Evaluation of C-Reactive Protein in Patients with Chronic Obstructive Pulmonary Disease

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is associated with evidence of systemic oxidative stress, activation of circulating inflammatory cells and increased plasma level of proinflamatory cytokines which include C-reactive protein (CRP). CRP is one biomarker of extrapulmonary or systemic consequences of COPD that can be detected. AIM: The aim of this research is to determine whether the level of CRP statistically significantly correlates with the level of bronchial obstruction and the accompanying co-morbidities in patients with COPD. MATERIAL AND METHODS: This study included 80 patients with exacerbation of COPD, hospitalised at the Institute for Lung Diseases and Tuberculosis in Skopje. We measured the level of CRP in the blood in all of these patients in fasting conditions. The classification of COPD patients by the severity of airflow limitation was made according to the actual version of the Global initiative for chronic Obstructive Lung Disease (GOLD). The Student’s Independent Samples t-test was used for the statistic analysis of the data. RESULTS: In 52 (65%) of the patients with exacerbation of COPD we detected an increase of the mean value of CRP. The statistical analysis using the Student’s t-test showed statistically significant differences in the mean value of CRP in patients with different level of bronchial obstruction. Hypertension, heart failure, diabetes mellitus, hyperlipidemia, coronary disease, and CVI were confirmed as co-morbidities in 45 (73.1%) of the patients, hypertension being the most frequent one (40%). The statistical analysis using the Student’s t-test showed statistically significant difference of the mean value of CRP (p< 0.01) depending on the number of co-morbidities. CONCLUSION: In 52 (65%) of the patients with exacerbation of COPD, were detected an increase of the mean value of CRP. The mean values of CRP statistically significantly correlate with the level of bronchial obstruction and the number of co-morbidities in patients with COPD.


Introduction
Chronic Obstructive Pulmonary Disease (COPD) is a major cause of chronic morbidity and mortality throughout the world [1]. It is primarily characterized by the presence of airflow limitation resulting from airways inflammation and remodelling often associated with parenchymal destruction and development of emphysema [2].
Increasing evidence suggests that COPD is a complex disease involving more than airflow obstruction [1].
In many patients the disease is associated with several systemic manifestations that can effectively result in impaired functional capacity, worsening dyspnea, and reduced health-related quality of life [2,3]. The most common manifestations include the presence of concomitant cardiovascular compromise, diabetes, malnutrition involving primary the loss and dysfunction of skeletal muscles, osteoporosis, clinical depression and anxiety [3][4][5][6]. Currently, the GOLD definition of COPD includes the words "some significant extrapulmonary effects that may contribute to the severity in individual patients". It has suggested that COPD should be renamed a "chronic systemic inflammatory syndrome" [7,8]. COPD is associated with evidence of systemic oxidative stress, activation of circulating inflammatory cells and increased plasma level of proinflamatory cytokines which include C-reactive protein (CRP), IL-6, fibrinogen, leucocytes and TNF [3,5,7,9].
Patients with COPD have higher circulating levels of IL-6 [2,7]. This cytokine is a potent stimulator of CRP production by the liver and may account for the increase in circulating CRP found in patients with COPD [2]. It is an acute-phase protein synthesized predominantly by the hepatocytes in response to tissue damage or inflammation reflecting the total systemic burden of inflammation of individuals [5]. CRP is one biomarker of extrapulmonary or systemic consequences of COPD that can be detected clinically and that could also be measured.
The aim of this research is to determine whether the level of CRP in patients with COPD statistically significantly correlates with the level of bronchial obstruction and the accompanying comorbidities.

Material and Methods
This study included 80 patients with exacerbation of COPD, hospitalised at the Institute for Lung Diseases and Tuberculosis. Out of these 80 patients, 48 were male and 32 were female. We measured the level of CRP in the blood in all of these patients in fasting conditions. The classification of COPD patients by the severity of airflow limitation was made according to the actual version of the Global initiative for chronic Obstructive Lung Disease (GOLD) i.e. GOLD 1, GOLD 2, GOLD 3 and GOLD 4 (mild, moderate, severe, very severe airways obstruction) [8].

