COPD as a Lung Disease with Systemic Consequences – Clinical Impact, Mechanisms, and Potential for Early Intervention

The natural course of chronic obstructive pulmonary disease (COPD) is complicated by the development of systemic consequences and co-morbidities. These may be major features in the clinical presentation of COPD, prompting increasing interest. Systemic consequences may be defined as non-pulmonary manifestations of COPD with an immediate cause-and-effect relationship, whereas co-morbidities are diseases associated with COPD. The major systemic consequences/co-morbidities now recognized are: deconditioning, exercise intolerance, skeletal muscle dysfunction, osteoporosis, metabolic impact, anxiety and depression, cardiovascular disease, and mortality. The mechanisms by which these develop are unclear. Probably many factors are involved. Two appear of paramount importance: systemic inflammation, which presents in some patients with stable disease and virtually all patients during exacerbations, and inactivity, which may be a key link to most COPD-related co-morbidities. Further studies are required to determine the role of inflammatory cells/mediators involved in systemic inflammatory processes in causing co-morbidities; the link between activity and co-morbidities; and how COPD therapy may affect activity. Both key mechanisms appear to be influenced significantly by COPD exacerbations. Importantly, although the prevalence of systemic consequences increases with increasing severity of airflow obstruction, both systemic consequences and co-morbidities are already present in the Global Initiative for Chronic Obstructive Lung Disease Stage II. This supports the concept of early intervention in chronic obstructive pulmonary disease. Although at present early intervention studies in COPD are lacking, circumstantial evidence suggests that current treatments may influence events leading to the systemic consequences and co-morbidities, and thus may affect the clinical manifestations of the disease.

[1]  T L Petty,et al.  Obstructive lung disease and low lung function in adults in the United States: data from the National Health and Nutrition Examination Survey, 1988-1994. , 2000, Archives of internal medicine.

[2]  Kazuhisa Miyashita,et al.  Effects of physical exercise on depression, neuroendocrine stress hormones and physiological fitness in adolescent females with depressive symptoms. , 2006, European journal of public health.

[3]  P. Jones,et al.  Physiological and symptom determinants of exercise performance in patients with chronic airway obstruction. , 2000, Respiratory medicine.

[4]  F. Maltais,et al.  Histochemical and morphological characteristics of the vastus lateralis muscle in patients with chronic obstructive pulmonary disease. , 1998, Medicine and science in sports and exercise.

[5]  W. Katon,et al.  The association between depressive symptoms and health status in patients with chronic pulmonary disease. , 2001, General hospital psychiatry.

[6]  D. Klein,et al.  Smoking and panic attacks: an epidemiologic investigation. , 1999, Archives of general psychiatry.

[7]  M C Neale,et al.  Smoking and major depression. A causal analysis. , 1993, Archives of general psychiatry.

[8]  M. Decramer,et al.  Interleukin-6 Causes Myocardial Failure and Skeletal Muscle Atrophy in Rats , 2005, Circulation.

[9]  Thierry Troosters,et al.  Physical activity and hospitalization for exacerbation of COPD. , 2006, Chest.

[10]  J. Bourbeau,et al.  Tiotropium for stable chronic obstructive pulmonary disease: a meta-analysis , 2006, Thorax.

[11]  N. Hanania,et al.  The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD. , 2003, Chest.

[12]  J. Polivy,et al.  Dieting and binging. A causal analysis. , 1985, The American psychologist.

[13]  N. Chavannes,et al.  Local and systemic inflammation in patients with chronic obstructive pulmonary disease: soluble tumor necrosis factor receptors are increased in sputum. , 2002, American journal of respiratory and critical care medicine.

[14]  E. Wouters,et al.  Different patterns of chronic tissue wasting among patients with chronic obstructive pulmonary disease. , 1999, Clinical nutrition.

[15]  S. Spencer,et al.  Prednisolone response in patients with chronic obstructive pulmonary disease: results from the ISOLDE study , 2003, Thorax.

[16]  H. Beckwitt,et al.  Chronic obstructive bronchopulmonary disease. II. Oxygen transport in two clinical types. , 1968, The American journal of medicine.

[17]  B. Steele,et al.  Correlates of Physical Activity in Chronic Obstructive Pulmonary Disease , 2001, Nursing research.

[18]  D. Mellström,et al.  Smoking is associated with lower bone mineral density and reduced cortical thickness in young men. , 2007, The Journal of clinical endocrinology and metabolism.

[19]  S. M. Lee,et al.  Dose-response effect of oxygen on hyperinflation and exercise endurance in nonhypoxaemic COPD patients. , 2001, The European respiratory journal.

[20]  R. Ziegler,et al.  Reduced Pulmonary Function in Patients with Spinal Osteoporotic Fractures , 1998, Osteoporosis International.

