Changing landscape of pediatric eosinophilic gastrointestinal diseases highlighted by updated consensus criteria

To the Editor,

Eosinophilic gastrointestinal diseases (EGIDs) are chronic inflammatory disorders driven by abnormal mucosal eosinophilia. While eosinophilic esophagitis (EoE) has experienced a marked increase in Western countries, non‐EoE EGIDs also impose substantial clinical morbidity. ¹ However, the long‐term epidemiological trajectory of non‐EoE EGIDs has remained obscure, largely due to the historical lack of standardized diagnostic frameworks. Indeed, a comprehensive meta‐analysis highlighted that previous epidemiological studies were limited by the use of highly variable or unspecified histologic cutoffs. ²

In 2024, the first international consensus guidelines established by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) marked a critical milestone by defining standardized, site‐specific histologic thresholds for pediatric EGIDs. ³ Yet, the longitudinal impact of strictly applying these updated criteria to real‐world cohorts, particularly in non‐Western populations where non‐EoE EGIDs have historically predominated, remains unevaluated. Furthermore, largely due to the scarcity of large‐scale, histologically confirmed pediatric cohorts, previous epidemiological reports rely heavily on administrative codes, ¹ , ² , ⁴ , ⁵ precluding the retrospective application of these updated histology‐based criteria and failing to account for ascertainment bias driven by increasing endoscopy utilization.

To address these gaps, we retrospectively analyzed pediatric patients (aged <15 years; 1838 patients, 4216 procedures) undergoing endoscopy at a Japanese tertiary center from fiscal year (FY) 2007–2024, following Ethics Committee approval (No. 20230219) (Figure 1). Archived pathology data were systematically re‐evaluated by a single pathologist, who was blinded to clinical characteristics and final EGID classification, to extract peak eosinophil counts per high‐power field (eos/HPF) for each gastrointestinal segment, strictly applying the updated 2024 criteria. Biopsies were generally obtained from predefined gastrointestinal sites, with the routine and most frequent sampling pattern consisting of eight sites during esophagogastroduodenoscopy (EGD) and seven sites during colonoscopy (CS), as detailed in the Supporting Information. Additional sampling was performed based on clinical indication, endoscopic findings, and the treating endoscopist's judgment. To ensure diagnostic specificity, we excluded patients with secondary causes of gastrointestinal eosinophilia (e.g., inflammatory bowel disease) and “criteria‐discordant cases”, defined as meeting conventional Japanese criteria (e.g., ≥20 eos/HPF for non‐EoE EGIDs) but not the 2024 criteria by site‐specific thresholds (Table S1). Diagnostic yields (diagnosed cases per total endoscopies) were calculated. Overall 18‐year temporal trends in these yields were evaluated using the Cochran‐Armitage test. Furthermore, to explicitly assess the differential expansion between EoE and non‐EoE EGIDs while accounting for historical changes in disease awareness and endoscopic thresholds, we stratified the cohort into an early period (FY2007–2015) and a late period (FY2016–2024) and compared them using Fisher's exact test for categorical variables and the Mann–Whitney U test for continuous parameters.

FIGURE 1.

Flowchart of histological reevaluation and case classification in pediatric EGIDs (2007–2024). Diagnostic yields were calculated using procedure‐specific denominators: Overall EGIDs were based on all endoscopically evaluated patients (n = 1838); EoE and upper‐tract non‐EoE EGIDs on patients who underwent esophagogastroduodenoscopy (n = 1396); and lower‐tract non‐EoE EGIDs on patients who underwent colonoscopy (n = 1337). Patients with secondary causes of eosinophilia (e.g., inflammatory bowel disease) were excluded in accordance with the ESPGHAN/NASPGHAN guidelines. “Criteria‐discordant eosinophilia,” defined as cases meeting conventional Japanese histologic criteria but not the updated 2024 international consensus thresholds, was excluded from the definitive EGID cohort. Among the 60 patients with EoE, 10 had concomitant upper‐tract non‐EoE EGIDs, indicating multisegment involvement. EGIDs, eosinophilic gastrointestinal diseases; EoC, eosinophilic colitis; EoD, eosinophilic duodenitis; EoE, eosinophilic esophagitis; EoG, eosinophilic gastritis; EoI, eosinophilic ileitis; ESPGHAN: European Society for Pediatric Gastroenterology, Hepatology and Nutrition; NASPGHAN: North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.

