Food Allergies and Drug Hypersensitivity

IgE-mediated (Type I) triggers

• Foods: the major allergens recognized in US labeling law are milk, egg, peanut, tree nut, wheat, soy, fish, crustacean shellfish, and sesame (added by the FASTER Act). Peanut/tree nut/shellfish dominate adult fatal reactions.
• Drugs: β-lactams (penicillins, cephalosporins) via hapten formation on carrier proteins; also neuromuscular blockers, platinum chemotherapeutics, and some monoclonal antibodies.
• Alpha-gal syndrome: IgE to galactose-α-1,3-galactose after Lone Star tick bite → delayed (3–6 h) anaphylaxis to mammalian meat — the classic "anaphylaxis in the middle of the night after a steak dinner" stem.

Non-IgE mechanisms

• Direct mast cell activation (pseudoallergy): vancomycin infusion reaction, opioids, and radiocontrast act on MRGPRX2/direct degranulation — no prior sensitization required, so a first exposure can react.
• COX-1 inhibition: NSAID-exacerbated respiratory disease (shunting to cysteinyl leukotrienes), not IgE.
• T-cell/HLA-restricted: HLA-B*57:01–abacavir, HLA-B*15:02–carbamazepine (FDA advises screening in patients of Southeast Asian ancestry), HLA-B*58:01–allopurinol.

Non-modifiable risk factors

• Atopic diathesis: eczema (including filaggrin loss-of-function), asthma, allergic rhinitis; personal/family atopy.
• Age: milk/egg/soy/wheat in young children; shellfish/nut in adults. Female sex predominates in reported drug hypersensitivity.
• Clonal/hereditary mast cell disease: systemic mastocytosis or hereditary α-tryptasemia (elevated baseline tryptase) predicts severe reactions.

Modifiable risk factors

• Delayed dietary introduction: the NIAID-sponsored 2017 Addendum Guidelines recommend early introduction of peanut-containing food in infants with severe eczema and/or egg allergy (LEAP-based) — avoidance increases risk.
• Uncontrolled asthma: the strongest modifiable predictor of fatal food anaphylaxis.
• Cofactors amplifying a reaction: exercise (food-dependent exercise-induced anaphylaxis, classically ω-5 gliadin/wheat), alcohol, NSAIDs, acute infection, menses.
• Antibiotic exposure pattern: frequent, prolonged, or parenteral courses raise sensitization risk.
• β-blockers/ACE inhibitors: do not cause allergy but blunt response to epinephrine and worsen severity.

IgE-Mediated (Type I Hypersensitivity) Reactions

• Sensitization phase: Initial allergen exposure triggers Th2 cell activation → B cells produce allergen-specific IgE → IgE binds high-affinity FcεRI receptors on mast cells and basophils, creating sensitized state
• Re-exposure (degranulation): Allergen cross-links IgE on mast cell/basophil surfaces → rapid release of preformed mediators (histamine, tryptase, heparin) → immediate symptoms (within minutes to 2 hours)
• Late-phase reaction (4-12 hours later): Newly synthesized mediators (leukotrienes, prostaglandins, cytokines) cause prolonged inflammation, recruitment of eosinophils and neutrophils

Non-IgE-Mediated Reactions

• Type II (Cytotoxic): IgG/IgM antibodies bind drug-hapten complexes on cell surfaces → complement activation or ADCC → hemolytic anemia (e.g., penicillin + RBCs), thrombocytopenia
• Type III (Immune Complex): Soluble antigen-antibody complexes deposit in tissues → complement activation → vasculitis, serum sickness (e.g., cefaclor, antibiotics)
• Type IV (Cell-Mediated): Sensitized T cells (CD8+ and CD4+) recognize processed allergen on APCs → delayed inflammatory response (24-72 hours) → contact dermatitis, drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS)

