References

pulmo

Пульмонология

PULMONOLOGIYA

0869-01892541-9617

Scientific and Practical Journal “PULMONOLOGIYA” LLC

10.18093/0869-0189-2019-29-2-216-228

pulmo-1148

Research Article

ОБЗОРЫ

REVIEW

Т2-бронхиальная астма: характеристика эндотипа и биомаркеры

Т2-high and T2-low bronchial asthma, endotype characteristics and biomarkers

Ненашева

Н. М.

Nenasheva

Natal'ya M.

Ненашева Наталья Михайловна – д. м. н., профессор кафедры клинической аллергологии Федерального государственного бюджетного образовательного учреждения дополнительного профессионального образования «Российская медицинская академия непрерывного профессионального образования» Министерства здравоохранения Российской Федерации; тел.: (499) 196-19-54;

123995, Москва, ул. Баррикадная, 2, стр. 1

Natal'ya M. Nenasheva, Doctor of Medicine, Professor, Department of Clinical Allergology, Russian Federal Academy of Continued Medical Education, Healthcare Ministry of Russia, tel.: (499) 196-19-54;

ul. Barrikadnaya 2/1, Moscow, 123995

1444031@gmail.com

Федеральное государственное бюджетное образовательное учреждение дополнительного профессионального образования «Российская медицинская академия непрерывного профессионального образования» Министерства здравоохранения Российской ФедерацииРоссияFederal State Budgetary Educational Institution of Further Professional Education "Russian Medical Academy of Continuing Professional Education" of the Ministry of Health of the Russian FederationRussian Federation

2019

01072019

292216228

2019

Ненашева Н.М.

Nenasheva N.M.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://journal.pulmonology.ru/pulm/article/view/1148

Бронхиальная астма (БА) – гетерогенное по своей природе и вариабельное по течению заболевание. Насущной задачей в оптимизации терапии БА, особенно тяжелой (ТБА), является установление патобиологических механизмов, лежащих в основе формирования фенотипов, или т. н. эндотипов БА. Несмотря на то, что автор настоящей статьи признает, что не-Т2-эндотип БА является не менее серьезной проблемой, настоящая статья посвящена Т2-эндотипу БА (Т2-БА), при этом акцент на изучении Т2-БА обусловлен тем фактом, что существующие на сегодняшний день биологические препараты предназначены именно для популяции пациентов с БА и Т2-опосредованным воспалением. В статье обсуждаются современные характеристики неконтролируемой, трудной для лечения и ТБА, механизмы формирования эозинофильного воспаления при Т2-БА, основные клетки и медиаторы, а также биомаркеры Т2-БА.

Bronchial asthma is a heterogeneous disease with variable course. Identification of pathobiological mechanisms of asthma phenotype, also called as asthma endotypes, is an urgent task to optimize treatment of asthma, especially of severe asthma. Although the author recognizes that T2-low asthma is a serious problem, this article is devoted to the T2-high asthma endotype. Currently, biological agents are available for T2-high asthma only, so the focus on T2 high asthma is important. Current characteristics of uncontrolled, difficult-to-treat and severe asthma, mechanisms of eosinophilic inflammation in T2-high asthma, main cells and mediators involved in the disease, and biomarkers of T2-high asthma were discussed in the article.

Т2-бронхиальная астматяжелая бронхиальная астмафенотипэндотипинтерлейкины-4-5-13биомаркеры Т2-воспалениябиологическая терапия бронхиальной астмы

T2-high asthmasevere asthmaphenotypeendotypeinterleukin 4interleukin 5interleukin 13biomarkers of T2 inflammationbiological therapy for asthma

References1

Soriano J.B., Abajobir A.A., Abate K.H. et al. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir. Med. 2017; 5 (9): 691–706. DOI: 10.1016/S2213-2600(17)30293-X.

Bousqet J., Mantzouranis E., Cruz A.A. et al. Uniform definition of asthma severity, control and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J. Allergy Clin. Immunol. 2010; 126 (5): 926–938. DOI: 10.1016/j.jaci.2010.07.019.

