The value of C-reactive protein as a marker of systemic inflammation in stable chronic obstructive pulmonary disease

1. Introduction 

Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality throughout the world and it is the fourth leading cause of death [1]. It is the only major worldwide disorder in which the morbidity and mortality are increasing, and further increases are expected in the coming decades [2]. The airflow obstruction in COPD is also an important contributor to other common causes of morbidity and mortality, including ischemic heart disease, arrhythmias, and strokes [3]. For every 10% decrease in forced expiratory volume in one second (FEV1), cardiovascular mortality increases 28% and non-fatal coronary event increases 20% in mild-to-moderate COPD [4]. There is growing evidence that persistent low-grade systemic inflammation is present in COPD, which may contribute to the pathogenesis of atherosclerosis and cardiovascular disease [3]. Moreover, the presence of a systemic inflammatory response strongly influences the quality of life and increases mortality, leading to weight loss, muscle wasting, and tissue depletion [5], [6].

Systemic aspects of COPD include oxidative stress and altered circulating levels of inflammatory mediators and acute-phase proteins [3], [5], [6], [7], [8], [9]. C-reactive protein (CRP), an acute-phase protein synthesized predominantly by hepatocytes in response to tissue damage or inflammation, has attracted much attention recently. It reflects the total systemic burden of inflammation in several disorders including cardiovascular diseases, COPD, osteoporosis, and even depression [3], [7], [8], [9], [10]. The main clinical value of CRP is its ability to reveal early inflammation when other clinical parameters are equivocal [10]. CRP has been shown to upregulate the production of proinflammatory cytokines [11].

Tumor necrosis factor-alpha (TNF-α) has been implicated as a mediator of cachexia in such clinical conditions as cancer, chronic heart failure, and cystic fibrosis [6], [12]. Circulating levels of the proinflammatory cytokines TNF-α and interleukin-6 (IL-6) have been reported to be elevated in COPD patients [6], [8], [13]. Although the underlying mechanisms that induce and control the inflammatory process in COPD are still unknown, systemic inflammation and/or its markers may provide new therapeutic targets for COPD management.

The present cross-sectional study was designed to evaluate circulating CRP levels in order to determine the value of CRP as a biomarker of systemic inflammation and as an indicator of malnutrition or severity of COPD in stable COPD patients in comparison to the proinflammatory cytokines TNF-α and IL-6.

2. Methods 

3. Results 

The characteristics of the study population and data from the pulmonary function testing are outlined in Table 1. There was no reversibility in either subjects or controls. Sixty percent of the patients had severe or very severe COPD (FEV1 <50%) and 40% had moderate COPD (FEV1 50–80%).

Table 1. Characteristics and pulmonary function tests of COPD patients and control subjects (mean±SD)

		COPD	Controls	p
	Subjects (n)	35	30	–
	Age (years)	65.6±7.8	63.2±7.6	0.061
	BMI (kg m−2)	24.06±5.41	25.32±3.07	0.152
	Smoking (pack-years)	59.80±27.46	16.77±15.78	<0.001
	FVC (% predicted)	77.15±13.10	89.40±10.35	<0.001
	FEV1 (% predicted)	51.36±12.49	85.09±10.24	<0.001
	FEV1/FVC %	52.38±10.00	76.03±5.21	<0.001

COPD: Chronic obstructive pulmonary disease; BMI: Body mass index; FVC: Forced vital capacity; FEV1: Forced expiratory volume in one second.

Mean serum CRP, TNF-α, and IL-6 concentrations of COPD and control subjects are shown in Table 2. Serum CRP was significantly higher in stable COPD patients than in control subjects (p<0.001). A comparison of serum CRP, TNF-α, and IL-6 concentrations in COPD patients with severe and moderate airflow obstruction is given in Table 3. There was no difference in CRP level, but TNF-α was higher in the severe COPD group (p=0.046). There was no difference in serum CRP, TNF-α, or IL-6 concentrations of COPD patients on inhaled steroids and those not on inhaled steroids (p>0.05 for all). When the COPD patients with a low BMI were compared to those with a normal-to-high BMI, there was a significant difference in CRP (p=0.034) and in TNF-α (p=0.037; Table 4).

Table 2. Serum CRP, TNF-α, and IL-6 levels of COPD patients and control subjects (mean±SD)

		COPD (n=35)	Control (n=30)	p
	CRP	10.97±14.00	1.20±1.34	<0.001
	TNF-α	16.27±51.39	11.43±11.91	0.239
	IL-6	67.51±114.57	59.15±100.38	0.195

COPD: Chronic obstructive pulmonary disease; CRP: C-reactive protein (mg/L); IL-6: Interleukin-6 (pg/ml); TNF-α: Tumor necrosis factor-alpha (pg/ml).

Table 3. Comparison of serum CRP, TNF-α, and IL-6 concentrations of COPD patients with severe (Group 1, FEV1 <50%) or mild-to-moderate airflow obstruction (Group 2, FEV1≥50%) (mean±SD)

		Group 1 (n=21)	Group 2 (n=14)	p
	CRP	11.09±17.79	10.89±11.29	0.249
	TNF-α	32.87±79.69	5.21±6.40	0.046
	IL-6	75.91±142.72	54.89±52.04	0.702

COPD: Chronic obstructive pulmonary disease; FEV1: Forced expiratory volume in one second; CRP: C-reactive protein (mg/L); TNF-α: Tumor necrosis factor-alpha (pg/ml); IL-6: Interleukin-6 (pg/ml).

