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ABSTRACT |
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INTRODUCTION
METHODS
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DISCUSSION
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Weight loss in chronic obstructive airways disease (COPD) is associated with an increased energy cost of breathing. To determine an association between body composition and the inflammatory
response we studied 80 clinically stable patients. Body composition was determined anthropometrically and skeletal muscle mass
was determined as the creatinine-height index (CHI). Forty patients had their nitrogen balance determined. Circulating concentrations of interleukin 6 (IL-6), tumor necrosis factor 
(TNF-),
and their soluble receptors were determined for 68 patients. Body
mass index (BMI) was normal (> 20 kg/m2) in 55 patients, of
whom 17 (31%) had a low CHI (< 80% predicted). A reduced CHI
was associated with increased circulating levels of IL-6 (p = 0.001),
TNF- (p = 0.032) and their soluble receptors IL-6sr (p = 0.002),
TNF-sr1 (p = 0.03), and TNF-sr2 (p = 0.001). Patients with a
normal BMI and low CHI had inflammatory mediator levels similar
to patients with a low BMI and CHI; both were significantly greater
than in those with a normal BMI and CHI. Nitrogen balance was
similar between normal and low CHI groups, although nitrogen excretion was significantly increased in the low CHI group. Skeletal muscle loss in COPD is probably multifactorial in origin, but our
data suggest a link with systemic inflammation, even when weight
loss is inapparent.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Keywords: body composition; chronic obstructive pulmonary disease
Weight loss is a characteristic of advanced chronic obstructive pulmonary disease (COPD), is associated with a greater susceptibility to exacerbations of respiratory symptoms, and is an independent predictor of outcome (1). Weight loss may involve all tissue compartments, although loss of skeletal muscle may be particularly important because of wasting of respiratory muscles with loss of power and endurance (4). An inapparent and possibly asymptomatic loss of skeletal muscle may occur in up to 25% of patients with a normal body weight (5, 6).
It is widely accepted that weight loss is due to a negative energy balance. A noncatabolic, hypermetabolic state has been proposed as the underlying mechanism, this being due to excess energy expenditure secondary to an increased oxygen cost of breathing imposed by the mechanical disadvantages of airway obstruction and hyperinflation (7, 8). However, in a range of respiratory disorders resting energy expenditure (REE) (9) was independent of the oxygen cost of breathing, the severity of COPD, and total energy expenditure (10, 11). A reduced intake of energy is a possible additional factor contributing to weight loss. Although studies of intake do not support this, energy intake could be low for the metabolic demands (12). Hence, weight loss in COPD is unlikely to be simple malnutrition, a conservative adaptation to deficient intake of energy and substrates.
Pulmonary inflammation or tissue hypoxia might contribute to weight loss (13, 14) either directly through inflammatory mediators or through catabolic intermediary metabolism.
Supporting this possibility is the presence of various inflammatory mediators in airway secretions and inflammatory cell
infiltration (15). A causal link between inflammatory status and weight maintenance in COPD remains unproven, although tumor necrosis factor (TNF-) has been implicated
as a factor in weight loss (14, 18, 19). The situation in COPD
might be analogous to that in cystic fibrosis (CF), where
weight loss is related to a sustained catabolic response linked
to chronic inflammation and abnormal pulmonary mechanics (20). In clinically stable patients with CF plasma TNF- accounted for approximately 33% of the variation in the increased REE, while the oxygen cost of breathing accounted
for approximately 50% (20, 21). Likely candidates linking
inflammation and metabolic effects in CF, and possibly in
COPD, are cytokines, such as interleukin 1
(I-1) and IL-6,
interferon 
, and TNF-, or stress hormones possibly regulated by cytokines (20, 23, 24).
Understanding the mechanism of weight loss in COPD is
important because of its link to a poor prognosis and because
it is a cause of cachexia in a major nonmalignant respiratory
disorder. In addition, the underlying mechanisms may be common to other inflammatory disorders. We hypothesized that
skeletal muscle loss would be associated with evidence of an
inflammatory and catabolic response, and the severity of lung
disease. To test this we determined skeletal muscle mass and
its relationship to lung function, circulating IL-6, TNF-, and
their soluble receptors in ambulant patients with COPD.
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Patients
Community-based patients were recruited from a hospital respiratory
clinic when clinically stable with no recorded infection, exacerbation
of respiratory symptoms, or change in medication 2 mo before the
study. COPD was diagnosed on the basis of a history of cigarette
smoking, respiratory symptoms, and a < 10% reversibility to a 2-agonist bronchodilator, with further confirmation during a 1-yr period
of follow-up (25). Patients with metabolic or neoplastic disease, or
cardiac failure, were excluded. All patients were receiving inhaled 2-agonist, ipratropium bromide, and corticosteroid treatment. Four
were undergoing regular oral corticosteroid therapy. Forty-five (15 current smokers) age- and sex-related subjects free of lung disease
acted as control subjects for inflammatory mediator determinations. This
study was approved by the local Research Ethics Committee and written informed consent was given by all subjects.
