Thomas A. Neff Lecture Systemic Inflammation and Comorbidities in Chronic Obstructive Pulmonary Disease Alvar Agustı´1,2 and Rosa Faner1,2 1
Thorax Institute, Hospital Clinic, Institut d’Investigacions Biome`diques August Pi i Sunyer, University of Barcelona, Barcelona; and 2FISIB, CIBER Enfermedades Respiratorias (CIBERES), Mallorca, Spain
The relationship between systemic inflammation and comorbidities in patients with chronic obstructive pulmonary disease (COPD) is unclear. This article discusses (1) the prevalence and clinical impact of comorbidities in COPD; (2) the current knowledge on definition, prevalence, consequences, and treatment of systemic inflammation in COPD; and (3) the relationship of systemic inflammation and lung cancer in COPD. Keywords: chronic bronchitis; emphysema; lung cancer; inflammome
Chronic obstructive pulmonary disease (COPD) is a complex disease with pulmonary and extrapulmonary manifestations (1). The link between these domains of the disease is unclear. On the one hand, the latter could be the consequence of the former, the socalled “systemic effects” of COPD (2). On the other hand, they may represent the cooccurrence of highly prevalent diseases (cardiovascular, metabolic, muscular, and bone disorders) in aged patients (comorbidities) (3). Because many of these diseases, including normal ageing, are characterized by low-grade chronic systemic inflammation (“inflamm-ageing”) (4), it has been hypothesized that systemic inflammation may be an important pathogenic link between the pulmonary and extrapulmonary components of COPD (5). This article discusses (1) the prevalence and clinical impact of comorbidities in COPD; (2) the current knowledge on definition, prevalence, consequences, and treatment of systemic inflammation in COPD; and (3) the relationship of systemic inflammation and lung cancer in COPD.
COMORBIDITIES IN COPD Many different studies have shown that comorbidities occur more frequently in patients with COPD than in smokers and neversmoker control subjects of similar age (6, 7). The ECLIPSE study, for instance, has recently shown in a large cohort of patients with COPD (n ¼ 2164) with a wide range of airflow limitation severity (from GOLD II to GOLD IV) that a number of concomitant diseases were significantly more prevalent in patients than in smokers (n ¼ 337) and never-smoker (n ¼ 245) control subjects of similar age (Table 1) (8). More importantly, this study showed that their prevalence was similar in different GOLD stages (Table 2) (8). This is clinically relevant because the widespread concept of comorbid diseases being characteristic of severe COPD is probably not correct. Hence, in clinical practice, comorbidities should be looked for in any patient with COPD (irrespective of (Received in original form August 21, 2011; accepted in final form August 25, 2011) Supported by grants FIS PS09/00629 and PS10/00523. Correspondence and requests for reprints should be addressed to Dr. Alvar Agustı´, M.D., Ph.D., Institut del To`rax, Hospital Clı´nic, Villarroel 170, Escala 3, Planta 5, 08036 Barcelona, Spain. E-mail:
[email protected] Proc Am Thorac Soc Vol 9, Iss. 2, pp 43–46, May 1, 2012 Copyright ª 2012 by the American Thoracic Society DOI: 10.1513/pats.201108-050MS Internet address: www.atsjournals.org
the degree of airflow limitation present) and, as discussed below, treated appropriately if present. Comorbidities affect substantially the natural course of COPD, as elegantly illustrated by Mannino and colleagues (9). These investigators used logistic regression models (adjusted for age, sex, race, smoking, body mass index, and education) in 20,296 subjects included in the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study and showed that, over a 5-year follow-up, the presence of diabetes, hypertension, and cardiovascular disease was associated with a higher risk of hospitalization and mortality at any given GOLD stage of airflow limitation (9). A higher number of comorbidities contributed more significantly to adverse outcomes (mortality and hospitalizations) than the increase in airflow limitation severity (Figure 1). The appropriate management of comorbidities in clinical practice is a challenge because most clinical practice guidelines (CPGs) have been developed to improve the quality of health care of single diseases and rarely discuss how to manage concomitant disorders. Boyd and colleagues (10) showed that most CPGs do not modify or discuss the applicability of their recommendations for older patients with multiple comorbidities. If the relevant CPGs were strictly followed, a hypothetical 79-year-old woman with COPD, type 2 diabetes, osteoporosis, hypertension, and osteoarthritis would be prescribed an average of 12 medications, with a monthly cost of about $400 and, more importantly, a significant risk of undesirable effects (10). This complexity needs to be taken into account when developing measures to improve the quality of the care of older patients with complex comorbidities (10), and a network of guidelines for chronic diseases needs to be designed and implemented (11).
