1.中山大学附属第三医院,耳鼻咽喉头颈外科,广东 广州510630
2.中山大学附属第三医院,变态反应科,广东 广州510630
白瑜蓉,博士生,研究方向:鼻黏膜炎症发病机制和治疗研究。
[ "张雅娜中山大学附属第三医院博士生导师,中山大学“百人计划”引进人才。聚焦于鼻黏膜慢性炎症疾病发病机制和治疗策略的研究。研究成果发表在 J Exp Med,JAllergy Clin Immunol,Am J Respir and Crit Care Med和J Immunol等期刊。张雅娜教授目前担任教育部学位论文评审专家及包括《中山大学学报(医学科学版)》在内的多个杂志 审 稿 人 ,主 持 国 家 自 然 科 学 基 金 等 项 目 。 E-mail: zhangyn95@mail.sysu.edu.cn" ]
收稿:2022-08-02,
纸质出版:2022-09-20
移动端阅览
白瑜蓉,张雅娜.2型生物制剂和亚洲慢性鼻窦炎[J].中山大学学报(医学科学版),2022,43(05):720-729.
BAI Yu-rong,ZHANG Ya-na.Type 2 Biologics and Asian Chronic Rhinosinusitis[J].Journal of Sun Yat-sen University(Medical Sciences),2022,43(05):720-729.
白瑜蓉,张雅娜.2型生物制剂和亚洲慢性鼻窦炎[J].中山大学学报(医学科学版),2022,43(05):720-729. DOI: 10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).2022.0505.
BAI Yu-rong,ZHANG Ya-na.Type 2 Biologics and Asian Chronic Rhinosinusitis[J].Journal of Sun Yat-sen University(Medical Sciences),2022,43(05):720-729. DOI: 10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).2022.0505.
慢性鼻窦炎(CRS)是一种高异质性疾病,不同种族和地域的CRS患者表现为不同的流行病学和内在型特征。尽管经历了充分和规律的药物和手术治疗,仍有相当比例的CRS患者治疗后复发。复发性、难治性CRS为CRS的临床治疗提出了严峻挑战。2型生物制剂的问世,为难治性、复发性CRS的治疗带来了曙光。近年来,靶向2型炎症的生物制剂在治疗西方国家患者的难治性CRS方面表现出了令人鼓舞的治疗效果。但是由于炎症特征存在异质性,西方CRS患者以嗜酸粒细胞性2型炎症为主,而亚洲CRS患者更多地表现为1型炎症、3型炎症及混合性2型炎症。因此,2型生物制剂对于亚洲CRS患者的治疗效果仍需进一步验证。此外,针对亚洲CRS患者特有炎症分型的新型生物制剂研发将是未来重要的研究方向。在这篇综述中,我们将讨论2型生物制剂的研究回顾、亚洲CRS患者的炎症内在型特征、目前生物制剂的治疗现状和问题,以及未来的治疗展望。
Chronic rhinosinusitis (CRS) is a highly heterogeneous disease with various epidemiological and immunopathological characteristics among patients of distinct races and regions. Despite adequate and proper medical and endoscopic surgical treatment, a significant proportion of patients with CRS still experience postoperative recurrence. Difficult-to-treat severe CRS represents a number of management challenges to the practicing clinician. The advent of type 2 biologics provides a new option for the treatment of refractory and relapsed CRS. Currently, biologics targeting type 2 inflammation have been shown to be effective in improving clinical outcomes, and become a promising therapy of refractory nasal polyps in patients from western countries. However, the therapeutic effect of biologics targeting type 2 inflammation still needs to be further verified in Asian CRS patients since patients with CRS in Asia present more type 1 and type 3 inflammatory endotype as well as mixed type 2 inflammation. In addition, the development of new biologics targeting the specific endotype of Asian CRS patients will be an important research orientation in the future. In this review, we discuss the historical perspective of type 2 biologics, the inflammatory endotype characteristics of CRS in Asian, current treatment status and potential therapeutic prospects.
Fokkens WJ , Lund VJ , Hopkins C , et al . European position paper on rhinosinusitis and nasal polyps 2020 [J]. Rhinology , 2020 , 58 ( Suppl S29 ): 1 - 464 .
