Hypersensitivity Reactions (Types I–IV)
Contents (8)
Hypersensitivity reactions are excessive or inappropriate immune responses to antigens that cause tissue damage. The Gell and Coombs classification divides these into four types based on immune mechanism: Type I (IgE-mediated, immediate), Type II (cytotoxic antibody), Type III (immune complex), and Type IV (T-cell mediated, delayed). Hypersensitivity reactions account for significant morbidity worldwide and represent a critical understanding point for diagnosis and management of allergic and autoimmune conditions.
Type I triggers (IgE cross-linking on mast cells)
- Foods: peanut, tree nut, shellfish, milk, egg, wheat, soy, sesame — the leading cause of anaphylaxis in children
- Hymenoptera venom: bee, wasp, fire ant — a leading cause of fatal anaphylaxis in adults
- Drugs and biologics: beta-lactams, neuromuscular blockers, chlorhexidine; iodinated contrast and opioids cause direct (non-IgE) mast cell activation that is clinically identical
- Latex: cross-reacts with banana, avocado, kiwi, chestnut (latex–fruit syndrome)
Type II triggers (antibody against cell-surface antigen): drug–hapten complexes (penicillin, cephalosporins, quinine, methyldopa), transfusion of ABO-incompatible blood, Rh alloimmunization, and autoantigens (Graves', myasthenia gravis, Goodpasture, hyperacute graft rejection).
Type III triggers (immune complexes): heterologous antisera and monoclonal antibodies (serum sickness), beta-lactams (serum sickness–like reaction), persistent infection (streptococcal, hepatitis B/C, endocarditis), and chronic autoantigen exposure (SLE, cryoglobulinemia). Inhaled organic antigens cause hypersensitivity pneumonitis with a mixed III/IV mechanism.
Type IV triggers (T-cell mediated): haptens penetrating skin — urushiol (poison ivy), nickel (the most common contact allergen), neomycin, fragrances, para-phenylenediamine; drugs causing delayed exanthem, DRESS, SJS/TEN; mycobacterial antigen in tuberculin testing; allogeneic MHC in acute cellular rejection and GVHD.
Non-modifiable risk factors
- Atopy and family history: filaggrin loss-of-function variants and the atopic march (eczema → food allergy → asthma → rhinitis)
- HLA alleles predicting severe type IV drug reactions: HLA-B*57:01 (abacavir), HLA-B*15:02 (carbamazepine SJS/TEN in Southeast Asian ancestry), HLA-B*58:01 (allopurinol) — the FDA and CDC/HHS antiretroviral guidelines require HLA-B*57:01 screening before abacavir
- Clonal mast cell disease, older age, and cardiovascular disease predict fatal anaphylaxis
Modifiable risk factors: poorly controlled asthma, a well-recognized risk factor for severe and fatal food-induced anaphylaxis per AAAAI/ACAAI practice parameters; delayed epinephrine administration; concurrent beta blockers or ACE inhibitors; exercise, alcohol, and NSAID cofactors; repeated parenteral drug exposure; and occupational allergen contact.
