Pepsin is an enzyme that helps digest protein secreted only from the gastric chief cell in an inactive state. Pepsin is a good marker for acidic gastroesophageal reflux (GER). Its presence in sputum or saliva is considered pathologic. In GER, cough is stimulated by broncho-esophageal neurogenic reflex and aspiration of gastric contents into the airways. GER is the most common cause of cough. Gastric acid reflux is also thought to play a role in Interstitial Lung Disease (ILD) etiology. In many studies, pepsin and bile acid levels in bronchial lavage were high in patients with interstitial lung disease and chronic cough. In our study, we aimed to evaluate pepsin levels in bronchial lavage in patients with ILD and chronic cough and to investigate the relationship between symptoms and reflux treatment.

Between January 2021 and February 2022, 212 patients who underwent bronchoscopy in our tertiary clinic were evaluated. These patients were divided into three groups: 52 patients with interstitial lung disease, 81 patients with chronic cough, and 79 patients who underwent bronchoscopy with a pre-diagnosis of lung cancer as the control group. Bronchial lavage obtained by bronchoscopy was analyzed for pepsin levels.

Shortness of breath and cough were the most common symptoms in all three groups. Pepsin levels were 16.71 ± 8.6 ng/ml in the chronic cough group, 15.6 ± 8.9 ng/ml in the ILD group, and 10.58 ± 5.4 ng/ml in the lung cancer (control) group. Pepsin levels in the ILD and chronic cough group were statistically significantly higher than in the lung cancer group (p:0.00). There was no statistical difference between the ILD group and the chronic cough group regarding pepsin levels. It was found that pepsin levels were lower in the three groups who received anti-reflux treatment. There was no difference in pepsin levels between ILD subgroups.

Pepsin levels in bronchial lavage were higher in the ILD and chronic cough groups. This suggests that reflux may be involved in the etiology of chronic cough and ILD. Low pepsin values in patients receiving anti-reflux therapy have shown that occult reflux may occur. In our study, the high level of pepsin in bronchial lavage, especially in the chronic cough and ILD group, may be instructive in the etiology and treatment planning of the disease.

Finding a simple, effective and rapid diagnostic method to improve the diagnosis of gastroesophageal reflux-induced chronic cough (GERC) is indicated. Our objective was to determine the diagnostic value of the pepsin concentration in saliva and induced sputum for GERC.

171 patients with chronic cough were enrolled. The diagnosis and treatment followed the chronic cough diagnosis and treatment protocol. Saliva and induced sputum were collected, and the pepsin concentration was determined using Peptest. A Gastroesophageal Reflux Diagnostic Questionnaire (GerdQ) was completed. The diagnostic value of the pepsin concentration in saliva and induced sputum for GERC was analysed and compared.

The salivary pepsin concentration predicted GERC with an area under the receiver operating characteristic curve (AUC) of 0.845. The optimal cut-off value was 76.10 ng·mL-1, the sensitivity was 83.58% and the specificity was 82.69%. The pepsin concentration in the induced sputum supernatant for GERC had an AUC of 0.523. When GerdQ was used for GERC diagnosis, the AUC was 0.670 and the diagnostic value of salivary pepsin was better compared to GerdQ (DeLong test, p=0.0008). Salivary pepsin had a comparable diagnostic value to GerdQ (AUC 0.779 versus 0.826; p=0.4199) in acidic GERC. Salivary pepsin had superior diagnostic value compared to GerdQ (AUC 0.830 versus 0.533; p<0.0001) in non-acidic GERC.

A salivary pepsin concentration >76.10 ng·mL-1 is of good diagnostic value for GERC, especially in non-acidic GERC. The pepsin concentration in induced sputum has a low diagnostic value.

Gastroesophageal reflux disease (GERD) might be either a cause or comorbidity in children with extraesophageal problems especially as refractory respiratory symptoms, without any best methods or criterion for diagnosing it in children.

To evaluate the prevalence of extraesophageal GERD using conventional and combined-video, multichannel intraluminal impedance-pH (MII-pH), and to propose novel diagnostic parameters.

The study was conducted among children suspected of extraesophageal GERD at King Chulalongkorn Memorial Hospital between 2019 and 2022. The children underwent conventional and/or combined-video MII-pH. The potential parameters were assessed and receiver operating characteristic was used for the significant parameters.

Of 51 patients (52.9% males), aged 2.24 years were recruited. The common problems were cough, recurrent pneumonia, and hypersecretion. Using MII-pH, 35.3% of the children were diagnosed with GERD by reflux index (31.4%), total reflux events (3.9%), and symptom indices (9.8%) with higher symptom recorded in the GERD group (94 vs 171, P = 0.033). In the video monitoring group (n = 17), there were more symptoms recorded (120 vs 220, P = 0.062) and more GERD (11.8% vs 29.4%, P = 0.398) by symptom indices. Longest reflux time and mean nocturnal baseline impedance were significant parameters for diagnosis with receiver operating characteristic areas of 0.907 (P = 0.001) and 0.726 (P = 0.014).

