2022 Impact Factor
2022 Impact Factor
, Kee Wook Jung,* In Ja Yoon, Hee Kyong Na, Ji Yong Ahn, Jeong Hoon Lee, Do Hoon Kim, Kee Don Choi, Ho June Song, Gin Hyug Lee, and Hwoon-Yong Jung
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Since high-resolution manometry (HRM) was introduced in the 2000s, it has become the standard test in most motility centers to diagnose esophageal motility disorders.1 Further, the Chicago classification, presented initially in 2009, has been accepted worldwide in categorizing esophageal motility disorders by interpreting this HRM. The first 3 versions of the Chicago classification were continuously updated between 2009 and 2015, and there have been several studies since the Chicago classification version 3.0 (CC v3.0) in 2015.2 Recently, the Chicago classification version 4.0 (CC v4.0) reflecting these results was announced with the assistance of an international HRM Working Group composed of 52 diverse experts over 2 years.3,4
The recently updated CC v4.0 emphasizes the importance of clinical relevance and establishes more rigorous criteria based on the standardized protocol, including supine and upright positions and provocative maneuvers. Moreover, to guide clinical decisions for inconclusive diagnoses on HRM, supportive tests such as timed barium esophagography (TBE) or endoluminal functional lumen imaging probe (FLIP) are strongly recommended in CC v4.0.5 However, the diagnostic accuracy of CC v4.0 compared with that of CC v3.0 remains unclear.
This study investigates the diagnostic accuracy and differences between CC v3.0 and v4.0 and further reinforced the importance of provocative or adjunctive tests, which are newly included in CC v4.0, for improving the diagnostic accuracy of an esophageal motility disorder.
A total of 290 patients, who underwent esophageal HRM for possible esophageal motility disorders between May 2020 and February 2021, were eligible for this study. Among them, 46 patients who met the following criteria were excluded: (1) peroral endoscopic myotomy (POEM) status (n = 41), (2) Heller myotomy status (n = 2), and (3) esophageal balloon dilatation status (n = 3). Finally, 244 patients were included and analyzed (Fig. 1). Each patient was diagnosed both by the CC v3.0 and CC v4.0 criteria to compare the diagnostic results. The medical records were reviewed retrospectively. All patients provided informed consent before the test. The institutional review board of Asan Medical Center approved this study (Approval No. 2022-0502).
Figure 1. Algorithm of enrolled patients. CC v3.0, Chicago classification version 3.0; CC v4.0, Chicago classification version 4.0; EGJ, esophagogastric junction; HRM, high-resolution manometry; POEM, peroral endoscopic myotomy; WNL, within normal limit.
An HRM catheter composed of 32 circumferential sensors and 16 impedance sensors (InSight Ultima; Diversatek, Highlands Ranch, CO, USA) was used for this study. It was positioned from the terminal portion of the proximal esophageal segment through the distal esophagus and into the proximal stomach. The esophageal HRM protocol included a 30-second interval without swallowing to assess the basal esophagogastric junction (EGJ) pressure and morphology, followed by ten 5 mL swallows of normal saline solution in the supine position.6 Moreover, it included additional positional change (upright position) and provocative testing, including the rapid drink challenge (RDC) while upright and multiple rapid swallows (MRS) while supine, designed by CC v4.0. The RDC test directed the patient to drink 200 mL of water in the upright position as fast as possible.7 In the MRS test, 2 mL of water was swallowed 5 times, separated by 2-3-second intervals.8
Since the integrated relaxation pressure (IRP) differs between catheter and system manufacturers regarding normal values, our institution used Diversatek’s products to standardize 22 mmHg for the supine and 15 mmHg for the upright position.3 Manometric data were analyzed using the Zvu Advanced GI Diagnostic Software (Diversatek) by 1 investigator (K.W.J.).9
