Systematic Review: Variability in Definitions of Fibrostenosis in Eosinophilic Oesophagitis

ABSTRACT

Background

Fibrostenosis is a serious complication of eosinophilic oesophagitis, but there is a lack of consensus regarding its definition and assessment. This poses a barrier in clinical care and research.

Aim

To perform a systematic review to examine existing definitions and diagnostic methods of detection regarding fibrostenosis in eosinophilic oesophagitis.

Methods

We searched MEDLINE, Cochrane Library, EMBASE, Scopus, and Web of Science and included studies of paediatric and adult eosinophilic oesophagitis patients with fibrostenosis based on endoscopy, imaging, histopathology, functional studies, and biomarkers. We excluded studies with <10 patients. We chose fibrostenosis as the umbrella term, encompassing all definitions.

Results

We identified 230 studies. The four categories of fibrostenosis definitions were: (1) structural findings (stricture, rings, and/or narrowings) (n=204, 88.7%), (2) histology (n=85, 37.0%), (3) functional (functional lumen imaging probe) (n=15, 6.5%), and (4) biomarkers (n=7, 3.0%). Multiple definitions were used in 78 studies. Methods used to detect structural fibrostenosis included Eosinophilic Oesophagitis Endoscopic Reference Score fibrostenotic components, luminal diameter (endoscopy or imaging), need for dilation, and endoscopist or radiologist global impression. Methods used to detect histologic fibrostenosis included Eosinophilic Oesophagitis Histologic Scoring System lamina propria fibrosis, pathologist global impression, and basal zone hyperplasia. Methods used to detect functional fibrostenosis included distensibility and compliance.

Conclusions

Significant variability exists in definitions and diagnostic methods of detection regarding fibrostenosis in eosinophilic oesophagitis. Lack of agreement hampers progress in further investigating this complication. Development of consensus criteria is necessary to provide clarity for clinical care and research.

Significant variability exists in definitions and diagnostic methods of detection regarding fibrostenosis in eosinophilic oesophagitis. Lack of consensus poses a barrier in clinical care and research.

Abbreviations

EGJ

oesophagogastric junction

EoE

eosinophilic oesophagitis

EoE‐HSS

EoE Histologic Scoring System

EREFS

EoE Endoscopic Reference Score

FLIP

functional lumen imaging probe

LPF

lamina propria fibrosis

MeSH

medical subject heading

mL

millilitre

mm

millimetre

PRISMA

preferred reporting items for systematic review and meta‐analyses

1. Introduction

Eosinophilic oesophagitis (EoE) is a chronic inflammatory condition characterised by oesophageal eosinophilia, the disease burden of which is increasing in both incidence and prevalence [1, 2, 3, 4, 5]. EoE is a progressive disease with three distinct clinical phenotypes based on the presence of inflammation and excessive accumulation of extracellular matrix: inflammatory, fibrostenotic, or mixed inflammatory and fibrostenotic. The natural history of untreated EoE involves oesophageal remodelling leading to fibrostenosis [4, 6, 7], frequently resulting in dysphagia, food impactions and repeated endoscopic dilations.

Currently, there is a lack of consensus regarding the definition of fibrostenosing EoE [8, 9, 10]. In this systematic review, fibrostenosis was chosen as the umbrella term, encompassing all definitions related to luminal narrowing and remodelling. Definitions include structural (e.g., stricture), histology, functional (functional lumen imaging probe), and biomarkers. There is also a wide range of diagnostic methods of detection used in the scientific literature and in clinical practice for each definition. For example, methods of detection may include radiographic oesophageal lumen diameter or EoE Endoscopic Reference Score (EREFS) [11]. The lack of consensus poses a challenge for investigating fibrostenosis as a clinical problem and discovering treatments directed against fibrostenosis in EoE. The aim of this systematic review was to comprehensively summarise existing definitions and diagnostic methods of detection in the literature regarding fibrostenosis in adult and paediatric EoE patients.

2. Methods

2.1. Screening Strategy

We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Review and Meta‐Analyses (PRISMA) guidelines [12]. Studies were identified by searching Medline (via Ovid SP), Embase (via Ovid SP), Web of Science (via Clarivate Analytics), Scopus (via Elsevier), Cinahl (via EBSCOhost), and Cochrane (via Wiley). The databases were searched from the start of databases through 06/2024, limited to English literature. Each database was searched using medical subject headings (MeSH) and keywords and synonyms derived from them, including eosinophilic oesophagitis, fibrosis, fibrostenosis, obstruction, stenosis, rings, and stricture. Food impaction was omitted, as a food impaction can occur due to inflammation without fibrostenosis. A detailed description of the search strategies for each of the databases is listed in Tables S1–S4. Identified studies were first screened in abstract form, with the removal of duplicates and the exclusion of abstracts outside of eligibility criteria. Full‐text articles were then reviewed to identify those meeting inclusion criteria. All references of full‐text articles were also reviewed manually to identify any additional relevant publications. The final identified studies were then used for data extraction (Table S5).

2.2. Eligibility Criteria

Eligibility criteria were set a priori by the study authors. The study protocol was added to PROSPERO under ID CRD42024558352. Inclusion criteria were original studies with the following study designs: prospective cohort studies, retrospective cohort studies, cross‐sectional studies, case–control studies, case series involving at least 10 patients, consensus statements, randomised or non‐randomised observational cohort studies, survey‐based studies, pilot studies, validation studies, open‐label trials, and randomised controlled trials; patients with EoE and fibrostenosis (defined as fibrosis, stenosis, obstruction, rings, stricture, narrowing, fibrostenosis). Exclusion criteria were narrative reviews or editorials, commentary articles, letters to the editor, languages other than English, studies with fewer than 10 patients, murine models, conference abstracts, pre‐clinical studies (in vitro, human oesophageal biopsies or fibroblasts), non‐fibrotic causes of stenosis (e.g., muscle spasm), or studies about EoE not evaluating fibrostenosis.

2.3. Outcomes of Interest

The outcomes of interest were definitions, diagnostic modalities, and methods of detection used for fibrostenotic EoE.

2.4. Study Selection and Data Extraction

Two reviewers (NF, CMaruggi) independently screened all abstracts identified and selected studies for inclusion based on eligibility criteria. They also extracted data in duplicate. Any disagreements regarding eligibility for inclusion or data extraction were resolved through consensus with a third reviewer (CAB). The following variables were extracted from each of the studies: first author name, journal, year of publication, study design, number of patients, patient cohort (adult, paediatric), definition of fibrostenosis, diagnostic modality, and methods used to describe fibrostenosis for each modality.

