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<article article-type="research-article" dtd-version="1.3" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:lang="ru"><front><journal-meta><journal-id journal-id-type="publisher-id">pulmo</journal-id><journal-title-group><journal-title xml:lang="ru">Пульмонология</journal-title><trans-title-group xml:lang="en"><trans-title>PULMONOLOGIYA</trans-title></trans-title-group></journal-title-group><issn pub-type="ppub">0869-0189</issn><issn pub-type="epub">2541-9617</issn><publisher><publisher-name>Scientific and Practical Journal “PULMONOLOGIYA” LLC</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.18093/0869-0189-2020-30-4-437-445</article-id><article-id custom-type="elpub" pub-id-type="custom">pulmo-2150</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="ru"><subject>ОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯ</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="en"><subject>ORIGINAL STUDIES</subject></subj-group></article-categories><title-group><article-title>Биомаркеры воспаления дыхательных путей у пациентов с тяжелой бронхиальной астмой в реальной клинической практике</article-title><trans-title-group xml:lang="en"><trans-title>Biomarkers of airways inflammation in patients with severe asthma in a real clinical practice</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0003-1544-4336</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Сергеева</surname><given-names>Г. Р.</given-names></name><name name-style="western" xml:lang="en"><surname>Sergeeva</surname><given-names>G. R.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Сергеева Галина Раисовна – кандидат медицинских наук, доцент кафедры пульмонологии</p><p>195015, Санкт-Петербург, ул. Кирочная, 41 </p></bio><bio xml:lang="en"><p>Galina R. Sergeeva, Candidate of Medicine, Associate Professor, Department of Pulmonology</p><p>ul. Kirochnaya 41, Saint Petersburg, 191015</p></bio><email xlink:type="simple">sergeevagr@mail.ru</email><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-8574-6869</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Емельянов</surname><given-names>А. В.</given-names></name><name name-style="western" xml:lang="en"><surname>Emel'yanov</surname><given-names>A. V.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Емельянов Александр Викторович – доктор медицинских наук, профессор, заведующий кафедрой пульмонологии</p><p>195015, Санкт-Петербург, ул. Кирочная, 41 </p></bio><bio xml:lang="en"><p>Aleksandr V. Emel'yanov, Doctor of Medicine, Professor, Head of Department of Pulmonology</p><p>ul. Kirochnaya 41, Saint Petersburg, 191015</p></bio><email xlink:type="simple">emelav@inbox.ru</email><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0003-4616-3166</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Лешенкова</surname><given-names>Е. В.</given-names></name><name name-style="western" xml:lang="en"><surname>Leshenkova</surname><given-names>E. V.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Лешенкова Евгения Владиславовна – кандидат медицинских наук, доцент кафедры пульмонологии</p><p>195015, Санкт-Петербург, ул. Кирочная, 41 </p></bio><bio xml:lang="en"><p>Eugenia V. Leshenkova, Candidate of Medicine, Associate Professor, Department of Pulmonology</p><p>ul. Kirochnaya 41, Saint Petersburg, 191015</p></bio><email xlink:type="simple">leshenkova@mail.ru</email><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Знахуренко</surname><given-names>А. А.</given-names></name><name name-style="western" xml:lang="en"><surname>Znakhurenko</surname><given-names>A. A.