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Abstract

Objective:

This study aimed to determine the prevalence, subtypes, and control status of chronic rhinosinusitis (CRS) among patients with severe asthma receiving biologic therapy in a tertiary allergy clinic.

Methods:

A single-center, cross-sectional observational study was conducted in adult patients with severe asthma receiving biologics for at least 6 months. CRS diagnosis and control were assessed based on European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) 2020 criteria. The Sinonasal Outcome Test-22 (SNOT-22) was also administered. Statistical analyses were performed using appropriate univariate and multivariate methods.

Results:

Among 148 patients with severe asthma receiving biologic therapy, 97 (65.5%) were diagnosed with comorbid CRS. Of these, 68 (45.9%) had CRS with nasal polyps (CRSwNP) and 29 (19.5%) had CRS without nasal polyps (CRSsNP). A total of 54 patients (55.6%) were treated with omalizumab and 43 (44.3%) with mepolizumab. Overall, 32.9% of patients had controlled CRS, 36.0% were partly controlled, and 30.9% were uncontrolled. In multivariable ordinal regression analysis, the presence of N-ERD and higher BMI were associated with poorer CRS control, whereas early-onset asthma and prior maintenance systemic corticosteroid use were associated with better control, suggesting that these factors may be related to CRS control status in this population.

Conclusions:

CRS is highly prevalent among patients with severe asthma receiving biologics, and approximately one-third remain uncontrolled despite treatment. These findings emphasize the importance of regular upper airway assessment and may inform future strategies for optimizing biologic selection and treatment outcomes in this population.

Keywords

rhinosinusitis asthma nasal polyps biologics omalizumab mepolizumab

Introduction

Chronic rhinosinusitis is a prevalent upper respiratory tract condition characterized by persistent inflammation of the sinonasal cavities.¹ It is commonly classified into 2 subtypes as CRSwNP and CRSsNP. Patients with CRSwNP predominantly exhibit a type 2 inflammation pattern, marked by eosinophilia and elevated levels of immunoglobulin E (IgE), interleukin-4 (IL-4), IL-5, and IL-13.² Stratifying CRS based on endotype can facilitate personalized treatment approaches by targeting the specific pathophysiological mechanisms underlying the condition in each patient.^1,3

The incidence of CRS is estimated to be between 6% and 15% in the general population.⁴ Asthma is commonly associated with CRS, particularly in patients with CRSwNP, with prevalence rates ranging from 30% to 70%. The frequency of CRSwNP in asthma correlates with disease severity; while CRSwNP occurs in 10% to 30% of individuals with mild asthma, this rate increases to 70% to 90% in those with severe asthma.^5,6 Recent advancements in biologics for severe asthma have also highlighted their potential in treating CRSwNP, supported by high-level evidence from recent studies.⁵ However, accurately defining disease control and severity in CRS is crucial for both selecting appropriate treatments and for effective follow-up. The 2020 EPOS update redefined CRS control by incorporating the visual analog scale (VAS) to assess symptom severity in research settings and encouraged further investigation on this topic.¹

At our tertiary allergy clinic, many patients with severe asthma receiving biologics also have comorbid CRS, consistent with prior reports. This cross-sectional study aims to determine the prevalence and subtypes of CRS among patients with severe asthma receiving biologics at our center, to evaluate the level of CRS control, and to identify factors associated with CRS control status.

Materials and Methods

Study population and data collection: This single-center, cross-sectional, observational study was conducted between January 1 and February 28, 2022, at the Department of Immunology and Allergy, Ankara University Faculty of Medicine. Patients aged 18 years or older with a diagnosis of CRS who had been receiving biologics for severe asthma for more than 6 months were eligible for inclusion. All participants had demonstrated clinical benefit from biologics based on standard asthma response criteria⁷ and had continued therapy accordingly. At the time of data collection, all patients were receiving regular medium- or high-dose inhaled corticosteroids in combination with additional controller medications for asthma, as well as intranasal corticosteroids for CRS, in line with international guidelines.^1,7 Data were collected during a single outpatient visit using a combination of electronic hospital records and structured face-to-face interviews. All relevant information was recorded in a standardized case report form (Supplemental Form 1).

