A series of symptoms, signs or diseases, such as dysphonia, hysteria, cough, subglottic stenosis, dysphonia, laryngeal spasm, laryngeal contact granuloma, asthma, and even chronic sinusitis and laryngeal cancer, are associated with LPRD. However, there is still a lack of a diagnostic method with high sensitivity and specificity, good patient acceptance and easy operation that has been widely recognized by clinicians. Although the RSI and RFS are proven clinical tools, they do not include many common symptoms and reflux signs and they do not take into account the frequency of symptoms[3, 14-17]. Moreover, the patients' own emotional and psychological factors and variations in different doctors' scores on laryngoscopy always influence the results. Objective examination is needed to clarify the existence of reflux. The pH monitoring is an objective diagnostic method that accurately reflects the changes of H+ in the esophagus and/or airway. In 1969, ambulatory catheter-based esophageal pH monitoring was used to diagnose GERD. In 1989, dual-probe esophageal pH monitoring was used to diagnose LPRD by Wiener et al. . However, studies have shown that 45% of patients receiving dual-sensor esophageal pH monitoring have misplaced proximal sensors. The Dx-pH monitoring system provides accurate probe positioning (0.5-1 cm below the uvula) and appear to be more sensitive than traditional pH monitoring in evaluation of patients with extraesophageal reflux.
In the analysis of 24h pH monitoring data, the Ryan Score is calculated according to the number of episodes in which pH falls below the normal range, the length of the longest episode, and the total percentage of time spent below threshold. As the pH threshold differs from the upright position and supine position, Ryan score is calculated respectively. However, the Ryan score still has some shortcomings that restrict its application. First, the Ryan score was obtained based on samples from 55 normal people. The standard for normal persons was merely to exclude typical GERD symptoms such as acid reflux and heartburn, and no laryngoscopy was performed. Actually, many LPRD patients do not have gastrointestinal symptoms. Second, the pH threshold of 5.5 in the upright position and 5.0 in the supine position may be inaccurate as the pepsin is still active at pH 6.5, which can cause airway mucosal damage. In computational methods, there is no difference in the degree of discrimination between events below the threshold. Our study found that the original pH distribution data obtained by dynamic monitoring between normal people and LPRD patients are not normally distributed and that these distributions overlap. However, the Ryan score obtained only from the data of normal people cannot explain the overlap of the data distribution. Although the current clinical application shows that the Ryan score can predict the efficacy of anti-reflux surgery, a negative Ryan score is still not a sufficient indicator for the exclusion of LPRD patients which means a large number of patients are misdiagnosed. Hence, a more accurate diagnostic criteria of Dx-pH monitoring for LPRD is needed.
In contrast to studies in which simple statistics were used to characterize the pH variation at the pharynx, advanced statistical methods were employed to develop W score to exploit the possibility of discriminating LPRD from normal subjects. To propose the new score, machine learning methods, which used both labelled and big unlabelled data, were employed to analyze the long-term pH data and semi-supervised learning was used to alleviate the imperfectness in data and reference test by exploring the underlying data patterns. However, it still needs further clinical verification but it is quite challenging as the lack of golden standard to diagnose LPRD. Although there are many problems in the empirical treatment, including standard of starting treatment, poor compliance, high cost, low follow-up rate and placebo effects especially, many experts insist it is a reliable and effective method of LPR diagnosis[4, 6, 22, 23]. We did this multi-center retrospective study by analyzing the data of 108 patients who underwent a formal course of anti-reflux therapy.
In our research, the inclusion criteria for anti-reflux therapy was not in accordance with the commonly used criteria (RSI > 13 and RFS > 7). Based on our previous clinical experience, patients with RSI<13 can also benefit from anti-reflux therapy. Therefore, we compared the effective rate between patients with RSI of 10-13 and patients with RSI >13, and the result showed no significant difference. In addition to RSI and RFS, we also used VAS in combination, special for suspected LPR patients with single symptom or chief complaint not included in RSI. Although acid-suppressing therapy (PPIs and/or H2-antagonists) and GI prokinetic agents were given to ensure that patients with nonacid reflux were effectively treated without omission. Unfortunately, alginates were not given to Chinese patients due to the lack of domestic clinical drug license. Anti-reflux surgery is considered to be effective for some patients with poor medication treatment, but it had not been involved in this research . The follow-up period was 2-3 months, which also reduced the false negative results caused by insufficient treatment time in some patients. We found that the sensitivity of the W score was significantly higher than that of the Ryan score, which decreased the misdiagnosis of LPRD, and the specificity of the two scores was not significantly different. More LPRD patients could be screened out through the W score and benefit from anti-reflux treatment in clinical practice.
Compared with Ryan score, the sensitivity of W index is obviously improved, but the specificity is not high enough which needs to be improved further.
Our study has several limitations. We regarded the efficacy of anti-reflux therapy after 2-3 months as the diagnostic criterion, nevertheless, the placebo effect could not be elicited. Patients who were ineffective for anti-reflux drugs might be effective for surgery, so underestimation of diagnosis may also exist. In addition, the W score was verified only by a retrospective analysis; therefore, further validation before clinical application will be needed. At last, although alkali reflux does exist in clinical practice, W score could not pick up this kind of patient as Ryan score and more work should be done to improve it.