Viewpoint
From COPD to chronic systemic inflammatory syndrome?
Leonardo M Fabbri, Klaus F Rabe
Chronic obstructive pulmonary disease (COPD) is
characterised by poorly reversible airflow limitation that
is usually progressive and associated with an abnormal
inflammatory 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 airflow limitation at spirometry.1 However, increasing
evidence suggests that clinical features of COPD and
airflow 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 inflammatory 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,
definitions of COPD have focused on the lungs based on
the simplified idea that inhalation of particles and gases
will mainly affect the respiratory tract. However, cigarette
smoke causes not only airway and lung inflammation
but also systemic cellular and humoral inflammation,
systemic oxidative stress, striking changes of vasomotor
and endothelial function, and enhanced circulating
concentrations of several procoagulant factors.5,6 These
systemic effects of smoking could contribute substantially
to the development not only of the airways and lung
abnormalities characteristic of COPD but also of chronic
diseases—eg, 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.4–7
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 affect
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
www.thelancet.com Vol 370 September 1, 2007
in the next few decades as populations age,10 a prospect Lancet 2007; 370: 797–99
that is of great concern to health authorities.9 See Editorial page 713
Chronic diseases typically develop together.4,9,11 COPD is Department of Oncology,
associated with chronic heart failure in more than 20% of Haematology, and Respiratory
Diseases, University of Modena
patients12 and with osteoporosis in up to 70% of
and Reggio Emilia, Modena,
patients—in part, independently from treatment with Italy (Prof L M Fabbri MD); and
steroids, decreased physical activity, or both.13 Furthermore, Department of Pulmonary
in a small study, almost 50% of patients with COPD had Medicine, Leiden University
Medical Center, Leiden,
one or more components of the metabolic syndrome.14
Netherlands (Prof K F Rabe MD)
Conversely, chronic heart failure is associated, in more
Correspondence to:
than 50% of patients, with arterial hypertension and Prof Klaus F Rabe, Department of
coronary or peripheral artery diseases, with diabetes Pumonary Medicine, University
in 20–30%, and with anaemia in 20–30%.15 Type 2 diabetes Medical Center,
PO Box 9600NL-2300, Leiden,
is linked to hypertension in more than 70% of individuals
Netherlands
and to cardiovascular diseases and obesity in more k.f.rabe@lumc.nl
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 fifth have
five 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
inflammation.19,20 C-reactive protein is almost invariably
increased in all components of the chronic systemic
inflammatory syndrome,21 suggesting that this
acute-phase protein could represent the sentinel
biomarker to all chronic diseases.
Metabolic syndrome was defined by the clustering of
specific risk factors for cardiovascular disease with
common underlying pathophysiological findings (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 definition, the
metabolic syndrome has stimulated an enormous
amount of interest and research, to the point that it now
has its own ICD-9 (International Classification 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 diseases—eg, diabetes,
obesity, hypertension, and cardiovascular disease.
797
 Viewpoint
Second, a comprehensive diagnostic approach to chronic
disorders is needed. Finally, all risk factors should be
approached with lifestyle modifications (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 inflammatory 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; inflammatory refers to the
association of all components with inflammation; 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 inflammatory 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 guidelines1,23–25 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
modifiers of severity of the chronic syndrome (eg,
depression).
Severity of chronic systemic inflammatory syndrome
should be ascertained by combination of these different
components. Indeed, the present approach of defining
severity of COPD by spirometry has obvious limitations.
For example, diagnosis of moderate COPD using a
Panel: Diagnostic components of chronic systemic
inflammatory 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.
798
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 0·7 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 inflammatory 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 affecting 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/benefit 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 effects of smoking.
Risk factors for chronic diseases are well recognised,
and preventive and prophylactic approaches—such as
smoking prevention and cessation, weight control and
diet, and exercise and rehabilitation—are feasible and
effective and possibly represent the only approach that
can tackle all components of chronic systemic
inflammatory 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 diseases—particularly COPD—is 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 identification 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
beneficial effects in COPD. Statins, which are used
mainly as lipid-lowering agents for treatment of metabolic
syndrome, have potent anti-inflammatory properties that
positively affect 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 beneficial effects 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
www.thelancet.com Vol 370 September 1, 2007

the introduction of an overarching idea such as chronic
systemic inflammatory syndrome will improve
recognition of chronic comorbid disorders and will affect
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.
Conflict 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 Pfizer;
and has received grant support from Altana Pharma, AstraZeneca,
Boehringer Ingelheim, Menarini, Miat, Schering Plough, Chiesi
Farmaceutici, GlaxoSmithKline, Merck Sharp & Dohme, UCB, and
Pfizer. KFR has been a consultant for, participated in advisory board
meetings, and received lecture fees from AstraZeneca, Boehringer
Ingelheim, Chiesi Farmaceutici, Pfizer, 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, Pfizer, 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: 205–10.
