Urticaria and recurrent hives

Urticaria is the appearance of wheals, angioedema or both, caused mainly by mast cell activation.

Wheal. A transient itchy or burning, erythematous or pale oedematous plaque. Each lesion fades within 24 hours and leaves normal skin.

Angioedema. Swelling of the deep dermis, subcutis or mucosa. It is painful or tight rather than itchy and lasts up to 72 hours. It occurs with wheals in about half of chronic cases. Isolated angioedema without wheals needs a different work up.

Duration. Acute urticaria lasts under 6 weeks. Chronic urticaria lasts 6 weeks or longer.

Classification. Acute spontaneous urticaria, chronic spontaneous urticaria (no specific trigger), and chronic inducible urticaria (symptomatic dermographism, cold, delayed pressure, solar, heat, vibratory, cholinergic, contact and aquagenic).

Mechanisms. Mast cells and basophils release histamine, platelet activating factor and leukotrienes. In chronic spontaneous disease, IgG autoantibodies to the high affinity IgE receptor or to IgE (type IIb autoimmunity) and IgE autoantibodies to autoantigens (type I autoimmunity) both operate. Bradykinin mediated angioedema arises from C1 inhibitor deficiency or ACE inhibitor use.

Key distinctions. Wheals lasting over 24 hours, painful or burning, leaving bruising or pigment, point to urticarial vasculitis. Angioedema without wheals, recurrent abdominal pain and a family history suggest hereditary angioedema.

Severity scales. The Urticaria Activity Score over 7 days sums daily wheal count and itch scores (0 to 3 each, range 0 to 42 weekly). A weekly score of 0 means free of disease, 1 to 6 well controlled, 7 to 15 mild, 16 to 27 moderate and 28 to 42 severe. The Urticaria Control Test ranges from 0 to 16, and under 12 means poor control.

History

• Duration of each wheal, number of episodes each day or week, time of day, and whether lesions leave marks.
• Triggers: foods in the preceding 2 hours, drugs (aspirin, NSAIDs, opioids, penicillins, ACE inhibitors, contrast media, vancomycin), insect stings, latex, infection, exercise, heat, cold, pressure, sunlight, water, vibration, stress, menses.
• Associated features: fever, arthralgia, weight loss, abdominal pain, flushing, diarrhoea, bone pain.
• Family history of angioedema or autoimmune disease; previous thyroid disease, coeliac disease, lupus, chronic infection, parasites; travel to helminth endemic areas.
• Impact on sleep and quality of life.

Examination

• Wheals (size, number, central pallor), angioedema sites (lips, eyelids, tongue, hands, genitalia), purpura, residual pigmentation, scale.
• Dermographism: stroke the back with a firm blunt tool; a wheal within 10 minutes is a positive result.
• Provocation tests when history suggests: ice cube on the forearm for up to 5 minutes and observe for 10 minutes after removal (cold); sustained pressure of 3 to 4.5 kg for 10 to 15 minutes with review at 6 to 8 hours (delayed pressure); exercise or warm bath (cholinergic); timed light exposure (solar); water compress (aquagenic).
• Darier sign (urtication on stroking a brown macule) in mastocytosis.
• Airway, voice, work of breathing, blood pressure and pulse.

Red flags

• Tongue, lip or throat swelling, voice change, stridor, wheeze, dysphagia, hypotension, vomiting or collapse after exposure (anaphylaxis).
• Angioedema without wheals, especially with abdominal pain, family history, or ACE inhibitor use.
• Painful or burning wheals lasting over 24 hours, bruising, fever, arthralgia, or low complement (vasculitis).
• Fever, bone pain and monoclonal protein (Schnitzler syndrome).
• Fever with periodic urticaria from childhood, deafness and conjunctivitis (cryopyrin associated syndromes).
• Weight loss, night sweats, lymphadenopathy.

Special groups

• Pregnancy: urticaria may reflect pemphigoid gestationis or polymorphic eruption, so look for periumbilical papules and blisters.
• Children: acute urticaria is usually viral or food related.
• Older adults: bullous pemphigoid can present with urticarial plaques.
• Region specific: helminth infections (strongyloidiasis, ascariasis, schistosomiasis, filariasis) in endemic areas.

Spontaneous and inducible urticaria

• Acute spontaneous urticaria (viral infection, drug, food, stings, latex).
• Chronic spontaneous urticaria.
• Symptomatic dermographism.
• Cold urticaria.
• Delayed pressure urticaria.
• Cholinergic urticaria.
• Solar urticaria.
• Aquagenic urticaria.
• Heat urticaria.
• Vibratory angioedema.
• Contact urticaria.

