Urticaria

• Urticaria, commonly known as hives, is a skin condition characterized by the sudden appearance of raised, itchy welts on the skin.
• These welts can vary in size and shape and may appear anywhere on the body.
• Urticaria can be acute or chronic, depending on the duration and recurrence of the symptoms.
• Angioedema: Can occur with urticaria, characterized by localized nonpitting edema of the subcutaneous or interstitial tissue, which may be painful and warm.
• 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

• Similar pathophysiologic mechanisms: histamine release from mast cells/basophils.
• IgE Mediated: Common in allergic reactions.
• Non-IgE and Nonimmunologic: Includes direct mast cell activation, proteases from aeroallergens, complement system activation
• Autoimmune Component: A subset of chronic urticaria patients may have antibodies to IgE and the high-affinity IgE receptor

• non-IgE mediated:
  • Autoimmune disease
  • Aeroallergens
  • bacterial/viral/fungal infections – Infections are most common cause in children.
  • cryoglobulinemia
  • vasculitis
  • lymphoma
• IgE mediated:
  • Aeroallergens
  • contact allergen
  • Food allergens
    • eggs, fish, cheese, tomatoes, others
  • Insect venom
    • bees, wasps, jellyfish, mosquitoes
  • insect venom
  • medications
  • parasitic infections.
• Nonimmunologically mediated:
  • Contact allergen
  • physical stimuli (cold, heat, pressure)
  • medications
  • mastocytosis
  • light
  • Water

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: affecting superficial dermis = urticaria : occurs anywhere on body, especially the limbs and trunk.
2. Deep: affecting subcutaneous tissue = Angiooedema: non-pitting, non-pruritic Swelling involving deeper layers of the skin, particularly in areas such as the face, lips, tongue, and throat.

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

Treatment of Acute Urticaria and Angioedema

1. Second-Generation H1 Antihistamines: First-line medication, possibly titrated to higher doses if needed.
2. H2 Antihistamines: Add if symptoms are not controlled with H1 antihistamines.
3. Corticosteroids: Prednisone or prednisolone for 3 to 10 days in severe cases.
4. Epinephrine Autoinjectors: Prescribe for patients at risk of anaphylaxis.
5. Follow-Up: Evaluate treatment success and tolerance in 2 to 6 weeks.
6. Emergency Treatment for Severe Angioedema: IM epinephrine and airway management for angioedema of the larynx or tongue.

Daytime Antihistamines (Step 1):

• Cetirizine: 10 mg once daily.
• Desloratadine: 5 mg once daily.
• Fexofenadine: 180 mg once daily.
• Levocetirizine: 5 mg once daily.
• Loratadine: 10 mg once daily.

Nighttime Sedating Antihistamines (Step 2):

• Cyproheptadine: 4 mg once daily.
• Dexchlorpheniramine: 2 mg once daily.
• Pheniramine: 45.3 mg once daily.
• Promethazine: 50 mg once daily.
• Alimemazine (Trimeprazine): 10 mg once daily.

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

Angiodema

• involves the reticular dermis, subcutaneous, and submucosal layers 
• occurs anywhere but especially peri-orbital region, lips, tongue, uvula, soft palate, or larynx.
• tends to feel thick and firm. 
• can be painful and can also feel warm to the touch. 
• may be histamine-mediated or non-histamine-mediated:
  1. histamine-mediated angioedema may co-exist with urticaria and is mast-cell mediated
     1. e.g. anaphylaxis, allergies, some drug reactions
  2. non-histaminergic (bradykinin-mediated) angioedema tends to be more severe, more prolonged and less responsive to adrenaline
     1. includes ACEI-related angioedema and both hereditary and acquired C1 esterase inhibitor deficiency – Rx: FFP

• Cuases
  • Hereditary angioedema (HAE) (type 1 and type 2)
    1. C1 esterase inhibitor deficiency (functionally abnormal C1-INH leads to bradykinin over-production)
    2. affects 1/50,000 people
    3. 50% present with recurrent episodes of angioedema by age 10 years
    4. type 1 has low antigen and functional levels of C1-INH
    5. type 2 has normal antigen levels but low functional levels of c1-INH
    6. HAE without C1-INH deficiency has also been described
  • Acquired
    1. Medications
       1. ACE Inhibitors (ACEI)
          1. up to 1% incidence
          2. angioedema is a class effect and is not dose dependent – symptoms can occur any time from a few hours up to 10 years after the initial dose (Winters et al, 2013)
          3. more common in African Americans and patients on immunosuppressants
          4. note that angioedema can occur in patients switched to an angiotensin receptor blocker
          5. role of adrenaline, steroids and antihistamines
             • unlikely to be be effective for ACEI-related angioedema
               • this a bradykinin-mediated condition, not related to mast cell degranulation
               • many ACEI-related angioedema cases can be managed by observation alone, without pharmacotherapy or intubation
               • most ACEI-related angioedema cases resolve over 24-48h
               • the apparent effectiveness of therapies may be confounded by spontaneous resolution of the angioedema
             • should be adminstered if the underlying cause of angioedema is uncertain (i.e. anaphylaxis is possible)
          6. FFP
             • possible therapy for ACEI-related angioedema (case reports), thought to be beneficial in most cases
             • FFP contains ACE (kininase II), which degrades bradykinin
             • risk of viral transmission, allergic reactions, and volume overload and a possibility of worsening symptoms in HAE (by providing additional substrate, kininogen)
       2. NSAIDS
          1. usually localised to the face +/- uritcaria
       3. Opiates
       4. Dextrans
    2. Acquired C1 esterase inhibitor deficiency due to an underlying lymphoproliferative disorder and/or an antibody directed against C1-INH
    3. Food
    4. Latex
    5. Local trauma
    6. Hymenoptera envenomations and other insect stings
  • Idiopathic most cases are thought to be histamine-mediated

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.