References

pulmo

Пульмонология

PULMONOLOGIYA

0869-01892541-9617

Scientific and Practical Journal “PULMONOLOGIYA” LLC

10.18093/0869-0189-2021-31-3-272-295

pulmo-2364

Research Article

КЛИНИЧЕСКИЕ РЕКОМЕНДАЦИИ

CLINICAL GUIDELINES

Лечение тяжелой бронхиальной астмы: рекомендации Европейского респираторного общества и Американского торакального общества

Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline

https://orcid.org/0000-0003-0979-8234

Holguin

сопредседатель со стороны ATS

Кафедра пульмонологии и медицины критических состояний

Денвер

Fernando Holguin is ERS co-chair

Pulmonary Sciences and Critical Care Medicine

CU Anschutz Research Complex II, 12700 East 19th Avenue, 9C03, Aurora, CO 80045

fernando.holguin@ucdenver.edu

https://orcid.org/0000-0002-9731-4828

Cardet

J. C.

Cardet

J. C.

Кафедра аллергологии и иммунологии

Тампа

Juan Carlos Cardet

Allergy and Immunology

Tampa

Chung

K. F.

Chung

K. F.

Отделение экспериментальной медицины и исследований, Национальный институт сердца и легкого

Лондон

Kian Fan Chung

Experimental Studies Medicine, National Heart and Lung Institute

London

Diver

Отделение респираторной биомедицины

Лейчестер

Sarah Diver

Respiratory Biomedical Unit

Leicester

Ferreira

D. S.

Ferreira

D. S.

Отделение аллергологии и иммунологии, Больнично-клинический комплексКуритиба

Школа общественного здоровья и профилактической медициныМельбурн, Австралия

Diogenes S. Ferreira

Alergia e Imunologia, Complexo Hospital de ClinicasCuritiba

School of Public Health and Preventive MedicineMelbourne

Fitzpatrick

Отделение пульмонологии, аллергологии и иммунологии, муковисцидоза и сна

Атланта

Anne Fitzpatrick

Division of Pulmonology Allergy/Immunology, Cystic Fibrosis and Sleep

Atlanta

https://orcid.org/0000-0002-9949-6012

Gaga

Отделение респираторной медицины и центр бронхиальной астмы

Афины

Mina Gaga

Respiratory Medicine Dept and Asthma Centre

Athens

https://orcid.org/0000-0001-6115-4343

Kellermeyer

Биомедицинская библиотека

Денвер

Liz Kellermeyer

Biomedical Library

Denver

Khurana

Кафедра пульмонологии и критических состояний

Рочестер

Sandhya Khurana

Pulmonary Diseases and CriticalCare

Rochester

Knight

Биомедицинская библиотека

Денвер

Shandra Knight

Biomedical Library

Denver

McDonald

V. M.

McDonald

V. M.

Школа медицинских сестер

Ньюкасл

Vanessa M. McDonald

School of Nursing

Newcastle

Morgan

R. L.

Morgan

R. L.

Кафедра методов исследования здоровья, доказательных данных и оценки воздействия

Гамильтон

Rebecca L. Morgan

Health Research Methods, Evidence and Impact

Hamilton

Ortega

V. E.

Ortega

V. E.

Кафедра пульмонологии, медицины критических состояний, аллергических и иммунологических заболеваний