Urticarial mimics and serious causes

• Anaphylaxis.
• Urticarial vasculitis.
• Hypocomplementaemic urticarial vasculitis syndrome.
• Schnitzler syndrome.
• Cryopyrin associated periodic syndromes.
• Adult onset Still disease.
• Serum sickness like reaction.
• Systemic lupus erythematosus.
• Bullous pemphigoid, urticarial phase.
• Pemphigoid gestationis.
• Cutaneous and systemic mastocytosis.
• Morbilliform and fixed drug eruptions.
• Erythema multiforme.
• Sweet syndrome.
• Papular urticaria.
• Viral exanthems.

Angioedema without wheals

• Hereditary angioedema (C1 inhibitor deficiency or dysfunction).
• Acquired C1 inhibitor deficiency (lymphoproliferative or autoimmune disease).
• ACE inhibitor induced angioedema.
• Angioedema with normal C1 inhibitor.
• Superior vena cava syndrome and facial cellulitis (swelling mimics).
• Contact dermatitis of the eyelids.
• Thyroid eye disease.

Associated conditions

• Autoimmune thyroid disease.
• Coeliac disease.
• Helminth infection.
• Chronic hepatitis B and C.
• Lymphoma.

Step 1. Exclude anaphylaxis and airway risk. Check the airway, breathing and circulation before anything else.

Step 2. Acute urticaria. The diagnosis is clinical and tests are not needed. When an IgE mediated trigger is suspected (symptoms within 2 hours of a food, drug or sting), skin prick testing or specific IgE is directed by the history.

Step 3. Chronic spontaneous urticaria. First line tests are full blood count with differential (eosinophilia suggests parasites, drugs or mastocytosis; leucopenia suggests lupus) and CRP or ESR. Extend only when the history points to a cause.

• TSH and thyroid peroxidase antibodies, total IgE.
• Tissue transglutaminase IgA with total IgA.
• Stool microscopy for ova and parasites and Strongyloides serology when exposure is likely.
• Hepatitis B and C serology, HIV test.
• ANA and complement C3 and C4 when vasculitis or lupus is suspected.
• Baseline serum tryptase: over 20 ng/mL suggests mastocytosis.
• Testing for Helicobacter pylori is of uncertain value.
• Allergen panels and food elimination diets are not useful in chronic spontaneous urticaria without a clear history.

Step 4. Suspected vasculitis. Skin punch biopsy (4 mm) of a lesion less than 24 hours old, with direct immunofluorescence. Add urinalysis, creatinine, C3, C4, C1q antibodies, ANA, ANCA, cryoglobulins, hepatitis B and C serology, and serum protein electrophoresis.

Step 5. Isolated or recurrent angioedema. Measure C4 (low between attacks in over 90% of hereditary angioedema), C1 inhibitor level and C1 inhibitor function (under 50% of normal supports deficiency or dysfunction). A low C1q level supports acquired deficiency. Normal C4 between attacks makes types I and II unlikely.

Step 6. Inducible urticaria. Directed provocation tests with threshold testing (cold, pressure, temperature) to document severity.

Step 7. After an acute reaction suspected to be anaphylaxis. Serum tryptase taken 1 to 2 hours after onset (up to 6 hours), with a baseline sample at least 24 hours after full recovery. A rise over 1.2 times baseline plus 2 micrograms/L supports mast cell activation.

Limits. The autologous serum skin test and basophil tests are not routine. Many chronic cases remain without an identified cause, and a normal screen does not mean serious disease is missed.

Immediate: anaphylaxis or airway angioedema.

• Adrenaline 0.5 mg (0.5 mL of 1 mg/mL) intramuscularly into the anterolateral thigh in adults and children over 12 years. Repeat every 5 minutes if there is no response. Children 6 to 12 years: 0.3 mg. Children 6 months to 6 years: 0.15 mg. Children under 6 months: 0.1 to 0.15 mg.
• High flow oxygen, lie flat with legs raised, intravenous crystalloid 500 to 1000 mL bolus for hypotension.
• Chlorphenamine and hydrocortisone are adjuncts only and must not delay adrenaline.
• Observe for at least 6 hours after resolution (12 to 24 hours after severe or refractory reactions, because biphasic reactions occur).
• Discharge with adrenaline autoinjectors (0.3 mg for weight over 30 kg; 0.15 mg for 15 to 30 kg), training and a written plan.

