INTRODUCTION
Obstructive sleep apnea (OSA) is characterized by recurrent episodes of partial or complete upper airway obstruction during sleep, resulting in intermittent hypoxia and fragmented sleep architecture. Clinically, it presents with symptoms such as loud snoring, gasping during sleep, and excessive daytime sleepiness [1]. Several anatomical and physiological factors contribute to OSA, including obesity, soft tissue hypertrophy, and craniofacial skeletal abnormalities. These can increase the tissue pressure around the upper airway, narrowing or collapsing during inspiration.
The site of obstruction in OSA is not uniform and can involve various levels of the upper airway, such as the retropalatal, retroglossal, and hypopharyngeal regions [2]. The retropalatal (behind the soft palate) and retroglossal (behind the tongue) sites are most commonly implicated. Identifying the specific anatomical level of obstruction is essential for diagnosis and tailoring treatment strategies, ranging from continuous positive airway pressure to site-specific surgical interventions [3].
Alterations in the natural anatomy of the eustachian tube(ET) and soft palate, along with the generation of negative intrapharyngeal pressure during obstructive episodes, are key contributors to eustachian tube dysfunction (ETD) in individuals with OSA [4]. Additionally, extraesophageal reflux, particularly laryngopharyngeal reflux (LPR), can lead to inflammatory changes in the nasopharynx and ET, further impairing function.
Gastroesophageal reflux disease (GERD) in patients with OSA may exacerbate ETD, highlighting the complex bidirectional interactions between these conditions [5,6]. This interaction likely stemmed from mechanical obstruction, mucosal inflammation, and pressure dynamics in the upper aerodigestive tract. Clinical studies have documented a high prevalence of LPR in OSA, and improvements in OSA symptoms following anti-reflux therapy further support a pathophysiological link between the two disorders [7].
Recognizing and addressing these overlapping mechanisms are crucial for the comprehensive management of patients with OSA, particularly those presenting with concurrent GERD or ETD.
This observational study investigated the potential correlation between the anatomical site of upper airway obstruction in OSA and the presence of ETD and reflux disorders. This study sought to offer deeper insights into the multifactorial interplay between OSA, ETD, and gastroesophageal reflux by exploring these associations. A better understanding of these relationships may facilitate more individualized and comprehensive management strategies for patients presenting with overlapping symptoms or comorbidities.
METHODS
This observational study will be conducted between January 2022 and June 2023. Ethical clearance was obtained from the AIIMS Institute Ethics Committee (approval numbers: IECPG-125/24.02.2022, RT-27/24.03.2022). The study was prospectively registered with the Clinical Trials Registry of India (CTRI) (under registration number: REF/2022/05/053914 [DE]).
Patients aged 18 years and above with a confirmed diagnosis of OSA via Level 1 polysomnography (PSG) were recruited after providing written informed consent. Initial screening for OSA involved validated clinical tools, including the STOP-BANG questionnaire and the Epworth Sleepiness Scale (EPSS), alongside direct clinical examination for upper airway anatomical abnormalities [8,9]. The EPSS is a self-report questionnaire that assesses daytime sleepiness by evaluating the likelihood of dozing off during various routine activities.
To determine the anatomical site of obstruction in the upper airway, patients underwent either apneagraphy or sleep MRI based on clinical feasibility and availability [10]. Further assessment included evaluation for reflux disorders and ETD using standardized instruments: the Eustachian Tube Dysfunction Questionnaire-7 (ETDQ-7) and the Gastroesophageal Reflux Disease Questionnaire (GERD-Q). Objective diagnostic tests such as pH monitoring and the Toynbee test were also conducted to substantiate the clinical findings. The exclusion criteria included patients younger than 18 years, having had surgery, or being unwilling to participate in the study.
All statistical analyses were performed using the IBM SPSS Statistics software (IBM Corp.). Fisher’s exact and chi-square tests were used to evaluate the associations between qualitative variables. The Mann–Whitney U test was used to compare quantitative variables between the groups, as the data did not follow a normal distribution. Statistical significance was set at p<0.05.