Chung K.F., Wenzel S.E., Brozek J.L. et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur. Respir. J. 2014; 43 (2): 343–373. DOI: 10.1183/09031936.00202013.

GINA 2018. Difficult-to-Treat & Severe Asthma in adolescent and adult patients: Diagnosis and management. A GINA Pocket Guide for Health Professionals. Available at: https://ginasthma.org/wp-content/uploads/2018/11/GINA-SA-FINAL-wms.pdf [Accessed: March 6, 2019].

Архипов В.В., Григорьева Е.В., Гавришина Е.В. Контроль над бронхиальной астмой в России: результаты многоцентрового наблюдательного исследования НИКА. Пульмонология. 2011; (6): 87–93.

Arkhipov V.V., Grigor’yeva E.V., Gavrishina E.V. [Asthma control in Russia: results of NIKA multi-center observational study]. Pul’monologiya. 2011; (6): 87–93 (in Russian).

Харитонс М.А., Рамазанова К.А. Современные представления о лечении бронхиальной астмы. Терра Медика Нова. 2001; (1). Доступно на: https://medi.ru/info/6513/ [Дата обращения: 06.03.19].

Kharitons M.A., Ramazanova K.A. [Current view on treatment of bronchial asthma]. Terra Medika Nova. 2001; (1). Available at: https://medi.ru/info/6513/ [Accessed: March 6, 2019] (in Russian).

Астафьева Н.Г., Гамова И.В., Удовиченко Е.Н. и др. Клинические фенотипы бронхиальной астмы у подростков: трудности диагностики и терапии. Лечащий врач. 2015; (4): 20–23.

Astaf’yeva N.G., Gamova I.V., Udovichenko E.N. et al. [Clinical phenotypes of asthma in adolescents, diagnostic and therapeutic problems]. Lechashchiy vrach. 2015; (4): 20–23 (in Russian).

Куличенко Т.В. Омализумаб у детей с бронхиальной астмой: показания к применению. Педиатрическая фармакология. 2007; 4 (6): 51–55.

Kulichenko T.V. [Omalizumab for children with bronchial asthma: indications]. Pediatricheskaya farmakologiya. 2007; 4 (6): 51–55 (in Russian).

Busse W.W., Banks-Schlegel S., Wenzel S.E. Pathophysiology of severe asthma. J. Allergy Clin. Immunol. 2000; 106 (6): 1033–1042. DOI: 10.1067/mai.2000.111307.

O'Byrne P.M., Naji N., Gauvreau G.M. Severe asthma: future treatments. Clin. Exp. Allergy. 2012; 42 (5): 706–711. DOI: 10.1111/j.1365-2222.2012.03965.x.

Hekking P.P., Wener R.R., Amelink M. et al. The prevalence of severe refractory asthma. J. Allergy Clin. Immunol. 2015; 135 (4): 896–902. DOI: 10.1016/j.jaci.2014.08.042.

Miller M.K., Lee J.H., Miller D.P., Wenzel S.E. Recent asthma exacerbations: a key predictor of future exacerbations. Respir. Med. 2007; 101 (3): 481–489. DOI: 10.1016/j.rmed.2006.07.005.

Bai T.R., Vonk J.M., Postma D.S., Boezen H.M. Severe exacerbations predict excess lung function decline in asthma. Eur. Respir. J. 2007; 30 (3): 452–456. DOI: 10.1183/09031936.00165106

Федеральные клинические рекомендации по диагностике и лечению бронхиальной астмы. М.: Российское респираторное общество, Российская ассоциация аллергологов и клинических иммунологов; 2018. Доступно на: http://spulmo.ru/obrazovatelnye-resursy/federalnye-klinicheskie-rekomendatsii/ [Дата обращения: 16.03.19].

