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Year : 2019  |  Volume : 25  |  Issue : 3  |  Page : 155-161

Intranasal hyaluronic acid improves the audiological outcomes of children with otitis media with effusion

1 Department of Translational Medicine, Otolaryngology, University of Rome “Tor Vergata,” ,Rome, Italy
2 Department of Translational Medicine, Otolaryngology;Departement of System Medicine, Neuroscience Unit, University of Rome “Tor Vergata,” Rome, Italy
3 Department of Environmental and Occupational Medicine, National Institute for Insurance Against Accidents at Work (INAIL), Rome, Italy
4 Department of Applied Clinical Sciences and Biotechnology, L'Aquila University, Coppito, Italy

Date of Submission12-Nov-2018
Date of Decision09-Jun-2019
Date of Acceptance19-Jun-2019
Date of Web Publication18-Oct-2019

Correspondence Address:
Dr. Federica Martino
Viale Giulio Agricola, 6 00174 Rome
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/indianjotol.INDIANJOTOL_107_18

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Background/Aim: We evaluated the efficacy and compliance of a therapeutic approach based on intranasally-administered hyaluronic acid (HA) in the treatment of chronic otitis media with effusion (OME) in pediatric patients. Materials and Methods: Forty-four pediatric patients were enrolled and randomized into two groups: the first one (Group A) received a treatment based on HA and Group B was treated with saline solution only. Both therapies were intranasally administered by compressed-air nebulizer and Rinowash, a nebulizer designed to treat the upper airway structures. Patients were evaluated by medical history, otoscopy, pure-tone audiometry, and impedentiometry at 0 (T0), 4 (T1), 12 (T2), and 16 (T3) weeks. Results: The analysis of tympanometric and audiometric data, such as the evaluation of otoscopic improvements, showed significant differences between the two groups. After just 1 month of therapy, (T1) tympanometric evaluation showed greater improvements in Group A. Data on the audiometric threshold improvements, measured at different stages of the treatment, showed a greater improvement of the mean/median value of the auditory thresholds in patients treated with HA than in patients of Group B. Conclusion: The absence of side effects and the results observed make this therapeutic approach a potential valid alternative in the difficult long-term management of OME.

Keywords: Children hearing loss, hyaluronic acid, medical treatment, otitis media with effusion, rinowash

How to cite this article:
Topazio D, Passali FM, Cama A, Martino F, Mauro RD, Tirabasso A, Varakliotis T, Girolamo SD. Intranasal hyaluronic acid improves the audiological outcomes of children with otitis media with effusion. Indian J Otol 2019;25:155-61

How to cite this URL:
Topazio D, Passali FM, Cama A, Martino F, Mauro RD, Tirabasso A, Varakliotis T, Girolamo SD. Intranasal hyaluronic acid improves the audiological outcomes of children with otitis media with effusion. Indian J Otol [serial online] 2019 [cited 2022 Jan 26];25:155-61. Available from: https://www.indianjotol.org/text.asp?2019/25/3/155/269545

  Introduction Top

The otitis media with effusion (OME) is defined as chronic inflammation of the middle ear characterized by the accumulation of nonpurulent fluid in the middle ear space, with no symptoms and signs of acute inflammation.[1],[2] It has multiple etiologies and unknown pathogenesis. Its onset may be related to upper airways inflammations, adenoid hypertrophy, craniofacial anomalies, and local or systemic immunitary disorders often related to  Eustachian tube More Details dysfunctions.[3],[4] OME has a negative impact on patients' quality of life as various degrees of hearing impairment may affect patients since childhood.[5],[6] In younger patients and in the most severe cases, the hearing loss can result in language disorders and neurocognitive deficits.[7] Although the absence of acute symptoms makes it difficult to elaborate epidemiological assessment, it is estimated that 80% of children experience at least one episode of otitis media during their childhood, with a peak of incidence between 1 and 5 years old.[8] OME occurs commonly during childhood; as much as 90% of children (80% of individual ears) have at least 1 episode of OME by the age of 10. Many episodes of OME resolve spontaneously within 3 months, but 5%–10% of episodes last >1 year; 30%–40% of children have recurrent episodes.[9],[10],[11]

