Respiratory and locomotor muscle blood flow measurements using near-infrared spectroscopy and indocyanine green dye in health and disease.

Measuring respiratory and locomotor muscle blood flow during exercise is pivotal for understanding the factors limiting exercise tolerance in health and disease. Traditional methods to measure muscle blood flow present limitations for exercise testing. This article reviews a method utilising near-infrared spectroscopy (NIRS) in combination with the light-absorbing tracer indocyanine green dye (ICG) to simultaneously assess respiratory and locomotor muscle blood flow during exercise in health and disease. NIRS provides high spatiotemporal resolution and can detect chromophore concentrations. Intravenously administered ICG binds to albumin and undergoes rapid metabolism, making it suitable for repeated measurements. NIRS-ICG allows calculation of local muscle blood flow based on the rate of ICG accumulation in the muscle over time. Studies presented in this review provide evidence of the technical and clinical validity of the NIRS-ICG method in quantifying respiratory and locomotor muscle blood flow. Over the past decade, use of this method during exercise has provided insights into respiratory and locomotor muscle blood flow competition theory and the effect of ergogenic aids and pharmacological agents on local muscle blood flow distribution in COPD. Originally, arterial blood sampling was required via a photodensitometer, though the method has subsequently been adapted to provide a local muscle blood flow index using venous cannulation. In summary, the significance of the NIRS-ICG method is that it provides a minimally invasive tool to simultaneously assess respiratory and locomotor muscle blood flow at rest and during exercise in health and disease to better appreciate the impact of ergogenic aids or pharmacological treatments.

An International Validation of the "DECAF Score" to Predict Disease Severity and Hospital Mortality in Acute Exacerbation of COPD in the UAE.

The DECAF score (the Dyspnea, Eosinopenia, Consolidation, Academia, and Atrial fibrillation score) has been adopted in some hospitals to predict the severity of Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD). However, DECAF score has not been widely evaluated or used in Middle Eastern countries. The present study aimed to validate the DECAF score for predicting in-hospital mortality in patients with AECOPD in the United Arab Emirates (UAE). This was a retrospective, observational study conducted in 19 hospitals in the UAE. Data were retrieved from the electronic records of patients admitted for AECOPD in 17 hospitals across the country. Patients aged more than 35 years who were diagnosed with AECOPD were included in the study. The validation of the DECAF Score for inpatient death, 30-days death, and 90-day readmission was conducted using the Area Under the Receiver Operator curve (AUROC). The AUROCDECAF curves for inpatient death, 30-days death, and 90-day readmission were 0.8 (95% CI: 0.8-0.9), 0.8 (95% CI: 0.7-0.8), and 0.8 (95% CI: 0.8-0.8), respectively. The model was a satisfactory fit to the data (Hosmer-Lemeshow statistic = 0.195, Nagelkerke R2 = 31.7%). There were significant differences in means of length of stay across patients with different DECAF score (P = .008). Patients with a DECAF score of 6 had the highest mean length of stay, which was 29.8 ± 31.4 days. Patients with a DECAF score of 0 had the lowest mean length of stay, which was 3.6 ± 2.0 days. The DECAF score is a strong predictive tool for inpatient death, 30 days mortality and 90-day readmission in UAE hospital settings. The DECAF score is an effective tool for predicating mortality and other disease outcomes in patients with AECOPD in the UAE; hence, clinicians would be more empowered to make appropriate clinical decisions by using the DECAF score.

Admission blood eosinophil count, inpatient death and death at 1 year in exacerbating patients with COPD.

BACKGROUND: Blood eosinophil counts have been studied in patients with stable chronic obstructive pulmonary disease (COPD) and are a useful biomarker to guide inhaled corticosteroid use. Less is known about eosinophil counts during severe exacerbation. METHODS: In this retrospective study, 2645 patients admitted consecutively with COPD exacerbation across six UK hospitals were included in the study, and the clinical diagnosis was confirmed by a respiratory specialist. The relationship between admission eosinophil count, inpatient death and 1-year death was assessed. In a backward elimination, Poisson regression analysis using the log-link function with robust estimates, patients' markers of acute illness and stable-state characteristics were assessed in terms of their association with eosinopenia. RESULTS: 1369 of 2645 (52%) patients had eosinopenia at admission. Those with eosinopenia had a 2.5-fold increased risk of inpatient death compared with those without eosinopenia (12.1% vs 4.9%, RR=2.50, 95% CI 1.88 to 3.31, p<0.001). The same mortality risk with eosinopenia was seen among the subgroup with pneumonic exacerbation (n=788, 21.3% vs 8.5%, RR=2.5, 95% CI 1.67 to 2.24, p<0.001). In a regression analysis, eosinopenia was significantly associated with: older age and male sex; a higher pulse rate, temperature, neutrophil count, urea and C reactive protein level; a higher proportion of patients with chest X-ray consolidation and a reduced Glasgow Coma Score; and lower systolic and diastolic blood pressure measurements and lower oxygen saturation, albumin, platelet and previous admission counts. DISCUSSION: During severe COPD exacerbation, eosinopenia is common and associated with inpatient death and several markers of acute illness. Clinicians should be cautious about using eosinophil results obtained during severe exacerbation to guide treatment decisions regarding inhaled corticosteroid use.

