International consensus statements now subdivide chronic rhinosinusitis (CRS) into several phenotypes and endotypes, including the presence of polyps (CRSwNP) and eosinophilia (eCRSwNP). Biological treatments aimed at blocking eosinophilic inflammation in CRSwNP via interleukin 5 (IL5) or the interleukin 5 receptor (IL5R) have demonstrated limited efficacy thus far.
Objective
To review the pathophysiology of eCRSwNP, the evidence for mepolizumab (anti-IL5) and benralizumab (anti-IL5R) in CRSwNP, and to highlight areas for future research and therapeutic intervention.
Methods
Primary and secondary literature search.
Results
Clinical trials on mepolizumab and benralizumab in CRSwNP are limited and restricted by trial design which prevents direct comparison with other interventions, including surgery. Both agents would appear to provide some benefit in reducing nasal polyp size but limited clinical patient benefit. Molecular biological research highlights that eCRSwNP can occur in the absence of IL5 and that other cells/cytokines play an important part in the disease’s pathophysiology.
Conclusion
Blockade of IL5/IL5R alone would appear to provide limited “real life” clinical benefit in patients with CRSwNP due to the complexities of the pathophysiology of the condition. Therapy aimed at several simultaneous cytokine targets has logic but well-designed trials are unlikely to be forthcoming in the short term due to the financial cost and commercial conflicts of interest.
FokkensWJLundVJHopkinsC, et al.European Position paper on rhinosinusitis and nasal polyps 2020. Rhinology. 2020;58(Suppl S29):1–464. doi: 10.4193/Rhin20.600[published Online First: 20200220].
2.
VanderhaegenTGenglerIDendoovenA, et al.Eosinophils in the field of nasal polyposis: towards a better understanding of biologic therapies. Clin Rev Allergy Immunol. 2022;62(1):90–102. https://doi.org/10.1007/s12016-021-08844-7.
3.
RadajewskiKWierzchowskaMGrzankaD, et al.Tissue remodelling in chronic rhinosinusitis - review of literature. Otolaryngol Pol. 2019;73(5):1–4. doi: 10.5604/01.3001.0013.4121.
4.
HamadaKOishiKChikumotoA, et al.Impact of sinus surgery on type 2 airway and systemic inflammation in asthma. J Asthma. 2021;58(6):750–758. doi: 10.1080/02770903.2020.1729380[published Online First: 20200219].
5.
GillASSmithKAMeeksH, et al.Asthma increases long-term revision rates of endoscopic sinus surgery in chronic rhinosinusitis with and without nasal polyposis. Int Forum Allergy Rhinol. 2021;11(8):1197–1206. doi: 10.1002/alr.22779[published Online First: 20210224].
HellingsPWVerhoevenEFokkensWJ. State-of-the-art overview on biological treatment for CRSwNP. Rhinology. 2021;59(2):151–163. https://doi.org/10.4193/Rhin20.570.
8.
BachertCHanJKDesrosiersMY, et al.Efficacy and safety of benralizumab in chronic rhinosinusitis with nasal polyps: a randomized, placebo-controlled trial. J Allergy Clin Immunol. 2022;149(4):1309–1317.e12. doi: 10.1016/j.jaci.2021.08.030[published Online First: 20210929].
9.
GelardiMGiancasproRCassanoM. Chronic rhinosinusitis with nasal polyps recurrence: not only eosinophils and neutrophils. Am J Otolaryngol. 2022;43(3):103447. https://doi.org/10.1016/j.amjoto.2022.103447.
10.
WechslerMEMunitzAAckermanSJ, et al.Eosinophils in health and disease: a state-of-the-art review. Mayo Clin Proc. 2021;96(10):2694–2707. https://doi.org/10.1016/j.mayocp.2021.04.025.
11.
ToroMDCAntonioMAAlves Dos ReisMG, et al.Achieving the best method to classify eosinophilic chronic rhinosinusitis: a systematic review. Rhinology J. 2021;59(4):330–339. https://doi.org/10.4193/Rhin20.512.
12.
