Mehul S. Patel

Quadriceps wasting and physical inactivity in patients with COPD

Quadriceps weakness is an important complication of advanced chronic obstructive pulmonary disease (COPD) but few data exist concerning muscle bulk in early disease. We hypothesised that quadriceps bulk, measured by ultrasound rectus femoris cross-sectional area (USRFCSA), would be reduced in mild, as well as advanced, COPD compared with controls, and would correlate with physical activity. 161 patients with stable COPD and 40 healthy subjects had a measurement of USRFCSA and wore a multisensor armband to record physical activity. USRFCSA was reduced in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I patients compared with healthy subjects (p=0.0002). Stage II–IV patients had reduced USRFCSA (p<0.0001) compared with controls but were not significantly different from those with stage I disease. Physical activity level was reduced in stage I (p=0.002) and stage II–IV disease compared with controls. Using regression analysis, physical activity level was independently associated with USRFCSA in stage I (p=0.01) but not stage II–IV disease, where residual volume to total lung capacity ratio was the only independent predictor of physical activity level. Quadriceps wasting exists in patients with mild, as well as advanced, COPD, and is independently associated with physical inactivity in GOLD stage I disease. The identification of these patients may guide early lifestyle and therapeutic interventions.

The five-repetition sit-to-stand test as a functional outcome measure in COPD

Background Moving from sitting to standing is a common activity of daily living. The five-repetition sit-to-stand 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 Georges 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.

Reliability and validity of 4-metre gait speed in COPD

In community-dwelling older adults, usual gait speed over 4 m (4MGS) consistently predicts greater risk of adverse health outcomes. The aims of the present study were to assess the reliability of the 4MGS and the relationship with established health outcome measures in chronic obstructive pulmonary disease (COPD). Test-retest and interobserver reliability of the 4MGS were measured in 80 and 58 COPD patients, respectively. In 586 COPD patients, the 4MGS, as well as forced expiratory volume in 1 s (FEV1), the incremental shuttle walk (ISW), Medical Research Council (MRC) dyspnoea scale and St George’s Respiratory Questionnaire (SGRQ) were measured. Participants were stratified according to “slow” (<0.8 m·s−1) or “normal” 4MGS (≥0.8 m·s−1). Intra-class correlation coefficients for test-retest and interobserver reliability were 0.97 and 0.99, respectively. There was a significant positive correlation between 4MGS with ISW (&rgr; = 0.78; p<0.001) and a negative correlation with MRC dyspnoea scale and SGRQ (&rgr; = -0.55 and -0.44; p<0.001 for both). COPD patients with slow 4MGS had significantly reduced ISW and higher MRC dyspnoea scale and SGRQ than those with preserved walking speed, despite similar FEV1 % predicted. The 4MGS is reliable in COPD, correlates with exercise capacity, dyspnoea and health-related quality of life, and has potential as a simple assessment tool in COPD.

The COPD Assessment Test (CAT): Short- and Medium-term Response to Pulmonary Rehabilitation

Abstract Background: The COPD Assessment Test (CAT) is a recently introduced instrument to assess health-related quality of life in COPD. We aimed to evaluate the longitudinal change in CAT following Pulmonary Rehabilitation (PR), and test the relationship between CAT and CRQ-Self Report (SR) over time. We hypothesised that the CAT would show similar responsiveness to PR as the CRQ-SR both in the short and medium-term. Methods: 118 COPD patients completed an eight-week outpatient multidisciplinary PR programme. CAT, CRQ-SR and the incremental shuttle walk (ISW) were measured prior to starting PR (T1), completion of PR (T2) and 6 months after completion of PR (T3). Results: There was a significant improvement in CAT, CRQ-SR and ISW immediately following PR (p < 0.001). Although there was decline between T2 and T3, CAT, CRQ-SR and ISW remained significantly better at T3 compared with T1 (ANOVA p < 0.001). Both between T1-T2 and between T2-T3, change in CAT correlated significantly with change in CRQ (both r  = -0.44 and p < 0.001). The slope of the relationship between CAT change and CRQ-SR change at T1-T2 and T2-T3 was not significantly different (ANCOVA: intercept p  =  0.79, interaction effect p  =  0.95). Conclusions: In COPD, the CAT score is immediately responsive to PR and remains improved at 6 months. There is no significant difference in the short and medium term changes in the CAT and CRQ-SR following PR. We propose that for most clinical indications for assessing health-related quality of life in COPD, the CAT is a robust and practical alternative to longer-established instruments such as the CRQ-SR.