Greater exercise tolerance in COPD during acute intermittent compared to continuous shuttle walking protocols: A proof-of-concept study.

Objectives: Ground-based walking is a simple training modality which would suit pulmonary rehabilitation (PR) settings with limited access to specialist equipment. Patients with COPD are, however, unable to walk uninterruptedly at a relatively fast walking pace to optimise training benefits. We compared an intermittent (IntSW) to a continuous (CSW) shuttle walking protocol.Methods: In 14 COPD patients (mean ± SD. FEV1: 45 ± 21% predicted) we measured walking distance, cardiac output (CO), arterial oxygen saturation (SpO2), and symptoms during (a) an IntSW protocol, consisting of 1-min walking alternating with 1-min rest, and (b) a CSW protocol, both sustained at 85% of predicted VO2 peak to the limit of tolerance (Tlim).Results: Median (IQR) distance was greater (p = 0.001) during the IntSW protocol (735 (375-1107) m) than the CSW protocol (190 (117-360) m). At iso-distance (distance at Tlim during CSW) the IntSW compared to the CSW protocol was associated with lower CO (8.6 ± 2.6 vs 10.3 ± 3.7 L/min; p = 0.013), greater SpO2 (92 ± 6% versus 90 ± 7%; p = 0.002), and lower symptoms of dyspnoea (2.8 ± 1.3 vs 4.9 ± 1.4; p = 0.001) and leg discomfort (2.3 ± 1.7 vs 4.2 ± 2.2; p = 0.001). At Tlim symptoms of dyspnoea and leg discomfort did not differ between the IntSW (4.4 ± 1.9 and 3.6 ± 2.1, respectively) and the CSW protocol.Conclusions: The IntSW protocol may provide important clinical benefits during exercise training in the PR settings because it allows greater work outputs compared to the CSW.

Oxygen therapy and inpatient mortality in COPD exacerbation.

BACKGROUND: In hospitalised patients with exacerbation of Chronic Obstructive Pulmonary Disease, European and British guidelines endorse oxygen target saturations of 88%-92%, with adjustment to 94%-98% if carbon dioxide levels are normal. We assessed the impact of admission oxygen saturation level and baseline carbon dioxide on inpatient mortality. METHODS: Patients were identified from the prospective Dyspnoea, Eosinopenia, Consolidation, Acidaemia and Atrial Fibrillation (DECAF) derivation study (December 2008-June 2010) and the mixed methods DECAF validation study (January 2012 to May 2014). In six UK hospitals, of 2645 patients with COPD exacerbation, 1027 patients were in receipt of supplemental oxygen at admission. All had a clinical history of COPD and obstructive spirometry. These patients were subdivided into the following groups: admission oxygen saturations of 87% or less, 88%-92%, 93%-96% or 97%-100%. Inpatient mortality was calculated for each group and expressed as ORs. The DECAF score and National Early Warning Score 2 (excluding oxygen saturation) were used in binary logistic regression to adjust for baseline risk. RESULTS: In patients with COPD receiving supplemental oxygen, oxygen saturations above 92% were associated with higher mortality and an adverse dose-response. Compared with the 88%-92% group, the adjusted risk of death (OR) in the 93%-96% and 97%-100% groups was 1.98 (95% CI 1.09 to 3.60, p=0.025) and 2.97 (95% CI 1.58 to 5.58, p=0.001). In the subgroup with normocapnia, the mortality signal remained significant in both the 93%-96% and 97%-100% groups. CONCLUSIONS: Inpatient mortality was lowest in those with oxygen saturations of 88%-92%. Even modest elevations in oxygen saturations above this range (93%-96%) were associated with an increased risk of death. A similar mortality trend was seen in both patients with hypercapnia and normocapnia. This shows that the practice of setting different target saturations based on carbon dioxide levels is not justified. Treating all patients with COPD with target saturations of 88%-92% will simplify prescribing and should improve outcome. TRIAL REGISTRATION NUMBER: UKCRN ID 14214.

Predictors of NIV Treatment in Patients with COPD Exacerbation Complicated by Respiratory Acidaemia.

Non-invasive ventilation (NIV) treatment decisions are poorly understood for patients with COPD exacerbation complicated by acute hypercapnic respiratory failure and respiratory acidaemia (ECOPD-RA). We identified 420 NIV-eligible patients from the DECAF study cohorts admitted with an ECOPD-RA. Using bivariate and multivariate analyses, we examined which indices were associated with clinicians' decisions to start NIV, including whether the presence of pneumonia was a deterrent. Admitting hospital, admission from institutional care, partial pressure of oxygen, cerebrovascular disease, pH, systolic blood pressure and white cell count were all associated with the provision of NIV. Of these indices, only pH was also a predictor of inpatient death. Those not treated with NIV included those with milder acidaemia and higher (and sometimes excessive) oxygen levels, and a frailer population with higher Extended Medical Research Council Dyspnoea scores, presumably deemed not suitable for NIV. Pneumonia was not associated with NIV treatment; 34 of 111 (30.6%) NIV-untreated patients had pneumonia, whilst 107 of 309 (34.6%) NIV-treated patients had pneumonia (p = 0.483). In our study, one in four NIV-eligible patients were not treated with NIV. Clinicians' NIV treatment decisions are not based on those indices most strongly associated with mortality risk. One of the strongest predictors of whether a patient received a life-saving treatment is which hospital they attended. Further research is required to aid in the risk stratification of this patient group which may help standardise and improve care.