The prevalence of extraesophageal GERD in children was not high as expected. The diagnostic yield of symptom indices increased using video monitoring. Long reflux time and mean nocturnal baseline impedance are novel parameters that should be integrated into the GERD diagnostic criteria in children.

Gastroesophageal reflux (GER) in children is very common and refers to the involuntary passage of gastric contents into the esophagus. This is often physiological and managed conservatively. In contrast, GER disease (GERD) is a less common pathologic process causing troublesome symptoms, which may need medical management. Apart from abnormal transient relaxations of the lower esophageal sphincter, other factors that play a role in the pathogenesis of GERD include defects in esophageal mucosal defense, impaired esophageal and gastric motility and clearance, as well as anatomical defects of the lower esophageal reflux barrier such as hiatal hernia. The clinical manifestations of GERD in young children are varied and nonspecific prompting the necessity for careful diagnostic evaluation. Management should be targeted to the underlying aetiopathogenesis and to limit complications of GERD. The following review focuses on up-to-date information regarding of the pathogenesis, diagnostic evaluation and management of GERD in children.

Laryngopharyngeal reflux may affect people of any age; still, most of the accumulated knowledge concerns adults, and evidence regarding pediatric populations remains relatively restricted. This study aims to review the most recent and emerging aspects of pediatric laryngopharyngeal reflux from the last ten years. It also attempts to identify gaps in knowledge and highlight discrepancies that future research should urgently address.

An electronic search of the MEDLINE database was conducted, limited to January 2012 through December 2021. Non-English language articles, case reports, and studies that concerned a purely or predominantly adult population were excluded. The information from the articles with the most relevant contribution was initially categorized by theme and subsequently synthesized into a narrative form.

86 articles were included, of which 27 were review articles, eight were surveys, and 51 were original articles. Our review systematically maps the research done in the last decade and provides an updated overview and the current state-of-the-art in this subject.

Despite discrepancies and heterogeneity in accumulating research, evidence gathered so far endorses a need for refining an escalating multiparameter diagnostic approach. A step-wise therapeutic plan appears to be the most reasonable management approach, starting with behavioral changes for mild to moderate, uncomplicated cases and escalating to personalized pharmacotherapy options for severe or nonresponsive cases. Surgical options could be considered in the most severe cases when potentially life-threatening symptoms persist despite maximal medical therapy. Over the past decade, the amount of available evidence has been gradually increasing; however, its strength remains low. Several aspects remain markedly under-addressed, and further adequately powered, multicenter, controlled studies with uniformity in diagnostic procedures and criteria are urgently needed.

Saliva testing is a vital method for clinical applications, for its noninvasive features, richness in substances, and the huge amount. Due to its direct anatomical connection with oral, digestive, and endocrine systems, clinical usage of saliva testing for these diseases is promising. Furthermore, for other diseases that seeming to have no correlations with saliva, such as neurodegenerative diseases and psychological diseases, researchers also reckon saliva informative. Tremendous papers are being produced in this field. Updated summaries of recent literature give newcomers a shortcut to have a grasp of this topic. Here, we focused on recent research about saliva biomarkers that are derived from humans, not from other organisms. The review mostly addresses the proceedings from 2016 to 2022, to shed light on the promising usage of saliva testing in clinical diagnostics. We recap the recent advances following the category of different types of biomarkers, such as intracellular DNA, RNA, proteins and intercellular exosomes, cell-free DNA, to give a comprehensive impression of saliva biomarker testing.

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.

Saliva is a complex physiologic fluid that contains an abundance of biological analytes, or biomarkers. Recent research has shown that these biomarkers may be able to convey the physiologic health of a person. Work has been done linking derangements in these salivary biomarkers to a wide variety of pathologic disorders ranging from oncologic diseases to atopic conditions. The specific area of interest for this review paper is esophageal disorders. Particularly because the diagnosis and management of esophageal disorders often includes invasive testing such as esophagogastroduodenoscopy, prolonged pH monitoring, and biopsy. The aim of this review will be to explore salivary biomarkers (pepsin, bile, epidermal growth factor, and micro-RNA) that are being studied as they relate specifically to esophageal disorders. Finally, it will explore the benefits of salivary testing and identify areas of possible future research.

Gastroesophageal reflux disease (GERD) continues to be among the most common diseases seen by gastroenterologists, surgeons, and primary care physicians. Our understanding of the varied presentations of GERD, enhancements in diagnostic testing, and approach to patient management have evolved. During this time, scrutiny of proton pump inhibitors (PPIs) has increased considerably. Although PPIs remain the medical treatment of choice for GERD, multiple publications have raised questions about adverse events, raising doubts about the safety of long-term use and increasing concern about overprescribing of PPIs. New data regarding the potential for surgical and endoscopic interventions have emerged. In this new document, we provide updated, evidence-based recommendations and practical guidance for the evaluation and management of GERD, including pharmacologic, lifestyle, surgical, and endoscopic management. The Grading of Recommendations, Assessment, Development, and Evaluation system was used to evaluate the evidence and the strength of recommendations. Key concepts and suggestions that as of this writing do not have sufficient evidence to grade are also provided.