Federal Guidelines on Diagnosis and Treatment of Bronchial Asthma. Moscow: Russian Respiratory Society, Russian Association of Allergologists and Clinical Immunologists, 2018. Available at: http://spulmo.ru/obrazovatelnye-resursy/federalnye-klinicheskie-rekomendatsii/ [Accessed 16.03.19] (in Russian).

Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Updated 2018. Available at: https://ginasthma.org/wp-content/uploads/2018/04/wms-GINA-2018-report-V1.3-002.pdf [Дата обращения: 16.03.19].

Ненашева Н.М. Бронхиальная астма. Современный взгляд на проблему. М.: ГЭОТАР-Медиа; 2018.

Nenasheva N.M. [Bronchial asthma. A state-of-art]. Moscow: GEOTAR-Media; 2018 (in Russian).

Anderson G.P. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet. 2008; 372 (9643): 1107–1019. DOI: 10.1016/S0140-6736(08)61452-X.

Woodruff P.G., Modrek B., Choy D.F. et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am. J. Respir. Crit. Care Med. 2009; 180 (5): 388–395. DOI: 10.1164/rccm.200903-0392OC.

Bhakta N.R., Woodruff P.G. Human asthma phenotypes: from the clinic, to cytokines, and back again. Immunol. Rev. 2011; 242 (1): 220–232. DOI: 10.1111/j.1600-065X.2011.01032.x.

Brusselle G.G., Maes T., Bracke K.R. Eosinophils in the spotlight: Eosinophilic airway inflammation in nonallergic asthma. Nat. Med. 2013; 19 (8): 977–979. DOI: 10.1038/nm.3300.

Wenzel S. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat. Med. 2012; 18 (5): 716–725. DOI: 10.1038/nm.2678.

Сергеева Г.Р., Емельянов А.В., Коровина О.В. и др. Тяжелая бронхиальная астма: характеристика пациентов в клинической практике. Терапевтический архив. 2015; 87 (12): 26–31. DOI: 10.17116/terarkh2015871226-31.

Sergeeva G.R., Emelyanov A.V., Korovina O.V. et al. [Severe asthma: description of patients in clinical practice]. Terapevticheskiy arkhiv. 2015; 87 (12): 26–31. DOI: 10.17116/terarkh2015871226-31 (in Russian).

Denlinger L.C., Phillips B.R., Ramrathan S. et al. Inflammatory and comorbid features of patients with severe asthma and frequent exacerbations. Am. J. Respir. Crit. Care Med. 2017; 195 (3): 302–313. DOI: 10.1164/rccm.201602-0419OC.

Kupczyk M., ten Brinke A., Sterk P.J. et al. Frequent exacerbators – a distinct phenotype of severe asthma. Clin. Exp. Allergy. 2013; 44 (2): 212–221. DOI: 10.1111/cea.12179.

Price D., Wilson A.M., Chisholm A. et al. Predicting frequent asthma exacerbations using blood eosinophil count and other patient data routinely available in clinical practice. J. Asthma Allergy. 2016; 9: 1–12. DOI: 10.2147/JAA.S97973.

Castro M., Zangrilli J., Wechlser M.E. et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicenter, parallel, double-blind, randomized, placebo-controlled, phase 3 trials. Lancet Respir. Med. 2015; 3 (5): 355–366. DOI: 10.1016/S2213-2600(15)00042-9.

Pavord I.D., Korn S., Howarth P. et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012; 380 (9842): 651–659. DOI: 10.1016/S0140-6736(12)60988-X.

Bleecker E.R., FitzGerald J.M., Chanez P. et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016; 388 (10056): 2115–2127. DOI: 10.1016/S0140-6736(16)31324-1.

Hanania N.A., Alpan O., Hamilos D.L. et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann. Intern. Med. 2011; 154 (9): 573–582. DOI: 10.7326/0003-4819-154-9-201105030-00002.