TYPE I (IgE-MEDIATED, IMMEDIATE)
- Sensitization phase: Initial antigen exposure → processing by antigen-presenting cells → Th2 differentiation → B cell activation and IgE production → IgE binds to Fc receptors on mast cells and basophils
- Re-exposure phase: Antigen cross-links surface IgE → rapid mast cell/basophil degranulation within seconds to minutes → release of preformed mediators (histamine, tryptase, heparin) and newly synthesized mediators (leukotrienes, prostaglandins, platelet-activating factor)
- Mechanism of tissue damage: Mediators increase vascular permeability, cause smooth muscle contraction, induce mucus secretion, promote vasodilation; late-phase reaction (4-12 hours) involves eosinophil and neutrophil recruitment via chemokines
TYPE II (CYTOTOXIC ANTIBODY)
- IgG or IgM antibodies bind to antigens on cell surfaces (drug-hapten complexes, viral antigens, self-antigens)
- Complement activation via classical pathway → C3b opsonization and C5a generation → membrane attack complex formation → cell lysis
- Antibody-dependent cellular cytotoxicity (ADCC): NK cells and macrophages recognize Fc regions on antibody-coated cells → direct cell killing
- Result: hemolysis, thrombocytopenia, or neutropenia depending on target cell
TYPE III (IMMUNE COMPLEX)
- Antigen-antibody complex formation in slight antibody excess → small immune complexes remain soluble and circulate
- Complexes deposit in tissue (especially where blood filtration occurs: glomeruli, blood vessel walls, joints) → complement activation → C3a and C5a generation → inflammation
- Neutrophil recruitment and infiltration → release of proteolytic enzymes → vasculitis and tissue necrosis
- Typically requires repeated antigen exposure (serum sickness, post-streptococcal glomerulonephritis)
TYPE IV (T-CELL MEDIATED, DELAYED)
- Sensitization: antigen processing via MHC II (exogenous) or MHC I (endogenous) → Th1 or Th17 differentiation → memory T cell formation
- Re-exposure: antigen-specific T cells recognize MHC-peptide complex on antigen-presenting cells → cytokine release (IFN-γ, TNF-α, IL-2)
- Macrophage activation → recruitment of additional inflammatory cells → delayed onset (24-72 hours)
- Cytotoxic T lymphocyte (CTL) response: CD8+ T cells directly kill antigen-presenting cells via perforin/granzyme or Fas-FasL interactions
TYPE I (IMMEDIATE)
- Cutaneous manifestations: urticaria (localized or generalized), angioedema (deeper dermal/mucosal swelling); pruritus; may appear within minutes of exposure
- Respiratory symptoms: bronchospasm with wheezing, stridor (laryngeal edema), dyspnea, rhinitis, nasal congestion
- Gastrointestinal symptoms: oral pruritus, nausea, vomiting, diarrhea, abdominal cramping
- Cardiovascular collapse: anaphylaxis with hypotension, syncope, shock; pallor, diaphoresis, altered mental status
- Timing: symptoms appear within minutes to 2 hours; biphasic anaphylaxis can occur with delayed second wave (up to 12 hours later)
TYPE II (CYTOTOXIC)
- Drug-induced hemolytic anemia: jaundice, dark urine, pallor, fatigue, dyspnea; spherocytes and polychromasia on blood smear; elevated indirect bilirubin and LDH
- Thrombocytopenia: petechiae, purpura, bleeding gums, epistaxis; risk of severe bleeding
- Agranulocytosis: fever, pharyngitis, oral ulcers, severe infections
- Graves' disease (anti-TSH receptor antibodies): hyperthyroid symptoms (palpitations, tremor, weight loss, heat intolerance)
TYPE III (IMMUNE COMPLEX)
- Serum sickness: fever, arthralgia/arthritis (typically knees, wrists, ankles), lymphadenopathy, rash (often urticarial but may be maculopapular); appears 7-10 days after antigen exposure
- Post-streptococcal glomerulonephritis: hematuria (cola-colored urine), proteinuria, hypertension, edema, elevated creatinine 1-3 weeks after strep throat
- Systemic lupus erythematosus (SLE): photosensitive rash, malar rash, oral ulcers, arthritis, pleuritis, glomerulonephritis
- Vasculitis: palpable purpura (lower extremities and buttocks prominent), can affect multiple organs
TYPE IV (DELAYED)
- Contact dermatitis: pruritic, vesicular rash at site of contact; appears 24-72 hours after exposure (poison ivy, nickel, latex); well-demarcated borders
- Tuberculin skin test (Mantoux test): induration at injection site measured at 48-72 hours; indicates prior or current TB exposure
- Drug reactions: maculopapular rash, systemic symptoms; more common with certain drugs (sulfonamides, anticonvulsants, antiretrovirals)
- Graft-versus-host disease (GVHD): skin involvement (erythema, desquamation), diarrhea, hepatic dysfunction; occurs days to weeks post-transplant
Clinical Pearl: A single allergen exposure can trigger multiple hypersensitivity types simultaneously. For example, penicillin can cause immediate anaphylaxis (Type I), hemolytic anemia (Type II), serum sickness (Type III), and maculopapular rash (Type IV).