Gastroesophageal reflux disease (GERD) continues to be among the most common diseases seen by gastroenterologists, surgeons, and primary care physicians. Our understanding of the varied presentations of GERD, enhancements in diagnostic testing, and approach to patient management have evolved. During this time, scrutiny of proton pump inhibitors (PPIs) has increased considerably. Although PPIs remain the medical treatment of choice for GERD, multiple publications have raised questions about adverse events, raising doubts about the safety of long-term use and increasing concern about overprescribing of PPIs. New data regarding the potential for surgical and endoscopic interventions have emerged. In this new document, we provide updated, evidence-based recommendations and practical guidance for the evaluation and management of GERD, including pharmacologic, lifestyle, surgical, and endoscopic management. The Grading of Recommendations, Assessment, Development, and Evaluation system was used to evaluate the evidence and the strength of recommendations. Key concepts and suggestions that as of this writing do not have sufficient evidence to grade are also provided.

Bile reflux may cause for lung allograft rejection, yet there are no studies that determine (i) the relationship between gastric and lung bile concentrations, (ii) whether bile is present in lungs of nontransplant patients, (iii) the relationship between gastric dysmotility and lung bile, (iv) the impact of reflux therapies on lung bile, and (v) whether lung bile worsens outcomes in nontransplant patients. This study will address these gaps in the literature.

We prospectively recruited lung transplant (LTX) patients and nontransplant patients with respiratory symptoms (RP) and collected paired gastric and lung samples. Bile concentration and composition of samples was assessed using liquid chromatography-mass spectrometry. Bile results were compared with clinical parameters, including the presence of esophagitis, gastric dysmotility, and/or pathologic gastroesophageal reflux.

Seventy patients (48 RP and 22 LTX) were recruited. Overall, 100% of gastric and 98% of bronchoalveolar lavage samples contained bile. The mean gastric bile concentrations in RP and LTX patients were 280 ± 703 nmol/L and 1,004 ± 1721 nmol/L, respectively (P = 0.02). There was no difference in lung bile concentrations between RP (9 ± 30 nmol/L) and LTX (11 ± 15 nmol/L, P = 0.7). Patients with delayed gastric emptying had higher lung bile concentrations (15.5 ± 18.8 nmol/L) than patients with normal gastric emptying (4.8 ± 5.7 nmol/L, P = 0.05) independently of reflux burden. Proton pump inhibitor use increased the proportion of unconjugated gastric bile acids. High lung bile concentrations were associated with an increased risk of hospitalization and longer hospital stays in RP patients (P < 0.05).

Lung bile is almost universally present in symptomatic patients, and higher concentrations are associated with poorer respiratory outcomes.

To study the value of multitime point salivary pepsin testing (MTPSPT) for the diagnosis of laryngopharyngeal reflux (LPR).

Prospective noncontrolled.

For patients who met the enrollment criteria, the reflux symptom index (RSI) and reflux finding score (RFS) were calculated and salivary pepsin testing was performed. The pepsin test was performed every hour from 7:00 a.m. to 6:00 p.m. by collecting fresh saliva samples. A single positive test result was needed for the diagnosis of LPR. The consistency in the diagnosis of LPR between the two methods was compared with the weighted Cohen's kappa statistic.

A total of 204 patients were included. The kappa value between the two methods was 0.566 (p = .00). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of MTPSPT were 76.43%, 85.94%, 92.24%, and 62.5%, respectively. We also compared a single pepsin measure at 7 a.m. with the screening results based on the RSI and RFS, and found a much lower kappa agreement value (0.223, p = .00). The sensitivity, specificity, PPV, NPV, and false-negative rate of pepsin testing at 7 a.m. (fasting) were 37.86%, 92.18%, 91.38%, 40.41%, and 58.57%, respectively.

The use of the result of a single salivary pepsin test in the morning yields a relatively higher rate of missed diagnosis of LPR, and multitime point testing through a day increased the accuracy and sensitivity of detection of LPR twofold compared to a single morning fasting sample.

3.

Gastro-oesophageal reflux disease (GERD) is a common disorder in adults and children. The global prevalence of GERD is high and increasing. Non-erosive reflux disease is the most common phenotype of GERD. Heartburn and regurgitation are considered classic symptoms but GERD may present with various atypical and extra-oesophageal manifestations. The pathophysiology of GERD is multifactorial and different mechanisms may result in GERD symptoms, including gastric composition and motility, anti-reflux barrier, refluxate characteristics, clearance mechanisms, mucosal integrity and symptom perception. In clinical practice, the diagnosis of GERD is commonly established on the basis of response to anti-reflux treatment; however, a more accurate diagnosis requires testing that includes upper gastrointestinal tract endoscopy and reflux monitoring. New techniques and new reflux testing parameters help to better phenotype the condition. In children, the diagnosis of GERD is primarily based on history and physical examination and treatment vary with age. Treatment in adults includes a combination of lifestyle modifications with pharmacological, endoscopic or surgical intervention. In refractory GERD, optimization of proton-pump inhibitor treatment should be attempted before a series of diagnostic tests to assess the patient's phenotype.

