Eosinophils and T2 inflammation in severe asthma

Agamemnon Bakakos , Nektarios Anagnostopoulos , Petros Bakakos

Exploration of Asthma & Allergy ›› 2024, Vol. 2 ›› Issue (5) : 399 -409.

PDF (1284KB)
Exploration of Asthma & Allergy ›› 2024, Vol. 2 ›› Issue (5) :399 -409. DOI: 10.37349/eaa.2024.00053
Open Access Review
research-article
Eosinophils and T2 inflammation in severe asthma
Author information +
History +
PDF (1284KB)

Abstract

Asthma is a common chronic inflammatory disease of the airways that affects more than 330 million people globally. Severe asthma, despite being 5–10% of the total asthmatic population presents significant morbidity and high cost due to health care utilization. The management of severe asthma has dramatically changed with the use of biologics. However, biologics have been approved only for patients with severe asthma with type-2 mediated inflammation. Eosinophils are central in the T2 inflammatory process in asthma and this stands true for the severe form of the disease as well. In this review, we discuss basic insights into the pathogenesis of severe asthma related to eosinophilic inflammation and the pivotal role of T2 cytokines which have also become along with eosinophils the target of biologics. Novel biologics such as tezepelumab have demonstrated efficacy regardless of the blood eosinophil count and have shown promise for T2 low asthma, although to a lesser degree.

Keywords

Asthma / severe asthma / eosinophils / T2 inflammation

Cite this article

Download citation ▾
Agamemnon Bakakos, Nektarios Anagnostopoulos, Petros Bakakos. Eosinophils and T2 inflammation in severe asthma. Exploration of Asthma & Allergy, 2024, 2 (5) : 399-409 DOI:10.37349/eaa.2024.00053

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

2022 GINA Report, Global Strategy for Asthma Management and Prevention [Internet]. ginasthma.org; c2024 [cited 2023 Feb 28]. Available from: https://ginasthma.org/gina-reports/

[2]

Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014; 43: 343-73.

[3]

Holguin F, Cardet JC, Chung KF, Diver S, Ferreira DS, Fitzpatrick A, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020; 55: 1900588.

[4]

Brusselle GG, Koppelman GH. Biologic Therapies for Severe Asthma. N Engl J Med. 2022; 386: 157-71.

[5]

Schoettler N, Strek ME. Recent Advances in Severe Asthma: From Phenotypes to Personalized Medicine. Chest. 2020; 157: 516-28.

[6]

Global Initiative for Asthma. Difficult-To-Treat & Severe Asthma in Adolescent and Adult Patients, 2019. Available from: https://ginasthma.org/

[7]

Sweeney J, Patterson CC, Menzies-Gow A, Niven RM, Mansur AH, Bucknall C, et al. Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data from the Optimum Patient Care Research Database and the British Thoracic Difficult Asthma Registry. Thorax. 2016; 71: 339-46.

[8]

Bakakos P, Kostikas K, Loukides S, Makris M, Papadopoulos NG, Steiropoulos P, et al. Reducing Tolerance for SABA and OCS towards the Extreme Ends of Asthma Severity. J Pers Med. 2022; 12: 504.

[9]

Price DB, Trudo F, Voorham J, Xu X, Kerkhof M, Ling Zhi Jie J, et al. Adverse outcomes from initiation of systemic corticosteroids for asthma: long-term observational study. J Asthma Allergy. 2018; 11: 193-204.

[10]

Settipane RA, Kreindler JL, Chung Y, Tkacz J. Evaluating direct costs and productivity losses of patients with asthma receiving GINA 4/5 therapy in the United States. Ann Allergy Asthma Immunol. 2019; 123: 564-72.e3.

[11]

Ozdemir C, Kucuksezer UC, Akdis M, Akdis CA. The concepts of asthma endotypes and phenotypes to guide current and novel treatment strategies. Expert Rev Respir Med. 2018; 12: 733-43.

[12]

Kuruvilla ME, Lee FE, Lee GB. Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease. Clin Rev Allergy Immunol. 2019; 56: 219-33.

[13]

Ricciardolo FLM, Sprio AE, Baroso A, Gallo F, Riccardi E, Bertolini F, et al. Characterization of T2-Low and T2-High Asthma Phenotypes in Real-Life. Biomedicines. 2021; 9: 1684.

[14]

Harada N, Makita N, Fukui K, Nishida K, Oneda K, Tashiro N. A Retrospective Claims Database Study to Clarify Disease Burden of Severe Asthma Patients with Type 2 High or Low Inflammation. J Asthma Allergy. 2023; 16: 83-93.

