What is urticaria, including its classification, pathophysiology, diagnostic work‑up, and recommended management?

Urticaria: Comprehensive Overview

Definition and Classification

Urticaria is defined by itchy wheals (with surrounding erythema resolving within 24 hours), angioedema (deeper swelling lasting up to 72 hours), or both, and is classified as acute (<6 weeks duration) or chronic (>6 weeks duration). 1

Key Clinical Features

• Individual wheals in ordinary urticaria last 2–24 hours before resolving without scarring 2
• Angioedema can occur with or without wheals and may persist up to 3 days if untreated 2
• The pathognomonic triad consists of: central swelling of various sizes with or without erythema, pruritus (or occasional burning), and complete resolution typically within 1–24 hours 3
• Urticaria affects up to 20% of individuals worldwide in their lifetime 4

Classification by Duration

• Acute urticaria: symptoms lasting <6 weeks 1, 5
• Chronic urticaria (CU): symptoms persisting >6 weeks 1, 5
• Episodic chronic urticaria: intermittent flares in chronic disease 6

Classification by Subtype

Physical urticarias are triggered by specific stimuli and typically resolve within 1 hour (except delayed-pressure urticaria) 1, 2:

• Dermographism: wheals induced by stroking or scratching the skin 1
• Cold urticaria: triggered by cold exposure 1
• Cholinergic urticaria: induced by stimuli that trigger sweating (acetylcholine release when core temperature rises), not simply overheating per se 7
• Delayed-pressure urticaria: develops 2–6 hours after pressure application and fades within 48 hours 2
• Contact urticaria: occurs only after percutaneous or mucosal allergen exposure, resolving within 2 hours 2

Chronic spontaneous urticaria (CSU): wheals arise without identifiable external trigger 1, 4

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Pathophysiology

The fundamental mechanism involves cutaneous mast cell activation with release of histamine and other inflammatory mediators, though acute and chronic urticaria have distinct etiological profiles. 5

Acute Urticaria Triggers

• Infections (especially viral) are the most common identifiable cause in children 8, 3
• Allergic reactions to foods (nuts, fish, eggs, milk), drugs, and latex 2, 3
• Physical stimuli: pressure, cold, heat, exercise 2
• Idiopathic: no cause identified in approximately 50% of acute cases 5

Chronic Urticaria Mechanisms

• Autoimmune etiology: at least 30% of chronic urticaria patients have circulating functional autoantibodies against high-affinity IgE receptor (FcεRI) or against IgE itself 1, 8
• Chronic infections: occult bacterial, viral, or parasitic infections 5, 8
• Food additives intolerance: preservatives, colorants 5
• Idiopathic: causative factor identified in only 20% of chronic cases in children 8

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Diagnostic Work-Up

The diagnosis of urticaria is primarily clinical; investigations should be guided by history and not performed routinely in all patients. 2

History and Physical Examination

Key historical elements to document:

• Duration of individual wheals: lesions persisting >24 hours suggest urticarial vasculitis rather than ordinary urticaria 1, 2
• Temporal pattern: acute vs. chronic, episodic vs. continuous 1
• Trigger identification: recent food exposures (especially common allergens), medications (especially NSAIDs, ACE inhibitors), infections, physical stimuli 2, 3
• Associated symptoms: fever and malaise suggest autoinflammatory syndromes (Muckle-Wells syndrome, Schnitzler syndrome) rather than ordinary urticaria 9
• Angioedema without wheals: requires immediate evaluation for C1-esterase inhibitor deficiency or ACE-inhibitor-induced angioedema 2
• Aggravating factors: overheating, emotional stress, alcohol, aspirin/NSAIDs 2

Laboratory Testing

For acute/episodic urticaria:

• No routine investigations are required unless history suggests a specific trigger 1, 2
• IgE-mediated reactions can be confirmed by skin-prick testing and specific IgE fluoroimmunoassay when environmental allergens are suspected 2

