Erica P.A. Rutten

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.

Vitamin D status is associated with bone mineral density and functional exercise capacity in patients with chronic obstructive pulmonary disease

Background. Chronic obstructive pulmonary disease (COPD) is associated with several extrapulmonary effects that contribute to the severity of the disease. Vitamin D is suggested to play a role in COPD and its related extrapulmonary effects. Aims. To determine the prevalence of vitamin D deficiency and its relation with bone density, muscle strength, and exercise capacity in patients with COPD. Methods. Our cross-sectional study included patients with moderate to very severe COPD. We collected data on lung function, body composition, bone density, quadriceps muscle strength, 6-minute walking distance, and plasma 25-hydroxyvitamin D (25(OH)D) concentration. Vitamin D deficiency was defined as plasma 25(OH)D concentration below 50 nmol/L. Results. In total, 151 COPD patients were included; 87 patients (58%) had vitamin D deficiency. Plasma 25(OH)D concentration was positively associated with bone density (P = 0.005) and 6-minute walking distance (P < 0.001) after adjustment for potential confounders. Plasma 25(OH)D concentration was not associated with quadriceps muscle strength. Conclusions. The majority of COPD patients had vitamin D deficiency. Plasma 25(OH)D concentration was positively associated with bone density and exercise capacity. Intervention studies are necessary to determine whether vitamin D supplementation is of benefit in the prevention or treatment of osteoporosis and poor exercise capacity in patients with COPD.

Skeletal muscle glutamate metabolism in health and disease: state of the art

Purpose of reviewGlutamate is an amino acid of interest because it participates in many metabolic pathways. However, there is evidence that skeletal muscle glutamate metabolism is disturbed in disease. This review presents current knowledge regarding the metabolic function and regulation of glutamate in skeletal muscle under physiological and pathophysiological circumstances. Furthermore, several options for modulating muscle glutamate concentration in order to improve glutamate metabolism are discussed. Recent findingsThe high correlation between muscle glutamate concentration and muscle glutathione concentration suggests that glutamate plays a determining role in the glutathione synthesis pathway. During exercise, glutamate plays a central role in energy provision because it participates in the tricarboxylic acid and the purine nucleotide cycles. However, a consistent finding in several diseases is reduced skeletal muscle glutamate. Remarkably, only few studies focused on modulation of muscle glutamate status either by exercise or by nutritional supplementation. There are several options for modulating glutamate metabolism, but the specific effects of the individual options require further elucidation. Nutritional supplementation of glutamate or its precursors glutamine, (ornithine) α-ketoglutarate, or the branched chain amino acids can influence muscle glutamate status. SummarySpecific intervention studies must be conducted to investigate the effect of supplementation on skeletal muscle glutamate turnover and its related metabolic and functional consequences in healthy individuals and in patients with acute or chronic disease.

Bone attenuation on routine chest CT correlates with bone mineral density on DXA in patients with COPD

Chronic obstructive pulmonary disease (COPD), although primarily a disease of the lungs, is associated with extrapulmonary effects such as muscle weakness and osteoporosis. Fractures owing to osteoporosis cause significant morbidity and mortality, particularly in patients with COPD. To prevent osteoporotic fractures, it is important to diagnose osteoporosis in an early stage and to start anti‐osteoporotic therapy in at‐risk patients. Because routine chest computed tomography (CT) is increasingly used to assess the extent of emphysema and airways disease in patients with COPD, we investigated whether simple attenuation measurement of the thoracic spine on routine chest CT may provide useful information on bone health in patients with COPD. Fifty‐eight patients with moderate to very severe COPD were included in our study. The average attenuation of thoracic vertebrae 4, 7, and 10 on chest CT was correlated with the lowest bone mineral density (BMD) of the hip and lumbar spine (L1 to L4) on dual‐energy X‐ray absorptiometry (DXA) in patients with COPD. The inter‐ and intra‐observer variabilities of the attenuation measurements were low as shown by Bland‐Altman plots. Pearsons correlation coefficient between the average attenuation of the three thoracic vertebrae and the lowest BMD of the hip and lumbar spine was high (r = 0.827, p < 0.001). A receiver‐operating characteristic (ROC) analysis of the area under the curve for osteoporosis was 0.969 (p < 0.001), corresponding to an attenuation threshold of 147 Hounsfield Units (HU). In conclusion, our data demonstrated that bone attenuation measured on routine chest CT correlated strongly with BMD assessed on DXA in patients with COPD. Routine chest CT may provide useful information on bone health in patients with COPD.

Abdominal fat mass contributes to the systemic inflammation in chronic obstructive pulmonary disease.

UNLABELLED BACK GROUND & AIMS: Altered body composition in chronic obstructive pulmonary disease (COPD) is often reflected by muscle wasting, while only few studies have focused on abdominal fat mass. The contribution of abdominal fat mass to the systemic inflammation often present in COPD has not been examined yet. The aim of the present study was to investigate if abdominal fat mass contributes to the systemic inflammation in patients with moderate to severe COPD. METHODS Muscle wasting (fat free mass index <17.1 kg/m(2) for men and 14.6 kg/m(2) for women) and abdominal fat mass (android/gynoid %fat mass >1.0 for men and >0.8 for women) were assessed by dual-energy X-ray absorptiometry in 295 patients with moderate to severe COPD (175 men). Plasma C-reactive protein (CRP) concentration was analysed by high sensitive (HS)-ELISA. RESULTS Diffusion capacity was higher in patients with abdominal obesity. In addition, fat mass index was a significant determinant for plasma CRP concentration. In a subgroup of patients with CRP<5 mg/l (n=168), CRP was positively associated with abdominal fat mass. In addition, a significant proportion of abdominal obese patients had muscle wasting, and CRP levels were higher in these patients compared to the patients without abdominal obesity. CONCLUSION Abdominal fat mass contributes to the systemic inflammation in COPD. This study provides further evidence for systemic phenotyping of patients with COPD incorporating besides markers of muscle mass also markers of abdominal obesity.

