L-19 Urticaria: Hives

• Urticaria is commonly known as hives.
• Kelsey Reindel, D.O. is presenting on this topic

Lecture Objectives

• Discuss the etiology, evaluation, diagnosis, and treatment of acute urticaria
• Discuss the etiology, evaluation, diagnosis, and treatment of chronic urticaria

Primary Morphology (Lesion Type)

• Macule is a flat lesion less than 1 cm, without elevation or depression
• Patch is a flat lesion greater than 1 cm, without elevation or depression
• Plaque is a flat, elevated lesion, usually greater than 1 cm
• Papule is an elevated, solid lesion less than 1 cm
• Nodule is an elevated, solid lesion greater than 1 cm
• Vesicle is an elevated, fluid-filled lesion, usually less than 1 cm
• Pustule is an elevated, pus-filled lesion, usually less than 1 cm
• Bulla is an elevated, fluid-filled lesion, usually greater than 1 cm
• Size varies
• Demarcation can be well-demarcated or not well-demarcated
• Colors can be white, red, purple, brown, yellow, black, or blue

Secondary Morphology

• Serum (Dry crust)
• Fissure
• Lichenification
• Erosion
• Ulceration
• Scaling
• Wheal
• Distribution can be extensor, generalized, or photodistributive

Defining Urticaria

• Size is various
• Color is Erythematous (red)
• Demarcation is Well-Demarcated
• Distribution on the trunk, extremities, and areas exposed to pressure
• Shape Polycyclic, Annular, or Geographic
• Morphology is Annular/Polycyclic, Erythematous, Well-Demarcated, Transient, Edematous Plaque without Scaling and a notable flare (Wheal)
• Round - nummular, discoid (shape)
• Annular is ring-shaped (shape, configuration, grouping)
• Arcuate - part of a ring, arc-shaped (shape, configuration, grouping)
• Concentric - rings within rings (configuration)
• Polycyclic - formed from confluent annuli (configuration)
• Gyrate - forms spirals (configuration)
• Figurate - figure-forming (shape, configuration)
• Linear - forms a line (shape, configuration, grouping)
• Serpiginous - wavy, snake-like (shape, configuration, grouping)
• Whorled - forms swirls (shape, configuration)
• Reticulate - retiform, net-like, lacy (shape, configuration)
• Herpetiform - herpes-like (configuration, grouping)
• Agminate - clustered (grouping)
• Rash of round, red welts on the skin that forms after Mast Cell Degranulation
• Characterized by superficial Dermal edema
• Intensely Pruritic
• May or may not be associated with Angioedema
• A fleeting time course (30 minutes to 24 hours) with skin returning to normal
• Can be Acute, Chronic, or Physical

Pathophysiology

• Mast Cell Dependant & IgE Dependant:
• Drugs
• Pollens
• Foods
• Insect Stings
• Latex
• Parasitic
• Mast Cell Dependant, IgE Independent:
• Opiates
• Antibiotics- Vancomycin
• Curare
• Muscle Relaxants
• Radiographic Contrast
• “Stinging Nettle”
• Mast Cell & IgE Independent:
• Hereditary Angioneuritic Edema
• Aspirin
• Type 1 Hypersensitivity Reactions
• Requires exposure to a protein that is large enough to serve as an antigen
• Intradermal edema due to Capillary and Venous Vasodilation: -- Histamine -- Bradykinin -- Vasoactive Chemicals
• Non-immune mediated mast cell activation:
  • Direct nonallergic activation of mast cells (antigens act directly on mast cell instead of on the IgE Receptor)

Identifiable causes of urticaria:

• Infections Viral Parasitic Bacterial
• IgE-mediated allergic cases: Medications Insects: -- Stinging (yellow jackets, bees, wasps, hornets, fire ants) -- Biting (Triatoma [kissing bugs]) Foods Blood products (urticarial transfusion reaction) Latex (contact or inhaled) Contact allergens (animal saliva, raw foods) Aeroallergens (rare) Food additives
• Direct mast cell activation: Narcotics/opiates Muscle relaxants (eg, succinylcholine) Radiocontrast agents Vancomycin
• Physical stimuli: Dermatographism Delayed pressure Cold Cholinergic Vibratory Aquagenic Solar Exertion/exercise
• Miscellaneous mechanisms: Nonsteroidal anti-inflammatory drugs Serum sickness Transfusion reactions (distinct from IgE-mediated reactions) Hormone-associated (progesterone) Stinging nettle
• IgE: immunoglobulin E.

