Urticaria

• Urticaria (“hives”) is characterized by transient, pruritic, erythematous wheals involving the superficial dermis.
  • Lesions typically last <24 hours and may recur.
  • Urticaria can be acute or chronic, depending on the duration and recurrence of the symptoms.
• Angioedema: may occur with or without urticaria.
  • It is characterized by sudden, localized, non-pitting swelling of the deeper dermis, subcutaneous, or submucosal tissues.
  • It is often painless but may be associated with discomfort or warmth.
• Pruritus: The intense itching can cause significant impairment in daily functioning and disrupt sleep.

Clinical Recommendations

• Rule out underlying anaphylaxis in patients presenting with urticaria.
• Extensive laboratory workup for urticaria is not generally recommended.
• Second-generation H1 antihistamines are safe and effective symptomatic therapy.
• Higher doses of second-generation H1 antihistamines can be used if needed.
• Short course of systemic corticosteroids may help control severe cases.
• First-generation H1 antihistamines, H2 antihistamines, and leukotriene receptor antagonists can be added for chronic urticaria.

Urticaria Characteristics

• Appearance: Wheals can appear on any part of the skin, pale to brightly erythematous, often with surrounding erythema.
• Lesions: Can be round, polymorphic, or serpiginous, rapidly growing and coalescing.
• Angioedema Locations: Primarily affects face, lips, mouth, upper airway, genitalia, extremities.
• Onset: Rapid, usually occurring over minutes.
• Resolution: Individual lesions typically resolve in 1-24 hours without treatment, though new wheals can erupt. Angioedema may take days to resolve.

Etiology and Pathophysiology

A. IgE-Mediated Hypersensitivity (Type I)

• Pathway:
  • First exposure → sensitisation → production of allergen-specific IgE antibodies by B cells (stimulated by Th2 cells, IL-4, IL-13).
  • IgE binds to high-affinity FcεRI receptors on mast cells and basophils.
  • On re-exposure to the allergen → allergen cross-links adjacent IgE molecules → immediate degranulation.
  • Release of histamine, prostaglandins, leukotrienes, cytokines → vascular leakage, vasodilation → urticaria, angioedema, anaphylaxis if systemic.
• Timing:
  • Sensitisation phase: First exposure → no symptoms yet, immune system prepares.
  • Elicitation phase: Second exposure or later → symptoms occur within minutes.
• Examples:
  • Aeroallergen
  • contact allergen
  • Food allergens
    • eggs, fish, cheese, tomatoes, others
  • Insect venom
    • bees, wasps, jellyfish, mosquitoes
  • medications
  • parasitic infections.

B. Non-IgE-Mediated Immunologic Activation

• Pathway:
  • Autoimmune urticaria: Autoantibodies (e.g., IgG anti-FcεRIα or anti-IgE) bind directly to mast cells → trigger degranulation without IgE-allergen cross-linking.
  • Infection-associated urticaria: Viral, bacterial, parasitic infections cause mast cell activation via cytokines, toll-like receptors (TLRs), complement activation (e.g., C3a, C5a = anaphylatoxins).
• Timing:
  • For non-IgE and non-immunologic mechanisms, there is no sensitisation phase — reaction can occur on first exposure.
  • Symptoms can occur even during first infection or autoimmune trigger.
• Examples:
  • Chronic spontaneous urticaria
  • Serum sickness (immune complexes activating complement)
  • Autoimmune urticaria
    • anti-IgE or anti-FcεRI antibodies
  • Viral/bacterial/fungal infections (especially in children)
  • Complement activation
    • e.g., hereditary angioedema types I/II → C1 esterase inhibitor deficiency

C. Non-immunologic Direct Mast Cell Activation

• Pathway:
  • Direct physical or chemical stimulation of mast cells → degranulation → histamine release.
  • No antibodies, no immune sensitisation needed.
• Timing:
  • Can occur on first exposure — no immune memory required.
• Examples:
  • Cold urticaria: Cold exposure → direct activation of mast cells.
  • Pressure urticaria: Sustained pressure → mast cell degranulation.
  • Mastocytosis
  • Direct mast cell degranulation (e.g., opioids, radiocontrast media)

Desensitisation (Tolerance Induction)

• What it is: Gradual exposure to small amounts of an allergen to “retrain” the immune system to tolerate it.
• Mechanism:
  • Induces regulatory T cells (Tregs) that suppress Th2 responses.
  • Reduces specific IgE.
  • Increases blocking IgG4 antibodies (which neutralize allergen before it can cross-link IgE).
• Examples:
  • Oral immunotherapy for peanut allergy
  • Venom immunotherapy (bees, wasps)
  • Drug desensitisation protocols (e.g., penicillin allergy desensitisation)
• Important: Desensitisation is specific to IgE-mediated allergy.
  It does not apply to non-IgE or non-immunologic triggers.

