Introduction
Chronic rhinosinusitis (CRS) is an important clinical problem in otolaryngology due to its significant impact on the quality of life and health of the population [1]. Despite the growing awareness about the diagnosis and treatment of this disease, its actual prevalence is not yet well described [2]. Non-pathogenicity and low specificity of existing clinical criteria for diagnosis, the complexity of differential diagnosis of CRS (allergic/non-allergic rhinitis), incomplete examination at the outpatient level are factors that complicate diagnosis and treatment of the condition. Its formation is influenced by both local and systemic factors [3]. The prevalence of PRS in Europe and the USA is 11–15%. The disease significantly affects the quality of life of patients, reduces their socio-economic activity, which in turn leads to serious problems of the healthcare system [2].
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease of the mucous membrane of the nose and adjacent cavities, characterized by transformation of the mucosa, including capillary circulation, involvement of secretory gland cells, the formation and repeated growth of polyps, which arise from lymphadenoid swelling tissue cells, eosinophils and neutrophils [4].
Nasal polyps are swollen overgrowths of the mucous membrane in the paranasal sinuses, resulting from long-term inflammation. They are found in 20% of individuals with CRS. Common symptoms of nasal polyps include nasal congestion, obstruction of nasal canals, and loss or reduction of smell (anosmia or hyposmia). They are more commonly seen in patients with chronic asthma, aspirin-exacerbated respiratory disease (AERD), CRS, and cystic fibrosis [5].
The frequency of CRSwNP is between 2% and 4% worldwide, and it frequently coexists with type 2 inflammation and asthma. Currently regarded as typified by continuous inflammation that is an excessive immunological response to external stimuli. Over the last 20 years, there has been a significant change in the medical and surgical treatment of CRS [6]. IgE is the oldest target of biological agents, which is also considered a biomarker of T2 inflammation, as high levels of IgE can increase the inflammatory response from mast cells and basophils. The ultimate goal of anti-IgE treatment is to loosen the binding of basophils to IgE and replace them with new basophils that will not be sensitized to Ig and therefore will not lead to a distorted inflammatory response [7–9].
In the treatment of CRSwNP, glucocorticoids are considered a traditional and effective therapeutic drug because they potentially promote the expansion and function of Tregs. However, its effects on Tregs in different kinds of CRS need to be further studied. Monoclonal antibodies are a promising therapeutic option because they can block specific chemokines [10, 11].
The research evidence highlights an existing strong connection between CRSwNP and asthma, emphasizing the shared inflammatory mechanisms in both the nasal and bronchial airways. Studies have shown a direct correlation between the inflammatory profiles of nasal and bronchial biopsies in CRSwNP patients, reinforcing the idea of a “united airways” concept [12]. This concept suggests that inflammation in the nasal mucosa and lower airways is interconnected, a phenomenon that has been observed not only in CRSwNP patients but also in asthma patients who also have comorbid allergic rhinitis. This united airways concept plays a crucial role in understanding the pathophysiology of asthma and CRSwNP and may influence how these conditions are treated, suggesting that therapeutic strategies targeting both the nasal and bronchial airways might be more effective for patients with these comorbid conditions [13].
Many studies have presented data advocating the use of biological therapies for CRSwNP, particularly focusing on treatments targeting type 2 inflammation, which is a key factor in the pathophysiology of CRSwNP and related conditions [14]. Dupilumab is indicated as an effective biologic currently approved by both the US FDA and the European Medicines Agency (EMA) for use as an add-on maintenance treatment in adult patients with inadequately controlled CRSwNP. This monoclonal antibody targets IL-4Rα, which plays a crucial role in the inflammatory process [15, 16].
Other biologic therapies that have shown promise in reducing nasal polyp size, nasal congestion, and improving other CRSwNP symptoms include omalizumab, an anti-IgE monoclonal antibody, which is FDA-approved for treating allergic asthma and chronic idiopathic urticaria, and mepolizumab, an anti-IL-5 antibody, which is FDA-approved for treating asthma and eosinophilic granulomatosis with polyangiitis [17]. A subgroup analysis of pooled data from two phase 3 studies of omalizumab found improvements in nasal polyp size and congestion in patients with and without AERD [18].
