Pathophysiology of Non-IgE-Mediated Food Allergy

Figures & data

Table 1 Acute vs Chronic FPIES

	Acute FPIES	Chronic FPIES
Age of onset	2–7 months of age	2–7 months of age
Symptom onset	Follows intermittent food exposures and includes emesis (within 1–4 hours), diarrhea (within 24 hours), lethargy, and pallor	Follows daily food ingestion and includes emesis (within 1–4 hours), diarrhea (within 24 hours, usually 5–10 hours, and may be chronic), poor weight gain/FTT
Clinical features	Vomiting, pallor, lethargy without skin or respiratory symptoms. May also include watery or bloody diarrhea, hypotension, abdominal distention, hypothermia	Intermittent but progressive vomiting and diarrhea, dehydration, metabolic acidosis, poor weight gain, FTT
Laboratory findings	Leukocytosis, neutrophilia, thrombocytosis, metabolic acidosis, methemoglobinemia	Leukocytosis, neutrophilia, thrombocytosis, metabolic acidosis, methemoglobinemia
Symptom resolution	Resolves within 24 hours after food elimination	Resolves within 3–10 days of food elimination and switching to hypoallergenic formula
Average age of resolution based on triggering food	Soy: 12 months (range 6 months to >22 years) Grains: 35 months Milk: 3 years Other solids: 42 months

Table 2 Inflammatory Responses Implicated in FPIES

Study	Year	Country	Population	Elevated Cytokines
Berin C, Lozano-Ojalvo D, Agashe C et al^Citation45	2021	United States	23 children with history of FPIES (11 reactors, 12 outgrown) undergoing supervised FPIES OFCs	Increased IL-17 family cytokines (IL-17A, IL-22, IL-17C, and CCL20) in symptomatic OFCs. Increased IL-2 and increased inflammatory markers (IL-8, oncostatin M, leukemia inhibitory factor, TNF-α, IL-10, and IL-6). Increased mucosal damage marker regenerating family member 1 alpha (REG1A).
Kimura M, Ito Y, Shimomura M et al^Citation36	2017	Japan	6 OFCS in 4 patients with FPIES	IL-2, IL-5, and IL-8 were elevated in all 4 positive OFCs.
Morita H, Nomura I, Orihara K et al^Citation42	2013	Japan	65 patients with GI food allergies, 12 with IgE-mediated cow’s milk allergy (CMA) with non-gastrointestinal symptoms with milk ingestion, and 12 asymptomatic controls	Increased IL-3, IL-5, and IL-13 in peripheral blood mononuclear cells from those with GI food allergies
Mori F, Barni S, Cianferoni A et al^Citation41	2009	Italy	Double-blind placebo-controlled OFC to rice in an 8-month-old boy during an acute FPIES reaction and after FPIES resolution	Increased IL-4 (positive OFC) Increased IL-10 (negative OFC done 6 months after initial positive OFC)

Table 3 Summary of EGIDs

Disorder	EoE^Citation71,Citation72,Citation86^–^Citation90,Citation92,Citation94,Citation104	EG^Citation73,Citation100,Citation104	EGE^Citation73,Citation101,Citation102,Citation104,Citation125
Clinical features	Abdominal pain, dysphagia, nausea, emesis, esophageal food impaction, heartburn, diarrhea, chest pain, bloody stools, failure to thrive	Abdominal pain, vomiting, diarrhea, bloody stools, iron-deficiency anemia, malabsorption, protein losing enteropathy, and failure to thrive (mucosal form); GI obstructive symptoms (muscularis form)	Abdominal pain, vomiting, diarrhea, bloody stools, iron-deficiency anemia, malabsorption, protein losing enteropathy, and failure to thrive (mucosal form); GI obstructive symptoms (muscularis form)
Endoscopic findings	Furrows, white plaques, loss of vascular pattern, rings, stricture, shearing	Micronodules (and/or polyposis) often with aggregates of lymphocytes and eosinophils	Flattening of small intestinal villi
Histologic findings	Eosinophils on biopsy	Eosinophils on biopsy	Eosinophils on biopsy
Associated inflammatory cytokine	IL-5, IL-13, IL-15, plasma basic fibroblast growth factor	IL-4, IL-5, IL-13	IL-3, GM-CSF, and IL-5

