What are the causes of severe urticaria in adults?

Etiology of Severe Urticaria in Adults

Despite thorough evaluation, many cases of severe urticaria remain idiopathic (unexplained), but specific etiologies can be identified through systematic clinical assessment guided by the pattern and duration of symptoms. 1

Primary Etiologic Categories

Immunologic Mechanisms

Autoimmune urticaria accounts for approximately one-third of chronic cases, characterized by:

• Circulating functional autoantibodies against the high-affinity IgE receptor (FcεRI) or against IgE itself 2, 3
• Strong association with thyroid autoimmunity (14% prevalence vs. 6% in controls) 1
• Associated autoimmune conditions including Hashimoto's thyroiditis, rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome 3, 4

IgE-mediated allergic reactions to:

• Environmental allergens (latex, nuts, fish) 1
• Foods and food additives 5
• Medications (particularly antibiotics) 3
• Insect stings 3

Non-Immunologic Drug Reactions

Direct mast cell degranulation occurs independently of IgE receptor activation with:

• Opioids (e.g., codeine) 1
• Radiocontrast media 1
• NSAIDs and aspirin (mechanism involves leukotriene formation and histamine release) 1
• Dietary pseudoallergens including salicylates, azo dyes, and food preservatives 1

ACE inhibitor-induced angioedema results from inhibition of kinin breakdown, presenting as angioedema without wheals 1

Infectious Associations

Helicobacter pylori infection shows the strongest evidence:

• Meta-analysis demonstrates chronic urticaria resolution more likely when antibiotic therapy successfully eradicates H. pylori (Quality of evidence I, Strength of recommendation B) 1

Other proposed infections have limited supporting evidence:

• Dental abscesses 1
• Gastrointestinal candidiasis 1
• Helminth infections (can cause eosinophilia detectable on screening) 1

Physical Triggers

Mechanical stimuli:

• Delayed pressure urticaria 1
• Symptomatic dermographism 1
• Vibratory angioedema 1

Thermal stimuli:

• Cholinergic urticaria (sweating stimulus) 1
• Cold contact urticaria 1
• Localized heat urticaria 1

Other physical triggers:

• Aquagenic urticaria 1
• Solar urticaria 1
• Exercise-induced anaphylaxis 1

Systemic Diseases

Urticarial vasculitis presents with:

• Small vessel vasculitis on histology 1
• Wheals persisting for days (vs. 2-24 hours in ordinary urticaria) 1
• Potential joint and renal involvement 1

Autoinflammatory syndromes (critical to recognize in severe cases):

• Spontaneous wheals with pyrexia and malaise 1, 6
• Hereditary: Cryopyrin-associated periodic syndromes (CIAS1 mutations) 1, 6
• Acquired: Schnitzler syndrome 1, 6
• Erythrocyte sedimentation rate always elevated (vs. normal in ordinary chronic urticaria) 1, 6

Celiac disease shows significantly higher prevalence in children and adolescents with severe chronic urticaria compared to controls 1

Contact Urticaria

Percutaneous or mucosal absorption of allergens or chemicals:

• Localized reactions at contact site 1
• Can progress to systemic reactions or anaphylaxis in highly sensitized individuals 1
• Wheals typically last up to 2 hours 1

Critical Clinical Pitfalls

Malignancy is NOT statistically associated with urticaria despite individual case reports 1—avoid unnecessary oncologic workup unless other clinical indicators present.

Occult infections (dental, gastrointestinal candidiasis) have little supporting evidence 1—do not pursue extensive infectious workup without specific clinical indicators.

Fever with urticaria mandates consideration of autoinflammatory syndromes rather than ordinary urticaria 6—check ESR, which will be elevated in these conditions.

Duration of individual wheals is diagnostically critical:

• 2-24 hours: ordinary urticaria 1
• <1 hour: most physical urticarias 1
• 2-6 hours to develop, up to 48 hours to fade: delayed pressure urticaria 1
• Days: urticarial vasculitis 1