despite a significantly higher improvement of P Imax in the IMT group., Competing Interests: Conflict of interest: None declared., (Copyright ©ERS 2018.)

The value of inspiratory muscle training (IMT) in pulmonary rehabilitation in chronic obstructive pulmonary disease (COPD) is unclear. The RIMTCORE (Routine Inspiratory Muscle Training within COPD Rehabilitation) randomised controlled trial examined the effectiveness of IMT added to pulmonary rehabilitation.In total, 611 COPD patients (Global Initiative for Chronic Obstructive Lung Disease stage II-IV) received a 3-week inpatient pulmonary rehabilitation, of which 602 patients were included in the intention-to-treat analyses. The intervention group (n=300) received highly intensive IMT and the control group (n=302) received sham IMT. The primary outcome was maximal inspiratory pressure ( P Imax ). The secondary outcomes were 6-min walk distance, dyspnoea, quality of life and lung function. Outcomes were assessed pre- and post-pulmonary rehabilitation. ANCOVA was used.The intervention group showed higher effects in P Imax (p<0.001) and forced inspiratory volume in 1 s (p=0.013). All other outcomes in both study groups improved significantly, but without further between-group differences. Sex and pulmonary rehabilitation admission shortly after hospitalisation modified quality of life effects.IMT as an add-on to a 3-week pulmonary rehabilitation improves inspiratory muscle strength, but does not provide additional benefits in terms of exercise capacity, quality of life or dyspnoea. A general recommendation for COPD patients to add IMT to a 3-week pulmonary rehabilitation cannot be made., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2018.)

Our understanding of the mechanisms of dyspnoea in fibrotic interstitial lung disease (ILD) is incomplete. The aims of this study were two-fold: 1) to determine whether dyspnoea intensity is better predicted by neural respiratory drive (NRD) or neuromechanical uncoupling (NMU) of the respiratory system in fibrotic ILD, and 2) to examine the effect of breathing 60% oxygen on NRD, NMU and dyspnoea ratings.Fourteen patients with fibrotic ILD were included. Visit 1 comprised a familiarisation incremental cycle exercise test, Visit 2 comprised a normoxic incremental cycling test to address Aim 1, and Visits 3 and 4 consisted of constant-load cycling while breathing room air or 60% oxygen to address Aim 2. Diaphragmatic electromyography (EMGdi) was used as a surrogate of NRD. NMU was calculated as the ratio between EMGdi (%max) and tidal volume (%vital capacity).On adjusted analysis, NMU and its constituents were all significantly associated with dyspnoea ratings during incremental cycling, with EMGdi having the strongest correlation. The between-treatment change in dyspnoea ratings during constant load cycling was only correlated with change in exercise endurance time and NMU.Dyspnoea more strongly reflected the level of EMGdi than NMU in fibrotic ILD. However, the improvement in dyspnoea with 60% oxygen was better predicted by improvements in NMU., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2018.)

Patients with chronic obstructive pulmonary disease (COPD) often suffer episodes of exacerbation (ECOPD) that impact negatively the course of their disease. ECOPD are heterogeneous events of unclear pathobiology and non-specific diagnosis. Network analysis is a novel research approach that can help unravelling complex biological systems. We hypothesised that the comparison of multi-level ( i.e. , clinical, physiological, biological, imaging and microbiological) correlation networks determined during ECOPD and convalescence can yield novel patho-biologic information . In this proof-of-concept study we included 86 patients hospitalised because of ECOPD in a multicentre study in Spain. Patients were extensively characterised both during the first 72 h of hospitalisation and during clinical stability, at least 3 months after hospital discharge.We found that 1) episodes of ECOPD are characterised by disruption of the network correlation observed during convalescence; and 2) a panel of biomarkers that include increased levels of dyspnoea, circulating neutrophils and C-reactive protein (CRP) has a high predictive value for ECOPD diagnosis (AUC 0.97).We conclude that ECOPD 1) are characterised by disruption of network homeokinesis that exists during convalescence; and 2) can be identified objectively by using a panel of three biomarkers (dyspnoea, circulating neutrophils and CRP levels) frequently determined in clinical practice., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Dyspnoea is a principal presenting symptom in pulmonary arterial hypertension (PAH), and often the most distressing. The pathophysiology of PAH is relatively well understood, with the primary abnormality of pulmonary vascular disease resulting in a combination of impaired cardiac output on exercise and abnormal gas exchange, both contributing to increased ventilatory drive. However, increased ventilatory drive is not the sole explanation for the complex neurophysiological and neuropsychological symptom of dyspnoea, with other significant contributions from skeletal muscle reflexes, respiratory muscle function, and psychological and emotional status. In this review, we explore the physiological aspects of dyspnoea in PAH, both in terms of the central cardiopulmonary abnormalities of PAH and the wider, systemic impact of PAH, and how these interact with common comorbidities. Finally, we discuss its relationship with disease severity., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at err.ersjournals.com, (Copyright ©ERS 2017.)

