Look above the IRP: predicting abnormal confirmatory testing in patients with esophagogastric junction outflow obstruction

Abstract

Background:

Esophagogastric junction outflow obstruction (EGJOO) is a manometric diagnosis based on Chicago Classification version 4.0 (CC4.0) that requires confirmatory testing for clinical relevancy. However, it is still unclear which patients will respond to therapy.

Objectives:

To evaluate manometric and clinical predictors of abnormal confirmatory testing for patients with EGJOO.

Design:

This was a prospective observational study of patients with manometric EGJOO and chest pain or dysphagia who underwent confirmatory testing.

Methods:

Patients with EGJOO on manometry were enrolled and underwent timed barium esophagram or endoFLIP. A subset of patients was given validated surveys, including Eckardt scores (ES) and PROMIS-10.

Results:

For patients with a CC4.0 EGJOO diagnosis, abnormal peristalsis (OR = 7.0, 95% CI = 1.01–44.6, p = 0.04) and increases in ES (OR = 2.34 95% CI = 1.13–4.86, p = 0.02) were associated with positive confirmatory testing.

Conclusion:

Patients with potentially actionable EGJOO were more likely to have an abnormal peristaltic subtype of EGJOO or higher ES.

Plain language summary

Predicting abnormal confirmatory testing in patients with esophagogastric junction outflow obstruction (EGJOO)

Esophagogastric junction outflow obstruction (EGJOO) is a diagnosis based on esophageal manometry, which is a test that measures the muscles of the esophagus. EGJOO is when the lower esophageal sphincter is tight and does not relax well. This diagnosis requires confirmatory testing for clinical relevancy, as it can be seen commonly on testing without always having relevancy to a patient’s presentation. We evaluated predictors of abnormal confirmatory testing for patients with EGJOO. Patients with EGJOO on manometry were enrolled and underwent two types of confirmatory testing and some patients were given surveys about symptoms of difficulty swallowing and quality of life. Patients with EGJOO diagnosis were more likely to have abnormal confirmatory testing with higher scores of symptom severity or if they had other types of abnormal muscle changes in the esophagus.

Introduction

The clinical significance of a manometric diagnosis of esophagogastric junction outflow obstruction (EGJOO) has evolved since its initial description. Currently, a conclusive diagnosis of EGJOO as per the most recent Chicago Classification version 4.0 (CC4.0) requires some intact peristalsis in the setting of an elevated median integrated relaxation pressure (IRP) in multiple positions and elevated intrabolus pressure in at least 20% of supine swallows. To have clinical relevancy, this manometric finding requires symptoms of dysphagia and/or chest pain, and confirmatory testing with either an abnormal timed barium esophagram or distensibility measured by luminal functional lumen imaging probe (FLIP) in the absence of a secondary cause for the elevated IRP. ¹ EGJOO is common and the natural history is variable, with reports of spontaneous symptom resolution as well as progression to achalasia.^2–4 Thus, the optimal management of EGJOO ranges from clinical observation to targeted lower esophageal sphincter (LES) disruption. However, it is unclear how to identify those patients who have a likely achalasia variant and will respond well to LES therapy.

As noted, the CC4.0 includes the new requirement of IRP elevation in two positions and an elevated intrabolus pressure to reduce further testing for patients who are unlikely to have esophagogastric pathology. Recent studies show only 18%–20% of patients with EGJOO based on Chicago Classification version 3.0 (CC3.0) retained their diagnosis by the more stringent CC4.0.^5,6 The CC4.0 further defined patients with EGJOO by the presence of normal or abnormal peristalsis, but it is unknown if this has implications for predicting abnormal confirmatory testing. Our aim was to evaluate manometric and clinical predictors of abnormal confirmatory testing. We hypothesized that patients with EGJOO and abnormal peristalsis were more likely to have abnormal confirmatory testing compared to patients with normal peristalsis.

