Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease

Overview

Journal Clin Rev Allergy Immunol

Specialty Allergy & Immunology

Date 2018 Sep 13

PMID 30206782

Citations 450

Authors

Merin E Kuruvilla

F Eun-Hyung Lee

Gerald B Lee

Affiliations

Soon will be listed here.

Abstract

The model of asthma as a single entity has now been replaced by a much more complex biological network of distinct and interrelating inflammatory pathways. The term asthma is now considered an umbrella diagnosis for several diseases with distinct mechanistic pathways (endotypes) and variable clinical presentations (phenotypes). The precise definition of these endotypes is central to asthma management due to inherent therapeutic and prognostic implications. This review presents the molecular mechanisms behind the heterogeneity of airway inflammation in asthmatic patients. Asthma endotypes may be broadly regarded as type 2 (T2) high or T2-low. Several biologic agents have been approved for T2-high asthma, with numerous other therapeutics that are incipient and similarly targeted at specific molecular mechanisms. Collectively, these advances have shifted existing paradigms in the approach to asthma to tailor novel therapies.

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References

Wenzel S, Schwartz L, Langmack E, Halliday J, Trudeau J, Gibbs R . Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med. 1999; 160(3):1001-8. DOI: 10.1164/ajrccm.160.3.9812110. View

MacFarlane A, Kon O, Smith S, Zeibecoglou K, Khan L, Barata L . Basophils, eosinophils, and mast cells in atopic and nonatopic asthma and in late-phase allergic reactions in the lung and skin. J Allergy Clin Immunol. 2000; 105(1 Pt 1):99-107. DOI: 10.1016/s0091-6749(00)90184-2. View

Chung K . Airway smooth muscle cells: contributing to and regulating airway mucosal inflammation?. Eur Respir J. 2000; 15(5):961-8. DOI: 10.1034/j.1399-3003.2000.15e26.x. View

. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001; 69(3):89-95. DOI: 10.1067/mcp.2001.113989. View

Kepley C, McFeeley P, Oliver J, Lipscomb M . Immunohistochemical detection of human basophils in postmortem cases of fatal asthma. Am J Respir Crit Care Med. 2001; 164(6):1053-8. DOI: 10.1164/ajrccm.164.6.2102025. View

Miranda C, Busacker A, Balzar S, Trudeau J, Wenzel S . Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol. 2004; 113(1):101-8. DOI: 10.1016/j.jaci.2003.10.041. View

Ying S, OConnor B, Ratoff J, Meng Q, Mallett K, Cousins D . Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol. 2005; 174(12):8183-90. DOI: 10.4049/jimmunol.174.12.8183. View

Hahn C, Islamian A, Renz H, Nockher W . Airway epithelial cells produce neurotrophins and promote the survival of eosinophils during allergic airway inflammation. J Allergy Clin Immunol. 2006; 117(4):787-94. DOI: 10.1016/j.jaci.2005.12.1339. View

Heijink I, Kies P, Kauffman H, Postma D, van Oosterhout A, Vellenga E . Down-regulation of E-cadherin in human bronchial epithelial cells leads to epidermal growth factor receptor-dependent Th2 cell-promoting activity. J Immunol. 2007; 178(12):7678-85. DOI: 10.4049/jimmunol.178.12.7678. View

10.

Brown J, Wilson T, Metcalfe D . The mast cell and allergic diseases: role in pathogenesis and implications for therapy. Clin Exp Allergy. 2007; 38(1):4-18. DOI: 10.1111/j.1365-2222.2007.02886.x. View

11.

Nair P, Pizzichini M, Kjarsgaard M, Inman M, Efthimiadis A, Pizzichini E . Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009; 360(10):985-93. DOI: 10.1056/NEJMoa0805435. View

12.

Al-Ramli W, Prefontaine D, Chouiali F, Martin J, Olivenstein R, Lemiere C . T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma. J Allergy Clin Immunol. 2009; 123(5):1185-7. DOI: 10.1016/j.jaci.2009.02.024. View

13.

Woodruff P, Modrek B, Choy D, Jia G, Abbas A, Ellwanger A . T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009; 180(5):388-95. PMC: 2742757. DOI: 10.1164/rccm.200903-0392OC. View

14.

Colsoul B, Nilius B, Vennekens R . On the putative role of transient receptor potential cation channels in asthma. Clin Exp Allergy. 2009; 39(10):1456-66. DOI: 10.1111/j.1365-2222.2009.03315.x. View

15.

Prefontaine D, Lajoie-Kadoch S, Foley S, Audusseau S, Olivenstein R, Halayko A . Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells. J Immunol. 2009; 183(8):5094-103. DOI: 10.4049/jimmunol.0802387. View

16.

Moore W, Meyers D, Wenzel S, Teague W, Li H, Li X . Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2009; 181(4):315-23. PMC: 2822971. DOI: 10.1164/rccm.200906-0896OC. View

17.

Paul W . What determines Th2 differentiation, in vitro and in vivo?. Immunol Cell Biol. 2010; 88(3):236-9. DOI: 10.1038/icb.2010.2. View

18.

Stone K, Prussin C, Metcalfe D . IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol. 2010; 125(2 Suppl 2):S73-80. PMC: 2847274. DOI: 10.1016/j.jaci.2009.11.017. View

19.

Nyenhuis S, Schwantes E, Evans M, Mathur S . Airway neutrophil inflammatory phenotype in older subjects with asthma. J Allergy Clin Immunol. 2010; 125(5):1163-5. PMC: 3298970. DOI: 10.1016/j.jaci.2010.02.015. View

20.

Hastie A, Moore W, Meyers D, Vestal P, Li H, Peters S . Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J Allergy Clin Immunol. 2010; 125(5):1028-1036.e13. PMC: 2878277. DOI: 10.1016/j.jaci.2010.02.008. View