TYPE I (IMMEDIATE)
- Clinical history: temporal relationship between exposure and symptoms (minutes to hours); prior similar reactions
- Skin prick testing (SPT): gold standard for IgE-mediated allergies; wheal ≥3 mm indicates sensitization; must hold antihistamines 3-7 days prior
- Serum-specific IgE testing: useful when skin testing contraindicated (severe eczema, dermographism, inability to hold antihistamines); quantitative (kUA/L); >0.35 kUA/L typically considered positive
- Tryptase level: drawn during or immediately after anaphylaxis (peak at 15-30 minutes); elevated tryptase supports diagnosis; normal level does not exclude anaphylaxis
- Basophil activation test (BAT): research tool measuring CD63/CD203c expression on basophils after allergen exposure
TYPE II (CYTOTOXIC)
- Direct antiglobulin test (Coombs test): detects antibodies or complement bound to RBC surface; positive in hemolytic anemia; specific subtypes (IgG vs. IgM vs. complement) help identify mechanism
- Complete blood count: anemia, reticulocytosis, spherocytes on smear, thrombocytopenia, or neutropenia depending on target cell
- Chemistry panel: elevated indirect bilirubin, elevated LDH, decreased haptoglobin (consumed by free hemoglobin)
- Drug-specific antibody testing: available for certain drugs (quinine, sulfonamides) but rarely performed; diagnosis usually clinical
Immediate stabilisation — anaphylaxis (type I)
- Epinephrine (alpha-1/beta-1/beta-2 agonist): 0.3 mg IM (0.01 mg/kg, pediatric max 0.3 mg) into the anterolateral thigh, repeat every 5–15 minutes as needed. Per the AAAAI/ACAAI Joint Task Force anaphylaxis practice parameter this is first-line and has no absolute contraindication; alpha-1 vasoconstriction reverses hypotension and mucosal edema, beta-2 bronchodilates, and beta receptor signaling stabilises mast cells
- Airway, position, volume: early intubation for stridor or oropharyngeal edema; keep the patient supine with legs elevated (upright posture risks empty ventricle syndrome); rapid isotonic crystalloid for distributive shock
Adjuncts — never a substitute for epinephrine
- H1 antihistamines (cetirizine, diphenhydramine) relieve urticaria/pruritus only
- H2 blockers (famotidine) and systemic glucocorticoids (methylprednisolone) do not reverse shock; the Joint Task Force notes steroids do not reliably prevent biphasic reactions
- Inhaled beta-2 agonist (albuterol) for refractory bronchospasm
Escalation: continuous IV epinephrine infusion with hemodynamic monitoring for refractory shock; glucagon for patients on beta blockers (bypasses blocked beta receptors via direct adenylyl cyclase stimulation); vasopressors for persistent hypotension.
Definitive/longitudinal care: allergen avoidance, prescription of two epinephrine autoinjectors with an anaphylaxis action plan, and allergy referral. Allergen immunotherapy is the only disease-modifying therapy — subcutaneous venom immunotherapy is highly protective after systemic sting reactions, and FDA-approved oral immunotherapy exists for peanut. Anti-IgE (omalizumab) is used for allergic asthma and as adjunct in food allergy.
Other types: type II and III — withdraw the culprit drug or clear the antigen; corticosteroids, IVIG, and rituximab for immune cytopenias (ASH ITP guidelines list steroids first-line, with splenectomy reserved for refractory disease); serum sickness is self-limited with NSAIDs/steroids. Type IV contact dermatitis — topical corticosteroids (triamcinolone) plus avoidance; extensive poison ivy needs a systemic steroid taper over 2–3 weeks (short bursts cause rebound). SJS/TEN requires drug withdrawal and burn-unit supportive care.
Contraindicated/avoid: delaying epinephrine while giving antihistamines, IV epinephrine bolus outside arrest (arrhythmia, hypertensive crisis), and re-challenge with a drug that caused SJS/TEN or DRESS.
