Clinical and transcriptomic features of persistent exacerbation‐prone severe asthma in U‐BIOPRED cohort

Abstract

Background Exacerbation‐prone asthma is a feature of severe disease. However, the basis for its persistency remains unclear. Objectives To determine the clinical and transcriptomic features of frequent exacerbators (FEs) and persistent FEs (PFEs) in the U‐BIOPRED cohort. Methods We compared features of FE (≥2 exacerbations in past year) to infrequent exacerbators (IE, <2 exacerbations) and of PFE with repeat ≥2 exacerbations during the following year to persistent IE (PIE). Transcriptomic data in blood, bronchial and nasal epithelial brushings, bronchial biopsies and sputum cells were analysed by gene set variation analysis for 103 gene signatures. Results Of 317 patients, 62.4% had FE, of whom 63.6% had PFE, while 37.6% had IE, of whom 61.3% had PIE. Using multivariate analysis, FE was associated with short‐acting beta‐agonist use, sinusitis and daily oral corticosteroid use, while PFE was associated with eczema, short‐acting beta‐agonist use and asthma control index. CEA cell adhesion molecule 5 ( CEACAM5) was the only differentially expressed transcript in bronchial biopsies between PE and IE. There were no differentially expressed genes in the other four compartments. There were higher expression scores for type 2, T‐helper type‐17 and type 1 pathway signatures together with those associated with viral infections in bronchial biopsies from FE compared to IE, while there were higher expression scores of type 2, type 1 and steroid insensitivity pathway signatures in bronchial biopsies of PFE compared to PIE. Conclusion The FE group and its PFE subgroup are associated with poor asthma control while expressing higher type 1 and type 2 activation pathways compared to IE and PIE, respectively.

Frequent exacerbators in severe asthma: Focus on clinical and transcriptional factors

“…In conclusion, the study by Hoda and colleagues 7 has provided new data on transcriptional factors in blood and airway samples associated with frequent exacerbations in severe asthma. Interestingly, increased CEACAM5 expression in bronchial biopsies was associated with frequent exacerbator status, whereas transcripts in other compartments did not differ between exacerbator subgroups.…”

“…In the U‐BIOPRED study, former smoking was associated with increased exacerbations at baseline, 7 whereas in the UK Severe Asthma Registry population, a past smoking history correlated with frequent exacerbations only in patients on maintenance oral corticosteroids 3 . Unexpectedly, Hoda and colleagues 7 found that current smoking status was associated with a reduced risk of persistent frequent exacerbations, whereas other studies have reported that current smoking status 8 or high pack‐year history 1 was associated with an increased risk of exacerbations in severe asthma. The reason for the contrasting findings is uncertain but may be due to differences between study populations in the proportion of current and former smokers, cumulative smoking history, oral corticosteroid use, or other variables.…”

“… 9 The binding of bacteria to CEACAMs is thought to mediate bacterial adhesion and contribute to colonisation of the airways. Hoda and colleagues 7 speculate that CEACAM5 could be involved in exacerbations due to bacterial infections among frequent exacerbators, possibly after viral respiratory infections. 9 Confirmation of these findings could lead to the development of therapies targeting the epithelial CEACAM5 receptor among frequent exacerbators.…”

“…In the current issue of Clinical and Translational Medicine , Hoda and colleagues 7 reported the results of a study designed to provide insights into the clinical and immunological factors underlying frequent exacerbations in 420 adults with severe asthma recruited to the U‐BIOPRED (the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcome) cohort. Baseline clinical variables and transcriptional data in blood, bronchial and nasal epithelial brushings, bronchial biopsies, and sputum cells among frequent exacerbators, defined as ≥ 2 exacerbations in the previous year, were compared with infrequent exacerbators, defined as a maximum of one exacerbation in the previous year.…”

“…Over 100 gene signatures that might be involved in frequent exacerbations among adults with asthma were examined in the different biological samples collected by Hoda and colleagues 7 . CEA Cell Adhesion Molecule 5 (CEACAM5) expression in bronchial biopsies was increased in frequent exacerbators compared to infrequent exacerbators, whereas transcripts in other compartments did not differ between exacerbator subgroups.…”