Уинстон-Сейлем

Victor E. Ortega

Pulmonary, Critical Care, Allergy and Immunologic Diseases

Winston-Salem

Rigau

Барселона

David Rigau

Barcelona

Subbarao

Педиатрическое отделение

Торонто

Padmaja Subbarao

Dept of Pediatrics

Toronto

Tonia

Институт социальной и профилактической медицины

Берн

Thomy Tonia

Institute of Social and Preventive Medicine

Bern

Adcock

I. M.

Adcock

I. M.

Группа молекулярно-клеточной биологиии, Национальный институт сердца и легкого

Лондон

Ian M. Adcock

Molecular Cell Biology Group, National Heart and Lung Institute

London

Bleecker

E. R.

Bleecker

E. R.

Отделение генетики, кафедра геномики и точной медицины

Тусон

Eugene R. Bleecker

Division of Genetics, Genomics and Precision Medicine

Tucson

Brightling

Отделение респираторных исследований

Лейчестер

Chris Brightling

Dept of Respiratory Sciences

Leicester

Boulet

L. P.

Boulet

L. P.

Отделение респираторной медицины

Квебек

Louis-Philippe Boulet

Respiratory Medicine

Quebec

Cabana

Отделение общей педиатрии

Сан-Франциско

Michael Cabana

Division of General Pediatrics

San Francisco

Castro

Кафедра пульмонологии и медицины критических состояний

Сент-Луис

Mario Castro

Division of Pulmonary and Critical Care Medicine

St Louis

Chanez

Кафедра респираторных заболеваний

Марсель

Pascal Chanez

Dept of Respiratory Diseases

Marseille

Custovic

Кафедра педиатрических аллергических заболеваний, Национальный институт сердца и легкого

Лондон

Adnan Custovic

Paediatric Allergy, National Heart and Lung Institute

London

Djukanovic

Отделение респираторных биомедицинских исследований

Саутгемптон

Ratko Djukanovic

Respiratory Biomedical Research

Southampton

Frey

Кафедра педиатрии

Базель

Urs Frey

Dept of Pediatrics

Basel

Frankemölle

Лозанна

Betty Frankemölle

Lausanne

https://orcid.org/0000-0001-5865-489X

Gibson

Школа медицины и общественного здоровья

Ньюкасл

Peter Gibson

School of Medicine and Public Health

Newcastle

https://orcid.org/0000-0001-8464-0547

Hamerlijnck

Лозанна

Dominique Hamerlijnck

Lausanne

Jarjour

Биомедицинская библиотека

Денвер

Nizar Jarjour

Biomedical Library

Denver

Konno

Отделение респираторной медицины, факультет медицины и Высшая медицинская школа

Хоккайдо

Satoshi Konno

Dept of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine

Hokkaido

Shen

Кафедра респираторной медицины и медицины критических состояний

Ханчжоу

Huahao Shen

Dept of Respiratory and Critical Care Medicine

Hangzhou

Vitary

Институт бронхиальной астмы

Питтсбург

Cathy Vitary

Asthma Institute

Pittsburgh

Bush

Кафедра педиатрии, Национальный институт сердца и легкого

сопредседатель со стороны ERS

Лондон

Andy Bush is ERS co-chair

Dept of Paediatrics

London

Университет КолорадоСоединённые Штаты АмерикиUniversity of ColoradoUnited States

Университет Южной ФлоридыСоединённые Штаты АмерикиUniversity of South FloridaUnited States

Имперский колледж ЛондонаВеликобританияImperial College LondonUnited Kingdom

Университет ЛейчестераВеликобританияUniversity of LeicesterUnited Kingdom

Федеральный университет Параны; Университет МонашаБразилияUniversidade Federal do Parana; Monash UniversityBrazil

Университет ЭмориСоединённые Штаты АмерикиEmory UniversityUnited States

Торакальный госпитальГрецияAthens Chest HospitalGreece

Больница «Национальное еврейское здоровье»Соединённые Штаты АмерикиNational Jewish HealthUnited States

Университет РочестераСоединённые Штаты АмерикиUniversity of RochesterUnited States

Университет НьюкаслаАвстралияUniversity of NewcastleAustralia

Университет МакмастераКанадаMcMaster UniversityCanada

Медицинская школа Уэйк-Форест,Соединённые Штаты АмерикиWake Forest School of MedicineUnited States

Ибероамериканский центр КохрейнаИспанияIberoamerican Cochrane CentreSpain

Больница СикКидсКанадаSickKidsCanada

Университет БернаШвейцарияUniversity of BernSwitzerland

Имперский Колледж ЛондонаВеликобританияImperial College of LondonUnited Kingdom

Университет АризоныСоединённые Штаты АмерикиUniversity of ArizonaUnited States

Университет ЛаваляКанадаLaval UniversityCanada

Калифорнийский университет Сан-ФранцискоСоединённые Штаты АмерикиUniversity of California San FranciscoUnited States

