Frits M.E. Franssen

Clusters of Comorbidities Based on Validated Objective Measurements and Systemic Inflammation in Patients with Chronic Obstructive Pulmonary Disease

RATIONALE Comorbidities contribute to disease severity and mortality in patients with chronic obstructive pulmonary disease (COPD). Comorbidities have been studied individually and were mostly based on self-reports. The coexistence of objectively identified comorbidities and the role of low-grade systemic inflammation in the pathophysiology of COPD remain to be elucidated. OBJECTIVES To cluster 13 clinically important objectively identified comorbidities, and to characterize the comorbidity clusters in terms of clinical outcomes and systemic inflammation. METHODS A total of 213 patients with COPD (FEV1, 51 ± 17% predicted; men, 59%; age, 64 ± 7 yr) were included prospectively. Comorbidities were based on well-known cut-offs identified in the peer-reviewed English literature. Systemic inflammatory biomarkers were determined in all patients. Self-organizing maps were used to generate comorbidity clusters. MEASUREMENTS AND MAIN RESULTS A total of 97.7% of all patients had one or more comorbidities and 53.5% had four or more comorbidities. Five comorbidity clusters were identified: (1) less comorbidity, (2) cardiovascular, (3) cachectic, (4) metabolic, and (5) psychological. Comorbidity clusters differed in health status but were comparable with respect to disease severity. An increased inflammatory state was observed only for tumor necrosis factor (TNF) receptors in the metabolic cluster (geometric mean [lower and upper limit]; TNF-R1, 2,377 [1,850, 3,055] pg/ml, confidence, 98.5%; TNF-R2, 4,080 [3,115, 5,344] pg/ml, confidence, 98.8%) and only for IL-6 in the cardiovascular cluster (IL-6, 3.4 [1.8, 6.6] pg/ml; confidence, 99.8%). CONCLUSIONS Multimorbidity is common in patients with COPD, and different comorbidity clusters can be identified. Low-grade systemic inflammation is mostly comparable among comorbidity clusters. Increasing knowledge on the interactions between comorbidities increases the understanding of their development and contributes to strategies for prevention or improved treatment.

An Official American Thoracic Society/European Respiratory Society Statement: Update on Limb Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

BACKGROUND Limb muscle dysfunction is prevalent in chronic obstructive pulmonary disease (COPD) and it has important clinical implications, such as reduced exercise tolerance, quality of life, and even survival. Since the previous American Thoracic Society/European Respiratory Society (ATS/ERS) statement on limb muscle dysfunction, important progress has been made on the characterization of this problem and on our understanding of its pathophysiology and clinical implications. PURPOSE The purpose of this document is to update the 1999 ATS/ERS statement on limb muscle dysfunction in COPD. METHODS An interdisciplinary committee of experts from the ATS and ERS Pulmonary Rehabilitation and Clinical Problems assemblies determined that the scope of this document should be limited to limb muscles. Committee members conducted focused reviews of the literature on several topics. A librarian also performed a literature search. An ATS methodologist provided advice to the committee, ensuring that the methodological approach was consistent with ATS standards. RESULTS We identified important advances in our understanding of the extent and nature of the structural alterations in limb muscles in patients with COPD. Since the last update, landmark studies were published on the mechanisms of development of limb muscle dysfunction in COPD and on the treatment of this condition. We now have a better understanding of the clinical implications of limb muscle dysfunction. Although exercise training is the most potent intervention to address this condition, other therapies, such as neuromuscular electrical stimulation, are emerging. Assessment of limb muscle function can identify patients who are at increased risk of poor clinical outcomes, such as exercise intolerance and premature mortality. CONCLUSIONS Limb muscle dysfunction is a key systemic consequence of COPD. However, there are still important gaps in our knowledge about the mechanisms of development of this problem. Strategies for early detection and specific treatments for this condition are also needed.

