Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction
Eleanor M. Dunican, Brett M. Elicker, David S. Gierada, Scott K. Nagle, Mark L. Schiebler, John D. Newell, Wilfred W. Raymond, Marrah E. Lachowicz-Scroggins, Selena Di Maio, Eric A. Hoffman, Mario Castro, Sean B. Fain, Nizar N. Jarjour, Elliot Israel, Bruce D. Levy, Serpil C. Erzurum, Sally E. Wenzel, Deborah A. Meyers, Eugene R. Bleecker, Brenda R. Phillips, David T. Mauger, Erin D. Gordon, Prescott G. Woodruff, Michael C. Peters, John V. Fahy, The National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP)
Eleanor M. Dunican, Brett M. Elicker, David S. Gierada, Scott K. Nagle, Mark L. Schiebler, John D. Newell, Wilfred W. Raymond, Marrah E. Lachowicz-Scroggins, Selena Di Maio, Eric A. Hoffman, Mario Castro, Sean B. Fain, Nizar N. Jarjour, Elliot Israel, Bruce D. Levy, Serpil C. Erzurum, Sally E. Wenzel, Deborah A. Meyers, Eugene R. Bleecker, Brenda R. Phillips, David T. Mauger, Erin D. Gordon, Prescott G. Woodruff, Michael C. Peters, John V. Fahy, The National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP)
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Clinical Research and Public Health Pulmonology

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. TRIAL REGISTRATION. Clinicaltrials.gov NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01759186, NCT01716494, and NCT01760915. FUNDING. NIH grants P01 HL107201, R01 HL080414, U10 HL109146, U10 HL109164, U10 HL109172, U10 HL109086, U10 HL109250, U10 HL109168, U10 HL109257, U10 HL109152, and P01 HL107202 and National Center for Advancing Translational Sciences grants UL1TR0000427, UL1TR000448, and KL2TR000428.

Authors

Eleanor M. Dunican, Brett M. Elicker, David S. Gierada, Scott K. Nagle, Mark L. Schiebler, John D. Newell, Wilfred W. Raymond, Marrah E. Lachowicz-Scroggins, Selena Di Maio, Eric A. Hoffman, Mario Castro, Sean B. Fain, Nizar N. Jarjour, Elliot Israel, Bruce D. Levy, Serpil C. Erzurum, Sally E. Wenzel, Deborah A. Meyers, Eugene R. Bleecker, Brenda R. Phillips, David T. Mauger, Erin D. Gordon, Prescott G. Woodruff, Michael C. Peters, John V. Fahy, The National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP)

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Figure 2

Development and distribution of the CT mucus score in asthma patients and healthy subjects.

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Development and distribution of the CT mucus score in asthma patients an...
(A) Mucus plug with branching (yellow arrow) seen in longitudinal section is identified as a tubular opacification (frontal plane). (B) Mucus plug (yellow arrow) with extensive branching seen in longitudinal section (transverse plane). (C) Mucus plug (yellow arrow) seen in cross-section is identified as rounded opacification (transverse plane). (D) Schematic representation showing how MDCTs were evaluated to generate the mucus score. Airways within the 2 cm peripheral zone on MDCT (shown in red) or airways that were partially occluded were excluded from assessment. Mucus plugs were defined as complete occlusion of an airway. Each bronchopulmonary segment was assessed and scored for the presence or absence of 1 or more mucus plug(s), and the segment scores were summed to generate the mucus score. (E) Segment score in healthy patients and patients with asthma. (F) Frequency distribution of segment score in patients with asthma. The color code above the x axis defines 3 mucus groups: green indicates patients with a mucus score of 0 (zero mucus group); blue indicates patients with mucus scores between 0.5 and 3.5 (low mucus group); and orange indicates patients with mucus scores of 4.0 or more (high mucus group). (G) Sankey bar graph showing the change in mucus score in 25 asthmatic subjects from SARP 1/2 to SARP 3. (H) Pie chart of segments with mucus plugging on baseline scan; 65% of these segments had mucus plugging on rescan. Pie chart of segments with no mucus plugging on baseline scan; 79% of these segments had no mucus plugging on rescan. (I) MDCTs showing a mucus plug occluding the airway (yellow arrow) of the right lower lobe in 2010 and a mucus plug occluding the same airway, visible more proximally (yellow arrow) and branching into the adjacent airway, in 2013. ***P < 0.001, unequal variances t test.