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Home > Books > Updates in Otorhinolaryngology [Working Title]
Open access peer-reviewed chapter - ONLINE FIRST
Written By
Joon Kon Kim
Submitted: 10 October 2024 Reviewed: 04 November 2024 Published: 13 March 2025
DOI: 10.5772/intechopen.1008250
Updates in Otorhinolaryngology
Edited by Georgios Giourgos
From the Edited Volume
Updates in Otorhinolaryngology [Working Title]
Georgios Giourgos
Abstract
Chronic rhinosinusitis is a major ENT disease that makes daily life uncomfortable. Symptoms of chronic rhinosinusitis often include nasal congestion, purulent rhinorrhea, postnasal drip, and olfactory impairment. If symptoms persist, medical treatment, which is a reversible method, or surgical treatment, which is an irreversible method that structurally changes the paranasal cavity, could be considered. Currently, antibiotics with mucociliary agents can be used as typical medical treatment, and sinus irrigation with saline solution may also be considered. Surgical treatment is commonly performed through endoscopic sinus surgery, and an open approach can also be considered for structures that are difficult to access. For refractory CRS that does not respond to phenotype-specific treatment, the treatment is performed by examining the endotypes of CRS. Treatment based on the representative endotype checks the presence or absence of type 2 inflammation and provides customized treatment using biologics and hormonal treatment accordingly.
Keywords
- chronic rhinosinusitis
- recent treatment
- medical treatment
- surgical treatment
- phenotype
- endotype
Author Information
Joon Kon Kim*
- Department of Otorhinolaryngology, Eulji University College of Medicine, Daejeon, SouthKorea
- Department of Otorhinolaryngology-Head and Neck surgery, Seoul National University of College of Medicine, Seoul, SouthKorea
*Address all correspondence to: konddang@icloud.com
1. Introduction
It is important to understand immune cells and cytokines-related pathway for clarifying chronic rhinosinusitis (CRS) occurrence mechanism. Diverse immune cells such as T cells, antigen-presenting cells, and innate lymphocyte cells are involved in the CRS generation. Progressing CRS serially, sinonasal mucosa remodeling is developed and nasal polyp is often formed by a synchronization of sinonasal immunity and cross-linked fibrin deposition.
2. Chronic rhinosinusitis
CRS is defined by an inflammation of the paranasal mucosa with olfactory symptoms such as anosmia and hyposmia, nasal obstruction, rhinorrhea, and facial pain lasting more than 12weeks. In general, CRS occurs in 5–12% of the global population [1]. Phenotype of CRS is classified into CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP). CRSwNP can be divided into eosinophilic CRSwNP (eosCRSwNP) or non-eosinophilic CRSwNP (non-eosCRSwNP) according to the eosinophil levels of the polyp tissues.
CRS is diagnosed by medical history, physical examination with nasal endoscopy, and mucosal inflammation of radiological evaluation. There are diverse methods of treatments of CRS such as topical nasal sprays, nasal irrigation, antibiotics, steroids, immunomodulators, and surgical treatments. According to the guideline of worldwide consensus, for example, European Position Paper on Chronic Rhinosinusitis and Nasal Polyps 2020 (EPOS2020) and European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA), the treatment of CRS can be done step by step. In case of failure of CRS treatment, biologics were used successfully as additional treatment option for an improvement in the quality of life.
3. CRS pathophysiology
The mechanisms related to CRS pathogenesis connect to each other between immunity and environmental factors. Exogenous factors that are pathogens such as bacteria, viruses, and fungi as well as external environmental materials such as allergens and air pollutants trigger a commencement of the protection of nasal cavity/paranasal sinus at the cell-immune level. This protective immune mechanism occurs with innate immunity and adaptive immunity serially. The immunities are involved in epithelial proinflammatory cytokine production, toll-like receptors (TLRs) activation, chemo-sensory cell activation, and mucociliary clearance. After repeated immunologic defense, the nasal cavity and paranasal sinus change to chronic inflammation state. There is cell tight junction disruption, tissue remodeling, and bacteria dysbiosis in a chronic inflammation. The immunological changes manifest into forms such as nasal obstruction, rhinorrhea, and loss of smell.
