Biologics for the treatment of severe asthma: Current status report 2023

Severe asthma is associated with increased use of healthcare services, signifi- cant deterioration in the quality of life, and high disease and economic burden on patients and societies. Additional treatments are required for severe forms of asthma. Biological agents are recommended for the treatment of severe asthma. In this current status report, we aimed to evaluate the efficacy, effec- tiveness, and safety data of approved biologics; omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, and tezepelumab, in the treatment of severe asthma and appropriate patient profiles for these biologics. Pubmed and Cochrane databases based on randomized controlled trials, posthoc analyses, meta-analyses, and real-life studies examining the efficacy and effec- tiveness of biologics in severe asthma were searched, and the results of these studies on important asthma outcomes were reviewed. Existing studies have shown that all the approved biologic agents targeting cells, receptors, and mediators involved in type 2 inflammation in the bronchial wall in severe asthma significantly reduce asthma exacerbations, reduce the need for oral corticosteroids, and improve asthma control, quality of life, and pulmonary functions. Characterizing the asthma endotype and phenotype in patients with severe asthma and determining which treatment would be more approp- riate for a particular patient is an essential step in personalized treatment.

Anahtar Kelime:

Ağır astım tedavisinde biyolojikler: Güncel durum raporu 2023

Öz:

Ağır astım; sağlık hizmeti kullanımında artış, yaşam kalitesinde önemli derecede bozulma ve hasta ve toplum üzerinde yüksek hasta- lık yükü ve ekonomik yük ile ilişkilidir. Ağır astım formları için ek tedaviler gereklidir. Biyolojik ajanlar ağır astımda önerilen son basa- mak seçeneklerdir. Bu güncel durum raporunda biyolojiklerin (omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, tezepelumab) ağır astımdaki etkinlik, etkililik ve güvenlilik verilerini ve bu biyolojikler için uygun hasta profillerini değerlendirmek amaçlanmıştır. Bu amaç doğrultusunda Pubmed ve Cochrane veri tabanlarında ağır astımda kullanım onayı almış biyolojiklerin ağır astımda etkisinin değerlendirildiği randomize kontrollü çalışmalar, post-hoc analizler, meta-analizler ve gerçek yaşam çalışmaları bulunmuş ve biyolojiklerin ağır astım üzerindeki etkilerini değerlendirmek için gözden geçirilmiştir. Mevcut çalışmalar bronş mukoza- sındaki tip 2 inflamasyonda rol alan hücreler, reseptörler ve medyatörleri hedefleyen biyolojiklerin tümünün astım ataklarını anlamlı şekilde azalttığını, oral kortikosteroid ihtiyacını azalttığını, astım kontrolü, yaşam kalitesi ve solunum fonksiyonlarında düzelme sağla- dığını göstermiştir. Ağır astımlı hastalarda astım endotipinin ve fenotipinin doğru belirlenmesi ve buna uygun biyolojik tedavinin seçilmesi kişiselleşmiş tedavi yaklaşımın temel noktasıdır.

Anahtar Kelime:

Belge Türü: Makale Makale Türü: Derleme Erişim Türü: Erişime Açık

1. Gelincik A, Mungan D, Karakaya G, Paçacı Çetin G, Yılmaz İ, Öztop N, ve ark. Astımda biyolojik ilaçların kul- lanımı güncel durum raporu 2022. Ankara: Buluş Tasarım; 2022.
2. James SL, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi N, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018; 392(10159): 1789-858. https:// doi.org/10.1016/S0140-6736(18)32279-7
3. GINA. Global strategy for asthma management and pre- vention 2021. Available from: https://ginasthma.org/ gina-reports/
4. Wenzel SE. Severe adult asthmas: Integrating clinical fea- tures, biology, and therapeutics to improve outcomes. Am J Respir Crit Care Med 2021; 203(7): 809-21. https://doi. org/10.1164/rccm.202009-3631CI
5. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014; 43(2): 343-73. https://doi. org/10.1183/09031936.00202013
6. GINA. Severe asthma pocket guide 2019. Available from: https://ginasthma.org/wp-content/uploads/2019/04/ GINA-Severe-asthmaPocket-Guide-v2.0-wms-1.pdf.