SYSTEMIC INFLAMMATION IN COPD A number of different studies and metaanalyses have shown that patients with clinically stable COPD often have elevated levels of circulating leukocytes, C-reactive protein (CRP), IL-6, IL-8, fibrinogen, and TNF-a (2, 12–18). However, many relevant questions remain unanswered (19): (1) The prevalence of systemic inflammation in COPD has not been well defined because previous studies have often involved small numbers of subjects. More importantly, the definition of systemic inflammation itself is unclear because there is no clear consensus on the type, number, and value of inflammatory biomarkers needed to establish the diagnosis. (2) These biomarkers show significant intersubject variability; some patients with COPD have abnormal levels, whereas others have values within the normal range. (3) Most previous studies are cross-sectional, so their temporal stability is not well established (20). (4) The effects of potential confounders, such as sex, smoking status, comorbidities present, or treatment with antiinflammatory drugs, have often not been considered. (5) Their relationship with relevant clinical outcomes of the disease has not been firmly established (21, 22). The inflammatory response is a highly complex network of different cells and
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TABLE 1. PREVALENCE OF SELF-REPORTED COMORBIDITIES AT BASELINE IN THE ECLIPSE STUDY*
Heart trouble, % Heart attack, % Stroke, % Heart failure, % Arrhythmia, % Osteoporosis, % Diabetes, % Inflammatory bowel disease, % Peptic ulcer, % Reflux/heartburn, % Depression requiring treatment, %
COPD (n ¼ 2,164)
Smoking Control Subjects (n ¼ 337)
Nonsmoking Control Subjects (n ¼ 245)
P Value
26†,‡ 9†,‡ 4x 7†,‡ 12†,x 14†,‡ 10‡ 5k 11‡ 27x 17
11 3 2 1 5 5 7 2 7x 29x 15
9 1 1 0 7 5 5 4 3 19 14
,0.001 ,0.001 0.018 ,0.001 ,0.001 ,0.001 0.003 0.127 ,0.001 0.031 0.506
Definition of abbreviation: COPD ¼ chronic obstructive pulmonary disease. * Adapted by permission from Reference 8. y P , 0.01 vs. smoking control subjects. z P , 0.01 vs. nonsmoking control subjects. x P , 0.05 vs. nonsmoking control subjects in the year before the study. k P , 0.05 vs. smoking control subjects in the year before the study.
TABLE 2. PREVALENCE OF SELF-REPORTED COMORBIDITIES AT BASELINE IN THE ECLIPSE STUDY BY GOLD STAGES OF AIRFLOW LIMITATION AND SEX* GOLD II
Heart trouble, % Heart attack, % Stroke, % Heart failure, % Arrhythmia, % Osteoporosis, % Diabetes, % Inflammatory bowel disease, % Peptic ulcer, % Reflux/heartburn, % Depression requiring treatment, %
Women (n ¼ 380)
Men (n ¼ 574)
19 5 5 4 10 28 9 9 10 36 23
GOLD III P Value
Women (n ¼ 293)
Men (n ¼ 618)
30 13 4 9 14 5 13 4
,0.001 ,0.001 0.544 0.002 0.068 ,0.001 0.079 0.003
17 6 3 3 8 32 5 6
12 29 11
0.283 0.022 ,0.001
10 30 32
GOLD IV P Value
Women (n ¼ 77)
Men (n ¼ 219)
P Value
GOLD Stage within Women
GOLD Stage within Men
30 10 3 8 15 7 10 3
,0.001 0.033 0.805 0.003 0.010 ,0.001 0.010 0.016
22 1 4 11 12 29 7 12
27 10 3 9 10 7 13 4
0.343 0.011 0.645 0.597 0.684 ,0.001 0.154 0.019
0.632 0.280 0.557 0.007 0.604 0.601 0.138 0.156
0.687 0.275 0.467 0.884 0.315 0.415 0.341 0.308
11 20 10
0.728 0.002 ,0.001
11 27 26
7 19 12
0.239 0.138 0.004
0.959 0.163 0.036
0.082 0.001 0.846
* Adapted by permission from Reference 8.
