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. 2022 Apr;12(4):e816.
doi: 10.1002/ctm2.816.

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

Uruj Hoda  1 , Stelios Pavlidis  2 , Aruna T Bansal  3 , Kentaro Takahashi  1   4 , Sile Hu  3 , Francois Ng Kee Kwong  1 , Christos Rossios  1 , Kai Sun  3 , Pankaj Bhavsar  1 , Matthew Loza  5 , Frederic Baribaud  5 , Pascal Chanez  6 , Stephen J Fowler  7 , Ildiko Horvath  8 , Paolo Montuschi  9 , Florian Singer  10 , Jacek Musial  11 , Barbro Dahlen  12 , Norbert Krug  13 , Thomas Sandstrom  14 , Dominic E Shaw  15 , Rene Lutter  16 , Louise J Fleming  1 , Peter H Howarth  17 , Massimo Caruso  18 , Ana R Sousa  19 , Julie Corfield  20 , Charles Auffray  21 , Bertrand De Meulder  21 , Diane Lefaudeux  21 , Sven-Erik Dahlen  12 , Ratko Djukanovic  17 , Peter J Sterk  16 , Yike Guo  3 , Ian M Adcock  1 , Kian Fan Chung  1 ; U-BIOPRED study group
Affiliations

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

Uruj Hoda et al. Clin Transl Med. 2022 Apr.

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.

Keywords: CEACAM5; asthma exacerbations; frequent exacerbators; persistent frequent exacerbators; severe asthma.

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Conflict of interest statement

Dr Singer reports honoraria for lectures and presentations from Novartis Pharma Switzerland and Vertex Pharmaceuticals Switzerland, outside the submitted work. Dr Shaw has received speaker fees from Chiesi and Astra Zeneca and advisory board fees from Adherium, Nuvoair, Astra Zeneca and Chiesi. Dr Loza is employed by and own stock in Johnson & Johnson. Dr. SE Dahlén reports personal fees from AstraZeneca, Cayman Chemicals, GSK, Novartis, Regeneron, Sanofi and Teva for consultancies outside the submitted work. Drs Auffray, Demulder and Lefaudeux report grants from the IMI (U‐BIOPRED n°115010 and eTRIKS n°115446). Dr Fowler has received grants from Boehringer Ingelheim and fees from Chiesi, outside of the current work. Dr Djukanovic reports receiving fees for lectures at symposia organised by Novartis, AstraZeneca and TEVA, consultation for TEVA and Novartis as members of advisory boards, and participation in a scientific discussion about asthma organised by GlaxoSmithKline. He is a co‐founder and current consultant and has shares in Synairgen, a University of Southampton spin out company. Dr Sterk reports grants from public–private funding by the Innovative Medicines Initiative (IMI), outside the submitted work. Dr Chung has received honoraria for participating in Advisory Board meetings of GSK, AZ, Roche, Novartis, Merck, BI, TEVA and Shionogi regarding treatments for asthma, chronic obstructive pulmonary disease and chronic cough and has also been remunerated for speaking engagements. The other authors have no disclosures in relation to this work. U‐BIOPRED was supported by an Innovative Medicines Initiative Joint Undertaking (No. 115010), resources from the European Union's Seventh Framework Programme (FP7/2007‐2013) and EFPIA companies’ in‐kind contribution (www.imi.europa.eu). KFC and IMA are funded by UK Research and Innovation (UKRI). KFC is an Emeritus Senior Investigator of the UK National Institute for Health Research (NIHR). CEW is funded by the Swedish Heart Lung Foundation (HLF 20180290, HLF 20200693). We acknowledge the contribution of the whole U‐BIOPRED team as listed in the Supporting Information repository file.

Figures

FIGURE 1
FIGURE 1
Expression scores (ES) of gene signatures in endobronchial biopsies of frequent exacerbators (FE) compared to infrequent exacerbators (IE). The gene signature number indicates the signature tabulated in Table S2. The p significance value is as indicated
FIGURE 2
FIGURE 2
Expression scores (ES) of gene signatures in endobronchial biopsies of persistent frequent exacerbators (PFE) compared to persistent infrequent exacerbators (PIE). The gene signature number indicates the signature tabulated in Table S2. The p significance value is as indicated
See this image and copyright information in PMC

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