Eustachian tube dysfunction in patients with house dust mite-allergic rhinitis

Background One of the important pathogeneses of eustachian tube dysfunction (ETD) is nasal inflammatory disease. The prevalence of allergic rhinitis (AR) in adults ranges from 10 to 30% worldwide. However, research on the status of eustachian tubes in AR patients is still very limited. Methods This prospective controlled cross-sectional study recruited 59 volunteers and 59 patients with AR from Sun Yat-sen Memorial Hospital. Visual analogue scale (VAS) scores for AR symptoms and seven-item Eustachian Tube Dysfunction Questionnaire (ETDQ-7) scores were collected for both groups. Nasal endoscopy, tympanography and eustachian tube pressure measurement (tubomanometry, TMM) were used for objective assessment. All AR patients underwent 1 month of treatment with mometasone furoate nasal spray and oral loratadine. Then, the nasal condition and eustachian tube status were again evaluated. Results TMM examination revealed that 22 patients (39 ears, 33.1%) among the AR patients and 5 healthy controls (7 ears, 5.9%) had abnormal eustachian pressure. Twenty-two AR patients (37.3%) and 9 healthy controls had an ETDQ-7 score ≥ 15. With regard to nasal symptoms of AR, the VAS scores of nasal obstruction were correlated with the ETDQ-7 scores, and the correlation coefficient was r = 0.5124 (p < 0.0001). Nasal endoscopic scores were also positively correlated with ETDQ-7 scores, with a correlation coefficient of 0.7328 (p < 0.0001). After 1 month of treatment, VAS scores of nasal symptoms, endoscopic scores and ETDQ-7 scores were significantly decreased in AR patients (p < 0.0001), and TMM examination also suggested that eustachian tube function was significantly improved after treatment (p < 0.0001). Conclusions AR patients, especially those with severe nasal obstruction, could have ETD. The local conditions of the pharyngeal orifices of the eustachian tubes are closely related to the symptoms of ETD. After treatment with nasal glucocorticoids and oral antihistamines, eustachian tube function can significantly improve as nasal symptoms subside. Trial registration Chinese Clinical Trial Registery (ChiCTR2000029071) Registered 12 January 2020—Retrospectively registered, http://www.chictr.org.cn/edit.aspx?pid=48328&htm=4


Background
Eustachian tubes maintain middle ear ventilation and pressure balance, enable mucus clearance and protect the middle ear from pathogens and sounds. Eustachian tube dysfunction (ETD) is estimated to affect 1% of adults and 40% of children [1][2][3]. Prolonged EDT may cause otitis media effusion (OME), especially in children. Obstructive ETD, the most common subtype, usually results from Page 2 of 11 Ma et al. Clin Transl Allergy (2020) 10:30 inflammatory conditions. For example, smoking, chronic rhinosinusitis (CRS), allergic rhinitis (AR) and laryngopharyngeal reflux [4] have been proposed as potential contributing factors affecting eustachian tube function [5]. Some studies have shown that the incidence of ETD in CRS patients is 48.5-68% [6,7]. AR affects more than 500 million people worldwide [8]. In China, the prevalence of self-reported AR has been reported to be 9.8% in children and 17.6% in adults [9], and it is still rising [10]. According to the severity of symptoms and quality of life, AR could be divided into mild and moderate-severe AR [8]. Moderate-severe AR is more likely to affect the quality of life and social functioning than mild AR [11,12]. ETD is widely considered to be an important comorbidity associated with AR [13]. However, the nasal symptoms of AR are uncomfortable and might cause patients not to notice ETD symptoms. Lack of proper control of AR for long periods may lead to chronic ETD that necessitates further treatment or even balloon dilation of the eustachian tube (BDET) [14][15][16]. However, to date, the precise incidence of ET inflammation in AR and the therapeutic efficacy of anti-allergy treatment for ETD have not been well characterized.
The aim of this study was to comprehensively assess eustachian tube function in patients with AR and to determine the main nasal symptoms and local factors that contribute most to ETD.

