Modern methods of diagnosis and treatment of severe bronchial asthma (systematic review)

Currently, the prevalence of bronchial asthma (BA) is steadily increasing worldwide. Official statistics show that severe BA accounts for 5–10% of cases in the severity profile of this disease, and when treated with high doses of corticosteroids, uncontrolled symptoms persist in most people, which significantly reduces their quality of life. This supports the relevance of finding new strategies for the treatment of severe BA. The aim of the review was to analyze and summarize published data on modern approaches to the diagnosis and treatment of severe BA.

Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 3,177 sources were found. Excluding publications that were unavailable for viewing allowed us to leave 578 sources, of which 120 papers were relevant to the study topic to some extent. Of these, 63 sources were selected that contained the information necessary for the study and met the selection criteria for the studies: 28 of them were review articles and 35 were original studies (randomized controlled, cohort, and case-control studies). The work presents a description of phenotypes and endotypes, as well as characteristics of modern biomarkers of severe BA.

Particular attention is paid to a new approach to the treatment of severe BA. The conducted studies, systematized in this article, indicate that a detailed description of asthma phenotypes and endotypes can help identify new biomarkers and therapeutic targets specific to each endotype. Profound knowledge of the patient’s phenotype and endotype can determine a personalized approach to the treatment of severe BA.

1. Tan T., Yang F., Wang Z., Gao F., Sun L. Mediated Mendelian randomization analysis to determine the role of immune cells in regulating the effects of plasma metabolites on childhood asthma. Medicine (Baltimore). 2024;103(30):e38957. DOI: 10.1097/MD.0000000000038957.

2. Kelly A., Lavender P. Epigenetic approaches to identifying asthma endotype. Allergy Asthma Immunol. Res. 2024;16(2):130–141. DOI: 10.4168/aair.2024.16.2.130.

3. Komlósi Z.I., van de Veen W., Kovács N., Szűcs G., Sokolowska M., O’Mahony L. et al. Cellular and molecular mechanisms of allergic asthma. Mol. Aspects Med. 2022;85:100995. DOI: 10.1016/j.mam.2021.100995.

4. Lambrecht B.N., Hammad H., Fahy J.V. The Cytokines of asthma. Immunity. 2019;50:975–991. DOI: 10.1016/j.immuni.2019.03.018.

5. Rogers L., Jesenak M., Bjermer L., Hanania N.A., Seys S.F., Diamant Z. Biologics in severe asthma: A pragmatic approach for choosing the right treatment for the right patient. Respir. Med. 2023;218:107414. DOI: 10.1016/j.rmed.2023.107414.

6. Jackson D.J., Heaney L.G., Humbert M., Kent B.D., Shavit A., Hiljemark L. et al. Reduction of daily maintenance inhaled corticosteroids in patients with severe eosinophilic asthma treated with benralizumab (SHAMAL): a randomised, multicentre, open-label, phase 4 study. Lancet. 2024;403(10423):271–281. DOI: 10.1016/S0140-6736(23)02284-5.

7. Wenzel S.E. Severe Adult asthmas: integrating clinical features, biology, and therapeutics to improve outcomes. Am. J. Respir. Crit. Care Med. 2021;203(7):809–821. DOI: 10.1164/rccm.202009-3631CI.

8. Клинические рекомендации «Бронхиальная астма» (письмо Министерства здравоохранения Российской Федерации от 22.08.2024 № 37). М., 2024:60–65.

9. Diamant Z., Vijverberg S., Alving K., Bakirtas A., Bjermer L., Custovic A. et al. Toward clinically applicable biomarkers for asthma: An EAACI position paper. Allergy. 2019;74(10):1835– 1851. DOI: 10.1111/all.13806.

10. Levy M.L., Bacharier L.B., Bateman E., Boulet L.P., Brightling C., Buhl R. et al. Key recommendations for primary care from the 2022 Global Initiative for Asthma (GINA) update. NPJ Prim. Care Respir. Med. 2023;33(1):7. DOI: 10.1038/s41533-023-00330-1.

11. Malinovschi A., Rydell N., Fujisawa T., Borres M.P., Kim C.K. Clinical potential of eosinophil-derived neurotoxin in asthma management. J. Allergy Clin. Immunol. Pract. 2023;11(3):750–761. DOI: 10.1016/j.jaip.2022.11.046.

12. Laidlaw T.M., Menzies-Gow A., Caveney S., Han J.K., Martin N., Israel E. et al. Tezepelumab efficacy in patients with severe, uncontrolled Asthma with comorbid nasal polyps in NAVIGATOR. J. Asthma Allergy. 2023;16:915–932. DOI: 10.2147/JAA.S413064.

