medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/2079-701X-2022-16-18-56-63medsovet-7120Research ArticleМУКОВИСЦИДОЗCYSTIC FIBROSISИнгаляции маннитола для детей с муковисцидозом: эффективность и безопасностьMannitol therapy for children with cystic fibrosis: efficacy and safetyhttps://orcid.org/0000-0002-2367-9920СимоноваО. И.SimonovaO. I.

Симонова Ольга Игоревна, доктор медицинских наук, заведующий пульмонологическим отделением, Федеральное государственное автономное учреждение «Национальный медицинский исследовательский центр здоровья детей» Министерства здравоохранения Российской Федерации; профессор кафедры педиатрии и детской ревматологии, Первый Московский государственный медицинский университет имени И.М. Сеченова (Сеченовский Университет); руководитель службы муковисцидоза медико-генетического отделения, Морозовская детская городская клиническая больница

119926, Москва, Ломоносовский проспект, д. 2, стр. 1,

119991, Москва, ул. Трубецкая, д. 8, стр. 2,

119049, 4-й Добрынинский переулок, д. 1/9

Olga I. Simonova, Dr. Sci. (Med.), Head of Pulmonology Department, National Medical Research Center for Children’s Health; Professor of the Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University (Sechenov University); Head of the Cystic Fibrosis Service of the Medical Genetic Department, Morozovsky Municipal Children Clinical Hospital

2, Bldg. 1, Lomonosovsky Ave., Moscow, 119926,

8, Bldg. 2, Trubetskaya St., Moscow, 119991,

1/9, 4th Dobryninsky Lane, Moscow, 119049

oisimonova@mail.ruhttps://orcid.org/0000-0002-3881-3483ГориноваЮ. В.GorinovaYu. V.

Горинова Юлия Викторовна, кандидат медицинских наук, старший научный сотрудник лаборатории редких и наследственных болезней у детей, врач-пульмонолог

119926, Москва, Ломоносовский проспект, д. 2, стр. 1

Yulia V. Gorinova, Cand. Sci. (Med.), Senior Researcher, Laboratory of Rare and Hereditary Diseases in Children, Pulmonologist

2, Bldg. 1, Lomonosovsky Ave., Moscow, 119926

ygorinova@yandex.ruhttps://orcid.org/0000-0003-4155-2226ВысоколоваО. В.VysokolovaO. V.

Высоколова Ольга Владимировна, врач-педиатр медико-генетического отделения

119049, Москва, 4-й Добрынинский переулок, д. 1/9

Olga V. Vysokolova, Pediatrician of the Medical Genetic Department

1/9, 4th Dobryninsky Lane, Moscow, 119049

olgapopowa@list.ruhttps://orcid.org/0000-0002-8329-386XМухинаМ. А.MukhinaM. A.

Мухина Мария Алексеевна, врач-педиатр медико-генетического отделения

119049, Москва, 4-й Добрынинский переулок, д. 1/9

 

Mariya A. Mukhina, Pediatrician of the Medical Genetic Department

1/9, 4th Dobryninsky Lane, Moscow, 119049

mariemuch@yandex.ruhttps://orcid.org/0000-0001-7090-0395ЯкушинаЕ. Е.YakushinaE. E.

Елена Евгеньевна Якушина, врач-педиатр медико-генетического отделения

119049, Москва, 4-й Добрынинский переулок, д. 1/9

 

Elena E. Yakushina, Pediatrician of the Medical Genetic Department

1/9, 4th Dobryninsky Lane, Moscow, 119049

palidum@yandex.ruНациональный медицинский исследовательский центр здоровья детей; Первый Московский государственный медицинский университет имени И.М. Сеченова (Сеченовский Университет); Морозовская детская городская клиническая больницаРоссияNational Medical Research Center for Children’s Health; Sechenov First Moscow State Medical University (Sechenov University); Morozovsky Municipal Children Clinical HospitalRussian FederationНациональный медицинский исследовательский центр здоровья детейРоссияNational Medical Research Center for Children’s HealthRussian FederationМорозовская детская городская клиническая больницаРоссияMorozovsky Municipal Children Clinical HospitalRussian Federation20221410202216185663Copyright © Симонова О.И., Горинова Ю.В., Высоколова О.В., Мухина М.А., Якушина Е.Е., 20222022Симонова О.И., Горинова Ю.В., Высоколова О.В., Мухина М.А., Якушина Е.Е.Simonova O.I., Gorinova Y.V., Vysokolova O.V., Mukhina M.A., Yakushina E.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-sovet.pro/jour/article/view/7120