This study explored the benefits of a hand-held fan as perceived by patients with chronic breathlessness and their carers.A secondary multimethod analysis was conducted of interview data collected in three clinical trials. Two researchers independently coded level of benefit qualitatively reported by each patient. Univariate and multivariate statistics were used to explore perceived benefit as a factor of sex, age and diagnosis. Qualitative analysis used an integrative method.133 patients commented on the fan, of whom 72 had a carer. Diagnoses included nonmalignant (n=91, 68.4%) and malignant (n=21, 15.8%) conditions. Of 111 patients who provided codable data, four (3.6%) perceived no benefit, 16 (14.4%) were uncertain, 80 (72.0%) perceived some benefit and 11 (10.0%) perceived very substantial benefit. Multivariate analysis was inconclusive. Benefit was described in terms of shorter recovery time, especially after activity. 10 (7.5%) patients said the fan reduced their need for home oxygen or inhaled β-agonist medications. Negative perceptions of a few included dislike of the cooling sensation and embarrassment in public.Findings suggest that a hand-held fan is a portable intervention with few disadvantages from which most patients with chronic breathlessness will derive benefit alongside other nonpharmacological and pharmacological strategies. Research is needed to optimise guidance on fan administration., Competing Interests: Conflict of interest: None declared., (Copyright ©ERS 2017.)

The objective of this study was to investigate the reliability, feasibility and analytical impact of home-based measurement of forced vital capacity (FVC) and dyspnoea as clinical endpoints in idiopathic pulmonary fibrosis (IPF).Patients with IPF performed weekly home-based assessment of FVC and dyspnoea using a mobile hand-held spirometer and self-administered dyspnoea questionnaires. Weekly variability in FVC and dyspnoea was estimated, and sample sizes were simulated for a hypothetical 24-week clinical trial using either traditional office-based interval measurement or mobile weekly assessment.In total, 25 patients were enrolled. Mean adherence to weekly assessments over 24 weeks was greater than 90%. Compared with change assessment using baseline and 24-week measurements only, weekly assessment of FVC resulted in enhanced precision and power. For example, a hypothetical 24-week clinical trial with FVC as the primary endpoint would require 951 patients using weekly home spirometry compared with 3840 patients using office spirometry measures at weeks 1 and 24 only. The ability of repeated measures to reduce clinical trial sample size was influenced by the correlation structure of the data.Home monitoring can improve the precision of endpoint assessments, allowing for greater efficiency in clinical trials of therapeutics for IPF., (Copyright ©ERS 2017.)

Asthma is a heterogeneous condition, with dyspnoea during exercise affecting individuals to a variable degree. This narrative review explores the mechanisms and measurement of exertional dyspnoea in asthma and summarises the available evidence for the efficacy of various interventions on exertional dyspnoea. Studies on the mechanisms of dyspnoea in asthma have largely utilised direct bronchoprovocation challenges, rather than exercise, which may invoke different physiological mechanisms. Thus, the description of dyspnoea during methacholine challenge can differ from what is experienced during daily activities, including exercise. Dyspnoea perception during exercise is influenced by many interacting variables, such as asthma severity and phenotype, bronchoconstriction, dynamic hyperinflation, respiratory drive and psychological factors. In addition to the intensity of dyspnoea, the qualitative description of dyspnoea may give important clues as to the underlying mechanism and may be an important endpoint for future interventional studies. There is currently little evidence demonstrating whether pharmacological or non-pharmacological interventions specifically improve exertional dyspnoea, which is an important area for future research., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at err.ersjournals.com, (Copyright ©ERS 2017.)

