Precision Medicine in Severe Asthma: Practical Phenotyping and Evidence-Based Selection of Biologic Therapy
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Abstract
Precision Medicine in Severe Asthma: Practical Phenotyping and Evidence-Based Selection of Biologic Therapy Article Type: Review Author : Zouheir J. Alameh, MD, DSc, FCCP Affiliation: Alameh Clinic, Aley, Lebanon Corresponding Author: Zouheir J. Alameh, MD, DSc, FCCP; Alameh Clinic, Aley, Lebanon; Email: [email protected] Manuscript Word Count (approx.): 7745 Abstract Word Count: 230 Abstract Severe asthma is a heterogeneous syndrome in which persistent symptoms and recurrent exacerbations continue despite optimized high-dose inhaled corticosteroids and additional controller therapy. Biologic agents now offer targeted treatment for patients with Type 2 airway inflammation, but real-world selection remains challenging because phenotypes overlap, biomarkers fluctuate, and head-to-head trials are limited. This narrative review synthesizes contemporary guideline frameworks and pivotal randomized trials into a clinic-ready phenotyping workflow and a practical selection approach for currently available biologics. We outline a stepwise pathway that begins with confirmation of the asthma diagnosis and identification of modifiable drivers of poor control (adherence, inhaler technique, exposures, and comorbidities), followed by structured assessment of Type 2 biomarkers and treatable traits. Key signals used to align therapy include exacerbation burden, maintenance oral corticosteroid dependence, allergic sensitization with total immunoglobulin E eligibility, blood eosinophil counts, and fractional exhaled nitric oxide, interpreted in the context of systemic steroid exposure and comorbid disease (e.g., chronic rhinosinusitis with nasal polyps or atopic dermatitis). We summarize practical selection cues for anti-IgE, anti-interleukin-5/interleukin-5 receptor alpha, anti-interleukin-4 receptor alpha, and upstream epithelial cytokine blockade, and propose treat-to-target reassessment at 4-6 months using predefined response domains (exacerbations, steroid reduction, symptom control, lung function, and comorbidity outcomes). A structured, auditable precision-medicine pathway can improve biologic matching, support safer steroid tapering, and guide timely continuation or mechanism switching when response is inadequate.
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References
2. Global Initiative for Asthma. Difficult-to-Treat & Severe Asthma in Adolescent and Adult Patients: Diagnosis and Management. A Short GINA Guide for Health Professionals. Version 5.0. 2024. Available from: www.ginasthma.org/reports. Accessed March 2026.
3. Holguin F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55(1):1900588.
4. Brusselle GG, Koppelman GH. Biologic therapies for severe asthma. N Engl J Med. 2022;386(2):157-171. doi: 10.1056/NEJMra2032506.
5. Agusti A, Bel E, Thomas M, et al. Treatable traits: toward precision medicine of chronic airway diseases. Eur Respir J. 2016;47(2):410-419.
6. Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. N Engl J Med. 2017;377(10):965-976.
7. Fahy JV. Type 2 inflammation in asthma—present in most, absent in many. Nat Rev Immunol. 2015;15(1):57-65.
8. Wenzel SE. Severe adult asthma: integrating clinical features, biology, and therapeutics to improve outcomes. Am J Respir Crit Care Med. 2021;203(7):809-821.
9. Gyawali B, Georas SN, Khurana S. Biologics in severe asthma: a state-of-the-art review. Eur Respir Rev. 2025;34(175):240088. doi: 10.1183/16000617.0088-2024.
10. Agusti A, Bafadhel M, Beasley R, et al. Moving toward a treatable traits model of care for obstructive airway diseases. Respir Med. 2021;187:106572.
11. Gibson PG, McDonald VM, Marks GB. Asthma in adults. Lancet. 2020;396(10263):761-773.
12. Kavanagh JE, Hearn AP, Jackson DJ. A pragmatic guide to choosing biologic therapies in severe asthma. Breathe (Sheff). 2021;17(4):210144. doi: 10.1183/20734735.0144-2021.