Models of care across the continuum of exacerbations for patients with chronic obstructive pulmonary disease.

Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with significant morbidity and mortality, and treatments require a multidisciplinary approach to address patient needs. This review considers different models of care across the continuum of exacerbations (1) chronic care and self-management interventions with the action plan, (2) domiciliary care for severe exacerbation and the impact on readmission prevention and (3) the discharge care bundle for management beyond the acute exacerbation episode. Self-management strategies include written action plans and coaching with patient and family support. Self-management interventions facilitate the delivery of good care, can reduce exacerbations associated with admission, be cost-effective and improve quality of life. Hospitalization as a complication of exacerbation is not always unavoidable. Domiciliary care has been proposed as a solution to replace part, and perhaps even all, of the patient's in-hospital stay, and to reduce hospital bed days, readmission rates and costs; low-risk patients can be identified using risk stratification tools. A COPD discharge bundle is another potentially important approach that can be considered to improve the management of COPD exacerbations complicated by hospital admission; it comprised treatments that have demonstrated efficacy, such as smoking cessation, personalized pharmacotherapy and non-pharmacotherapy such as pulmonary rehabilitation. COPD bundles may also improve the transition of care from the hospital to the community following exacerbation and may reduce readmission rates. Future models of care should be personalized - providing patient education aiming at behaviour changes, identifying and treating co-morbidities, and including outcomes that measure quality of care rather than focusing only on readmission quantity within 30 days.

Comparison of early warning scores in patients with COPD exacerbation: DECAF and NEWS score.

BACKGROUND: The National Early Warning Score 2 (NEWS2) includes two oxygen saturation scales; the second adjusts target saturations to 88%-92% for those with hypercapnic respiratory failure. Using this second scale in all patients with COPD exacerbation ('NEWS2All COPD') would simplify practice, but the impact on alert frequency and prognostic performance is unknown. Admission NEWS2 score has not been compared with DECAF (dyspnoea, eosinopenia, consolidation, acidaemia, atrial fibrillation) for inpatient mortality prediction. METHODS: NEWS, NEWS2 and NEWS2All COPD and DECAF were calculated at admission in 2645 patients with COPD exacerbation attending consecutively to one of six UK hospitals, all of whom met spirometry criteria for COPD. Alert frequency and appropriateness were assessed for all NEWS iterations. Prognostic performance was compared using the area under the receiver operating characteristic (AUROC) curve. Missing data were imputed using multiple imputation. FINDINGS: Compared with NEWS, NEWS2 reclassified 3.1% patients as not requiring review by a senior clinician (score≥5). NEWS2All COPD reduced alerts by 12.6%, or 16.1% if scoring for injudicious use of oxygen was exempted. Mortality was low in reclassified patients, with no patients dying the same day as being identified as low risk. NEWS2All COPD was a better prognostic score than NEWS (AUROC 0.72 vs 0.65, p<0.001), with similar performance to NEWS2 (AUROC 0.72 vs 0.70, p=0.090). DECAF was superior to all scores (validation cohort AUROC 0.82) and offered a more clinically useful range of risk stratification (DECAF=1.2%-25.5%; NEWS2=3.5%-15.4%). CONCLUSION: NEWS2All COPD safely reduces the alert frequency compared with NEWS2. DECAF offers superior prognostic performance to guide clinical decision-making on admission, but does not replace repeated measures of NEWS2 during hospitalisation to detect the deteriorating patient.

Home treatment of COPD exacerbation selected by DECAF score: a non-inferiority, randomised controlled trial and economic evaluation.

BACKGROUND: Previous models of Hospital at Home (HAH) for COPD exacerbation (ECOPD) were limited by the lack of a reliable prognostic score to guide patient selection. Approximately 50% of hospitalised patients have a low mortality risk by DECAF, thus are potentially suitable. METHODS: In a non-inferiority randomised controlled trial, 118 patients admitted with a low-risk ECOPD (DECAF 0 or 1) were recruited to HAH or usual care (UC). The primary outcome was health and social costs at 90 days. RESULTS: Mean 90-day costs were £1016 lower in HAH, but the one-sided 95% CI crossed the non-inferiority limit of £150 (CI -2343 to 312). Savings were primarily due to reduced hospital bed days: HAH=1 (IQR 1-7), UC=5 (IQR 2-12) (P=0.001). Length of stay during the index admission in UC was only 3 days, which was 2 days shorter than expected. Based on quality-adjusted life years, the probability of HAH being cost-effective was 90%. There was one death within 90 days in each arm, readmission rates were similar and 90% of patients preferred HAH for subsequent ECOPD. CONCLUSION: HAH selected by low-risk DECAF score was safe, clinically effective, cost-effective, and preferred by most patients. Compared with earlier models, selection is simpler and approximately twice as many patients are eligible. The introduction of DECAF was associated with a fall in UC length of stay without adverse outcome, supporting use of DECAF to direct early discharge. TRIAL REGISTRATION NUMBER: Registered prospectively ISRCTN29082260.