[21]  R. Casaburi,et al.  Physiologic benefits of exercise training in rehabilitation of patients with severe chronic obstructive pulmonary disease. , 1997, American journal of respiratory and critical care medicine.

[22]  K. Westerterp,et al.  Total free living energy expenditure in patients with severe chronic obstructive pulmonary disease. , 1997, American journal of respiratory and critical care medicine.

[23]  E. Wouters,et al.  Skeletal muscle weakness is associated with wasting of extremity fat-free mass but not with airflow obstruction in patients with chronic obstructive pulmonary disease. , 2000, The American journal of clinical nutrition.

[24]  Everett M. Rogers,et al.  Consensus Development Conference , 1984 .

[25]  A. Granata,et al.  Osteoporosis and male age-related hypogonadism: role of sex steroids on bone (patho)physiology. , 2006, European journal of endocrinology.

[26]  N. Anthonisen,et al.  Contemporary management of chronic obstructive pulmonary disease: scientific review. , 2003, JAMA.

[27]  H. Chrystyn,et al.  Dose response relation to oral theophylline in severe chronic obstructive airways disease. , 1988, BMJ.

[28]  J. V. van Noord,et al.  Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium , 2002, European Respiratory Journal.

[29]  C. Jenkins,et al.  The TORCH (TOwards a Revolution in COPD Health) survival study protocol , 2004, European Respiratory Journal.

[30]  M. Tsukino,et al.  Longitudinal deteriorations in patient reported outcomes in patients with COPD. , 2007, Respiratory medicine.

[31]  D. Sin,et al.  The relationship between reduced lung function and cardiovascular mortality: a population-based study and a systematic review of the literature. , 2005, Chest.

[32]  F. Maltais,et al.  The metabolic syndrome in patients with chronic obstructive pulmonary disease. , 2005, Journal of cardiopulmonary rehabilitation.

[33]  T. Seemungal,et al.  Acute Exacerbations of Chronic Obstructive Pulmonary Disease Are Accompanied by Elevations of Plasma Fibrinogen and Serum IL-6 Levels , 2000, Thrombosis and Haemostasis.

[34]  E. Wouters,et al.  Prevalence and characteristics of nutritional depletion in patients with stable COPD eligible for pulmonary rehabilitation. , 1993, The American review of respiratory disease.

[35]  D. Mannino,et al.  Obstructive and restrictive lung disease and functional limitation: data from the Third National Health and Nutrition Examination , 2003, Journal of internal medicine.

[36]  B. J. Zebb,et al.  The catastrophic misinterpretation of physiological distress. , 1999, Behaviour research and therapy.

[37]  S. Nolen-Hoeksema,et al.  Explaining the gender difference in depressive symptoms. , 1999, Journal of personality and social psychology.

[38]  N. Anthonisen,et al.  Body weight in chronic obstructive pulmonary disease. The National Institutes of Health Intermittent Positive-Pressure Breathing Trial. , 1989, The American review of respiratory disease.

[39]  Thierry Troosters,et al.  American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation. , 2006, American journal of respiratory and critical care medicine.

[40]  Amir Sharafkhaneh,et al.  Quality of life in patients with chronic obstructive pulmonary disease and comorbid anxiety or depression. , 2006, Psychosomatics.

[41]  W. Kannel,et al.  Mortality associated with respiratory function and symptoms in advanced age. The Framingham Study. , 1989, The American review of respiratory disease.

[42]  E. Wouters,et al.  Nutritional support in patients with chronic obstructive pulmonary disease during hospitalization for an acute exacerbation; a randomized controlled feasibility trial. , 2004, Clinical nutrition.

[43]  L. Forkert,et al.  Response of lung volumes to inhaled salbutamol in a large population of patients with severe hyperinflation. , 2002, Chest.

[44]  Ja Chronic Obstructive Pulmonary Disease , 1986 .

[45]  B. Make,et al.  Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD , 2004, European Respiratory Journal.

[46]  S. Suissa,et al.  Low-dose inhaled corticosteroids and the risk of acute myocardial infarction in COPD , 2005, European Respiratory Journal.

[47]  S. Mody,et al.  Haemoglobin level and its clinical impact in a cohort of patients with COPD , 2007, European Respiratory Journal.

[48]  P. Yellowlees,et al.  Psychiatric morbidity in patients with life‐threatening asthma: initial report of a controlled study , 1988, The Medical journal of Australia.

[49]  F. Dekker,et al.  Risk of depression in patients with chronic obstructive pulmonary disease and its determinants , 2002, Thorax.

[50]  B. Nordestgaard,et al.  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. , 2006, American journal of respiratory and critical care medicine.

[51]  W. MacNee,et al.  Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper , 2004, European Respiratory Journal.

