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The paper by Dentener et al1 is interesting and contributes to the understanding of the pathophysiology of chronic obstructive pulmonary disease (COPD). It is becoming clear that COPD is a systemic syndrome, and this paper suggests some potential mechanisms. However, a number of issues merit further comment.
It is noted that, in healthy controls, there is a wide range of C reactive protein (CRP) values extending well beyond what would be considered to be the normal range. The reason for this is unclear, but it does suggest that these individuals are not as healthy as described. In addition, patients with stable COPD have a range of CRP values that also extend beyond this normal range. This is not consistent with previous studies, which suggests that, in patients with stable COPD, the range of CRP values falls within the normal range.2 Although patients with bronchiectasis were excluded, it is possible that undiagnosed bronchiectasis may have been present. Previous work has shown that 29% of patients presenting with what appeared to be stable COPD had CT evidence of at least mild bronchiectasis.3 This could conceivably explain a wider range of CRP levels. In addition, it is interesting that after just 5 days of treatment for an acute exacerbation of COPD the CRP had returned to a level below that of the stable cohort in the study. Since standard treatment for an exacerbation is able to achieve this in just a few days, it suggests that the stable group may have contained individuals that were in fact not so stable.
The authors allude to the potential confounding effect of systemic corticosteroids in the study. The changes in total leucocyte count during the exacerbation are likely to be due to the effect of prednisolone, making it difficult to interpret the changes in leucocyte count. In stable patients the action of corticosteroids may also confound the results. It is possible that, even in patients using inhaled corticosteroids, leucocyte numbers could be affected since there may be significant bioavailability at higher doses. Leucocyte count should therefore not be used as a marker for systemic inflammation in these patients.
Finally, it would appear that the exacerbations of COPD might have been mild, despite the presence of severe COPD on lung function criteria. Although Paco2 was slightly higher and Pao2 slightly lower than in the stable group, these differences were small in magnitude. The pH was not significantly different and, in fact, the stable group contained individuals with a lower pH (range 7.30–7.50) than in the exacerbated group (pH 7.34–7.49). Although the mean CRP level appears higher than in stable patients, the range does not differ significantly. This may therefore have led to a less profound change in inflammatory markers than might have been expected, and a study looking at more severe exacerbations may be more revealing.
Dr Kelly has some concerns about the levels of C reactive protein (CRP) in the healthy controls and patients with clinically stable COPD in our study. The control group used consisted of randomly selected subjects over 50 years of age and living in the same area as the patients. These subjects had no evidence of COPD based on questionnaires and lung function testing, did not exhibit any acute or chronic disease, and were not taking medication. Based on these selection criteria, this group was considered a healthy population control group. Although two of the 23 control subjects had enhanced CRP levels, the reason for which is unknown, they were not excluded in order to prevent bias. Non-parametric tests were used to compare the CRP levels between controls and COPD patients, and therefore the results are not affected by these two outliers.
Concerning the diagnosis of COPD, all patients in our study underwent high resolution computed tomographic scanning to exclude the presence of bronchiectasis.
There is increasing evidence that COPD is characterised by systemic effects which, among other factors, are reflected by enhanced circulating levels of inflammatory mediators in the circulation.1 In line with the observations of increased levels of the acute phase proteins CRP and lipopolysaccharide binding protein (LBP) in patients in a clinically stable condition in this study and in previous studies by our group,2 an association between increased plasma levels of the acute phase protein fibrinogen with reduced lung function and increased risk of COPD has recently been reported.3 Yasuda et al also reported enhanced CRP levels in patients with stable COPD.4 It should be noted from these studies2,4 that only part of the patient population exhibited enhanced acute phase protein levels, as was also the case in our study. This indicates that, although all patients were in a clinically stable condition, subgroups can be discriminated based upon inflammatory characteristics. This could be a factor contributing to the discrepancy between the studies by Gompertz et al5 and ours. No relationship was observed between CRP level and severity of disease,4 whereas separation of patients into normometabolic and hypermetabolic subgroups revealed enhanced levels of CRP in the latter group.2 Further research is needed to elucidate the cause for the production of these acute phase proteins in subgroups of clinically stable COPD patients and its involvement in the pathogenesis of the disease. It is of interest to note that, although only some of the clincally stable patients had enhanced CRP levels, almost all patients who had an exacerbation of disease had increased CRP levels on day 1 of the exacerbation which declined during treatment.
We agree with Dr Kelly that treatment with corticosteroids could affect the leucocyte count in patients with clinically stable COPD. As reported in our paper, increased circulating levels of leucocytes were observed in the subgroup of clinically stable COPD patients treated with oral corticosteroids compared with those who did not receive oral corticosteroids. However, comparison of subgroups of patients without corticosteroid treatment (oral or inhaled or both) with control subjects still revealed significantly increased leucocyte counts (data not shown). This indicates that the enhanced levels of circulating leucocytes are not solely due to corticosteroid use, and could be a marker of the systemic inflammatory process in COPD. In line with this hypothesis, Noguera et al reported enhanced circulating levels of polymorphonuclear cells in patients with stable COPD, none of whom had received steroids before the start of the study (oral or inhaled).6
As discussed in our paper, administration of prednisolone during treatment of an exacerbation is most probably the cause for the observed rise in leucocyte counts. In order to determine the effect an of exacerbation on leucocyte counts, studies are currently being performed in our hospital in which blood from patients with an exacerbation is collected before the start of treatment.
COPD comprises a heterogeneous group of conditions characterised by chronic airflow limitation and destruction of lung parenchyma with clinical manifestations of dyspnoea, cough, sputum production, and impaired exercise tolerance. The definition of an acute exacerbation of COPD is still imprecise, and is generally based on varying combinations of symptoms. Rodriguez-Roisin et al suggested staging COPD exacerbations based on use of health care.7 They defined three levels of severity: mild, moderate and severe. During a mild exacerbation the patient has an increased need for medication which he/she can manage in their own environment; patients with a moderate exacerbation have an increased need for medication and need to seek additional medical assistance; the patient with a severe exacerbation recognises obvious and/or rapid deterioration in his/her condition requiring admission to hospital. Based on this definition, the patients included in our study were suffering from severe exacerbations of disease. Only limited information is so far available concerning (changes of) inflammatory markers during exacerbations.
In our study the kinetics of pro- and anti-inflammatory markers have been analysed in patients with COPD during the first 7 days in hospital for an exacerbation of the disease. The results showed a significant decline in systemic levels of both CRP (at day 3) and LBP (at day 7) compared with day 1, whereas levels of the anti-inflammatory mediator soluble IL-1 receptor II dramatically increased (until day 5). This change in levels of inflammatory mediators may contribute to the clinical improvement of the patients. Additional studies are required to obtain more insight into the role of the inflammatory processes in the pathogenesis of exacerbations which could contribute to measurable parameters, in order to define the severity or outcome of disease more accurately.
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