Study subjects
This study was approved by the Sun Yat-sen Memorial Hospital Institutional Review Board. We recruited consecutive adult AR patients (aged 18-60) who visited Sun Yat-sen Memorial Hospital from June 2019 to January 2020 due to their nasal symptoms. The AR subjects represented the outpatients of ENT clinic in a tertiary hospital. AR was diagnosed according to the criteria of the Initiative on Allergic Rhinitis and its Impact on Asthma (ARIA) [17]. The inclusion criteria included (1) clinical symptoms of AR evidenced by nasal obstruction, itching, sneezing and watery rhinorrhoea; (2) pale nasal mucosa, watery secretions or inferior turbinate hypertrophy; and (3) a positive skin prick test (SPT) for house dust mite or specific immunoglobulin E (sIgE) to Dermatophagoides pteronyssinus (Der p1). The exclusion criteria were as follows: (1) a history of CRS or rhinitis; (2) a history of chronic otitis media (COM) or otitis media with effusion (OME); (3) a history of acute upper respiratory tract infection (AURT) in the last 4 weeks and (4) a history of glucocorticoid or antihistamine use within the last 4 weeks. Healthy volunteers aged 18-60 were collected at the same time for control group. The inclusion criteria for control group included (1) without any nasal or ear symptoms; (2) no abnormal nose and ear signs were found by endoscopy and (3) SPT excluded allergic diseases. The exclusion criteria were as follows: (1) a history of CRS, rhinitis; (2) a history of COM or OME; (3) a history of AURT in the last 4 weeks and (4) a history of glucocorticoid or antihistamine use within the last 4 weeks. We eventually included 59 AR patients and 59 healthy controls. More details for the definition of AR could be found in Additional file 1: Table S1-2 and Figure S1.

Evaluation and intervention
All patients were asked to complete a visual analogue scale (VAS) assessment for nasal symptoms, because the VAS score was significantly related to the rhinoconjunctivitis quality of life questionnaire (RQLQ) score and was considered a simple and effective method for assessing AR [18]. The severity of AR was classified as "mild" or "moderate/severe" on the basis of four symptoms (sleep disturbance, impairment of daily activities, leisure and/ or sport, impairment of school or work, and troublesome symptoms). We defined as mild AR if all symptoms were absent, moderate/severe AR if there was at least one symptom [8]. The VAS score for each symptom ranged from 0 to 10. The 7-item Eustachian Tube Dysfunction Questionnaire (ETDQ-7) was used for evaluation of ETD symptoms, and the threshold for ETD was considered to be a score of 14.5, as described in a previous study [19]. Then, nasal endoscopy was performed to record the endoscopic score, and acoustic immittance and eustachian tube pressure measurement (tubomanometry, TMM) tests were performed to evaluate eustachian tube function. Tympanogram tracings are classified as type A (normal), type B (suggesting fluid in the middle ear space), and type C (indicating a significantly negative pressure in the middle ear).The Tubomanometry (SPIG-GLE & THEIS Medizintechnik GmbH, Germany) was used for eustachian tube pressure measurement. With the application of excess pressure into the nose and rhinopharynx during swallowing, the tubomanometry can record the opening parameters of the Eustachian tube and the pressure equalization function of the middle ear, which reflects the status of eustachian tube at the time of testing. A value of R < 1 in TMM were considered to be normal. The nasal endoscopic scores for the pharyngeal orifices of eustachian tubes ranged from 0 to 20, and the method and representative pictures are shown in Table 1 and Fig. 1. All the AR patients took loratadine 10 mg and mometasone furoate sprayed twice on each nostril daily for 1 month. Other treatments including nasal lavage and nasal decongestants were not allowed in this study. After 1 month of treatment, all the parameters above were assessed again.

