February 2018 | Feabhra 2018

Mucus Plugs in Asthma Linked to Eosinophilia and Airflow Obstruction

Wed, 7 February 18 13:01

Mucus plugs are a plausible mechanism of chronic obstruction in severe asthma, and EPO-generated oxidants may mediate mucus plug formation.  That was the conclusion of a clinical study reported recently in the Journal of Clinical Investigations by a multi-institutional collaboration led by the University of California, San Francisco. Lead author in the study was Dr Eleanor Dunican, now consultant respiratory physician at St Vincent’s University Hospital and Associate Professor at the UCD School of Medicine.

Asthma is a complex and heterogeneous condition with multiple underlying inflammatory and structural airflow abnormalities that lead to symptomatic disease.  Researchers have sought to develop methods to characterise different asthma types with a view to developing personalise, targeted therapies.  Dr Dunican and colleagues developed a non-invasive method of measuring airway mucus accumulation in asthma using multi-detector computed tomography. Using this imaging technique, the group were able to demonstrate a reproducible ‘mucus score’ and established that mucus plugging was common among patients with severe asthma. Subjects with high mucus scores had more severe airflow obstruction and higher indices of eosinophilic airway inflammation.

The clinical evaluation of this methodology involved 146 subjects with asthma and 22 controls and analysed the relationship between mucus plug scores, forced expiratory volume in 1 second (FEV1) and airway eosinophils.  The researchers also used airway mucus gel models to examine if oxidants generated by eosinophil peroxidase (EPO) promoted mucus plug formation by oxidising cysteine thiol moieties.

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 patients with asthma persisted in the same segment for many years.  A high mucus score (plugs in 4 or more segments) occurred in 67% of cases with FEV1 of less than 60% of predicted volume, 19% with FEV1 of 60-80% and 6% of subjects with FEV1 greater than 80%.  High mucus score was also associated with marked increases in sputum eosinophils and EPO.  EPO catalysed oxidation of thiocyanate and bromide by hydrogen peroxide in vitro to generate oxidants that crossline cysteine thiol groups and stiffen thiolated hydrogels.

In an accompanying commentary in the same journal, Steven Georas of the University of Rochester Medical Centre noted that

the development of the radiographic mucus score represents an elegant example of translational research that will further our understanding of asthma heterogeneity.

He observed that while the study had shown association between high mucus scores and airflow obstruction, it is difficult to know if this association is causal.  Future longitudinal studies might provide some insight into whether high mucus scores precede the development of airflow obstruction in at-risk subjects.  It is hoped that non-invasive radiographic methods such as that described here will help clinicians define specific asthma sub-sets and assist in the evaluation of targeted therapies.

Original Research Article

Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. 

Dunican EM, Elicker BM, Gierada DS, Nagle SK, Schiebler ML, Newell JD, Raymond WW, Lachowicz-Scroggins ME, Di Maio S, Hoffman EA, Castro M, Fain SB, Jarjour NN, Israel E, Levy BD, Erzurum SC, Wenzel SE, Meyers DA, Bleecker ER, Phillips BR, Mauger DT, Gordon ED, Woodruff PG, Peters MC, Fahy JV; National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP).

J Clin Invest. 2018 Feb 5. pii: 95693. doi: 10.1172/JCI95693. [Epub ahead of print] PMID: 29400693

Commentary

All plugged up - noninvasive mucus score to assess airway dysfunction in asthma.

Georas SN. J Clin Invest. 2018 Feb 5. pii: 99726. doi: 10.1172/JCI99726. PMID: 29400694