Otitis media with effusion (OME) refers to the presence of fluid in the middle ear without the clinical signs or symptoms of acute middle ear infection [1,2]. OME represents one of the most common causes of hearing impairment in children, with more than 90% of children experiencing at least one episode before the age of 10 years, most commonly between the ages of 6 months and 4 years [3]. The pathogenesis of OME is multifactorial and primarily associated with eustachian tube dysfunction, leading to impaired middle ear ventilation, negative pressure, and subsequent fluid accumulation within the tympanic cavity [4]. Additionally, immunological and inflammatory processes contribute to the development and persistence of middle ear effusion [5]. Early and appropriate treatment of OME is important to prevent hearing impairment, speech delay, and developmental problems in children. Current guidelines from the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) recommend myringotomy with ventilation tube insertion (VTI) for children with persistent OME (>3 months) or for groups with high risk such as those with cleft lip/palate or other craniofacial anomalies [6]. However, simple myringotomy with aspiration of middle ear effusion alone has limited therapeutic value because the incision usually heals within a few days, while VTI may be associated with complications such as tube otorrhea [7-9].

Steroids are biologically active compounds with potent antiinflammatory properties and have been investigated for OME because they may reduce middle ear inflammation and mucin production and improve Eustachian tube function [10]. Although systemic and intranasal steroids have been proposed as alternatives to surgery, previous evidence has not demonstrated sustained benefit for effusion resolution or hearing outcomes [11]. Recently, intratympanic (IT) steroid administration has gained more attention as a more effective delivery method, providing high local drug concentrations in the middle ear while minimizing systemic absorption [12]. Previous studies have suggested beneficial effects of IT steroid therapy. A study comparing IT steroids to placebo in children over 12 and adults with OME demonstrated improvements in symptoms and quality of life for the steroid group [13]. Similarly, another study investigating the use of IT steroids as an adjunct to myringotomy and VTI in children reported lower rates of symptom recurrence and postoperative complications [14]. However, the evidence remains limited and clinically heterogeneous. Therefore, this systematic review and meta-analysis evaluated the effectiveness and safety of IT corticosteroid therapy compared with standard management in patients with persistent or treatment-resistant OME.

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [15]. The methodology adhered to the recommendations outlined in the Cochrane Handbook for Systematic Reviews of Interventions [16].

This meta-analysis offers an updated overview of the available evidence on IT corticosteroid therapy for persistent or treatment-resistant OME. The findings suggest that IT corticosteroid therapy may improve audiological outcomes, in-cluding PTA hearing thresholds within two distinct clinical profiles and the pooled ABG, while also reducing OME recurrence and tympanosclerosis. These potential benefits were not accompanied by significant increases in treatmentrelated adverse events, including otorrhea and permanent tympanic membrane perforation. However, Type A tympanogram normalization was not statistically significantly improved, indicating that functional hearing recovery may not necessarily correspond to complete physiological restoration of middle ear ventilation.

The biological mechanisms underlying the efficacy of IT steroids involve multi-targeted anti-inflammatory and physiological actions within the middle ear. OME is characterized by secretory transformation of the middle ear epithelium, subepithelial edema, and the infiltration of inflammatory cells [21]. IT steroids act by inhibiting the arachidonic acid cascade, thereby reducing the production of inflammatory mediators and lipopolysaccharides known to induce middle ear effusion [22]. Furthermore, steroids are noted to inhibit mucin production and enhance Eustachian tube function by promoting the secretion of surfactants and improving the transport capacity of the ciliary epithelium [13,23,24]. This direct application allows for higher local drug concentrations compared to systemic delivery, which often fails to achieve therapeutic levels in the middle ear space without significant systemic side effects [12,14].

Eosinophilic otitis media should be considered in patients with recurrent or treatment-resistant middle ear effusion. This condition is characterized by eosinophil-rich, often highly viscous middle ear effusion and is commonly associated with bronchial asthma and chronic rhinosinusitis with nasal polyps [25,26]. It has been shown to respond well to corticosteroid therapy; therefore, IT corticosteroid administration may reduce local eosinophilic inflammation and improve middle ear symptoms [27].

To explore the heterogeneity observed in the PTA analysis, we combined the overlapping subgroup analyses into a single exploratory comparison between pediatric patients treated with IT methylprednisolone (MPS)+ventilation tube insertion (VTI) and adult patients treated with IT dexamethasone (DEX) without VTI. Both clinical profiles showed significant PTA improvement compared with their respective control groups, although the pooled effect was larger in the adult IT DEX without VTI profile. However, this finding should be interpreted cautiously because age group, corticosteroid type, and treatment strategy were completely collinear, with the same two studies contributing to each side of the comparison. Therefore, it is not possible to determine whether the larger effect was related to age, corticosteroid type, or VTI use, and the result should not be interpreted as evidence that one patient group or treatment approach is superior to the other. The nonsignificant findings in the study-design subgroups should also be interpreted cautiously because of the small number of studies and limited statistical power. Although all four individual studies reported statistically significant improvements in PTA favoring IT corticosteroid therapy, the pooled estimates did not reach statistical significance in either the RCT or nonrandomized-study subgroup, likely because of the small number of studies, substantial clinical heterogeneity, and resulting wide CIs. In adult cohorts resistant to conventional antibiotics and decongestants, Paksoy, et al. [22] reported a substantial air-bone gap improvement of 9.91 dB following IT dexamethasone. Similarly, Barati, et al. [20] found that adult patients achieved faster audiological recovery, with a mean air-bone gap of 16.4 dB at one month compared to 24.7 dB in those receiving standard saline irrigation and intranasal steroids. Although these individual findings support a potential benefit of IT steroid therapy in treatment-resistant OME, they cannot establish whether the observed improvement was independently related to adult age, IT DEX administration, or the absence of VTI.