In addition to esophageal HRM with provocative tests, additional supportive tests such as TBE or FLIP are also recommended in CC v4.0. In case of inconclusive HRM diagnosis of achalasia in patients with dysphagia, TBE and FLIP were performed to distinguish achalasia more accurately and guide clinical decisions.3
In diagnosing esophagogastric junction outflow obstruction (EGJOO) by CC v4.0, a manometric diagnosis and clinically relevant symptoms, including dysphagia or non-cardiac chest pain, are required. The manometric diagnosis is defined as an elevated median IRP in both supine and upright positions and ≥ 20% swallows with elevated intrabolus pressure with evidence of peristalsis. EGJOO is subdivided depending on the context of the peristaltic pattern as follows: spastic features (features of type III achalasia), hypercontractile features, ineffective motility, and absence of disordered peristalsis.3
In the past, the hypercontractile esophagus, called Jackhammer esophagus, also required both a manometric diagnosis and relevant clinical symptoms, including dysphagia or non-cardiac chest pain. The manometric diagnosis is defined as ≥ 20% hypercontractile swallows in the supine position. Moreover, on manometry, the distal esophageal spasm is defined as the presence of at least 20% of premature contractions (a distal latency shorter than 4.5 seconds), and the clinically relevant symptoms include dysphagia or non-cardiac chest pain.3
Ineffective esophageal motility (IEM) is defined as ineffective swallows over 70%, or at least 50% of swallows failed (distal contractile integral [DCI] < 100 mmHg·s·cm). Absence of contractility is defined as 100% failed peristalsis (DCI < 100 mmHg·s·cm) and normal median IRP in the upright or supine position.3
Descriptive variables are summarized as medians (interquartile range [IQR]). The proportion of diagnoses of motility disorders between CC v3.0 and CC v4.0 was compared using chi-squared tests. Statistical significance was set at
Two-hundred forty-four patients were included and investigated (Fig. 1). The median age was 59 (IQR, 45-66) years, and 46.7% (n = 114) were males. Of these, 53.3% (n = 130) and 61.9% (n = 151) were categorized as normal by CC v3.0 and CC v4.0, respectively. There was a significant decrease in the total diagnosis proportion of motility disorders by CC v4.0 than by CC v3.0 (46.7% vs 38.1%,
In a comparison between CC v3.0 and CC v4.0, 88.5% (n = 216) diagnoses were consistent between the 2, and 11.5% (n = 28) were shifted to a new diagnosis by CC v4.0, which mainly resulted from the diagnostic proportion change in the following order: EGJOO, IEM, and achalasia (Supplementary Table). Figure 2 shows the proportion of esophageal motility disorder diagnosis by CC v3.0 and CC v4.0.
Figure 2. The proportion of esophageal motility disorder diagnosis; (A) Chicago classification version 3.0 (CC v3.0) and (B) Chicago classification version 4.0 (CC v4.0). EGJOO, esophagogastric junction outflow obstruction; IEM, ineffective esophageal motility; WNL, within normal limit.
A total of 41 patients were diagnosed with EGJOO by CC v3.0. Of these, 15 patients were changed to normalcy by position (n = 2) and symptom (n = 13) by CC v4.0. Two patients showed elevated IRP in the supine position that decreased to the normal range in the upright position. Thirteen patients had elevated IRP in both the supine and upright positions but complained of atypical symptoms such as epigastric soreness, regurgitation, or nausea and were eventually classified as normal by CC v4.0. There were no significant differences in the HRM findings between those diagnosed by CC v3.0, diagnosis-changed group, and CC v4.0 (Table 1). The diagnosis of 26 patients with EGJOO was consistent by both CC v3.0 and CC v4.0, and they were classified as having no disordered peristalsis (n = 22, 84.6%), ineffective motility (n = 3, 11.5%), and hypercontractile features (n = 1, 3.8%).
