Viewpoint

From COPD to chronic systemic inammatory syndrome?

Leonardo M Fabbri, Klaus F Rabe

Chronic obstructive pulmonary disease (COPD) is characterised by poorly reversible airow limitation that is usually progressive and associated with an abnormal inammatory response of the lungs to noxious particles or gases, particularly cigarette smoke.1 A diagnosis of COPD should be considered in any current or previous smoker older than 40 years who has symptoms of cough, sputum production, or dyspnoea.1 Diagnosis and assessment of severity of COPD are based on the degree of airow limitation at spirometry.1 However, increasing evidence suggests that clinical features of COPD and airow limitation are poorly correlated and a comprehensive approach, including imaging2 and assessment of exercise tolerance and body-mass index,3 is needed. In this Viewpoint, we aim to convey the message that COPD can no longer be judged a disease only of the lungs. We propose to add the term chronic systemic inammatory syndrome to the diagnosis of COPD to stimulate discussion around the frequent complex chronic comorbidities in people with COPD and to provoke a new view of the disease in general. Cigarette smoking is the major risk factor for COPD and is one of the most important risk factors for all chronic diseases and some cancers.4 Up to now, denitions of COPD have focused on the lungs based on the simplied idea that inhalation of particles and gases will mainly aect the respiratory tract. However, cigarette smoke causes not only airway and lung inammation but also systemic cellular and humoral inammation, systemic oxidative stress, striking changes of vasomotor and endothelial function, and enhanced circulating concentrations of several procoagulant factors.5,6 These systemic eects of smoking could contribute substantially to the development not only of the airways and lung abnormalities characteristic of COPD but also of chronic diseaseseg, cardiovascular diseases, metabolic disorders, and some cancers that are induced by smoking in combination with or without other risk factors such as obesity, hyperlipidaemia, and increased blood pressure. Such chronic diseases can develop either with COPD or independently of the disorder.47 The most common comorbidities described in association with COPD are skeletal muscle abnormalities, hypertension, diabetes, coronary-artery disease, heart failure, pulmonary infections, cancer, and pulmonary vascular disease.4,7 Chronic comorbid diseases aect health outcomes in COPD;4 in fact, patients with COPD mainly die of non-respiratory disorders such as cardiovascular diseases or cancer.8 Chronic diseases account for a large proportion of human illness and include cardiovascular disease, cancer, chronic respiratory diseases, and diabetes.9 An unprecedented increase in chronic diseases is expected
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in the next few decades as populations age,10 a prospect that is of great concern to health authorities.9 Chronic diseases typically develop together.4,9,11 COPD is associated with chronic heart failure in more than 20% of patients12 and with osteoporosis in up to 70% of patientsin part, independently from treatment with steroids, decreased physical activity, or both.13 Furthermore, in a small study, almost 50% of patients with COPD had one or more components of the metabolic syndrome.14 Conversely, chronic heart failure is associated, in more than 50% of patients, with arterial hypertension and coronary or peripheral artery diseases, with diabetes in 2030%, and with anaemia in 2030%.15 Type 2 diabetes is linked to hypertension in more than 70% of individuals and to cardiovascular diseases and obesity in more than 80%.16 Diabetes is independently associated with reduced lung function, which together with obesity could further worsen the severity of COPD.17 Almost half of all people aged 65 years or older have at least three chronic medical conditions, and a fth have ve or more,11 with costs rising exponentially in patients with two or more comorbid chronic diseases.11,18 The strongest predictive factors of increased cost in COPD patients are age, chronic symptoms such as chronic dyspnoea and wheezing, and comorbidities; comorbid diseases account for more than 50% of health-care resources.4 Potentially, the common mechanism by which major risk factors such as smoking, hyperlipidaemia, obesity, and hypertension lead to chronic disease is systemic inammation.19,20 C-reactive protein is almost invariably increased in all components of the chronic systemic inammatory syndrome,21 suggesting that this acute-phase protein could represent the sentinel biomarker to all chronic diseases. Metabolic syndrome was dened by the clustering of specic risk factors for cardiovascular disease with common underlying pathophysiological ndings (eg, insulin resistance). This paradigm was useful because it drew attention to the fact that cardiovascular disease risk factors sometimes cluster and it served as a helpful reminder to clinicians to take a broad approach to treatment for such patients. Since its denition, the metabolic syndrome has stimulated an enormous amount of interest and research, to the point that it now has its own ICD-9 (International Classication of Diseases, 9th edition) code (277.7). Although, strictly speaking, the metabolic syndrome is not a syndrome in its own right,22 introduction of the term stimulated development of three fundamental ideas. First, one or more risk factors can be associated with and cause simultaneous development of diseaseseg, diabetes, obesity, hypertension, and cardiovascular disease.