ChippsBEJarjourNCalhounWJ, et al.A comprehensive analysis of the stability of blood eosinophil levels. Ann Am Thorac Soc. 2021;18(12):1978–1987. https://doi.org/10.1513/AnnalsATS.202010-1249OC.
Machado-CarvalhoLRoca-FerrerJPicadoC. Prostaglandin E2 receptors in asthma and in chronic rhinosinusitis/nasal polyps with and without aspirin hypersensitivity. Respir Res. 2014;15(1):100. doi: 10.1186/s12931-014-0100-7[published Online First: 20140826].
15.
JankowskiR. Eosinophils in the pathophysiology of nasal polyposis. Acta Otolaryngol. 1996;116(2):160–163. doi: 10.3109/00016489609137813.
16.
VieiraBMde Souza Dos SantosMCMasid-de-BritoD, et al.Potent stimulation of eosinopoiesis in murine bone-marrow by myriadenolide is mediated by cysteinyl-leukotriene signaling. Int Immunopharmacol. 2019;72:82–91. doi: 10.1016/j.intimp.2019.04.002[published Online First: 20190406].
17.
PałganKBartuziZ. Platelet activating factor in allergies. Int J Immunopathol Pharmacol. 2015;28(4):584–589. doi: 10.1177/0394632015600598[published Online First: 20151020].
18.
ArmengotMGarínLCardaC. Eosinophil degranulation patterns in nasal polyposis: an ultrastructural study. Am J Rhinol Allergy. 2009;23(5):466–470. doi: 10.2500/ajra.2009.23.3357.
19.
KatoYTakabayashiTSakashitaM, et al.Expression and functional analysis of CST1 in intractable nasal polyps. Am J Respir Cell Mol Biol. 2018;59(4):448–457. doi: 10.1165/rcmb.2017-0325OC.
20.
MasuokaMShiraishiHOhtaS, et al.Periostin promotes chronic allergic inflammation in response to Th2 cytokines. J Clin Invest. 2012;122(7):2590–2600. doi: 10.1172/jci58978[published Online First: 20120611].
21.
ChenCLYaoYPanL, et al.Common fibrin deposition and tissue plasminogen activator downregulation in nasal polyps with distinct inflammatory endotypes. J Allergy Clin Immunol. 2020;146(3):677–681. doi: 10.1016/j.jaci.2020.02.010[published Online First: 20200226].
22.
KouzakiHMatsumotoKKikuokaH, et al.Endogenous protease inhibitors in airway epithelial cells contribute to eosinophilic chronic rhinosinusitis. Am J Respir Crit Care Med. 2017;195(6):737–747. doi: 10.1164/rccm.201603-0529OC.
23.
ImotoYKatoATakabayashiT, et al.Increased thrombin-activatable fibrinolysis inhibitor levels in patients with chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2019;144(6):1566–74.e6. doi: 10.1016/j.jaci.2019.08.040[published Online First: 20190925].
24.
ShimizuSOgawaTTakezawaK, et al.Tissue factor and tissue factor pathway inhibitor in nasal mucosa and nasal secretions of chronic rhinosinusitis with nasal polyp. Am J Rhinol Allergy. 2015;29(4):235–242. doi: 10.2500/ajra.2015.29.4183.
25.
TakabayashiTKatoAPetersAT, et al.Excessive fibrin deposition in nasal polyps caused by fibrinolytic impairment through reduction of tissue plasminogen activator expression. Am J Respir Crit Care Med. 2013;187(1):49–57. doi: 10.1164/rccm.201207-1292OC[published Online First: 20121115].
26.
SmithPKHarperJI. Serine proteases, their inhibitors and allergy. Allergy. 2006;61(12):1441–1447. doi: 10.1111/j.1398-9995.2006.01233.x.
27.
DobzanskiAKhalilSMLaneAP. Nasal polyp fibroblasts modulate epithelial characteristics via Wnt signaling. Int Forum Allergy Rhinol. 2018;8(12):1412–1420. doi: 10.1002/alr.22199[published Online First: 20180817].
28.
HommaHKamiyaKKusunokiT, et al.Multiplex analyses of cytokine and chemokine release from the cultured fibroblast of nasal polyps: the effect of IL-17A. Acta Otolaryngol. 2013;133(10):1065–1072. doi: 10.3109/00016489.2013.796091.
