Food Allergies

• Sensitization and IgE Production: Upon initial exposure to food allergen, professional antigen-presenting cells (APCs)—particularly dendritic cells in gut-associated lymphoid tissue (GALT)—process allergenic proteins and present them via MHC Class II to naive CD4+ T helper cells. Certain genetic backgrounds and altered intestinal barrier function promote Th2 polarization (rather than normal tolerogenic response) through IL-4 and IL-13 production. Activated Th2 cells provide CD40-CD40L costimulation and IL-4/IL-13 signals to B cells, driving class-switch recombination from IgM to IgE-secreting plasma cells. The specific food allergens that trigger this response are typically small heat-stable proteins (13-40 kDa), often with enzymatic or structural properties that promote immune activation.

• Sensitization Phase (Immediate Hypersensitivity): IgE antibodies bind with high affinity (Kd ~10⁻¹¹ M) to FcεRI receptors on mast cells (tissue-resident) and basophils (circulating). This creates a primed state where the individual is sensitized but may be asymptomatic. Upon re-exposure to the allergen, cross-linking of adjacent FcεRI by multivalent allergen triggers rapid intracellular signaling through Lyn and Syk tyrosine kinases, activating phospholipase C (PLC), which cleaves PIP₂ into IP₃ and DAG, causing calcium mobilization from intracellular stores and triggering degranulation.

• Immediate Degranulation (Minutes): Mast cells and basophils release pre-formed mediators stored in cytoplasmic granules: histamine (causes pruritus, flushing, urticaria, bronchospasm, hypotension through H1 and H2 receptors), tryptase (marker of mast cell degranulation; levels >11.4 ng/mL within 15-60 minutes of symptom onset support anaphylaxis diagnosis), heparin (anticoagulant), and chymase. These mediators produce the classic immediate reactions: oral allergy syndrome (OAS), acute urticaria, angioedema, wheezing, and hypotension.

• Late-Phase Reaction (4-12 hours): Following degranulation, mast cells and activated basophils synthesize and secrete newly formed mediators including leukotrienes (LTC₄, LTD₄, LTE₄—potent bronchoconstrictor and vasoactive mediators), prostaglandins (PGD₂), and cytokines (IL-4, IL-5, TNF-α, IL-13). Simultaneously, preformed mediators recruit and activate eosinophils and neutrophils via eotaxin and CXCL8 chemotaxis. This late-phase response explains biphasic anaphylaxis and prolonged inflammatory symptoms (eczema flare, angioedema recurrence).

Non-IgE-Mediated Mechanisms represent 30-40% of food allergies and involve primarily T-cell mediated immunity

• Cell-Mediated Food Allergies: Food protein-induced enterocolitis syndrome (FPIES), food protein-induced allergic colitis, and celiac disease (distinct: autoimmune against tissue transglutaminase) involve CD8+ and CD4+ T-cell responses to processed food antigens. Antigen-presenting cells in the lamina propria present food peptides to tissue-resident memory T cells (Trm cells), which produce IFN-γ and TNF-α, recruiting macrophages and neutrophils causing localized inflammation. FPIES characteristically presents 1-4 hours post-exposure with acute onset vomiting, diarrhea, and hypotension but notably without IgE positivity or urticaria/angioedema.

• Mixed IgE/Non-IgE Mechanisms: Food-protein induced atopic dermatitis (eczema) involves both IgE sensitization (detectable specific IgE) and persistent Th2-driven inflammation with recruitment of eosinophils and production of IL-31 (pruritogenic cytokine). Eosinophilic gastrointestinal disorders (EGIDs): eosinophilic esophagitis (EoE), eosinophilic gastritis, and eosinophilic colitis involve IgE and/or IgG4-mediated responses leading to massive eosinophil infiltration of the esophageal (or gastric/colonic) mucosa, with evidence of Th2 and IgE class-switched responses to food allergens. Histology shows ≥15 eosinophils per high-power field in EoE. These conditions present with dysphagia, food impaction, chest pain, or chronic diarrhea depending on location.