7. Bavbek S, Çelik G, Ediger D, Mungan D, Sin B, Demirel YS, et al. Severity and associated risk factors in adult asth- ma patients in Turkey. Ann Allergy Asthma Immunol 2000; 85(2): 134-9. https://doi.org/10.1016/S1081- 1206(10)62453-2
8. Chung KF. Personalised medicine in asthma: Time for action: Number 1 in the Series “Personalised medicine in respiratory diseases” edited by Renaud Louis and Nicolas Roche. Eur Respir Rev 2017; 26(145). https://doi. org/10.1183/16000617.0064-2017
9. Bessa V, Tseliou E, Bakakos P, Loukides S. Noninvasive evaluation of airway inflammation in asthmatic patients who smoke: Implications for application in clinical prac- tice. Ann Allergy Asthma Immunol 2008; 101(3): 226-32. https://doi.org/10.1016/S1081-1206(10)60485-1
10. GINA. Global strategy for asthma management and pre- vention. Available from: https://ginasthma.org/wp-con- tent/uploads/2019/06/GINA-2019-main-report-June- 2019-wms.pdf.
11. Breiteneder H, Peng YQ, Agache I, Diamant Z, Eiwegger T, Fokkens WJ, et al. Biomarkers for diagnosis and prediction of therapy responses in allergic diseases and asthma. Allergy 2020; 75(12): 3039-68. https://doi.org/10.1111/ all.14582
12. Pelaia C, Crimi C, Vatrella A, Tinello C, Terracciano R, Pelaia G. Molecular targets for biological therapies of severe asthma. Front Immunol 2020; 11: 603312. https:// doi.org/10.3389/fimmu.2020.603312
13. Anderson GP. Endotyping asthma: New insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet 2008; 372(9643): 1107-19. https://doi. org/10.1016/S0140-6736(08)61452-X
14. Kuruvilla ME, Lee FEH, Lee GB. Understanding asthma phenotypes, endotypes, and mechanisms of disease. Clin Rev Allergy Immunol 2019; 56: 219-33. https://doi. org/10.1007/s12016-018-8712-1
15. Wenzel SE. Asthma phenotypes: The evolution from clini- cal to molecular approaches. Nat Med 2012; 18(5): 716- 25. https://doi.org/10.1038/nm.2678
16. Holguin F, Cardet JC, Chung KF, Diver S, Ferreira DS, Fitzpatrick A, et al. Management of severe asthma: A European respiratory society/American thoracic society guideline. Eur Respir J 2020; 55(1). https://doi. org/10.1183/13993003.00588-2019
17. Nelson RK, Bush A, Stokes J, Nair P, Akuthota P. Eosinophilic asthma. J Allergy Clin Immunol Pract 2020; 8(2): 465-73. https://doi.org/10.1016/j.jaip.2019.11.024
18. Abadoğlu Ö, Aydın Ö, Bavbek S, Büyüköztürk S, Çelik GE, Ediger D, ve ark. Astım Tanı ve Tedavi Rehberi 2020 Güncellemesi. Çelik GE, editor. Buluş Tasarım: Ankara. 2020.
