Non-esophageal Eosinophilic GI Diseases Are Underdiagnosed

In This Article

Abstract and Introduction

Abstract

Background: Non-oesophageal gastrointestinal eosinophilic diseases (EGID) are considered rare. However, low disease awareness among clinicians and pathologists may contribute to underdiagnosis.

Aims: To determine how frequently requests to evaluate for EGID accompany gastrointestinal biopsies and in what proportion of suspected cases pathologists address these requests, either confirming or refuting the clinical suspicion.

Methods: All cases in which biopsy requisitions included an explicit suspicion of EGID were extracted from a large clinicopathologic database and manually reviewed for accuracy. The diagnoses for these cases were then analysed to determine whether clinical suspicions were confirmed, refuted or ignored.

Results: Eosinophilic oesophagitis (EoE) was suspected in 12.8% of 903,516 patients with biopsies and confirmed in 14.9% of them. A suspicion of eosinophilic gastritis accompanied <0.001% of 1,438,206 gastric biopsy sets and was confirmed in 11.5% of them; eosinophilic duodenitis was suspected in 0.02% of ~675,519 patients with duodenal biopsies and confirmed in 8.0% of these; eosinophilic colitis was mentioned in <0.001% of 2,504,485 patients with colonic biopsies and confirmed in 0.1% of them. Less than 3% of endoscopists mentioned non-oesophageal EGID in the requisition, while most expressed a clinical suspicion of Barrett oesophagus, Helicobacter pylori gastritis, celiac disease and microscopic colitis (in 21.2%, 49.2%, 1% and 6.4% of the cases, respectively).

Conclusions: Gastroenterologists and pathologists commonly address and diagnose EoE. In contrast, both clinical suspicion and diagnosis of non-oesophageal EGID are extremely rare. Increased clinical awareness might result in a better understanding of the epidemiology and improved diagnosis of these still elusive conditions.

Introduction

Eosinophilic gastrointestinal diseases (EGIDs) are chronic inflammatory conditions characterised by persistent gastrointestinal (GI) symptoms and pathologically elevated levels of activated eosinophils in the GI tract.^[1] The manifestations of eosinophilic esophagitis (EoE) have been characterised^[2] and guidelines for the clinical and histopathologic components of the diagnosis are accepted by most clinicians and pathologists.^[3,4] In contrast, non-oesophageal EGID, which include eosinophilic gastritis, duodenitis and colitis (EoG, EoD and EoC),^[5] present with nonspecific symptoms (early satiety, nausea and vomiting, abdominal pain and cramping, bloating, and diarrhoea) that overlap with other common GI conditions, such as functional dyspepsia, irritable bowel syndrome or inflammatory bowel disease. Significant endoscopic findings are frequently absent and, when present, are non-specific.^[6] As a result, clinicians may not suspect EGIDs and many patients face a long delay with suboptimal care before the correct diagnosis is made.^[7]

The final diagnosis of EGID hinges on a histopathologic report of biopsies with significantly elevated mucosal eosinophilic infiltrates. However, pathologists' awareness of EGIDs is reportedly low, requests to consider EGID in the requisitions that accompany GI biopsies are believed to be rare, there are no accepted thresholds for normal eosinophilic counts in the gastrointestinal tissues (which makes counting eosinophils an unpopular exercise), and there are no guidelines on which to base the diagnosis.^[8–10] While most pathologists are now aware of EoE, evaluate the numbers of eosinophils in squamous oesophageal biopsy specimens and, when their density is elevated, report the peak number of eosinophils in a high-power field (hpf), a diagnosis of EGID remains a curiosity.

While a low awareness of EGID by both clinicians and pathologists is often invoked to explain the rarity of these diagnoses,^[11] it has never been studied systematically or quantified. This study was designed with two primary goals: to determine how frequently a request to evaluate for EGID accompanies a GI biopsy specimen, and in what proportion of suspected cases the pathologist addresses the request in the histopathologic report, either by confirming or refuting the clinical suspicion.