В статье описаны механизмы развития мукостаза и поражения легких при муковисцидозе. Рассматриваются виды муколитической терапии, значение ингаляционной терапии. Авторы представили собственную классификацию мукоактивных средств. Обсуждается принцип действия, преимущество и  эффективность мукоактивного препарата на  основе молекулы маннитола по результатам многоцентровых рандомизированных клинических исследований, в т. ч. проведенных у детей с муковисцидозом. Представлен собственный опыт применения маннитола на базе ГБУЗ «Морозовская ДГКБ ДЗМ» и проведенных 42 BIDA-тестов на его переносимость, из них 38 тестов пройдено удовлетворительно. Представлены различные клинические примеры, демонстрирующие неудачу в прохождении теста на переносимость ввиду нарастания признаков дыхательной недостаточности (появление одышки), пример повторного прохождения данного теста спустя 8 месяцев с удовлетворительными результатами, развитие кровохарканья у пациента, наблюдающегося в пульмонологическом отделении ФГАУ «НМИЦ здоровья детей» Минздрава России. Описан случай применения данного препарата у подростка, при этом после введения к имеющейся базовой терапии ингаляций маннитола зафиксирована отчетливая положительная динамика показателей по флоуметрии: ОФВ – 74%Д (значительный прирост на 14%). Таким образом, авторы отметили, что маннитол эффективен у детей с муковисцидозом старше 6  лет, его применение характеризуется хорошей комплаентностью и  общей приверженностью к  терапии ввиду удобства использования: отсутствия необходимости в дополнительных технических средствах для проведения ингаляции в виде растворов вне дома и экономии общего свободного времени. Важное замечание, отмеченное авторами, заключается в том, что BIDA-тест следует проводить в состоянии полной клинико-лабораторной ремиссии для получения объективных результатов.

The article describes the mechanisms of mucostasis and lung damage in cystic fibrosis. Types of mucolytic therapy and importance of inhalation therapy are considered. The authors presented their own classification of mucoactive agents. The principle of action, advantages and efficacy of mucoactive drugs based on the mannitol molecule are discussed based on the results of multicenter randomized clinical trials, including those conducted in children with cystic fibrosis. The authors present their own experience in the use of mannitol at the Morozovsky Municipal Children Clinical Hospital and 42 BIDA tests for its tolerability, of which 38 tests were passed satisfactorily. We present various clinical cases demonstrating the failure of a tolerance test due to increased signs of respiratory failure (dyspnea), an example of a repeat test 8 months later with satisfactory results, the development of hemoptysis in a patient seen in the pulmonology department of the National Medical Research Center for Children’s Health. The case was described in an adolescent, and after mannitol inhalation was added to the existing basic therapy, there was a clear positive trend in flowmetry: FEV1-74% (a significant increase of 14%). Thus, the authors noted that mannitol is effective in children with cystic fibrosis over 6 years of age; its use is characterized by good compliance and general adherence to therapy due to convenience of use: no need for additional technical means to perform inhalation in the form of solutions outside the home and saving overall free time. An important observation noted by the authors is that the BIDA test should be performed in complete clinical and laboratory remission to obtain objective results.