Katial R.K., Bensch G.W., Busse W.W. et al. Changing paradigms in the treatment of severe asthma: The role of biologic therapies. J. Allergy Clin. Immunol. Pract. 2017; 5 (2, Suppl.): S1–S14. DOI: 10.1016/j.jaip.2016.11.029.

Fajt M.L., Wenzel S.E. Development of new therapies for severe asthma. Allergy Asthma Immunol. Res. 2017; 9 (1): 3–14. DOI: 10.4168/aair.2017.9.1.3.

Israel E., Reddel H.K. Severe and difficult-to-treat asthma in adults. N. Engl. J. Med. 2017; 377 (10): 965–976. DOI: 10.1056/NEJMra1608969.

Li B.W., Hendriks R.W. Group 2 innate lymphoid cells in lung inflammation. Immunology. 2013; 140 (3): 281–287. DOI: 10.1111/imm.12153.

Kim H.Y., Umetsu D.Т., Dekruyff R.Н. Innate lymphoid cells in asthma: Will they take your breath away? Eur. J. Immunol. 2016; 46 (4): 795–806. DOI: 10.1002/eji.201444557.

Kau A.L., Korenblat P.E. Anti-interleukin 4 and 13 for asthma treatment in the era of endotypes. Curr. Opin. Allergy Clin. Immunol. 2014; 14 (6): 570–575. DOI: 10.1097/ACI.0000000000000108.

Gandhi N.A., Bennett B.L., Graham N.M. et al. Targeting key proximal drivers of type 2 inflammation in disease. Nat. Rev. Drug Discov. 2016; 15 (1): 35–50. DOI: 10.1038/nrd4624.

Coffman R.L. Converging discoveries: The first reports of IL-4. J. Immunol. 2013; 190 (3): 847–848. DOI: 10.4049/jimmunol.1203368.

Wills-Karp M. Interleukin-13 in asthma pathogenesis. Immunol. Rev. 2004; 202: 175–190. DOI: 10.1111/j.0105-2896.2004.00215.x

Brusselle G., Kips J., Joos G. et al. Allergen-induced airway inflammation and bronchial responsiveness in wild-type and interleukin-4-deficient mice. Am. J. Respir. Cell Mol. Biol. 1995; 12 (3): 254–259. DOI: 10.1165/ajrcmb.12.3.7873190.

Gavett S.H., O’Hearn D.J., Karp C.L. et al. Interleukin-4 receptor blockade prevents airway responses induced by antigen challenge in mice. Am. J. Physiol. 1997; 272 (2, Pt 1): L253–L261. DOI: 10.1152/ajplung.1997.272.2.L253.

Corry D.B., Folkesson H.G., Warnock M.L. et al. Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J. Exp. Med. 1996; 183 (1): 109–117. DOI: 10.1084/jem.183.1.109.

Henderson W.R. Jr, Chi E.Y., Maliszewski C.R. Soluble IL-4 receptor inhibits airway inflammation following allergen challenge in a mouse model of asthma. J. Immunol. 2000; 164 (2): 1086–1095. DOI: 10.4049/jimmunol.164.2.1086.

Dabbagh K., Takeyama K., Lee H.M. et al. IL-4 induces mucin gene expression and goblet cell metaplasia in vitro and in vivo. J. Immunol. 1999; 162 (10): 6233–6237.

Tepper R.I., Levinson D.А., Stanger B.Z. et al. IL-4 induces allergic-like inflammatory disease and alters T cell development in transgenic mice. Cell. 1990; 62 (3): 457–467.

Wills-Karp M., Luyimbazi J., Xu X. et al. Interleukin-13: central mediator of allergic asthma. Science. 1998; 282 (5397): 2258–2261.

Grünig G., Warnock M., Wakil A. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science. 1998; 282 (5397): 2261–2263.

Zhu Z., Homer R.J., Wang Z. et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J. Clin. Invest. 1999; 103 (6): 779–788. DOI: 10.1172/JCI5909.

