THE IMPORTANCE OF FOLLOW-UP OF ESOPHAGEAL EOSINOPHILIA IN CHILDREN WITH SEVERE COW’S MILK ALLERGYTo the Editor:The current understanding of the intricate interplay between food allergy (FA) and eosinophilic esophagitis (EoE) remains incomplete, particularly in patients with severe manifestations of FA or those undergoing oral immunotherapy (OIT). EoE has been recognized as part of the atopic march1, as it shares type 2 inflammation and poses a risk of progression to other atopic diseases, including IgE-mediated food allergy (IgE-FA). However, the incidence of EoE even before food reintroduction2 raises doubts about whether this group represents a subtype of FA and how esophageal changes develop. In clinical practice, there are concerns about underdiagnosing EoE and its potential long-term complications, especially in children whose symptoms are often nonspecific and may be masked by adaptive behaviors3. The proposed longitudinal study aims to characterize esophageal eosinophilia (EE) in children with IgE-mediated cow’s milk allergy (IgE-CMA) and compare clinical and endoscopic findings between patients with and without esophageal symptoms over one year of follow-up.Patients aged 6 to 18 years were recruited from a Brazilian IgE-CMA reference center between 2019-2022. They underwent a standard routine, which included inquiries about esophageal symptoms, laboratory tests, and esophagogastroduodenoscopy (EGD) with biopsy. With the assistance of caregivers, patients verbally reported the frequency and intensity of esophageal symptoms over the last month. Adaptive eating behaviors were assessed using the IMPACT acronym4. Patients who confirmed the persistence of at least one esophageal symptom were classified as symptomatic. Caregivers completed the Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) v2.05during the same visit. The specific IgEs for CM, α-lactalbumin, β-lactoglobulin, casein, egg, soy, wheat, peanut, Brazil nut, codfish, and shrimp were measured using the ImmunoCAP® method. Serum levels of eosinophils and total IgE were also collected.Subsequently, all patients underwent EGD, with at least 4-6 esophageal biopsies (proximal/mid and distal esophagus), along with gastric and duodenal biopsies. Macroscopic characteristics were described using the Endoscopic Reference Score (EREFS)6, completed by the same endoscopist. The histological evaluation included eosinophil count per high-power field (hpf) in each region. Biopsies were evaluated by a single pathologist trained in the EoE Histologic Scoring System (EoEHSS)7 for both proximal/mid and distal regions. The presence of ≥ 15 eos/hpf in the esophageal mucosa was designated as EE. After excluding other causes of EE, symptomatic patients were classified as EoE, while asymptomatic patients were classified as asymptomatic esophageal eosinophilia (aEE). EGD was repeated after at least 8 weeks of treatment for EoE or 1-year follow-up without intervention for aEE. See supplemental data for the detailed methodology.Thirty-three patients with IgE-CMA were assessed. Most were male (57.6%) with a median age of 8.75 years. 84.8% had other atopic conditions, with nearly all reporting prior CM anaphylaxis (87.8%), and 75.7% still reacted to baked milk. The frequency of EE was 45.4%, with 21.2% diagnosed with EoE and 24.2% with aEE. Regarding clinical data, statistically significant differences were not observed between the groups with and without EE (see Table 1). Laboratory tests showed higher results in the EE group but without statistical significance. The percentage of patients sensitized to other food allergens besides CM was similar between the two groups.Comparing patients with EoE and aEE, most of the clinical data did not differ statistically between the groups. A higher median age was found in those with EoE (10.3 vs 8.2 years, p=0.03), along with higher specific IgE values for CM and casein (p=0.02 and p=0.008, respectively). The percentage of patients sensitized to another food allergen was higher in the EoE group (85.7% vs 50%), but this difference did not reach statistical significance. The eosinophil count in the esophagus was statistically similar between the groups, with a predominance of non-diffuse distribution in both. None of the patients exhibited eosinophilia in the stomach or duodenum suggestive of other eosinophilic gastrointestinal diseases8.Table 2 illustrates the comparison of scores between the EoE and aEE groups. EoE patients had significantly higher median PEESS v2.0 total scores (p=0.01), particularly in domains associated with pain and dysphagia (p=0.02). Specifically, four questions were able to distinguish patients with EoE (1, 9, 11, and 12). EREFS scores were similar between the groups, although the frequency of abnormal macroscopy was higher in EoE patients (100% vs 37.5%, p=0.02). EoEHSS also showed no significant differences between the groups. During the follow-up period (see Table 3), most EoE patients achieved clinical and histological remission with omeprazole treatment, including the resolution of fibrosis. Among the 8 patients with aEE, 6 (75%) remained asymptomatic after one year. Of the 6 repeated EGDs, 3 revealed normal histology. The remaining 3 exhibited persistent fibrosis, involving 2 patients who maintained aEE and one who developed EoE.This is the first follow-up study in patients with IgE-CMA that evaluated EE beyond eosinophil counts, utilizing standardized EoE scores in childhood. A high frequency of EE was observed, particularly associated with severe cases of IgE-CMA, highlighting the importance of EoE screening among FA-IgE patients. Given the absence of reliable clinical markers for predicting EE, the challenge persists in identifying symptomatic patients who require EGD. While the use of PEESS contributed to EoE diagnosis in this study, we acknowledge the practical limitations of understanding sporadic complaints or oligosymptomatic patients. To grade PEESS questions or to assess the social impacts of symptoms could provide deeper insights into esophageal involvement. Another noteworthy finding of this study is the possibility of disease activity even before symptom onset, as endoscopic and histological features related to EE were similar between symptomatic and asymptomatic patients. However, since we still lack markers to define active EoE aside from clinical symptoms, debates continue regarding whether aEE should be considered a precursor to EoE or merely a transient phenomenon9.Diagnosing EoE is a relevant concern in IgE-FA patients, especially for those eligible for OIT. In this study, patients with EoE were distinguished from those with aEE by older age and higher levels of CM-specific IgE. However, due to the low incidence of EoE during this follow-up, predicting which aEE patients should be treated over time remains challenging. The phenotype definition could also contribute to understanding this progression. In both EE groups, our results suggest the predominance of a non-fibrostenotic phenotype with favorable outcomes over a period without changes in CM intake: (1) EREFS and EoESS features were mainly inflammatory, regardless of symptom presence, with most showing reversal of fibrosis during follow-up. (2) Histologic remission occurred spontaneously in asymptomatic patients or after omeprazole treatment in the majority of patients with EoE. As this is a small sample of pediatric patients followed for a short period, further follow-up studies will be necessary to confirm whether other IgE-FA groups exhibit a similar disease course.In line with previous research involving FA patients2,10, this study suggests that EoE originates from the sustained activity of inflammatory mediators, regardless of the presence of a food antigen in the esophagus. Especially in atopic individuals, characterized by type 2 immune dysregulation, further investigation is warranted to determine whether eosinophils play a protective or harmful role over time. Consequently, conducting additional research to elucidate the natural progression of EoE, including its underlying mechanisms and factors influencing its course, is essential. This deeper understanding not only promises to facilitate the development of more effective diagnostic and prognostic tools but also to pave the way for timely therapeutic interventions.Word count: 1999Keywords: eosinophilic esophagitis, esophageal eosinophilia, cow’s milk allergy, children, PEESS, EREFS, EoEHSS
