Shedding Light on FIRE Syndrome: An Overview of a Novel Condition in Eosinophilic Esophagitis
Abstract
:1. Introduction
2. Reported Cases of FIRE Syndrome: Insights from the Literature
2.1. Methods
2.2. The Main Characteristics of Reported Cases
3. Clinical Presentation of FIRE Syndrome
4. The Main Elicitors of FIRE Syndrome Symptoms
5. Diagnostic Criteria
6. Proposed Pathogenic Mechanisms
7. Potential Management Strategies and Challenges
7.1. Dietary Interventions
7.2. Pharmacologic Approaches Targeting Immediate Hypersensitivity
7.2.1. Histamine Receptor Antagonists
7.2.2. Mast-Cell-Targeted Therapies
7.3. Biologic Therapies
7.3.1. Anti-IL-4/IL-13 Therapy: Dupilumab
7.3.2. Anti-IgE Therapy: Omalizumab
7.4. Allergen Immunotherapy
7.5. Neuroimmune Modulators
7.6. Mucosal Protective and Barrier-Enhancing Agents
Therapy | Use in EoE | Use in FIRE Syndrome |
---|---|---|
Dietary elimination | Effective (6-, 4-, 2-, or 1-food elimination diet, or elemental diet) | Main strategy |
Swallowed topical corticosteroids | Effective | One case showed improvement; needs further study |
Proton pump inhibitors | Used but not always effective | No improvement reported; needs further study |
Antihistamines (H1R, H2R, H4R antagonists) | Potential use (H1R expression elevated in EoE) | Potential symptom relief; needs further study |
Mast cell stabilizers (Cromolyn, Ketotifen) | Cromolyn showed no benefit in pediatric EoE; ketotifen helped EoGID patients | Could reduce histamine, prostaglandin, and leukotriene release; needs further study |
Leukotriene antagonist (Montelukast) | High doses showed symptomatic improvement but no long-term benefit | Could be useful; long-term effectiveness unclear; needs further study |
Anti-IL4R and IL13R therapy (Dupilumab) | Effective, symptomatic, histopathologic, and endoscopic benefit | Could be beneficial by reducing T2 inflammation; needs further study |
Anti-IgE therapy (Omalizumab) | No proven benefit | Could help considering the IgE-mediated mechanism; needs further study |
Allergen immunotherapy (AIT) | EPIT showed potential benefit in reducing eosinophilic inflammation | Hypothetical role (pollen AIT for plant-based triggers); needs further study |
TRPV1 and ASIC blockers | AMG-9810 reduced acid-induced responses in animal models | Potential for pain relief; limited clinical evidence; needs further study |
Mucosal protective agents (Sucralfate, sodium hyaluronate, sodium alginate) | Under investigation | Could improve mucosal barrier and symptom relief; needs further study |
8. Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AID | Activation-induced cytidine deaminase |
AIT | Allergen immunotherapy |
AR | Allergic rhinitis |
ASICs | Acid-sensing ion channels |
ATP | Adenosine triphosphate |
CD40L | CD40 ligand |
CGRP | Calcitonin gene-related peptide |
CSs | Corticosteroids |
CSR | Class switch recombination |
EGIDs | Eosinophilic gastrointestinal diseases |
EoE | Eosinophilic esophagitis |
EPIT | Epicutaneous immunotherapy |
EPT | Esophageal prick tests |
FIRE | Food-Induced Immediate Response of the Esophagus |
GERD | Gastroesophageal reflux disease |
GITRL | Glucocorticoid-induced tumor-necrosis-factor-receptor-related protein ligand |
GLTs | Germline transcripts |
HPF | High-power field |
HR | Histamine receptor |
IgE | Immunoglobulin E |
IL | Interleukin |
ILC2s | Type 2 innate lymphoid cells |
MeSH | Medical Subject Heading |
MHC II | Major Histocompatibility Complex Class II |
mRNA | Messenger Ribonucleic Acid |
OIT | Oral immunotherapy |
PAMPs | Pathogen-associated molecular patterns |
PFAS | Pollen-food allergy syndrome |
PPIs | Proton pump inhibitors |
sIgE | Specific immunoglobulin E |
SPINK 7 | Serine Peptidase Inhibitor Kazal Type 7 |
SPT | Skin prick test |
TCR | T cell receptor |
TRPV1 | Transient receptor potential vanilloid 1 |
TSLP | Thymic stromal-derived lymphopoietin |
VAS | Visual analog scale |
References
- Hill, D.A.; Grundmeier, R.W.; Ramos, M.; Spergel, J.M. Eosinophilic Esophagitis Is a Late Manifestation of the Allergic March. J. Allergy Clin. Immunol. Pract. 2018, 6, 1528–1533. [Google Scholar] [CrossRef] [PubMed]
- Dellon, E.S.; Liacouras, C.A.; Molina-Infante, J.; Furuta, G.T.; Spergel, J.M.; Zevit, N.; Spechler, S.J.; Attwood, S.E.; Straumann, A.; Aceves, S.S.; et al. Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis: Proceedings of the AGREE Conference. Gastroenterology 2018, 155, 1022–1033.e10. [Google Scholar] [CrossRef] [PubMed]
- Biller, J.A.; Winter, H.S.; Grand, R.J.; Allred, E.N. Are Endoscopic Changes Predictive of Histologic Esophagitis in Children? J. Pediatr. 1983, 103, 215–218. [Google Scholar] [CrossRef] [PubMed]
