Importance of mucus burden and mucociliary impairment in asthma.

We read with interest the study by Guntur et al1Guntur V.P. Manka L.A. Moore C.M. Wynn E. Vladar E.K. Alam R. et al.Refractory neutrophilic asthma and ciliary genes.J Allergy Clin Immunol. 2022; 149: 1970-1980Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar titled “Refractory neutrophilic asthma and ciliary genes.” This article showed that the dysregulation and downregulation of ciliary genes may contribute to the development of refractory asthma (RA), particularly its subgroup cilium-deficient RA. The cilium-deficient RA showed both type 2 and non–type 2 inflammation and a high risk of subclinical infection with findings of “mucus,” “bronchiectasis/bronchial dilatation,” or “tree-in-bud” on chest computed tomography (CT). Furthermore, the upregulation of S100A8 was found in RA, which may contribute to poor mucus clearance, considering that S100A8 activates airway epithelium to produce mucin 5AC. Their study showed that the importance of mucociliary impairment and mucus burden in the development of RA must be well recognized. We examined the association between the “tree-in-bud” pattern on chest CT and a single-nucleotide polymorphism of rs2523870, a variant located near a risk gene of diffuse panbronchiolitis (DPB), that is, HCG22 on chromosome 6p21.3, in patients with asthma. The tree-in-bud pattern, which may reflect the presence of bronchiolitis, is typically a feature of DPB, a sinopulmonary syndrome mainly affecting Asians,2Hijikata M. Matsushita I. Tanaka G. Tsuchiya T. Ito H. Tokunaga K. et al.Molecular cloning of two novel mucin-like genes in the disease-susceptibility locus for diffuse panbronchiolitis.Hum Genet. 2011; 129: 117-128Crossref PubMed Scopus (49) Google Scholar and is often accompanied by bronchiectasis with neutrophilic airway inflammation and subclinical infection. The putative protein product of HCG22 is a secreted mucin that lacks a transmembrane domain and is most closely related to peritrophin A, which has chitin-binding ability.3Jeong S. Patel N. Edlund C.K. Hartiala J. Hazelett D.J. Itakura T. et al.Identification of a novel mucin gene HCG22 associated with steroid-induced ocular hypertension.Invest Ophthalmol Vis Sci. 2015; 56: 2737-2748Crossref PubMed Scopus (22) Google Scholar Notably, the minor C allele of rs2523870 is also the risk allele for late-onset asthma.4Yatagai Y. Hirota T. Sakamoto T. Yamada H. Masuko H. Kaneko Y. et al.Variants near the HLA complex group 22 gene (HCG22) confer increased susceptibility to late-onset asthma in Japanese populations.J Allergy Clin Immunol. 2016; 138: 281-3. e213Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar This study was approved by the Kyoto University Medical Ethics Committee (G0436). In 106 patients with asthma who had stored genetic specimens in our hospital after providing written informed consent, there were 37 TT, 45 TC, and 24 CC genotypes of rs2523870. Most patients had data available for 2 times, with an average of 8.8 years apart, for blood tests and 6.5 years apart for CT, exhaled nitric oxide, and pulmonary function tests. Patients with the CC genotype had a higher frequency of chronic rhinosinusitis with nasal polyps, higher blood eosinophil counts in the past, and more lobes with the tree-in-bud in the past and present and received higher doses of inhaled corticosteroids in the past and more doses of oral corticosteroids currently than did patients with TT or TC genotypes (Table I). The current modified Reiff score, the radiological extent of bronchiectasis, tended to be higher for the CC genotype. Despite the small sample size in this single-institution study, a variant near HCG22, a risk gene of DPB, may be associated with the tree-in-bud pattern in patients with asthma and disease refractoriness requiring higher doses of corticosteroids. Because sputum cells were not examined in this study, whether patients had eosinophilic bronchiolitis5Cordier J.F. Cottin V. Khouatra C. Revel D. Proust C. Freymond N. et al.Hypereosinophilic obliterative bronchiolitis: a distinct, unrecognised