[52]  D. Górecka,et al.  Smokers with airway obstruction are more likely to quit smoking , 2006, Thorax.

[53]  John E Connett,et al.  Smoking and lung function of Lung Health Study participants after 11 years. , 2002, American journal of respiratory and critical care medicine.

[54]  B. Celli,et al.  Exercise Endurance in COPD Effect of Fluticasone Propionate/Salmeterol on Lung Hyperinflation and , 2006 .

[55]  D. Mannino,et al.  Lung function and mortality in the United States: data from the First National Health and Nutrition Examination Survey follow up study , 2003, Thorax.

[56]  S. Rennard,et al.  Rescue! Therapy and the paradox of the Barcalounger , 2003, European Respiratory Journal.

[57]  J. Roca,et al.  Training Depletes Muscle Glutathione in Patients with Chronic Obstructive Pulmonary Disease and Low Body Mass Index , 2006, Respiration.

[58]  D. Hansell,et al.  Effect of bronchoscopic lung volume reduction on dynamic hyperinflation and exercise in emphysema. , 2005, American journal of respiratory and critical care medicine.

[59]  R. Zuwallack,et al.  A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease , 2002, European Respiratory Journal.

[60]  M. Tsukino,et al.  Exercise capacity deterioration in patients with COPD: longitudinal evaluation over 5 years. , 2005, Chest.

[61]  X. Busquets,et al.  Enhanced neutrophil response in chronic obstructive pulmonary disease , 2001, Thorax.

[62]  S. Rennard,et al.  Bradykinin stimulates bronchial epithelial cells to release neutrophil and monocyte chemotactic activity. , 1992, The American journal of physiology.

[63]  Christer Janson,et al.  Anxiety and Depression are Related to the Outcome of Emergency Treatment in Patients with Obstructive Pulmonary Disease. , 2002, Chest.

[64]  L. Wollin,et al.  Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke. , 2005, American journal of respiratory and critical care medicine.

[65]  S. Morzorati,et al.  Priming of experimental anxiety by repeated subthreshold GABA blockade in the rat amygdala , 1995, Brain Research.

[66]  S. Johnston,et al.  Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. , 2006, American journal of respiratory and critical care medicine.

[67]  E. Wouters,et al.  Are patients with COPD psychologically distressed? , 2005, European Respiratory Journal.

[68]  N. Payne,et al.  Results at 1 year of outpatient multidisciplinary pulmonary rehabilitation: a randomised controlled trial , 2000, The Lancet.

[69]  X. Busquets,et al.  Expression of adhesion molecules and G proteins in circulating neutrophils in chronic obstructive pulmonary disease. , 1998, American journal of respiratory and critical care medicine.

[70]  F. Maltais,et al.  Improvements in symptom-limited exercise performance over 8 h with once-daily tiotropium in patients with COPD. , 2005, Chest.

[71]  Steven Piantadosi,et al.  A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. , 2003, The New England journal of medicine.

[72]  C. Vogelmeier,et al.  Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. , 2007, American journal of respiratory and critical care medicine.

[73]  R. White,et al.  Anxiety and depression in severe chronic obstructive pulmonary disease: the effects of pulmonary rehabilitation. , 1999, Journal of cardiopulmonary rehabilitation.

[74]  A. Yohannes,et al.  Depression and anxiety in elderly outpatients with chronic obstructive pulmonary disease: prevalence, and validation of the BASDEC screening questionnaire , 2000, International journal of geriatric psychiatry.

[75]  M. Hyland,et al.  A qualitative study of compliance with medication and lifestyle modification in Chronic Obstructive Pulmonary Disease (COPD). , 2004, Primary care respiratory journal : journal of the General Practice Airways Group.

[76]  Andrew H. Miller,et al.  Neuropsychiatric Adverse Effects of Interferon-α , 2005 .

[77]  D. Niewoehner The impact of severe exacerbations on quality of life and the clinical course of chronic obstructive pulmonary disease. , 2006, The American journal of medicine.

[78]  D. Coultas,et al.  Health care utilization in chronic obstructive pulmonary disease. A case-control study in a health maintenance organization. , 2000, Archives of internal medicine.

[79]  D. Rainnie,et al.  The Amygdala, Panic Disorder, and Cardiovascular Responses , 2003, Annals of the New York Academy of Sciences.

[80]  Cotes Je,et al.  LONG TERM DOMICILIARY OXYGEN THERAPY IN CHRONIC HYPOXIC COR PULMONALE COMPLICATING CHRONIC BRONCHITIS AND EMPHYSEMA Report of the Medical Research Council Working Party , 1981, The Lancet.

[81]  K. Lorig,et al.  Effect of a self-management program on patients with chronic disease. , 2001, Effective clinical practice : ECP.