Because of the great variability in OME evolution, it is recommended to observe patients for 3 months at least before starting therapy. Pharmacological treatments with antihistamines, decongestants, antibiotics, and corticosteroids have shown partial and short-term efficacy. The surgical approach is only recommended in cases of persisting OME for at least 4 months or in cases of severe hearing impairment.[12]

Biological and clinical experimental observations have justified the use of hyaluronic acid (HA) in various medical fields including otolaryngology.[13],[14]

The aim of the present study is to evaluate the efficacy of HA (Yabro®), intranasally administered by Rinowash nasal douche, a nebulizer designed to treat upper airway structures that nebulizes particles with a median aerodynamic diameter of >10 μ, as adjuvant treatment of childhood OME, compared to the treatment based on saline solution only.

  Materials And Methods Top

In this prospective randomized study, as inclusion criteria, we enrolled children with an age range of 4–10 years old, who experienced bilateral conductive hearing loss with exudative OME for more than 3 months at the time of recruitment, documented by medical history otoscopy and functional examinations (pure-tone audiometry [PTA] and tympanometry). OME is defined as a collection of fluid in the middle ear without signs or symptoms of acute ear infection. Fluid in the middle ear reduces tympanic membrane and middle ear function, leading to conductive hearing loss, “fullness” in the ear, and occasional pain resulting from pressure changes. Children with OME often have a conductive hearing loss on pure-tone audiometry that measures at 25 dB, a level, that is, 10 dB worse than the level for children with normal hearing.[15] On the contrary, we excluded children with unilateral OME, history of ear surgery or ear tubes, anatomical craniofacial abnormalities, adenoids hypertrophy (evaluated by video rhinoscopy), other acute or chronic concomitant inflammatory diseases of the upper airways, concomitant antibiotic or corticosteroids therapy, and children with bone conduction impairment at the PTA examination. Moreover, children with known risk factors for OME such as allergy or exposure to second-hand smoke, which were investigated thanks to a careful anamnestic collection conducted on parents, were not included in this study.

Patients were randomly divided 1:1 through a random number generator into two groups (22 patients per group). Those in Group A were treated with HA (Yabro®) administered by Rinowash micronized nasal douche, whereas patients in Group B were treated with intranasal saline solution administered in the same way.

The treatment schedules for patients in Group A included:

  • Three months of active treatment with Yabro® (1 ampoule) + saline solution (2 cc) once a day for the first 15 days of each month. In the remaining 15 days of each month, therapy consisted of saline nebulization only (twice a day)
  • A month of maintenance therapy with saline nebulization twice a day.

The treatment schedule for patients in Group B provided:

  • Four months of treatment with only saline intranasal nebulization, twice a day.

At the time of recruitment (T0), after 1 (T1), 3 (T2), and 4 (T3) months of therapy, all the patients were evaluated by PTA (hearing threshold was calculated for the frequencies of 250, 500, 1000, 2000, and 4000 Hz) and impedentiometry. Medical history was collected, and otoscopy was previously performed at every stage of the follow-up.

At the time of recruitment, parents were properly educated to exclusively use our therapeutic scheme on the treatment and to refer any antibiotic or anti-inflammatory therapy administered during the follow-up period to avoid distortions in our results. Verbal and written consent to the treatment was obtained for each patient from parents. All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional and National Research Committee, with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study protocol was approved by the Local Ethics Committee.

Statistical method

Statistical analysis was performed using the SPSS version. 17.0 Inc., Chicago, IL, USA. Available data were described using frequency distribution for categorical variables, and mean, median, standard deviation, and range for quantitative variables. To compare the frequency distribution, the Chi-square test (with Yates correction) was applied. A model of analysis of variance (ANOVA) was used to assess the effects of the treatment on the audiometric examination values. Tukey's post-hoc test was performed to examine the significance of audiometric differences.

