Urticaria (Hives)

Acute urticaria — widespread wheals with central pallor and surrounding erythematous flare

Definition

Urticaria consists of transient, pruritic, edematous plaques (wheals) with pale centers and red borders — the classic "wheal and flare" reaction. Individual lesions reflect localized dermal edema from transvascular fluid extravasation and resolve within <24 hours, although new lesions may continuously appear. Angioedema represents the same process in the subcutaneous/submucosal layer.

Epidemiology

~15–20% of the population experiences at least one episode during their lifetime
Acute urticaria: seen equally in both sexes; common in children with atopic dermatitis
Chronic urticaria: more common in women in their 40s–50s; peaks in the 3rd–4th decade overall
50% of patients with chronic urticaria have disease lasting ≥5 years
Dermographism alone affects ~5% of the general population

Classification (EAACI 2013 Consensus)

Duration	Type	Subtypes
Acute	<6 weeks	Spontaneous
Chronic	≥6 weeks	Spontaneous (CSU) — no identifiable trigger
		Inducible — physical stimuli

Inducible (Physical) Urticaria Types:

Symptomatic dermographism — linear wheals from minor pressure/scratching; most common physical type
Cold urticaria — exposed skin after cold exposure; risk of wheezing and syncope (avoid cold water swimming); associated with cryoglobulins; autosomal dominant form linked to cryopyrin dysfunction
Delayed pressure urticaria (DPU) — urticaria/angioedema hours after sustained pressure
Heat urticaria — provoked by local heat application
Solar urticaria — within minutes of sun exposure; skin sign of erythropoietic protoporphyria
Cholinergic urticaria — small wheals with large flares; triggered by heat, exercise, or emotion; occasionally associated with wheezing
Vibratory angioedema — vibratory stimuli
Aquagenic urticaria — water contact regardless of temperature
Contact urticaria — direct skin contact with causative agent

Pathophysiology

Common final pathway: Local mast cell degranulation → release of histamine, bradykinin, kallikrein, acetylcholine, slow-reacting substance of anaphylaxis → dermal edema and vasodilation.

Mechanisms:

Immunologic	Nonimmunologic
IgE-dependent (type I hypersensitivity)	Direct mast cell degranulation (opioids, contrast dye, strawberries, lobster)
Autoimmune: functional IgE autoantibodies releasing histamine from mast cells	NSAID/aspirin inhibition (non-IgE; effects persist weeks)
Immune complex–mediated (type III)	Vasoactive stimuli
Complement-kinin dependent (C1-esterase inhibitor deficiency → hereditary angioedema)

Causes / Triggers

Category	Examples
Drugs	Penicillin (most common), aspirin/NSAIDs, opioids (virtually any medication can cause urticaria)
Foods	Shellfish, tree nuts, peanuts, eggs; histamine releasers: strawberries, lobster
Infections	Viral (rhinovirus, rotavirus, hepatitis B/C, EBV, coxsackievirus, SARS-CoV-2); occult Candida, dermatophytes, Helicobacter pylori, parasites
Contact	Animal dander/saliva, plants, cosmetics, topical medications, textiles
Systemic diseases	Mastocytosis, thyroid disease (hypo/hyperthyroidism), SLE, Sjögren's, rheumatoid arthritis, celiac disease, type 1 DM, Schnitzler's syndrome, Still's disease, serum sickness, hepatitis B/C, cryoglobulinemia, HES, malignancy
Physical	Cold, pressure, heat, sun, exercise, vibration, water
Idiopathic	~50% of CSU has no identifiable cause

Clinical Features

Morphology: Raised, blanching, erythematous papules/plaques; pale center; red border
Pruritus: Often intense; stinging or prickling sensation also common
Duration of individual lesions: <24 hours (key diagnostic feature)
Angioedema: Eyelids, lips, tongue, larynx, GI tract — occurs in combination with or separate from urticaria; laryngeal involvement is life-threatening
Urticarial vasculitis: Individual lesions persist >24 hours, may leave bruising; associated with hypocomplementemia and systemic vasculitis

Diagnosis

Acute urticaria: Usually clinical; no routine workup needed for a single episode.