Table 1. Distribution of EGD biopsies by site in 1,776,198 unique patients; a same-day bi-directional procedure was performed on 383,513 of these patients. The percentages refer to the 1,776,198 unique patients as the denominator
Biopsy sites	Patients with biopsy (%)
Oesophagus	903,516 (50.8)
Stomach	1,438,206 (81.2)
Duodenum	675,519 (37.6)
Oesophagus only	212,977 (12.1)
Stomach only	491,487 (27.9)
Duodenum only	74,199 (4.0)
Oesophagus + Duodenum only	24,734 (1.4)
Oesophagus + Stomach only	370,133 (21.1)
Stomach + Duodenum only	280,914 (43.8)
Oesophagus + Stomach + Duodenum	285,672 (16.2)
Colon (+ any upper GI sample)	383,513 (21.3)

Table 2. This table summarises all EGID-related findings in this study. The connotation 'specific EGID' in the first column refers to the eosinophilic condition affecting each segment of the GI tract listed in the four right columns (EoE, EoG, EoD/EoN and EoC, respectively). 'Suspected cases confirmed' reports number and percentage of histopathological diagnoses that confirmed the suspicion expressed in the requisition. 'Request to r/o addressed by pathologist when diagnosis not confirmed' are cases in which the pathologist explained in a comment that the request was seen, considered and the suspected entity was not detected
	Oesophagus	Stomach	Duodenum	Colon
Unique patients with biopsies	903,516	1,438,206	675,519	2,504,485
Reported history of specific EGID	1545 (1.7%)	11 (<0.001%)	3 (<0.001%)	22 (<0.001%)
Reported suspicion of specific EGID	115,848 (12.8%)	148 (<0.01%)	106 (0.016%)	290 (0.01%)
Histopathologic diagnosis of specific EGID	53,386 (5.9%)	957 (0.07%)	137 (0.02%)	683 (0.27%)
Suspected cases confirmed (%)	17,295 (14.9%)	17 (11.5%)	11 (8.0%)	3 (0.1%)
Request to r/o addressed by pathologist when diagnosis not confirmed (%)	43,442 (37.5%)	12 (9.2%)	12 (9.5%)	41 (14.2%)
Endoscopists contributing EGD with biopsies	3391	3640	3324	8592
Endoscopists mentioning specific EGID (%)	2788 (82.2%)	104 (2.9%)	70 (2.1%)	166 (1.9%)

Table 3. Temporal trends of the frequency of requests to consider EGIDs that accompanied gastrointestinal mucosal biopsies. The numbers of requests for the years 2008–2010 and 2018–2020 increased by ~30% for EoE, remained unchanged at minimal levels for EoG or EoD, and decreased for EoC and EoN
	2008–2010	2018–2020	OR (95% CI)
EGDs with oesophageal biopsies	171,319	149,190
Requests to rule out EoE	18,268 (10.7%)	20,002 (13.4%)	1.30 (1.27–1.33)
EGDs with Gastric or Duodenal biopsies	301,726	193,283
Requests to rule out a non-oesophageal EGID	42 (0.012%)	34 (0.019%)	1.18 (0.76–1.84)
Colonoscopies	468,388	436,792
Requests to rule out EoC or EoN	74	41	0.59 (0.41–0.87)

Table 4. Associations of two or more EGIDs in 1,776,198 unique patients who underwent EGD; 383,513 patients also had a same-day bi-directional procedure with colonic biopsies. The index EGID is the eosinophilic condition used to determine the number of patients who also had another EGID. The column 'patients with pertinent biopsies' depicts the number of patients who had all combinations of biopsy set listed in the first column on the left. 'Patients with index condition' is the number of subject in each group who had the condition listed in italics in the first column on the left. The last column depicts the number of patients who had the index condition as well as the combinations of conditions listed in the first column on the left
Index EGID and associations	Patients with pertinent biopsies (n)	Patients with index EGID (n)	Patients with all EGIDs (%)
Eosinophilic oesophagitis (EoE)
EoE + EoG	665,805	32,261	162 (0.50)
EoE + EoD	320,406	16,161	22 (0.14)
EoE + EoC	186,105	9892	11 (0.11)
EoE + EoG + EoD	295.672	14,479	10 (0.07)
EoE + EoG + EoD + EoC	80,191	4040	1 (0.02)
Eosinophilic gastritis (EoG)
EoG + EoD	576,586	425	42 (9.88)
EoG + EoC	313,215	251	62 (24.70)
EoG + EoD + EoC	159,482	164	3 (1.83)
Eosinophilic duodenitis (EoD)
EoD+ EoC	195,915	40	7 (17.50)

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Non-oesophageal Eosinophilic Gastrointestinal Diseases Are Undersuspected Clinically and Underdiagnosed Pathologically

Abstract and Introduction

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Introduction

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