Given the high rate of polyp recurrence following endoscopic sinus surgery, the optimization of post-surgical management is of critical clinical importance in CRSwNP. Surgical intervention, while effective in improving sinus ventilation and removing inflammatory tissue, does not address the underlying immunopathology, especially in patients with type 2 inflammation. Therefore, adjunctive pharmacologic therapies, such as intranasal corticosteroids and biologics like omalizumab, are essential for maintaining long-term disease control, minimizing recurrence, and improving quality of life. Combining systemic or topical steroids with targeted biologic agents postoperatively offers a rational approach aimed at suppressing residual inflammation, modulating immune dysregulation, and achieving sustained remission in refractory or comorbid cases. This integrated strategy is especially relevant for patients with asthma or aspirin-exacerbated respiratory disease (AERD), in whom standard therapies often fail to provide lasting benefits.
The targeted use of biologics may have even greater benefits in patients who have both asthma and CRSwNP, as well as those with comorbid AERD. The ongoing research and use of these therapies offer a promising future for managing these complex conditions.
Aim
The aim of the presented study is to assess the comparative efficacy of CRSwNP therapy with combined use of steroids and a biologic agent, omalizumab.
Material and methods
Study participants
One hundred and four participants diagnosed with chronic rhinosinusitis who underwent excision of polyps were involved in two interventional groups of the randomized control study 20 days following the surgery. The patients received treatment at the “Immunology & Allergology Clinic” of Erebuni Medical Center and at the specialized ENT service of Shengavit Medical Center. This randomized clinical trial was conducted in February 2017 – March 2024. The first group (ST-group) included 56 patients who received 2 injections of Diprospan 1 ml (ORGANON HEIST, BV (Belgium)) with a 15-day interval, while the other group (STO) received initial injection of omalizumab (Xolair 300 mg, Prescribing Information. Genentech, Inc. and Novartis Pharmaceuticals Corporation) followed by a Diprospan injection with a 15-day interval and the second omalizumab dosage was received 15 days after the Diprospan injection. The treatment protocol was repeated in 6 months following the last injection of the first therapy session.
The inclusion criteria for patients were as follows: age 18–60 years, histologically confirmed diagnosis of CRSwNP (Eosinophilic polyps) and confirmed diagnosis of “bronchial asthma” for subgroup A, operated not earlier than 20 days before the study start date.
The exclusion criteria of the study included confirmed diagnosis of any disorder contraindicating the administration of agents used for the therapy, pregnancy and breastfeeding period, intolerance to therapy compounds, oncological diseases, previous therapy with monoclonal antibodies (within 6 months prior to the study), patients with other causes of nasal polyps (e.g. cystic fibrosis, ciliary dyskinesia) and documented recent history (within 6 months) of inadequate response (partial or non-response) to steroid therapy.
The randomization of patients was performed following enrolment and prior to the surgery. To maintain blinding, coded kits containing ST or combined agents were used to mask treatment assignment.
Assessment of the extent and severity of CRS
Sino-Nasal Outcome Test 22 (SNOT-22) is one of the most widely used quality-of-life instruments for sinonasal conditions [1–3] and is intended for populations of people with rhinosinusitis, rather than simply rhinitis. The SNOT-22 is a self-administered multiple-choice 22-item test that is usually scored with a simple summary score (0–5). This instrument assesses a broad range of health and health-related quality-of-life problems including physical problems, functional limitations, and emotional consequences. It is divided into 4 subscales or domains related to 4 different areas rhinological, ear/facial-related problems, sleep disorders and psychological issues. The extracted principal factors, referred to as “domains”, were named “nasal symptoms”, “otologic symptoms”, “sleep symptoms”, and “emotional symptoms”[19]. The minimal score is 0, the maximal – 110.
The severity of clinical symptoms was evaluated 3 times: at the baseline, 1 month and 24 months following the surgery. The individual item scores in SNOT-22 range from 0 to 5.
