In this study we confirm that CRP levels are raised in patients with moderate to severe COPD. This increase seems to be independent of clinically significant IHD. It was also independent of cigarette smoking and reduced in patients using ICS, probably reflecting the systemic inflammatory process in patients with severe disease.
Several epidemiological studies have found a significant relationship between pulmonary function and cause specific mortality due to IHD.9,10,11,12
Sin and Man,11
using population based data from NHANES III, studied 6629 patients including 2070 with mild, moderate, and severe COPD. Using a low sensitivity CRP assay (lowest detectable level 0.22 mg/dl) and a coding scheme to calculate a cardiac infarction injury score with a resting ECG, they concluded that moderate and severe COPD was associated with a higher level of CRP and increased occurrence of ischaemic changes on the ECG. Similarly, Mannino and co‐workers,12
also using data from NHANES III, described an association between the severity of COPD and the level of CRP. A recognised limitation of both studies is that participants might have had undiagnosed or asymptomatic IHD that is associated with lower levels of pulmonary function and a high short term mortality risk.9,21
Our study expands these observations. Firstly, we excluded the presence of clinically significant or subclinical IHD using a comprehensive medical examination and exercise test with continuous ECG monitoring instead of a resting ECG alone.11
We also excluded other conditions associated with increased CRP levels including acute and chronic infection, chronic inflammatory diseases (rheumatological, gastrointestinal) and known malignancies. A follow up questionnaire and physical examination more than 1 year after the initial examination further excluded the possibility that any of these conditions were responsible for the increased level of CRP. Secondly, we used a high sensitivity CRP test to obtain more accurate values than in the two previous studies.11,12
We observed no difference in the mean CRP level between control smokers and non‐smokers, despite the fact that the former group was younger than the latter. Similarly, there was no difference among the patients with COPD who were current smokers and those who were ex‐smokers. These findings may be due to a lack of power to determine a difference between the two groups, the absence of an inflammatory response in the smokers, or persistent inflammation in COPD patients even after smoking cessation as seen in human lung samples.22
A recent study23
did report an association between cigarette smoking and a high CRP concentration (p<0.001), but the data were not shown. In that study it was unclear if COPD was ruled out in the group of smokers who had a raised CRP level. The observation that CRP levels did not differ between smoker and non‐smoker controls, and between smoker and ex‐smoker patients with COPD, also suggests that the increase in CRP levels may represent a phenotype of CRP responders. Little is known about the reason why some persons exposed to cigarette smoke develop clinically important COPD whereas others do not. We speculate that there may be individuals with an “inherited” inflammatory genetic profile (a proportion of our control never smoker population had CRP levels above 3 mg/l). If they are “exposed” to environmental factors (such as smoking or pollution), they have a higher risk of developing COPD.
Although our study fails to provide a mechanism, it does point out that the differences may precede the exposure to the trigger (cigarette smoking). It would be extremely interesting to determine CRP levels in teenagers before or around the time they begin to smoke to gain some insight into the presence in the general population of possible “inflammatory” phenotypes.
The CRP level in patients with COPD was lower in ICS users than in non‐users (fig 4). These results are in agreement with a recent publication by Sin et al13
in which they showed that withdrawal of ICS from patients with mild and moderate disease was associated with a 71% increase in the baseline CRP level. It would be interesting to study larger groups of patients with COPD treated with ICS24,25
or withdrawn from ICS26
to determine if the changes in the number of COPD exacerbations and quality of life observed in those studies correlate with changes in the CRP level.
The mean CRP level in the patients with COPD in our study was similar to that reported by Mannino et al
It contrast, the values reported in epidemiological studies of controls and patients who eventually developed IHD is at least three times lower.23
This finding further supports the concept that the increase in the CRP level in patients with severe COPD cannot be attributed only to concomitant IHD. CRP is a marker of systemic inflammation and has been associated with an increased risk of incident myocardial infarction and stroke.6,8
As suggested by others,11,13
it is possible that the persistent systemic inflammation in patients with COPD may contribute to the pathogenesis of atherosclerosis and cardiovascular disease and explain a high risk of cardiovascular mortality in patients with mild and moderate COPD. If we use the CRP levels of <1, 1–3 and >3 mg/l to represent low, moderate and high risk groups for future cardiovascular events,6,19,20
almost 60% of the COPD patients in our study would be categorised as high risk (data not shown).
One important finding of our study is that the CRP level remained unchanged in the majority of patients retested after adjustment for age, sex, BMI, and FEV1
% predicted. This finding is in agreement with a recent report23
that included 379 patients who provided paired blood samples for CRP analysis with a mean time between samples of 12 years and a within person correlation of 0.59 (95% CI 0.52 to 0.66). Similar correlations have also been reported in other studies of normal subjects,27
and we have now reported it in patients with COPD.
There was no association between selected pulmonary function test measurements (FEV1, Tlco) and CRP levels in COPD patients. A probable explanation is that our study was limited to patients with moderate to severe disease in whom the narrow range of these parameters probably failed to show any association. However, we found an association between the CRP level and the BMI and 6MWT that may prove clinically important. These clinical parameters probably reflect the systemic effects of COPD, and the CRP level is a measure of the systemic inflammation observed in patients with COPD.
Our study has some limitations. The patients with COPD included in the cohort were selected and therefore excluded patients in the community with milder forms of the disease. There were patients with known IHD in the COPD and control groups, but there was no difference in the mean CRP level when these patients were excluded. We carefully sought to exclude clinically important IHD, the biggest confounder of the studies published to date. The patients studied underwent a complete medical interview, a physical examination, and a cardiopulmonary exercise test with ECG monitoring to rule out possible unstable IHD and those with “silent” or subclinical IHD. However, the sensitivity and specificity of the exercise test in asymptomatic patients is unknown and may never be known because a coronary angiography, the “gold standard” for diagnosing coronary artery disease, is not indicated in asymptomatic patients.28
Patients with a recent acute exacerbation of COPD, arthritis, clinical evidence of acute or chronic infection, or other chronic inflammatory process were also excluded from the analysis. Our findings are in agreement with the larger epidemiological studies and serve to complement them. Finally, even though a large proportion of patients with COPD die from cardiac causes,13
many will die from COPD.5
To state simply that concomitant heart disease is the reason for the increased CRP levels in patients with COPD may not fully explain the findings reported here and may underestimate its importance as an independent biomarker of COPD.
In conclusion, we have confirmed that CRP levels are significantly raised in patients with COPD and this increase is not related to smoking per se or to concomitant clinical or subclinical IHD. The CRP level remains stable over time in normal individuals and in patients with COPD, and was lower in patients treated with ICS.