Heterogeneity in the measurement and reporting of outcomes in studies of electronic cigarette use in adolescents: a systematic analysis of observational studies.

OBJECTIVE: To examine consistency between cross-sectional studies of conventional and electronic cigarette use among adolescents in terms of the measurement, analysis and reporting of parameters. DESIGN: A systematic analysis of cross-sectional studies of conventional and electronic cigarette use in adolescents, to identify measured and reported parameters. DATA SOURCES: Studies examining use of electronic and conventional cigarette use in adolescents were identified by searching the SCOPUS database in August 2015. STUDY SELECTION: The selection criteria for studies were: cross-sectional studies, in English, on e-cigarette use in adolescents. Two reviewers independently selected relevant studies from the search. 60 abstracts were identified, from which 31 papers were eligible for review (23 unique studies). DATA EXTRACTION: Measured and reported parameters were identified and tabulated. These included the prevalence of cigarette and/ or electronic cigarette use, and the definitions of terms. Data were extracted independently by two reviewers. DATA SYNTHESIS: With regards basic parameters of 'ever' or 'current' use of electronic or conventional cigarettes, there were 31 unique measured parameters across 23 studies. Of 16/23 studies in which authors collected information on dual current use, prevalence was reported in 11/16, with six different definitions of 'dual use'. CONCLUSIONS: There are substantial differences in measurement and reporting of parameters across observational studies of electronic and conventional cigarette use in adolescents. These studies are at risk of reporting bias, and results are difficult to interpret. A core outcome set that should be measured and reported in all observational studies is required, using structured consensus techniques.

Early Supported Discharge/Hospital At Home For Acute Exacerbation of Chronic Obstructive Pulmonary Disease: A Review and Meta-Analysis.

A systematic review and meta-analysis was performed to assess the safety, efficacy and cost of Early Supported Discharge (ESD) and Hospital at Home (HAH) compared to Usual Care (UC) for patients with acute exacerbation of COPD (AECOPD). The structure of ESD/HAH schemes was reviewed, and analyses performed assuming return to hospital during the acute period (prior to discharge from home treatment) was, and was not, considered a readmission. The pre-defined search strategy completed in November 2014 included electronic databases (Medline, Embase, Amed, BNI, Cinahl and HMIC), libraries, current trials registers, national organisations, key respiratory journals, key author contact and grey literature. Randomised controlled trials (RCTs) comparing ESD/HAH to UC in patients admitted with AECOPD, or attending the emergency department and triaged for admission, were included. Outcome measures were mortality, all-cause readmissions to 6 months and cost. Eight RCTs were identified; seven reported mortality and readmissions. The structure of ESD/HAH schemes, particularly selection criteria applied and level of support provided, varied considerably. Compared to UC, ESD/HAH showed a trend towards lower mortality (RRMH = 0.66; 95% CI 0.40-1.09, p = 0.10). If return to hospital during the acute period was not considered a readmission, ESD/HAH was associated with fewer readmissions (RRMH = 0.74, 95% CI: 0.60-0.90, p = 0.003), but if considered a readmission, the benefit was lost (RRMH = 0.84; 95% CI 0.69-1.01, p = 0.07). Costs were lower for ESD/HAH than UC. ESD/HAH is safe in selected patients with an AECOPD. Further research is required to define optimal criteria to guide patient selection and models of care.

Potentiators (specific therapies for class III and IV mutations) for cystic fibrosis.

