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Urticaria, Pediatric

Basics

Description

- Anaphylaxis - Hypersensitivity reaction after exposure to an antigen - Producing respiratory compromise secondary to airway edema, urticarial rash, pruritus, and hypotension; can lead to shock

- Non " Гґimmune mediated - Degranulation of mast cells secondary to other non-IgE reactions such as physical changes, chemicals, some medications such as beta-lactams and sulfa-containing drugs, and some foods

- Viral infections are thought to make up Гі Е‚ в•ќ80% of all cases of acute urticaria in children. Most commonly isolated causes include the following viruses: - Epstein-Barr - Coxsackievirus A and B - Hepatitis A, B, and C

- Idiopathic: Most have an unknown cause, but many feel that an association with an autoimmune mechanism is likely. - Physical ( Гі Е‚ в•ќ20 " Гґ30%) - Dermatographism (9%): Stroking of skin using mild to moderate pressure with fingernail or hard object causes linear urticaria at site of contact. - Cholinergic (5%): diffuse erythema and elevated but pale urticarial lesions; intense pruritus; associated with sweating reflex, so often associated with overheating or exertion; may be worsened in combination with other triggers in specific combinations - Cold (3%): Urticarial lesions present at areas of skin exposed to low temperatures; familial and nonhereditary forms - Aquagenic: Urticarial lesions arise when the patient is exposed to water (e.g., bathtub, swimming pool). - Delayed pressure/vibratory: Deep or prolonged pressure on skin produces significant urticaria and often angioedema. Vibratory urticaria is a form of delayed pressure urticaria caused by repetitive vibration (e.g., use of a jackhammer).

- Systemic disease - Rheumatologic - Urticarial vasculitis: erythematous wheals that resemble urticaria but histologically appear as leukocytoclastic vasculitis; often presents with systemic symptoms and lasts >24 hours - Cryopyrin-associated periodic syndromes can present with urticaria, such as Muckle-Wells syndrome: chronic recurrent urticaria, deafness, amyloidosis, and arthritis.

- Description of rash: Lesions may not be present at time of exam due to transient nature. Digital photos are often useful. - Duration of symptoms, acute versus chronic: - If acute (<6 weeks), ask about - Viral symptoms including rhinorrhea, cough, fever, congestion, malaise - Any medications (prescription or over the counter) or any herbal remedies - Any new foods or beverages - Any new exposures to perfumes, chemicals, or other skin products

- If chronic (>6 weeks) - History of previous episodes including timing, exposures, any past history of urticaria or angioedema - Other symptoms or variations in presentation - Symptoms of systemic diseases, such as hyperthyroidism, systemic lupus erythematosus (SLE), juvenile idiopathic arthritis, myositis, amyloidosis, infections, and lymphoma - Duration of lesions

- Appearance of rash: classic wheal and flare appearance - Respiratory: Look for evidence of stridor, wheezing, or dyspnea. If present, be concerned for airway compromise or lower airway edema from an anaphylactic reaction. - Facial or neck swelling: concern for possible airway compromise - A full physical exam should be performed to look for signs of systemic disease or malignancy, such as - Upper respiratory tract infections - Thyromegaly - Lymphadenopathy or splenomegaly to suggest lymphoma - Joint examination for any evidence of connective tissue disease, arthritis, or SLE

- If symptoms are atypical, last >1 year, or are suggestive of urticarial vasculitis - Complement studies - ANA titer - Liver function tests - Skin punch biopsy

- Viral exanthema - Atopic dermatitis - Contact dermatitis - Insect bites - Maculopapular drug rash - Erythema multiforme - Plant-induced eruptions - Henoch-Sch Гў Г‚nlein purpura - SLE - Autoinflammatory disease - Systemic onset juvenile idiopathic arthritis - Cryopyrin-associated periodic syndromes: familial cold autoinflammatory syndrome, Muckle-Wells syndrome, neonatal onset multisystem inflammatory disease (NOMID) - Mevalonate kinase deficiency - Tumor necrosis factor-receptor " Гґassociated periodic syndrome (TRAPS)

- Combined H1 and H2 antagonists - H2 antagonists: added as 2nd agent because skin cells have both H1 and H2 receptors and a synergistic effect can be achieved by addition of an H2 blocker - Ranitidine (Zantac): 2 " Гґ4 mg/kg/day divided twice daily

