Urticaria, Angioedema & Erythema Multiforme
A high-yield Step 1 lesson separating superficial-dermal urticaria from deep angioedema, contrasting histamine-mediated (allergic) with bradykinin-mediated (ACE-inhibitor and hereditary C1-INH deficiency) swelling, and HSV-triggered erythema multiforme target lesions from drug-induced SJS/TEN.
One spectrum, different mechanisms
Urticaria and angioedema are two ends of one edematous spectrum. Urticaria (hives) is edema of the superficial dermis producing transient, intensely pruritic wheals; angioedema is edema of the deep dermis and subcutis/submucosa, giving non-pitting swelling of the face, lips, tongue, and airway. Both result when vasoactive mediators — chiefly histamine (mast-cell) or bradykinin — raise vascular permeability. Erythema multiforme (EM) is mechanistically separate: a T-cell–mediated (type IV) reaction, most often triggered by HSV, that produces fixed target lesions. The high-yield task is to separate histamine-driven swelling (allergic, itchy, antihistamine-responsive) from bradykinin-driven swelling (ACE inhibitor, C1-INH deficiency), and to separate EM target lesions from SJS/TEN.
- Wheal: blanching, edematous, pruritic plaque; each lesion lasts <24 h and clears without scarring (lesions migrate)
- Mechanism: mast-cell/basophil degranulation → histamine + leukotrienes → vasodilation and ↑ permeability of the superficial dermis
- Type I (IgE) hypersensitivity (foods, drugs, insect venom) or non-IgE/direct mast-cell activation (opioids, vancomycin "red man," radiocontrast; NSAIDs via COX-1)
- Acute <6 wk (infection, food, drug) vs chronic ≥6 wk (often idiopathic/autoimmune)
- Physical urticarias: dermatographism, cholinergic (heat/exercise), cold, pressure
- Treatment: second-generation H1 antihistamines first-line; add H2 blocker/short steroid course; omalizumab for refractory chronic urticaria
Angioedema — three mechanisms to separate
| Feature | Histaminergic (allergic) | ACE-inhibitor | Hereditary (C1-INH def.) |
|---|---|---|---|
| Mediator | Histamine | Bradykinin | Bradykinin |
| Urticaria / itch | Yes (often with hives) | No | No |
| Onset | Minutes, with trigger | Any time after start (days–years) | Recurrent, since childhood |
| Inheritance | — | — | Autosomal dominant |
| Key labs | — | — | ↓ C4 (screen), ↓ C1-INH; C1q normal |
| Epi / antihistamine / steroid | Works | Poor response | No response |
| Treatment | Epinephrine, antihistamine, steroid | Stop ACE-i permanently; protect airway (icatibant tried, evidence mixed) | C1-INH concentrate, icatibant, ecallantide; danazol prophylaxis |
A 58-year-old Black man on lisinopril for 8 months wakes with progressive swelling of the lips and tongue. There is no urticaria, pruritus, or wheezing, and no new food or drug exposure. Vitals are stable and the airway is patent.
Diagnosis: ACE-inhibitor–induced angioedema — blocked degradation of bradykinin lets it accumulate.
Next step: stop the ACE inhibitor permanently and monitor/protect the airway. Because it is bradykinin-mediated, it responds poorly to epinephrine, antihistamines, and steroids; escalate to airway control if it progresses (icatibant has been used in severe cases, though trial evidence is mixed). Onset ranges from days to years after starting the drug and is more common in Black patients. Do not rechallenge with another ACE inhibitor.
A 24-year-old woman develops symmetric target lesions on the dorsal hands, forearms, and palms about 10 days after a cold sore (herpes labialis). Each lesion shows three zones: a dusky/blistered center, a pale edematous ring, and an erythematous outer halo. She has a few oral erosions, <10% BSA involved, and is not systemically ill.
Diagnosis: Erythema multiforme, HSV-triggered (a type IV reaction).
Next step: supportive care — acyclovir does not shorten the acute episode, but chronic suppressive antivirals prevent recurrent HSV-associated EM. Distinguish from SJS/TEN (drug-triggered, widespread dusky macules, epidermal detachment, severe mucosal/systemic disease). In children, Mycoplasma pneumoniae is another important trigger.
Erythema multiforme vs SJS/TEN
| Feature | Erythema multiforme | SJS / TEN |
|---|---|---|
| Trigger | HSV (#1), Mycoplasma | Drugs (sulfa, anticonvulsants, allopurinol, NSAIDs) |
| Lesion | Raised typical targets, 3 zones | Atypical/flat targets, dusky macules → confluent |
| Distribution | Acral: extremities, palms/soles, face | Trunk/face → widespread |
| Mucosa | Minimal; EM major = mucosal (usually oral) | Severe, ≥2 sites |
| Epidermal detachment | None/minimal | SJS <10%, overlap 10–30%, TEN >30% BSA |
| Nikolsky sign | Negative | Positive |
| Course | Self-limited; recurs with HSV | Life-threatening; stop drug, supportive/burn-unit care |
- Defect: ↓ or dysfunctional C1 esterase inhibitor (autosomal dominant) → unopposed kallikrein activity → excess bradykinin (the swelling culprit); chronic classical-pathway activation also consumes C4
- Screening lab: persistently low C4 (even between attacks); confirm with C1-INH level (type 1, low) or function (type 2, normal level but low function)
- C1q: normal in hereditary; low in acquired C1-INH deficiency (lymphoproliferative/autoimmune, older adults)
- No urticaria or itch; attacks of face, extremities, bowel (colicky pain, mimics surgical abdomen), and larynx (can be fatal)
- Triggers to avoid: trauma/dental work, stress, ACE inhibitors, and estrogens
- Acute Rx: C1-INH concentrate, icatibant (B2-receptor antagonist), ecallantide (kallikrein inhibitor) — not epinephrine/antihistamine/steroid
- Prophylaxis: attenuated androgens (danazol) raise C1-INH synthesis
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