- Attwood, S.E.A.; Smyrk, T.C.; Demeester, T.R.; Jones, J.B. Esophageal Eosinophilia with Dysphagia: A Distinct Clinicopathologic Syndrome. Dig. Dis. Sci. 1993, 38, 109–116. [Google Scholar] [CrossRef]
- Straumann, A.; Schoepfer, A. Update on Basic and Clinical Aspects of Eosinophilic Oesophagitis. Gut 2014, 63, 1355–1363. [Google Scholar] [CrossRef]
- Navarro, P.; Arias, Á.; Arias-González, L.; Laserna-Mendieta, E.J.; Ruiz-Ponce, M.; Lucendo, A.J. Systematic Review with Meta-analysis: The Growing Incidence and Prevalence of Eosinophilic Oesophagitis in Children and Adults in Population-based Studies. Aliment. Pharmacol. Ther. 2019, 49, 1116–1125. [Google Scholar] [CrossRef]
- Thomsen, S.F. Epidemiology and Natural History of Atopic Diseases. Eur. Clin. Respir. J. 2015, 2, 24642. [Google Scholar] [CrossRef]
- Muir, A.; Falk, G.W. Eosinophilic Esophagitis: A Review. JAMA 2021, 326, 1310. [Google Scholar] [CrossRef]
- Barni, S.; Arasi, S.; Mastrorilli, C.; Pecoraro, L.; Giovannini, M.; Mori, F.; Liotti, L.; Saretta, F.; Castagnoli, R.; Caminiti, L.; et al. Pediatric Eosinophilic Esophagitis: A Review for the Clinician. Ital. J. Pediatr. 2021, 47, 230. [Google Scholar] [CrossRef]
- Ruano-Zaragoza, M.; Hill, S.; Nurmatov, U.; Reese, I.; Vieira, M.C.; Dupont, C.; Venter, C.; Walsh, J.; Yonamine, G.; Beauregard, A.; et al. Systematic Review of Feeding Difficulties in Children with Eosinophilic Esophagitis: An EAACI Task Force Report. Pediatr. Allergy Immunol. 2025, 36, e70087. [Google Scholar] [CrossRef]
- Chen, J.W.; Kao, J.Y. Eosinophilic Esophagitis: Update on Management and Controversies. BMJ 2017, 359, j4482. [Google Scholar] [CrossRef] [PubMed]
- Votto, M.; Castagnoli, R.; De Filippo, M.; Brambilla, I.; Cuppari, C.; Marseglia, G.L.; Licari, A. Behavioral Issues and Quality of Life in Children with Eosinophilic Esophagitis. Minerva Pediatr. 2020, 72, 424–432. [Google Scholar] [CrossRef] [PubMed]
- Schoepfer, A.M.; Safroneeva, E.; Bussmann, C.; Kuchen, T.; Portmann, S.; Simon, H.; Straumann, A. Delay in Diagnosis of Eosinophilic Esophagitis Increases Risk for Stricture Formation in a Time-Dependent Manner. Gastroenterology 2013, 145, 1230–1236.e2. [Google Scholar] [CrossRef] [PubMed]
- Murray, F.R.; Kreienbuehl, A.S.; Greuter, T.; Nennstiel, S.; Safroneeva, E.; Saner, C.; Schindler, V.; Schlag, C.; Schoepfer, A.M.; Schreiner, P.; et al. Diagnostic Delay in Patients with Eosinophilic Esophagitis Has Not Changed Since the First Description 30 Years Ago: Diagnostic Delay in Eosinophilic Esophagitis. Am. J. Gastroenterol. 2022, 117, 1772–1779. [Google Scholar] [CrossRef]
- Warners, M.J.; Van Rhijn, B.D.; Verheij, J.; Smout, A.J.P.M.; Bredenoord, A.J. Disease Activity in Eosinophilic Esophagitis Is Associated with Impaired Esophageal Barrier Integrity. Am. J. Physiol.-Gastrointest. Liver Physiol. 2017, 313, G230–G238. [Google Scholar] [CrossRef]
- Biedermann, L.; Holbreich, M.; Atkins, D.; Chehade, M.; Dellon, E.S.; Furuta, G.T.; Hirano, I.; Gonsalves, N.; Greuter, T.; Gupta, S.; et al. Food-induced Immediate Response of the Esophagus—A Newly Identified Syndrome in Patients with Eosinophilic Esophagitis. Allergy 2021, 76, 339–347. [Google Scholar] [CrossRef]
- Holbreich, M.; Straumann, A. Features of Food-Induced Immediate Response in the Esophagus (FIRE) in a Series of Adult Patients with Eosinophilic Esophagitis. Allergy 2021, 76, 2893–2895. [Google Scholar] [CrossRef]
- Votto, M.; Naso, M.; De Filippo, M.; Marseglia, A.; Raffaele, A.; Marseglia, G.L.; Licari, A. Food-induced Immediate Response of the Esophagus: A First Report in the Pediatric Age. Allergy 2022, 77, 711–712. [Google Scholar] [CrossRef]
- Koken, G.; Ertoy Karagol, H.I.; Polat Terece, S.; Cavdar, Z.; Cetin, K.; Egritas Gurkan, O.; Sari, S.; Dalgic, B.; Bakirtas, A. Food-Induced Immediate Response of the Esophagus in Pediatric Eosinophilic Esophagitis. Allergy 2023, 78, 3235–3240. [Google Scholar] [CrossRef]
- Williamson, P.; Aceves, S. Allergies and Eosinophilic Esophagitis—Current Updates for the Pediatric Gastroenterologist. Curr. Gastroenterol. Rep. 2019, 21, 56. [Google Scholar] [CrossRef]
- Capucilli, P.; Cianferoni, A.; Grundmeier, R.W.; Spergel, J.M. Comparison of Comorbid Diagnoses in Children with and Without Eosinophilic Esophagitis in a Large Population. Ann. Allergy Asthma. Immunol. 2018, 121, 711–716. [Google Scholar] [CrossRef] [PubMed]
- Visaggi, P.; Savarino, E.; Sciume, G.; Chio, T.D.; Bronzini, F.; Tolone, S.; Frazzoni, M.; Pugno, C.; Ghisa, M.; Bertani, L.; et al. Eosinophilic Esophagitis: Clinical, Endoscopic, Histologic and Therapeutic Differences and Similarities between Children and Adults. Ther. Adv. Gastroenterol. 2021, 14, 1756284820980860. [Google Scholar] [CrossRef] [PubMed]