For chronic urticaria with severe disease or poor antihistamine response:

• Complete blood count with differential: to detect eosinophilia or leukopenia 1, 2
• Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP): normally normal in ordinary urticaria; elevated in vasculitis and autoinflammatory syndromes 1, 2
• Total IgE level: low or very low total IgE suggests autoimmune urticaria 2
• IgG-anti-thyroid peroxidase (TPO) level: high levels seen in autoimmune urticaria 1, 2
• Thyroid function tests: to screen for autoimmune thyroid disease 2
• Autologous serum skin test (ASST): reasonably sensitive and specific marker for histamine-releasing autoantibodies in specialized centers 1, 2

Specialized Testing for Mimics and Complications

For suspected urticarial vasculitis:

• Lesional skin biopsy is essential to histologically confirm small-vessel vasculitis (leukocytoclasia, endothelial damage, perivascular fibrin, red-cell extravasation) 1, 2
• Complement testing (C3, C4) differentiates normocomplementemic from hypocomplementemic disease 2

For angioedema without wheals:

• Serum C4 measurement is highly sensitive (>95%) for C1-inhibitor deficiency as initial screening 2
• If C4 is low, perform quantitative and functional C1-inhibitor assays for confirmation 2
• Type I hereditary angioedema (HAE): low immunochemical and functional C1-inhibitor 2
• Type II HAE: normal antigenic level but reduced functional activity 2
• Acquired C1-inhibitor deficiency: reduced C1q in addition to low C1-inhibitor 2

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Disease Activity and Impact Assessment

Patients with chronic urticaria should be assessed for disease activity, quality of life impairment, and disease control at the first and every follow-up visit using validated patient-reported outcome measures (PROMs). 1

The 2022 international guideline recommends 6 validated instruments for assessment, all available in multiple languages free of charge 1:

• Disease activity scores
• Quality of life measures
• Disease control assessments

Management decisions should be based on these assessments, most importantly disease control measurements. 1

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Management

General Measures and Trigger Avoidance

Identify and eliminate avoidable triggers:

• Aspirin and NSAIDs should be avoided because they trigger mast-cell degranulation and worsen urticaria 2
• Physical triggers: avoid overheating, tight clothing (pressure), extreme temperatures 2
• Dietary triggers: eliminate identified food allergens 1
• Medications: discontinue suspected causative drugs 3

First-Line Pharmacologic Treatment

Second-generation H1 antihistamines at standard doses are the cornerstone of therapy for all forms of urticaria. 1, 2

• Approximately 40% of patients achieve adequate symptom control with antihistamine monotherapy 1, 2
• Non-sedating H1 antihistamines are preferred over sedating agents 1
• For children, verify age-specific dosing and formulation restrictions against product labeling 2

Dose Escalation Strategy

When standard-dose antihistamines are insufficient, increase the dose of second-generation H1 antihistamines up to 4-fold above the manufacturer's licensed recommendation, as the potential benefits outweigh risks. 1

This practice has become common and is supported by guideline consensus, though it exceeds licensed dosing 1.

Adjunctive Therapies for Resistant Cases

Combination strategies for inadequate response to high-dose H1 antihistamines:

• H2 antihistamines added to H1 agents may improve control, though evidence is limited and benefit is mainly for associated dyspepsia 1, 2
• Sedating antihistamines at night can be added for nocturnal symptom control 1
• Antileukotriene agents (leukotriene receptor antagonists) may benefit a small subgroup of chronic urticaria patients 1, 8

Corticosteroid Use

Short-course oral corticosteroids should be restricted to specific indications:

• Severe acute urticaria or angioedema affecting the mouth 1
• Delayed-pressure urticaria or urticarial vasculitis may require more prolonged treatment 1
• For children, use lower doses than the adult regimen of 50 mg daily for 3 days 2
• Long-term oral corticosteroids should be avoided; they are reserved only for selected severe cases under specialist supervision 2

Advanced Immunomodulating Therapies

For chronic autoimmune urticaria with disabling disease unresponsive to optimal conventional treatments:

• Omalizumab (anti-IgE monoclonal antibody) 6
• Cyclosporine has been used with good success in resistant cases 8
• Tacrolimus is an alternative immunomodulator 8

These agents should be restricted to specialist-supervised care 1.