2.5. Risk of Bias

Two reviewers (NF, CMaruggi) independently assessed all studies for risk of bias. The following were used: Cochrane ROB2.0 Tool for randomised controlled trials, ROBINS‐I V2 for non‐randomised studies of interventions, Joanna Briggs Institute critical appraisal checklist for cross‐sectional studies and case series, and the Ottawa‐Newcastle scale for cohort and case–control studies (Table S6) [13, 14, 15, 16, 17, 18, 19]. Any discrepancies in scoring were resolved via discussion among the two reviewers, and if no resolution was achieved, the final decision was made by CAB.

2.6. Terminology

In this review article, fibrostenosis was chosen as the umbrella term, encompassing all definitions related to fibrosis, luminal narrowing, stenosis, and remodelling (e.g., fibrosis, stenosis, obstruction, rings, stricture, narrowing, narrow calibre oesophagus, fibrostenosis, remodelling).

3. Results

Of 7324 studies, 4098 were duplicates and excluded. A total of 3226 studies underwent abstract review. Of these, 2363 were excluded due to not meeting eligibility criteria. 863 studies were assessed in full‐text format, with 633 excluded due to only being available in abstract form, review articles, editorials, commentaries, letters to the editor, pre‐clinical studies, fewer than 10 patients, or articles not pertaining to fibrostenotic EoE. A total of 230 studies were included in the final qualitative analysis (Figure 1): cohort (n=151), cross‐sectional (n=24), case series (n=18), randomised control trials (n=15), case–control (n=8), survey‐based (n=5), consensus (n=3), validation (n=2), open‐label trials (n=2), and pilot studies (n=2). 110 studies were exclusively adult patients, and 56 studies were exclusively paediatric patients (Table S5).

FIGURE 1.

PRISMA diagram of included studies. Flow diagram of the number of records identified, included and excluded, and the reasons for exclusions.

3.1. Definitions

In the 230 studies, the following definitions were used to diagnose fibrostenosis (non‐exclusive): (1) structural (e.g., strictures) (n=204, 88.7%); (2) histology (n=85, 37.0%); (3) functional (functional lumen imaging probe) (n=15, 6.5%); 4) biomarkers (n=7, 3.0%) (Tables 1 and 2). Multiple definitions in the same publication were used in 78 studies [7, 24, 30, 31, 32, 33, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 225, 226, 249]. In these studies, more than one definition was accepted and did not require all definitions to be present. Multiple methods of detection in the same publication were used in 148 studies [7, 11, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 225, 226, 249].

TABLE 1.

Definitions and diagnostic methods of detection for fibrostenosis in eosinophilic esophagitis.

	Method of detection	Gold standard	Accuracy	Other
Definition: stuctural (stricture, rings, and/or narrowings) (N=204)
Endoscopy (N=202)	EREFS (N=111)	None	N/A	Interobserver agreement [11] – Ring: k=0.40 – Stricture: k=0.52 – Narrowing: k=0.30 Predictive ability to identify EoE from control (AUC) [20] – Fibrotic subscore: 0.825 – Inflammatory subscore: 0.936 – Total EREFS: 0.934
	Dilation (N=89)	None	N/A	N/A
	Endoscopist discretion (N=73)	Oesophagram (radiologist discretion)	20% [21]	N/A
	Luminal diameter (N=25)	Oesophagram (narrowing or tablet delay [22]; <10th percentile healthy controls [23])	45% [22]	Sensitivity: 14.7% Specificity: 79.2% [23]
	Luminal narrowing (N=16)	None	N/A	N/A
Imaging (N=12)	Luminal narrowing by oesophageal length (N=5)	Endoscopy (based on resistance or inability to pass endoscope) [24]	70.6% [24]	N/A
	Outside of 90%–95% percentile range for healthy controls (N=4)	Healthy control [23, 25, 26, 27]	N/A	N/A
	Luminal narrowing (N=4)	Endoscopy (EREFS) [28]	74%	Detection using oesophagram versus endoscopy [28] –Fibrostenosis: 74% versus 84% (p=0.07) –Stricture: 58% versus 40% (p=0.01) –Rings: 26% versus 71% (p<0.01)
	Barium tablet delay or retention (N=2)	None	N/A	N/A
	Radiologist discretion (N=1)	None	N/A	N/A
	Luminal diameter (N=1)	None	N/A	N/A
	Oesophageal luminal diameter<15mm (N=1)	None	N/A	N/A
Definition: histology (N=85)
Lamina propria fibrosis (N=84)	EoE‐HSS: LPF stage & grade (N=33)	None	N/A	Interobserver agreement – Kendall's coefficient: 0.8 & 0.82 [29] – ƙ=−0.03 and‐0.05 [30] Intra‐rater reliability – experts: ƙ=0.61 & 0.58 [31] Intra‐observer agreement [30] – 30years experience: ƙ=0.69 and 0.76 – <30years experience: ƙ=−0.03 to 0.35 & −0.5 to 0.2
	Pathologist discretion (N=31)	None	N/A	N/A
	Other severity scoring systems (N=11)	None	N/A	N/A
	Presence LPF (N=9)	None	N/A	N/A
	Extracellular matrix remodelling or deposition (N=1)	None	N/A	N/A
	Presence of LPF or BZH. Presence of DEC if no lamina propria (EoE‐HSS) (N=1)	None	N/A	N/A
Basal zone hyperplasia (N=3)	Pathologist discretion (N=1)	None	N/A	N/A
	Remodelling score (N=1)	None	N/A	N/A
	Architectural features of EoE‐HSS (N=1)	None	N/A	N/A
Definition: functional (functional lumen imaging probe) (N=15)
Distensibility (N=14)	Distensibility Plateau (N=7)	History food impaction & healthy controls EREFS: fibrostenotic subscore EREFS: rings, stricture Endoscopic stricture	N/A	<17mm predictive of food impactions [32, 33] and based on healthy controls [34] – <13mm captures majority of food impactions [32] – <14mm severely abnormal based on healthy controls [34] <17mm versus ≥17mm: 3 [2–3] versus 2 [1–3], p<0.05 [33]; DP and subscore correlation: r=−0.57, p<0.05 [32] <17mm versus ≥17mm: 83% versus 96% rings & 59% versus 100% strictures, p<0.05 [33]; Rings or stricture: DP mean 13.2±2.8 versus 17.3±2.0mm, p=0.0005 [35]. DP and rings 3: Spearman's r=−0.46, p<0.0001) [36]. Stricture versus none: DP median 18 versus 20mm, p<0.001 [33]
	Distensibility (N=5)	LPF EREFS: ring, stricture	N/A	Absence versus presence: 14.5 versus 13mm, p=0.046 [37] Absence versus presence: 16 versus 13mm, p<0.0001 [37]
	Distensibility slope (N=2)	EREFS rings 3	N/A	Spearman's r=−0.33, p=0.004 [36]
	Distensibility index (N=2)	EREFS: rings or stricture	N/A	Presence versus absence: mean 3.7±1.8 versus 6.6±1.8mm2/mmHg, p=0.0003 [35]
Compliance (N=5)	Compliance	EREFS Healthy Control	N/A	Rings 2 or 3 versus Rings 0 or 1: median 0.09 versus 0.25mL/mmHg, p<0.001 [33] Stricture presence versus absence: median 0.14 versus 0.31, p<0.001 [33] <0.2 versus ≥0.2mL/mmHg: median 3 versus 2 fibrostenotic subscore, p<0.05 [33] 2 ≤450mm3/mmHg (abnormal); <300mm3/mmHg (severely abnormal) [33]
EGJ diameter (N=1)	Maximum EGJ diameter	Healthy control	N/A	≤16mm (abnormal) [38] <12mm (severely abnormal) [38]
Definition: biomarkers (N=7)
Human oesophageal biopsies	Vimentin, E‐cadherin expression (N=2)	None	N/A	N/A
	TGFβ1 and pSMAD2/3 expression (N=1)	None	N/A	N/A
	TGFβ1 expression (N=1)	None	N/A	N/A
	Plasminogen Activator Inhibitor −1 expression (N=1)	None	N/A	N/A
	Profibrogenic gene expression (N=1)	None	N/A	N/A
	PRO‐C3; CTX‐III; PRO‐C6 (N=1)	None	N/A	N/A