- Poncet, P.; Sénéchal, H.; Charpin, D. Update on Pollen-Food Allergy Syndrome. Expert Rev. Clin. Immunol. 2020, 16, 561–578. [Google Scholar] [CrossRef] [PubMed]
- Attwood, S.; Epstein, J. Eosinophilic Oesophagitis: Recent Advances and Practical Management. Frontline Gastroenterol. 2021, 12, 644–649. [Google Scholar] [CrossRef]
- Yapar, D.; Karagol, H.I.E.; Terece, S.P.; Duztas, D.T.; Gurkan, O.E.; Sari, S.; Dalgic, B.; Bakirtas, A. A Novel Pediatric Eosinophilic Esophagitis Symptoms and Adaptive Behavior Scale for Different Ages: GaziESAS v2.0. Pediatr. Allergy Immunol. 2023, 34, e13974. [Google Scholar] [CrossRef]
- Letner, D.; Farris, A.; Khalili, H.; Garber, J. Pollen-Food Allergy Syndrome Is a Common Allergic Comorbidity in Adults with Eosinophilic Esophagitis. Dis. Esophagus 2018, 31, dox122. [Google Scholar] [CrossRef]
- Al-Shaikhly, T.; Cox, A.; Nowak-Wegrzyn, A.; Cianferoni, A.; Katelaris, C.; Ebo, D.G.; Konstantinou, G.N.; Brucker, H.; Yang, H.-J.; Protudjer, J.L.P.; et al. An International Delphi Consensus on the Management of Pollen-Food Allergy Syndrome: A Work Group Report of the AAAAI Adverse Reactions to Foods Committee. J. Allergy Clin. Immunol. Pract. 2024, 12, 3242–3249.e1. [Google Scholar] [CrossRef]
- Burk, C.M.; Shreffler, W.G. Triggers for Eosinophilic Esophagitis (EoE): The Intersection of Food Allergy and EoE. J. Allergy Clin. Immunol. 2024, 153, 1500–1509. [Google Scholar] [CrossRef]
- Spergel, J.M.; Brown-Whitehorn, T.F.; Cianferoni, A.; Shuker, M.; Wang, M.-L.; Verma, R.; Liacouras, C.A. Identification of Causative Foods in Children with Eosinophilic Esophagitis Treated with an Elimination Diet. J. Allergy Clin. Immunol. 2012, 130, 461–467.e5. [Google Scholar] [CrossRef]
- Spergel, J.; Aceves, S.S. Allergic Components of Eosinophilic Esophagitis. J. Allergy Clin. Immunol. 2018, 142, 1–8. [Google Scholar] [CrossRef]
- Lucendo, A.J.; Arias, Á.; González-Cervera, J.; Yagüe-Compadre, J.L.; Guagnozzi, D.; Angueira, T.; Jiménez-Contreras, S.; González-Castillo, S.; Rodríguez-Domíngez, B.; De Rezende, L.C.; et al. Empiric 6-Food Elimination Diet Induced and Maintained Prolonged Remission in Patients with Adult Eosinophilic Esophagitis: A Prospective Study on the Food Cause of the Disease. J. Allergy Clin. Immunol. 2013, 131, 797–804. [Google Scholar] [CrossRef] [PubMed]
- Kennedy, K.V.; Umeweni, C.N.; Alston, M.; Dolinsky, L.; McCormack, S.M.; Taylor, L.A.; Bendavid, A.; Benitez, A.; Mitchel, E.; Karakasheva, T.; et al. Esophageal Remodeling Correlates with Eating Behaviors in Pediatric Eosinophilic Esophagitis. Am. J. Gastroenterol. 2024, 119, 1167–1176. [Google Scholar] [CrossRef] [PubMed]
- Kaymak, T.; Hruz, P.; Niess, J.H. Immune System and Microbiome in the Esophagus: Implications for Understanding Inflammatory Diseases. FEBS J. 2022, 289, 4758–4772. [Google Scholar] [CrossRef] [PubMed]
- Fortea, M.; Hacour, L.; Sancho, F.; Boada, C.; Sevillano-Aguilera, C.; González-Castro, A.M.; Salvo-Romero, E.; Lobo, B.; Guagnozzi, D.; Ceulemans, L.J.; et al. Characterization of Immune Cell Populations and Acid-Sensing Receptors in the Human Esophagus. Gastroenterol. Insights 2024, 15, 819–834. [Google Scholar] [CrossRef]
- Mastracci, L.; Bruzzone, M.; Pacella, E.; Tinelli, C.; Zentilin, P.; Savarino, E.; De Silvestri, A.; Fiocca, R.; Grillo, F. The Contribution of Intraepithelial Inflammatory Cells to the Histological Diagnosis of Microscopic Esophagitis. Esophagus 2016, 13, 80–87. [Google Scholar] [CrossRef]
- Cipriani, G.; Gibbons, S.J.; Kashyap, P.C.; Farrugia, G. Intrinsic Gastrointestinal Macrophages: Their Phenotype and Role in Gastrointestinal Motility. Cell. Mol. Gastroenterol. Hepatol. 2016, 2, 120–130.e1. [Google Scholar] [CrossRef]
- Underwood, B.; Troutman, T.D.; Schwartz, J.T. Breaking down the Complex Pathophysiology of Eosinophilic Esophagitis. Ann. Allergy Asthma. Immunol. 2023, 130, 28–39. [Google Scholar] [CrossRef]
- Lucendo, A.J.; Navarro, M.; Comas, C.; Pascual, J.M.; Burgos, E.; Santamaría, L.; Larrauri, J. Immunophenotypic Characterization and Quantification of the Epithelial Inflammatory Infiltrate in Eosinophilic Esophagitis Through Stereology: An Analysis of the Cellular Mechanisms of the Disease and the Immunologic Capacity of the Esophagus. Am. J. Surg. Pathol. 2007, 31, 598–606. [Google Scholar] [CrossRef]
- Vicario, M.; Blanchard, C.; Stringer, K.F.; Collins, M.H.; Mingler, M.K.; Ahrens, A.; Putnam, P.E.; Abonia, J.P.; Santos, J.; Rothenberg, M.E. Local B Cells and IgE Production in the Oesophageal Mucosa in Eosinophilic Oesophagitis. Gut 2010, 59, 12–20. [Google Scholar] [CrossRef]
