Eva C. Creutzberg

Raised CRP levels mark metabolic and functional impairment in advanced COPD

Background: C-reactive protein (CRP) is often used as a clinical marker of acute systemic inflammation. Since low grade inflammation is evident in chronic diseases such as chronic obstructive pulmonary disease (COPD), new methods have been developed to enhance the sensitivity of CRP assays in the lower range. A study was undertaken to investigate the discriminative value of high sensitivity CRP in COPD with respect to markers of local and systemic impairment, disability, and handicap. Methods: Plasma CRP levels, interleukin 6 (IL-6) levels, body composition, resting energy expenditure (REE), exercise capacity, health status, and lung function were determined in 102 patients with clinically stable COPD (GOLD stage II–IV). The cut off point for normal versus raised CRP levels was 4.21 mg/l. Results: CRP levels were raised in 48 of 102 patients. In these patients, IL-6 (p<0.001) and REE (adjusted for fat-free mass, p = 0.002) were higher while maximal (p = 0.040) and submaximal exercise capacity (p = 0.017) and 6 minute walking distance (p = 0.014) were lower. The SGRQ symptom score (p = 0.003) was lower in patients with raised CRP levels, as were post-bronchodilator FEV1 (p = 0.031) and reversibility (p = 0.001). Regression analysis also showed that, when adjusted for FEV1, age and sex, CRP was a significant predictor for body mass index (p = 0.044) and fat mass index (p = 0.016). Conclusions: High sensitivity CRP is a marker for impaired energy metabolism, functional capacity, and distress due to respiratory symptoms in COPD.

Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial

Background: Guidelines recommend inhaled corticosteroids (ICS) as maintenance treatment for patients with chronic obstructive pulmonary disease (COPD) with a post-bronchodilator forced expiratory volume in 1 second (FEV1) <50% predicted and frequent exacerbations, although they have only a small preventive effect on the accelerated decline in lung function. Combined treatment with ICS and long acting β2 agonists (LABA) may provide benefit to the stability of COPD, but it is unknown if withdrawal of ICS will result in disease deterioration. Methods: The effects of 1 year withdrawal of the ICS fluticasone propionate (FP) after a 3 month run-in treatment period with FP combined with the LABA salmeterol (S) (500 μg FP + 50 μg S twice daily; SFC) were investigated in patients with COPD in a randomised, double blind study. 497 patients were enrolled from 39 centres throughout the Netherlands; 373 were randomised and 293 completed the study. Results: The drop out rate after randomisation was similar in the two groups. Withdrawal of FP resulted in a sustained decrease in FEV1: mean (SE) change from baseline −4.4 (0.9)% (S) v −0.1 (0.9)% (SFC); adjusted difference 4.1 (95% CI 1.6 to 6.6) percentage points (p<0.001). Corresponding figures for the FEV1/FVC ratio were −3.7 (0.8)% (S) v 0.0 (0.8)% (SFC) (p = 0.002). The annual moderate to severe exacerbation rate was 1.6 and 1.3 in the S and SFC groups, respectively (adjusted rate ratio 1.2; 95% CI 0.9 to 1.5; p = 0.15). The mean annual incidence rate of mild exacerbations was 1.3 (S) v 0.6 (SFC), p = 0.020. An immediate and sustained increase in dyspnoea score (scale 0–4; mean difference between groups 0.17 (0.04), p<0.001) and in the percentage of disturbed nights (6 (2) percentage points, p<0.001) occurred after withdrawal of fluticasone. Conclusions: Withdrawal of FP in COPD patients using SFC resulted in acute and persistent deterioration in lung function and dyspnoea and in an increase in mild exacerbations and percentage of disturbed nights. This study clearly indicates a key role for ICS in the management of COPD as their discontinuation leads to disease deterioration, even under treatment with a LABA.

Efficacy of Nutritional Supplementation Therapy in Depleted Patients With Chronic Obstructive Pulmonary Disease