Lancet 2007; 370: 79799 See Editorial page 713 Department of Oncology, Haematology, and Respiratory Diseases, University of Modena and Reggio Emilia, Modena, Italy (Prof L M Fabbri MD); and Department of Pulmonary Medicine, Leiden University Medical Center, Leiden, Netherlands (Prof K F Rabe MD) Correspondence to: Prof Klaus F Rabe, Department of Pumonary Medicine, University Medical Center, PO Box 9600NL-2300, Leiden, Netherlands k.f.rabe@lumc.nl

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Second, a comprehensive diagnostic approach to chronic disorders is needed. Finally, all risk factors should be approached with lifestyle modications (eg, smoking cessation, weight loss, physical activity), and every associated chronic comorbid disorder should be treated simultaneously. We hereby propose an overarching approach to diagnosis, assessment of severity, and management of COPD and its frequent comorbidities. In patients older than 40 years, with a smoking history of more than 10 pack-years, who develop clinical and functional abnormalities compatible with COPD, we suggest not to restrict the diagnostic approach to COPD alone but to search for signs of the more general disorder chronic systemic inammatory syndrome, with detailed description of clinical and functional abnormalities of the respiratory, cardiovascular, and metabolic systems. The term chronic refers to the slow and progressive development of the abnormalities; systemic refers to the fact that risk factors act directly or indirectly on all target organs simultaneously; inammatory refers to the association of all components with inammation; and syndrome refers to the association of several clinically recognisable features, signs, symptoms, or characteristics that generally arise together, so that the presence of one feature alerts the doctor to the presence of the others. Diagnosis of chronic systemic inammatory syndrome can be established by the presence of at least three of the six components listed in the panel. COPD, chronic heart failure, and metabolic syndrome are diagnosed according to current international guidelines1,2325 after comprehensive assessment of lung, cardiac, and metabolic functions. Other chronic disorders, such as coronary and peripheral artery diseases, anaemia, osteoporosis, and rheumatoid arthritis, could be included either as additional comorbidities, as complications (eg, steroid-induced osteoporosis), or as independent modiers of severity of the chronic syndrome (eg, depression). Severity of chronic systemic inammatory syndrome should be ascertained by combination of these dierent components. Indeed, the present approach of dening severity of COPD by spirometry has obvious limitations. For example, diagnosis of moderate COPD using a
Panel: Diagnostic components of chronic systemic inammatory syndrome Age older than 40 years Smoking for more than 10 pack-years Symptoms and abnormal lung function compatible with COPD Chronic heart failure Metabolic syndrome Increased C-reactive protein
At least three components are needed for diagnosis.