Activity-related breathlessness is twice as common among females as males in the general population and is associated with adverse health outcomes. We tested whether this sex difference is explained by the lower absolute forced expiratory volume in 1 s (FEV 1 ) or forced vital capacity (FVC) in females.This was a cross-sectional analysis of 3250 subjects (51% female) aged 38-67 years across 13 countries in the population-based third European Community Respiratory Health Survey. Activity-related breathlessness was measured using the modified Medical Research Council (mMRC) scale. Associations with mMRC were analysed using ordered logistic regression clustering on centre, adjusting for post-bronchodilator spirometry, body mass index, pack-years smoking, cardiopulmonary diseases, depression and level of exercise.Activity-related breathlessness (mMRC ≥1) was twice as common in females (27%) as in males (14%) (odds ratio (OR) 2.21, 95% CI 1.79-2.72). The sex difference was not reduced when controlling for FEV 1 % predicted (OR 2.33), but disappeared when controlling for absolute FEV 1 (OR 0.89, 95% CI 0.69-1.14). Absolute FEV 1 explained 98-100% of the sex difference adjusting for confounders. The effect was similar within males and females, when using FVC instead of FEV 1 and in healthy never-smokers.The markedly more severe activity-related breathlessness among females in the general population is explained by their smaller spirometric lung volumes., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Our aim was to comprehensively validate the 1-min sit-to-stand (STS) test in chronic obstructive pulmonary disease (COPD) patients and explore the physiological response to the test.We used data from two longitudinal studies of COPD patients who completed inpatient pulmonary rehabilitation programmes. We collected 1-min STS test, 6-min walk test (6MWT), health-related quality of life, dyspnoea and exercise cardiorespiratory data at admission and discharge. We assessed the learning effect, test-retest reliability, construct validity, responsiveness and minimal important difference of the 1-min STS test.In both studies (n=52 and n=203) the 1-min STS test was strongly correlated with the 6MWT at admission (r=0.59 and 0.64, respectively) and discharge (r=0.67 and 0.68, respectively). Intraclass correlation coefficients (95% CI) between 1-min STS tests were 0.93 (0.83-0.97) for learning effect and 0.99 (0.97-1.00) for reliability. Standardised response means (95% CI) were 0.87 (0.58-1.16) and 0.91 (0.78-1.07). The estimated minimal important difference was three repetitions. End-exercise oxygen consumption, carbon dioxide output, ventilation, breathing frequency and heart rate were similar in the 1-min STS test and 6MWT.The 1-min STS test is a reliable, valid and responsive test for measuring functional exercise capacity in COPD patients and elicited a physiological response comparable to that of the 6MWT., (Copyright ©ERS 2017.)

This review aims to establish the impact of oxygen therapy on dyspnoea, health-related quality of life (HRQoL), exercise capacity and mortality in interstitial lung disease (ILD).We included studies that compared oxygen therapy to no oxygen therapy in adults with ILD. No limitations were placed on study design or intervention type. Two reviewers independently evaluated studies for inclusion, assessed risk of bias and extracted data. The primary outcome was dyspnoea.Eight studies evaluated the acute effects of oxygen (n=1509). There was no effect of oxygen therapy on modified Borg dyspnoea score at end exercise (mean difference (MD) -0.06 units, 95% CI -0.24-0.13; two studies, n=27). However, effects on exercise outcomes consistently favoured oxygen therapy. One study showed reduction in dyspnoea at rest with oxygen in patients who were acutely unwell (MD visual analogue scale 30 mm versus 48 mm, p<0.05; n=10). Four studies of long-term oxygen therapy (n=2670) had high risk of bias and no inferences could be drawn.This systematic review showed no effects of oxygen therapy on dyspnoea during exercise in ILD, although exercise capacity was increased. Future trials should evaluate whether acute improvements in exercise capacity with oxygen can be translated into improved physical activity and HRQoL., (Copyright ©ERS 2017.)

Interstitial lung diseases (ILDs) represent a heterogeneous group of pathologies characterised by alveolar and interstitial damage, pulmonary inflammation (usually associated with fibrosis), decreased lung function and impaired gas exchange, which can be attributed to either a known or an unknown aetiology. Dyspnoea is one of the most common and disabling symptoms in patients with ILD, significantly impacting quality of life. The mechanisms causing dyspnoea are complex and not yet fully understood. However, it is recognised that dyspnoea occurs when there is an imbalance between the central respiratory efferent drive and the response of the respiratory musculature. The respiratory derangement observed in ILD patients at rest is even more evident during exercise. Pathophysiological mechanisms responsible for exertional dyspnoea and reduced exercise tolerance include altered respiratory mechanics, impaired gas exchange, cardiovascular abnormalities and peripheral muscle dysfunction.This review describes the respiratory physiology of ILD, both at rest and during exercise, and aims to provide comprehensive and updated evidence on the clinical utility of the cardiopulmonary exercise test in the assessment and management of these pathological entities. In addition, the role of exercise training and pulmonary rehabilitation programmes in the ILD population is addressed., (Copyright ©ERS 2017.)