  • Urticarial lesions are best described as raised, pruritic, circumscribed erythematous papules.Single lesions may coalesce as they enlarge, forming generalized, raised, erythematous areas.Transient, typically lasting several hoursAlso known as "hives " ЕЃ or "nettle rash " ЕЃAcute: <6 weeks ' durationChronic: >6 weeks ' duration
  • Other similar but non-urticarial entities:AngioedemaUrticarial-like lesionsForm in the deep dermal, subcutaneous, and submucosal layersAnaphylaxisHypersensitivity reaction after exposure to an antigenProducing respiratory compromise secondary to airway edema, urticarial rash, pruritus, and hypotension; can lead to shock

Epidemiology

  • Female-to-male ratio of 3:2
  • No variation in race

Incidence

Lifetime incidence of 15 " Гґ25% Г© ГЎ

General Prevention

When a trigger is identified, avoidance is the main preventive measure. Г© ГЎ

Pathophysiology

  • Immune mediatedAntigen is cross-linked to IgE on a mast cell.This causes mast cell activation, leading to the release of vasoactive mediators, such as histamine, leukotrienes, prostaglandin D2, platelet-activating factor, and other vasoactive mediators.These vasoactive mediators cause pruritus, vasodilatation, and capillary leak, which lead to the characteristic findings.Common triggers include some medications such as penicillins, foods such as milk or eggs, and envenomations.
  • Non " Гґimmune mediatedDegranulation of mast cells secondary to other non-IgE reactions such as physical changes, chemicals, some medications such as beta-lactams and sulfa-containing drugs, and some foods
  • Autoimmune mediatedDegranulation of mast cells caused by cross-linking of IgE by IgG or IgG binding to the high-affinity IgE (Fc Г„ ГЃRI) receptor on mast cells

Etiology

Acute urticaria Г© ГЎ

  • Viral infections are thought to make up Гі Е‚ в•ќ80% of all cases of acute urticaria in children. Most commonly isolated causes include the following viruses:Epstein-BarrCoxsackievirus A and BHepatitis A, B, and C
  • Parasitic infections
  • Bacterial infections (especially group A strep)
  • Medications: most frequently reported include the following:
  • Radiocontrast
  • Foods
  • Transfusion of blood products
  • Food additives and dyes
  • Natural remedies including cranberry, feverfew, glucosamine, and ginger
  • Insect venom including bees, wasps, hornets

Chronic urticaria Г© ГЎ

  • Idiopathic: Most have an unknown cause, but many feel that an association with an autoimmune mechanism is likely.
  • Physical ( Гі Е‚ в•ќ20 " Гґ30%)Dermatographism (9%): Stroking of skin using mild to moderate pressure with fingernail or hard object causes linear urticaria at site of contact.Cholinergic (5%): diffuse erythema and elevated but pale urticarial lesions; intense pruritus; associated with sweating reflex, so often associated with overheating or exertion; may be worsened in combination with other triggers in specific combinationsCold (3%): Urticarial lesions present at areas of skin exposed to low temperatures; familial and nonhereditary formsAquagenic: Urticarial lesions arise when the patient is exposed to water (e.g., bathtub, swimming pool).Delayed pressure/vibratory: Deep or prolonged pressure on skin produces significant urticaria and often angioedema. Vibratory urticaria is a form of delayed pressure urticaria caused by repetitive vibration (e.g., use of a jackhammer).
  • Mast cell diseaseUrticaria pigmentosa: excessive number of mast cells in skin, bone marrow, lymph nodes, and other tissues; flares characterized by pruritus, flushing, tachycardia, nausea, and vomitingSystemic mastocytosis
  • Systemic diseaseRheumatologicUrticarial vasculitis: erythematous wheals that resemble urticaria but histologically appear as leukocytoclastic vasculitis; often presents with systemic symptoms and lasts >24 hoursCryopyrin-associated periodic syndromes can present with urticaria, such as Muckle-Wells syndrome: chronic recurrent urticaria, deafness, amyloidosis, and arthritis.NeoplasmsInfections: parasites especially noted to cause chronic urticariaAutoimmune: antibodies to IgE or IgE receptor (Fc Г„ ГЃRI)

Diagnosis

History

  • Description of rash: Lesions may not be present at time of exam due to transient nature. Digital photos are often useful.
  • Duration of symptoms, acute versus chronic:If acute (<6 weeks), ask aboutViral symptoms including rhinorrhea, cough, fever, congestion, malaiseAny medications (prescription or over the counter) or any herbal remediesAny new foods or beveragesAny new exposures to perfumes, chemicals, or other skin productsIf chronic (>6 weeks)History of previous episodes including timing, exposures, any past history of urticaria or angioedemaOther symptoms or variations in presentationSymptoms of systemic diseases, such as hyperthyroidism, systemic lupus erythematosus (SLE), juvenile idiopathic arthritis, myositis, amyloidosis, infections, and lymphomaDuration of lesions