Вашингтонский университетСоединённые Штаты АмерикиWashington UniversityUnited States

Университет Экс-МарсельФранцияUniversity of Aix-MarseilleFrance

Имперский колледж ЛондонаВеликобританияImperial College of LondonUnited Kingdom

Университет СаутгемптонаВеликобританияUniversity of SouthamptonUnited Kingdom

Университетская детская больницаШвейцарияUniversity Children’s HospitalSwitzerland

Европейский легочный фондШвейцарияEuropean Lung FoundationSwitzerland

Университет ХоккайдоЯпонияHokkaido UniversityJapan

Вторая больница при медицинском факультете Чжэцзянского университетаКитайThe Second Affiliated Hospital of Zhejiang University School of MedicineChina

Университет ПиттсбургаСоединённые Штаты АмерикиUniversity of PittsburghUnited States

Имперский колледж ЛондонаВеликобританияImperial College London, National Heart and Lung InstituteUnited Kingdom

2021

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Copyright © Holguin F., Cardet J., Chung K.F., Diver S., Ferreira D.S., Fitzpatrick A., Gaga M., Kellermeyer L., Khurana S., Knight S., McDonald V.M., Morgan R.L., Ortega V.E., Rigau D., Subbarao P., Tonia T., Adcock I.M., Bleecker E.R., Brightling C., Boulet L., Cabana M., Castro M., Chanez P., Custovic A., Djukanovic R., Frey U., Frankemölle B., Gibson P., Hamerlijnck D., Jarjour N., Konno S., Shen H., Vitary C., Bush A., 2021

2021

Holguin F., Cardet J., Chung K., Diver S., Ferreira D.S., Fitzpatrick A., Gaga M., Kellermeyer L., Khurana S., Knight S., McDonald V.M., Morgan R.L., Ortega V.E., Rigau D., Subbarao P., Tonia T., Adcock I.M., Bleecker E.R., Brightling C., Boulet L., Cabana M., Castro M., Chanez P., Custovic A., Djukanovic R., Frey U., Frankemölle B., Gibson P., Hamerlijnck D., Jarjour N., Konno S., Shen H., Vitary C., Bush A.

Holguin F., Cardet J., Chung K.F., Diver S., Ferreira D.S., Fitzpatrick A., Gaga M., Kellermeyer L., Khurana S., Knight S., McDonald V.M., Morgan R.L., Ortega V.E., Rigau D., Subbarao P., Tonia T., Adcock I.M., Bleecker E.R., Brightling C., Boulet L., Cabana M., Castro M., Chanez P., Custovic A., Djukanovic R., Frey U., Frankemölle B., Gibson P., Hamerlijnck D., Jarjour N., Konno S., Shen H., Vitary C., Bush A.

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/2364

В документе изложены клинические рекомендации по лечению тяжелой бронхиальной астмы (БА). Проведено подробное обобщение доказательных данных, в т. ч. метаанализов, для анализа всех имеющихся доказательств по вопросам, сформулированным объединенной рабочей группой Европейского респираторного (European Respiratory Society – ERS) и Американского торакального (American Thoracic Society – ATS) обществ. Доказательства оценивались по методике GRADE (Grading of Recommendations, Assessment, Development and Evaluation). Мультидисциплинарной рабочей группой экспертов по БА обсуждались обобщенные доказательные данные и сформулированы рекомендации в форме ответов на 6 конкретных вопросов. После сопоставления желательных и нежелательных последствий, качества доказательных данных, доступности и приемлемости различных вмешательств рабочей группой сформулированы следующие предложения:

