Lowie E.G.W. Vanfleteren

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.

Determinants of Underdiagnosis of COPD in National and International Surveys.

BACKGROUND COPD ranks within the top three causes of mortality in the global burden of disease, yet it remains largely underdiagnosed. We assessed the underdiagnosis of COPD and its determinants in national and international surveys of general populations. METHODS We analyzed representative samples of adults aged ≥ 40 years randomly selected from well-defined administrative areas worldwide (44 sites from 27 countries). Postbronchodilator FEV1/FVC < lower limit of normal (LLN) was used to define chronic airflow limitation consistent with COPD. Undiagnosed COPD was considered when participants had postbronchodilator FEV1/FVC < LLN but were not given a diagnosis of COPD. RESULTS Among 30,874 participants with a mean age of 56 years, 55.8% were women, and 22.9% were current smokers. Population prevalence of (spirometrically defined) COPD ranged from 3.6% in Barranquilla, Colombia, to 19.0% in Cape Town, South Africa. Only 26.4% reported a previous lung function test, and only 5.0% reported a previous diagnosis of COPD, whereas 9.7% had a postbronchodilator FEV1/FVC < LLN. Overall, 81.4% of (spirometrically defined) COPD cases were undiagnosed, with the highest rate in Ile-Ife, Nigeria (98.3%) and the lowest rate in Lexington, Kentucky (50.0%). In multivariate analysis, a greater probability of underdiagnosis of COPD was associated with male sex, younger age, never and current smoking, lower education, no previous spirometry, and less severe airflow limitation. CONCLUSIONS Even with substantial heterogeneity in COPD prevalence, COPD underdiagnosis is universally high. Because effective management strategies are available for COPD, spirometry can help in the diagnosis of COPD at a stage when treatment will lead to better outcomes and improved quality of life.

Moving from the Oslerian paradigm to the post-genomic era: are asthma and COPD outdated terms?

In the majority of cases, asthma and chronic obstructive pulmonary disease (COPD) are two clearly distinct disease entities. However, in some patients there may be significant overlap between the two conditions. This constitutes an important area of concern because these patients are generally excluded from randomised controlled trials (mostly because of smoking history in the case of asthma or because of significant bronchodilator reversibility in the case of COPD). As a result, their pathobiology, prognosis and response to therapy are largely unknown. This may lead to suboptimal management and can limit the development of more personalised therapeutic options. Emerging genetic and molecular information coupled with new bioinformatics capabilities provide novel information that can pave the way towards a new taxonomy of airway diseases. In this paper we question the current value of the terms ‘asthma’ and ‘COPD’ as still useful diagnostic labels; discuss the scientific and clinical progress made over the past few years towards unravelling the complexity of airway diseases, from the definition of clinical phenotypes and endotypes to a better understanding of cellular and molecular networks as key pathogenic elements of human diseases (so-called systems medicine); and summarise a number of ongoing studies with the potential to move the field towards a new taxonomy of airways diseases and, hopefully, a more personalised approach to medicine, in which the focus will shift from the current goal of treating diseases as best as possible to the so-called P4 medicine, a new type of medicine that is predictive, preventive, personalised and participatory.

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.

New Reference Values for Body Composition by Bioelectrical Impedance Analysis in the General Population: Results From the UK Biobank

BACKGROUND Low fat-free mass (FFM) is a risk factor for morbidity and mortality in elderly and patient populations. Therefore, measurement of FFM is important in nutritional assessment. Bioelectrical impedance analysis (BIA) is a convenient method to assess FFM and FFM index (FFMI; FFM/height(2)). Although reference values have been established for individuals with normal body weight, no specific cutoff values are available for overweight and obese populations. Also, limited studies accounted for the age-related decline in FFM. OBJECTIVE To determine BMI- and age-specific reference values for abnormal low FFM(I) in white-ethnic men and women free of self-reported disease from the general population. DESIGN The UK Biobank is a prospective epidemiological study of the general population from the United Kingdom. Individuals in the age category 45 to 69 years were analyzed. In addition to body weight, FFM and FFMI were measured using a Tanita BC-418MA. Also, self-reported chronic conditions and ethnic background were registered, and lung function was assessed using spirometry. RESULTS After exclusion of all individuals with missing data, nonwhite ethnicity, self-reported disease, body mass index (BMI) less than 14 or 36 kg/m(2) or higher, and/or an obstructive lung function, reference values for FFM and FFMI were derived from 186,975 individuals (45.9% men; age: 56.9 ± 6.8 years; BMI: 26.5 ± 3.6 kg/m(2); FFMI 18.3 ± 2.4 kg/m(2)). FFM and FFMI were significantly associated with BMI and decreased with age. Percentiles 5, 10, 25, 50, 75, 90, and 95 were calculated for FFM, FFMI, and fat mass (index), after stratification for gender, age, and BMI. CONCLUSIONS Using the UK Biobank dataset, new reference values for body composition assessed with BIA were determined in white-ethnic men and women aged 45 to 69 years. Because these reference values are BMI specific, they are of broad interest for overweight and obese populations.