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Знахуренко Антонина Александровна – ассистент кафедры пульмонологии</p><p>195015, Санкт-Петербург, ул. Кирочная, 41 </p></bio><bio xml:lang="en"><p>Antonina A. Znakhurenko, Assistant Professor, Department of Pulmonology</p><p>ul. Kirochnaya 41, Saint Petersburg, 191015</p></bio><email xlink:type="simple">znakhurenko@inbox.ru</email><xref ref-type="aff" rid="aff-1"/></contrib></contrib-group><aff-alternatives id="aff-1"><aff xml:lang="ru"><institution>Федеральное государственное бюджетное образовательное учреждение высшего образования «Северо-Западный государственный медицинский университет имени И.И.Мечникова» Министерства здравоохранения Российской Федерации</institution><country>Россия</country></aff><aff xml:lang="en"><institution>I.I.Mechnikov State North-West Medical University, Healthcare Ministry of Russia</institution><country>Russian Federation</country></aff></aff-alternatives><pub-date pub-type="collection"><year>2020</year></pub-date><pub-date pub-type="epub"><day>17</day><month>10</month><year>2020</year></pub-date><volume>30</volume><issue>4</issue><fpage>437</fpage><lpage>445</lpage><permissions><copyright-statement>Copyright &amp;#x00A9; Сергеева Г.Р., Емельянов А.В., Лешенкова Е.В., Знахуренко А.А., 2020</copyright-statement><copyright-year>2020</copyright-year><copyright-holder xml:lang="ru">Сергеева Г.Р., Емельянов А.В., Лешенкова Е.В., Знахуренко А.А.</copyright-holder><copyright-holder xml:lang="en">Sergeeva G.R., Emel'yanov A.V., Leshenkova E.V., Znakhurenko A.A.</copyright-holder><license xml:lang="ru" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>Данная работа распространяется под лицензией Creative Commons Attribution 4.0.</license-p></license><license xml:lang="en" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>This work is licensed under a Creative Commons Attribution 4.0 License.</license-p></license></permissions><self-uri xlink:href="https://journal.pulmonology.ru/pulm/article/view/2150">https://journal.pulmonology.ru/pulm/article/view/2150</self-uri><abstract><p>Тяжелая бронхиальная астма (БА) является гетерогенным заболеванием, представленным разными фенотипами и эндотипами, для диагностики которых используются различные биомаркеры. Частота фенотипов и эндотипов тяжелой БА в реальной клинической практике изучена недостаточно.</p><p>Целью исследования явилась оценка биомаркеров Т2-воспаления дыхательных путей у пациентов с тяжелой БА.</p><sec><title>Материалы и методы</title><p>Материалы и методы. Обследованы взрослые амбулаторные пациенты (n = 96; 34 % – мужчины; возраст – 18–78 лет) с тяжелой БА. Исследование функции легких выполнялось методом спирометрии (спирограф 2120, Vitalograph, Великобритания) с оценкой обратимости обструкции. Оценка чувствительности к основным ингаляционным аллергенам осуществлялась с помощью кожных проб и / или уровней специфического иммуноглобулина (Ig) E в сыворотке крови. Содержание эозинофилов в периферической крови определялось импедансным методом на автоматическом гемоанализаторе. Уровень оксида азота выдыхаемого воздуха (FeNO) измерялся при помощи хемилюминисцентного газоанализатора (Logan 4100, Великобритания), уровень общего IgE сыворотки крови определялся методом иммунофлюоресцентного анализа. Контроль над БА и качество жизни пациентов оценивались при помощи русскоязычных версий Опросника по контролю над БА (Asthma Control Questionnaire – ACQ-5) и респираторного вопросника Госпиталя Святого Георгия (St. George's Respiratory Questionnaire – SGRQ). Статистический анализ проводился с использованием параметрических и не - параметрических методов пакета прикладных программ Statistica 10.