• Peanuts (legume, often cross-reactive with tree nuts): Most common cause of severe/fatal food anaphylaxis in developed countries; 10-15% of tree nut-allergic patients react to peanuts; high heat stability causes persistence after cooking; oral allergy syndrome rare because peanut allergens are thermal-stable and can reach the gastrointestinal tract
• Tree nuts (almonds, cashews, walnuts, pecans, Brazil nuts, pistachios): Often multiple nut cross-reactivity (e.g., cashew-pistachio, walnut-pecan); risk of severe anaphylaxis; clinically significant pollens may cause OAS
• Milk proteins (primarily casein and whey): Most common allergen in infants/young children (<5 years); cow's milk allergy affects ~1-2% of infants; improves with age (90% tolerant by age 5-10); pasteurization may reduce but not eliminate allergenicity
• Eggs (primary allergens: ovomucoid and ovalbumin): Second most common pediatric allergen; often outgrown by school age (~70% tolerance by age 5); heating at high temperature may denature allergen allowing tolerance to baked goods before whole egg
• Fish (parvalbumin—heat-stable protein; tropomyosin in shellfish): High-risk for anaphylaxis; cross-reactivity among fish species high; shellfish cross-reactivity rare due to different major allergens
• Shellfish (crustaceans: shrimp, crab, lobster; mollusks: clams, mussels, oysters): Tropomyosin is major allergen; high cross-reactivity among crustaceans; associated with atopic occupational asthma in seafood processors
• Soy (legume): Common in processed foods; many soy-allergic patients tolerate soy oil (refined, allergen removed); cross-reactivity with peanut possible but <40%
• Wheat (gluten and other storage proteins): Distinct from celiac disease (autoimmune); includes wheat-dependent exercise-induced anaphylaxis (WDEIA)—paradoxical condition where wheat allergen only causes anaphylaxis when exercise occurs within 2-4 hours post-ingestion

Primary Risk Factors for IgE-Mediated Food Allergy

• Atopic Diseases: Strong association with atopic dermatitis (eczema), asthma, and allergic rhinitis; presence of multiple atopic conditions increases food allergy risk 3-4 fold; the "atopic march" concept suggests progression from AD → food allergy → allergic rhinitis → asthma
• Family History: Parental history of any atopy increases child's risk to ~30%; if both parents atopic, risk rises to ~60%; specific food allergy in parent increases child's risk ~4-fold
• Genetic Polymorphisms: FLG (filaggrin) mutations cause compromised skin barrier → increased allergen sensitization; STAT6 and TIM4 polymorphisms enhance Th2 responses
• Early-Life Exposures: Very early introduction of allergen (<3 months) or delayed introduction (after 12 months) both increase sensitization risk; optimal window for tolerance induction appears to be 4-6 months with concurrent intact barrier; paradoxically, early high-dose allergen exposure may promote tolerance ("dose threshold effect"); vitamin D deficiency associated with increased risk
• Timing and Route of First Exposure: Exposure through disrupted skin barrier (via eczema/dermatitis) or mucosal inflammation (viral gastroenteritis) promotes sensitization more than intact mucosal exposure
• Microbiota Composition: Dysbiosis characterized by reduced Faecalibacterium and Akkermansia and altered Clostridium cluster IV/XIVa (butyrate producers) correlates with increased food allergy risk

Secondary Risk Factors and Predisposing Conditions

• Severe Atopic Dermatitis: 30-50% of moderate-to-severe AD patients have food allergies; AD serves as sensitization portal for food antigens
• Pre-existing IgE-Mediated Conditions: Prior anaphylaxis to food, asthma, or allergic rhinitis; asthma + food allergy = higher risk of fatal anaphylaxis
• Immunodeficiency States: Notably IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked; mutations in FOXP3 transcription factor) presents with severe food allergies due to absent Tregs; selective IgA deficiency increases food allergy risk
• Gastrointestinal Conditions: Eosinophilic esophagitis frequently associated with multiple food allergies; inflammatory bowel disease increases risk; H. pylori eradication paradoxically associated with increased allergies
• Occupational/Environmental Exposures: Food-processing workers exposed to high allergen concentrations show elevated occupational asthma risk