Arterial stiffness in patients with COPD: the role of systemic inflammation and the effects of pulmonary rehabilitation

Clear evidence for an association between systemic inflammation and increased arterial stiffness in patients with chronic obstructive pulmonary disease (COPD) is lacking. Moreover, the effects of pulmonary rehabilitation on arterial stiffness are not well studied. We aimed to 1) confirm increased arterial stiffness in COPD; 2) evaluate its correlates including systemic inflammation; and 3) study whether or not it is influenced by pulmonary rehabilitation. Aortic pulse-wave velocity (APWV) was determined in 168 healthy volunteers, and APWV and inflammatory markers were determined in 162 COPD patients during baseline evaluation of a pulmonary rehabilitation programme. A complete post-pulmonary rehabilitation dataset was collected in 129 patients. It was found that APWV was increased in COPD patients when compared with controls, blood pressure and age predicted baseline APWV, and systemic inflammatory markers were not independently related to APWV. Although baseline APWV was predictive for the change in APWV after pulmonary rehabilitation (r= -0.77), on average APWV did not change (10.7±2.7 versus 10.9±2.5 m·s−1; p=0.339). Arterial stiffness in COPD is not related to systemic inflammation and does not respond to state-of-the-art pulmonary rehabilitation. These results emphasise the complexity of cardiovascular risk and its management in COPD. Arterial stiffness in COPD is not related to systemic inflammation and does not respond to pulmonary rehabilitation http://ow.ly/tGW42

The prevalence of chronic obstructive pulmonary disease in Maastricht, the Netherlands

BACKGROUND Chronic obstructive pulmonary disease (COPD) is an increasing public health problem worldwide. Although epidemiologic data on COPD are important to raise awareness of the burden of disease, there are no actual spirometry-based data on the prevalence of COPD in the Netherlands. METHODS Using the Burden of Obstructive Lung Disease (BOLD) protocol and study design, a population-based sample of adults, aged ≥ 40 years, in the area of Maastricht, the Netherlands was surveyed. Post-bronchodilator spirometry and questionnaires with information on smoking history and reported respiratory disease were collected. COPD was defined as post-bronchodilator FEV(1)/FVC ratio < 0,7 (GOLD) or < the lower limit of normal (LLN) (95th percentile) of the population distribution for FEV(1)/FVC. Data were statistically weighted for the total number of people in the Maastricht population. RESULTS Overall prevalence of COPD was 24%, and was higher for men (28.5%) than for women (195%). (unweighted p = 0.002) The prevalence of GOLD stage 2 or higher COPD was 10%. The prevalence of LLN-defined COPD was 19% and 10% for stage 2 or higher. Overall prevalence of current smoking was 23%. The prevalence of COPD increased with age and amount of pack-years, although 14% of never smokers fulfilled spirometric criteria for COPD. The prevalence of doctor-diagnosed COPD was only 8.8%. CONCLUSION Almost one quarter of the Maastricht population aged ≥ 40 years had COPD. Considering the ageing population and still an important smoking prevalence, this burden is bound to increase and imposes great demands to public health care and society in the Netherlands.

Frequency and Relevance of Ischemic Electrocardiographic Findings in Patients With Chronic Obstructive Pulmonary Disease

Cardiovascular disease is common in patients with chronic obstructive pulmonary disease (COPD) but often remains unrecognized. Ischemic electrocardiographic (ECG) changes are associated with a higher risk of dying from coronary heart disease but have never been systematically evaluated in COPD. Also, their relation to clinical outcome has not been studied. We aimed to determine the frequency of ischemic ECG changes and its relevance in relation to clinical outcome and predictors of impaired survival in patients with COPD. Clinical characteristics, pulmonary function, and co-morbidities were assessed in 536 patients with COPD during baseline assessment of a comprehensive pulmonary rehabilitation program. Moreover, electrocardiograms at rest were obtained in all patients. All electrocardiograms were scored independently by 2 cardiologists using the Minnesota scoring system. Major or minor Q or QS pattern, ST junction and segment depression, T-wave items, or left bundle branch block were considered ischemic ECG changes. One hundred thirteen patients (21%) had ischemic ECG changes. Moreover, 42 of 293 patients (14%) without self-reported cardiovascular co-morbidities had ischemic ECG changes. In addition, patients with ischemic ECG changes had higher dyspnea grades (Modified Medical Research Council (mMRC) 2.9 ± 1.1 vs 2.6 ± 1.1, p = 0.032), worse exercise performance (6-minute walking distance 387 ± 126 vs 425 ± 126 m, p = 0.004), more systemic inflammation (high-sensitivity C-reactive protein 11.2 ± 16.2 vs 7.9 ± 10.7 mmol/l, p = 0.01), higher scores on the Charlson Co-morbidity Index (1.8 ± 0.9 vs 1.5 ± 0.8 points), and higher scores BODE (5.3 ± 3.7 vs 4.5 ± 3.4 points, p = 0.033) and on ADO indexes (5.2 ± 1.7 vs 4.8 ± 1.7 points, p = 0.029) compared to patients without ischemic ECG changes, whereas forced expiratory volume in the first second was similar (40.8 ± 15.2% vs 42.6% ± 15.9%, p = 0.30). In conclusion, ischemic ECG changes are common in patients with COPD and associated with poor clinical outcome irrespective of forced expiratory volume in the first second. These results suggest an important role for cardiovascular disease in impaired survival in these patients.

Objectively identified comorbidities in COPD: impact on pulmonary rehabilitation outcomes

Pulmonary rehabilitation (PR) is a comprehensive intervention recognised as a core component in the treatment of patients with chronic obstructive pulmonary disease (COPD) [1]. Comorbidities are highly prevalent in patients with COPD entering PR [2–4], which may be associated with the change in exercise performance and health status after PR [3–5]. Nonetheless, previous studies used self-reported and/or chart-based comorbidities, and only the impact of individual comorbidities or arbitrarily grouped comorbidities were studied [3, 4]. Patients with COPD and multiple comorbidities can still benefit from pulmonary rehabilitation http://ow.ly/LXAWc