• использовать антитела к интерлейкину (IL)-5 и рецептору IL-5 у взрослых больных тяжелой неконтролируемой эозинофильной БА;• начинать анти-IL-5-терапию у взрослых больных с тяжелой БА при уровне эозинофилов в периферической крови ≥ 150 кл. / мкл;• использовать пограничные значения для выявления подростков и взрослых с наиболее вероятной эффективностью анти-IgE-терапии при уровне эозинофилов в крови ≥ 260 кл. / мкл и фракции оксида азота в выдыхаемом воздухе ≥ 19,5 ppb;• использовать ингаляционный тиотропия бромид у подростков и взрослых с тяжелой БА, не контролируемой терапией 4–5-й ступени согласно Глобальной инициативе по БА (Global Initiative for Asthma – GINA), или терапию 5-й ступени согласно Национальной программе по обучению больных и профилактике БА (National Asthma Education and Prevention Program – NAEPP);• для снижения частоты обострений БА у пациентов с персистирующими симптомами или БА, не контролируемой терапией 5-й ступени по GINA или NAEPP, независимо от фенотипа БА, применять пробную долговременную терапию макролидами;• использовать антитела к IL-4, -13 у взрослых пациентов с тяжелой эозинофильной или глюкокортикостероид-зависимой БА, независимо от уровня эозинофилов в крови.

При появлении новых доказательств эти рекомендации могут быть пересмотрены.

This document provides clinical recommendations for the management of severe asthma. Comprehensive evidence syntheses, including metaanalyses, were performed to summarise all available evidence relevant to the European Respiratory Society/American Thoracic Society Task Force’s questions. The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of asthma experts, who made specific recommendations on six specific questions. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made the following recommendations:

• suggest using anti-interleukin (IL)-5 and anti-IL-5 receptor α for severe uncontrolled adult eosinophilic asthma phenotypes;• suggest using a blood eosinophil cut-point ≥150 μL−1 to guide anti-IL-5 initiation in adult patients with severe asthma;• suggest considering specific eosinophil (≥260 μL−1) and exhaled nitric oxide fraction (≥19.5 ppb) cut-offs to identify adolescents or adults with the greatest likelihood of response to anti-IgE therapy;• suggest using inhaled tiotropium for adolescents and adults with severe uncontrolled asthma despite Global Initiative for Asthma (GINA) step 4 – 5 or National Asthma Education and Prevention Program (NAEPP) step 5 therapies;• suggest a trial of chronic macrolide therapy to reduce asthma exacerbations in persistently symptomatic or uncontrolled patients on GINA step 5 or NAEPP step 5 therapies, irrespective of asthma phenotype;• suggest using anti-IL-4/13 for adult patients with severe eosinophilic asthma and for those with severe corticosteroid-dependent asthma regardless of blood eosinophil levels.

These recommendations should be reconsidered as new evidence becomes available.

Данная работа финансировалась ERS и ATS. Сведения о финансировании в рамках подготовки настоящей статьи были переданы в реестр финансирования Crossref Funder Registry.

With thanks to the European Lung Foundation severe asthma patient advisory group who provided input on patient views and preferences via teleconferences, through their attendance at the ATS and ERS Congresses, and in writing.

References1

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.

Guyatt G.H., Oxman A.D., Vist G.E. et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008; 336: 924–926. DOI: 10.1136/bmj.39489.470347.AD.

Wedzicha J., Miravitlles M., Hurst J.R. et al. Management of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur. Respir. J. 2017; 49 (3): 1600791. DOI: 10.1183/13993003.00791-2016.

Wedzicha J.A., Calverley P.M.A., Albert R.K. et al. Prevention of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur. Respir. J. 2017; 50 (3): 1602265. DOI: 10.1183/13993003.02265-2016.

Santanello N.C., Zhang J., Seidenberg B. et al. What are minimal important changes for asthma measures in a clinical trial? Eur. Respir. J. 1999; 14 (1): 23–27. DOI: 10.1034/j.1399-3003.1999.14a06.x.

Juniper E.F., Svensson K., Mork A.C. et al. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir. Med. 2005; 99 (5): 553–558. DOI: 10.1016/j.rmed.2004.10.008.

Juniper E.F., Guyatt G.H., Willan A., Griffith L.E. Determining a minimal important change in a disease-specific quality of life questionnaire. J. Clin. Epidemiol. 1994; 47 (1): 81–87. DOI: 10.1016/0895-4356(94)90036-1.