To categorize CRS endotyping, T lymphocyte is classified according to several types of T lymphocyte and T lymphocyte–producing cytokines. T lymphocyte is classified into T1, T2, and T3. T1 type produces IFN-γ representatively, and T1 type has additional cytokines that are CXCL9, CXCL11, GZMG, ZNF683, FCRL6, and SLCO1B3. IFN-γ is presented by Th1 cells, cytotoxic T cells, and group 1 innate lymphocyte cells (ILC1s). T2 type secretes IL-4, IL-5, IL-13, EPX, CCL18, CCL26, CCR3, CST1, CST2, CLCA1, FCER2, POSTIN, PTGDR2, and SIGLEC8. These cytokines are also shown by Th2 cells, ILC2s, and eosinophils. T3 type is characterized by IL-17A. IL-17A is shown by Th17 cells and ILC3s. T3 type possesses other cytokines that are IL1B, IL8, CXCL1, CXCL2, CXCL6, CCL20, CHI3L1, SAA1, SAA2, and NOX1 [2]. According to the published literatures, these endotypes can match each patient, and some patients may have mixed endotypes (T1-T2, T2-T3, and T1-T3). There are few people who do not express elevated levels of any kind of biomarkers [3]. Patients having this characteristic are T untypeable (Tun). T2 type is usually presented in patients with CRSwNP, and non-T2 type (T1 or T3) is seen in patients with CRSwNP. Western countries have T2 type-CRSwNP more than Asian countries. Because of different immunological and environmental factors from Western/Asian countries, there is disparate bacterial entity in the CRS. To differentiate CRS types, CRS can be divided into eosinophilic, neutrophilic, pauci-granulocytic, and granulocytic.
Phenotypic classification is determined from the presence or absence of nasal polyps, and comorbidities define the phenotypic classification [4]. Nasal cavity and paranasal sinus mucosa have an important function to differentiate CRS, and epithelial cells of mucosa play a crucial role that is associated with the initiation and regulation of immune responses. CD4+ T cell expansion corresponds to raising up type 2 cytokines and immunoglobulins in NPs [5].
4. Phenotypes of CRS
CRS is chronic inflammation of the mucosa from the nasal cavity/paranasal sinuses. CRS affects up to 12% of the Western population [6]. According to EPOS 2020 guidelines, CRS is diagnosed by the confirmation of 2 or more symptoms for 12weeks or more continuous weeks with objective confirmation using computed tomography (CT) and nasal endoscopy. CRS phenotypes are divided according to nasal polyp existence and nonexistence because of different CRS treatment courses: CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). In addition to CRSwNP and CRSsNP, there were other observable characteristics of CRS phenotypes.
4.1 Aspirin-exacerbated respiratory disease (AERD)
AERD is defined by three characteristics that are (1) nasal polyp, (2) asthma, and (3) sensitivity to cyclooxygenase type 1 inhibitors. Respiratory airway symptoms are aggravated by blocking cyclooxygenase type 1. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) bring about this blocking reaction. Actually, AERD generation does not reveal entirely. There is high production of cysteinyl leukotrienes and prostaglandin D2 with lower levels of prostaglandin E2 with increased eosinophil activation. The prevalence of AERD among adult asthma patients has been reported to range between 7 and 21%, whereas 9–16% of patients with CRSwNP have been identified as having AERD [7, 8]. AERD is usually presented to be more prevalent in the Western countries than in Asian countries. The clinical diagnosis of AERD is confirmed by the presence of nasal polyps, asthma, and sensitivity to cyclooxygenase type 1 inhibitors. AERD occurs at a younger age and with a more severe clinical presentation compared with the typical patient with nasal polyposis [9]. AERD is confirmed by a history taking from a patient who experienced aspirin and NSAID hypersensitivity. Because aspirin and NSAID hypersensitivity can be gradual, it may not be easily recognized. Symptoms of AERD such as rhinorrhea, nasal obstruction, epiphora, conjunctival edema, laryngospasm, or bronchospasm typically occur within hours after the administration of aspirin and NSAIDs. Stevens WW et al. and Mascia K et al. showed that AERD patients have significantly decreased FEV1 relative to other CRS patients with asthma [7, 10]. Treatment of AERD can include aggressive surgery. Other treatments such as newly available biologics and ASA desensitization can be applied as alternatives.
