# Shedding Light on FIRE Syndrome: An Overview of a Novel Condition in Eosinophilic Esophagitis
## 8 Conclusions and Future Directions  
FIRE syndrome represents a novel and distinct esophageal hypersensitivity reaction, proposed as a potential clinical phenotype within the eosinophil esophagitis spectrum. It is characterized by a rapid-onset, reproducible esophageal response, often manifesting as retrosternal discomfort or pain following specific trigger exposure. This distinct clinical presentation differentiates it from classical EoE or oral allergy syndrome. Given the limited number of cases reported so far, there is a lack of diagnostic criteria and optimal therapeutic approaches, which can contribute to misdiagnosis and suboptimal management of these patients, highlighting the need for greater awareness and research. This review reflects the current state of knowledge, which is limited by the small number and nature of the available studies included. The reports on FIRE syndrome, represented by only observational or descriptive studies and case reports, are subject to significant limitations, including selection bias, reporting bias, and lack of standardized \begin{table}
\begin{tabular}{c c c} \hline
**T**** therapy** & **Use in EoE** & **Use in FIRE Syndrome** \\ \hline Swallowed topical & & One case showed \\ corticosteroids & Effective & improvement; needs \\  & & further study \\ \hline Proton pump inhibitors & Used but not & No improvement reported; \\  & always effective & needs further study \\ \hline Antihistamines (H1R, H2R, & Potential use (H1R & Potential symptom relief; \\ H4R antagonists) & expression elevated in EoE) & needs further study \\ \hline Mast cell stabilizers & & Cromolyn showed no & Could reduce histamine, \\  (Cromolyn, Ketotifen) & benefit in pediatric EoE; & prostaglandin, and \\  & ketotifen helped & leukotriene release; needs \\  & EoGID patients & further study \\ \hline Leukotriene antagonist & & High doses showed & Could be useful; long-term \\  (Montelukast) & symptomatic improvement & effectiveness unclear; \\  & but no long-term benefit & needs further study \\ \hline Anti-IL4R and IL13R & & Effective, symptomatic, \\   therapy (Duplumab) & histopathologic, and & Could be beneficial by \\  & & histopathologic, and \\  & endoscopic benefit & needs further study \\ \hline Anti-IgE therapy & & Could help considering the \\  (Omalizumab) & No proven benefit & IgE-mediated mechanism; \\  & & needs further study \\ \hline Allergen immunotherapy (AIT) & EPIT showed potential & Hypothetical role (pollen \\  & benefit in reducing & AIT for plant-based \\  & eosinophil inflammation & triggers); needs \\  & & further study \\ \hline TRPV1 and ASIC blockers & & AMG-9810 reduced & Potential for pain relief; \\  & acid-induced responses in & limited clinical evidence; \\  & animal models & needs further study \\ \hline Mucosal protective agents & & Could improve mucosal \\  (Sucralfate, sodium & & barrier and symptom relief; \\   hyaluron, sodium & & needs further study \\   alginate) & & \\ \hline \end{tabular}
\end{table} 
Table 4: _Cont._diagnostic criteria or specific biomarkers. However, the evidence is valuable for hypothesis generation and clinical awareness. The conclusions drawn in this paper represent early-stage observations that require further validation. Well-designed prospective studies, such as controlled trials and mechanistic investigations, are needed to validate the proposed diagnostic algorithm and therapeutic strategies. Exploring the role of epithelial barrier disruption, local IgE-mediated pathways, mast cell-nerve interaction, and esophageal pain signaling might provide insights into the pathophysiology of FIRE syndrome while also marking the opportunity to advance knowledge regarding the immune processes in the esophagus. FIRE syndrome remains an underdiagnosed clinical syndrome while our knowledge is still limited. We wish to underscore the importance of increased awareness of this syndrome and to encourage other clinicians or researchers to publish their cases.