Definition of severe asthma: Severe asthma was defined according to the Global Initiative for Asthma (GINA) guidelines for difficult-to-treat and severe asthma. It is characterized by poor symptom control, which includes frequent symptoms, increased reliever use, activity limitation due to asthma, and nighttime waking caused by asthma. Additionally, frequent exacerbations (2 or more per year requiring corticosteroids, or 1 or more serious exacerbations requiring hospitalization) indicate uncontrolled asthma. Severe asthma is a subgroup of patients who remain uncontrolled despite adherence to optimal therapy and treatment of contributory factors, or whose condition worsens when high-dose treatment is decreased.^8,9

Definition of non-steroidal anti-inflammatory drug exacerbated respiratory disease (N-ERD): N-ERD was defined as a clear history of respiratory symptoms developing within 1 to 2 hours after ingestion of a non-steroidal anti-inflammatory drug.¹⁰

Selection and dose of biologics: The choice of biologic was made in accordance with current international guidelines and national reimbursement criteria for severe asthma management, considering each patient’s clinical phenotype, biomarker profile, and comorbidities. At the time the study was conducted, omalizumab and mepolizumab were covered under the national reimbursement program. Omalizumab was prescribed to patients with documented perennial allergic sensitization and baseline serum IgE levels within the approved dosing range. The dose was calculated according to the manufacturer’s recommendations, based on body weight and baseline IgE level, and administered subcutaneously every 2 or 4 weeks at a total dose ranging from 150 to 750 mg. Mepolizumab was selected for patients with an eosinophilic phenotype, defined by elevated peripheral blood eosinophil counts and was administered as 100 mg subcutaneously every 4 weeks. Due to the biologic selection criteria, all patients in the cohort had type 2 inflammation, as evidenced by eosinophilia and/or atopy.

Chronic rhinosinusitis diagnosis: The diagnosis was made when nasal congestion and/or mucopurulent nasal or postnasal discharge was accompanied by additional symptoms such as facial pain, headache, and/or loss of smell for more than 12 weeks, and confirmed by objective findings on paranasal sinus computed tomography (CT) and/or nasal endoscopy.^1,3 The subtype of CRS was determined based on the results of nasal endoscopy and/or paranasal sinus CT.

Chronic rhinosinusitis control parameters: Control status was evaluated according to EPOS 2020.¹ Each patient was evaluated for nasal blockage, rhinorrhea/postnasal drip, facial pain/pressure, sense of smell, and sleep disturbance/fatigue using a 10 cm VAS scale. Symptoms with a VAS above 5 were considered present, while those with a score of 5 or less were regarded as absent or not bothersome. Rescue treatment was defined according to EPOS 2020 criteria as short courses of systemic corticosteroids and/or antibiotics prescribed for CRS exacerbations. Information was obtained through structured patient interviews and review of electronic medical records whenever available. The condition was classified as controlled if all parameters were absent, partly controlled with the presence of at least 1, and uncontrolled if 3 or more parameters were present.¹

Sinonasal Outcome Test-22 (SNOT-22): The Turkish-validated SNOT-22 questionnaire was administered by patients during face-to-face interviews and recorded. The questionnaire consists of 22 items, with patients rating each item from 0 (no problem) to 5 (worst problem). The total score ranges from 0 to 110, with higher scores indicating a poorer quality of life.¹¹

Ethical approval and informed consent: This study was approved by the Ankara University Faculty of Medicine Ethics Committee (approval number: İ3-162-20). Patients who provided written informed consent after receiving a detailed explanation of the study were included.

Statistical analysis: Statistical evaluation was made with SPSS version 14 (SPSS Inc., Chicago, IL, USA). The Kolmogorov-Smirnov test was used to assess the assumption of normality. Normally distributed continuous variables are expressed as mean ± standard deviation and continuous variables that did not have normal distribution are expressed as median (minimum-maximum). Categorical variables are presented as frequencies (n) and percentages (%). Comparisons between independent groups were made using the chi-square test for categorical variables, the Mann–Whitney U test for non-normally distributed continuous variables, and one-way analysis of variance (ANOVA) or the Kruskal–Wallis test where appropriate. No missing data were observed for outcome measures or covariates included in the analyses; therefore, all statistical analyses were performed using complete-case data without imputation. Multivariable ordinal logistic regression analysis was performed to evaluate factors associated with CRS control status. A parsimonious model was constructed based on univariate analyses and clinical relevance. Model assumptions, goodness-of-fit, and multicollinearity were systematically assessed. To address potential confounding related to differences in biologic exposure duration, time on biologic therapy was additionally evaluated in sensitivity analyses and treated as a continuous variable. Additional exploratory subgroup analyses were performed to evaluate CRS control status and SNOT-22 scores according to N-ERD status and CRS subtype (CRSwNP vs CRSsNP), with effect sizes presented as odds ratios or mean differences with 95% confidence intervals.