Emergencies (type I)
- Asphyxial death from laryngeal edema or refractory bronchospasm — signalled by stridor, hoarseness, or a silent chest; food-triggered fatalities are predominantly respiratory. Emergency
- Distributive shock with cardiovascular collapse — massive mediator-driven vasodilation and capillary leak; up to a third of intravascular volume can shift to the interstitium within minutes. Venom- and drug-triggered fatalities are predominantly cardiovascular. Emergency
- Biphasic anaphylaxis — recurrence hours after apparent resolution without re-exposure; predicted by severe initial presentation and by needing more than one epinephrine dose, which is why the AAAAI/ACAAI practice parameter individualises observation time. Emergency
- Kounis syndrome — mast cell mediators provoke coronary vasospasm or plaque rupture; chest pain with ischemic ECG changes during an allergic reaction
Type II/III sequelae: severe hemolysis with hyperbilirubinemia, pigment nephropathy, and high-output failure; thrombocytopenic bleeding including intracranial hemorrhage (emergency); agranulocytosis with overwhelming sepsis (fever plus oral ulcers is the red flag); immune-complex glomerulonephritis progressing to CKD, signalled by persistent proteinuria, hypertension, and rising creatinine; vasculitic organ infarction.
Type IV sequelae: secondary bacterial superinfection of excoriated contact dermatitis (honey-crusting, expanding erythema); chronic lichenified dermatitis with occupational disability; SJS/TEN with mucosal sloughing, positive Nikolsky sign, fluid loss, sepsis, and permanent ocular scarring/symblepharon — ophthalmology must be consulted early (emergency); DRESS with eosinophilia, hepatitis, myocarditis, and delayed autoimmune thyroiditis months later.
Treatment-related
- Epinephrine: tachyarrhythmia, hypertensive crisis, and myocardial ischemia — overwhelmingly from IV bolus or dosing errors rather than IM use
- Systemic glucocorticoids: hyperglycemia, HPA-axis suppression, osteoporosis, and rebound dermatitis after an abrupt stop
- Rituximab/immunosuppression: hypogammaglobulinemia, hepatitis B reactivation, PML
- Immunotherapy: systemic reaction during build-up dosing, which is why injections are given only in a supervised setting with epinephrine available
- Epinephrine IM in the anterolateral thigh is always the single best next step in anaphylaxis — before antihistamines, before steroids, before labs. A stem where the resident gives diphenhydramine first is testing this exact error.
- Anaphylaxis is a clinical diagnosis. Hypotension or two organ systems involved after a likely allergen is enough. Serum tryptase only confirms retrospectively — it peaks roughly 15–120 minutes after symptom onset, so draw within about 3 hours and obtain a baseline level later for comparison; a normal value never excludes anaphylaxis, and it is often normal in food-triggered episodes.
- Type II vs Type III: type II antibody attacks an antigen fixed to a cell or matrix (Coombs-positive hemolysis, Graves', Goodpasture — linear immunofluorescence); type III involves soluble complexes that deposit later (serum sickness, PSGN — lumpy-bumpy granular immunofluorescence with low C3). Timing separates them too: type III symptoms appear 7–10 days after first exposure.
- Arthus reaction = localized type III at a vaccine/injection site with edema and necrosis at 4–12 hours — distinct from delayed type IV induration.
- PPD/tuberculin is the prototype type IV: read induration, not erythema, at 48–72 hours. Transplant analogue: hyperacute rejection is type II (preformed antibody, minutes); acute cellular rejection and GVHD are type IV.
- Nickel is the most common contact allergen; urushiol causes the linear vesicular streaks of poison ivy. The rash is not spread by blister fluid — a favourite distractor.
- Penicillin allergy label: most patients labeled allergic tolerate penicillin. Cephalosporin cross-reactivity in true penicillin allergy is about 1–3%, driven by shared R1 side chains, not the beta-lactam ring — the old 10% figure is obsolete. A prior type IV maculopapular rash does not preclude cephalosporin use. Prior SJS/TEN or DRESS to any beta-lactam does preclude it. For prior penicillin anaphylaxis, the 2022 AAAAI/ACAAI drug allergy practice parameter and IDSA/CDC stewardship guidance support giving a cephalosporin with a dissimilar R1 side chain; avoid agents sharing the R1 side chain (amoxicillin–cefadroxil, ampicillin–cephalexin/cefaclor).
- **Screen HLA-B*57:01 before abacavir** — the classic exam pairing of pharmacogenomics with a delayed T-cell reaction.