BACKGROUND: Cystic fibrosis is the most common inherited life-shortening illness in Caucasians and caused by a mutation in the gene that codes for the cystic fibrosis transmembrane regulator protein (CFTR), which functions as a salt transporter. This mutation most notably affects the airways of people with cystic fibrosis. Excess salt absorption by defective CFTR dehydrates the airway lining and leads to defective mucociliary clearance. Consequent accumulation of thick, sticky mucus makes the airway prone to chronic infection and progressive inflammation; respiratory failure often ensues. Additionally, abnormalities with CFTR lead to systemic complications like malnutrition, diabetes and subfertility.Since the discovery of the causative gene, our understanding of the structure and function of CFTR and the impact of different mutations has increased and allowed pharmaceutical companies to design new mutation-specific therapies targeting the underlying molecular defect. Therapies targeting mutation classes III and IV (CFTR potentiators) aim to normalise airway surface liquid and help re-establish mucociliary clearance, which then has a beneficial impact on the chronic infection and inflammation that characterizes lung disease in people with cystic fibrosis. These therapies may also affect other mutations. OBJECTIVES: To evaluate the effects of CFTR potentiators on clinically important outcomes in children and adults with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Last search: 05 March 2015.We searched the EU Clinical Trials Register, clinicaltrials.gov (US Clinical Trials Register) and the International Clinical Trials Registry Platform (ICTRP). Last search of clinical trial registries: 06 February 2014. SELECTION CRITERIA: Randomised controlled trials of parallel design comparing CFTR potentiators to placebo in people with cystic fibrosis. In a post hoc change we excluded trials combining CFTR potentiators with other mutation-specific therapies. These will be considered in a separate review. DATA COLLECTION AND ANALYSIS: The authors independently extracted data and assessed the risk of bias in included trials; they contacted trial authors for additional data. Meta-analyses were undertaken on outcomes at a number of time points. MAIN RESULTS: We included four randomised controlled trials (n = 378), lasting from 28 days to 48 weeks, comparing the potentiator ivacaftor to placebo. Trials differed in terms of design and participant eligibility criteria, which limited the meta-analyses. The phase 2 trial (n = 19) and two phase 3 trials (adult trial (n = 167), paediatric trial (n = 52)), recruited participants with the G551D mutation (class III). The fourth trial (n = 140) enrolled participants homozygous for the ΔF508 mutation (class II).Risks of bias in the trials were moderate. Random sequence generation, allocation concealment and blinding of trial personnel were well-documented. Participant blinding was less clear throughout all trials; in three trials, some participant data were excluded from the analysis. Selective outcome reporting was apparent in three trials. All trials were sponsored by industry and supported by other non-pharmaceutical funding bodies.No trial reported any deaths. Significantly higher quality of life scores in the respiratory domain were reported by the adult phase 3 G551D trial at 24 weeks, mean difference 8.10 (95% confidence interval (CI) 4.77 to 11.43) and 48 weeks, mean difference 8.60 (95% CI 5.27 to 11.93); but not by the paediatric phase 3 G551D trial. The adult phase 3 G551D trial reported improvements in relative change from baseline in forced expiratory volume at one second at 24 weeks, mean difference 16.90% (95% CI 13.60 to 20.20) and 48 weeks, mean difference 16.80% (95% CI 13.50 to 20.10); as did the paediatric G551D trial at 24 weeks, mean difference 17.4% (P < 0.0001)). No improvements in quality of life or lung function were reported in the ΔF508 participants.Combined data from both phase 3 G551D trials demonstrated increased reporting of cough, odds ratio 0.57 (95% CI 0.33 to 1.00) and increased episodes of decreased pulmonary function, odds ratio 0.29 (95% CI 0.10 to 0.82) in the placebo group. The adult phase 3 G551D trial demonstrated increased reporting of dizziness amongst the ivacaftor group, OR 10.55 (95% CI 1.32 to 84.47). No trial showed a difference between treatment arms in the number of participants interrupting or discontinuing the trial drug.In the phase 3 G551D trials, fewer participants assigned to ivacaftor developed serious pulmonary exacerbations. When considering all data for exacerbations, participants taking ivacaftor in the adult phase 3 G551D study developed fewer exacerbations, odds ratio 0.54 (95% CI 0.29 to 1.01). In the other G551D studies and in the ΔF508 study, there was no difference between groups in the number of participants who developed pulmonary exacerbations.Combined data from both phase 3 G551D trials demonstrated significant improvements in absolute change from baseline in forced expiratory volume at one second (% predicted) at 24 weeks, mean difference 10.80% (95% CI 8.91 to 12.69) and 48 weeks, mean difference 10.44% (95% CI 8.56 to 12.32); also in weight at 24 weeks, mean difference 2.37 kg (95% CI 1.68 to 3.06) and 48 weeks, mean difference 2.75 kg (95% CI 1.74 to 3.75). No improvements in these outcomes were reported in the ΔF508 participants.Significant reductions in sweat chloride concentration were reported in both G551D and ΔF508 participants: in combined data from both phase 3 G551D trials at 24 weeks, mean difference -48.98 mmol/L (95% CI -52.07 to -45.89) and 48 weeks, mean difference -49.03 mmol/L (95% CI -52.11 to -45.94); and from the ΔF508 trial at 16 weeks, mean difference -2.90 mmol/L (95% CI -5.60 to -0.20). AUTHORS' CONCLUSIONS: Both G551D phase 3 trials (n = 219) demonstrated a clinically relevant impact of the potentiator ivacaftor on outcomes at 24 and 48 weeks, providing evidence for the use of this treatment in adults and children (over six years of age) with cystic fibrosis and the G551D mutation (class III). There is no evidence to support the use of ivacaftor in people with the ΔF508 mutation (class II) (n = 140). Trials on ivacaftor in people with different mutations are ongoing.

Development and evaluation of a tool to optimise inhaler selection prior to hospital discharge following an exacerbation of COPD.

