> Table of Contents > Urticaria
Urticaria
Irina Pechenko, MD
Katie L. Westerfield, DO
image BASICS
DESCRIPTION
  • A cutaneous lesion involving edema of the epidermis and/or dermis presenting with acute onset and pruritis, returning to normal skin appearance within 24 hours
  • Pathophysiology is primarily mast cell degranulation and subsequent histamine release.
  • Angioedema may occur with urticaria although angioedema is characterized by sudden pronounced erythematous edema of the lower dermis and subcutis; may take up to 72 hours to remit.
  • Pruritus and burning are more commonly associated with urticaria; pain more often with angioedema.
    • Spontaneous urticaria: acute: persists <6 weeks
  • Specific extrinsic triggers drugs, foods, infections, envenomation, allergens, and autoimmune
  • Underlying etiology may be difficult to pinpoint.
    • Chronic spontaneous urticaria: persists >6 weeks with >2 episodes/week off-treatment
  • Recurrent acute urticaria: if symptoms occur <2 times a week.
  • For those with chronic urticaria, 40% have concurrent angioedema.
  • Chronic infection, pseudoallergy, malignancy including mastocytosis, autoimmunity (especially thyroid), and medications may underlie the remaining 20% (1).
  • Inducible urticaria
    • Dermatographism: “skin writing” or the appearance of linear wheals at the site of any type of irritation. This is the most common physical urticaria.
    • Cold urticaria: Wheals occur within minutes of rewarming after cold exposure; 95% idiopathic but can be due to infections (mononucleosis, HIV), neoplasia, or autoimmune diseases.
    • Delayed pressure urticaria: Urticaria occurs 0.5 to 12 hours after pressure to skin (e.g., from elastic or shoes), may be pruritic and/or painful, and may not subside for several days.
    • Solar urticaria: from sunlight exposure, usually UV; onset in minutes; subsides within 2 hours
    • Heat urticaria: from direct contact with warm objects or air; rare
    • Vibratory urticaria/angioedema: very rare; secondary to vibrations (e.g., motorcycle)
    • Cholinergic urticaria: due to brief increase of core body temperature from exercise, baths, or emotional stress; small pin-sized (5 to 10 mm) wheals surrounded by an erythema but also can have larger wheals. This is the second most common form.
    • Adrenergic urticaria: also caused by stress; extremely rare; vasoconstricted, blanched skin around pink wheals as opposed to cholinergic's erythematous surrounding
    • Contact urticaria: wheals at sites where chemical substances contact the skin, may be either IgE-dependent (e.g., latex) or IgE-independent (e.g., stinging nettle)
    • Aquagenic and solar urticaria: small wheals after contact with water of any temperature or UV light, respectively; rare
  • System(s) affected: integumentary
  • Synonym(s): hives; wheals
EPIDEMIOLOGY
Incidence
  • Equally distributed across all ages: female > male (2:1 in chronic urticaria)
  • In 20% of patients, chronic urticaria lasts >10 years (1).
Prevalence
  • 5-25% of the population
  • Of people with urticaria, 40% have no angioedema, 40% have urticaria and angioedema, and 20% have angioedema with no urticaria.
  • Up to 3% of the population has chronic idiopathic urticaria.
ETIOLOGY AND PATHOPHYSIOLOGY
  • Mast cell degranulation with release of inflammatory reactants, which leads to vascular leakage, inflammatory cell extravasation, and dermal (angioedema) and/or epidermal (wheals/hives) edema
  • Histamine, cytokines, leukotrienes, and proteases are main active substances released.
  • Spontaneous acute urticaria
    • Bacterial infections: strep throat, sinusitis, otitis, urinary tract
    • Viral infections: rhinovirus, rotavirus, hepatitis B, mononucleosis, herpes
    • Foods: peanuts, tree nuts, seafood, milk, soy, fish, wheat, and eggs; tend to be IgE-mediated; pseudoallergenic foods such as strawberries, tomatoes, preservatives, and coloring agents contain histamine.
    • Drugs: IgE-mediated (e.g., penicillin and other antibiotics), direct mast cell stimulation (e.g., aspirin, NSAIDs, opiates)
    • Inhalant, contact, ingestion, or occupational exposure (e.g., latex, cosmetics)
    • Parasitic infection; insect bite/sting
    • Transfusion reaction
  • Spontaneous chronic urticaria
    • Chronic subclinical allergic rhinitis, eczema, and other atopic disorders
    • Chronic indolent infections: Helicobacter pylori, fungal, parasitic (Anisakis simplex, strongyloidiasis), and chronic viral infections (hepatitis)
    • Collagen vascular disease (cutaneous vasculitis, serum sickness, lupus)
    • Thyroid autoimmunity, especially Hashimoto
    • Hormonal: pregnancy and progesterone
    • Autoimmune antibodies to the IgE receptor &agr; chain on mast cells and to the IgE antibody
    • Chronic medications (e.g., NSAIDs, hormones, ACE inhibitors). NSAID sensitivity demonstrated almost in half of adults with chronic urticaria and presents with a worsening of symptoms 4 hours after ingestion (2)[A].
