Structural Predictors of Lung Function Decline in Young Smokers with Normal Spirometry.

Rationale: Chronic obstructive pulmonary disease (COPD) due to tobacco smoking commonly presents when extensive lung damage has occurred. Objectives: We hypothesized that structural change would be detected early in the natural history of COPD and would relate to loss of lung function with time. Methods: We recruited 431 current smokers (median age, 39 yr; 16 pack-years smoked) and recorded symptoms using the COPD Assessment Test (CAT), spirometry, and quantitative thoracic computed tomography (QCT) scans at study entry. These scan results were compared with those from 67 never-smoking control subjects. Three hundred sixty-eight participants were followed every six months with measurement of postbronchodilator spirometry for a median of 32 months. The rate of FEV1 decline, adjusted for current smoking status, age, and sex, was related to the initial QCT appearances and symptoms, measured using the CAT. Measurements and Main Results: There were no material differences in demography or subjective CT appearances between the young smokers and control subjects, but 55.7% of the former had CAT scores greater than 10, and 24.2% reported chronic bronchitis. QCT assessments of disease probability-defined functional small airway disease, ground-glass opacification, bronchovascular prominence, and ratio of small blood vessel volume to total pulmonary vessel volume were increased compared with control subjects and were all associated with a faster FEV1 decline, as was a higher CAT score. Conclusions: Radiological abnormalities on CT are already established in young smokers with normal lung function and are associated with FEV1 loss independently of the impact of symptoms. Structural abnormalities are present early in the natural history of COPD and are markers of disease progression. Clinical trial registered with www.clinicaltrials.gov (NCT03480347).

Photoreception and transcriptomic response to light during early development of a teleost with a life cycle tightly controlled by seasonal changes in photoperiod.

Light cues vary along the axis of periodicity, intensity and spectrum and perception of light is dependent on the photoreceptive capacity encoded within the genome and the opsins expressed. A global approach was taken to analyze the photoreceptive capacity and the effect of differing light conditions on a developing teleost prior to first feeding. The transcriptomes of embryos and alevins of Atlantic salmon (Salmo salar) exposed to different light conditions were analyzed, including a developmental series and a circadian profile. The results showed that genes mediating nonvisual photoreception are present prior to hatching when the retina is poorly differentiated. The clock genes were expressed early, but the circadian profile showed that only two clock genes were significantly cycling before first feeding. Few genes were differentially expressed between day and night within a light condition; however, many genes were significantly different between light conditions, indicating that light environment has an impact on the transcriptome during early development. Comparing the transcriptome data from constant conditions to periodicity of white light or different colors revealed overrepresentation of genes related to photoreception, eye development, muscle contraction, degradation of metabolites and cell cycle among others, and in constant light, several clock genes were upregulated. In constant white light and periodicity of green light, genes associated with DNA replication, chromatin remodeling, cell division and DNA repair were downregulated. The study implies a direct influence of light conditions on the transcriptome profile at early developmental stages, by a complex photoreceptive system where few clock genes are cycling.

Free-Breathing Functional Pulmonary Proton MRI: A Novel Approach Using Voxel-Wise Lung Ventilation (VOLVE) Assessment in Healthy Volunteers and Patients With Chronic Obstructive Pulmonary Disease.

