Nasal polyps commonly result from type 2 inflammation mediated by type 2 cytokines in the upper respiratory tract. Type 2 inflammation was previously referred to as “T helper cell 2 (Th2)-mediated inflammation,” since it involves an acquired immune response mediated by Th2 cells. However, following the discovery that cells involved in innate immunity play an important role in Th2 cell-mediated inflammation, it was later renamed as “type 2 inflammation.” [8,15]

The most important inflammatory cytokines in type 2 inflammation are interleukin (IL)-4, IL-13, and IL-5 [8,16]. The respiratory mucosa releases epithelial-derived cytokines, such as IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), in response to the presence of foreign bacteria, viruses, or irritants, which then stimulate type 2 innate lymphoid cells (ILC2) to secrete major cytokines, such as IL-5 and IL-13. Researchers have recently discovered that ILC2 produces IL-4, which induces the differentiation of Th0 (naïve T cells) to Th2 cells. IL-4 and IL-13, which are released later, induce class switching of B cell isotypes to produce immunoglobulin E (IgE). Furthermore, they inhibit tissue plasminogen activator, thus interfering with fibrinolysis and inducing fibrin cross-linking via M2 macrophage polarization, which subsequently leads to tissue remodeling and polypogenesis. IL-4 induces Th2 cell differentiation and IL-13 acts on epithelial cells to induce goblet cell hyperplasia and increase mucous secretions. IL-5 is involved in the activation, recruitment, and survival of eosinophils, which plays an essential role in type 2 inflammation (Fig. 1).

The European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA), which is an international nonprofit organization, published an expert board meeting on severe uncontrolled type 2 CRSwNP [17]. They defined “uncontrolled” CRSwNP as the condition when symptoms persist or recur within 2 years after long-term use of topical steroids or after at least one course of systemic corticosteroid treatment or surgery. They also defined “severe” disease as CRSwNP with nasal polyp scores of at least 4 out of 8, requiring additional treatments apart from topical steroids because of main symptoms, such as reduction of smell/taste, nasal congestion, and nasal discharge, and accessory symptoms, such as post-nasal drip and facial pain/pressure, persisting after the initial treatment.

By definition, severe uncontrolled CRSwNP is associated with type 2 inflammation and refers to cases of CRS in which the treatment response to pharmacotherapy or surgery is poor. Hence, a new treatment strategy using an immunological approach must be developed.

The association between type 2 inflammation and CRSwNP is reported to be 15%–85%, varying between regions and ethnicities [10,18]. Wang et al. [18] reported high levels of type 2 inflammatory cytokines in patients from Benelux, Germany, Australia, and Japan; a mixed profile of type 1, type 2, and type 3 cytokines in patients from Beijing, China; and low levels of type 2 cytokines in those from Cheongdu, China.

Zhang et al. [11] reported regional and racial differences in nasal polyps and an eosinophilic shift, indicating a high relative prevalence of type 2 inflammation in Asian countries. These immunological changes have also been observed in Korea [19].

Karin et al. [20] analyzed the levels of IgE, eosinophil cationic protein (ECP), and IL-5 in Belgian patients at two different time points and reported an increased incidence of type 2 inflammation in the latter group compared to that in the earlier group. These immunological changes in CRSwNP have also been confirmed in Western countries and show a global trend. Based on the immunological mechanism of CRS, the eosinophilic shift was renamed as “type 2 inflammatory shift.” [20] This shift mean that there will be more severe cases where CRS is difficult to treat in the future.

The International Consensus Statement on Allergy and Rhinology: Rhinosinusitis 2021 (ICAR statement) by the American Rhinologic Society recommends the use of a topical corticosteroid spray or corticosteroid nebulizer, corticosteroid irrigation, and short-term administration of systemic corticosteroids as the primary care for CRSwNP [21]. Corticosteroideluting implants, macrolide antibiotics, and leukotriene inhibitors may also be considered for the treatment of CRSwNP (Table 1). Surgery could be considered if a patient does not respond to pharmacotherapy within 3–4 weeks, depending on the Sino-Nasal Outcome Test-22 (SNOT-22) scores.

