Small airway dysfunction in asthma: diagnostic, pathogenetic and therapeutic aspects
https://doi.org/10.36604/1998-5029-2025-96-141-153
Abstract
In recent years, increasing attention has been paid to the role of the small airways (SA) in the pathophysiological and clinical aspects of asthma. The article summarizes the main methods for assessing impaired SA function—spirometry, body plethysmography, impulse oscillometry, fractional exhaled-nitric-oxide analysis, inert-gas washout tests and computed tomography—and notes the absence of a single standard technique for identifying SA dysfunction. The pathogenetic mechanisms underlying SA dysfunction in asthma are discussed, with an emphasis on the key roles of cytokines, eicosanoids (polyunsaturated-fatty-acid metabolites) and plasmalogens in the complex network of mediators that regulate chronic airway inflammation. The potential for correcting SA dysfunction with modern pharmacological agents aimed at restoring lung function is considered. The studies analyzed highlight the importance of early evaluation of SA status and identification of triggers that drive SA dysfunction in asthma.
Supporting agencies: This study was not sponsored
About the Author
А. V. Yurenko
Vladivostok Branch of Far Eastern Scientific Centre of Physiology and Pathology of Respiration – Research Institute of Medical Climatology and Rehabilitation Treatment
Russian Federation
Russian Federation
Alla V. Yurenko, MD, PhD (Med.), Senior Staff Scientist, general practitioner
Laboratory of Rehabilitative Treatment
690105; 73g Russkaya Str.; Vladivostok
References
1. Yi F., Jiang Z., Li H., Guo C., Lu H., Luo W., Chen Q., Lai K. Small airway dysfunction in cough variant asthma: prevalence, clinical, and pathophysiological features. Front. Physiol. 2022; 12:761622. doi: 10.3389/fphys.2021.761622
2. Fassakhov R.S. [Significant role of small respiratory tracts: new possibilities of cyclesonide in therapy of bronchial asthma]. Meditsinskiy sovet = Medical Council 2017; 18:56‒60 (in Russian). doi: 10.21518/2079-701X-2017-18-56-60
3. Burgel P.R., Bergeron A., de Blic J., Bonniaud P., Bourdin A., Chanez P., Chinet T., Dalphin J.C., Devillier P., Deschildre A., Didier A., Kambouchner M., Knoop C., Laurent F., Nunes H., Perez T., Roche N., Tillie-Leblond I., Dusser D. Small airways diseases, excluding asthma and COPD : an overview. Eur. Respir. Rev. 2013; 22(128):131–147. doi: 10.1183/09059180.00001313
4. Takeda T., Oga T., Niimi A., Matsumoto H., Ito I., Yamaguchi M., Matsuoka H., Jinnai M., Otsuka K., Oguma T., Nakaji H., Chin K., Mishima M. Relationship between small airway function and health status, dyspnea and disease control in asthma. Respiration 2010; 80(2):120–26. doi: 10.1159/000242113
5. Bonini M., Usmani O.S. The role of the small airways in the pathophysiology of asthma and chronic obstructive pulmonary disease. Ther. Adv. Respir. Dis. 2015; 9(6):281–293. doi: 10.1177/1753465815588064
6. King G.G., Chung L.P., Usmani O.S., Nilsen K., Thompson B.R. Improving asthma outcomes: clinicians' perspectives on peripheral airways. J. Allergy Clin. Immunol. Glob. 2024; 3(2):100228. doi: 10.1016/j.jacig.2024.100228
7. Мineeva Е.Е., Аntonyuk М.V., Yurenko А.V., Gvozdenko Т.А., Uksumenko А.А. [Small airways dysfunction and the state of lung function in mild asthma]. Bûlleten' fiziologii i patologii dyhaniâ = Bulletin of Physiology and Pathology of Respiration 2020; 78:76–83 (in Russian). doi: 10.36604/1998-5029-2020-78-76-83
8. Kraft M., Richardson M., Hallmark B., Billheimer D., Van den Berge M., Fabbri L.M., Van der Molen T., Nicolini G., Papi A., Rabe K.F., Singh D., Brightling C., Siddiqui S. The role of small airway dysfunction in asthma control and exacerbations: a longitudinal, observational analysis using data from the ATLANTIS study. Lancet Respir. Med. 2022; 10(7):661–668. doi: 10.1016/S2213-2600(21)00536-1
9. Lipworth B., Manoharan A., Anderson W. Unlocking the quiet zone: the small airway asthma phenotype. Lancet Respir. Med. 2014; 2(6):497–506. doi: 10.1016/S2213-2600(14)70103-1
10. Churyukina E.V. [Small airways – a «silent zone» or an active participant in the pathological process in bronchial asthma? Possibilities of pharmacological influence]. Farmakologiya i Farmakoterapiya 2022; 4:50–57 (in Russian). doi: 10.46393/27132129_2022_4_50
11. Aisanov Z.R, Kalmanova E.N. [The lesion of small airways in patients with asthma: new data, new paradigm]. Prakticheskaya pul'monologiya = The Journal of Practical Pulmonology 2019; 1:6–14 (in Russian).
