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Red flags

• Angioedema WITHOUT urticaria or pruritus is bradykinin-mediated — think hereditary angioedema (C1-INH deficiency), ACE inhibitor-induced angioedema, or acquired C1-INH deficiency; adrenaline, antihistamines, and corticosteroids are NOT effective and giving repeated doses while the airway closes is a documented cause of death.
• Any wheal that lasts more than 24 hours, leaves bruising or residual pigmentation, or is painful rather than pruritic is urticarial vasculitis until proven otherwise — perform a 4 mm punch skin biopsy with immunofluorescence and check complement; this is a leukocytoclastic vasculitis, not ordinary chronic urticaria, and the management is different.
• Acute attacks of hereditary angioedema do NOT respond to adrenaline, antihistamines, or corticosteroids — give C1 inhibitor concentrate 20 units per kg IV or icatibant 30 mg SC immediately and secure the airway; laryngeal oedema is the leading cause of death.
• ACE inhibitor angioedema can occur years after starting therapy — any patient on an ACE inhibitor with lip or tongue swelling and no urticaria has ACE inhibitor angioedema until proven otherwise; stop the drug permanently and NEVER rechallenge.
• Cold contact urticaria can progress to anaphylaxis on cold water immersion — a documented cause of drowning; warn the patient explicitly, advise never to swim alone, and ensure adrenaline availability.
• An elevated serum tryptase (especially above 20 micrograms per litre) in recurrent unexplained urticaria or anaphylaxis suggests systemic mastocytosis or a clonal mast cell disorder — request bone marrow evaluation (KIT D816V mutation, CD25, tryptase stain).
• Extensive food and inhalant allergy panels are NOT indicated in chronic spontaneous urticaria — CSU is driven by autoimmunity or intrinsic mast cell activation, not IgE-mediated food allergy; broad panels produce false positives, drive unnecessary elimination diets, and delay guideline-directed treatment.
• Sedating first-generation antihistamines (promethazine, chlorpheniramine, hydroxyzine) impair cognition, reaction time, and sleep architecture even when the patient does not feel sleepy, and increase falls in older adults — the guideline explicitly recommends second-generation non-sedating agents for chronic urticaria.