4.2 Allergic fungal rhinosinusitis
Allergic fungal rhinosinusitis (AFRS) is an IgE-mediated noninvasive fungal disease of the nasal and paranasal sinuses. It occurs in less than 10% of CRSwNP cases. Patients with AFRS are also more likely to have lower socioeconomic status based on the results from retrospective studies [11]. The general symptoms of AFRS are rhinorrhea, nasal obstruction, and decreased sense of smell, and the severe symptoms of the disease are visual changes, proptosis, headaches, and diplopia. The symptoms usually present unilaterally. During the endoscopic evaluation of AFRS, there are thick brownish allergic mucins that have a peanut butter–like appearance with nasal polyps and proteinaceous debris. There are eosinophils and fungal hyphae, evaluating the content of AFRS mucin. Bent and Kuhn [12] represents the criteria to confirm AFRS. The major criteria of AFRS are (1) nasal polyposis, (2) fungi on staining, (3) eosinophilic mucin without fungal invasion into sinus tissue, (4) type 1 hypersensitivity of fungi, and (5) characteristic radiological findings with soft tissue differential densities on CT scanning. And, The minor criteria of AFRS are (1) bone erosion, (2) Charcot-Leyden crystals, (3) unilateral disease, (4) type 1 hypersensitivity to fungi, and (5) positive fungal culture. The appropriate treatment of AFRS is surgical approach with corticosteroid treatment.
4.3 Eosinophilic granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis (EGPA, so-called Churg-Strauss syndrome) is a rare disease, which is involved in the small-vessel vasculitis-affected asthma and eosinophilia. The incidence of EGPA is 0.5–6.8 cases per 1,000,000 adults per year occurring most often in adults aged 40–60years of age [13]. The progress of EGPA has three phases: allergic, eosinophilic, and vasculitic. Allergic phase presents with symptoms of asthma, allergic rhinitis, and sinusitis. And, eosinophilic phase shows blood and tissue eosinophilia. Vasculitic phase displays the abnormal vascular disorder such as peripheral neuropathy, purpura, and pauci-immune necrotizing glomerulonephritis. EGPA usually has the comorbidity of asthma. The representative symptoms of EGPA are nasal obstruction, rhinorrhea, smell dysfunction, and sneezing. In the published papers, there is no appropriate diagnosis of EGPA. As an alternative diagnosis, pathological biopsy identified vasculitis/eosinophilic inflammatory process even if the biopsy is not useful to make a diagnosis. According to the symptoms of EGPA, conservative treatment can be done such as nasal saline irrigation or topical intranasal steroid treatment. Surgical treatment is not recommended, and biological medication (i.e., IL-5 receptor-targeting agent) can be chosen.
4.4 Cystic fibrosis
Cystic fibrosis (CF) is a benign disease, which inherits autosomal-recessive characteristics. CF is a defect, which is derived from the cystic fibrosis transmembrane receptor (CFTR) gene through chloride channels. CF expresses significantly the increase of nasal secretion in the upper and lower airways prohibiting mucociliary function. Therefore, there is a high risk of infections. On radiologic imaging, CF patients have a higher incidence of underdeveloped sinuses compared with other adult patients. CF is diagnosed by performing a sweat chloride test, genetic analysis, and clinical presentation. A sweat chloride test is done by spotting a solution on the forearm or thigh and doing electrical stimulation, which is related to sweating. While examining the chloride, the level of chloride of CF should be higher than that in a normal patient. And, CF is verified by evaluating the CFTR mutation for the genetic test.
4.5 Immunodeficiency
Patients with refractory CRS continuously should be considered for immunodeficiency. Immunodeficient patients with CRS can be further categorized as having a primary or secondary immunodeficiency. Primary immunodeficiency is direct defect of immune response such as B cell, T cell, and other immune cell dysfunction. Secondary immunodeficiency is a result of indirect influence related to other diseases such as HIV or chemotherapy. The CRS-influenced immunodeficiency can be difficult to mark off idiopathic CRS. Therefore, meticulous history taking and evaluation should be chosen. Characteristic of immunodeficiency-related CRS is the rapid recurrence of symptoms and nasal polyps. The representative immunodeficiency is IgA immunodeficiency. There are other immunodeficiencies such as IgG and IgM immunodeficiency.
