Airway Remodelling Rather Than Cellular Infiltration Characterizes Both Type2 Cytokine Biomarker-high and -low Severe Asthma

Overview

Journal Allergy

Specialty Allergy & Immunology

Date 2022 May 17

PMID 35579040

Authors

Latifa Khalfaoui

Fiona A Symon

Simon Couillard

Beverley Hargadon

Rekha Chaudhuri

Steve Bicknell

Adel H Mansur

Rahul Shrimanker

Timothy S C Hinks

Ian D Pavord

Stephen J Fowler

Vanessa Brown

Lorcan P McGarvey

Liam G Heaney

Cary D Austin

Peter H Howarth

Joseph R Arron

David F Choy

Peter Bradding

Affiliations

Soon will be listed here.

Abstract

Background: The most recognizable phenotype of severe asthma comprises people who are blood eosinophil and FeNO-high, driven by type 2 (T2) cytokine biology, which responds to targeted biological therapies. However, in many people with severe asthma, these T2 biomarkers are suppressed but poorly controlled asthma persists. The mechanisms driving asthma in the absence of T2 biology are poorly understood.

Objectives: To explore airway pathology in T2 biomarker-high and -low severe asthma.

Methods: T2 biomarker-high severe asthma (T2-high, n = 17) was compared with biomarker-intermediate (T2-intermediate, n = 21) and biomarker-low (T2-low, n = 20) severe asthma and healthy controls (n = 28). Bronchoscopy samples were processed for immunohistochemistry, and sputum for cytokines, PGD and LTE measurements.

Results: Tissue eosinophil, neutrophil and mast cell counts were similar across severe asthma phenotypes and not increased when compared to healthy controls. In contrast, the remodelling features of airway smooth muscle mass and MUC5AC expression were increased in all asthma groups compared with health, but similar across asthma subgroups. Submucosal glands were increased in T2-intermediate and T2-low asthma. In spite of similar tissue cellular inflammation, sputum IL-4, IL-5 and CCL26 were increased in T2-high versus T2-low asthma, and several further T2-associated cytokines, PGD and LTE , were increased in T2-high and T2-intermediate asthma compared with healthy controls.

Conclusions: Eosinophilic tissue inflammation within proximal airways is suppressed in T2 biomarker-high and T2-low severe asthma, but inflammatory and structural cell activation is present, with sputum T2-associated cytokines highest in T2 biomarker-high patients. Airway remodelling persists and may be important for residual disease expression beyond eosinophilic exacerbations. Registered at ClincialTrials.gov: NCT02883530.

Citing Articles

The potential role of n-3 fatty acids and their lipid mediators on asthmatic airway inflammation.

Tian Y, Sun J, Jiao D, Zhang W Front Immunol. 2024; 15:1488570.

PMID: 39720728 PMC: 11666451. DOI: 10.3389/fimmu.2024.1488570.

The Role of Galectins in Asthma Pathophysiology: A Comprehensive Review.

Portacci A, Iorillo I, Maselli L, Amendolara M, Quaranta V, Dragonieri S Curr Issues Mol Biol. 2024; 46(5):4271-4285.

PMID: 38785528 PMC: 11119966. DOI: 10.3390/cimb46050260.

Advances in non-type 2 severe asthma: from molecular insights to novel treatment strategies.

Liu T, Woodruff P, Zhou X Eur Respir J. 2024; 64(2).

PMID: 38697650 PMC: 11325267. DOI: 10.1183/13993003.00826-2023.

The effects of inhaled corticosteroids on healthy airways.

Marchi E, Hinks T, Richardson M, Khalfaoui L, Symon F, Rajasekar P Allergy. 2024; 79(7):1831-1843.

PMID: 38686450 PMC: 7616167. DOI: 10.1111/all.16146.

A real-world pharmacovigilance study of mepolizumab in the FDA adverse event reporting system (FAERS) database.

Zou F, Zhu C, Lou S, Cui Z, Wang D, Ou Y Front Pharmacol. 2024; 14:1320458.

PMID: 38186645 PMC: 10771301. DOI: 10.3389/fphar.2023.1320458.