Results

Study population and patients’ characteristics: An initial cohort of 161 patients receiving biologics for severe asthma was identified. Among them, 148 volunteers who completed 6 months of treatment were evaluated for the presence of CRS. Ninety-seven patients (65.5%) with a confirmed diagnosis of comorbid CRS were included in the study. Of these, 68 patients (45.9%) had CRSwNP, and 29 (19.5%) had CRSsNP. Flow chart of the study is presented in Figure 1. The majority of patients in our study were women (n = 67, 69%) and the mean age of the study group was 48.7 (±13.3) years. The mean age of asthma onset was 32.8 (±13) years. Fifty-four patients (55.7%) were atopic, and among them, 45 (46.3%) had perennial allergen sensitization. The median BMI for all patients was 27 (range 15-48.3). Additionally, 38 patients (39.1%) were classified as having N-ERD. In the overall cohort, 69 patients (71%) had a history of endoscopic sinus surgery (ESS); 36 had undergone more than 1 procedure (37%). The median time period between the last ESS and the evaluation was 6 years (range 1-19). Following initiation of biologics, 12 patients (12.4%) underwent ESS.

Figure 1.

Flow chart of the study.

Fifty-four patients (55.6%) were on omalizumab, and 43 patients (44.3%) were on mepolizumab treatment. The mean ages of the patients in these groups were 52.9 ± 12.5 years and 43.5 ± 12.5 years, respectively (P = .001). The median follow-up period for biologics at the time of evaluation for all patients was 24 months (range: 6-131 months). This period was longer in patients receiving omalizumab (51 months [range: 6-131] vs 14 months [range: 6-36], [P < .001]). Atopy (P = .02) and perennial allergen sensitization (P = .001) were more common in the omalizumab group, while absolute eosinophil count before biologics was higher in mepolizumab group (P = .03). Patients’ BMI was significantly higher in the omalizumab group compared to the mepolizumab group (median BMI: 27.8 vs 25.7, respectively; P = .01). Demographic and clinical characteristics of the study population are presented in Table 1.

Table 1.

Demographic and Clinical Characteristics of the Study Population.

Demographic and clinical characteristics	Total n = 97	Omalizumab n = 55	Mepolizumab n = 42	P ^a
Age, mean ± SD	48.7 ± 13.3	52.9 ± 12.5	43.5 ± 12.5	.001
Female, n (%)	67 (69.1)	41 (74.5)	26 (61.9)	.1
CRSwNP, n (%)	68 (70.1)	41 (75.9)	27 (70.1)	.23
CRSsNP, n (%)	29 (29.9)	13 (24.1)	16 (37.2)	.23
BMI, median(min-max)	27.1 (15-48)	27.8 (18-48)	25.7 (15-41)	.01
Age of asthma onset, mean ± SD	32.8 ± 13	34.6 ± 12.8	30.7 ± 13.2	.1
Atopy, n (%)	54 (55.7)	36 (66.7)	18 (41.9)	.02
Perennial allergen sensitization, n (%)	45 (46.3)	33 (61.1)	12 (27.9)	.001
N-ERD, n (%)	38(39.1)	20 (37)	18 (41.9)	.78
Follow up time on BT, months, median(min-max)	24 (6-131)	51 (6-131)	14 (6-36)	<.001
Serum total IgE ng/ml, median (min-max)	224 (4-2375)	210 (17-2375)	229 (4-1749)	.83
Absolute eosinophil count × 10⁶/L, before BT, median (min-max)	1020 (80-8400)	865 (80-8400)	1170 (300-6210)	.03
History of more than 1 ESS, n (%)	36 (37.1)	24 (44.4)	12 (27.9)	.14
CRS control status
Controlled	32 (32.9)	13(24.1)	19(44.2)
Partly controlled	35 (36)	23(42.6)	12(27.9)	.1
Uncontrolled	30 (30.9)	18(33.3)	12(27.9)
SNOT-22, median (min-max)	23 (3-86)	24 (3-64)	23(3-86)	.91

Note. Percentages for categorical variables represent column percentages. Bold values indicate statistically significant results (p < 0.05).

Abbreviations: BMI, body mass index; BT, biological treatment; CRS, chronic rhinosinusitis; CRSsNP, chronic sinusitis without nasal polyps; CRSwNP, chronic sinusitis with nasal polyps; ESS, endoscopic sinus surgery; IgE, immunoglobulin E; N-ERD, non-steroidal anti-inflammatory drug exacerbated respiratory disease; SNOT-22, 22-item sino-nasal outcome test.

Given for comparison of omalizumab and mepolizumab groups.