Bel E.H., Wenzel S.E., Thompson P.J. et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N. Engl. J. Med. 2014; 371 (13): 1189–1197. DOI: 10.1056/NEJMoa1403291.

Ortega H.G., Liu M.C., Pavord I.D. et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N. Engl. J. Med. 2014; 371 (13): 1198–1207. DOI: 10.1056/NEJMoa1403290.

Chupp G.L., Bradford E.S., Albers F.C. et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir. Med. 2017; 5 (5): 390–400. DOI: 10.1016/S2213-2600(17)30125-X.

Bjermer L., Lemiere C., Maspero J. et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest. 2016; 150 (4): 789–798. DOI: 10.1016/j.chest.2016.03.032.

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.

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

Corren J., Weinstein S., Janka L. et al. Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. 2016; 150 (4): 799–810. DOI: 10.1016/j.chest.2016.03.018.

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.

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.

FitzGerald J.M., Bleecker E.R., Nair P. et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016; 388 (10056): 2128–2141. DOI: 10.1016/S0140-6736(16)31322-8.

Nair P., Wenzel S., Rabe K.F. et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N. Engl. J. Med. 2017; 376 (25): 2448–2458. DOI: 10.1056/NEJMoa1703501.

Park H.S., Kim M.K., Imai N. et al. A phase 2a study of benralizumab for patients with eosinophilic asthma in South Korea and Japan. Int. Arch. Allergy Immunol. 2016; 169: 135–145. DOI: 10.1159/000444799.

Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. 2019. Available at: http://ginasthma.org/2019-gina-report-global-strategy-for-asthma-management-and-prevention [Accessed: October 28, 2019].

National Institute for Health and Care Excellence. Mepolizumab for treating severe refractory eosinophilic asthma. TA431. 2017. Available at: www.nice.org.uk/guidance/ta431 [Accessed: October 1, 2019].

National Institute for Health and Care Excellence. Reslizumab for treating severe eosinophilic asthma. TA479. 2017. Available at: www.nice.org.uk/guidance/ta479 [Accessed: October 01, 2019].

National Institute for Health and Care Excellence. Benralizumab for treating severe eosinophilic asthma. TA565. 2019. Available at: www.nice.org.uk/guidance/ta565 [Accessed: October 01, 2019].

Institute for Clinical and Economic Review. Biologic therapies for treatment of asthma associated with type 2 inflammation: effectiveness, value, and value-based price benchmarks. 2018. Available at: https://icer-review.org/wp-content/uploads/2018/04/ICER_Asthma_Draft_Report_092418v1.pdf [Accessed: October 01, 2019].

Nair P., Pizzichini M.M., Kjarsgaard M. et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N. Engl. J. Med. 2009; 360 (10): 985–993. DOI: 10.1056/NEJMoa0805435.

Ortega H.G., Yancey S.W., Mayer B. et al. 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.

Mukherjee M., Aleman Paramo F., Kjarsgaard M. et al. Weight-adjusted intravenous reslizumab in severe asthma with inadequate response to fixed-dose subcutaneous mepolizumab. Am. J. Respir. Crit. Care Med. 2018; 197 (1): 38–46. DOI: 10.1164/rccm.201707-1323OC.

Khatri S., Moore W., Gibson P.G. et al. Assessment of the long-term safety of mepolizumab and durability of clinical response in patients with severe eosinophilic asthma. J. Allergy Clin. Immunol. 2019; 143 (5): 1742–1751. DOI: 10.1016/j.jaci.2018.09.033.

Busse W.W., Bleecker E.R., FitzGerald J.M. et al. Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial. Lancet Respir. Med. 2019; 7 (1): 46–59. DOI: 10.1016/S2213-2600(18)30406-5.

National Institute for Health and Care Excellence. Asthma: diagnosis, monitoring and chronic asthma management. 2017. Available at: www.nice.org.uk/guidance/ng80 [Accessed: October 28, 2019].

Ledford D., Busse W., Trzaskoma B. et al. A randomized multicenter study evaluating Xolair persistence of response after long-term therapy. J. Allergy Clin. Immunol. 2017; 140 (1): 162–169. DOI: 10.1016/j.jaci.2016.08.054.

