Divya Mohan

Phenotypic Characteristics Associated With Reduced Short Physical Performance Battery Score in COPD

BACKGROUND The Short Physical Performance Battery (SPPB) is commonly used in gerontology, but its determinants have not been previously evaluated in COPD. In particular, it is unknown whether pulmonary aspects of COPD would limit the value of SPPB as an assessment tool of lower limb function. METHODS In 109 patients with COPD, we measured SPPB score, spirometry, 6-min walk distance, quadriceps strength, rectus femoris cross-sectional area, fat-free mass, physical activity, health status, and Medical Research Council dyspnea score. In a subset of 31 patients with COPD, a vastus lateralis biopsy was performed, and the biopsy specimen was examined to evaluate the structural muscle characteristics associated with SPPB score. The phenotypic characteristics of patients stratified according to SPPB were determined. RESULTS Quadriceps strength and 6-min walk distance were the only independent predictors of SPPB score in a multivariate regression model. Furthermore, while age, dyspnea, and health status were also univariate predictors of SPPB score, FEV 1 was not. Stratification by reduced SPPB score identified patients with locomotor muscle atrophy and increasing impairment in strength, exercise capacity, and daily physical activity. Patients with mild or major impairment defined as an SPPB score < 10 had a higher proportion of type 2 fibers (71% [14] vs 58% [15], P = .04). CONCLUSIONS The SPPB is a valid and simple assessment tool that may detect a phenotype with functional impairment, loss of muscle mass, and structural muscle abnormality in stable patients with COPD.

Quantification of lung PET images: challenges and opportunities.

Millions of people are affected by respiratory diseases, leading to a significant health burden globally. Because of the current insufficient knowledge of the underlying mechanisms that lead to the development and progression of respiratory diseases, treatment options remain limited. To overcome this limitation and understand the associated molecular changes, noninvasive imaging techniques such as PET and SPECT have been explored for biomarker development, with 18F-FDG PET imaging being the most studied. The quantification of pulmonary molecular imaging data remains challenging because of variations in tissue, air, blood, and water fractions within the lungs. The proportions of these components further differ depending on the lung disease. Therefore, different quantification approaches have been proposed to address these variabilities. However, no standardized approach has been developed to date. This article reviews the data evaluating 18F-FDG PET quantification approaches in lung diseases, focusing on methods to account for variations in lung components and the interpretation of the derived parameters. The diseases reviewed include acute respiratory distress syndrome, chronic obstructive pulmonary disease, and interstitial lung diseases such as idiopathic pulmonary fibrosis. Based on review of prior literature, ongoing research, and discussions among the authors, suggested considerations are presented to assist with the interpretation of the derived parameters from these approaches and the design of future studies.

Evaluating the Role of Inflammation in Chronic Airways Disease: The ERICA Study

Abstract Extrapulmonary manifestations are recognized to be of increasing clinical importance in Chronic Obstructive Pulmonary disease. To investigate cardiovascular and skeletal muscle manifestations of COPD, we developed a unique UK consortium funded by the Technology Strategy Board and Medical Research Council comprising industry in partnership with 5 academic centres. ERICA (Evaluating the Role of Inflammation in Chronic Airways disease) is a prospective, longitudinal, observational study investigating the prevalence and significance of cardiovascular and skeletal muscle manifestations of COPD in 800 subjects. Six monthly follow up will assess the predictive value of plasma fibrinogen, cardiovascular abnormalities and skeletal muscle weakness for death or hospitalization. As ERICA is a multicentre study, to ensure data quality we sought to minimise systematic observer error due to variations in investigator skill, or adherence to operating procedures, by staff training followed by assessment of inter- and intra-observer reliability of the four key measurements used in the study: pulse wave velocity (PWV), carotid intima media thickness (CIMT), quadriceps maximal voluntary contraction force (QMVC) and 6-minute walk distance (6MWT). This report describes the objectives and methods of the ERICA trial, as well as the inter- and intra-observer reliability of these measurements.

Using laser capture microdissection to study fiber specific signalling in locomotor muscle in COPD: A pilot study

Quadriceps dysfunction is important in chronic obstructive pulmonary disease (COPD), with an associated increased proportion of type II fibers. Investigation of protein synthesis and degradation has yielded conflicting results, possibly due to study of whole biopsy samples, whereas signaling may be fiber‐specific. Our objective was to develop a method for fiber‐specific gene expression analysis.

