Şiddetli Astımda Yeni Tedavi Yaklaşımları ve Biyobelirteçler: Güncel Bir İnceleme

Abstract

Bu çalışmanın amacı, şiddetli astımda biyolojik tedavilerin etkinliğini değerlendirmek ve hastalık yönetiminde kullanılan temel biyobelirteçlerin klinik karar verme sürecindeki rolünü ortaya koymaktır. 2015–2024 yılları arasında PubMed, Web of Science, Cochrane ve Google Scholar veri tabanlarında “severe asthma”, “biomarker”, “biologic therapy” anahtar kelimeleri kullanılarak taranan çalışmalar sistematik olarak incelendi. Tip 2 yüksek ve Tip 2 düşük astım alt tipleri; kullanılan biyobelirteçler (kan eozinofil sayısı, FeNO, periostin, IgE) ve uygulanan biyolojik tedaviler (omalizumab, mepolizumab, benralizumab, dupilumab, tezepelumab) klinik sonuçlara göre değerlendirildi. Literatür analizi, Tip 2 yüksek astımda biyobelirteçlerin tedavi yanıtını öngörmede güçlü belirteçler olduğunu göstermiştir. Özellikle yüksek eozinofil düzeyi ve artmış FeNO değerleri, IL-5 ve IL-4/IL-13 hedefli biyolojik ajanlara olumlu yanıt ile ilişkili bulundu. Tip 2 düşük astım hastalarında ise mevcut biyolojik tedavilere yanıt sınırlı olup, alarmin hedefli tedaviler (tezepelumab) ve azitromisin gibi alternatif yaklaşımlar öne çıkmıştır. Biyolojik tedaviler, şiddetli astım yönetiminde önemli bir ilerleme sağlamış olsa da, doğru tedavi seçimi için fenotip ve biyobelirteç temelli yaklaşım kritik öneme sahiptir. Tip 2 yüksek astımda biyobelirteçler tedavi yanıtını değerlendirmede etkili olurken, Tip 2 düşük astım için yeni hedeflere yönelik araştırmalara ihtiyaç duyulmaktadır. Kişiselleştirilmiş tedavi stratejilerinin geliştirilmesi, ileri dönem astım yönetiminin temelini oluşturacaktır.

Keywords

• Şiddetli Astım
• Biyobelirteç
• Biyolojik Tedavi
• Tip 2 Yüksek Astım
• Tip 2 Düşük Astım
• Kişiselleştirilmiş Tıp.

Supporting Institution

Finansman beyanı: Yazarlar bu makalenin araştırılması ve/veya yazarlığı için hiçbir finansal destek almamışlardır.

Ethical Statement

Etik Komite: Çalışma protokolü için etik komiteden onay alınmamıştır.

New Treatment Approaches and Biomarkers in Severe Asthma: An Updated Review

Abstract

This study aims to evaluate the effectiveness of biological treatments in severe asthma and to reveal the role of basic biomarkers used in disease management in the clinical decision-making process. A systematic review was conducted using the keywords "severe asthma," "biomarker," and "biologic therapy" in PubMed, Web of Science, Cochrane, and Google Scholar databases between 2015 and 2024. Type 2 high and Type 2 low asthma subtypes were evaluated based on the biomarkers used (blood eosinophil count, FeNO, periostin, and IgE), as well as the biological treatments applied (omalizumab, mepolizumab, benralizumab, dupilumab, and tezepelumab), and their corresponding clinical outcomes. Literature analysis has shown that biomarkers are strong predictors of treatment response in patients with Type 2 asthma. In particular, high eosinophil counts and increased FeNO levels were associated with a favorable response to biologic agents targeting IL-5 and IL-4/IL-13. In patients with Type 2 low asthma, the response to existing biologic therapies is limited, and alternative approaches such as alarmin-targeted therapies (tezepelumab) and azithromycin have emerged. While biologic therapies have made significant progress in the management of severe asthma, a phenotype- and biomarker-based approach is critical for accurate treatment selection. While biomarkers are effective in assessing treatment response in Type 2 high asthma, research is needed to identify new targets for Type 2 low asthma. The development of personalized treatment strategies will form the basis of future asthma management.

Keywords

• Severe Asthma
• Biomarker
• Biological Therapy
• Type 2 High Asthma
• Type 2 Low Asthma
• Personalized Medicine.