BACKGROUND: In respiratory medicine, there is a need for sensitive measures of regional lung function that can be performed using standard imaging technology, without the need for inhaled or intravenous contrast agents. PURPOSE: To describe VOxel-wise Lung VEntilation (VOLVE), a new method for quantifying regional lung ventilation (V) and perfusion (Q) using free-breathing proton MRI, and to evaluate VOLVE in healthy never-smokers, healthy people with smoking history, and people with chronic obstructive pulmonary disease (COPD). STUDY TYPE: Prospective pilot. POPULATION: Twelve healthy never-smoker participants (age 30.3 ± 12.5 years, five male), four healthy participants with smoking history (>10 pack-years) (age 42.5 ± 18.3 years, one male), and 12 participants with COPD (age 62.8 ± 11.1 years, seven male). FIELD STRENGTH/SEQUENCE: Single-slice free-breathing two-dimensional fast field echo sequence at 3 T. ASSESSMENT: A novel postprocessing was developed to evaluate the MR signal changes in the lung parenchyma using a linear regression-based approach, which makes use of all the data in the time series for maximum sensitivity. V/Q-weighted maps were produced by computing the cross-correlation, lag and gradient between the respiratory/cardiac phase time course and lung parenchyma signal time courses. A comparison of histogram median and skewness values and spirometry was performed. STATISTICAL TESTS: Kruskal-Wallis tests with Dunn's multiple comparison tests to compare VOLVE metrics between groups; Spearman correlation to assess the correlation between MRI and spirometry-derived parameters; and Bland-Altman analysis and coefficient of variation to evaluate repeatability were used. A P-value <0.05 was considered significant. RESULTS: Significant differences between the groups were found for ventilation between healthy never-smoker and COPD groups (median XCCV, LagV, and GradV) and perfusion (median XCCQ, LagQ, and GradQ). Minimal bias and no significant differences between intravisit scans were found (P range = 0.12-0.97). DATA CONCLUSION: This preliminary study showed that VOLVE has potential to provide metrics of function quantification. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

DYNamic Assessment of Multi-Organ level dysfunction in patients recovering from COVID-19: DYNAMO COVID-19.

We evaluated the impacts of COVID-19 on multi-organ and metabolic function in patients following severe hospitalised infection compared to controls. Patients (n = 21) without previous diabetes, cardiovascular or cerebrovascular disease were recruited 5-7 months post-discharge alongside controls (n = 10) with similar age, sex and body mass. Perceived fatigue was estimated (Fatigue Severity Scale) and the following were conducted: oral glucose tolerance (OGTT) alongside whole-body fuel oxidation, validated magnetic resonance imaging and spectroscopy during resting and supine controlled exercise, dual-energy X-ray absorptiometry, short physical performance battery (SPPB), intra-muscular electromyography, quadriceps strength and fatigability, and daily step-count. There was a greater insulin response (incremental area under the curve, median (inter-quartile range)) during the OGTT in patients [18,289 (12,497-27,448) mIU/min/L] versus controls [8655 (7948-11,040) mIU/min/L], P < 0.001. Blood glucose response and fasting and post-prandial fuel oxidation rates were not different. This greater insulin resistance was not explained by differences in systemic inflammation or whole-body/regional adiposity, but step-count (P = 0.07) and SPPB scores (P = 0.004) were lower in patients. Liver volume was 28% greater in patients than controls, and fat fraction adjusted liver T1, a measure of inflammation, was raised in patients. Patients displayed greater perceived fatigue scores, though leg muscle volume, strength, force-loss, motor unit properties and post-exercise muscle phosphocreatine resynthesis were comparable. Further, cardiac and cerebral architecture and function (at rest and on exercise) were not different. In this cross-sectional study, individuals without known previous morbidity who survived severe COVID-19 exhibited greater insulin resistance, pointing to a need for physical function intervention in recovery.

Association between antidepressants with pneumonia and exacerbation in patients with COPD: a self-controlled case series (SCCS).

OBJECTIVE: To assess whether antidepressant prescriptions are associated with an increased risk of pneumonia and chronic obstructive pulmonary disease (COPD) exacerbation. METHODS: A self-controlled case series was performed to investigate the rates of pneumonia and COPD exacerbation during periods of being exposed to antidepressants compared with non-exposed periods. Patients with COPD with pneumonia or COPD exacerbation and at least one prescription of antidepressant were ascertained from The Health Improvement Network in the UK. Incidence rate ratios (IRR) and 95% CI were calculated for both outcomes. RESULTS: Of 31 253 patients with COPD with at least one antidepressant prescription, 1969 patients had pneumonia and 18 483 had a COPD exacerbation. The 90-day risk period following antidepressant prescription was associated with a 79% increased risk of pneumonia (age-adjusted IRR 1.79, 95% CI 1.54 to 2.07). These associations then disappeared once antidepressants were discontinued. There was a 16% (age-adjusted IRR 1.16, 95% CI 1.13 to 1.20) increased risk of COPD exacerbation within the 90 days following antidepressant prescription. This risk persisted and slightly increased in the remainder period ((age-adjusted IRR 1.38, 95% CI 1.34 to 1.41), but diminished after patients discounted the treatment. CONCLUSION: Antidepressants were associated with an increased risk of both pneumonia and exacerbation in patients with COPD, with the risks diminished on stopping the treatment. These findings suggest a close monitoring of antidepressant prescription side effects and consideration of non-pharmacological interventions.