Vastus Lateralis Fiber Shift Is an Independent Predictor of Mortality in Chronic Obstructive Pulmonary Disease

To the Editor: Quadriceps weakness and atrophy is present in approximately 30% of patients with chronic obstructive pulmonary disease (COPD) in secondary care (1, 2). The quadriceps also displays a shift in fiber type so that there are fewer type I (oxidative) fibers and more type II (glycolytic) fibers (3). Pulmonary rehabilitation only partially addresses this fiber shift (4). Muscle mass (5) and strength (6) are both associated with increased mortality, but the prognostic significance of fiber shift is unknown. In a retrospective multicenter analysis of 392 patients from four sites (see Tables E1–E4 in the online supplement), mortality data were collated, as part of audit procedures, on outpatients with stable COPD who had undergone a vastus lateralis biopsy between 1995 and 2013. Data from these subjects have been previously published (e.g., References 2, 4, 5). Fiber proportion, reported as the percentage of type II fibers (type II fiber %), was established by immunohistochemistry. Fiber shift, evaluated as a dichotomous variable, was considered to have occurred when the proportion of type II fibers was greater than 68% (men) or greater than 65% (women) based on normal ranges established from an age-matched healthy population published by Natanek and colleagues (3). Body mass index (BMI), fat-free mass index (FFMI), dominant leg isometric quadriceps maximum voluntary contraction (QMVC and QMVC/BMI), mid-thigh cross-sectional area determined by computed tomography scan (MTCSA), residual volume normalized to total lung capacity (RV/TLC), and percent predicted value for the carbon monoxide transfer factor corrected for hemoglobin (TLCOc), when available, were included in subanalyses. Data were analyzed for the whole dataset and also after splitting the group into those with an FEV1 less than 50% predicted and those with an FEV1 greater than or equal to 50% predicted. Further details on the methodology and statistical analyses are presented in the online supplement. Some of the results of this study have been previously reported in abstract form (7). Patients were followed up for a median of 1,699 days (127–6,601 d); 102 of 392 (26.7%) patients died during follow-up (Table E6). Cohort characteristics are presented in Tables 1 and ​and22 and Tables E1–E5. One hundred fifty-one patients had Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I/II disease and 241 had GOLD stage III/IV disease. Those who died were older and had a lower FEV1 % predicted, and there was a greater male preponderance (Table E6A). One hundred seventy-seven (45.1%) of the patients had fiber shift. The patients who died had a higher percentage of type II fibers (69.5% [62.2, 76.3%] vs. 66.0% [54.0, 74.2%]; P = 0.002) and a higher proportion of them exhibited fiber shift (58% vs. 41%, P = 0.004). BMI, FFMI, QMVC, MTCSA, and TLCOc were all lower, and RV/TLC higher, in those who died (Table E6B). Table 1. Core Characteristics of the Cohort (n = 392) in Addition to Univariate and Multivariate Analyses Including Type II Fiber Proportion Dichotomized into the Occurrence of Fiber Shift Table 2. Core Characteristics of the Cohort (n = 392) in Addition to Univariate and Multivariate Analyses Including Type II Fiber Proportion as a Continuous Measure In the cohort considered as a whole, both type II fiber % and the presence of fiber shift were univariate predictors of mortality, as were age and FEV1 % predicted (Tables 1 and ​and2).2). In a multivariate analysis including fiber shift as a dichotomous variable, fiber shift was retained, as were age and FEV1 % predicted, Table 1. When age, FEV1 % predicted, and type II fiber % were entered into a multivariate analysis, age and FEV1 % predicted were retained as independent predictors, but the association between fiber type and mortality just missed statistical significance (Table 2). The relationship between FEV1 and fiber proportion is shown in Figure 1A, and survival as a function of fiber shift, adjusted for age and FEV1, is shown in Figure 1B. Additional data regarding other lung function and muscle parameters are presented in Tables E7–E10. FEV1 expressed in liters and TLCOc were also univariate predictors of mortality; however, RV/TLC was not. When including TLCOc in the analysis (n = 209), fiber shift, age, FEV1 % predicted, and TLCOc were all independent predictors of mortality. In other subanalyses, BMI, FFMI, QMVC, QMVC/BMI, and MTCSA were not univariate predictors of mortality. Figure 1. (A) The relationship between type II fiber percentage and FEV1 % predicted (dashed lines demonstrate the 95% confidence interval), and (B) survival curves for those with fiber shift (n = 177) and those without fiber shift (n = 215) after adjusting for ... When limiting the analysis to those with an FEV1 greater than or equal to 50% predicted, age was the only predictor of mortality (hazard ratio [HR], 1.16; 95% CI, 1.07, 1.25; P < 0.0001; Table E11). In a multivariate analysis confined to those with an FEV1 less than 50%, fiber shift was retained as an independent predictor (HR, 1.71; 95% CI, 1.08, 2.71; P = 0.02), as were age (HR, 1.06; 95% CI, 1.03, 1.09; P < 0.0001), and FEV1 % predicted (HR, 0.96; 95% CI, 0.94, 0.99; P = 0.002; Table E12A). In a separate analysis confined to those with an FEV1 less than 50%, type II fiber % was not retained as an independent predictor (HR, 1.014; 95% CI, 0.996, 1.032; P = 0.13), whereas age and FEV1 % predicted were (Table E12B). Fiber shift in the vastus lateralis of patients with COPD was associated with increased mortality, although this association was weaker when lung function and age were included in the analysis. This finding was pronounced in patients with GOLD stage III/IV disease but undetectable in those with GOLD stage I/II disease. The relationship between skeletal muscle atrophy (5) and weakness (6) with mortality has been previously noted in COPD. However, we believe the present analysis is timely because we (3) and others (8) have recently shown that the nature of skeletal muscle involvement in COPD is heterogeneous rather than uniform. No prior study has related quadriceps biopsy appearances to long-term outcome in COPD. Given the known relationship between exercise capacity and survival (9), these data are consistent with our prior studies, which demonstrated a relationship between fiber shift (although not fiber atrophy) and impaired exercise capacity (3) and functional performance (10). Nevertheless, it remains unclear whether fiber shift causes poor exercise tolerance or is a manifestation of exercise intolerance and reduced physical activity, which are both associated with increased mortality in COPD (9, 11). Both concepts can be supported by in vivo models that demonstrate that muscle disuse results in type I to type II fiber shift (12) and that fiber shift toward a type I fiber predominance increases exercise performance (13). Due to the retrospective nature of the current analysis, exercise performance and physical activity data were not available for inclusion in this report, so a causative role for fiber shift in mortality cannot be demonstrated from this study. A prospective study would have been preferable and could also have considered other factors of relevance, including pulmonary rehabilitation over the intervening period. Despite the limitations of the current study, it is doubtful that a prospective study of comparable size and duration will ever be done. Interest in pharmacological management of skeletal muscle dysfunction is growing (14), and addressing fiber shift may eventually become a therapeutic possibility. Further studies to address whether the reversal of fiber shift is of benefit are of value.