</p></sec><sec><title>Результаты</title><p>Результаты. У подавляющего большинства (93 %) пациентов с тя - желой БА выявлен хотя бы один из критериев Т2-воспаления дыхательных путей (уровень эозинофилов ≥ 150 кл. / мкл и / или FeNO ≥ 20 ppb, клинически значимая гиперчувствительность к аллергенам или потребность в регулярной терапии системными глюкокортикостероидами. Уровни биомаркеров значимо не различались при наличии гормональной зависимости и ее отсутствии. Среди маркеров наиболее часто отмечались аллергия и уровень эозинофилов ≥ 150 кл / мкл. У 72 % больных выявлено одновременное повышение уровня нескольких биомаркеров.</p></sec><sec><title>Заключение</title><p>Заключение. В большинстве случаев тяжелой БА в реальной клинической практике отмечается Т2-эндотип заболевания, при выявлении которого назначается биологическая терапия. Более чем у половины больных установлен перекрест показаний для назначения разных препаратов моноклональных антител к основным цитокинам Т2-воспаления.</p></sec></abstract><trans-abstract xml:lang="en"><p>Severe asthma is a heterogeneous disease consisting of several endotypes and phenotypes diagnosed due to different biomarkers. Frequency of different endotypes and phenotypes in real clinical practice needs further investigation.</p><p>The aim of this study was to assess biomarkers of T2-inflammation in patients with severe asthma in a single secondary care center.</p><sec><title>Methods</title><p>Methods. We examined 96 adult outpatients (34% male) with severe asthma. Data collected included demographics, smoking history, asthma exacerbations during previous 12 months, medication use, comorbidities. Lung function tests were assessed by using the Spirograph 2120 (Vitalograph, Great Britain). Blood eosinophils (Eos) were measured by automatic haemoanalyser. Atopic status was determined by positive skin prick-test (&gt; 3 mm) and/or serum specific IgE to common inhalant allergens. Serum total IgE levels were assessed by immunofluorescence assay. FeNO was measured by a chemiluminescence analyzer (Model LR4000; Logan Research, Rochester, UK). Presence of allergy, need for regular oral steroid use, blood Eos ≥ 150 cell/μl and FeNO ≥ 20 ppb were considered as markers of T2-driven inflammation. Asthma control and quality of life were assessed by using Russian versions of ACQ-5 and St. George's Respiratory Questionnaire (SGRQ). Statistical analyses were performed with Statistica Ver. 10.0 (StatSoft, Inc., USA).</p></sec><sec><title>Results</title><p>Results. The majority of patients with severe asthma (93%) have at least one or more elevated markers (presence of allergy, need for regular oral steroid use, Eos ≥ 150 cell/μl or FeNO ≥ 20 ppb) of T2-inflammation. Biomarkers levels did not differ in non-steroid-dependent and steroid-dependent patients. The most frequent markers were allergy and blood Eos ≥ 150 cell/μl. Two or more elevated biomarkers were revealed in 72% of patients.</p></sec><sec><title>Conclusion</title><p>Conclusion. The majority of patients with severe asthma in real clinical practice have signs of T2-inflammation. It seems that many severe asthmatics have indications for prescription of biological and can be treated by more than one of monoclonal antibodies against major cytokines of T2-inflammation.</p></sec></trans-abstract><kwd-group xml:lang="ru"><kwd>бронхиальная астма</kwd><kwd>биомаркеры</kwd><kwd>Т2-воспаление</kwd></kwd-group><kwd-group xml:lang="en"><kwd>аsthma</kwd><kwd>biomarkers</kwd><kwd>T2-inflammation</kwd></kwd-group></article-meta></front><back><ref-list><title>References</title><ref id="cit1"><label>1</label><citation-alternatives><mixed-citation xml:lang="ru">Global Initiative for Asthma. Updated 2020. Available at: www.ginasthma.org [Accessed: June 20, 2020].