19. Kopp MV. Omalizumab: Anti-IgE therapy in allergy. Curr Allergy Asthma Rep 2011; 11: 101-6. https://doi. org/10.1007/s11882-010-0173-4
20. Abraham I, Alhossan A, Lee C, Kutbi H, MacDonald K. Real life effectiveness studies of omalizumab in adult patients with severe allergic asthma: Systematic review. Allergy 2016; 71(5): 593-610. https://doi.org/10.1111/ all.12815
21. Humbert M, Beasley R, Ayres J, Slavin R, Hébert J, Bousquet J, et al. Benefits of omalizumab as add on therapy in patients with severe persistent asthma who are inadequate- ly controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 2005; 60(3): 309- 16. https://doi.org/10.1111/j.1398-9995.2004.00772.x
22. Vignola A, Humbert M, Bousquet J, Boulet LP, Hedgecock S, Blogg M, et al. Efficacy and tolerability of anti immuno- globulin E therapy with omalizumab in patients with concomitant allergic asthma and persistent allergic rhini- tis: SOLAR. Allergy 2004; 59(7): 709-17. https://doi. org/10.1111/j.1398-9995.2004.00550.x
23. Rubin A, Souza-Machado A, Andradre-Lima M, Ferreira F, Honda A, Matozo T, et al. Effect of omalizumab as add-on therapy on asthma-related quality of life in severe allergic asthma: A Brazilian study (QUALITX). J Asthma. 2012 ;49(3): 288-93. https://doi.org/10.3109/02770903.2012 .660297
24. Busse WW, Morgan WJ, Gergen PJ, Mitchell HE, Gern JE, Liu AH, et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med 2011; 364(11): 1005-15. https://doi.org/10.1056/NEJMoa1009705
25. Ledford D, Busse W, Trzaskoma B, Omachi TA, Rosén K, Chipps BE, et al. A randomized multicenter study evaluat- ing Xolair persistence of response after long-term therapy. J Allergy Clin Immunol Pract 2017; 140(1): 162-9.e2. https://doi.org/10.1016/j.jaci.2016.08.054
26. Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev 2014; (1): CD003559. https://doi. org/10.1002/14651858.CD003559.pub4
27. Adachi M, Kozawa M, Yoshisue H, Milligan KL, Nagasaki M, Sasajima T, et al. Real-world safety and efficacy of omali- zumab in patients with severe allergic asthma: A long-term post-marketing study in Japan. Respir Med 2018; 141: 56-63. https://doi.org/10.1016/j.rmed.2018.06.021
28. Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014; 371(13): 1189-97. https://doi.org/10.1056/ NEJMoa1403291
29. Chupp GL, Bradford ES, Albers FC, Bratton DJ, Wang-Jairaj J, Nelsen LM, et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma con- trol in severe eosinophilic asthma (MUSCA): A randomised, double-blind, placebo-controlled, parallel-group, multi- centre, phase 3b trial. Lancet Respir Med 2017; 5(5): 390- 400. https://doi.org/10.1016/S2213-2600(17)30125-X
30. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014; 371(13): 1198-207. https://doi.org/10.1056/NEJMoa1403290
31. Drick N, Seeliger B, Welte T, Fuge J, Suhling H. Anti-IL-5 therapy in patients with severe eosinophilic asthma-clini- cal efficacy and possible criteria for treatment response. BMC Pulm Med 2018; 18(1): 1-9. https://doi. org/10.1186/s12890-018-0689-2
32. Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick L, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asth- ma. Am J Respir Crit Care Med 2007; 176(11): 1062-71. https://doi.org/10.1164/rccm.200701-085OC
33. Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, et al. Mepolizumab and exacerbations of refracto- ry eosinophilic asthma. N Engl J Med 2009; 360(10): 973- 84. https://doi.org/10.1056/NEJMoa0808991
34. Khatri S, Moore W, Gibson PG, Leigh R, Bourdin A, Maspero J, et al. Assessment of the long-term safety of mepolizumab and durability of clinical response in patients with severe eosinophilic asthma. J Allergy Clin Immunol 2019; 143(5): 1742-51.e7. https://doi.org/10.1016/j.jaci.2018.09.033