Cardinal Symptoms by Timing and Mechanism

IgE-Mediated Food Allergy—Immediate Reactions (minutes to 2 hours)

• Oral Allergy Syndrome (OAS): Localized pruritus and angioedema of lips, tongue, palate, and pharynx caused by heat-labile proteins in fresh fruits, vegetables, and nuts; due to pollen-food cross-reactivity (e.g., birch pollen cross-reacts with apple, pear, cherry; ragweed with melons; latex protein with banana/avocado); symptoms resolve with swallowing or heating; characteristically does NOT progress to systemic symptoms in uncomplicated OAS, though severe cases may have oropharyngeal angioedema; triggered by exposure in mouths with pre-existing allergic rhinitis from pollen
• Acute Urticaria and Pruritus: Widespread wheal and flare reactions appearing within 10-30 minutes of allergen ingestion; mediated by histamine and leukotrienes; intensely pruritic; typically resolves within 1-2 hours after allergen elimination
• Angioedema: Non-pitting, well-demarcated swelling of deeper dermis and subcutaneous tissues, particularly lips, tongue, pharynx, eyelids, hands, genitalia; can be life-threatening if pharyngeal/laryngeal edema develops (compromises airway); mediated by bradykinin and leukotriene release; may occur with or without concurrent urticaria
• Gastrointestinal Symptoms (IgE-mediated, appearing 30 minutes to 2 hours post-ingestion): Nausea, crampy abdominal pain, vomiting, and diarrhea; in children, may present as colic-like symptoms or failure to thrive if repeated exposure; itching or burning sensation in throat; due to mast cell activation in gut and increased intestinal permeability
• Lower Airway Involvement: Wheezing, dyspnea, cough, bronchospasm; appears within 30 minutes to 1-2 hours; mechanism involves leukotriene-induced airway smooth muscle contraction and mucus secretion; indicates risk of progression to anaphylaxis; may be life-threatening, particularly in asthmatics with concurrent food allergy
• Systemic Manifestations (Anaphylaxis): Hypotension, syncope, severe dyspnea, loss of consciousness; represents multi-organ involvement with cardiovascular collapse due to massive histamine and leukotriene-induced vasodilation and increased vascular permeability; mortality risk increases with biphasic reactions (rebound 1-72 hours after initial resolution) or protracted reactions lasting >12 hours

Non-IgE-Mediated Reactions—Delayed Presentations

• Food Protein-Induced Enterocolitis Syndrome (FPIES): Characteristically presents 1-4 hours post-ingestion with profuse vomiting, explosive watery diarrhea, abdominal cramping, and dehydration; infants may have lethargy, hypothermia, or even shock if severe; absence of urticaria/angioedema/wheezing is key feature distinguishing from IgE-mediated anaphylaxis; common culprits in infants: rice cereal, oat cereal, cow's milk formula, egg, soy; chronic FPIES with repeated low-level exposure may present as failure to thrive, chronic diarrhea, and malabsorption; diagnosis supported by serum tryptase NEGATIVE (unlike anaphylaxis), no specific IgE, but

• Key history elements: identity and form of the food (raw vs. baked), latency to symptoms (minutes–2 h favors IgE; 1–4 h of profuse emesis favors FPIES), reproducibility, and cofactors (exercise, NSAIDs, alcohol) that lower the reaction threshold as in wheat-dependent exercise-induced anaphylaxis.