13. Van Hulst G., Bureau F., Desmet C.J. Eosinophils as drivers of severe eosinophilic asthma: endotypes or plasticity? Int. J. Mol. Sci. 2021;22(18):10150. DOI: 10.3390/ijms221810150.

14. Ali M.M., Wolfe M.G., Mukherjee M., Radford K., Patel Z., White D. et al. A sputum bioassay for airway eosinophilia using an eosinophil peroxidase aptamer. Sci. Rep. 2022;12:22476. DOI: 10.1038/s41598-022-26949-7.

15. Tang M., Charbit A.R., Johansson M.W., Jarjour N.N., Denlinger L.C., Raymond W.W. et al. National heart lung and blood institute severe Asthma Research Program Utility of eosinophil peroxidase as a biomarker of eosinophilic inflammation in asthma. J. Allergy Clin. Immunol. 2024;154(3):580– 591.e6. DOI: 10.1016/j.jaci.2024.03.023.

16. Agache I., Eguiluz-Gracia I., Cojanu C., Laculiceanu A., Del Giacco S., Zemelka-Wiacek M. et al. Advances and highlights in asthma in 2021. Allergy. 2021;76(11):3390–3407. DOI: 10.1111/all.15054.

17. Chung K.F., Dixey P., Abubakar-Waziri H., Bhavsar P., Patel P.H., Guo S. et al. Characteristics, phenotypes, mechanisms and management of severe asthma. Med. J. 2022;135(10):1141– 1155. DOI: 10.1097/CM9.0000000000001990.

18. Pérez de Llano L., Dacal Rivas D., Blanco Cid N., Martin Robles I. Phenotype-guided asthma therapy: an alternative approach to guidelines. J. Asthma Allergy. 2021;14:207– 217. DOI: 10.2147/JAA.S266999.

19. Plavsic A., Bonaci-Nikolic B., Milenkovic B., Miskovic R., Kusic N., Dimitrijevic M. et al. Asthma inflammatory phenotypes: how can we distinguish them? J. Clin. Med. 2024;13(2):526. DOI: 10.3390/jcm13020526.

20. Yang D., Han Z., Oppenheim J.J. Alarmins and immunity. Immunol. Rev. 2017;280:41–56. DOI: 10.1111/imr.12577

21. Amat F., Labbé A. Biomarkers for severe allergic asthma in children: could they be useful to guide disease control and use of omalizumab? Expert Rev. Respir. Med. 2018;12(6):475– 482. DOI: 10.1080/17476348.2018.1475233.

22. Longo C., Blais L., Brownell M., Quail J.M., Sadatsafavi M., Forget A. et al. Association between asthma control trajectories in preschoolers and disease remission. Eur. Respir. J. 2021;57:2001897. DOI: 10.1183/13993003.01897-2020.

23. Ogulur I., Pat Y., Ardicli O., Barletta E., Cevhertas L., Fernandez-Santamaria R. et al. Advances and highlights in biomarkers of allergic diseases. Allergy. 2021;76:3659–3686. DOI:10.1111/all.15089

24. Tota M., Łacwik J., Laska J., Sędek Ł., Gomułka K. The role of eosinophil-derived neurotoxin and vascular endothelial growth factor in the pathogenesis of eosinophilic asthma. Cells. 2023;12(9):1326. DOI: 10.3390/cells12091326

25. Janulaityte I., Januskevicius A., Kalinauskaite-Zukauske V., Palacionyte J., Malakauskas K. Asthmatic eosinophils promote contractility and migration of airway smooth muscle cells and pulmonary fibroblasts in vitro. Cells. 2021;10(6):1389. DOI: 10.3390/cells10061389.

26. Tsuda T., Maeda Y., Nishide M., Koyama S., Hayama Y., Nojima S. et al. Eosinophil-derived neurotoxin enhances airway remodeling in eosinophilic chronic rhinosinusitis and correlates with disease severity. Int. Immunol. 2019;31:33–40. DOI: 10.1093/intimm/dxy061.

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

28. Xu L., Huang X., Chen Z., Yang M., Deng J. Eosinophil peroxidase promotes bronchial epithelial cells to secrete asthma-related factors and induces the early stage of airway remodeling. Clin. Immunol. 2024;263:110228. DOI: 10.1016/j.clim.2024.110228.

29. Tony S.R., Haque N., Siddique A.E., Khatun M., Rahman M., Islam Z. et al. Elevated serum periostin levels among arsenic-exposed individuals and their associations with the features of asthma. Chemosphere. 2022;298:134277. DOI: 10.1016/j.chemosphere.2022.134277.

30. Baldo D.C., Romaldini J.G., Pizzichini M.M.M., Cançado J.E.D., Dellavance A., Stirbulov R. Periostin as an important biomarker of inflammatory phenotype T2 in Brazilian asthma patients. J. Bras Pneumol. 2023;49(1):e20220040. DOI: 10.36416/18063756/e20220040.

