Reflux finding score is associated with gastroesophageal flap valve status in patients with laryngopharyngeal reflux disease: a retrospective study

Endoscopic grading of gastroesophageal flap valve (GEFV) is simple and reproducible and offers useful information for reflux activity. To investigate the potential correlation between GEFV grading and reflux finding score (RFS) in patients with laryngopharyngeal reflux disease (LPRD), 225 consecutive Patients with suspected LPRD who underwent both routine upper gastrointestinal endoscopy and laryngoscope were enrolled in our study. Patients with a RFS of more than 7 were diagnosed with LPRD. The GEFV was graded as I through IV according to Hill’s classification and was classified into two groups: normal GEFV group (grades I and II) and the abnormal GEFV group (grades III and IV). The percent of GEFV grades I to IV was 39.1%, 39.1%, 12.4%, and 9.3%, respectively. Age was significantly related to an abnormal GEFV (p = 0.002). Gender, BMI, smoke and alcohol were not related to GEFV grade. Fifty-one patients (22.67%) had positive RFS. Reflux finding scores were higher in GEFV grades III and IV than I and II (p < 0.05). Endoscopic grading of GEFV is well correlated with reflux finding score in patients with LPRD. This is a simple and useful technique that provides valuable diagnostic information of LPRD.


RFS and EE.
For patients with EE, 46 (35.06%) a negative RFS and 17 (33.33%) had a positive RFS. There was no significant difference on RFS within the groups by endoscopic findings in oesophagus (p > 0.05) (see Table 4).

Discussion
Gastroesophageal reflux disease (GERD), a chronic disorder with increasing prevalence globally, is caused mainly by incompetence of the antireflux barriers at the oesophagogastric junction. The lower oesophageal sphincter (LES) along with the flap valve works together and forms a powerful antireflux barrier. The flap valve is formed by the oblique angle at which the oesophagus enters and integrates with the stomach. Once a system was created to describe and classify GEFV, there has been ongoing research assessing the relationship of endoscopic oesophagitis and gastroesophageal flap valve in patients with symptomatic gastroesophageal reflux [13][14][15] . In our study, we found that grade of GEFV was correlated with age of the patient and the oesophagitis. The findings that abnormal GEFV (grades III and IV) was more frequent in patients with oesophagitis and elderly patients are consistent with results of previous reports [13][14][15][16] . LES pressure was significantly lower and gastroesophageal reflux in the probe were significantly higher in the abnormal GEFV group compared to the normal GEFV group 14 .
Laryngopharyngeal reflux is an extraoesophageal variant of gastroesophageal reflux disease (GERD) that affects the larynx, pharynx, and upper aerodigestive tract. Patients presenting with extraoesophageal refluxrelated signs and symptoms are estimated to account for 10% of an otolaryngologist's practice. A wide spectrum of disorders has been associated with the presence of LPR, including chronic laryngitis, hoarseness, laryngeal carcinoma, globus sensation, cough, subglottic stenosis, vocal process granuloma, and possibly chronic sinusitis. However, at present, there is no validated instrument whose purpose is to document the physical findings and severity of LPR. The available diagnostic methods for LPR include 24 h ambulatory pH monitoring, gastroesophageal endoscopy, laryngoscope, and RSI. The 24 h ambulatory pH monitoring has good sensitivity and specificity, but the clinical application has been limited due its discomfort and its high cost. RSI is a noninvasive method for LPR, however its subjective nature causes the high possibility of response bias in patient self-assessment questionnaires. Laryngoscopy is still the standard for LPR diagnosis accompanied by the RFS. In addition, RFS may accurately document treatment efficacy in patients with LPR 17 . In our present study, we found that increased GEFV grade was significantly associated with an increased reflux finding score, and the frequency of LPR was significantly higher in the abnormal GEFV group compared to the normal GEFV group. Another study by Kaplan also showed that endoscopic grading of GEFV is a simple and useful technique that may provide an accurate diagnosis of laryngopharyngeal and gastroesophageal reflux 11 .
Although LPR is widely regarded as an extraoesophageal manifest of GERD, some researchers did not find significant relationship between LPR and endoscopic oesophagitis and stated that LPR and GERD are not the same diseases 18 . Interestingly, we also found that RFS had no correlation with endoscopic findings in oesophagus even though GEFV was correlated with both RFS and the oesophagitis. In the above-mentioned study 11 , Kaplan did not find any correlation between reflux symptom index and degree of oesophageal mucosal injury according to LA classification. Speculatively, abnormal GEFV plays an important role in GERD and LRP. Ultimately, our findings suggest that LRP may have a more complicated pathogenesis oesophageal motility patterns, the function of pharynx and upper oesophageal sphincter, and mechanisms of airway protection.
To our knowledge, the present study is the first study that evaluates the correlation between GEFV findings and RFS. We displayed the statistically significant relationship between the two most commonly used objective methods, i.e., gastroscopy and laryngoscopy. In recent years, minimally invasive endoscopic intervention of GEFV, such as anti-reflux mucosectomy (ARMS), has been introduced refractory GERD and achieved satisfactory results. Undoubtedly, our study provides theoretical basis for the feasibility of endoscopic treatment of LPR. However, this study has some limitations. Firstly, an obvious limitation of such an analysis is the retrospective, single-centered and non-randomized design inevitably leading to a selection bias. Secondly, oesophageal mucosal injury was not classified according to LA classification due to the small study population. Thirdly, RFS is non-specific. Although we have made some restrictions on the inclusion criteria of cases, it may be positive in some diseases that are difficult to be identified from LPRD, such as allergic rhinitis, vasomotor rhinitis or chronic rhinosinusitis. This could affect the analysis results to some extent. In addition, the patients did not undergo 24 h pH monitoring and RSI evaluation. Therefore, more comprehensive analysis is not possible due to the lack of such data.
In conclusion, the frequency of both GERD and LPRD was significantly higher in the abnormal GEFV group than in the normal GEFV group. We supposed that gastroesophageal endoscopy can be performed to ensure the diagnosis of LPR by evaluating the GEFV. Further research is needed in a larger sample and well-controlled studies are needed to confirm the reliability of this study.