Assessment of skin functional properties
Assessment of skin functional properties was conducted using the multi-parameter skin analysis system, Dermalab Combo SkinLab (DermaLab® COMBO SkinLab, Denmark). Nasal membrane moisture was measured (determination of the degree of hydration of the epithelium). Similarly the TMWL-metry (determination of the level of trans-mucosal water loss) as an indicator of the nasal mucosa integrity was applied to assess transepidermal water loss (TEWL) critical for skin integrity. Additionally pH-metry (evaluation of mucosal membrane acid-alkaline balance) was performed. The study environment was designed according to research protocol requirements to ensure high accuracy of obtained data: the testing of the patient was performed in a special room (with a temperature of 24 ±2.00°C and a relative humidity of 50 ±10%). The patients spent at least 20 min in the room before the procedure, and had not applied any topical agents to the mucous membrane within the preceding 2 h prior to the tests.
Modified Lund-Mackay Postoperative Endoscopy Score (MLMES)
The modified Lund-Mackay Postoperative Endoscopy Score (MLMES) applies to all participants who previously underwent sinus surgery. It was used to assess the postoperative status of study participants. Each patient underwent anterior rhinoscopy assessment within 1 month after the surgery, then 12 and 24 months following the therapy baseline. MLMES encompasses the endoscopic appearances of all cavities (left and right maxillary, ethmoid, sphenoid and frontal sinuses and olfactory fossa) quantifying mucosal inflammation (0–6: 0 = normal mucosa, 1 = mild oedematous mucosa with patent cavity, 2 = severely oedematous mucosa with compromised cavity, 3 = mild polypoid mucosa with patent cavity, 4 = severe polypoid mucosa with compromised cavity, 5 = polyp confined within cavity, 6 = polyp extending beyond cavity), mucus (0–2: 0 = none, 1 = clear and thin, 2 = thick and eosinophilic) and purulent discharge (0–2: 0 = absent, 2 = present)). This system produces a score of 0–100. Draf III cavities are scored as two frontal sinuses separately. Non-pneumatized sinuses and intact sinuses that have not undergone surgery are scored as 0. The olfactory fossa is evaluated by assessing the cleft between the nasal septum and the middle turbinate anteriorly and the superior turbinate posteriorly [20].
Computed tomography of nasal sinuses
The CT scan was performed within 1 month after the operation, then 12 and 24 months after the therapy start. The patients underwent computed tomography of the paranasal sinuses using CT with standard parameters (Toshiba Prime 160). On each side, the significance of computed tomographic changes in the form of decreased transparency of the maxillary, frontal, sphenoid sinuses, anterior and posterior cells of the ethmoid labyrinth was assessed via the scale: 0 – normal, 1 – partial shading, 2 – complete shading of the sinus. Thus, the maximum score was 20, the minimum score was 0. The system includes an assessment of the optical density of the image in the projection of the polyp in the nasal cavity, darkening of the paranasal sinuses, and the ratio of the darkening area in the nasal cavity to the area of the nasal cavity on the frontal section [21].
Statistical analysis
Statistical data processing was performed using the statistical software package SPSS 23 (Statistical Package for Social Sciences 23) to determine any significant difference in pre- and post-interventional scores between the groups. For a comparative analysis of the group results (between the interventional and control groups) obtained before and after intervention, the Kolmogorov-Smirnov test was used revealing the pattern of data distribution, followed by the Student’s parametric test for the comparison of group means. When using the Student test for independent samples, the calculation depended on the statistical significance of differences in the variance of the compared groups.
Results
The socio-demographic characteristics for the groups are presented in Table 1. Average age of the study participants was 49.4 ±3.1 and 44.1 ±4.2 years old in clinical groups I and II respectively. Male patients were 30 (53.6%) and 21 (55.3%) and the BMI values were 24.9 ±2.1 kg/m2 and 24.3 ±2.3 kg/m2 in clinical groups I and II, respectively, reaching the highest limit of reference range for the normal weight. The smokers and former smokers were 21 (37.5%) and 14 (36.9%) in clinical groups I and II, respectively.