31. Takahashi K., Meguro K., Kawashima H., Kashiwakuma D., Kagami S.I., Ohta S. et al. Serum periostin levels serve as a biomarker for both eosinophilic airway inflammation and fixed airflow limitation in well-controlled asthmatics. J. Asthma. 2019;56(3):236–243. DOI: 10.1080/02770903.2018.1455855.

32. Panettieri R.A. Jr., Sjöbring U., Péterffy A., Wessman P., Bowen K., Piper E. 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.

33. Ono J., Takai M., Kamei A., Ohta S., Nair P., Izuhara K. et al. A novel assay for improved detection of sputum periostin in patients with asthma. PloS One. 2023;18(2):e0281356. DOI: 10.1371/journal.pone.0281356.

34. Kumar K., Singh M., Mathew J.L., Vaidya P.C., Verma Attri S. Serum periostin level in children with bronchial asthma. Indian. J. Pediatr. 2023;90(5):438–442. DOI: 10.1007/s12098-022-04282-1.

35. Макаревич А.Э. Клинические аспекты тяжелой бронхиальной астмы. Лечебное дело. 2023;3(86):7–23.

36. Чулков В.С., Минина Е.Е., Медведева Л.В. Использование в клинической практике метода индуцированной мокроты у пациентов с бронхиальной астмой. Acta Biomedica Scientifica. 2022;7(5–2):42–55. DOI: 10.29413/ABS.2022-7.5-2.5.

37. Gonem S., Berair R., Singapuri A., Hartley R., Laurencin M.F.M., Bacher G. et al. Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: A single-centre, randomised, double-blind, parallel-group, placebo-controlled trial. Lancet Respir. Med. 2016;4:699–707. DOI: 10.1016/S2213-2600(16)30179-5.

38. 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.

39. Hanania N.A., Noonan M., Corren J., Korenblat P., Zheng Y., Fischer S.K. et al. Lebrikizumab in moderate-to-severe asthma: Pooled data from two randomised placebo-controlled studies. Thorax. 2015;70:748–756. DOI: 10.1136/thoraxjnl-2014-206719.

40. Aldakheel F.M., Thomas P.S., Bourke J.E., Matheson M.C., Dharmage S.C., Lowe A.J. Relationships between adult asthma and oxidative stress markers and pH in exhaled breath condensate: a systematic review. Allergy. 2016;71(6):741–757. DOI: 10.1111/all.12865.

41. Van Veen I.H., Ten Brinke A., Sterk P.J., Sont J.K., Gauw S.A., Rabe K.F. et al. Exhaled nitric oxide predicts lung function decline in difficult-to-treat asthma. Eur. Respir. J. 2008;32(2):344–349. DOI: 10.1183/09031936.00135907.

42. Van Veen I.H., Ten Brinke A., Sterk P.J., Sont J.K., Gauw S.A., Rabe K.F. et al. The utility of fractional exhaled nitric oxide suppression in the identification of nonadherence in difficult asthma. Am. J. Respir. Crit. Care Med. 2012;186(11):1102– 1108. DOI: 10.1164/rccm.201204-0587OC.

43. Loureiro C.C., Duarte I.F., Gomes J., Carrola J., Barros A.S., Gil A.M. et al. Urinary metabolomic changes as a predictive biomarker of asthma exacerbation. J. Allergy Clin. Immunol. 2014;133(1):261–3.e1–5. DOI: 10.1016/j.jaci.2013.11.004.

44. Tiotiu A. Biomarkers in asthma: state of the art. Asthma Res. Pract. 2018;4:10. DOI: 10.1186/s40733-018-0047-4.

45. Cowan D.C., Taylor D.R., Peterson L.E., Cowan J.O., Palmay R., Williamson A. et al. Biomarker-based asthma phenotypes of corticosteroid response. J. Allergy Clin. Immunol. 2015;135(4):877–883.e1. DOI: 10.1016/j.jaci.2014.10.026.

46. Chung K.F. Precision medicine in asthma: Linking phenotypes to targeted treatments. Curr. Opin. Pulm. Med. 2018;24(1):4– 10. DOI: 10.1097/MCP.0000000000000434.

47. Papi A., Saetta M., Fabbri L. Severe asthma: phenotyping to endotyping or vice versa? Eur. Respir. J. 2017;49(2):1700053. DOI: 10.1183/13993003.00053-2017.

48. Baines K.J., Simpson J.L., Wood L.G., Scott R.J., Gibson P.G. Transcriptional phenotypes of asthma defined by gene expression profiling of induced sputum samples. J. Allergy Clin. Immunol. 2011;127(1):153–160, 160.e1–9. DOI: 10.1016/j.jaci.2010.10.024.

