INTRODUCTION
The Eustachian tube (ET) is a complex osseocartilaginous structure located between the nasopharynx and the middle ear. It plays a crucial role in pressure equalization, mucociliary clearance, and middle ear protection [1,2]. Dilatory ET dysfunction typically arises from mucosal inflammation that restricts valve dilation, thereby preventing proper middle ear ventilation. Patients may experience symptoms such as ear fullness, hearing loss, otalgia, tinnitus, pressure, and auditory disturbances, which can eventually lead to conditions like acute or chronic otitis media and cholesteatoma formation [3,4].
Despite various proposed treatments for dilatory ET dysfunction, effective long-term solutions remain elusive. Medical management (MM) typically involves nasal steroids, decongestants, and antihistamines to improve nasal and ET mucosal conditions [5]. Surgical approaches, such as bony ET widening, have largely been abandoned due to their failure to restore long-term ET function and the risk of internal carotid artery (ICA) injury. Endoscopic removal of inflamed cartilaginous ET tissue using a laser or microdebrider has also shown limited success [6,7]. Balloon eustachian tuboplasty (BET), first introduced in 2010 in a human cadaver study, represents a promising innovation in endoluminal ET treatment and offers a new therapeutic avenue for this disorder [8]. Several studies have reported significant improvements in both subjective and objective outcomes following BET [1,4,9-12]. Reported success rates for BET range from 36% to 80%, with sustained improvements in symptoms and middle ear function observed for more than 2 years [10]. However, most randomized controlled trials (RCTs) have focused on simpler cases of ET dysfunction related to tympanic membrane retraction or chronic otitis media with effusion (OME), where only fluid is present in the middle ear [9,11-14].
This multicenter study evaluated the efficacy and safety of BET using an Eustachian tube balloon catheter (ETBC; Earloon, Eustachian Tube Dilation System, Genoss Co. Ltd.) in combination with MM, compared to MM alone, in adult patients with chronic suppurative otitis media (COM) accompanied by chronic dilatory ET dysfunction.
MATERIALS AND METHODS
The study protocol was approved by the Institutional Review Boards of three medical centers (No. 2020-1132, No. 2020-10- 100, and No. B-2011-648-003). The study was registered with the Korean Clinical Research Information Service (Registered on January 25, 2021, registration number KCT0005817) and adhered to the Declaration of Helsinki and Korean Good Clinical Practice guidelines. All patients provided written informed consent after receiving a detailed explanation of the trial. We followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines [15].
Study design
This prospective, multicenter, RCT assessed the efficacy and safety of BET in patients with COM and dilatory ET dysfunction, conducted between January 2021 and June 2023 at three tertiary medical centers in South Korea. This study aimed to establish the superiority of BET combined with MM over MM alone in treating dilatory ET dysfunction in patients with both COM and ET dysfunction. Participants from each center were randomly assigned (1:1) to either the BET plus MM or MM-only groups. An independent statistician generated a random allocation sequence based on stratification factors, and a stratified block randomization method was used to assign participants. Given the nature of the trial, neither the patients nor treating physicians were blinded to the randomization allocation.
Patients
Eligible patients were adults aged 19 to 80 years with chronic dilatory ET dysfunction, defined by a failed Valsalva maneuver. Patients with COM accompanied by dilatory ET dysfunction that had persisted for more than 6 months were enrolled. COM was diagnosed when patients had a history of recurrent otorrhea history for more than one year, along with tympanic membrane perforation or adhesion, with or without cholesteatoma. Among them, patients who underwent mastoidectomy or tympanoplasty and had accompanying ET dysfunction persisting for more than one month postoperatively were also enrolled. Patients with the following conditions were excluded: (1) diagnosis of patulous ET dysfunction; (2) fluctuating sensorineural hearing loss; (3) acute otitis media; (4) cleft palate or history of cleft palate repair; (5) craniofacial abnormalities; and (6) pregnancy or breastfeeding.