Aggravating Factors

• Heat: Exposure to heat can worsen the welts.
• Viral Infections: Viral illnesses can exacerbate CSU.
• Tight Clothing: Pressure from tight clothing can aggravate the condition.
• Drug Pseudoallergy: Non-allergic reactions to drugs such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and opiates can worsen CSU.
• Food Pseudoallergy: Non-allergic reactions to food additives such as salicylates, azo dye food coloring agents (e.g., tartrazine), and benzoate preservatives can trigger or worsen CSU.

Classification

• Acute urticaria: Recurs within less than six weeks.
• Chronic urticaria: Lasts longer than six weeks.
• Lifetime prevalence: Urticaria ~20%, chronic urticaria 0.5%-5%.

CLASSIFICATION ACCORDING TO SITE

1. Superficial (Superficial Dermis)

• Manifestation: Urticaria (hives)
• Description:
  • Transient, well-circumscribed, erythematous, edematous wheals.
  • Pruritic (itchy).
  • Typically appears anywhere on the body but more commonly on the limbs and trunk.
• Pathophysiology: Mast cell activation → histamine release → vasodilation and dermal edema (superficial layer).

2. Deep (Subcutaneous Tissue / Deeper Dermis)

• Manifestation: Angioedema
• Description:
  • Localized, deeper swelling involving the dermis, subcutaneous tissue, mucosa, or submucosal tissues.
  • Typically non-pitting, non-pruritic (although mild discomfort or tingling may occur).
  • Commonly affects face, eyelids, lips, tongue, throat, and sometimes extremities.
  • Can compromise the airway if it involves the tongue or larynx → emergency.
• Pathophysiology: Same mechanism as urticaria (histamine, bradykinin-mediated vascular permeability), but affecting deeper layers.

Key Clarifications:

Feature	Urticaria	Angioedema
Layer Involved	Superficial dermis	Deeper dermis and subcutaneous/mucosal tissue
Appearance	Raised, erythematous, well-defined wheals	Localized, deep, diffuse swelling
Itchiness	Usually pruritic	Usually non-pruritic
Duration	Wheals typically last <24 hours	Swelling may last up to 72 hours
Risk	Generally benign	Risk of airway obstruction if affecting larynx/tongue

Clinical History and Examinaiton

1. Clinical Diagnosis:
   • Diagnosis of urticaria is usually clinical.
2. History and Physical Examination:
   • First Step: Conduct a history and physical examination to characterize lesions and identify causes.
3. History Elements:
   • Onset and Timing: Consider menstrual cycle association if suspected.
   • Location and Severity: Document symptom location and severity.
   • Associated Symptoms: Identify symptoms suggesting anaphylaxis.
   • Environmental Triggers: Note potential environmental triggers.
   • Medication and Supplement Use: Include new or recently changed dosages.
   • Allergies: Record any known allergies.
   • Recent Infections: Document any recent infections.
   • Travel History: Note any recent travel.
   • Family History: Include family history of urticaria and angioedema.
   • Review of Systems: Identify possible causes and symptoms of systemic illnesses.
   • Sexual History: Document to assess risk of infectious causes.
   • Illicit Drug Use History: Note any illicit drug use.
   • Transfusion History: Include history of blood transfusions.
4. Physical Examination:
   • Vital Signs: Check vital signs.
   • Lesion Identification: Identify and characterize current lesions and their extent.
   • Testing for Dermatographism: Stroke with blunt end of a pen or tongue blade to test for urticaria pattern.
   • Cardiopulmonary Examination: Rule out anaphylaxis and infectious causes.
   • Other Examinations:
     • Eyes
     • Ears
     • Nose
     • Throat
     • Lymph Nodes
     • Abdomen
     • Musculoskeletal System
5. Clinical Clues:
   • Utilize history and physical examination findings to suggest certain etiologies for urticaria.