Bachert C , Marple B , Schlosser RJ , et al . Adult chronic rhinosinusitis [J]. Nat Rev Dis Primers , 2020 , 6 ( 1 ): 86 .
Shi JB , Fu QL , Zhang H , et al . Epidemiology of chronic rhinosinusitis: results from a cross-sectional survey in seven Chinese cities [J]. Allergy , 2015 , 70 ( 5 ): 533 - 539 .
Deconde AS , Mace JC , Levy JM , et al . Prevalence of polyp recurrence after endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis [J]. Laryngoscope , 2017 , 127 ( 3 ): 550 - 555 .
Lou H , Meng Y , Piao Y , et al . Cellular phenotyping of chronic rhinosinusitis with nasal polyps [J]. Rhinology , 2016 , 54 ( 2 ): 150 - 159 .
Bachert C , Zhang N , Cavaliere C , et al . Biologics for chronic rhinosinusitis with nasal polyps [J]. J Allergy Clin Immunol , 2020 , 145 ( 3 ): 725 - 739 .
Alsharif S , Jonstam K , Van Zele T , et al . Endoscopic sinus surgery for Type-2 CRS wNP: an endotype-based retrospective study [J]. Laryngoscope , 2019 , 129 ( 6 ): 1286 - 1292 .
Jonstam K , Swanson BN , Mannent LP , et al . Dupilumab reduces local type 2 pro-inflammatory biomarkers in chronic rhinosinusitis with nasal polyposis [J]. Allergy , 2019 , 74 ( 4 ): 743 - 752 .
Bachert C , Han JK , Desrosiers M , 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 [J]. Lancet , 2019 , 394 ( 10209 ): 1638 - 1650 .
Gevaert P , Omachi TA , Corren J , et al . Efficacy and safety of omalizumab in nasal polyposis: 2 randomized phase 3 trials [J]. J Allergy Clin Immunol , 2020 , 146 ( 3 ): 595 - 605 .
Han JK , Bachert C , Fokkens W , et al . Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial [J]. Lancet Respir Med , 2021 , 9 ( 10 ): 1141 - 1153 .
Bachert C , Han JK , Desrosiers MY , et al . Efficacy and safety of benralizumab in chronic rhinosinusitis with nasal polyps: a randomized, placebo-controlled trial [J]. J Allergy Clin Immunol , 2022 , 149 ( 4 ): 1309 - 1317.e1312 .
Bachert C , Han JK , Wagenmann M , et al . EUFOREA expert board meeting on uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) and biologics: definitions and management [J]. J Allergy Clin Immunol , 2021 , 147 ( 1 ): 29 - 36 .
姚银 , 曾明 , 刘争 . 慢性鼻窦炎伴鼻息肉的生物靶向治疗 [J]. 中华耳鼻咽喉头颈外科杂志 , 2022 , 57 ( 2 ): 231 - 236 .
Yao Y , Zeng M , Liu Z . Biologics in chronic rhinosinusitis with nasal polyps [J]. Chin J Otorhinolaryngol Head Neck Surg , 2022 , 57 ( 2 ): 231 - 236 .
Manson ML , Säfholm J , James A , et al . IL-13 and IL-4, but not IL-5 nor IL-17A, induce hyperresponsiveness in isolated human small airways [J]. J Allergy Clin Immunol , 2020 , 145 ( 3 ): 808 - 817.e802 .
Wynn TA . Type 2 cytokines: mechanisms and therapeutic strategies [J]. Nat Rev Immunol , 2015 , 15 ( 5 ): 271 - 282 .
Mullol J , Laidlaw TM , Bachert C , et al . Efficacy and safety of dupilumab in patients with uncontrolled severe chronic rhinosinusitis with nasal polyps and a clinical diagnosis of NSAID-ERD: results from two randomized placebo-controlled phase 3 trials [J]. Allergy , 2022 , 77 ( 4 ): 1231 - 1244 .
Tversky J , Lane AP , Azar A . Benralizumab effect on severe chronic rhinosinusitis with nasal polyps (CRSwNP): a randomized double-blind placebo-controlled trial [J]. Clin Exp Allergy , 2021 , 51 ( 6 ): 836 - 844 .