Methods
Study design. From September 2017 through September 2018, the data of RFS and GEFV of consecutive patients with suspected LPRD from our hospital were collected and analysed retrospectively in the study. Regardless of whether having reflux and/or heartburn, the patients were enrolled in the study if they presented with at least one of the following symptoms: hoarseness or problem with their voice, throat clearing, excess throat mucus, postnasal drip, chronic cough, breathing difficulties or choking episodes, dysphagia, or discomfort in  www.nature.com/scientificreports www.nature.com/scientificreports/ throat lasting more than a month. All patients underwent both routine upper gastrointestinal endoscopy and TV fibrolaryngoscope after written informed consent was obtained. We excluded patients who had known oesophageal disease such as cancer, achalasia, stricture, active peptic ulcer disease or prior history of upper gastrointestinal surgery; used antibiotics or proton pump inhibitors (PPIs), mucosal protective agents or gastroprokinetic agents within 1 week; or had difficulty tolerating upper gastrointestinal endoscopy and TV fibrolaryngoscope. This study was approved by the Ethics Committee of the 306 th Hospital (Approved Document Number: K2017-06), and all the patients provided written informed consent for the endoscopy and TV fibrolaryngoscope and use of data for research purposes. And all experiments were performed in accordance with relevant guidelines and regulations.
Endoscopy and GEFV. Upper gastrointestinal endoscopy was performed using flexible video endoscopy XQ260/H260 (Olympus Co. Ltd, Tokyo, Japan) or EG29-i10 (Pentax Medical, Tokyo, Japan) under intravenous anaesthesia in each patient. The GEFV was inspected with a retroflexed endoscope and graded I to IV according to the Hill classification. Examples of Hill flap valve grades I-IV are shown in Fig. 1. All endoscopic procedures were performed by experienced endoscopists, and the GEFVs of all patients in this study were evaluated by two endoscopists (L.Y.L & M.W). Disagreements among the evaluators were resolved by discussion. GEFV grades I and II were regarded as normal, while grades III and IV were abnormal. Erosive oesophagitis (EE) was defined as presence of oesophageal mucosal breaks. Nonerosive reflux disease (NERD) was defined as the presence of classic GERD symptoms in the absence of oesophageal mucosal injury during upper endoscopy.
Reflux finding score. RFS rating scales were developed by Belafsky 17 for the assessment of the patients with LPR, as shown in Table 5. The reflux finding score is an 8-item clinical severity scale used to interpret the most common laryngoscopic findings related to LPR. RFS was analyzed and evaluated by 2 senior doctors (W.W & G.W). The final figure of RFS is an average of these two sets of data. Patients with a RFS of higher than 7 were diagnosed with LPRD.  Table 5. Reflux finding score rating scales.