Supporting Institution

Funding statement: The authors received no financial support for the research and/or authorship of this article.

Ethical Statement

Ethics Committee: Approval from the ethics committee was not obtained for the study protocol

References

1. Agache, I., Beltran, J., Akdis, C., Akdis, M., Canelo‐Aybar, C., Canonica, G. W., . . . Del Giacco, S. (2020). Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI Guidelines‐recommendations on the use of biologicals in severe asthma. Allergy, 75(5), 1023-1042.
2. Ajaykumar, C. B., Rajkumar, S., Suresh, B., Birappa, G., Gowda, D. A. A., Jayachandran, A., . . . Ramakrishna, S. (2025). Chapter Five - Advances in applications of the CRISPR/Cas9 system for respiratory diseases. In V. Singh (Ed.), Progress in Molecular Biology and Translational Science (Vol. 210, pp. 127-147): Academic Press.
3. Bardin, P., Kanniess, F., Gauvreau, G., Bredenbröker, D., & Rabe, K. (2015). Roflumilast for asthma: efficacy findings in mechanism of action studies. Pulmonary Pharmacology & Therapeutics, 35, S4-S10.
4. Bleecker, E. R., FitzGerald, J. M., Chanez, P., Papi, A., Weinstein, S. F., Barker, P., . . . Werkström, V. (2016). 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. The Lancet, 388(10056), 2115-2127.
5. Blockmans, D., Penn, S. K., Setty, A. R., Schmidt, W. A., Rubbert-Roth, A., Hauge, E. M., . . . Merkel, P. A. (2025). A Phase 3 Trial of Upadacitinib for Giant-Cell Arteritis. N Engl J Med, 392(20), 2013-2024. doi:10.1056/NEJMoa2413449
6. Brightling, C. E., Gaga, M., Inoue, H., Li, J., Maspero, J., Wenzel, S., . . . Bleecker, E. R. (2021). Effectiveness of fevipiprant in reducing exacerbations in patients with severe asthma (LUSTER-1 and LUSTER-2): two phase 3 randomised controlled trials. The Lancet Respiratory Medicine, 9(1), 43-56. doi:10.1016/S2213-2600(20)30412-4
7. Brightling, C. E., Nair, P., Cousins, D. J., Louis, R., & Singh, D. (2021). Risankizumab in severe asthma—a phase 2a, placebo-controlled trial. New England journal of medicine, 385(18), 1669-1679.
8. Busse, W. W., Holgate, S., Kerwin, E., Chon, Y., Feng, J., Lin, J., & Lin, S. L. (2013). Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med, 188(11), 1294-1302. doi:10.1164/rccm.201212-2318OC