syndrome.Eur Respir J. 2013; 41: 1126-1134Crossref PubMed Scopus (41) Google Scholar or mixed airway inflammation with a risk of subclinical infection was unclear.TABLE IPatients’ background according to genotypes of rs2523870CharacteristicCC (n = 24)TT/CT (n = 82)P valueSex: female, n (%)16 (66.7)55 (67.1).97Body mass index (kg/m2)21.9 ± 4.223.3 ± 4.1.25Age at asthma onset (y)50.9 ± 12.251.3 ± 17.1.60Smoking history, no/past/current, n13/10/053/26/1.56Comorbid of diffuse panbronchiolitis, n (%)01 (1.2).59Comorbid of CRSwNP, n (%)5 (20.8)4 (4.9).01Recent data Modified Reiff score2.1 ± 2.41.5 ± 2.8.07 No. of lobes with tree-in-bud pattern1.3 ± 2.00.7 ± 1.5.049 Blood neutrophil count (/μL)3913 ± 14924182 ± 2120.98 Eosinophil count (/μL)302 ± 294252 ± 257.72 Serum C-reactive protein (mg/dL) (n)0.63 ± 0.66 (14)0.96 ± 2.22 (51).54 Serum total IgE (IU/mL) (n)295.3 ± 434.7 (19)346.5 ± 430.6 (56).63 FEV1/FVC (%)71.7 ± 11.770.8 ± 12.8.99 Feno (ppb)49.5 ± 52.135.6 ± 36.9.11 Pseudomonas aeruginosa+ in sputum, n (%)3 (25.0)5 (11.9).26 Gram-negative bacteria+ in sputum, n (%)0 (0)5 (11.9).21 ICS dose (μg/d) (eq. to FP) (n)687.5 ± 430.9551.2 ± 391.2.14 Macrolide therapy, n (%)2 (8.3)9 (11.0).71 Maintenance OCS, n (%)6 (25.0)7 (8.5).03Past data Modified Reiff score (n)1.0 ± 1.3 (22)0.8 ± 1.4 (66).14 No. of lobes with tree-in-bud pattern1.7 ± 2.1 (22)0.6 ± 1.3 (66).02 Blood neutrophil count (/μL)3750 ± 15623937 ± 1718.83 Eosinophil count (/μL)458 ± 343421 ± 956.03 Serum C-reactive protein (mg/dL) (n)0.18 ± 0.24 (18)0.44 ± 1.11 (55).59 Serum total IgE (IU/mL)479.5 ± 581.7386.2 ± 640.7.56 FEV1/FVC (%)69.8 ± 12.470.0 ± 11.6.86 Feno (ppb)55.9 ± 49.948.5 ± 46.4.28 Pseudomonas aeruginosa+ in sputum, n (%)0 (0)2 (3.6).44 Gram-negative bacteria+ in sputum, n (%)2 (12.5)4 (7.3).51 ICS dose (μg/d) (n)656.3 ± 328.1513.0 ± 300.5.03 Macrolide therapy, n (%)2 (8.3)7 (8.5).97 Maintenance OCS, n (%)2 (8.3)5 (6.1).70Continuous variables are expressed as mean ± SD. The numbers of data were 24 for CC and 82 for TT and CT genotypes, if not otherwise specified. P values were calculated using the Wilcoxon rank-sum test, χ2 test, and Fisher exact test.CRSwNP, Chronic rhinosinusitis with nasal polyps; Feno, fractional exhaled nitric oxide; FP, fluticasone propionate; FVC, forced vital capacity; ICS, inhaled corticosteroid; OCS, oral corticosteroid. Open table in a new tab Continuous variables are expressed as mean ± SD. The numbers of data were 24 for CC and 82 for TT and CT genotypes, if not otherwise specified. P values were calculated using the Wilcoxon rank-sum test, χ2 test, and Fisher exact test. CRSwNP, Chronic rhinosinusitis with nasal polyps; Feno, fractional exhaled nitric oxide; FP, fluticasone propionate; FVC, forced vital capacity; ICS, inhaled corticosteroid; OCS, oral corticosteroid. In conclusion, the findings supported that mucus burden, which may impair mucociliary function, is relevant to the development of RA. Further studies are needed to clarify the mechanisms underlying mucociliary impairment regardless of the inflammatory phenotype. Refractory neutrophilic asthma and ciliary genesJournal of Allergy and Clinical ImmunologyVol. 149Issue 6PreviewRefractory asthma (RA) remains poorly controlled, resulting in high health care utilization despite guideline-based therapies. Patients with RA manifest higher neutrophilia as a result of increased airway inflammation and subclinical infection, the underlying mechanisms of which remain unclear. Full-Text PDF ReplyJournal of Allergy and Clinical ImmunologyVol. 151Issue 5PreviewWe read with enthusiasm the correspondence by Nomura et al1 in reference to our original article “Refractory neutrophilic asthma and ciliary genes.”2 In their comment, Nomura et al identified a single-nucleotide polymorphism (SNP), rs2523870, that correlated with findings on chest imaging, specifically the “tree-in-bud” pattern. This computed tomography finding is often consistent with a nonspecific bronchiolitis pattern and may also be seen in patients with asthma who exhibit increased mucus burden, as was seen in our patient population. Full-Text PDF