Dear Editor

The authors wish to thank Fimognari and colleagues for highlighting the difficult issue of defining chronic obstructive pulmonary disease (COPD). In most circumstances, a spirometric cutoff is used to define COPD, but there is no uniform consensus on what that should be and different expert panels have promulgated different spirometric cutoff values [1-4]. COPD is a disease characterized by lung inflammation and patient symptoms (most notably dyspnea). Studies have shown that the relationship between airway inflammation and patient symptoms with forced expiratory volume in one second (FEV1) is a continuum, and not threshold- dependent [5,6]. Thus, any attempts to impose FEV1 (or FEV1 to forced vital capacity, FVC, ratio) limits in defining COPD are bound to be arbitrary and contentious. Rather than relying on arbitrary cutoffs, 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 (e.g. worst FEV1 quartile to best quartile group). This method avoids imposing any arbitrary constraints in the definition of COPD and allows maximal utilization 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 wherein a FEV1 to FVC ratio was not used to define COPD (Mendall, Dahl, and Engstrom’s studies [7-9]) and re-analyzed the C-reactive protein (CRP) and fibrinogen data. Even after the exclusion of these studies, the standardized 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 standardized 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 reports [10] because the study sample was taken from the same source population as Mannino and colleague’s study [11], which was included in the meta-analysis.

Don D. Sin Wen Qi Gan S. F. Paul Man Department of Medicine, University of British Columbia, Vancouver, Canada

Ambikaipakan Senthilselvan. Department of Public Health Sciences, University of Alberta, Edmonton, Canada

References

(1) Fabbri LM, Hurd SS; GOLD Scientific Committee. Global Strategy for the Diagnosis, Management and Prevention of COPD: 2003 update. Eur Respir J. 2003; 22:1-2.

(2) The COPD Guidelines Group of the Standards of Care Committee of the British Thoracic Society. British Thoracic Society guidelines for the management of chronic obstructive pulmonary disease. Thorax. 1997;52(suppl 5):S1-S28.

(3) Siafakas NM, Vermeire P, Pride NB, et al. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). The European Respiratory Society Task Force. Eur Respir J. 1995;8:1398-420.

(4) American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1995; 152:S77-S120.

(5) Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350:2645-53.

(6) Sin DD, Jones RL, Mannino DM, Paul Man SF. Forced expiratory volume in 1 second and physical activity in the general population. Am J Med. 2004;117:270-3.

(7) Mendall MA, Strachan DP, Butland BK, et al. C-reactive protein: relation to total mortality, cardiovascular mortality and cardiovascular risk factors in men. Eur Heart J 2000;21:1584-90.

(8) Dahl M, Tybjaerg-Hansen A, Vestbo J, et al. Elevated plasma fibrinogen associated with reduced pulmonary function and increased risk of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1008-11.

(9) Engstrom G, Lind P, Hedblad B, et al. Lung function and cardiovascular risk: relationship with inflammation-sensitive plasma proteins. Circulation 2002;106:2555-60.

(10) Sin DD, Man SF. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation 2003;107:1514-9.

(11) Mannino DM, Ford ES, Redd SC. Obstructive and restrictive lung disease and markers of inflammation: Data from the third national health and nutrition examination. Am J Med 2003;114:758-62.

Dear Editor

in a recent issue of the Journal, Gan WQ et al. published a systematic review and meta-analysis of 14 reports which confirmed the strong association between COPD and biological markers of systemic inflammation [1]. In 6 reports, COPD was diagnosed according to the presence of a FEV1/FVC ratio lower than 0.7. However, in the remaining 8 studies this measure was not available, and authors assumed as affected by COPD all participants in the lowest quartile of FEV1% and, for one study [2], of FVC%. In these cases, the corresponding highest quartile group served as control. Since a COPD diagnosis based on the decreased FEV1/FVC ratio was lacking in 8 reports, the possibility cannot be excluded that a certain number of patients included in the meta-analysis did not have COPD, but a restrictive ventilatory defect. This could be particularly true for participants to the study by Engstrom [2], who were characterized only by a low FVC.

According to the current GOLD guidelines [3], only a 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 an homogenous decrease of all dynamic lung volumes (FEV1, FVC, PEF), without any alteration of FEV1/FVC ratio, and are thus considered as having “impaired lung function”. The occurrence of respiratory symptoms [4], the systemic inflammation [2] and the increased risk of cardiovascular disease [5] are the only features that restrictive subjects share with COPD. In fact, whereas COPD is characterized by a decrease in BMI and blood lipids, restrictive subjects often have abdominal obesity, insulin-resistance and other metabolic risk factors [6].

Although we believe that most of the included patients were really affected by COPD, the possible inclusion of restrictive patients may have altered the statistical conclusions of the meta-analysis. In addition, the choice of selecting patients in the lowest quartile of FEV1 or FVC hindered 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 the two groups of restrictive and COPD patients have different features, the generic term ”impaired lung function” should not be used. Future studies about the role of inflammation and other cardiovascular risk conditions in respiratory patients, as well as those investigating the outcome of these subjects, should clearly distinguish restrictive from COPD patients.

References

(1) Gan WQ, Man SFP, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 2004; 59: 574-580

(2) Engstrom G, Lind P, Hedblad B et al. Lung function and cardiovascular risk. Relationship with inflammatory-sensitive plasma protein. Circulation 2002; 106: 2555-2560

(3) Global Initiative for Chronic Obstructive Lung Disease (GOLD). Publication no. 2701. Bethesda, National Institute for Health, 2001 (2004 update).

(4) Mannino DM, Ford ES, Redd SC. Obstructive and restrictive lung disease and functional limitation: data from the Third national Health and Nutrition Examination. Journal of Internal Medicine 2003; 254: 540-547

(5) Hole DJ, Watt GC, Davey-Smith G et al. Impaired lung function and mortality risk in men and women: findings from the Renfrew and Paisley prospective population study. BMJ 1996; 313: 711-715

(6) Lawlor DA, Ebrahim S, Davey-Smith G. Associations of measures of lung function with insulin resistance and type 2 diabetes: findings from the British Women’s heart and health Study. Diabetologia 2004; 47: 195-203

(7) Sin DD, Man SFP. Why are patients with obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in Chronic Obstructive Pulmonary Disease. Circulation 2003; 107: 1514-1519