- Mishra, A.; Schlotman, J.; Wang, M.; Rothenberg, M.E. Critical Role for Adaptive T Cell Immunity in Experimental Eosinophilic Esophagitis in Mice. J. Leukoc. Biol. 2007, 81, 916–924. [Google Scholar] [CrossRef]
- Stavnezer, J.; Schrader, C.E. IgH Chain Class Switch Recombination: Mechanism and Regulation. J. Immunol. 2014, 193, 5370–5378. [Google Scholar] [CrossRef] [PubMed]
- Blanchard, C.; Mingler, M.K.; Vicario, M.; Abonia, J.P.; Wu, Y.Y.; Lu, T.X.; Collins, M.H.; Putnam, P.E.; Wells, S.I.; Rothenberg, M.E. IL-13 Involvement in Eosinophilic Esophagitis: Transcriptome Analysis and Reversibility with Glucocorticoids. J. Allergy Clin. Immunol. 2007, 120, 1292–1300. [Google Scholar] [CrossRef]
- Stavnezer, J.; Guikema, J.E.J.; Schrader, C.E. Mechanism and Regulation of Class Switch Recombination. Annu. Rev. Immunol. 2008, 26, 261–292. [Google Scholar] [CrossRef] [PubMed]
- Takhar, P.; Corrigan, C.J.; Smurthwaite, L.; O’Connor, B.J.; Durham, S.R.; Lee, T.H.; Gould, H.J. Class Switch Recombination to IgE in the Bronchial Mucosa of Atopic and Nonatopic Patients with Asthma. J. Allergy Clin. Immunol. 2007, 119, 213–218. [Google Scholar] [CrossRef]
- Fagarasan, S.; Muramatsu, M.; Suzuki, K.; Nagaoka, H.; Hiai, H.; Honjo, T. Critical Roles of Activation-Induced Cytidine Deaminase in the Homeostasis of Gut Flora. Science 2002, 298, 1424–1427. [Google Scholar] [CrossRef] [PubMed]
- Takhar, P.; Smurthwaite, L.; Coker, H.A.; Fear, D.J.; Banfield, G.K.; Carr, V.A.; Durham, S.R.; Gould, H.J. Allergen Drives Class Switching to IgE in the Nasal Mucosa in Allergic Rhinitis. J. Immunol. 2005, 174, 5024–5032. [Google Scholar] [CrossRef]
- Warners, M.J.; Terreehorst, I.; Van Den Wijngaard, R.M.; Akkerdaas, J.; Van Esch, B.C.A.M.; Van Ree, R.; Versteeg, S.A.; Smout, A.J.P.M.; Bredenoord, A.J. Abnormal Responses to Local Esophageal Food Allergen Injections in Adult Patients with Eosinophilic Esophagitis. Gastroenterology 2018, 154, 57–60.e2. [Google Scholar] [CrossRef]
- Kleuskens, M.T.A.; Haasnoot, M.L.; Garssen, J.; Bredenoord, A.J.; Van Esch, B.C.A.M.; Redegeld, F.A. Transcriptomic Profiling of the Acute Mucosal Response to Local Food Injections in Adults with Eosinophilic Esophagitis. J. Allergy Clin. Immunol. 2024, 153, 780–792. [Google Scholar] [CrossRef]
- Byrne, A.M.; Goleva, E.; Chouiali, F.; Kaplan, M.H.; Hamid, Q.A.; Leung, D.Y.M. Induction of GITRL Expression in Human Keratinocytes by T H2 Cytokines and TNF-α: Implications for Atopic Dermatitis. Clin. Exp. Allergy 2012, 42, 550–559. [Google Scholar] [CrossRef]
- Wang, Y.; Liu, B.; Niu, C.; Zou, W.; Yang, L.; Wang, T.; Tian, D.; Luo, Z.; Dai, J.; Li, Q.; et al. Blockade of GITRL/GITR Signaling Pathway Attenuates House Dust Mite-Induced Allergic Asthma in Mice through Inhibition of MAPKs and NF-κB Signaling. Mol. Immunol. 2021, 137, 238–246. [Google Scholar] [CrossRef]
- Simon, D.; Radonjic-Hösli, S.; Straumann, A.; Yousefi, S.; Simon, H.-U. Active Eosinophilic Esophagitis Is Characterized by Epithelial Barrier Defects and Eosinophil Extracellular Trap Formation. Allergy 2015, 70, 443–452. [Google Scholar] [CrossRef] [PubMed]
- Kleuskens, M.T.A.; Bek, M.K.; Al Halabi, Y.; Blokhuis, B.R.J.; Diks, M.A.P.; Haasnoot, M.L.; Garssen, J.; Bredenoord, A.J.; van Esch, B.C.A.M.; Redegeld, F.A. Mast Cells Disrupt the Function of the Esophageal Epithelial Barrier. Mucosal Immunol. 2023, 16, 567–577. [Google Scholar] [CrossRef] [PubMed]
- Lowry, M.A.; Vaezi, M.F.; Correa, H.; Higginbotham, T.; Slaughter, J.C.; Acra, S. Mucosal Impedance Measurements Differentiate Pediatric Patients with Active Versus Inactive Eosinophilic Esophagitis. J. Pediatr. Gastroenterol. Nutr. 2018, 67, 198–203. [Google Scholar] [CrossRef] [PubMed]
- Katzka, D.A.; Tadi, R.; Smyrk, T.C.; Katarya, E.; Sharma, A.; Geno, D.M.; Camilleri, M.; Iyer, P.G.; Alexander, J.A.; Buttar, N.S. Effects of Topical Steroids on Tight Junction Proteins and Spongiosis in Esophageal Epithelia of Patients with Eosinophilic Esophagitis. Clin. Gastroenterol. Hepatol. 2014, 12, 1824–1829.e1. [Google Scholar] [CrossRef]
- Marietta, E.V.; Geno, D.M.; Smyrk, T.C.; Becker, A.; Alexander, J.A.; Camilleri, M.; Murray, J.A.; Katzka, D.A. Presence of Intraepithelial Food Antigen in Patients with Active Eosinophilic Oesophagitis. Aliment. Pharmacol. Ther. 2017, 45, 427–433. [Google Scholar] [CrossRef]
- Ravi, A.; Marietta, E.V.; Geno, D.M.; Alexander, J.A.; Murray, J.A.; Katzka, D.A. Penetration of the Esophageal Epithelium by Dust Mite Antigen in Patients with Eosinophilic Esophagitis. Gastroenterology 2019, 157, 255–256. [Google Scholar] [CrossRef]
- Reithofer, M.; Jahn-Schmid, B. Allergens with Protease Activity from House Dust Mites. Int. J. Mol. Sci. 2017, 18, 1368. [Google Scholar] [CrossRef]
