Sinonasal Intervention Reduces the Need for Pressure Equalization Tube Placement in Atopic Adults

ABSTRACT

Objectives

To determine the impact of management of upper airway atopic disease on middle ear and eustachian tube function in adults.

Methods

The TriNetX Research Network was queried to construct cohorts of adult patients with atopic disorders of the upper airway (defined by ICD‐10 codes for asthma, allergic rhinitis, and chronic rhinosinusitis with nasal polyposis) with concurrent eustachian tube dysfunction (ETD) undergoing medical or surgical intervention for their atopic disease, including monoclonal antibody (mAb) therapy (e.g., dupilumab, mepolizumab, omalizumab), topical nasal steroid spray (fluticasone propionate), functional endoscopic sinus surgery (FESS), septoplasty with inferior turbinate submucosal resection (BITSMR), and allergy immunotherapy. The primary measured outcome was the difference in the rate of pressure equalization tube (PET) placement before and after each intervention.

Results

FESS demonstrated an absolute risk reduction (ARR) of 10.0% (p < 0.05, 95% confidence interval [CI] 8.9%–11.1%), septoplasty/BITSMR 7.5% (p < 0.05, 95% CI 6.3%–8.7%), mAb 5.5% (p < 0.05, 95% CI 4.1%–6.8%), nasal steroid spray (fluticasone proprionate) 0.9% (p < 0.05, 95% CI 0.8%–1.0%), and allergy immunotherapy 2.4% (p < 0.05, 95% CI 1.5%–3.2%). Individually, the three mAb—dupilumab, mepolizumab, and omalizumab—exhibited ARR of 6.5% (p < 0.05%, 95% CI 4.8%–8.3%), 6.8% (p < 0.05, 95% CI 2.6%–11.0%), and 3.4% (p < 0.05, 95% CI 1.4%–5.4%), respectively, without significant differences in rates of PET placement among the three (p = 0.18).

Conclusion

Management of upper airway atopic disorders via both medical and surgical intervention is associated with improvement in middle function as measured by the need for PET placement.

Level of Evidence

3.

Surgical and medical management of atopic sinonasal diseases decreases the risk of middle ear disease and the subsequent need for pressure equalization tubes.

1. Introduction

The association between atopic conditions of the respiratory tract (allergic rhinitis, asthma, chronic rhinosinusitis with nasal polyposis [CRSwNP]) and diseases of the middle ear requiring pressure equalization tube (PET) placement, such as eustachian tube dysfunction (ETD) and otitis media with effusion (OME), has been well studied in the literature, especially in the pediatric setting [1, 2, 3]. The pathophysiology is thought to involve Th2‐mediated inflammatory changes to the soft tissue surrounding the distal eustachian tube (ET) causing edema and obstruction, ultimately resulting in the development of negative middle ear pressure and effusion [4]. Furthermore, pathologic evaluation of middle ear effusion and mucosa of the torus tubarius in atopic patients exhibits significantly higher levels of eosinophils and IL‐4 cytokines, suggesting that the impact of atopy goes beyond simple mechanical obstruction of the ET [5].

While PET placement remains the mainstay of treatment for patients with OME, including in patients with atopy, other therapies for underlying Th2‐mediated inflammatory conditions may yield positive results and potentially eliminate the need for invasive otologic procedures. In pediatric patients treated with intranasal corticosteroids, Crowson et al. demonstrated a significant reduction in the need for PET, and Bilgili et al. showed improved Eustachian Tube Scores (ETS‐7) and decreased adenoid prominence on endoscopy [6, 7]. Additionally, allergy immunotherapy remains a cost‐effective mainstay treatment for management of atopic disorders; Hurst et al. demonstrated that adult and pediatric patients on maintenance allergen immunotherapy had significantly improved symptoms and rates of OME, with allergen immunotherapy providing complete resolution of effusion and drainage in 85% of 127 ears and significant improvement in 5.5% [6, 7, 8].

In recent years, several novel monoclonal antibodies targeted at inflammatory mediators in the Th2 pathway have shown utility in the treatment of atopic diseases including asthma, eczema, eosinophilic esophagitis, and nasal polyposis. Several studies have explored the effect of these biologics on middle ear function, with some studies showing good patient response, albeit with small sample sizes [9, 10]. With continued advancement in the development and understanding of biologics for atopic conditions, there is an ongoing need to examine the impact of these targeted therapies on Th2‐related middle ear dysfunction.