Common medications or surgical procedures for CRS have limitations in clinical settings. Nasal irrigation with saline or short-term use of topical steroids, leukotriene inhibitors, or antibiotics, which are commonly used to treat CRSwNP, lack clinical effectiveness and only play a role in maintenance at a time before the formation of nasal polyps. The effects of systemic corticosteroids used to treat loss of smell are not sustained and are reverted once the patient stops using them [22]. Furthermore, systemic corticosteroids cannot be prescribed for long-term use as they can lead to side effects, such as hyperglycemia, hypertension, mood swings, and sleep disorders, as well as increased risk of fracture due to osteoporosis, infection due to immunosuppression, ophthalmological problems (e.g., cataract and glaucoma), obesity due to hormonal changes, and neuropsychological problems (e.g., depression and anxiety) [14]. Therefore, the European Position Paper on Rhinosinusitis and Nasal Polyps 2020 (EPOS 2020) [23], ICAR 2021 [21], and Global Initiative for Asthma (GINA) 2019 guideline [24] mutually recommend against the continuous use of systemic corticosteroids considering their side effects.

Although surgical intervention is more effective than pharmacotherapy, the postoperative recurrence and reoperation rates of CRS are high at 40%–79% and 36%, respectively [9,12,25,26]. These high rates suggest that although the surgical removal of polyps may manage to ventilate the paranasal sinuses and restore mucociliary movements, it cannot completely suppress inflammation because severe uncontrolled CRSwNP is the result of an immunological response associated with type 2 inflammation.

Biologics used for CRSwNP target cytokines and cells that mediate type 2 inflammation (Fig. 1) [27]. Monoclonal antibodies targeting IL-5, which regulates eosinophils involved in type 2 inflammation, include mepolizumab and reslizumab, and the biologics inhibiting IL-5 receptor (R) α, which is an eosinophil receptor, include benralizumab [17]. Omalizumab inhibits free IgE, which regulates cell differentiation into basophils and mast cells by binding to the FcεRI [23,28]. In signaling pathways, type I receptor consists of IL-4Rα and common gamma chain, binding to IL-4 only while type II receptor consists of IL-4Rα and IL-13Rα1, binding to both IL-4 and IL-13. The IL-4Rα subunit exists in type I and type II receptors commonly. Dupilumab is a monoclonal antibody that targets IL-4Rα to inhibit both IL-4 and IL-13 simultaneously. By inhibiting IL-4 and IL-13, which are the major upstream cytokines in the type 2 inflammatory pathway, dupilumab can also down-regulate the chemotaxis of eosinophils in the periphery [27].

The use of dupilumab for CRSwNP has been approved by the US Food and Drug Administration and the European Medicines Agency. In Korea, it was approved by the Ministry of Food and Drug Safety in the first half of 2021. Omalizumab was approved in the United States and Europe in 2020, and Korea in the first half of 2021. Reslizumab, mepolizumab, and benralizumab have been approved for severe asthma in and outside Korea, but not for CRSwNP (Table 2).

Up to date, there is no clinical consensus on indication of biologics for CRSwNP. Fujieda et al. [29] reported that dupilumab produce consistent improvement in symptoms irrespective of eosinophilic status of CRSwNP through the posthoc analysis of dupilumab phase 3 study. Therefore, they concluded that blood eosinophil level may not be an appropriate biomarker for biologics efficacy in CRSwNP.

Meanwhile, according to the EPOS 2020 [23], biologics can be indicated for CRSwNP in patients with bilateral nasal polyps with or without a previous history of surgery satisfying at least three of the following five conditions: 1) type 2 inflammation (≥10 tissue eosinophils/high-power field, ≥250 blood eosinophils/μL, or total IgE ≥100 kU/L); 2) need for at least two courses of systemic corticosteroids or ≥3 months of systemic corticosteroid use; 3) reduced quality of life (SNOT-22 scores ≥40); 4) reduced sense of smell in the smell test; and 5) asthma requiring inhaled corticosteroids [23].

Additionally, the EPOS 2020 presented five evaluation criteria for assessing the treatment response of biologics: 1) reduced nasal polyp size; 2) reduced need for systemic corticosteroids; 3) improved quality of life; 4) improved sense of smell; and 5) reduced impact of co-morbidities [23]. The treatment responses are graded as “excellent” (all five criteria satisfied), “moderate” (3–4 criteria satisfied), “poor” (1–2 criteria satisfied), or “no response” (0 criteria satisfied). Treatment should be discontinued if “no response” is observed in any of the criteria.

According to the EUFOREA expert board meeting [17], 6 months after initiation of therapy had been proposed as the time point to evaluate the treatment response for whether to continue biologics treatment or whether to perform surgery if it does not work.

