Introduction

Provocative maneuvers are increasingly being performed during esophageal high-resolution manometry (HRM) in an attempt to increase the yield of the test. Recently, straight leg raise maneuver (SLR) (i.e., wet swallow with raised straight legs in supine position) has been proposed as a novel provocative test to evaluate esophageal reflux barrier and contraction reserve (CR) (i.e., augmentation of the esophageal contractile vigor following multiple rapid swallows, MRS). The rationale is that SLR augments intra-abdominal pressure, which has been shown to augment the contractile vigor of the esophagus.

Aims & Methods

The primary aim of this study was to investigate the relationship between the CR after multiple rapid swallows (MRS) and contractile vigor following SLR (i.e., obstructive stress reserve, OSR) in patients with normal esophageal manometry compared to those with ineffective esophageal motility (IEM). The secondary aim was to assess the characteristics of OSR in patients referred for gastroesophageal reflux disease (GERD) symptoms with normal manometry compared to those with IEM.
Between Nov 2021-Sep 2022, consecutive patients reporting GERD symptoms who underwent high-resolution manometry (HRM) were enrolled in two different esophageal centers (Pisa and Milano). GERD symptoms, height, and weight were recorded for all patients. Distal contractile integral (DCI) was analyzed during single water swallows (SS) (10 × 5 mL), MRS (3 × 2 mL), and SLR (2x5 mL). Preserved esophageal CR was defined as MRS/SS ratio was >1. Preserved OSR was defined as SLR/SS ratio >1. Data comparisons were performed using the independent sample t-test or the chi-square test, as appropriate. Pearson's correlation coefficient was used to investigate the correlation between the DCI following MRS and DCI during SLR in patients with normal peristalsis (group Normal) and IEM (Group IEM).

Results

Table 1: High Resolution Manometry in patients with Normal HRM group and IEM group

	HRM normal (196)	IEM (46)	p
EGJ type 3	26	6	0.061
EGJ-CI	50.5±28.9	43.9±30.4	0.169
DCI mean (ss)	1622.5±935.9	449.3±451.3	<0.001
Ineffective (failed) mean	15 (5)	85 (35)	<0.001
DCI mean (MRS)	2103.4±1753.1	778.5±1124.8	<0.001
MRS/SS ratio	1.4±1.4	1.7±1.8	0.218
DCI mean (SLR)	3347.1±2456.5	1647.2±2521.8	<0.001
SLR/SS ratio	2.4±1.8	3±2.6	0.014

242 patients (145 female, mean age: 53.7±14.8 years) were enrolled. Heartburn was reported as the main symptom in 165/242 (68.2%) patients and mean BMI 23.5±6.3. Esophageal HRM was normal in 196/242 (81%) patients (122 female, mean age 54.6±14.7yrs and mean BMI 23.6±6.7) and IEM was detected in 46/242 (19%) patients (23 female; 52.9±15.4yrs and mean BMI 22.9±4.9) patients (p=NS). All detail of manometric tests was reported in Table 1.
Esophageal CR was observed during MRS in 110/196 (56.1%) in the normal HRM group and 25/46 (54.3%) (p=0.87) in the IEM group and OSR was seen in 131/196 (66.8%) and 31/46 (67.4%) (p>0.99) in IEM following SLR. The DCI response following MRS correlated with the DCI response following SLR. Pearson's correlation coefficient was 0.479 (p < 0.01).

Conclusion

Swallowing against the resistance of increased intra-abdominal pressure from SLR improves esophageal body peristaltic performance and predicts esophageal body CR. The DCI response following SLR in patients with GERD is comparable to the DCI response after SS and MRS.

Disclosure

Conference Speech: Reckitt Benckiser; Malesci; Sofar; Alfa-Sigma;
Dr Falk; Cadigroup; Sanofi Genzyme, Alfa Sigma.
Advisory: Astra Zeneca.

Introduction

Ineffective esophageal motility (IEM) is a rare motility disorder characterized by weak or failed peristalsis at high-resolution manometry (HRM). There is an established association between IEM and gastroesophageal reflux-disease (GERD) symptoms. However, it is unclear why some patients present with dysphagia. In this study we aimed to investigated whether dysphagia in IEM is associated with specific HRM or pH-impedance monitoring (MII-pH) findings.