Surgical management is frequently performed to address sinonasal inflammation and obstruction associated with multisystem atopic disease. Prior studies have suggested that septoplasty with inferior turbinate reduction and functional endoscopic sinus surgery (FESS) may have a role in middle ear ventilation [11]. The mechanism for how these procedures impact ET function is not well understood, but may be due to improved delivery of topical medications such as intranasal steroids or altering the impact of nasal airflow sensation on upper respiratory tract muscle tone.

TriNetX is a large, international, multi‐institutional database of anonymized electronic health records (EHRs). This platform was utilized to explore the relationship between medical and surgical interventions for atopic sinonasal disease and middle ear function, as measured by the incidence of OME and the need for PET placement in patients with allergic rhinitis, allergic asthma, and CRSwNP.

2. Materials and Methods

The TriNetX Research Network (TriNetX, Cambridge, MA) is an expansive network that methodically acquires, refreshes, and consolidates anonymized EHRs from a wide array of healthcare facilities globally, including hospitals, primary care facilities, and specialized treatment centers. The details of the network's operations have been extensively documented in earlier publications [12]. The data utilized were de‐identified and provided in summarized tables at the aggregate level rather than at the individual level, thus no Institutional Review Board (IRB) approval was required.

Cohorts were created using International Classification of Disease, 10th edition, (ICD‐10) and concurrent procedural terminology (CPT) codes. Atopic patients included in our study were defined by a history of any of the following atopic diseases: asthma (ICD‐10 J45), allergic rhinitis (ICD‐10 J30), or CRSwNP (ICD‐10 J32 and ICD‐10 J33), aged 18 and older with a diagnosis of ETD, as defined by ICD‐10 codes H69.8 (other specified disorders of the Eustachian tube) or H69.9 (unspecified Eustachian tube disorder). These cohorts were then divided based on the intervention received after the diagnosis of atopic disease and ETD. Intervention groups included Th2‐targeted monoclonal antibody (mAb) therapy (dupilumab, mepolizumab, or mepolizumab), topical nasal steroid spray (fluticasone propionate), FESS, surgery for nasal obstruction (septoplasty and inferior turbinate reduction), and allergy immunotherapy. The TriNetX database was filtered for relevant procedural CPT codes for each of the various surgical cohorts. The FESS cohort included the following CPT codes: 31294, 1014607, 1005792, 1014606, 1031038, 1005805, 1035648, 31276, 1035649, 1005808, and 1020541. Relevant procedural CPT codes for the septoplasty with inferior turbinate reduction included procedural CPT code 30520 in addition to any of the following procedural CPT codes to detail inferior turbinate reduction: 30130, 30140, 30930, or 1005744. Relevant procedural CPT codes for allergy immunotherapy, both sublingual and subcutaneous, included any of the following: 95115, 95117, 95165, or 95199.

The primary outcome for middle ear function was the prevalence of PET placement in each cohort in the period 5 years prior and 3 years following intervention (PET as early as 13 years of age). The post‐intervention prevalence of 3 years was selected to best capture individuals during periods of optimized treatment, based upon data showing an average mAb therapy duration of 2–4 years with remission rates up to 9 months [13].CPT codes corresponding to PET placement are included 69433 and 69436.

Demographic information including age, sex, and race was collected for each cohort. Analyses were conducted using the TriNetX analytics software, Microsoft Excel (Redmond, WA), and JMP version 17.0.0 SAS Institute Inc. (Cary, NC). Absolute risk reduction (ARR) was calculated for each intervention, and differences in PET placement post‐intervention were directly compared between the three mAb of interest using the chi‐squared test. A p‐value < 0.05 was considered statistically significant.

3. Results

The demographic breakdown of each cohort is listed by atopic disease diagnosis in Table 1. All medical and surgical interventions studied demonstrated statistically significant improvement in the prevalence of PET placement (Table 2). FESS demonstrated an ARR of 10.0% (p < 0.05, 95% CI 8.9%–11.1%), septoplasty/septoplasty with inferior turbinate submucosal resection (BITSMR) 7.5% (p < 0.05, 95% CI 6.3%–8.7%), mAb 5.5% (p < 0.05, 95% CI 4.1%–6.8%), fluticasone proprionate nasal spray 0.9% (p < 0.05, 95% CI 0.8%–1.0%), and allergy immunotherapy 2.4% (p < 0.05, 95% CI 1.5%–3.2%). Individually, the three mAb—dupilumab, mepolizumab, and omalizumab—exhibited ARR of 6.5% (p < 0.05%, 95% CI 4.8%–8.3%), 6.8% (p < 0.05, 95% CI 2.6%–11.0%), and 3.4% (p < 0.05, 95% CI 1.4%–5.4%), respectively. The results of the chi‐squared analysis did not demonstrate significant differences in rates of PET placement among the three interventions (p = 0.18). Figure 1 summarizes these findings.