Body Composition
Height, weight, mid-upper arm circumference (MAC), wrist circumference, and skinfold thickness at four sites were determined by one observer and the body mass index (BMI), mid-arm muscle circumference (MAMC), fat mass (26), and fat-free mass (FFM) were calculated (27). Ideal body weight (IBW) was derived from the Metropolitan Life Insurance tables (28). The creatinine height index (CHI%) was determined as the ratio of the measured 24-h urinary creatinine to the ideal 24-h urinary creatinine on the basis of standards corrected for age, height, and sex (29). A subgroup of 40 patients completed a 3-d dietary recall diary and their 24-h urinary urea nitrogen (N2) was determined, from which N2 balance, N2 excretion, and the protein catabolic rate were calculated as follows (29):
N2 balance = N2 intake (g) 
[urinary urea N2 (g) + 4]
Protein catabolic rate = (24-h urinary urea N2 (g) + 4) × 6.25
Lung Function and Inflammatory Mediators
The FEV1, FVC, and transfer factor (TLCO) and transfer coefficient
(KCO) for carbon monoxide were determined. Venous blood was obtained from 68 of the 80 patients, the remaining 12 being unwilling to
give a sample. Plasma and serum were stored at 70° C and assays
were performed on batched samples with the assayist blind to the
identity of the patients. Circulating C-reactive protein (CRP), neutrophil elastase 1 anti-proteinase complex (NEAPC), IL-6, IL-6 soluble
receptor (IL-6sr), TNF-, and TNF- soluble receptors 1 and 2 (TNF-sr1 and TNF-sr2) were determined with enzyme-linked immunosorbent assays (22).
Statistical Analysis
Analysis of variance (ANOVA) was used to determine differences between patient groups on the basis of their CHI (< 80%pred and > 80%pred). The Student t test was used for analysis of differences between groups and p < 0.01 was accepted as indicating significance to allow for multiple t tests on related variables. For normally distributed data the mean, standard deviation, or 95% confidence interval (CI) were determined. For nonnormally distributed data log10 transformation was carried out before analysis and data presented as geometric mean and 95% CI. Correlation coefficients between parameters in the study were determined by the Pearson method. Multivariate analysis was used to assess the contribution of lung function and systemic inflammation indicators to the variance of nutritional markers.
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RESULTS |
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RESULTS
DISCUSSION
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Population Characteristics
Eighty patients, 46 male, were recruited with a mean (SD) FEV1%pred of 31.2 (8.2)% (range, 18-58%), height of 164 (9) cm, weight of 62.6 (12.8) kg, and age of 68.0 (7.1) yr.
Characteristics of Groups Defined by BMI
A low BMI (< 20 kg/m2) occurred in 25 patients: mean of 19.0 (0.8) kg/m2 compared with 24.9 (3.7) kg/m2 in the remaining patients, p < 0.01. Of the 55 patients with a normal BMI, 17 (31%) had skeletal muscle depletion (CHI < 80%pred). In the low-BMI group 16 (64%) of 25 patients had skeletal muscle depletion.
The energy intake was similar in the low- and normal BMI groups: 1,919.6 (1,725.0, 2,135.5) and 1,851.0 (1,635.7, 2,095.6) kcal/d, respectively, p = 0.3. The groups had similar nitrogen, fat, and carbohydrate intake.
Characteristics of Groups Defined by Skeletal Muscle Mass
The mean CHI% and BMI of the skeletal muscle-depleted group (CHI < 80%pred) were significantly less than for the replete group (CHI > 80%pred) (Table 1). Both the skeletal muscle-depleted and replete groups had a similar mean age (SD) of 67.6 (6.6) and 68.1 (7.4) yr, respectively, p = 0.667. Other markers of skeletal muscle mass, including the absolute FFM, FFM:IBW%, MAC, MAMC, triceps skinfold thickness, and absolute fat mass, were also significantly less in the skeletal muscle-depleted group. The TLCO and KCO were significantly reduced in the skeletal muscle-depleted group, while PaO2 and PaCO2 were similar between the groups (Table 1).
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Energy intake was similar in the two groups (Table 1). No difference in nitrogen, fat, or carbohydrate intake was found between the two groups.