post-bronchodilator forced expiratory volume in 1 s (FEV1) of more than 50% but less than 80% and a FEV1/FVC (forced vital capacity) ratio of less than 07 has very limited clinical value if the simultaneous presence of chronic heart failure, diabetes, or both, is ignored. Our main reason for suggesting the introduction of the term chronic systemic inammatory syndrome is to emphasise the importance of complex risk factors (eg, smoking, obesity, hypertension) in development not only of primary disease (ie, COPD, chronic heart failure, or metabolic syndrome) but also of systemic and complex abnormalities aecting other organs, which are induced by smoking or by interaction of major risk factors. To ascertain the public-health perspective of this approach, the cost/benet ratio of the assessment and treatment of every component will have to be tested in properly designed randomised clinical trials of appropriate disease-management plans. Implementation of these studies is feasible, and we expect that a proposal to search for the most frequent chronic comorbidities of COPD will be a helpful reminder to clinicians of the complexity of the eects of smoking. Risk factors for chronic diseases are well recognised, and preventive and prophylactic approachessuch as smoking prevention and cessation, weight control and diet, and exercise and rehabilitationare feasible and eective and possibly represent the only approach that can tackle all components of chronic systemic inammatory syndrome. Amending pharmacological treatment algorithms to account for the many aspects of the syndrome will probably be more complex, because drugs are usually developed for individual diseases or target organs. However, since pharmacological treatment of chronic diseasesparticularly COPDis mainly symptomatic, a more comprehensive approach to management of COPD and its comorbidities might provide an opportunity to modify the natural history of COPD, allowing for identication of novel targets for treatment. This idea is especially relevant for disorders that seem to be more preventable and treatable than COPD, such as cardiovascular and metabolic disorders. Cardiovascular drugs have already been reported to have benecial eects in COPD. Statins, which are used mainly as lipid-lowering agents for treatment of metabolic syndrome, have potent anti-inammatory properties that positively aect COPD, chronic heart failure, and vascular diseases.26,27 Similarly, drugs developed and used to treat respiratory diseases (eg, inhaled bronchodilators and steroids) could have substantial benecial eects for cardiovascular diseases.28,29 Clinical practice guidelines in general seem to ignore the fact that most patients with a chronic disease have additional comorbidities. Guidelines designed largely by specialty-dominated committees for management of individual diseases provide clinicians with little advice for caring for people with several chronic diseases, resulting frequently in poly-pharmacia.11 We suggest that
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the introduction of an overarching idea such as chronic systemic inammatory syndrome will improve recognition of chronic comorbid disorders and will aect patients care, particularly that of elderly people. Not only will clinicians have to agree to change their approach to treating chronic diseases but also our health-care system must rise to this major challenge.
Conict of interest statement LMF has served as a consultant to and been paid lecture fees by Altana Pharma, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche, and Pzer; and has received grant support from Altana Pharma, AstraZeneca, Boehringer Ingelheim, Menarini, Miat, Schering Plough, Chiesi Farmaceutici, GlaxoSmithKline, Merck Sharp & Dohme, UCB, and Pzer. KFR has been a consultant for, participated in advisory board meetings, and received lecture fees from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Pzer, Novartis, Altana Pharma, Merck Sharp & Dohme, and GlaxoSmithKline. The Department of Pulmonolary Medicine, of which KFR is Director, received grants from Altana Pharma, Novartis, Bayer, AstraZeneca, Pzer, Merck Sharp & Dohme, Exhale Therapeutics, Boehringer Ingelheim, Roche, and GlaxoSmithKline between 2001 and 2006. Acknowledgments We thank M McKenney for assistance with the manuscript and E Veratelli for secretarial assistance. References 1 Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of COPD: 2006 update. Am J Respir Crit Care Med (published online May 16, 2007). DOI:10.1164/rccm.200703-456SO 2 Omori H, Nakashima R, Otsuka N, et al. Emphysema detected by lung cancer screening with low-dose spiral CT: prevalence, and correlation with smoking habits and pulmonary function in Japanese male subjects. Respirology 2006; 11: 20510. 3 Celli BR, Cote CG, Marin JM, et al. The body-mass index, airow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004; 350: 100512. 4 Mannino DM, Watt G, Hole D, et al. The natural history of chronic obstructive pulmonary disease. Eur Respir J 2006; 27: 62743. 5 Yanbaeva DG, Dentener MA, Creutzberg EC, Wesseling G, Wouters EF. Systemic eects of smoking. Chest 2007; 131: 155766. 6 Agusti A. Thomas A Ne lecture: chronic obstructive pulmonary diseasea systemic disease. Proc Am Thorac Soc 2006; 3: 47881. 7 Fabbri LM, Rabe KF. Multiple chronic diseases. In: Proceedings of a European Respiratory Society Research Seminar. Rome, Italy; Feb 1112, 2007. Available at: http://www.ersnet.org/ers/lr/browse/ default.aspx?id=31439 (accessed Aug 8, 2007). 8 McGarvey LP, John M, Anderson JA, Zvarich M, Wise RA. Ascertainment of cause-specic mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax 2007; 62: 41115. 9 Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367: 174757. 10 Kirkwood TB. Understanding the odd science of aging. Cell 2005; 120: 43747. 11 Boyd CM, Darer J, Boult C, Fried LP, Boult L, Wu AW. Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: implications for pay for performance. JAMA 2005; 294: 71624.

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