12. McNulty W., Usmani O.S. Techniques of assessing small airways dysfunction. Eur. Clin. Respir. J. 2014; 1:25898. doi: 10.3402/ecrj.v1.25898
13. Kameneva M.Yu., Cherniak A.V., Aisanov Z.R., Avdeev S.N., Babak S.L., Belevskiy A.S., Beresten N.F., Kalmanova E.N., Malyavin A.G., Perelman Ju.M., Prikhodko A.G., Struchkov P.V., Chikina S.Yu., Chushkin M.I. [Spirometry : national guidelines for the testing and interpretation of results]. Russian Pulmonology 2023; 33(3):307–340 (in Russian). doi: 10.18093/0869-0189-2023-33-3-307-340
14. Pisi R., Aiello M., Frizzelli A., Feci D., Aredano I., Manari G., Calzetta L., Pelà G., Chetta A. Detection of small airway dysfunction in asthmatic patients by spirometry and impulse oscillometry system. Respiration 2023; 102(7):1–8. doi: 10.1159/000531205
15. Carr T.F., Altisheh R., Zitt M. Small airways disease and severe asthma. World Allergy Organ. J. 2017; 10(1):20. doi: 10.1186/s40413-017-0153-4
16. Toumpanakis D., Usmani O.S. Small airways in asthma: pathophysiology, identification and management. Chin. Med. J. Pulm. Crit. Care Med. 2023; 1(3):171–180. doi: 10.1016/j.pccm.2023.07.002
17. Avdeev S.N. [A role of small airways in bronchial asthma]. Russian Pulmonology 2010; 6:87–97 (in Russian). doi: 10.18093/0869-0189-2010-6-87-97
18. Kameneva M.Yu., Tishkov A.V., Trofimov V.I. [New approaches to differential diagnostics of syndromes of ventilation disorders]. Bûlleten' fiziologii i patologii dyhaniâ = Bulletin of Physiology and Pathology of Respiration 2017; 65:8–15 (in Russian). doi: 10.12737/article_59aca3bd1aa8e8.39408462
19. Savushkina О.I., Chernyak А.V. [Theoretical and methodological aspects of body plethysmography and clinical applications]. Bûlleten' fiziologii i patologii dyhaniâ = Bulletin of Physiology and Pathology of Respiration 2016; 60:117–124 (in Russian). doi: 10.12737/20131
20. Perez T., Chanez P., Dusser D., Devillier P. Small airway impairment in moderate to severe asthmatics without significant proximal airway obstruction. Respir. Med. 2013; 107(11):1667–1674. doi: 10.1016/j.rmed.2013.08.009
21. [Bodyplectisimography]. Moscow: Rossiyskoe respiratornoe obshchestvo. Rossiyskaya assotsiatsiya spetsialistov funktsional'noy diagnostiki; 2024 (in Russian). Available at: https://spulmo.ru/upload/kr/BPG_2024_draft.pdf
22. Chernyak A.V., Savushkina O.I., Pashkova T.L., Kryukov EV. [Diagnosis of small airway dysfunction in patients with chronic obstructive pulmonary disease]. Almanach of Clinical Medicine 2020; 48(5):307–315 (in Russian). doi: 10.18786/2072-0505-2020-48-019
23. Mustafina M.H., Chernjak A.V. [Methods of washing out inert gases: significance in the diagnosis of respiratory diseases]. Prakticheskaya pul'monologiya = The Journal of Practical Pulmonology 2014; (1):39–44 (in Russian).