Aims & Methods

Adults (≥18 y) who underwent HRM for upper gastrointestinal symptoms who were diagnosed with IEM according to Chicago v4.0 between January 2021 and November 2024 were included. Patients’ gender, age, symptoms (dysphagia, chest pain, heartburn, regurgitation, belching), response to proton pump inhibitor (PPI) treatment and HRM data were recorded. All patients underwent MII-pH. Wilcoxon rank sum test, Pearson's chi-squared test and Fisher's exact test were used for comparisons. Significance was set at p<0.05.

Results

In the study period, 54 patients were diagnosed with IEM. Of them, 33 (61%) did not report dysphagia (IEM-GERD), while 21 (39%) had dysphagia (IEM-DYSPHAGIA). Of note, patients with or without dysphagia had a comparable prevalence of heartburn, chest pain, regurgitation, and erosive esophagitis. In addition, IEM-GERD and IEM-DYSPHAGIA were comparable in age and response to PPI treatment. IEM-GERD and IEM-DYSPHAGIA did not show significant differences in EGJ type, EGJ contractile integral (EGJ-CI), integrated relaxation pressure (IRP), percentage of ineffective or failed swallows, or the rapid drinking challenge (RDC) findings (p>0.05 for all), demonstrating an overall similar pathophysiology of peristalsis and EGJ opening. In terms of MII-pH, there was no statistical difference in GERD-related parameters between IEM-GERD and IEM-DYSPHAGIA, who showed comparable values of acid exposure time (AET), mean nocturnal baseline impedance (MNBI), symptoms association indexes (SI), and post-reflux swallow-induced peristatlic wave index (PSPW-I) (p>0.05 for all).

Conclusion

We showed that dysphagia in IEM is not explained by impaired EGJ outflow or worse peristalsis. IEM with and without dysphagia have a similar proportion of GERD symptoms, comparable MII-pH findings, and respond similarly to PPI treatment. Our findings suggest that dysphagia in IEM could be a symptomatic manifestation of GERD.
​

Introduction

The evaluation of gastroesophageal reflux disease (GERD) often includes the analysis of symptom-reflux correlation metrics such as the Symptom Index (SI) and Symptom Association Probability (SAP). These tools provide critical insights into the temporal relationship between reflux episodes and symptom perception, aiding in the identification of patients most likely to benefit from a tailored PPI treatment.

Aims & Methods

The aim of this study was to evaluate a continuous series of patients responsive to PPI treatment and differentiate those with GERD and those without. a series of consecutive patients with NERD o grade A esophagitis underwent monitoring tests for esophageal pathophysiology (MIIpH 24h).
All patients were evaluated for epidemiological and anthropometric characteristics and clinical presentation (GERDQ). According to the aim of this study we decided to enroll only patients that were full responders to the treatment with PPIs longer that 3 months. Treatment response was evaluated with (VAS). Evaluated pathophysiological parameters: acid exposure time (AET), reflux number, mean nocturnal baseline impedance (MNBI) and SI and SAP were calculated. Patients were divided in proven GERD or negative GERD according to the Lyon 2.0 Consensus thresholds.

Results

We enrolled throughout the last six months 83 patients (57 female) with an adequate heartburn relief with a standard therapy with PPIs. Patients were divided in proven 26 GERD (16 F, mean age 58.6 yr, BMI 27.9) and 57 Negative GERD (41 F, mean age 53.2 yr, BMI 24.5). Heartburn relief (VAS) was similar in the two different groups (p=NS) and similarly the duration of the treatment with the full dose of PPIs. The parameters able to distinguish GERD from non-GERD were: AET, Reflux events number and MNBI (p<0.01) from pathophysiological point of view and higher BMI and male sex from epidemiological characteristics (p<0.001). For details see Table 1.