Note: When available, additional information is provided such as accuracy, interobserver agreement, sensitivity, specificity and more. There are two articles that are not part of the systematic review but included in this table, as they are the reference for healthy control thresholds for distensibility plateau and oesophagogastric junction diameter [34, 38].

Abbreviations: AUC, area‐under‐the‐curve; BZH, basal zone hyperplasia; CCL18, CC chemokine ligand 18; CTX‐III, cross‐linked type III collagen; DEC, dyskeratotic epithelial cells; DP, distensibility plateau; EGJ, oesophagogastric junction; EoE‐HSS, Eosinophilic Oesophagitis Histologic Scoring System; EREFS, EoE Endoscopic References Score; FGF9, fibroblast growth factor 9; hpf, high power field; ICD, international classification of diseases; IL‐5, interleukin‐5; LPF, lamina propria fibrosis; ng, nanogram; PRO‐C3 and C6, type III and type VI collagen; pSMAD2/3, phospho‐SMAD2/3; TGFβ₁, transforming growth factor beta.

TABLE 2.

Details on detection for fibrostenosis in eosinophilic oesophagitis.

	Method of detection	Literature
Definition: structural (N = 204) [7, 11, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224]
Endoscopy (N = 202) [7, 11, 20, 21, 22, 23, 24, 25, 26, 28, 30, 31, 32, 33, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224]	EREFS a	N = 111 [7, 11, 20, 28, 32, 33, 35, 36, 37, 39, 40, 45, 46, 49, 50, 54, 55, 56, 57, 59, 60, 61, 62, 65, 67, 68, 70, 71, 72, 73, 74, 76, 78, 79, 80, 81, 83, 84, 85, 86, 87, 88, 89, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 110, 115, 122, 124, 126, 127, 128, 130, 131, 133, 136, 137, 138, 147, 148, 150, 151, 152, 153, 156, 157, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 214, 216, 219, 220, 221, 224]
	Presence (present or absent)	N = 28 [37, 46, 49, 56, 57, 59, 67, 73, 87, 92, 102, 115, 124, 130, 131, 152, 153, 161, 166, 167, 168, 185, 214, 216, 219, 220, 221, 224]
	2Severity (scoring of rings/strictures)	2 N = 63 [11, 28, 35, 36, 39, 40, 50, 54, 55, 59, 60, 61, 62, 65, 68, 70, 72, 74, 76, 78, 79, 80, 83, 84, 85, 86, 88, 89, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101, 103, 104, 110, 136, 147, 148, 150, 151, 156, 157, 159, 160, 162, 163, 164, 165, 169, 170, 171, 172, 180, 181, 182, 183, 184]
	3Fibrostenotic subscore	3 N = 30 [7, 20, 32, 33, 45, 71, 81, 84, 89, 97, 99, 101, 104, 122, 126, 127, 128, 133, 137, 138, 163, 165, 173, 174, 175, 176, 177, 178, 179, 180]
	Dilation	N = 89 [20, 23, 26, 32, 33, 35, 40, 44, 48, 49, 50, 51, 52, 53, 54, 55, 56, 60, 61, 67, 76, 77, 81, 82, 93, 94, 95, 96, 97, 106, 107, 108, 109, 111, 112, 113, 115, 116, 117, 118, 119, 120, 121, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 150, 151, 152, 153, 154, 155, 156, 159, 160, 161, 162, 164, 186, 187, 188, 189, 190, 191, 192, 193]
	Endoscopist discretion	N = 79 [20, 23, 26, 32, 33, 35, 40, 48, 49, 50, 51, 52, 53, 54, 55, 56, 60, 61, 67, 76, 77, 81, 93, 94, 95, 96, 97, 106, 107, 109, 111, 112, 113, 115, 117, 118, 119, 120, 121, 123, 124, 126, 127, 128, 129, 130, 131, 132, 133, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 150, 151, 152, 153, 155, 156, 159, 160, 161, 162, 164, 186, 187, 188, 189, 193]
	2For a stricture	2 N = 5 [82, 108, 134, 154, 190]
	3ICD code	3 N = 3 [116, 125, 191]
	4Patient reported history	4 N = 1 [192]
	5For a decreased lumen diameter	5 N = 1 [44]
	Endoscopist discretion	N = 73 [20, 21, 23, 25, 26, 30, 31, 41, 42, 43, 44, 48, 50, 51, 52, 53, 58, 63, 64, 66, 69, 75, 77, 82, 105, 106, 107, 108, 111, 112, 113, 117, 118, 119, 121, 123, 132, 134, 135, 140, 141, 142, 143, 144, 145, 146, 147, 148, 154, 155, 157, 160, 162, 164, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 215, 217]
	Lumen diameter b	N = 25 [7, 22, 24, 41, 44, 46, 49, 56, 60, 83, 105, 106, 108, 109, 110, 113, 114, 120, 122, 129, 139, 149, 211, 212, 218]
	< 7 mm versus 7–10 mm versus 11–13 mm	N = 6 [24, 44, 49, 120, 122, 139]
	2< 10 mm	2 N = 8 [22, 46, 83, 108, 129, 149, 211, 218]
	3Dilator size causing mucosal disruption	3 N = 7 [41, 60, 106, 109, 113, 114, 211]
	4< 6 mm	4 N = 2 [105, 149]
	5< 17 mm (17 mm dilator: moderate resistance)	5 N = 1 [212]
	6≤ 14 mm (via bougie cap)	6 N = 1 [110]
	7Severity score	7 N = 1 [7]
	8Endoscopist discretion	8 N = 1 [56]
	Luminal narrowing c	N = 16 [11, 22, 44, 47, 77, 79, 90, 109, 114, 116, 125, 129, 151, 213, 222, 223]
	Stricture (< 5 cm length)	N = 4 [90, 109, 114, 151]
	2Stricture (≤ 1 cm length)	2 N = 1 [44]
	3Stricture (fixed, isolated)	3 N = 3 [22, 77, 129]
	4Stricture (ICD code)	4 N = 4 [116, 125, 222, 223]
	5Ring severity (grade 0–3)	5 N = 1 [213]
	6Ring presence	6 N = 1 [90]