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.

CrossTalk proposal: Training the respiratory muscles does not improve exercise tolerance

If effective, respiratory muscle training (RMT) is surely the most unfortunate therapy in medicine. Over 35 years have elapsed since the seminal work of Leith and Bradley (Leith & Bradley, 1976), yet despite being relatively cheap and free of side effects, RMT finds limited favour beyond specialist sporting activities and remains the tool of the enthusiast. Several caveats require consideration when assessing whether RMT improves exercise tolerance. The first is whether RMT can improve performance in healthy humans and, as claimed, a range of diseases. In this context, although a 0.7% reduction in swimming time was not deemed worthwhile, a 1.5% reduction was (Kilding et al. 2010). In contrast, an

Growth differentiation factor-15 is associated with muscle mass in chronic obstructive pulmonary disease and promotes muscle wasting in vivo.

Loss of muscle mass is a co‐morbidity common to a range of chronic diseases including chronic obstructive pulmonary disease (COPD). Several systemic features of COPD including increased inflammatory signalling, oxidative stress, and hypoxia are known to increase the expression of growth differentiation factor‐15 (GDF‐15), a protein associated with muscle wasting in other diseases. We therefore hypothesized that GDF‐15 may contribute to muscle wasting in COPD.

Response of the COPD Assessment Test to pulmonary rehabilitation in unselected chronic respiratory disease.

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.

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.