TABLE 1.

Demographics data for atopic patient cohorts, divided by intervention.

	FESS	Septo ITR	Dupilumab	Mepolizumab	Omalizumab	Combined mAb	Immunotherapy	Fluticasone
Total, n	6016	3389	1148	278	681	2220	4553	94,813
Age ± SD (years) a	47.0 ± 19.1	42.6 ± 15.8	51.4 ± 17.3	57.0 ± 4.9	46.2 ± 18.4	50.3 ± 17.6	45.9 ± 17.3	44.8 ± 20.3
Sex (%)
Female	56.9	55.7	64.2	70.9	75.9	69.3	64.2	66.7
Male	40.5	41.8	33.7	27.7	20.7	28.3	30.9	31.9
Unknown	2.6	2.5	2.1	3.6	3.4	2.4	4.9	1.3
Ethnicity (%)
Hispanic	6.6	6.7	4.4	3.6	6.5	4.8	5.5	7.0
Not Hispanic	74.1	76.7	81.1	80.6	78.7	80.5	79.5	74.7
Unknown	19.3	16.6	14.5	15.8	14.8	14.6	15.0	18.3
Race (%)
Asian	2.4	1.9	3.3	3.6	2.8	3.0	2.5	2.2
Black	7.1	5.1	10.5	10.1	10.0	10.1	6.8	8.4
Other	3.6	4.4	4.6	10.8	5.1	2.5	3.0	3.2
Unknown	9.7	9.8	7.4	8.3	10.0	9.1	10.6	10.1
White	77.2	78.7	75.7	74.5	74.3	75.6	77.1	76.0

Abbreviations: Combined mAb, patients on dupilumab, mepolizumab, or omalizumab; FESS, functional endoscopic sinus surgery; Immunotherapy, allergy immunotherapy; Septo ITR, septoplasty with inferior turbinate reduction.

^a Age in years with standard deviation was recorded at the age of the index event (Time when the patient received/began the intervention).

TABLE 2.

Prevalence of tympanostomy tube placement in patients with airway atopic disease, divided by intervention.

	FESS	Septo ITR	Dupilumab	Mepolizumab	Omalizumab	Combined mAb	Immunotherapy	Fluticasone
Pre‐intervention	949	374	96	29	37	179	260	2696
	(15.8%)	(11.0%)	(8.3%)	(10.4%)	(5.4%)	(8.1%)	(5.8%)	(2.8%)
Post‐intervention	348	120	21	10	14	58	151	1855
	(5.8%)	(3.5%)	(1.8%)	(3.6%)	(2.0%)	(2.6%)	(3.3%)	(1.9%)
Difference	601	254	75	19	23	121	109	841
Absolute risk reduction	10.0% [8.9%–11.1%] a	7.5% [6.3%–8.7%] a	6.5% [4.8%–8.3%] a	6.8% [2.6%–11.0%] a	3.4% [1.4%–5.4%] a	5.5% [4.1%–6.8%] a	2.4% [1.5%–3.5%] a	0.9% [0.8%–1.0%] a

Note: Confidence interval presented in brackets.

Abbreviations: Combined mAb, patients on dupilumab, mepolizumab, or omalizumab; FESS, functional endoscopic sinus surgery; Immunotherapy, allergy immunotherapy; Septo ITR, septoplasty with inferior turbinate reduction.

^a Statistical significance.

FIGURE 1.

Risk of pressure equalization tube placement pre‐ and post‐intervention. ARR, absolute risk reduction; Combined mAb, patients on dupilumab, mepolizumab, or omalizumab; FESS, functional endoscopic sinus surgery; Immunotherapy, allergy immunotherapy; Septo ITR, septoplasty with inferior turbinate reduction. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]

4. Discussion

ETD is a highly prevalent condition, with an incidence of up to 35% in adults with concomitant allergy diagnosis [4]. Treatment often requires procedures such as PET placement. However, given PETs inherently extrude after a period of time (even in the case of long lasting PETs), many patients require repeat ear tube placement. Thus, other management options that address the underlying allergic etiology may directly or indirectly improve ETD and decrease the risk for requiring PET placement. The unified airway concept proposes that the upper and lower airways, including the middle ear subsite, originate from ectoderm with similar structural and physiological features, exhibiting similar reactivity and inflammatory response [14]. The ET is contiguous with the sinonasal and nasopharyngeal airway and is postulated to exhibit similar behavior in response to allergic stimuli [14]. The higher concentrations of eosinophils, T lymphocytes, IL‐4, and IL‐5 present in the unified respiratory mucosa of atopic patients and the enhanced response to these inflammatory mediators increase concentrations of neutrophils, which subsequently lead to higher levels of cytotoxic materials such as myeloperoxidase in the middle ear and ET [5, 15].