Table 1 . High-resolution Manometry Findings Between Chicago Classification Versions 3.0 and 4.0 in Patients With Esophagogastric Junction Outflow Obstruction
| HRM findings | CC v3.0 (n = 41) | Diagnosis-changeda (n = 15) | CC v4.0 (n = 26) | |
|---|---|---|---|---|
| Supine IRP (mmHg) | 27.0 (25.0-31.0) | 26.0 (25.0-31.0) | 28.5 (25.0-31.1) | 0.909 |
| Supine DCI (mmHg·s·cm) | 1612.0 (870.0-2323.0) | 1389.0 (631.0-2349.0) | 1754.5 (1172.8-2328.3) | 0.803 |
| Supine DL (sec) | 7.4 (6.8-9.0) | 8.0 (7.0-9.0) | 7.0 (6.0-9.0) | 0.057 |
| Upright IRP (mmHg) | 24.0 (19.0-29.5) | 23.0 (17.0-33.0) | 24.5 (20.0-28.3) | 0.786 |
| Upright DCI (mmHg·s·cm) | 1310.0 (520.0-2007.5) | 1310.0 (521.0-2207.0) | 1317.5 (460.5-1863.5) | 0.891 |
| Upright DL (sec) | 7.2 (6.4-8.3) | 8.0 (7.0-8.0) | 7.0 (6.0-8.0) | 0.468 |
| MRS-IRP (mmHg)b | 24.0 (17.5-30.0) | 24.0 (21.0-32.0) | 23.5 (16.8-28.5) | 0.701 |
| MRS-DCI (mmHg·s·cm)c | 861.0 (387.0-2371.5) | 1092.0 (372.0-2391.0) | 842.5 (412.5-2366.3) | 0.975 |
| RDC-IRP (mmHg)d | 20.1 (16.0-24.0)e | 22.0 (16.0-27.0) | 20.5 (13.5-23.8)f | > 0.999 |
aDiagnosis changed from esophagogastric junction outflow obstruction (EGJOO) to normalcy.
bIntegrated relaxation pressure (IRP) during multiple rapid swallows (MRS).
cDistal contractile integral (DCI) during MRS.
dIRP during rapid drink challenge (RDC).
en = 39.
fn = 24.
HRM, high-resolution manometry; CC v3.0, Chicago classification version 3.0; CC v4.0, Chicago classification version 4.0; DL, distal latency.
Data are presented as median (interquartile range).
Twenty-seven patients were diagnosed with IEM by CC v3.0. In 6 patients, the IEM diagnosis was changed to normalcy by CC v4.0 for the following reasons: 5 of them showed 60% ineffective swallows, and the other patient had 50% ineffective swallows. In 5 patients, the IEM diagnosis by CC v3.0 was changed to achalasia by CC v4.0. For 4 of them, the diagnosis was changed by using an additional test, FLIP. In the case of the other patient, HRM reported 80% ineffective swallows and normal IRP. However, the esophagography, which showed EGJ narrowing with upstream esophageal dilatation, and the results of provocative test RDC supported the diagnosis of achalasia (Fig. 3). This patient is being closely followed up in the outpatient clinic without endoscopic treatment because of their age (88 years) and poor general condition. The remaining 16 patients were consistently diagnosed with IEM by both CC v3.0 and CC v4.0. Table 2 shows the HRM findings of IEM by CC v3.0, diagnosis-changed group, and CC v4.0. There was a significant difference in the median supine DCI value between the 3 groups (307.0 vs 430.0 vs 242.5,
Table 2 . High-resolution Manometry Findings Between Chicago Classification Versions 3.0 and 4.0 in Patients of Ineffective Esophageal Motility
| HRM findings | CC v3.0 (n = 27) | Diagnosis changeda (n = 11) | CC v4.0 (n = 16) | |
|---|---|---|---|---|
| Supine IRP (mmHg) | 15.3 (11.0-17.4) | 16.3 (12.4-19.5) | 140.0 (8.8-16.9) | 0.457 |
| Supine DCI (mmHg·s·cm) | 307.0 (152.0-392.6)d | 430.0 (296.9-523.1)d,e | 242.5 (93.1-330.3)e | < 0.001 |
| Supine DL (sec) | 6.4 (6.0-8.6) | 6.7 (5.9-9.7) | 6.4 (5.8-7.9) | 0.769 |
| Upright IRP (mmHg) | 14.0 (7.5-17.3) | 14.0 (9.0-17.3) | 13.0 (6.5-17.8) | 0.673 |
| Upright DCI (mmHg·s·cm) | 134.5 (51.8-435.8) | 466.5 (77.0-798.5) | 116.0 (45.8-247.8) | 0.013 |
| Upright DL (sec) | 7.1 (6.2-8.5) | 8.1 (6.5-8.6) | 6.9 (6.2-8.4) | 0.746 |
| MRS-IRP (mmHg)b | 12.5 (10.0-18.3) | 16.0 (10.8-20.0) | 11.5 (9.3-15.8) | 0.565 |
| MRS-DCI (mmHg·s·cm)c | 114.0 (33.0-482.3) | 226.0 (33.0-553.0) | 110.5 (28.5-257.3) | 0.795 |
aDiagnosis changed from ineffective esophageal motility to others (6 normalcy, 5 achalasia).