- Angerami Almeida, K.; De Queiroz Andrade, E.; Burns, G.; Hoedt, E.C.; Mattes, J.; Keely, S.; Collison, A. The Microbiota in Eosinophilic Esophagitis: A Systematic Review. J. Gastroenterol. Hepatol. 2022, 37, 1673–1684. [Google Scholar] [CrossRef]
- Chen, S.; Jiang, D.; Zhuang, Q.; Hou, X.; Jia, X.; Chen, J.; Lin, H.; Zhang, M.; Tan, N.; Xiao, Y. Esophageal Microbial Dysbiosis Impairs Mucosal Barrier Integrity via Toll-like Receptor 2 Pathway in Patients with Gastroesophageal Reflux Symptoms. J. Transl. Med. 2024, 22, 1145. [Google Scholar] [CrossRef]
- Aceves, S.S. Local Antigen Deposition in Eosinophilic Esophagitis: Implications for Immune Activation. Gastroenterology 2019, 157, 17–20. [Google Scholar] [CrossRef]
- Doherty, T.A.; Baum, R.; Newbury, R.O.; Yang, T.; Dohil, R.; Aquino, M.; Doshi, A.; Walford, H.H.; Kurten, R.C.; Broide, D.H.; et al. Group 2 Innate Lymphocytes (ILC2) Are Enriched in Active Eosinophilic Esophagitis. J. Allergy Clin. Immunol. 2015, 136, 792–794.e3. [Google Scholar] [CrossRef] [PubMed]
- Doshi, A.; Khamishon, R.; Rawson, R.; Duong, L.; Dohil, L.; Myers, S.J.; Bell, B.; Dohil, R.; Newbury, R.O.; Barrett, K.E.; et al. Interleukin 9 Alters Epithelial Barrier and E-cadherin in Eosinophilic Esophagitis. J. Pediatr. Gastroenterol. Nutr. 2019, 68, 225–231. [Google Scholar] [CrossRef] [PubMed]
- Kirsch, R.; Bokhary, R.; Marcon, M.A.; Cutz, E. Activated Mucosal Mast Cells Differentiate Eosinophilic (Allergic) Esophagitis from Gastroesophageal Reflux Disease. J. Pediatr. Gastroenterol. Nutr. 2007, 44, 20–26. [Google Scholar] [CrossRef] [PubMed]
- Bolton, S.M.; Kagalwalla, A.F.; Arva, N.C.; Wang, M.-Y.; Amsden, K.; Melin-Aldana, H.; Dellon, E.S.; Bryce, P.J.; Wershil, B.K.; Wechsler, J.B. Mast Cell Infiltration Is Associated with Persistent Symptoms and Endoscopic Abnormalities Despite Resolution of Eosinophilia in Pediatric Eosinophilic Esophagitis. Am. J. Gastroenterol. 2020, 115, 224–233. [Google Scholar] [CrossRef]
- Nelson, M.; Zhang, X.; Pan, Z.; Spechler, S.J.; Souza, R.F. Mast Cell Effects on Esophageal Smooth Muscle and Their Potential Role in Eosinophilic Esophagitis and Achalasia. Am. J. Physiol.-Gastrointest. Liver Physiol. 2021, 320, G319–G327. [Google Scholar] [CrossRef]
- Elieh Ali Komi, D.; Wöhrl, S.; Bielory, L. Mast Cell Biology at Molecular Level: A Comprehensive Review. Clin. Rev. Allergy Immunol. 2020, 58, 342–365. [Google Scholar] [CrossRef]
- Zhang, S.; Shoda, T.; Aceves, S.S.; Arva, N.C.; Chehade, M.; Collins, M.H.; Dellon, E.S.; Falk, G.W.; Gonsalves, N.; Gupta, S.K.; et al. Mast Cell-pain Connection in Eosinophilic Esophagitis. Allergy 2022, 77, 1895–1899. [Google Scholar] [CrossRef]
- Otani, I.M.; Anilkumar, A.A.; Newbury, R.O.; Bhagat, M.; Beppu, L.Y.; Dohil, R.; Broide, D.H.; Aceves, S.S. Anti–IL-5 Therapy Reduces Mast Cell and IL-9 Cell Numbers in Pediatric Patients with Eosinophilic Esophagitis. J. Allergy Clin. Immunol. 2013, 131, 1576–1582.e2. [Google Scholar] [CrossRef]
- Dusenkova, S.; Ru, F.; Surdenikova, L.; Nassenstein, C.; Hatok, J.; Dusenka, R.; Banovcin, P.; Kliment, J.; Tatar, M.; Kollarik, M. The Expression Profile of Acid-Sensing Ion Channel (ASIC) Subunits ASIC1a, ASIC1b, ASIC2a, ASIC2b, and ASIC3 in the Esophageal Vagal Afferent Nerve Subtypes. Am. J. Physiol.-Gastrointest. Liver Physiol. 2014, 307, G922–G930. [Google Scholar] [CrossRef]
- Yu, S.; Kollarik, M.; Ouyang, A.; Myers, A.C.; Undem, B.J. Mast Cell-Mediated Long-Lasting Increases in Excitability of Vagal C Fibers in Guinea Pig Esophagus. Am. J. Physiol.-Gastrointest. Liver Physiol. 2007, 293, G850–G856. [Google Scholar] [CrossRef]
- Hu, Y.; Liu, Z.; Yu, X.; Pasricha, P.J.; Undem, B.J.; Yu, S. Increased Acid Responsiveness in Vagal Sensory Neurons in a Guinea Pig Model of Eosinophilic Esophagitis. Am. J. Physiol.-Gastrointest. Liver Physiol. 2014, 307, G149–G157. [Google Scholar] [CrossRef] [PubMed]
- Wu, L.; Oshima, T.; Shan, J.; Sei, H.; Tomita, T.; Ohda, Y.; Fukui, H.; Watari, J.; Miwa, H. PAR-2 Activation Enhances Weak Acid-Induced ATP Release through TRPV1 and ASIC Sensitization in Human Esophageal Epithelial Cells. Am. J. Physiol.-Gastrointest. Liver Physiol. 2015, 309, G695–G702. [Google Scholar] [CrossRef] [PubMed]
- Yu, M.; Chang, C.; Undem, B.J.; Yu, S. Capsaicin-Sensitive Vagal Afferent Nerve-Mediated Interoceptive Signals in the Esophagus. Molecules 2021, 26, 3929. [Google Scholar] [CrossRef] [PubMed]
- Krarup, A.L.; Villadsen, G.E.; Mejlgaard, E.; Olesen, S.S.; Drewes, A.M.; Funch-Jensen, P. Acid Hypersensitivity in Patients with Eosinophilic Oesophagitis. Scand. J. Gastroenterol. 2010, 45, 273–281. [Google Scholar] [CrossRef]