To evaluate the necessity of multiple salivary pepsin tests within a day when diagnosing laryngopharyngeal reflux.

Prospective cohort study.

Tertiary hospitals.

A total of 138 patients with signs and/or symptoms associated with laryngopharyngeal reflux were included. Salivary pepsin was detected on the day of 24-hour pH monitoring, and the results of salivary pepsin detected once in the morning and multiple times in 1 day were compared with the results of pH monitoring.

Among the 138 patients, pH monitoring results were positive in 112. Salivary pepsin was positive in 47 cases in the morning, which was not consistent with the results of pH monitoring (kappa value = 0.117). With the pH monitoring results as the standard, the salivary pepsin detected once in the morning had a sensitivity of 38.4% (43/112) and a specificity of 84.6% (22/26) for the diagnosis of laryngopharyngeal reflux. When salivary pepsin was detected multiple times per day, 102 patients tested positive. The consistency with pH monitoring was moderate (kappa value = 0.587). The sensitivity was 86.6% (97/112), and the specificity was 80.8% (21/26). Of the 97 patients with positive results from pH monitoring and salivary pepsin detected multiple times a day, 54 had negative findings for a single detection in the morning, indicating that 55.7% (54/97) of the true positive cases were missed.

Although a single detection of salivary pepsin in the morning is more economical, the sensitivity is too low, and it is necessary to detect it multiple times a day.

The Peptest^TM is a non-invasive diagnostic test for measuring the pepsin concentration in saliva, which is thought to correlate with laryngopharyngeal reflux (LPR). The aim of this study was to investigate the diagnostic value of the Peptest in detecting LPR based on 24-h multichannel intraluminal impedance-pH (MII-pH) monitoring using several hypopharyngeal reflux episodes as criterion for LPR.

Patients with suspected LPR were examined with the Reflux Symptom Index (RSI), Reflux Finding Score (RFS), fasting Peptest, and MII-pH monitoring. We calculated the accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the Peptest, RSI, and RFS based on the threshold of one and six hypopharyngeal reflux episodes.

Altogether, the data from 46 patients were analyzed. When one hypopharyngeal reflux episode was used as a diagnostic threshold for LPR, the accuracy, sensitivity, specificity, PPV, and NPV were, respectively, as follows: 35%, 33%, 100%, 100%, and 3%, for the Peptest; 39%, 40%, 0%, 95%, and 0%, for the RSI; and 57%, 58%, 0%, 96%, and 0%, for the RFS. The accuracy, sensitivity, specificity, PPV, and NPV of the Peptest for diagnosing gastroesophageal reflux disease (GERD) were 46%, 27%, 63%, 40.0%, and 48%, respectively.

A positive Peptest is highly supportive of a pathological LPR diagnosis. However, a negative test could not exclude LPR.

Although respiratory symptoms in children are often attributed to gastroesophageal reflux disease, establishing a clear diagnosis of extraesophageal reflux disease (EERD) can be challenging, as there are no sensitive or specific EERD biomarkers. The aim of this study was to evaluate the metabolite profile in bronchoalveolar (BAL) fluid from children with suspected EERD and assess the impact of reflux treatment on these metabolites. In this prospective pilot study, we performed nontargeted global metabolomic profiling on BAL fluid from 43 children undergoing testing with bronchoscopy, upper endoscopy, and multichannel intraluminal impedance with pH (pH-MII) for evaluation of chronic respiratory symptoms. Twenty-three (54%) patients had an abnormal pH-MII study. Seventeen (40%) patients were on proton pump inhibitors (PPIs) for testing. Levels of histamine, malate, adenosine 5'-monophosphate, and ascorbate were significantly lower in subjects with abnormal pH-MII studies compared to those normal studies. Furthermore, in children off PPI therapy, those with abnormal pH-MII studies had robust increases in a number of glycerophospholipids within phospholipid metabolic pathways, including derivatives of glycerophosphorylcholine, glycerophosphoglycerol, and glycerophosphoinositol, compared to those with normal pH-MII studies. These findings offer insight into the impact of reflux and PPIs on the lungs and provide a foundation for future studies using targeted metabolomic analysis to identify potential biomarkers of EERD.

Gastro-oesophageal reflux is routinely diagnosed with invasive intraluminal impedance pH probe monitoring. This study aimed to determine whether gastric pepsin A detected in saliva of children correlates with gastro-oesophageal reflux.

Patients undergoing probe monitoring were prospectively recruited between 2014 and 2016 at a paediatric hospital. Standard impedance and demographic data were obtained from electronic medical records. Salivary samples were collected during impedance and measured for gastric pepsin A with an enzyme-linked immunosorbent assay. Impedance probe and pepsin data were analysed and compared for correlation.

From 52 enrolled subjects, 28 males and 24 females with mean age 8.0 ± 5.9 and range 0.58-18.0 years, 417 salivary samples were collected. Positive pepsin was found in 14% of samples and 48% patients. The sensitivity of pepsin A in predicting an abnormal impedance was 43% and specificity, 50%. Among pepsin A positive samples, 72% corresponded with a gastro-oesophageal reflux episode. Pepsin peak levels significantly correlated with acidic reflux.