9. Busse, W. W., Wenzel, S. E., Casale, T. B., FitzGerald, J. M., Rice, M. S., Daizadeh, N., . . . Rowe, P. J. (2021). Baseline FeNO as a prognostic biomarker for subsequent severe asthma exacerbations in patients with uncontrolled, moderate-to-severe asthma receiving placebo in the LIBERTY ASTHMA QUEST study: a post-hoc analysis. The Lancet Respiratory Medicine, 9(10), 1165-1173.
10. Cahill, K. N., Katz, H. R., Cui, J., Lai, J., Kazani, S., Crosby-Thompson, A., . . . DiMango, E. (2017). KIT inhibition by imatinib in patients with severe refractory asthma. New England journal of medicine, 376(20), 1911-1920.
11. Casale, T. B., Luskin, A. T., Busse, W., Zeiger, R. S., Trzaskoma, B., Yang, M., . . . Chipps, B. E. (2019). Omalizumab effectiveness by biomarker status in patients with asthma: evidence from PROSPERO, a prospective real-world study. The Journal of Allergy and Clinical Immunology: In Practice, 7(1), 156-164. e151.
12. Castro, M., Corren, J., Pavord, I. D., Maspero, J., Wenzel, S., Rabe, K. F., . . . FitzGerald, J. M. (2018). Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. New England journal of medicine, 378(26), 2486-2496.
13. Castro, M., Zangrilli, J., Wechsler, M. E., Bateman, E. D., Brusselle, G. G., Bardin, P., . . . Korn, S. (2015). Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. The Lancet Respiratory Medicine, 3(5), 355-366. Corren, J., Menzies-Gow, A., Chupp, G., Israel, E., Korn, S., Cook, B., . . . Molfino, N. A. (2023). Efficacy of tezepelumab in severe, uncontrolled asthma: pooled analysis of the PATHWAY and NAVIGATOR clinical trials. American journal of respiratory and critical care medicine, 208(1), 13-24.
14. Corren, J., Parnes, J. R., Wang, L., Mo, M., Roseti, S. L., Griffiths, J. M., & van der Merwe, R. (2017). Tezepelumab in adults with uncontrolled asthma. New England journal of medicine, 377(10), 936-946.
15. Corren, J., Pham, T. H., Garcia Gil, E., Sałapa, K., Ren, P., Parnes, J. R., . . . Griffiths, J. M. (2022). Baseline type 2 biomarker levels and response to tezepelumab in severe asthma. Allergy, 77(6), 1786-1796.
16. D’Aiuto, V., Mormile, I., Granata, F., Romano, A., Della Casa, F., Mignogna, G., . . . Rossi, F. W. (2025). Eosinophil-driven vs. eosinophil-associated severe asthma: Practical implications for target treatment. International Journal of Molecular Sciences, 26(4), 1729.
17. D’Amato, M., Pastore, D., Lupia, C., Candia, C., Bruni, A., Garofalo, E., . . . Vatrella, A. (2025). Biologic Therapy in Severe Asthma: A Phenotype-Driven and Targeted Approach. Journal of Clinical Medicine, 14(13), 4749.
18. Davidescu, L., Ursol, G., Korzh, O., Deshmukh, V., Kuryk, L., Nortje, M.-M., . . . Israel, E. (2022). Efficacy and safety of masitinib in corticosteroid-dependent severe asthma: a randomized placebo-controlled trial. Journal of asthma and allergy, 737-747.
19. Esensten, J. H., Helou, Y. A., Chopra, G., Weiss, A., & Bluestone, J. A. (2016). CD28 Costimulation: From Mechanism to Therapy. Immunity, 44(5), 973-988. doi:10.1016/j.immuni.2016.04.020
20. FitzGerald, J. M., Bleecker, E. R., Nair, P., Korn, S., Ohta, K., Lommatzsch, M., . . . Sproule, S. (2016). 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. The Lancet, 388(10056), 2128-2141.
21. Food, U., & Administration, D. (2020). DUPIXENT (dupilumab) prescribing information. Silver Spring, MA, USA: US Food and Drug Administration.
22. Fouka, E., Domvri, K., Gkakou, F., Alevizaki, M., Steiropoulos, P., Papakosta, D., & Porpodis, K. (2022). Recent insights in the role of biomarkers in severe asthma management. Frontiers in medicine, 9, 992565.
23. Gandhi, N. A., Bennett, B. L., Graham, N. M., Pirozzi, G., Stahl, N., & Yancopoulos, G. D. (2016). Targeting key proximal drivers of type 2 inflammation in disease. Nature reviews Drug discovery, 15(1), 35-50.
24. Gauvreau, G., Boulet, L. P., Cockcroft, D., FitzGerald, J., Mayers, I., Carlsten, C., . . . Larché, M. (2014). OX 40L blockade and allergen‐induced airway responses in subjects with mild asthma. Clinical & Experimental Allergy, 44(1), 29-37.
