Single food allergy and reasons for multiple exclusions: a prospective study.To the Editor,Food allergies (FA) present an increasing global challenge, influenced by factors such as genetic predisposition, ethnicity, age, and cultural dietary practices. Consequently, making predictions about future allergic reactions remains challenging and uncertain (1). For instance, in Brazil, it is estimated that approximately 6% of children under the age of three and 3.5% of adults suffer from FA, some studies even report a prevalence over 10% (1,2).Patients diagnosed with IgE-mediated FA must adhere to strict dietary restrictions to avoid potential life-threatening anaphylactic reactions. Such restrictions are crucial but come with significant consequences as increased nutritional risks, higher costs for special meal preparations and medical care with potential social and psychological impacts on both the individual and their family (3-6). The impact of FA on quality of life is frequently surrounded by persistent fear of adverse reactions after consuming certain foods (3).To better manage FA, it is important to understand the reasons behind the exclusion of additional foods beyond the primary allergen. This study aims to explore whether patients with confirmed IgE-mediated FA tend to exclude other foods and to identify possible reasons for such exclusions.This is a cross-sectional analysis conducted at a tertiary referral outpatient setting in Brazil with patients from 2011 to 2022. Were considered as truly FA patients with: recurrent clinical history consistent with IgE-mediated reactions or anaphylaxis, associated with positive specific IgE or a positive oral challenge test with IgE-mediated reactions. Patients with anaphylaxis due to non-food allergens, mixed or non-IgE-mediated food allergies, or comorbidities requiring restrictive diets unrelated to IgE-mediated reactions were excluded.Out of 305 patients followed,180 met the inclusion criteria. Data on the epidemiology and allergens excluded were extracted from institutional electronic medical records, with supplementary data obtained through telephone interviews when necessary for questionnaire completion. The primary diagnosticated allergen was categorized as F1, while additional excluded foods were classified as F2. Descriptive statistical analyses were taken via SAS 9.4 software. Qualitative variables were reported as frequencies and percentages, and quantitative variables as means and standard deviations. The study was approved by the local Ethics Commitee (Comitê de ética do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - CAAE number: 77471224.7.0000.0068) and  all persons involved had provided their informed consent to be a part in the study.Most of the patients, predominantly male, were diagnosed with allergies before six months of age. The most common F1 was milk (77.78%), followed by egg (17.22%). Anaphylaxis was reported in 70.56% of the patients, with a complete F1 epidemiological profile seen in Table 1 and 2.Of the patients, 55% excluded at least one F2, with an average of 1.57 exclusions per patient, ranging from 1 to 12, and 14 detected F2s. The primary reasons for excluding additional foods were an isolated positive specific IgE test (32.24%), and symptoms attributed to foods without diagnostic confirmation (21.86%), as detailed in Table 3. This can be considered a  pioneer study in Latin America, as it examines FA within the dietary diversity of this population, and addresses the existence of other food exclusions.As supported by international literature (4), there was a high number of secondary exclusions in patients with IgE-mediated allergies. However, new foods are becoming significant on this list, such as fruits, abundant on the local diet.Milk and eggs are prevalent in Brazilian dietary guidelines, both as whole foods and in preparations since the start of complementary feeding (1,2), which explains why milk was the most described F1, followed by eggs, a widely consumed protein. Peanuts, a food strongly associated with FA in the Northern hemisphere, was less common among the studied population, as they are less used in daily local diet (1,2).Among children with secondary exclusions, the most frequent was eggs. In this context, excluding such a common food from the daily diet increases the risk of impacting nutritional development and quality of life, especially for children in growth and neuropsychomotor development stages. This highlights the importance of understanding the reasons for food exclusions in order to mitigate the risks, as well as the consequences, associated with their removal from the diet (1,3,5,6).Surprisingly, the primary cause of excluding a second food was not a second IgE-mediated allergy but rather the presence of laboratory tests without symptoms or symptoms without laboratory confirmation/criteria for IgE-mediated FA, emphasizing the importance of accurate diagnosis, avoiding misdiagnosis through indiscriminate requests for unproven diagnostic tests or specific IgEs, which can by itself lead to the development of an IgE-mediated FA upon reinsertion, as demonstrated studies involving patients with atopic dermatitis (1,9)Although fatal anaphylaxis is rare, around 30% of individuals with IgE-mediated FA seek emergency treatment for allergy-related reactions (4). This ongoing fear can prevent patients and their families from trying new foods (neophobia) and may result in a cycle of unnecessary food exclusions, which could further exacerbate nutritional deficiencies and contribute to the development of additional allergies. In fact  the combination of fear and indiscriminate specific IgE testing can pose a risk of misdiagnosis, highlighting the importance of knowledge of diagnostic and screening criteria to reduce the findings of sensitization in asymptomatic patients or those without compatible IgE-mediated reactions and unnecessary exclusions.Based on the profile of secondary exclusions, it is increasingly important for the medical community to be aware that there are no reasons to alter the age and pattern of complementary feeding introduction, with no restriction of potentially allergenic foods, preventing unnecessary food exclusions, increasing the risk of selective eating, and neophobia (1,2,3,6,8). In this study’s case, patients who started excluding foods based only on sensitization, might become truly allergic to those foods upon re-insertion, increasing the risk of FA in a potentially preventable manner.Only about 20% of patients were truly F2 allergic, also suggesting the possibility of associations among some allergies, more than just antigenic similarity, but also syndromic other phenotypes as multiple FA. This needs to be explored in future research, like the association between milk and eggs or eggs and nuts allergies. It is important to understand IgE-mediated symptoms and to recognize when to value symptoms arising from non-immunological situations, such as food contamination, viral urticaria, worsening of atopic dermatitis lesions, among others, due to the risk of incorrect diagnosis and unnecessary food exclusions (2,9).The study has also several limitations: it was conducted at a single center and relied mostly on secondary data, which may introduce bias and limit the generalizability of the findings. The sample was limited by convenience, and not all excluded foods were diagnostically tested via oral food challenges (gold standard).This study demonstrates that patients with IgE-mediated FA frequently exclude additional foods usually based on non-confirmatory tests and fear of reactions. Such practices can lead to unnecessary nutritional, social, and economic consequences. A comprehensive approach to FA management, incorporating accurate diagnostic methods and careful consideration of clinical history and test results, is crucial for improving patient outcomes and quality of life.Kind Regards,Paula Mendonça P.S Gomes-MD1, Isadora C.M. Francescantonio-MD1, Beni Morgenstern-MD,PHD1, Mayra B. Dorna-MD,PHD1, Antonio C. Pastorino-MD,PHD1, Ana Paula M Castro-MD,PHD1Affiliations: 1- Allergy and Immunology Department - Instituto da Criança- University of São Paulo, São Paulo, SP, BrazilConflict of interest: the authors have no conflict of interest to declareWord Count: 1173Keywords : Food-Allergies, IgE Mediated, motivation
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