49. Kuruvilla M.E., Lee F.E., Lee G.B. Understanding asthma phenotypes, endotypes, and mechanisms of disease. Clin. Rev. Allergy Immunol. 2019;56(2):219–233. DOI: 10.1007/s12016-018-8712-1.

50. Bartel D.P. MicroRNAs: Target recognition and regulatory functions. Cell. 2009;136:215–233. DOI: 10.1016/j.cell.2009.01.002.

51. Kyyaly M.A., Sanchez-Elsner T., He P., Sones C.L., Arshad S.H., Kurukulaaratchy R.J. Circulating miRNAs-A potential tool to identify severe asthma risk? Clin. Transl. Allergy. 2021;11(4):e12040. DOI: 10.1002/clt2.12040.

52. Atashbasteh M., Mortaz E., Mahdaviani S.A., Jamaati H., Allameh A. Expression levels of plasma exosomal miR-124, miR-125b, miR-133b, miR-130a and miR-125b-1-3p in severe asthma patients and normal individuals with emphasis on inflammatory factors. Allergy Asthma Clin. Immunol. 2021;17(1):51. DOI: 10.1186/s13223-021-00556-z.

53. Cañas J.A., Valverde-Monge M., Rodrigo-Muñoz J.M., Sastre B., Gil-Martínez M., García-Latorre R. et al. Serum microRNAs as tool to predict early response to Benralizumab in severe eosinophilic asthma. J. Pers. Med. 2021;11(2):76. DOI: 10.3390/jpm11020076.

54. Gil-Martínez M., Lorente-Sorolla C., Rodrigo-Muñoz J.M., Lendínez M.Á., Núñez-Moreno G., de la Fuente L. et al. Analysis of differentially expressed microRNAs in serum and lung tissues from individuals with severe asthma treated with oral glucocorticoids. Int. J. Mol. Sci. 2023;24(2):1611. DOI: 10.3390/ijms24021611.

55. Heffler E., Allegra A., Pioggia G., Picardi G., Musolino C., Gangemi S. MicroRNA profiling in asthma: potential biomarkers and therapeutic targets. Am. J. Respir. Cell Mol. Biol. 2017;57(6):642–650. DOI: 10.1165/rcmb.2016-0231TR.

56. Lacedonia D., Palladino G.P., Foschino-Barbaro M.P., Scioscia G., Carpagnano G.E. Expression profiling of miRNA-145 and miRNA-338 in serum and sputum of patients with COPD, asthma, and asthma-COPD overlap syndrome phenotype. Int. J. Chron. Obstruct. Pulmon. Dis. 2017;12:1811–1817. DOI: 10.2147/COPD.S130616.

57. McGregor M.C., Krings J.G., Nair P., Castro M. Role of biologics in asthma. Am. J. Respir. Crit. Care Med. 2019;199(4):433–445. DOI: 10.1164/rccm.201810-1944CI.

58. Lampalo M., Štajduhar A., Rnjak D., Safić Stanić H., Popović-Grle S. Effectiveness of biological therapy in severe asthma: a retrospective real-world study. Croat. Med. J. 2025;66(1):3–12. DOI: 10.3325/cmj.2025.66.3.

59. Contreras N., Escolar-Peña A., Delgado-Dolset M.I., Fernández P., Obeso D., Izquierdo E. et al. Multiomic integration analysis for monitoring severe asthma treated with mepolizumab or omalizumab. Allergy. 2025;80(7):1899–1911. DOI: 10.1111/all.16434.

60. Djukanović R., Brinkman P., Kolmert J., Gomez C., Schofield J. et al. Biomarker Predictors of Clinical Efficacy of the Anti-IgE Biologic Omalizumab in Severe Asthma in Adults: Results of the SoMOSA Study. Am. J. Respir. Crit. Care Med. 2024;210(3):288–297. DOI: 10.1164/rccm.202310-1730OC.

61. Rojo-Tolosa S., Sánchez-Martínez J.A., Caballero-Vázquez A., Pineda-Lancheros L.E., González-Gutiérrez M.V., PérezRamírez C. et al. Single nucleotide polymorphisms as biomarkers of mepolizumab and benralizumab treatment response in severe eosinophilic asthma. Int. J. Mol. Sci. 2024;25(15):8139. DOI: 10.3390/ijms25158139.

62. Harada S., Sasano H., Ueda S., Sandhu Y., Abe S., Tanabe Y. et al. Skin surface lipid-RNA profile obtained from patients with severe asthma after benralizumab treatment. J. Asthma Allergy. 2024;17:1103–1113. DOI: 10.2147/JAA.S490832.

63. Hillson K., Saglani S., Bush A. The new biologic drugs: which children with asthma should get what? Pediatr. Pulmonol. 2024;59(12):3057–3074. DOI: 10.1002/ppul.27218.