25. Gibson, P. G., Yang, I. A., Upham, J. W., Reynolds, P. N., Hodge, S., James, A. L., . . . Baraket, M. (2017). Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. The Lancet, 390(10095), 659-668.
26. Gibson, P. G., Yang, I. A., Upham, J. W., Reynolds, P. N., Hodge, S., James, A. L., . . . Simpson, J. L. (2019). Efficacy of azithromycin in severe asthma from the AMAZES randomised trial. ERJ Open Res, 5(4). doi:10.1183/23120541.00056-2019
27. GINA. (2025). Global Initiative for Asthma, reprinted with permission. www.ginasthma.org. Guida, G., Bagnasco, D., Carriero, V., Bertolini, F., Ricciardolo, F. L. M., Nicola, S., . . . Canonica, G. W. (2022). Critical evaluation of asthma biomarkers in clinical practice. Frontiers in medicine, 9, 969243.
28. Hachim, M. Y., Elemam, N. M., Ramakrishnan, R. K., Hachim, I. Y., Salameh, L., Mahboub, B., . . . Hamid, Q. (2020). Confounding patient factors affecting the proper interpretation of the periostin level as a biomarker in asthma development. Journal of asthma and allergy, 23-37.
29. Heijink, I., & Van Oosterhout, A. (2006). Strategies for targeting T-cells in allergic diseases and asthma. Pharmacology & therapeutics, 112(2), 489-500.
30. Hiday, R. (2025). Asthma Guideline Updates. Accessed: Jan, 8. Holguin, F., Cardet, J. C., Chung, K. F., Diver, S., Ferreira, D. S., Fitzpatrick, A., . . . Bush, A. (2020). Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J, 55(1). doi:10.1183/13993003.00588-2019
31. Hom, S., & Pisano, M. (2017). Reslizumab (Cinqair): an interleukin-5 antagonist for severe asthma of the eosinophilic phenotype. Pharmacy and Therapeutics, 42(9), 564.
32. Hoque, F., & Nayak, R. (2025). Focused Overview of the 2024 Global Initiative for Asthma Guidelines. APIK Journal of Internal Medicine, 13(1), 4-12.
33. Israel, E., Denlinger, L. C., Bacharier, L. B., LaVange, L. M., Moore, W. C., Peters, M. C., . . . Noel, P. (2021). PrecISE: Precision Medicine in Severe Asthma: an adaptive platform trial with biomarker ascertainment. Journal of Allergy and Clinical Immunology, 147(5), 1594-1601.
34. Janson, C., Bjermer, L., Lehtimäki, L., Kankaanranta, H., Karjalainen, J., Altraja, A., . . . Hellgren, J. (2022). Eosinophilic airway diseases: basic science, clinical manifestations and future challenges. European Clinical Respiratory Journal, 9(1), 2040707.
35. Kau, A. L., Rosen, A. L., & Rosas-Salazar, C. (2024). Can Therapeutic Targeting of the Human Microbiome Influence Asthma Management? A Pro/Con Debate. The Journal of Allergy and Clinical Immunology: In Practice, 12(4), 863-869. doi:https://doi.org/10.1016/j.jaip.2023.12.053
36. Kelsen, S. G., Agache, I. O., Soong, W., Israel, E., Chupp, G. L., Cheung, D. S., . . . Brightling, C. E. (2021). Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: A randomized clinical trial. J Allergy Clin Immunol, 148(3), 790-798. doi:10.1016/j.jaci.2021.03.044
37. Khurana, S., Bush, A., & Holguin, F. (2020). Management of severe asthma: summary of the European Respiratory Society/American Thoracic Society task force report. Breathe, 16(2), 200058.
38. Kim, Y. J., & Bunyavanich, S. (2025). Microbial influencers: the airway microbiome’s role in asthma. The Journal of Clinical Investigation, 135(4).
39. Kravčenia, B., & Maślanka, T. (2024). Mycophenolate Mofetil, an Inhibitor of Inosine Monophosphate Dehydrogenase, and Tofacitinib, a Janus Kinase Inhibitor, Attenuate Airway Inflammation and Hyperresponsiveness in a Mouse Model of Allergic Asthma. Molecules, 29(22). doi:10.3390/molecules29225293
40. Kumagai, T., Iwata, A., Furuya, H., Kato, K., Okabe, A., Toda, Y., . . . Nakajima, H. (2024). A distal enhancer of GATA3 regulates Th2 differentiation and allergic inflammation. Proc Natl Acad Sci U S A, 121(27), e2320727121. doi:10.1073/pnas.2320727121
41. Kuruvilla, M. E., Lee, F. E.-H., & Lee, G. B. (2019). Understanding asthma phenotypes, endotypes, and mechanisms of disease. Clinical reviews in allergy & immunology, 56, 219-233.