Statistical analysis
Statistical analysis was performed with GraphPad Prism (ver-sion 7.00 for MacOS, GraphPad Software, La Jolla, San Diego, CA, USA; http://www.graph pad.com). Descriptive analyses were utilized to describe the sample characteristics, and the data are presented as number (%), mean ± standard deviation (SD), or median (inter-quartile range, IQR) according to the tests of normality. The Chi square tests for categorical variables and the paired or unpaired Student's t tests or Wilcoxon rank sum tests for continuous variables were performed. Spearman or Pearson correlation coefficient analyses were applied to assess the correlation between VAS scores and ETDQ-7 scores, depending on the results of the normality test. Chi square tests were used to compare the categorical data. A p value < 0.05 was considered to indicate significance. Considering that the same patient has two ears, our statistical analyses for Tympanometry and TMM tests were performed on the number of ears.

Table 1 Nasal endoscopic for pharyngeal orifices of eustachian tube
Posterior turbinate swelling 0 = no swelling, 1 = mild (still has gap with nasal septum) 2 = severe (very close to nasal septum)

Results
A total of 59 new patients diagnosed with AR (118 AR ears) and 59 volunteers (118 healthy ears) were included in the study. The clinical characteristics of the two groups were shown in Table 2.
To explore the reasons for the poor improvements in eustachian tube function in the 8 AR patients, we compared the nasal conditions after treatment between these 8 AR patients with ETDQ scores ≥ 15 (the uncontrolled-ETD group) and patients with ETDQ scores < 15 (the controlled-ETD group). We found that after 1 month of treatment, the nasal obstruction VAS scores (p = 0.0019) and nasal endoscopic scores (p = 0.0006) were significantly higher in the uncontrolled-ETD group. This suggests that uncontrolled AR symptoms, especially nasal obstruction, might contribute to irreversible ETD (Fig. 4).

Discussion
ETD is a well-recognized comorbid manifestation of inflammatory diseases of the nasal cavity and nasal sinus [13]. However, due to the lack of appropriate ETD-specific assessment instruments, quantification of the prevalence of ETD had been limited before [20]. The TMM test was reported by Estève et al. [21] and has been widely used to evaluate eustachian tubes objectively [22]. The R value has a sensitivity of 0.91 in detecting the ET opening, but not specific [23]. Research showed that the interval correlation (ICC) was 0.68 for the TMM with 30 mbar, 0.62 for the TMM with 40 mbar and 0.61 for the TMM with 50 mbar in ETD patients, which means ET function change over time and TMM can only give a snapshot view on ET function [22]. The ETDQ-7 has been used as a validated patient-reported tool for assessment of the presence and severity of ETD symptoms since 2012. When 14.5 points are selected as the cut-off point, ETDQ-7 can provide 100% sensitivity and 100% specificity for classifying patients as ETD [19]. A recent study showed that the incidence of ETD in CRS patients is 48.5-68% [6,7]. However, the prevalence of ETD in AR and the relationship between these conditions are still poorly understood.
Nasal VAS scores and ETDQ-7 scores were used to assess symptoms of the nose and eustachian tubes in our study. According to the subjective symptom scores, approximately 37.3% of AR patients had ETD, while up to 51.4% of moderate/severe AR patients had ETD. Among the four major symptoms of AR, nasal obstruction showed a moderate correlation with ETDQ-7 score. This means that more severe AR or a greater degree of nasal obstruction is more likely to cause ETD. Many patients with severe AR are prone to concomitant inferior turbinate hypertrophy [24] and torus tubarius swelling, causing both nasal obstruction and ETD [25]. Previous studies have shown that patients with nasal obstruction due to inferior turbinate enlargement or nasal septum deviation have significantly higher ETDQ-7 scores than healthy controls [26]. These results suggest that nasal obstruction is closely related to ETD. Furthermore, studies on nasal aerodynamics have shown that nasal resistance is significantly increased during nasal obstruction and that oral breathing can cause negative pressure in the nasopharynx and further negative pressure in the middle ear, which could aggravate ETD [27]. Similarly, nasal  obstruction is also the most frequent nasal symptom in adult otitis media with effusion, which is considered closely related to ETD [28,29].
Objective measures were also included in our study. Tympanograms, TMM test results and nasal endoscopic scores were taken for every AR patient. According to the TMM test results, 33.1% of AR patients had ETD, and 44.6% had severe AR combined with ETD. Nasal endoscopic scores for the pharyngeal orifices of eustachian tubes exhibited a strong correlation with ETDQ-7 scores. This suggests that the local conditions of the pharyngeal orifices of the eustachian tubes are closely related to ETD. Moreover, we found that the same patients could have different nasal endoscopic scores on the left and right sides. This could also explain why some AR patients only had unilateral ETD.
Our study also revealed that treatment with loratadine and mometasone furoate effectively improved nasal symptoms and significantly decreased ETDQ-7 scores and the frequency of abnormal TMM test results in AR patients. Both objective and subjective scores showed good consistency before and after treatment. Intranasal corticosteroids and antihistamines are recommended for treating perennial AR [30]. Although these medicines can also be applied for ETD, there is little evidence on effective medical treatments for ETD [31,32]. Our study revealed that nasal steroids and antihistamines are efficient for ETD treatment in AR patients. However, it is worth noting that long-term use of these drugs may cause epistaxis, dry throat, and sedating antihistamines have been reported to cause seizures, sedation and gastrointestinal upset in children. Thus, it is important for a doctor to determine whether the potential efficacy of these treatments warrants the risk of side effects. In our study, only 2 patients had epistaxis and 5 patients had dry throat, any other side effects were not reported.