	True GERD (26)	Negative GERD (57)	p
Age	58.6±12.7	53.2±14.4	0.104
Female	16/26	41/75	0.001
Heartburn Improvement (VAS)	80.8±14.9	75.6±15.4	0.153
Treatment duration (months)	6.1±2.4	5.9±2.9	0.447
GERDQ	9±2.1	9.1±1.9	0.831
AET	11.6±6.5	1.7±1.5	<0.0001
Reflux events	49.3±23.3	24.7±11.3	<0.0001
SI/SAP positive	2/26	5/57	>0.99
MNBI	1169.7±515.2	3342.4±978.2	<0.0001

Conclusion

Only MIIpH variables are able to distinguish patients with proven GERD from those with no GERD.

References

Gyawali CP, Yadlapati R, Fass R, Katzka D, Pandolfino J, Savarino E, Sifrim D, Spechler S, Zerbib F, Fox MR, Bhatia S, de Bortoli N, Cho YK, Cisternas D, Chen CL, Cock C, Hani A, Remes Troche JM, Xiao Y, Vaezi MF, Roman S. Updates to the modern diagnosis of GERD: Lyon consensus 2.0. GUT 2024 Jan 5;73(2):361-371.

Disclosure

Conference Speech: Reckitt Benckiser; Malesci; Dr Falk, PharmaLine, AlfaSigma, Sanofi-Genzyme.
Advisory Board: Dr Falk; Astra Zeneca; Sanofi Genzyme, AlfaSigma
Research grant: Dr Falk; Sanofi Genzyme

Introduction

Up to 40% of patients with heartburn (HB) do not respond to proton pump inhibitors (PPI). In absence of objective gastroesophageal reflux disease (GERD) evidence, functional esophageal disorders (FEDs) defined by Rome IV criteria, such as functional heartburn (FH) and reflux hypersensitivity (RH), represent a possible cause. Paroxetine may have a therapeutic role in these conditions. We investigated the efficacy of paroxetine in patients with FH and RH.

Aims & Methods

We investigated the efficacy of paroxetine in patients with FH and RH.
We enrolled consecutive outpatients with negative endoscopy and PPI-refractory HB who were treated with paroxetine following a diagnosis of FH or RH on pH-impedance monitoring (MII-pH) performed off therapy at Pisa University Hospital. Demographics, symptoms, PPI response rates, paroxetine dose and response, and MII-pH findings were recorded. Patients were classified, according to Rome IV criteria, into group A (FH) and group B (RH). All patients received either paroxetine 10mg or 20mg daily according to individual HB response.
An adequate response to SSRI was defined as HB relief >60% on a VAS questionnaire. In addition, anxiety levels were assessed using the corresponding items of Hospital Anxiety and Depression Scale (HADS) questionnaire at baseline and after 8 weeks.

Results

57 patients were included (44 F), median age 53 years (40-62) mean BMI 24 (22-26), of these, 42 had FH and 15 had RH. The groups were comparable in age, sex distribution, BMI, and symptoms. Table 1 reports clinical data.
On MII-pH, RH patients had higher total, recumbent and upright AET, higher number of total refluxes, and lower values of MNBI (p<0.001 for all) and PSPW (p<0.05) compared to FH. Table 1 reports MII-pH details. FH showed higher anxiety scores at baseline compared to RH (all p<0.001). Although FH more frequently required a higher dose of paroxetine to achieve symptoms relief (p<0.001), response to paroxetine was comparable between FH vs RH (69% vs 53%, respectively) (p=0.4). SSRI outcomes has been evaluated by means of HADS questionnaire (anxiety) that changed from a 16 (IQR 13.2, 17.8) to 9 (IQR 7, 10) in FH patients and from 11 (IQR 9.5, 12) to 6 (IQR 5, 8) in RH patients. At least 37/42 (88%) of patients with FH required standard dose of paroxetine compared to 12/15 (80%) of patients with RH who required only 10mg of paroxetine to reach symptomatic relief.
On ROC curve analysis, anxiety scores at baseline predicted the dose of paroxetine required for HB control in patients with FH and RH, with an area under the curve of 0.84 (CI, 0.71-0.96).