Zhang YN , Song J , Wang H , et al . Nasal IL-4(+)CXCR5(+)CD4(+) T follicular helper cell counts correlate with local IgE production in eosinophilic nasal polyps [J]. J Allergy Clin Immunol , 2016 , 137 ( 2 ): 462 - 473 .
Cao PP , Zhang YN , Liao B , et al . Increased local IgE production induced by common aeroallergens and phenotypic alteration of mast cells in Chinese eosinophilic, but not non-eosinophilic, chronic rhinosinusitis with nasal polyps [J]. Clin Exp Allergy , 2014 , 44 ( 5 ): 690 - 700 .
Chan MA , Gigliotti NM , Dotson AL , et al . Omalizumab may decrease IgE synthesis by targeting membrane IgE+ human B cells [J]. Clin Transl Allergy , 2013 , 3 ( 1 ): 29 .
Holgate ST . New strategies with anti-IgE in allergic diseases [J]. World Allergy Organ J , 2014 , 7 ( 1 ): 17 .
Mitchell PD , El-Gammal AI , O'byrne PM . Anti-IgE and biologic approaches for the treatment of asthma [J]. Handb Exp Pharmacol , 2017 , 237 : 131 - 152 .
Wu Q , Zhang Y , Kong W , et al . Which is the best biologic for nasal polyps: dupilumab, omalizumab, or mepolizumab? a network Meta-analysis [J]. Int Arch Allergy Immunol , 2022 , 183 ( 3 ): 279 - 288 .
Gevaert P , Saenz R , Corren J , et al . Long-term efficacy and safety of omalizumab for nasal polyposis in an open-label extension study [J]. J Allergy Clin Immunol , 2022 , 149 ( 3 ): 957 - 965.e953 .
Zhu R , Owen R , Wilkins J , et al . Pharmacokinetics and exposure-efficacy relationships of omalizumab in patients with nasal polyps [J]. Pulm Pharmacol Ther , 2021 , 71 : 102080 .
Symowski C , Voehringer D . Th2 cell-derived IL-4/IL-13 promote ILC2 accumulation in the lung by ILC2-intrinsic STAT6 signaling in mice [J]. Eur J Immunol , 2019 , 49 ( 9 ): 1421 - 1432 .
Vatrella A , Fabozzi I , Calabrese C , et al . Dupilumab: a novel treatment for asthma [J]. J Asthma Allergy , 2014 , 7 : 123 - 130 .
Buchheit KM , Sohail A , Hacker J , et al . Rapid and sustained effect of dupilumab on clinical and mechanistic outcomes in aspirin-exacerbated respiratory disease [J]. J Allergy Clin Immunol , 2022 , S0091- 6749 ( 22)00542 - 5 .
Laporte SL , Juo ZS , Vaclavikova J , et al . Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system [J]. Cell , 2008 , 132 ( 2 ): 259 - 272 .
Lelegren MJ , Son SY , Han JK , et al . A review of phase Ⅲ clinical trials of US FDA-approved biologic therapies for chronic rhinosinusitis with nasal polyposis [J]. Immunotherapy , 2022 , 14 ( 8 ): 655 - 662 .
Fujieda S , Matsune S , Takeno S , et al . The effect of dupilumab on intractable chronic rhinosinusitis with nasal polyps in Japan [J]. Laryngoscope , 2021 , 131 ( 6 ): E1770 - e1777 .
Lee SE , Hopkins C , Mullol J , et al . Dupilumab improves health related quality of life: results from the phase 3 SINUS studies [J]. Allergy , 2022 , 77 ( 7 ): 2211 - 2221 .
Bachert C , Khan AH , Hopkins C , et al . Rapid and continuing improvements in nasal symptoms with dupilumab in patients with severe CRSwNP [J]. J Asthma Allergy , 2022 , 15 : 557 - 563 .
Kilty SJ , Lasso A . Canadian real-world study of access and clinical results using dupilumab for chronic rhinosinusitis with polyps [J]. J Otolaryngol Head Neck Surg , 2022 , 51 ( 1 ): 17 .