</mixed-citation><mixed-citation xml:lang="en">Global Initiative for Asthma. Updated 2020. Available at: www.ginasthma.org [Accessed: June 20, 2020].</mixed-citation></citation-alternatives></ref><ref id="cit2"><label>2</label><citation-alternatives><mixed-citation xml:lang="ru">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.</mixed-citation><mixed-citation xml:lang="en">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.</mixed-citation></citation-alternatives></ref><ref id="cit3"><label>3</label><citation-alternatives><mixed-citation xml:lang="ru">de Carvalho-Pinto R.M., Cukier A., Angelini L. et al. Clinical characteristics and possible phenotypes of an adult severe asthma population. Respir. Med. 2012; 106 (1): 47–56. DOI: 10.1016/j.rmed.2011.08.013.</mixed-citation><mixed-citation xml:lang="en">de Carvalho-Pinto R.M., Cukier A., Angelini L. et al. Clinical characteristics and possible phenotypes of an adult severe asthma population. Respir. Med. 2012; 106 (1): 47–56. DOI: 10.1016/j.rmed.2011.08.013.</mixed-citation></citation-alternatives></ref><ref id="cit4"><label>4</label><citation-alternatives><mixed-citation xml:lang="ru">Российское респираторное общество. Федеральные клинические рекомендации по диагностике и лечению бронхиальной астмы. Пересмотр 2019. Доступно на: https://spulmo.ru [Дата обращения: 20.06.20].</mixed-citation><mixed-citation xml:lang="en">Russian Respiratory Society. Federal clinical guidelines for the diagnosis and treatment of bronchial asthma. Updated 2019. Available at: https://spulmo.ru [Accessed: June 20, 2020] (in Russian).</mixed-citation></citation-alternatives></ref><ref id="cit5"><label>5</label><citation-alternatives><mixed-citation xml:lang="ru">Федосеев Г.Б., Успенская Е.П., Коровина О.В. Клини - ко-этиопатогенетические варианты бронхиальной аст - мы: диагностика и лечение. Проблемы пульмонологии. 1980; 8: 275.</mixed-citation><mixed-citation xml:lang="en">Fedoseev G.B., Uspenskaya E.P., Korovina O.V. [Clinical and etiopathogenetic variants of bronchial asthma: diagnosis and treatment]. Problemy pul'monologii. 1980; 8: 275 (in Russian).</mixed-citation></citation-alternatives></ref><ref id="cit6"><label>6</label><citation-alternatives><mixed-citation xml:lang="ru">Haldar P., Pavord I.D., Shaw D.E. et al. Cluster analysis and clinical asthma phenotypes. Am. J. Respir. Crit. Care Med. 2008; 178 (3): 218–224. DOI: 10.1164/rccm.200711-1754OC.</mixed-citation><mixed-citation xml:lang="en">Haldar P., Pavord I.D., Shaw D.E. et al. Cluster analysis and clinical asthma phenotypes. Am. J. Respir. Crit. Care Med. 2008; 178 (3): 218–224. DOI: 10.1164/rccm.200711-1754OC.</mixed-citation></citation-alternatives></ref><ref id="cit7"><label>7</label><citation-alternatives><mixed-citation xml:lang="ru">Wenzel S. Severe asthma: from characteristics to phenotypes to endotypes. Clin. Exp. Allergy. 2012; 42 (5): 650–658. DOI: 10.1111/j.1365-2222.2011.03929.x.</mixed-citation><mixed-citation xml:lang="en">Wenzel S. Severe asthma: from characteristics to phenotypes to endotypes. Clin. Exp. Allergy. 2012; 42 (5): 650–658. DOI: 10.1111/j.1365-2222.2011.03929.x.</mixed-citation></citation-alternatives></ref><ref id="cit8"><label>8</label><citation-alternatives><mixed-citation xml:lang="ru">Schleich F., Brusselle G., Louis R. et al. Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR). Respir. Med. 2014; 108 (12): 1723–1732. DOI: 10.1016/j.rmed.2014.10.007.</mixed-citation><mixed-citation xml:lang="en">Schleich F., Brusselle G., Louis R. et al. Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR). Respir. Med. 2014; 108 (12): 1723–1732. DOI: 10.1016/j.rmed.2014.10.007.