[82]  T. Wilt,et al.  Use of spirometry for case finding, diagnosis, and management of chronic obstructive pulmonary disease (COPD). , 2005, Evidence report/technology assessment.

[83]  J. Yzermans,et al.  Prevalence of depression in patients with chronic obstructive pulmonary disease: a systematic review , 1999, Thorax.

[84]  Y. Schutz,et al.  The cost of breathing in stable chronic obstructive pulmonary disease. , 1995, Clinical science.

[85]  J. Compston,et al.  Assessment of fracture risk and its application to screening for postmenopausal osteoporosis (WHO Technical Report Series No 843) , 1995 .

[86]  D. V. van Thiel,et al.  Nutritional status and lung function in patients with emphysema and chronic bronchitis. , 1983, Chest.

[87]  Hunter Am,et al.  The nutritional status of patients with chronic obstructive pulmonary disease. , 1981 .

[88]  M. Vest,et al.  Respiratory function, cognitions, and panic in chronic obstructive pulmonary patients. , 1992, Behaviour research and therapy.

[89]  B. Celli,et al.  Effect of fluticasone propionate/salmeterol on lung hyperinflation and exercise endurance in COPD. , 2006, Chest.

[90]  T. Seemungal,et al.  Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease , 2002, Thorax.

[91]  J. Wedzicha,et al.  Ambulatory oxygen for chronic obstructive pulmonary disease. , 2002, The Cochrane database of systematic reviews.

[92]  L. Wehren The epidemiology of osteoporosis and fractures in geriatric medicine. , 2003, Clinics in geriatric medicine.

[93]  J. Mege,et al.  Tumor necrosis factor-alpha levels and weight loss in chronic obstructive pulmonary disease. , 1994, American journal of respiratory and critical care medicine.

[94]  W. Bailey,et al.  Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. , 1995, JAMA.

[95]  G. Prigatano,et al.  Quality of life and its predictors in patients with mild hypoxemia and chronic obstructive pulmonary disease. , 1984, Archives of internal medicine.

[96]  F. Karatas,et al.  Antioxidant vitamins (A, C and E) and malondialdehyde levels in acute exacerbation and stable periods of patients with chronic obstructive pulmonary disease. , 2004, Clinical and investigative medicine. Medecine clinique et experimentale.

[97]  Tamara B Harris,et al.  Daily activity energy expenditure and mortality among older adults. , 2006, JAMA.

[98]  B. Kayahan,et al.  Psychological outcomes of an outpatient pulmonary rehabilitation program in patients with chronic obstructive pulmonary disease. , 2006, Respiratory medicine.

[99]  François Maltais,et al.  Exercise-induced quadriceps oxidative stress and peripheral muscle dysfunction in patients with chronic obstructive pulmonary disease. , 2003, American journal of respiratory and critical care medicine.

[100]  M. Decramer,et al.  Short- and long-term effects of outpatient rehabilitation in patients with chronic obstructive pulmonary disease: a randomized trial. , 2000, The American journal of medicine.

[101]  B. Make,et al.  Treatments for COPD. , 2005, Respiratory medicine.

[102]  J. Greenleaf,et al.  Effects of 3-day bed rest on physiological responses to graded exercise in athletes and sedentary men. , 2001, Journal of applied physiology.

[103]  G. Verleden,et al.  Hypogonadism, quadriceps weakness, and exercise intolerance in chronic obstructive pulmonary disease. , 2005, American journal of respiratory and critical care medicine.

[104]  S. Quintana,et al.  Mortality after hospitalization for COPD. , 2002, Chest.

[105]  Fernando Holguin,et al.  Comorbidity and mortality in COPD-related hospitalizations in the United States, 1979 to 2001. , 2005, Chest.

[106]  I. Pavord,et al.  Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. , 2003, American journal of respiratory and critical care medicine.

[107]  C. Rochester IMPROVEMENT IN EXERCISE TOLERANCE WITH THE COMBINATION OF TIOTROPIUM AND PULMONARY REHABILITATION IN PATIENTS WITH COPD , 2005 .

[108]  D. Mannino,et al.  Obstructive lung disease deaths in the United States from 1979 through 1993. An analysis using multiple-cause mortality data. , 1997, American journal of respiratory and critical care medicine.

[109]  D. O’Donnell,et al.  Combined physiological effects of bronchodilators and hyperoxia on exertional dyspnoea in normoxic COPD , 2006, Thorax.

[110]  W. MacNee,et al.  Systemic oxidative stress in asthma, COPD, and smokers. , 1996, American journal of respiratory and critical care medicine.

[111]  M. Decramer,et al.  Corticosteroids contribute to muscle weakness in chronic airflow obstruction. , 1994, American journal of respiratory and critical care medicine.