42. Kwon, O., Senna, M. M., Sinclair, R., Ito, T., Dutronc, Y., Lin, C. Y., . . . King, B. (2023). Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata over 52 Weeks of Continuous Therapy in Two Phase III Trials (BRAVE-AA1 and BRAVE-AA2). Am J Clin Dermatol, 24(3), 443-451. doi:10.1007/s40257-023-00764-w
43. Lugogo, N. L., & Akuthota, P. (2021). Type 2 biomarkers in asthma: yet another reflection of heterogeneity. The Journal of Allergy and Clinical Immunology: In Practice, 9(3), 1276-1277.
44. Makabe, K., Okada, H., Tachibana, N., Ishikura, H., Ito, N., Tanaka, M., . . . Saito, T. (2024). Baricitinib ameliorates inflammatory and neuropathic pain in collagen antibody-induced arthritis mice by modulating the IL-6/JAK/STAT3 pathway and CSF-1 expression in dorsal root ganglion neurons. Arthritis Res Ther, 26(1), 121. doi:10.1186/s13075-024-03354-1
45. Matucci, A., Vivarelli, E., Nencini, F., Maggi, E., & Vultaggio, A. (2021). Strategies Targeting Type 2 Inflammation: From Monoclonal Antibodies to JAK-Inhibitors. Biomedicines, 9(10), 1497. Retrieved from https://www.mdpi.com/2227-9059/9/10/1497
46. Menzies-Gow, A., Corren, J., Bourdin, A., Chupp, G., Israel, E., Wechsler, M. E., . . . Bowen, K. (2021). Tezepelumab in adults and adolescents with severe, uncontrolled asthma. New England journal of medicine, 384(19), 1800-1809.
47. Menzies-Gow, A., Mansur, A. H., & Brightling, C. E. (2020). Clinical utility of fractional exhaled nitric oxide in severe asthma management. European Respiratory Journal, 55(3).
48. Menzies-Gow, A., Wechsler, M. E., Brightling, C. E., Korn, S., Corren, J., Israel, E., . . . Nguyen, T. T. D. (2023). Long-term safety and efficacy of tezepelumab in people with severe, uncontrolled asthma (DESTINATION): a randomised, placebo-controlled extension study. The Lancet Respiratory Medicine, 11(5), 425-438. doi:10.1016/S2213-2600(22)00492-1
49. Miyokawa, R., Kivler, C., Louie, S., Godor, D., Tan, L., & Kenyon, N. (2020). Self-administered mepolizumab in the management of severe asthma: usability and patient acceptance. Patient preference and adherence, 1669-1682.
50. Murphy, K., Jacobs, J., Bjermer, L., Fahrenholz, J. M., Shalit, Y., Garin, M., . . . Castro, M. (2017). Long-term safety and efficacy of reslizumab in patients with eosinophilic asthma. The Journal of Allergy and Clinical Immunology: In Practice, 5(6), 1572-1581. e1573.
51. Murugesan, N., Saxena, D., Dileep, A., Adrish, M., & Hanania, N. A. (2023). Update on the role of FeNO in asthma management. Diagnostics, 13(8), 1428.
52. Nair, P., Wenzel, S., Rabe, K. F., Bourdin, A., Lugogo, N. L., Kuna, P., . . . Goldman, M. (2017). Oral glucocorticoid–sparing effect of benralizumab in severe asthma. New England journal of medicine, 376(25), 2448-2458.
53. O'Byrne, P. M., Metev, H., Puu, M., Richter, K., Keen, C., Uddin, M., . . . Nair, P. (2016). Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, placebo-controlled trial. The Lancet Respiratory Medicine, 4(10), 797-806. doi:10.1016/S2213-2600(16)30227-2
54. Oppenheimer, J., Hoyte, F. C., Phipatanakul, W., Silver, J., Howarth, P., & Lugogo, N. L. (2022). Allergic and eosinophilic asthma in the era of biomarkers and biologics: similarities, differences and misconceptions. Annals of Allergy, Asthma & Immunology, 129(2), 169-180.
55. Ortega, H. G., Yancey, S. W., Mayer, B., Gunsoy, N. B., Keene, O. N., Bleecker, E. R., . . . Pavord, I. D. (2016). Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. The Lancet Respiratory Medicine, 4(7), 549-556.
56. Ouyang, L., Su, G., Quan, J., Xiong, Z., & Lai, T. (2023). Emerging roles and therapeutic implications of HDAC2 and IL-17A in steroid-resistant asthma. Chinese Medical Journal Pulmonary and Critical Care Medicine, 1(2), 108-112. doi:https://doi.org/10.1016/j.pccm.2023.04.003
