Abilities of Oropharyngeal pH Tests and Salivary Pepsin Analysis to Discriminate Between Asymptomatic Volunteers and Subjects With Symptoms of Laryngeal Irritation

doi:10.1016/j.cgh.2015.11.017

Clinical Gastroenterology and Hepatology

Volume 14, Issue 4, April 2016, Pages 535-542.e2

https://doi.org/10.1016/j.cgh.2015.11.017 Get rights and content

Background & Aims

It has been a challenge to confirm the association between laryngeal symptoms and physiological reflux disease. We examined the ability of oropharyngeal pH tests (with the Restech Dx-pH system) and salivary pepsin tests (with Peptest) to discriminate between asymptomatic volunteers (controls) and subjects with a combination of laryngeal and reflux symptoms (laryngeal ± reflux).

Methods

We performed a physician-blinded prospective cohort study of 59 subjects at a single academic institution. Adult volunteers were recruited and separated into 3 groups on the basis of GerdQ and Reflux Symptom Index scores: controls (n = 20), laryngeal symptoms (n = 20), or laryngeal + reflux symptoms (n = 19). Subjects underwent laryngoscopy and oropharyngeal pH tests and submitted saliva samples for analysis of pepsin concentration. Primary outcomes included abnormal acid exposure and composite (RYAN) score for oropharyngeal pH tests and abnormal mean salivary pepsin concentration that was based on normative data.

Results

Complete oropharyngeal pH data were available from 53 subjects and complete salivary pepsin data from 35 subjects. We did not observe any significant differences between groups in percent of time spent below pH 4.0, 5.0, 5.5, 6.0, or RYAN scores or percent of subjects with positive results from tests for salivary pepsin (53% vs 40% vs 75%; P = .50, respectively). The laryngeal + reflux group had a significantly higher estimated mean concentration of salivary pepsin (117.9 ± 147.4 ng/mL) than the control group (32.4 ± 41.9 ng/mL) or laryngeal symptom group (7.5 ± 11.2 ng/mL) (P = .01 and P = .04, respectively).

Conclusions

By using current normative thresholds, oropharyngeal pH testing and salivary pepsin analysis are not able to distinguish between healthy volunteers and subjects with a combination of laryngeal and reflux symptoms.

Section snippets

Methods

The Northwestern University institutional review board approved the study protocol.

We conducted a physician-blinded prospective cohort pilot study at a single academic medical center. Adult subjects were recruited from January 2014 to February 2015. Subjects were excluded if pregnant, allergic to anesthetic spray used during laryngoscopy, unable to discontinue PPI for 5 days before initial testing, or because of the presence of significant comorbidities compromising the subject’s health and

Results

Fifty-nine subjects were recruited; 20 were healthy volunteers, 20 met criteria for the laryngeal cohort, and 19 met criteria for the laryngeal + reflux cohort. Two subjects from each cohort, a total of 6 subjects, were excluded because of oropharyngeal pH data recording error. Thus, 53 subjects were included in the oropharyngeal pH analysis: 18 controls, 18 laryngeal, and 17 laryngeal + reflux. Saliva samples were collected from 35 total subjects: 20 controls, 6 laryngeal, and 9 laryngeal +

Conclusions

Minimally invasive diagnostic tools to identify patients with LPR are needed; thus, we examined the ability of 2 novel diagnostic modalities, oropharyngeal pH testing and salivary pepsin analysis, to reliably discriminate between asymptomatic and symptomatic patients. On the basis of current normative thresholds both oropharyngeal pH testing with the Restech Dx-pH system and salivary pepsin analysis with Peptest could not distinguish between healthy volunteers and symptomatic subjects. Trends

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Cited by (66)