Results
The mean values of CRP in patients with different level of bronchial obstruction are shown in Table 2. The statistical analysis conducted using the Student's t-test showed significant statistical differences in the mean values of CRP in patients with different level of bronchial obstruction. The highest mean value of CRP was registered in patients with very severe bronchial obstruction (GOLD 4).
The frequency and distribution of comorbidities in patients with COPD is shown in Figure  1. The mean values of CRP in correlation with the number of co-morbidities are shown in Table 3. The statistical analysis conducted using the Student's t-test showed statistically significant increase of the mean value of CRP (p< 0.01) in correlation with the number of co-morbidities.

Discussion
COPD is a complex disease involving more than airflow obstruction [1]. COPD is associated with evidence of systemic oxidative stress, activation of circulating inflammatory cells and increased plasma level of proinflamatory cytokines. Individuals with COPD had significantly raised levels of several markers of inflammation which include C-reactive protein (CRP), IL-6, fibrinogen, leucocytes and TNF [2-5, 7, 9, 10]. Our retrospective study also registers increase of the mean value of CRP in 52 (65 %) of the patients.
Rennard and his associates [2] reported on the relationship between FEV1 and levels of various systemic inflammatory markers such as CRP. This analysis indicated that reduced lung function significantly correlated with the elevated levels of systemic inflammatory markers.
Nillawar and his associates [10], in their study carried out with 45 patients with COPD, point out that there is statistically significant increase of the value of CRP, whose mean value of FEV 1 was 45.27 % +/-15%. In our study, in 52 (65%) of the patients with exacerbation of COPD, were detected an increase of the mean value of CRP.
The statistical analysis of the mean values of CRP using the Student's t-test showed statistically significant increase of the mean values of CRP in correlation with the level of bronchial obstruction (Р < 0.05; P < 0.01).
In many patients, COPD is associated with several systemic manifestations that can effectively result in impaired functional capacity, worsening dyspnoea, and reduced health-related quality of life [2,3]. In our study, hypertension, hеart failure, diabetes mellitus, hyperlipidaemia, coronary disease, CVI were confirmed as co-morbidities in 45 (73.1%) of the patients, hypertension being the most frequent one (40%).
Several studies have demonstrated a strong relationship between COPD and cardiovascular disease with COPD patients having a two-fold increase in risk for morbidity and mortality due to a cardiovascular disease [5,10,11]. The underlying mechanism is still not fully understood. However, COPD is recognized as a systemic inflammation which might extend beyond the lungs causing other co-morbidities. Consequently, the inflammatory state in patients with COPD might lead to the development of atherosclerosis, which is also known as an inflammatory process. It is thought that the inflammation observed in COPD patients plays a significant role in the pathogenesis of atherosclerosis. Furthermore, in patients with both COPD and cardiovascular disease, increasing C-reactive protein levels are present, which confirms the presence of a systemic inflammation [12]. The relationship between COPD, systemic inflammation and a cardiovascular disease is of particular importance, since more than one half of all patients with COPD die due to cardiovascular causes.
Rutten and his associates [13] point out that 20% of the patients with COPD had a non-diagnosed left-sided heart failure. Our study also demonstrates 23% of left-sided heart failure in patients with COPD.
Leonardo and his associates [14] indicate that 20% of the patients had left-sided heart weakness, and 50% of the patients had one or more components of metabolic syndrome. According to data, the prevalence of diabetes in COPD varies from 2% (Sidney [15]), 12% (Mapel and associates [16]) to 16% (Wash and Thomasov [17]). In our study, we registered hyperlipidemia in 12.5%, and diabetes in 15% of the patients. The systematic inflammation accounts for the connection between COPD and diabetes mellitus type 2. The diabetes is independently associated with reduction of the lung function, and the frequently common obesity may additionally deteriorate the clinical picture in patients with COPD. Recent studies suggest that raised level of CRP, IL 6 and TNF result in alteration of the metabolic processes and resistance to insulin.
In our study, too, the statistical analysis conducted with the Student's t-test, demonstrated statistically significant increase of the mean value of CRP (p < 0.01) depending on the number of comorbidities.
In conclusion, in 52 (65%) of the patients with exacerbation of COPD, were detected an increase of the mean value of CRP. The mean values of CRP statistically significantly correlate with the level of bronchial obstruction and the number of comorbidities in patients with COPD.