The purpose of cardiopulmonary exercise testing (CPET) in the obese person, as in any cardiopulmonary exercise test, is to determine the patient's exercise tolerance, and to help identify and/or distinguish between the various physiological factors that could contribute to exercise intolerance. Unexplained dyspnoea on exertion is a common reason for CPET, but it is an extremely complex symptom to explain. Sometimes obesity is the simple answer by elimination of other possibilities. Thus, distinguishing among multiple clinical causes for exertional dyspnoea depends on the ability to eliminate possibilities while recognising response patterns that are unique to the obese patient. This includes the otherwise healthy obese patient, as well as the obese patient with potentially multiple cardiopulmonary limitations. Despite obvious limitations in lung function, metabolic disease and/or cardiovascular dysfunction, obesity may be the most likely reason for exertional dyspnoea. In this article, we will review the more common cardiopulmonary responses to exercise in the otherwise healthy obese adult with special emphasis on dyspnoea on exertion., (Copyright ©ERS 2016.)

Exertional dyspnoea is among the dominant symptoms in patients with chronic heart failure and progresses relentlessly as the disease advances, leading to reduced ability to function and engage in activities of daily living. Effective management of this disabling symptom awaits a better understanding of its underlying physiology.Cardiovascular factors are believed to play a major role in dyspnoea in heart failure patients. However, despite pharmacological interventions, such as vasodilators or inotropes that improve central haemodynamics, patients with heart failure still complain of exertional dyspnoea. Clearly, dyspnoea is not determined by cardiac factors alone, but likely depends on complex, integrated cardio-pulmonary interactions.A growing body of evidence suggests that excessively increased ventilatory demand and abnormal "restrictive" constraints on tidal volume expansion with development of critical mechanical limitation of ventilation, contribute to exertional dyspnoea in heart failure. This article will offer new insights into the pathophysiological mechanisms of exertional dyspnoea in patients with chronic heart failure by exploring the potential role of the various constituents of the physiological response to exercise and particularly the role of abnormal ventilatory and respiratory mechanics responses to exercise in the perception of dyspnoea in patients with heart failure., (Copyright ©ERS 2016.)

Dyspnoea and activity limitation can occur in smokers who do not meet spirometric criteria for chronic obstructive pulmonary disease (COPD) but the underlying mechanisms are unknown.Detailed pulmonary function tests and sensory-mechanical relationships during incremental exercise with respiratory pressure measurements and diaphragmatic electromyography (EMGdi) were compared in 20 smokers without spirometric COPD and 20 age-matched healthy controls.Smokers (mean±sd post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity 75±4%, mean±sd FEV1 104±14% predicted) had greater activity-related dyspnoea, poorer health status and lower physical activity than controls. Smokers had peripheral airway dysfunction: higher phase-III nitrogen slopes (3.8±1.8 versus 2.6±1.1%·L(-1)) and airway resistance (difference between airway resistance measured at 5 Hz and 20 Hz 19±11 versus 12±7% at 5 Hz) than controls (p<0.05). Smokers had significantly (p<0.05) lower peak oxygen uptake (78±40 versus 107±45% predicted) and ventilation (61±26 versus 97±29 L·min(-1)). Exercise ventilatory requirements, operating lung volumes and cardio-circulatory responses were similar. However, submaximal dyspnoea ratings, resistive and total work of breathing were increased in smokers compared with controls (p<0.05); diaphragmatic effort (transdiaphragmatic pressure/maximumal transdiaphragmatic pressure) and fractional inspiratory neural drive to the diaphragm (EMGdi/maximal EMGdi) were also increased (p<0.05) mainly reflecting the reduced denominator.Symptomatic smokers at risk for COPD had greater exertional dyspnoea and lower exercise tolerance compared with healthy controls in association with greater airways resistance, contractile diaphragmatic effort and fractional inspiratory neural drive to the diaphragm., (Copyright ©ERS 2016.)

Activity-related dyspnoea is often the most distressing symptom experienced by patients with chronic obstructive pulmonary disease (COPD) and can persist despite comprehensive medical management. It is now clear that dyspnoea during physical activity occurs across the spectrum of disease severity, even in those with mild airway obstruction. Our understanding of the nature and source of dyspnoea is incomplete, but current aetiological concepts emphasise the importance of increased central neural drive to breathe in the setting of a reduced ability of the respiratory system to appropriately respond. Since dyspnoea is provoked or aggravated by physical activity, its concurrent measurement during standardised laboratory exercise testing is clearly important. Combining measurement of perceptual and physiological responses during exercise can provide valuable insights into symptom severity and its pathophysiological underpinnings. This review summarises the abnormal physiological responses to exercise in COPD, as these form the basis for modern constructs of the neurobiology of exertional dyspnoea. The main objectives are: 1) to examine the role of cardiopulmonary exercise testing (CPET) in uncovering the physiological mechanisms of exertional dyspnoea in patients with mild-to-moderate COPD; 2) to examine the escalating negative sensory consequences of progressive respiratory impairment with disease advancement; and 3) to build a physiological rationale for individualised treatment optimisation based on CPET., (Copyright ©ERS 2016.)