Improving lung health in low-income and middle-income countries: from challenges to solutions.

Low-income and middle-income countries (LMICs) bear a disproportionately high burden of the global morbidity and mortality caused by chronic respiratory diseases (CRDs), including asthma, chronic obstructive pulmonary disease, bronchiectasis, and post-tuberculosis lung disease. CRDs are strongly associated with poverty, infectious diseases, and other non-communicable diseases (NCDs), and contribute to complex multi-morbidity, with major consequences for the lives and livelihoods of those affected. The relevance of CRDs to health and socioeconomic wellbeing is expected to increase in the decades ahead, as life expectancies rise and the competing risks of early childhood mortality and infectious diseases plateau. As such, the World Health Organization has identified the prevention and control of NCDs as an urgent development issue and essential to the achievement of the Sustainable Development Goals by 2030. In this Review, we focus on CRDs in LMICs. We discuss the early life origins of CRDs; challenges in their prevention, diagnosis, and management in LMICs; and pathways to solutions to achieve true universal health coverage.

Joint patient and clinician priority setting to identify 10 key research questions regarding the long-term sequelae of COVID-19.

Given the large numbers of people infected and high rates of ongoing morbidity, research is clearly required to address the needs of adult survivors of COVID-19 living with ongoing symptoms (long COVID). To help direct resource and research efforts, we completed a research prioritisation process incorporating views from adults with ongoing symptoms of COVID-19, carers, clinicians and clinical researchers. The final top 10 research questions were agreed at an independently mediated workshop and included: identifying underlying mechanisms of long COVID, establishing diagnostic tools, understanding trajectory of recovery and evaluating the role of interventions both during the acute and persistent phases of the illness.

Whole-body and muscle responses to aerobic exercise training and withdrawal in ageing and COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients exhibit lower peak oxygen uptake (V'O2 peak), altered muscle metabolism and impaired exercise tolerance compared with age-matched controls. Whether these traits reflect muscle-level deconditioning (impacted by ventilatory constraints) and/or dysfunction in mitochondrial ATP production capacity is debated. By studying aerobic exercise training (AET) at a matched relative intensity and subsequent exercise withdrawal period we aimed to elucidate the whole-body and muscle mitochondrial responsiveness of healthy young (HY), healthy older (HO) and COPD volunteers to whole-body exercise. METHODS: HY (n=10), HO (n=10) and COPD (n=20) volunteers were studied before and after 8 weeks of AET (65% V'O2 peak) and after 4 weeks of exercise withdrawal. V'O2 peak, muscle maximal mitochondrial ATP production rate (MAPR), mitochondrial content, mitochondrial DNA (mtDNA) copy number and abundance of 59 targeted fuel metabolism mRNAs were determined at all time-points. RESULTS: Muscle MAPR (normalised for mitochondrial content) was not different for any substrate combination in HO, HY and COPD at baseline, but mtDNA copy number relative to a nuclear-encoded housekeeping gene (mean±sd) was greater in HY (804±67) than in HO (631±69; p=0.041). AET increased V'O2 peak in HO (17%; p=0.002) and HY (21%; p<0.001), but not COPD (p=0.603). Muscle MAPR for palmitate increased with training in HO (57%; p=0.041) and HY (56%; p=0.003), and decreased with exercise withdrawal in HO (-45%; p=0.036) and HY (-30%; p=0.016), but was unchanged in COPD (p=0.594). mtDNA copy number increased with AET in HY (66%; p=0.001), but not HO (p=0.081) or COPD (p=0.132). The observed changes in muscle mRNA abundance were similar in all groups after AET and exercise withdrawal. CONCLUSIONS: Intrinsic mitochondrial function was not impaired by ageing or COPD in the untrained state. Whole-body and muscle mitochondrial responses to AET were robust in HY, evident in HO, but deficient in COPD. All groups showed robust muscle mRNA responses. Higher relative exercise intensities during whole-body training may be needed to maximise whole-body and muscle mitochondrial adaptation in COPD.