Introduction: Rates of mortality and re-admission after a hospitalised exacerbation of COPD are high and resistant to change. COPD guidelines do not give practical advice about the optimal selection of inhaled drugs and device in this situation. We hypothesised that a failure to optimise inhaled drug and drug delivery prior to discharge from hospital after an exacerbation would be associated with a modifiable increased risk of re-admission and death. We designed a study to 1) develop a practical inhaler selection tool to use at the point of hospital discharge and 2) implement this tool to understand the potential impact on modifying inhaler prescriptions, clinical outcomes, acceptability to clinicians and patients, and the feasibility of delivering a definitive trial to demonstrate potential benefit. Methods: We iteratively developed an inhaler selection tool for use prior to discharge following a hospitalised exacerbation of COPD using surveys with multiprofessional clinicians and a focus group of people living with COPD. We surveyed clinicians to understand their views on the minimum clinically important difference (MCID) for death and re-admission following a hospitalised exacerbation of COPD. We conducted a mixed-methods implementation feasibility study using the tool at discharge, and collated 30- and 90-day follow-up data including death and re-admissions. Additionally, we observed the tool being used and interviewed clinicians and patients about use of the tool in this setting. Results: We completed the design of an inhaler selection tool through two rounds of consultations with 94 multiprofessional clinicians, and a focus group of four expert patients. Regarding MCIDs, there was majority consensus for the following reductions from baseline being the MCID: 30-day readmissions 5-10%, 90-day readmissions 10-20%, 30-day mortality 5-10% and 90-day mortality 5-10%. 118 patients were assessed for eligibility and 26 had the tool applied. A change in inhaled medication was recommended in nine (35%) out of 26. Re-admission or death at 30 days was seen in 33% of the switch group and 35% of the no-switch group. Re-admission or death at 90 days was seen in 56% of the switch group and 41% of the no-switch group. Satisfaction with inhalers was generally high, and switching was associated with a small increase in the Feeling of Satisfaction with Inhaler questionnaire of 3 out of 50 points. Delivery of a definitive study would be challenging. Conclusion: We completed a mixed-methods study to design and implement a tool to aid optimisation of inhaled pharmacotherapy prior to discharge following a hospitalised exacerbation of COPD. This was not associated with fewer re-admissions, but was well received and one-third of people were eligible for a change in inhalers.

Global mortality and readmission rates following COPD exacerbation-related hospitalisation: a meta-analysis of 65 945 individual patients.

Background: Exacerbations of COPD (ECOPD) have a major impact on patients and healthcare systems across the world. Precise estimates of the global burden of ECOPD on mortality and hospital readmission are needed to inform policy makers and aid preventive strategies to mitigate this burden. The aims of the present study were to explore global in-hospital mortality, post-discharge mortality and hospital readmission rates after ECOPD-related hospitalisation using an individual patient data meta-analysis (IPDMA) design. Methods: A systematic review was performed identifying studies that reported in-hospital mortality, post-discharge mortality and hospital readmission rates following ECOPD-related hospitalisation. Data analyses were conducted using a one-stage random-effects meta-analysis model. This study was conducted and reported in accordance with the PRISMA-IPD statement. Results: Data of 65 945 individual patients with COPD were analysed. The pooled in-hospital mortality rate was 6.2%, pooled 30-, 90- and 365-day post-discharge mortality rates were 1.8%, 5.5% and 10.9%, respectively, and pooled 30-, 90- and 365-day hospital readmission rates were 7.1%, 12.6% and 32.1%, respectively, with noticeable variability between studies and countries. Strongest predictors of mortality and hospital readmission included noninvasive mechanical ventilation and a history of two or more ECOPD-related hospitalisations <12 months prior to the index event. Conclusions: This IPDMA stresses the poor outcomes and high heterogeneity of ECOPD-related hospitalisation across the world. Whilst global standardisation of the management and follow-up of ECOPD-related hospitalisation should be at the heart of future implementation research, policy makers should focus on reimbursing evidence-based therapies that decrease (recurrent) ECOPD.

Real-World Gait Detection Using a Wrist-Worn Inertial Sensor: Validation Study.