    • Malignancy
    • Physical stimuli (cold, heat, vibration, pressure) in physical urticaria
Genetics
No consistent pattern known: Chronic urticaria has increased frequency of HLA-DR4 and HLA-D8Q MHC II alleles.
image DIAGNOSIS
PHYSICAL EXAM
  • Single/multiple raised, polymorphic indurated plaques with central pallor and edema with an erythematous flare
  • Evaluate for underlying conditions including thyroid abnormalities (nodules), bacterial, viral, or fungal infection (e.g., fever).
DIFFERENTIAL DIAGNOSIS
  • Anaphylaxis (may present with urticaria)
  • Morbilliform or fixed drug eruptions
  • Erythema multiforme
  • Systemic lupus erythematous (SLE), vasculitis, and polyarteritis
  • Angioedema without urticaria
  • Urticaria pigmentosa/systemic mastocytosis
  • Bullous pemphigoid (urticarial stage)
  • Arthropod bite
  • Atopic/contact dermatitis
  • Viral exanthem
DIAGNOSTIC TESTS & INTERPRETATION
  • Directed by clinical suspicion of underlying cause:
    • Allergy skin tests and radioallergosorbent test (RAST) for inhaled allergens, insects, drugs, or foods
    • Infection: Consider pharyngeal culture, LFTs, mononucleosis test, urinalysis in appropriate setting.
  • Chronic urticaria (idiopathic or spontaneous CIU/CSU) (3): Extensive lab testing is not indicated and has not proven to improve outcome nor is it cost-effective. Limit lab testing according to clinical history and indication. Skin or IgE testing should be limited to specific history of provoking allergen (4)[C].
    • CBC, ESR, and CRP is recommended by most guidelines.
    • Thyroid function tests, LFTs, and urinalysis are recommended by several guidelines.
    • Consider allergy skin tests and RAST for inhaled allergens, insects, drugs, or foods; total IgE level.
    • Autoimmune: ESR, ANA, RF, complement (e.g., CH50, C3, C4), cryoglobulins in urticarial vasculitis
    • Tests for H. pylori (e.g., antibodies) in dyspeptic patients. Consider stool for ova and parasites in at-risk individuals.
    • Autologous serum skin testing: injection of serum under skin to test for presence of IgE receptor-activating antibodies
    • Consider malignancy workup, including serum protein electrophoresis and immunofixation in the proper setting.
  • P.1091

  • Use the Urticaria Activity Score (UAS7) for assessing CSU.
  • Recently was developed Urticaria Control Test (UCT)
    • The tool to assess disease control in patients with chronic urticaria (spontaneous and inducible) (5)[A].
Diagnostic Procedures/Other
  • Food and drug reactions: elimination of (or challenges with) suspected agents
  • Physical and special forms of urticaria: challenge tests:
    • Dermatographism: Stroke skin lightly with rounded object and observe for surrounding urticaria.
    • Cold urticaria: ice cube test: Place ice cube on skin for 5 minutes; observe for 10 to 15 minutes.
    • Cholinergic: Exercise to the point of sweating/partial immersion in 42°C bath for 10 minutes.
    • Solar: exposure to different wavelengths of light
    • Delayed pressure: Apply 5-lb sandbag to back for 20 minutes; observe 6 hours later.
    • Aquagenic: Apply water at various temperatures.
    • Vibratory: Apply vibration 4 to 5 minutes with a lab mixing device; observe.
  • Skin biopsy with lesions lasting >24 hours
image TREATMENT
ISSUES FOR REFERRAL
Referral to an allergist, immunologist, or dermatologist for recalcitrant cases
MEDICATION
First Line
  • 2nd-generation antihistamine (H1) blockers are the first-line treatment of any urticaria in which avoidance of stimulus is impossible or not feasible (6,7)[A]:
    • Fexofenadine (Allegra): 180 mg/day
    • Loratadine (Claritin): 10 mg/day, increasing to 30 mg/day if needed; only medication studied for safe use in pregnancy
    • Desloratadine (Clarinex): 5 mg/day (8)[A]
    • Cetirizine (Zyrtec): 10 mg/day, increasing to 30 mg per day if needed
    • Levocetirizine (Xyzal): 5 mg/day; requires weightbased dosing in children (8)[A]
    • Rupatadine: novel H1 antagonist with antiplateletactivating factor activity
  • 1st-generation antihistamines (H1; for patients with sleep disturbed by itching):
    • Older children and adults: hydroxyzine or diphenhydramine 25 to 50 mg q6h
    • Children <6 years of age: diphenhydramine 12.5 mg q6-8h (5 mg/kg/day) or hydroxyzine (10 mg/5 mL) 2 mg/kg/day divided q6-8h
  • Precautions and notes: Drowsiness and dry mouth and eyes in 1st-generation H1 blockers (elderly)
Second Line
Doubling the typical 2nd-generation H1 blocker dosages should be attempted before adding 1stgeneration H1 or H2 blockers (6,7,8)[A].