Step 2 — first-line testing for suspected IgE-mediated allergy

• Skin prick testing (SPT): introduces allergen to dermal mast cells; a wheal ≥3 mm larger than the negative control is positive. High sensitivity/negative predictive value, poor specificity — a negative SPT is most useful for ruling out.
• Serum allergen-specific IgE (fluorescent enzyme immunoassay): detectable values above the assay's lower limit indicate sensitization; higher values raise the probability of clinical reactivity, and titers falling over time predict outgrowing milk/egg allergy. Neither SPT wheal size nor sIgE level predicts reaction severity.
• Component-resolved diagnostics: IgE to the stable storage protein Ara h 2 distinguishes true peanut allergy from birch-pollen cross-sensitization (Ara h 8), which causes only oral allergy syndrome.

Step 3 — confirmatory/gold standard

• Oral food challenge, ideally double-blind, placebo-controlled, performed with resuscitation capability. Indicated when history and testing disagree or to prove resolution.
• Supervised graded challenge/reintroduction is also the diagnostic standard for FPIES, diagnosed by international consensus criteria (repetitive emesis 1–4 h after the food, lethargy/pallor, absent cutaneous and respiratory features).

• Tests to avoid: the AAAAI/ACAAI Joint Task Force practice parameters advise against food-specific IgG/IgG4 panels, indiscriminate large allergen panels, applied kinesiology, and hair analysis — all generate false positives and unnecessary elimination diets.

Immediate stabilization of anaphylaxis (AAAAI/ACAAI Joint Task Force anaphylaxis practice parameter)

• Intramuscular epinephrine is first-line and time-critical: 0.3 mg IM (adult/child ≥30 kg) or 0.15 mg IM (child <30 kg) into the anterolateral thigh, repeated every 5–15 minutes as needed. Alpha-1 agonism reverses vasodilation and mucosal edema; beta-2 agonism relieves bronchospasm; beta-1 supports inotropy; it also stabilizes mast cells. Delay in administration is the strongest predictor of fatal outcome — there is no absolute contraindication in anaphylaxis.
• Position supine with legs elevated; abrupt upright posture during distributive shock can precipitate the empty ventricle syndrome.
• Adjuncts, never substitutes: high-flow oxygen, large-volume isotonic crystalloid for fluid-responsive hypotension, inhaled beta-2 agonist (albuterol) for residual wheeze, H1 antihistamines (cetirizine, diphenhydramine) for cutaneous itch only.
• Refractory anaphylaxis: continuous IV epinephrine infusion with monitoring; glucagon if the patient is beta-blocked and unresponsive to epinephrine; additional vasopressors and airway management for progressive laryngeal edema.
• Observation after resolution because of biphasic reactions; the Joint Task Force recommends risk-stratified rather than fixed observation, and advises against routine glucocorticoids or antihistamines to prevent biphasic reactions.

Long-term management

• Strict avoidance of the culprit protein plus label-reading education remains the foundation per NIAID guidelines.
• Prescribe two epinephrine autoinjectors, a written anaphylaxis action plan for home/school, and medical identification.
• Allergen immunotherapy: FDA-approved oral immunotherapy with peanut allergen powder (Palforzia) for eligible children raises the reaction threshold — it desensitizes, it does not cure, and epinephrine must be carried.
• Anti-IgE biologic: omalizumab is FDA-approved to reduce reactions to accidental exposure in IgE-mediated food allergy; it binds free IgE and downregulates FcεRI.
• Prevention: the NIAID addendum guidelines recommend early introduction of peanut protein around 4–6 months, with SPT/sIgE evaluation first in infants with severe eczema or egg allergy.