24. Zinellu E., Piras B., Ruzittu G.G.M., Fois S.S., Fois A.G., Pirina P. Recent advances in inflammation and treatment of small airways in asthma. Int. J. Mol. Sci. 2019; 20(11):2617. doi: 10.3390/ijms20112617
25. Kiryukhina L.D., Chernyak A.V. [Oscillometry: clinical significance and applications]. Russian Pulmonology 2023; 33(6):798–808 (in Russian). doi: 10.18093/0869-0189-2023-33-6-798-808
26. Williamson P.A., Clearie K., Menzies D., Vaidyanathan S., Lipworth B.J. Assessment of small-airways disease using alveolar nitric oxide and impulse oscillometry in asthma and COPD. Lung 2011; 189(2):121–129. doi: 10.1007/s00408-010-9275-y
27. Abdo M., Trinkmann F., Kirsten A.M., Pedersen F., Herzmann C., von Mutius E., Kopp M.V., Hansen G., Waschki B., Rabe K.F., Watz H., Bahmer T. Small airway dysfunction links asthma severity with physical activity and symptom control. J. Allergy Clin. Immunol. Pract. 2021; 9(9):3359–3368.e1. doi: 10.1016/j.jaip.2021.04.035
28. Brillet P.Y., Debray M.P., Golmard J.L., Ould Hmeidi Y., Fetita C., Taillé C., Aubier M., Grenier P.A. Computed tomography assessment of airways throughout bronchial tree demonstrates airway narrowing in severe asthma. Acad. Radiol. 2015; 22(6):734–742. doi: 10.1016/j.acra.2014.12.026
29. Yogev D., Chatarji S., Carl L., Levy L., Goldberg T., Feinberg O., Illouz S., Spector R., Parmet Y, Tejman-Yarden S. A comparative study of CT-based volumetric assessment methods for total lung capacity with the development of an adjustment factor: incorporating VR imaging for improved accuracy. Virtual Reality 2024; 28(1):2. doi: 10.1007/s10055-023-00892-y
30. King G.G., Farrow C.E., Chapman D.G. Dismantling the pathophysiology of asthma using imaging. Eur. Respir. Rev. 2019; 28:180111. doi 10.1183/16000617.0111-2018
31. Roos J.E., McAdams H.P., Kaushik S.S., Driehuys B. Hyperpolarized gas MR imaging: technique and applications. Magn. Reson. Imaging Clin. N. Am. 2015; 23(2):217–229. doi: 10.1016/j.mric.2015.01.003
32. Eddy R.L., Matheson A.M., Svenningsen S., Knipping D., Licskai C., McCormack D.G., Parraga G. Nonidentical twins with asthma: spatially matched CT airway and MRI ventilation abnormalities. Chest 2019; 156(6):e111–e116. doi: 10.1016/j.chest.2019.08.004
33. van Beek E.J., Wild J.M., Kauczor H.U., Schreiber W., Mugler J.P., de Lange EE. Functional MRI of the lung using hyperpolarized 3-helium gas. J. Magn. Reson. Imaging. 2004; 20(4):540–554. doi: 10.1002/jmri.20154
34. Usmani O.S., Singh D., Spinola M., Bizzi A., Barnes P.J. The prevalence of small airways disease in adult asthma : a systematic literature review. Respir. Med. 2016; 116:19–27. doi: 10.1016/j.rmed.2016.05.006
35. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention (Update 2020-2024). Available at: https://ginasthma.org
36. Beinart D., Goh E.S.Y., Boardman G., Chung L.P. Small airway dysfunction measured by impulse oscillometry is associated with exacerbations and poor symptom control in patients with asthma treated in a tertiary hospital subspecialist airways disease clinic. Front. Allergy 2024; 5:1403894. doi: 10.3389/falgy.2024.1403894
37. Nenasheva N.M. [The role of small airways in bronchial asthma]. Atmosfera. Pul'monologiya i allergologiya 2010; 4:27–33 (in Russian).