Similarities in skeletal muscle strength and exercise capacity between renal transplant and hemodialysis patients

Exercise intolerance is common in hemodialysis (HD) and renal transplant (RTx) patients. Aim of the study was to assess to what extent exercise capacity and skeletal muscle strength of RTx patients differ from HD patients and healthy controls and to elucidate potential determinants of exercise capacity in RTx patients. Exercise capacity, muscle strength, lean body mass (LBM) and physical activity level (PAL) were measured by cycle‐ergometry, isokinetic dynamometry, DEXA and Baecke Questionnaire, respectively, in 35 RTx, 16 HD and 21 controls. VO2peak and muscle strength of the RTx patients were significantly lower compared to controls (p < 0.01), but not different compared to HD patients. In RTx patients, strength (p < 0.001), PAL (p = 0.001) and age (p = 0.045) were significant predictors of VO2peak. Muscle strength was related to LBM (p = 0.001) and age (p = 0.001), whereas gender (p < 0.001) and renal function (p = 0.01) turned out to be significant predictors of LBM. No effects of corticosteroids were observed. Exercise capacity and muscle strength seem equally reduced in RTx and HD patients compared to controls. In RTx patients, muscle strength and PAL are highly related to exercise capacity. Renal function appears to be a significant predictor of LBM, and through the LBM, of muscle strength and exercise capacity.

Nutritional assessment and therapy in COPD: a European Respiratory Society statement

Nutrition and metabolism have been the topic of extensive scientific research in chronic obstructive pulmonary disease (COPD) but clinical awareness of the impact dietary habits, nutritional status and nutritional interventions may have on COPD incidence, progression and outcome is limited. A multidisciplinary Task Force was created by the European Respiratory Society to deliver a summary of the evidence and description of current practice in nutritional assessment and therapy in COPD, and to provide directions for future research. Task Force members conducted focused reviews of the literature on relevant topics, advised by a methodologist. It is well established that nutritional status, and in particular abnormal body composition, is an important independent determinant of COPD outcome. The Task Force identified different metabolic phenotypes of COPD as a basis for nutritional risk profile assessment that is useful in clinical trial design and patient counselling. Nutritional intervention is probably effective in undernourished patients and probably most when combined with an exercise programme. Providing evidence of cost-effectiveness of nutritional intervention is required to support reimbursement and thus increase access to nutritional intervention. Overall, the evidence indicates that a well-balanced diet is beneficial to all COPD patients, not only for its potential pulmonary benefits, but also for its proven benefits in metabolic and cardiovascular risk. Metabolism and nutrition: shifting paradigms in COPD management http://ow.ly/As0xh

Efficacy of lower-limb muscle training modalities in severely dyspnoeic individuals with COPD and quadriceps muscle weakness: results from the DICES trial

Rationale Strength training and neuromuscular electrical stimulation (NMES) improve lower-limb muscle function in dyspnoeic individuals with chronic obstructive pulmonary disease (COPD). However, high-frequency NMES (HF-NMES) and strength training have never been compared head-to-head; and effects of low-frequency NMES (LF-NMES) have never been studied in COPD. Therefore, the optimal training modality to improve lower-limb muscle function, exercise performance and other patient-related outcomes in individuals with severe COPD remains unknown. Objectives To study prospectively the efficacy of HF-NMES (75 Hz), LF-NMES (15 Hz) or strength training in severely dyspnoeic individuals with COPD with quadriceps muscle weakness at baseline. Methods 120 individuals with COPD (FEV1: 33±1% predicted, men: 52%, age: 64.8±0.8 years) were randomised to HF-NMES, LF-NMES or strength training as part of a comprehensive inpatient pulmonary rehabilitation programme. No treadmill walking or stationary cycling was provided. Measurements and main results Groups were comparable at baseline. Quadriceps muscle strength increased after HF-NMES (+10.8 Newton-metre (Nm)) or strength training (+6.1 Nm; both p<0.01), but not after LF-NMES (+1.4 Nm; p=0.43). Quadriceps muscle endurance, exercise performance, lower-limb fat-free mass, exercise-induced symptoms of dyspnoea and fatigue improved significantly compared with baseline after HF-NMES, LF-NMES or strength training. The increase in quadriceps muscle strength and muscle endurance was greater after HF-NMES than after LF-NMES. Conclusions HF-NMES is equally effective as strength training in severely dyspnoeic individuals with COPD and muscle weakness in strengthening the quadriceps muscles and thus may be a good alternative in this particular group of patients. HF-NMES, LF-NMES and strength training were effective in improving exercise performance in severely dyspnoeic individuals with COPD and quadriceps weakness. Trial registration NTR2322