29.
TakabayashiTKatoAPetersAT, et al.Increased expression of factor XIII-A in patients with chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2013;132(3):584–592.e4. doi: 10.1016/j.jaci.2013.02.003[published Online First: 20130328].
30.
JiaoJZhangTZhangY, et al.Epidermal growth factor upregulates expression of MUC5AC via TMEM16A, in chronic rhinosinusitis with nasal polyps. Allergy Asthma Clin Immunol. 2020;16:40. doi: 10.1186/s13223-020-00440-2[published Online First: 20200527].
31.
ZhangYDeryckeLHoltappelsG, et al.Th2 cytokines orchestrate the secretion of MUC5AC and MUC5B in IL-5-positive chronic rhinosinusitis with nasal polyps. Allergy. 2019;74(1):131–140. doi: 10.1111/all.13489[published Online First: 20181011].
32.
BorishLCohenNAChuppG, et al.Evaluating enrollment and outcome criteria in trials of biologics for chronic rhinosinusitis with nasal polyps. Ann Allergy Asthma Immunol. 2022;129(2):160–168. https://doi.org/10.1016/j.anai.2022.04.004.
33.
AgacheISongYAlonso-CoelloP, et al.Efficacy and safety of treatment with biologicals for severe chronic rhinosinusitis with nasal polyps: a systematic review for the EAACI guidelines. Allergy. 2021;76(8):2337–2353. https://doi.org/10.1111/all.14809.
34.
GevaertPVan BruaeneNCattaertT, et al.Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol. 2011;128(5):989–988. https://doi.org/10.1016/j.jaci.2011.07.056.
35.
BachertCSousaARLundVJ, et al.Reduced need for surgery in severe nasal polyposis with mepolizumab: randomized trial. J Allergy Clin Immunol. 2017;140(4):1024–1031.e14. https://doi.org/10.1016/j.jaci.2017.05.044.
36.
HanJKBachertCFokkensW, et al.Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2021;9(10):1141–1153. https://doi.org/10.1016/S2213-2600(21)00097-7.
37.
TakabayashiTAsakaDOkamotoY, et al.A phase II, multicenter, randomized, placebo-controlled study of benralizumab, a humanized anti-IL-5R alpha monoclonal antibody, in patients with eosinophilic chronic rhinosinusitis. Am J Rhinol Allergy. 2021;35(6):861–870. doi: 10.1177/19458924211009429.
38.
PatelGBPetersAT. The role of biologics in chronic rhinosinusitis with nasal polyps. Ear Nose Throat J. 2021;100(1):44–47. doi: 10.1177/0145561320964653[published Online First: 20201009].
39.
YaoT-CWangJ-YChangS-M, et al.Association of oral corticosteroid bursts with severe adverse events in children. JAMA Pediatr. 2021;175(7):723–729. doi: 10.1001/jamapediatrics.2021.0433.
40.
TrifilieffAFujitaniYCoyleAJ, et al.IL-5 deficiency abolishes aspects of airway remodelling in a murine model of lung inflammation. Clin Exp Allergy. 2001;31(6):934–942. doi: 10.1046/j.1365-2222.2001.01084.x.
41.
DouganMDranoffGDouganSK. GM-CSF, IL-3, and IL-5 family of cytokines: regulators of inflammation. Immunity. 2019;50(4):796–811. doi: 10.1016/j.immuni.2019.03.022.
42.
ChanBCLLamCWKTamLS, et al.IL33: roles in allergic inflammation and therapeutic perspectives. Front Immunol. 2019;10:364. doi: 10.3389/fimmu.2019.00364[published Online First: 20190304].
43.
GevaertPHanJKSmithSG, et al.The roles of eosinophils and interleukin-5 in the pathophysiology of chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol. 2022;12(11):1413–1423. https://doi.org/10.1002/alr.22994.
44.
LaidlawTMPrussinCPanettieriRA, et al.Dexpramipexole depletes blood and tissue eosinophils in nasal polyps with no change in polyp size.Laryngoscope. 2019;129(2):e61–e66. doi: 10.1002/lary.27564[published Online First: 20181004].