- Han, X.; Zhang, Y.; Lee, A.; Li, Z.; Gao, J.; Wu, X.; Zhao, J.; Wang, H.; Chen, D.; Zou, D.; et al. Upregulation of Acid Sensing Ion Channels Is Associated with Esophageal Hypersensitivity in GERD. FASEB J. 2022, 36, e22083. [Google Scholar] [CrossRef]
- Ferreira, C.T.; Vieira, M.C.; Furuta, G.T.; Barros, F.C.L.F.D.; Chehade, M. Eosinophilic Esophagitis—Where Are We Today? J. Pediatr. 2019, 95, 275–281. [Google Scholar] [CrossRef]
- Kotchetkoff, E.C.D.A.; De Oliveira, L.C.L.; Sarni, R.O.S. Elimination Diet in Food Allergy: Friend or Foe? J. Pediatr. 2024, 100, S65–S73. [Google Scholar] [CrossRef]
- Merves, J.; Chandramouleeswaran, P.M.; Benitez, A.J.; Muir, A.B.; Lee, A.J.; Lim, D.M.; Dods, K.; Mehta, I.; Ruchelli, E.D.; Nakagawa, H.; et al. Altered Esophageal Histamine Receptor Expression in Eosinophilic Esophagitis (EoE): Implications on Disease Pathogenesis. PLoS ONE 2015, 10, e0114831. [Google Scholar] [CrossRef]
- Papadopoulou, A.; Amil-Dias, J.; Auth, M.K.; Chehade, M.; Collins, M.H.; Gupta, S.K.; Gutiérrez-Junquera, C.; Orel, R.; Vieira, M.C.; Zevit, N.; et al. Joint ESPGHAN/NASPGHAN Guidelines on Childhood Eosinophilic Gastrointestinal Disorders Beyond Eosinophilic Esophagitis. J. Pediatr. Gastroenterol. Nutr. 2024, 78, 122–152. [Google Scholar] [CrossRef]
- Tefferi, A.; Pardanani, A. Systemic Mastocytosis: Current Concepts and Treatment Advances. Curr. Hematol. Rep. 2004, 3, 197–202. [Google Scholar]
- Sinniah, A.; Yazid, S.; Flower, R.J. The Anti-Allergic Cromones: Past, Present, and Future. Front. Pharmacol. 2017, 8, 827. [Google Scholar] [CrossRef] [PubMed]
- Lieberman, J.A.; Zhang, J.; Whitworth, J.; Cavender, C. A Randomized, Double-Blinded, Placebo-Controlled Study of the Use of Viscous Oral Cromolyn Sodium for the Treatment of Eosinophilic Esophagitis. Ann. Allergy. Asthma. Immunol. 2018, 120, 527–531. [Google Scholar] [CrossRef] [PubMed]
- Silva, F.M.D.C.E.; De Oliveira, E.E.; Ambrósio, M.G.E.; Ayupe, M.C.; De Souza, V.P.; Menegati, L.M.; Reis, D.R.D.L.; Machado, M.A.; Macedo, G.C.; Ferreira, A.P. Disodium Cromoglycate Treatment Reduces TH2 Immune Response and Immunohistopathological Features in a Murine Model of Eosinophilic Esophagitis. Int. Immunopharmacol. 2020, 83, 106422. [Google Scholar] [CrossRef]
- Suzuki, J.; Kawasaki, Y.; Nozawa, R.; Isome, M.; Suzuki, S.; Takahashi, A.; Suzuki, H. Oral Disodium Cromoglycate and Ketotifen for a Patient with Eosinophilic Gastroenteritis, Food Allergy and Protein-Losing Enteropathy. Asian Pac. J. Allergy Immunol. 2003, 21, 193–197. [Google Scholar] [PubMed]
- Attwood, S.E.A. Eosinophilic Oesophagitis: A Novel Treatment Using Montelukast. Gut 2003, 52, 181–185. [Google Scholar] [CrossRef]
- Alexander, J.A.; Ravi, K.; Enders, F.T.; Geno, D.M.; Kryzer, L.A.; Mara, K.C.; Smyrk, T.C.; Katzka, D.A. Montelukast Does Not Maintain Symptom Remission After Topical Steroid Therapy for Eosinophilic Esophagitis. Clin. Gastroenterol. Hepatol. 2017, 15, 214–221.e2. [Google Scholar] [CrossRef]
- McLeod, J.J.A.; Baker, B.; Ryan, J.J. Mast Cell Production and Response to IL-4 and IL-13. Cytokine 2015, 75, 57–61. [Google Scholar] [CrossRef]
- Sindher, S.B.; Barshow, S.; Tirumalasetty, J.; Arasi, S.; Atkins, D.; Bauer, M.; Bégin, P.; Collins, M.H.; Deschildre, A.; Doyle, A.D.; et al. The Role of Biologics in Pediatric Food Allergy and Eosinophilic Gastrointestinal Disorders. J. Allergy Clin. Immunol. 2023, 151, 595–606. [Google Scholar] [CrossRef]
- Dellon, E.S.; Rothenberg, M.E.; Collins, M.H.; Hirano, I.; Chehade, M.; Bredenoord, A.J.; Lucendo, A.J.; Spergel, J.M.; Aceves, S.; Sun, X.; et al. Dupilumab in Adults and Adolescents with Eosinophilic Esophagitis. N. Engl. J. Med. 2022, 387, 2317–2330. [Google Scholar] [CrossRef]
- Shirley, M. Dupilumab: First Global Approval. Drugs 2017, 77, 1115–1121. [Google Scholar] [CrossRef]
- Burchett, J.R.; Dailey, J.M.; Kee, S.A.; Pryor, D.T.; Kotha, A.; Kankaria, R.A.; Straus, D.B.; Ryan, J.J. Targeting Mast Cells in Allergic Disease: Current Therapies and Drug Repurposing. Cells 2022, 11, 3031. [Google Scholar] [CrossRef] [PubMed]
- Wedi, B.; Traidl, S. Anti-IgE for the Treatment of Chronic Urticaria. ImmunoTargets Ther. 2021, 10, 27–45. [Google Scholar] [CrossRef] [PubMed]
- Agache, I.; Rocha, C.; Pereira, A.; Song, Y.; Alonso-Coello, P.; Solà, I.; Beltran, J.; Posso, M.; Akdis, C.A.; Akdis, M.; et al. Efficacy and Safety of Treatment with Omalizumab for Chronic Spontaneous Urticaria: A Systematic Review for the EAACI Biologicals Guidelines. Allergy 2021, 76, 59–70. [Google Scholar] [CrossRef] [PubMed]
- Riggioni, C.; Oton, T.; Carmona, L.; Du Toit, G.; Skypala, I.; Santos, A.F. Immunotherapy and Biologics in the Management of IgE-mediated Food Allergy: Systematic Review and Meta-analyses of Efficacy and Safety. Allergy 2024, 79, 2097–2127. [Google Scholar] [CrossRef]
