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Lo C.-Y.,UK National Heart and Lung Institute | Lo C.-Y.,NIHR Respiratory Biomedical Research Unit | Lo C.-Y.,Chang Gung University | Michaeloudes C.,UK National Heart and Lung Institute | And 8 more authors.
Journal of Allergy and Clinical Immunology | Year: 2015

Background Patients with severe asthma are less responsive to corticosteroid therapy and show increased airway remodeling. The mesenchymal progenitors, fibrocytes, may be involved in the remodeling of asthmatic airways. We propose that fibrocytes in severe asthma are different from those in nonsevere asthma. Objectives To examine the survival, myofibroblastic differentiation, and C-C chemokine receptor 7 (CCR7) expression in blood fibrocytes from patients with severe and nonsevere asthma and study the effect of corticosteroids on fibrocyte function. Methods The nonadherent non-T-cell fraction of blood mononuclear cells was isolated from healthy subjects and patients with nonsevere and severe asthma. Total and differentiating fibrocytes were identified by their expression of CD45, collagen I, and α-smooth muscle actin using flow cytometry. The expression of CCR7 and of the glucocorticoid receptor was measured by using flow cytometry. Results Increased numbers of circulating fibrocytes, with greater myofibroblastic differentiation potential, were observed in patients with severe asthma. Dexamethasone induced apoptosis, leading to reduction in the number of cultured fibrocytes and total nonadherent non-T cells from healthy subjects and patients with nonsevere asthma but not from patients with severe asthma. Dexamethasone reduced CCR7 expression in fibrocytes from patients with nonsevere asthma but not from patients with severe asthma. Glucocorticoid receptor expression was attenuated in fibrocytes from patients with severe asthma. Conclusions Patients with severe asthma have elevated numbers of circulating fibrocytes that show enhanced myofibroblastic differentiation and that are less responsive to the effects of corticosteroids. © 2015 American Academy of Allergy, Asthma & Immunology.


Simonds A.K.,NIHR Respiratory Biomedical Research Unit
European Respiratory Review | Year: 2013

While obstructive sleep apnoea syndrome dominates discussion of the prevalence of sleep disordered breathing, nocturnal hypoventilation remains extremely prevalent in those with chronic ventilatory disorders and in the natural history of these conditions pre-dates the development of daytime ventilatory failure. In this review the clinical management of chronic hypoventilation in neuromuscular disease will be considered and then compared with that in obesity hypoventilation syndrome. In simple terms these conditions illustrate the polar opposite ends of the spectrum, as in neuromuscular disease the reduced capacity of the respiratory system is unable to withstand a normal respiratory load, and in obesity hypoventilation syndrome the normal capacity of the respiratory system is unable to tolerate a substantially increased ventilatory load. © ERS 2013.


Kon S.S.C.,NIHR Respiratory Biomedical Research Unit | Clark A.L.,Harefield Pulmonary Rehabilitation Unit | Dilaver D.,Harefield Pulmonary Rehabilitation Unit | Canavan J.L.,NIHR Respiratory Biomedical Research Unit | And 4 more authors.
Respirology | Year: 2013

Background and objective The COPD Assessment Test (CAT) is a recently introduced, simple-to-use health status instrument that takes less time to complete than better-established health status instruments. In chronic obstructive pulmonary disease (COPD) patients, the CAT improves with pulmonary rehabilitation (PR), and changes correlate with improvements in longer-established health status instruments such as the Chronic Respiratory Questionnaire (CRQ). Increasing numbers of non-COPD patients are referred for PR, but it is not known whether the CAT is responsive to PR in these populations. Methods The CAT score was prospectively measured in 365 consecutive patients (255 COPD, 110 non-COPD) before and after an 8-week PR programme. Pre to post change in CAT was calculated for COPD and non-COPD patients, and correlated with change in the CRQ. Results For both non-COPD and COPD patients, there was a similar and significant improvement in the mean (95% confidence interval) CAT score following PR (non-COPD: -2.1 (-1.0, -3.2) vs COPD: -3.0 (-2.2, -3.8); P = 0.19). Change in CAT was significantly correlated with all domains of the CRQ in non-COPD patients (all P < 0.01). Conclusions As in COPD patients, the CAT is immediately responsive to PR in non-COPD patients. Even in unselected chronic respiratory disease patients undergoing PR, the CAT is a practical alternative to longer-established health status questionnaires. This study demonstrates that the CAT is responsive to PR in both patients with and without COPD. © 2013 The Authors. Respirology © 2013 Asian Pacific Society of Respirology.


Simonds A.K.,NIHR Respiratory Biomedical Research Unit | Hare A.,NIHR Respiratory Biomedical Research Unit
Clinical medicine (London, England) | Year: 2013

There is now substantial evidence supporting the use of non-invasive ventilation in acute hypercpanic exacerbations of chronic respiratory failure, and early trials show nocturnal ventilatory support may benefit chronic heart failure patients with sleep disordered breathing. Attention is now being focused on innovative modes which adapt respiratory support to the user's ventilatory pattern, eg adaptive service ventilation and assured volume delivery 'intelligent' ventilation.