CRS control status: Overall, 32.9% of the cohort had controlled CRS, 36.0% were partly controlled, and 30.9% were uncontrolled. In the univariate analysis, several statistically significant associations were observed between clinical variables and CRS control status. Patients with controlled CRS had a significantly lower median age compared with partly controlled patients (P = .005), and a lower median body mass index (BMI) compared with uncontrolled patients (P = .01). Early-onset asthma was more frequent in the controlled group than in the partly controlled and uncontrolled groups (P < .001). Prior maintenance systemic corticosteroid use was more common among patients with controlled CRS compared with those with uncontrolled disease (P < .001). N-ERD was more common in uncontrolled CRS group without statistical significance. Although not statistically significant, the mepolizumab group had a numerically higher proportion of controlled CRS (44.2% vs 24.1%) and fewer uncontrolled cases (27.9% vs 33.3%) compared with the omalizumab group. Conversely, partly controlled CRS was more common with omalizumab (42.6% vs 27.9%). Overall, there was no significant difference in CRS control between omalizumab and mepolizumab groups. The distribution of CRS control categories is shown in Table 2 and Figure 2.

Table 2.

Relationship of Different Variables with EPOS CRS Control Status.

Patient characteristics	Controlled n = 32	Partly controlled n = 35	Uncontrolled n = 30	P
CRSwNP, n ( %)	20 (29.4)	23 (33.8)	25 (36.8)	.15
CRSsNP, n (%)	12 (41.4)	12 (41.4)	5 (17.2)	.15
Age, median (min-max)	40 (21-72)*	56 (19-73)*	49(31-74)	.005
Female, n (%)	25 (37.3)	20 (29.9)	22 (32.8)	.14
BMI, median(min-max)	24 (15-41)*	27 (20-48)	28 (20-40)*	.01
Early onset asthma, n (%)	9 (81.8)^a	1 (9.1)	1 (9.1)	<.001
Atopy, n (%)	17 (31.5)	20 (37.0)	17 (31.5)	.93
Perennial allergen sensitization, n (%)	15 (33.3)	14 (31.1)	16 (35.6)	.56
N-ERD, n (%)	9 (23.7)	12 (31.6)	17 (44.7)	.06
Serum IgE ng/ml, median (min-max)	197 (17-1365)	303 (18-2325)	190 (4-1749)	.41
Absolute eosinophil × 10⁶/L, before BT, median (min-max)	1150 (80-8400)	920 (170-5200)	995 (300-2900)	.4
Absolute eosinophil × 10⁶/L, at evaluation time, median (min-max)	140 (20-1360)	250 (0-1460)	375 (0-1500)	.1
Follow up time on BT, months, median(min-max)	17.5 (6-125)	31 (8-131)	26 (6-60)	.37
Maintanence OCS before BT, n (%)	20 (44.4)*	17 (37.8)	8 (17.8)*	.03
Maintanence OCS at evaluation time, n (%)	13 (41.9)	13 (41.9)	5 (16.1)	.09
Omalizumab, n (%)	13 (24.1)	23 (42.6)	18 (33.3)	.1
Mepolizumab, n (%)	19 (44.2)	12 (27.9)	12 (27.9)	.1
History of more than 1 ESS, n (%)	7 (19.4)	15 (41.7)	14 (38.9)	.09
SNOT-22, median (min-max)	12 (3-54)	20 (3-56)	41.5 (23-86)^a	<.001

Note. Percentages for categorical variables represent row percentages. Bold values indicate statistically significant results (p < 0.05).

Abbreviations: BMI, body mass index; BT, biological treatment; CRS, chronic rhinosinusitis; CRSsNP, chronic sinusitis without nasal polyps; CRSwNP, chronic sinusitis with nasal polyps; ESS, endoscopic sinus surgery; EPOS, European position paper on rhinosinusitis and nasal polyps; HDM, house dust mite; IgE, immunoglobulin E; NERD, non-steroidal anti-inflammatory drug exacerbated respiratory disease; OCS, oral corticosteroid; SNOT-22, 22-item sino-nasal outcome test.

Signed variable was found to be different from the other 2 variables.

The P-value of the significant difference between the 2 signed variables.

Figure 2.

Chronic rhinosinusitis control status of patients on omalizumab and mepolizumab treatments.

In multivariable ordinal logistic regression, the presence of N-ERD (OR = 2.27, 95% CI: 1.02-5.26, P = .046) and higher body mass index (BMI; OR = 1.08 per unit increase, 95% CI: 1.01-1.16, P = .037) were independently associated with poorer CRS control, whereas early-onset asthma (OR = 0.09, 95% CI: 0.02-0.51, P = .006) and prior maintenance systemic corticosteroid use (OR = 0.41, 95% CI: 0.19-0.92, P = .029) were independently associated with better CRS control. Age and sex were not independently associated with CRS control. These results are summarized in Table 3 and illustrated in Figure 3.