First, our analysis revealed a marked expansion of overall EGIDs, predominantly driven by non‐EoE EGIDs. The diagnostic yield of definitive EGIDs exhibited a continuous upward trend over the 18‐year period. Overall yield rose from 1.8% (early) to 7.1% (late) (3.9‐fold increase, p < .001; Figure 2A,B, Table 1). Notably, even when comparing these distinct periods to account for evolving clinical practices, the expansion of non‐EoE EGIDs outpaced that of EoE. While EoE diagnostic yields increased 2.3‐fold (2.1% to 4.9%, p = .034), non‐EoE EGIDs exhibited a 9.3‐fold increase (0.3% to 2.8%, p < .001) (Figure 2A,B, Table 1).

FIGURE 2.

Temporal trends in diagnostic yield and clinical characteristics of pediatric EGIDs (2007–2024). (A) Comparison of diagnostic yields between the Early (Fiscal Year 2007–2015) and Late (Fiscal Year 2016–2024) periods. Diagnostic yields (%) were calculated per EGD for EoE and upper‐tract non‐EoE EGIDs and per CS for lower‐tract non‐EoE EGIDs. Statistical significance was determined by Fisher's exact test. (B) Temporal trends in diagnostic yields for overall EGIDs, EoE, and non‐EoE EGIDs. Dotted lines and shaded areas represent linear regression models with 95% confidence intervals. (C) “Criteria‐discordant cases.” Left: Table showing site‐specific eosinophil thresholds used to define discordant cases (meeting conventional Japanese criteria but not the updated 2024 international consensus thresholds). Right: Annual trends in the frequency of discordant cases among EGD and CS procedures. (D) Venn diagram illustrating the overlap of disease involvement across the upper and lower gastrointestinal tracts. (E) Comparison of peripheral blood parameters between patients with isolated EoE (n = 53) and those with multisegment disease (n = 12). Markers represent individual patients; the line represents the median. Statistical significance was determined by the Mann–Whitney U test. In panels A and E: *p < .05; **p < .01; ****p < .0001. EGD, esophagogastroduodenoscopy; CS, colonoscopy; EoE, eosinophilic esophagitis; EGIDs, eosinophilic gastrointestinal diseases.

TABLE 1.

Temporal comparison of clinical characteristics of patients with definitive EGIDs and comparison between isolated EoE and multisegment disease.

Characteristics	2007–2024 EGIDs	Temporal Trends			EoE Subtype Analysis
		Early Period (2007–2015) EGIDs	Late Period (2016–2024) EGIDs	p value (Early vs. Late)	Isolated EoE	Multisegment disease	p value (EoE vs. Multisegment)
	n = 105	n = 9	n = 96		n = 53	n = 12
Male, n (%)	74 (70)	7 (78)	67 (70)	>.999	34 (64)	9 (75)	.737
Age at diagnosis, years, median (IQR)	9.0 (4.5–12.0)	10 (4.5–13.0)	9.0 (4.3–12.0)	.741	9.0 (6.0–11.5)	5.5 (2.3–10.0)	.190
Comorbid of allergic diseases, n (%)
Any allergic diseases	59 (56)	7 (78)	52 (54)	.293	31 (58)	6 (50)	.749
Atopic dermatitis	15 (14)	1 (11)	14 (15)	>.999	9 (17)	1 (8)	.673
Allergic rhinitis	41 (39)	6 (67)	35 (36)	.149	21 (40)	5 (42)	>.999
Bronchial asthma	6 (6)	0 (0)	6 (6)	>.999	4 (8)	0 (0)	>.999
Food allergy	27 (26)	2 (22)	25 (26)	>.999	15 (28)	2 (17)	.494
Symptoms, n (%)
Dysphagia	7 (7)	0 (0)	7 (7)	>.999	6 (11)	1 (8)	>.999
Reflux/Heartburn	4 (4)	0 (0)	4 (4)	>.999	3 (6)	0 (0)	>.999
Vomiting	39 (37)	5 (56)	34 (35)	.287	21 (40)	7 (58)	.335
Abdominal pain	74 (70)	7 (78)	67 (70)	>.999	32 (60)	8 (67)	.754
Diarrhea	28 (27)	1 (11)	27 (28)	.439	10 (19)	2 (17)	>.999
Bloody stool/Melena	15 (14)	0 (0)	15 (16)	.352	1 (2)	2 (17)	.085
Appetite loss	9 (9)	1 (11)	8 (8)	.569	1 (2)	0 (0)	>.999
Ascites	2 (2)	0 (0)	2 (2)	>.999	4 (8)	1 (8)	>.999
Body weight loss	14 (13)	0 (0)	14 (15)	.604	8 (15)	1 (8)	>.999
Laboratory findings, median (IQR)
Hemoglobin (Hb), g/dL	12.9 (12.0–13.8)	13.8 (11.9–14.9)	12.9 (12.0–13.7)	.265	12.9 (12.1–13.8)	11.9 (10.1–13.0)	.030
Peripheral eosinophil counts, /μL	429 (201–778)	199 (154–694)	445 (209–779)	.197	435 (260–697)	892 (592–1469)	.002
Albumin (Alb), g/dL	4.4 (4.0–4.6)	4.4 (4.2–4.6)	4.4 (4.0–4.6)	.850	4.4 (4.3–4.6)	4.1 (3.5–4.3)	.002
Total IgE, IU/mL	332 (106–815)	149 (72–940)	367 (129–818)	.380	430 (181–844)	248 (97–693)	.225