Limitation
To our knowledge, this is the first pilot study on ETD in AR and to find that AR can cause ETD. However, there are some limitations. First, our study involved a referral system and a single centre; thus, the ETD cases may not reflect the epidemiology of ETD in all AR populations. Second, this study was not based on a double-blinded, randomized controlled trial. Third, although certain characteristics, such as smoking, laryngopharyngeal reflux and atopy, are not known to be risk factors for ETD, these factors were not considered in our analysis. Then, other nasal symptoms like itching, sneezing and rhinorrhoea showed very weak correlations with ETDQ-7; this may be caused by insufficient sample size. Finally, we used only oral antihistamines and nasal mometasone furoate for AR patients with ETD; other treatment approaches that can help to improve eustachian tube function, such as Buteyko breathing and Valsalva training, were not included in our study.
In conclusion, AR patients, especially those with severe nasal obstruction, are more likely to have ETD than individuals without AR. ETD in patients with AR is mainly characterized by ear blockage and ear pressure, and the appearance of symptoms is usually associated with the onset of rhinitis, which should attract attention in clinical work. Both ETDQ-7 scoring and TMM are effective means of assessing eustachian tube function in AR patients. Regular treatment for AR can reduce patients' nasal symptoms and effectively improve eustachian tube function.  . 4 After 1 month of treatment in HDM-allergic rhinitis patients, improvements in nasal condition affect recovery from eustachian tube dysfunction (ETD). Nasal symptoms of itching (a), sneezing (c) and rhinorrhoea (d) were not significantly different between the controlled-ETD group (ETDQ-7 score < 15 after treatment) and the uncontrolled-ETD group (ETDQ-7 score ≥ 15 after treatment). The VAS scores for nasal obstruction (b) and the nasal endoscopic scores (e) were higher in the uncontrolled-ETD group than in the controlled-ETD group (p < 0.01) Ma et al. Clin Transl Allergy (2020) 10:30
Additional file 1. Table S1. The degree of skin prick test. Table S2. The degree of specific immunoglobulin E level in serum. Figure S1. Specific immunoglobulin E levels to the 8 common allergens in AR patients. Figure S2. Treatment results of nasal symptom, ETDQ-7 and endoscopic scores in AR patients compared with control group.