Hypersensitivity Reactions

• Definition: Hypersensitivity reactions are immune responses that are excessive, misdirected, or inappropriately sustained against an antigen that is otherwise harmless (pollen, drug, food) or self-derived. The Gell and Coombs scheme divides them into four types by effector mechanism, as outlined above.
• Why it matters: The mechanism dictates both timing and therapy. An IgE-mediated reaction kills within minutes through airway obstruction and distributive shock and requires intramuscular epinephrine; a T-cell–mediated reaction unfolds over days and epinephrine is useless. Misclassifying a delayed morbilliform drug rash as "anaphylaxis" leads to lifelong, often incorrect, allergy labels — the penicillin-allergy label being the most consequential example, since it drives use of broader, costlier, and more toxic antibiotics.
• Overlap: Many diseases are mechanistically mixed. Systemic lupus erythematosus involves both type II (anti-erythrocyte, anti-platelet antibodies) and type III (nephritis) injury; chronic asthma begins as type I and becomes dominated by chronic eosinophilic/T-cell inflammation.

Epidemiology worth recalling

• Atopy (allergic rhinitis, atopic dermatitis, asthma, food allergy) affects a large minority of the US population and clusters in families; it typically begins in childhood and follows the atopic march from eczema and food allergy in infancy to rhinitis and asthma later.
• Anaphylaxis is uncommon but not rare, with a lifetime prevalence on the order of a few percent; food is the leading trigger in children, and drugs and stinging insect venom become relatively more important in adults.
• Fatal anaphylaxis is rare, and deaths cluster in patients with poorly controlled asthma, delayed epinephrine administration, and peanut/tree nut or beta-lactam exposure.
• Type IV reactions are the most common form of drug hypersensitivity overall — the benign delayed maculopapular exanthem far outnumbers true IgE-mediated drug allergy. Allergic contact dermatitis (nickel, poison ivy urushiol) is the everyday clinical example.

Type I triggers (IgE)

• Foods: peanut, tree nuts, shellfish, fish, milk, egg, wheat, soy, sesame — the last added to US labeling law.
• Drugs: beta-lactams (the classic true IgE allergen), neuromuscular blockers, platinum chemotherapeutics.
• Venoms and latex: Hymenoptera stings; natural rubber latex, with cross-reactivity to banana, avocado, kiwi, chestnut (latex–fruit syndrome).
• Direct mast cell activators (non-IgE but clinically identical): vancomycin infused rapidly (vancomycin infusion reaction, formerly "red man"), opioids, radiocontrast, and fluoroquinolones acting at MRGPRX2.

Non-modifiable risk factors

• Genetic atopy: family history, filaggrin loss-of-function mutations predisposing to epicutaneous sensitization through a defective skin barrier.
• HLA alleles: HLA-B*57:01 with abacavir hypersensitivity, HLA-B*15:02 with carbamazepine-induced SJS/TEN in patients of Southeast Asian ancestry, HLA-B*58:01 with allopurinol severe reactions — the FDA and ACR endorse targeted screening in the relevant populations.
• Clonal mast cell disease or elevated baseline tryptase (including hereditary alpha-tryptasemia) predisposes to severe venom and idiopathic anaphylaxis.

Modifiable risk factors

• Uncontrolled asthma — the strongest predictor of fatal food anaphylaxis.
• Beta blockers and ACE inhibitors — blunt the response to endogenous and administered epinephrine and impair angiotensin-mediated compensation.
• Cofactors at the time of exposure: exercise, alcohol, NSAIDs, acute infection.
• Parenteral rather than oral drug administration, and repeated intermittent courses of a sensitizing drug.

Type I — sensitization then effector phase

• First exposure: antigen is processed by dendritic cells, Th2 cells release IL-4 and IL-13 driving B-cell class switching to IgE, and IL-5 recruits eosinophils. IgE binds high-affinity FcεRI on mast cells and basophils, arming them for months.
• Re-exposure cross-links adjacent IgE molecules → immediate release of preformed granule contents (histamine, tryptase, heparin) within minutes, then newly synthesized arachidonic acid products (leukotrienes C4/D4/E4, prostaglandin D2, platelet-activating factor).
• Histamine at H1 receptors causes vasodilation, increased venular permeability (wheal and flare, angioedema), bronchial smooth muscle contraction, and pruritus; the resulting plasma extravasation — a large fraction of intravascular volume can shift into the interstitium rapidly — produces distributive shock with a relative hypovolemic component. Leukotrienes sustain bronchospasm and mucus secretion, explaining the late-phase response hours later.