</mixed-citation></citation-alternatives></ref><ref id="cit9"><label>9</label><citation-alternatives><mixed-citation xml:lang="ru">Nenasheva N., Belevsky A., Kravchenko N. et al. Pre - liminary analysis of the data of patients with severe bron - chial asthma included in the Russian National Register of Severe Asthma (RSAR). Eur. Respir. J. 2019; 54 (Suppl. 63): PA4261. DOI: 10.1183/13993003.congress-2019.PA4261.</mixed-citation><mixed-citation xml:lang="en">Nenasheva N., Belevsky A., Kravchenko N. et al. Pre - liminary analysis of the data of patients with severe bron - chial asthma included in the Russian National Register of Severe Asthma (RSAR). Eur. Respir. J. 2019; 54 (Suppl. 63): PA4261. DOI: 10.1183/13993003.congress-2019.PA4261.</mixed-citation></citation-alternatives></ref><ref id="cit10"><label>10</label><citation-alternatives><mixed-citation xml:lang="ru">van Bragt J.J.M.N., Adcock I.M., Bel E.H. et al. Cha - racteristics and treatment regimens across ERS SHARP severe asthma registries. Eur. Respir. J. 2020; 55 (1): 1901163. DOI: 10.1183/13993003.01163-2019.</mixed-citation><mixed-citation xml:lang="en">van Bragt J.J.M.N., Adcock I.M., Bel E.H. et al. Cha - racteristics and treatment regimens across ERS SHARP severe asthma registries. Eur. Respir. J. 2020; 55 (1): 1901163. DOI: 10.1183/13993003.01163-2019.</mixed-citation></citation-alternatives></ref><ref id="cit11"><label>11</label><citation-alternatives><mixed-citation xml:lang="ru">Wang E., Wechsler M.E., Tran T.N. et al. Characterization of severe asthma worldwide. Data from the International Severe Asthma Registry. Chest. 2020; 157 (4): 790–804. DOI: 10.1016/j.chest.2019.10.053.</mixed-citation><mixed-citation xml:lang="en">Wang E., Wechsler M.E., Tran T.N. et al. Characterization of severe asthma worldwide. Data from the International Severe Asthma Registry. Chest. 2020; 157 (4): 790–804. DOI: 10.1016/j.chest.2019.10.053.</mixed-citation></citation-alternatives></ref><ref id="cit12"><label>12</label><citation-alternatives><mixed-citation xml:lang="ru">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.</mixed-citation><mixed-citation xml:lang="en">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.</mixed-citation></citation-alternatives></ref><ref id="cit13"><label>13</label><citation-alternatives><mixed-citation xml:lang="ru">Pavord I.D., Afzalnia S., Menzies-Gow A., Heaney L.G. The current and future role of biomarkers in type 2 cytokinemediated asthma management. Clin. Exp. Allergy. 2017; 47 (2): 148–160. DOI: 10.1111/cea.12881.</mixed-citation><mixed-citation xml:lang="en">Pavord I.D., Afzalnia S., Menzies-Gow A., Heaney L.G. The current and future role of biomarkers in type 2 cytokinemediated asthma management. Clin. Exp. Allergy. 2017; 47 (2): 148–160. DOI: 10.1111/cea.12881.</mixed-citation></citation-alternatives></ref><ref id="cit14"><label>14</label><citation-alternatives><mixed-citation xml:lang="ru">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.</mixed-citation><mixed-citation xml:lang="en">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.</mixed-citation></citation-alternatives></ref><ref id="cit15"><label>15</label><citation-alternatives><mixed-citation xml:lang="ru">Malinovschi A., Janson C., Borres M., Alving K. Simult - aneously increased fraction of exhaled nitric oxide levels and blood eosinophil counts relate to increased asthma morbidity. J .Allergy Clin. Immunol. 2016; 138 (5): 1301–1308.e2. DOI: 10.1016/j.jaci.2016.01.044.</mixed-citation><mixed-citation xml:lang="en">Malinovschi A., Janson C., Borres M., Alving K. Simult - aneously increased fraction of exhaled nitric oxide levels and blood eosinophil counts relate to increased asthma morbidity. J .Allergy Clin. Immunol. 2016; 138 (5): 1301–1308.e2. DOI: 10.1016/j.jaci.2016.01.044.