Dysfunctional breathing is a term describing breathing disorders where chronic changes in breathing pattern result in dyspnoea and other symptoms in the absence or in excess of the magnitude of physiological respiratory or cardiac disease. We reviewed the literature and propose a classification system for the common dysfunctional breathing patterns described. The literature was searched using the terms: dysfunctional breathing, hyperventilation, Nijmegen questionnaire and thoraco-abdominal asynchrony. We have summarised the presentation, assessment and treatment of dysfunctional breathing, and propose that the following system be used for classification. 1) Hyperventilation syndrome: associated with symptoms both related to respiratory alkalosis and independent of hypocapnia. 2) Periodic deep sighing: frequent sighing with an irregular breathing pattern. 3) Thoracic dominant breathing: can often manifest in somatic disease, if occurring without disease it may be considered dysfunctional and results in dyspnoea. 4) Forced abdominal expiration: these patients utilise inappropriate and excessive abdominal muscle contraction to aid expiration. 5) Thoraco-abdominal asynchrony: where there is delay between rib cage and abdominal contraction resulting in ineffective breathing mechanics.This review highlights the common abnormalities, current diagnostic methods and therapeutic implications in dysfunctional breathing. Future work should aim to further investigate the prevalence, clinical associations and treatment of these presentations., (Copyright ©ERS 2016.)

Dyspnoea is a prominent symptom of chronic obstructive pulmonary disease (COPD). Recent multidimensional dyspnoea questionnaires like the Multidimensional Dyspnea Profile (MDP) individualise the sensory and affective dimensions of dyspnoea. We tested the MDP in COPD outpatients based on the hypothesis that the importance of the affective dimension of dyspnoea would vary according to clinical characteristics.A multicentre, prospective, observational, real-life study was conducted in 276 patients. MDP data were compared across various categories of patients (modified Medical Research Council (mMRC) dyspnoea score, COPD Assessment Test (CAT) score, Global Initiative for Chronic Obstructive Lung Disease (GOLD) airflow obstruction categories, GOLD "ABCD" categories, and Hospital Anxiety and Depression Scale (HADS)). Univariate and multivariate regressions were conducted to explore factors influencing the affective dimension of dyspnoea. Cluster analysis was conducted to create homogeneous patient profiles.The MDP identified a more marked affective dimension of dyspnoea with more severe mMRC, CAT, 12-item Short-Form Health Survey mental component, airflow obstruction and HADS. Multivariate analysis identified airflow obstruction, depressive symptoms and physical activity as determinants of the affective dimension of dyspnoea. Patients clustered into an "elderly, ex-smoker, severe disease, no rehabilitation" group exhibited the most marked affective dimension of dyspnoea.An affective/emotional dimension of dyspnoea can be identified in routine clinical practice. It can contribute to the phenotypic description of patients. Studies are needed to determine whether targeted therapeutic interventions can be designed and whether they are useful., (Copyright ©ERS 2016.)

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing diaphragm weakness that can be partially compensated by inspiratory neck muscle recruitment. This disappears during sleep, which is compatible with a cortical contribution to the drive to breathe. We hypothesised that ALS patients with respiratory failure exhibit respiratory-related cortical activity, relieved by noninvasive ventilation (NIV) and related to dyspnoea.We studied 14 ALS patients with respiratory failure. Electroencephalographic recordings (EEGs) and electromyographic recordings of inspiratory neck muscles were performed during spontaneous breathing and NIV. Dyspnoea was evaluated using the Multidimensional Dyspnea Profile.Eight patients exhibited slow EEG negativities preceding inspiration (pre-inspiratory potentials) during spontaneous breathing. Pre-inspiratory potentials were attenuated during NIV (p=0.04). Patients without pre-inspiratory potentials presented more advanced forms of ALS and more severe respiratory impairment, but less severe dyspnoea. Patients with pre-inspiratory potentials had stronger inspiratory neck muscle activation and more severe dyspnoea during spontaneous breathing.ALS-related diaphragm weakness can engage cortical resources to augment the neural drive to breathe. This might reflect a compensatory mechanism, with the intensity of dyspnoea a negative consequence. Disease progression and the corresponding neural loss could abolish this phenomenon. A putative cognitive cost should be investigated., (Copyright ©ERS 2016.)