[112]  W. Bailey,et al.  Loss of bone density with inhaled triamcinolone in Lung Health Study II. , 2004, American journal of respiratory and critical care medicine.

[113]  K R Westerterp,et al.  Total daily energy expenditure relative to resting energy expenditure in clinically stable patients with COPD. , 1997, Thorax.

[114]  B. Celli,et al.  Pulmonary rehabilitation and the BODE index in COPD , 2005, European Respiratory Journal.

[115]  A. Foresi,et al.  Effect of heliox breathing on dynamic hyperinflation in COPD patients. , 2004, Chest.

[116]  R. Schwartz,et al.  Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-κB activation in response to tumor necrosis factor α , 1998 .

[117]  A Senthilselvan,et al.  Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis , 2004, Thorax.

[118]  F. Maltais,et al.  Reduction of hospital utilization in patients with chronic obstructive pulmonary disease: a disease-specific self-management intervention. , 2003, Archives of internal medicine.

[119]  F. Maltais,et al.  Contractile leg fatigue after cycle exercise: a factor limiting exercise in patients with chronic obstructive pulmonary disease. , 2003, American journal of respiratory and critical care medicine.

[120]  S. Gordon,et al.  Waging war on modern chronic diseases: primary prevention through exercise biology , 2000, Journal of applied physiology.

[121]  C. D. Mathers,et al.  Chronic obstructive pulmonary disease: current burden and future projections , 2006, European Respiratory Journal.

[122]  M. Belman,et al.  Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease. , 1996, American journal of respiratory and critical care medicine.

[123]  John Connett,et al.  The Effects of a Smoking Cessation Intervention on 14.5-Year Mortality , 2005, Annals of Internal Medicine.

[124]  T. Keistinen,et al.  The COPD-induced hospitalization burden from first admission to death. , 2007, Respiratory medicine.

[125]  C. Dulberg,et al.  Relationship of lung function to severity of osteoporosis in women. , 1990, The American review of respiratory disease.

[126]  X. Busquets,et al.  Skeletal muscle apoptosis and weight loss in chronic obstructive pulmonary disease. , 2002, American journal of respiratory and critical care medicine.

[127]  Mitchell Rs,et al.  CHRONIC OBSTRUCTIVE BRONCHOPULMONARY DISEASE. I. CLINICAL FEATURES. , 1964 .

[128]  A. Buist,et al.  The Lung Health Study. Baseline characteristics of randomized participants. , 1993, Chest.

[129]  D. O’Donnell,et al.  Measurement of symptoms, lung hyperinflation, and endurance during exercise in chronic obstructive pulmonary disease. , 1998, American journal of respiratory and critical care medicine.

[130]  Is 12-hour oxygen as effective as 24-hour oxygen in advanced chronic obstructive pulmonary disease with hypoxemia? (The nocturnal oxygen therapy trial--NOTT) , 1980, Chest.

[131]  K. Engedal,et al.  High prevalence of anxiety symptoms in hospitalized geriatric patients , 2001, International journal of geriatric psychiatry.

[132]  B. Celli,et al.  Gender and COPD in patients attending a pulmonary clinic. , 2006, Chest.

[133]  Florent Richy,et al.  Strategies for the prevention of hip fracture. , 2003, The American journal of medicine.

[134]  D. Mannino,et al.  Chronic obstructive pulmonary disease surveillance--United States, 1971-2000. , 2002, Respiratory care.

[135]  C. Cooper The connection between chronic obstructive pulmonary disease symptoms and hyperinflation and its impact on exercise and function. , 2006, The American journal of medicine.

[136]  M. Lebowitz,et al.  Death certificate reporting of confirmed airways obstructive disease. , 1991, American journal of epidemiology.

[137]  John R Hurst,et al.  Exacerbations and time spent outdoors in chronic obstructive pulmonary disease. , 2005, American journal of respiratory and critical care medicine.

[138]  X. Busquets,et al.  Systemic effects of chronic obstructive pulmonary disease , 2003, European Respiratory Journal.

[139]  T. De,et al.  Parenteral nutrition before gastrointestinal surgery. , 1982 .

[140]  F. Forastiere,et al.  Co-morbidity contributes to predict mortality of patients with chronic obstructive pulmonary disease. , 1997, The European respiratory journal.

[141]  J. Wedzicha,et al.  COPD exacerbations: definitions and classifications , 2003, European Respiratory Journal.

[142]  P. Kannus,et al.  Osteoporotic fractures of the proximal humerus in elderly Finnish persons: Sharp increase in 1970-1998 and alarming projections for the new millennium , 2000, Acta orthopaedica Scandinavica.

[143]  A. Rifkin,et al.  The prevalence of anxiety disorders in patients with chronic obstructive pulmonary disease. , 1990, The American journal of psychiatry.