Although the PTA estimates were statistically significant, their clinical relevance should be interpreted cautiously. The overall improvement of approximately 5.6 dB may be close to the test-retest variability of pure-tone audiometry, while the additional improvement of approximately 4 dB observed in the pediatric IT MPS plus VTI profile was modest and may not represent a clearly perceptible or clinically meaningful hearing benefit. Future trials should prespecify clinically meaningful hearing thresholds and incorporate patient-centered outcomes, including functional hearing, communication, and quality of life.

An important finding of the present analysis was the lack of significant improvement in Type A tympanogram normalization, despite the significant audiological improvement observed in PTA and air-bone gap outcomes. Since tympanogram normalization reflects restoration of middle ear ventilation and complete effusion resolution, this negative finding should be interpreted carefully. In the exploratory combined subgroup analysis, neither pediatric patients treated with ITS+VT nor adolescent/adult patients treated with ITS without VT showed a significant improvement in Type A tympanogram normalization, and the difference between the two clinical profiles was not statistically significant. Also, separate subgroup analyses according to corticosteroid type and study design also showed no significant improvement. This may indicate that IT corticosteroid therapy primarily improves hearing by reducing mucosal inflammation and effusion viscosity rather than fully restoring Eustachian tube function or middle ear pressure regulation. Therefore, while IT steroid therapy may provide meaningful functional hearing benefits, its effect on complete middle ear physiological recovery remains uncertain and warrants further investigation with longer follow-up durations.

Differences in corticosteroid formulation and clinical setting may have contributed to between-study variability. At the individual-study level, Yang, et al. [13] reported more sustained effects with lipophilic budesonide than with water-soluble dexamethasone. The lipophilic properties of budesonide may allow it to form fatty-acid conjugates within the middle ear mucosa, potentially prolonging local drug exposure [13]. Moreover, Amer, et al. [14] and Abdelazeem, et al. [19] reported reductions in postoperative tympanosclerosis within the pediatric IT corticosteroid-plus-VTI clinical context.

The findings of this meta-analysis may have important implications for the management of persistent or treatmentresistant OME. Current guidelines, including those of the AAO-HNS, emphasize the generally favorable natural history of OME while recognizing the limited effectiveness of standard medical therapy [6]. Our results suggest that IT steroid therapy may represent a useful adjunctive or rescue option for patients who do not respond adequately to conventional treatment. The observed reductions in OME recurrence (RR=0.27) and tympanosclerosis (RR=0.21) may help reduce the consequences of prolonged conductive hearing loss and repeated middle ear interventions [24]. For adults with chronic Eustachian tube dysfunction, this therapy offers a less invasive alternative to repeated VTI, which is often associated with permanent perforation and chronic otorrhea.4,22

The strengths of this meta-analysis include the evaluation of both audiological and clinical safety outcomes, the use of study-design-specific risk-of-bias tools, and the application of leave-one-out sensitivity analyses. Low heterogeneity was observed for several secondary outcomes, including air-bone gap improvement, OME recurrence, tympanosclerosis, and treatment-related adverse events. The leave-one-out sensitivity analysis indicated that no single study disproportionately influenced the overall PTA estimate. To ensure methodological transparency, the complete collinearity among age group, corticosteroid type, and VTI strategy was explicitly recognized, and these variables were combined into bundled clinical profiles rather than analyzed as independent treatmenteffect modifiers.

However, several limitations warrant cautious interpretation of these findings. Substantial heterogeneity was observed in the overall PTA analysis (I²=71.88%), which may reflect differences in corticosteroid type, dosage, administration frequency, comparator treatment, patient characteristics, and follow-up duration across the included studies. Most importantly, treatment strategy, corticosteroid type, and age group were completely collinear in the PTA analysis because the pediatric studies evaluated IT MPS+VTI, whereas the adult studies evaluated IT DEX without VTI. Similarly, age group and VT use were completely collinear in the Type A tympanogram analysis because the pediatric study evaluated ITS+VT, whereas the adolescent/adult studies evaluated ITS without VT. Consequently, these subgroup comparisons represented bundled clinical profiles and could not identify any individual characteristic as an independent treatment-effect modifier. We were unable to perform a patient-level analysis for the PTA outcome because all contributing studies reported earlevel data and did not provide the paired summary statistics or within-patient correlations required for valid adjustment. The restriction to English-language publications, may have resulted in the omission of relevant evidence and introduced potential language and selection bias. Follow-up durations ranged from 1 to 24 months, and outcomes were assessed at different time points across studies, which may have limited direct comparability and contributed to PTA heterogeneity. Publication-bias assessment was not performed because Doi plots, Luis Furuya-Kanamori Index indices, funnel plots, and regression-based tests are unreliable when only a small number of studies are available. The included studies generally had small sample sizes. Moreover, the pediatric IT corticosteroid-plus-VTI clinical profile for Type A tympanogram normalization was represented by only one study, further limiting the precision and reliability of that profile estimate.

In conclusion, IT corticosteroid therapy may represent a potential adjunctive or rescue option for persistent or treatment-resistant OME. It was associated with PTA improvement within two bundled clinical profiles, improvement in the air-bone gap, and reductions in OME recurrence and tympanosclerosis, with no statistically significant increase in adverse events detected. However, the absence of significant improvement in Type A tympanogram normalization, the substantial heterogeneity in PTA outcomes, and the complete collinearity of key clinical variables require cautious interpretation. Future large, multicenter RCTs should determine standardized dosing strategies, evaluate clinically meaningful and patient-centered hearing outcomes, and assess long-term safety and cost-effectiveness. Until such evidence is available, the use of IT corticosteroid therapy as a rescue or adjunctive treatment should be individualized.