38. Moldaver D.M., Larché M., Rudulier C.D. An update on lymphocyte subtypes in asthma and airway disease. Chest 2017; 151(5):1122–1130. doi: 10.1016/j.chest.2016.10.038
39. Gordon E.D., Palandra J., Wesolowska-Andersen A., Ringel L., Rios C.L., Lachowicz-Scroggins M.E., Sharp L.Z., Everman J.L., MacLeod H.J., Lee J.W., Mason R.J., Matthay M.A., Sheldon R.T., Peters M.C., Nocka K.H., Fahy J.V., Seibold M.A. IL1RL1 asthma risk variants regulate airway type 2 inflammation. JCI Insight. 2016; 1(14):e87871. doi: 10.1172/jci.insight.87871
40. Hough K.P., Curtiss M.L., Blain T.J., Liu R.M., Trevor J., Deshane J.S., Thannickal V.J. Airway Remodeling in Asthma. Front. Med (Lausanne) 2020; 7:191. doi: 10.3389/fmed.2020.00191
41. Doherty T., Broide D. Cytokines and growth factors in airway remodeling in asthma. Curr. Opin. Immunol. 2007; 19(6):676–680. doi: 10.1016/j.coi.2007.07.017
42. Hudey S.N., Ledford D.K., Cardet J.C. Mechanisms of non-type 2 asthma. Curr. Opin. Immunol. 2020; 66:123–128. doi: 10.1016/j.coi.2020.10.002
43. Kudo M., Melton A.C., Chen C., Engler M.B., Huang K.E., Ren X., Wang Y., Bernstein X., Li J.T., Atabai K., Huang X., Sheppard D. IL-17A produced by αβ T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nat. Med. 2012; 18(4):547–554. doi: 10.1038/nm.2684
44. Yurenko A.V., Antonyuk M.V., Mineeva E.E., Khodosova K.K. [Pathophysiological relation between the systemic inflammation and the state of small airways in mild asthma with obesity]. Medical Immunology (Russia) 2022; 24(6):1205–1218 (in Russian). doi: 10.15789/1563-0625-PRB-2388
45. Grainge C.L., Davies D.E. Epithelial injury and repair in airways diseases. Chest 2013; 144(6):1906–1912. doi: 10.1378/chest.12-1944
46. Borish L. The role of leukotrienes in upper and lower airway inflammation and the implications for treatment. Ann. Allergy Asthma Immunol. 2002; 88(4-1):16–22. doi: 10.1016/s1081-1206(10)62024-8
47. Denisenko Y.K., Novgorodtseva T.P., Zhukova N.V., Antonyuk M.V., Lobanova E.G., Kalinina E.P. [Association of fatty acid metabolism with systemic inflammatory response in chronic respiratory diseases]. Biomedical chemistry 2016; 62(3):341–347 (in Russian). doi: 10.18097/PBMC20166203341
48. Sordillo J.E., Lutz S.M., Kelly R.S., McGeachie M.J., Dahlin A., Tantisira K., Clish C., Lasky-Su J., Wu A.C. Plasmalogens mediate the effect of age on bronchodilator response in individuals with asthma. Front. Med. (Lausanne) 2020; 7:38. doi: 10.3389/fmed.2020.00038
49. Yurenko A.V., Novgorodtseva T.P., Denisenko Yu.K., Antonyuk M.V., Mineeva E.E. [The role of fatty acids and lipid inflammatory mediators in the development of small airway dysfunction in asthma complicated with obesity]. Acta Biomedica Scientifica 2023; 8(2):50–64 (in Russian). doi: 10.29413/ABS.2023-8.2.6
50. Battaglia S., den Hertog H., Timmers M.C., Lazeroms S.P., Vignola A.M., Rabe K.F., Bellia V., Hiemstra P.S., Sterk P.J. Small airways function and molecular markers in exhaled air in mild asthma. Thorax 2005; 60:639–644. doi: 10.1136/thx.2004.03527
51. Trischler J., Müller C.M., Könitzer S., Prell E., Korten I., Unverzagt S., Lex C. Elevated exhaled leukotriene B in the small airway compartment in children with asthma. Ann. Allergy Asthma Immunol. 2015; 114(2):111–116. doi: 10.1016/j.anai.2014.11.022
52. Knayzhevskay N.P., Anaev E.Kh., Kameleva A.A., Safoshkina E.V., Kirichenko N.D. [Targeted therapy in bronchial asthma. Benralizumab: focus on patients using systemic glucocorticosteroids]. Medical Council 2020; (17):9–16 (in Russian). doi: 10.21518/2079-701X-2020-17-9-16
53. Tufvesson E., Nihlberg K., Westergren-Thorsson G., Bjermer L. Leukotriene receptors are differently expressed in fibroblast from peripheral versus central airways in asthmatics and healthy controls. Prostaglandins Leukot. Essent. Fatty Acids. 2011; 85(2):67–73. doi: 10.1016/j.plefa.2011.04.025
54. Kraft M., Cairns C.B., Ellison M.C., Pak J., Irvin C., Wenzel S. Improvements in distal lung function correlate with asthma symptoms after treatment with oral montelukast. Chest 2006; 130(6):1726–1732. doi: 10.1378/chest.130.6.1726
55. Denisenko Y., Novgorodtseva T., Antonyuk M., Yurenko A., Gvozdenko T., Kasyanov S., Ermolenko E., Sultanov R. 1-O-alkyl-glycerols from squid berryteuthis magister reduce inflammation and modify fatty acid and plasmalogen metabolism in asthma associated with obesity. Mar. Drugs 2023; 21(6):351. doi: 10.3390/md21060351
Review
For citations:
Yurenko А.V. Small airway dysfunction in asthma: diagnostic, pathogenetic and therapeutic aspects. Bulletin Physiology and Pathology of Respiration. 2025;(96):141-153. (In Russ.) https://doi.org/10.36604/1998-5029-2025-96-141-153
Views:
131
Email this article 