Airway remodeling in subjects with severe asthma with or without chronic persistent airflow obstruction

Background

The patterns of airway remodeling and the biomarkers that distinguish different subtypes of severe asthma are unknown.

Objectives

We sought to characterize subjects with severe asthma with and without chronic persistent airflow obstruction with respect to airway wall remodeling (histopathologic and radiologic) and specific sputum biomarkers.

Methods

Subjects with severe asthma with chronic persistent (n = 16) or intermittent (n = 18) obstruction were studied. Endobronchial biopsy specimens were analyzed for airway smooth muscle area, epithelial detachment, basement membrane thickness, and submucosal fibrosis. Levels of eosinophil cationic protein, myeloperoxidase, matrix metalloproteinase 9, tissue inhibitor of matrix metalloproteinase 1 (ELISA), and 27 cytokines (multiplex assay) and differential cell counts were measured in induced sputum. Airway thickness was measured by means of high-resolution computed tomographic scanning.

Results

Chronic persistent obstruction was associated with earlier age of onset, longer disease duration, more inflammatory cells in the sputum, and greater smooth muscle area (15.65% ± 2.69% [n = 10] vs 8.96% ± 1.99% [n = 14], P = .0325). No differences between groups were found for any of the biomarker molecules measured in sputum individually. However, principal component analysis revealed that the dominant variables in the chronic persistent obstruction group were IL-12, IL-13, and IFN-γ, whereas IL-9, IL-17, monocyte chemotactic protein 1, and RANTES were dominant in the other group. Airway imaging revealed no differences between groups.

Conclusion

Subjects with severe asthma with chronic persistent obstruction have increased airway smooth muscle with ongoing T_H1 and T_H2 inflammatory responses. Neither airway measurements on high-resolution computed tomographic scans nor sputum analysis seem able to identify such patients.

Key words: Severe asthma, remodeling, airway smooth muscle, fibrosis, reticular basement membrane, inflammation, cytokines, high-resolution computed tomographic scan, biopsy, sputum

Abbreviations used: ASM, Airway smooth muscle, ATS, American Thoracic Society, CT, Computed tomography, ECP, Eosinophil cationic protein, FeNO, Fraction of exhaled nitric oxide, HRCT, High-resolution computed tomography, MCP, Monocyte chemotactic protein, MIP, Macrophage inflammatory protein, MMP, Matrix metalloproteinase, MPO, Myeloperoxidase, RBM, Reticular basement membrane, SMA, Smooth muscle area, TIMP, Tissue inhibitor of matrix metalloproteinase, WA%, Wall area percentage