Bradykinin mediated angioedema (hereditary or acquired). Adrenaline, antihistamines and corticosteroids do not work, although adrenaline is still given if anaphylaxis cannot be excluded. Treat with one of:

• Plasma derived C1 inhibitor concentrate 20 U/kg intravenously over 10 minutes.
• Icatibant 30 mg subcutaneously, repeated after at least 6 hours, maximum 3 injections in 24 hours.
• Fresh frozen plasma 2 units if neither is available.
• Secure the airway early for laryngeal attacks.
• Long term prophylaxis (specialist): lanadelumab 300 mg subcutaneously every 2 weeks, berotralstat 150 mg orally once daily, or subcutaneous C1 inhibitor. Tranexamic acid 1 g orally 2 to 3 times daily is less effective. Avoid oestrogens and ACE inhibitors. Give short term prophylaxis with C1 inhibitor before dental or surgical procedures.

ACE inhibitor angioedema. Stop the drug permanently, do not rechallenge, and use an angiotensin receptor blocker only with caution because cross reactivity can occur. Watch the airway for at least 24 hours after laryngeal or tongue involvement.

Chronic spontaneous and inducible urticaria: stepwise therapy.

• Step 1: second generation H1 antihistamine at the licensed dose, taken regularly rather than as needed.
• Cetirizine 10 mg orally once daily (5 mg daily when creatinine clearance is under 50 mL/min or in hepatic impairment; avoid under 10 mL/min).
• Fexofenadine 180 mg orally once daily (60 mg daily in kidney impairment).
• Loratadine 10 mg orally once daily (10 mg on alternate days when creatinine clearance is under 30 mL/min or in severe hepatic impairment).
• Bilastine 20 mg orally once daily, 1 hour before or 2 hours after food.
• Desloratadine 5 mg orally once daily.
• Step 2: if control is inadequate after 2 to 4 weeks, increase the dose up to 4 times the licensed daily dose (for example cetirizine 10 mg up to 4 times daily, maximum 40 mg daily). This is off label but widely used. Monitor sedation and, in kidney or hepatic impairment, avoid dose escalation without specialist advice.
• Step 3: if symptoms persist for 2 to 4 weeks at the higher dose, add omalizumab 300 mg subcutaneously every 4 weeks (age 12 years and over), with the first doses given in a supervised setting. Review at 6 months and attempt to stop or lengthen the interval if disease control is complete. Evidence is strongest for chronic spontaneous urticaria.
• Step 4: ciclosporin 3 to 5 mg/kg orally daily in 2 divided doses (specialist). Monitor blood pressure, creatinine (stop if it rises over 30% from baseline), potassium, magnesium and lipids. Avoid in uncontrolled hypertension and kidney impairment. It has many CYP3A4 interactions.
• Short course for severe flares: prednisolone 20 to 40 mg orally once daily for 3 to 10 days, maximum 10 days. Avoid long term steroids.
• Montelukast 10 mg orally at night is an add on of limited benefit.
• Avoid first generation antihistamines as regular therapy because of sedation and anticholinergic effects. Chlorphenamine 4 mg orally at night may be used briefly.

Trigger measures. Avoid aspirin and NSAIDs if they provoke flares. For cold urticaria, avoid sudden whole body cold exposure such as swimming. Delayed pressure urticaria responds poorly to antihistamines and often needs omalizumab. Cholinergic urticaria: avoid overheating and use the antihistamine ladder.

Urticarial vasculitis. Specialist treatment: colchicine 0.5 mg orally twice daily (reduce in kidney impairment; interacts with clarithromycin and ciclosporin), dapsone 50 to 100 mg daily after G6PD testing, or prednisolone.

Special groups.

• Pregnancy: cetirizine or loratadine are used when needed; short courses of prednisolone are acceptable.
• Children: cetirizine 6 to 11 years 5 mg twice daily, 2 to 5 years 2.5 mg twice daily.

Monitoring. Record the weekly activity score at each visit. Review at 2 to 4 weeks for step changes. When well controlled, reduce treatment gradually.

Referral and escalation. Allergy or immunology for suspected hereditary angioedema, anaphylaxis or inducible urticaria with systemic reactions. Dermatology for disease uncontrolled despite fourfold antihistamine dose, or suspected vasculitis. Haematology for suspected mastocytosis or monoclonal gammopathy.

Admission criteria. Airway involvement, anaphylaxis, hypotension, laryngeal angioedema, or inability to control symptoms.

Discharge and follow up. Antihistamine plan, trigger diary, and written advice. Safety net advice: return immediately for throat or tongue swelling, breathlessness, voice change, dizziness or collapse.