  Results Top

We enrolled children and randomized them into two groups (22 in Group A and 22 in Group B); the studied population consisted of 33 males and 11 females with an average age range of 6.34 ± 1.83 years old [Table 1] and [Table 2]. Compliance and adherence to the treatment were excellent in both groups, and all the children were closely followed by parents and physicians during the follow-up months. There were no statistically significant differences in demographic characteristics between the two groups [Table 1] and [Table 2]. We analyzed the distribution of results of the tympanometric test, aggregated for all ears and assessed them at baseline and at different times of follow-up as well. At baseline (T0), a Type B tympanogram was found in 23 ears of Group B (52.27%) versus 18 in Group A (40.91%); a Type C tympanogram was found in 21 ears of Group B (47.73%) versus 26 of Group A (59.09%). After just 1 month of therapy (T1), the tympanometric evaluation showed greater improvements in Group A. The average improvement in tympanometry progressed throughout the subsequent stages of the therapy, up to T3 where 40.91% of the ears of patients in Group A showed a Type A tympanogram versus 18.18% of patients in Group B [Figure 1], [Figure 2], [Figure 3]. However, only after stage T3, the improvements resulted to be statistically significant (P = 0.019) by applying the Chi-square test with Yates correction [Table 3].
Table 1: Distribution of patients by gender and treatment group

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Table 2: Age

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Figure 1: Tympanogram (Type A, Type B, and Type C) detected at the various follow-up step (T0, T1, T2 E T3) for Group A

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Figure 2: Tympanogram (Type A, Type B, and Type C) detected at the various follow-up step (T0, T1, T2 E T3) for Group B

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Figure 3: Tympanogram (Type A, Type B and Type C) detected at the various follow-up step (T0, T1, T2 E T3) for Groups A and B

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Table 3: Prevalence of tympanogram types (A, B, or C) for all ears (per group) in the different stages of trial (T) and P (Chi-squared test)

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Data about the audiometric threshold improvements, observed in Groups A and B at the different stages of treatment, are listed in [Table 4].
Table 4: Note the significance of differences in pure-tone audiometry values between the two groups for each frequency (the only exception at 250 Hz between pure-tone audiometry values in T0 and T1)

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[Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8] show a greater improvement of the mean/median value of the auditory thresholds in patients treated with HA than in patients of Group B at the different stages of treatment.
Figure 4: Comparison of pure-tone audiometry differences in T0 and pure-tone audiometry values at T1, T2, and T3 follow-up step in the two groups (A and B) for 250 Hz

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Figure 5: Comparison of pure-tone audiometry differences in T0 and pure-tone audiometry values at T1, T2, and T3 follow-up step in the two groups (A and B) for 500 Hz

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Figure 6: Comparison of pure-tone audiometry differences in T0 and pure-tone audiometry values at T1, T2, and T3 follow-up step in the two Groups (A and B) for 1000 Hz

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Figure 7: Comparison of pure-tone audiometry differences in T0 and pure-tone audiometry values at T1, T2, and T3 follow-up step in the two Groups (A and B) for 2000 Hz

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Figure 8: Comparison of pure-tone audiometry differences in T0 and pure-tone audiometry values at T1, T2, and T3 follow-up step in the two Groups (A and B) for 4000 Hz

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Furthermore, a model of ANOVA with Tukey post-hoc test was applied and showed significant differences in audiometric improvements between the two groups at the end of the 4-month therapy; no significant statistical differences were found for the frequency of 250 Hz between T0 and T1.