Diagnosing Laryngopharyngeal Reflux: A Comparison between 24-hour pH-Impedance Testing and Pharyngeal Probe (Restech) Testing, with Introduction of the Sataloff Score
2023, Journal of Voice
Citation Excerpt :
Further research is needed to investigate this speculation. Without an adequate barrier to refluxate, the oropharynx will be unable to mitigate pepsin deposition.17-21 In this study, Restech demonstrated a significant correlation with RSI, possibly due to inflammation from refluxate in the oropharynx for prolonged periods of time.
The purpose of this study was to compare the diagnostic utility of pH monitoring using 24-hour esophageal pH-Impedance (HEMII-pH) testing versus pharyngeal pH (Restech) testing (Respiratory Technology Corporation, Houston, Texas) for diagnosing laryngopharyngeal reflux (LPR).
Retrospectively, patients were reviewed who had completed a Reflux Symptom Index (RSI) survey and stroboscopy within 60 days before or after undergoing simultaneous esophageal pH-Impedance monitoring and Restech testing. Reflux Finding Score (RFS) was determined by 4 blinded observers. 80.45% of patients were on anti-reflux medications at the time of study and had incomplete response to treatment for reflux. Improvement on reflux treatment was determined by evaluating presenting pre-pH monitoring RFS, post treatment RFS, and improvement of symptoms. Pearson correlation coefficients were calculated to assess relationships among RSI, RFS, and test results from HEMII-pH and Restech tests.
Eighty-seven patients were included in the analysis. The inter-rater reliability of the RFS determination was 74.57%, and the intra-rater reliability was 67.00%. Subjects who had a positive RYAN Score had a significant correlation with RFS (r of 0.222 and p-value of 0.0492). There was no correlation between RFS and number or percent time of reflux events, longest event, total number of events, or percent of time at alkaline pH for either HEMII-PH or Restech test. RSI correlated better with HEMII-pH test than with Restech for percent time spent in both upright (r of 0.226 and p-value of 0.029) and supine position (r of 0.261 and a p-value of 0.032). Restech correlated better with total patient symptom Scores including cough, heartburn, burping, and throat clearing, with a r of 0.242 and a p-value of 0.048. Restech detected more percent time in reflux for total reflux, supine reflux, and upright reflux (p-value less than 0.0001). Restech also detected longer event times than Impedance (p-value of less than 0.0001). When diagnosis of LPR is based on the definition of CRC, the Sataloff Score test had 70.45% sensitivity and 80.95% specificity. The RYAN Score had a sensitivity of 72%, and a specificity of 56.45%, and the Wu Score had a sensitivity of 62.16%, and specificity of 54.05%. When the Sataloff and Wu Score were used together, the sensitivity was 71.45%, specificity 100%, positive predictive value of 100%, and a negative predictive value of 59.46%.
The amount of time of reflux events correlates with symptoms better than the number of events. The HEMII-pH test was able to detect more events of pH<4 than Restech, possibly because there might have been more acid events below than above the upper esophageal sphincter, while Restech detected more total events. Restech recorded longer event times than HEMII-pH test. Since length of time correlates with RFS (probably reflecting laryngeal inflammation), and since laryngeal clearance of acid is more similar to pharyngeal than esophageal clearance, this finding might prove valuable clinically. The Sataloff Score has a sensitivity of 70.45%, and a specificity of 80.95% and appears useful clinically to detect mild to moderate that is missed by the RYAN Score. A combination of Sataloff Score and Wu Score may be clinically valuable to identify LPR with an increased sensitivity of 71.45% and increased specificity of 100%. The Wu Score is not yet available for the general clinical use, but the Sataloff Score is.
AGA Clinical Practice Update on the Diagnosis and Management of Extraesophageal Gastroesophageal Reflux Disease: Expert Review
2023, Clinical Gastroenterology and Hepatology
The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update is to review the available evidence and expert advice regarding the clinical management of patients with suspected extraesophageal gastroesophageal reflux disease.
This article provides practical advice based on the available published evidence including that identified from recently published reviews from leading investigators in the field, prospective and population studies, clinical trials, and recent clinical guidelines and technical reviews. This best practice document is not based on a formal systematic review. The best practice advice as presented in this document applies to patients with symptoms or conditions suspected to be related to extraesophageal reflux (EER). This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the CPUC and external peer review through standard procedures of Clinical Gastroenterology and Hepatology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations.
Gastroenterologists should be aware of potential extraesophageal manifestations of gastroesophageal reflux disease (GERD) and should inquire about such disorders including laryngitis, chronic cough, asthma, and dental erosions in GERD patients to determine whether GERD may be a contributing factor to these conditions.
Development of a multidisciplinary approach to extraesophageal (EER) manifestations is an important consideration because the conditions are often multifactorial, requiring input from non-gastroenterology (GI) specialties. Results from diagnostic testing (ie, bronchoscopy, thoracic imaging, laryngoscopy, etc) from non-GI disciplines should be taken into consideration when gastroesophageal reflux (GER) is considered as a cause for extraesophageal symptoms.
Currently, there is no single diagnostic tool that can conclusively identify GER as the cause of EER symptoms. Determination of the contribution of GER to EER symptoms should be based on the global clinical impression derived from patients’ symptoms, response to GER therapy, and results of endoscopy and reflux testing.
Consideration should be given toward diagnostic testing for reflux before initiation of proton pump inhibitor (PPI) therapy in patients with potential extraesophageal manifestations of GERD, but without typical GERD symptoms. Initial single-dose PPI trial, titrating up to twice daily in those with typical GERD symptoms, is reasonable.
Symptom improvement of EER manifestations while on PPI therapy may result from mechanisms of action other than acid suppression and should not be regarded as confirmation for GERD.
In patients with suspected extraesophageal manifestation of GERD who have failed one trial (up to 12 weeks) of PPI therapy, one should consider objective testing for pathologic GER, because additional trials of different PPIs are low yield.
Initial testing to evaluate for reflux should be tailored to patients’ clinical presentation and can include upper endoscopy and ambulatory reflux monitoring studies of acid suppressive therapy.
Testing can be considered for those with an established objective diagnosis of GERD who do not respond to high doses of acid suppression. Testing can include pH-impedance monitoring while on acid suppression to evaluate the role of ongoing acid or non-acid reflux.