Of the 40 patients undertaking N2 excretion studies, 22 were skeletal muscle depleted and 18 were replete. Their mean FEV1, TLCO, and FFM values were not different from those of the group of 80 patients. There was no difference in N2 balance between the groups: 6.8 (4.5, 9.2) and 9.1 (7.3, 10.5), p = 0.3, but 24-h N2 excretion was greater in the depleted patients, 6.2 (5.0, 7.6) g/d compared with 3.2 (2.3, 4.3) g/d in the replete patients (p = 0.001). The N2 output related to FFM determined by anthropometry was also greater in depleted patients: 29.5 (14) mg/kg compared with 12.5 (6) mg/kg in replete patients, p < 0.001. The calculated protein catabolic rate was also greater in patients with skeletal muscle depletion: 65.2 (57.9, 75.5) g/d compared with 46.6 (41.5, 52.4) g/day in the replete patients, p = 0.001. Seven patients (four with a normal CHI and three with a low CHI) were in negative nitrogen balance.
Inflammatory Status
Of the 68 patients from whom we obtained blood samples 29 had skeletal muscle depletion and 39 had a normal CHI. Circulating CRP was similar for the skeletal muscle-depleted and
replete groups, but was greater for both groups than in the
healthy subjects: geometric mean (95% CI) 1.30 (0.80, 2.00)
µg/ml, p = 0.001 (Table 2). Similarly, geometric mean NEAPC
was greater in the patients compared with the healthy subjects, but was not different between the two groups of patients. Circulating concentrations of IL-6, IL-6sr, and TNF-sr1, and TNF-sr2 were significantly greater in the skeletal
muscle-depleted group compared with the replete group (Table 2). A multivariate analysis with CHI as the dependent variable and lung function and inflammatory parameters as independent variables showed that KCO (p < 0.01) had 31.9%
impact on the variance of the CHI, while IL-6 (p < 0.05) and
TNF- (p < 0.05) together explained 40.4% of the variance
of the CHI. These effects were preserved with FEV1 as a covariate.
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The circulating cytokine data were further analyzed to define the relationship to hidden skeletal muscle loss. Forty-three of the 68 patients had a BMI > 20 kg/m2. The cytokine
data for these patients was compared using a low (n = 13) or
normal CHI (n = 30), where the former group comprises patients with hidden skeletal muscle loss. Patients with a normal BMI and skeletal muscle depletion had significantly raised circulating IL-6, soluble IL-6 receptor, TNF-, and soluble TNF-
receptors 1 and 2 (Figures 1 and 2). Circulating concentrations
of IL-6, TNF-, and their soluble receptors in patients with a
normal BMI and skeletal muscle loss and those with a low
BMI and skeletal muscle loss were not different (Figures 1
and 2).
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For the 68 patients as a group the concentrations of circulating cytokines were related to the CHI: IL-6 (r = 0.4, p = 0.001), IL-6sr (r = 0.3, p = 0.02), TNF- (r = 0.3, p = 0.005), and TNF-sr1 (r = 0.2, p = 0.09), and TNF-sr2 (r = 0.4, p = 0.001). No relationship was found between N2
balance and the inflammatory mediators.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Our data support the view that weight loss, particularly loss of
FFM and skeletal muscle mass, is associated with the host inflammatory response. This relationship was strengthened by
the finding of increased circulating IL-6, TNF-, and their soluble receptors in association with loss of skeletal muscle mass
in subjects with a normal BMI and the overall inverse relationship between these cytokines and skeletal muscle mass.
The increased N2 excretion, excess N2 loss for FFM, and calculated protein catabolic rate associated with a reduced FFM
and skeletal muscle mass suggest a protein catabolic state that
could be related to the increased circulating proinflammatory
cytokines. Abnormalities in amino acid distribution between
muscle and the circulation have been reported and were related to a low FFM, suggesting an enhanced turnover (30, 31).
This is in keeping with our report of high protein catabolic
rate and negative nitrogen balance in some patients with COPD.
These reports are at variance with the view that weight loss in COPD is due purely to excessive energy expenditure secondary to inefficient pulmonary mechanics causing a noncatabolic-hypermetabolic state (7, 8). The reduced FEV1, TLCO, and KCO associated with the depleted skeletal muscle mass indicates a link with the severity of injury to airways and gas exchange areas of the lungs. Taken together, our data suggest a likely multifactorial basis for weight loss in COPD.
The BMI was of limited value for determining changes in body composition and did not identify patients with skeletal muscle depletion. The CHI, a direct index of skeletal muscle mass, was associated with other indices of skeletal muscle mass, indicating the advantage of this measure over the BMI. Although skeletal muscle mass decreases with age (32), there was no difference in age between our CHI-defined groups to explain the differences found. Skeletal muscle depletion in 41% of our 80 largely unselected patients is similar to reports based on bioelectric impedance and dual-energy X-ray absorptiometry (DEXA) scanning (5, 6). Hidden loss of skeletal muscle in approximately one-third of patients with a normal BMI is greater than the reported prevalence of 15 and 26% in patients with a > 90% IBW (5, 6).