Hanania N.A., Wenzel S., Rosen K. 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 (8): 804–811. DOI: 10.1164/rccm.201208-1414OC.

Busse W., Spector S., Rosen K. et al. High eosinophil count: a potential biomarker for assessing successful omalizumab treatment effects. J. Allergy Clin. Immunol. 2013; 132 (2): 485–486. DOI: 10.1016/j.jaci.2013.02.032.

Izuhara K., Ohta S., Ono J. Using periostin as a biomarker in the treatment of asthma. Allergy Asthma Immunol. Res. 2016; 8 (6): 491–498. DOI: 10.4168/aair.2016.8.6.491.

Casale T.B., Chipps B.E., Rosen K. et al. Response to omalizumab using patient enrichment criteria from trials of novel biologics in asthma. Allergy. 2018; 73 (2): 490–497. DOI: 10.1111/all.13302.

Busse W., Corren J., Lanier B.Q. et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J. Allergy Clin. Immunol. 2001; 108 (2): 184–190. DOI: 10.1067/mai.2001.117880.

Soler M., Matz J., Townley R. et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur. Respir. J. 2001; 18 (2): 254–261. DOI: 10.1183/09031936.01.00092101.

Humbert M., Taille C., Mala L. et al. Omalizumab effectiveness in patients with severe allergic asthma according to blood eosinophil count: the STELLAIR study. Eur. Respir. J. 2018; 51 (5): 1702523. DOI: 10.1183/13993003.02523-2017.

British Thoracic Society, Scottish Intercollegiate Guidelines Network. British Guideline on the Management of Asthma. SIGN 158. 2019. Available at: www.sign.ac.uk [Accessed: October 28, 2019].

Kerstjens H.A.M., Disse B., Schroder-Babo W. et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J. Allergy Clin. Immunol. 2011; 128 (2): 308–314. DOI: 10.1016/j.jaci.2011.04.039.

Kerstjens H.A.M., Engel M., Dahl R. et al. Tiotropium in asthma poorly controlled with standard combination therapy. N. Engl. J. Med. 2012; 367 (13): 1198–1207. DOI: 10.1056/NEJMoa1208606.

Hamelmann E., Bernstein J.A., Vandewalker M. et al. A randomised controlled trial of tiotropium in adolescents with severe symptomatic asthma. Eur. Respir. J. 2017; 49 (1): 1601100. DOI: 10.1183/13993003.01100-2016.

Kerwin E., Wachtel A., Sher L. et al. Efficacy, safety, and dose response of glycopyrronium administered by metered dose inhaler using co-suspension delivery technology in subjects with intermittent or mild-to-moderate persistent asthma: a randomized controlled trial. Respir. Med. 2018; 139: 39–47. DOI: 10.1016/j.rmed.2018.04.013.

Lee L.A., Briggs A., Edwards L.D. et al. A randomized, three-period crossover study of umeclidinium as monotherapy in adult patients with asthma. Respir. Med. 2015; 109 (1): 63–73. DOI: 10.1016/j.rmed.2014.10.009.

Lee L.A., Yang S., Kerwin E. et al. The effect of fluticasone furoate/umeclidinium in adult patients with asthma: a randomized, dose-ranging study. Respir. Med. 2015; 109 (1): 54–62. DOI: 10.1016/j.rmed.2014.09.012.

Peters S.P., Bleecker E.R., Kunselman S.J. et al. Predictors of response to tiotropium versus salmeterol in asthmatic adults. J. Allergy Clin. Immunol. 2013; 132 (5): 1068–1074. DOI: 10.1016/j.jaci.2013.08.003.

Kerstjens H.A., Moroni-Zentgraf P., Tashkin D.P. et al. Tiotropium improves lung function, exacerbation rate, and asthma control, independent of baseline characteristics including age, degree of airway obstruction, and allergic status. Respir. Med. 2016; 117: 198–206. DOI: 10.1016/j.rmed.2016.06.013.