Organ-Level Effects

• Skin: Mast cell degranulation in dermis → vasodilation, increased vascular permeability → urticaria, angioedema
• GI tract: Smooth muscle contraction + mucosal edema → abdominal cramping, vomiting, diarrhea
• Respiratory: Airway smooth muscle contraction + mucosal edema → bronchospasm, laryngeal edema, wheezing
• Cardiovascular: Peripheral vasodilation + increased vascular permeability → hypotension, shock

IgE-Mediated Food Allergy (Immediate-Type)

• Oral allergy syndrome: Pruritis and angioedema of lips, tongue, palate within minutes of eating raw fruits/vegetables; typically mild and localized to mouth
• Cutaneous: Urticaria and pruritus within 15-30 minutes; angioedema of face, lips, tongue
• GI symptoms: Nausea, vomiting, abdominal cramping, diarrhea (often accompanies cutaneous findings)
• Respiratory: Rhinitis, cough, wheezing, bronchospasm, stridor (due to laryngeal edema)
• Anaphylaxis: Biphasic presentation possible — initial resolution followed by recurrence 4-12 hours later; cardiovascular collapse, loss of consciousness (most common cause of food-related death)

Non-IgE-Mediated Food Reactions

• Food protein-induced enterocolitis syndrome (FPIES): Delayed vomiting (1-3 hours post-ingestion), followed by diarrhea; can progress to dehydration and shock; more common in infants
• Food protein-induced allergic colitis: Bloody diarrhea in infants; typically resolves with antigen avoidance
• Celiac disease and wheat allergy distinction: Celiac is autoimmune-mediated villous atrophy; wheat allergy is IgE-mediated; both present with GI symptoms but different pathophysiology

Drug Hypersensitivity Reactions

• Immediate reactions (IgE-mediated): Rash, pruritus, urticaria/angioedema within 1 hour of administration; most common with β-lactams, NSAIDs, ACE inhibitors
• Delayed reactions (Type IV): Maculopapular rash, fever appearing 5-7 days after drug initiation; classic with antibiotics (trimethoprim-sulfamethoxazole, amoxicillin), anticonvulsants
• Severe delayed reactions: DRESS syndrome (fever, rash, facial edema, lymphadenopathy, hepatosplenomegaly, atypical lymphocytes, elevated liver enzymes); SJS/toxic epidermal necrolysis (TEN) (mucosal involvement, widespread blistering, >30% skin involvement in TEN); serum sickness-like reaction (fever, arthralgias, lymphadenopathy, rash 7-10 days after exposure)
• Aspirin/NSAID sensitivity: Triad of asthma, chronic rhinosinusitis with nasal polyps, and NSAID-induced bronchospasm/anaphylaxis; mediated by COX-1 inhibition → increased leukotriene production, NOT IgE-mediated

Important Clinical Pearls

• Tolerance develops naturally to many food allergies (80% of children outgrow milk/egg allergy by age 5; peanut/tree nut allergy more persistent)
• Cross-reactivity exists (e.g., shellfish cross-reactivity due to tropomyosin protein; tree nut cross-reactivity; birch pollen cross-reacts with apple, carrot — oral allergy syndrome)
• Penicillin allergy self-reporting is inaccurate — only ~10% of patients reporting penicillin allergy have true IgE-mediated allergy on testing

Clinical History (Most Important First Step)

• Detailed temporal relationship: Time between exposure and symptom onset (immediate = IgE-mediated; delayed = non-IgE)
• Reproducibility: Does reaction occur with each exposure?
• Symptom pattern: Helps differentiate IgE-mediated (urticaria, angioedema, anaphylaxis) from non-IgE (GI symptoms predominant, delayed rash)
• Distinguish from intolerance: Lactose intolerance (osmotic diarrhea, no immune mechanism), food poisoning (community outbreak pattern), food aversion