	7Schatzki's ring severity (narrow vs. wide)	7 N = 1 [47]
	8Narrowing of majority of oesophagus	8 N = 5 [11, 79, 109, 114, 151]
	9Narrowing more diffuse than focal stricture	9 N = 1 [129]
10Short versus long narrowing	10 N = 1 [44]
Imaging (N = 12) [21, 22, 23, 24, 25, 26, 27, 28, 44, 89, 108, 158]	Luminal narrowing by oesophageal length d	N = 5 [22, 23, 24, 26, 44]
	Stricture (≤ 1 cm)	N = 2 [24, 44]
	2Stricture (1–8 cm)	2 N = 2 [23, 26]
	3Narrowing severity (short vs. long)	3 N = 2 [24, 44]
	4Ring (≤ 1 cm)	4 N = 2 [23, 26]
	5Diffuse	5 N = 1 [22]
	Outside of 90%–95% percentile range for healthy controls	N = 4 [23, 25, 26, 27]
	Luminal narrowing	N = 4 [22, 28, 108, 158]
	Barium tablet delay or retention	N = 2 [22, 28]
	Radiologist discretion	N = 1 [21]
	Luminal diameter	N = 1 [158]
	Oesophageal luminal diameter < 15 mm	N = 1 [89]
Definition: histology (N = 85) [7, 24, 29, 30, 31, 35, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 92, 102, 103, 104, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248]
LPF (N = 84) [7, 24, 29, 30, 31, 35, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 102, 103, 104, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248]	EoE‐HSS: LPF stage & grade	N = 33 [7, 29, 30, 31, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 102, 104, 237, 238, 239, 240, 241, 242, 243, 245, 246]
	Pathologist discretion	N = 31 [35, 39, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 234, 235, 236, 244, 247, 248]
	Other severity scoring systems e	N = 11 [40, 68, 69, 70, 103, 225, 226, 227, 231, 232, 233]
	Score of 1–3	N = 4 [225, 226, 231, 232]
	2Grade of 2	2 N = 4 [68, 69, 227, 233]
	3Grade (mild, moderate, severe)	3 N = 3 [40, 70, 103]
	Presence LPF f	N = 9 [24, 37, 41, 42, 43, 44, 228, 229, 230]
	Extracellular matrix remodelling or deposition	N = 1 [40]
	Presence of LPF or BZH. Presence of DEC if no lamina propria (EoE‐HSS)	N = 1 [7]
Basal zone hyperplasia (N = 3) [39, 74, 92]	Pathologist discretion	N = 1 [39]
	Remodelling score g	N = 1 [92]
	Architectural features of EoE‐HSS h	N = 1 [74]
Definition: functional (N = 15) [32, 33, 35, 36, 37, 74, 77, 90, 92, 94, 95, 97, 98, 99, 249]
Distensibility (N = 14) [32, 33, 35, 36, 37, 74, 77, 90, 92, 94, 95, 97, 98, 99]	Distensibility plateau	N = 7 [32, 33, 77, 95, 97, 98, 99]
	≤ 17 mm (abnormal)	N = 6 [32, 33, 95, 97, 98, 99]
	2< 13 mm (severe)	2 N = 2 [32, 95]
	3< 14 mm (severe)	3 N = 1 [99]
	4< 15 mm (abnormal)	4 N = 1 [77]
	Distensibility	N = 5 [37, 74, 90, 92, 94]
	Distensibility slope	N = 2 [36, 95]
	Distensibility index	N = 2 [35, 90]
Compliance (N = 5) [33, 92, 97, 99, 249]	Compliance
	< 0.2 mL/mmHg (abnormal)	N = 3 [33, 92, 249]
	2≤ 450 mm3/mmHg (abnormal)	2 N = 2 [97, 99]
	3< 300 mm3/mmHg (severely abnormal)	3 N = 1 [99]
Diameter (N = 1) [99]	Maximum EGJ diameter ≤ 16 mm (abnormal) < 12 mm (severely abnormal)	N = 1 [99] N = 1 [99]
Definition: biomarkers (N = 7) [71, 74, 101, 102, 225, 226, 249]
Human oesophageal biopsies	Vimentin, E‐cadherin expression –immunostaining: Percentage epithelial cells positive for vimentin, the total vimentin expression per cell, mean & total expression of E‐cadherin across pixels in each cell membrane, ratio total vimentin expression to total E‐cadherin expression per cell. Machine learning algorithm	N = 2 [71, 74]
	TGFβ 1 and pSMAD2/3 expression –immunostaining: Number of positive cells/hpf at 400× light microscopy	N = 1 [225]
	TGFβ1 expression (no further detail)	N = 1 [102]
	Plasminogen Activator Inhibitor −1 expression –immunochemistry: Imaging software to quantify area of positive stain	N = 1 [249]
	Profibrogenic gene expression –qPCR, mRNA: IL5, TGFβ1, FGF9, and CCL18	N = 1 [226]
	PRO‐C3; CTX‐III; PRO‐C6 –biomarkers measured via enzyme linked immunosorbent assays and expressed as ng/mL	N = 1 [101]
Multiple definitions: N = 78 [7, 24, 30, 31, 32, 33, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 225, 226, 249]
Multiple methods of detection: N = 148 [7, 11, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 225, 226, 249]

Abbreviations: BZH, basal zone hyperplasia; cm, centimetre; CCL18, CC chemokine ligand 18; CTX‐III, cross‐linked type III collagen; DEC, dyskeratotic epithelial cells; EGJ, oesophagogastric junction; EoE‐HSS, Eosinophilic Oesophagitis Histologic Scoring System; EREFS, EoE Endoscopic References Score; FGF9, fibroblast growth factor 9; hpf, high power field; ICD, international classification of diseases; IL5, interleukin‐5; LPF, lamina propria fibrosis; mm, millimetre; mL, millilitre; ng, nanogram; PRO‐C3 and C6, type III and type VI collagen; pSMAD2/3, phospho‐SMAD2/3; TGFβ₁, transforming growth factor beta.