Emergencies

• Anaphylaxis with fatal airway obstruction — laryngeal/pharyngeal angioedema from histamine- and bradykinin-mediated vascular leak. Signaled by stridor, hoarseness, "lump in the throat," or drooling. Give IM epinephrine immediately and prepare for a difficult airway.
• Distributive/cardiovascular collapse — massive vasodilation plus transudation of up to a large fraction of intravascular volume into the interstitium. Signaled by hypotension, tachycardia, syncope; in children hypotension is a late sign, so tachycardia and pallor matter.
• Biphasic anaphylaxis — late-phase leukotriene/cytokine generation and eosinophil recruitment cause recurrence typically within hours after apparent resolution, without re-exposure. Risk factors include severe initial reaction and delayed epinephrine.
• Refractory anaphylaxis — persistent shock despite repeated IM epinephrine; suspect concurrent beta-blocker/ACE-inhibitor use blunting compensatory catecholamine and angiotensin responses.
• Fatal asthma exacerbation — coexisting asthma is the classic comorbidity in food-related anaphylaxis deaths; bronchospasm may dominate over cutaneous findings.
• FPIES shock — profuse emesis with hypovolemia, metabolic acidosis, and neutrophilia; methemoglobinemia has been reported in severe infantile FPIES and presents with cyanosis unresponsive to oxygen.

Chronic disease complications

• Nutritional deficiency and growth faltering from broad or unsupervised elimination diets — milk avoidance without substitution risks calcium/vitamin D deficiency and rickets; flagged by falling weight-for-length percentiles.
• Eosinophilic esophagitis sequelae — chronic eosinophilic inflammation drives subepithelial fibrosis with strictures and food impaction; a sudden inability to swallow after meat or bread is the presenting emergency.
• Psychosocial morbidity — anticipatory anxiety, restricted social eating, and reduced quality of life; documented as a core outcome in NIAID guideline discussions.

Treatment-related complications

• Epinephrine: expected tremor, palpitations, headache, pallor; myocardial ischemia or arrhythmia mainly with IV bolus dosing or underlying coronary disease. Digital ischemia after inadvertent autoinjector injection into a finger.
• Oral immunotherapy: dose-related systemic reactions (cofactors such as exercise, illness, or empty stomach lower the threshold) and treatment-emergent eosinophilic esophagitis presenting with dysphagia or persistent abdominal pain, often requiring discontinuation.
• Omalizumab: anaphylaxis to the biologic itself, hence supervised initial dosing.

• Epinephrine IM is always the single best next step in food-triggered anaphylaxis — before antihistamines, before steroids, before labs, before an airway. If a stem offers "IV diphenhydramine" or "IV methylprednisolone" as the first action, it is the distractor. Adult dose 0.3 mg IM anterolateral thigh; 0.15 mg for a small child.
• Anaphylaxis is a clinical diagnosis (NIAID/FAAN criteria). Do not wait for tryptase; a normal tryptase does not exclude it, and food-induced anaphylaxis often has normal levels.
• Sensitization ≠ allergy. A positive skin prick test or detectable specific IgE without a clinical history does not warrant food avoidance; the double-blind placebo-controlled oral food challenge is the gold standard. IgG food panels are never appropriate (AAAAI/ACAAI practice parameters).
• Oral allergy syndrome = itchy lips/mouth with raw fruits or vegetables in a patient with pollen allergy (birch–apple, ragweed–melon, latex–banana/avocado), resolving with cooking, because the cross-reacting profilins are heat-labile — this is not peanut-type allergy and does not require an autoinjector for isolated OAS.
• FPIES: profuse repetitive emesis, pallor, lethargy ± shock 1–4 hours after rice/oat/milk in an infant, with no urticaria, no wheeze, and negative specific IgE — treat with IV fluids (and ondansetron), not epinephrine.
• Asthma plus food allergy is the association examiners test — the classic profile of fatal peanut anaphylaxis is an adolescent with asthma, delayed epinephrine, and an untreated wheeze.
• Early is protective: per the NIAID addendum guidelines, introduce peanut around 4–6 months in high-risk infants (severe eczema and/or egg allergy) after SPT/sIgE evaluation. Avoidance does not prevent allergy.
• Outgrowing pattern: milk, egg, soy, and wheat allergies commonly resolve in childhood; peanut, tree nut, fish, and shellfish are usually lifelong. Tropomyosin = shellfish, parvalbumin = fish, Ara h 2 = peanut, ovomucoid = egg (predicts intolerance of baked egg).