Table 3.

Multivariable Ordinal Logistic Regression Analysis of Factors Associated with CRS Control in Severe Asthma Patients Receiving Biologic Therapy.

Factors	Adjusted OR	95% CI	P-value
Age (per year)	0.98	0.95-1.02	.332
BMI (per kg/m²)	1.08	1.01-1.16	.037
Early-onset asthma (yes vs no)	0.09	0.02-0.51	.006
N-ERD (yes vs no)	2.27	1.02-5.26	.046
Prior maintenance OCS use (yes vs no)	0.41	0.19-0.92	.029
Sex (female vs male)	0.67	0.29-1.59	.370

Bold values indicate statistically significant results (p < 0.05).

Abbreviations: BMI, body mass index; CRS, chronic rhinosinusitis; N-ERD, NSAID-exacerbated respiratory disease; OCS, oral corticosteroids.

Figure 3.

Forest plot showing factors associated with CRS control in severe asthma patients receiving biologic therapy based on multivariable ordinal logistic regression analysis.

In sensitivity analyses, time on biologic therapy was additionally included as a continuous covariate in the multivariable model, which did not materially change the direction or magnitude of the observed associations. Similarly, in an analysis restricted to patients treated within the overlapping exposure window of 6 to 36 months (n = 49), no significant differences in CRS control status were observed between biologic agents. In exploratory subgroup analyses, N-ERD was significantly associated with poorer CRS control (ordinal OR = 2.46, 95% CI: 1.14-5.32; P = .022). CRS subtype showed a non-significant trend toward poorer control in CRSwNP compared with CRSsNP (ordinal OR = 2.04, 95% CI: 0.90-4.61; P = .086).

SNOT-22 scores: The median SNOT-22 score for the overall cohort was 23 (3-86). Median scores were 24 (3-64) in the omalizumab group and 23 (3-86) in the mepolizumab group, with no significant difference between the groups. The median SNOT-22 score was statistically similar in the controlled (12 [3-54]) and partly controlled (20 [3-56]) groups, but was higher in the uncontrolled group (41.5 [23-86]) than in either of the other groups (P < .001; Table 2). In additional subgroup analyses, patients with N-ERD had significantly higher SNOT-22 scores compared with those without N-ERD (mean difference = 9.78 points, 95% CI: 2.47-17.09; P = .009). No significant difference in SNOT-22 scores was observed between CRSwNP and CRSsNP (mean difference = −5.44 points, 95% CI: −13.44-2.57; P = .181).

Outcomes for CRSwNP and CRSsNP: Controlled, partly controlled, and uncontrolled CRS was present in 29.4%, 33.8%, and 36.8% of CRSwNP patients, and 41.4%, 41.4%, and 17.2% of CRSsNP patients, respectively. Although the control rate was higher and the uncontrolled rate was lower in the CRSsNP group, the difference was not statistically significant. At the time of assessment, VAS scores were similar between the 2 groups, except for the sense of smell score, which was significantly higher in CRSwNP patients (median 3 vs 0, P = .02). The median SNOT-22 scores were also similar between the CRSwNP and CRSsNP groups: 28 (range 3-86) versus 21 (range 5-64), respectively.

Discussion

This single-center, cross-sectional study describes the distribution of CRS control per EPOS 2020 among patients with severe asthma receiving biologic therapy. CRS was present in 65.5% of the cohort; within the CRS subgroup, 32.9% were controlled, 36.0% partly controlled, and 30.9% uncontrolled. These findings provide a real-world snapshot of CRS control in this population.

Chronic rhinosinusitis, as a common comorbidity of asthma, is associated with more severe disease.¹² Previous studies report CRS prevalence in asthmatics ranging from 26.8% to 40.6%, depending on disease severity and population.^13,14 Our finding of a 65.5% CRS prevalence in severe asthma patients aligns with this trend and underscores the importance of managing upper airway involvement in this group.

Our study was inspired by the cross-sectional design employed by van der Veen et al., although the patient populations, interventions, and follow-up durations differ substantially. Van der Veen et al. assessed CRS outcomes 3 to 5 years after sinus surgery and reported that approximately 19.5% of patients were well controlled, 36.8% were partly controlled, and 43.7% were uncontrolled. In our cohort of severe asthma patients receiving biologic therapy, 32.9% were controlled, 36.0% partly controlled, and 30.9% uncontrolled. While these results are not directly comparable due to methodological differences, both studies underscore the persistent challenge of achieving CRS control in clinical practice.