Bachert C , Corren J , Lee SE , et al . Dupilumab efficacy and biomarkers in chronic rhinosinusitis with nasal polyps: association between dupilumab treatment effect on nasal polyp score and biomarkers of type 2 inflammation in patients with chronic rhinosinusitis with nasal polyps in the phase 3 SINUS-24 and SINUS-52 trials [J]. Int Forum Allergy Rhinol , 2021 , 10.1002/alr.22964.
Derycke L , Eyerich S , Van Crombruggen K , et al . Mixed T helper cell signatures in chronic rhinosinusitis with and without polyps [J]. PLoS One , 2014 , 9 ( 6 ): e97581 .
Van Crombruggen K , Taveirne S , Holtappels G , et al . Innate lymphoid cells in the upper airways: importance of CD117 and IL-1RI expression [J]. Eur Respir J , 2018 , 52 ( 6 ): 1800742 .
Simon HU , Yousefi S , Schranz C , et al . Direct demonstration of delayed eosinophil apoptosis as a mechanism causing tissue eosinophilia [J]. J Immunol , 1997 , 158 ( 8 ): 3902 - 3908 .
Bachert C , Sousa AR , Lund VJ , et al . Reduced need for surgery in severe nasal polyposis with mepolizumab: randomized trial [J]. J Allergy Clin Immunol , 2017 , 140 ( 4 ): 1024 - 1031.e1014 .
Brusselle GG , Gevaert P . Mepolizumab for chronic rhinosinusitis with nasal polyps [J]. Lancet Respir Med , 2021 , 9 ( 10 ): 1081 - 1082 .
Detoraki A , Tremante E , D'amato M , et al . Mepolizumab improves sino-nasal symptoms and asthma control in severe eosinophilic asthma patients with chronic rhinosinusitis and nasal polyps: a 12-month real-life study [J]. Ther Adv Respir Dis , 2021 , 15 : 17534666211009398 .
Bachert C , Sousa AR , Han JK , et al . Mepolizumab for chronic rhinosinusitis with nasal polyps: Treatment efficacy by comorbidity and blood eosinophil count [J]. J Allergy Clin Immunol , 2022 , 149 ( 5 ): 1711 - 1721.e1716 .
Lipworth B , Chan R , Misirovs R , et al . Mepolizumab response in severe chronic rhinosinusitis with nasal polyps is dissociated from blood eosinophil levels [J]. J Allergy Clin Immunol , 2022 , 149 ( 5 ): 1817 .
Ortega HG , Yancey SW , Mayer B , et al . Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies [J]. Lancet Respir Med , 2016 , 4 ( 7 ): 549 - 556 .
Walter S , Ho J , Alvarado R , et al . Mepolizumab decreases tissue eosinophils while increasing type-2 cytokines in eosinophilic chronic rhinosinusitis [J]. Clin Exp Allergy , 2022 , 10.1111/cea.14152.
Buchheit KM , Lewis E , Gakpo D , et al . Mepolizumab targets multiple immune cells in aspirin-exacerbated respiratory disease [J]. J Allergy Clin Immunol , 2021 , 148 ( 2 ): 574 - 584 .
Yasruel Z , Humbert M , Kotsimbos TC , et al . Membrane-bound and soluble alpha IL-5 receptor mRNA in the bronchial mucosa of atopic and nonatopic asthmatics [J]. Am J Respir Crit Care Med , 1997 , 155 ( 4 ): 1413 - 1418 .
Gevaert P , Bachert C , Holtappels G , et al . Enhanced soluble interleukin-5 receptor alpha expression in nasal polyposis [J]. Allergy , 2003 , 58 ( 5 ): 371 - 379 .
Takabayashi T , Asaka D , Okamoto Y , 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 [J]. Am J Rhinol Allergy , 2021 , 35 ( 6 ): 861 - 870 .
Canonica GW , Harrison TW , Chanez P , et al . Benralizumab improves symptoms of patients with severe, eosinophilic asthma with a diagnosis of nasal polyposis [J]. Allergy , 2022 , 77 ( 1 ): 150 - 161 .