Pepsin A was presented in saliva of children undergoing gastro-oesophageal reflux disease investigation. Positive pepsin A was associated with a gastro-oesophageal reflux episode, and its peak value correlated with acidic reflux. Salivary pepsin as a marker for gastro-oesophageal reflux needs further investigation.

Salivary pepsin measurement has been reported to be useful for diagnosing gastroesophageal reflux disease (GERD). This study aimed to clarify the usefulness of salivary pepsin measurement in patients with proton pump inhibitor (PPI)-refractory GERD symptoms without erosive esophagitis.

One hundred and two patients were included. Over seven days after terminating PPI treatment, all patients underwent a 24-h pH-impedance test and salivary pepsin measurement. In patients whose main symptoms included laryngopharyngeal symptoms, a hypopharyngeal multichannel intraluminal impedance (HMII) test was performed, whereas in other patients, a conventional combined multichannel intraluminal impedance-pH (MII-pH) test was performed. In the HMII tests, patients were divided into abnormal proximal exposure (APE) and non-APE groups. Salivary pepsin concentrations were compared according to acid exposure time (AET) values and were also compared between the APE and non-APE groups.

The median salivary pepsin concentration in patients with AET > 6% was significantly higher than that in patients with AET ≤ 6% (345.0 [170.0-469.3] ng/mL vs. 120.0 [97.0-290.1] ng/mL, p < 0.01). The sensitivity, specificity, positive predictive value, and negative predictive value of a positive test (> 109 ng/mL) to diagnose patients with AET > 6% were 75.0%, 51.3%, 32.1%, and 86.9%, respectively. There was no significant difference between concentrations in the APE group and concentrations in the non-APE group.

In patients with PPI-refractory nonerosive reflux disease, salivary pepsin measurement may help diagnose patients who have conclusive evidence of reflux, whereas it is not adequate for identifying patients with APE.

Airway reflux is implicated in the pathophysiology of a wide range of adult and pediatric upper and lower airway diseases. However, the diagnosis of proximal reflux-associated disease remains challenging due to evolving clinical criteria and institutional and regional variances in diagnostic practices. Evidence suggests that nonacidic contents of reflux may serve as both pathologic mediators of and biomarkers for reflux in the upper airway. Furthermore, they offer potential pharmaceutical and surgical intervention targets and are the focus of novel clinical diagnostic tools currently under investigation.

Background: Reflux aspiration secondary to gastroesophageal reflux disease (GERD) is one of the causes of chronic gastrointestinal and respiratory morbidity in children with esophageal atresia (EA). Currently there are no simple, validated non-invasive tests for the diagnosis of reflux aspiration in children. Objectives: The aim of this pilot study was to investigate pepsin detected in exhaled breath condensate (EBC) and saliva as a potential non-invasive marker of reflux aspiration in children with EA. Methods: EBC and saliva samples were prospectively collected from children with EA aged between 5 and 18 years attending a multidisciplinary EA Clinic. Pepsin in the samples was assayed by two methods, a commercial lateral flow device, the Peptest™ and an enzyme-linked immunosorbent assay (ELISA) and correlated with validated gastrointestinal and respiratory symptom questionnaires and objective measures of GERD and respiratory function. Results: EBC were collected from 18 children with EA, 15/18 also provided salivary samples. Pepsin was not detected in any of the EBC samples using the Peptest™ and only 1/14 (7.1%) samples by the ELISA. However, pepsin was detected in 33 and 83% of saliva samples when analyzed with Peptest™ and the ELISA respectively. Salivary pepsin levels were significantly higher in children with reflux symptoms or wheeze. Pepsin was detected by the Peptest™ in the saliva of 5/5 (100%) children with histological evidence of reflux esophagitis compared with 0/2 (0%) in children with normal histology (p = 0.048). Conclusions: Salivary pepsin was detected in a large proportion of children with EA and was significantly associated with GERD symptoms or wheeze. The role of salivary pepsin as a potential non-invasive marker of reflux aspiration in children with EA needs further validation in future studies with larger cohorts.

This study aimed to investigate the reflux characteristics in patients with gastroesophageal reflux-related chronic cough (GERC) complicated by laryngopharyngeal reflux (LPR).

Patients with chronic cough were recruited. Reflux symptom index (RSI) scoring, cough symptom scoring, assessment of capsaicin cough sensitivity, and multichannel intraluminal impedance and pH monitoring (MII-pH) were performed.

RSI score in GERC patients was significantly higher than that in patients with atopic cough (AC), cough variant asthma, eosinophilic bronchitis (EB), and upper airway cough syndrome (UACS) (P<0.05). The RSI score in non-acid GERC patients was significantly higher than that in acid GERC patients (P=0.003). The cut-off value of the RSI score was defined as 19 during diagnosis of non-acid GERC. In the RSI ≥19 group, there was more proximal reflux and more significant gas and non-acid reflux, and the efficacy of a combined use of baclofen or gabapentin was better than that of the RSI <19 group (P<0.05). The efficacy of proton pump inhibitor (PPI) at a routine dosage together with prokinetic agents in the RSI <19 group was better than that in the RSI ≥19 group (P=0.009).