In the screening phase, all patients underwent detailed medical history assessment and physical examination including both otoscopy and nasal endoscopy. All patients were asked to perform a Valsalva maneuver to evaluate ET function. They were instructed to take a deep breath, close their mouth, and pinch their nose. Then, they were asked to exhale gently but forcefully, as if trying to blow air out of their nose while keeping their mouth and nose closed. Patients were instructed to maintain this pressure for 5–10 seconds before releasing and resuming normal breathing. A successful Valsalva maneuver was defined as the bulging of the tympanic membrane observed during endoscopic examination or when a patient felt the air passage through a perforation of the tympanic membrane or a ventilation tube in place. Temporal bone computed tomography (CT) scans were performed to assess the overall status of the middle ear and inner ear, and to confirm the absence of bony dehiscence of the ICA. Pure tone audiometry (PTA), speech audiometry (SA), and the Eustachian Tube Dysfunction Questionnaire-7 (ETDQ-7) were assessed in all enrolled patients at baseline.
Treatment
The ETBC for BET was a 6-mm wide by 20-mm long balloon catheter, stored at room temperature (1 °C to 30 °C) in a dark, dry location. BET was performed under local anesthesia in the operating room. All patients were placed in the supine position and received topical anesthesia via surgical pledgets soaked in normal saline containing 4% lidocaine and 1:1,000 epinephrine, which were placed into the nasal cavity and on the nasopharyngeal opening of the ET for 5 minutes under a 0° endoscope view. Most procedures were performed under the guidance of a 0° endoscope without much difficulty; however, in a few cases where the ET orifice was not clearly visible, a 30° endoscope was used. In cases of severe septal deviation, the procedure was performed inserting a 70° endoscope into the opposite nasal cavity. Under endoscopic guidance, the ETBC was advanced to the ET orifice and then inserted into the cartilaginous ET until it reached the first mild resistance approaching the narrowest diameter before the bony-cartilaginous isthmus. The balloon was then inflated to 10 atm for 1 minute and subsequently deflated. Next, the EBTC was inserted deeper until it reached mild resistance and was inflated again to 10 atm for 1 minute. After removing the ETBC, the ET status was confirmed using an endoscope to check for active bleeding. In patients with middle ear effusion, a ventilation tube was inserted into the tympanic membrane for immediate effusion resolution, either before or simultaneously with BET when needed (Table 1). In the recovery room, the patients were monitored for adverse reactions and returned home after full recovery. On the day of BET, patients in the investigational cohort began a fluticasone furoate (Avamys, GlaxoSmithKline) nasal steroid spray regimen, consisting of two sprays in each nostril once daily. Fig. 1 is an example case of a BET procedure.
Patients in the control cohort began the same MM on the day of randomization and also underwent ventilation tube insertion in cases with middle ear effusion. In both cohorts, patients with tympanic membrane perforation participated in the trial without any additional measures. We considered that a ventilation tube or tympanic membrane perforation was less likely to affect the ability to perform the Valsalva maneuver, which was the main effectiveness outcome. Participants in the investigational cohort visited the outpatient clinic 2 weeks post-procedure for examination of the operation site around the ET and evaluation for adverse events, including bleeding, hematoma, pain or tenderness, and ET stenosis. The 8-week and 1-year post-procedure follow-ups included physical examinations and evaluations of the Valsalva maneuver, PTA, SA, and ETDQ-7.
Participants in the control cohort visited the outpatient clinic after 8 weeks of MM for evaluation of improvement in dilatory ET dysfunction. The physical examination included the Valsalva maneuver, PTA, SA, and ETDQ-7. These participants were allowed to crossover to BET if they showed no improvement in ET function (still failed Valsalva maneuver) at the 8-week follow-up and agreed to the procedure. After BET, the participants had the same follow-up protocols as the investigational cohort. If the patient was under control cohort and had not undergone BET after the 8-week follow-up, they had the 1-year follow-up visit. Adverse events were also monitored in the control cohort during the follow-up period.
