Introduction
Laryngopharyngeal reflux disease (LPRD) refers to inflammation of the pharyngeal or laryngeal mucosa due to reflux of the gastric and duodenal contents into the esophagus.Reference Salihefendic, Zildzic and Cabric1 The prevalence is extremely variable, ranging between 23.9 and 34.4 per cent among different populations, thereby demonstrating a significant burden of this disease in the community.Reference Massawe, Nkya, Abraham, Babu, Moshi and Kahinga2 If untreated, LPRD can result in various manifestations including chronic cough, throat irritation and voice changes due to the chronic inflammation of the laryngeal mucosa in response to contact with the corrosive refluxate. Some rarer but grave complications such as subglottic stenosis and laryngeal carcinoma have also been documented as a long-term sequela of LPRD.Reference Brown and Shermetaro3
The fact that the hypopharynx and larynx bear the brunt of the damage in chronic LPRD is well known. The acidic contents may however also reach up to the oropharynx and even as high up as the nasopharynx, especially when the patient is in a recumbent supine position. The Eustachian tube (which serves as a bridge between the middle ear and the nasopharynx) may therefore be exposed to the refluxate leading to Eustachian tube dysfunction due to mucosal oedema and inflammation.Reference Zhen, Zhao, Wang, Zhang and Zhong4 Therefore, the ventilation and drainage of secretions from the middle ear may be grossly affected leading to alteration of middle ear physiology. In the early stages of chronic LPRD, this change may be silent and the patient may not have any complaints attributable to the ear. However, even at this early stage, investigations may pick up abnormalities of middle ear function.
Even though the role of Eustachian tube in maintenance of middle ear physiology is well established, research into the role of LPRD in affecting middle ear function has been very limitedReference Mukherjee and Chatterji5 and a clear cause-and-effect relationship between the two has never been proven.
The present study aims to identify patients with silent middle ear dysfunction due to underlying LPRD and reassess their middle ear function after treatment with a standard regimen consisting of drugs such as proton pump inhibitors (PPI) and prokinetic agents.Reference Belafsky, Postma and Koufman6 Despite a rigorous search, we have failed to find any such similar work in the current medical literature.
Materials and methods
The study was a hospital-based prospective interventional cohort study carried out over a duration of six months. Before commencement of the study, clearance was taken from the Institutional Ethics Committee.
The objectives of the study were as follows: firstly, to identify patients with LPRD who have no apparent complaints related to the ear; secondly, to assess their middle ear function; thirdly, to administer a combination of PPI and prokinetic agents to those patients with abnormal middle ear function; fourthly, to assess the middle ear function at the fourth, sixth and eighth week of the treatment.
The exclusion criteria for the study were as follows: firstly, patients with known pre-existing otologic disease or those in whom otoscopy revealed the presence of abnormalities; secondly, patients with a history of upper respiratory tract infections in the month preceding the study or during the course of the study; thirdly, patients with any other comorbidities known to cause hearing loss.
Participants were counselled regarding the study and informed written consent was obtained.
Patients above 18 years of age presenting to the outpatient department of our hospital with complaints suggestive of LPRD with no pre-existing otogenic complaints were considered for participation. This was followed by a questionnaire to calculate the Reflux Symptom Index (RSI) (proposed by Belafsky et al.Reference Belafsky, Postma and Koufman6) which is a subjective scale where symptoms suggestive of LPRD are graded according to their severity. This was followed by endoscopic evaluation of the larynx and calculation of Reflux Finding Score (RFS) (also proposed by Belafsky et al.).Reference Belafsky, Postma and Koufman6, Reference Browning, Weir, Kelly and Swan7 Patients with RFS greater than or equal to 7 and RSI greater than or equal to 13 were considered to be suffering from LPRD.
All the cases were evaluated by pure tone audiometry (PTA) and tympanometry (using probe frequency of 226 Hz) for the assessment of middle ear function and findings were noted. Participants with deranged middle ear function were then chosen for further evaluation. Those patients were then prescribed a course of treatment for LPRD as per the standard regimen.Reference Browning, Weir, Kelly and Swan7 This involved the administration of PPIs twice daily to ensure a 24-hour coverage. Pantoprazole 40 mg was administered 12 hourly, with the morning dose being a fixed-dose-combination (FDC) of 40 mg Pantoprazole and 30 mg of Domperidone sustained-release capsules. This approach enabled the dual administration of both PPIs and prokinetic agents as part of the treatment regimen.
The patients were followed up serially after four, six and eight weeks, and PTA and tympanometry were repeated on each occasion to assess any changes in middle ear function.
Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, Version 23.0, IBM Corp, Armonk, NY) was used for statistical analysis of the results. Pearson’s chi-squared test, unpaired Student’s t-test and univariate logistic regression analysis were performed. All p-values of less than 0.05 was considered as statistically significant.
