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Small Airways Dysfunction and Neutrophilic Inflammation in Bronchial Biopsies and BAL in COPD^*

Thérèse S. Lapperre, MD; Luuk N. A. Willems, MD, PhD; Wim Timens, MD, PhD; Klaus F. Rabe, MD, PhD; Pieter S. Hiemstra, MSc, PhD; Dirkje S. Postma, MD, PhD; Peter J. Sterk, MD, PhD; the GLUCOLD Study Group

^* From the Department of Pulmonology (Drs. Lapperre, Willems, Rabe, Hiemstra, and Sterk), Leiden University Medical Center, Leiden; and Departments of Pulmonology (Dr. Postma) and Pathology (Dr. Timens), Groningen University Medical Center, Groningen and Leiden, the Netherlands. A list of GLUCOLD study members is given in the ^Appendix.

Correspondence to: Thérèse S. Lapperre, MD, Lung Function Lab, C2-P, Department of Pulmonology, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, NL-2300 RC Leiden, the Netherlands; email: t.s.lapperre{at}lumc.nl

Abstract

Background: The single-breath N₂ test (sbN₂-test) is closely related to small airways pathology in resected lung specimens of smokers. We investigated whether uneven ventilation and airway closure are associated with specific markers of airway inflammation as obtained by bronchial biopsies, BAL, and induced sputum in patients with manifest COPD.

Methods: Fifty-one patients with stable COPD not receiving corticosteroids were examined in a cross-sectional study (43 men; mean [SD] age, 63 ± 8 years; exsmokers and smokers; median pack-years, 41 [interquartile range, 31 to 51 pack-years]). Postbronchodilator spirometry (FEV₁, 63 ± 8% of predicted) and sbN₂-test (slope of phase III [N₂], closing capacity [CC]/total lung capacity [TLC] percentage of predicted) were performed. Inflammatory cell counts were assessed in bronchial biopsies, BAL (only in the first half of patients), and induced sputum. Neutrophil elastase (NE), secretory leukocyte proteinase inhibitor (SLPI), and interleukin-8 levels were determined in BAL fluid.

Results: N₂ increased with subepithelial neutrophil numbers in bronchial biopsies (rs = 0.337, p = 0.017) and with NE levels (rs = 0.443, p = 0.039), NE/neutrophil ratio (rs = 0.575, p = 0.005) and SLPI levels (rs = 0.484, p = 0.022) in BAL. CC/TLC was associated with BAL neutrophil numbers (rs = 0.448, p = 0.048). The sbN₂-test was not associated with any other inflammatory cell type in BAL or biopsies, nor with inflammatory cell counts in sputum. Of importance, the correlations between N₂ and BAL NE/neutrophil ratio, and between CC/TLC and BAL neutrophil numbers remained significant when adjusting for FEV₁ percentage of predicted.

Conclusions: The results of the sbN₂-test are associated with neutrophilic inflammation in bronchial biopsies and BAL in patients with COPD. Our findings support a role of neutrophilic inflammation in the pathogenesis of small airways dysfunction in COPD.

Key Words: airway closure • COPD • induced sputum • neutrophil elastase • neutrophils • secretory leukocyte proteinase inhibitor • single-breath nitrogen washout test • uneven distribution of ventilation