Table 1
Baseline characteristics of ST and STO groups
| Indicator | Group I N = 56 | Group II N = 48 |
|---|---|---|
| Age | 49.4 ±3.1 | 44.1 ±4.2 |
| Male | 30 (53.6%) | 21 (43.8%) |
| BMI | 24.9 ±2.1 | 24.3 ±2.3 |
| Smokers | 18 (32.1%) | 14 (29.1%) |
| Former smokers | 3 (5.4%) | 3 (6.25%) |
To estimate the efficacy of the implemented therapy methods (ST vs. STO), the comparison of data from primary and subsequent measurements as well as between group assessments were performed. Tables 1 and 2 show the shifts in clinical signs for both intervention groups before and after the ST and STO combined therapies (mean ± SD and CV coefficient of variation were estimated) respectively. Analysis of data derived from these two tables suggests that combined therapy resulted in a significant improvement of studied outcome parameters. According to the study results, the clinical manifestations of chronic RS that documented in the study had improved after the conducted therapies showing reliable changes in all assessed clinical and functional parameters.
In the course of the therapy, patients of group I had a reliable decrease of the SNOT-22 indicators (mean difference [MD] 40.37%, p < 0.001) at 12 months. However, after 24 months, the level of clinical manifestations was almost restored. The 12-month period assessment revealed the parametric values of patients of group I did not show reliable differences from the levels at study baseline [MD] 14.68%, p = 0.073).
The SNOT-22 indices of clinical group II had a pronounced tendency to decrease (MD = 81.98 %, p < 0.0001) at 12 months. The levels after 24 months showed reliable differences from the initial rates (MD = 75.23%, p < 0.0001).
In patients of group I, the assessment after 12 months of therapy resulted in a significant increase of MLMES parametric values (MD = 40%, p < 0.001) with an even more remarkable increase after 24 months (MD = 240%, p < 0.001) compared with the study baseline measures. Corresponding indicators in patients of group II after 12 months were similar (p = 1.00) and after 24 months were significantly decreased while comparing with study baseline (MD = 40%, p < 0.001) and similar to the control group (p = 1.0).
CT scan scores were changed after the applied therapy in both interventional groups. The percentage of deviation after treatment was 41.9% and 100% vs. 22.6% and 3.33% in group I and group II, respectively after 12 and 24 months of treatment. The significant increase was observed in group I after 12 months (p < 0.001) and after 24 months (p < 0.0001). In group II there was a remarkable decline of assessment scores (p = 0.032) after 12 months with a further decrease after treatment completion.
The evaluation of treatment results included also functional parameters (moisture, TMWL and pH) of the nasal mucous membrane to estimate its overall condition at the study baseline, 12 and 24 months after the intervention. The initial between group assessment did not reveal significant discrepancy of parametric values of moisture, TMWL and pH (p = 0.707, p = 0.914, and p = 0.923 for moisture, TMWL and pH, respectively). Insignificant increase in the moisture score was observed in group I and statistically significant between group difference was detected at the therapy completion (p < 0.0001) after 24 months (15.34% and 2.98% vs. 34.79% and 31.97% for groups I and II respectively at 12 and 24 months) (Table 3).
Table 2
Changes of parametric scores in ST and STO groups treated with different protocols
Table 3
Between group and within group analysis of changes of parameters in patients with complicated CRSwNP treated with steroid monotherapy and combined STO therapy
Reliable decline of TMWL scores was detected in group I, yet an improvement was registered in the scores of group II (16.51% and 5.25% in group I vs. 27.54% and 30.62% in group II after 12 and 24 months, respectively). The statistical analysis of intergroup data showed that post-treatment mean values of TMWL assessment were significantly different (p < 0.001).
The results of pH assessment were reliably increased (p < 0.01) with relatively lower scores in group I (by 8.17%, and 12.58% vs. 37.39% and 36.50% after 12 and 24 months in group I and group II, respectively).