Type II — antibody against a fixed cell or matrix antigen

• IgG/IgM binding fixes complement to C3b (opsonization, splenic clearance) and the C5b-9 membrane attack complex (intravascular lysis), or engages FcγRIII on NK cells and macrophages for antibody-dependent cellular cytotoxicity.
• Antibody may instead be functional rather than lytic: stimulating (TSH receptor antibodies in Graves) or blocking (acetylcholine receptor antibodies in myasthenia, intrinsic factor antibodies in pernicious anemia). Linear deposition along basement membrane in Goodpasture reflects a continuous, uniformly distributed antigen.

Type III — soluble antigen

• Antibody excess makes large complexes that phagocytes clear; slight antigen excess makes intermediate-sized complexes that circulate and lodge where filtration pressure is high — glomerular capillaries, synovium, skin venules, choroid plexus.
• Deposited complexes fix complement, generating C3a/C5a anaphylatoxins that recruit neutrophils; frustrated phagocytosis releases proteases and reactive oxygen species → fibrinoid necrosis and leukocytoclastic vasculitis. Complement consumption lowers serum C3 and C4.

Type IV — no antibody at all

• Haptenized peptide presented on MHC primes CD4+ Th1 cells; on re-exposure IFN-γ and TNF activate macrophages, upregulate endothelial adhesion molecules, and recruit mononuclear cells over 48–72 hours — hence induration rather than a wheal. Persistent antigen drives granuloma formation. CD8+ cytotoxic T cells directly kill keratinocytes in SJS/TEN.

• Cutaneous (present in the large majority): urticaria, flushing, pruritus, non-pitting angioedema of lips, tongue, periorbital tissue — mast cell histamine and vascular leak. Absence of skin findings does not exclude anaphylaxis and is more common in drug- and venom-triggered cases.
• Respiratory: stridor and hoarseness from laryngeal edema (upper airway), wheeze and chest tightness from bronchospasm (lower airway).
• Cardiovascular: hypotension, tachycardia, syncope from vasodilation plus plasma extravasation. Patients on beta blockers may show paradoxical bradycardia and refractory hypotension.
• Gastrointestinal: crampy abdominal pain, vomiting, diarrhea from intestinal smooth muscle contraction — often the earliest sign in food-triggered anaphylaxis in children.
• Sense of impending doom is a classic descriptor.

Type II

• Acute hemolytic transfusion reaction: fever, chills, flank pain, hemoglobinuria, and DIC minutes into an ABO-mismatched unit — clerical error is the usual stem.
• Organ-specific autoimmunity: Graves ophthalmopathy and thyrotoxicosis; fluctuating ptosis and diplopia in myasthenia; flaccid intraepidermal bullae with a positive Nikolsky sign in pemphigus vulgaris; hemoptysis plus nephritic urine in Goodpasture.

Type III

• Serum sickness: fever, urticarial or palpable purpuric rash, symmetric polyarthralgias, and lymphadenopathy 7–14 days after a foreign protein or a chimeric antibody. A serum sickness–*like* reaction follows cefaclor and other drugs.
• Post-streptococcal glomerulonephritis: cola-colored urine, periorbital edema, and hypertension roughly 1–3 weeks after pharyngitis or impetigo in a school-aged child.
• Arthus reaction: intense local edema, induration, and hemorrhage at a vaccine or toxoid injection site in a hyperimmunized adult, hours after the shot.

Type IV

• Allergic contact dermatitis: pruritic vesicular, weeping eczema in a geometric or linear distribution (watchband, earring, poison ivy streaks) two to three days after contact.
• Delayed drug exanthem: morbilliform rash starting on the trunk around day 7–10 of an antibiotic. Fever, facial edema, eosinophilia, and transaminitis signal DRESS; mucosal erosions and skin detachment signal SJS/TEN.
• Tuberculin skin test: firm induration, not erythema, read at 48–72 hours.

Anaphylaxis is a clinical diagnosis — do not wait for any test.

• NIAID/FAAN clinical criteria (endorsed by the AAAAI/ACAAI Joint Task Force and paralleled by the World Allergy Organization): met by (1) acute onset of skin/mucosal involvement plus either respiratory compromise or hypotension/end-organ dysfunction; (2) two or more organ systems involved rapidly after a likely allergen; or (3) hypotension after exposure to a known allergen for that patient.
• Serum total tryptase: drawn within a few hours of symptom onset and compared with a baseline level obtained after recovery — a significant rise supports mast cell activation. A normal tryptase does not exclude anaphylaxis, particularly food-triggered events. A persistently elevated baseline tryptase should prompt evaluation for clonal mast cell disease or hereditary alpha-tryptasemia.