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

Disturbed Intestinal Integrity in Patients With COPD Effects of Activities of Daily Living

BACKGROUND COPD is accepted to be a multicomponent disease with various comorbidities. To our knowledge, the contribution of the GI tract to the systemic manifestation of COPD has never been investigated. This metabolically active organ may experience recurring local oxygen deficits during daily life, leading to disturbed intestinal integrity in patients with COPD. METHODS Eighteen patients with moderate COPD (mean FEV₁, 55 ± 3% predicted) and 14 matched healthy control subjects were tested on two occasions: a baseline measurement at rest and, on another day, during the performance of activities of daily living (ADLs). To assess enterocyte damage, plasma intestinal fatty acid binding protein (IFABP) levels were determined, whereas urinary excretion of orally ingested sugar probes was measured using liquid chromatography and mass spectrometry to assess GI permeability. RESULTS Plasma IFABP concentrations were not different between patients with COPD and healthy control subjects at rest. In contrast, 0- to 3-h urinary lactulose to rhamnose and sucralose to erythritol ratios and 5- to 24-h urinary sucralose to erythritol ratios were significantly higher in patients with COPD compared with control subjects, indicating increased permeability of the small intestine and colon. Furthermore, the performance of ADLs led to significantly increased plasma IFABP concentrations in patients with COPD but not in control subjects. Similarly, the intestinal permeability difference between patients and control subjects was intensified. CONCLUSIONS Besides an altered intestinal permeability in patients with COPD when at rest, performing ADLs led to enterocyte damage in addition to intestinal hyperpermeability in patients with COPD but not in control subjects, indicating functional alteration in the GI tract. Hence, intestinal compromise should be considered as a new component of the multisystem disorder COPD. TRIAL REGISTRY ISRCTN Register; No.: ISRCTN33686980; URL: www.controlled-trials.com.

Highly elevated C-reactive protein levels in obese patients with COPD: A fat chance?

BACKGROUND & AIMS Chronic obstructive pulmonary disease (COPD) has been recognized as a multi component disease. Currently, limited data are available about determining factors of systemic inflammation in COPD, in particular C-reactive protein (CRP). The aim was to determine whether and to what extent COPD patients with a low, high or obese body mass index (BMI) are more likely to have elevated CRP levels compared to normal-weight COPD patients. Furthermore, we aimed to explore the effects of clinically relevant covariates on the likelihood of having elevated CRP levels. METHODS In 628 elderly patients with moderate to severe COPD (61% male), lung function and BMI were assessed before entering pulmonary rehabilitation. In addition, blood was collected in the fasted state. High-sensitive C-reactive protein (CRP) was classified into: normal, < or =3; elevated, >3-5 and highly elevated, >5mg/l. RESULTS Obese COPD patients (BMI> or =30 kg/m(2)) were 3.3 times more likely (95% CI, 1.5-7.0, p=0.002) to have highly elevated CRP levels compared to normal weight (BMI 21-24.9 kg/m(2)) COPD patients after taking clinically relevant confounders into account. In contrast, COPD patients with a low BMI (<21 kg/m(2)) were 2 times less likely (OR, 0.5; 95% CI, 0.3-0.9, p=0.022) to have highly elevated CRP levels compared to normal-weight peers. CONCLUSION Obese BMI is associated with highly elevated CRP levels in patients with COPD. These findings are suggestive for an adipocyte-induced systemic inflammation in COPD.

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.

Gender differences in the adipose secretome system in chronic obstructive pulmonary disease (COPD): A pivotal role of leptin

BACKGROUND COPD is characterized by a multi-component character involving a state of low-grade systemic inflammation and an increased prevalence of cardiovascular co-morbidity. The role of circulating leptin and other adipokines in the involvement of the systemic inflammation in COPD is only studied scarcely. OBJECTIVE To investigate gender related differences in the adipokine metabolism in relation to systemic inflammatory biomarkers in clinically stable subjects with COPD. METHODS In total, 91 clinically stable COPD patients and 35 healthy control subjects, matched for body mass index (BMI) with the COPD subjects, were included. Lung function measurement and body composition were performed in patients with COPD. In the total group, plasma concentration of the adipokines (leptin, adiponectin and resistin) and systemic inflammatory biomarkers C-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor α (TNFα), and its soluble receptors 55 and 75 (sTNFα-R55, R75) were analyzed. RESULTS The COPD group was characterized by increased levels of CRP, IL-6 and leptin. Plasma adiponectin and resistin concentrations were not different between the COPD and the control group. Within the COPD group, there was a significant interaction between gender and BMI on the leptin/fat mass ratio. In COPD women, a significant correlation between leptin and CRP was present. CONCLUSIONS In men with clinically stable COPD, leptin, adiponectin and resistin appear to be physiologically regulated, while in women, leptin metabolism is altered. Leptin secretion is increased in COPD women when compared to healthy women and compared to COPD men, and to a greater extent in overweight women with COPD.