Methods

This was a prospective IRB-approved study (Protocol 849922) at the University of Pennsylvania Health System. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement (Supplemental Material). ⁷ Patients with chest pain or dysphagia and manometric EGJOO who subsequently underwent FLIP or timed barium esophagram were enrolled over the study period consecutively. The decision to pursue either FLIP or timed barium esophagram (TBE) was made based on a discussion between the ordering provider and the patient. Manometry was performed according to the CC protocol released at the time, so patients underwent either CC3.0 (10 swallows) or CC4.0 (10 supine swallows and 5 upright swallows) for a manometric diagnosis. Additionally, provocative testing with the rapid drink challenge and multiple rapid swallows were performed for patients in the CC4.0 cohort. Patients were excluded if they had a hiatal hernia >3 cm, prior foregut surgery, gastroparesis, eosinophilic esophagitis, anatomical esophageal or gastric obstruction including stricture, or erosive esophagitis (LA Grade B or higher). For all patients who underwent FLIP, baseline Eckardt scores (ES) and PROMIS-10 surveys were obtained pre-procedure. The ES questionnaire is widely used in evaluating the efficacy of achalasia treatments. ⁸ PROMIS-10 is a validated survey containing 10 questions assessing the overall quality of health that is separated into physical and mental health components. ⁹ Patients were characterized as having an abnormal FLIP if the distensibility index was <2 mm²/mmHg in combination with reduced esophagogastric junction opening (<12 mm) at 60 or 70 mL. Any retention of barium on timed barium esophagram was considered abnormal. Peristaltic subtypes were identified based on CC4.0 as shown in Figure 1.

Figure 1.

Figure demonstrates examples of contractile patterns associated with EGJOO with subtypes as follows: EGJOO with normal peristalsis, EGJOO with hypercontractile features, EGJOO with spastic features, and EGJOO with IEM.

EGJOO, esophagogastric junction outflow obstruction; IEM, ineffective esophageal motility.

Statistical analysis

We used univariate logistic regression to evaluate whether disordered peristalsis, ES, or PROMIS-10 scores were independently associated with increased odds of abnormal confirmatory testing with stratification by type of peristaltic abnormality. A sample size calculation was not performed prior to the initiation of the study, as this was part of a larger prospective study evaluating long-term outcomes. Significance was assessed at p < 0.05.

Results

In a total cohort of 51 patients, 24 (47.1%) had abnormal confirmatory testing with characteristics further described in Table 1. The patients with the Chicago 3 diagnosis of EGJOO were diagnosed prior to the Chicago 4.0 and only had 10 swallows. The 30 patients in the Chicago 4.0 cohort had 2 positions and met criteria based on the Chicago 4.0.

Table 1.

Characteristics of patients diagnosed with EGJOO on manometry.

Patient characteristics	All EGJOO	EGJOO based on Chicago Classification based on v3.0	EGJOO based on Chicago Classification based on v4.0
N	51	21	30
Sex
Male	35.3% (n = 18)	38.1% (n = 8)	33.3% (n = 10)
Female	64.7% (n = 33)	61.9% (n = 13)	66.7% (n = 20)
Age, years (mean ± SD)	61.3 ± 12.3	61.6 ± 11.7	61.0 ± 12.9
Peristaltic pattern
Normal	52.9% (n = 27)	52.4% (n = 11)	53.3% (n = 16)
Hypercontractile	15.7% (n = 8)	9.5%(n = 2)	20.0% (n = 6)
Spastic	7.84% (n = 4)	9.5% (n = 2)	6.7% (n = 2)
IEM	19.6% (n = 10)	19.1% (n = 4)	20.0% (n = 6)
Combination	3.92% (n = 2)	9.5% (n = 2)	0.0% (n = 0)

The table demonstrates the baseline characteristics of the cohort of patients diagnosed with EGJOO.

EGJOO, esophagogastric junction outflow obstruction; IEM, ineffective esophageal motility.

Of the cohort, 35 patients had endoFLIP for confirmation and 15 patients had timed barium esophagram. 1 patient had both timed barium esophagram and endoFLIP. Of the people who had endoFLIP, 21 people (58.33%) did not have confirmed EGJOO and 15 people (41.67%) did have confirmed EGJOO. Of the people who had TBE, 7 people (43.75%) did not have confirmed EGJOO and 9 people (56.25%) did have confirmed EGJOO. There was no statistically significant difference in the odds of positive confirmatory testing depending on the choice of test.