Possible Etiologies:

CLINICAL CLUE	POSSIBLE ETIOLOGY
Abdominal pain, dizziness, hypotension, large erythematous patches, shortness of breath, stridor, tachycardia	Anaphylaxis
Dermatographism, physical stimuli	Physical urticaria
Food ingestion temporally related to symptoms	Food allergy
High-risk sexual behavior or illicit drug use history	Hepatitis B or C (cryoglobulinemia) virus, human immunodeficiency virus
Infectious exposure, symptoms of upper respiratory tract or urinary tract infections	Infection
Joint pain, uveitis, fever, systemic symptoms	Autoimmune disease
Medication use or change	Medication allergy or direct mast cell degranulation
Pregnancy	Pruritic urticarial papules and plaques of pregnancy
Premenstrual flare-up	Autoimmune progesterone dermatitis
Smaller wheals (1 to 3 mm); burning or itching; brought on by heat, exercise, or stress	Cholinergic urticaria
Thyromegaly, weight gain, cold intolerance	Hypothyroidism
Travel	Parasitic or other infection
Weight loss (unintentional), fevers, night sweats	Lymphoma
Wheals lasting longer than 24 hours, nonblanching papules, burning or other discomfort, residual hyperpigmentation, fevers, arthralgias	Urticarial vasculitis

Conditions That May Be Confused with Urticaria

CONDITION	DISTINGUISHING CHARACTERISTICS
Arthropod bites	Lesions lasting several days, insect exposure history
Atopic dermatitis	Maculopapular, scaling, characteristic distribution
Bullous pemphigoid	Lesions lasting more than 24 hours, blistering, Nikolsky sign (light friction causes erosion or vesicle)
Contact dermatitis	Indistinct margins, papular, persistent lesions, epidermal component present
Erythema multiforme	Lesions lasting several days, iris-shaped papules, target appearance, may have fever
Fixed-drug reactions	Offending drug exposure, not pruritic, often bullous, hyperpigmentation
Henoch-Schönlein purpura	Lower extremity distribution, purpuric lesions, systemic symptoms
Mastocytoma	Yellow to orange pigmentation, Darier sign (a wheal and flare-up reaction produced by stroking the lesion), flushing, bullae, occurs most commonly in children
Mastocytosis, diffuse cutaneous	Normal to yellow-brown skin color, diffuse thickening, bullae
Morbilliform drug reactions	Maculopapular, associated with medication use
Pityriasis rosea	Lesions lasting weeks, herald patch, Christmas tree pattern, often not pruritic
Urticaria pigmentosa	Smaller lesions (1 to 3 mm), orange to brown pigmentation, Darier sign (a wheal and flare-up reaction produced by stroking the lesion)
Viral exanthem	Not pruritic, prodrome, fever, maculopapular lesions, individual lesions lasting days

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Treatment of Acute Urticaria and Angioedema

1. Immediate assessment & red flags

Red flag	Action
Stridor, voice change, tongue/lip swelling	IM adrenaline 0.01 mg/kg (max 0.5 mg) into mid-lat thigh, call ambulance, airway support.
Hypotension, wheeze, syncope	Treat as anaphylaxis (above), IV access, fluid resuscitation.

2. Non-pharmacological measures (first 24 h)

• Remove/avoid trigger when identifiable (e.g. stop NSAID, cool shower after exercise).
• Limit aggravators – hot baths, alcohol, tight clothing, spicy food.
• Cool compresses / calamine for symptomatic relief.
• Topical corticosteroids and topical antihistamine gels are not effective. Allergy Australia

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3. Pharmacological ladder (community setting)