4.6 Primary ciliary dyskinesia
Normal mucosa of nasal cavity and paranasal sinus is pseudostratified columnar-ciliated epithelium. Primary ciliary dyskinesia (PCD) impairs the cilia movement. Symptoms of PCD are nasal obstruction and rhinorrhea because of static mucociliary function. PCD is a rare disorder with the incidence estimated at 1:15,000–30,000 births [14]. Saccharin test is the method to evaluate PCD. Saccharin test checks the nasal flow time from inferior turbinate to nasopharynx compared with normal nasal mucosa flow. In the case of delayed nasal flow of saccharin test, PCD can be diagnosed. There is also another screening test for PCD, nasal nitric oxide test that checks lower levels of nitric oxide of nasal cavity and paranasal sinus.
5. Reboot surgery
CRS accompanied by asthma, AERD, and atopy has a higher recurrence rate of CRS.
Refractory CRSwNP is treated by recurrent surgical treatments to deal with the recurrence of pathologic lesions. The concept of surgical approach changes from simple polyp extraction to the recovery of sinonasal mucosal function. Because of the high recurrence rates of CRSwNP, more extended approaches are proposed for new concepts such as (1) to widely access the sinuses, (2) to open them for local treatment, and (3) to reduce the inflammatory load. Actually, “stripping of the mucosa” procedure is not recommended because of the fear of scarring, inflammation of the denuded bone, and non-functional mucosa [15]. But CRSwNP is characterized by the high recurrence of disease morbidity and more systemic disease tendency than CRSwNP. Sinus surgery for CRSwNP should be performed to improve the quality of life and the patient’s symptoms. So, “reboot surgery” is introduced to advance CRSwNP treatment effect, recently. The main point of reboot surgery is to remove the sinus mucosa inflammation entirely. After this surgical approach, there is the recovery of sinonasal mucosa grown from preserved normal mucosa within several weeks. The range of the procedure is to remove totally the ethmoid sinus and maxillary sinus mucosa adding the orbital lamina and skull base mucosa. Furthermore, in the case of CRSwNP extended to the frontal sinus, a Draft 3 procedure should be considered. “Full reboot surgery” is the procedure of removing the maxillary sinus, ethmoid sinus, and frontal sinus mucosa, otherwise, “partial reboot.”
The reboot technique begins with a middle meatal antrostomy widely and a complete removal of all the mucosa from the maxillary sinus including the alveolar recess mucosa. In the case of the pathologic lesion extended to lamina orbitalis, skull base, and the lateral aspects of the middle turbinate, the mucosa of these structures is stripped. Additionally, sphenoid sinus lesion is needed for very careful reboot surgery owing to critical structures such as internal carotid artery and optic nerve. The range of reboot surgery at the sphenoid sinus is the floor and medial parts of the sphenoid sinus. For an example of frontal sinus, the procedure is done by removing the anterior skull base mucosa and is performed by widening the frontal sinus opening. Middle turbinate should be preserved as a landmark of postoperative care. Superior turbinate should also be protected, but in the case of blocking the surgical route, this structure can be removed. And, Draf III procedure is performed to achieve a full reboot surgery. The frontal sinus mucosa is completely removed from the posterior and anterior walls. “Peering of the sinus mucosa” derives from the concept that there is a nasal mucosa growth over the sinus walls from the edges of the anterior nasal cavity and the inferior turbinate, and there is no remnant paranasal mucosa. Mucosa recovery is 4–6weeks, but there is a delay of epithelization of mucosa in a situation with infection. For example, type 2 inflammation causes the delay of mucosa healing because type 2 inflammation-producing cytokines such as IL-4 and IL-13 weaken epithelial tight junction expression[16].