The p38 mitogen activated protein kinase inhibitor losmapimod in chronic obstructive pulmonary disease patients with systemic inflammation, stratified by fibrinogen: A randomised double-blind placebo-controlled trial

Background Cardiovascular disease is a major cause of morbidity and mortality in COPD patients. Systemic inflammation associated with COPD, is often hypothesised as a causal factor. p38 mitogen-activated protein kinases play a key role in the inflammatory pathogenesis of COPD and atherosclerosis. Objectives This study sought to evaluate the effects of losmapimod, a p38 mitogen-activated protein kinase (MAPK) inhibitor, on vascular inflammation and endothelial function in chronic obstructive pulmonary disease (COPD) patients with systemic inflammation (defined by plasma fibrinogen >2·8g/l). Methods This was a randomised, double-blind, placebo-controlled, Phase II trial that recruited COPD patients with plasma fibrinogen >2.8g/l. Participants were randomly assigned by an online program to losmapimod 7·5mg or placebo tablets twice daily for 16 weeks. Pre- and post-dose 18F-Fluorodeoxyglucose positron emission tomography co-registered with computed tomography (FDG PET/CT) imaging of the aorta and carotid arteries was performed to quantify arterial inflammation, defined by the tissue-to-blood ratio (TBR) from scan images. Endothelial function was assessed by brachial artery flow-mediated dilatation (FMD). Results We screened 160 patients, of whom, 36 and 37 were randomised to losmapimod or placebo. The treatment effect of losmapimod compared to placebo was not significant, at -0·05 for TBR (95% CI: -0·17, 0·07), p = 0·42, and +0·40% for FMD (95% CI: -1·66, 2·47), p = 0·70. The frequency of adverse events reported was similar in both treatment groups. Conclusions In this plasma fibrinogen-enriched study, losmapimod had no effect on arterial inflammation and endothelial function at 16 weeks of treatment, although it was well tolerated with no significant safety concerns. These findings do not support the concept that losmapimod is an effective treatment for the adverse cardiovascular manifestations of COPD.

Surrogate markers of cardiovascular risk and chronic obstructive pulmonary disease

Cardiovascular disease is a common comorbidity and cause of mortality in chronic obstructive pulmonary disease. A better understanding of mechanisms of cardiovascular risk in chronic obstructive pulmonary disease patients is needed to improve clinical outcomes. We hypothesized that such patients have increased arterial stiffness, wave reflections, and subclinical atherosclerosis compared with controls and that these findings would be independent of smoking status and other confounding factors. A total of 458 patients with a diagnosis of chronic obstructive pulmonary disease and 1657 controls (43% were current or ex-smokers) with no airflow limitation were matched for age, sex, and body mass index. All individuals underwent assessments of carotid–femoral (aortic) pulse wave velocity, augmentation index, and carotid intima–media thickness. The mean age of the cohort was 67±8 years and 58% were men. Patients with chronic obstructive pulmonary disease had increased aortic pulse wave velocity (9.95±2.54 versus 9.27±2.41 m/s; P<0.001), augmentation index (28±10% versus 25±10%; P<0.001), and carotid intima–media thickness (0.83±0.19 versus 0.74±0.14 mm; P<0.001) compared with controls. Chronic obstructive pulmonary disease was associated with increased levels of each vascular biomarker independently of physiological confounders, smoking, and other cardiovascular risk factors. In this large case-controlled study, chronic obstructive pulmonary disease was associated with increased arterial stiffness, wave reflections, and subclinical atherosclerosis, independently of traditional cardiovascular risk factors. These findings suggest that the cardiovascular burden observed in this condition may be mediated through these mechanisms and supports the concept that chronic obstructive pulmonary disease is an independent risk factor for cardiovascular disease.

S53 Studying fibre specific gene expression in COPD using laser capture micro-dissection in human skeletal muscle

Background Approximately 30% of patients with Chronic Obstructive Pulmonary Disease (COPD) exhibit peripheral skeletal muscle dysfunction and a shift towards type II glycolytic fibres in the quadriceps compared to healthy controls (Nanatek et al, 2013). Previous work to elucidate the molecular mechanisms underlying these changes has relied on whole biopsy samples and may have missed fibre-specific pathways; thus a method to evaluate fibre specific signalling pathways would be useful. Objective To describe a novel laser capture micro-dissection (LCM) method to examine fibre-specific signalling in quadriceps biopsies. Methods First larger Intercostal muscle biopsies were used to validate the methodology since they yielded more RNA. Fibres were classified as type-2 positive or type-2 negative based on immunoreactivity with a type-2 fibre specific anti-myosin Heavy Chain Alexa FLUOR 488 antibody. The type-2 negative fibre population was hence assumed to contain type-1 fibres, which was confirmed by the type-2 negative fibre population exhibiting a higher myhc7/2 mRNA ratio and expressing higher levels of genes associated with type-1 fibres, e.g. TNNT-1 and STARS, and lower levels of genes associated with type-2 fibres, e.g. TGF-B, myostatin, GAPDH and HDAC-4 (n = 2). We then examined OCT-embedded vastus lateralis muscle biopsy specimens. 10micron cryosections underwent fixation with 4% paraformaldehyde before immunostaining. LCM (PALM Microbeam, Zeiss, UK) was used to capture type I and type II fibre populations, before RNA extraction with RNAeasy FFPE kit (Qiagen, USA) and rtPCR to obtain cDNA. Sybr-II qPCR was performed on fibre populations for target genes MHC I, MHC IIa, MHC IIx, HDAC-4 and RPLPO. Results Preliminary results from three 10micron slices indicate that this technique is feasible to study fibre-specific signalling in COPD. LCM following immunostaining captures distinct fibre populations (Figure 1) confirmed by a higher MHC I content in ‘type I fibres’, with ‘type II’ fibres containing more MHC IIa, MHC IIx and HDAC-4 as would be expected. Gene expression is normalised against RPLPO. Abstract S53 Figure 1. Gene expression (normalised for RPLPO) for Type I (red) and Type II (blue) quadriceps muscle fibres in COPD using three 10 micron sections for Laser Capture Micro-Dissection. Fold difference compared to type I fibres shown Conclusion LCM can be used to study fibre specific inflammatory signalling in the skeletal muscle of COPD patients and immunostaining with MHC antibodies is a feasible way to distinguish between fibre types when capturing composite fibre populations.

