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In a recent issue of Thorax Gan et al1 published a systematic review and meta-analysis of 14 reports which confirmed the strong association between COPD and biological markers of systemic inflammation. In six reports COPD was diagnosed by the presence of a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC ratio) lower than 0.7. However, in the remaining eight studies this measure was not available, and the authors assumed that all participants in the lowest quartile of FEV1% (and, in one study,2 of FVC%) had a diagnosis of COPD. In these cases the corresponding highest quartile group served as control. Since a COPD diagnosis based on a decreased FEV1/FVC ratio was lacking in eight reports, the possibility cannot be excluded that a certain number of patients included in the meta-analysis did not have COPD but, rather, a restrictive ventilatory defect. This could be particularly true for participants in the study by Engstrom et al2 who were characterised only by a low FVC.
According to the current GOLD guidelines,3 only an FEV1/FVC ratio lower than 0.7 indicates airflow obstruction, thus allowing a COPD diagnosis. Indeed, in the absence of particular pulmonary diseases, many subjects show a homogenous decrease in all dynamic lung volumes (FEV1, FVC, PEF) without any change in the FEV1/FVC ratio, and are thus considered to have “impaired lung function”. The occurrence of respiratory symptoms,4 systemic inflammation,2 and the increased risk of cardiovascular disease5 are the only features that subjects with restrictive disease share with COPD. In fact, whereas COPD is characterised by a decrease in body mass index and blood lipids, subjects with restrictive disease often have abdominal obesity, insulin resistance, and other metabolic risk factors.6
Although we believe that most of the included patients were affected by COPD, the possible inclusion of patients with restrictive lung disease may have altered the statistical conclusions of the meta-analysis.
In addition, the decision to select patients in the lowest quartile of FEV1 and FVC prevented the authors from confirming the absence of inflammation in mild COPD (GOLD stage I and II), a finding previously reported by the same group in a study not included in this meta-analysis.7
Because patients with restrictive lung disease and those with COPD have different features, the generic term “impaired lung function” should not be used. Future studies of the role of inflammation and other cardiovascular risk conditions in patients with respiratory disease, and those investigating the outcome in these subjects, should clearly distinguish between these two groups of patients.
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Authors’ reply
We wish to thank Dr Fimognari and colleagues for highlighting the difficult issue of defining chronic obstructive pulmonary disease (COPD). In most circumstances a spirometric cut off is used to define COPD, but there is no uniform consensus on what that should be and different expert panels have promulgated different spirometric cut off values.1–4 COPD is a disease characterised by lung inflammation and patient symptoms (most notably dyspnoea). Studies have shown that the relationship between airway inflammation and patient symptoms with forced expiratory volume in 1 second (FEV1) is a continuum and is not threshold dependent.5,6 Thus, any attempts to impose FEV1 (or the ratio of FEV1 to forced vital capacity (FVC)) limits in defining COPD are bound to be arbitrary and contentious. Rather than relying on arbitrary cut off values for large population based studies, it is reasonable (and useful) to compare the outcome of interest—in this case, systemic inflammation—between extremes of FEV1 (that is, worst FEV1 quartile to best quartile group). This method avoids imposing any arbitrary constraints in the definition of COPD and allows maximal utilisation of the data points. However, a potential limitation of this approach is the possibility of diagnostic misclassification between restrictive and obstructive lung diseases. To specifically address this concern, we excluded population based studies in which a FEV1/FVC ratio was not used to define COPD7–9 and reanalysed the C-reactive protein (CRP) and fibrinogen data. Even after the exclusion of these studies, the standardised mean difference in the CRP level between COPD and control subjects was 0.68 units (95% confidence interval (CI) 0.38 to 0.98) or 4.85 mg/l (95% CI 1.92 to 7.78). For the fibrinogen data, the standardised mean difference between COPD and control subjects was 0.48 units (95% CI 0.43 to 0.54) or 0.42 g/l (95% CI 0.00 to 0.84). These results indicate that the possible contamination of individuals with restrictive defect in the groups with low FEV1 or FVC did not influence the overall findings. Finally, we did not include data from one of our previous reports10 because the study sample was taken from the same source population as the study by Mannino and colleagues11 which was included in the meta-analysis.