Step	Medicine	Standard adult dose*	Key points
1	Non-sedating H1 antihistamine (first-line)	cetirizine 10 mg OD fexofenadine 180 mg OD loratadine 10 mg OD	Start immediately; onset ≈ 30 min. Double the daily dose if still symptomatic after 1 h (safe up to 4× in short courses).
		Paediatric cetirizine doses:	6-11 mo 0.25 mg/kg OD (max 2.5 mg) 1-2 y 2.5 mg BD 2-6 y 5 mg OD or 2.5 mg BD 6-12 y 10 mg OD or 5 mg BD
2	Night-time sedating H1 if sleep-disturbing itch	promethazine 25-50 mg nocte (adolescent/adult)	Limit to a few nights; avoid if driving next morning or in young children.
3	Short oral corticosteroid if severe or refractory (no airway compromise)	prednisolone 0.5–1 mg/kg (≤60 mg) daily × 3–5 days	Does not prevent relapse; taper unnecessary for ≤5 days.
4	H2 blocker (evidence modest)	famotidine 20 mg BD	Consider if partial response and drug available.
other:	Epinephrine autoinjector supply	EpiPen 150 µg (<20 kg) or 300 µg (≥20 kg)	For any patient who has had tongue/laryngeal oedema or systemic features.

*ETG Dermatology (2025 update) and ASCIA dosing recommendations.

4. Follow-up & when to refer

• Review at 1–2 weeks – ensure complete resolution and adherence, reinforce trigger avoidance.
• Refer to clinical immunology/allergy if:
  • recurrent episodes beyond 6 weeks (i.e. evolving chronic spontaneous urticaria),
  • recurrent angio-oedema, or
  • unclear trigger requiring skin-prick/IgE testing. Allergy Australia

5. Patient education / safety-netting

• Provide written factsheet (ASCIA “Hives (urticaria)”) and an ASCIA Action Plan if adrenaline prescribed.
• Advise to seek urgent care for breathing or swallowing difficulty, syncope, or rash plus vomiting/abdominal pain (possible anaphylaxis).
• Emphasise that antihistamines are symptom-relievers, not curative; prevent spontaneous wheals while medicine is in system.

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Chronic urticaria

2 types

1. chronic spontaneous urticaria
2. Inducible urticaria

Chronic spontaneous urticaria :

• mainly idiopathic (cause unknown)
• An autoimmune cause is likely
• About half of investigated patients carry functional IgG autoantibodies to immunoglobulin IgE or high-affinity receptor FcεRIα.
• also been associated with:
  • Chronic underlying infection, such as Helicobacter pylori (bowel parasites)
  • Chronic autoimmune diseases, such as systemic lupus erythematosus, thyroid disease, coeliac disease, vitiligo, and others.
• Weals in chronic spontaneous urticaria may be aggravated by:
  • Heat
  • Viral infection
  • Tight clothing
  • Drug pseudoallergy—aspirin, nonsteroidal anti-inflammatory drugs, opiates
  • Food pseudoallergy—salicylates, azo dye food colouring agents such as tartrazine (102), benzoate preservatives (210-220), and other food additives.

Chronic Inducible urticaria:

• is a response to a physical stimulus.

Type of inducible urticaria	Examples of stimuli inducing wealing
Dermographism	Stroking or scratching the skin Tight clothing Towel drying after a hot shower
Cold urticaria	Cold air on exposed skinCold waterIce block Cryotherapy
Cholinergic urticaria	Sweat induced by exercise Sweat induced by emotional upset Hot shower
Contact urticaria	Eliciting substance absorbed through the skin or mucous membrane Allergens (IgE-mediated): white flour, cosmetics, textiles, latex, saliva, meat, fish, vegetables Pseudoallergens or irritants: stinging nettle, hairy caterpillar, medicines
Delayed pressure urticaria	Pressure on affected skin several hours earlier Carrying heavy bag Pressure from a seat belt Standing on a ladder rung Sitting on a horse
Solar urticaria	Sun exposure to non-habituated body sites Often spare face, neck, hands May involve long wavelength UV or visible light
Heat urticaria	Hot water bottle Hot drink
Vibratory urticaria	Jackhammer
Aquagenic urticaria	Hot or cold waterFresh, salt, or chlorinated water

Invastigations (chronic urticaria):

1. Full Blood Examination: Check for eosinophilia which might indicate parasitic infection.
2. Skin Prick Tests and Radioallergosorbent Tests (RAST): Identify specific IgE-mediated allergies.
3. Investigations for Systemic Conditions:
   • Conduct if the patient has fever, joint or bone pain, and malaise.
   • Tests for chronic infections (e.g., Helicobacter pylori).
4. Patients with Angioedema without Weals:
   • Ask about ACE inhibitor drug use.
   • Test for complement C4, C1-INH levels, function, and antibodies; and C1q.
5. Biopsy:
   • Can be non-specific but may be done to rule out other conditions.
6. Autoimmune Testing:
   • ANA and DNA binding tests for urticarial vasculitis.

