Unrecognized ciliary motility disorders in neutrophilic severe asthma exacerbations

BackgroundAirway bacterial infections are frequent in severe asthma and are often under-appreciated as contributors to symptoms and exacerbations. We report our experience using integrative diagnostic methods to identify ciliary motility disorders as contributors to neutrophilic exacerbations in patients with severe asthma.MethodsTargeted exome sequencing for primary ciliary dyskinesia (PCD) was performed on 52 patients with severe asthma who met predefined criteria (≥ 3 respiratory infections or intense sputum neutrophilia, within a 2-year period, along with evidence of type 2 inflammation, including peripheral or sputum eosinophilia, elevated fractional exhaled nitric oxide (FeNO), or elevated serum immunoglobulin E), and without other obvious immunodeficiencies. A subset of patients with PCD-related gene variant(s) underwent ciliary beat frequency (CBF) analysis from nasal epithelial brushings (N = 20 with analyzable data), nasal nitric oxide (nNO) measurement (N = 15), and T1/2/17 sputum cytokine assays (N = 18).ResultsAmong 52 patients (mean age 54.2 ± 15.1 years; 59.6% female), 32(61.5%) had PCD-related gene variants. CBF was reduced in 19/20(95%) patients who underwent motility studies (mean CBF of 8.8 ± 2.7 Hz; normal 14.2 ± 1.0 Hz), and correlated significantly with FEV1 (rs=0.65, P = 0.0017) and inversely with peak sputum neutrophils (rs=-0.62, P = 0.0097). Subnormal nNO levels (< 250 nL/min) were observed in 12/15(80%) patients; 3/15(20%) were < 77 nL/min (PCD threshold). 5 patients showed FeNO discordance (> 25 ppb). Cytokines associated with inflammasome activation were increased in sputum in majority of patients with PCD-related gene variants. Sputum-guided strategy and 7% hypertonic saline treatment enable significant inhaled corticosteroid doses reduction across the entire population and airway-eosinophilia subgroup (P = 0.0026 and P = 0.0273). Oral corticosteroid doses were reduced in 6/8(75%), and biologics were not initiated in 26/32(81.3%). FEV1 improved by 130 ± 291mL, P = 0.0273.ConclusionsCiliary dyskinesias are prevalent in patients with severe asthma. Identifying ciliary motility disorders can guide effective treatment and reduce unnecessary biologics use in severe asthma when symptoms are infection-driven. Even variants of uncertain significance in PCD-related genes may be associated with airway infections due to ciliary dysfunction, proven by ciliary beat frequency analysis. nNO could be a useful screening tool, but its optimal cutoff in this population needs further study.