To date, omalizumab, mepolizumab and dupilumab have been approved by the FDA for the treatment of CRSwNP in patients unresponsive to standard therapies. All have been proven to improve disease-specific quality of life, dupilumab has also been shown to reduce disease severity.¹⁵ Real-world studies have reported that omalizumab improved symptom scores and/or the nasal polyp score (NPS) at 6 to 12 months in patients with CRSwNP and severe allergic asthma.^16,17 A recent randomized controlled trial also demonstrated that omalizumab reduces polyp tissue regeneration and decreases relapse frequency.¹⁸ Mepolizumab has been shown to improve SNOT-22 scores after 12 months of treatment.¹⁹ Real-life studies show that in patients with severe asthma and CRSwNP, biologic treatments (anti-IgE, anti-IL-5/R, anti-IL-4R) led to significant improvements in SNOT-22, VAS, and CT scores after 6 months.^20-22 However, due to the cross-sectional design of our study and the lack of baseline CRS control data prior to biologic initiation, it is not possible to draw definitive conclusions regarding the direct impact of biologic therapy on CRS symptom improvement in our cohort. Nonetheless, the observation that approximately two-thirds of patients had either controlled or partly controlled CRS, along with the low rate of endoscopic sinus surgery (12.4%) during follow-up, might suggest a favorable trend in CRS management under biologic treatment in real-life clinical practice.

There are limited data on CRS control among patients with severe asthma receiving biologics. In a prospective study of 40 patients with severe asthma who received omalizumab, mepolizumab, or benralizumab for 52 weeks, the proportion of patients with uncontrolled CRS decreased from 82.5% at baseline to 37.5% after treatment. Following treatment, 15% of patients achieved controlled CRS, 47.5% were partly controlled, and 37.5% remained uncontrolled.²³ The proportion of patients with uncontrolled CRS on biologics was 30.9% in our study, closely aligning with the post-treatment outcomes reported in this study.

In multivariable analysis, early-onset asthma and prior maintenance oral corticosteroid use were independently associated with better CRS control, whereas N-ERD and higher BMI were independently associated with poorer CRS control (Table 3, Figure 3). Although age-related differences in inflammatory profiles and treatment responsiveness have been reported previously,^24,25 age was not independently associated with CRS control in our cohort after multivariable adjustment, despite showing an association in univariate analyses. Early-onset asthma, typically associated with allergic sensitization and type 2 inflammation, is known to respond more favorably to corticosteroids and anti-IgE therapy.^26,27 This may support the united airway hypothesis and the effectiveness of biologics targeting type 2 inflammation in this subgroup. The observation that patients with prior OCS use were more likely to have controlled CRS may also reflect a steroid-responsive disease profile. In addition, our findings are consistent with prior evidence linking higher BMI to worse CRS outcomes, possibly due to the pro-inflammatory effects of obesity and its association with non-type 2 inflammation.²⁸ Lastly, the presence of N-ERD was independently associated with poorer CRS control, which is consistent with previous evidence linking N-ERD to more severe and treatment refractory CRS.²⁹ Subgroup analyses also suggested higher symptom burden and poorer control among patients with N-ERD, consistent with these observations. While these findings are exploratory, they may inform future hypotheses regarding clinical and biological predictors of CRS control in patients with severe asthma receiving biologic therapy.

In patients with severe asthma, the selection of biologic therapies is guided by current international guidelines and limited to agents approved for use in our country. The higher prevalence of atopy and perennial allergen sensitization in the omalizumab group, along with the elevated eosinophil counts observed in the mepolizumab group, likely reflects an endotype-driven approach to biologic prescribing in our cohort. The longer duration of biologic use in the omalizumab group is presumably due to its earlier national approval and wider availability. Nevertheless, sensitivity analyses accounting for treatment duration yielded similar findings, suggesting that differences in biologic exposure time may not have affected the main results. Additionally, while most existing literature and therapeutic indications primarily focus on CRSwNP, this study also included patients with CRSsNP, who similarly exhibited features of type 2 inflammation. This highlights the need to recognize CRSsNP as part of the type 2–high airway disease spectrum and to ensure its inclusion in future clinical studies and treatment strategies. Future longitudinal studies with larger cohorts may benefit from applying propensity score–based or weighting approaches to better address confounding by indication in comparative analyses of biologic therapies.

This study has several limitations. First, its single-center, cross-sectional design permits only observational associations and does not allow for conclusions about causality. The absence of standardized data on CRS control prior to biologic initiation limits the ability to assess treatment-related changes over time. Additionally, CRS control was evaluated primarily through patient-reported outcomes, without objective radiologic or endoscopic confirmation, which may introduce subjective bias. Although information on rescue treatment was supported by medical record review whenever possible, some degree of recall bias related to patient-reported data cannot be completely excluded. Moreover, at the time of data collection, only omalizumab and mepolizumab were licensed and reimbursed in our country; therefore, the potential effects of other biologic agents, such as dupilumab or benralizumab, could not be assessed. Although sensitivity analyses accounted for treatment duration, differences in biologic exposure time between groups cannot be completely excluded as a potential source of residual confounding.

