Brazilian guideline for the use of immunobiologicals in chronic rhinosinusitis with nasal polyps ‒ 2024 update

Anselmo-Lima, Wilma T.; Romano, Fabrizio R.; Tamashiro, Edwin; Roithmann, Renato; Dinarte, Vanessa R.P.; Piltcher, Otavio B.; Miyake, Marcel M.; Fornazieri, Marco A.; Nakanishi, Marcio; Bezerra, Thiago F.P.; Dolci, Ricardo L.L.; Mello Jr, João F.; Lessa, Marcus M.; Voegels, Richard L.; Kosugi, Eduardo M.; Sakano, Eulalia; Valera, Fabiana C.P.

doi:10.1016/j.bjorl.2024.101394

Wilma T. Anselmo-Lima ^⁎⁎ Corresponding author. E-mail:wtalima@fmrp.usp.br (W.T. Anselmo-Lima)

Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Oftalmologia, Otorrinolaringologia, Cirurgia de Cabeça e Pescoço, Ribeirão Preto, SP, Brazil

https://orcid.org/0000-0001-9146-2320

Fabrizio R. Romano

Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil

Universidade de São Paulo (FMRP-USP), Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto, SP, Brazil

Edwin Tamashiro

Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Oftalmologia, Otorrinolaringologia, Cirurgia de Cabeça e Pescoço, Ribeirão Preto, SP, Brazil

Renato Roithmann

Universidade Luterana do Brasil, Canoas, RS, Brazil

Vanessa R.P. Dinarte

Faculdade de Medicina de Marília (FAMEMA), Marilia, SP, Brazil

Otavio B. Piltcher

Faculdade de Medicina da Universidade Federal do Rio Grande do Sul (FAMED-UFRGS), Departamento de Oftalmologia e Otorrinolaringologia, Porto Alegre, RS, Brazil

Marcel M. Miyake

Universidade de São Paulo (FMRP-USP), Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto, SP, Brazil

Santa Casa de Misericórdia, Hospital de São Paulo, Departamento de Otorrinolaringologia, São Paulo, SP, Brazil

Marco A. Fornazieri

Universidade Estatual de Londrina, Londrina, PR, Brazil

Pontifícia Universidade Católica do Paraná (PUCPR), Câmpus Londrina, Londrina, PR, Brazil

Marcio Nakanishi

Universidade de Brasília, Faculdade de Medicina, Programa de Pós-Graduação, Brasilia, DF, Brazil

Thiago F.P. Bezerra

Universidade Federal de Pernambuco, Recife, PE, Brazil

Ricardo L.L. Dolci

Santa Casa de São Paulo, São Paulo, SP, Brazil

João F. Mello Jr

Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil

Marcus M. Lessa

Faculdade de Medicina da Universidade Federal da Bahia, Salvador, BA, Brazil

Richard L. Voegels

Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil

Eduardo M. Kosugi

Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Otorrinolaringologia e Cirurgia de Cabeça e Pescoço, São Paulo, SP, Brazil

Eulalia Sakano

Universidade Estadual Paulista, Faculdade de Ciências Médicas, Departamento de Oftalmologia/Otorrinolaringologia, Campinas, SP, Brazil

Fabiana C.P. Valera

Universidade de São Paulo (FMRP-USP), Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto, SP, Brazil

Peer Review under the responsibility of Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial.

⁎ Corresponding author. E-mail:wtalima@fmrp.usp.br (W.T. Anselmo-Lima)

Conflicts of interest

The authors declare no conflicts of interest.

Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Oftalmologia, Otorrinolaringologia, Cirurgia de Cabeça e Pescoço, Ribeirão Preto, SP, Brazil

Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil

Universidade de São Paulo (FMRP-USP), Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto, SP, Brazil

Universidade Luterana do Brasil, Canoas, RS, Brazil

Faculdade de Medicina de Marília (FAMEMA), Marilia, SP, Brazil

Faculdade de Medicina da Universidade Federal do Rio Grande do Sul (FAMED-UFRGS), Departamento de Oftalmologia e Otorrinolaringologia, Porto Alegre, RS, Brazil

Santa Casa de Misericórdia, Hospital de São Paulo, Departamento de Otorrinolaringologia, São Paulo, SP, Brazil

Universidade Estatual de Londrina, Londrina, PR, Brazil

Pontifícia Universidade Católica do Paraná (PUCPR), Câmpus Londrina, Londrina, PR, Brazil

Universidade de Brasília, Faculdade de Medicina, Programa de Pós-Graduação, Brasilia, DF, Brazil

Universidade Federal de Pernambuco, Recife, PE, Brazil

Santa Casa de São Paulo, São Paulo, SP, Brazil

Faculdade de Medicina da Universidade Federal da Bahia, Salvador, BA, Brazil

Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Otorrinolaringologia e Cirurgia de Cabeça e Pescoço, São Paulo, SP, Brazil

Universidade Estadual Paulista, Faculdade de Ciências Médicas, Departamento de Oftalmologia/Otorrinolaringologia, Campinas, SP, Brazil

Study	Method	Participants	Intervention	Outcomes/Results
Mostafa (2020) ²¹21 Mostafa BE, Fadel M, Mohammed MA, Hamdi TAH, Askoura AM. Omalizumab versus intranasal steroids in the post-operative management of patients with allergic fungal rhinosinusitis. Eur Arch Otorhinolaryngol. 2020;277:121-8.	BRCT	20 patients with AFRS	Omalizumab single dose of 150 mg two weeks post-surgery (n = 10)	Significant improvement in both groups, but the group taking Omalizumab showed a better clinical and endoscopic response.
	BRCT	20 patients with AFRS	Topical corticosteroid 2× daily for 6-months starting 2-weeks after surgery (n = 10)
Pinto et al. (2010) ²⁸28 Pinto JM, Mehta N, DiTineo M, Wang J, Baroody FM, Naclerio RM. A randomized, double-blind, placebo-controlled trial of anti-IgE for chronic rhinosinusitis. Rhinology. 2010;48:318-24.	DBPCCT	14 patients with CRSwNP/CRSsNP	Omalizumab at the beginning of the study and every 4-weeks for 24-weeks (n = 7)	No statistically significant alterations were observed in any of the outcomes, except for an improvement in SNOT-20 in several time intervals in the Omalizumab group.
	DBPCCT	14 patients with CRSwNP/CRSsNP	Placebo for 24-weeks (n = 7)
Gevaert et al. (2013) ²⁷27 Gevaert P, Calus L, Van Zele T, Blomme K, De Ruyck N, Bauters W, et al. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol. 2013;131:110-6.e1.	DBPCCT	24 patients with CRSwNP and asthma	Omalizumab maximum dose of 375 mg subcutaneously (4-8 subcutaneous doses for 16-weeks (n = 16)	Significant improvements were observed in all outcomes in the Omalizumab group, except for nasal airflow and olfaction.
	DBPCCT	24 patients with CRSwNP and asthma	Placebo for 16 weeks (n = 8)
Gevaert et al. (2020) ³³33 Gevaert P, Omachi TA, Corren J, Mullol J, Han J, Lee SE, et al. Efficacy and safety of omalizumab in nasal polyposis: 2 randomized phase 3 trials. J Allergy Clin Immunol. 2020;146:595-605.	DBPCCT ‒ Phase 3	Polyp 1 138 patients with CRSwNP	Omalizumab 75-600 mg per subcutaneous injection every 2 or 4 weeks, depending on the total IgE serum levels and body weight for 24 weeks (n = 134)	Omalizumab was well tolerated and significantly improved the endoscopic and clinical results of the patients with CRSwNP with an adequate response to intranasal corticosteroids. When compared to the Placebo group.
	DBPCCT ‒ Phase 3	Polyp 2 127 patients with CRSwNP	Placebo for 24 weeks (n = 138)