Circulating levels of CRP, NEAPC, IL-6, and TNF- were
greater in patients than in non-COPD subjects, indicating an
acute-phase inflammatory response was present in clinically
stable patients and is similar to our findings in CF (20, 22). In
infection or injury the acute inflammatory response is associated with a parallel catabolic response, which may be coregulated by cytokine networks (33). In chronic conditions, such as
infection with human immunodeficiency virus (HIV), cardiac
failure, and CF, there may be a continuous inflammatory response with a sustained catabolic response causing alterations
in body composition and cachexia (20, 23, 24). This may be
mediated by metabolically active cytokines produced either at
the site of inflammation, in the circulation, in hypoxic tissues,
or in the presence of lipopolysaccharide (LPS) (33). Such
cytokines may act directly after carriage on soluble receptors,
or indirectly through stress hormones such as noradrenaline,
adrenaline, and corticosteroids. Raised levels of IL-8, CRP,
LPS-binding protein (LBP), and TNF- and its soluble receptors in the circulation or airways of patients with COPD support our findings and validate using circulating mediators to
monitor the inflammatory response (14, 18, 19).
The relationship between nutritional status and inflammation is unclear, with conflicting reports relating to circulating immunoreactive TNF- and low body weight in COPD (14,
18, 19). Similar levels in patients with a normal IBW and non-COPD subjects support our findings. LPS-stimulated TNF-
production by peripheral blood monocytes in vitro was greater
in weight-losing patients (19), and might explain increased circulating TNF- and the potential production of cytokines at
sites of tissue hypoxia or in the presence of LPS. A link between inflammation and body composition was reported in 8 of 30 patients with COPD (14). This study was limited by low-sensitivity assays for TNF-, CRP, IL-6, and IL-8, which were
virtually undetectable in healthy subjects and in most of the
patients. Subdivision of the patients by a CRP > 5 µg/ml, the
detection limit of the assay, identified eight with raised LBP,
IL-8, and both TNF- soluble receptors and a low FFM. Our
study was designed to determine associations between lung
function, inflammation, and skeletal muscle mass. The inflammatory data were generated by the application of assays of
high sensitivity by laboratory staff unaware of the nutritional
status of the patients, and no subject had undetectable levels
of the measured mediators. Although multivariate analysis requires cautious interpretation, our finding that the variance of
the CHI is largely accounted for by the KCO, IL-6, and TNF-
strongly implicates severity of lung disease and the systemic
inflammatory response in the genesis of altered body composition. Hence, our study gives more powerful evidence of an
association between skeletal muscle loss and the inflammatory
state in COPD. We determined IL-6 and TNF- and their soluble receptors because of their relationship to fat, protein, and
skeletal muscle depletion and the stress response in disease states, and their potential homeostatic role in health (20, 33,
34, 36, 37).
This study supports a hypothesis linking inflammatory and catabolic states, in addition to other factors, such as physical inactivity and excess energy expenditure, both of which we did not assess, to the genesis of weight loss in COPD. In addition, it is possible to propose from this work a sequence of changes in body composition related to the progression of COPD. Initially, body mass and composition are normal and associated with moderately severe pulmonary disease and mild intermittent or continuous inflammatory and catabolic responses. Later, as the pulmonary disease progresses, there is preferential loss of skeletal muscle or body protein, which reflects a more consistent catabolic response maintained in parallel with the host inflammatory response. Eventually the inflammatory and metabolic responses become continuous and disadvantageous to the host as they are present with an established loss of body composition and weight, and the associated effects of enhanced morbidity and mortality. Our findings do not establish a causal relationship between inflammatory and catabolic status and altered body composition in COPD, but suggest that further research may yield insights into weight loss and cachexia in COPD and, possibly, other nonmalignant causes of cachexia.
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Footnotes |
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Correspondence and requests for reprints should be addressed to D. J. Shale, MD, Section of Respiratory Medicine, University of Wales College of Medicine, Llandough Hospital and Community NHS Trust, Penarth, South Glamorgan, CF64 2XX UK. E-mail: shaledj{at}cf.ac.uk
(Received in original form August 18, 2000 and accepted in revised form July 9, 2001).
Acknowledgments:
Supported by the British Lung Foundation, the British Thoracic Society, and the
Astra Foundation (UK). A.A.I. and L.S.N. are supported by the Cystic Fibrosis
Trust (UK).