References

Hartl S, Breyer M, Burghuber O, Ofenheimer A, Schrott A, Urban M . Blood eosinophil count in the general population: typical values and potential confounders. Eur Respir J. 2020; 55(5). DOI: 10.1183/13993003.01874-2019. View

Tiotiu A, Badi Y, Kermani N, Sanak M, Kolmert J, Wheelock C . Association of Differential Mast Cell Activation with Granulocytic Inflammation in Severe Asthma. Am J Respir Crit Care Med. 2021; 205(4):397-411. DOI: 10.1164/rccm.202102-0355OC. View

Ortega H, Yancey S, Mayer B, Gunsoy N, Keene O, Bleecker E . Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med. 2016; 4(7):549-556. DOI: 10.1016/S2213-2600(16)30031-5. View

Wenzel S . Severe asthma in adults. Am J Respir Crit Care Med. 2005; 172(2):149-60. DOI: 10.1164/rccm.200409-1181PP. View

Begueret H, Berger P, Vernejoux J, Dubuisson L, Marthan R, Tunon-de-Lara J . Inflammation of bronchial smooth muscle in allergic asthma. Thorax. 2006; 62(1):8-15. PMC: 2111285. DOI: 10.1136/thx.2006.062141. View

Bradding P, Arthur G . Mast cells in asthma--state of the art. Clin Exp Allergy. 2015; 46(2):194-263. DOI: 10.1111/cea.12675. View

Berry M, Morgan A, Shaw D, Parker D, Green R, Brightling C . Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax. 2007; 62(12):1043-9. PMC: 2094295. DOI: 10.1136/thx.2006.073429. View

Carroll N, Mutavdzic S, James A . Increased mast cells and neutrophils in submucosal mucous glands and mucus plugging in patients with asthma. Thorax. 2002; 57(8):677-82. PMC: 1746401. DOI: 10.1136/thorax.57.8.677. View

Wilson S, Ward J, Sousa A, Corfield J, Bansal A, De Meulder B . Severe asthma exists despite suppressed tissue inflammation: findings of the U-BIOPRED study. Eur Respir J. 2016; 48(5):1307-1319. DOI: 10.1183/13993003.01129-2016. View

10.

Hinks T, Zhou X, Staples K, Dimitrov B, Manta A, Petrossian T . Innate and adaptive T cells in asthmatic patients: Relationship to severity and disease mechanisms. J Allergy Clin Immunol. 2015; 136(2):323-33. PMC: 4534770. DOI: 10.1016/j.jaci.2015.01.014. View

11.

Manson M, Safholm J, James A, Johnsson A, Bergman P, Al-Ameri M . IL-13 and IL-4, but not IL-5 nor IL-17A, induce hyperresponsiveness in isolated human small airways. J Allergy Clin Immunol. 2019; 145(3):808-817.e2. DOI: 10.1016/j.jaci.2019.10.037. View

12.

Venkayya R, Lam M, Willkom M, Grunig G, Corry D, Erle D . The Th2 lymphocyte products IL-4 and IL-13 rapidly induce airway hyperresponsiveness through direct effects on resident airway cells. Am J Respir Cell Mol Biol. 2002; 26(2):202-8. DOI: 10.1165/ajrcmb.26.2.4600. View

13.

Choy D, Modrek B, Abbas A, Kummerfeld S, Clark H, Wu L . Gene expression patterns of Th2 inflammation and intercellular communication in asthmatic airways. J Immunol. 2010; 186(3):1861-9. PMC: 3981556. DOI: 10.4049/jimmunol.1002568. View

14.

Arron J, Choy D, Laviolette M, Kelsen S, Hatab A, Leigh R . Disconnect between sputum neutrophils and other measures of airway inflammation in asthma. Eur Respir J. 2013; 43(2):627-9. DOI: 10.1183/09031936.00117013. View

15.

Kuo C, Pavlidis S, Loza M, Baribaud F, Rowe A, Pandis I . T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED. Eur Respir J. 2017; 49(2). DOI: 10.1183/13993003.02135-2016. View

16.

Kuyper L, Pare P, Hogg J, Lambert R, Ionescu D, Woods R . Characterization of airway plugging in fatal asthma. Am J Med. 2003; 115(1):6-11. DOI: 10.1016/s0002-9343(03)00241-9. View

17.

Du Rand I, Blaikley J, Booton R, Chaudhuri N, Gupta V, Khalid S . British Thoracic Society guideline for diagnostic flexible bronchoscopy in adults: accredited by NICE. Thorax. 2013; 68 Suppl 1:i1-i44. DOI: 10.1136/thoraxjnl-2013-203618. View

18.

Castro M, Corren J, Pavord I, Maspero J, Wenzel S, Rabe K . Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med. 2018; 378(26):2486-2496. DOI: 10.1056/NEJMoa1804092. View

19.

Djukanovic R, Wilson J, Britten K, Wilson S, Walls A, Roche W . Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am Rev Respir Dis. 1992; 145(3):669-74. DOI: 10.1164/ajrccm/145.3.669. View

20.

Singhania A, Rupani H, Jayasekera N, Lumb S, Hales P, Gozzard N . Altered Epithelial Gene Expression in Peripheral Airways of Severe Asthma. PLoS One. 2017; 12(1):e0168680. PMC: 5207492. DOI: 10.1371/journal.pone.0168680. View