маннитолBIDA-тестнарушение бронхиальной проходимостимукостазмукоцилиарный транспортmannitolBIDA testbronchial permeability disordermucostasismucociliary transportmucoviscidosischildrenReferencesКапранов Н.И., Каширская Н.Ю., Кондратьева Е.И. (ред.). Муковисцидоз. 2-е изд., переработанное и дополненное. М.: Медпрактика-М; 2021. 680 с. Режим доступа: http://www.medpractika.ru/books/new/?id=316.Kapranov N.I., Kashirskaya N.Y., Kondratieva E.I. Cystic fibrosis. 2nd ed. Moscow: Medpraktika-M; 2021. 680 с. (In Russ.) Available at: http://www.medpractika.ru/books/new/?id=316.Boucher R.C. Evidence for airway surface dehydration as the initiating event in CF airway disease. J Int Med. 2007;261(1):5–16. https://doi.org/10.1111/j.1365-2796.2006.01744x.Boucher R.C. Evidence for airway surface dehydration as the initiating event in CF airway disease. J Int Med. 2007;261(1):5–16. https://doi.org/10.1111/j.1365-2796.2006.01744x.O’Sullivan B.P., Flume P. The clinical approach to lung disease in patients with cystic fibrosis. Semin Respir Crit Care Med. 2009;30(5):505–513. https://doi.org/10.1055/s-0029-1238909/.O’Sullivan B.P., Flume P. The clinical approach to lung disease in patients with cystic fibrosis. Semin Respir Crit Care Med. 2009;30(5):505–513. https://doi.org/10.1055/s-0029-1238909/.Flume P.A., Robinson K.A., O’Sullivan B.P., Finder J.D., Vender R.L., WilleyCourand D.-B. et al. Cystic fibrosis pulmonary guidelines: airway clearance therapies. Respir Care. 2009;54(4):522–537. Available at: https://pubmed.ncbi.nlm.nih.gov/19327189/.Flume P.A., Robinson K.A., O’Sullivan B.P., Finder J.D., Vender R.L., WilleyCourand D.-B. et al. Cystic fibrosis pulmonary guidelines: airway clearance therapies. Respir Care. 2009;54(4):522–537. Available at: https://pubmed.ncbi.nlm.nih.gov/19327189/.Орлов А.В., Симонова О.И., Рославцева Е.А., Шадрин Д.И. М90 Муковисцидоз (клиническая картина, диагностика, лечение, реабилитация, диспансеризация). 2-е изд., дополненное и переработанное. СПб.: Изд-во СЗГМУ им. И.И. Мечникова; 2014. 160 с. Режим доступа: http://ostrovaru.com/biblioteka/otdelnye-izdaniya/1192/.Orlov A.V., Simonova O.I., Roslavtseva E.A., Shadrin D.I. M90 Mucoviscidosis (clinical picture, diagnosis, treatment, rehabilitation, dispensary). 2nd ed. St Petersburg: I.I. Mechnikov Northwestern State Medical University; 2014. 160 p. (In Russ.) Available at: http://ostrovaru.com/biblioteka/otdelnye-izdaniya/1192/.Giordani B., Amato A., Majo F., Ferrari G., Quattrucci S., Minicucci L. Italian Cystic Fibrosis Registry. Report. 2011–2014. Registro italiano Fibrosi Cistica. Rapporto 2011–2014. Epidemiol Prev. 2018;42(1):1–32. https://doi.org/10.19191/EP18.1-S1.P001.001.Giordani B., Amato A., Majo F., Ferrari G., Quattrucci S., Minicucci L. Italian Cystic Fibrosis Registry. Report. 2011–2014. Registro italiano Fibrosi Cistica. Rapporto 2011–2014. Epidemiol Prev. 2018;42(1):1–32. https://doi.org/10.19191/EP18.1-S1.P001.001.Villaverde-Hueso A., Sánchez-Díaz G., Molina-Cabrero F.J., Gallego E., Posada de la Paz M., Alonso-Ferreira V. Mortality Due to Cystic Fibrosis over a 36-Year Period in Spain: time Trends and Geographic Variations. Int J Environ Res Public Health. 2019;16(1):119. https://doi.org/10.3390/ijerph16010119.Villaverde-Hueso A., Sánchez-Díaz G., Molina-Cabrero F.J., Gallego E., Posada de la Paz M., Alonso-Ferreira V. Mortality Due to Cystic Fibrosis over a 36-Year Period in Spain: time Trends and Geographic Variations. Int J Environ Res Public Health. 