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-alpha (TNF-alpha). OBJECTIVES: In this study, infliximab, an anti-TNF-alpha 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.

Systemic effects of smoking.

Smoking is one of the major lifestyle factors influencing the health of human beings. Life-long cigarette smokers have a higher prevalence of common diseases such as atherosclerosis and COPD with significant systemic impact. The present review evaluates current knowledge concerning possible pathways through which cigarette smoking can affect human health, with special focus on extrapulmonary effects. Long-term smoke exposure can result in systemic oxidants-antioxidants imbalance as reflected by increased products of lipid peroxidation and depleted levels of antioxidants like vitamins A and C in plasma of smokers. A low-grade systemic inflammatory response is evident in smokers as confirmed by numerous population-based studies: elevated levels of C-reactive protein (CRP), fibrinogen, and interleukin-6, as well as increased counts of WBC have been reported. Furthermore, rheologic, coagulation and endothelial function markers like hematocrit, blood and/or plasma viscosity, fibrin d-dimer, circulating adhesion molecules (intracellular adhesion molecule-1, selectins), tissue plasminogen activator antigen, and plasminogen activator inhibitor type I are altered in chronic cigarette smokers. Although most of smoking-induced changes are reversible after quitting, some inflammatory mediators like CRP are still significantly raised in ex-smokers up to 10 to 20 years after quitting, suggesting ongoing low-grade inflammatory response persisting in former smokers. New longitudinal epidemiologic and genetic studies are required to evaluate the role of smoking itself and possible gene/environment interplay in initiation and development of smoking-induced common diseases affecting humans.

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)-alpha, 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-alpha, lymphotoxin (LT)-alph 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.

COPD as a multicomponent disease: inventory of dyspnoea, underweight, obesity and fat free mass depletion in primary care.

AIMS: To describe the distribution of COPD disease severity in primary care based on airway obstruction, and to assess the extent to which dyspnoea scores, body mass index (BMI) and fat free mass (FFM) index contribute to the distribution of COPD severity in primary care. DESIGN: Cross sectional population-based study. METHODS: 317 patients with COPD were recruited from an outpatient disease management programme. Prevalence of moderate to severe dyspnoea, underweight, obesity and FFM depletion by GOLD stage were measured. RESULTS: According to GOLD guidelines, 29% of patients had mild COPD, 48% moderate, 17% severe and 5% very severe. A substantial number of patients classified as GOLD stage 2 reported severe dyspnoea (28.1%) and/or suffered from FFM depletion (16.3%). Prevalence of low body weight strongly increased in GOLD stage 4. Prevalence of obesity is highest in GOLD stages 1 and 2. CONCLUSION: The use of a multidimensional grading system, taking into account dyspnoea as well as the nutritional status of COPD patients, is likely to influence the distribution of disease severity in a primary care population. This might have implications for prevention, non-medical treatment, and estimates of health care utilisation in primary care.

Pulmonary cachexia, systemic inflammatory profile, and the interleukin 1beta -511 single nucleotide polymorphism.

BACKGROUND: Cachexia is common in chronic obstructive pulmonary disease (COPD) and is thought to be linked to an enhanced systemic inflammatory response. OBJECTIVE: We investigated differences in the systemic inflammatory profile and polymorphisms in related inflammatory genes in COPD patients. DESIGN: A cross-sectional study was performed in 99 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease stages II-IV), who were stratified by cachexia based on fat-free mass index (FFMI; in kg/m2: <16 for men and <15 for women) and compared with healthy control subjects (HCs). Body composition was determined by bioelectrical impedance analysis. Plasma concentrations and gene polymorphisms of interleukin 1beta (IL-1beta -511), IL-6 (IL-6 -174), and the tumor necrosis factor system (TNF-alpha -308 and lymphotoxin-alpha +252) were determined. Plasma C-reactive protein, leptin, and urinary pseudouridine (as a marker of cellular protein breakdown) were measured. RESULTS: Fat mass, leptin, and pseudouridine were significantly different (P < 0.001) between noncachectic patients (NCPs) and cachectic patients (CPs: n = 35); the systemic inflammatory cytokine profile was not. NCPs had a body compositional shift toward a lower fat-free mass and a higher fat mass compared with HCs. CPs and NCPs had a greater systemic inflammatory response (P < 0.05) than did HCs, as reflected in C-reactive protein, soluble TNF-R75, and IL-6 concentrations. The overall distribution of the IL-1beta -511 polymorphism was significantly different between the groups (P < 0.05). CONCLUSIONS: In COPD patients, who are characterized by an elevated systemic inflammatory response, cachexia is not discriminatory for the extent of increase in inflammatory status. This study, however, indicates a potential influence of genetic predisposition on the cachexia process.