[144]  Andrew H. Miller,et al.  Neuropsychiatric adverse effects of interferon-alpha: recognition and management. , 2005, CNS drugs.

[145]  R. Zuwallack,et al.  Improvement in resting inspiratory capacity and hyperinflation with tiotropium in COPD patients with increased static lung volumes. , 2003, Chest.

[146]  R. Pauwels,et al.  Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial , 2003, The Lancet.

[147]  J. Lammers,et al.  Expression of priming-associated cellular markers on neutrophils during an exacerbation of COPD. , 2006, Respiratory medicine.

[148]  H. Kopera,et al.  Briefe an die Redaktion , 1989, Klinische Wochenschrift.

[149]  Victor F. Froelicher,et al.  Exercise capacity and mortality among men referred for exercise testing. , 2002, The New England journal of medicine.

[150]  M. Decramer,et al.  Clinical Trial Design Considerations in Assessing Long‐Term Functional Impacts of Tiotropium in COPD: The Uplift Trial , 2004, COPD.

[151]  E. R. Sutherland,et al.  Inhaled corticosteroids reduce the progression of airflow limitation in chronic obstructive pulmonary disease: a meta-analysis , 2003, Thorax.

[152]  R. Stockley,et al.  NEUTROPHILS FROM SUBJECTS WITH CHRONIC OBSTRUCTIVE LUNG DISEASE SHOW ENHANCED CHEMOTAXIS AND EXTRACELLULAR PROTEOLYSIS , 1987, The Lancet.

[153]  A. Anzueto,et al.  One-year analysis of longitudinal changes in spirometry in patients with COPD receiving tiotropium. , 2005, Pulmonary pharmacology & therapeutics.

[154]  M. Decramer,et al.  Muscle weakness is related to utilization of health care resources in COPD patients. , 1997, The European respiratory journal.

[155]  M. Maes,et al.  Major depression and activation of the inflammatory response system. , 1999, Advances in experimental medicine and biology.

[156]  E. Wouters,et al.  Raised CRP levels mark metabolic and functional impairment in advanced COPD , 2005, Thorax.

[157]  K. P. Van de Woestijne,et al.  Weight changes in the terminal stages of chronic obstructive pulmonary disease. Relation to respiratory function and prognosis. , 1967, The American review of respiratory disease.

[158]  R. Stockley,et al.  Chronic Obstructive Pulmonary Disease, inflammation and co-morbidity – a common inflammatory phenotype? , 2006, Respiratory research.

[159]  M. Bugiani,et al.  Predictors of survival in a group of patients with chronic airflow obstruction. , 1998, Journal of clinical epidemiology.

[160]  D. Sin,et al.  The risk of osteoporosis in Caucasian men and women with obstructive airways disease. , 2003, The American journal of medicine.

[161]  E. Wouters,et al.  Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease. , 1996, Thorax.

[162]  D. O’Donnell,et al.  Effect of salmeterol on the ventilatory response to exercise in chronic obstructive pulmonary disease , 2004, European Respiratory Journal.

[163]  E. Wouters Local and systemic inflammation in chronic obstructive pulmonary disease. , 2005, Proceedings of the American Thoracic Society.

[164]  D. Niewoehner,et al.  Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator , 2005, Annals of Internal Medicine.

[165]  Bartolome Celli,et al.  Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. , 2007, The New England journal of medicine.

[166]  M. Decramer,et al.  CHRONIC OBSTRUCTIVE PULMONARY DISEASE Muscle force during an acute exacerbation in hospitalised patients with COPD and its relationship with CXCL8 and IGF-I , 2003 .

[167]  C. Rosen,et al.  A rational approach to evidence gaps in the management of osteoporosis. , 2005, The American journal of medicine.

[168]  P. Palange,et al.  Effect of heliox on lung dynamic hyperinflation, dyspnea, and exercise endurance capacity in COPD patients. , 2004, Journal of applied physiology.

[169]  E. Wouters,et al.  Body composition and mortality in chronic obstructive pulmonary disease. , 2005, The American journal of clinical nutrition.

[170]  S. Cummings,et al.  Tumor necrosis factor-alpha polymorphism, bone strength phenotypes, and the risk of fracture in older women. , 2005, The Journal of clinical endocrinology and metabolism.

[171]  N. Keim,et al.  The prevalence and determinants of nutritional changes in chronic obstructive pulmonary disease. , 1984, Chest.

[172]  E. Culham,et al.  Thoracic Kyphosis, Rib Mobility, and Lung Volumes in Normal Women and Women With Osteoporosis , 1994, Spine.

[173]  X. Busquets,et al.  [Systemic inflammation during exacerbations of chronic obstructive pulmonary disease]. , 2002, Archivos de bronconeumologia.