LPR overlaps with GERC in part. GERC patients with higher RSI scores may present more proximal reflux, non-acid reflux, and gas reflux, and get better efficacy with neuromodulators (gabapentin or baclofen) used as an add-on therapy.

Pepsin represents a potential biomarker for extraesophageal reflux disease when detected in airways, however a direct role for pepsin in lung dysfunction has not been clearly established. Children experiencing gastroesophageal and extraesophageal reflux are often prescribed proton pump inhibitors (PPIs) to reduce gastric acid associated damage to esophageal and airway mucosa. The potential of pepsin and gastric fluid, from children that were either on or off PPI therapy, to cause inflammation and damage using a human in vitro co-culture model of the airway mucosa was evaluated herein. Exposure of the airway model to acidic solutions caused cellular damage and loss of viability, however, acid alone did not disrupt barrier integrity or instigate neutrophil trans-epithelial migration without pepsin. Gastric fluid from patients on PPI therapy exhibited only a slightly higher pH yet had significantly higher concentrations of pepsin and elicited more barrier disruption and neutrophil trans-epithelial migration compared to gastric fluid from patients off PPIs. Inflammatory and damaging responses observed with gastric fluid from patients on PPIs were largely driven by pepsin. These results indicate the potential for PPI usage to raise concentrations of pepsin in gastric fluid, which may enhance the pathological impact of micro-aspirations in children with extraesophageal reflux.

Gastro-oesophageal reflux disease (GERD) is difficult to diagnose without invasive testing. Peptest (RD Biomed, Hull, UK) is a recently marketed diagnostic tool which aims to quantify salivary pepsin as a marker of reflux, providing a rapid alternative to invasive procedures.

To evaluate optimal timing for sampling, and to evaluate the accuracy of Peptest against an independent measure.

Thirty diagnosed GERD patients (12 female, mean age 49 [range 20-72]) and 20 asymptomatic subjects (14 female, mean age 56 [range 21-56]) were subject to diurnal saliva sampling, with additional samples for 60 minutes following self-reported reflux symptoms and triggering of a proximal reflux alarm. Saliva samples were split and were analysed by both Peptest and ELISA with operators for each blinded to sample identity.

Salivary pepsin was detectable in most patients and most volunteers. Peptest scores were significantly lower for patients than controls (P < 0.005). ELISA scores showed no difference between patients and controls. There was no effect of diurnal sampling time (P = 0.75) or time after symptoms (P = 0.76) on Peptest readout. There was no correlation between Peptest and Pepsin ELISA (P = 0.55); Bland-Altman analysis suggested no agreement between the tests (P = 0.414). Receiver-operator curve suggests that neither Peptest (P = 0.3328) nor pepsin (P = 0.4476) is useful for predicting GERD.

Salivary pepsin is not a reliable tool for the diagnosis of GERD.

To evaluate the analytical parameters of a lateral flow (LF) pepsin immunoassay (Peptest) and assess its suitability in the diagnostics of gastroesophageal reflux disease (GERD).

Peptest is a noninvasive assay to analyze pepsin in saliva, intended for use in GERD diagnostics. Although commercialized, fundamental studies on its performance are missing. The assay therefore requires basic analytical parameter evaluation to assess its suitability in clinical practice.

Assay reaction's time dependence, reader device repeatability, and individual LF devices and longitudinal pepsin concentration reproducibility in individual subjects was evaluated. Salivary pepsin was analyzed in 32 GERD patients with extraesophageal reflux symptoms and 13 healthy individuals.

The assay's signal increase is not completed at the recommend readout time and continues to increase for another 25 minutes. The relative standard deviation of measurement was good when using the same LF device, ranging from 2.3% to 12.9%, but the reproducibility of 10 different individual LF devices was poor. The random error when analyzing the same saliva sample on 10 LF devices was as high as 36 ng/mL and this value is thus suggested as the positivity cut-off. Pepsin concentration in individual subjects during a 10-day period varied significantly. The sensitivity of the Peptest was 36.8% in the group with acid reflux and 23.1% in the group with weakly acid reflux. The specificity was 61.5%.

The Peptest assay's sensitivity and specificity is low, the results are highly variable and it should not be used as a near-patient diagnostic method in primary care.

Pediatric aerodigestive programs appear to be rapidly proliferating and provide multidisciplinary, coordinated care to complex, medically fragile children. Pediatric subspecialists are considered essential to these programs. This study evaluated the state of these programs in 2017 by surveying their size, composition, prevalence, and the number of patients that they serve.

The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Aerodigestive Special Interest Group leadership distributed an 11-question survey to the Pediatric Gastroenterology International Listserv. The mean time of the programs' existence, number of half-day clinics, number of procedure days, number of patients evaluated, and the lead primary specialty were evaluated.