Note: Data are presented as number (%) or median (IQR). The “Temporal Trends” section compares all definitive EGID cases between the Early Period (FY2007–2015) and Late Period (FY2016–2024). The “EoE Subtype Analysis” compares patients with isolated EoE against those with multisegment disease (involving both the esophagus and other gastrointestinal segments). p values were calculated by Fisher's exact test for categorical variables and by the Mann–Whitney U test for continuous variables. EGIDs, eosinophilic gastrointestinal diseases; EoE, eosinophilic esophagitis; Hb, hemoglobin; IgE, immunoglobulin E; IQR, interquartile range.

Second, we observed a concurrent increase in “criteria‐discordant” mucosal eosinophilia. Applying the 2024 criteria revealed that such cases also increased over time, particularly in the lower gastrointestinal tract (43.3% of lower‐tract procedures; p < .0001; Figure 2C). This finding likely reflects a background rise in mucosal eosinophilia exceeding the physiologic baseline reported for Japanese children. ⁶ Despite these increases, the clinical demographic profile of definitive EGID cases, including age, sex, and allergic comorbidities, remained stable across periods (all p > .05; Table 1). Notably, allergic comorbidities, including food allergy, allergic rhinitis, and atopic dermatitis, were common (56% overall) and remained consistent across disease subtype and study period, suggesting that the expanding non‐EoE EGID population retains an atopic clinical context. Clinical awareness and biopsy decision‐making likely evolved during the study period, including increased recognition of EGIDs, broader consideration of multisegment sampling, and greater attention to biopsies from macroscopically nonspecific mucosa. These changes may have increased detection of both EoE and non‐EoE EGIDs, particularly because non‐EoE EGIDs can show patchy inflammation and nonspecific endoscopic findings. Nevertheless, stable demographic and allergic profiles across periods and parallel increases in definitive and discordant cases suggest that ascertainment changes alone do not fully explain the observed expansion.

Finally, to identify predictors for concurrent lower‐tract disease in confirmed EoE, we compared isolated EoE against 12 multisegment cases (concurrent EoE and non‐EoE EGIDs). This multisegment subgroup presented a distinct systemic profile: higher peripheral blood eosinophil counts and reduced hemoglobin and albumin levels (Figure 2D,E, Table 1).

By systematically applying the 2024 criteria to an 18‐year cohort, we revealed a profound expansion of pediatric EGIDs. This finding aligns with previous data suggesting that the rise in EoE is outpacing the increase in endoscopy utilization, ⁷ arguing against detection bias. While a previous meta‐analysis estimated the historical prevalence of non‐EoE EGIDs in symptomatic patients to be approximately 1.9%, ² our data reveal a recent overall diagnostic yield (7.1%) that exceeds this baseline. Contrary to the historically static Asian phenotype dominated by non‐EoE EGIDs, ⁸ , ⁹ we observed a rapid, concurrent rise in EoE, mirroring Western trends. Notably, our period‐stratified analysis demonstrated that non‐EoE EGID expansion disproportionately outpaced EoE. This distinct pattern suggests an evolving dual burden: acquiring the Western phenotype (i.e., EoE) while further expanding the burden of non‐EoE EGIDs. Although multiple clinical, diagnostic, and environmental factors may contribute to differences between Japanese and Western cohorts, two factors appear particularly relevant to interpreting our findings: biopsy strategy and the diagnostic context in Japan. First, in our tertiary pediatric center, endoscopic evaluation commonly included multisegment sampling beyond the esophagus, which may increase detection of patchy gastric, duodenal, ileal, or colonic eosinophilia compared with cohorts in which biopsies are more symptom‐directed or esophagus‐focused. Second, conventional Japanese criteria used lower histologic thresholds for non‐EoE EGIDs than the updated 2024 site‐specific criteria (Table S1), which may have increased clinical awareness and referral of suspected non‐EoE EGIDs. Thus, our cohort likely reflects both a rise in EoE resembling Western trends and a Japanese/Asian clinical context that is well positioned to detect non‐EoE EGIDs.