This document reviews 1) the measurement properties of commonly used exercise tests in patients with chronic respiratory diseases and 2) published studies on their utilty and/or evaluation obtained from MEDLINE and Cochrane Library searches between 1990 and March 2015.Exercise tests are reliable and consistently responsive to rehabilitative and pharmacological interventions. Thresholds for clinically important changes in performance are available for several tests. In pulmonary arterial hypertension, the 6-min walk test (6MWT), peak oxygen uptake and ventilation/carbon dioxide output indices appear to be the variables most responsive to vasodilators. While bronchodilators do not always show clinically relevant effects in chronic obstructive pulmonary disease, high-intensity constant work-rate (endurance) tests (CWRET) are considerably more responsive than incremental exercise tests and 6MWTs. High-intensity CWRETs need to be standardised to reduce interindividual variability. Additional physiological information and responsiveness can be obtained from isotime measurements, particularly of inspiratory capacity and dyspnoea. Less evidence is available for the endurance shuttle walk test. Although the incremental shuttle walk test and 6MWT are reliable and less expensive than cardiopulmonary exercise testing, two repetitions are needed at baseline. All exercise tests are safe when recommended precautions are followed, with evidence suggesting that no test is safer than others., (Copyright ©ERS 2016.)

This study was designed to investigate the association of perceived dyspnoea intensity with cortical oxygenation and cortical activation during exercise in patients with chronic obstructive pulmonary disease (COPD) and exertional hypoxaemia.Low-intensity exercise was performed at a constant work rate by patients with COPD and exertional hypoxaemia (n=11) or no hypoxaemia (n=16), and in control participants (n=11). Cortical oxyhaemoglobin (oxy-Hb) and deoxyhaemoglobin (deoxy-Hb) concentrations were measured by multichannel near-infrared spectroscopy. Increased deoxy-Hb is assumed to reflect impaired oxygenation, whereas decreased deoxy-Hb signifies cortical activation.Exercise decreased cortical deoxy-Hb in control and nonhypoxaemic patients. Deoxy-Hb was increased in hypoxaemic patients and oxygen supplementation improved cortical oxygenation. Decreased deoxy-Hb in the pre-motor cortex (PMA) was significantly correlated with exertional dyspnoea in control participants and patients with COPD without hypoxaemia. In contrast, increased cortical deoxy-Hb concentration was correlated with dyspnoea in patients with COPD and hypoxaemia. With the administration of oxygen supplementation, exertional dyspnoea was correlated with decreased deoxy-Hb in the PMA of COPD patients with hypoxaemia.During exercise, cortical oxygenation was impaired in patients with COPD and hypoxaemia compared with control and nonhypoxaemic patients; this difference was ameliorated with oxygen supplementation. Exertional dyspnoea was related to activation of the pre-motor cortex in COPD patients., (Copyright ©ERS 2015.)

The aim of the present study was to profile a multidimensional response to pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD).Dyspnoea, exercise performance, health status, mood status and problematic activities of daily life were assessed before and after a 40-session pulmonary rehabilitation programme in 2068 patients with COPD (mean forced expiratory volume in 1 s of 49% predicted). Patients were ordered by their overall similarity concerning their multidimensional response profile, which comprises the overall response on MRC dyspnoea grade, 6MWD, cycle endurance time, Canadian Occupational Performance Measure performance and satisfaction scores, Hospital Anxiety and Depression Scale anxiety and depression, and St George's Respiratory Questionnaire total score, using a novel non-parametric regression technique.Patients were clustered into four groups with distinct multidimensional response profiles: n=378 (18.3%; "very good responder"), n=742 (35.9%; "good responder"), n=731 (35.4%; "moderate responder"), and n=217 (10.5%; "poor responder"). Patients in the "very good responder" cluster had higher symptoms of dyspnoea, number of hospitalisations <12 months, worse exercise performance, worse performance and satisfaction scores for problematic activities of daily life, more symptoms of anxiety and depression, worse health status, and a higher proportion of patients following an inpatient PR programme compared to the other three clusters.A multidimensional response outcome needs to be considered to study the efficacy of pulmonary rehabilitation services in patients with COPD, as responses to regular outcomes are differential within patients with COPD., (Copyright ©ERS 2015.)