Main Types of Urticaria

• Acute:
  • <6 weeks duration
  • Often relieved within hours to days
  • A trigger is usually easily identified
  • Food, insect bites, drug reaction, infection
• Chronic
  • Recurrent
  • Signs and symptoms recurring on most days of the week for >6 weeks
  • Most often Idiopathic

Chronic Urticaria

• Chronic Spontaneous Urticaria (CSU):
  • Greater than 6 weeks
  • Signs and Symptoms recurring on most days of the week
  • No specific cause or trigger
  • Can have associated Headache, Fatigue, Joint Pain, GI symptoms
  • There is a strong association between chronic spontaneous urticaria and other immune disorders, particularly autoimmune thyroid disease.
• Epidemiology:
  • CSU affects ~1% of the US population, believed to be similar worldwide.
  • Affects males and females
  • Females >> males
  • Children & adults can suffer from CSU; however, it's more prevalent in the third to fifth decade of life.
• Chronic Inducible Urticaria (CIU)
  • Greater than 6 weeks
  • Signs and Symptoms recurring on most days of the week
  • Commonly, these stimuli that provoke weals to develop include stroking or scratching the skin (dermographism), exercise, and emotional upset (cholinergic urticaria).
  • Less common forms of chronic inducible urticaria are triggered by cold, heat, pressure, sunlight (solar urticaria), contact with water or various chemicals (contact urticaria), or vibration.
• Epidemiology:
  • CSU affects ~2% of the US population, believed to be similar worldwide.
  • Affects males and females
  • Females >> males

Physical Urticaria

• Inciting factors and diagnostic tests for physical and other inducible urticarias:
  • Symptomatic dermographism (urticaria factitia): -- Inciting Trigger: Firm stroking, scratching, pressure -- Diagnostic Test: Moderate stroking of the skin with a blunt, smooth object or dermographometer.
  • Delayed-pressure urticaria/angioedema -- Inciting Trigger: Application of pressure 0.5 to 12 hours before onset of symptoms -- Diagnostic Test: Sling with weights placed over arm or shoulder for 15 minutes. Patient reports symptoms over the next 24 hours.
  • Cholinergic urticaria -- Inciting Trigger: Elevation of body temperature (exercise, hot water, strong emotion, hot or spicy food) -- Diagnostic Test: Exercise using a machine to the point of sweating, then continue for 15 minutes. Then, passive heating of one/both arms in 42°C warm water bath to cause an increase in body temperature of ≥1°C
  • Cold contact urticaria -- Inciting Trigger: Exposure of skin to cold air, cold liquids, or cold objects -- Diagnostic Test: Ice cube test - Melting ice cube in thin plastic bag for 5 minutes.
  • Heat contact urticaria -- Inciting Trigger: Warm object in direct contact with the affected skin -- Diagnostic Test: Application of a test tube containing 45°C water or a metal cylinder heated to 45°C to skin for 5 minutes.
  • Exercise-induced urticaria/anaphylaxis -- Inciting Trigger: Physical exertion -- Diagnostic Test: Treadmill testing
  • Aquagenic urticaria -- Inciting Trigger: Skin contact with water of any temperature -- Diagnostic Test: Application of 35°C water in compress to upper body for 30 minutes.
  • Solar urticaria -- Inciting Trigger: Exposure of skin to sunlight (triggering wavelengths vary) -- Diagnostic Test: Exposure of normally covered skin to UVA , UVB, and visible light (projector)
  • Vibratory urticaria/angioedema -- Inciting Trigger: Lawn mowing, riding a motorcycle, horseback riding, mountain biking, exposure to vibrating machinery, holding some steering wheels -- Diagnostic Test: Vortex mixer is held against the skin for 10 minutes.

Evaluation

• Usually Always Clinical
• The first step in evaluating urticaria and angioedema is a history and physical examination to characterize the lesions and help identify causes
• "Hives" is often used nonspecifically
• Check if the patient had hives in the past or other allergic disorders
• Is there any signs of systemic disease? -- Unexplained fever, weight loss, arthralgias, arthritis, bone pain
• Is there a possible etiology from the patient's history?
• Was the patient in his/her usual state of health? Any recent bacterial or viral infections?
• Any recent MSK complaints for which NSAIDs may have been used? -Recent travel (Parasitic infection)
• Sexual History
• Previous recent food, drink, exercise, physical activity, temperatures, insect bites, supplements or medications
• Physical examination -- Vital signs -- Anaphylaxis? -- Lesions should always be visualized -- Showing the patient a photo of wheal/hives can sometimes help -- Asking the patient if they took photos of the lesion
• Symptoms and signs of anaphylaxis: -- Skin :Feeling of warmth, flushing (erythema), itching, urticaria, angioedema, and "hair standing on end" (pilor erection) -- Oral : Itching or tingling of lips, tongue, or palate, Edema of lips, tongue, uvula, metallic taste -- Respiratory : Nose- Itching, congestion, rhinorrhea, and sneezing, Laryngeal, Itching and "tightness" in the throat, dysphonia, hoarseness, stridor, Lower airways - Shortness of breath (dyspnea), chest tightness, cough, wheezing, and cyanosis -- Gastrointestinal : Nausea, abdominal pain, vomiting, diarrhea, and dysphagia (difficulty swallowing) -- Cardiovascular : Feeling of faintness or dizziness; syncope, altered mental status, chest pain, palpitations, tachycardia, bradycardia or other dysrhythmia, hypotension, tunnel vision, difficulty hearing, urinary or fecal incontinence, and cardiac arrest -- Neurologic : Anxiety, apprehension, sense of impending doom, seizures, headache and confusion; young children may have sudden behavioral changes (cling, cry, become irritable, cease to play) -- Ocular: Periorbital itching, erythema and edema, tearing, and conjunctival erythema -- Other Uterine cramps in women and girls