Treatment (chronic urticaria)

1. non-pharmacological
   • Avoid Identifiable Causes: Identify and avoid known triggers.
   • Elimination Diets: Temporary elimination diets under medical supervision may help in a small number of cases.
   • Topical Preparations: Use soothing preparations if urticaria is localized (e.g., crotamiton 10%, or phenol 1% in oily calamine or menthol 1% cream).
   • Lukewarm Baths: With Pinetarsol or similar soothing bath oil.
   • Avoid Aggravating Factors: Avoid excessive heat, spicy foods, and alcohol, Avoid aspirin and NSAIDs which can worsen symptoms.
2. Pharmacological
   • First-Line Treatment (from AFP):
     • Second-generation H1 Antihistamines:
       • Initial treatment.
       • Should be dosed daily for improved symptom control, not on an as-needed basis.
         • Cetirizine 10 mg (adult) orally
           1.  once daily in the morning (child 1 to 2 years: 0.25 mg/kg orally, twice daily; child 2 to 5 years: 5 mg orally, daily [can divide into two doses]; child 6 to 12 years: 10 mg orally, daily [can divide into two doses])
         • Desloratadine 5 mg (child 6 to 11 months: 1 mg; child 1 to 5 years: 1.25 mg; child 6 to 11 years: 2.5 mg) orally, once daily in the morning
         • Fexofenadine 180 mg (adult) orally, once daily in the morning (child 6 to 23 months: 15 mg twice daily; child 2 to 11 years: 30 mg twice daily)
         • Levocetirizine 5 mg (adult and child older than 12 years) orally, once daily in the morning
         • Loratadine 10 mg (child 1 to 2 years: 2.5 mg; child 2 to 12 years and less than 30 kg: 5 mg; child 2 to 12 years and more than 30 kg: 10 mg) orally, once daily in the morning.
     • Second-Line Treatment (if first-line is insufficient):
       • Titrate Up: Increase the dose of second-generation H1 antihistamines up to 2-4 times the usual dose.
       • Alternative Antihistamine: Add a different second-generation H1 antihistamine.
       • Nighttime Antihistamine: Add first-generation H1 antihistamines at nighttime.
       • H2 Antihistamines: Add H2 antihistamines.
       • Leukotriene Receptor Antagonists: Add medications like montelukast (Singulair) and zafirlukast (Accolate), especially in patients with NSAID intolerance or cold urticaria.
     • Third-Line Treatment (if second-line is insufficient):
       • High-Potency Antihistamines: Add and titrate high-potency antihistamines like hydroxyzine or doxepin (tricyclic antidepressant with strong antihistaminic effect).
       • Fourth-Line Treatment:
         • Referral to Subspecialist: For use of immunomodulatory agents.
         • Effective Agents: Omalizumab (Xolair) and cyclosporine (Sandimmune) have the most robust data supporting their use.
     • Flare-Up Management:
       • Corticosteroids: Use a three- to 10-day burst of corticosteroids (prednisone or prednisolone up to 1 mg/kg/day); long-term use is not recommended due to adverse effects.
       • Topical Corticosteroids: Potent topical corticosteroids may be beneficial in localized delayed-pressure urticaria.
     • Stepping Down Treatment:
       • Once symptoms are adequately controlled, physicians should consider stepping down treatment sequentially.

TREATMENT OF CHRONIC URTICARIA

Papular urticaria

1. This is a hypersensitivity to insect bites or insects in the environment, particularly seen in children aged 2–6 years. 
2. The lesions are grouped together, often as clusters of very itchy papules.
3. Common urticaria tends to come and go within hours but the lesions of papular urticaria persist.
4. The treatment for insect bites includes antipruritics and topical corticosteroids, e.g. betamethasone dipropionate 0.05% ointment or cream tds until resolved.