bIntegrated relaxation pressure (IRP) during multiple rapid swallows (MRS).
cDistal contractile integral (DCI) during MRS.
d
e
HRM, high-resolution manometry; DL, distal latency; RDC, rapid drink challenge.
Data are presented as median (interquartile range).
Figure 3. The esophageal high-resolution manometry (HRM) and esophagography results of patient whose diagnosis was changed from ineffective esophageal motility by Chicago classification version 3.0 (CC v3.0) to achalasia by CC v4.0. (A) Marked dilation of the distal esophagus with food stasis is observed on esophagogastroduodenoscopy. (B) Esophagography shows esophagogastric junction narrowing with upstream esophageal dilatation and contrast media stasis. (C) The rapid drink challenge (RDC) test of HRM shows pan-esophageal pressurization supporting the diagnosis of achalasia (RDC integrated rapid pressure; 16 mmHg).
The diagnostic rate of achalasia increased from 11.1% (n = 27) by CC v3.0 to 13.9% (n = 34) by CC v4.0. The diagnoses of 27 patients with achalasia was consistent by both CC v3.0 and CC v4.0.
Of patients diagnosed with achalasia, IEM, and hypercontractile esophagus by CC v3.0, 25 underwent additional FLIP, and the diagnosis was changed from IEM to achalasia based on the FLIP results in four patients. One of them showed segmental wall thickening in the distal esophagus on computed tomography and incomplete relaxation of the lower esophageal sphincter (LES) with slightly prolonged esophageal emptying time on esophagography. The patient underwent endoscopic ultrasound and fine-needle aspiration to determine whether there was infiltrative esophagitis. However, the pathologic results reported chronic esophagitis and no evidence of eosinophilic esophagitis. The FLIP was additionally performed, and the distensibility index of LES was determined to be lower than normal (0.5 mm2/mmHg at 50 mL, 1.8 mm2/mmHg at 60 mL, and 1.9 mm2/mmHg at 70 mL). By combining these results, it was finally diagnosed as achalasia by CC 4.0 (Fig. 4). Another 3 patients (2 with absent contractility and 1 with IEM by CC v3.0) were newly diagnosed with achalasia based on the provocative test and barium esophagography results by CC v4.0. Two of them who were diagnosed with absent contractility by CC v3.0 showed elevated IRP (over 15 mmHg) in an upright position, and the esophagography was consistent with achalasia diagnosis with passage disturbance.
Figure 4. The esophageal high-resolution manometry (HRM), esophagography, and FLIP results of a patient whose diagnosis was changed from IEM by Chicago classification version 3.0 (CC v3.0) to achalasia by CC v4.0. (A) The HRM shows normal integrated rapid pressure (IRP) and 60% ineffective swallows, and rapid drink challenge (RDC) test shows spastic lower esophageal contraction (RDC IRP; 9 mmHg). (B) Esophagography shows delayed and incomplete relaxation of lower esophageal sphincter (LES) with slightly prolonged esophageal emptying time. (C) The distensibility index of the LES was determined to be lower than normal (0.5 mm2/mmHg at 50 mL, 1.8 mm2/mmHg at 60 mL, and 1.9 mm2/mmHg at 70 mL).
Table 3 shows the HRM findings of achalasia by CC v3.0, diagnosis-changed group, and CC v4.0. The median IRP values of the supine and upright positions, MRS, and RDC tests were significantly different between the 3 groups. The median IRP values were lower in the diagnosis-changed group than in the CC v3.0 and CC v4.0 groups, and especially, the median supine IRP of the diagnosis-changed group was 18.3 (IQR, 14.3-21.1), which was within the normal range.