Laboratory Work-Up

• Laboratory workup is not necessary in the absence of indications of an underlying cause
• Targeted testing is appropriate if the history or physical examination suggests a specific cause or underlying disease
• Allergy testing is not recommended unless there is a specific indication of an allergic cause
• An allergic cause is possible if the clinical history reveals a specific trigger
• A specific IgE blood test can be ordered - a positive result is suggestive, although not diagnostic, of allergy, and a negative result does not exclude allergy
• Skin tests with fresh food/allergen can be performed by an allergy specialist, are probably the most convenient, inexpensive, and sensitive ways to detect food hypersensitivity

Differential Diagnosis (Pruritic)

• Conditions That May Be Confused with Urticaria:
  • 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
  • Mastocytosis and diffuse cutaneous: Normal to yellow-brown skin color, diffuse thickening, bullae
  • Morbilliform drug reactions: Maculopapular, associated with medication use

Differential Diagnosis (Non-Pruritic)

• Pityriasis rosea: Lesions lasting weeks, herald patch, Christmas tree pattern, often not pruritic
• Viral exanthem: Not pruritic, prodrome, fever, maculopapular lesions, individual lesions lasting days
• Henoch-Schönlein purpura: Lower extremity distribution, purpuric lesions, systemic symptoms
• Urticarial Vasculitis: should be considered when the hives are painful rather than pruritic, last longer than 48 hours, leave residual bruising or pigmentation changes, or recur whenever glucocorticoids are tapered

Urticaria Treatment

• Avoidance of Triggers
• 2nd generation H1 antihistamines PRN(Cetirizine, Levocetirizine, loratadine, desloratadine, fexofenadine) are first-line medication for the treatment of acute urticaria -- 1st generation? -- Lipophilic and readily cross the blood-brain barrier – sedation, Diphenhydramine, chlorpheniramine, hydroxyzine
• If symptoms are uncontrolled with 2nd generation H1 antihistamines, H2 antihistamines such as cimetidine (Tagamet), famotidine (Pepcid), and ranitidine (Zantac) may be added
• In severe cases, corticosteroids such as prednisone or prednisolone may be added for three to 10 days to control symptoms

Urticaria with Angioedema Treatment

• Treatment of acute angioedema is largely the same as treatment for urticaria, although corticosteroids may be more commonly recommended
• Angioedema of the larynx and massive angioedema of the tongue are medical emergencies. Require IM epinephrine and airway management
• Patients with angioedema that previously threatened airway compromise should be prescribed epinephrine autoinjectors

Chronic Urticaria Treatment

• Step 1: Start second-generation H₁ antihistamine, if insufficient control proceed to step 2
• Step 2: One or more of the following: -- Titrate second-generation H₁ antihistamine to two to four times normal dose -- Add a different second-generation H₁ antihistamine -- Add H₂ antihistamine -- Add first-generation H₁ antihistamine at night -- Add leukotriene receptor antagonist
• Step 3: Add high-potency antihistamine hydroxyzine or doxepin and titrate as tolerated, if insufficient control proceed to step 4
• Step 4: Consider referrals for immunomodulatory therapy such as omalizumab (Xolair) or cyclosporine (Sandimmune)
• Avoidance of Triggers
• CSU is episodic & self limited
• The average duration of disease is two to five years, patients without a trigger or underlying disorder identified has a rate of spontaneous remission at one year of approximately 30 to 50 percent
• Inducing tolerance can be useful in cold urticaria, cholinergic urticaria, and solar urticaria. Tolerance induction lasts only a few days, and consistent daily exposure is required to maintain tolerance

Summary

• Urticaria presents with intensely pruritic wheals, sometimes subcutaneous or interstitial tissue edema
• Lifetime prevalence of about 20%, often self-limited/benign, causes significant discomfort, continuemonths to years, uncommonly represent a serious systemicdisorder/life-threatening allergic reaction
• Urticaria is caused by immunoglobulin E- and non-immunoglobulin E-mediated release of histamine and other inflammatory mediators from mast cells and basophils
• Diagnosis is made clinically; anaphylaxis must be ruled out. Chronic urticaria is idiopathic in 80% to 90% of cases
• Only a limited nonspecific laboratory workup should be considered
• The mainstay of treatment is avoidance of triggers, if identified
• The first-line pharmacotherapy is second-generation H₁ antihistamines, which can be titrated to greater than standard doses
• First-generation H₁ antihistamines, H₂ antihistamines, leukotriene receptor antagonists, potent antihistamines, and brief corticosteroid bursts may be used as adjunctive treatment
• For refractory chronic urticaria, patients can be referred to subspecialists
• More than one-half of patients with chronic urticaria will have resolution or improvement of symptoms within a year