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References |
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DISCUSSION
REFERENCES
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 C E Weekes, P W Emery, and M Elia Dietary counselling and food fortification in stable COPD: a randomised trial Thorax, April 1, 2009; 64(4): 326 - 331. [Abstract] [Full Text] [PDF]
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F M E Franssen, D E O'Donnell, G H Goossens, E E Blaak, and A M W J Schols Obesity and the lung: 5 {middle dot} Obesity and COPD Thorax, December 1, 2008; 63(12): 1110 - 1117. [Abstract] [Full Text] [PDF]
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E Sapey, D Bayley, A Ahmad, P Newbold, N Snell, and R A Stockley Inter-relationships between inflammatory markers in patients with stable COPD with bronchitis: intra-patient and inter-patient variability Thorax, June 1, 2008; 63(6): 493 - 499. [Abstract] [Full Text] [PDF]
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 J. A. Falk, O. A. Minai, and Z. Mosenifar Inhaled and Systemic Corticosteroids in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, May 1, 2008; 5(4): 506 - 512. [Abstract] [Full Text] [PDF]
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 K. M. Kunisaki, K. L. Rice, E. N. Janoff, T. S. Rector, and D. E. Niewoehner Exhaled nitric oxide, systemic inflammation, and the spirometric response to inhaled fluticasone propionate in severe chronic obstructive pulmonary disease: A prospective study Therapeutic Advances in Respiratory Disease, April 1, 2008; 2(2): 55 - 64. [Abstract] [PDF]
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P. D. Wagner Possible mechanisms underlying the development of cachexia in COPD Eur. Respir. J., March 1, 2008; 31(3): 492 - 501. [Abstract] [Full Text] [PDF]
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M. Cazzola, W. MacNee, F. J. Martinez, K. F. Rabe, L. G. Franciosi, P. J. Barnes, V. Brusasco, P. S. Burge, P. M. A. Calverley, B. R. Celli, et al. Outcomes for COPD pharmacological trials: from lung function to biomarkers Eur. Respir. J., February 1, 2008; 31(2): 416 - 469. [Abstract] [Full Text] [PDF]
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 M. A. Smith, J. S. Moylan, J. D. Smith, W. Li, and M. B. Reid IFN-{gamma} does not mimic the catabolic effects of TNF-{alpha} Am J Physiol Cell Physiol, December 1, 2007; 293(6): C1947 - C1952. [Abstract] [Full Text] [PDF]
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M. Doucet, A. P. Russell, B. Leger, R. Debigare, D. R. Joanisse, M.-A. Caron, P. LeBlanc, and F. Maltais Muscle Atrophy and Hypertrophy Signaling in Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., August 1, 2007; 176(3): 261 - 269. [Abstract] [Full Text] [PDF]
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 K. Tomoda, M. Yoshikawa, T. Itoh, S. Tamaki, A. Fukuoka, K. Komeda, and H. Kimura Elevated Circulating Plasma Adiponectin in Underweight Patients With COPD Chest, July 1, 2007; 132(1): 135 - 140. [Abstract] [Full Text] [PDF]
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R. Sabit, C. E. Bolton, P. H. Edwards, R. J. Pettit, W. D. Evans, C. M. McEniery, I. B. Wilkinson, J. R. Cockcroft, and D. J. Shale Arterial Stiffness and Osteoporosis in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., June 15, 2007; 175(12): 1259 - 1265. [Abstract] [Full Text] [PDF]
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J. Vestbo Systemic inflammation and progression of COPD Thorax, June 1, 2007; 62(6): 469 - 470. [Full Text] [PDF]
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M. C Steiner Sarcopaenia in chronic obstructive pulmonary disease Thorax, February 1, 2007; 62(2): 101 - 103. [Full Text] [PDF]
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C. E Bolton, R. Broekhuizen, A. A Ionescu, L. S Nixon, E. F M Wouters, D. J Shale, and A. M W J Schols Cellular protein breakdown and systemic inflammation are unaffected by pulmonary rehabilitation in COPD Thorax, February 1, 2007; 62(2): 109 - 114. [Abstract] [Full Text] [PDF]
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V. M. Pinto-Plata, G. Livnat, M. Girish, H. Cabral, P. Masdin, P. Linacre, R. Dew, L. Kenney, and B. R. Celli Systemic Cytokines, Clinical and Physiological Changes in Patients Hospitalized for Exacerbation of COPD Chest, January 1, 2007; 131(1): 37 - 43. [Abstract] [Full Text] [PDF]
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C. P. Hersh, D. T. Miller, D. J. Kwiatkowski, and E. K. Silverman Genetic determinants of C-reactive protein in COPD Eur. Respir. J., December 1, 2006; 28(6): 1156 - 1162. [Abstract] [Full Text] [PDF]