Complication rate of reboot surgery is identical to the rate of endoscopic sinus surgery (ESS). In the case adjacent to lamina orbitalis/skull base, fine surgical movement should be chosen to avoid a complication. Checking the SNOT-22 after reboot surgery is a useful method for an evaluation of surgical result. Recovery time of smell postoperatively usually is several weeks unless there is critical olfactory nerve complication.
6. Surgery outcome and predictors
ESS is an appropriate treatment to solve CRSwNP and CRSsNP. But ESS is not a perfect resolution to these diseases because of some recurrence rates. To predict a result of ESS success, there are diverse parameters of prediction, for example, postoperative smell outcome, quality of life improvement, and postoperative polyp recurrence/sinusitis rate. According to these predictive parameters, long-term postoperative follow-up can be evaluated and improve quality of life postoperatively.
6.1 Symptoms and quality-of-life improvement and prediction
In published literatures, there are improvements in quality of life (QOL) and nasal symptoms following ESS. Most of these studies are non-randomized uncontrolled (level III), and only few randomized controlled trials are available [17].
6.2 Polyp recurrence and revision surgery and prediction
To predict a polyp recurrence, it is useful to check a mucosal eosinophilia. There is no appropriate consensus of eosinophilic CRS tissue eosinophilia definition. To define tissue eosinophilia, there are diverse criteria in literature. Some papers present that eosinophilic CRS is related to eosinophil count/HPF (400xmagnification). The eosinophil count/HPF of papers defines various measurement as a cutoff value of eosinophilic sinusitis. For example, there are “5” [18], “20” [19], “70” [20], “100” [21], and “120” [22] that are cutoff values of eosinophilic sinusitis. Another evaluation of eosinophilic sinusitis is to check the proportion of eosinophil cells. In general, most studying groups evaluate 10% as the proportion-cutoff value. The other evaluation of eosinophilic sinusitis is to assess the clinical data such as serum eosinophil count (>5%), ethmoid predominant lesion by CT, comorbidity of asthma, and NSAID intolerance. Additionally, there are other clinical parameters such as the ratio of total ethmoid sinus scores and maxillary sinus scores for both sides (E/M ratio) and polypoid changes of the middle turbinate to predict polyp recurrence [23]. There are also other prediction parameters, for example, Charcot-Leyden crystal (CLC), eosinophil cationic protein (ECP), eotaxin-3, periostin, and IL-5.
7. Biologics in chronic rhinosinusitis with nasal polyps
In cases of recalcitrant CRSwNP, postoperative recurrent CRSwNP, and uncontrolled severe CRSNP, there is poor efficacy of diverse treatment despite medical and surgical approaches (topical nasal glucocorticosteroid, oral glucocorticosteroid, and endoscopic sinus surgery). Additionally, there are fewer effective outcomes in a case with asthma. Gevaert P et al. showed omalizumab, a new treatment agent for severe asthma, targets free IgE. This agent prevents binding to IgE receptors. The coverage of omalizumab expanded to CRSwNP [24]. Proof-of-concept studies with reslizumab and mepolizumab (biologics against IL-5) in CRSwNP were done in 2006/2011. This study’s results actually focused on asthma than on CRSwNP. Benralizumab also targets IL-5 and functions an anti-IL-5 receptor antagonist. Dupilumab is an anti-IL-4 receptor antagonist, the first biologic for the indication of CRSwNP. Phase 2 and 3 studies are related to dupilumab published [9, 25] (Table 1). Biologics, for example, mepolizumab, omalizumab, and dupilumab, can considerably reduce the nasal polyp score, Lund-Mackay CT score, and nasal and sinus symptoms. Evaluating SNOT-22, there is an improvement of score following the use of biologics (Table 2). In cases of CRSwNP with comorbidity such as asthma, biologics such as dupilumab and omalizumab can increase lung function and asthma control. The mechanism of biologics is to reduce blood/tissue eosinophils and serum IgE levels. For example, dupilumab reduces type 2 inflammation in polyp tissue and the polyp size in polyp tissue. Dupilumab presented that antagonism of IL-4Rα signaling suppresses type 2 cytokine-dependent process, such as mucosal IgE formation, the expression of chemokines attracting inflammatory cells [27].