Device-assessed sleep and physical activity in individuals recovering from a hospital admission for COVID-19: a multicentre study.

BACKGROUND: The number of individuals recovering from severe COVID-19 is increasing rapidly. However, little is known about physical behaviours that make up the 24-h cycle within these individuals. This study aimed to describe physical behaviours following hospital admission for COVID-19 at eight months post-discharge including associations with acute illness severity and ongoing symptoms. METHODS: One thousand seventy-seven patients with COVID-19 discharged from hospital between March and November 2020 were recruited. Using a 14-day wear protocol, wrist-worn accelerometers were sent to participants after a five-month follow-up assessment. Acute illness severity was assessed by the WHO clinical progression scale, and the severity of ongoing symptoms was assessed using four previously reported data-driven clinical recovery clusters. Two existing control populations of office workers and individuals with type 2 diabetes were comparators. RESULTS: Valid accelerometer data from 253 women and 462 men were included. Women engaged in a mean ± SD of 14.9 ± 14.7 min/day of moderate-to-vigorous physical activity (MVPA), with 12.1 ± 1.7 h/day spent inactive and 7.2 ± 1.1 h/day asleep. The values for men were 21.0 ± 22.3 and 12.6 ± 1.7 h /day and 6.9 ± 1.1 h/day, respectively. Over 60% of women and men did not have any days containing a 30-min bout of MVPA. Variability in sleep timing was approximately 2 h in men and women. More severe acute illness was associated with lower total activity and MVPA in recovery. The very severe recovery cluster was associated with fewer days/week containing continuous bouts of MVPA, longer total sleep time, and higher variability in sleep timing. Patients post-hospitalisation with COVID-19 had lower levels of physical activity, greater sleep variability, and lower sleep efficiency than a similarly aged cohort of office workers or those with type 2 diabetes. CONCLUSIONS: Those recovering from a hospital admission for COVID-19 have low levels of physical activity and disrupted patterns of sleep several months after discharge. Our comparative cohorts indicate that the long-term impact of COVID-19 on physical behaviours is significant.

Patient-related outcomes in patients referred to a respiratory clinic with persisting symptoms following non-hospitalised COVID-19.

Survivors of COVID-19 can present with varied and persisting symptoms, regardless of hospitalisation. We describe the ongoing symptoms, quality of life and return to work status in a cohort of non-hospitalised COVID-19 survivors with persisting respiratory symptoms presenting to clinic, who consented and completed patient-reported outcome measures. We identified fatigue, reduced quality of life and dysregulated breathing alongside the breathlessness. Those with co-existent fatigue had worse mood and quality of life and were less likely to have returned to normal working arrangements compared to those without fatigue. For non-hospitalised people with persisting symptoms following COVID-19 referred to a respiratory assessment clinic, there was a need for a wider holistic assessment, including return to work strategies.

Developing good practice by understanding how UK medical schools address low level concerns: a survey study.

In the literature, a distinction is made between low-level concerns and what is regarded as fitness to practise concerns. The General Medical Council expects all UK medical schools to have a transparent process in place about how concerns about its medical students are identified monitored and responded to. However, internationally, there is currently no well-established consensus on what is good practice in managing low-level concerns. Furthermore, currently, there is little information on how the UK medical schools vary in the processes they implement to monitor and respond to low-level concerns of their students. An online survey was developed and informed by the literature and sent to all UK medical schools to better understand their low-level concerns process. Of 39 medical schools invited, 25 participated. The data indicate variations between medical schools in the processes implemented. These variations can potentially influence the quality of the data; for example, whether there is a named person co-ordinating concerns between medical schools and placement providers. Furthermore, the data identify primary-care-based learning as offering missed opportunities where low-level concerns could be picked up. Key areas identified within the data for further work include how to quality assure that processes are equitable and how to bring more consistency to what sanctions are common and how these are decided up on.