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 R. C. J. Langen, A. M. W. J. Schols, M. C. J. M. Kelders, J. L. J. van der Velden, E. F. M. Wouters, and Y. M. W. Janssen-Heininger Muscle Wasting and Impaired Muscle Regeneration in a Murine Model of Chronic Pulmonary Inflammation Am. J. Respir. Cell Mol. Biol., December 1, 2006; 35(6): 689 - 696. [Abstract] [Full Text] [PDF]
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 J. C. Roos, A. J. Ostor, H. Okamoto, M. A. Dentener, E. F.M. Wouters, D.L. Scott, and G.H. Kingsley Tumor Necrosis Factor Inhibitors for Rheumatoid Arthritis N. Engl. J. Med., November 9, 2006; 355(19): 2046 - 2048. [Full Text] [PDF]
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P. Joppa, D. Petrasova, B. Stancak, and R. Tkacova Systemic Inflammation in Patients With COPD and Pulmonary Hypertension. Chest, August 1, 2006; 130(2): 326 - 333. [Abstract] [Full Text] [PDF]
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E. F. M. Wouters Approaches to Improving Health Status in Chronic Obstructive Pulmonary Disease: One or Several? Proceedings of the ATS, May 1, 2006; 3(3): 262 - 269. [Abstract] [Full Text] [PDF]
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T. Similowski, A. Agusti, W. MacNee, and B. Schonhofer The potential impact of anaemia of chronic disease in COPD Eur. Respir. J., February 1, 2006; 27(2): 390 - 396. [Abstract] [Full Text] [PDF]
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J. Vestbo, E. Prescott, T. Almdal, M. Dahl, B. G. Nordestgaard, T. Andersen, T. I. A. Sorensen, and P. Lange Body Mass, Fat-Free Body Mass, and Prognosis in Patients with Chronic Obstructive Pulmonary Disease from a Random Population Sample: Findings from the Copenhagen City Heart Study Am. J. Respir. Crit. Care Med., January 1, 2006; 173(1): 79 - 83. [Abstract] [Full Text] [PDF]
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S Yende, G W Waterer, E A Tolley, A B Newman, D C Bauer, D R Taaffe, R Jensen, R Crapo, S Rubin, M Nevitt, et al. Inflammatory markers are associated with ventilatory limitation and muscle dysfunction in obstructive lung disease in well functioning elderly subjects Thorax, January 1, 2006; 61(1): 10 - 16. [Abstract] [Full Text] [PDF]
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M. Van Vliet, M. A. Spruit, G. Verleden, A. Kasran, E. Van Herck, F. Pitta, R. Bouillon, and M. Decramer Hypogonadism, Quadriceps Weakness, and Exercise Intolerance in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., November 1, 2005; 172(9): 1105 - 1111. [Abstract] [Full Text] [PDF]
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A. Couillard and C. Prefaut From muscle disuse to myopathy in COPD: potential contribution of oxidative stress Eur. Respir. J., October 1, 2005; 26(4): 703 - 719. [Abstract] [Full Text] [PDF]
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G. C. Donaldson, T. A. R. Seemungal, I. S. Patel, A. Bhowmik, T. M. A. Wilkinson, J. R. Hurst, P. K. MacCallum, and J. A. Wedzicha Airway and Systemic Inflammation and Decline in Lung Function in Patients With COPD Chest, October 1, 2005; 128(4): 1995 - 2004. [Abstract] [Full Text] [PDF]
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M. Montes de Oca, S. H. Torres, J. De Sanctis, A. Mata, N. Hernandez, and C. Talamo Skeletal muscle inflammation and nitric oxide in patients with COPD Eur. Respir. J., September 1, 2005; 26(3): 390 - 397. [Abstract] [Full Text] [PDF]
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W D-C Man, N S Hopkinson, F Harraf, D Nikoletou, M I Polkey, and J Moxham Abdominal muscle and quadriceps strength in chronic obstructive pulmonary disease Thorax, September 1, 2005; 60(9): 718 - 722. [Abstract] [Full Text] [PDF]
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D. D. Sin, L. Wu, and S. F. P. Man The Relationship Between Reduced Lung Function and Cardiovascular Mortality: A Population-Based Study and a Systematic Review of the Literature Chest, June 1, 2005; 127(6): 1952 - 1959. [Abstract] [Full Text] [PDF]
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E. F. M. Wouters Local and Systemic Inflammation in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 26 - 33. [Abstract] [Full Text] [PDF]
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W. MacNee Pulmonary and Systemic Oxidant/Antioxidant Imbalance in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 50 - 60. [Abstract] [Full Text] [PDF]
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S. F. van Eeden, A. Yeung, K. Quinlam, and J. C. Hogg Systemic Response to Ambient Particulate Matter: Relevance to Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 61 - 67. [Abstract] [Full Text] [PDF]