| Mepolizumab | Omalizumab | Dupilumab | Mepolizumab | |
|---|---|---|---|---|
| Year | 2011 | 2013 | 2016, 2019 | 2017 |
| Target molecule | IL-5 | IgE | IL-4 receptor alpha | IL-5 |
| Study designa | Single center | Two centers | Multicenter (13 sites) | Multicenter (6 sites) |
| NO. (verum/placebo) | 30 (20/10) | 23 (15/8) | 60 (30/30) | 105 (54/51) |
| Asthma % (verum/placebo) | 43% (50%/30%) | 100% (100%/100%) | 58% (63%/53%) | 78% (81%/75%) |
| Former surgery % (verum/placebo) | 77% (75%/80%) | 83% (87%/75%) | 58% (63%/ 53%) | 100% (100%/100%) |
| End point and last visit (weeks) | 8w/48w | 16w/20w | 16w/16w | 25w/25w |
| Therapeutic effects | Significant reduction of polyp scores; reduction of blood eosinophil counts, serum ECP, and IL-5Rα, IL-6, MPO in nasal secretion | Significant reduction of polyp and CT scores, and improvement of symptoms of upper and lower airway and AQLQ | Significant reduction of polyp and CT scores, and improvement of smelling, symptoms, and quality of life (SNOT-22); improvement of FEV1 and ACQ5. Reduced plasma eotaxin-3, serum and nasal secretion tIgE, and nasal tissue tIgE, IL13, ECP, PARK, Eotaxin 1,2,3 | Significant reduction of polyp score, and improvement of smelling, symptoms, and quality of life (SNOT-22) |
Table 1.
Biologics information developed in the recent real-world field.
All these studies were randomized, double-blind, placebo-controlled studies.
tIgE: total serum immunoglobulin E; AQLQ: Asthma Quality of Life Questionnaire; ACQ5: 5-item Asthma Control Questionnaire, PnIF: Peak Nasal Inspiratory Flow, FEV1: forced expiratory volume; SNOT-22: Sino-nasal outcome test-22; ECP: eosinophil cationic protein; IL-5Rα: IL-5: receptor α subunit; TARC: Thymus and Activation-Regulated Chemokine; PARK: pulmonary and activation-regulated chemokine; MPO: myeloperoxidase. Table 1. refers to Zhang and Bachert [9].
| Characteristic pattern | Dupilumab | Mepolizumab | Omalizumab |
|---|---|---|---|
| CRSwNP | |||
| Reduction of endoscopic nasal polyp score | O | O | O |
| Lund-Mackay CT scan score improvement | O | - | O |
| Reduction of relevant nasal symptoms | O | O | O |
| Increase in smell (UPSIT and VAS) | O | O | O |
| Increase in quality of life (SNOT-22) | O | O | O |
| Asthma | |||
| Increase in lung function (FEV1) | O | - | O |
| Asthma control (ACQ and AQLQ) | O | - | O |
| Biomarker | |||
| Reduction in blood eosinophil numbers | - | O | - |
| Reduction in serum IgE levels | O | - | O |
| Reduction in tissue eosinophil numbers | O | O | - |
Table 2.
Biologics selection of each characteristic pattern.
Reference: Bachert C etal. [26].
7.1 IL-5 targeting agent
Biologics associated with IL-5 are reslizumab and mepolizumab. IL-5 is released by innate lymphoid cells (ILC2), Th2 cells, mast cells, γδ-T cells, and eosinophils. IL-5 binds to the α subunit of the IL-5 receptor (IL-5Rα) in the transmembrane form and soluble form. Reslizumab and mepolizumab act to retain IL-5 in serum and mucosal tissues. The action is important for the migration, chemotaxis and recruitment, activation, proliferation, maturation, and survival of eosinophil [28]. For example, benralizumab is an anti-IL-5 treatment agent that is a humanized mAb that binds with high affinity to the α-chain of the human IL-5R. The function of this agent is to block IL-5R activation and signal transduction. Benralizumab attaches to FcgR receptor that elevates the antibody-dependent cell-mediated cytotoxicity (ADCC) function [29].