The forced oscillation technique can identify expiratory flow limitation (EFL) when a large difference in inspiratory and expiratory reactance (ΔXrs) occurs. However, flow limitation can vary from breath to breath, and so we compared a multiple-breath ΔXrs approach to the traditional breath-by-breath assessment of EFL. We investigated the within- and between-day reproducibility and the factors that affect the size of ΔXrs when used as a continuous measurement over multiple breaths. In addition, we examined how multiple-breath ΔXrs relates to the sensation of breathlessness. 425 moderate to very severe chronic obstructive pulmonary disease (COPD) patients and 229 controls were included. Spirometry and impedance measurements were performed on a MasterScope CT Impulse Oscillation System. Median ΔXrs approached zero in healthy controls with little variation between measurements. COPD patients generally had higher ΔXrs and higher variability. The COPD patients with ΔXrs >0.1 kPa · L(-1) · s(-1) were prone to be more breathless and had a higher modified Medical Research Council dyspnoea scale score. In controls, the 95th percentile of ΔXrs was as low as 0.07 kPa · L(-1) · s(-1). We describe a new method to assess EFL at a patient level and propose a cut-off, mean ΔXrs >0.1 kPa · L(-1) · s(-1), as a way to identify COPD patients who are more likely to report dyspnoea., (Copyright ©ERS 2015.)

Ventilatory inefficiency during exercise is a key pathophysiological feature of chronic obstructive pulmonary disease. Currently, it is unknown how this physiological marker relates to clinically relevant outcomes as resting ventilatory impairment progresses across disease stages. Slope and intercept of the linear region of the ventilation-carbon dioxide output relationship and the ratio between these variables, at the lowest point (nadir), were contrasted in 316 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1-4 (forced expiratory volume in 1 s, ranging from 148% pred to 12% pred) and 69 aged- and gender-matched controls, Compared to controls, slope and intercept were higher in GOLD stages 1 and 2, leading to higher nadirs (p<0.05). Despite even larger intercepts in GOLD stages 3 and 4, slopes diminished as disease evolved (from mean±sd 35±6 in GOLD stage 1 to 24±5 in GOLD stage 3, p<0.05). As a result, there were no significant differences in nadirs among patient groups. Higher intercepts, across all stages (p<0.01), and to a lesser extent lower slopes in GOLD stages 2-4 (p<0.05), were related to greater mechanical constraints, worsening pulmonary gas exchange, higher dyspnoea scores, and poorer exercise capacity. Increases in the ventilation intercept best indicate the progression of exercise ventilatory inefficiency across the whole spectrum of chronic obstructive pulmonary disease severity., (Copyright ©ERS 2015.)

The aim of this study was to test the hypothesis that neural respiratory drive, measured using diaphragm electromyogram (EMGdi) activity expressed as a percentage of maximum (EMGdi%max), is closely related to breathlessness in chronic obstructive pulmonary disease. We also investigated whether neuroventilatory uncoupling contributes significantly to breathlessness intensity over an awareness of levels of neural respiratory drive alone. EMGdi and ventilation were measured continuously during incremental cycle and treadmill exercise in 12 chronic obstructive pulmonary disease patients (forced expiratory volume in 1 s±sd was 38.7±14.5 % pred). EMGdi was expressed both as EMGdi%max and relative to tidal volume expressed as a percentage of predicted vital capacity to quantify neuroventilatory uncoupling. EMGdi%max was closely related to Borg breathlessness in both cycle (r=0.98, p=0.0001) and treadmill exercise (r=0.94, p=0.005), this relationship being similar to that between neuroventilatory uncoupling and breathlessness (cycling r=0.94, p=0.005; treadmill r=0.91, p=0.01). The relationship between breathlessness and ventilation was poor when expansion of tidal volume became limited. In chronic obstructive pulmonary disease the intensity of exertional breathlessness is closely related to EMGdi%max. These data suggest that breathlessness in chronic obstructive pulmonary disease can be largely explained by an awareness of levels of neural respiratory drive, rather than the degree of neuroventilatory uncoupling. EMGdi%max could provide a useful physiological biomarker for breathlessness in chronic obstructive pulmonary disease., (Copyright ©ERS 2015.)

The purpose of this study was to determine if a dissociation existed between respiratory drive, as estimated by diaphragmatic electromyography (EMGdi), and its pressure-generating capacity during exercise in mild chronic obstructive pulmonary disease (COPD) and whether this, if present, had negative sensory consequences. Subjects meeting spirometric criteria for mild COPD (n=16) and age and sex-matched controls (n=16) underwent detailed pulmonary function testing and a symptom limited cycle test while detailed ventilatory, sensory and respiratory mechanical responses were measured. Compared with controls, subjects with mild COPD had greater ventilatory requirements throughout submaximal exercise. At the highest equivalent work rate of 60 W, they had a significantly higher: total work of breathing (32±17 versus 16±7 J·min(-1); p<0.01); EMGdi (37.3±17.3 versus 17.9±11.7% of maximum; p<0.001); and EMGdi to transdiaphragmatic pressure ratio (0.87±0.38 versus 0.52±0.27; p<0.01). Dyspnoea-ventilation slopes were significantly higher in mild COPD than controls (0.17±0.12 versus 0.10±0.05; p<0.05). However, absolute dyspnoea ratings reached significant levels only at high levels of ventilation. Increased respiratory effort and work of breathing, and a wider dissociation between diaphragmatic activation and pressure-generating capacity were found at standardised work rates in subjects with mild COPD compared with controls. Despite these mechanical and neuromuscular abnormalities, significant dyspnoea was only experienced at higher work rates., (©ERS 2014.)