Results
A total of 50 participants with both LPRD and asymptomatic middle ear dysfunction were followed up for two months. Hence, a total of 100 ears were evaluated over the duration of the study.
The demographic distribution of cases is represented in Table 1 and Figure 1.
(A) Age distribution of participants. (B) Gender distribution of participants.
Distribution of patients according to age and gender
Maximum number of the participants (32 per cent) belonged to the age group of 41–50 years followed closely by those in the age group of 31–40 years (28 per cent). The mean age was found to be 41.7 ± 11.6115 years; 36 patients (72 per cent) were females and 14 patients (28 per cent) were males.
The distribution of the patients as per the pre-intervention and post-intervention PTA (after eight weeks of follow-up) are depicted in Table 2.
Prior to treatment, most of the patients had hearing thresholds between 25 and 35 dB with 66 per cent of the ears falling in that category. However, after eight weeks of treatment, 72 per cent of the ears had thresholds between 20 and 30 dB thus showing an improvement of hearing. Overall, the mean pre-treatment PTA for the 100 ears was 31.42 ± 7.67 dB, and the mean post-intervention PTA at the third follow-up (at eight weeks) was 28.24 ± 7.17 dB. Using the unpaired Student’s t-test, a significant improvement was found in the post-intervention hearing thresholds compared to the pre-treatment values (p = 0.003).
Figure 2A shows the data depicted in Table 2 in the form of the line diagram, with the shift of the curve to the left, thus depicting the improvement in hearing thresholds after eight weeks of treatment. Furthermore, Figure 2B depicts the decrease in the mean and the median PTA values over each serial evaluation, thus confirming a clear statistical improvement in auditory thresholds.
(A) Variation of pure tone average (PTA) between initial presentation and final follow-up after eight weeks. (B) Variation of mean and median PTA over each successive presentation.
Distribution according to PTA (pre-intervention) and PTA (post-intervention, at eighth week of follow-up)
PTA = pure tone average.
Tympanometry done at the initial visit and the third follow-up visit was also analysed statistically. Table 3 shows the comparison between the pre-intervention tympanometry and the post-intervention tympanometry (done at the eighth week of follow-up).
Distribution according to curve obtained on the tympanogram pre-treatment and at eighth week of follow-up (post-intervention)
Analysis of the tympanograms revealed that the proportion of A curves increased from 36 per cent to 74 per cent post-intervention, and that of B- and C-curves decreased from 56 to 26 per cent, and from 8 per cent to none, respectively. The data were found to be statistically significant using the Pearson’s chi-squared test (p < 0.001). It was also found that, while there was no change in the pattern of the curves during the first follow-up visit (at the fourth week), the proportion of B-curves started to reduce during the second follow-up visit (at sixth week) to 36 per cent, and that of the C-curves also decreased to half of the previous proportions (4 per cent). The above data, depicting the changes of the tympanogram curves are depicted in Figure 3A.
(A) Tympanogram variation: Pre-treatment, at sixth week and eighth week. (B) Variation of mean and median compliance over each successive presentation.
The mean and median compliance was also charted to find out improvement with each subsequent visit. The mean pre-treatment compliance was found to be 0.39 ± 0.49, and the mean post-treatment compliance was 0.7 ± 0.57. p-Value for the same was found to be less than 0.001 using the unpaired Student’s t-test. The variation of the compliance over the follow-up visits are depicted in Figure 3B.
Discussion
LPRD is a disorder that affects as many as every third individual in certain nations.Reference Mishra, Agrawal, Chauhan and Kaushik8 However, considering the significance of the disease, the relationship between middle ear disorders and LPRD is still an extremely new and emerging area of research with hardly any work being done in this field to date.
Prolonged impairment of middle ear ventilation due to long-standing Eustachian tube dysfunction can result in complications such as retraction pockets, middle ear atelectasis and adhesive otitis media. These may further lead to development of squamosal type of chronic otitis media with its own set of intra-cranial and intra-temporal complications over time.Reference Hamrang-Yousefi, Ng and Andaloro9 As LPRD may affect Eustachian tube function and cause altered middle ear physiology, the present study was designed to investigate if treatment of LPRD can reverse these changes and restore middle ear function. After extensive review of literature, we could not find any previous research work in this domain.