7.2 IgE targeting agent
The biologic associated with IgE is omalizumab, representatively. Immunoglobulin E (IgE) antibodies are mediated by allergic reaction and function through bindingto Fc receptors FcεRI on mast cells basophils, and dendritic cells and FcεRII/CD23 on B cells. After IgE stimulation, antigen-presenting cells (APCs) act in serial response with leukotrienes, prostaglandins, IL-4, IL-5, and IL-13. This continual cascade mechanism results in eosinophil aggregation. Omalizumab antagonizes IgE-related reaction of APCs. IgE functions to induce mast cell mediators that maintain the inflammatory reaction [30]. Gevaert P et al. show that omalizumab has a positive effect to treat respiratory tract infection regardless of allergy [24]. This study was designed by a randomized, double-blind, placebo-controlled trial of allergic and non-allergic patients with nasal polyps and comorbid asthma. In the study, there were two groups that are omalizumab treatment group and placebo group (omalizumab, n=16; placebo, n=8). Nasal polyp score of endoscopic exam and Lund-Mackay score of CT were used in the study. This study proved that omalizumab treatment group had clinically significant improvement with reducing the nasal polyp size.
7.3 IL-4 receptor alpha targeting agent
A first study related to dupilumab was published in the United States and Europe in the years 2013/2014. The study design was randomized, double-blind, placebo-controlled design. Total participated patients were 60, 30 refractory CRSwNP to intranasal corticosteroids plus dupilumab (a 600-mg loading dose followed by 300mg weekly) and 30 placebo control group did this study design protocol. Treatment response comparison of two groups is demonstrated by nasal polyp score, Lund-Mackay CT total score SNOT-22, and smell function test (UPSIT). During the study, adverse effects were revealed. Nasopharyngitis (33% with placebo, 47% with dupilumab), injection site reactions (7% vs. 40%), and headache (17% vs. 20%) were presented. According to many kinds of literature, it is an effective treatment that topical steroid treatment with blocking a type 2 immune response such as antagonizing IL-4 and IL-13 controls CRSwNP.
8. Clinical application of biologics
The positive effect of biologics is revealed by many literature. Despite a lot of merits of biologics, there are some limitations of clinical application in the real world. First, high price of biologics appliance is a burden for CRSwNP patients. Sustainable biologics injection without follow-up loss is another burden. Appropriate selection of type 2 immune disease-CRSwNP patient is the other consideration to attain the optimal effect. There are still debating points whether biologics treatment could be started before or after surgical approach. EPOS2020 recommended the use of biologics in the treatment of CRSwNP to improve QOL and prevent polyposis progression. Until now, there are no certain markers to predict treatment responses for biologics. According to published literature, there is no definitely predictive characteristic to evaluate the biologics treatment. Therefore, recent papers checked data after a biologics use. One of the most believable values is the recovery of the olfactory function after treatment. There are some evaluations of olfactory function such as the Sniffin’ Sticks test and SNOT-22. Efficacy of dupilumab is usually checked by an evaluation of nasal polyp size, olfaction, and symptom clearance at weeks 24 and 52 after biologics treatment. Following this topic, there are summaries of biologics application and side effects in the following paragraphs [9, 31] (Table 3 and 4). Papacharalampous GX et al. [32] reviewed about the comparison of omalizumab, dupilumab, and mepolizumab’s efficacy. In the aspects of treatment impact on nasal polyp score and sense of smell, dupilumab was the most effective agent. A recent paper reported the safety of biologics for atopic diseases during pregnancy [33]. This literature reviewed seven cases evaluating the consequences in seven women and their offspring who were exposed to dupilumab during pregnancy. According to this study, there were seven live births and one premature birth. Other literatures showed that paternal use of dupilumab does not affect male fertility and fetal outcomes [34]. In 2023, EPOS and EUFOREA progressed the evaluation of pregnant women biologics use and the change of biologics treatment (Table 5). Rosso C et al. present that the best fits with each biologic are mandatory to personalize the therapy [35]. Dupilumab is the most effective agent for type 2 CRSwNP, at present. In many cases of dupilumab as the first-line treatment for CRSwNP, there is a high rate of adverse effects, particularly hyper-eosinophilia. In an occurrence case of hyper-eosinophilia using dupilumab, a recommendation should be made to change to another biologic agent, especially omalizumab.