Alternative treatment methods to acid suppressive therapy (eg, lifestyle modifications, alginate-containing antacids, external upper esophageal sphincter compression device, cognitive-behavioral therapy, neuromodulators) may serve a role in management of EER symptoms.
Shared decision-making should be performed before referral for anti-reflux surgery for EER when the patient has clear, objectively defined evidence of GERD. However, a lack of response to PPI therapy predicts lack of response to anti-reflux surgery and should be incorporated into the decision process.
Diagnostic utility of salivary pepsin in laryngopharyngeal reflux: a systematic review and meta-analysis
2023, Brazilian Journal of Otorhinolaryngology
Citation Excerpt :
Fagan plots manifested a PLR of 2 and a NLR of 0.58, with 65% and 37% of the posttest probability for PLR and NLR, respectively (Fig. 3d). Of these 16 studies, the cutoff value of 16 ng/mL was utilized in six studies;13,14,20–23 and the cutoff value of 50 ng/mL was used in four studies.14,18,21,25 In addition, other used cutoff values were 25 ng/mL, 74 ng/mL, 75 ng/mL, 100 ng/mL, 150 ng/mL, 210 ng/mL, and 216 ng/mL.
Salivary pepsin has emerged as a biomarker for Laryngopharyngeal Reflux (LPR), which, however, has been questioned for its efficacy due to a lack of supporting medical data. Therefore, this study analyzed the diagnostic value of salivary pepsin for LPR and assessed a better cutoff value.
Studies were searched in PubMed, Embase, and Cochrane Library from their receptions to October 1, 2021. Then, RevMan 5.3 and Stata 14.0 were utilized to summarize the diagnostic indexes for further meta-analysis. Data were separately extracted by two reviewers according to the trial data extraction form of the Cochrane Handbook. The risk of bias in Randomized Control Trials (RCTs) was evaluated with the Cochrane Risk of Bias Tool.
A total of 16 studies matched the criteria and were subjected to meta-analysis. The results revealed a pooled sensitivity of 61% (95% CI 50%–71%), a pooled specificity of 67% (95% CI 48%–81%), a positive likelihood ratio of 2 (95% CI 1.2–2.8), a negative likelihood ratio of 0.58 (95% CI 0.47‒0.72), and the area under the receiver operating characteristic curve of 0.67 (95% CI 0.63‒0.71). Subgroup analyses indicated that the cutoff value of pepsin at 50 ng/mL had a higher degree of diagnostic accuracy than that of pepsin at 16 ng/mL in cohort studies.
The review demonstrated low diagnostic performance of salivary pepsin for LPR and that the cutoff value of 50 ng/mL pepsin had superior diagnostic accuracy. Nevertheless, the diagnostic value may vary dependent on the utilized diagnostic criteria. Therefore, additional research is needed on the improved way of identifying salivary pepsin in the diagnosis of LPR, and also longer-term and more rigorous RCTs are warranted to further assess the effectiveness of salivary pepsin.
Failed Swallows on High-Resolution Manometry Independently Correlates With Severity of LPR Symptoms
2022, Journal of Voice
Abnormal esophageal motility is prevalent in gastroesophageal reflux disease patients; however, its relationship with laryngopharyngeal reflux (LPR) symptom severity remains unclear. Altered esophageal transit may contribute to LPR symptoms. We aimed to examine the relationship between reflux symptom index (RSI), a validated questionnaire for LPR symptoms, and abnormal esophageal motility on high-resolution manometry (HRM).
A total of 133 consecutive patients (55.9 ± 14.6 years, 69.9% female) with suspected LPR referred for HRM and multichannel intraluminal impedance-pH study (MII-pH) at a tertiary center from March 2015 to October 2017 were included. RSI questionnaire was prospectively collected prior to motility testing. Authors analyzing HRM and MII-pH were blinded to RSI findings. Statistical analyses were performed using Student's t test or Pearson's correlation (univariate) and general linear regression (multivariable).
Mean RSI was higher among patients with ineffective esophageal motility than those with normal motility (23.7 vs 18.6, P = 0.01). Significant positive correlation was found between RSI and percent failed swallows (R² = 0.21, P = 0.03), but not percent weak swallows. On multivariable analysis, percent ineffective (failed or weak) swallows was significantly associated with RSI (β-coefficient: 0.072, P = 0.05) after controlling for age, gender, BMI, smoking, prior PPI use, and reflux on MII-pH. When analyzed separately, percent failed swallows (β-coefficient: 0.095, P= 0.02), but not percent weak swallows, independently predicted higher RSI.
Ineffective swallows, particularly failed swallows, are independently associated with higher RSI in patients with suspected LPR, even after controlling for reflux on MII-pH. Esophageal dysmotility may play a role in suspected LPR symptoms independent of reflux. HRM should be routinely considered in evaluating these patients.
Predictive Value of Laryngeal Mucosa Pepsin in Therapeutic Response of Laryngopharyngeal Reflux
2022, Journal of Voice
Citation Excerpt :
However, saliva or sputum pepsin concentrations vary throughout the day12,16 and tend to be affected by external factors such as the food type,17 the time of eating,18 swallowing, or spitting, making it difficult to determine the optimal sampling time. A study conducted by Yadlapati et al found that Peptest™ was not able to distinguish between healthy volunteers and subjects with a combination of laryngeal and reflux symptoms.19 Another two meta-analyses20,21 also concluded that pepsin in saliva/sputum had only moderate value in the diagnosis of LPR.
To investigate the predictive capability of pepsin level in the laryngeal mucosa to the therapeutic effect of proton-pump inhibitors in patients with suspected laryngopharyngeal reflux (LPR), so as to verify whether it can be referred to as a biomarker of LPR.
Prospective case study.
Sixty patients with clinical empiric LPR were enrolled, with an reflux symptom index (RSI) ≥ 13 and an reflux finding score (RFS) > 7 as screening criteria. Biopsy specimens from the interarytenoid mucosa were obtained under topical anesthesia for pepsin immunohistochemical staining. Two parameters were observed in these patients with different pepsin levels after the administration of esomeprazole for 12 weeks: the RSI and the RFS.
Among the 60 cases, 35 cases were negative or weakly positive for pepsin (Pepsin(-) group), and 25 cases were moderately positive or strongly positive for pepsin (Pepsin(+) group). After therapy, the RSI significantly decreased from 17.00 (15.00, 19.00) to 6.00 (5.00, 11.00) in the Pepsin(+) group (Z = -4.38, P < 0.01), but no difference was found in the RFS (T = 1.48, P > 0.05). No significant difference was observed in the RSI (T = 2.01, P > 0.05) or the RFS (T = 2.01, P > 0.05) in the Pepsin(-) group either before or after therapy. An improvement in the RSI ≥ 50% was taken as the standard of effective therapy. The effective rate in the Pepsin(+) group was 72.0% (18/25), while it was 14.3% (5/35) in the Pepsin(-) group. There was a significant difference in the effective rate between the two groups (χ² = 20.55, P < 0.01).
Proton-pump inhibitors exhibited better effects in patients with higher pepsin levels in the laryngeal mucosa. Laryngeal mucosa pepsin may serve as an ideal indicator to screen patients suitable for proton-pump inhibitor therapy and a reliable biomarker to identify patients with LPR.
Salivary pepsin as an independent predictor of treatment response for laryngopharyngeal reflux: prospective cohort study with multivariate analysis
2023, Scientific Reports