Table 1: demographic, clinical and pH-imopedance findings

	Functional Heartburn (42 pts)	Reflux Hypersensitivity (15 pts)	P
Female (%)	35 (83%)	9 (60%)	0.082
BMI (median, IQR)	24 (21, 26)	24 (23, 26)	>0.9
Age (median, IQR)	53 (39, 61)	49 (42, 62)	0.4
Total AET (median, IQR)	0.2 (0.1, 0.8)	1.4 (0.9, 2)	<0.001
Reflux events (median, IQR)	18 (12, 27)	38 (32, 40)	<0.001
MNBI (median, IQR)	3617 (3040, 3945)	2670 (2447, 2882)	<0.001
PSPW-index (median, IQR)	72 (66, 77)	64 (63, 66)	0.004
SI/SAP positivity	0	15 (100%)	N/A
PPI Response rate, VAS	10% (10, 30)	40% (40, 50)	<0.001

Conclusion

Baseline anxiety scores predict whether patients with FH or RH will respond to low dose (10mg) or high-dose (20mg) paroxetine. These results suggest that patients with FH or RH who have high anxiety scores, should be treated with paroxetine 20mg, while 10mg could be adequate for patients with low anxiety levels at baseline.

Disclosure

Conference Speech: Reckitt Benckiser; Malesci; Sofar; Alfa-Sigma;
Dr Falk; Cadigroup; Sanofi Genzyme.
Advisory: Astra-Zeneca

Introduction

There is a known discrepancy between symptoms reporting and histological disease activity in patients with eosinophilic esophagitis (EoE) such that patients with EoE in histological remission may still report symptoms while patients with histologically active EoE may report few or no symptoms. Esophageal symptom-specific anxiety, hypervigilance, and adaptive behaviours at mealtime may affect dysphagia reporting in EoE but this has not been investigated.

Aims & Methods

We investigated the role of esophageal symptom-specific anxiety, hypervigilance, and adaptive behaviours at mealtime on dysphagia reporting in patients with EoE.
Consecutive adults (>18 years) with histologically active or inactive EoE (i.e., ≥15 or <15 eosinophils/high-power field) at their last upper endoscopy (EGD) were prospectively enrolled. For each patient, esophageal hypervigilance, anxiety, and adaptive behaviours were assessed prior to the EGD by a physician who was blind to patients’ treatment status and histological disease activity. Esophageal anxiety and hypervigilance were assessed using the validated Esophageal Hypervigilance and Anxiety Scale (EHAS) with a 30-day recall, while the validated Dysphagia Symptom Questionnaire (DSQ) and Dysphagia Symptom Score (DSS) were used for quantification of dysphagia. A structured interview (Pisa adaptation questionnaire, PiEAQ) was used for the assessment of adaptive behaviours (including: drinking water to push the bolus, lubricating food, chewing for long, and blending food) over the 30 days prior to the EGD. Kruskal-Wallis Rank Sum Test and Pearson’s Chi-squared were used for comparisons as appropriate. ROC curve analysis was used to calculate the diagnostic accuracy (AUC). Significance threshold was p<0.05.

Results

Seventy-one patients were included. Sixty-two percent (n=44) had histologically active EoE and 38% (n=27) were in histological remission. High anxiety, hypervigilance, and use of adaptive behaviours were found in 49.3%, 46.5%, and 56.3% of patients, respectively. Higher levels of anxiety were associated with an increased severity of dysphagia according to DSQ and DSS scores (p=0.02 and p=0.003, respectively), whereas this was not true for hypervigilance (p=0.79 and p=0.24, respectively). Adaptive behaviours were significantly more commonly used by histologically active EoE compared to EoE in remission (72.3% vs 29.6%, p<0.001). The DSQ and DSS scores of patients using any or a combination of adaptive behaviours were comparable to those of patients not using any adaptive behaviour at mealtime (p>0.1 for all comparisons), suggesting a marginal impact of adaptive behaviours on dysphagia reporting. Based on ROC curve analysis, the AUC of the DSQ for the assessment of histological disease activity was 0.72 (DeLong 95% CI, 0.60-0.83), while the AUC of the DSS was 0.69 (DeLong 95% CI, 0.56-0.82). Dysphagia reporting adjustments based on anxiety or hypervigilance sub-scores of the EHAS or on the presence of adaptive behaviours at mealtime did not modify the performance of the DSQ and DSS.