In Vivo Testing

• Skin prick testing (SPT): Gold standard for IgE-mediated reactions; small amount of allergen extract injected intradermally → wheal-and-flare response if IgE-sensitized; high sensitivity (~90%) but low specificity (positive in sensitized but non-allergic individuals); results available within 15 minutes; contraindicated in severe reaction history or if patient on antihistamines
• Intradermal testing: Higher sensitivity but higher risk; reserved for specific allergens when SPT negative but clinical suspicion high (e.g., drug allergy workup)

In Vitro Testing

• Serum-specific IgE (ImmunoCAP, RAST): Detects allergen-specific IgE in blood; useful when SPT contraindicated or unavailable; lower sensitivity than SPT; more expensive but unaffected by antihistamines; quantitative levels do NOT correlate with symptom severity
• Tryptase levels: Elevated (>11.4 ng/mL) during/shortly after anaphylaxis; rises within 15 minutes, peaks at 1 hour, returns to baseline by 3 hours; baseline tryptase >8 suggests mastocytosis

Immediate stabilization — anaphylaxis

• Epinephrine (alpha-1 vasoconstriction, beta-1 inotropy, beta-2 bronchodilation and mast cell stabilization): intramuscular into the anterolateral thigh, 0.3 mg in adults (0.01 mg/kg in children; 0.15 mg autoinjector for smaller children), repeat every 5–15 min as needed. The AAAAI/ACAAI Joint Task Force Anaphylaxis Practice Parameter states there is no absolute contraindication to epinephrine in anaphylaxis.
• Adjuncts, never substitutes: supine positioning with legs elevated (upright posture risks empty ventricle syndrome), high-flow oxygen, large-volume isotonic crystalloid for distributive shock, inhaled beta-2 agonist (albuterol) for refractory bronchospasm.
• Refractory shock: IV epinephrine infusion in a monitored setting; glucagon for patients on beta blockers (bypasses the blocked receptor via direct adenylate cyclase stimulation).
• Airway: early intubation for stridor/laryngeal edema before edema makes it impossible.

Symptomatic and second-line

• H1 antihistamines (cetirizine, diphenhydramine) relieve urticaria/pruritus only; H2 blockers and systemic glucocorticoids are adjunctive. The Joint Task Force emphasizes that steroids do not reliably prevent biphasic reactions and must not delay epinephrine.

Definitive/long-term

• Strict allergen avoidance plus two epinephrine autoinjectors and a written anaphylaxis action plan — the cornerstone per NIAID guidelines.
• Peanut oral immunotherapy (FDA-approved defatted peanut powder) induces desensitization, not cure; reactions during dosing are expected.
• Anti-IgE monoclonal antibody (omalizumab) is FDA-approved to reduce reaction severity from accidental exposure in IgE-mediated food allergy.
• Penicillin allergy delabeling: the 2022 Drug Allergy Practice Parameter supports direct oral amoxicillin challenge for low-risk histories and skin testing ± challenge otherwise. Cephalosporins with dissimilar R1 side chains are safe in most penicillin-allergic patients (cross-reactivity ~1–3%).
• Drug desensitization (graded escalating doses inducing temporary mast cell unresponsiveness) when the drug is irreplaceable — e.g., CDC STI guidelines direct penicillin desensitization for syphilis in pregnancy. Tolerance is lost once the drug is stopped.

Contraindicated

• Never rechallenge or desensitize after SJS/TEN, DRESS, AGEP, or drug-induced hepatitis — these are T-cell mediated and desensitization does not protect.
• Avoid beta blockers/ACE inhibitors when feasible in patients with recurrent anaphylaxis.

