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Dissociation of Lung Function and Airway Inflammation in Chronic Obstructive Pulmonary Disease: Is It a Real or Statistical Phenomenon?
To the Editor.
We read with interest the article by Lapperre and colleagues (1) wherein it is concluded that "airflow limitation, airway inflammation, and features commonly associated with asthma are separate and largely independent factors in the pathophysiology of COPD." This statement seems to be much too definitive, considering the limitations of the study.
First, the conclusions are based entirely on the factor analysis. The literature data (2, 3), as well as our experience with this analysis (4), indicate that results are highly dependent on the selected set of variables, the relationships between them (linear or nonlinear), and the criteria used about factor structure, and suggest that one should be very careful in their interpretation.
Second, the study is cross-sectional, not longitudinal, which, combined with the heterogeneity of multifaceted chronic obstructive pulmonary disease (COPD), and a variable natural history of the individual disease (5), might be another reason for the authors to arrive at the conclusion about the dissociation of lung function and airway inflammation.
Relationships between airway inflammation and lung function in COPD do exist, but they are not simple and easily detectable, because even the exacerbations are associated with a lower and more variable inflammatory response than those in patients with asthma (6).
These considerations do not diminish the importance of the findings of Lapperre and colleagues (1) regarding the multi- dimensional profile of COPD and necessity for comprehensive evaluation of the disease.
Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
STEFAN KOSTIANEV
BLAGOI MARINOV
Medical University of Plovdiv
Plovdiv, Bulgaria
References
1. Lapperre TS, Snoeck-Stroband JB, Gosman MME, Stolk J, Sont JK, Jansen DF, Kerstjens HAM, Postma DS, Sterk PJ, and the Glucold Study Group. Dissociation of lung function and airway inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:499-504.
2. Mardia KV, Kent JT, Bibby JM. Factor analysis. In: Mardia KV, Kent JT, Bibby JM, editors. Multivariate analysis. London, UK: Academic Press; 1979. pp. 255-280.
3. Lawlor DA, Ebrahim S, May M, Davey Smith G. (Mis)use of factor analysis in the study of insulin resistance syndrome. Am J Epldemiol 2004;159:1013-1018.
4. Kostianev SS, Hodzhev VA, Todorov IT, Hristova AS, Mandulova PV, Iluchev DH. A factor analysis of dyspnea indexes and lung function parameters in patients with chronic obstructive pulmonary disease. Folia Med (Plovdiv) 2001;43:27-31.
5. Celli BR, MacNee W, and Committee Members. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ ERS position paper. Eur Respir J 2004;23:932-946.
6. Bhowmik A, Seemungal TAR, Sapsford RJ, Wedzicha JA. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax 2000;55:114-120.
From the Authors:
We thank Drs. Kostianev and Marinov for their letter discussing some of the potential limitations of our study, thereby questioning our conclusion that "airflow limitation, airway inflammation, and features commonly associated with asthma are separate and largely independent factors in the pathophysiology of COPD" (1).
We fully agree that the results of factor analysis are dependent on the selected set of variables (2), and we purposely addressed this in the article. For this reason, we also performed additional factor analyses, including different sets of variables, such as pack- years smoked, or neutrophil and eosinophil numbers instead of percentages. As mentioned in the article, these additional analyses resulted in similar factor structures, all suggestive of the independence of inflammatory and functional variables. Nevertheless, repeating the analysis with inclusion of more direct markers of airway inflammation known to be involved in chronic obstructive pulmonary disease (COPD), such as CD8^sup +^ lymphocytes, B lymphocytes, or macrophages in the airway wall or parenchyma, may be very valuable. However, histology was not available when we performed the present analysis. We would like to emphasize that standard criteria about factor structure were applied. However, the factor structure does not exclude associations between parameters in different factors. As shown in the article, there were linear relationships between some of the functional and inflammatory markers in our study.
We performed the factor analysis on cross-sectional data of a large group of well-characterized patients. Because exacerbations do indeed influence the inflammatory response, the measurements were postponed if patients experienced a respiratory tract infection within the previous 2 weeks, or an exacerbation requiring oral steroids within the previous 2 months. The patients are presently being followed up longitudinally for 2.5 years, and we intend to monitor the variables included in the factor analysis during this period. We agree with Drs. Kostianev and Marinov that longitudinal studies are needed to investigate whether changes in lung function are associated with changes in inflammation in COPD. We hope to be able to report on this in the future.
Factor analysis is an exploratory analysis, serving to generate hypotheses rather than testing them. Our results do suggest that, although there are univariate linear correlations between functional and inflammatory parameters in stable COPD (as have been reported by many others [3]), these entities represent different dimensions in the pathophysiology of COPD. This may have consequences for the development of therapy, which seems to require more than an antiinflammalory strategy alone.
Conflict of Interest Statement: T.S.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; P.J.S. is a member of the Department of Pulmonology at Leiden University Medical Center, which has received grants from AltanaPharma ($222,616), Novartis ($90,640), Bayer ($61,762), AstraZeneca ($113,155), Pfizer ($406,000), Merck, Sharp & Dohme ($118,000), Exhale Therapeutics ($90,000), and GlaxoSmithKline ($299,495) in 2001-2004.
THRSE S. LAPPERRE
PETER, J. STERK
Leiden University Medical Center
Leiden, The Netherlands
References
1. Lapperre TS, Snoeck-Stroband JB, Gosman MM, Stolk J, Sont JK, Jansen DF, Kerstjens HA, Postma DS, Sterk PJ, and the Glucold Study Group. Dissociation of lung function and airway inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:499-504.
2. Stevens J. Exploratory and confirmatory factor analysis. In: Stevens J, editor. Applied multivariate statistics for the social sciences. Mahwah, NJ: Lawrence Erlbaum Associates; 1996. pp. 362- 428.
3. Barnes PJ, Shapiro SD, Pauwels RA. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J 2003;22:672-688.
Copyright American Thoracic Society Jun 1, 2005
Source: American Journal of Respiratory and Critical Care Medicine
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