BACKGROUND: Wrist-worn inertial sensors are used in digital health for evaluating mobility in real-world environments. Preceding the estimation of spatiotemporal gait parameters within long-term recordings, gait detection is an important step to identify regions of interest where gait occurs, which requires robust algorithms due to the complexity of arm movements. While algorithms exist for other sensor positions, a comparative validation of algorithms applied to the wrist position on real-world data sets across different disease populations is missing. Furthermore, gait detection performance differences between the wrist and lower back position have not yet been explored but could yield valuable information regarding sensor position choice in clinical studies. OBJECTIVE: The aim of this study was to validate gait sequence (GS) detection algorithms developed for the wrist position against reference data acquired in a real-world context. In addition, this study aimed to compare the performance of algorithms applied to the wrist position to those applied to lower back-worn inertial sensors. METHODS: Participants with Parkinson disease, multiple sclerosis, proximal femoral fracture (hip fracture recovery), chronic obstructive pulmonary disease, and congestive heart failure and healthy older adults (N=83) were monitored for 2.5 hours in the real-world using inertial sensors on the wrist, lower back, and feet including pressure insoles and infrared distance sensors as reference. In total, 10 algorithms for wrist-based gait detection were validated against a multisensor reference system and compared to gait detection performance using lower back-worn inertial sensors. RESULTS: The best-performing GS detection algorithm for the wrist showed a mean (per disease group) sensitivity ranging between 0.55 (SD 0.29) and 0.81 (SD 0.09) and a mean (per disease group) specificity ranging between 0.95 (SD 0.06) and 0.98 (SD 0.02). The mean relative absolute error of estimated walking time ranged between 8.9% (SD 7.1%) and 32.7% (SD 19.2%) per disease group for this algorithm as compared to the reference system. Gait detection performance from the best algorithm applied to the wrist inertial sensors was lower than for the best algorithms applied to the lower back, which yielded mean sensitivity between 0.71 (SD 0.12) and 0.91 (SD 0.04), mean specificity between 0.96 (SD 0.03) and 0.99 (SD 0.01), and a mean relative absolute error of estimated walking time between 6.3% (SD 5.4%) and 23.5% (SD 13%). Performance was lower in disease groups with major gait impairments (eg, patients recovering from hip fracture) and for patients using bilateral walking aids. CONCLUSIONS: Algorithms applied to the wrist position can detect GSs with high performance in real-world environments. Those periods of interest in real-world recordings can facilitate gait parameter extraction and allow the quantification of gait duration distribution in everyday life. Our findings allow taking informed decisions on alternative positions for gait recording in clinical studies and public health. TRIAL REGISTRATION: ISRCTN Registry 12246987; https://www.isrctn.com/ISRCTN12246987. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2021-050785.

Determinants of recovery from post-COVID-19 dyspnoea: analysis of UK prospective cohorts of hospitalised COVID-19 patients and community-based controls.

Background: The risk factors for recovery from COVID-19 dyspnoea are poorly understood. We investigated determinants of recovery from dyspnoea in adults with COVID-19 and compared these to determinants of recovery from non-COVID-19 dyspnoea. Methods: We used data from two prospective cohort studies: PHOSP-COVID (patients hospitalised between March 2020 and April 2021 with COVID-19) and COVIDENCE UK (community cohort studied over the same time period). PHOSP-COVID data were collected during hospitalisation and at 5-month and 1-year follow-up visits. COVIDENCE UK data were obtained through baseline and monthly online questionnaires. Dyspnoea was measured in both cohorts with the Medical Research Council Dyspnoea Scale. We used multivariable logistic regression to identify determinants associated with a reduction in dyspnoea between 5-month and 1-year follow-up. Findings: We included 990 PHOSP-COVID and 3309 COVIDENCE UK participants. We observed higher odds of improvement between 5-month and 1-year follow-up among PHOSP-COVID participants who were younger (odds ratio 1.02 per year, 95% CI 1.01-1.03), male (1.54, 1.16-2.04), neither obese nor severely obese (1.82, 1.06-3.13 and 4.19, 2.14-8.19, respectively), had no pre-existing anxiety or depression (1.56, 1.09-2.22) or cardiovascular disease (1.33, 1.00-1.79), and shorter hospital admission (1.01 per day, 1.00-1.02). Similar associations were found in those recovering from non-COVID-19 dyspnoea, excluding age (and length of hospital admission). Interpretation: Factors associated with dyspnoea recovery at 1-year post-discharge among patients hospitalised with COVID-19 were similar to those among community controls without COVID-19. Funding: PHOSP-COVID is supported by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19. The views expressed in the publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health and Social Care.COVIDENCE UK is supported by the UK Research and Innovation, the National Institute for Health Research, and Barts Charity. The views expressed are those of the authors and not necessarily those of the funders.

Laboratory and free-living gait performance in adults with COPD and healthy controls.

Background: Gait characteristics are important risk factors for falls, hospitalisations and mortality in older adults, but the impact of COPD on gait performance remains unclear. We aimed to identify differences in gait characteristics between adults with COPD and healthy age-matched controls during 1) laboratory tests that included complex movements and obstacles, 2) simulated daily-life activities (supervised) and 3) free-living daily-life activities (unsupervised). Methods: This case-control study used a multi-sensor wearable system (INDIP) to obtain seven gait characteristics for each walking bout performed by adults with mild-to-severe COPD (n=17; forced expiratory volume in 1 s 57±19% predicted) and controls (n=20) during laboratory tests, and during simulated and free-living daily-life activities. Gait characteristics were compared between adults with COPD and healthy controls for all walking bouts combined, and for shorter (≤30 s) and longer (>30 s) walking bouts separately. Results: Slower walking speed (-11 cm·s-1, 95% CI: -20 to -3) and lower cadence (-6.6 steps·min-1, 95% CI: -12.3 to -0.9) were recorded in adults with COPD compared to healthy controls during longer (>30 s) free-living walking bouts, but not during shorter (≤30 s) walking bouts in either laboratory or free-living settings. Double support duration and gait variability measures were generally comparable between the two groups. Conclusion: Gait impairment of adults with mild-to-severe COPD mainly manifests during relatively long walking bouts (>30 s) in free-living conditions. Future research should determine the underlying mechanism(s) of this impairment to facilitate the development of interventions that can improve free-living gait performance in adults with COPD.