OBJECTIVE Weight loss and muscle wasting adversely affect morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). Maintenance systemic glucocorticosteroids, prescribed in a substantial number of patients, further contribute to muscle weakness. We investigated the efficacy of oral nutritional supplementation therapy in depleted patients with COPD. METHODS The therapy consisted of daily two to three oral liquid nutritional supplements (mean +/- standard deviation: 2812 +/- 523 kJ/24 h) incorporated into an 8-wk inpatient pulmonary rehabilitation program in 64 (49 men) depleted patients with COPD. Endpoints were body weight, fat-free mass by bioelectrical impedance analysis, respiratory and peripheral muscle function (maximal inspiratory mouth pressure and handgrip strength, respectively), exercise performance (incremental bicycle ergometry), and disease-specific health status by St. Georges Respiratory Questionnaire. Forty-eight percent of the patients were treated with low-dose oral glucocorticosteroids as maintenance medication (dose equivalent to 7.6 +/- 2.5 mg of methylprednisolone per day). RESULTS Increases in body weight (2.1 +/- 2.1 kg, P < 0.001) and fat-free mass (1.1 +/- 2.0 kg, P < 0.001) were seen. Further, maximal inspiratory mouth pressure (4 +/- 10 cm of H(2)O, P = 0.001), handgrip strength (1.2 +/- 3.1 kg, P = 0.004), and peak workload (7 +/- 11 W, P = 0.001) significantly improved. Clinically significant improvements in the items symptoms (9 +/- 16 points, P < 0.001) and impact (4 +/- 15 points, P = 0.043) of St. Georges Respiratory Questionnaire were achieved. Oral glucocorticosteroid treatment significantly impaired the response to nutritional supplementation therapy with respect to maximal inspiratory mouth pressure, peak workload, and St. Georges Respiratory Questionnaire symptom score. CONCLUSIONS Nutritional supplementation therapy implemented in a pulmonary rehabilitation program was effective in depleted patients with COPD. However, oral glucocorticosteroid treatment attenuated the anabolic response to nutritional supplementation.

Systemic anti-inflammatory mediators in COPD: increase in soluble interleukin 1 receptor II during treatment of exacerbations

BACKGROUND The aim of this study was to test the hypothesis that the chronic inflammatory process present in chronic obstructive pulmonary disease (COPD) is due to a defective endogenous anti-inflammatory mechanism. METHODS Systemic levels of the anti-inflammatory mediators soluble interleukin 1 receptor II (sIL-1RII), soluble tumour necrosis factor receptor p55 (sTNF-R55) and sTNF-R75, and of C reactive protein (CRP) and lipopolysaccharide binding protein (LBP) were analysed in 55 patients with stable COPD (median forced expiratory volume in one second (FEV1) 34% predicted (range 15–78)) and compared with levels in 23 control subjects. In addition, changes in these mediators were studied in 13 patients with COPD (median FEV1 34% predicted (range 19–51)) during the first 7 days in hospital with an exacerbation of the disease. RESULTS Patients with stable COPD were characterised by a systemic inflammatory process indicated by an increased leucocyte count (7.2 (4.7–16.4)v 4.8 (3.5–8.3) × 109/l), raised levels of CRP (11.8 (1.1–75.0) v 4.1 (0.6–75.0) μg/ml) and LBP (45.6 (8.1–200.0)v 27.9 (14.1–71.5) μg/ml), and moderate increases in both sTNF-Rs. In contrast, the sIL-1RII level did not differ between patients and controls (4.53 (2.09–7.60)v 4.63 (3.80–5.93) ng/ml). During treatment of disease exacerbations, systemic levels of both CRP (at day 3) and LBP (at day 7) were significantly reduced compared with day 1, whereas sIL-1RII levels increased. CONCLUSIONS These data suggest an imbalance in systemic levels of pro- and anti-inflammatory mediators in patients with stable COPD. The increase in the anti-inflammatory mediator sIL-1RII during treatment of exacerbations may contribute to the clinical improvement.

Effect of infliximab on local and systemic inflammation in chronic obstructive pulmonary disease: A pilot study

Background: Chronic obstructive pulmonary disease (COPD) with cachexia is characterized by inflammation reflected by increased levels of tumor necrosis factor-α (TNF-α). Objectives: In this study, infliximab, an anti-TNF-α antibody, was evaluated for its effects on systemic (plasma) and local (exhaled breath condensate, EBC) inflammation in cachectic patients with COPD. Also, baseline levels of new inflammatory markers were compared to control subjects. Methods: Sixteen cachectic patients with moderate to severe COPD were examined for inflammatory status at baseline and compared to 25 control subjects. Patients were randomized (1:1) to receive infliximab (5 mg/kg) or placebo at weeks 0, 2 and 6. Patients were evaluated at weeks 8 and 12 and followed through week 26. Results: EBC analysis revealed increased levels of several novel inflammatory markers, including macrophage migration inhibitory factor, IL-12, RANTES and sICAM-1, in patients with COPD compared to controls. EBC levels of inflammatory markers were unchanged in patients receiving infliximab. In addition, systemic levels of acute-phase proteins (C-reactive protein, fibrinogen and lipopolysaccharide-binding protein), IL-6 and soluble TNF receptor (sTNFR) 55 had not changed at weeks 8 or 12. Small increases in circulating levels of sTNFR75, myeloperoxidase and Clara cell protein 16 were seen at week 8, but not at week 12. Conclusions: In this small study, infliximab did not produce an observable decrease in local inflammation in cachectic patients with COPD and had minor effects on systemic inflammation. The detection of new inflammatory markers in EBC can help to further characterize local inflammatory processes in COPD.