Figure 1. Hazard ratio (95% confidence interval) of death within 5-year follow-up (Cox proportional hazard model adjusted for age, sex, race, smoking status, education level, and body mass index) by severity of airflow limitation and presence of 0, 1, 2, or 3 comorbid diseases (diabetes, hypertension, or cardiovascular disease [CVD]). Reproduced with permission from reference (9). GOLD ¼ stages of airflow limitation according to the Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (40); GOLD 0 ¼ presence of respiratory symptoms with normal spirometry; Normal ¼ subjects with normal lung function for each comorbid disease; R ¼ restricted, FEV1/FVC > 0.70 and FVC , 80% reference value.
molecules (23, 24), and addressing this complexity is key for a better understanding and treatment of COPD (11, 25, 26). Results not yet published from the ECLIPSE study (8, 27) have begun to delineate the systemic “inflammome” (28) of COPD, which is the prevalence, network structure, and temporal stability of these inflammatory biomarkers in COPD. Preliminary results in this cohort show that persistent systemic inflammation is associated with significantly worse outcomes (mortality and exacerbations rate) during 3-year follow-up and that this is largely independently of the pulmonary component of the disease alluded to above, raising the possibility that systemic inflammation may be a specific therapeutic target in these patients. Contrary to early expectations (29), inhaled steroids do not seem to influence significantly systemic inflammation in COPD (30). The role of roflumilast, a novel oral phosphodiesterase-4 inhibitor (31, 32), needs to be explored in this setting. On the other hand, the use of statins (hydroxymethylglutaryl CoA reductase inhibitors), angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with COPD looks promising for pulmonary and cardiovascular outcomes (Figure 2) (33). Statins, in particular, can have substantial benefits in COPD through the following potential pathways: (1) inhibition of cytokine production (IL-6, IL-8, TNF-a, CRP) and neutrophil infiltration into the lung, (2) inhibition of small airways fibrosis, (3) antioxidant
Agustı´ and Faner: Systemic Inflammation and Comorbidities in COPD
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Figure 2. Beneficial effect of statins, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) on cardiovascular and respiratory morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). Reproduced by permission from Reference 33.
and antiinflammatory effects on skeletal muscle, (4) reduced inflammatory response to pulmonary infection, and (5) inhibition of the development (or reversal) of epithelial–mesenchymal transition, a precursor event to lung cancer (34) (see below).
LUNG CANCER AND SYSTEMIC INFLAMMATION Smoking is the main risk factor of COPD and lung cancer, but not all smokers develop COPD or lung cancer. Recent epidemiological evidence shows that the risk of developing lung cancer is higher among smokers with COPD than among smokers with normal lung function (35, 36), suggesting an interaction between COPD and lung cancer. The chronic pulmonary (and systemic) inflammation that occurs in smokers who develop COPD is a likely pathogenic candidate (7). The potential role of the persistent pulmonary inflammation that characterizes COPD is out of the scope of this presentation and is not discussed here. Numerous studies have investigated the relationship between systemic inflammation and some of the extrapulmonary manifestations of lung cancer, such as cancerrelated anorexia/cachexia (37, 38), but the potential pathogenic relationship between systemic inflammation and lung cancer has been much less investigated. Sin and colleagues showed that baseline CRP levels predicted cancer-specific mortality over 7 to 8 years of follow-up in patients with COPD (18). More recently, Pine and colleagues used logistic regression models (adjusted for smoking, stage, histology, age, and sex) to investigate the relationship between serum levels of CRP, IL-6, and IL-8 and lung cancer in 270 patients and 296 control subjects participating in the National Cancer Institute-Maryland study (39); results were later validated in 532 patients and 595 control subjects in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (39). Overall, these
investigators showed that high serum levels of IL-6 and IL-8 were indeed associated with lung cancer and that a combination of IL-8 and CRP was better than either marker alone in predicting lung cancer (39). This field of investigation deserves future work.
CONCLUSIONS Persistent systemic inflammation in COPD may be associated with a number of undesirable extrapulmonary (comorbidities) and pulmonary (lung cancer) effects. Hence, the possibility that treating systemic inflammation in patients with COPD might reduce them merits further research. Author disclosures are available with the text of this article at www.atsjournals.org.
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