Nevertheless, this study offers a valuable real-world snapshot of CRS control among patients with severe asthma receiving biologic therapy in a considerable number of patients for this specific clinical population. As the concept of disease control gains prominence in the management of chronic airway diseases, routine assessment of CRS status becomes increasingly relevant in optimizing outcomes. Furthermore, the observation that CRS may remain uncontrolled despite well-controlled asthma highlights the need for independent evaluation of upper airway disease during follow-up. In selected cases, persistent CRS symptoms could prompt clinicians to reconsider the adequacy of current biologic therapy and potentially explore switching strategies.

In conclusion, this real-life observational study underscores the high prevalence of comorbid CRS among patients with severe asthma receiving biologics, and reveals that CRS control remains suboptimal in approximately one-third of patients. These findings highlight the importance of routinely evaluating upper airway disease alongside asthma management and suggest that future longitudinal and multicenter studies are warranted to identify predictive factors and optimize biologic selection for comprehensive airway control.

Supplemental Material

sj-docx-1-aor-10.1177_00034894261434347 – Supplemental material for Control Status of Chronic Rhinosinusitis in Severe Asthma Patients Receiving Biologics: A Real-World Cross-Sectional Study

Supplemental material, sj-docx-1-aor-10.1177_00034894261434347 for Control Status of Chronic Rhinosinusitis in Severe Asthma Patients Receiving Biologics: A Real-World Cross-Sectional Study by Sevgi Çolak, Zeynep Çelebi Sözener, Ömür Aydin, Mustafa Çolak, Sevim Bavbek, Betül Ayşe Sin, Yavuz Selim Demirel and Dilşad Mungan in Annals of Otology, Rhinology & Laryngology

Footnotes

ORCID iDs

Sevgi Çolak

Ömür Aydin

Mustafa Çolak

Sevim Bavbek

Betül Ayşe Sin

Dilşad Mungan

Ethical Considerations

This study was approved by the Ankara University Faculty of Medicine Ethics Committee (approval number: İ3-162-20), and informed consent was obtained from all participants.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.*

Supplemental Material

Supplemental material for this article is available online.

References

Fokkens

Lund

Hopkins

, et al. EPOS 2020. ORL-HNS. 2020;29:1-464.

Hopkins

Chronic rhinosinusitis with nasal polyps. N Engl J Med. 2019;381(1):55-63. doi:10.1056/NEJMcp1800215

Orlandi

Kingdom

Smith

, et al. International consensus statement on allergy and rhinology: rhinosinusitis 2021. Int Forum Allergy Rhinol. 2021;11(3):213-739. doi:10.1002/alr.22741

Hirsch

Stewart

Sundaresan

, et al. Nasal and sinus symptoms and chronic rhinosinusitis in a population-based sample. Allergy. 2017;72(2):274-281. doi:10.1111/all.13042

Fokkens

Lund

Bachert

, et al. EUFOREA consensus on biologics for CRSwNP with or without asthma. Allergy. 2019;74(12):2312-2319. doi:10.1111/all.13875

Çelebi Sözener

Özdel Öztürk

Aydın

Bavbek

Mungan

. Overview of asthma patients followed up in a tertiary clinic. Eur Ann Allergy Clin Immunol. 2023;55(06):283-293. doi:10.23822/EurAnnACI.1764-1489.256

2024 GINA Main Report - Global Initiative for Asthma - GINA. https://ginasthma.org/2024-report/

2019 GINA Main Report - Global Initiative for Asthma - GINA. https://ginasthma.org/gina-reports/

2024 Diagnosis and Management of Difficult-to-treat and Severe Asthma - Global Initiative for Asthma - GINA. https://ginasthma.org/wp-content/uploads/2024/11/GINA-Severe-Asthma-Guide-2024-WEB-WMS.pdf

10.

Kowalski

Agache

Bavbek

, et al. Diagnosis and management of NSAID-exacerbated respiratory disease (N-ERD)-a EAACI position paper. Allergy. 2019;74(1):28-39. doi:10.1111/all.13599

11.

Hancı

Altun

Şahin

Altıntoprak

Cingi

Turkish translation, cross-cultural adaptation and validation of the sinonasal outcome test (SNOT)-22. ENT Updates. 2015;5(2):51-57. doi:10.2399/jmu.2015002001

12.