Endpoints and assessments
The primary effectiveness outcome was the normalization of the Valsalva maneuver at the 8-week follow-up. Additional secondary outcomes included improved ETDQ-7 scores and decreased air-bone gap (ABG) analyzed at 8 weeks. Since not all enrolled participants had completed the 1-year follow-up (as of December 2023), we decided to first analyze the results of the short-term follow-up (8 weeks after the BET procedure).
Hearing thresholds were determined by PTA. The mean hearing levels were calculated as the average of the hearing thresholds at 0.5, 1, 2, and 4 kHz (four-frequency average). The word recognition score (WRS) was calculated as the percentage of monosyllabic words that the patient repeated correctly in SA. Patient-reported improvement in ET function was mainly evaluated using the ETDQ-7 [16], which includes seven questions with responses ranging from 1 (no problem) to 7 (severe problem). These questions ask about ET dysfunction symptoms present over the past month, including (1) pressure in the ears; (2) pain in the ears; (3) a feeling that the ears are clogged or underwater; (4) ear symptoms during a cold or sinusitis; (5) crackling or popping sounds in the ears; (6) ringing in the ears; and (7) muffled hearing. The ETDQ-7 score was the sum of the scores for all seven questions. The scores range from 7 to 49, with scores ≥14.5 indicating ET dysfunction [17].
Statistical analysis
To determine the required sample size for this study, we used PASS sample size software version 15.0.7 for Windows. The power (1-ß error) was set at 0.8, with a type I error (α) of 0.05. Based on the RCT by Poe et al. [11], tympanogram normalization at the 6-week-follow-up was observed in 51.8% of investigational patients compared to 13.9% of controls. Consequently, the power analysis indicated that a sample size of 24 participants per group, accounting for an anticipated dropout rate of approximately 10%, would be sufficient to detect the differences between groups.
Continuous and discrete variables are presented as means or medians with standard deviations, and frequencies and percentages, respectively. Statistical analysis was performed using IBM SPSS Statistics for Windows version 24.0 (IBM Corp.). P<0.05 was considered statistically significant. Pearson’s chi-square test was used to compare the distribution of categorical variables between the two groups. Independent-sample t-test was used to compare normally distributed continuous variables between the two groups. A paired t-test was used to compare values before and after the procedure to assess for changes over time.
RESULTS
Demographics and baseline characteristics
A total of 133 participants across three investigational centers were assessed for eligibility and provided written informed consent before being randomly assigned (1:1) to either the BET group (n=65) or the MM-only (control) group (n=68). One participant in the BET group was excluded after a computed tomography scan rendered him ineligible for the procedure, and four participants who underwent BET subsequently withdrew from the trial. In the control group, 12 participants were excluded. This resulted in 116 participants (121 ears in total; 62 ears in the BET group and 59 ears in the control group) being included in the primary efficacy endpoint analysis at 8 weeks post-procedure. Among the 56 participants (59 ears) in the control arm who completed the 8-week evaluation, 48 participants (51 ears, 86.4%) crossed over to receive BET. Fig. 2 shows the participant flow of the trial. Each ear was treated as an independent observation in the analysis.
Demographics and baseline characteristics were similar between the two treatment groups (Table 1). Patients with persistent middle ear effusion underwent ventilation tube insertion either before or concurrently with the trial. Of the 121 ears, 102 (84.3%) either retained the ventilation tube on the tympanic membrane or exhibited tympanic membrane perforation during the trial. The status of the tympanic membrane did not differ significantly between the groups, and no significant differences in ABG were observed based on tympanic membrane status within each group.
Of the 121 ears, 67 (55.4%) had previously undergone surgery for COM (with or without cholesteatoma) prior to trial enrollment; the types of mastoidectomy and middle ear surgery are detailed in Table 1. There were no significant differences in the types of surgeries performed between the groups. The remaining 54 ears had COM without any prior surgical intervention, combined with ET dysfunction.