Study	Method	Participants	Intervention	Outcomes/Results
Gevaert et al. (2006) ⁵⁶56 Gevaert P, Lang-Loidolt D, Lackner A, Stammberger H, Staudinger H, Van Zele T, et al. Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps. J Allergy Clin Immunol. 2006;118:1133-41.	DBPCCT	24 CRSwNP Reslizumab arm: dose 3 mg/kg Placebo arm: dose 1 mg/kg	Reslizumab single EV dose (30 min) or placebo	No difference in safety and tolerance between arms
	Two centers		Controls after 48 h and 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36 weeks	Significant reduction in blood eosinophiles in the medication arm with return to baseline on week 12. Rebound eosinophilia on week 24 (1 mg/kg) and week 32 (3 mg/kg)
	Two centers			Reduction in polyp volume Only in patients with increased levels of nasal IL-5
Gevaert et al. (2011) ⁴⁴44 Gevaert P, Van Bruaene N, Cattaert T, Van Steen K, Van Zele T, Acke F, et al. Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol. 2011;128:989-95.e1-8.	DBPCCT	30 CRSwNP	2 injections with a 28-day interval	Significant improvement in the nasal polyp score and in the tomographic score in 12/20 (mepolizumab arm) compared to the placebo arm with 1/10
		20 Mepolizumab 750 mg
		10 placebo
Bachert et al. (2017) ⁶⁰60 Bachert C, Sousa AR, Lund VJ, Scadding GK, Gevaert P, Nasser S, et al. Reduced need for surgery in severe nasal polyposis with mepolizumab: Randomized trial. J Allergy Clin Immunol. 2017;140:1024-31.e14.	DBPCCT	105 CRSwNP with recurrent disease	Mepolizumab (750 mg of 30‒30 days), 6 doses	Significant difference in the need for surgical intervention on week 25
		54 Mepolizumab	Placebo 30‒30 days, 6 doses	Mepolizumab arm: 16 patients (30%)
		52 placebo		Placebo arm: 5 (10%)
				Significant reduction in polyp VAS; endoscopic score, symptoms, SNOT-22, on behalf of the arm
				Mepolizumab
				Absence of difference in olfaction between arms
Bachert et al. (2022) ⁵⁸58 Bachert C, Han JK, Desrosiers MY, Gevaert P, Heffler E, Hopkins C, et al. Efficacy and safety of benralizumab in chronic rhinosinusitis with nasal polyps: A randomized, placebo-controlled trial. J Allergy Clin Immunol. 2022;149:1309-17.e12.	DBPCCT	413 CRSwNP	30 mg SC 4‒4 weeks 3 initial doses followed by 30 mg SC 8‒8 weeks, both groups of which had intranasal corticosteroids	Benralizumab reduced the nasal polyp score 0.570 (p < 0.001)
		207 Benralizumab vs. 206 placebo		Benralizumab reduced the nasal obstruction score by 0.270 (p < 0.005)
		207 Benralizumab vs. 206 placebo		No difference in time of first indication for surgery or SNOT-22
Han JK et al. (2021) ⁵⁹59 Han JK, Bachert C, Fokkens W, Desrosiers M, Wagenmann M, Lee SE, et al. Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2021;9:1141-53.	DBPCCT	407 CRSwNP (all with at least one CENS)	100 mg Mepolizumab SC 4‒4-weeks, 52-weeks vs. placebo, SC, 4‒4 weeks, 52-weeks	Reduction in nasal polyp score (p < 0.0001)
		206 Mepo. (189 completed the study) vs. 201 placebo (184 completed)	69 Mepo. vs. 65 placebo were still followed up for 76 weeks	Visual nasal obstruction scale (p < 0.0001)
			69 Mepo. vs. 65 placebo were still followed up for 76 weeks	Occurrence of new surgeries and significantly lower systemic corticosteroid use in the Mepo. arm, as well as olfaction, nasal inspiratory flow, SNOT-22