Meanwhile, Table 3 summarizes the results of previous clinical trials on biologics for CRSwNP.

Dupilumab is one of the two drugs approved for CRSwNP in Korea, the United States, and Europe. Bachert et al. [30] reported a significant reduction in nasal polyp scores in an treatment group (dupilumab+topical steroids) when compared to the control group (topical steroids) in their 16-week randomized controlled trial analyzing 60 patients with CRSwNP.

A large-scale multinational, multi-center study systematically analyzing the long-term effects and safety of dupilumab (LIBERTY SINUS-24 and -52) was later published [31]. The patients included in the study were diagnosed with severe uncontrolled type 2 CRSwNP based on their previous surgical history, nasal polyp scores, Lund-Mackay (LM) computed tomography scores, SNOT-22 scores, sense of smell, and comorbidities. The patients were divided into two groups: SINUS-24 group (n=276), in which the patients were subcutaneously administered dupilumab every 2 weeks for 6 months (24 weeks), and SINUS-52 group (n=448), which received dupilumab every 2 weeks for 6 months and thereafter every 1 month (4 weeks) for an additional 6 months. The treatment groups were compared with the control group, which received topical steroids at different time points. The least-square mean differences or the mean change from baseline in the nasal polyp, nasal congestion, and LM scores after 6 months (24 weeks) of treatment (SINUS-24) were -2.06 (95% confidence interval [CI] -2.43 to -1.69, p<0.0001), -0.89 (95% CI -1.07 to -0.71, p<0.0001), and -7.44 (95% CI -8.35 to -6.53, p<0.0001), respectively, indicating that dupilumab is significantly superior to the topical steroids. The least-square mean differences in the respective scores after 24 weeks of SINUS-52 study were -1.80 (95% CI -2.10 to -1.51, p<0.0001), -0.87 (95% CI -1.03 to -0.71), and -5.13 (95% CI -5.80 to -4.46, p<0.0001), respectively, indicating that long-term administration of biologics was also effective. Interestingly, no significant difference was found according to the administration interval (2 weeks vs. 1 month) between 6 months and 1 year of treatment, indicating that an administration interval of 1 month may be considered during the maintenance period. On radiologic examination, the effect of dupilumab was also observed in both paranasal sinuses after 24 weeks of treatment, and a significant improvement was observed after 52 weeks. Fast improvements were also observed following dupilumab administration. The sense of smell started to improve in the early period of treatment (within 1 month), and similar improvements were observed even in patients with comorbidities, such as asthma and hypersensitivity to NSAIDs.

Numerous studies have examined subjective improvements in symptoms following dupilumab administration in patients with severe uncontrolled type 2 CRSwNP. According to a randomized controlled study that evaluated the SNOT-22 test, a 36-Item Short-Form Health Survey, and a five-dimension EuroQoL visual analog scale questionnaire (EQ-5D VAS) among 60 patients with CRSwNP not responsive to topical steroids, the major symptoms among the patients included a reduced sense of smell, nasal congestion, purulent discharge, post-nasal drip, and reduced attention [32]. The study reported that the patients in the dupilumab group had taken fewer sick leaves than that in the control group and had shown a higher productivity in their workplaces [32]. In a study that evaluated the EQ-5D VAS among patients with asthma, significant improvements were observed in the dupilumab group compared to that in the control group [33].

Jonstam et al. [34] measured changes in biomarkers following the administration of dupilumab in patients with type 2 inflammation. They reported reductions in eotaxin-3 and total IgE levels in nasal secretions as well as reductions in ECP, eotaxin-2, eotaxin-3, IgE, and IL-13 levels in nasal polyp tissues. Takabayashi et al. [35] reported that the level of urinary leukotriene E4, which is a marker of leukotriene dysmetabolism, decreased while the blood eosinophil count temporarily increased in the beginning (16 weeks) after the administration of dupilumab.

Dupilumab not only improves subjective symptoms but also reduces the treatment burden. According to the aforementioned study with the SINUS-52 group, dupilumab can reduce the use of systemic corticosteroids and need for surgery by 74.6% and 89.4%, respectively [31].

Common side effects of dupilumab include nasopharyngitis, headache, nasal bleeding, and injection-site rash. Conjunctivitis, treatment-emergency eosinophilia, eosinophilic granulomatosis with polyangiitis, eosinophilia accompanied by joint pain, nasal polyps, or asthma aggravation may occur rarely [21,31].