Changes in the incidence of successful Valsalva maneuver (the primary outcome)
Participants in the BET group were instructed to perform a Valsalva maneuver during physical examinations of the ET at baseline, 2 weeks, and 8 weeks post-procedure. In contrast, participants in the control group performed the maneuver at baseline and at the 8-week follow-up. In the BET group, 38.7% of ears (24/62) exhibited a successful Valsalva maneuver at 2 weeks and 46.8% (29/62) at 8 weeks post-procedure, compared to 0% at baseline. In the control group, 15.3% of ears (9/59) demonstrated a successful Valsalva maneuver at 8 weeks. The incidence of a successful Valsalva maneuver at 8 weeks was significantly higher in the BET group than in the control group (P<0.001, Pearson’s chi-square test) (Fig. 3A).
Subgroup analyses revealed that neither prior surgical history nor the status of the tympanic membrane significantly affected treatment outcomes in either the investigational or control groups (Supplementary Table 1).
Improvement in ETDQ-7 scores
Subjective symptom improvement related to ET dysfunction was evaluated by assessing changes in overall ETDQ-7 scores from baseline to the 8-week follow-up. Baseline ETDQ-7 scores were similar between the BET and control groups (20.87±9.62 vs. 22.25±10.07, respectively; P=0.441, independent t-test) (Table 2). In both groups, ETDQ-7 scores decreased significantly after the procedure, indicating symptom improvement. However, the BET group experienced a significantly greater improvement, with an average reduction of –6.2±9.4 compared to –2.6±8.6 in the control group (P=0.028, independent t-test) (Fig. 3B).
Changes in audiograms
Table 2 presents the hearing levels in the BET and control groups, as assessed using PTA and SA. Baseline bone and air conduction thresholds were similar between the two groups. However, in the BET group, the air conduction threshold improved significantly, decreasing from 45.6±22.3 dB HL to 39.6±24.1 dB HL (P<0.001, paired t-test) after the procedure. Moreover, the ABG decreased more significantly in the BET group (–5.8±11.4 dB HL) compared to the control group (–1.2±10.5 dB HL) at the 8-week follow-up (P=0.023, independent t-test) (Fig. 3C). In the control group, the decrease in ABG during the 8-week follow-up was not statistically significant (P=0.387, paired t-test). Additionally, WRS from SA showed no significant differences or changes between the groups.
Complications
No serious procedure- or device-related adverse events were reported in either the BET or control groups during the 8-week follow-up. There were no instances of postoperative patulous ET dysfunction, massive bleeding, or false passage formation in the BET group. Additionally, no medication-related adverse events were observed in either group.
DISCUSSION
To our knowledge, this study is the first and largest RCT to compare the safety and effectiveness of BET versus MM alone in patients with COM and chronic dilatory ET dysfunction. While previous research has primarily focused on ET dysfunction associated with intractable OME [9,11-14], our study targeted a more severe form of ET dysfunction that results in structural changes in the middle ear and COM. This distinction is significant because ET dysfunction is a major contributor to COM and can adversely affect postoperative outcomes. In summary, the BET group achieved a significantly higher rate of successful Valsalva maneuvers, reported greater subjective symptom improvement, and exhibited a more substantial reduction in ABG compared to the control group.
BET has emerged as a minimally invasive treatment for dilatory ET dysfunction, as supported by several RCTs. Poe et al. [11] demonstrated that 51.8% of patients in the BET group experienced tympanogram normalization at 6 weeks compared to 13.9% in the MM-only group, along with a normalized ETDQ-7 score in 56.2% versus 8.5% of patients. Similarly, Meyer et al. [14] reported that 47.1% of patients in the BET group achieved a positive Valsalva maneuver at 6 weeks, compared to 14.3% in the MM group, with overall ETDQ-7 scores improving by –2.9±1.4 in the BET group versus –0.6±1.0 in the control group. Choi et al. [9] found that a navigation-guided BET group exhibited greater tympanogram improvement and a higher rate of positive Valsalva maneuver (36.6% vs. 15.8%) compared to controls. Our findings align with these previous studies, even though they were conducted in patients with COM and ET dysfunction. In our prior retrospective study, we observed that 62% of patients with COM and persistent ET dysfunction following tympanomastoidectomy could successfully perform the Valsalva maneuver after BET—a success rate higher than the 47.1% observed in the present study [1]. This discrepancy may be attributable to the use of both endoscopic and fluoroscopic guidance in our previous study, which enabled precise monitoring of the balloon catheter’s position and inflation status, thereby reducing the risk of false passage creation [18]. Moreover, COM may represent a more severe form of ET dysfunction, leading to diminished post-BET performance. Existing literature supports the role of both anatomical and functional abnormalities of the ET in the pathogenesis of COM [19,20]. Reduced ciliary function in the middle ear and ET mucosa compromises the clearance of middle ear secretions, and malfunction of the ET leads to negative middle ear pressure, tympanic membrane retraction, and fluid accumulation. Doyle [21] reported that failure of the ET to open causes inflammation and mucosal disturbances in COM. Furthermore, Paltura et al. [22] also demonstrated that ET diameter itself was correlated with COM.