2019;16(1):119. https://doi.org/10.3390/ijerph16010119.Keogh R.H., Szczesniak R., Taylor-Robinson D., Bilton D. Up-to-date and projected estimates of survival for people with cystic fibrosis using baseline characteristics: a longitudinal study using UK patient registry data. J Cyst Fibros. 2018;17(2):218–227. https://doi.org/10.1016/j.jcf.2017.11.019.Keogh R.H., Szczesniak R., Taylor-Robinson D., Bilton D. Up-to-date and projected estimates of survival for people with cystic fibrosis using baseline characteristics: a longitudinal study using UK patient registry data. J Cyst Fibros. 2018;17(2):218–227. https://doi.org/10.1016/j.jcf.2017.11.019.Spoonhower K.A., Davis P.B. Epidemiology of cystic fibrosis. Clin Chest Med. 2016;37(1):1–8. https://doi.org/10.1016/j.ccm.2015.10.002.Spoonhower K.A., Davis P.B. Epidemiology of cystic fibrosis. Clin Chest Med. 2016;37(1):1–8. https://doi.org/10.1016/j.ccm.2015.10.002.Каширская Н.Ю., Кондратьева Е.И., Красовский С.А., Старинова М.А., Воронкова А.Ю., Амелина Е.Л., Ашерова И.К. (ред.) Регистр больных муковисцидозом в Российской Федерации. 2019 г. М.: Медпрактика-М; 2021. 68 с. Режим доступа: https://mukoviscidoz.org/doc/registr/site_Registre_2019.pdf.Kashirskaya N.Y., Kondratyeva E.I., Krasovsky S.A., Starinova M.A., Voronkova A.Y., Amelina E.L., Asherova I.K. Registry of cystic fibrosis patients in the Russian Federation. 2019. Moscow: Medpraktika-M; 2021. 68 p. (In Russ.) Available at: https://mukoviscidoz.org/doc/registr/site_Registre_2019.pdf.Flume P.A., O’Sullivan B.P., Robinson K.A., Goss C.H., Mogayzel P.J.Jr., Willey Courand D.B. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007;176(10):957–569. https://doi.org/10.1164/rccm.200705-664OC.Flume P.A., O’Sullivan B.P., Robinson K.A., Goss C.H., Mogayzel P.J.Jr., Willey Courand D.B. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007;176(10):957–569. https://doi.org/10.1164/rccm.200705-664OC.Mogayzel P.J., Naureckas E.T., Robinson K.A., Mueller G., Hadjiliadis D., Hoag J.B. et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2013;187(7):680–689. https://doi.org/10.1164/rccm.201207-1160OE.Mogayzel P.J., Naureckas E.T., Robinson K.A., Mueller G., Hadjiliadis D., Hoag J.B. et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2013;187(7):680–689. https://doi.org/10.1164/rccm.201207-1160OE.Robinson M., Hemming A.L., Regnis J.A., Wong A.G., Bailey D.L., Bautovich G.J. Effect of increasing doses of hypertonic saline on mucociliary clearance in patients with cystic fibrosis. Thorax. 1997;52(10):900–903. https://doi.org/10.1136/thx.52.10.900.Robinson M., Hemming A.L., Regnis J.A., Wong A.G., Bailey D.L., Bautovich G.J. Effect of increasing doses of hypertonic saline on mucociliary clearance in patients with cystic fibrosis. Thorax. 1997;52(10):900–903. https://doi.org/10.1136/thx.52.10.900.Reeves E.P., McCarthy C., McElvaney O.J., Vijayan M.S.N., White M.M., Dunlea D.M. et al. Inhaled hypertonic saline for cystic fibrosis: reviewing the potential evidence for modulation of neutrophil signalling and function. World J Crit Care Med. 2015;4(3):179–191. https://doi.org/10.5492/wjccm.v4.i3.179.Reeves E.P., McCarthy C., McElvaney O.J., Vijayan M.S.N., White M.M., Dunlea D.M. et al. Inhaled hypertonic saline for cystic fibrosis: reviewing the potential evidence for modulation of neutrophil signalling and function. World J Crit Care Med. 2015;4(3):179–191. https://doi.org/10.5492/wjccm.v4.i3.179.Ratjen F. Restoring airway surface liquid in cystic fibrosis. N Engl J Med. 2006;(354):291–293. https://doi.org/10.1056/NEJMe058293.Ratjen F. Restoring airway surface liquid in cystic fibrosis. N Engl J Med. 2006;(354):291–293. https://doi.org/10.1056/NEJMe058293.Lin A.H.A., Kendrick J.G., Wilcox P.G., Quon B.S. Patient knowledge and pulmonary medication adherence in adult patients with cystic fibrosis. Patient Prefer Adherence. 