35. Lugogo N, Domingo C, Chanez P, Leigh R, Gilson MJ, Price RG, et al. Long-term efficacy and safety of mepolizumab in patients with severe eosinophilic asthma: A multi-center, open-label, phase IIIb study. Clin Ther 2016; 38(9): 2058- 70.e1. https://doi.org/10.1016/j.clinthera.2016.07.010
36. Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): A multicentre, double-blind, placebo-controlled trial. Lancet 2012; 380(9842): 651-9. https://doi. org/10.1016/S0140-6736(12)60988-X
37. Pertzov B, Unterman A, Shtraichman O, Shitenberg D, Rosengarten D, Kramer MR. Efficacy and safety of mepoli- zumab in a real-world cohort of patients with severe eosin- ophilic asthma. J Asthma 2021; 58(1): 79-84. https://doi. org/10.1080/02770903.2019.1658208
38. Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: Results from two multicentre, parallel, double-blind, randomised, place- bo-controlled, phase 3 trials. Lancet Respir Med 2015; 3(5): 355-66. https://doi.org/10.1016/S2213-2600(15)00042-9
39. Bjermer L, Lemiere C, Maspero J, Weiss S, Zangrilli J, Germinaro M. Reslizumab for inadequately controlled asth- ma with elevated blood eosinophil levels: A randomized phase 3 study. Chest 2016; 150(4): 789-98. https://doi. org/10.1016/j.chest.2016.03.032
40. Corren J, Weinstein S, Janka L, Zangrilli J, Garin M. Phase 3 study of reslizumab in patients with poorly controlled asth- ma: Effects across a broad range of eosinophil counts. Chest 2016; 150(4): 799-810. https://doi.org/10.1016/j. chest.2016.03.018
41. Castro M, Mathur S, Hargreave F, Boulet LP, Xie F, Young J, et al. Reslizumab for poorly controlled, eosinophilic asth- ma: A randomized, placebo-controlled study. Am J Respir Crit Care Med 2011; 184(10): 1125-32. https://doi. org/10.1164/rccm.201103-0396OC
42. Ibrahim H, O’Sullivan R, Casey D, Murphy J, MacSharry J, Plant B, et al. The effectiveness of Reslizumab in severe asthma treatment: A real-world experience. Respir Res 2019; 20(1): 1-5. https://doi.org/10.1186/s12931-019- 1251-3
43. Wechsler ME, Peters SP, Hill TD, Ariely R, DePietro MR, Driessen MT, et al. Clinical outcomes and health-care resource use associated with reslizumab treatment in adults with severe eosinophilic asthma in real-world practice. Chest 2021; 159(5): 1734-46. https://doi.org/10.1016/j. chest.2020.11.060
44. US FDA. Highlights of Prescribing Information. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/ label/2016/761033lbl.pdf.
45. FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, et al. 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-con- trolled phase 3 trial. Lancet 2016; 388(10056): 2128-41. https://doi.org/10.1016/S0140-6736(16)31322-8
46. Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dos- age inhaled corticosteroids and long-acting β2-agonists (SIROCCO): A randomised, multicentre, placebo-con- trolled phase 3 trial. Lancet 2016; 388(10056): 2115-27. https://doi.org/10.1016/S0140-6736(16)31324-1
47. Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med 2017; 376(25): 2448-58. https://doi.org/10.1056/NEJMoa1703501
48. Kavanagh JE, Hearn AP, Dhariwal J, d’Ancona G, Douiri A, Roxas C, et al. Real-world effectiveness of benralizumab in severe eosinophilic asthma. Chest 2021; 159(2): 496-506. https://doi.org/10.1016/j.chest.2020.08.2083
49. Pelaia C, Crimi C, Benfante A, Caiaffa MF, Calabrese C, Carpagnano GE, et al. Therapeutic effects of benralizum- ab assessed in patients with severe eosinophilic asthma: Real-life evaluation correlated with allergic and non-aller- gic phenotype expression. J Asthma Allergy 2021: 163-73. https://doi.org/10.2147/JAA.S297273
50. Drick N, Milger K, Seeliger B, Fuge J, Korn S, Buhl R, et al. Switch from IL-5 to IL-5-receptor α antibody treatment in severe eosinophilic asthma. J Asthma Allergy 2020: 605- 14. https://doi.org/10.2147/JAA.S270298