  • H2-specific antihistamines (beneficial as adjuvants): cimetidine, ranitidine, nizatidine, famotidine
Third Line
  • Corticosteroids: prednisolone 20 to 50 mg/day for max of 10 days; best used only for exacerbations; avoid chronic use (6,7)[C].
  • Doxepin: tricyclic antidepressant with strong H1- and H2-blocking properties; 10 to 30 mg at bedtime; sedation limits usefulness (6)[C].
  • Leukotriene antagonists (montelukast, zileuton, and zafirlukast): safe and worth trying in chronic, unresponsive cases; useful alone but best used in addition to antihistamines; limited data on use in treating acute urticaria (2)[A]
  • Refractory symptoms
    • Omalizumab: anti-IgE; effective, expensive. 150 to 300 mg SQ q2-4wk. Restricted to allergists and those who can manage acute anaphylaxis (3,6,9,11)[A], significantly reduce the urticarial symptoms of CIU/CSU at 12 weeks. The best effects is reached with omalizumab dose 300 mg (3)[A]. Omalizumab is currently the only licensed treatment for H1-antihistamine-refractory chronic spontaneous urticaria, has a favorable risk/benefit ratio, and was well tolerated in clinical studies (2).
    • Cyclosporine: well-studied, effective (2.5 to 5 mg/kg/day); best used in combination with antihistamines; significant renal side effects (6,7)[C]
    • Methotrexate: antifolate; proven useful in recalcitrant cases; GI upset most common complaint; long-term requires LFT monitoring
    • UV therapy decreases number of mast cells; has shown promise in the treatment of mastocytosisinduced urticaria (7)[C].
  • Adding Vitamin D 4,000 U/day for 12 weeks may decrease the symptoms and USS score (10)[C].
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Educating patient on use of EpiPen as pathophysiology similar. If the airway is threatened, immediate consult to evaluate for laryngeal edema and need for airway access.
image ONGOING CARE
PROGNOSIS
Resolution of acute symptoms: 70% <72 hours. chronic urticaria: 35% symptom-free in a year; another 30% will see symptom reduction
REFERENCES
1. Leru P. Urticaria—an allergologic, dermatologic or multidisciplinary disease? Rom J Intern Med. 2013;51(3-4):125-130.
2. Cavkaytar O, Arik Yilmaz E, Buyuktiryaki B, et al. Challenge-proven aspirin hypersensitivity in children with chronic spontaneous urticaria. Allergy. 2015;70(2):153-160.
3. Saini SS, Bindslev-Jensen C, Maurer M, et al. Efficacy and safety of omalizumab in patients with chronic idiopathic/spontaneous urticaria who remain symptomatic on H1 antihistamines: a randomized, placebo-controlled study. J Invest Dermatol. 2015;135(1):67-75.
4. Choosing Wisely initiative of ABIM: American Academy of Allergy, Asthma & Immunology recommendation. http://www.choosingwisely.org/wp-content/uploads/2015/02/AAAAI-Choosing-Wisely-List.pdf.
5. Weller K, Groffik A, Church MK, et al. Development and validation of the Urticaria Control Test: a patient-reported outcome instrument for assessing urticaria control. J Allergy Clin Immunol. 2014;133(5):1365-1372, 1372.e1-1376.e1.
6. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA(2) LEN/EDF/WAO guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update. Allergy. 2014;69(7):868-887.
7. Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014;133(5):1270-1277.
8. Staevska M, Popov TA, Kralimarkova T, et al. The effectiveness of levocetirizine and desloratadine in up to 4 times conventional doses in difficult-to-treat urticaria. J Allergy Clin Immunol. 2010;125(3):676-682.
9. Maurer M, Rosén K, Hsieh HJ, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med. 2013;368(10):924-935.
10. Rorie A, Goldner WS, Lyden E, et al. Beneficial role for supplemental vitamin D3 treatment in chronic urticaria: a randomized study. Ann Allergy Asthma Immunol. 2014;112(4):376-382.
11. Zuberbier T, Maurer M. Omalizumab for the treatment of chronic urticaria. Expert Rev Clin Immunol. 2015;11(2):171-180.
Additional Reading
&NA;
  • Maurer M, Weller K, Bindslev-Jensen C, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA2LEN task force report. Allergy. 2011;66(3): 317-330.
  • Poonawalla T, Kelly B. Urticaria: a review. Am J Clin Dermatol. 2009;10(1):9-21.
  • Zuberbier T, Balke M, Worm M, et al. Epidemiology of urticaria: a representative cross-sectional survey. Clin Exp Dermatol. 2010;35(8):869-873.
Codes
&NA;
ICD10
  • L50.9 Urticaria, unspecified
  • L50.1 Idiopathic urticaria
  • L50.8 Other urticaria
Clinical Pearls
&NA;
  • “Chronic urticaria” with <2 episodes/week should be approached as acute.
  • Antihistamines are the best studied and most efficacious therapy but may require higher-than-normal doses for efficacy.
  • Lesions lasting >24 hours should be evaluated for urticarial vasculitis.