Short physical performance battery as a practical tool to assess mortality risk in chronic obstructive pulmonary disease.

RATIONALE: chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and common in older adults. The BODE Index is the most recognised mortality risk score in COPD but includes a 6-minute walk test (6MWT) that is seldom available in practise; the BODE Index may be better adopted if the 6MWT was replaced. OBJECTIVES: we investigated whether a modified BODE Index in which 6MWT was replaced by an alternative measure of physical capacity, specifically the short physical performance battery (SPPB) or components, retained its predictive ability for mortality in individuals with COPD. METHODS: we analysed 630 COPD patients from the ERICA cohort study for whom UK Office for National Statistics verified mortality data were available. Variables tested at baseline included spirometry, 6MWT, SPPB and its components (4-m gait speed test [4MGS], chair stand and balance). Predictive models were developed using stratified multivariable Cox regression, and assessed by C-indices and calibration plots with 10-fold cross-validation and replication. RESULTS: during median 2 years of follow-up, 60 (10%) individuals died. There was no significant difference between the discriminative ability of BODE6MWT (C-index 0.709, 95% confidence interval [CI], 0.680-0.737), BODESPPB (C-index 0.683, 95% CI, 0.647-0.712), BODE4MGS (C-index 0.676, 95% CI, 0.643-0.700) and BODEBALANCE (C-index 0.686, 95% CI, 0.651-0.713) for predicting mortality. CONCLUSIONS: the SPPB, and its 4MGS and balance components, can potentially be used as an alternative to the 6MWT in the BODE Index without significant loss of predictive ability in all-cause mortality.

Respiratory and Cardiovascular Outcomes in Survivors of Extremely Preterm Birth at 19 Years.

Rationale: Growth and development during adolescence may modify the respiratory and vascular differences seen among extremely preterm (EP) individuals in childhood and early adolescence.Objectives: To assess the trajectory of respiratory and cardiovascular outcomes during transition to adulthood in a national longitudinal cohort study of births before 26 weeks of gestation in the United Kingdom and Ireland.Methods: A total of 129 EP participants and 65 control subjects attended for a center-based evaluation at 19 years of age. Standardized measures of spirometry, hemodynamics, functional capacity, and markers of inflammation were obtained from EP subjects with and without neonatal bronchopulmonary dysplasia and term-born control subjects at 19 years of age and compared with previous assessments.Measurements and Main Results: Compared with the control group, the EP group was significantly impaired on all spirometric parameters (mean FEV1z-score, -1.08 SD [95% confidence interval, -1.40 to -0.77]) and had lower fractional exhaled nitric oxide concentrations (13.9 vs. 24.4 ppb; P < 0.001) despite a higher proportion with bronchodilator reversibility (27% vs. 6%). The EP group had significantly impaired exercise capacity. All respiratory parameters were worse after neonatal bronchopulmonary dysplasia, and respiratory function differences were similar at 11 and 19 years. The augmentation index was 6% higher in the EP group and associated with increased total peripheral resistance (difference in means, 96.4 [95% confidence interval, 26.6-166.2] dyne/s/cm-5) and elevation in central, but not peripheral, blood pressure. Central systolic and diastolic blood pressures increased more quickly during adolescence in the EP group than in the control group.Conclusions: Clinicians should address both cardiovascular and respiratory risks in adult survivors of extremely preterm birth.

The burden of chronic respiratory diseases in adults in Nepal: A systematic review.