The ICAR 2021 states that dupilumab has an evidence level of A (verified by numerous randomized controlled trials) and recommends using dupilumab for severe CRSwNP that does not respond to medical or surgical treatments as its benefits outweigh its harms [21].

Omalizumab has been approved for use in CRSwNP in Korea. Gevaert et al. [36] conducted a phase 3 double-blind randomized controlled trial on the efficacy and safety of omalizumab. Similar to the aforementioned phase 3 trial on dupilumab (LIBERTY SINUS-24 and -52), this trial involved two groups. The study compared an experimental group, which received omalizumab and topical steroids at 2- or 4-week intervals, and a control group, which received topical steroids only. The experimental group was further divided into two groups (POLYP1 and POLYP2), following a replicate study design. A total of 138 patients in POLYP1 and 127 patients in POLYP2 showed nasal polyp scores ≥6 and SNOT-22 scores of approximately 60, indicating that severe CRSwNP significantly reduces the quality of life. The mean changes in the nasal polyp score for omalizumab vs. control from baseline at week 24 were -1.08 vs. 0.06 (95% CI -1.59 to -0.69, p<0.0001) in POLYP1 and -0.90 vs. -0.31 (95% CI -1.05 to -0.12, p=0.0140) in POLYP2, respectively. The mean changes for omalizumab vs. control in the nasal congestion score from baseline to week 24 were -0.89 vs. -0.35 (95% CI -0.84 to -0.25, p=0.0004) in POLYP1 and -0.70 vs. -0.20 (95% CI -0.80 to -0.19, p=0.0017) in POLYP2, respectively. Likewise, the mean changes in SNOT-22 score for omalizumab vs. control from baseline at week 24 were -24.7 vs. -8.6 (95% CI -21.86 to -10.38, p<0.0001) and -21.6 vs. -6.6 (95% CI -21.26 to -8.82, p<0.0001), respectively. These results indicate that omalizumab is significantly superior to the control treatment. While other studies have also reported positive results for omalizumab in terms of clinical symptom improvements, most of them examined a small number of patients with CRSwNP and failed to systematically analyze their results [37-41]. Furthermore, there is still a lack of studies investigating the changes in biomarkers following the administration of omalizumab.

According to the abovementioned phase 3 trial, 50.4% of all patients experienced at least one side effect of omalizumab, but most of them were tolerable and were not specific to omalizumab as similar side effects were observed in the control group [36]. Headache is the most common side effect of omalizumab (8%), followed by nasopharyngitis (6%), injection-site rash (4%), asthma aggravation (4%), abdominal pain (3%), joint pain (3%), lumbar pain (3%), dizziness (3%), and nasal bleeding (3%). Anaphylaxis may occur in rare cases.

ICAR 2021 states that omalizumab has an evidence level of B (verified by a small number of randomized controlled trials), which weakly recommends it as a treatment option for patients with severe CRSwNP accompanied by uncontrolled allergic asthma.

Mepolizumab and reslizumab inhibits IL-5, which is a major driver of type 2 inflammation, and benralizumab targets IL-5Rα. Therefore, mepolizumab, reslizumab, and benralizumab can regulate the eosinophils activation and survival theoretically. However, few studies have systematically examined the effects of mepolizumab, reslizumab, and benralizumab on rhinosinusitis. Recently, Han et al. [42] reported that mepolizumab treatment improved nasal polyp size and nasal obstruction compared with control among 407 patients with recurrent, refractory severe CRSwNP in phase 3 study. This suggest that mepolizumab provides an effective add-on treatment option in recurred cases after the surgical treatment.

Studies have reported that mepolizumab effectively reduces the nasal polyp size [43] and risk of reoperation [44] in severe CRSwNP. ICAR 2021 states that the evidence level for mepolizumab is C and recommends it for severe CRSwNP accompanied by poorly controlled eosinophilic asthma.

Reslizumab has an evidence level of C based on a randomized controlled trial reporting that it reduces the nasal polyp size in patients with CRSwNP [45]. Reslizumab may be considered as a treatment option for severe CRSwNP accompanied by poorly controlled eosinophilic asthma [21].