^a Presence of EREFS means that there were rings and/or stricture identified on EREFS but no scoring performed. Severity of EREFS means that the scoring (grade of rings and stricture) was provided. Of note, only 1 article used rings 2–3 [172], but all other articles used rings 1–3. Fibrostenotic subscore of EREFS means that the fibrostenotic subscore was provided.

^b If not otherwise mentioned, lumen diameter was measured based on resistance or inability to pass an endoscope with a corresponding outer diameter (e.g., neonatal, paediatric, adult). The severity score entailed: 1 point for present but scope passes easily; 2 points for present but requires dilation or snug fit with standard endoscope; 15 points: unable to pass standard upper endoscope or repeated dilations in adult or any dilation in child

^c Ring severity was graded as 0 (normal), 1 (mild), 2 (moderate), and 3 (severe) with no further details. Ring presence was defined as circumferential mucosal plications during maximal insufflation, oriented in a perpendicular plane. Schatzki's ring severity was defined as either narrow (difficult to pass standard endoscope) or wide (easy to pass endoscope). Short versus long narrowing: short refers to 1 cm to one‐third oesophageal length, and long refers to more than one‐third oesophageal length.

^d Narrowing severity defined as short (1 cm to one‐third of oesophageal length) or long (more than one‐third oesophageal length)

^e (1) Score of 1–3 was based on collagen bundle thickness, accumulation, and number of fibroblasts using H&E or Masson's trichrome staining. (2) LPF defined as Grade 2 was based on dense and compact collagen deposition on Masson's trichrome staining. (3) Mild, moderate, or severe LPF was based on deposition of extracellular matrix on H&E stain with minimal detail.

^f Presence of fibrosis was based on dense collagen deposition with or without compression or elongation of intact fibroblasts. This was assessed on Masson's trichrome staining, light microscopy, or digital morphometry.

^g Remodelling Score: H&E staining. Composite of: severity of basal zone hyperplasia (scored 0–3), presence/absence of dilated intercellular spaces (scored 0/1), and the presence/absence of epithelial desquamation (scored 0/1). Maximum score of 5

^h Architectural features EoE‐HSS. Combination of any of the following features using grade and severity: basal zone hyperplasia, dilated intercellular spaces, dyskeratotic epithelial cells, and lamina propria fibrosis

Table 1 provides the broad definitions and methods of detection as well as associated literature, such as accuracy and interobserver agreement. Table 2 provides more details on the definitions and methods of detection along with citations for the 230 studies. Tables S7 and S8 provide the details on the definitions and methods of detection along with citations for adult and paediatric studies, respectively. Table S9 provides details listed per study.

3.2. Definition: Structural

The structural definition of fibrostenosis included stricture, rings, and/or narrowings [7, 11, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224]. Out of the 204 studies, structural findings were found on endoscopy (n=202, 99.0%) [7, 11, 20, 21, 22, 23, 24, 25, 26, 28, 30, 31, 32, 33, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224] or imaging (n=12, 5.9%) [21, 22, 23, 24, 25, 26, 27, 28, 44, 89, 108, 158].

3.2.1. Endoscopic Methods of Detection

Of 202 studies using endoscopy to detect stricture, rings and/or narrowings, the majority relied on the EoE Endoscopic Reference Score (EREFS) (n=111, 55.0%) [7, 11, 20, 28, 32, 33, 35, 36, 37, 39, 40, 45, 46, 49, 50, 54, 55, 56, 57, 59, 60, 61, 62, 65, 67, 68, 70, 71, 72, 73, 74, 76, 78, 79, 80, 81, 83, 84, 85, 86, 87, 88, 89, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 110, 115, 122, 124, 126, 127, 128, 130, 131, 133, 136, 137, 138, 147, 148, 150, 151, 152, 153, 156, 157, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 214, 216, 219, 220, 221, 224]. This validated endoscopic scoring system assesses fibrostenotic features (rings and/or strictures) [11]. 28 studies reported the presence or absence of fibrostenotic features [37, 46, 49, 56, 57, 59, 67, 73, 87, 92, 102, 115, 124, 130, 131, 152, 153, 161, 166, 167, 168, 185, 214, 216, 219, 220, 221, 224], 63 studies reported the scoring (rings: 0–3, stricture 0–1) [11, 28, 35, 36, 39, 40, 50, 54, 55, 59, 60, 61, 62, 65, 68, 70, 72, 74, 76, 78, 79, 80, 83, 84, 85, 86, 88, 89, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101, 103, 104, 110, 136, 147, 148, 150, 151, 156, 157, 159, 160, 162, 163, 164, 165, 169, 170, 171, 172, 180, 181, 182, 183, 184], and 30 calculated a fibrostenotic subscore [7, 20, 32, 33, 45, 71, 81, 84, 89, 97, 99, 101, 104, 122, 126, 127, 128, 133, 137, 138, 163, 165, 173, 174, 175, 176, 177, 178, 179, 180]. EREFS scoring provided in Table S10.

The next most commonly used method of detection was oesophageal dilation (n=89, 44.1%) [20, 23, 26, 32, 33, 35, 40, 44, 48, 49, 50, 51, 52, 53, 54, 55, 56, 60, 61, 67, 76, 77, 81, 82, 93, 94, 95, 96, 97, 106, 107, 108, 109, 111, 112, 113, 115, 116, 117, 118, 119, 120, 121, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 150, 151, 152, 153, 154, 155, 156, 159, 160, 161, 162, 164, 186, 187, 188, 189, 190, 191, 192, 193]. This was often retrospective and based on the endoscopy report with limited (if any) description (n=79) [20, 23, 26, 32, 33, 35, 40, 48, 49, 50, 51, 52, 53, 54, 55, 56, 60, 61, 67, 76, 77, 81, 93, 94, 95, 96, 97, 106, 107, 109, 111, 112, 113, 115, 117, 118, 119, 120, 121, 123, 124, 126, 127, 128, 129, 130, 131, 132, 133, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 150, 151, 152, 153, 155, 156, 159, 160, 161, 162, 164, 186, 187, 188, 189, 193]. Other studies provided more details: stricture requiring dilation (n=5) [82, 108, 134, 154, 190], ICD code (n=3) [116, 125, 191], patient reported history (n=1) [192], and a decreased lumen diameter requiring dilation (n=1) [44].

73 studies (36.1%) extracted data from the endoscopy report alone regarding strictures, rings, and/or narrowings [20, 21, 23, 25, 26, 30, 31, 41, 42, 43, 44, 48, 50, 51, 52, 53, 58, 63, 64, 66, 69, 75, 77, 82, 105, 106, 107, 108, 111, 112, 113, 117, 118, 119, 121, 123, 132, 134, 135, 140, 141, 142, 143, 144, 145, 146, 147, 148, 154, 155, 157, 160, 162, 164, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 227, 250]. There were no further details or criteria given.