51. Harrison TW, Chanez P, Menzella F, Canonica GW, Louis R, Cosio BG, et al. Onset of effect and impact on health-related quality of life, exacerbation rate, lung function, and nasal polyposis symptoms for patients with severe eosinophilic asthma treated with benralizumab (ANDHI): A randomised, controlled, phase 3b trial. Lancet Respir Med 2021; 9(3): 260-74. https://doi.org/10.1016/S2213-2600(20)30414-8
52. Farne HA, Wilson A, Milan S, Banchoff E, Yang F, Powell CV. Anti IL 5 therapies for asthma. Cochrane Database Syst Rev 2022; (7): CD010834. https://doi. org/10.1002/14651858.CD010834.pub4
53. Tian BP, Zhang GS, Lou J, Zhou HB, Cui W. Efficacy and safety of benralizumab for eosinophilic asthma: A system- atic review and meta-analysis of randomized controlled trials. J Asthma 2018; 55(9): 956-65. https://doi.org/10.1 080/02770903.2017.1379534
54. Wang FP, Liu T, Lan Z, Li SY, Mao H. Efficacy and safety of anti-interleukin-5 therapy in patients with asthma: A sys- tematic review and meta-analysis. PLoS One 2016; 11(11): e0166833. https://doi.org/10.1371/journal. pone.0166833
55. Zayed Y, Kheiri B, Banifadel M, Hicks M, Aburahma A, Hamid K, et al. Dupilumab safety and efficacy in uncon- trolled asthma: A systematic review and meta-analysis of randomized clinical trials. J Asthma 2019; 56(10): 1110-9. https://doi.org/10.1080/02770903.2018.1520865
56. Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, 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 randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 2016; 388(10039): 31-44. https://doi.org/10.1016/S0140- 6736(16)30307-5
57. Busse WW, Maspero JF, Rabe KF, Papi A, Wenzel SE, Ford LB, et al. Liberty Asthma QUEST: Phase 3 randomized, double-blind, placebo-controlled, parallel-group study to evaluate dupilumab efficacy/safety in patients with uncontrolled, moderate-to-severe asthma. Adv Ther 2018; 35: 737-48. https://doi.org/10.1007/s12325-018-0702-4
58. Agache I, Song Y, Rocha C, Beltran J, Posso M, Steiner C, et al. Efficacy and safety of treatment with dupilumab for severe asthma: A systematic review of the EAACI guide- lines-recommendations on the use of biologicals in severe asthma. Allergy 2020; 75(5): 1058-68. https://doi. org/10.1111/all.14268
59. Dupin C, Belhadi D, Guilleminault L, Gamez AS, Berger P, De Blay F, et al. Effectiveness and safety of dupilumab for the treatment of severe asthma in a real life French multi centre adult cohort. Clin Exp Allergy 2020; 50(7): 789-98. https://doi.org/10.1111/cea.13614
60. Renner A, Marth K, Patocka K, Idzko M, Pohl W. Dupilumab rapidly improves asthma control in predomi- nantly anti IL5/IL5R pretreated Austrian real life severe asthmatics. Immun Inflamm Dis 2021; 9(3): 624-7. https://doi.org/10.1002/iid3.434
61. Thelen JC, van Zelst CM, van Brummelen SE, Rauh S, Kappen JH, Braunstahl GJ. Efficacy and safety of dupilum- ab as add-on therapy for patients with severe asthma: A real-world Dutch cohort study. Respir Med 2023; 206: 107058. https://doi.org/10.1016/j.rmed.2022.107058
62. Allakhverdi Z, Comeau MR, Jessup HK, Yoon BRP, Brewer A, Chartier S, et al. Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J Exp Med 2007; 204(2): 253-8. https://doi.org/10.1084/ jem.20062211
63. Verstraete K, Peelman F, Braun H, Lopez J, Van Rompaey D, Dansercoer A, et al. Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma. Nat Commun 2017; 8(1): 14937. https://doi. org/10.1038/ncomms14937
64. Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med 2017; 377(10): 936-46. https://doi. org/10.1056/NEJMoa1704064