Confirming the type I trigger (after the acute event)

• Skin prick testing is the first-line allergen test; wheal-and-flare read at ~15 minutes against histamine and saline controls. Antihistamines must be held beforehand.
• Serum allergen-specific IgE when skin testing is not possible (extensive dermatitis, dermatographism, inability to stop antihistamines).
• Oral food challenge, supervised, is the gold standard for food allergy per the NIAID guidelines, because sensitization on testing is not the same as clinical allergy.
• Penicillin allergy evaluation: skin testing followed by graded amoxicillin challenge; most labeled patients are not allergic and can be de-labeled.

Immediate stabilization of anaphylaxis (AAAAI/ACAAI Joint Task Force Anaphylaxis Practice Parameter)

• Epinephrine, intramuscular, anterolateral thigh — the only first-line drug and the only one that reduces mortality. Adult 0.3–0.5 mg of 1:1000; pediatric 0.01 mg/kg. Alpha-1 agonism reverses vasodilation and mucosal edema, beta-2 agonism relieves bronchospasm, beta-1 support augments cardiac output, and mast cell beta-2 stimulation limits further mediator release. Repeat every 5–15 minutes as needed. There is no absolute contraindication to epinephrine in anaphylaxis.
• Position supine with legs elevated (or left lateral in pregnancy); abrupt sitting or standing has been associated with fatal empty ventricle syndrome.
• Airway and volume: high-flow oxygen, early intubation or surgical airway if stridor progresses, and aggressive isotonic crystalloid for the massive capillary leak.

Escalation and refractory disease

• Continuous IV epinephrine infusion with hemodynamic monitoring when repeated IM doses fail.
• Glucagon: for patients on beta blockers, because it activates adenylyl cyclase downstream of the blocked beta receptor.
• Inhaled beta-2 agonist (albuterol) as an adjunct for persistent bronchospasm.
• H1 antihistamines and glucocorticoids are adjuncts only — they relieve itch and urticaria but do not treat airway obstruction or shock, and the Joint Task Force explicitly does not recommend them to prevent biphasic reactions. Giving diphenhydramine instead of epinephrine is the classic exam error.
• Observation after resolution, with duration individualized to reaction severity and epinephrine requirement, followed by prescription of two epinephrine autoinjectors, an anaphylaxis action plan, and allergy referral.

Definitive and disease-modifying therapy

• Allergen avoidance and, for venom and aeroallergens, subcutaneous or sublingual immunotherapy — venom immunotherapy is highly protective against future sting anaphylaxis.
• Oral immunotherapy for peanut allergy in eligible children (FDA-approved product available); anti-IgE monoclonal antibody (omalizumab) for allergic asthma and to raise reaction thresholds in food allergy.
• Drug desensitization when an essential drug (penicillin in neurosyphilis or pregnancy, aspirin in coronary disease with AERD) cannot be substituted — temporary tolerance only.

Emergencies

• Asphyxia from laryngeal angioedema and bronchospasm — the predominant mechanism of death in food-triggered anaphylaxis, while cardiovascular collapse predominates in drug- and venom-triggered fatalities (median time to arrest is shortest with intravenous drug exposure). Hoarseness, stridor, or tongue swelling mandates immediate epinephrine and preparation for a surgical airway; delay converts an easy intubation into an impossible one.
• Refractory distributive shock — massive plasma extravasation plus vasoplegia; suspect when hypotension persists after repeated IM epinephrine, and consider beta blockade (give glucagon) or underlying mast cell disorder.
• Biphasic anaphylaxis — recurrence hours after apparent resolution without re-exposure, driven by late-phase mediators. More likely after severe initial reactions or delayed/multiple epinephrine doses; corticosteroids do not reliably prevent it.
• Acute hemolytic transfusion reaction (type II) — free hemoglobin causes pigment nephropathy and acute kidney injury, and tissue factor release triggers DIC. Stop the transfusion immediately, maintain urine output, and return the unit for clerical and serologic check.
• SJS/TEN (type IV, cytotoxic T cell–mediated keratinocyte apoptosis) — mucosal erosions plus a positive Nikolsky sign; managed like a burn, often in a burn unit, with immediate withdrawal of the culprit drug.
• DRESS — fever, facial edema, eosinophilia, atypical lymphocytosis, and hepatitis weeks after starting an anticonvulsant, allopurinol, or sulfonamide; myocarditis and fulminant hepatitis are the killers, and thyroiditis can appear months later.