The purpose of this study was to investigate whether differences in physiological responses to weight-bearing (walking) and weight-supported (cycle) exercise influence dyspnoea perception in obese chronic obstructive pulmonary disease (COPD) patients, where such discrepancies are probably exaggerated. We compared metabolic, ventilatory and perceptual responses during incremental treadmill and cycle exercise using a matched linearised rise in work rate in 18 (10 males and eight females) obese (mean ± sd body mass index 36.4 ± 5.0 kg·m(-2)) patients with COPD (forced expiratory volume in 1 s 60 ± 11% predicted). Compared with cycle testing, treadmill testing was associated with a significantly higher oxygen uptake, lower ventilatory equivalent for oxygen and greater oxyhaemoglobin desaturation at a given work rate (p<0.01). Cycle testing was associated with a higher respiratory exchange ratio (p<0.01), earlier ventilatory threshold (p<0.01) and greater peak leg discomfort ratings (p=0.01). Ventilation, breathing pattern and operating lung volumes were similar between tests, as were dyspnoea/work rate and dyspnoea/ventilation relationships. Despite significant between-test differences in physiological responses, ventilation, operating lung volumes and dyspnoea intensity were similar at any given external power output during incremental walking and cycling exercise in obese COPD patients. These data provide evidence that either exercise modality can be selected for reliable evaluation of exertional dyspnoea in this population in research and clinical settings., (©ERS 2014.)

The value and timing of multidimensional assessments in chronic obstructive pulmonary disease (COPD) remains unclear because there is little information about their variability and relationship to outcome. The aim of this study was to determine the progression of COPD using clinical and spirometric variability over time with mortality as the outcome. We determined the annual intra-individual variability of forced expiratory volume in 1 s (FEV1) and BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index in 403 patients with at least five measurements. The pattern was defined as "stable" if the annual change remained constant in ≥66% of the observations and "unstable" if it did not meet that threshold. We explored the minimum number of yearly observations that related to mortality in the 704 patients of the cohort. The "unstable" pattern of FEV1 was seen in 53% and 40% of patients using a threshold of 40 mL·year(-1) and 100 mL·year(-1), respectively. There was a slightly more "stable" pattern in the BODE index (62% for 1 point). A profile associated with mortality was defined by a baseline measurement followed by annual measurements for 2 years of the BODE index, but not its individual components, including FEV1 (p<0.001). Progression of COPD measured using FEV1 is inconsistent and relates poorly to outcome. Monitoring the more stable BODE index better assesses disease progression.

The BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index is well-validated for mortality prediction in chronic obstructive pulmonary disease (COPD). Concentrations of plasma pro-adrenomedullin, a surrogate for mature adrenomedullin, independently predicted 2-year mortality among inpatients with COPD exacerbation. We compared accuracy of initial pro-adrenomedullin level, BODE and BODE components, alone or combined, in predicting 1-year or 2-year all-cause mortality in a multicentre, multinational observational cohort with stable, moderate to very severe COPD. Pro-adrenomedullin was significantly associated (p<0.001) with 1-year mortality (4.7%) and 2-year mortality (7.8%) and comparably predictive to BODE regarding both (C statistics 0.691 versus 0.745 and 0.635 versus 0.679, respectively). Relative to using BODE alone, adding pro-adrenomedullin significantly improved 1-year and 2-year mortality prognostication (C statistics 0.750 and 0.818, respectively; both p<0.001). Pro-adrenomedullin plus BOD was more predictive than the original BODE including 6-min walk distance. In multivariable analysis, pro-adrenomedullin (likelihood ratio Chi-squared 13.0, p<0.001), body mass index (8.5, p=0.004) and 6-min walk distance (7.5, p=0.006) independently foretold 2-year survival, but modified Medical Research Council dyspnoea score (2.2, p=0.14) and forced expiratory volume in 1 s % predicted (0.3, p=0.60) did not. Pro-adrenomedullin plus BODE better predicts mortality in COPD patients than does BODE alone; pro-adrenomedullin may substitute for 6-min walk distance in BODE when 6-min walk testing is unavailable.