Thirty-four programs responded. Twenty-five were based in academic centers. Thirty-one programs were located across the United States. The average time of program existence was 5.3 years (standard deviation [SD] = 4.3; range 1-17 years). Approximately 64.7% were started in the past 5 years. Twelve programs were based in the division of gastroenterology. The average number of gastroenterologists serving aerodigestive programs was 2 (SD = 1.1). The mean number of half-day clinic sessions and procedure days were 2.8 (SD = 2.9) and 2.6 (SD = 2), respectively. New and follow-up visits per year in each program averaged 184 (SD = 168; range 10-750).

Pediatric aerodigestive programs are prevalent, proliferating, and serve a large number of complex patients across North America and the world. This survey demonstrated that programs are predominantly based in academic settings. The number of patients cared for by aerodigestive centers varies widely depending on size and age of program.

The diagnosis and management of gastro-esophageal reflux (GER) and GER disease (GERD) in infants and children remains a challenge. Published guidelines and position papers, along with Embase, MEDLINE, and the Cochrane Database were reviewed and summarized with the intent to propose a practical approach and management of GER and GERD for healthcare providers and to standardize and improve the quality of care for infants and children. For this purpose, 2 algorithms were developed, 1 for infants <12 months of age and the other for older children. None of the signs and symptoms of GER and GERD are specific and there is no gold standard diagnostic test or tool. Nutritional management is recommended as a first-line approach in infants, while in children, a therapeutic trial with antacid medication is advised for early management. The practical recommendations from this review are intended to optimize the management of GER in infants and older children and reduce the number of investigations and inappropriate use of medication.

BACKGROUND Gastroesophageal reflux disease (GERD) is very common. Salivary pepsin detection has previously been considered as a method for GERD diagnosis. We performed a meta-analysis to investigate the utility of salivary pepsin assay as a diagnostic tool of GERD. MATERIAL AND METHODS PubMed, Web of Science, the Cochran Library, and EMBASE (from January 1980 to 23 October 2018) were searched for pepsin in saliva for GERD diagnosis. We summarized the retrieved specificity, sensitivity, negative likelihood ratio (NLR), positive likelihood ratio (PLR), diagnostic odds ratio (DOR), and receiver operating characteristic (ROC) curves data in the meta-analysis. RESULTS In final analysis, a total of 5 studies were included. The summary sensitivity, specificity, NLR, and PLR were 0.60 (95% CI 0.41-0.76), 0.71 (95% CI 0.51-0.86), 0.56 (95% CI 0.34-0.93), and 2.1 (95% CI 1.1-4.1), respectively. The pooled DOR was 4 (95% CI 1.0-11.0) and area under the ROC was 0.70 (95% CI 0.66-0.74). CONCLUSIONS The meta-analysis showed that pepsin in saliva has moderate diagnostic value for GERD, and is not as helpful as previously thought.

To evaluate the prediction value of saliva pepsin detection for an 8-week proton pump inhibitor (PPI) response in patients with a Reflux Symptoms Index (RSI) score ≥13, which indicates possible laryngopharyngeal reflux.

Prospective individual single-cohort study.

Patients were recruited who had experienced chronic laryngopharyngeal symptoms (RSI score ≥13) for more than 3 months after excluding other etiologies. The patients received PPI (40 mg of esomeprazole once daily) treatment for 8 weeks. Prior to treatment, the patients submitted saliva/sputum samples that were collected during the time symptoms were observed. The samples were taken for pepsin detection, and performed using the commercially available Peptest lateral flow device. The association of the Peptest results and PPI response were statistically analyzed with the χ² test.

Seventy-four patients completed the study, and upon completion of PPI treatment, the mean RSI score was significantly reduced from 19.22 ± 5.18 to 8.99 ± 5.69. Forty-four (59.5%) patients exhibited a good response as defined by an RSI score reduction ≥50%. The results of the Peptest were semiquantitatively graded as 0, 1, 2, 3 (negative, weak positive, moderate positive and strong positive, respectively) based upon the visual intensity of the test sample line as compared to the control line. Twenty-four patients (32.4%) exhibited grade 3 strong positive results. The Peptest strong positive results (P < .05) were significantly associated with a good PPI response, with the positive predictive value being 79.2%.

Analysis of strong positive results for pepsin detection in saliva/sputum samples may be a useful, noninvasive method for predicting better PPI response in patients with suspected reflux induced chronic laryngopharyngeal symptoms.