25 studies (12.4%) specified criteria for the luminal diameter [7, 22, 24, 41, 44, 46, 49, 56, 60, 83, 105, 106, 108, 109, 110, 113, 114, 120, 122, 129, 139, 149, 211, 212, 218]. This was mostly based on resistance or inability to pass upper endoscopes (n=14) [22, 24, 44, 46, 49, 83, 105, 108, 120, 122, 129, 139, 149, 211]. This included adult, paediatric, and neonatal endoscopes. The next most commonly used criteria included measuring the luminal diameter by the dilator size that resulted in mucosal disruption (n=7) [41, 60, 106, 109, 113, 114, 211]. Other studies specified narrowings by the length of a segment with luminal constriction (Table 2).

3.2.2. Radiographic Methods of Detection

The only imaging used to detect stricture, ring and/or narrowing was a barium oesophagram. Of the 12 studies, 9 (75.0%) used oesophageal diameter or length of affected segment with inconsistent terminology [22, 23, 24, 26, 28, 44, 89, 108, 158]. For example, two studies defined a luminal narrowing of ≤1cm as a stricture [24, 44], whereas two other studies defined a luminal narrowing of ≤1cm as a ring and a luminal narrowing between 1 and 8cm in length as a stricture [23, 26]. Four studies (33.3%) defined an abnormal narrowing as a measurement outside of the 90%–95% percentile range for healthy controls [23, 25, 26, 27].

3.3. Definition: Histology

The definition of histology included 85 studies [7, 24, 29, 30, 31, 35, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 92, 102, 103, 104, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248]. For the most part, the histologic definition of fibrostenosis encompassed lamina propria fibrosis (LPF) (n=84; 98.8%) [7, 24, 29, 30, 31, 35, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 102, 103, 104, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248] with only three studies (3.5%) assessing basal cell hyperplasia [39, 74, 92]. Criteria for LPF included increased, thickened, and altered collagen deposition as well as alterations in fibroblasts and epithelial thickness.

3.3.1. Histologic Methods of Detection

Of the 85 studies, 44 (51.8%) studies used a severity scoring system for LPF [7, 29, 30, 31, 40, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 102, 103, 104, 225, 226, 227, 231, 232, 233, 237, 238, 239, 240, 241, 242, 243, 245, 246]. The grade and extent of LPF in the validated EoE histologic scoring system (EoE‐HSS) [29] are the most commonly used histologic scores (n=33) [7, 29, 30, 31, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 102, 104, 237, 238, 239, 240, 241, 242, 243, 245, 246]. Details on EoE‐HSS scoring are given in Table S11. Additional items of detection for LPF are listed in Tables 1 and 2. Presence of dense collagen deposition using Masson's trichrome staining was used in 9 studies with no detail on severity or quantification [24, 37, 41, 42, 43, 44, 228, 229, 230]. Pathologist discretion was used in 31 studies [35, 39, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 234, 235, 236, 244, 247, 248].

3.4. Definition: Functional

This definition encompasses functional lumen imaging probe (FLIP) parameters (N=15) [32, 33, 35, 36, 37, 74, 77, 90, 92, 94, 95, 97, 98, 99, 249].

3.4.1. FLIP Methods of Detection

Methods of detection include distensibility (n=14, 93.3%) [32, 33, 35, 36, 37, 74, 77, 90, 92, 94, 95, 97, 98, 99], compliance (n=5, 33.3%) [33, 92, 97, 99, 249], and maximum oesophagogastric junction diameter (n=1, 6.7%) [99]. More details are given below.

3.4.1.1. Distensibility Plateau

The most commonly utilised method of detection for distensibility was the distensibility plateau (n=7) [32, 33, 77, 95, 97, 98, 99]. Specific thresholds varied by study. An abnormal distensibility plateau were defined as ≤17mm (n=6) [32, 33, 95, 97, 98, 99] and a severely reduced distensibility plateau was defined as <13mm [32, 95] or <14mm [99]. Thresholds were initially determined using a history of food impaction as a surrogate marker [95], but were confirmed when assessing healthy controls [34]. Another study using thresholds defined an abnormal distensibility plateau as <15mm [77]. However, there was no clear rationale for this definition.

3.4.1.2. Distensibility, Distensibility Slope, Distensibility Index

The three other methods of distensibility detection include distensibility (n=5) [37, 74, 90, 92, 94], distensibility slope (n=2) [36, 95], and distensibility index (n=2) [35, 90]. Description regarding measurements can be found in Table S12.

3.4.1.3. Compliance

Five studies used compliance as a readout for fibrostenosis (Table S12) [33, 92, 97, 99, 249]. In a prospective cohort study of 171 adult EoE patients, a compliance of >0.2mL/mmHg was defined as normal [33]. There were limited details on how this cutoff was determined. In subsequent studies, abnormal compliance was defined as <450mm³/mmHg and severely abnormal compliance was defined as <300mm³/mmHg [97, 99]. Thresholds were determined using that same prospective cohort study, but analysing the data from healthy controls [33].

3.4.1.4. Oesophagogastric Junction (EGJ) Diameter

Lastly, one study used the maximum EGJ diameter to determine fibrostenosis [99]. Abnormal was defined as ≤16mm and severely abnormal was defined as <12mm based on data from healthy controls [38].

3.5. Definition: Biomarkers

7 studies used biomarkers as the definition of fibrostenosis with varying methods of detection listed in Tables 1 and 2 [71, 74, 101, 102, 225, 226, 249]. Examples include expression of vimentin, E‐cadherin, TGFβ₁, pSMAD2/3, SOX2, and plasminogen activator inhibitor‐1.

3.6. Oesophageal Luminal Diameter

Specific oesophageal luminal diameter thresholds were used in structural (endoscopic and imaging) and functional (FLIP) definitions (Figure 2). Endoscopic thresholds include <7mm, ≤10mm, and ≤13mm, which were determined by the resistance or inability to pass an endoscope [22, 24, 44, 46, 49, 83, 105, 108, 110, 120, 122, 129, 139, 149, 211, 218] When using oesophagram, the <10th percentile of healthy controls was frequently used, which corresponded to an oesophageal luminal diameter of ≤15mm [23, 25, 26, 27]. Tablet delay was less frequently used but corresponded to an oesophageal luminal diameter of ≤13mm [22]. Lastly, FLIP used thresholds of ≤16mm (abnormal) and <12mm (severely abnormal) [38].

FIGURE 2.

Fibrostenosis and oesophageal luminal diameters. Oesophageal luminal diameters that are highlighted by different methods of detection, such as endoscopy, imaging, and functional lumen imaging probe.