While chronic lung disease causes substantial global morbidity and mortality, global estimates have primarily been based on broad assumptions. Specific country data from low-income countries such as Nepal are limited. This review assessed primary evidence on chronic respiratory disease burden among adults in Nepal. A systematic search was performed in June 2019 (updated May 2020) for studies through nine databases. High levels of heterogeneity deemed a narrative synthesis appropriate. Among 27 eligible studies identified, most were low-moderate quality with cross-sectional and retrospective study design. Chronic lung diseases identified were chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis and restrictive lung diseases. Studies were categorised as: (i) community-based, (ii) hospital-based and (iii) comorbidity-related and disease burden. Reported disease prevalence varied widely (COPD, 1.67-14.3%; asthma, 4.2-8.9%). The prevalence of airflow obstruction was higher among rural dwellers (15.8%) and those exposed to household air pollution from domestic biomass burning as opposed to liquid petroleum gas users (Odds Ratio: 2.06). Several comorbidities, including hypertension and diabetes mellitus added to the disease burden. The review shows limited literature on lung disease burden in Nepal. Publications varied in terms of overall quality. Good quality research studies with prospective cohorts related to respiratory conditions are required.

European Respiratory Society guideline on long-term management of children with bronchopulmonary dysplasia.

This document provides recommendations for monitoring and treatment of children in whom bronchopulmonary dysplasia (BPD) has been established and who have been discharged from the hospital, or who were >36 weeks of postmenstrual age. The guideline was based on predefined Population, Intervention, Comparison and Outcomes (PICO) questions relevant for clinical care, a systematic review of the literature and assessment of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. After considering the balance of desirable (benefits) and undesirable (burden, adverse effects) consequences of the intervention, the certainty of the evidence, and values, the task force made conditional recommendations for monitoring and treatment of BPD based on very low to low quality of evidence. We suggest monitoring with lung imaging using ionising radiation in a subgroup only, for example severe BPD or recurrent hospitalisations, and monitoring with lung function in all children. We suggest to give individual advice to parents regarding daycare attendance. With regards to treatment, we suggest the use of bronchodilators in a subgroup only, for example asthma-like symptoms, or reversibility in lung function; no treatment with inhaled or systemic corticosteroids; natural weaning of diuretics by the relative decrease in dose with increasing weight gain if diuretics are started in the neonatal period; and treatment with supplemental oxygen with a saturation target range of 90-95%. A multidisciplinary approach for children with established severe BPD after the neonatal period into adulthood is preferable. These recommendations should be considered until new and urgently needed evidence becomes available.

Building toolkits for COPD exacerbations: lessons from the past and present.

In the nineteenth century, it was recognised that acute attacks of chronic bronchitis were harmful. 140 years later, it is clearer than ever that exacerbations of chronic obstructive pulmonary disease (ECOPD) are important events. They are associated with significant mortality, morbidity, a reduced quality of life and an increasing reliance on social care. ECOPD are common and are increasing in prevalence. Exacerbations beget exacerbations, with up to a quarter of in-patient episodes ending with readmission to hospital within 30 days. The healthcare costs are immense. Yet despite this, the tools available to diagnose and treat ECOPD are essentially unchanged, with the last new intervention (non-invasive ventilation) introduced over 25 years ago.An ECOPD is 'an acute worsening of respiratory symptoms that results in additional therapy'. This symptom and healthcare utility-based definition does not describe pathology and is unable to differentiate from other causes of an acute deterioration in breathlessness with or without a cough and sputum. There is limited understanding of the host immune response during an acute event and no reliable and readily available means to identify aetiology or direct treatment at the point of care (POC). Corticosteroids, short acting bronchodilators with or without antibiotics have been the mainstay of treatment for over 30 years. This is in stark contrast to many other acute presentations of chronic illness, where specific biomarkers and mechanistic understanding has revolutionised care pathways. So why has progress been so slow in ECOPD? This review examines the history of diagnosing and treating ECOPD. It suggests that to move forward, there needs to be an acceptance that not all exacerbations are alike (just as not all COPD is alike) and that clinical presentation alone cannot identify aetiology or stratify treatment.

Patient-reported outcome measures in the recovery of adults hospitalised with community-acquired pneumonia: a systematic review.