Kon S.S.C.,NIHR Respiratory Biomedical Research Unit | Dilaver D.,Harefield Pulmonary Rehabilitation Unit | Mittal M.,NIHR Respiratory Biomedical Research Unit | Nolan C.M.,NIHR Respiratory Biomedical Research Unit | And 7 more authors.
Thorax | Year: 2014

Background The Clinical COPD Questionnaire (CCQ) is a simple 10-item, health-related quality of life questionnaire (HRQoL) with good psychometric properties. However, little data exists regarding the responsiveness of the CCQ to pulmonary rehabilitation (PR) or the minimal clinically important difference (MCID). The study aims were to assess the responsiveness of the CCQ to PR, to compare the responsiveness of the CCQ to other HRQoL questionnaires and to provide estimates for the MCID. Methods The CCQ, St George's Respiratory Questionnaire (SGRQ), Chronic Respiratory Questionnaire (CRQ) and COPD Assessment Test (CAT) were measured in 261 patients with COPD before and after outpatient PR. Pre to post PR changes and Cohen's effect size were calculated. Changes in CCQ were compared with changes in other HRQoL questionnaires. Using an anchor-based approach and receiver operating characteristic (ROC) curves, the CCQ change cutoffs that identified patients achieving the known MCID for other health status questionnaires with PR were identified. Results The CCQ, SGRQ, CRQ and CAT all significantly improved with PR with an effect size of -0.39, -0.33, 0.62 and -0.25, respectively. CCQ change correlated significantly with change in SGRQ, CRQ and CAT (r=0.48, -0.56, 0.54, respectively; all p<0.001). ROC curves consistently identified a CCQ change cutoff of -0.4 as the best discriminating value to identify the MCID for the SGRQ, CRQ and CAT (area under curve: 0.71, 0.75 and 0.77, respectively; all p<0.001). Conclusions The CCQ is responsive to PR with an estimated clinically important improvement of -0.4 points. The CCQ is a practical alternative to more timeconsumingmeasures of HRQoL.


Jones S.E.,NIHR Respiratory Biomedical Research Unit | Jones S.E.,Outreach | Green S.A.,Imperial College London | Clark A.L.,Harefield Pulmonary Rehabilitation Unit | And 12 more authors.
Thorax | Year: 2014

Rationale Several randomised controlled trials support the provision of early pulmonary rehabilitation (PR) following hospitalisation for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, there is little real-world data regarding uptake, adherence and completion rates. Methods An audit was conducted to prospectively document referral, uptake, adherence and completion rates for early post-hospitalisation outpatient PR in Northwest London over a 12-month period. Results Out of 448 hospital discharges for AECOPD, 90 referrals for post-hospitalisation PR were received. Only 43 patients received and completed PR (9.6% of all hospital discharges) despite a fully commissioned PR service. Conclusions Despite the strong evidence base, there are poor referral and uptake rates for early outpatient PR following hospitalisation for AECOPD, with only a small proportion of the intended target population receiving this intervention.


Garfield B.E.,NIHR Respiratory Biomedical Research Unit | Canavan J.L.,NIHR Respiratory Biomedical Research Unit | Canavan J.L.,Royal Brompton and Harefield NHS Foundation Trust | Smith C.J.,NIHR Respiratory Biomedical Research Unit | And 6 more authors.
European Respiratory Journal | Year: 2012

Quantification of daily physical activity is of clinical interest in chronic obstructive pulmonary disease (COPD). Objective measures using activity monitors may take several days to obtain reliable results. The aim of our study was to evaluate the Stanford Seven-Day Physical Activity Recall questionnaire (PAR) against the SenseWear armband (SWA) and compare its validity with three other physical activity questionnaires. 43 COPD patients wore the SWA for 7 days. Patients completed the PAR, Baecke, Physical Activity Scale for the Elderly (PASE) and Zutphen questionnaires. Spearman rank correlation, intraclass correlation coefficients (ICC) and receiver-operating characteristics (ROC) curves were used to assess the relationship between the questionnaires and SWA. Assessed by PAR, time spent at ≥3.0 metabolic equivalents (METs) correlated significantly (r=0.54, p<0.001) with equivalent measures from SWA, with an ICC of 0.40. No relationship was seen between the other questionnaires and the SWA. The PAR predicted active patients (≥30 min at ≥3.0 METs or a physical activity level (PAL) ≥1.55) and very inactive patients (PAL <1.40) with an area under ROC curve of 0.83, 0.77 and 0.70, respectively. While the PAR did not measure physical activity sufficiently accurately to make individual recommendations, it was able to identify COPD patients at extremes of the physical activity spectrum, potentially reducing the number of patients requiring direct measurement. Copyright©ERS 2012.