Table 3 . High-resolution Manometry Findings Between Chicago Classification Versions 3.0 and 4.0 in Patients With Achalasia
| HRM findings | CC v3.0 (n = 27) | Diagnosis changeda (n = 7) | CC v4.0 (n = 34) | |
|---|---|---|---|---|
| Supine IRP (mmHg) | 39.0 (31.0-47.5)e | 18.3 (14.3-21.1)e,f | 37.0 (21.3-44.8)f | 0.002 |
| Supine DCI (mmHg·s·cm) | 919.0 (224.0-1868.0)e | 198.5 (16.7-334.6)e,f | 615.5 (192.3-1811.8)f | 0.031 |
| Supine DL (sec) | 3.5 (2.2-5.6) | 7.0 (4.9-9.0) | 3.8 (2.4-5.9) | 0.158 |
| Upright IRP (mmHg) | 34.0 (29.0-44.0)e | 15.5 (6.0-19.5)e,f | 32.0 (24.5-40.5)f | 0.002 |
| Upright DCI (mmHg·s·cm) | 240.0 (66.0-1944.0) | 69.0 (6.8-233.8) | 220.0 (52.5-608.0) | 0.248 |
| Upright DL (sec) | 3.5 (2.0-5.5)e | 7.5 (6.4-8.5)e,f | 4.4 (2.4-6.7)c | 0.027 |
| MRS-IRP (mmHg)b | 37.0 (29.0-45.5)e | 18.0 (13.3-19.5)e,f | 33.0 (22.0-42.0)f | 0.001 |
| MRS-DCI (mmHg·s·cm)c | 1039.0 (230.0-2730.0) | 193.5 (24.8-521.5) | 686.0 (221.0-2372.0) | 0.063 |
| RDC-IRP (mmHg)d | 32.0 (26.0-40.0)e,g | 14.0 (7.0-22.0)e,f | 27.5 (22.3-38.5)f,h | 0.001 |
aDiagnosis changed from others (2 absent contractility, 5 ineffective esophageal motility) to achalasia.
bIntegrated relaxation pressure (IRP) during multiple rapid swallows (MRS).
cDistal contractile integral (DCI) during MRS.
dIRP during rapid drink challenge (RDC).
e
f
gn = 25.
hn = 32.
HRM, high-resolution manometry; DL, distal latency.
Data are presented as median (interquartile range).
The CC v4.0 presents several modifications aimed at reducing over-diagnosis and simply distinguishing between the disorders of EGJ outflow and peristalsis.3,10 It also emphasizes the need for supportive tests for inconclusive manometric patterns and clinically relevant symptoms. We investigated the change in diagnosis between CC v3.0 and CC v4.0, and the diagnosis was changed by 11.5% (n = 28). Depending on the diagnostic criteria of CC v4.0, 15 EGJOO and 6 IEM patients were changed to normalcy. The diagnoses of 5 patients with IEM and 2 with absent contractility were changed to achalasia by CC v4.0. Consequently, the most significant change in CC v4.0 for the interpretation of HRM is the increased stringency in the diagnostic criteria for EGJOO and IEM, and it can diagnose achalasia more accurately by using provocative or adjunctive tests.
The definition of IEM is more stringent in CCv 4.0, which requires more than 70% of ineffective swallows or over 50% of failed swallows.4,11 In our study, the diagnoses of 11 patients with IEM by CC v3.0 were changed to normalcy by CC v4.0. Six of them represented ineffective swallows, between 50-70%. It might be related to the result that the median DCI value of the diagnosis-changed group was significantly higher than that of the CC v3.0 and CC v4.0 groups.