Acid feflux
Reflux symptoms were initially evaluated using the GERD-Q, a validated six-item instrument designed to assess the frequency, severity, and impact of GERD symptoms on the quality of life. Participants recalled symptoms over the preceding one-week period, with each item scored from 0 (never) to 3 (very frequent). A total score greater than 8 indicated a high likelihood of GERD.
For objective diagnosis, 24-hour in-house pH monitoring was performed using a pH/impedance monitoring catheter (outer diameter 2.3 mm, Comfortec, Z/pH catheters; Sandhill Scientific). Recordings were analyzed using BioView analysis software (Sandhill Scientific), with manual adjustments for accuracy. The software computed the DeMeester Score, a composite score derived from six parameters: reflux episodes, duration, and acid exposure time. A DeMeester Score of <14.7, indicating the absence of clinically significant reflux, was considered within the normal range (Fig. 1) [11].
Salivary pepsin
Saliva samples were collected in the early morning using sterile universal containers and immediately stored at 4°C. Samples were processed by cold centrifugation at 4,000 rpm for 15 minutes at 4°C. The supernatant was then aliquoted and stored at -20°C until further analysis.
For pepsin quantification, 100 µL of the thawed sample was added to the wells of a human pepsin (PP) ELISA kit (Catalog No: E-EL-H2050). The plates were incubated at 37°C for 90 minutes. On addition of all reagents, incubated again at 37°C for 15 minutes.
The optical density (OD) was measured spectrophotometrically at 450±2 nm. The OD value was directly proportional to the sample’s concentration of human PP. Final pepsin concentrations were calculated using a standard curve generated from known concentrations of the standard.
ET function
ET function was assessed using both subjective and objective methods. The ETDQ-7 was administered to all participants. This validated instrument consists of seven questions, each scored on a scale of 0 to 7, reflecting the frequency and severity of symptoms over the past month [12]. A total score of ≤14.5 was considered within normal limits, whereas scores above 14.5 indicated possible ETD.
In addition to the questionnaire, the Toynbee test was performed to objectively assess the tubal function. In this test, the middle ear pressure was increased to 250 daPa, and the patient was instructed to swallow repeatedly. The ET function was partially impaired if residual pressure remained after five swallows. The function was completely impaired if no pressure neutralization occurred, indicating complete ETD [13,14].
Site of obstruction
Apneagraphy: a multi-channel pressure catheter was employed to accurately determine the anatomical site of upper airway obstruction in patients with OSA. This device typically comprises four transducers: two pressure sensors, two temperature sensors, and a positional marker located at the lower border of the soft palate. Proper positioning of the measurement points is essential for correctly attributing obstruction to specific airway segments [15]. Obstruction was categorized based on the pattern of pressure and temperature changes as upper airway obstruction (typically occurring at the level of the palate) or lower airway obstruction, typically at the base of the tongue (retroglossal).
The catheter was programmed to initiate recording at a predefined time and could continuously acquire data for up to six hours. After the sleep study was completed, the recorded data were analyzed using Apnea Analysis version 6.61 MRA software (MRA Medical). This software allowed a comprehensive review of pressure and temperature data, facilitating the identification of obstruction patterns and their severity (Fig. 2).
Sleep MRI was employed in select cases to localize the site of upper airway obstruction, particularly when apneagraphy was unavailable or malfunctioning. During the procedure, the participants were positioned supine with the neck in a neutral position inside the MRI gantry. Natural sleep was allowed without sedative medications, and vital signs were continuously monitored throughout the imaging session.
Dynamic imaging was triggered when the patient exhibited clinical signs of snoring and oxygen desaturation greater than 4%. MRI sequences were obtained from axial: T1 dynamic (awake and asleep) and T2 DIXON; sagittal: T1 dynamic (awake and asleep).