Conclusion

Esophageal anxiety, hypervigilance, and adaptive behaviours can be found in half of EoE patients regardless of histological disease activity. Esophageal anxiety contributes to dysphagia severity in patients with EoE, while hypervigilance does not. The use of adaptive behaviours is associated with histologically active EoE and represents a clinical marker of disease activity but does not affect dysphagia reporting.

		Patients with high esophageal anxiety (n=35)	Patients with low esophageal anxiety (n=36)	p value
Full population n=71 (EHAS subscore cut-off>8)	DSQ	3 [0-5]	2 [0-3]	p=0.02
	DSS	5 [0-6]	2 [0-3]	p=0.003
		Patients with high esophageal hypervigilance (n=33)	Patients with low esophageal hypervigilance (n=38)
Full population n=71 (EHAS subscore cut-off>11)	DSQ	2 [0-3]	2 [0-3]	p=0.79
	DSS	3 [0-6]	2 [0-4]	p=0.24

Introduction

The distinction between eosinophilic esophagitis (EoE) and other causes of dysphagia in clinical practice can be difficult without histology. In addition, failure to collect esophageal biopsies represents one of the reasons for a delayed diagnosis in patients with EoE. Current guidelines recommend multiple esophageal biopsies in all patients reporting dysphagia although this may not be cost-effective.

Aims & Methods

To optimize resources allocation in the diagnostic workup of EoE, we developed and thereafter validated on an independent cohort of patients two point-of-care machine learning (ML) tools to predict a diagnosis of EoE: 1) based on clinical history data alone and 2) based on clinical-endoscopic findings, prior to the results of esophageal biopsies. This was a two-step multi-center international study conducted in three European tertiary referral centers for EoE (London, Pisa, and Padua). We build predictive ML models based on retrospectively extracted clinical data alone (age at diagnosis, sex, presence or absence of heartburn, chest pain, postprandial nausea/dyspepsia, history of food impaction requiring endoscopic removal, allergic rhinitis, asthma, nasal polyposis) and on clinical and upper endoscopy (EGDS) (exudates, rings, edema, furrows, stricture) data collected from 273 EoE and 55 non-EoE dysphagia (NED) patients in London. We performed an external validation of the models on an independent cohort of 93 prospectively enrolled patients reporting dysphagia at Pisa and Padua University Hospitals. The performance of the models was described with area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). We then developed a freely downloadable software for use in clinical practice at the point-of-care.

Results

The machine learning model trained on clinical data alone showed AUC of 0.82, and sensitivity, specificity, PPV, and NPV of 0.75, 0.82, 0.82, 0.75, respectively, for the diagnosis of EoE in the external validation cohort. Among clinical data alone, the patients’ age at diagnosis and sex had the highest predictive ability. The machine learning model trained on a combination of clinical and endoscopic data showed AUC of 0.93, and sensitivity, specificity, PPV, and NPV of 0.88, 0.95, 0.95, 0.87, respectively, in the external validation cohort. Among clinical and endoscopic data, the patients’ age at diagnosis, esophageal rings at endoscopy, and sex had the highest predictive ability. The models’ performance in the development and external validation cohorts is reported in Table 1.

Conclusion

The international external validation of our ML tools, as well as the freely available software, allow generalizability of our findings to other settings. Our software can be easily used at the point-of-care to optimize resources allocation in the diagnostic workup of EoE and 1) Support the clinical suspicion of EoE even in the absence of endoscopic findings, 2) Support decision making in performing repeat EGDS in patients in whom biopsies had been omitted, 3) Support decision making in performing repeat EGDS in patients with persistent EoE symptoms who had non-diagnostic levels of eosinophils at a previous EGDS performed while on proton-pump inhibitors, 4) Avoid unnecessary biopsies in very low-risk patients.