Emergencies

• Anaphylactic shock and asphyxia — EMERGENCY: laryngeal edema plus distributive shock; signaled by stridor, hoarseness, hypotension, or the deceptive "feeling of impending doom." Delayed epinephrine is the single factor most consistently associated with fatality.
• Biphasic anaphylaxis — EMERGENCY: recurrence 4–12 h after apparent resolution from late-phase leukotriene/cytokine generation; predicted by severe initial presentation and need for repeat epinephrine, hence a period of observation before discharge.
• Toxic epidermal necrolysis / SJS — EMERGENCY: keratinocyte apoptosis (granulysin, Fas-FasL) → full-thickness epidermal detachment, positive Nikolsky sign, transepidermal fluid loss, hypothermia, and sepsis (the usual cause of death). Manage like a burn: stop the culprit drug, burn-unit-level supportive care.
• DRESS-related organ failure — EMERGENCY: eosinophil-driven injury with HHV-6 reactivation; hepatitis is the leading cause of death; myocarditis presents late with heart failure or arrhythmia. Signal findings are eosinophilia, atypical lymphocytosis, and rising transaminases weeks after drug start.
• FPIES shock: profuse repetitive emesis 1–3 h after ingestion with lethargy, hypotension, and methemoglobinemia — often misdiagnosed as sepsis.

Chronic sequelae

• Ocular scarring in SJS/TEN: symblepharon, corneal neovascularization, blindness — mandates early ophthalmology involvement.
• Autoimmune thyroiditis months after DRESS resolution.
• Nutritional deficiency and growth faltering from overly broad elimination diets; anxiety and impaired quality of life in food-allergic families.
• Eosinophilic esophagitis: may emerge during oral immunotherapy — dysphagia and food impaction.

Treatment-related

• Epinephrine: tachyarrhythmia, tremor, and demand ischemia, particularly with IV dosing errors in older adults — an argument for the IM route.
• First-generation H1 blockers: sedation and anticholinergic delirium; masking of early symptoms.
• Retained penicillin allergy label: drives vancomycin/fluoroquinolone/clindamycin use → more MRSA, VRE, C. difficile colitis, surgical site infection, and longer stays — the harm the 2022 Drug Allergy Practice Parameter targets with delabeling.

• Epinephrine IM is always the single best next step in anaphylaxis — before antihistamines, steroids, fluids, or labs. The classic distractor is diphenhydramine or IV methylprednisolone; both are adjuncts. Two organ systems involved (or hypotension after a known allergen) is enough to act.
• Anaphylaxis is a clinical diagnosis. Tryptase supports it retrospectively but a normal level does not exclude it, especially in food-triggered reactions.
• ~90% of patients labeled "penicillin-allergic" tolerate penicillin. For a low-risk history (remote, benign rash, no anaphylaxis), the 2022 AAAAI/ACAAI Drug Allergy Practice Parameter supports direct oral amoxicillin challenge. Cephalosporin cross-reactivity is roughly 1–3% and is driven by shared R1 side chains, not the beta-lactam ring — the 10% figure is obsolete.
• Early peanut introduction prevents peanut allergy. Per the NIAID 2017 addendum (LEAP), infants with severe eczema and/or egg allergy should have peanut introduced early, after evaluation. Advising avoidance is the wrong answer.
• HLA associations examiners love: *HLA-B*57:01*–abacavir hypersensitivity (screen before prescribing), *HLA-B*15:02*–carbamazepine SJS/TEN in Southeast Asian ancestry, *HLA-B*58:01*–allopurinol SCAR.
• **Mucosal involvement plus a positive *Nikolsky sign* = SJS/TEN, not a simple morbilliform drug eruption. Fever, facial edema, eosinophilia, and transaminitis weeks after starting an anticonvulsant or sulfonamide** = DRESS. Neither is ever desensitized or rechallenged.
• Vancomycin infusion reaction ("red man") is direct mast cell degranulation, not IgE — slow the infusion and premedicate with antihistamine; it is not an allergy label. Same logic for radiocontrast and opioids.
• Steaks and tick bites: delayed anaphylaxis hours after red meat in a patient from the southeastern US = alpha-gal syndrome. Aspirin-exacerbated respiratory disease (asthma, nasal polyps, NSAID reaction) is COX-1 mediated — treat with leukotriene modifiers and consider aspirin desensitization, not epinephrine avoidance counseling alone.