65. Wechsler ME, Menzies-Gow A, Brightling CE, Kuna P, Korn S, Welte T, et al. Evaluation of the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-de- pendent asthma (SOURCE): A randomised, placebo-con- trolled, phase 3 study. Lancet Respir Med 2022; 10(7): 650-60. https://doi.org/10.1016/S2213-2600(21)00537-3
66. Hoy SM. Tezepelumab: First approval. Drugs 2022; 82(4): 461-8. https://doi.org/10.1007/s40265-022-01679-2

APA	ÇETİN g, KEPIL ÖZDEMIR S, Can Bostan Ö, Oztop N, Celebi Sozener Z, KARAKAYA G, Gelincik A, Yilmaz I, Mungan D, Bavbek S (2023). Biologics for the treatment of severe asthma: Current status report 2023. , 176 - 187. 10.5578/tt.20239921
Chicago	ÇETİN gülden,KEPIL ÖZDEMIR SEÇIL,Can Bostan Özge,Oztop Nida,Celebi Sozener Zeynep,KARAKAYA GÜL,Gelincik Aslı,Yilmaz Insu,Mungan Dilşad,Bavbek Sevim Biologics for the treatment of severe asthma: Current status report 2023. (2023): 176 - 187. 10.5578/tt.20239921
MLA	ÇETİN gülden,KEPIL ÖZDEMIR SEÇIL,Can Bostan Özge,Oztop Nida,Celebi Sozener Zeynep,KARAKAYA GÜL,Gelincik Aslı,Yilmaz Insu,Mungan Dilşad,Bavbek Sevim Biologics for the treatment of severe asthma: Current status report 2023. , 2023, ss.176 - 187. 10.5578/tt.20239921
AMA	ÇETİN g,KEPIL ÖZDEMIR S,Can Bostan Ö,Oztop N,Celebi Sozener Z,KARAKAYA G,Gelincik A,Yilmaz I,Mungan D,Bavbek S Biologics for the treatment of severe asthma: Current status report 2023. . 2023; 176 - 187. 10.5578/tt.20239921
Vancouver	ÇETİN g,KEPIL ÖZDEMIR S,Can Bostan Ö,Oztop N,Celebi Sozener Z,KARAKAYA G,Gelincik A,Yilmaz I,Mungan D,Bavbek S Biologics for the treatment of severe asthma: Current status report 2023. . 2023; 176 - 187. 10.5578/tt.20239921
IEEE	ÇETİN g,KEPIL ÖZDEMIR S,Can Bostan Ö,Oztop N,Celebi Sozener Z,KARAKAYA G,Gelincik A,Yilmaz I,Mungan D,Bavbek S "Biologics for the treatment of severe asthma: Current status report 2023." , ss.176 - 187, 2023. 10.5578/tt.20239921
ISNAD	ÇETİN, gülden vd. "Biologics for the treatment of severe asthma: Current status report 2023". (2023), 176-187. https://doi.org/10.5578/tt.20239921

APA	ÇETİN g, KEPIL ÖZDEMIR S, Can Bostan Ö, Oztop N, Celebi Sozener Z, KARAKAYA G, Gelincik A, Yilmaz I, Mungan D, Bavbek S (2023). Biologics for the treatment of severe asthma: Current status report 2023. Tüberküloz ve Toraks, 71(2), 176 - 187. 10.5578/tt.20239921
Chicago	ÇETİN gülden,KEPIL ÖZDEMIR SEÇIL,Can Bostan Özge,Oztop Nida,Celebi Sozener Zeynep,KARAKAYA GÜL,Gelincik Aslı,Yilmaz Insu,Mungan Dilşad,Bavbek Sevim Biologics for the treatment of severe asthma: Current status report 2023. Tüberküloz ve Toraks 71, no.2 (2023): 176 - 187. 10.5578/tt.20239921
MLA	ÇETİN gülden,KEPIL ÖZDEMIR SEÇIL,Can Bostan Özge,Oztop Nida,Celebi Sozener Zeynep,KARAKAYA GÜL,Gelincik Aslı,Yilmaz Insu,Mungan Dilşad,Bavbek Sevim Biologics for the treatment of severe asthma: Current status report 2023. Tüberküloz ve Toraks, vol.71, no.2, 2023, ss.176 - 187. 10.5578/tt.20239921
AMA	ÇETİN g,KEPIL ÖZDEMIR S,Can Bostan Ö,Oztop N,Celebi Sozener Z,KARAKAYA G,Gelincik A,Yilmaz I,Mungan D,Bavbek S Biologics for the treatment of severe asthma: Current status report 2023. Tüberküloz ve Toraks. 2023; 71(2): 176 - 187. 10.5578/tt.20239921
Vancouver	ÇETİN g,KEPIL ÖZDEMIR S,Can Bostan Ö,Oztop N,Celebi Sozener Z,KARAKAYA G,Gelincik A,Yilmaz I,Mungan D,Bavbek S Biologics for the treatment of severe asthma: Current status report 2023. Tüberküloz ve Toraks. 2023; 71(2): 176 - 187. 10.5578/tt.20239921
IEEE	ÇETİN g,KEPIL ÖZDEMIR S,Can Bostan Ö,Oztop N,Celebi Sozener Z,KARAKAYA G,Gelincik A,Yilmaz I,Mungan D,Bavbek S "Biologics for the treatment of severe asthma: Current status report 2023." Tüberküloz ve Toraks, 71, ss.176 - 187, 2023. 10.5578/tt.20239921
ISNAD	ÇETİN, gülden vd. "Biologics for the treatment of severe asthma: Current status report 2023". Tüberküloz ve Toraks 71/2 (2023), 176-187. https://doi.org/10.5578/tt.20239921