First‐line medical treatment for ETD often includes adequate use of a topical nasal steroid spray such as fluticasone proprionate. The hypothesized mechanism for the effect of topical nasal steroids on ETD involves anti‐inflammatory effects at the ET orifice, but existing data supporting their clinical efficacy appears limited. Previous studies have suggested that fluticasone nasal spray may be ineffective in treating ETD or its accompanying symptoms [16, 17, 18]. The current study demonstrated a minimally decreased risk of PET placement in patients treated with topical fluticasone, with an ARR of 0.9%, which supports the notion of a minimal effect of nasal steroids on middle ear function. However, it is possible that the efficacy of intranasal corticosteroids can be impacted by patient factors such as improper administration techniques, lack of adherence to a daily regimen, or inability for the medication to adequately reach the desired anatomical location. Nevertheless, the presented data suggest that fluticasone, although often utilized as a first‐line therapy for adults with ETD, may not provide substantial relief from ETD symptoms.

In recent years, mAbs targeted against Th2 cytokines have shown significant benefits in the management of upper and lower airway atopic inflammatory disease [19]. Dupilumab functions by binding to the IL‐4 alpha subunit, which is present on both IL‐4 and IL‐13 receptors, and inhibiting downstream signaling [20]. Mepolizumab is an IL‐5 antagonist, regulating and reducing the growth, recruitment, activation, and life cycle of eosinophils [21]. Lastly, omalizumab targets free IgE, preventing it from binding to the high affinity Fc‐epsilon receptor and thereby leading to decreased activation and expression on mast cells and basophils [22]. The goal of all three medications is to reduce airway inflammatory response and downstream mediators.

Consistent with a growing body of literature supporting the efficacy of these biologic therapies for atopic disease, the present study demonstrated a significantly positive effect of each mAb on middle ear function. Dupilumab, mepolizumab, and omalizumab demonstrated significant reductions in PET placement, with ARR of 6.5%, 6.8%, and 3.4%, respectively, or a combined decrease from 8.1% to 2.6%, with an average ARR of 5.5%. The improvement in ET function noted with these agents likely results from the reduction in inflammatory mediators in the upper airway and ET mucosa.

A similar positive effect on middle ear disease in atopic patients has been reported with allergen immunotherapy, although the mechanism of reduction of Th2‐mediated inflammation differs. Hurst demonstrated a complete resolution of middle ear effusion or drainage in 85% of 371 atopic individuals treated with immunotherapy [8]. The current data, while not specifically targeting the complete resolution of middle ear disease, nonetheless supports such findings, demonstrating a 2.4% ARR and a 42% overall reduction in relative risk of PET placement for patients treated with allergy immunotherapy. While allergy immunotherapy involves multiple broad immunologic changes including a switch from Th2 to Th1 T‐cell preponderance, upregulation of T‐regulatory cells, and IgG antibody mediated inhibition of the inflammatory cascade, biologics such as dupilumab, mepolizumab, and omalizumab specifically target the Th2 inflammatory cascade at IL‐4, IL‐5, and IgE, respectively [20, 21, 22, 23]. Despite different mechanisms of action, there was no significant difference between the rate of PET placement among the three biologic agents, suggesting similar efficacy in impairment of the allergic cascade and downregulation of inflammatory mediators present in the ET.

In addition to causing intrinsic inflammation within the ET and middle ear, atopic conditions can also contribute to ETD through functional or mechanical obstruction of the ET structure. Increased ET compliance leads to persistent collapse or inadequate opening, ultimately causing negative pressure within the middle ear space [24]. Optimizing nasal airflow can improve middle ear ventilation through maintaining the proper pressure gradient between the middle ear and nasopharynx, as suggested by strong correlations between ETDQ‐7 and SNOT‐22 or NOSE scores. Multiple studies have reported significant improvement in subjective ET function and symptoms in patients undergoing surgery for nasal airway obstruction [25]. Patients receiving septoplasty with inferior turbinate reduction experienced statistically significant improvements in reported symptoms and reductions in ETDQ7 scores [11, 26]. Evidence suggests surgical intervention targeted at sinus inflammatory disease can also lead to improvement in ET function; individuals with ETD undergoing FESS demonstrated significant improvement in symptoms postoperatively [27, 28].