Study	Method	Participants	Intervention	Outcomes/Results
Bachert (2019)⁸³83 Bachert C, Han JK, Desrosiers M, Hellings PW, Amin N, Lee SE, et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials. Lancet. 2019;394:1638-50.	DBPCCT	CRSwNP	SINUS-24 (24 weeks):	Significant improvement in both studies compared to the placebo:
		SINUS-24: 276 patients	• Dupilumab (300 mg 15/15d) (n = 143)	• SNOT-22
			• Placebo 15/15 d (n = 133)	• Rhinosinusitis disease severity (VAS)
		SINUS-52: 448 patients	SINUS-52: (52 weeks):	• Nasal congestion
			• Dupilumab (300 mg 15/15 d) (n = 150)	• UPSIT
			• Dupilumab (300 mg 15/15d for 24	• Nasal polyps
			• Weeks, and 30/30 d for 28 weeks (n = 145)	• Nasal endoscopy (Lund-Kennedy)
			• Placebo 15/15 d (n = 153)	• ACQ5
			Both studies:	• Pulmonary function (FEV1)
			Mometasone 100 μg/nostril 12/12 h for 4 weeks before and during the study.
Bachert (2016)⁸⁴84 Bachert C, Zinreich SJ, Hellings PW, Mullol J, Hamilos DL, Gevaert P, et al. Dupilumab reduces opacification across all sinuses and related symptoms in patients with CRSwNP. Rhinology. 2020;58:10-7.	DBPCCT	60 patients with CRSwNP refractory to INC	Dupilumab (starting with 600 mg, 300 mg per week) for 16 weeks (n = 30)	Significant improvement:
			Placebo for 16 weeks (n = 30)	• SNOT-22
			Mometasone 100 μg/nostril 12/12 h for 4 weeks before and during the study.	• Rhinosinusitis severity (VAS)
				• Nasal congestion
				• Olfaction (UPSIT)
				• Nasal polyps score (NPS)
				• CT (LMS)
				• ACQ6
				• FEV1

Categories of olfaction	UPSIT	CCCRC	MULTISCENT-20
Normosmia	Women: > 34	6 to 7	≥15
Normosmia	Men: > 31	6 to 7	≥15
Mild to severe hyposmia	Women: 17‒31	2 to 5.75	11 to 14
Mild to severe hyposmia	Men: 19‒34	2 to 5.75	11 to 14
Anosmia	Women: < 17	0 to 1.75	≤10
Anosmia	Men: < 19	0 to 1.75	≤10

Variables	Score
Sub-item ‒ Symptom severity ¹⁵⁴154 Toma S, Hopkins C. Stratification of SNOT-22 scores into mild, moderate or severe and relationship with other subjective instruments. Rhinology. 2016;54:129-33.
a) SNOT-22 (validated for Brazilian Portuguese)
< 20	0
20‒50	1
>50	2
b) VAS for nasal obstruction/congestion or rhinorrhea (consider the worst)
< 3	0
3‒7	1
> 7	2
c) Olfactory Test (UPSIT/Connecticut)
< 3 (normosmia or mild hyposmia)	0
3‒7 (moderate hyposmia)	1
> 7 (severe hyposmia or anosmia)	2
d) Number of previous surgeries
0	0
1	1
2	2
≥3 or contraindication for undergoing surgery	3
e) Use of systemic CS/year
0	0
1 or 2	1
> 2	2
Sub-item ‒ Extent of the disease
f) Polyp Size (Nasal Polyp Score ‒ bilateral)
0	0
1‒2	1
3‒4	2
≥ 5	3
g) Sinus opacification (Lund-Mackay - bilateral)
0‒4	0
5‒8	1
9‒16	2
>16	3
Sub-item ‒ Comorbidities
h) Asthma
No	0
Mild	1
Moderate/severe	2
i) NSAID Intolerance
No	0
Yes	2
Sub-item ‒ Biomarkers
j) Serum eosinophilia
< 150	0
150‒300	1
> 300	2
k) Tissue eosinophilia
< 10	0
10‒43	1
> 43	2

[1] Peer Review under the responsibility of Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial.

Brasil

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Brazilian guideline for the use of immunobiologicals in chronic rhinosinusitis with nasal polyps ‒ 2024 update

Abstract

Introduction

Objectives

Results

Conclusions

Highlights