Nolasco S , Crimi C , Pelaia C , et al . Benralizumab effectiveness in severe eosinophilic asthma with and without chronic rhinosinusitis with nasal polyps: a real-world multicenter study [J]. J Allergy Clin Immunol Pract , 2021 , 9 ( 12 ): 4371 - 4380.e4374 .
Matsuno O , Minamoto S . Rapid effect of benralizumab for severe asthma with chronic rhinosinusitis with nasal polyps [J]. Pulm Pharmacol Ther , 2020 , 64 : 101965 .
Wang X , Zhang N , Bo M , et al . Diversity of T(H) cytokine profiles in patients with chronic rhinosinusitis: a multicenter study in Europe, Asia, and Oceania [J]. J Allergy Clin Immunol , 2016 , 138 ( 5 ): 1344 - 1353 .
Tomassen P , Vandeplas G , Van Zele T , et al . Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers [J]. J Allergy Clin Immunol , 2016 , 137 ( 5 ): 1449 - 1456.e1444 .
Yao Y , Zeng M , Liu Z . Revisiting Asian chronic rhinosinusitis in the era of type 2 biologics [J]. Clin Exp Allergy , 2022 , 52 ( 2 ): 231 - 243 .
Ma J , Shi LL , Deng YK , et al . CD8(+) T cells with distinct cytokine-producing features and low cytotoxic activity in eosinophilic and non-eosinophilic chronic rhinosinusitis with nasal polyps [J]. Clin Exp Allergy , 2016 , 46 ( 9 ): 1162 - 1175 .
Shi LL , Xiong P , Zhang L , et al . Features of airway remodeling in different types of Chinese chronic rhinosinusitis are associated with inflammation patterns [J]. Allergy , 2013 , 68 ( 1 ): 101 - 109 .
Wang H , Li ZY , Jiang WX , et al . The activation and function of IL-36γ in neutrophilic inflammation in chronic rhinosinusitis [J]. J Allergy Clin Immunol , 2018 , 141 ( 5 ): 1646 - 1658 .
Delemarre T , Bochner BS , Simon HU , et al . Rethinking neutrophils and eosinophils in chronic rhinosinusitis [J]. J Allergy Clin Immunol , 2021 , 148 ( 2 ): 327 - 335 .
Delemarre T , Holtappels G , De Ruyck N , et al . A substantial neutrophilic inflammation as regular part of severe type 2 chronic rhinosinusitis with nasal polyps [J]. J Allergy Clin Immunol , 2021 , 147 ( 1 ): 179 - 188 . e172.
Katotomichelakis M , Tantilipikorn P , Holtappels G , et al . Inflammatory patterns in upper airway disease in the same geographical area may change over time [J]. Am J Rhinol Allergy , 2013 , 27 ( 5 ): 354 - 360 .
Jiang WX , Cao PP , Li ZY , et al . A retrospective study of changes of histopathology of nasal polyps in adult Chinese in central China [J]. Rhinology , 2019 , 57 ( 4 ): 261 - 267 .
Shin SH , Ye MK , Kim JK , et al . Histological characteristics of chronic rhinosinusitis with nasal polyps: recent 10-year experience of a single center in Daegu, Korea [J]. Am J Rhinol Allergy , 2014 , 28 ( 2 ): 95 - 98 .
Kim SJ , Lee KH , Kim SW , et al . Changes in histological features of nasal polyps in a Korean population over a 17-year period [J]. Otolaryngol Head Neck Surg , 2013 , 149 ( 3 ): 431 - 437 .
Cao PP , Li HB , Wang BF , et al . Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese [J]. J Allergy Clin Immunol , 2009 , 124 ( 3 ): 478 - 484, 484 .e471-472.
Wang BF , Cao PP , Long XB , et al . Distinct mucosal immunopathologic profiles in atopic and nonatopic chronic rhinosinusitis without nasal polyps in Central China [J]. Int Forum Allergy Rhinol , 2016 , 6 ( 10 ): 1013 - 1019 .
Makihara S , Okano M , Fujiwara T , et al . Regulation and characterization of IL-17A expression in patients with chronic rhinosinusitis and its relationship with eosinophilic inflammation [J]. J Allergy Clin Immunol , 2010 , 126 ( 2 ): 397 - 400, 400 . e391-311.