Chronic spontaneous urticaria (CSU) — baseline workup:

CBC with differential
ESR and/or CRP
Thyroid function tests + anti-thyroid antibodies
Autologous serum skin test (ASST) — assesses for circulating histamine-releasing autoantibodies

Extended workup (based on history):

Infectious screen (H. pylori, hepatitis serology, stool parasites)
Allergen-specific IgE / skin prick testing
Tryptase (rule out mastocytosis)
ANA, complement levels (if vasculitis suspected)
Skin biopsy (if lesions >24h, non-blanching, or vasculitis suspected — biopsy shows perivascular eosinophilic/neutrophilic infiltrate)

Inducible urticarias: Provocation + threshold testing with the relevant stimulus (ice cube test for cold urticaria, dermographometer for symptomatic dermographism, etc.) — see Fitzpatrick's Table 41-1.

Differential Diagnosis

Drug eruption / morbilliform exanthem
Erythema multiforme (targetoid, non-transient)
Erythema marginatum
Urticarial bullous pemphigoid (lesions persist >24h; biopsy required)
Urticarial vasculitis
Still's disease (neutrophilic urticarial dermatosis — coincides with fever spikes)
Mastocytosis (urticaria pigmentosa)
Neutrophilic urticaria, papular urticaria

Management

Step 1 — Identify and remove triggers

Discontinue offending drug, allergen avoidance, treat underlying infection.

Step 2 — Pharmacotherapy (Stepwise)

Step	Agent	Notes
1st line	2nd-generation (non-sedating) H1 antihistamines	Cetirizine, fexofenadine, loratadine, desloratadine, bilastine — preferred for chronic use
Adjunct	H2 antihistamine (ranitidine/famotidine) added to H1 blocker	Modest additional benefit
Acute severe	Systemic corticosteroids	Prednisone or dexamethasone for moderate–severe episodes; 14–21 days with taper for recurrent urticaria; chronic steroid use NOT recommended
Refractory CSU	Omalizumab (anti-IgE monoclonal antibody)	Standard of care for H1-antihistamine-resistant CSU; approved and highly effective
Refractory CSU	Cyclosporine	Immunosuppressant for omalizumab failure/intolerance
Symptom relief	Hydroxyzine	Sedating H1 blocker; for acute pruritus relief

Anaphylaxis/angioedema with airway involvement: Epinephrine IM immediately → antihistamines + corticosteroids → observation.

Urticaria vs. Angioedema

Feature	Urticaria	Angioedema
Layer	Dermis	Subcutis / submucosa
Lesion	Wheal + flare, pruritic	Deep swelling, may be painful or burning
Sites	Anywhere	Face, lips, tongue, larynx, GI
Risk	Discomfort	Airway compromise (laryngeal)

Key Associations to Remember

Penicillin → most common drug cause (traces in dairy may sensitize)
Aspirin/NSAIDs → non-immunologic; effects persist weeks after stopping
Cholinergic urticaria + cold urticaria → common co-occurring inducible types
Cold urticaria + cryoglobulins → screen for hematologic/lymphoproliferative disease
Solar urticaria → consider erythropoietic protoporphyria (pitted nasal/hand scarring)
CSU + thyroid autoimmunity → well-established association (screen all CSU patients)
Omalizumab → backed by multiple RCTs and now guideline-recommended for antihistamine-refractory CSU (PMID 41182242 — 2025 Asian-Pacific clinical practice guideline)

Sources: Goldman-Cecil Medicine, Rosen's Emergency Medicine, Fitzpatrick's Dermatology, Harrison's Principles of Internal Medicine (22nd ed.), Dermatology 5e (Elsevier).

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