</mixed-citation></citation-alternatives></ref><ref id="cit16"><label>16</label><citation-alternatives><mixed-citation xml:lang="ru">Holguin F., Cardet J.C., Chung K.F. et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur. Respir. J. 2020; 55 (1): 1900588. DOI: 10.1183/13993003.00588-2019.</mixed-citation><mixed-citation xml:lang="en">Holguin F., Cardet J.C., Chung K.F. et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur. Respir. J. 2020; 55 (1): 1900588. DOI: 10.1183/13993003.00588-2019.</mixed-citation></citation-alternatives></ref><ref id="cit17"><label>17</label><citation-alternatives><mixed-citation xml:lang="ru">Busby J., Holweg C.T.J., Chai A. et al. Change in type-2 biomarkers and related cytokines with prednisolone in uncontrolled severe oral corticosteroid dependent asthmatics: an interventional open-label study. Thorax. 2019; 74 (8): 806–809. DOI: 10.1136/thoraxjnl-2018-212709.</mixed-citation><mixed-citation xml:lang="en">Busby J., Holweg C.T.J., Chai A. et al. Change in type-2 biomarkers and related cytokines with prednisolone in uncontrolled severe oral corticosteroid dependent asthmatics: an interventional open-label study. Thorax. 2019; 74 (8): 806–809. DOI: 10.1136/thoraxjnl-2018-212709.</mixed-citation></citation-alternatives></ref><ref id="cit18"><label>18</label><citation-alternatives><mixed-citation xml:lang="ru">Mesnil C., Raulier S., Paulissen G. et al. Lung-resident eosinophils represent a distinct regulatory eosinophil subset. J. Clin. Invest. 2016; 126 (9): 3279–3295. DOI: 10.1172/JCI85664.</mixed-citation><mixed-citation xml:lang="en">Mesnil C., Raulier S., Paulissen G. et al. Lung-resident eosinophils represent a distinct regulatory eosinophil subset. J. Clin. Invest. 2016; 126 (9): 3279–3295. DOI: 10.1172/JCI85664.</mixed-citation></citation-alternatives></ref><ref id="cit19"><label>19</label><citation-alternatives><mixed-citation xml:lang="ru">Januskevicius A., Jurkeviciute E., Janulaityte I. et al. Blood eosinophils subtypes and their survivability in asthma pati - ents. Cells. 2020; 9 (5): 1248. DOI: 10.3390/cells9051248.</mixed-citation><mixed-citation xml:lang="en">Januskevicius A., Jurkeviciute E., Janulaityte I. et al. Blood eosinophils subtypes and their survivability in asthma pati - ents. Cells. 2020; 9 (5): 1248. DOI: 10.3390/cells9051248.</mixed-citation></citation-alternatives></ref><ref id="cit20"><label>20</label><citation-alternatives><mixed-citation xml:lang="ru">Peters M.C., Kerr Sh., Dunican E.M. et al. Refractory airway type 2 inflammation in a large subgroup of asthmatic patients treated with inhaled corticosteroids. J. Allergy Clin. Immunol. 2019; 143 (1): 104–113.e14. DOI: 10.1016/j.jaci.2017.12.1009.</mixed-citation><mixed-citation xml:lang="en">Peters M.C., Kerr Sh., Dunican E.M. et al. Refractory airway type 2 inflammation in a large subgroup of asthmatic patients treated with inhaled corticosteroids. J. Allergy Clin. Immunol. 2019; 143 (1): 104–113.e14. DOI: 10.1016/j.jaci.2017.12.1009.</mixed-citation></citation-alternatives></ref><ref id="cit21"><label>21</label><citation-alternatives><mixed-citation xml:lang="ru">Сергеева Г.Р., Емельянов А.В. Коровина О.В. и др. Тяжелая бронхиальная астма: характеристика пациентов в клинической практике. Терапевтический архив. 2015; (12): 26–31. DOI: 10.17116/terarkh2015871226-31.</mixed-citation><mixed-citation xml:lang="en">Sergeeva G.R., Emel'yanov A.V. Korovina O.V. et al. [Severe asthma: characteristics of patients in clinical practice]. Terapevticheskiy arkhiv. 2015; (12): 26–31. DOI: 10.17116/terarkh2015871226-31 (in Russian).