The supportive investigations such as TBE and FLIP are accentuated in CC v4.0. Further, the IRP thresholds were described depending on the supine and upright positions, and different HRM systems, including RDC and MRS, were described in CC v4.0. Based on this knowledge, EGJOO and IEM met the complete redefinition. A manometric diagnosis of EGJOO is considered clinically inconclusive.3 A clinically relevant conclusive diagnosis requires related symptoms such as dysphagia or non-cardiac chest pain and at least 1 of the supportive tests like TBE or FLIP in addition to HRM results. Unfortunately, since there was no TBE in our center, we referred to the barium esophagography or FLIP results for the diagnosis of EGJOO. As a result, the diagnoses of 15 of 41 EGJOO patients were changed to normalcy by CC v4.0 in our study.
During rapid swallowing of water, complete EGJ relaxation and deglutitive inhibition of the esophageal body are induced.12 Hence, the RDC clarifies the function of EGJ, and especially when IRP is low or ambiguous, this test can be a useful assistant for diagnosing achalasia. According to a previous study, as IRP during RDC (RDC-IRP) is predictive of esophageal retention, it is an effective alternative test for TBE, and further invasive tests or strict follow-up are needed if RDC-IRP is over 10 mmHg.13,14 If RDC-IRP is elevated, EGJOO with esophageal retention may be suspected. In our study, the median RDC IRP was elevated over 20 mmHg in EGJOO patients on all of CC v3.0, diagnosis-changed group, and CC v4.0. Moreover, in the case of diagnosis-changed patients with achalasia, although the median supine IRP was normal, RDC IRP was elevated to 14 mmHg. The EGJ outflow disorders can be diagnosed even when panesophageal pressurization of > 20 mmHg is observed in RDC, as well as elevation of IRP.12 In fact, in our study, there was a patient whose diagnosis was changed from IEM to achalasia owing to the panesophageal pressurization observation during RDC.
The HRM cannot show the pressure signals by just the insertion of the catheter. It always needs the act of active swallowing by the examinee during the test for the visualization of pressure signals. As is known, IRP, which is the most important parameter in the diagnosis of hierarchical Chicago classification, is not robust and labile by many factors.15-17 However, FLIP can precisely measure the distensibility of EGJ even without active swallowing by the examinee during testing.18 Theoretically, achalasia is due to an inappropriate relaxation of EGJ, and FLIP, which can detect the distensibility of sphincter between esophagus and stomach, might be better tool compared with previously used HRM.4,18,19 Therefore, recently published CC v4.0 recommends the use of FLIP in the diagnosis of achalasia and other esophageal motility disorders. The diagnostic accuracy of FLIP compared with manometry is already proven.16,17 However, FLIP is rather expensive to perform for all patients with symptoms. In this study, the diagnoses of 4 of IEM patients were changed to achalasia by referring to additional FLIP results. The values of median IRP were normal, but the distensibility index of all these patients were lower than the normal value of 3 mm2/mmHg.
There were some limitations to this study. First, a selection bias may have occurred due to the single-center, retrospective study design. Second, since patients who were diagnosed prior to development of CC v4.0 were also included in this study, the supportive test which was recommend by CC v4.0 was not perfectly performed in some inconclusive cases on HRM. Third, our hospital accommodated only barium esophagography, not TBE. However, our study investigated a large number of patients and verified the diagnostic results consistent with the purpose of CC v4.0.
In conclusion, CC v4.0 is more rigorous than CC v3.0 for the diagnoses of EGJOO and IEM, and it can reduce inconclusive diagnoses on HRM. Moreover, CC v4.0 can diagnose achalasia with a higher accuracy by using provocative test and FLIP. Further studies on the treatment outcomes following diagnosis with CC v4.0 are needed.
Note: To access the supplementary table mentioned in this article, visit the online version of Journal of Neurogastroenterology and Motility at http://www.jnmjournal.org/, and at https://doi.org/10.5056/jnm22121.
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Conception and design, and drafting of the article: Jin Hee Noh and Kee Wook Jung; analysis and interpretation of the data, and critical revision of the article for intellectual content: and Jin Hee Noh, Kee Wook Jung, Ji Yong Ahn, Hee Kyong Na, Jeong Hoon Lee, Do Hoon Kim, Kee Don Choi, Ho June Song, Gin Hyug Lee, and Hwoon-Yong Jung.
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Jin Hee Noh Kee Wook Jung |
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