Urticaria and Angioedema: Clinical Algorithm for Diagnosis and Management

Urticaria is a common cause of pruritic skin wheals and/or angioedema, with transient lesions and an acute or chronic course. Diagnosis should begin with a detailed clinical history, identifying drugs, infections, foods, and physical triggers (cold, heat, pressure, exercise, contact), as well as red flags (pain, persistence longer than twenty-four hours, residual purpura, fever). The assessment is directed toward clinical confirmation and exclusion of alternative diagnoses, reserving laboratory tests for selected situations.
This algorithm presents a structured approach to urticaria, helping to identify patients who will benefit from additional investigation and stepwise therapeutic measures.

Initial assessment

Diagnosis of urticaria should begin with identifying suggestive signs and symptoms. Urticaria is characterised by erythematous, pruritic wheals, usually with central pallor, varying in size and shape, which may coalesce and are migratory; each individual lesion resolves within thirty minutes to twenty-four hours, without ecchymoses or residual pigmentation. Angioedema presents as a sudden, pronounced swelling of the deep dermis/subcutaneous tissue, erythematous or skin-coloured, with paraesthesias, burning, tightness or even pain (more than itch), and a slower resolution, up to seventy-two hours.

Temporal classification

After clinical confirmation, determine duration: up to six weeks defines acute urticaria; more than six weeks defines chronic urticaria. The pattern may be daily or intermittent and recurrent.

Angioedema without wheals

In recurrent angioedema without wheals, consider exposure to angiotensin-converting enzyme inhibitors. Other drug classes, less frequent but possible, include angiotensin receptor blockers, DPP-4 inhibitors and neprilysin inhibitors. If symptoms remit after discontinuation of the angiotensin-converting enzyme inhibitor, this usually occurs within days (rarely up to six months). Persistence after stopping the drug should raise suspicion of hereditary or acquired C1-inhibitor deficiency; order complement C4 and C1 esterase inhibitor, consider genetic testing, and refer to Allergy/Immunology.

Systemic signs

In the presence of unexplained recurrent fever, arthralgia or malaise, consider autoinflammatory urticarial syndromes. In such cases, request a complete blood count, erythrocyte sedimentation rate and C-reactive protein to screen for systemic inflammation.

Urticarial vasculitis

If individual lesions persist on average for more than twenty-four hours, suspect urticarial vasculitis. Features supporting this include persistent (rather than evanescent) episodes, lesions that are tender/painful rather than predominantly pruritic, lesions leaving purpura or bruise-like discolouration, and associated symptoms such as fever, marked malaise, arthralgia, hypertension, proteinuria or haematuria. If suspected, a skin biopsy of lesions is indicated.

Inducible forms

Assess whether lesions are triggered by physical stimuli: cold, heat, pressure, sunlight, water (aquagenic), cholinergic (heat, exercise or sweating), contact urticaria and vibratory angioedema. Confirmation is by standardised provocation tests. If inducible, classify as chronic inducible urticaria; otherwise, classify as chronic spontaneous urticaria.

Differential diagnosis

In acute urticaria: atopic dermatitis, contact dermatitis, drug eruptions, insect bites, bullous pemphigoid, minor erythema multiforme, plant reactions, viral exanthems, Frey syndrome (auriculotemporal), and Sweet syndrome. In chronic urticaria: urticarial vasculitis, papular urticaria, mastocytosis, autoinflammatory syndromes, C1 esterase inhibitor deficiency, systemic lupus erythematosus, polymorphic eruption of pregnancy, hypereosinophilic syndrome, and anaphylaxis.

Investigation

In acute urticaria, as it is usually self-limited, additional testing is not required beyond a focused history to identify triggers. Exceptions: suspected food allergy in sensitised patients or drug hypersensitivity (especially non-steroidal anti-inflammatory drugs), in which case consider skin prick testing, specific immunoglobulin E to allergens and a supervised oral food challenge where appropriate.

Treatment — first line

First-line therapy is a second-generation H1 antihistamine taken regularly. First-generation antihistamines should not be used routinely due to central nervous system adverse effects. If control is insufficient, the dose of the second-generation antihistamine may be increased progressively up to four times the usual dose, with reassessment every two to four weeks. After control, taper gradually. For severe flares, consider short, intermittent courses of oral prednisolone (rescue dose ~0.5 mg/kg). Montelukast may be added in refractory cases, acknowledging limited evidence.

Special populations

In children, consider screening for and treating parasitic infections when indicated. Second-generation H1 antihistamines approved for ages two to eleven include cetirizine, levocetirizine, loratadine and rupatadine, with dosing adjusted by age and weight. During pregnancy and breastfeeding, when necessary and after risk–benefit assessment, prefer cetirizine or loratadine.

Second line

If, despite optimising first-line therapy, symptom control remains insufficient, consider second-line treatments such as omalizumab or ciclosporin in refractory patients, under specialist supervision.