3.7. Comparing Adult and Paediatric Studies

Studies exclusively assessing adult versus paediatric patients were compared. Studies were excluded if both adult and paediatric patients were included or excluded if they were consensus, survey, or validation studies. Using Fisher's Exact Test and assuming a significance level of 0.05, structural definitions were more commonly used in adult studies compared with paediatric studies (98.2% vs. 69.6%, p<0.001). Alternatively, histologic definitions were more commonly used in paediatric studies than in adult studies (69.6% vs. 20.9%, p<0.001). There were no significant differences between frequencies of functional definitions, biomarker definitions, use of multiple definitions, and use of multiple methods of detection in adult and paediatric studies (9.1 vs. 8.9%; 2.7 vs. 5.4%; 32.7 vs. 46.5%; 66.4 vs. 57.1%). There were also no significant differences when comparing the frequencies of the specific methods of detection.

4. Discussion

Untreated eosinophilic oesophagitis can lead to remodelling and fibrostenosis with significant clinical implications [4, 6, 7]. However, there is no standardised definition of fibrostenosis in clinical practice or in clinical research studies. In this systematic review, we detected significant variability in the definitions of fibrostenosis as well as methods of detection. The two most common definitions included (1) structural presence of endoscopic or radiographic stricture, rings, and/or narrowings and (2) histologic presence of lamina propria fibrosis. However, many studies used more than one definition. The methods of detection for each modality were highly variable, and few validated scoring systems were used.

Regarding the structural definition of fibrostenosis, both endoscopy and radiology were used. A validated endoscopic scoring system (EREFS) for fibrostenotic EoE features exists. It is important to note that the reliability for determining the presence and severity of rings or strictures is limited. The interobserver agreement was only moderate for both (k=0.40 with 56% pairwise agreement; k=0.52 with 79% pairwise agreement, respectively) [11]. Novel techniques may help improve detection. For example, white light imaging combined with linked colour imaging had a superior interobserver agreement compared to white light imaging alone (stricture: ƙ=0.51 vs. 0.39, respectively, p=0.0072). However, the clinical applicability remains to be determined.

There were conflicting data comparing endoscopy to imaging regarding fibrostenosis identification. Three studies suggested that an oesophagram was superior to endoscopy for a diagnosis of a stricture (20%–45% strictures identified on endoscopy vs. 95.5%–100% on oesophagram) [21, 22, 23]. Given that an oesophagram was utilised as the gold standard, there is the possibility of a false positive by oesophagram. Using endoscopy as the gold standard, a different study found that barium oesophagram failed to identify small‐calibre oesophagus, ringed oesophagus, or stricture 29.4% of the time [24]. In a large retrospective cohort of 70 adult EoE patients, there was no significant difference between detection of fibrostenosis using an oesophagram and endoscopy (fibrotic subscore on EREFS): 74% and 84%, p=0.07 [28]. Overall, endoscopy is likely the more practical of the two methods. An oesophagram is solely diagnostic, but during an endoscopy, histology can be obtained and a therapeutic dilation performed.

Given that remodelling begins at the microscopic level, it is likely that early stages of fibrostenosis are missed in the current paradigm that uses endoscopy or imaging. Endoscopic biopsies can be very useful, but to date no standardised approach for histologic assessment has been developed. There is a standardised approach to obtaining biopsies (number and location), but it remains unclear if taking biopsies at the location of a ring or stricture would improve yield for detection of LPF. Only one validated scoring system (EoE‐HSS [29]) exists, but the majority of studies in this review did not use this score. For the EoE‐HSS, a strong interobserver agreement on stage and grade of fibrosis was noted (Kendall's coefficient: 0.8 and 0.82, respectively [29]), but the experience of the pathologist does play a role [30]. Artificial intelligence is a promising modality to aid pathologists with less experience (accuracy of 97% and 96% for assessing lamina propria and collagen deposition, respectively) [241]. Of note, the EoE‐HSS is a detailed and time‐consuming scoring system, which may limit the clinical applicability. Abbreviated scoring systems may be better adapted for clinical practice, but this will require future research and validation. For example, the histologic fibrostenotic component of the Index of Severity for Eosinophilic Esophagitis (I‐SEE) is clinically useful and is a simplified derivation of the EoE‐HSS [7]. However, the I‐SEE still requires validation. Lastly, a major limitation when relying on LPF is that the yield of obtaining adequate lamina propria without crush artefact can be low. Percentage of adequate lamina propria in routine oesophageal biopsies ranged from 15%–75.0% per individual biopsy (Table S13) [42, 68, 72, 73, 75, 78, 80, 236, 237]. However, taking multiple biopsies per patient, targeting distal oesophagus, and using a web‐based model to predict LPF are all methods to improve LPF detection. When multiple biopsies per patient are obtained, the yield can be as high as 96.2% [35, 42, 43, 49, 51, 73, 75, 78, 237] Incidence of evaluable lamina propria is higher in the distal oesophagus [42, 239]. At least 7 biopsies should be taken from the mid‐distal oesophagus as the probability of detecting LPF reached >95% [42]. Lastly, there is a promising web‐based model to predict LPF when there is inadequate lamina propria (grade and stage EoE‐HSS LPF: area under the curve with 95% confidence interval: 0.77 [0.69–0.84] and 0.75 [0.67–0.82], respectively; accuracy of 78% and 72%, respectively) [240].

Functional definitions (FLIP parameters) correlate significantly with endoscopic fibrostenotic findings [32, 33, 35, 36], but it remains unclear if FLIP will be useful as a primary or adjunctive modality for assessing fibrostenosis. Based on healthy controls and the risk of food impaction, thresholds for distensibility plateau (abnormal ≤17mm, severely abnormal <14mm), compliance (abnormal ≤450mm³/mmHg, severely abnormal <300mm³/mmHg), and EGJ diameter (abnormal ≤16mm, severely abnormal <12mm) have been defined. However, thresholds are based on a limited number of studies, which may require a larger validation cohort. Operational challenges may need to be overcome. FLIP is not readily available at all institutions or practices and incurs additional costs, and there have been no validation studies comparing reliability between community and academic endoscopists. However, there is research demonstrating that measurement technique may matter [96] Thus, standardisation of measurement is needed.

The inability to assess the transmural wall changes of the oesophagus remains a major limitation in the endoscopic and histopathologic assessment. Fibrostenosis is a transmural pathologic process, but our current methods provide minimal information regarding disease progression in deeper mural layers. As opposed to other disease states, such as inflammatory bowel diseases or diverticulitis, full‐thickness oesophageal resections are rarely performed in EoE, which greatly limits our knowledge and research capabilities. FLIP parameters, biomarkers, or other histologic assessments may hold promise for assessing oesophageal transmural properties and changes. However, future studies are needed.