Effect of ‘activity monitor-based’ counseling on physical activity and health-related outcomes in patients with chronic diseases: A systematic review and meta-analysis

Abstract Aim. This review evaluated the effects of activity monitor-based counseling on physical activity (PA) and generic and disease-specific health-related outcomes in adults with diabetes mellitus type II (DMII), chronic obstructive pulmonary disease (COPD), or chronic heart failure (CHF). Methods. Four electronic databases were searched for randomized controlled trials using activity monitor-based counseling versus control intervention or usual care in adults with DMII, COPD, or CHF. Pooled effect sizes were calculated using a random effects model. Results. Twenty-four articles were included: 21 DMII studies and 3 COPD studies. No CHF studies were identified. Pooled analysis showed that activity monitor-based counseling resulted in a significantly greater improvement in PA compared to control intervention or usual care in DMII. Furthermore, these interventions had a beneficial effect on hemoglobin A1c (HbA1c), systolic blood pressure, and body mass index (BMI) (P < 0.05), whereas no differences were found on diastolic blood pressure, and health-related quality of life. Meta-analysis of COPD studies was not possible due to lack of available data. Conclusion. Activity monitor-based counseling had a beneficial effect on PA, HbA1c, systolic blood pressure, and BMI in patients with DMII. Data in patients with COPD and CHF are limited or non-existing, respectively.

Changes in physical activity and all-cause mortality in COPD

Little is known about changes in physical activity in subjects with chronic obstructive pulmonary disease (COPD) and its impact on mortality. Therefore, we aimed to study changes in physical activity in subjects with and without COPD and the impact of physical activity on mortality risk. Subjects from the Copenhagen City Heart Study with at least two consecutive examinations were selected. Each examination included a self-administered questionnaire and clinical examination. 1270 COPD subjects and 8734 subjects without COPD (forced expiratory volume in 1 s 67±18 and 91±15% predicted, respectively) were included. COPD subjects with moderate or high baseline physical activity who reported low physical activity level at follow-up had the highest hazard ratios of mortality (1.73 and 2.35, respectively; both p<0.001). In COPD subjects with low baseline physical activity, no differences were found in survival between unchanged or increased physical activity at follow-up. In addition, subjects without COPD with low physical activity at follow-up had the highest hazard ratio of mortality, irrespective of baseline physical activity level (p≤0.05). A decline to low physical activity at follow-up was associated with an increased mortality risk in subjects with and without COPD. These observational data suggest that it is important to assess and encourage physical activity in the earliest stages of COPD in order to maintain a physical activity level that is as high as possible, as this is associated with better prognosis. Longitudinal decline to a low physical activity level in COPD is associated with a higher all-cause mortality risk http://ow.ly/yTDp8

Task-Related Oxygen Uptake During Domestic Activities of Daily Life in Patients With COPD and Healthy Elderly Subjects