Optimizing oral nutritional drink supplementation in patients with chronic obstructive pulmonary disease

Nutritional support is indicated in some patients with chronic obstructive pulmonary disease to restore nutritional status and improve functional capacity. However, the efficacy of nutritional supplements is sometimes disappointing, partly owing to a compensatory drop in habitual food intake. We retrospectively studied the effect of nutritional drink supplements, differing in portion size and energy content, on weight gain and body composition. Thirty-nine patients with stable chronic obstructive pulmonary disease, participating in an 8-week pulmonary rehabilitation programme and eligible for nutritional support, were studied. Group A ( n 19) received three portions of 125 ml (2380 kJ), whereas group B ( n 20) received three portions of 200 ml (3350 kJ) daily. The macronutrient composition of the regimens was similar (20 % protein, 60 % carbohydrates and 20 % fat). Lung function, body weight, body composition (by bio-electrical impedance analysis), habitual dietary intake (by dietary history) and resting energy expenditure (by ventilated hood) were determined. Weight gain was compared with expected weight as predicted by a computer simulation model. Although patients in both groups significantly increased in weight, this increase was higher in group A (A, 3·3 (sd 1·9) kg; B, 2·0 (sd 1·2) kg; P =0·019), while receiving less energy. The observed weight gain in group A was similar to that expected, but in group B it was lower than expected ( P

Systemic Inflammation in COPD: Is Genetic Susceptibility a Key Factor?

COPD is a multicomponent disease characterized by abnormal inflammatory response of the lungs to noxious particles that is accompanied by systemic effects like weight loss, muscle wasting, reduced functional capacity and impaired health status. A persistent low-grade systemic inflammatory response reflected by enhanced levels of acute phase proteins like C-reactive protein (CRP) and pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, is present in part of the COPD population. The production of inflammatory proteins is partly genetically determined. Several studies have shown that polymorphisms within genes coding for these inflammatory mediators may modulate systemic inflammatory responses. Among all of these genes, the TNF family (TNF-α, lymphotoxin (LT)-α and their receptors TNF-R55 and TNF-R75), interleukin (IL)-6 and CRP gene polymorphisms are the most prominent candidates. However, large carefully designed studies in well-characterized COPD cohorts are required to unravel the exact role of genetic background in the systemic component of this disease.

Acute Effects of Nebulized Salbutamol on Resting Energy Expenditure in Patients with Chronic Obstructive Pulmonary Disease and in Healthy Subjects

This study investigated the contribution of a single dose of salbutamol by nebulizer to the increased resting energy expenditure (REE) frequently found in patients with chronic obstructive pulmonary disease (COPD) (n = 22), in comparison with a younger (n = 15) and an older healthy (n = 10) control group. The rise in REE after nebulization of 5 mg salbutamol was significantly higher in younger (11.4%) compared to older healthy subjects (5.7%; p < 0.05) and patients with COPD (4.2%; p < 0.001), which also accounted for the increase in heart rate and the drop in the respiratory quotient. No differences in metabolic effects were found between older control subjects and patients with COPD. In conclusion, despite significant improvements in FEV1 and airway resistance, a significant rise in REE was observed in patients with COPD after nebulization of salbutamol. The metabolic effects of salbutamol were however not sufficient to explain totally the elevated REE seen in these patients.

POLYUNSATURATED FATTY ACIDS IMPROVE EXERCISE CAPACITY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

BACKGROUND Muscle wasting and decreased muscle oxidative capacity commonly occur in patients with chronic obstructive pulmonary disease (COPD). Polyunsaturated fatty acids (PUFA) have been shown to mediate several inflammatory and metabolic pathways which may be involved in the pathogenesis of muscle impairment in COPD. The aim of this study was to investigate the effect of PUFA modulation on systemic inflammation, reversal of muscle wasting, and functional status in COPD. METHODS Eighty patients with COPD (57 men) with forced expiratory volume in 1 second (FEV1) 37.3 (13.8)% predicted received 9 g PUFA or placebo daily in a double blind randomised fashion during an 8 week rehabilitation programme. Body composition (bioelectrical impedance), functional capacity (lung function, incremental cycle ergometry test, submaximal cycle test, isokinetic quadriceps strength) and inflammatory markers (C-reactive protein (CRP), interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha) were assessed at baseline and after 8 weeks. RESULTS Both groups had similar increases in weight, fat-free mass (FFM), and muscle strength. The peak load of the incremental exercise test increased more in the PUFA group than in the placebo group (difference in increase 9.7 W (95% CI 2.5 to 17.0), p = 0.009) even after adjustment for FFM. The duration of the constant work rate test also increased more in patients receiving PUFA (difference in increase 4.3 min (95% CI 0.6 to 7.9), p = 0.023). The positive effects of PUFA could not be attributed to a decrease in systemic levels of CRP, IL-6 and TNF-alpha. CONCLUSIONS This is the first study to show beneficial effects of PUFA on exercise capacity in patients with COPD.