57. Pavord, I. D., Deniz, Y., Corren, J., Casale, T. B., FitzGerald, J. M., Izuhara, K., . . . Harel, S. (2023). Baseline FeNO independently predicts the dupilumab response in patients with moderate-to-severe asthma. The Journal of Allergy and Clinical Immunology: In Practice, 11(4), 1213-1220. e1212.
58. Pelaia, C., Pelaia, G., Crimi, C., Maglio, A., Armentaro, G., Calabrese, C., . . . Vatrella, A. (2022). Biological therapy of severe asthma with dupilumab, a dual receptor antagonist of interleukins 4 and 13. Vaccines, 10(6), 974.
59. Pelaia, C., Pelaia, G., Crimi, C., Maglio, A., Gallelli, L., Terracciano, R., & Vatrella, A. (2021). Tezepelumab: a potential new biological therapy for severe refractory asthma. International Journal of Molecular Sciences, 22(9), 4369. Pongdee, T., & Li, J. T. (2025). Omalizumab safety concerns. Journal of Allergy and Clinical Immunology, 155(1), 31-35.
60. Rabe, K. F., Nair, P., Brusselle, G., Maspero, J. F., Castro, M., Sher, L., . . . Khan, A. (2018). Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. New England journal of medicine, 378(26), 2475-2485.
61. Ramphul, M., Lo, D. K., & Gaillard, E. A. (2021). Precision medicine for paediatric severe asthma: current status and future direction. Journal of asthma and allergy, 525-538.
62. Ray, A., & Kolls, J. K. (2017). Neutrophilic inflammation in asthma and association with disease severity. Trends in immunology, 38(12), 942-954.
63. Ricciardolo, F. L., Carriero, V., & Bertolini, F. (2021). Which therapy for non-type (T) 2/T2-low asthma. Journal of personalized medicine, 12(1), 10.
64. Saglani, S., Lloyd, C. M., & Bush, A. (2019). Biology and assessment of airway inflammation. In Kendig's Disorders of the Respiratory Tract in Children (pp. 101-119. e104): Elsevier.
65. Schoettler, N., & Strek, M. E. (2020). Recent advances in severe asthma: from phenotypes to personalized medicine. Chest, 157(3), 516-528.
66. Soendergaard, M. B., Hansen, S., Håkansson, K. E. J., von Bülow, A., Bjerrum, A. S., Schmid, J. M., . . . Bertelsen, B. B. (2025). Early Reduction of FeNO on Anti‐IL5 Biologics Is Associated With Clinical Remission of Severe Asthma. Allergy, 80(4), 986-995.
67. Specjalski, K., Romantowski, J., & Niedoszytko, M. (2023). YKL-40 as a possible marker of neutrophilic asthma. Frontiers in medicine, 10, 1115938.
68. Valverde-Molina, J., & García-Marcos, L. (2023). Microbiome and Asthma: Microbial Dysbiosis and the Origins, Phenotypes, Persistence, and Severity of Asthma. Nutrients, 15(3), 486. Retrieved from https://www.mdpi.com/2072-6643/15/3/486
69. Wechsler, M. E., Ruddy, M. K., Pavord, I. D., Israel, E., Rabe, K. F., Ford, L. B., . . . Martincova, R. (2021). Efficacy and safety of itepekimab in patients with moderate-to-severe asthma. New England journal of medicine, 385(18), 1656-1668.
70. Wenzel, S., Castro, M., Corren, J., Maspero, J., Wang, L., Zhang, B., . . . Joish, V. N. (2016). Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. The Lancet, 388(10039), 31-44.
71. Xue, M., Xu, S., Su, L., He, S., Wu, B., Ji, C., . . . Cai, G. (2021). Surfactant protein-A inhibits thymic stromal lymphopoietin-mediated T follicular helper cell differentiation and IgE production in asthma. Clin Immunol, 231, 108822. doi:10.1016/j.clim.2021.108822
72. Yamasaki, A., Okazaki, R., & Harada, T. (2022). Neutrophils and asthma. Diagnostics, 12(5), 1175.
73. Yoshihara, T., Morimoto, T., Hirata, H., Murayama, M., Nonaka, T., Tsukamoto, M., . . . Mawatari, M. (2023). Mechanisms of tissue degeneration mediated by periostin in spinal degenerative diseases and their implications for pathology and diagnosis: A review. Frontiers in medicine, 10, 1276900.
74. Yuan, X., Yang, L., Gao, J., Wang, B., & Li, Z. (2025). RNA modulation in asthma: unraveling the role of splicing and non-coding RNAs in disease pathogenesis. J Asthma, 62(5), 741-750. doi:10.1080/02770903.2024.2444305
75. Zhang, J., Zheng, X., Luo, W., & Sun, B. (2024). Cross-domain microbiomes: the interaction of gut, lung and environmental microbiota in asthma pathogenesis. Frontiers in Nutrition, 11, 1346923.