[15]

Frøssing L, Klein DK, Hvidtfeldt M, Obling N, Telg G, Erjefält JS, et al. Distribution of type 2 biomarkers and association with severity, clinical characteristics and comorbidities in the BREATHE real-life asthma population. ERJ Open Res. 2023; 9: 00483-2022.

[16]

Hammad H, Lambrecht BN. The basic immunology of asthma. Cell. 2021; 184: 1469-85.

[17]

Bakakos A, Loukides S, Bakakos P. Severe Eosinophilic Asthma. J Clin Med. 2019; 8: 1375.

[18]

Papi A, Brightling C, Pedersen SE, Reddel HK. Asthma. Lancet. 2018; 391: 783-800.

[19]

Ying S, O’Connor B, Ratoff J, Meng Q, Mallett K, Cousins D, et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol. 2005; 174: 8183-90.

[20]

Zhou B, Comeau MR, Smedt TD, Liggitt HD, Dahl ME, Lewis DB, et al. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat Immunol. 2005; 6: 1047-53.

[21]

Ziegler SF, Roan F, Bell BD, Stoklasek TA, Kitajima M, Han H. Chapter Four - The Biology of Thymic Stromal Lymphopoietin (TSLP). Adv Pharmacol. 2013; 66: 129-55.

[22]

Kitajima M, Lee H, Nakayama T, Ziegler SF. TSLP enhances the function of helper type 2 cells. Eur J Immunol. 2011; 41: 1862-71.

[23]

Diver S, Russell RJ, Brightling CE. New and emerging drug treatments for severe asthma. Clin Exp Allergy. 2018; 48: 241-52.

[24]

Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax. 2002; 57: 875-9.

[25]

Doe C, Bafadhel M, Siddiqui S, Desai D, Mistry V, Rugman P, et al. Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD. Chest. 2010; 138: 1140-7.

[26]

Russell RJ, Brightling C. Pathogenesis of asthma: implications for precision medicine. Clin Sci (Lond). 2017; 131: 1723-35.

[27]

Tanaka J, Watanabe N, Kido M, Saga K, Akamatsu T, Nishio A, et al. Human TSLP and TLR3 ligands promote differentiation of Th17 cells with a central memory phenotype under Th2-polarizing conditions. Clin Exp Allergy. 2009; 39: 89-100.

[28]

Gao H, Ying S, Dai Y. Pathological Roles of Neutrophil-Mediated Inflammation in Asthma and Its Potential for Therapy as a Target. J Immunol Res. 2017; 2017: 1-12.

[29]

Couillard S, Laugerud A, Jabeen M, Ramakrishnan S, Melhorn J, Hinks T, et al. Derivation of a prototype asthma attack risk scale centred on blood eosinophils and exhaled nitric oxide. Thorax. 2022; 77: 199-202.

[30]

Ntontsi P, Loukides S, Bakakos P, Kostikas K, Papatheodorou G, Papathanassiou E, et al. Clinical, functional and inflammatory characteristics in patients with paucigranulocytic stable asthma: Comparison with different sputum phenotypes. Allergy. 2017; 72: 1761-7.

[31]

Gevaert P, Omachi TA, Corren J, Mullol J, Han J, Lee SE, et al. Efficacy and safety of omalizumab in nasal polyposis: 2 randomized phase 3 trials. J Allergy Clin Immunol. 2020; 146: 595-605.

[32]

Han JK, Bachert C, Fokkens W, Desrosiers M, Wagenmann M, Lee SE, et al. Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2021; 9: 1141-53.

[33]

Bachert C, Han JK, Desrosiers M, Hellings PW, Amin N, Lee SE, et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials. Lancet. 2019; 394: 1638-50.

[34]

Maurer M, Rosén K, Hsieh H, Saini S, Grattan C, Gimenéz-Arnau A, et al. Omalizumab for the Treatment of Chronic Idiopathic or Spontaneous Urticaria. N Engl J Med. 2013; 368: 924-35.

[35]

Blauvelt A, Bruin-Weller Md, Gooderham M, Cather JC, Weisman J, Pariser D, et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet. 2017; 389: 2287-303.

[36]

Carr TF, Zeki AA, Kraft M. Eosinophilic and Noneosinophilic Asthma. Am J Respir Crit Care Med. 2018; 197: 22-37.

[37]

Tliba O, Jr RAP. Paucigranulocytic asthma: Uncoupling of airway obstruction from inflammation. J Allergy Clin Immunol. 2019; 143: 1287-94.

[38]

Moore WC, Hastie AT, Li X, Li H, Busse WW, Jarjour NN, et al. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol. 2014; 133: 1557-63.e5.

[39]

Cowan DC, Cowan JO, Palmay R, Williamson A, Taylor DR. Effects of steroid therapy on inflammatory cell subtypes in asthma. Thorax. 2010; 65: 384-90.