13. Buhl R. Anti-IgE: lessons from clinical trials in patients with severe persistent allergic asthma. Eur Respir Rev. 2007;16(104):73-77.
14. Humbert M, Beasley R, Ayres J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent allergic asthma. Allergy. 2005;60(3):309-316.
15. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):651-659.
16. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371(13):1198-1207.
17. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189-1197.
18. Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma (SIROCCO). Lancet. 2016;388(10056):2115 -2127.
19. FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab as add-on treatment for patients with severe, uncontrolled eosinophilic asthma (CALIMA). Lancet. 2016;388(10056):2128-2141.
20. Nair P, Wenzel S, Rabe KF, et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma (ZONDA). N Engl J Med. 2017;376(25):2448-2458.
21. Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with elevated eosinophil levels. Lancet Respir Med. 2015;3(5):355-366.
22. Corren J, Weinstein S, Janka L, et al. Phase 3 study of reslizumab in patients with poorly controlled asthma and elevated eosinophils. Chest. 2016;150(4):799-810.
23. Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma (QUEST). N Engl J Med. 2018;378(26):2486-2496.
24. Busse WW, Maspero JF, Rabe KF, et al. LIBERTY ASTHMA QUEST: phase 3 randomized, double-blind, placebo-controlled study of dupilumab in uncontrolled asthma. Adv Ther. 2018;35(5):737-748.
25. Rabe KF, Nair P, Brusselle G, et al. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma (VENTURE). N Engl J Med. 2018;378(26):2475-2485.
26. Corren J, Parnes JR, Wang L, et al. Tezepelumab in adults with uncontrolled asthma (PATHWAY). N Engl J Med. 2017;377(10):936-946.
27. Menzies-Gow A, Corren J, Bourdin A, et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma (NAVIGATOR). N Engl J Med. 2021;384(19):1800-1809.
28. Wechsler ME, Menzies-Gow A, Brightling CE, et al. Evaluation of the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma (SOURCE). Lancet Respir Med. 2022;10(7):650-660.
29. Abi Saleh W, Alameh Z, Bacha ZA, et al. Prevalence of the eosinophilic phenotype among severe asthma patients in Lebanon: results of the PREPARE study. Allergy Asthma Clin Immunol. 2023;19(1):80.
30. Lombardi C, Comberiati P, Ridolo E, et al. Anti-IL-5 pathway agents in eosinophilic-associated disorders across the life span. Drugs. 2024;84(12):1359-1381.
31. Jackson DJ, Wechsler ME, et al. Twice-yearly depemokimab in severe asthma with an eosinophilic phenotype. N Engl J Med. 2024;391(24):2337-2349. doi: 10.1056/NEJMoa2406673.
32. Oberle AJ, Abbas F, et al. Biologic management in severe asthma for adults: an American College of Chest Physicians clinical practice guideline. Chest. 2026;169(2):336-348. doi: 10.1016/j.chest.2025.08.042
33. Haldar P, Brightling CE, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360:973-984.
34. Wenzel S, Castro M, et al. 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 randomized, double-blind, placebo-controlled phase 2b dose-ranging trial. Lancet. 2016;388:31-44.
35. Couillard S, Jackson DJ, Pavord ID, Wechsler ME. Choosing the right biologic for the right patient with severe asthma. Chest. 2025;167(2):330-342.
36. Bourdin A, Brusselle G, Couillard S, et al. Phenotyping of severe asthma in the era of broad-acting anti-asthma biologics. J Allergy Clin Immunol Pract. 2024;12(4):809-823.
37. Howell I, Mahdi M, Mahmood HR, et al. Fractional exhaled nitric oxide and the response to prednisolone for asthma attacks in patients treated with anti-IL5/5Rα therapy: a prospective observational study. Eur Respir J. 2025; 66(5):2501229. doi:10.1183/13993003.01229-2025
38. Namazy J, Cabana MD, Scheuerle AE, et al. The Xolair Pregnancy Registry (EXPECT): the safety of omalizumab use during pregnancy. J Allergy Clin S