3 Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow
obstruction, dyspnea, and exercise capacity index in chronic
obstructive pulmonary disease. N Engl J Med 2004; 350: 1005–12.
4 Mannino DM, Watt G, Hole D, et al. The natural history of chronic
obstructive pulmonary disease. Eur Respir J 2006; 27: 627–43.
5 Yanbaeva DG, Dentener MA, Creutzberg EC, Wesseling G,
Wouters EF. Systemic effects of smoking. Chest 2007; 131: 1557–66.
6 Agusti A. Thomas A Neff lecture: chronic obstructive pulmonary
disease—a systemic disease. Proc Am Thorac Soc 2006; 3: 478–81.
7 Fabbri LM, Rabe KF. Multiple chronic diseases. In: Proceedings of a
European Respiratory Society Research Seminar. Rome, Italy;
Feb 11–12, 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-specific mortality in COPD: operations of
the TORCH Clinical Endpoint Committee. Thorax 2007; 62: 411–15.
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: 1747–57.
10 Kirkwood TB. Understanding the odd science of aging. Cell 2005;
120: 437–47.
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: 716–24.
www.thelancet.com Vol 370 September 1, 2007
Viewpoint
12 Rutten FH, Cramer MJ, Lammers JW, Grobbee DE, Hoes AW. Heart
failure and chronic obstructive pulmonary disease: an ignored
combination? Eur J Heart Fail 2006; 8: 706–11.
13 Jorgensen NR, Schwarz P, Holme I, Henriksen BM, Petersen LJ,
Backer V. The prevalence of osteoporosis in patients with chronic
obstructive pulmonary disease: a cross sectional study. Respir Med
2007; 101: 177–85.
14 Marquis K, Maltais F, Duguay V, et al. The metabolic syndrome in
patients with chronic obstructive pulmonary disease.
J Cardiopulm Rehabil 2005; 25: 226–32.
15 Dahlstrom U. Frequent non-cardiac comorbidities in patients with
chronic heart failure. Eur J Heart Fail 2005; 7: 309–16.
16 Walker CG, Zariwala MG, Holness MJ, Sugden MC. Diet, obesity
and diabetes: a current update. Clin Sci (Lond) 2007; 112: 93–111.
17 Poulain M, Doucet M, Major GC, et al. The effect of obesity on
chronic respiratory diseases: pathophysiology and therapeutic
strategies. CMAJ 2006; 174: 1293–99.
18 Charlson M, Charlson RE, Briggs W, Hollenberg J. Can disease
management target patients most likely to generate high costs? The
impact of comorbidity. J Gen Intern Med 2007; 22: 464–69.
19 Sevenoaks M, Stockley R. Chronic obstructive pulmonary disease,
inflammation and co-morbidity: a common inflammatory
phenotype? Respir Res 2006; 7: 70.
20 MacNee W. Pulmonary and systemic oxidant/antioxidant imbalance
in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;
2: 50–60.
21 Broekhuizen R, Wouters EF, Creutzberg EC, Schols AM. Raised
CRP levels mark metabolic and functional impairment in advanced
COPD. Thorax 2006; 61: 17–22.
22 Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome:
time for a critical appraisal—joint statement from the American
Diabetes Association and the European Association for the Study of
Diabetes. Diabetes Care 2005; 28: 2289–304.
23 Swedberg K, Cleland J, Dargie H, et al. Guidelines for the diagnosis
and treatment of chronic heart failure: executive summary (update
2005). Eur Heart J 2005; 26: 1115–40.
24 Ryden L, Standl E, Bartnik M, et al. Guidelines on diabetes,
pre-diabetes, and cardiovascular diseases: executive summary.
Eur Heart J 2007; 28: 88–136.
25 Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and
management of the metabolic syndrome: an American Heart
Association/National Heart, Lung, and Blood Institute Scientific
Statement. Circulation 2005; 112: 2735–52.
26 van der Harst P, Voors A, van Gilst W, Bohm M, van Veldhuisen D.
Statins in the treatment of chronic heart failure: biological and
clinical considerations. Cardiovasc Res 2006; 3: e333.
27 Mancini GB, Etminan M, Zhang B, Levesque LE, FitzGerald JM,
Brophy JM. Reduction of morbidity and mortality by statins,
angiotensin-converting enzyme inhibitors, and angiotensin
receptor blockers in patients with chronic obstructive pulmonary
disease. J Am Coll Cardiol 2006; 47: 2554–60.
28 Sin DD, Man SF. Do chronic inhaled steroids alone or in
combination with a bronchodilator prolong life in chronic
obstructive pulmonary disease patients? Curr Opin Pulm Med 2007;
13: 90–97.
29 Calverley PM, Anderson JA, Celli B, et al. Salmeterol and
fluticasone propionate and survival in chronic obstructive
pulmonary disease. N Engl J Med 2007; 356: 775–89.
799