[174]  N. Anthonisen,et al.  Mortality in COPD: role of comorbidities , 2006, European Respiratory Journal.

[175]  R. Casaburi,et al.  Exercise training decreases ventilatory requirements and exercise-induced hyperinflation at submaximal intensities in patients with COPD. , 2006, Chest.

[176]  D. Tashkin The role of patient-centered outcomes in the course of chronic obstructive pulmonary disease: how long-term studies contribute to our understanding. , 2006, The American journal of medicine.

[177]  D. Mannino,et al.  Low lung function and incident lung cancer in the United States: data From the First National Health and Nutrition Examination Survey follow-up. , 2003, Archives of internal medicine.

[178]  H. Besedovsky,et al.  Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1. , 1987, Science.

[179]  Alan D. Lopez,et al.  Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study , 1997, The Lancet.

[180]  P. Calverley,et al.  Maintenance therapy with budesonide and formoterol in chronicobstructive pulmonary disease , 2003, European Respiratory Journal.

[181]  D. Bates,et al.  Prevention of Exacerbations of Chronic Obstructive , 2005 .

[182]  A. Ionescu,et al.  Associated loss of fat-free mass and bone mineral density in chronic obstructive pulmonary disease. , 2004, American journal of respiratory and critical care medicine.

[183]  P. Young,et al.  Ambulatory oxygen improves quality of life of COPD patients: a randomised controlled study , 2002, European Respiratory Journal.

[184]  Steven De Peuter,et al.  Dyspnea: the role of psychological processes. , 2004, Clinical psychology review.

[185]  J. Nurnberger,et al.  Is cholinergic sensitivity a genetic marker for the affective disorders? , 1994, American journal of medical genetics.

[186]  D. Postma,et al.  Prevalence of nutritional depletion in a large out-patient population of patients with COPD. , 2006, Respiratory medicine.

[187]  Helle Bruunsgaard,et al.  Physical activity and modulation of systemic low‐level inflammation , 2005, Journal of leukocyte biology.

[188]  C. Cooper,et al.  Recent developments in inhaled therapy in stable chronic obstructive pulmonary disease , 2005, BMJ : British Medical Journal.

[189]  Thierry Troosters,et al.  Characteristics of physical activities in daily life in chronic obstructive pulmonary disease. , 2005, American journal of respiratory and critical care medicine.

[190]  J. Barberà,et al.  Effects of Endurance Training on Skeletal Muscle Bioenergetics in Chronic Obstructive Pulmonary Disease , 1999 .

[191]  Abdullah Alsaeedi,et al.  The effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a systematic review of randomized placebo-controlled trials. , 2002, The American journal of medicine.

[192]  D. Mannino,et al.  Global Initiative on Obstructive Lung Disease (GOLD) classification of lung disease and mortality: findings from the Atherosclerosis Risk in Communities (ARIC) study. , 2006, Respiratory medicine.

[193]  McDonald,et al.  Depression and Chronic Obstructive Pulmonary Disease: Treatment Trials. , 1998, Seminars in clinical neuropsychiatry.

[194]  Andrus Viidik,et al.  Age and gender differences in negative affect—Is there a role for emotion regulation? , 2005 .

[195]  G. FitzGerald,et al.  Chronic obstructive pulmonary disease is associated with an increase in urinary levels of isoprostane F2alpha-III, an index of oxidant stress. , 1998, American journal of respiratory and critical care medicine.

[196]  C. Prefaut,et al.  Does oxidative stress alter quadriceps endurance in chronic obstructive pulmonary disease? , 2004, American journal of respiratory and critical care medicine.

[197]  C. Nemeroff,et al.  Higher than normal plasma interleukin-6 concentrations in cancer patients with depression: preliminary findings. , 2001, The American journal of psychiatry.

[198]  R. Teague,et al.  Correlates of daily impairment in COPD. , 1988 .

[199]  M. Sullivan,et al.  Functional status and well being in chronic obstructive pulmonary disease with regard to clinical parameters and smoking: a descriptive and comparative study. , 1996, Thorax.

[200]  S. Powers,et al.  Mechanisms of disuse muscle atrophy: role of oxidative stress. , 2005, American journal of physiology. Regulatory, integrative and comparative physiology.

[201]  Z. Nahas,et al.  Functional impairment in COPD patients: the impact of anxiety and depression. , 2000, Psychosomatics.

[202]  M. Mador,et al.  Effect of pulmonary rehabilitation on quadriceps fatiguability during exercise. , 2001, American journal of respiratory and critical care medicine.

[203]  J. Stockman,et al.  Mortality in Relation to Smoking: 50 Years' Observations on Male British Doctors , 2006 .