Szefler S.J., Murphy K., Harper T. 3 rd et al. A phase III randomized controlled trial of tiotropium add-on therapy in children with severe symptomatic asthma. J. Allergy Clin. Immunol. 2017; 140 (5): 1277–1287. DOI: 10.1016/j.jaci.2017.01.014.

National asthma education and prevention program. Guidelines for the diagnosis and management of asthma 2007 (EPR-3). Available at: www.nhlbi.nih.gov/health-topics/guidelines-for-diagnosis-management-of-asthma [Accessed: October 28, 2019].

Brusselle G.G., VanderStichele C., Jordens P. et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013; 68 (4): 322–329. DOI: 10.1136/thoraxjnl-2012-202698.

Gibson P.G., Yang I.A., Upham J.W. et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017; 390 (10095): 659–668. DOI: 10.1016/S0140-6736(17)31281-3.

Strunk R.C., Bacharier L.B., Phillips B.R. et al. Azithromycin or montelukast as inhaled corticosteroid-sparing agents in moderate-to-severe childhood asthma study. J. Allergy Clin. Immunol. 2008; 122 (6): 1138–1144. DOI: 10.1016/j.jaci.2008.09.028.

Hahn D.L., Grasmick M., Hetzel S., Yale S. Azithromycin for bronchial asthma in adults: an effectiveness trial. J. Am. Board Fam. Med. 2012; 25 (4): 442–459. DOI: 10.3122/jabfm.2012.04.110309.

Sutherland E.R., King T.S., Icitovic N. et al. A trial of clarithromycin for the treatment of suboptimally controlled asthma. J. Allergy Clin. Immunol. 2010; 126 (4): 747–753. DOI: 10.1016/j.jaci.2010.07.024.

Simpson J.L., Powell H., Boyle M.J. et al. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am. J. Respir. Crit. Care Med. 2008; 177 (2): 148–155. DOI: 10.1164/rccm.200707-1134OC.

Taylor S.L., Leong L.E.X., Mobegi F.M. et al. Long-term azithromycin reduces Haemophilus influenzae and increases antibiotic resistance in severe asthma. Am. J. Respir. Crit. Care Med. 2019; 200 (3): 309–317. DOI: 10.1164/rccm.201809-1739OC.

British Thoracic Society, Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. 2016. SIGN 153. Available at: www.brit-thoracic.org.uk/quality-improvement/guidelines/asthma [Accessed: October 28, 2019].

Wenzel S., Castro M., Corren J. et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of mediumto-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomized double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016; 388 (10039): 31–44. DOI: 10.1016/S0140-6736(16)30307-5.

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.

Rabe K.F., Nair P., Brusselle G. et al. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N. Engl. J. Med. 2018; 378 (26): 2475–2485. DOI: 10.1056/NEJMoa1804093.

B rown T., Jones T., Gove K. et al. Randomised controlled trials in severe asthma: selection by phenotype or stereotype. Eur. Respir. J. 2018; 52 (6): 1801444. DOI: 10.1183/13993003.01444-2018.

Agusti A., Bel E., Thomas M. et al. Treatable traits: toward precision medicine of chronic airway diseases. Eur. Respir. J. 2016; 47 (2): 410–419. DOI: 10.1183/13993003.01359-2015.

Pavord I.D., Beasley R., Agusti A. et al. After asthma: redefining airways diseases. Lancet. 2018; 391 (10118): 350–400. DOI: 10.1016/S0140-6736(17)30879-6.

Shrimanker R., Beasley R., Kearns C. Letting the right one in: evaluating the generalisability of clinical trials. Eur. Respir. J. 2018; 52 (6): 1802218. DOI: 10.1183/13993003.02218-2018.

Pavord I.D., Chanez P., Criner G.J. et al. Mepolizumab for eosinophilic chronic obstructive pulmonary disease. N. Engl. J. Med. 2017; 377 (17): 1613–1629. DOI: 10.1056/NEJMoa1708208.

Kerkhof M., Sonnappa S., Postma D.S. et al. Blood eosinophil count and exacerbation risk in patients with COPD. Eur. Respir. J. 2017; 50 (1): 1700761. DOI: 10.1183/13993003.00761-2017.