A recent phase 3 trial (OSTRO) of benralizumab in severe CRSwNP were conducted and presented [46]. Benralizumab significantly reduced nasal polyp score and nasal blockage score compared with control group. In subgroup analysis, comorbid asthma and higher eosinophil counts were associated with greater effect and with asthma being the strongest predictor.

Hellings et al. [47] reviewed phase 2 and 3 trials on CRSwNP and compared the effects of several biologics. Although the direct comparison was not easy because of the methodological heterogeneity among the clinical trials, all biologics showed positive effects compared to the control treatment, with slight differences among themselves. Peters et al. [48] reported that dupilumab had consistently greater improvements in outcomes versus omalizumab at week 24 in indirect treatment comparison of biologics in CRSwNP. Also, greater improvements in nasal polyp scores were observed after 52 weeks of dupilumab administration compared to that with omalizumab [47]. However, even in the case of dupilumab, which achieved the greatest improvements, the nasal polyp scores were decreased from 5.64 to 3.75 in 24 weeks group and also decreased from 6.18 to 4.46 in 52 weeks group with clinically insignificant changes from baseline. In contrast, dupilumab achieved the highest improvement while mepolizumab and omalizumab achieved considerable improvements in terms of symptom improvement based on SNOT-22 scores. In detail, the SNOT-22 scores were decreased from 48.00 to 18.58 in 24 weeks group of dupilumab, from 51.01 to 23.89 in 52 weeks group of dupilumab, from 51.50 to 28.80 in mepolizumab, from 59.80 to 35.10 in POLYP1 group of omalizumab, and from 59.20 to 37.61 in POLYP2 group of omalizumab, respectively.

A previous study demonstrated that dupilumab is superior to mepolizumab and omalizumab in restoring the sense of smell. Improvements in the sense of smell were observed within 2–3 months of dupilumab administration, and the sense of smell was maintained thereafter [31]. Radiological comparison using LM scores could not be concluded because of a lack of studies measuring them.

Based on these findings, dupilumab is superior to other biologics in terms of improvements in nasal polyp scores and sense of smell. All biologics, including dupilumab, omalizumab, and mepolizumab, effectively improved the quality of life.

The choice of biologics for CRSwNP often depends on whether a biologic has been approved for use in a country. There is a lack of information on detailed indications of biologics, optimal choices of biologics based on clinical situations, or whether one biologic is more effective than the others. More follow-up studies are expected to be published in the near future. Furthermore, it may be difficult to use biologics on a wide scale in Korea because the Korean insurance system does not cover them, resulting in financial burden on patients. Additionally, the long-term efficacy of biologics has not been thoroughly examined. Future studies are needed, which elucidate the use of biologics in clinical treatments based on basic immunological research.

As mentioned by the EPOS 2020, the indications for and efficacy of biologics are clinically determined. However, since the prevalence of type 2 inflammation and the histopathological and immunological characteristics of CRSwNP differ between Korea and the Western countries [49], the indications and evaluation criteria proposed by the EPOS 2020 may not be directly applicable in Korea. The evaluation criteria that account for the characteristics of type 2 inflammation in the Korean population must be developed. The clinical criteria for a treatment response suggested by the EPOS 2020 are also abstract and ambiguous, and there is no international consensus on how to evaluate the treatment response. Other objective criteria based on blood parameters or endoscopic/radiographic results are needed.

In one of the phase 3 trials, biologics were administered at 2- or 4-week intervals for 24 or 52 weeks. However, it is impractical to apply the same administration period and interval to all patients in an actual clinical situation, because factors—such as symptoms, severity, and compliance—must be considered. A detailed protocol must be established to determine whether the efficacy of biologics remains the same regardless of when it is administered (before or after surgery), the appropriate administration timing, and whether alternating or repeated administration of biologics is possible. It is also essential to establish how to adjust the dose and duration of administration during the maintenance period according to the patient’s condition. All these challenges with the use of biologics for CRSwNP would become valuable research topics in the future.

Other immunological mechanisms of biologics, aside from the inhibition of type 2 inflammation, such as the inhibition of type 1 inflammation and regulation of epithelial-derived cytokines (e.g., IL-25, IL-33, and TSLP), as well as B cells that have not undergone IgE isotype switching may be considered [50]. While basic research is actively being conducted on these topics [51-54], further clinical research is needed until the biologics using these mechanisms can be practically used. Whether these biologics can inhibit upstream mechanisms and regulate signaling pathways will be elucidated in the future.