Fibrinogen does not relate to cardiovascular or muscle manifestations in COPD: cross-sectional data from the ERICA study

Cardiovascular and skeletal muscle manifestations constitute important comorbidities in COPD, with systemic inflammation proposed as a common mechanistic link. Fibrinogen has prognostic role in COPD. We aimed to determine whether aortic stiffness and quadriceps weakness are linked in COPD, and whether they are associated with the systemic inflammatory mediator—fibrinogen. Aortic pulse wave velocity (aPWV), quadriceps maximal volitional contraction (QMVC) force and fibrinogen were measured in 729 patients with stable, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages II–IV COPD. The cardiovascular and muscular manifestations exist independently (P=0.22, χ2). Fibrinogen was not associated with aPWV or QMVC (P=0.628 and P=0.621, respectively), making inflammation, as measured by plasma fibrinogen, an unlikely common aetiological factor.

P94 Cardiorespiratory physiology in patients with copd according to blood eosinophilia: data from the erica cohort

Introduction Blood eosinophils level in Chronic Obstructive Pulmonary Disease (COPD) is a candidate biomarker for Regulatory qualification as a drug development tool identifying individuals who may benefit from targeted therapies. Current evidence focused on association with exacerbations and response to therapy, however the association of eosinophilia with cardiorespiratory physiology has not been determined. Methods The ERICA (Evaluating the Role of Inflammation in Chronic Airway Disease) study is a large multicentre study of patients with COPD.1 Aortic pulse wave velocity (PWV), carotid intimal thickness (CIMT) and spirometry were measured. Health Status (CAT) was recorded. From the full blood count, both absolute and percentage eosinophil counts were considered. We used previously validated cut offs2 of 0.3 × 109 cells/L and 2% to compare aortic PWV, CIMT and spirometry variables using a Student’s t-test. A multivariate model was then built to examine the effect after adjusting for confounding factors. Results 519 subjects were included in this analysis. Of these, 58% were men, mean (SD) age of 66.9 (7.6) years with a median smoking history of 42 pack years. Mean (SD) resting heart rate was 75 (13)bpm, mean arterial pressure 104 (12) mmHg and percentage predicted FEV152.5 (16.1)%. When comparing high and low eosinophil groups at both 0.3 × 109 cells/L and 2% cut-offs there was no difference in smoking status or pack years, spirometry variables or CAT score. There was no difference in prevalence of ischaemic heart disease, stroke or diabetes. Aortic PWV or CIMT were not different between groups. Multiple regression confirmed this (Table). Abstract P94 Table 1 Cardiorespiratory variables * Absolute eosinophil count Percentage eosinophil count Beta co-efficient 95% CI p-value Beta co-efficient 95% CI p-value Aortic PWV (m/s) 0.23 −1.3 to 1.7 0.77 0.090 −0.29 to 0.47 0.64 CIMT (mm)Diameter rightDiameter left 0.160.17 −0.60 to 0.91−0.56 to 0.89 0.690.65 0.040.05 −0.15 to 0.23−0.13 to 0.23 0.710.59 FEV1 (L) 0.10 −0.11 to 0.51 0.21 0.06 −0.02 to 0.13 0.15 FVC (L) 0.17 −0.29 to 0.64 0.46 0.12 0.01 to 0.23 0.04 * Adjustment for sex, age, MAP, HR, FEV1, FVC, smoking pack years, history of diabetes and peripheral vascular disease Conclusions A phenotype defined by blood eosinophilia does not relate to cardiorespiratory physiological variables in subjects with COPD. References Mohan Det al. Journal of COPD2015. Negewo Net al. Respirology2017.

Longitudinal follow-up of quadriceps strength and function in a COPD cohort after 3 years

Skeletal muscle weakness is a distinct extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD), which is associated with a poor prognosis [1] and may represent a novel therapeutic target [2]. However, there are only sparse longitudinal data from prospective studies on skeletal muscle weakness and its relationship with disease progression in COPD. Previous studies have been cross-sectional in nature, and have failed to correlate data with baseline measures of exercise performance or systemic inflammation. The short physical performance battery may be a useful endpoint in assessing impact on skeletal muscle dysfunction http://ow.ly/xf8z30dOFMz