- Zuberbier, T.; Wood, R.A.; Bindslev-Jensen, C.; Fiocchi, A.; Chinthrajah, R.S.; Worm, M.; Deschildre, A.; Fernandez-Rivas, M.; Santos, A.F.; Jaumont, X.; et al. Omalizumab in IgE-Mediated Food Allergy: A Systematic Review and Meta-Analysis. J. Allergy Clin. Immunol. Pract. 2023, 11, 1134–1146. [Google Scholar] [CrossRef]
- Wood, R.A.; Togias, A.; Sicherer, S.H.; Shreffler, W.G.; Kim, E.H.; Jones, S.M.; Leung, D.Y.M.; Vickery, B.P.; Bird, J.A.; Spergel, J.M.; et al. Omalizumab for the Treatment of Multiple Food Allergies. N. Engl. J. Med. 2024, 390, 889–899. [Google Scholar] [CrossRef]
- Casale, T.B.; Fiocchi, A.; Greenhawt, M. A Practical Guide for Implementing Omalizumab Therapy for Food Allergy. J. Allergy Clin. Immunol. 2024, 153, 1510–1517. [Google Scholar] [CrossRef]
- Clayton, F.; Fang, J.C.; Gleich, G.J.; Lucendo, A.J.; Olalla, J.M.; Vinson, L.A.; Lowichik, A.; Chen, X.; Emerson, L.; Cox, K.; et al. Eosinophilic Esophagitis in Adults Is Associated with IgG4 and Not Mediated by IgE. Gastroenterology 2014, 147, 602–609. [Google Scholar] [CrossRef]
- Spergel, J.M.; Elci, O.U.; Muir, A.B.; Liacouras, C.A.; Wilkins, B.J.; Burke, D.; Lewis, M.O.; Brown-Whitehorn, T.; Cianferoni, A. Efficacy of Epicutaneous Immunotherapy in Children with Milk-Induced Eosinophilic Esophagitis. Clin. Gastroenterol. Hepatol. 2020, 18, 328–336.e7. [Google Scholar] [CrossRef]
- Spergel, J.M.; Muir, A.B.; Liacouras, C.A.; Burke, D.; Lewis, M.O.; Brown-Whitehorn, T.; Cianferoni, A. Sustained Milk Consumption after 2 Years Post–Milk Epicutaneous Immunotherapy for Eosinophilic Esophagitis. Allergy 2021, 76, 1573–1576. [Google Scholar] [CrossRef]
- Dioszeghy, V.; Mondoulet, L.; Dhelft, V.; Ligouis, M.; Puteaux, E.; Dupont, C.; Benhamou, P.-H. The Regulatory T Cells Induction by Epicutaneous Immunotherapy Is Sustained and Mediates Long-term Protection from Eosinophilic Disorders in Peanut-sensitized Mice. Clin. Exp. Allergy 2014, 44, 867–881. [Google Scholar] [CrossRef] [PubMed]
- Furci, F.; Ricciardi, L. Plant Food Allergy Improvement after Grass Pollen Sublingual Immunotherapy: A Case Series. Pathogens 2021, 10, 1412. [Google Scholar] [CrossRef] [PubMed]
- Alvaro-Lozano, M.; Akdis, C.A.; Akdis, M.; Alviani, C.; Angier, E.; Arasi, S.; Arzt-Gradwohl, L.; Barber, D.; Bazire, R.; Cavkaytar, O.; et al. Allergen Immunotherapy in Children User’s Guide. Pediatr. Allergy Immunol. 2020, 31, 1–101. [Google Scholar] [CrossRef] [PubMed]
- Peles, S.; Medda, B.K.; Zhang, Z.; Banerjee, B.; Lehmann, A.; Shaker, R.; Sengupta, J.N. Differential Effects of Transient Receptor Vanilloid One (TRPV1) Antagonists in Acid-Induced Excitation of Esophageal Vagal Afferent Fibers of Rats. Neuroscience 2009, 161, 515–525. [Google Scholar] [CrossRef]
- Kumar, V.; Kumar, V.; Devi, K.; Kumar, A.; Khan, R.; Singh, R.P.; Rajarammohan, S.; Kondepudi, K.K.; Chopra, K.; Bishnoi, M. Intrarectal Capsazepine Administration Modulates Colonic Mucosal Health in Mice. Int. J. Mol. Sci. 2022, 23, 9577. [Google Scholar] [CrossRef]
- Ugawa, S.; Ueda, T.; Ishida, Y.; Nishigaki, M.; Shibata, Y.; Shimada, S. Amiloride-Blockable Acid-Sensing Ion Channels Are Leading Acid Sensors Expressed in Human Nociceptors. J. Clin. Investig. 2002, 110, 1185–1190. [Google Scholar] [CrossRef]
- Bulsiewicz, W.J.; Shaheen, N.J.; Hansen, M.B.; Pruitt, A.; Orlando, R.C. Effect of Amiloride on Experimental Acid-Induced Heartburn in Non-Erosive Reflux Disease. Dig. Dis. Sci. 2013, 58, 1955–1959. [Google Scholar] [CrossRef]
- Savarino, E. Drugs for Improving Esophageal Mucosa Defense: Where Are We Now and Where Are We Going? Ann. Gastroenterol. 2017, 30, 585. [Google Scholar] [CrossRef]
- Goyal, A.; Cheng, Y. Recent Discoveries and Emerging Therapeutics in Eosinophilic Esophagitis. World J. Gastrointest. Pharmacol. Ther. 2016, 7, 21. [Google Scholar] [CrossRef]
- Dorofeyev, A.E.; Dyadyk, O.O.; Zvyagintseva, T.D.; Chychula, Y.V.; Rudenko, N.N.; Stukalo, A.A. Mucus Barrier Correction as a Target in Complex Treatment of Gastroesophageal Reflux Disease. Gastroenterol. Hepatol. Open Access 2021, 12, 22–26. [Google Scholar] [CrossRef]
Author and Publication Year | No. of Cases | Age | Sex | Atopic Comorbidities | FIRE Syndrome Triggers | Symptoms | Severity (VAS) | Latency (min) | Symptom Duration (min) | SPT to Trigger | Management |
---|---|---|---|---|---|---|---|---|---|---|---|
Biedermann et al. 2020 [16] | 95 | Mean 46.4 (SD not reported) | 41.7% M 35.2% F | Present in 69.20% | Fruits, wine, vegetables, nuts, honey, cheese, fish, beer, vinegar | Narrowing, burning sensation, pain, pressure, choking sensation, anxiety | Median 7 [IQR 5–8]; range 2–10. | <5 for majority | 120 for majority | N/A | Avoidance |