  Discussion Top

OME is frequently observed in the pediatric population. It has chronic course, multifactorial etiology, and uncertain pathogenesis.[16] It is characterized by the accumulation of exudate at the level of the tympanic cavity, which leads to a conductive hearing loss of various degrees.[17],[18] It has a significant impact on the patients' quality of life and sometimes, in younger patients and the most severe cases, it can result in language disorders and neurocognitive deficits.[18]

At present, there is no long-term effective medical treatment for OME (20). On the contrary, ear tubes look effective in the management of OME, although their implantation is not without risks and side effects.[19]

Since bacterial agents and mediators of inflammation seem to be both involved in the OME pathogenesis, antibiotics and corticosteroids are the most used in the medical approach. Although the efficacy of antibiotics has been supported by several authors, their chronic use can lead, especially in children, to various side effects and the development of antibiotic resistance.[20]

The use of corticosteroids is still widely discussed. Persico et al. found a better response in patients treated with ampicillin and prednisolone compared to those treated with ampicillin only.[21] Niederman et al. showed better therapeutic responses after a 2-week daily treatment with dexamethasone compared with placebo.[22] Other studies reported a nonsignificant response to topical and systemic corticosteroids; Macknin and Jones found no improvements in treatments with dexamethasone for 2 weeks compared with placebo.[23]

Some years ago, the American Academy of Family Physicians, the American Academy of Otolaryngology, head-and-neck surgery, and the American Academy of Pediatrics Subcommittee on OME established that medical therapy with antibiotics and corticosteroids has not a long-term efficacy, and as a consequence, this treatment option should not be used as a routine treatment for OME.[24],[25]

HA is universally recognized as the major constituent of the extracellular molecular matrix and it is diffusely present at the level of the upper airways, where it plays a central role in respiratory physiology by acting in multiple homeostatic mechanisms.[26] The administration of HA prevents the diffusion of macromolecules, regulates the migration of cells involved in inflammatory processes, increases the tissue hydration facilitating the removal of allergens, and catabolizes.[27] It also integrates the glycoprotein component adjusting the mucociliary clearance, thus preventing the action of allergenic factors and/or inflammatory conditions.[28],[29]

Because of its pharmacological properties, HA has been widely used in several medical fields. in otorhinolaryngology, it has been tested and clinically used in inflammatory processes (chronic sinusitis, pharyngitis, tonsillitis, and rhinitis), in the phoniatric field, and in postoperative mucosal laryngeal and intranasal remodeling.[30],[31]

The absence of side effects, even in long-term treatments, and its intrinsic pharmacological properties make HA a potential ally in the treatment of OME.

Some studies have tested the effectiveness of the administration of HA in patients with upper airway diseases with positive preliminary results. Cioffi et al. have recently demonstrated clinically significant improvements in subacute and chronic OME thanks to intranasal administration of HA associated with hypertonic solution, compared with the administration of hypertonic solution alone. This study confirms the efficacy of HA in treatment, just by assigning scores to reference criteria such as the medical history (days of school lost), clinical items (sense of fullness in the ear and reported hearing loss), and otoscopic items (opaque eardrums, retraction, and hydro-aerial levels).[30] In addition, a recent study conducted by Torretta et al.[31] studied the efficacy of HA on the basis of endoscopic and clinical parameters. To the best of our knowledge, this study is the first to offer an instrumental and objective evaluation of the efficacy of HA in the treatment of OME, thanks to the use of impedentiometry and PTA, and compared with the previous studied, it confirms the safety and the document positive effect of topically administered HA solution on children with middle ear disease.

The analysis of the collected data showed statistically significant differences between the two groups in terms of tympanometric [Table 3] and audiometric improvements [Table 4] and [Figure 1], [Figure 2], [Figure 3], [Figure 4]. The results we obtained confirm the theoretical efficacy of the HA and make it a viable therapeutic alternative in the difficult management of patients with OME. Furthermore, the high tolerability of the proposed treatment along with the parents' degree of satisfaction for the experienced benefits seems to be essential for adequate compliance to therapy.[32],[33]

  Conclusion Top

The present trial shows how treatment with HA administered through the use of a nebulizer can be objectively adjuvant and has long-term benefits in OME. The absence of side effects, the high rate of adherence to therapy, and the objective improvements we experienced make this new therapeutic approach a valid ally in the difficult management of patients with OME.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]

  [Table 1], [Table 2], [Table 3], [Table 4]

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