[40]

Saglani S, Lloyd CM. Novel concepts in airway inflammation and remodelling in asthma. Eur Respir J. 2015; 46: 1796-804.

[41]

Rothenberg ME, Hogan SP. THE EOSINOPHIL. Annu Rev Immunol. 2006; 24: 147-74.

[42]

Chakir J, Shannon J, Molet S, Fukakusa M, Elias J, Laviolette M, et al. Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-β, IL-11, IL-17, and type I and type III collagen expression. J Allergy Clin Immunol. 2003; 111: 1293-8.

[43]

Hafez I, Stolpe A, Lindau M. Compound Exocytosis and Cumulative Fusion in Eosinophils. J Biol Chem. 2003; 278: 44921-8.

[44]

Pease JE. Asthma, Allergy and Chemokines. Curr Drug Targets. 2006; 7: 3-12.

[45]

Nussbaum JC, Dyken SJV, Moltke Jv, Cheng LE, Mohapatra A, Molofsky AB, et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature. 2013; 502: 245-8.

[46]

Bartemes KR, Iijima K, Kobayashi T, Kephart GM, McKenzie AN, Kita H. IL-33-Responsive LineageCD25+CD44hi Lymphoid Cells Mediate Innate Type 2 Immunity and Allergic Inflammation in the Lungs . J Immunol. 2012; 188: 1503-13.

[47]

Doherty TA, Khorram N, Lund S, Mehta AK, Croft M, Broide DH. Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production . J Allergy Clin Immunol. 2013; 132: 205-13.

[48]

Bousquet J, Chanez P, Lacoste JY, Barnéon G, Ghavanian N, Enander I, et al. Eosinophilic Inflammation in Asthma. N Engl J Med. 1990; 323: 1033-9.

[49]

Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick L, et al. ; International Mepolizumab Study Group. A Study to Evaluate Safety and Efficacy of Mepolizumab in Patients with Moderate Persistent Asthma. Am J Respir Crit Care Med. 2007; 176: 1062-71.

[50]

Petsky HL, Cates CJ, Kew KM, Chang AB. Tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils): a systematic review and meta-analysis. Thorax. 2018; 73: 1110-9.

[51]

Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012; 380: 651-9.

[52]

Fowler SJ, Tavernier G, Niven R. High blood eosinophil counts predict sputum eosinophilia in patients with severe asthma. J Allergy Clin Immunol. 2015; 135: 822-4.e2.

[53]

Wagener AH, Nijs SBd, Lutter R, Sousa AR, Weersink EJM, Bel EH, et al. External validation of blood eosinophils, FENO and serum periostin as surrogates for sputum eosinophils in asthma . Thorax. 2015; 70: 115-20.

[54]

Hastie AT, Moore WC, Li H, Rector BM, Ortega VE, Pascual RM, et al. Biomarker surrogates do not accurately predict sputum eosinophil and neutrophil percentages in asthmatic subjects. J Allergy Clin Immunol. 2013; 132: 72-80.e12.

[55]

Korevaar DA, Westerhof GA, Wang J, Cohen JF, Spijker R, Sterk PJ, et al. Diagnostic accuracy of minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and meta-analysis. Lancet Respir Med. 2015; 3: 290-300.

[56]

Ullmann N, Bossley CJ, Fleming L, Silvestri M, Bush A, Saglani S. Blood eosinophil counts rarely reflect airway eosinophilia in children with severe asthma. Allergy. 2013; 68: 402-6.

[57]

Katz LE, Gleich GJ, Hartley BF, Yancey SW, Ortega HG. Blood Eosinophil Count Is a Useful Biomarker to Identify Patients with Severe Eosinophilic Asthma. Ann Am Thorac Soc. 2014; 11: 531-6.

[58]

Bousquet J, Rabe K, Humbert M, Chung KF, Berger W, Fox H, et al. Predicting and evaluating response to omalizumab in patients with severe allergic asthma. Respir Med. 2007; 101: 1483-92.

[59]

Wahn U, Martin C, Freeman P, Blogg M, Jimenez P. Relationship between pretreatment specific IgE and the response to omalizumab therapy. Allergy. 2009; 64: 1780-7.

[60]

Bousquet J, Humbert M, Gibson PG, Kostikas K, Jaumont X, Pfister P, et al. Real-World Effectiveness of Omalizumab in Severe Allergic Asthma: A Meta-Analysis of Observational Studies. J Allergy Clin Immunol Pract. 2021; 9: 2702-14.

[61]

Agache I, Beltran J, Akdis C, Akdis M, Canelo-Aybar C, Canonica GW, et al. Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma. Allergy. 2020; 75: 1023-42.