2017;(11):691–698. https://doi.org/10.2147/PPA.S129088.Lin A.H.A., Kendrick J.G., Wilcox P.G., Quon B.S. Patient knowledge and pulmonary medication adherence in adult patients with cystic fibrosis. Patient Prefer Adherence. 2017;(11):691–698. https://doi.org/10.2147/PPA.S129088.Sawicki G.S., Sellers D.E., Robinson W.M. High treatment burden in adults with cystic fibrosis: challenges to disease self-management. J Cyst Fibros. 2009;8(2):91–96. https://doi.org/10.1016/j.jcf.2008.09.007.Sawicki G.S., Sellers D.E., Robinson W.M. High treatment burden in adults with cystic fibrosis: challenges to disease self-management. J Cyst Fibros. 2009;8(2):91–96. https://doi.org/10.1016/j.jcf.2008.09.007.Blau H., Mussaffi H., Mei Zahav M., Prais D., Livne M., Czitron B.M. Microbial contamination of nebulizers in the home treatment of cystic fibrosis. Child Care Health Dev. 2007;33(4):491–495. https://doi.org/10.1111/j.1365-2214.2006.00669.x.Blau H., Mussaffi H., Mei Zahav M., Prais D., Livne M., Czitron B.M. Microbial contamination of nebulizers in the home treatment of cystic fibrosis. Child Care Health Dev. 2007;33(4):491–495. https://doi.org/10.1111/j.1365-2214.2006.00669.x.Riquena B., De Freitas L., Monte V., Lopes A.J., Vicente L., Ferreira Da SilvaFilho R. et al. Microbiological contamination of nebulizers used by cystic fibrosis patients: an underestimated problem. J Bras Pneumol. 2019;45(03):e20170351. https://doi.org/10.1590/1806-3713/e20170351.Riquena B., De Freitas L., Monte V., Lopes A.J., Vicente L., Ferreira Da SilvaFilho R. et al. Microbiological contamination of nebulizers used by cystic fibrosis patients: an underestimated problem. J Bras Pneumol. 2019;45(03):e20170351. https://doi.org/10.1590/1806-3713/e20170351.Robinson M., Daviskas E., Eberl S., Baker J., Chan H.K., Anderson S.D. The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study. Eur Respir J. 1999;(14):678–685. https://doi.org/10.1034/j.1399-3003.1999.14c30.x.Robinson M., Daviskas E., Eberl S., Baker J., Chan H.K., Anderson S.D. The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study. Eur Respir J. 1999;(14):678–685. https://doi.org/10.1034/j.1399-3003.1999.14c30.x.Daviskas E., Anderson S.D., Jaques A., Charlton B. Inhaled mannitol improves the hydration and surface properties of sputum in patients with cystic fibrosis. Chest. 2010;137(4):861–868. https://doi.org/10.1378/chest.09-2017.Daviskas E., Anderson S.D., Jaques A., Charlton B. Inhaled mannitol improves the hydration and surface properties of sputum in patients with cystic fibrosis. Chest. 2010;137(4):861–868. https://doi.org/10.1378/chest.09-2017.Bilton D., Robinson P., Cooper P., Gallagher C.G., Kolbe J., Fox H. Inhaled dry powder mannitol in cystic fibrosis: an efficacy and safety study. Eur Respir J. 2011;(38):1071–1080. https://doi.org/10.1183/09031936.00187510.Bilton D., Robinson P., Cooper P., Gallagher C.G., Kolbe J., Fox H. Inhaled dry powder mannitol in cystic fibrosis: an efficacy and safety study. Eur Respir J. 2011;(38):1071–1080. https://doi.org/10.1183/09031936.00187510.Aitken M.L., Bellon G., De Boeck K., Flume P.A., Fox H.G., Geller D.E. et al. Long-term inhaled dry powder mannitol in cystic fibrosis: an international randomized study. Am J Respir Crit Care Med. 2012;185(6):645–652. https://doi.org/10.1164/rccm.201109-1666OC.Aitken M.L., Bellon G., De Boeck K., Flume P.A., Fox H.G., Geller D.E. et al. Long-term inhaled dry powder mannitol in cystic fibrosis: an international randomized study. Am J Respir Crit Care Med. 2012;185(6):645–652. https://doi.org/10.1164/rccm.201109-1666OC.Hurt K., Bilton D. Inhaled mannitol for the treatment of cystic fibrosis. Expert Rev Respir Med. 2012;6(1):19–26. https://doi.org/10.1586/ers.11.87.Hurt K., Bilton D. Inhaled mannitol for the treatment of cystic fibrosis. Expert Rev Respir Med. 2012;6(1):19–26. https://doi.org/10.1586/ers.11.87.