Clinical cases — Urticaria

Case 1 — Cold-induced urticaria

A 24-year-old woman develops pruritic wheals minutes after exposure to cold wind and when holding iced drinks; episodes resolve within less than 24 hours. No medications. What is the most appropriate confirmatory test?

  1. Total IgE
  2. Skin prick test with an inhalant panel
  3. Standardised cold provocation test (e.g., ice cube/TempTest)
  4. Immediate skin biopsy
See answer
✅ c) Standardised cold provocation test.
Rationale: Inducible urticarias are confirmed with standardised provocation tests. Total IgE and inhalant panels do not confirm this subtype; biopsy is not first line in typical, evanescent urticaria.

Case 2 — Uncontrolled chronic spontaneous urticaria

A 38-year-old man with daily wheals for 8 weeks. Taking cetirizine 10 mg/day with good adherence but still has itch and lesions. No systemic signs. What is the next best therapeutic step?

  1. Start a first-generation antihistamine at night
  2. Gradually up-titrate the second-generation H1 antihistamine to up to 4× the usual dose
  3. Prednisolone for 14 days as maintenance
  4. Immediate omalizumab as second line
See answer
✅ b) Gradually up-titrate the second-generation H1 antihistamine to up to four times the usual dose.
Rationale: Up-titration of a second-generation H1 antihistamine is the recommended next step, with reassessment every 2–4 weeks. First-generation antihistamines are not routine; corticosteroids only as short rescue courses; omalizumab/ciclosporin are for refractory cases after optimisation.

Case 3 — Isolated angioedema on an ACE inhibitor

A 62-year-old woman has episodes of lip and tongue swelling without wheals; she has been on enalapril for 6 months. No itch; each episode lasts 48–72 hours. What is the best initial approach?

  1. Increase the dose of the H1 antihistamine
  2. Stop the ACE inhibitor and re-evaluate; if persistent, test C4 and C1 esterase inhibitor
  3. Request total IgE to exclude atopy
  4. Start ciclosporin
See answer
✅ b) Stop the ACE inhibitor and re-evaluate; if persistent, test C4 and C1 esterase inhibitor.
Rationale: Angioedema without wheals in ACE inhibitor users suggests a bradykinin-mediated mechanism. Stopping the ACE inhibitor is the priority; if episodes persist, investigate C1 esterase inhibitor deficiency (hereditary/acquired). Total IgE is not useful; immunosuppressants are not first line here.

Frequently Asked Questions about Urticaria

1) What is urticaria and how does it differ from angioedema?

Urticaria consists of erythematous, pruritic wheals that are evanescent (each lesion resolves within 30 minutes to 24 hours) and leave no residual pigmentation. Angioedema is a sudden swelling of the deep dermis/subcutaneous tissue, with tightness/burning/pain more than itch, and slower resolution (up to 72 hours). They may occur separately or together.

2) When is it acute and when is it chronic?

Acute when the total duration of episodes is ≤ six weeks; chronic when > six weeks, with a daily or recurrent pattern.

3) Which signs should raise suspicion of urticarial vasculitis?

Lesions that persist > 24 hours, are tender/painful, and leave purpura or bruise-like discolouration. If there is fever, marked malaise, arthralgia, hypertension, proteinuria/haematuria, consider a confirmatory biopsy.

4) Which tests should be ordered in acute urticaria?

Usually none are required beyond a focused history for triggers. Exceptions: suspected food allergy or drug hypersensitivity (e.g., non-steroidal anti-inflammatory drugs), when skin prick testing, specific IgE, and, in an appropriate setting, a supervised oral challenge may be considered.

5) In chronic urticaria — do I need lab tests?

In the absence of systemic signs, assessment is mainly clinical. With unexplained fever, arthralgia or malaise, a complete blood count, erythrocyte sedimentation rate and C-reactive protein can help screen for systemic inflammation.

6) What should I do for angioedema without wheals in a patient on an ACE inhibitor?

Stop the angiotensin-converting enzyme inhibitor and re-evaluate (remission in days, rarely up to six months). If symptoms persist, test C4 and C1 esterase inhibitor to exclude hereditary/acquired angioedema.

7) Are there “inducible” urticarias? How do I confirm them?

Yes: triggered by cold, heat, pressure, sunlight, water (aquagenic), cholinergic (heat/exercise/sweating), contact, and vibration. Confirm with standardised provocation tests. If positive, classify as chronic inducible urticaria; otherwise, spontaneous.

8) Is total IgE useful for diagnosis?

No for routine screening/diagnosis of urticaria. Reserve for specific contexts (e.g., selected allergic diseases) — it does not change management in most urticaria cases.

9) What is first-line treatment?

Second-generation H1 antihistamines taken regularly. If control is insufficient, gradually up-titrate to up to four times the usual dose, with reassessment every two to four weeks. First-generation antihistamines are not routine.

10) What about severe exacerbations?

A short course of oral prednisolone may be considered as rescue therapy.

Autor: Filipe Cerca, MD