BACKGROUND Patients with COPD generally have a poor peak aerobic capacity and, therefore, may experience more inconvenience during domestic activities of daily life (ADLs). Yet, task-related oxygen uptake and symptom perception during ADLs have been studied rarely in COPD. Therefore, it remains unknown whether and to what extent differences may exist in task-related oxygen uptake and symptom perception during ADLs in patients with COPD after stratification for sex; GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage; Medical Research Council (MRC) dyspnea grade; or score on the BMI, obstruction, dyspnea, exercise capacity (BODE) index. METHODS Ninety-seven patients with COPD and 20 healthy elderly subjects performed the following five self-paced domestic ADLs with 4-min rest intervals: putting on socks, shoes, and vest; folding eight towels; putting away groceries; washing four dishes, cups, and saucers; and sweeping the floor for 4 min. Task-related oxygen uptake was assessed using an Oxycon Mobile device, whereas Borg scores were used to assess task-related dyspnea and fatigue. RESULTS Patients with COPD used a significantly higher proportion of their peak aerobic capacity and ventilation to perform ADLs than did the healthy subjects, accompanied by higher task-related Borg dyspnea scores. Patients with GOLD stage IV, MRC dyspnea grade 5, or BODE score ≥ 6 points had the highest task-related oxygen uptake and dyspnea perception during the performance of domestic ADLs. Results showed no sex-related differences. CONCLUSION Patients with COPD experience a relatively high metabolic load and symptom perception during the performance of ADLs that is not the same as seen in their healthy peers, particularly in patients with GOLD stage IV, MRC dyspnea grade 5, or BODE score ≥ 6 points.

Differential response to pulmonary rehabilitation in COPD: multidimensional profiling

The aim of the present study was to profile a multidimensional response to pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD). Dyspnoea, exercise performance, health status, mood status and problematic activities of daily life were assessed before and after a 40-session pulmonary rehabilitation programme in 2068 patients with COPD (mean forced expiratory volume in 1 s of 49% predicted). Patients were ordered by their overall similarity concerning their multidimensional response profile, which comprises the overall response on MRC dyspnoea grade, 6MWD, cycle endurance time, Canadian Occupational Performance Measure performance and satisfaction scores, Hospital Anxiety and Depression Scale anxiety and depression, and St Georges Respiratory Questionnaire total score, using a novel non-parametric regression technique. Patients were clustered into four groups with distinct multidimensional response profiles: n=378 (18.3%; “very good responder”), n=742 (35.9%; “good responder”), n=731 (35.4%; “moderate responder”), and n=217 (10.5%; “poor responder”). Patients in the “very good responder” cluster had higher symptoms of dyspnoea, number of hospitalisations <12 months, worse exercise performance, worse performance and satisfaction scores for problematic activities of daily life, more symptoms of anxiety and depression, worse health status, and a higher proportion of patients following an inpatient PR programme compared to the other three clusters. A multidimensional response outcome needs to be considered to study the efficacy of pulmonary rehabilitation services in patients with COPD, as responses to regular outcomes are differential within patients with COPD. Efficacy of pulmonary rehabilitation in patients with COPD needs to be assessed using a multidimensional response http://ow.ly/RsfYK

Management of chronic obstructive pulmonary disease beyond the lungs

Chronic obstructive pulmonary disease (COPD) is an umbrella term that covers many clinical subtypes with clearly different pulmonary and extra-pulmonary characteristics, but with persistent airflow limitation in common. This insight has led to the development of a more personalised approach in bronchodilator therapy, prevention of exacerbations, and advanced treatments (such as non-invasive ventilation and lung volume reduction techniques). However, systemic manifestations and comorbidities of COPD also contribute to different clinical phenotypes and warrant an individualised approach as part of integrated disease management. Alterations in bodyweight and composition, from cachexia to obesity, demand specific management. Psychological symptoms are highly prevalent, and thorough diagnosis and treatment are necessary. Moreover, prevention of exacerbations requires interventions beyond the lungs, including treatment of gastro-oesophageal reflux disease, reduction of cardiovascular risks, and management of dyspnoea and anxiety. In this Review, we discuss the management of COPD beyond the respiratory system and propose treatment strategies on the basis of the latest research and best practices.