Горинова Ю.В., Красовский С.А., Симонова О.И., Амелина Е.Л. Ингаляционный маннитол – новый муколитический препарат для лечения муковисцидоза. Пульмонология. 2016;26(6):760–765. https://doi.org/10.18093/0869-0189-2016-26-6-760-765.Gorinova Yu.V., Krasovskiy S.A., Simonova O.I., Amelina E.L. Inhaled mannitol as a new mucolytic for treatment of cystic fibrosis. Pulmonologiya. 2016;26(6):760–765. (In Russ.) https://doi.org/10.18093/0869-0189-2016-26-6-760-765.Zemanick E.T., Harris J.K., Conway S., Konstan M.W., Marshall B., Quittner A.L. et al. Measuring and improving respiratory outcomes in cystic fibrosis lung disease: opportunities and challenges to therapy. J Cyst Fibrosis. 2010;9(1):1–16. https://doi.org/10.1016/j.jcf.2009.09.003.Zemanick E.T., Harris J.K., Conway S., Konstan M.W., Marshall B., Quittner A.L. et al. Measuring and improving respiratory outcomes in cystic fibrosis lung disease: opportunities and challenges to therapy. J Cyst Fibrosis. 2010;9(1):1–16. https://doi.org/10.1016/j.jcf.2009.09.003.Flume P.A., O’Sullivan B.P., Robinson K.A., Goss C.H., Mogayzel Jr. P.J., Willey-Courand D.B. et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007;176(10):957–969. https://doi.org/10.1164/rccm.200705-664OC.Flume P.A., O’Sullivan B.P., Robinson K.A., Goss C.H., Mogayzel Jr. P.J., Willey-Courand D.B. et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007;176(10):957–969. https://doi.org/10.1164/rccm.200705-664OC.Daviskas E., Anderson S.D., Brannan J.D., Chan H.K., Eberl S., Bautovich G. Inhalation of drypowder mannitol increases mucociliary clearance. Eur Respir J. 1997;(10):2449–2454. https://doi.org/10.1183/09031936.97.10112449.Daviskas E., Anderson S.D., Brannan J.D., Chan H.K., Eberl S., Bautovich G. Inhalation of drypowder mannitol increases mucociliary clearance. Eur Respir J. 1997;(10):2449–2454. https://doi.org/10.1183/09031936.97.10112449.Anderson S.D., Brannan J., Spring J., Spalding N., Rodwell L.T., Chan K. et al. A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol. Am J Respir Crit Care Med. 1997;156(3):758–765. https://doi.org/10.1164/ajrccm.156.3.9701113.Anderson S.D., Brannan J., Spring J., Spalding N., Rodwell L.T., Chan K. et al. A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol. Am J Respir Crit Care Med. 1997;156(3):758–765. https://doi.org/10.1164/ajrccm.156.3.9701113.Brannan J.D., Anderson S.D., Perry C.P., Freed-Martens R., Lassig A.R., Charlton B. The safety and efficacy of inhaled dry powder mannitol as a bronchial provocation test for airway hyperresponsiveness: a phase 3 comparison study with hypertonic (4.5%) saline. Respir Res. 2005;6(1):144. https://doi.org/10.1186/1465-9921-6-144.Brannan J.D., Anderson S.D., Perry C.P., Freed-Martens R., Lassig A.R., Charlton B. The safety and efficacy of inhaled dry powder mannitol as a bronchial provocation test for airway hyperresponsiveness: a phase 3 comparison study with hypertonic (4.5%) saline. Respir Res. 2005;6(1):144. https://doi.org/10.1186/1465-9921-6-144.Jaques A.J., Daviskas E., Turton J.A., McKay K., Cooper P., Stirling R.G. et al. Inhaled mannitol improves lung function in cystic fibrosis. Chest. 