An important factor influencing treatment decisions is cost, particularly when comparing more affordable interventions, such as allergy immunotherapy and intranasal corticosteroids (e.g., fluticasone), to the significantly higher expense of targeted biologic therapies. The annual cost of allergy immunotherapy varies depending on factors such as route of administration (sublingual vs. subcutaneous), dosing frequency, formulation strength, and duration of treatment, with estimates ranging from $500 to $1200 per year for an average duration of 4 years [8, 29]. In contrast, the cost of dupilumab is substantially higher, averaging between $30,000 and $40,000 per year, though patient out‐of‐pocket expenses can vary based on insurance coverage and assistance programs [30]. Given this stark cost disparity, particularly for long‐term management of atopic disease, financial considerations may play a crucial role in treatment selection and accessibility. Differences in duration of treatment vary widely across the interventions, thereby making cost estimations of various long‐term treatments difficult. Further research is warranted to determine whether the potential benefits of biologic therapies in reducing the need for ear tube placement justify their significantly higher cost when compared to more conventional treatments.

In the present study, the risk of PET placement after FESS and septoplasty/BITSMR was reduced by 10.0% and 7.5%, respectively. The substantial reduction in the need for intervention for impaired middle ear function following nasal surgery adds additional evidence to a growing body of literature suggesting that these procedures improve ET function and normalize the pressure gradient between the middle ear and nasopharynx. While these sinonasal procedures are significantly more invasive than tympanostomy and would not be appropriate substitutes for PET placement, it is encouraging nonetheless to note an improvement in ETD with these procedures, but the exact mechanisms by which they impact the ET require further study.

Analysis of this large TriNetX data set demonstrates a substantial improvement in middle ear disease across multiple medical and surgical treatments for sinonasal atopic inflammation, yet there are limitations to this study. TriNetX only stores diagnoses and procedural codes in aggregate, restricting the ability to compare individual patient outcomes. Similarly, the TriNetX dataset does not distinguish between the difference in sensitivity of skin prick testing compared to in vitro or intradermal testing, thus the method and accuracy in which patient diagnoses are made is unclear [31]. Likewise, the database relies on the use of ICD and CPT codes to identify and build cohorts, which ultimately depends upon the accuracy of data entered into the patient's chart. Utilization of ICD and CPT codes may also limit the precision of inclusion and exclusion criteria. In particular, ICD‐10 code does not have a specific diagnosis for eosinophilic otitis media. Eosinophilic otitis media is an intractable disease affecting a small percentage of patients with middle ear effusion that often does not respond to conventional treatments such as PET placement [32, 33]. However, given that there is no specific ICD‐10 code for this disease process, patients with eosinophilic otitis media, who would not improve with PET placement, could not be excluded.

The ability to compare the relative efficacy of various surgical and medical interventions has the potential to provide significant insight into optimizing decision‐making and risk–benefit analysis for the treatment of atopic middle ear disease. These conclusions are limited, however, by likely differences in disease severity between intervention cohorts, as demonstrated by varying pre‐intervention prevalence of PET placement (with greater prevalence likely implying greater severity in disease).

Given that all three mAbs included in this study are currently approved by the Federal Drug Administration (FDA) for the atopic diseases of interest, the assumption of similar disease severity in patients undergoing therapy with any of these medications was made, allowing for direct comparison of the efficacy of each therapy in managing middle ear disease. However, multiple factors may impact real‐world decision‐making and which mAb patients ultimately receive. For example, the timing of FDA approval of mAb for specific diseases varies and thus drives clinician selection and preference of mAb. Moreover, experiential and data‐driven analyses comparing the efficacy of each mAb for specific disease processes may influence patient and physician preferences on a disease‐specific and patient‐driven basis [26, 34]. Thus, the selection and choice of mAb are not completely randomized and may impact differences in baseline disease severity between mAb cohorts.

5. Conclusion

The results of this large, multinational cohort study support a growing body of literature suggesting that medical and surgical interventions for atopic and obstructive sinonasal disease have beneficial effects on middle ear function, as measured by the need for PET placement. Further research could utilize more granular patient quality‐of‐life and outcomes measures to better elucidate the relative clinical benefits of these therapies.

Conflicts of Interest

The authors declare no conflicts of interest.

Lee L., Bentan M. A., Mastoloni E., and Schuman T. A., “Sinonasal Intervention Reduces the Need for Pressure Equalization Tube Placement in Atopic Adults,” The Laryngoscope 135, no. 9 (2025): 3064–3070, 10.1002/lary.32207.