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S. F. P. Man and D. D. Sin Effects of Corticosteroids on Systemic Inflammation in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 78 - 82. [Abstract] [Full Text] [PDF]
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S. I. Rennard Clinical Approach to Patients with Chronic Obstructive Pulmonary Disease and Cardiovascular Disease Proceedings of the ATS, April 1, 2005; 2(1): 94 - 100. [Abstract] [Full Text] [PDF]
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G. C. Donaldson, T. M. A. Wilkinson, J. R. Hurst, W. R. Perera, and J. A. Wedzicha Exacerbations and Time Spent Outdoors in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., March 1, 2005; 171(5): 446 - 452. [Abstract] [Full Text] [PDF]
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W. Q. Gan, S.F. P. Man, and D. D. Sin The Interactions Between Cigarette Smoking and Reduced Lung Function on Systemic Inflammation Chest, February 1, 2005; 127(2): 558 - 564. [Abstract] [Full Text] [PDF]
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S. Sethi Musculoskeletal Effects of Chronic Obstructive Pulmonary Disease: Prevalent, Linked, but Ignored Am. J. Respir. Crit. Care Med., December 15, 2004; 170(12): 1267 - 1268. [Full Text] [PDF]
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C. E. Bolton, A. A. Ionescu, K. M. Shiels, R. J. Pettit, P. H. Edwards, M. D. Stone, L. S. Nixon, W. D. Evans, T. L. Griffiths, and D. J. Shale Associated Loss of Fat-free Mass and Bone Mineral Density in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., December 15, 2004; 170(12): 1286 - 1293. [Abstract] [Full Text] [PDF]
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T. Vassilakopoulos, C. Roussos, and S. Zakynthinos The immune response to resistive breathing Eur. Respir. J., December 1, 2004; 24(6): 1033 - 1043. [Abstract] [Full Text] [PDF]
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T. Itoh, N. Nagaya, M. Yoshikawa, A. Fukuoka, H. Takenaka, Y. Shimizu, Y. Haruta, H. Oya, M. Yamagishi, H. Hosoda, et al. Elevated Plasma Ghrelin Level in Underweight Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., October 15, 2004; 170(8): 879 - 882. [Abstract] [Full Text] [PDF]
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 J. S. Rana, M. A. Mittleman, J. Sheikh, F. B. Hu, J. E. Manson, G. A. Colditz, F. E. Speizer, R. G. Barr, and C. A. Camargo Jr Chronic Obstructive Pulmonary Disease, Asthma, and Risk of Type 2 Diabetes in Women Diabetes Care, October 1, 2004; 27(10): 2478 - 2484. [Abstract] [Full Text] [PDF]
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T. Vassilakopoulos, M. Divangahi, G. Rallis, O. Kishta, B. Petrof, A. Comtois, and S. N. A. Hussain Differential Cytokine Gene Expression in the Diaphragm in Response to Strenuous Resistive Breathing Am. J. Respir. Crit. Care Med., July 15, 2004; 170(2): 154 - 161. [Abstract] [Full Text] [PDF]
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C. Coronell, M. Orozco-Levi, R. Mendez, A. Ramirez-Sarmiento, J.B. Galdiz, and J. Gea Relevance of assessing quadriceps endurance in patients with COPD Eur. Respir. J., July 1, 2004; 24(1): 129 - 136. [Abstract] [Full Text] [PDF]
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W Q Gan, S F P Man, A Senthilselvan, and D D Sin Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis Thorax, July 1, 2004; 59(7): 574 - 580. [Abstract] [Full Text] [PDF]
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O. Gluck and G. Colice Recognizing and Treating Glucocorticoid-Induced Osteoporosis in Patients With Pulmonary Diseases Chest, May 1, 2004; 125(5): 1859 - 1876. [Abstract] [Full Text] [PDF]
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I. Godoy, A.O. Campana, R.R.C. Geraldo, C.R. Padovani, and S.A.R Paiva Cytokines and dietary energy restriction in stable chronic obstructive pulmonary disease patients Eur. Respir. J., December 1, 2003; 22(6): 920 - 925. [Abstract] [Full Text] [PDF]
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A. A. Ionescu, W. D. Evans, R. J. Pettit, L. S. Nixon, M. D. Stone, and D. J. Shale Hidden Depletion of Fat-Free Mass and Bone Mineral Density in Adults With Cystic Fibrosis Chest, December 1, 2003; 124(6): 2220 - 2228. [Abstract] [Full Text] [PDF]
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A.W. Boots, G.R.M.M. Haenen, and A. Bast Oxidant metabolism in chronic obstructive pulmonary disease Eur. Respir. J., November 2, 2003; 22(46_suppl): 14s - 27s. [Abstract] [Full Text] [PDF]
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A.A. Ionescu and E. Schoon Osteoporosis in chronic obstructive pulmonary disease Eur. Respir. J., November 2, 2003; 22(46_suppl): 64s - 75s. [Abstract] [Full Text] [PDF]