2 Laryngoscope, 129:709-714, 2019.

The purpose of this review is to outline the recent developments in the field of extraesophageal reflux disease and provide clinically relevant recommendations. The recommendations outlined in this review are based on expert opinion and on relevant publications from PubMed and EMbase. The Clinical Practice Updates Committee of the American Gastroenterological Association proposes the following recommendations: Best Practice Advice 1: The role of a gastroenterologist in patients referred for evaluation of suspected extra esophageal symptom is to assess for gastroesophageal etiologies that could contribute to the presenting symptoms. Best Practice Advice 2: Non-GI evaluations by ENT, pulmonary and/or allergy are essential and often should be performed initially in most patients as the cause of the extraesophageal symptom is commonly multifactorial or not esophageal in origin. Best Practice Advice 3: Empiric therapy with aggressive acid suppression for 6-8 weeks with special focus on response of the extraesophageal symptoms can help in assessing association between reflux and extraesophageal symptoms. Best Practice Advice 4: No single testing methodology exists to definitively identify reflux as the etiology for the suspected extra esophageal symptoms. Best Practice Advice 5: Constellation of patient presentation, diagnostic test results and response to therapy should be employed in the determination of reflux as a possible etiology in extra esophageal symptoms. Best Practice Advice 6: Testing may need to be off or on proton pump inhibitor (PPI) therapy depending on patients' presenting demographics and symptoms in assessing the likelihood of abnormal gastroesophageal reflux. A. On therapy testing may be considered in those with high probability of baseline reflux (those with previous esophagitis, Barrett's esophagus or abnormal pH). B. Off therapy testing may be considered in those with low probability of baseline reflux with the goal of identifying moderate to severe reflux at baseline. Best Practice Advice 7: Lack of response to aggressive acid suppressive therapy combined with normal pH testing off therapy or impedance-pH testing on therapy significantly reduces the likelihood that reflux is a contributing etiology in presenting extraesophageal symptoms. Best Practice Advice 8: Surgical fundoplication is discouraged in those with extra esophageal reflux symptoms unresponsive to aggressive PPI therapy. Best Practice Advice 9: Fundoplication should only be considered in those with a mechanical defect (e.g., hiatal hernia), moderate to severe reflux at baseline off PPI therapy who have continued reflux despite PPI therapy and have failed more conservative non-GI treatments.

This document serves as an update of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) 2009 clinical guidelines for the diagnosis and management of gastroesophageal reflux disease (GERD) in infants and children and is intended to be applied in daily practice and as a basis for clinical trials. Eight clinical questions addressing diagnostic, therapeutic and prognostic topics were formulated. A systematic literature search was performed from October 1, 2008 (if the question was addressed by 2009 guidelines) or from inception to June 1, 2015 using Embase, MEDLINE, the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Clinical Trials. The approach of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) was applied to define and prioritize outcomes. For therapeutic questions, the quality of evidence was also assessed using GRADE. Grading the quality of evidence for other questions was performed according to the Quality Assessment of Studies of Diagnostic Accuracy (QUADAS) and Quality in Prognostic Studies (QUIPS) tools. During a 3-day consensus meeting, all recommendations were discussed and finalized. In cases where no randomized controlled trials (RCT; therapeutic questions) or diagnostic accuracy studies were available to support the recommendations, expert opinion was used. The group members voted on each recommendation, using the nominal voting technique. With this approach, recommendations regarding evaluation and management of infants and children with GERD to standardize and improve quality of care were formulated. Additionally, 2 algorithms were developed, 1 for infants <12 months of age and the other for older infants and children.

A detailed critique of objective measurements of gastroesophageal reflux disease (GERD) would improve management of patients suspecting of having reflux, leading to rational selection of treatment and better outcomes. Many diagnostic tests for GERD have been developed over the past decades. We analyze their development, positive- and negative-predictive values, and ability to predict response to treatment. These features are important for development of medical, surgical, and endoscopic therapies for GERD. We discuss the value of available diagnostic tests and review their role in management of patients with persistent reflux symptoms despite adequate medical or surgical treatment. This is becoming a significant health economic problem, due to the widespread use of proton pump inhibitors. GERD is believed to cause nonesophageal symptoms, such as those provoked by ear, nose, throat, or respiratory disorders. We analyze the value of GERD diagnostic tests in evaluation of these troublesome, nonesophageal symptoms.

Gastroesophageal reflux disease encompasses a wide spectrum of disorders related to the reflux of gastric contents into the esophagus. Extraesophageal reflux (EER) may be suspected in patients with unexplained chronic cough, pharyngolaryngeal symptoms, and asthma. For physicians, suspected EER is challenging as there is currently no tool that can reliably make a definitive diagnosis. Endoscopic signs are not specific, pharyngeal and proximal reflux monitoring are not reliable, and if distal pH or pH-impedance monitoring can identify patients with abnormal reflux, they cannot predict the response to therapy. Controlled randomized trials have failed to reliably demonstrate any benefit of high-dose proton-pump inhibitors over placebo in patients with laryngeal symptoms, chronic cough, and asthma. Overall, the role of gastroesophageal reflux has been largely overestimated in patients with suspected EER. Especially when proton-pump inhibitors failed to improve symptoms, other diagnosis should be considered, such as functional laryngeal disorders which are probably much more prevalent in these patients than pathologic gastroesophageal reflux.

Gastroesophageal reflux (GER) is a normal physiologic process. It is important to distinguish GER from GER disease (GERD) since GER does not require treatment. Although a diagnosis of GERD can largely be based on history and physical alone, endoscopy and pH impedance studies can help make the diagnosis when there in atypical presentation. In children and adolescents, lifestyle changes and acid suppression are first-line treatments for GERD. In infants, acid suppression is not effective, but a trial of hydrolyzed formula can be considered, as milk protein sensitivity can be difficult to differentiate from GER symptoms.