Organ damage from ongoing immune injury

• Type II: transfusion-related alloimmunization complicating future crossmatch; hemolytic disease of the fetus and newborn with kernicterus; thrombosis rather than bleeding in heparin-induced thrombocytopenia.
• Type III: rapidly progressive glomerulonephritis with crescents and irreversible chronic kidney disease; systemic vasculitis with digital or bowel infarction.
• Type IV: chronic granuloma formation with tissue destruction; lichenified, secondarily infected contact dermatitis; chronic allograft vasculopathy.

Treatment complications

• Epinephrine: tachyarrhythmia, hypertension, and myocardial ischemia — mostly with IV bolus dosing or dosing errors, which is one reason IM is preferred.
• Systemic corticosteroids: hyperglycemia, immunosuppression, osteoporosis, adrenal suppression.
• IVIG: aseptic meningitis, thrombosis, volume overload, and renal injury; plasmapheresis: citrate-induced hypocalcemia, coagulopathy, catheter complications.
• Immunotherapy and desensitization: can themselves precipitate anaphylaxis, hence administration only where epinephrine and resuscitation are available.

• The single best next step in a patient with urticaria plus stridor or hypotension after an exposure is IM epinephrine into the anterolateral thigh — not IV access, not diphenhydramine, not a tryptase level. The distractor answers are always an antihistamine, a steroid, or "obtain IV access first."
• Timing is the mechanism. Minutes = type I. Hours at an injection site in a hyperimmunized host = Arthus (type III). One to two weeks after foreign protein = serum sickness (type III). Two to three days after contact = type IV.
• Induration, not erythema, is what you measure in a tuberculin skin test, and it peaks at 48–72 hours because it takes that long to recruit Th1 cells and macrophages — the purest clinical demonstration of type IV.
• Immunofluorescence pattern separates type II from type III: linear basement-membrane IgG (anti-GBM/Goodpasture, a continuous antigen) versus granular "lumpy-bumpy" deposits (immune complexes in post-streptococcal GN and lupus nephritis).
• Low C3 and C4 with active disease points to complement-consuming immune complexes (type III); complement is not consumed in type I or type IV.
• Beta blockers make anaphylaxis refractory — the stem plants an elderly patient on metoprolol with persistent hypotension despite repeated epinephrine; the answer is glucagon, which bypasses the blocked beta receptor to raise cyclic AMP.
• Cephalosporin cross-reactivity in penicillin-allergic patients is roughly 1–3%, and it tracks with shared R1 side chains rather than the beta-lactam ring itself. The old 10% figure is historical and is a deliberate distractor; most patients labeled penicillin-allergic tolerate a structurally dissimilar cephalosporin.
• Not every reaction to a drug infusion is IgE-mediated. Rapid vancomycin infusion and radiocontrast cause direct mast cell degranulation without prior sensitization, so a first exposure can cause flushing and hypotension — skin testing is not indicated and the fix is slowing the infusion (with premedication for contrast), not lifelong avoidance.
• IgA-deficient patients can develop anaphylaxis to IgA-containing blood products from anti-IgA antibodies; the answer is washed red cells.

• Four types: Type I (IgE-mediated, immediate), Type II (cytotoxic, antibody-mediated), Type III (immune complex), Type IV (cell-mediated, delayed)
• Type I is immediate (minutes); Type IV is delayed (48-72 hours)
• Type I and II are antibody-mediated; Type III is immune complex; Type IV is T-cell mediated
• Most common on USMLE: Type I (anaphylaxis, allergies) and Type IV (contact dermatitis, TB skin test)

• Type I: Anaphylaxis (urticaria, angioedema, bronchospasm, hypotension, stridor) within minutes of exposure; food/drug allergy; seasonal allergies
• Type II: Hemolytic transfusion reaction (fever, jaundice, hemoglobinuria post-transfusion); Graves' disease; pemphigus vulgaris
• Type III: Serum sickness (fever, arthralgias, rash 7-10 days post-exposure to antigen); post-streptococcal glomerulonephritis
• Type IV: Contact dermatitis (delayed eczema 48-72 hrs); TB skin test (induration at 48-72 hrs); drug rash; graft-versus-host disease

• Confusing Type I with Type IV timing: Type I is immediate (minutes); Type IV is delayed (2-3 days). A rash appearing 3 days after drug exposure = Type IV, NOT Type I.
• Forgetting Type III is immune complex-mediated, not antibody alone: Must have both antigen AND antibody forming complexes; occurs 1-3 weeks after exposure (not immediate like Type I, not as delayed as Type IV).
• Assuming all allergic reactions are IgE-mediated: Many drug rashes are Type IV (delayed) or Type III (serum sickness-like), NOT Type I anaphylaxis.