Symptomatic and functional recovery are important patient-reported outcome measures (PROMs) in community-acquired pneumonia (CAP) that are increasingly used as trial end-points. This systematic review summarises the literature on PROMs in CAP.Comprehensive searches in accordance with the PRISMA statement were conducted to March 2017. Eligible studies included adults discharged from hospital following confirmed CAP and reporting PROMs.15 studies (n=5644 patients) were included; most were of moderate quality. Studies used a wide range of PROMs and assessment tools. At 4-6 weeks post-discharge, the commonest symptom reported was fatigue (45.0-72.6% of patients, three studies), followed by cough (35.3-69.7%) and dyspnoea (34.2-67.1%); corresponding values from studies restricted by age <65 years (two studies) were lower: fatigue 12.1-25.7%, cough 19.9-31.9% and dyspnoea 16.8-27.5%. Functional impairment 4 weeks post-discharge was reported in 18-51% of patients (two studies), while median time to return to normal activities was between 15 and 28 days (three studies).Substantial morbidity is reported by patients up to 6 weeks post-discharge. There is weak methodological consistency across existing studies. A core set of PROMs for use in future studies is suggested.

Outcome measures in a combined exercise rehabilitation programme for adults with COPD and chronic heart failure: A preliminary stakeholder consensus event.

Combined exercise rehabilitation for chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) is potentially attractive. Uncertainty remains as to the baseline profiling assessments and outcome measures that should be collected within a programme. Current evidence surrounding outcome measures in cardiac and pulmonary rehabilitation were presented by experts at a stakeholder consensus event and all stakeholders (n = 18) were asked to (1) rank in order of importance a list of categories, (2) prioritise outcome measures and (3) prioritise baseline patient evaluation measures that should be assessed in a combined COPD and CHF rehabilitation programme. The tasks were completed anonymously and related to clinical rehabilitation programmes and associated research. Health-related quality of life, exercise capacity and symptom evaluation were voted as the most important categories to assess for clinical purposes (median rank: 1, 2 and 3 accordingly) and research purposes (median rank; 1, 3 and 4.5 accordingly) within combined exercise rehabilitation. All stakeholders agreed that profiling symptoms at baseline were 'moderately', 'very' or 'extremely' important to assess for clinical and research purposes in combined rehabilitation. Profiling of frailty was ranked of the same importance for clinical purposes in combined rehabilitation. Stakeholders identified a suite of multidisciplinary measures that may be important to assess in a combined COPD and CHF exercise rehabilitation programme.

TAILS proteomics reveals dynamic changes in airway proteolysis controlling protease activity and innate immunity during COPD exacerbations.

Dysregulated protease activity is thought to cause parenchymal and airway damage in chronic obstructive pulmonary disease (COPD). Multiple proteases have been implicated in COPD, and identifying their substrates may reveal new disease mechanisms and treatments. However, as proteases interact with many substrates that may be protease inhibitors or proteases themselves, these webs of protease interactions make the wider consequences of therapeutically targeting proteases difficult to predict. We therefore used a systems approach to determine protease substrates and protease activity in COPD airways. Protease substrates were determined by proteomics using the terminal amine isotopic labeling of substrates (TAILS) methodology in paired sputum samples during stable COPD and exacerbations. Protease activity and specific protein degradation in airway samples were assessed using Western blotting, substrate assays, and ex vivo cleavage assays. Two hundred ninety-nine proteins were identified in human COPD sputum, 125 of which were proteolytically processed, including proteases, protease inhibitors, mucins, defensins, and complement and other innate immune proteins. During exacerbations, airway neutrophils and neutrophil proteases increased and more proteins were cleaved, particularly at multiple sites, consistent with degradation and inactivation. During exacerbations, different substrates were processed, including protease inhibitors, mucins, and complement proteins. Exacerbations were associated with increasing airway elastase activity and increased processing of specific elastase substrates, including secretory leukocyte protease inhibitor. Proteolysis regulates multiple processes including elastase activity and innate immune proteins in COPD airways and differs during stable disease and exacerbations. The complexity of protease, inhibitor, and substrate networks makes the effect of protease inhibitors hard to predict which should be used cautiously.