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<0.001). In both groups, fat-free mass and fat mass were gained in a ratio of 2:1, fat-free mass increasing primarily during the first 4 weeks. This study illustrates that there might be an optimum for the portion size of nutritional drink supplements in chronic obstructive pulmonary disease and that more is not always better.

A role for anabolic steroids in the rehabilitation of patients with COPD? A double-blind, placebo-controlled, randomized trial.

STUDY OBJECTIVES: Skeletal muscle weakness commonly occurs in patients with COPD. Long-term use of systemic glucocorticosteroids further contributes to muscle weakness. Anabolic steroids could be an additional mode of intervention to improve outcome of pulmonary rehabilitation by increasing physiologic functioning, possibly mediated by increasing erythropoietic function. PATIENTS AND METHODS: We randomly assigned 63 male patients with COPD to receive on days 1, 15, 29, and 43 a deep IM injection of 50 mg of nandrolone decanoate (ND) [Deca-Durabolin; N.V. Organon; Oss, The Netherlands] in 1 mL of arachis oil, or 1 mL of arachis oil alone (placebo) in a double-blind design. All patients participated in a standardized pulmonary rehabilitation program. Outcome measures were body composition by deuterium and bromide dilution, respiratory and peripheral muscle function, incremental exercise testing, and health status by the St. George's Respiratory Questionnaire. RESULTS: Treatment with ND relative to placebo resulted in higher increases in fat-free mass (FFM; mean, 1.7 kg [SD, 2.5] vs 0.3 kg [SD, 1.9]; p = 0.015) owing to a rise in intracellular mass (mean, 1.8 kg [SD, 3.1] vs - 0.5 kg [SD, 3.1]; p = 0.002). Muscle function, exercise capacity, and health status improved in both groups to the same extent. Only after ND were increases in erythropoietic parameters seen (erythropoietin: mean, 2.08 U/L [SD, 5.56], p = 0.067; hemoglobin: mean, 0.29 mmol/L [SD, 0.73], p = 0.055). In the total group, the changes in maximal inspiratory mouth pressure (PImax) and peak workload were positively correlated with the change in hemoglobin (r = 0.30, p = 0.032, and r = 0.34, p = 0.016, respectively), whereas the change in isokinetic leg work was correlated with the change in erythropoietin (r = 0.38, p = 0.013). In the patients receiving maintenance treatment with low-dose oral glucocorticosteroids (31 of 63 patients; mean, 7.5 mg/24 h [SD, 2.4]), greater improvements in PImax (mean, 6.0 cm H(2)O [SD, 8.82] vs - 2.18 cm H(2)O [SD, 11.08], p = 0.046), and peak workload (mean, 20.47 W [SD, 19.82] vs 4.80 W [SD, 7.74], p = 0.023) were seen after 8 weeks of treatment with ND vs placebo. CONCLUSIONS: In conclusion, a short-term course of ND had an overall positive effect relative to placebo on FFM without expanding extracellular water in patients with COPD. In the total group, the improvements in muscle function and exercise capacity were associated with improvements in erythropoietic parameters. The use of low-dose oral glucocorticosteroids as maintenance medication significantly impaired the response to pulmonary rehabilitation with respect to respiratory muscle function and exercise capacity, which could be restored by ND treatment.

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. George's 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. George's 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. George's 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 effects in COPD.

The pathogenesis and clinical manifestations of COPD are not restricted to pulmonary inflammation and structural remodeling. Rather, this disorder is associated with clinically significant systemic alterations in biochemistry and organ function. The systemic aspects of COPD include oxidative stress and altered circulating levels of inflammatory mediators and acute-phase proteins. Indeed, an impaired endogenous oxidant-antioxidant balance has been reported in patients experiencing exacerbations of COPD, and others have observed altered circulating levels of several cytokines and adhesion molecules in patients with stable disease. As in other chronic inflammatory conditions, weight loss, muscle wasting, and tissue depletion are commonly seen in COPD patients. Selective wasting of fat-free mass coupled with impaired respiratory and peripheral muscle function and a reduced capacity for exercise occur in COPD patients. Indeed, weight loss may directly impact poor prognosis in COPD patients. The mechanisms underlying weight loss and muscle wasting are incompletely understood but likely involve an imbalance in ongoing processes of protein degradation and replacement. This may include alterations in the relative levels or activities of endocrine hormones such as insulin, growth hormone, testosterone, and glucocorticoids. Furthermore, chronic systemic inflammation involving cytokines such as interleukin-1 and tumor necrosis factor-alpha may be associated with these hormonal changes and muscle wasting in COPD patients. This review includes a discussion of the mechanisms of skeletal muscle fiber protein metabolism/catabolism, the potential roles of endogenous cytokines in protein loss, and the possibility that novel drugs that inhibit cytokine signaling may provide benefits by reducing muscle wasting and cachexia, thereby improving the prognosis and quality of life among COPD patients.