| mAbs | Mechanism of action | Dose adult (>12 years) | Mode of application |
|---|---|---|---|
| Omalizumab | Binds free IgE | 75-600 mg (1–4 doses) every 2 or 4 weeks Determined by basal IgE levels, measured before starting treatment, and body weight(kg) | Subcutaneous: upper arm, thigh, or abdomen 75 mg or 150 mg powder and solvent for solution for injection. The reconstituted solution must be used immediately. |
| Dupilumab | Blocks IL-4Rα receptor | 300 mg every 2 weeks | Subcutaneous: upper arm, thigh, or abdomen 300 mg pre-filled syringe. Store in a refrigerator (2–8°C). Do not freeze. Do not shake. |
| Mepolizumab | Inhibits IL-5 | 100 mg every 4 weeks | Subcutaneous: upper arm, thigh, or abdomen 100 mg powder to be reconstituted with 1.2 ml of water for injections. The reconstituted solution must be used immediately. |
| Benralizumab | Inhibits binding of IL-5 to IL-5Rα receptor Direct eosinophil cytotoxic effects | 300 mg every 4 weeks for three times, and then 30mg every 8weeks | Subcutaneous: upper arm, thigh, or abdomen 30 mg pre-filled syringe. Store in a refrigerator (2–8°C). Do not freeze. Do not shake. |
| Reslizumab | Inhibits IL-5 | 3 mg/kg every 4 weeks | Intravenous infusion of 20–50 min through a sterile, non-pyrogenic, single use, low protein-binding infusion filter (0.2 μm). 2.5-ml or 10-ml vial. 1 ml contains 10 mg of reslizumab. Store in a refrigerator (2–8°C). Do not freeze. |
Table 3.
Biologics and biologics protocol.
Reference: Zhang and Bachert [9].
| Side effect (very common) | Side effect (common) | Very rare* | |
|---|---|---|---|
| Omalizumab | Pyrexia | Headache, injection site reactions, upper abdominal pain | Allergic granulomatous vasculitis (i.e., Churg-Strauss syndrome) Alopecia, arthralgia, idiopathic thrombocytopenia Joint swelling, myalgia Serum sickness |
| Mepolizumab | Headache | Back pain, eczema, hypersensitivity reaction, injection site reactions, lower respiratory tract infection | - |
| Dupilumab | Injection site reactions | Blepharitis, conjunctivitis, hypereosinophilia, eye pruritus, headache, oral herpes | Serum sickness |
| Benralizumab | - | Headache, hypersensitivity reactions, injection site reactions, pharyngitis, pyrexia | Anaphylactic reaction |
| Reslizumab | - | Blood creatine phosphokinase increased | - |
Table 4.
Biologics side effects.
Reference: Dorling et al. [31] and Zhang and Bachert [9].
| Topic | Content |
|---|---|
| 1. What biologics can be given to a pregnant woman? | Omalizumab is the only biologic until now that showed no increase in congenital anomalies or adverse outcomes in a registry of pregnant asthmatics treated with omalizumab. |
| 2. Can biologics work preventively? | There are no data suggesting that biologics can prevent CRS. |
| 3. Parameters to evaluate the “success” of biologics | Patient reported outcomes: SNOT-22, smell loss, congestion scores, comorbidities. ∙NP score, CT scan scores, smell tests. |
| 4. Follow-up period to check the response of CRSwNP | Expert board advises 16 weeks to be adjusted to 6 months. After 1 year, a second evaluation is necessary, and thereafter a yearly evaluation will suffice. |
| 5. Reasons to decrease/stop biologics | Side effects are seldom a reason to stop treatment with biologics. |
Table 5.
Updated information on indication and evaluation of biologics in CRSwNP according to EPOS/EUFOREA.
Reference: Fokkens WJ etal. [34].
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Written By
Joon Kon Kim
Submitted: 10 October 2024 Reviewed: 04 November 2024 Published: 13 March 2025
© The Author(s). Licensee IntechOpen. This content is distributed under the terms of the Creative Commons 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