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A.M.W.J. Schols Nutritional and metabolic modulation in chronic obstructive pulmonary disease management Eur. Respir. J., November 2, 2003; 22(46_suppl): 81s - 86s. [Abstract] [Full Text] [PDF]
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P. Panzner, J.-J. Lafitte, A. Tsicopoulos, Q. Hamid, and M. K. Tulic Marked Up-regulation of T Lymphocytes and Expression of Interleukin-9 in Bronchial Biopsies From Patients With Chronic Bronchitis With Obstruction Chest, November 1, 2003; 124(5): 1909 - 1915. [Abstract] [Full Text] [PDF]
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 I Sermet-Gaudelus, J C Souberbielle, I Azhar, J C Ruiz, P Magnine, V Colomb, C Le Bihan, D Folio, and G Lenoir Insulin-like growth factor I correlates with lean body mass in cystic fibrosis patients Arch. Dis. Child., November 1, 2003; 88(11): 956 - 961. [Abstract] [Full Text] [PDF]
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C E Bolton, A A Ionescu, W D Evans, R J Pettit, and D J Shale Altered tissue distribution in adults with cystic fibrosis Thorax, October 1, 2003; 58(10): 885 - 889. [Abstract] [Full Text] [PDF]
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M I Polkey Peripheral muscle weakness in COPD: where does it come from? Thorax, September 1, 2003; 58(9): 741 - 742. [Full Text] [PDF]
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M A Spruit, R Gosselink, T Troosters, A Kasran, G Gayan-Ramirez, P Bogaerts, R Bouillon, and M Decramer Muscle force during an acute exacerbation in hospitalised patients with COPD and its relationship with CXCL8 and IGF-I Thorax, September 1, 2003; 58(9): 752 - 756. [Abstract] [Full Text] [PDF]
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H.R. Gosker, B. Kubat, G. Schaart, G.J. van der Vusse, E.F.M. Wouters, and A.M.W.J. Schols Myopathological features in skeletal muscle of patients with chronic obstructive pulmonary disease Eur. Respir. J., August 1, 2003; 22(2): 280 - 285. [Abstract] [Full Text] [PDF]
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R.A. Rabinovich, M. Figueras, E. Ardite, N. Carbo, T. Troosters, X. Filella, J.A. Barbera, J.C. Fernandez-Checa, J.M. Argiles, and J. Roca Increased tumour necrosis factor-{alpha} plasma levels during moderate-intensity exercise in COPD patients Eur. Respir. J., May 1, 2003; 21(5): 789 - 794. [Abstract] [Full Text] [PDF]
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D. D. Sin and S.F. P. Man Why Are Patients With Chronic Obstructive Pulmonary Disease at Increased Risk of Cardiovascular Diseases?: The Potential Role of Systemic Inflammation in Chronic Obstructive Pulmonary Disease Circulation, March 25, 2003; 107(11): 1514 - 1519. [Abstract] [Full Text] [PDF]
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A.G.N. Agusti, A. Noguera, J. Sauleda, E. Sala, J. Pons, and X. Busquets Systemic effects of chronic obstructive pulmonary disease Eur. Respir. J., February 1, 2003; 21(2): 347 - 360. [Abstract] [Full Text] [PDF]
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T. Vassilakopoulos, P. Katsaounou, M.-H. Karatza, A. Kollintza, S. Zakynthinos, and C. Roussos Strenuous Resistive Breathing Induces Plasma Cytokines: Role of Antioxidants and Monocytes Am. J. Respir. Crit. Care Med., December 15, 2002; 166(12): 1572 - 1578. [Abstract] [Full Text] [PDF]
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J. H. Vernooy, M. Kucukaycan, J. A. Jacobs, N. H. Chavannes, W. A. Buurman, M. A. Dentener, and E. F. Wouters Local and Systemic Inflammation in Patients with Chronic Obstructive Pulmonary Disease: Soluble Tumor Necrosis Factor Receptors Are Increased in Sputum Am. J. Respir. Crit. Care Med., November 1, 2002; 166(9): 1218 - 1224. [Abstract] [Full Text] [PDF]
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K. Marquis, R. Debigare, Y. Lacasse, P. LeBlanc, J. Jobin, G. Carrier, and F. Maltais Midthigh Muscle Cross-Sectional Area Is a Better Predictor of Mortality than Body Mass Index in Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., September 15, 2002; 166(6): 809 - 813. [Abstract] [Full Text]
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M. I. Lewis Apoptosis as a Potential Mechanism of Muscle Cachexia in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., August 15, 2002; 166(4): 434 - 436. [Full Text] [PDF]
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M. J. TOBIN Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 642 - 662. [Full Text] [PDF]
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