Levy M.L., Winter R. Asthma deaths: what now? Thorax. 2015; 70 (3): 209–210. DOI: 10.1136/thoraxjnl-2015-206800.

Royal College of Physicians. National Review of Asthma Deaths 2012–2013. 2015. Available at: www.rcplondon.ac.uk/projects/national-review-asthma-deaths [Accessed: October 01, 2019].

Bush A., Saglani S., Fleming L. Severe asthma: looking beyond the amount of medication. Lancet Respir. Med. 2017; 5 (11): 844–846. DOI: 10.1016/S2213-2600(17)30379-X.

Green R.H., Shaw D. Strict adherence rules to obtain monoclonal therapy might cost lives. Lancet Respir. Med. 2017; 5 (9): 678–679. DOI: 10.1016/S2213-2600(17)30238-2.

Andersson C.K., Adams A., Nagakumar P. et al. Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function. J. Allergy Clin. Immunol. 2017; 139 (6): 1819–1829. DOI: 10.1016/j.jaci.2016.09.022.

Bossley C.J., Fleming L., Gupta A. et al. Pediatric severe asthma is characterized by eosinophilia and remodeling without TH 2 cytokines. J. Allergy Clin. Immunol. 2012; 129 (4): 974–982. DOI: 10.1016/j.jaci.2012.01.059.

Kuo C.S., Pavlidis S., Loza M. et al. 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): 1602135. DOI: 10.1183/13993003.02135-2016.

Travers J., Rothenberg M.E. Eosinophils in mucosal immune responses. Mucosal. Immunol. 2015; 8 (3): 464–475. DOI: 10.1038/mi.2015.2.

Normansell R., Walker S., Milan S.J. et al. Omalizumab for asthma in adults and children. Cochrane Database Syst. Rev. 2014; (1): CD003559. DOI: 10.1002/14651858.CD003559.pub4.

Corren J., Kavati A., Ortiz B. et al. Efficacy and safety of omalizumab in children and adolescents with moderate-to-severe asthma: a systematic literature review. Allergy Asthma Proc. 2017; 38 (4): 250–263. DOI: 10.2500/aap.2017.38.4067.

Odajima H., Ebisawa M., Nagakura T. et al. Long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with severe uncontrolled asthma. Allergol. Int. 2017; 66 (1): 106–115. DOI: 10.1016/j.alit.2016.06.004.

Saglani S., Bush A., Carroll W. et al. Biologics for paediatric severe asthma: trick or TREAT? Lancet Respir. Med. 2019; 7 (4): 294–296. DOI: 10.1016/S2213-2600(19)30045-1.

Nair P., O’Byrne P.M. The interleukin-13 paradox in asthma: effective biology, ineffective biologicals. Eur. Respir. J. 2019; 53 (2): 1802250. DOI: 10.1183/13993003.02250-2018.

Chung K.F. Tralokinumab unsuccessful for management of severe, uncontrolled asthma. Lancet Respir. Med. 2018; 6 (7): 480–481. DOI: 10.1016/S2213-2600(18)30194-2.

Busse W.W., Brusselle G.G., Korn S. et al. Tralokinumab did not demonstrate oral corticosteroid-sparing effects in severe asthma. Eur. Respir. J. 2019; 53 (2): 1800948. DOI: 10.1183/13993003.00948-2018.

Russell R.J., Chachi L., FitzGerald J.M. et al. Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial. Lancet Respir. Med. 2018; 6 (7): 499–510. DOI: 10.1016/S2213-2600(18)30201-7.

Panettieri R.A. Jr, Sjobring U., Peterffy A. et al. Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials. Lancet Respir. Med. 2018; 6 (7): 511–525. DOI: 10.1016/S2213-2600(18)30184-X.

Pilette C., Brightling C., Lacombe D., Brusselle G. Urgent need for pragmatic trial platforms in severe asthma. Lancet Respir. Med. 2018; 6 (8): 581–583. DOI: 10.1016/S2213-2600(18)30291-1.

Bousquet 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.

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