Table 4 Biologics Under Consideration for EoE

Biologic	Therapeutic Target	Mechanism of Action	Findings
Dupilumab	Anti-IL-4 and anti-IL-13	Human monoclonal antibody targeting alpha subunit of IL-4 receptor (IL-4Rα), modulates IL-4 and IL-13 signaling	Decrease in esophageal eosinophilia, endoscopic activity, and patient-reported symptoms^Citation113
Lirentelimab	Anti–siglec-8	Anti–siglec-8 antibody that depletes eosinophils and acts as a mast cell inhibitor	Decrease in tissue eosinophilia and symptoms in EG and eosinophilic duodenitis^Citation111,Citation115
Benralizumab	Anti-IL-5	Humanized monoclonal antibody against IL-5 receptor alpha-chain on eosinophils	Decrease in absolute eosinophil count in hypereosinophilic syndrome^Citation115,Citation126
Mepolizumab	Anti-IL-5	Humanized monoclonal antibody against IL-5 preventing receptor binding	Decrease in tissue eosinophilia Minor symptomatic improvement^Citation115,Citation127^–^Citation129
Reslizumab	Anti-IL-5	Humanized monoclonal antibody against IL-5 preventing receptor binding	Decrease in tissue eosinophilia^Citation115,Citation130^–^Citation132
QAX576	Anti-IL-13	Humanized monoclonal antibody against IL-13 that inhibits T cell secreted IL-13	Decrease in tissue eosinophilia No significant effect on clinical activity.^Citation116
RPC4046	Anti-IL-13	Humanized monoclonal antibody against IL-13 that prevents binding to receptor subunits IL13RA1 and IL13RA2	Decrease in tissue eosinophilia and endoscopic activity. Trend of reduction in dysphagia noted.^Citation117,Citation133
Omalizumab	Anti-IgE	Humanized monoclonal antibody against IgE	Not helpful in EoE^Citation114,Citation122,Citation123
Infliximab	Anti-TNF-α	Chimeric IgG1 monoclonal antibody and TNF-α inhibitor	Does not induce resolution of tissue eosinophilia or significant reduction of symptoms^Citation120
OC000459	Anti-CRTH2	Antagonist of chemoattractant receptors on Th2 cells (CRTH2) that interferes with prostaglandin pathway including prostaglandin D2	Decrease in tissue eosinophilia and symptoms^Citation121
Vedolizumab	Anti-α4β7	Humanized monoclonal antibody against α4β7	Clinical and histologic improvement of EoE^Citation134^–^Citation136
Tofacitinib	Janus kinase inhibitor (JAK1 and JAK 3)	JAK1 and JAK3 inhibitor	Clinical and histologic improvement of EoE^Citation137

Table 5 Comparison of FPIES, FPIAP, and FPE

Disorder	FPIES	FPIAP	FPE
Clinical features	Acute: repetitive, protracted vomiting, watery diarrhea, pallor lethargy, hypovolemic shock Chronic: intermittent yet progressive vomiting, watery diarrhea, weight loss, failure to thrive, lethargy, dehydration, metabolic derangements	Blood-streaked and/or mucus-containing stools, colicky behavior, increased bowel movements, anemia in severe cases	Protracted, non-bloody, diarrhea in the first 9 months of life, failure to thrive, vomiting, eczema, recurrent respiratory infections, abdominal distention, malabsorption
Endoscopic findings	Colitis, mucosal friability, and loss of vascular pattern	Focal erythema with lymphoid nodular hyperplasia	Lymphonodular hyperplasia of the duodenum and colon, villous atrophy
Histologic findings	Eosinophils in the lamina propria, focal eosinophilic infiltration of the epithelium on rectal mucosal biopsy; colitis with crypt abscesses, mucus depletion of rectal glands, and polymorphonuclear leukocytes within the lamina propria; partial villous atrophy and blunting	Eosinophilic infiltration and degranulation of the rectosigmoid colon in close proximity to the lymphoid nodules	Damage to villous architecture of the intestine: villous atrophy, lymphonodular hyperplasia of the duodenum and colon, increased intraepithelial lymphocytes (>25/100 epithelial cells) and marked eosinophil infiltration and degranulation in the mucosa; increased intestinal intraepithelial CD8+ T cells that are food-allergen specific
Inflammatory mediators of pathogenesis	Interleukin (IL)-1B, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-13, IL-17 family cytokines (IL-17A, IL-22, IL-17C, and CCL20), oncostatin M, leukemia inhibitory factor, TNF-α, and REG1A Evidence suggests broad innate immune cell activation and T lymphocyte (non Th2) mechanism	Increased TNF-α; decreased TGF-β1 receptor activity and TGF-β ligand expression Evidence suggests predominantly eosinophil mediated response	IFN-Y and IL-4 cytokines have been identified in jejunal biopsy specimens Evidence suggests T lymphocyte (Th2 and CD8 effector cells) predominant mechanisms
Diagnosis	Based on clinical history	Based on clinical history	Requires biopsy for histological confirmation, clinical history
Management	Removal of triggering food, supportive care with fluid rehydration (PO or IV), consider steroids and/or ondansetron for severe cases, guidance for further food introduction	Maternal elimination diet in breastfed infants, trial of extensively hydrolyzed or amino acid-based formula in either breastfed or formula-fed infants	Avoidance of triggering food, dietary support
Prognosis	Resolution of symptoms by age 1–5 years	Resolution of symptoms by age 12 months	Resolution of symptoms by age 24–36 months

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