Webb D.C., McKenzie A.N., Koskinen A.M. et al. Integrated signals between IL-13, IL-4, and IL-5 regulate airways hyperreactivity. J. Immunol. 2000; 165 (1): 108–113. DOI: 10.4049/jimmunol.165.1.108.

Kuperman D.A., Huang X., Koth L.L. et al. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat. Med. 2002; 8 (8): 885–889. DOI: 10.1038/nm734.

Gour N., Wills-Karp M. IL-4 and IL-13 signaling in allergic airway disease. Cytokine. 2015; 75 (1): 68–78. DOI: 10.1016/j.cyto.2015.05.014.

Rosenberg H.F., Dyer K.D., Foster P.S. Eosinophils: changing perspectives in health and disease. Nat. Rev. Immunol. 2013; 13 (1): 9–22. DOI: 10.1038/nri3341.

Louis R., Sele J., Henket M. et al. Sputum eosinophil count in a large population of patients with mild to moderate steroid-naive asthma: distribution and relationship with methacholine bronchial hyperresponsiveness. Allergy. 2002; 57 (10): 907–912.

Chung K.F. Personalised medicine in asthma: time for action. Eur. Respir. Rev. 2017; 26 (145): pii: 170064. DOI: 10.1183/16000617.0064-2017.

Ненашева Н.М. Значение биомаркеров в диагностике и терапии бронхиальной астмы. Практическая пульмонология. 2017; (4): 3–9.

Nenasheva N.M. [A role of biomarkers for diagnosis and treatment of asthma]. Prakticheskaya pul’monologiya. 2017; (4): 3–9 (in Russian).

de Groot J.C., Storm H., Amelink M. et al. Clinical profile of patients with adult-onset eosinophilic asthma. ERJ Open Res. 2016; 2 (2): pii: 00100-2015. DOI: 10.1183/23120541.00100-2015.

de Groot J.C., Ten Brinke A., Bel E.H. Management of the patient with eosinophilic asthma: a new era begins. ERJ Open Res. 2015; 1 (1): pii: 00024-2015. DOI: 10.1183/23120541.00024-2015.

Haldar P., Brightling C.E., Hargadon B. et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N. Engl. J. Med. 2009; 360 (10): 973–984. DOI: 10.1056/NEJMoa0808991.

Castro M., Mathur S., Hargreave F. et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am. J. Respir. Crit. Care Med. 2011; 184 (10): 1125–1132. DOI: 10.1164/rccm.201103-0396OC.

Wenzel S., Ford L., Pearlman D. et al. Dupilumab in persistent asthma with elevated eosinophil levels. N. Engl. J. Med. 2013; 368 (26): 2455–2466. DOI: 10.1056/NEJMoa1304048.

Castro M., Wenzel S.E., Bleecker E.R. et al. Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir. Med. 2014; 2 (11): 879–890. DOI: 10.1016/S2213-2600(14)70201-2.

Castro M., Corren J., Pavord I.D. et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N. Engl. J. Med. 2018; 378 (26): 2486–2496. DOI: 10.1056/NEJMoa1804092.

Fitzpatrick A.M. Biomarkers of asthma and allergic airway diseases. Ann. Allergy Asthma Immunol. 2015; 115 (5): 335–340. DOI: 10.1016/j.anai.2015.09.003.

Dweik R.A., Boggs P.B., Erzurum S.C. et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am. J. Respir. Crit. Care Med. 2011; 184 (5): 602–615. DOI: 10.1164/rccm.9120-11ST.

Smith A.D., Cowan J.O., Brasset K.P. et al. Exhaled nitric oxide: A predictor of steroid response. Am. J. Respir. Crit. Care Med. 2005; 172 (4): 453–459. DOI: 10.1164/rccm.200411-1498OC.

Hanania N.A., Wenzel S., Rosén K. et al. Exploring the effect of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am. J. Respir. Crit. Care Med. 2013; 187 (8): 804–811. DOI: 10.1164/rccm.201208-1414OC.

The authors declare that there are no conflicts of interest present.