[204]  N. Hanania,et al.  The Efficacy and Safety of Fluticasone Propionate (250 μg)/Salmeterol (50 μg) Combined in the Diskus Inhaler for the Treatment of COPD , 2003 .

[205]  F. Blasi,et al.  Anxiety and depression in COPD patients: The roles of gender and disease severity. , 2006, Respiratory medicine.

[206]  J. Wedzicha,et al.  Causes of death in patients with COPD and chronic respiratory failure. , 1997, Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace.

[207]  J. Barberà,et al.  Mitochondrial dysfunction in COPD patients with low body mass index , 2007, European Respiratory Journal.

[208]  G. Eifert,et al.  The effects of running and meditation on beta-endorphin, corticotropin-releasing hormone and cortisol in plasma, and on mood , 1995, Biological Psychology.

[209]  B. Celli,et al.  Gender associated differences in determinants of quality of life in patients with COPD: a case series study , 2006, Health and quality of life outcomes.

[210]  Elizabeth M. Borycki,et al.  Reduction of Hospital Utilization in Patients With Chronic Obstructive Pulmonary Disease: A Disease-Specific Self-management Intervention , 2003 .

[211]  T. Similowski,et al.  The potential impact of anaemia of chronic disease in COPD , 2006, European Respiratory Journal.

[212]  M. Render,et al.  Anthropometric and pulmonary function test profiles of outpatients with stable chronic obstructive pulmonary disease. , 1993, The American journal of medicine.

[213]  D. O’Donnell,et al.  Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease. , 2001, American journal of respiratory and critical care medicine.

[214]  B. Lipworth Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease , 2005, The Lancet.

[215]  E. Wouters,et al.  Disturbances in leptin metabolism are related to energy imbalance during acute exacerbations of chronic obstructive pulmonary disease. , 2000, American journal of respiratory and critical care medicine.

[216]  J. Barberà,et al.  Reduced muscle redox capacity after endurance training in patients with chronic obstructive pulmonary disease. , 2001, American journal of respiratory and critical care medicine.

[217]  P. Barnes,et al.  Chronic obstructive pulmonary disease. , 2000, The New England journal of medicine.

[218]  M. Decramer,et al.  Peripheral muscle weakness contributes to exercise limitation in COPD. , 1996, American journal of respiratory and critical care medicine.

[219]  G. Filley,et al.  CHRONIC OBSTRUCTIVE BRONCHOPULMONARY DISEASE. I. CLINICAL FEATURES. , 1964, The American review of respiratory disease.

[220]  S. Rennard,et al.  Acetylcholine stimulates bronchial epithelial cells to release neutrophil and monocyte chemotactic activity. , 1992, The American journal of physiology.

[221]  J. Zieliński,et al.  Emotional status does not alter exercise tolerance in patients with chronic obstructive pulmonary disease. , 1998, The European respiratory journal.

[222]  E. Wouters,et al.  Prevalence of an elevated resting energy expenditure in patients with chronic obstructive pulmonary disease in relation to body composition and lung function , 1998, European Journal of Clinical Nutrition.

[223]  A. Silman,et al.  The prevalence of vertebral deformity in European men and women: The european vertebral osteoporosis study , 1996, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[224]  Y. Lacasse,et al.  Midthigh muscle cross-sectional area is a better predictor of mortality than body mass index in patients with chronic obstructive pulmonary disease. , 2002, American journal of respiratory and critical care medicine.

[225]  J. Kanis,et al.  Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: Synopsis of a WHO report , 1994, Osteoporosis International.

[226]  R. Pauwels,et al.  Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. , 2001, American journal of respiratory and critical care medicine.

[227]  S. Anker,et al.  Neurohumoral activation as a link to systemic manifestations of chronic lung disease. , 2005, Chest.

[228]  Harry K. Genant,et al.  Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. , 1993, The American journal of medicine.

[229]  K. Kubo,et al.  Acetylcholine stimulates alveolar macrophages to release inflammatory cell chemotactic activity. , 1998, The American journal of physiology.

[230]  F. Maltais,et al.  Oxidative enzyme activities of the vastus lateralis muscle and the functional status in patients with COPD , 2000, Thorax.

[231]  F. Sériès,et al.  Upper airway mucosa temperature in obstructive sleep apnoea/hypopnoea syndrome, nonapnoeic snorers and nonsnorers. , 1998, The European respiratory journal.

[232]  S. Kivelä,et al.  Survival and cause of death among elderly chronic obstructive pulmonary disease patients after first admission to hospital. , 1997, Respiration; international review of thoracic diseases.

[233]  Susan R. Johnson,et al.  Osteoporosis prevention, diagnosis, and therapy. , 2001, JAMA.

[234]  R. Schwartz,et al.  Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-kappaB activation in response to tumor necrosis factor alpha. , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.