From the above study, it was found that most of the patients with LPRD and concurrent middle ear dysfunction presented in the age group of 41–50 years (32 per cent) followed by those in the age group of 31–40 years (28 per cent). The age group with the least affected individuals included those with ages more than 60 years (4 per cent). A study done by Massawe et al. showed that LPRD mostly affected individuals between the age group of 28 and 37 years. Individuals more than 68 years were least affected by the condition.Reference Massawe, Nkya, Abraham, Babu, Moshi and Kahinga2 Mishra et al. found that LPRD mostly affects middle aged individuals with 61 per cent of the participants belonging to the age group of 21 to 40 years.Reference Mishra, Agrawal and Artham10
Our study also demonstrated that a higher proportion of the disease is found among the female gender (72 per cent) and only 28 per cent affected were males. Mishra et al. in their study also found female preponderance (55 per cent).Reference Mishra, Agrawal and Artham10 However, Massawe et al. in their study failed to find any statistical correlation on the basis of gender with 51.2 per cent of the participants in their study being males and 48.8 per cent being females.Reference Massawe, Nkya, Abraham, Babu, Moshi and Kahinga2
Pantoprazole is a drug belonging to the benzimidazole subgroup of PPIs. It acts by irreversible inhibition of H+/K+ ATP pump resulting in reduced environmental pH.Reference Bernshteyn and Masood11 Domperidone increases the contractility of the gastric muscle by acting against the effects of dopamine on the neurons of the myenteric plexus.Reference Takahashi, Kurosawa, Wiley and Owyang12 The most effective regimen for treatment of LPRD involves administration of PPIs 12-hourly. Furthermore, some studies suggest that a combined administration of PPIs and prokinetics are superior to usage of PPIs alone.Reference Lechien, Mouawad, Barillari, Nacci, Khoddami and Enver13 The current study aimed to follow the above standardized approach for treatment of the participants. A treatment duration of two to three months has been suggested for symptomatic improvement of LPRD; hence, a similar time frame was kept for the present study.Reference Browning, Weir, Kelly and Swan7
In our study, we found that, after treatment for LPRD, there was a statistically significant improvement (p value = 0.003) in hearing thresholds following eight weeks of treatment. Moreover, tympanometry also showed improved middle ear function with the proportion of both B-curves (indicating fluid in the middle ear) and C-curves (indicating negative middle ear pressure) decreasing significantly and A-curves (indicating restoration of middle ear function) more than doubling in the patients after treatment. This finding was also statistically significant (p-value < 0.001). The reduction of the B-curves by 20 per cent and that of the C-curves by 4 per cent within six weeks itself was an indicator that silent middle ear dysfunction in the presence of LPRD can be reversed within six to eight weeks of treatment with anti-refluxates. This was also accompanied by an increase in the mean compliance values, which showed a continuous and steady rise with each follow-up visit.
The present study demonstrates that administration of anti-reflux therapy in patients with silent middle ear disease due to underlying LPRD can lead to a reversal of the middle ear dysfunction in a significant number of cases. This in turn will not only improve the middle ear function but also prevent the progression to other middle ear pathologies which are long-term sequelae of Eustachian tube dysfunction already outlined above.
• Laryngopharyngeal reflux disease (LPRD) can cause oedema and inflammation of the Eustachian tube mucosa. This can lead to middle ear dysfunction due to deranged function of the Eustachian tube. However, very little research had been done to study the association between LPRD and middle ear dysfunction and whether the alteration of middle ear function can be reversed by treatment of LPRD
• This study aimed to identify patients with LPRD with associated asymptomatic middle ear dysfunction and reassess if the latter can be reversed with treatment of LPRD
• Patients with Reflux Finding Score (RFS) greater than or equal to 7 and Reflux Symptom Index (RSI) greater than or equal to 13 were evaluated by audiological investigations, followed by administration of standard treatment for LPRD. Investigations were repeated on subsequent visits
• Over the course of treatment, a gradual improvement of auditory thresholds was noted along with improvement of middle ear compliance values in a significant number of cases
• LPRD may be a major factor in causing silent middle ear dysfunction. Prompt initiation of treatment for LPRD may be effective in restoration of normalcy of middle ear function
Conclusion
The sheer size of the population with LPRD denotes that it may be a major factor in the causation of Eustachian tube dysfunction and altered middle ear physiology. The latter, if long standing, can result in development of middle ear atelectasis and chronic otitis media and its associated complications over a period of time. Therefore, prompt detection of the impairment of middle ear function and early treatment of LPRD can prove to be a crucial step in rapid restoration of middle ear physiology and prevention of progress to other complications.
Data availability statement
Raw data was generated at Teerthankar Mahaveer Medical College and Research Center, Moradabad. Derived data supporting the findings of this study are available from the corresponding author on request.
Institutional ethics committee approval
IRB No and Date of Approval – IRB/12/2024, Date – 02/01/2024. Informed written consent was taken from the subjects regarding participation in the study. They were counselled regarding the study hypothesis, the investigations to be done and the fact that the study data would be sent for publication.
Source of support/grant
None.
Competing interests
None.
Disclaimer
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