There are several limitations to this systematic review. Many definitions and diagnostic methods of detection are not validated scoring systems. The majority of studies are retrospective, with few prospective or randomised controlled trials. There are very few studies that directly compare definitions or modalities with each other in the same patient. Non‐fibrotic causes of stenosis (e.g., muscle spasms) were not included. Given the heterogeneity of this systematic review, a meta‐analysis could not be performed. There are also multiple strengths of this article. This is the largest known systematic review to evaluate fibrostenosis in EoE. There have been systematic reviews of prevalence, treatment, perforation, natural history, and dilation among other topics, but none to our knowledge dedicated solely to fibrostenosis. A commonly accepted gold standard for fibrostenosis is missing, and our review provides the basis for future work in this area.

Based on this systematic review, we propose the following at this time: (1) In clinical practice, fibrostenosis should be defined as endoscopic findings (fibrostenotic parameters of the EREFS); and (2) in clinical research, there should be a combined assessment of endoscopic findings (fibrostenotic EREFS) and histopathologic findings (LPF on EoE‐HSS). Both EREFS and EoE‐HSS are validated scoring systems. FLIP can be used as an adjunctive measure in either scenario, but there is not enough data or widespread availability to support its primary use. Biomarkers, which may have future potential, are not a practical definition for fibrostenosis. Biomarkers are primarily a research‐only tool and are not readily available to clinicians and scientists.

In clinical practice, endoscopic evaluation is preferred for a few reasons. Endoscopy is more practical, as it is needed to diagnose and monitor response to therapy in EoE, while barium oesophagram is less frequently utilised. There is substantially more data behind the use of EREFS compared with imaging. For clinical research, it is reasonable to also include LPF on EoE‐HSS, as it may capture early findings of fibrostenosis that may not be endoscopically visible. For research, there is typically more time and resources available, which would allow for the collection of a sufficient number of biopsies and collaboration with an experienced GI pathologist. Further assessment is needed to determine clinically relevant thresholds of oesophageal lumen diameter, ring severity, and LPF severity.

Fibrostenosis is a challenging clinical problem for patients with EoE, resulting in dysphagia, food impactions, and repeated endoscopic dilations. In this systematic review, we show significant heterogeneity in definitions, diagnostic modalities, and methods of detection for fibrostenosis in EoE. Lack of agreement hampers progress in preventing, diagnosing, and managing this significant complication. Standardised definitions generated by EoE experts according to a UCLA/RAND process are a reasonable next step, which is already underway [251]. Only then will we have a robust basis for future investigation of fibrostenosing EoE.

Author Contributions

Claire A. Beveridge: conceptualization, investigation, writing – original draft, methodology, data curation, formal analysis, supervision, visualization, project administration, writing – review and editing. Natalie Farha: data curation, investigation. Christina Hermanns: data curation, investigation. Chiara Maruggi: data curation, investigation. Katherine Falloon: methodology. Shivani Thanawala: writing – review and editing. Mary Pat Harnegie: methodology, resources. J. Mark Brown: writing – review and editing. Andrei I. Ivanov: writing – review and editing. Evan S. Dellon: writing – review and editing. Gary W. Falk: writing – review and editing. Christopher Ma: writing – review and editing. Nirmala Gonsalves: writing – review and editing. Anthony Lembo: writing – review and editing. Amanda B. Muir: writing – review and editing. Scott Gabbard: writing – review and editing. Glenn T. Furuta: writing – review and editing. Florian Rieder: conceptualization, supervision, visualization, formal analysis, writing – original draft, writing – review and editing.

Conflicts of Interest

C.A.B.: consultant: Guidepoint, Takeda; speaking: GastroGirl. K.F.: grant funding: Crohn's and Colitis Foundation (916943), Pfizer (90146787); advisory panel: Janssen. E.S.D.: research funding: Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Celldex, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, Sanofi, Shire/Takeda; consultant: Abbvie, Adare/Ellodi, Akesobio, Alfasigma, ALK, Allakos, Amgen, Apollo, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biocryst, Bryn, Calypso, Celgene/Receptos/BMS, Celldex, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GI Reviewers, GSK, Holoclara, Invea, Knightpoint, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Sanofi, Shire/Takeda, Target RWE, Upstream Bio; educational grant: Allakos, Aqilion, Holoclara, Invea. G.W.F.: research funding: Celldex, Ellodi Pharmaceuticals, Nexteos, Arena/Pfizer, Bristol, Myers/Squibb, Regeneron/Sanofi, Lucid, Takeda; consulting: Ellodi Pharmaceuticals, Ubiquity Bio, Bristol Myers Squibb, Regeneron/Sanofi, Phathom Pharmaceuticals. C.M.: consultant: AbbVie, Alimentiv, Amgen, AVIR Pharma Inc., Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Forte Biosciences, Fresenius Kabi, Gilead, Janssen, McKesson, Mirador Therapeutics, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Takeda, Tillotts Pharma; speaker: AbbVie, Amgen, AVIR Pharma Inc., Alimentiv, Bristol Myers Squibb, Eli Lilly, Ferring, Fresenius Kabi, Janssen, Merck, Organon, Pendopharm, Pfizer, Sanofi, Takeda, Tillotts Pharma; royalties: Springer Publishing; research support: AbbVie, Eli Lilly, Ferring, Pfizer. N.G.: consultant: AstraZeneca, BMS, Sanofi, Regeneron, Takeda, Exact Sciences, Eupraxia, Uniquity; speaking: Takeda, Sanofi, Regeneron, BMS; royalties: Up‐to‐date. A.L.: consultant: Takeda, Ardelyx, Ironwood, Gemelli, Vibrant, Evoke, BioAmerica, Arena, Aeon, Amylyx, Pfizer, BMS, J&J. A.B.M.: medical advisory board: Regeneron/Sanofi, Bristol Meyers Squib, Uniquity, Takeda. S.G.: speaking: GastroGirl. G.T.F.: EnteroTrack (CMO). F.R.: consultant: Adiso, Adnovate, Agomab, Allergan, AbbVie, Arena, Astra Zeneca, Bausch & Lomb, Boehringer‐Ingelheim, Celgene/BMS, Celltrion, CDISC, Celsius, Cowen, Eugit, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, Granite, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Landos, Jannsen, Koutif, Mestag, Metacrine, Mirum, Mopac, Morphic, Myka Labs, Organovo, Origo, Palisade, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Sanofi, Surmodics, Surrozen, Takeda, Techlab, Teva, Theravance, Thetis, Tr1x Bio, UCB, Ysios, 89Bio. N.F., C.H., C.M., S.T., M.P.H., J.M.B., A.I.I.: none.

Supporting information

Data S1.

Data Availability Statement

Data available upon request. Added to PROSPERO under ID CRD42024558352.