Kotecha S.,University of Cardiff | Davies P.L.,University of Cardiff | Davies P.L.,Royal Hospital for Sick Children | Clark H.W.,NIHR Respiratory Biomedical Research Unit | McGreal E.P.,University of Cardiff
Thorax | Year: 2013

Background: Surfactant protein D (SP-D) is a soluble oligomeric C-type lectin known to protect against lipopolysaccharide and ventilator-induced lung injury in preterm lambs. Here we assess the expression and functional status of SP-D in bronchoalveolar lavage fluid (BALF) from preterm infants at risk of chronic lung disease (CLD) of prematurity and term controls. This is the first systematic evaluation of SP-D function in any clinical cohort. Methods: SP-D was quantified in BALF from 28 ventilated preterm infants and five ventilated term infants. SP-D lectin activity was tested in a zymosan binding assay followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and western blot in BALF from the same infants. SP-D lectin activity was also tested towards maltose-agarose and mannan for selected BALF samples. Results: SP-D expression was lower on day 1 in those preterm infants who subsequently developed CLD but increased over the first 5 days of life in term and preterm neonates. The percentage of neonatal SP-D capable of binding zymosan rarely exceeded 50% in any BALF sample and was 3.5 times lower in preterm infants than term infants on day 1 of life. Similar binding defects were observed towards maltose-agarose and mannan. SDS-PAGE analysis revealed that zymosan-bound SP-D was more highly oligomerised (≥12-mers) than unbound SP-D, which was composed primarily of trimers and lower oligomeric forms. Conclusions: Substantial and functionally relevant variation in the expression and oligomeric distribution of SP-D exists between preterm and term neonatal lung secretions. This has implications for proposed SP-D replacement therapy in this population.


Jones S.E.,NIHR Respiratory Biomedical Research Unit | Kon S.S.C.,NIHR Respiratory Biomedical Research Unit | Canavan J.L.,NIHR Respiratory Biomedical Research Unit | Patel M.S.,NIHR Respiratory Biomedical Research Unit | And 5 more authors.
Thorax | Year: 2013

Background Moving from sitting to standing is a common activity of daily living. The five-repetition sit-tostand test (5STS) is a test of lower limb function that measures the fastest time taken to stand five times from a chair with arms folded. The 5STS has been validated in healthy community-dwelling adults, but data in chronic obstructive pulmonary disease (COPD) populations are lacking. Aims To determine the reliability, validity and responsiveness of the 5STS in patients with COPD. Methods Test-retest and interobserver reliability of the 5STS was measured in 50 patients with COPD. To address construct validity we collected data on the 5STS, exercise capacity (incremental shuttle walk (ISW)), lower limb strength (quadriceps maximum voluntary contraction (QMVC)), health status (St George's Respiratory Questionnaire (SGRQ)) and composite mortality indices (Age Dyspnoea Obstruction index (ADO), BODE index (iBODE)). Responsiveness was determined by measuring 5STS before and after outpatient pulmonary rehabilitation (PR) in 239 patients. Minimum clinically important difference (MCID) was estimated using anchor-based methods. Results Test-retest and interobserver intraclass correlation coefficients were 0.97 and 0.99, respectively. 5STS time correlated significantly with ISW, QMVC, SGRQ, ADO and iBODE (r=-0.59, -0.38, 0.35, 0.42 and 0.46, respectively; all p<0.001). Median (25th, 75th centiles) 5STS time decreased with PR (Pre: 14.1 (11.5, 21.3) vs Post: 12.4 (10.2, 16.3) s; p<0.001). Using different anchors, a conservative estimate for the MCID was 1.7 s. Conclusions The 5STS is reliable, valid and responsive in patients with COPD with an estimated MCID of 1.7 s. It is a practical functional outcome measure suitable for use in most healthcare settings.


PubMed | University of Liverpool, Berkshire Healthcare NHS Foundation Trust, University of Nottingham, Imperial College London and 5 more.
Type: | Journal: Thorax | Year: 2017

Pulmonary rehabilitation (PR) improves exercise capacity and health status in patients with COPD, but many patients assessed for PR do not complete therapy. It is unknown whether socioeconomic deprivation associates with rates of completion of PR or the magnitude of clinical benefits bequeathed by PR.PR services across England and Wales enrolled patients to the National PR audit in 2015. Deprivation was assessed using Index of Multiple Deprivation (IMD) derived from postcodes. Study outcomes were completion of therapy and change in measures of exercise performance and health status. Univariate and multivariate analyses investigated associations between IMD and these outcomes.210 PR programmes enrolled 7413 patients. Compared with the general population, the PR sample lived in relatively deprived neighbourhoods. There was a statistically significant association between rates of completion of PR and quintile of deprivation (70% in the least and 50% in the most deprived quintiles). After baseline adjustments, the risk ratio (95% CI) for patients in the most deprived relative to the least deprived quintile was 0.79 (0.73 to 0.85), p<0.001. After baseline adjustments, IMD was not significantly associated with improvements in exercise performance and health status.In a large national dataset, we have shown that patients living in more deprived areas are less likely to complete PR. However, deprivation was not associated with clinical outcomes in patients who complete therapy. Interventions targeted at enhancing referral, uptake and completion of PR among patients living in deprived areas could reduce morbidity and healthcare costs in such hard-to-reach populations.

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