For all patients with EGJOO based on either CC3.0 or CC4.0, having a concurrent peristaltic abnormality was associated with an increased odds ratio of abnormal confirmatory testing (OR = 3.1, 95% CI = 0.1.06–10.5, p = 0.04). For the patients with EGJOO based on CC4.0 (n = 30), having a concurrent peristaltic abnormality was associated with increased odds (OR = 7.0, 95% CI = 1.09847–44.6075, p = 0.04) of having abnormal confirmatory testing. For the patients with EGJOO based on CC3.0 (n = 21), this was not statistically significant (OR = 2.0, 95% CI = 0.272–14.7, p = 0.496). When stratified by subtype of peristaltic abnormality, there were increased odds of having abnormal confirmatory testing in patients with hypercontractile/spastic esophagus (OR = 4.0, 95% CI = 0.95–16.78, p = 0.058) or ineffective esophageal motility (OR = 2.22, 95% CI = 0.74–10.44, p = 0.312), but neither finding was statistically significant.

Of the cohort, 38 patients had baseline ES recorded. The patients with abnormal confirmatory testing had a baseline ES of 5.68 ± 2.4 compared to patients with normal confirmatory testing (4.38 ± 2.78). The odds of having abnormal confirmatory testing were increased in patients with increases in ES, which was statistically significant in the patients with EGJOO based on CC4.0 but not CC3.0 (OR = 2.34 95% CI = 1.13–4.86, p = 0.02). Changes in baseline PROMIS-10 scores were not associated with an increase in the odds of having abnormal confirmatory testing.

Discussion

In this study, patients diagnosed with EGJOO with disordered peristalsis, particularly based on the more stringent CC4.0, had higher odds of abnormal confirmatory testing of potentially actionable EGJOO. In the CC4.0 cohort, increases in ES were also associated with a higher risk of abnormal confirmatory testing. These findings may help to risk stratify patients with EGJOO into clinically relevant subgroups, potentially guiding therapeutic options and follow-up, without adding significant risk or time to their testing.

Most of the prior literature on EGJOO has been based on CC3.0, but few have evaluated peristaltic patterns and confirmatory testing. ¹⁰ One study grouped patients with features of hypercontractile esophagus and distal esophageal spasm into a group deemed major mixed motility disorder (MMMD). This group was compared to patients with normal peristalsis or ineffective esophageal motility, with a total of 22 patients. The results revealed that patients in the MMMD group had lower pre-procedure distensibility index (DI) on FLIP and better response to LES-directed therapies. ⁵ Another study using EGJOO based on CC3.0 found that patients with abnormal peristalsis were more likely to have esophageal symptoms and impaired bolus transit, but confirmatory testing was not done. ¹¹ The strengths of our study include its prospective nature and that standardized patient-reported outcomes were collected prior to confirmatory testing.

Limitations

Our findings are limited by the small sample size and observational design, and may not be generalizable to all practice locations. In addition, the choice of confirmatory testing was made with the treating physician and patient and was not randomized. There is variation in the performance characteristics of these tests with previous work suggesting that TBE have different sensitivity. ¹² Regardless, our data did not suggest that there was a statistically significant difference between the two tests with the rate of positive confirmatory testing and is reflective of real-world clinical practice. As a sample size calculation was not performed as this was part of a longitudinal study on long-term outcomes, this may affect the statistical significance of our results. The inclusion of both cohorts of CC3.0 and CC4.0 introduces heterogeneity but is reflective of the testing available for clinical decision-making and the analysis of both groups separately demonstrates the different performance characteristics of the cohorts.

Conclusion

EGJOO with disordered peristalsis was associated with a higher risk of abnormal confirmatory testing, which may help risk stratify patients with this heterogeneous disorder. Furthermore, providers may benefit from the specification of the EGJOO subtype on every manometry read to assist in clinical decision-making. Further prospective studies with larger sample sizes are warranted to further evaluate these results.