Table 4. Comparison of serum CRP, TNF-α, and IL-6 concentrations of COPD patients with a low BMI (Group 1, BMI<21) or a normal-to-high BMI (Group 2, BMI≥21) (mean±SD)

		Group 1 (n=23)	Group 2 (n=12)	p
	CRP	17.07±18.23	7.36±9.53	0.034
	TNF-α	23.06±64.31	4.80±4.18	0.037
	IL-6	76.12±156.64	62.42±84.61	0.617

COPD: Chronic obstructive pulmonary disease; BMI: Body mass index (kg m−2); CRP: C-reactive protein (mg/L); TNF-α: Tumor necrosis factor-alpha (pg/ml); IL-6: Interleukin-6 (pg/ml).

4. Discussion 

The present study was performed to evaluate circulating CRP levels to determine the value of CRP as a biomarker of systemic inflammation and as an indicator of malnutrition or severity of COPD in stable COPD patients in comparison to the proinflammatory cytokines TNF-α and IL-6. Serum CRP levels were found to be significantly higher in stable COPD patients than in control subjects. When serum CRP, TNF-α, and IL-6 concentrations in COPD patients with severe and moderate airflow obstruction were compared, there was no difference in CRP level, but TNF-α was higher in severe and very severe COPD patients. Moreover, CRP and TNF-α levels were found to be higher in COPD patients with a low BMI.

Patients with COPD often have extrapulmonary organ involvement related to oxidative stress and systemic inflammation [18], [19]. In the early stages of the disease, the inflammatory process, initiated mainly by components of cigarette smoke, may be self-limiting and reversible. With time, pulmonary inflammation becomes persistent and extrapulmonary manifestations become evident. The mechanism of the systemic inflammation is not yet clear, but spilling over of reactive oxygen species and cytokines from airways into the systemic circulation or peripheral liberation of proinflammatory cytokines by inflammatory and/or structural cells have been postulated [20], [21]. Liberated proinflammatory mediators amplify their effect through their action on organs like bone marrow and liver. These organs produce more white blood cells, platelets, CRP, and fibrinogen when stimulated [3]. These processes usually interact, and more than one pathway may be operational at one time.

Gan and co-workers were the first to emphasize the importance of high CRP levels in COPD patients [8], [22]. They showed elevated CRP levels in stable COPD, which also predicted cardiovascular mortality [3], [8], [23]. Studies on circulating CRP levels in COPD demonstrated that CRP was further elevated during exacerbations [24], [25], with exercise [26], and with decreases in pharmacological therapy [27], [28]; it was also found to predict mortality [23]. High-sensitivity CRP was found to be a marker of impaired energy metabolism [29]. In the present study, serum CRP level was significantly higher in COPD patients than in control subjects, confirming the low-grade systemic inflammation in the stable phase of the disease.

Increased levels of several proinflammatory cytokines have been reported in the lungs and circulation of patients with COPD [6], [8], [13]. Blood levels of IL-6 and TNF-α and their soluble receptors are found to be two to three times higher in patients with COPD [30], [31]. IL-6 is known to be a powerful signaling cytokine for CRP expression by the liver and its serum levels have been reported to correlate with CRP levels in stable COPD patients [28]. TNF is implicated as a mediator of cachexia in many clinical conditions including COPD [32], [33], [34]. Increased levels of cytokines including plasma TNF receptors were reported in a subgroup of COPD patients with increased resting energy expenditure and decreased fat-free mass [5]. Serum TNF-α level was found higher in weight-losing COPD patients, whereas it was similar in healthy controls and weight-stable patients. Increased TNF-α production was considered to be a likely cause of weight loss [31].

In the present study, serum levels of TNF-α and IL-6 were higher in COPD patients, but the difference was not statistically significant, which can be explained by the small sample size with low statistical power. We compared CRP and cytokine levels of COPD patients with a low BMI to those with a normal-to-high BMI and found a significant difference in CRP and TNF-α levels. CRP was significantly higher in COPD patients with a low BMI and thus, like TNF-α, appears to be an indicator of malnutrition.

An inverse association had been reported between circulating CRP and FEV1 [3], [35]. In the present study, we assessed whether systemic inflammation was more pronounced in COPD patients with severe airflow obstruction and found that circulating TNF-α was higher in severe or very severe COPD, whereas there was no difference in serum CRP or IL-6 concentrations. Dentener et al. also found no correlation between CRP and lung function of stable COPD patients [36]. A correlation between FEV1 and sputum levels of sTNF-α receptors and a rise in TNF-α levels in induced sputum of patients with severe COPD had been reported previously [13], [37]. According to our results, circulating TNF-α may be considered an indicator of severity of disease in GOLD stage III–IV COPD patients.

Systemic and inhaled corticosteroids were shown to reduce the systemic inflammatory state induced by COPD [27], [28]. Sin et al. investigated the effects of oral (prednisone 30 mg/day) and high-dose inhaled corticosteroids (fluticasone 1000 and 2000 μg/day) in mild-to-moderate COPD patients [28]. They found that oral corticosteroids decreased CRP levels by 71% and inhaled corticosteroids by 50%. IL-6 was also decreased by 26% with inhaled corticosteroids. Pinto-Plata et al. reported that CRP levels were about 20% lower among those who used high-dose inhaled corticosteroids (budesonide 800–1200 μg or equivalent) [38]. In the present study, we did not find any difference in serum CRP, TNF-α, or IL-6 concentrations of COPD patients on or off inhaled steroids. However, the daily dose of inhaled corticosteroids in our study (400–800 μg budesonide equivalent dose/day, which may be considered a medium dose) was lower than that in both of these studies.

In summary, the present study confirms that circulating CRP levels are higher in stable COPD patients; consequently, they may be regarded as a valid biomarker of low-grade systemic inflammation. Moreover, CRP is significantly higher in COPD patients with a low BMI and thus, like TNF-α, may be considered an indicator of malnutrition in COPD patients. However, since our study population was limited in size, these conclusions should be confirmed by further studies.

5. Learning points