All sequences were obtained with a slice thickness of 4 mm in the midline sagittal and transverse planes, with a focus on the retroglossal and retropalatal regions. The anteroposterior diameter (cm), transverse diameter (cm), and reduction in the cross-sectional area (%) were evaluated for each zone.
A single radiologist reported throughout the study to ensure consistency and reduce interobserver variability (Fig. 3) [16].
Drug-induced sleep endoscopy (DISE) was reserved for cases where neither apneagraphy nor sleep MRI findings correlated with the clinical findings. However, DISE was not required for any of the patients in this cohort.
All statistical analyses were performed using GraphPad Prism Version 10.1.2 (GraphPad Software). The Shapiro–Wilk test was used to assess the normality of the data distribution. To compare quantitative variables, the Student’s t-test was used for parametric data, while the Mann–Whitney U test was used for non-parametric data. Statistical significance was set at p<0.05.
RESULTS
Demography
The study enrolled 63 subjects, 61 males and 2 females. The mean age of the participants was 40.4 years (range: 20–66 years) (Table 1). The mean body mass index (BMI) was 28.1 kg/m2. According to the Asian Body Mass Index classification, 10 participants were classified as overweight, 26 as preobese, and 21 as obese.
During OSA screening, the EPSS revealed that 35% of the participants had excessive daytime sleepiness, whereas 63% had an excessive need for daytime sleep. Based on the STOPBANG questionnaire, 62% of the patients were at high risk for OSA, and 38% were at moderate risk.
The mean Apnea-Hypopnea Index (AHI) was 36.1 episodes/hour (median: 32 episodes/hour). According to the AASM classification, 25% of patients had mild, 21% had moderate, and 54% had severe OSA. A statistically significant association was observed between BMI and OSA severity, with increasing severity in individuals with a higher BMI (Fisher’s exact test=19.2, p=0.001).
Site of obstruction
Of the 63 enrolled subjects, 57 (90.4%) underwent apneagraphy, while 6 underwent sleep MRI to determine the site of upper airway obstruction. Based on these findings, 48 patients (76.1%) had isolated or predominantly retroglossal obstruction, whereas 15 (23.9%) had isolated or predominantly retropalatal obstruction.
In total, 48 patients had retroglossal involvement, 15 had retropalatal involvement, and 27 exhibited obstruction at both levels. However, when classified based on the predominant site of obstruction, the 27 patients were divided as follows: 18 with retroglossal obstruction and 9 with retropalatal obstruction.
Regarding ETD, 36 patients were identified with subjective ETD based on the ETDQ-7 questionnaire, whereas 33 demonstrated objective ETD findings. The sensitivity and specificity of the ETDQ-7 in this cohort were 81.82% and 70%, respectively, with a positive predictive value (PPV) of (refer to Fig. 4).
In the GERD evaluation, 32 patients had subjective reflux symptoms, whereas 24 had objective findings based on pH monitoring. The GERD-Q showed a sensitivity, specificity, and PPV of 91.6%, 77%, and 71%, respectively. However, no statistically significant correlation existed between the DeMeester score and the obstruction site (Mann–Whitney test, p=0.74) (Fig. 4).
Among the 63 subjects analyzed, no statistically significant correlation was found between the site of obstruction (retropalatal vs. retroglossal) and the presence of ETD (chi-squared test, p=0.35) (Table 2). However, a significant association was observed between the obstruction site and ETD severity, suggesting that complete ETD is more likely in cases with retroglossal obstruction (p=0.02).
Additionally, there was no significant correlation between reflux disorders and the obstruction site (chi-squared test, p=0.66) (Fig. 5).
Of the 63 salivary pepsin samples analyzed, 56 had pepsin concentrations above 50 ng/ml, suggesting a reflux disorder. However, statistical analysis showed no significant correlation between salivary pepsin levels and the diagnosis of reflux disorder (Fisher’s exact test, p=0.412) or obstruction site (Mann–Whitney test, p=0.91) (Fig. 4).