Physical Exam

  • Appearance of rash: classic wheal and flare appearance
  • Respiratory: Look for evidence of stridor, wheezing, or dyspnea. If present, be concerned for airway compromise or lower airway edema from an anaphylactic reaction.
  • Facial or neck swelling: concern for possible airway compromise
  • A full physical exam should be performed to look for signs of systemic disease or malignancy, such asUpper respiratory tract infectionsThyromegalyLymphadenopathy or splenomegaly to suggest lymphomaJoint examination for any evidence of connective tissue disease, arthritis, or SLE

Diagnostic Tests & Interpretation

Lab

  • Testing is often fruitless unless indicated by history and physical examination.
  • Skin testing may be performed if the causative agent is thought to be 1 of several food items.
  • If symptoms are difficult to handle or persist >3 months, considerCBC with differentialESRThyroid studies (thyroid-stimulating hormone [TSH], free T4, antithyroglobulin, and antiperoxisomal antibody)
  • If symptoms are atypical, last >1 year, or are suggestive of urticarial vasculitisComplement studiesANA titerLiver function testsSkin punch biopsy

Differential Diagnosis

  • Viral exanthema
  • Atopic dermatitis
  • Contact dermatitis
  • Insect bites
  • Maculopapular drug rash
  • Erythema multiforme
  • Plant-induced eruptions
  • Henoch-Sch Гў Г‚nlein purpura
  • SLE
  • Autoinflammatory diseaseSystemic onset juvenile idiopathic arthritisCryopyrin-associated periodic syndromes: familial cold autoinflammatory syndrome, Muckle-Wells syndrome, neonatal onset multisystem inflammatory disease (NOMID)Mevalonate kinase deficiencyTumor necrosis factor-receptor " Гґassociated periodic syndrome (TRAPS)

Treatment

Emergent treatment: If with any difficulty breathing, stridor or wheezing, or other signs of anaphylaxis, give epinephrine 0.01 mL/kg of the 1:1,000 solution SC/IM. Г© ГЎ

Medication

  • Acute urticariaUsually self-resolving but can treat with 2nd-generation nonsedating antihistamines1st-generation antihistamines: diphenhydramine 1 mg/kg/dose or total 5 mg/kg/d divided PO q6h or hydroxyzine 2 mg/kg/day PO divided q6h for pruritus
  • Chronic urticaria: See below.

First Line

  • Antihistamines/H1 antagonists:
  • Less sedating, longer acting, and should be mainstay of therapyCetirizine (Zyrtec): Dosing varies by age from 2.5 to 10 mg daily.Loratadine (Claritin): 5 mg daily
  • Fexofenadine (Allegra): 6 months to <2 years of age, 15 mg twice daily; 2 " Гґ11 years of age, 30 mg twice daily; and >12 years of age, 60 mg twice daily. 1st-generation antihistamines are effective but more sedating:Diphenhydramine (Benadryl): 5 mg/kg/day divided q6hHydroxyzine (Atarax): 0.5 mg/kg/dose q6hCyproheptadine (Periactin): 2 mg up to 3 times a day: primary treatment for cold urticaria

Second Line

Increase 2nd-generation H1 antagonist dose to maximum for age. In adult guidelines, increasing the dose up to 4-fold is more effective. Г© ГЎ

Third Line

  • Addition of a second nonsedating 2nd-generation H1 antihistamine
  • Leukotriene inhibitors: minimal additive response noted in clinical studiesMontelukast (Singulair): 5 mg daily
  • Combined H1 and H2 antagonistsH2 antagonists: added as 2nd agent because skin cells have both H1 and H2 receptors and a synergistic effect can be achieved by addition of an H2 blockerRanitidine (Zantac): 2 " Гґ4 mg/kg/day divided twice daily
  • Doxepin (Sinequan): a tricyclic antidepressant. >12 years of age, 10 " Гґ50 mg/day and can slowly titer up to 100 mg/day; potent antihistamine but poorly tolerated due to sedation, hypotension, anticholinergic side effects, and massive weight gain
  • Other immune-modifying agents used in chronic urticaria:Other nonstandard therapies have been tried in small case studies: cyclosporine, colchicine, dapsone, IV immunoglobulin (IVIG), plasmapheresis, methotrexate, cyclophosphamide, calcium channel blockers, ephedrineCorticosteroids: Titer to lowest effective dose. Start with standard dose of 0.5 " Гґ1 mg/kg/day of prednisone; often poorly tolerated secondary to substantial side effects including hypertension, immunosuppression, hyperglycemia, physical changesOmalizumab: Anti-IgE antibody has been shown to reduce signs and symptoms of chronic urticaria in those at maximum standard therapies.