Discussion
Chronic rhinosinusitis with nasal polyps continues to pose substantial management challenges due to its recurrent nature, impact on quality of life, and frequent association with type 2 inflammatory diseases such as asthma. While corticosteroids like Diprospan (a combination of betamethasone dipropionate and betamethasone sodium phosphate) remain a mainstay of treatment, limitations in achieving sustained symptom control have prompted the integration of biologic therapies. Omalizumab, a monoclonal antibody targeting IgE, has emerged as a valuable therapeutic addition due to its ability to modulate upstream allergic inflammation [22, 23].
The current study evaluated the comparative efficacy of Diprospan alone versus a combined regimen of Diprospan and omalizumab (STO protocol) in adult patients with CRSwNP who had previously undergone endoscopic sinus surgery. The combination therapy resulted in significant clinical improvements across both subjective (e.g., SNOT scores) and objective parameters (e.g., mucosal moisture, TEWL, pH-metry, endoscopic and radiological scores), suggesting that omalizumab enhances and prolongs the anti-inflammatory effects of corticosteroids [24].
A key contextual consideration is the post-surgical status of the study population. Surgery in CRSwNP is intended to reduce the inflammatory burden, restore sinus drainage, and facilitate the action of topical or systemic pharmacologic agents. There is growing evidence that biologic therapies such as omalizumab may be more effective when administered post-operatively. For example, Bachert et al. [25] and Gevaert et al. [26] demonstrated that biologic efficacy – measured by polyp score reduction and symptom improvement – was more pronounced in patients who had undergone sinus surgery prior to receiving biologics, likely due to improved drug access and reduced mucosal obstruction.
Conversely, biologic monotherapy in non-operated patients has shown comparatively modest results. In the SYNAPSE study, the use of mepolizumab was associated with significantly better outcomes in previously operated patients compared to surgery-naïve individuals [27]. Similarly, the OSTRO trial with benralizumab reported enhanced effects in those with a history of sinus surgery, especially in patients with eosinophilic inflammation and comorbid asthma [28].
Our findings are consistent with this paradigm. In our study, the STO group achieved superior outcomes across multiple domains, including mucosal integrity indicators such as TEWL and pH balance markers rarely improved with pharmacotherapy alone in non-operated patients. These data suggest that surgery followed by biologic therapy not only improves symptom control but may also support mucosal healing and long-term disease stabilization.
Omalizumab, specifically, offers several advantages in this setting. Its mechanism of action – blocking free IgE and preventing mast cell and basophil activation – targets a central pathway in allergic CRSwNP [29]. Compared to other biologics like mepolizumab (anti-IL-5) or dupilumab (anti-IL-4Rα), omalizumab is particularly suited for patients with high serum IgE and allergic sensitizations. Moreover, its established safety profile in asthma and chronic spontaneous urticaria supports its long-term use in ENT indications [30].
Despite these promising findings, this study has limitations. It lacked a placebo control and blinding, and did not include a non-operated patient group for direct comparison. Additionally, potential costs and side effects associated with biologic therapy were not assessed. Further large-scale, randomized controlled trials are necessary to confirm these findings and to better define the role of surgery in optimizing biologic therapy for CRSwNP.
Combining omalizumab with corticosteroids in the post-surgical treatment of CRSwNP yields superior clinical outcomes compared to corticosteroids alone. These results support a stepwise treatment model, where surgery is followed by targeted biologic therapy to achieve comprehensive and sustained disease control in severe or refractory cases.
Conclusions
The combination of omalizumab and Diprospan (STO protocol) demonstrates superior efficacy in the post-operative management of CRSwNP compared to corticosteroid monotherapy. Patients receiving the combined regimen showed greater clinical, functional, and structural improvements following surgery, indicating a synergistic effect between systemic corticosteroids and anti-IgE therapy. These findings suggest that adjunctive biologic therapy post-surgery can enhance recovery, reduce symptom recurrence, and maintain long-term disease control. Importantly, the addition of omalizumab enabled a reduction in cumulative steroid exposure, potentially lowering the risk of adverse effects. While further studies are needed to confirm long-term outcomes and cost-effectiveness, this approach appears to be a promising strategy for optimizing post-surgical care in severe or refractory CRSwNP cases.