DISCUSSION
OSA is a complex disorder with multifactorial causes that affects various anatomical structures and physiological systems. Negative pharyngeal pressure generated during apneic events can have widespread effects beyond the respiratory system. Anatomical modifications of the upper airway, such as obesity-induced narrowing and soft tissue hypertrophy, contribute to airway obstruction.
The proximity of key anatomical structures, such as the ET orifice and lower esophageal sphincter to the site of obstruction in the upper airway, may play a crucial role in OSA-related complications. Studies have established that OSA can compromise ET function and promote acid reflux. However, no direct correlation has been found between these effects and the specific sites of upper airway obstruction [17].
The proposed hypothesis suggests that obstructions at different sites may influence nearby structures differently. If the obstruction is retropalatal, the proximity of the soft palate to the ET orifice may contribute to ETD. Conversely, if the obstruction is retroglossal, it may affect LES function, potentially exacerbating acid reflux. Understanding these interactions is essential for developing comprehensive management and treatment strategies for patients with OSA.
Several methods, including apneagraphy and sleep MRI, have been used to localize the obstruction site in OSA [2]. The variability in these methods highlights the inconsistencies in findings across different studies and underscores the complexity of accurately determining obstruction sites.
Apneagraphy involves a detailed evaluation of sleep in a physiological position under natural and comfortable conditions [15]. This method typically records data overnight while patients sleep in their habitual position, offering a more precise localization of the obstruction site. However, otolaryngologists do not commonly use it.
In contrast, sleep MRI and DISE are more widely adopted but have inherent limitations. Both require patients to be supine, which may not reflect their natural sleeping posture [16]. This artificial positioning could influence the results owing to gravity-dependent airway dynamics. Additionally, these procedures are conducted in a clinical setting (such as an operating theatre or radiology suite), which differs from the patient’s usual sleep environment and potentially affects the findings. Moreover, these investigations did not cover the entire sleep period, which may limit their ability to comprehensively assess obstruction sites.
Rama et al. [2] reported that current techniques, including catheter-based studies, CT, and MRI, may not consistently achieve the precise localization of obstruction sites in patients with OSA. Their study found that the primary site of obstruction was often the oropharynx, with frequent extension into the laryngopharynx. However, Rollheim et al. [18] and Rama et al. [2] also noted that airway collapse in OSA is often a combination of multiple levels, and isolated upper or lower airway obstruction is rarely observed.
Recent findings indicate that the retroglossal obstruction is the predominant site of collapse, which contradicts earlier studies by Singh et al. [15] and Achar and Kumar [19]. Additionally, Steinhart et al. [20] reported that upper airway narrowing is generally more pronounced in patients with OSA than in simple snorers, further emphasizing the complexity of obstruction patterns in OSA.
This is the first study to investigate the relationship between the site of obstruction in sleep-related breathing disorders (SRBD) and reflux disorders. Previous studies by Shepherd et al. [21] and Kuribayashi et al. [22] demonstrated that negative intrathoracic pressure can cause acid reflux into the esophagus.
Interestingly, despite the higher negative pressure generated by retroglossal obstruction than retropalatal obstruction, no significant difference in the occurrence of reflux was observed (p=0.18). Many patients in this study had mixed obstructions, indicating that the airway collapse occurred simultaneously at multiple sites. This complexity makes it challenging to attribute reflux to a single obstruction site.
Additional factors not assessed in this study may also influence the relationship between the obstruction site and reflux disorders. These include anatomical variations, physiological differences, and comorbidities. Given that the findings suggest that retroglossal collapse may affect the ET and lower esophageal sphincter function, further research is needed to explore these interactions and improve our understanding of their clinical implications.