</mixed-citation></citation-alternatives></ref><ref id="cit22"><label>22</label><citation-alternatives><mixed-citation xml:lang="ru">Albers F.C., Müllerová H., Gunsoy N.B. et al. Biologic treatment eligibility for real-world patients with severe asthma: the IDEAL study. J. Asthma. 2018; 55 (2): 152–160. DOI: 10.1080/02770903.2017.1322611.</mixed-citation><mixed-citation xml:lang="en">Albers F.C., Müllerová H., Gunsoy N.B. et al. Biologic treatment eligibility for real-world patients with severe asthma: the IDEAL study. J. Asthma. 2018; 55 (2): 152–160. DOI: 10.1080/02770903.2017.1322611.</mixed-citation></citation-alternatives></ref><ref id="cit23"><label>23</label><citation-alternatives><mixed-citation xml:lang="ru">Wynn T.A. Type 2 cytokines: mechanisms and therapeutic strategies. Nat. Rev. Immunol. 2015; 15 (5): 271–282. DOI: 10.1038/nri3831.</mixed-citation><mixed-citation xml:lang="en">Wynn T.A. Type 2 cytokines: mechanisms and therapeutic strategies. Nat. Rev. Immunol. 2015; 15 (5): 271–282. DOI: 10.1038/nri3831.</mixed-citation></citation-alternatives></ref><ref id="cit24"><label>24</label><citation-alternatives><mixed-citation xml:lang="ru">Agache I., Cojanu C., Laculiceanu A., Rogozea L. Critical points on the use of biologicals in allergic diseases and asthma. Allergy Asthma Immunol. Res. 2020; 12 (1): 24–41. DOI: 10.4168/aair.2020.12.1.24.</mixed-citation><mixed-citation xml:lang="en">Agache I., Cojanu C., Laculiceanu A., Rogozea L. Critical points on the use of biologicals in allergic diseases and asthma. Allergy Asthma Immunol. Res. 2020; 12 (1): 24–41. DOI: 10.4168/aair.2020.12.1.24.</mixed-citation></citation-alternatives></ref><ref id="cit25"><label>25</label><citation-alternatives><mixed-citation xml:lang="ru">Tran T.N., Zeiger R.S, Peters S.P. et al. Overlap of atopic, eosinophilic, and TH2-high asthma phenotypes in a general population with current asthma. Ann. Allergy Asthma Immu - nol. 2016; 116 (1): 37–42. DOI: 10.1016/j.anai.2015.10.027.</mixed-citation><mixed-citation xml:lang="en">Tran T.N., Zeiger R.S, Peters S.P. et al. Overlap of atopic, eosinophilic, and TH2-high asthma phenotypes in a general population with current asthma. Ann. Allergy Asthma Immu - nol. 2016; 116 (1): 37–42. DOI: 10.1016/j.anai.2015.10.027.</mixed-citation></citation-alternatives></ref><ref id="cit26"><label>26</label><citation-alternatives><mixed-citation xml:lang="ru">Chapman K.R., Albers F.C., Chipps B. et al. The clinical benefit of mepolizumab replacing omalizumab in uncontrolled severe eosinophilic asthma. Allergy. 2019; 74 (9): 1716–1726. DOI: 10.1111/all.13850.</mixed-citation><mixed-citation xml:lang="en">Chapman K.R., Albers F.C., Chipps B. et al. The clinical benefit of mepolizumab replacing omalizumab in uncontrolled severe eosinophilic asthma. Allergy. 2019; 74 (9): 1716–1726. DOI: 10.1111/all.13850.</mixed-citation></citation-alternatives></ref><ref id="cit27"><label>27</label><citation-alternatives><mixed-citation xml:lang="ru">Pérez de Llano L.A.P., Cosío B.G., Domingo C. et al. Efficacy and safety of reslizumab in patients with severe asthma with inadequate response to omalizumab: a multicenter, open-label pilot study. J. Allergy Clin. Immunol. Pract. 2019; 7 (7): 2277–2283.e2. DOI: 10.1016/j.jaip.2019.01.017.</mixed-citation><mixed-citation xml:lang="en">Pérez de Llano L.A.P., Cosío B.G., Domingo C. et al. Efficacy and safety of reslizumab in patients with severe asthma with inadequate response to omalizumab: a multicenter, open-label pilot study. J. Allergy Clin. Immunol. Pract. 2019; 7 (7): 2277–2283.e2. DOI: 10.1016/j.jaip.2019.01.017.</mixed-citation></citation-alternatives></ref></ref-list><fn-group><fn fn-type="conflict"><p>The authors declare that there are no conflicts of interest present.</p></fn></fn-group></back></article>