2008;133(6):1388–1396. https://doi.org/10.1378/chest.07-2294.Jaques A.J., Daviskas E., Turton J.A., McKay K., Cooper P., Stirling R.G. et al. Inhaled mannitol improves lung function in cystic fibrosis. Chest. 2008;133(6):1388–1396. https://doi.org/10.1378/chest.07-2294.Teper A., Jaques A., Charlton B. Inhaled mannitol in patients with cystic fibrosis: a randomised open-label dose response trial. J Cyst Fibros. 2011;10(1):1–8. https://doi.org/10.1016/j.jcf.2010.08.020.Teper A., Jaques A., Charlton B. Inhaled mannitol in patients with cystic fibrosis: a randomised open-label dose response trial. J Cyst Fibros. 2011;10(1):1–8. https://doi.org/10.1016/j.jcf.2010.08.020.Bilton D., Bellon G., Charlton B. et al. Pooled analysis of two large randomized phase III inhaled mannitol studies in cystic fibrosis. J Cystic Fibros. 2013;12(4):367–376. https://doi.org/10.1016/j.jcf.2012.11.002.Bilton D., Bellon G., Charlton B. et al. Pooled analysis of two large randomized phase III inhaled mannitol studies in cystic fibrosis. J Cystic Fibros. 2013;12(4):367–376. https://doi.org/10.1016/j.jcf.2012.11.002.De Boeck K., Haarman E., Hull J., Lands L.C., Moeller A., Munck A. et al. Inhaled dry powder mannitol in children with cystic fibrosis: A randomised efficacy and safety trial. J Cystic Fibros. 2017;16(3):380–387. https://doi.org/10.1016/j.jcf.2017.02.003.De Boeck K., Haarman E., Hull J., Lands L.C., Moeller A., Munck A. et al. Inhaled dry powder mannitol in children with cystic fibrosis: A randomised efficacy and safety trial. J Cystic Fibros. 2017;16(3):380–387. https://doi.org/10.1016/j.jcf.2017.02.003.Шерман В.Д., Воронкова А.Ю., Кондратьева Е.И., Жекайте Е.К., Черняк А.В. Опыт применения препарата маннитол (Бронхитол-Фармаксис) у пациентов детского возраста с муковисцидозом в Московском регионе. Пульмонология. 2019;29(4):436–442. https://doi.org/10.18093/0869-0189-2019-29-4-436-442.Sherman V.D., Voronkova A.Yu., Kondrat’yeva E.I., Zhekayte E.K., Chernyak A.V. An experience of treatment with inhaled mannitol in pediatric cystic fibrosis patients at Moscow region. Pulmonologiya. 2019;29(4):436–442. (In Russ.) https://doi.org/10.18093/0869-0189-2019-29-4-436-442.Геппе Н.А., Малахов А.Б., Зайцева О.В., Дегтярева М.В., Ильенкова Н.А., Калюжин О.В. и др. Спорные и нерешенные вопросы в терапии кашля у детей в амбулаторной практике. Педиатрия. Consilium Medicum. 2017;(4):40–45. Режим доступа: https://cyberleninka.ru/article/n/spornye-inereshennye-voprosy-v-terapii-kashlya-u-detey-v-ambulatornoy-praktike.Geppe N.A., Malakhov A.B., Zaytseva O.V., Degtyareva M.V., Ilyenkova N.A., Kalyuzhin O.V. et al. Controversial and unresolved issues in the treatment of cough in children in outpatient practice. Pediatrics. Consilium Medicum. 2017;(4):40–45. (In Russ.) Available at: https://cyberleninka.ru/article/n/spornyei-nereshennye-voprosy-v-terapii-kashlya-u-detey-v-ambulatornoy-praktike.Tural D.A., Yalçın E., Emiralioglu N., Ozsezen B., Sunman B., Buyuksahin H.N. et al. Comparison of inhaled mannitol/dornase alfa combination and daily dornase alfa alone in children with cystic fibrosis. Pediatr Pulmonol. 2022;(57):142–151. https://doi.org/10.1002/ppul.25740.Tural D.A., Yalçın E., Emiralioglu N., Ozsezen B., Sunman B., Buyuksahin H.N. et al. Comparison of inhaled mannitol/dornase alfa combination and daily dornase alfa alone in children with cystic fibrosis. Pediatr Pulmonol. 2022;(57):142–151. https://doi.org/10.1002/ppul.25740.

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