[62]

Hanania NA, Wenzel S, Rosén K, Hsieh H, Mosesova S, Choy DF, et al. Exploring the Effects of Omalizumab in Allergic Asthma: An Analysis of Biomarkers in the EXTRA Study. Am J Respir Crit Care Med. 2013; 187: 804-11.

[63]

Humbert M, Taillé C, Mala L, Gros VL, Just J, Molimard M, et al. Omalizumab effectiveness in patients with severe allergic asthma according to blood eosinophil count: the STELLAIR study. Eur Respir J. 2018; 51: 1702523.

[64]

Albers FC, Licskai C, Chanez P, Bratton DJ, Bradford ES, Yancey SW, et al. Baseline blood eosinophil count as a predictor of treatment response to the licensed dose of mepolizumab in severe eosinophilic asthma. Respir Med. 2019; 159: 105806.

[65]

Bettiol A, Urban ML, Dagna L, Cottin V, Franceschini F, Giacco SD, et al. ; European EGPA Study Group. Mepolizumab for Eosinophilic Granulomatosis With Polyangiitis: A European Multicenter Observational Study. Arthritis Rheumatol. 2022; 74: 295-306.

[66]

Roufosse F, Kahn J, Rothenberg ME, Wardlaw AJ, Klion AD, Kirby SY, et al. Efficacy and safety of mepolizumab in hypereosinophilic syndrome: A phase III, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2020; 146: 1397-405.

[67]

Vultaggio A, Aliani M, Altieri E, Bracciale P, Brussino L, Caiaffa MF, et al. Long-term effectiveness of benralizumab in severe eosinophilic asthma patients treated for 96-weeks: data from the ANANKE study. Respir Res. 2023; 24: 135.

[68]

Harb H, Chatila TA. Mechanisms of Dupilumab. Clin Exp Allergy. 2020; 50: 5-14.

[69]

Wechsler ME, Ford LB, Maspero JF, Pavord ID, Papi A, Bourdin A, et al. Long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma (TRAVERSE): an open-label extension study. Lancet Respir Med. 2022; 10: 11-25.

[70]

Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, et al. Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med. 2018; 378: 2475-85.

[71]

Din ATU, Malik I, Arshad D, Din ATU. Dupilumab for Atopic Dermatitis: The Silver Bullet We Have Been Searching for? Cureus. 2020; 12: e7565.

[72]

Marone G, Spadaro G, Braile M, Poto R, Criscuolo G, Pahima H, et al. Tezepelumab: a novel biological therapy for the treatment of severe uncontrolled asthma. Expert Opin Investig Drugs. 2019; 28: 931-40.

[73]

Menzies-Gow A, Corren J, Bourdin A, Chupp G, Israel E, Wechsler ME, et al. Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma. N Engl J Med. 2021; 384: 1800-9.

[74]

Corren J, Pham T, Gil EG, Sałapa K, Ren P, Parnes JR, et al. Baseline type 2 biomarker levels and response to tezepelumab in severe asthma. Allergy. 2022; 77: 1786-96.

[75]

Wechsler ME, Menzies-Gow A, Brightling CE, Kuna P, Korn S, Welte T, et al. Evaluation of the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma (SOURCE): a randomised, placebo-controlled, phase 3 study. Lancet Respir Med. 2022; 10: 650-60.

[76]

Menzies-Gow A, Wechsler ME, Brightling CE, Korn S, Corren J, Israel E, et al. Long-term safety and efficacy of tezepelumab in people with severe, uncontrolled asthma (DESTINATION): a randomised, placebo-controlled extension study. Lancet Respir Med. 2023; 11: 425-38.

[77]

Gauvreau GM, O’Byrne PM, Boulet L, Wang Y, Cockcroft D, Bigler J, et al. Effects of an Anti-TSLP Antibody on Allergen-Induced Asthmatic Responses. N Engl J Med. 2014; 370: 2102-10.

[78]

Diver S, Khalfaoui L, Emson C, Wenzel SE, Menzies-Gow A, Wechsler ME, et al. Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir Med. 2021; 9: 1299-312.

[79]

Sverrild A, Hansen S, Hvidtfeldt M, Clausson C, Cozzolino O, Cerps S, et al. The effect of tezepelumab on airway hyperresponsiveness to mannitol in asthma (UPSTREAM). Eur Respir J. 2021; 59: 2101296.

[80]

Suhling H, Skowasch D, Bergmann K, Mümmler C, Buhl R, Ehmann R, et al. Initiation, response assessment, and switch of antibody therapies in patients with severe asthma - A survey among German specialists. World Allergy Organ J. 2023; 16: 100844.

PDF (1284KB)

0

Accesses

0

Citation

Detail

Sections
Recommended

/