Salivary pepsin is not a reliable indicator of reflux disorders because various epidemiological factors influence its levels. One key issue is the lack of standardized cutoff values in different studies. In a 2018 meta-analysis, Guo et al. [23] demonstrated that salivary pepsin has only moderate diagnostic value for GERD and is not as clinically useful as previously believed. This limitation may stem from the heterogeneous study populations and variability in detection methods, contributing to inconsistent findings across studies.
Studies have shown that epithelial cells can internalize pepsin and reactivate in the Golgi complex at a pH of approximately 5.0. This reactivation may contribute to mitochondrial and Golgi complex damage, leading to cellular destruction at acidic and neutral pH levels. Consequently, salivary pepsin concentrations may not accurately reflect the true quantity of active pepsin in the system [11].
A population-based study suggested a significant association between SRBD, including OSA, and ETD. Patients with SRBD have a 1.54 times higher risk of developing ETD than those without such disorders [17].
In patients with OSA, inspiratory and expiratory upper airway resistance values were higher than those normal subjects during wakefulness and sleep. This increased resistance reflects the compromised airflow dynamics, which can contribute to ET dysfunction.
Moreover, classification based on ETD severity indicated a stronger association with retroglossal obstruction, particularly in cases of complete dysfunction. Respiratory muscles generate forces that decrease intraluminal upper airway pressure to maintain upper airway patency during inspiration. This tendency toward airway collapse further compromises ET function and exacerbates dysfunction in patients with OSA [24].
The severity of upper airway obstruction at different sites may affect ET function differently. The absence of a significant correlation between retropalatal obstruction and ETD suggests that factors other than anatomical obstruction at this site may contribute to ETD.
However, classification based on ETD severity revealed a strong association with retroglossal obstruction, particularly in cases of complete dysfunction. Retroglossal obstruction may exert greater pressure or influence on the ET, leading to its dysfunction. Additionally, GERD can cause peritubal inflammation, potentially contributing to ETD independent of upper airway obstruction. This aligns with our findings that showed a higher prevalence of ETD in patients with retroglossal obstructions [25].
Various confounding factors, including comorbidities and physiological mechanisms, may influence the relationship between upper airway obstruction and ET function. Although retropalatal obstruction does not appear to correlate directly with ETD, retroglossal obstruction—especially in the presence of negative pressure, GERD, or peritubal inflammation—may significantly impair ET function. Given the observed association between retroglossal obstruction, ETD, and GERD, a larger sample size is required to establish a definitive correlation.
Obesity and sinusitis are more prevalent in patients with OSA than in healthy individuals. These comorbidities can independently contribute to both ETD and GERD, making it difficult to determine the specific impact of the obstruction site on these disorders.
Nevertheless, the observation that ETD and GERD are more frequently associated with retroglossal obstruction suggests a potential link between the site of upper airway collapse and the development of these conditions in patients with OSA. However, multiple confounding factors complicate the establishment of a definitive relationship.
This study underscores the influence of retroglossal obstruction on both GERD and ETD, emphasizing the importance of personalized treatment strategies for the management of OSA. A multidisciplinary approach involving otolaryngologists, pulmonologists, and gastroenterologists is essential for comprehensive and effective patient care.
Large-scale studies that account for anatomical variations, physiological mechanisms, and coexisting conditions are needed to better define the relationship between obstruction sites and associated disorders. Ultimately, refining diagnostic techniques and implementing collaborative patient-specific treatment plans can improve outcomes in patients with OSA and concurrent GERD and ETD.
Conclusion
Both retroglossal and retropalatal obstructions may contribute to the development of ETD and GERD. A significant association between retroglossal collapse and complete ETD was identified, suggesting potential anatomical and functional interplay between lower pharyngeal obstruction and middle ear ventilation mechanisms. However, no correlation was found between the site of obstruction and GERD/LPR or between salivary pepsin levels and reflux symptoms, indicating a more complex or multifactorial relationship. Large-scale controlled studies are required to establish definitive correlations.
PDF Links
PubReader
ePub Link
XML Download
Full text via DOI
Download Citation 
Print 