Bresciani

Paradis

Des Roches

, et al. Rhinosinusitis in severe asthma. J Allergy Clin Immunol. 2001;107(1):73-80. doi:10.1067/mai.2001.111593

13.

Haselkorn

Chen

Miller

, et al. Asthma control and activity limitations: insights from the real-world evaluation of asthma control and treatment (REACT) study. Ann Allergy Asthma Immunol. 2010;104(6):471-477. doi:10.1016/j.anai.2010.04.006

14.

Canonica

Malvezzi

Blasi

, et al. Chronic rhinosinusitis with nasal polyps impact in severe asthma patients: evidences from the severe asthma network Italy (SANI) registry. Respir Med. 2020;166:105947. doi:10.1016/j.rmed.2020.105947.

15.

Chong

Piromchai

Sharp

, et al. Biologics for chronic rhinosinusitis. Cochrane Database Syst Rev. 2021;3(3):CD013513. doi:10.1002/14651858.CD013513.pub3

16.

Ruiz-Hornillos

Rodríguez Jiménez

Feliu Vila

Moreno Fernández

Hernández García

Domínguez-Ortega

Omalizumab as a therapeutic option for nasal polyposis in moderate-to-severe persistent allergic asthma: evidence from a prospective study in a real-world setting. J Investig Allergol Clin Immunol. 2020;30(6):470-472. doi:10.18176/jiaci.0602

17.

Tiotiu

Oprisanu

Rusu

, et al. Effectiveness of omalizumab in severe allergic asthma and nasal polyposis: a real-life study. J Investig Allergol Clin Immunol. 2020;30(1):49-57. doi:10.18176/jiaci.0391

18.

Noeiaghdam

Esmaeilzadeh

Faramarzi

, et al. Omalizumab efficacy in chronic rhinosinusitis patients with recurrent nasal polyps: an open-label, single-center, randomized, controlled study. Ann Otol Rhinol Laryngol. 2025;134:692-702. doi:10.1177/00034894251344426

19.

Detoraki

Tremante

D’Amato

, 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. Ther Adv Respir Dis. 2021;15:1-11. doi:10.1177/17534666211009398

20.

Mümmler

Dünzelmann

Kneidinger

, et al. Real-life effectiveness of biological therapies on symptoms in severe asthma with comorbid CRSwNP. Clin Transl Allergy. 2021;11(5):1-5. doi:10.1002/clt2.12049

21.

Bajpai

Marino

Rank

Donaldson

O’Brien

Lal

Benefits of biologic therapy administered for asthma on co-existent chronic rhinosinusitis: a real-world study. Int Forum Allergy Rhinol. 2021;11(8):1152-1161. doi:10.1002/alr.22774

22.

Demir

Tunakan Dalgic

Mete Gokmen

, et al. The effectiveness of biological agents on chronic rhinosinusitis with nasal polyposis in patients with comorbid asthma: a multicenter real-life study from Türkiye. Medicina (Kaunas). 2024;60(3). doi:10.3390/medicina60030448

23.

Bandi

Gallo

Preti

, et al. Effects of biological therapies on chronic rhinosinusitis in severe asthmatic patients. Acta Otorhinolaryngol Italica. 2020;40(6):435-443. doi:10.14639/0392-100X-N0716

24.

Vaitkus

Vitkauskienė

Simuntis

Vaitkus

Šiupšinskienė

Vaitkus

Chronic rhinosinusitis with nasal polyps: age and disease severity differences in the levels of inflammatory markers. Medicina (Kaunas). 2021;57(3). doi:10.3390/medicina57030282

25.

Ryu

Dhong

Park

, et al. Age-associated changes in chronic rhinosinusitis endotypes. Clin Exp Allergy. 2020;50(5):585-596. doi:10.1111/cea.13586

26.

Kaur

Chupp

Phenotypes and endotypes of adult asthma: moving toward precision medicine. J Allergy Clin Immunol. 2019;144(1):1-12. doi:10.1016/j.jaci.2019.05.031

27.

Darcey

Qualtrough

Difficult-to-treat & severe asthma in adolescent and adult patients. Gina. 2019;214(10):493-509. doi:10.1038/sj.bdj.2013.482

28.

Jung

Park

Kim

Yeo

SG.

Role of obesity in otorhinolaryngologic diseases. Curr Allergy Asthma Rep. 2019;19(7):34. doi:10.1007/s11882-019-0865-3

29.

Lilja

Koskinen

Virkkula

, et al. Factors affecting the control of chronic rhinosinusitis with nasal polyps: a comparison in patients with or without NERD. Allergy Rhinol. 2021;12:21526567211003844. doi:10.1177/21526567211003844