Concurrently, the parallel rise in “criteria‐discordant” cases highlights a broader increase in background mucosal eosinophilia. Consistent with the 2024 criteria emphasizing standardized definitions for definitive EGIDs, these cases should not be classified as definitive disease; however, they should not simply be dismissed as false positives. Prior Japanese criteria may retain value as a sensitive screening or follow‐up framework, and discordant cases may represent an intermediate phenotype, including mild, early, resolving, or secondary eosinophilic inflammation.

Moreover, after excluding identifiable secondary causes, our analysis of multisegment cases identified a distinct systemic profile characterized by peripheral eosinophilia, anemia, and hypoalbuminemia. Importantly, these findings validate the clinical signature recently reported in a U.S. pediatric cohort, ¹⁰ suggesting a cross‐population phenotype. This laboratory pattern may indicate that multisegment disease represents a broader inflammatory phenotype than isolated EoE. Peripheral eosinophilia may reflect greater systemic eosinophilic inflammation, whereas anemia and hypoalbuminemia may provide clinical clues to lower gastrointestinal or more extensive mucosal involvement. Therefore, these features should raise suspicion for multisegment EGID in patients with EoE. Before assigning this diagnosis, however, clinicians should consider secondary causes of multisegment eosinophilic inflammation, including inflammatory bowel disease, food allergy‐related disease, drug injury, parasitic or other infections, hypereosinophilic syndrome, and systemic eosinophilic or immune‐mediated disorders.

This study has certain limitations, primarily its single‐center retrospective design. In addition, although the routine and most frequent biopsy distribution consisted of eight sites during EGD and seven sites during CS, the exact number and proportion of procedures with biopsies available from each intended site could not be reliably reconstructed across the entire 18‐year study period. However, given the inherent challenges of performing systematic endoscopies in children, this comprehensively evaluated cohort provides exceptionally rare and valuable histological insights. Furthermore, our histology‐based reevaluation approach uniquely enabled uniform histologic evaluation by a single pathologist, ensuring strict and consistent application of the 2024 criteria across the entire 18‐year cohort.

In conclusion, applying the 2024 consensus criteria highlights a marked expansion of non‐EoE EGIDs alongside EoE. This changing landscape underscores the urgent need to look beyond the esophagus and emphasizes the necessity of international collaborative studies to continuously validate and refine diagnostic thresholds in a landscape of rapidly evolving gastrointestinal eosinophilia.

AUTHOR CONTRIBUTIONS

Masafumi Aoki: Funding acquisition; writing – original draft; data curation; investigation. Tokuhiro Kimura: Resources; writing – review and editing; validation. Tsuyoshi Sogo: Writing – review and editing; resources; project administration. Yuichiro Tanaka: Writing – review and editing; visualization. Mari Yamaguchi: Writing – review and editing; visualization. Kazuhiro Matsuyama: Writing – review and editing; visualization. Shingo Yamada: Data curation; formal analysis; writing – original draft; investigation. Kasumi Osonoi: Visualization; writing – review and editing. Shuichiro Umetsu: Resources; writing – review and editing; project administration. Tetsuo Shoda: Conceptualization; investigation; supervision; funding acquisition; writing – review and editing; methodology; software.

FUNDING INFORMATION

This study was supported by a grant from the Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics. Writing assistance: Shawna Hottinger provided editorial assistance as a medical writer funded by Cincinnati Children's Hospital Medical Center.

CONFLICT OF INTEREST STATEMENT

T.S. is coinventor of patents owned by Cincinnati Children's Hospital Medical Center. All other authors declare that they have no competing interests and no conflict of interest.

Supporting information

Table S1. Diagnostic thresholds for EGIDs and physiological reference values for tissue eosinophil counts across gastrointestinal segments.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.