Holbreich et al. 2021 [17] | 8 | 19 | M | AR, A, IgE FA (milk, egg, peanut, tree nut); PFAS (apple, banana) | Soy | Cramping | 7 | <1 | <30 | + | UKN |
39 | M | AR, IgE FA (peanut, tree nut); PFAS (fruits) | Melon | Chest tightness | 7 | <5 | <120 | N/A | UKN | ||
35 | M | AR, IgE FA (peanut); PFAS (fruits) | Beans | Chest tightness | 6 | <2 | <120 | + | UKN | ||
53 | M | AR, A | Craft beer | Chest tightness | 5 | <60 | <360 | N/A | UKN | ||
19 | M | AR, A, IgE FA (peanut, tree nut); PFAS (carrot, avocado) | Avocado, banana | Chest tightness | 8 | <1 | <120 | N/A | UKN | ||
37 | M | AR, IgE FA (peanut, tree nut) | Craft beer | Pain | 8 | <10 | <360 | N/A | UKN | ||
28 | M | AR, PFAS (pea, poultry) | Beans, melon | Pressure | 6 | <2 | <10 | + | UKN | ||
53 | F | AR, PFAS (soy) | Soy | Pain | 8 | <10 | <120 | + | UKN | ||
Votto et al. 2022 [18] | 1 | 9 | M | No | Honey, pumpkin seeds | Chest tightness, esophageal burn | UKN | 10 | 15 | + | Swallowed topical CSs |
Koken et al. 2023 [19] | 1 | 16 | F | AR | Vinegar | Narrowing, pressure | 2 | 5 | 30 | N/A | Avoidance |
Triggers | Symptoms | Timing and Duration | Severity | Diagnostic Features | Treatment and Management | |
---|---|---|---|---|---|---|
EoE | Solid, fibrous foods (bread, meat, rice) or dairy, wheat, and soy | Dysphagia, food impaction, abdominal pain, vomiting, regurgitation | Gradual progressive symptoms over weeks/months; chronic symptoms | Longstanding inflammation can lead to esophageal fibrosis and strictures with food bolus impaction | Symptoms + endoscopy + biopsy (eosinophilic infiltration) | Dietary elimination (6-food, 4-food, 2-food, or 1-food elimination diet), swallowed topical steroids (fluticasone, budesonide), proton pump inhibitors, biologics (Dupilumab) |
FIRE syndrome | Various foods or beverages (fruits, vegetables, nuts, dairy, honey, beans, wine, beer, milk, vinegar, and others) | Intense retrosternal discomfort or pain, tightening, burning or choking sensation, chest pressure, anxiety | Immediate onset, typically within 5 min, lasting <2 h | High-intensity symptoms, significant discomfort leading to avoidance behavior | Only clinical diagnosis based on rapid symptom onset and reproducibility | Avoidance of trigger foods, possible role of biologics (uncertain) |
PFAS | Fresh fruits and vegetables, nuts | Itching/burning of the oral mucosa, edema of the lips or tongue | Immediate onset (seconds to minutes); resolves within minutes to an hour | Mild to moderate symptoms, only in rare occasions systemic symptoms | Skin prick tests or sIgE for pollen-associated allergens | Avoidance of raw trigger foods; cooking may reduce allergenicity; antihistamines |
Proposed FIRE Syndrome Mechanism | Basis/Supporting Data | Evidence Type |
---|---|---|
Epithelial barrier dysfunction | Loss of tight junction proteins; allergen penetration with local antigen deposition | Histologic and transcriptomic data from EoE |
Local IgE-mediated response in the esophagus | Increased B cells and CSR gene expression; IgE + cells present; EPT studies in EoE | Clinical and molecular studies in EoE |
Mast cell activation and mediator release | Mast cells present in muscularis mucosa; correlation with pain in EoE; potential role in smooth muscle dysmotility | Histologic and observational data from EoE |
Neuroimmune signaling via TRPV1/ASICs | Upregulation in EoE; linked to pain in esophagitis | Experimental and transcriptomic data in esophagitis |
Local chemical irritation (e.g., vinegar, wine) | Potential role in pain generation via acid channels stimulation | Speculative; data derived from case series and case reports |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Ali, S.; Cernat, M.C.; Vintilă, M.R.; Berghea, E.C.; Bumbăcea, R.S. Shedding Light on FIRE Syndrome: An Overview of a Novel Condition in Eosinophilic Esophagitis. Appl. Sci. 2025, 15, 6375. https://doi.org/10.3390/app15116375
Ali S, Cernat MC, Vintilă MR, Berghea EC, Bumbăcea RS. Shedding Light on FIRE Syndrome: An Overview of a Novel Condition in Eosinophilic Esophagitis. Applied Sciences. 2025; 15(11):6375. https://doi.org/10.3390/app15116375
Chicago/Turabian StyleAli, Selda, Maria Cătălina Cernat, Mihaela Ruxandra Vintilă, Elena Camelia Berghea, and Roxana Silvia Bumbăcea. 2025. "Shedding Light on FIRE Syndrome: An Overview of a Novel Condition in Eosinophilic Esophagitis" Applied Sciences 15, no. 11: 6375. https://doi.org/10.3390/app15116375
APA StyleAli, S., Cernat, M. C., Vintilă, M. R., Berghea, E. C., & Bumbăcea, R. S. (2025). Shedding Light on FIRE Syndrome: An Overview of a Novel Condition in Eosinophilic Esophagitis. Applied Sciences, 15(11), 6375. https://doi.org/10.3390/app15116375