@article{547b28121bd14101a67edfc7831e9844,
title = "Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction",
abstract = "Background. The link between mucus plugs and airflow obstruction has not been established in chronic severe asthma, and the role of eosinophils and their products in mucus plug formation is unknown. Methods. In clinical studies, we developed and applied a bronchopulmonary segment-based scoring system to quantify mucus plugs on multidetector computed tomography (MDCT) lung scans from 146 subjects with asthma and 22 controls, and analyzed relationships among mucus plug scores, forced expiratory volume in 1 second (FEV1), and airway eosinophils. Additionally, we used airway mucus gel models to explore whether oxidants generated by eosinophil peroxidase (EPO) oxidize cysteine thiol groups to promote mucus plug formation. Results. Mucus plugs occurred in at least 1 of 20 lung segments in 58% of subjects with asthma and in only 4.5% of controls, and the plugs in subjects with asthma persisted in the same segment for years. A high mucus score (plugs in ≥ 4 segments) occurred in 67% of subjects with asthma with FEV1 of less than 60% of predicted volume, 19% with FEV1 of 60%-80%, and 6% with FEV1 greater than 80% (P < 0.001) and was associated with marked increases in sputum eosinophils and EPO. EPO catalyzed oxidation of thiocyanate and bromide by H2O2 to generate oxidants that crosslink cysteine thiol groups and stiffen thiolated hydrogels. Conclusion. Mucus plugs are a plausible mechanism of chronic airflow obstruction in severe asthma, and EPO-generated oxidants may mediate mucus plug formation. We propose an approach for quantifying airway mucus plugging using MDCT lung scans and suggest that treating mucus plugs may improve airflow in chronic severe asthma.",
author = "{The National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP)} and Dunican, {Eleanor M.} and Elicker, {Brett M.} and Gierada, {David S.} and Nagle, {Scott K.} and Schiebler, {Mark L.} and Newell, {John D.} and Raymond, {Wilfred W.} and Lachowicz-Scroggins, {Marrah E.} and {Di Maio}, Selena and Hoffman, {Eric A.} and Mario Castro and Fain, {Sean B.} and Jarjour, {Nizar N.} and Elliot Israel and Levy, {Bruce D.} and Erzurum, {Serpil C.} and Wenzel, {Sally E.} and Meyers, {Deborah A.} and Bleecker, {Eugene R.} and Phillips, {Brenda R.} and Mauger, {David T.} and Gordon, {Erin D.} and Woodruff, {Prescott G.} and Peters, {Michael C.} and Fahy, {John V.} and Patricia Noel and Robert Smith",
note = "Funding Information: We thank the volunteers who participated in these studies and Patricia Noel and Robert Smith from the Division of Lung Diseases, NHLBI, for their support and leadership of the SARP. We thank the investigators and coordinators in the SARP who contributed to this manuscript by recruiting and characterizing participants, collecting biospecimens, developing systems for lung imaging and analysis, and coordinating data collection and analysis (see Supplemental Acknowledgments). Additional acknowledgments and details of grant funding sources from the National Institutes of Health is also provided in the Supplemental Acknowledgments. Funding Information: Conflict of interest: E.M. Dunican, B.M. Elicker, D.S. Gierada, S.K. Nagle, M.L. Schiebler, J.D. Newell, and J.V. Fahy are listed as inventors on a provisional patent application (WO2017197360 A1) related to the development and application of the mucus score (Dunican score) as a biomarker and companion diagnostic tool in pulmonary disease. Role of funding source: This study was funded by the NIH and the National Center for Advancing Translational Sciences. The funding organization had no role in study design, data collection, analysis and interpretation of data, decision to publish, or preparation of the manuscript. Submitted: June 21, 2017; Accepted: December 19, 2017. Reference information: J Clin Invest. 2018;128(3):997–1009. https://doi.org/10.1172/JCI95693. Publisher Copyright: {\textcopyright} 2018 Blackwell Publishing Ltd. All rights reserved.",
year = "2018",
month = mar,
day = "1",
doi = "10.1172/JCI95693",
language = "English",
volume = "128",
pages = "997--1009",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
number = "3",
}