Regarding the mechanism of BET in managing ET dysfunction, histopathological studies suggest that the balloon may shear or compress inflamed portions of the ET epithelium while sparing the basal layer. This selective injury allows for rapid healing and replacement of lymphocytes and lymphoid follicles with thinner fibrous scar tissue. Consequently, BET can reduce the inflammatory burden and yield lasting improvement in ET dilation [23,24]. A study in rats observed epithelial damage immediately after BET [25]. However, the mucosal lining had regenerated by 1 week post-procedure, goblet cells had recovered by 4 weeks, and epithelial hyperplasia had decreased to nearly normal levels with neovascularization by 12 weeks. Kivekas et al. [23] reported that human biopsies obtained 5 weeks post-BET showed restoration of healthy ciliated pseudostratified columnar epithelium and replacement of lymphoid follicles with a thinner layer of fibrous tissue. In patients with COM, the ET mucosa is typically thickened and contains numerous glands, while the underlying submucosa harbors many inflammatory cells such as macrophages, plasma cells, and lymphocytes. By compressing these tissues and facilitating the regeneration of healthy mucosa with improved ET opening, BET may enhance middle ear ventilation and clearance in COM patients [19]. Nonetheless, considering the reported 36%–80% success rate of BET, ET stent placement could be a viable alternative for patients who do not respond to BET or who develop restenosis [26,27].
A key strength of our study is the demonstration of both objective and subjective improvements in ET dysfunction measures—namely, the Valsalva maneuver, PTA results, and ETDQ-7 scores—when compared with the control group. Nevertheless, the study has several limitations. Normal subjects are only able to perform the Valsalva maneuver 78%–86% of the time, meaning that an inability to perform the maneuver does not necessarily indicate ET dysfunction [18]. Accordingly, a control group was essential. Improved ET function was observed in 16.7% of the control group, suggesting that MM may enhance ET function through repeated Valsalva maneuver attempts. The absence of blinding may have introduced a placebo effect and potential bias, particularly in patient-reported outcomes. Additionally, the inclusion of bilateral ears in five patients complicated the evaluation of individual ear status using ETDQ-7 scores. The study also featured a relatively short follow-up period of 8 weeks post-BET; long-term outcomes, including those for crossover patients from the control group, will be reported upon completion of a 1-year follow-up. Finally, future research should consider including pediatric populations.
This study establishes BET as a superior treatment for adults with dilatory ET dysfunction alongside COM when compared to MM alone. Notably, no procedure- or device-related adverse events were observed, affirming a favorable risk-benefit ratio. Therefore, BET emerges as a safe and effective treatment option for chronic dilatory ET dysfunction coexisting with COM.
HIGHLIGHTS
▪ Balloon eustachian tuboplasty (BET) increased the likelihood of a successful Valsalva maneuver and reduced both Eustachian Tube Dysfunction Questionnaire-7 (ETDQ-7) scores and the air-bone gap in patients with chronic suppurative otitis media (COM) and eustachian tube (ET) dysfunction.
▪ No serious procedure- or device-related adverse events occurred in either group during the 8-week follow-up.
▪ BET combined with medical management (MM) proved superior to MM alone for treating dilatory ET dysfunction in patients with COM.
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