The effect of COVID rehabilitation for ongoing symptoms Post HOSPitalisation with COVID-19 (PHOSP-R): protocol for a randomised parallel group controlled trial on behalf of the PHOSP consortium.

INTRODUCTION: Many adults hospitalised with COVID-19 have persistent symptoms such as fatigue, breathlessness and brain fog that limit day-to-day activities. These symptoms can last over 2 years. Whilst there is limited controlled studies on interventions that can support those with ongoing symptoms, there has been some promise in rehabilitation interventions in improving function and symptoms either using face-to-face or digital methods, but evidence remains limited and these studies often lack a control group. METHODS AND ANALYSIS: This is a nested single-blind, parallel group, randomised control trial with embedded qualitative evaluation comparing rehabilitation (face-to-face or digital) to usual care and conducted within the PHOSP-COVID study. The aim of this study is to determine the effectiveness of rehabilitation interventions on exercise capacity, quality of life and symptoms such as breathlessness and fatigue. The primary outcome is the Incremental Shuttle Walking Test following the eight week intervention phase. Secondary outcomes include measures of function, strength and subjective assessment of symptoms. Blood inflammatory markers and muscle biopsies are an exploratory outcome. The interventions last eight weeks and combine symptom-titrated exercise therapy, symptom management and education delivered either in a face-to-face setting or through a digital platform ( www.yourcovidrecovery.nhs.uk ). The proposed sample size is 159 participants, and data will be intention-to-treat analyses comparing rehabilitation (face-to-face or digital) to usual care. ETHICS AND DISSEMINATION: Ethical approval was gained as part of the PHOSP-COVID study by Yorkshire and the Humber Leeds West Research NHS Ethics Committee, and the study was prospectively registered on the ISRCTN trial registry (ISRCTN13293865). Results will be disseminated to stakeholders, including patients and members of the public, and published in appropriate journals. Strengths and limitations of this study • This protocol utilises two interventions to support those with ongoing symptoms of COVID-19 • This is a two-centre parallel-group randomised controlled trial • The protocol has been supported by patient and public involvement groups who identified treatments of symptoms and activity limitation as a top priority.

Elexacaftor-Tezacaftor-Ivacaftor improve Gastro-Oesophageal reflux and Sinonasal symptoms in advanced cystic fibrosis.

Upper gastrointestinal and upper airway disease are common in cystic fibrosis (CF) and may contribute to lower airway infection and inflammation. In a longitudinal cohort study of 32 patients (23 men; median age 32.5 years) with advanced CF lung disease (median FEV1 24.8% predicted) starting elexacaftor-tezacaftor-ivacaftor, the reflux symptom index score fell from a pre-treatment median (IQR) of 15 (11-23) to 5 (2.8-7.3) (p<0.001), the Hull airway reflux score fell from a median of 26.5 (16.3-39) to 7.5 (4-12) (p<0.001), and the sinonasal outcome score from a median of 36.5 (22-24) to 20 (10-32) (p<0.001) at 6 months on treatment. Mean FEV1% predicted rose by 9.2 points, the median respiratory domain score of the CF Questionnaire-Revised rose by 27.8 points and mean body mass index rose by 2.6 kg/m2. In addition to improving lung function and weight, CFTR modulators improve upper airway and gastro-oesophageal reflux symptoms in advanced CF.

Using a learning health system to understand the mismatch between medicines supply and actual medicines use among adults with cystic fibrosis.

BACKGROUND: Studies in separate cohorts suggest possible discrepancies between inhaled medicines supplied (median 50-60%) and medicines used (median 30-40%). We performed the first study that directly compares CF medicine supply against use to identify the cost of excess medicines supply. METHODS: This cross-sectional study included participants from 12 UK adult centres with ≥1 year of continuous adherence data from data-logging nebulisers. Medicine supply was measured as medication possession ratio (MPR) for a 1-year period from the first suitable supply date. Medicine use was measured as electronic data capture (EDC) adherence over the same period. The cost of excess medicines was calculated as whole excess box(es) supplied after accounting for the discrepancy between EDC adherence and MPR with 20% contingency. RESULTS: Among 275 participants, 133 (48.4%) were females and mean age was 30 years (95% CI 29-31 years). Median EDC adherence was 57% (IQR 23-86%), median MPR was 74% (IQR 46-96%) and the discrepancy between measures was median 14% (IQR 2-29%). Even with 20% contingency, mean potential cost of excess medicines was £1,124 (95% CI £855-1,394), ranging from £183 (95% CI £29-338) for EDC adherence ≥80% to £2,017 (95% CI £1,507-2,526) for EDC adherence <50%. CONCLUSIONS: This study provides a conservative estimate of excess inhaled medicines supply cost among adults with CF in the UK. The excess supply cost was highest among those with lowest EDC adherence, highlighting the importance of adherence support and supplying medicine according to actual use. MPR provides information about medicine supply but over-estimates actual medicine use.