Wang ZZ , Song J , Wang H , et al . Stromal cells and B cells orchestrate ectopic lymphoid tissue formation in nasal polyps [J]. Allergy , 2021 , 76 ( 5 ): 1416 - 1431 .
Hamada S , Ogino E , Yasuba H . Cycling therapy with benralizumab and dupilumab for severe eosinophilic asthma with eosinophilic chronic rhinosinusitis and eosinophilic otitis media [J]. Allergol Int , 2021 , 70 ( 3 ): 389 - 391 .
Rathi VK , Scangas GA , Metson RB , et al . Out-of-pocket costs of biologic treatments for chronic rhinosinusitis with nasal polyposis in the medicare population [J]. Int Forum Allergy Rhinol , 2022 . Doi: 10.1002/alr.22976 http://dx.doi.org/10.1002/alr.22976 .
Bapat SP , Whitty C , Mowery CT , et al . Obesity alters pathology and treatment response in inflammatory disease [J]. Nature , 2022 , 604 ( 7905 ): 337 - 342 .
Wu Q , Chen J , Deng H , et al . Expert-level diagnosis of nasal polyps using deep learning on whole-slide imaging [J]. J Allergy Clin Immunol , 2020 , 145 ( 2 ): 698 - 701.e696 .
张雅娜 , 吴庆武 , 黄雪琨 , 等 . 基于人工智能的慢性鼻窦炎内在型诊断助力精准医学 [J]. 中华耳鼻咽喉头颈外科杂志 , 2022 , 57 ( 2 ): 222 - 226 .
Zhang YN , Wu QW , Huang XK , et al . Chronic rhinosinusitis endotype diagnosis based on artificial intelligence facilitates precision medicine [J]. Chin J Otorhinolaryngol Head Neck Surg , 2022 , 57 ( 2 ): 222 - 226 .
Wu Q , Chen J , Ren Y , et al . Artificial intelligence for cellular phenotyping diagnosis of nasal polyps by whole-slide imaging [J]. EBioMedicine , 2021 , 66 : 103336 .
Mota D , Rama TA , Severo M , et al . Potential cancer risk with omalizumab? a disproportionality analysis of the WHO's VigiBase pharmacovigilance database [J]. Allergy , 2021 , 76 ( 10 ): 3209 - 3211 .
Vinciguerra A , Rampi A , Yacoub MR , et al . Hypereosinophilia management in patients with type 2 chronic rhinosinusitis treated with dupilumab: preliminary results [J]. Eur Arch Otorhinolaryngol , 2022 , 10.1007/s00405-022-07389-5.
Morris J , Olonisakin TF , Moore JA , et al . Inhibiting the type 2 inflammatory pathway with dupilumab is associated with an increase in interleukin-4 and interleukin-18 production [J]. Int Forum Allergy Rhinol , 2022 , 10.1002/alr.23003.
Kychygina A , Cassagne M , Tauber M , et al . Dupilumab-associated adverse events during treatment of allergic diseases [J]. Clin Rev Allergy Immunol , 2022 , 62 ( 3 ): 519 - 533 .
Oykhman P , Paramo FA , Bousquet J , et al . Comparative efficacy and safety of monoclonal antibodies and aspirin desensitization for chronic rhinosinusitis with nasal polyposis: a systematic review and network meta-analysis [J]. J Allergy Clin Immunol , 2022 , 149 ( 4 ): 1286 - 1295 .
Cai S , Xu S , Lou H , et al . Comparison of different biologics for treating chronic rhinosinusitis with nasal polyps: a network analysis [J]. J Allergy Clin Immunol Pract , 2022 , S2213- 2198 ( 22)00235 - 5 .
Barroso B , Valverde-Monge M , Alobid I , et al . Smell improvement by anti-IgE and anti-IL-5 biologics in patients with CRSwNP and severe asthma. A real life study [J]. J Investig Allergol Clin Immunol , 2022 , 0 . Doi: 10.18176/jiaci.0812 http://dx.doi.org/10.18176/jiaci.0812 .
0
浏览量
542
下载量
2
CSCD
关联资源
相关文章
相关作者
相关机构
京公网安备11010802024621