Introduction

High resolution manometry (HRM) currently has a marginal role in the diagnosis of gastroesophageal reflux disease (GERD) except for the correct placement of pH-impedance (MII-pH) probes. However, a Manometric Score for Gerd Probability (i.e., the Milan Score) has been recently developed to predict a diagnosis of GERD based on HRM findings prior to pH monitoring studies.

Aims & Methods

In this study, we performed the external validation of the Milan Score in a high-volume tertiary referral center. HRM and MII-pH tracings of consecutive patients reporting GERD symptoms between 2019-2022 were retrospectively reviewed. Clinical, MII-pH, and HRM data were recorded for all patients. Patients with achalasia, body mass index>35 Kg/m^2, previous esophageal surgery, paraesophageal hiatal hernia, eosinophilic esophagitis and scleroderma were excluded. To calculate the Milan Score score, data on diagnosis of ineffective esophageal motility (IEM) according to Chicago Classification v4.0, esophagogastric junction contractile integral (EGJ-CI), EGJ morphology (i.e., type I, II or III), intraesophageal pressure (IEP) during reference ID and straight-leg raise (SLR) pressures were collected. A SLR maneuver was considered positive if >11mmHg. The Milan Score was calculated using the nomogram published in the Milan Score paper (United European Gastroenterology Journal 2024 [1]). Wilcoxon rank sum test, Pearson's chi-squared test and Fisher's exact test were used for comparison. ROC curve analysis was used to calculate the diagnostic accuracy (AUC) of the MSGP score.

Results

Of the 86 included patients, 36 (41.8%) had conclusive GERD based on acid exposure time (AET) > 6%, while 50 (58.2%) had AET<6%. Patients with AET>6% and AET< 6% were comparable in terms of age, weight, regurgitation, chest pain, dysphagia, erosive esophagitis, and HRM diagnosis. Patients with AET>6% more frequently had heartburn (p=0.009), EGJ type 3, MNBI < 1500 Ohms (p< 0.001) and positive symptoms index and symptoms association probability (p=0.007). The median Milan Score was 78 (IQR, 54-132) in patients with AET<6% and 164 (IQR, 125-198) in patients with AET>6% group. Based on ROC curve analysis, a Milan Score higher than 103 was associated with a diagnosis of conclusive GERD (i.e., AET>6%) with AUC of 0.78, with 70% specificity and 80% sensitivity.

Conclusion

The Milan Score has good performance in the diagnosis of GERD upon HRM recording, prior to MII-pH in patients reporting GERD symptoms. The Milan Score proved external validity and can be used as a screening test for GERD in patients undergoing HRM.

Characteristic	AET ≤6%, n = 50 (58%)​	AET>6%, n = 36 (42%)	p-value​​​​​
Ineffective esophageal motility	5 / 50 (10%)	5 / 35 (14%)	0.24
SLR >11mmHg	13/50 (26.0%)	26/36 (72.2%)	<0.001
EGJ-Contractile Index (CI)	42 (28, 55)	27 (13, 42)	0.015
Positive SI/SAP	2 / 50 (4.0%)	9 / 36 (25%)
EGJ type			0.005
1	26 / 50 (52%)	14 / 36 (39%)
2	20 / 50 (40%)	9 / 36 (25%)
3	4 / 50 (8.0%)	13 / 36 (36%)
Total Milan Score​​​​​	78 (54, 132)	164 (125, 198)	<0.001

References

[1] Siboni, S., Sozzi, M., Kristo, I., Boveri, S., Rogers, B. D., De Bortoli, N., Hobson, A., Louie, B. E., Lee, Y. Y., Tolone, S., Marabotto, E., Visaggi, P., Haworth, J., Ivy, M. L., Greenan, G., Masuda, T., Penagini, R., Barcella, B., Coletta, M., Theodorou, D., … Gyawali, C. P. (2024). The Milan score: A novel manometric tool for a more efficient diagnosis of gastro-esophageal reflux disease. United European gastroenterology journal, 10.1002/ueg2.12565. Advance online publication. https://doi.org/10.1002/ueg2.12565