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Emergency Management

For life-threatening presentations with laryngeal angioedema or anaphylaxis:

• Intramuscular epinephrine is the immediate first-line intervention 2, 8
• For children weighing approximately 15–30 kg, use a fixed-dose 150 µg epinephrine autoinjector 2
• Parenteral hydrocortisone may be given as an adjunct for severe laryngeal edema, recognizing delayed therapeutic effect 2
• If no significant improvement after the first epinephrine dose, administer a second dose 2
• Prescribe an epinephrine autoinjector for home use when history indicates risk of recurrent life-threatening attacks 2
• Adjunctive measures include antihistamines, fluids, and bronchodilators as required 8

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Prognosis

Acute Urticaria

• Most cases are self-limited and resolve spontaneously 5
• Lesions typically resolve within 2–3 hours without a trace 6

Chronic Urticaria

• Patients with wheals alone: many clear by 6 months 1
• Patients with wheals and angioedema: over 50% still have active disease after 5 years, indicating a poorer outlook 1
• A substantial proportion remains idiopathic despite thorough evaluation 2
• The prognosis for complete recovery has probably not changed over 40 years, though more potent antihistamines now available result in better disease control 1

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Important Differential Diagnoses and Mimics

Wheals persisting beyond 24 hours should raise suspicion for alternative diagnoses:

Urticarial Vasculitis

• Painful wheals that persist >24 hours and resolve with bruising or hyperpigmentation 2
• Systemic manifestations may include joint pain, renal involvement, fever, and fatigue 2
• Requires lesional skin biopsy for definitive diagnosis 2

Autoinflammatory Syndromes

• Spontaneous wheals accompanied by pyrexia (fever) and malaise distinguish these from ordinary urticaria 9
• Consider Cryopyrin-associated periodic syndromes (CAPS) such as Muckle-Wells syndrome (hereditary) 9
• Consider Schnitzler syndrome (acquired) 9

Angioedema Without Wheals

• Requires evaluation for C1-esterase inhibitor deficiency (hereditary or acquired) or ACE-inhibitor-induced angioedema because management differs fundamentally 2
• Abdominal pain may be the sole manifestation of C1-inhibitor deficiency, even without visible angioedema 2

Other Mimics

• Drug eruptions 3
• Viral eruptions 3
• Urticaria pigmentosa (mastocytosis) 6

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Common Pitfalls and How to Avoid Them

Extensive laboratory work-ups are unnecessary for typical acute urticaria and do not add clinical value. 2

• Avoid routine testing in acute/episodic urticaria unless history suggests a specific trigger 1, 2
• Reserve comprehensive testing for chronic urticaria with severe disease or poor response to antihistamines 2

Do not overlook urticarial vasculitis:

• Any wheal persisting >24 hours warrants skin biopsy 1, 2
• Failure to diagnose vasculitis delays appropriate systemic evaluation and treatment 2

Recognize angioedema without wheals as a distinct entity:

• Immediate C4 screening prevents delays in diagnosing life-threatening C1-inhibitor deficiency 2
• ACE-inhibitor-induced angioedema requires drug discontinuation, not antihistamines 2

Avoid long-term corticosteroids:

• Chronic steroid use for urticaria leads to significant adverse effects without addressing underlying pathology 2
• Reserve steroids for short courses in specific severe presentations 1, 2

Consider autoinflammatory disease when fever accompanies urticaria:

• Recurrent unexplained fever alongside urticarial lesions should prompt consideration of autoinflammatory disease rather than chronic spontaneous urticaria 9