Ongoing Care

Follow-up Recommendations

Patient Monitoring

  • Watch for signs and symptoms of anaphylaxis; this is the major complication.
  • Patients with chronic urticaria should follow up with their physician on a regular basis to monitor symptoms and response to therapies.

Prognosis

  • Chronic urticaria
  • Resolution in 50% by 12 months
  • Another 20% resolve by 5 years
  • 10 " Гґ20% >20 years; many of those who continue to have symptoms are felt to have an autoimmune etiology.
  • May have recurrences; physical urticaria subtypes are more likely to recur.

Complications

Anaphylaxis with resulting edema of the upper airway is the major life-threatening complication. The patient should seek immediate medical attention. Г© ГЎ

Additional Reading

  • Bailey Г© ГЎE, Shaker Г© ГЎM. An update on childhood urticaria and angioedema. Curr Opin Pediatr. 2008;20(4):425 " Гґ430. Г© ГЎ[View Abstract]
  • Dibbern Г© ГЎDA Jr. Urticaria: selected highlights and recent advances. Med Clin North Am. 2006;90(1):187 " Гґ209. Г© ГЎ[View Abstract]
  • Dibbern Г© ГЎDA Jr, Dreskin Г© ГЎS. Urticaria and angioedema: an overview. Immunol Allergy Clin North Am. 2004;24(2):141 " Гґ162. Г© ГЎ[View Abstract]
  • Kaplan Г© ГЎA, Ledford Г© ГЎD, Ashby Г© ГЎM, et al. Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy. J Allergy Clin Immunol. 2013;132(1):101 " Гґ109. Г© ГЎ[View Abstract]
  • Krause Г© ГЎK, Grattan Г© ГЎCE, Bindslev-Jensen Г© ГЎC, et al. How not to miss autoinflammatory disease masquerading as urticarial. Allergy. 2012;67(12);1465 " Гґ1474. Г© ГЎ[View Abstract]
  • Powell Г© ГЎRJ, Du Toit Г© ГЎGL, Siddique Г© ГЎN, et al. BSACI guidelines for the management of chronic urticaria and angio-oedema. Clin Exp Allergy. 2007;37(5):631 " Гґ650. Г© ГЎ[View Abstract]
  • Sheikh Г© ГЎJ. Advances in the treatment of chronic urticaria. Immunol Allergy Clin North Am. 2004;24(2):317 " Гґ334. Г© ГЎ[View Abstract]
  • Zuberbier Г© ГЎT, Asero Г© ГЎR, Bindslev-Jensen Г© ГЎC, et al. EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria. Allergy. 2009;64(10):1427 " Гґ1443. Г© ГЎ[View Abstract]

Codes

ICD09

  • 708.9 Urticaria, unspecified
  • 708.0 Allergic urticaria
  • 708.8 Other specified urticaria
  • 708.1 Idiopathic urticaria

ICD10

  • L50.9 Urticaria, unspecified
  • L50.0 Allergic urticaria
  • L50.6 Contact urticaria
  • L50.8 Other urticaria

SNOMED

  • 126485001 urticaria (disorder)
  • 402304007 Allergic contact urticaria (disorder)
  • 402408009 acute urticaria (disorder)
  • 51611005 Chronic urticaria (disorder)

FAQ

  • Q: When should I refer patients to a specialist, and to what specialty should I send them?
  • A: Often, referral is made when a trigger cannot be identified, if it is felt to be a food or medication trigger, and/or the symptoms persist for >6 weeks. Refer to a dermatologist or allergist " Гґimmunologist experienced in the evaluation and workup of urticaria.
  • Q: When should treatment with corticosteroids or other nonstandard therapies be used to treat chronic urticaria?
  • A: Typically, these medications carry significant side effects and should be reserved for those patients in whom the urticaria is causing significant alterations in activities of daily living.
  • Q: When does a patient need to be hospitalized or observed during an episode of urticaria?
  • A: Concerning signs include extensive angioedema, respiratory symptoms such as stridor or wheezing, or nausea/vomiting. Symptoms of anaphylaxis should be treated with epinephrine and the patient observed for several hours to ensure that symptoms do not recur.