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: Conflicts of interest These authors disclose the following: Rena Yadlapati is supported by T32 DK101363-02 grant. John E. Pandolfino is a consultant for Covidien, Sandhill Scientific, and Given. The remaining authors disclose no conflicts.

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Original articleAlimentary tractAbilities of Oropharyngeal pH Tests and Salivary Pepsin Analysis to Discriminate Between Asymptomatic Volunteers and Subjects With Symptoms of Laryngeal Irritation

Background & Aims

Methods

Results

Conclusions

Section snippets

Methods

Results

Conclusions

Clin Gastroenterol Hepatol

Otolaryngol Head Neck Surg

Surgery

J Gastrointest Surg

The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus

Am J Gastroenterol

The validity and reliability of the reflux finding score (RFS)

Laryngoscope

Prevalence of laryngeal irritation signs associated with reflux in asymptomatic volunteers: impact of endoscopic technique (rigid vs flexible laryngoscope)

Laryngoscope

Gastro-oesophageal reflux disease in chronic laryngitis: prevalence and response to acid-suppressive therapy

Aliment Pharmacol Ther

Original article
Alimentary tract
Abilities of Oropharyngeal pH Tests and Salivary Pepsin Analysis to Discriminate Between Asymptomatic Volunteers and Subjects With Symptoms of Laryngeal Irritation