The aim of this study was to characterise COPD patients with raised CRP levels with respect to lung function, systemic inflammation, body composition, exercise capacity, energy metabolism, and quality of life. The main findings were that, irrespective of FEV1, COPD patients with a raised plasma level of CRP had more impaired energy metabolism, increased disability as defined by impaired exercise capacity, and more distress due to respiratory symptoms than patients with normal CRP levels. In addition, patients with raised CRP levels had lower post‐bronchodilator FEV1 related to less reversibility in FEV1 after inhalation of a β agonist than patients with normal CRP levels.
Reports on the relation between CRP levels and lung function have not been consistent. Results from NHANES III excluding patients with COPD showed an inverse relation between systemic CRP and FEV1
This was also found in the Caerphilly Prospective Heart Disease Study which included only male patients with ischaemic heart disease.14
Although a smaller study did not find a correlation between CRP levels and lung function in patients with mild to severe COPD,15
CRP seems to increase with increasing severity of COPD.3,16
In this study we also found that post‐bronchodilator FEV1
and reversibility were more impaired in patients with raised levels of CRP.
Although the exact origin of systemic inflammation is unknown, lung biopsy examination clearly shows that local inflammation is more pronounced with worse lung function.17
The higher level of systemic inflammation in COPD patients with low reversibility suggests a more inflammation driven airflow limitation, although no direct data of local inflammation were obtained in our study. However, at least two other studies of patients in the stable state have not found a direct relationship between the pulmonary and systemic compartments, suggesting that pulmonary and systemic inflammation may be modulated separately.18
did not differ between the two groups, which suggests that exercise induced intermittent hypoxaemia did not differ between them. Differences in the presence of potentially pathogenic micro‐organisms (PPM) in the sputum might be another difference between the two patient groups as it has previously been shown that the presence of sputum PPM in patients with stable COPD is associated with greater systemic inflammation.19
Future studies are needed to explore the relationship between the systemic inflammatory response and the level of pulmonary inflammation.
The association between CRP and IL‐6 levels is well established. Previously, IL‐6 was identified as an “exercise factor”, being produced by contracting muscle and subsequently released into the blood. Under normal circumstances the IL‐6 gene is rapidly activated during exercise. It has been shown that IL‐6 gene transcription is mediated by the glycogen content20
and that increased IL‐6 expression is associated with increased glucose uptake during exercise.21
IL‐6 is therefore thought to act as an energy sensor in response to exercise. When contracting muscles are low in glycogen, IL‐6 is released to increase glucose uptake and induce lipolysis and gene transcription in abdominal subcutaneous fat.21
However, it has also been shown that murine myotubes express IL‐6 when exposed to oxidative stress,22
and that oral supplementation with antioxidants can attenuate exercise induced plasma IL‐6 in healthy humans.23
Fischer et al23
have shown that supplementation of vitamin C in combination with vitamin E resulted in lower exercise induced plasma IL‐6 levels, while no differences were found in muscle IL‐6 mRNA or in skeletal muscle IL‐6 protein expression. This suggests that the release of IL‐6 from the muscle was inhibited by the antioxidants.23
In COPD several changes have been reported that can influence the abovementioned process. Firstly, decreases in oxidative enzymes involved in carbohydrate and fatty acid oxidation have been reported in some patients with COPD.24
Furthermore, it has been shown that some COPD patients have impaired muscle glycogen content due to inactivity25
and have enhanced lactic acid production during cycling compared with healthy control subjects.27
Systemically, patients with COPD also have an imbalance between oxidants and antioxidants at rest and also after exercise, suggestive of increased oxidative stress.28
Moreover, Rabinovich et al29
have shown that, unlike healthy subjects, patients with COPD cannot adapt their muscle redox status to training.
We hypothesise that these changes could disturb the normal exercise induced rise in IL‐6 in COPD via an earlier and exacerbated induction of IL‐6 at a lower exercise load. IL‐6 would thus be a marker for impairment of exercise metabolism. Imbalances between oxidants and antioxidants could increase the release of IL‐6 independently of muscle intrinsic changes. Because IL‐6 is a strong inducer of acute phase proteins,30
the exacerbated increase in IL‐6 production of muscle could induce CRP, as illustrated by the strong correlation between CRP and IL‐6 in this study. Such an increase in CRP after exercise has been shown to occur in healthy subjects.23
Other studies have also shown an inverse relation between CRP and exercise capacity in healthy elderly subjects31
as well as in those with COPD.28
The increased demand for specific amino acid to generate CRP may increase muscle protein breakdown, increasing REE32
and inducing a vicious cycle of intrinsic muscle changes leading to decreased exercise capacity leading to more muscle impairment. CRP may thus be a marker of a repetitive supraphysiological increase in IL‐6 production of muscle in a subgroup of COPD patients. Previous research has also shown an association between systemic inflammation as measured by markers of the TNF system and weight loss.33
In this study we showed an association between CRP and BMI (when adjusted for post‐bronchodilation FEV1
, age, and sex) that could be attributed to FMI, but not to FFMI. The association between CRP and extent of obesity has previously been found in studies with non‐diabetic subjects.34
It has been proposed that inflammatory cytokines could be secreted by adipocytes and by inflammatory cells present in adipose tissue.35
Further research is needed to elucidate the effect of different cytokines on body composition and vice versa.
The cut off point used in this study is not the standard cut off point of 5 mg/l which is often used in clinical practice. Interestingly, our cut off point, determined as the 95th percentile of our own healthy age and sex matched controls, is very similar to the clinical cut off point. In addition, analysis using 3 or 5 mg/l as the cut off point provided the same results (data not shown).
High sensitivity CRP analysis has already been recommended for clinical application in the detection and prevention of cardiovascular disease.36
Since cardiovascular disease is a major cause of mortality in COPD,37
and CRP is a predictor of acute exacerbations of COPD,38
hospital admissions, and mortality in chronic respiratory failure39
and seems to be a marker for impaired exercise capacity and distress due to respiratory symptoms (as shown in this study), routine high sensitivity CRP analysis could prove to be of major clinical importance in COPD. Future research is needed to assess the value of CRP as a biomarker for measuring disease progress and the effects of treatment of COPD.