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Urticaria

Key Points

  • Urticaria is a very common disease with a lifetime prevalence of approximately 20%.
  • Individual lesions of urticaria typically present for less than 24 hours; persistence of a lesion greater than 24 hours is suggestive of a different diagnosis, such as urticarial vasculitis.
  • Urticaria (“hives”) may be an acute (less than 6 weeks) or chronic (more than 6 weeks) skin condition.
  • Acute urticaria is commonly an allergic or IgE-mediated reaction.
  • The underlying etiology of chronic urticaria may remain undetermined in many cases, and extensive diagnostic workup for an underlying cause is not recommended unless indicated by specific elements of the history and/or physical. A complete history and physical examination is the most important diagnostic tool.
  • In children, bacterial infections (streptococcal and mycoplasma infections) and viral infections (gastrointestinal and/or upper respiratory infections) are a common etiology or inciting factor.
  • The mainstay of urticaria treatment include: H1- and H2- antihistamines, and other immunomodulators, often in combination. Systemic corticosteroids should be reserved for acute, severe exacerbations and used for only short periods of time (1 week). Systemic corticosteroids are not recommended for the long-term management of chronic urticaria.

Initial Evaluation

Acute urticaria

  • Migrating pruritic edematous papules and plaques of variable size, surrounded by erythema or an area of vasoconstriction (i.e., wheal).
  • Can be intermittent, with the skin returning to normal appearance in less than 24 hours.
  • Causes include drug reactions, food allergy, systemic disorders, and infection.
  • The underlying cause may be undetermined in many cases.
  • The majority of acute reactions resolve within days to weeks.
  • Therapy is symptomatic and attempts to suppress symptoms until urticaria abates.

Chronic urticaria

  • Defined as urticaria lasting longer than 6 weeks.
  • May be idiopathic in up to 50% of cases or found in association with infection (bacterial, fungal, parasitic, viral), autoimmune disease (including production of auto-antibodies against the IgE receptor, triggering mast cell degranulation), or drug reaction. Whereas foods may be a relevant trigger for acute urticaria, the role of food allergies in chronic urticaria is controversial; a consistent, reproducible trigger is often not identified.
  • Because chronic urticaria may stem from an underlying systemic illness, it is important to perform a complete history and physical examination and pursue only basic laboratory testing and relevant diagnostic considerations. A cause is never found in a majority of cases.
  • The goal of therapy is to provide relief of symptoms.

Clinical presentation

Juicy pink to erythematous sometimes confluent into plaques, with edema and surrounding vasoconstriction (i.e., wheal).

Dermographic urticaria/ dermographism: results from frictional stress on the skin (such as scratching), eliciting rapid onset of urticarial lesions (1-5 minutes).


Differential diagnosis

It is imperative to determine whether the patient has urticaria alone or has a more systemic presentation with possible progression to angioedema or anaphylaxis. Careful review of symptoms of anaphylaxis, such as tongue, lip, or facial swelling, shortness of breath or wheezing, and diarrhea is necessary. Angioedema is characterized by deep tissue swelling (i.e., dermal or subcutaneous edema), pain more than itching, involvement of mucous membranes, and resolution that is slower than for urticaria (which typically resolves in < 24 hours); angioedema typically takes up to 72 hours to resolve.

Pathophysiology

  • Acute urticaria typically results from blood basophil or tissue mast cell degranulation triggered by IgE binding to antigens or through direct (non-IgE, non-immunologic) activation (by radiocontrast dye, NSAIDs, opiates, general anesthetics). This immune cell degranulation results in release of many immunologic mediators such as histamine (resulting in vasodilation and increased vascular permeability), leukotrienes, as well as cytokines and chemokines, resulting in local edema, erythema, as well as immune cell infiltrate.
  • Other mechanisms of urticaria, especially relevant to chronic urticaria, include:
    • Autoimmune: via IgE receptor crosslinking IgG
      • via anti-IgE IgG
      • via C5a
    • Physical urticaria: cold, pressure, cholinergic, vibratory, aquagenic, solar

Management of Urticaria

Initial diagnostic testing

  • Complete blood count with differential
  • ESR or CRP
  • Infectious disease workup (symptom-directed only; this is particularly important in children because of the high frequency of streptococcal or mycoplasma infection in association with urticaria)
  • Diagnostic maneuvers for cold or physical urticaria
  • Only limited additional testing as indicated by history and/or physical exam

First-line therapy: non-sedating H1-antihistamines (second generation)

  • Start with standard dosing
  • Escalate up to 4-fold dosing
  • Add a second agent

Initial therapy

  1. Treat with a non-sedating H1 antagonist antihistamine:
    • Loratadine (such as Claritin) 10 mg
    • Fexofenadine (such as Allegra) 180 mg
    • Cetirizine (such as Zyrtec) 10 mg
    • Levocetirizine (such as Xyzal) 2.5 mg
  2. Consider escalating the dose up to 4-fold dosing after 2 weeks. There is current data supporting that dose-escalation is effective for some, but not all, non-sedating H1 antihistamines.
  3. If urticaria is suppressed, treat the patient continually in order to maintain control of the process, with a slow taper once symptoms fully subside.
  4. Systemic steroids (such as prednisone) may be necessary for 3-7 days for severe, acute flares.
  5. Sedating H1 antagonist antihistamines are no longer recommended as first-line or long-term treatment of urticaria because of adverse effects associated with their use (such as sedation, anticholinergic effects) and due to the high efficacy and wide availability of non-sedating antihistamines.
    • Hydroxyzine (such as Atarax) 25 mg t.i.d. or q.i.d. with gradual dose escalation every 3-4 days to a maximum of 200 mg/day.
    • Diphenhydramine (such as Benadryl) 25 mg t.i.d. or q.i.d.
    • Doxepin (such as Sinequan). Begin therapy with 25 mg b.i.d. and increase the dose every 4-5 days to a maximum of 50 mg t.i.d. Because doxepin can prolong the PR interval and worsen conduction defects, obtain an EKG prior to therapy.

Subsequent therapy

  1. Add a leukotriene inhibitor, like montelukast (such as Singulair) 10 mg q day
  2. There is some evidence to support addition of other agents such as:
    • H2 antagonist antihistamine (such as ranitidine, famotidine, cimetidine)
    • Cyclosporine (such as Neoral or Sandimmune)
    • Dapsone
    • Hydroxychloroquine (such as Plaquenil)
    • Omalizumab (such as Xolair)
  3. A regimen with multiple agents in combination may be necessary to control symptoms.

When to refer to a dermatologist

  • If the diagnosis of urticaria is unclear.
  • For clarifying the diagnosis in rare cases of urticaria clearly in association with systemic symptoms (i.e., arthritis, fever, bone pain, paraproteinemia, ocular or other neurologic symptoms).
  • For long-term management of long-term urticaria, especially if it is highly steroid-dependent.

Clinical Cases

Case 1

  • 12-year-old girl
  • 3-day history of pruritic urticarial lesions on chest, back, and abdomen
  • No associated symptoms of fever, shortness of breath
  • 1 week ago: 2-day history of sore throat
  • No medications

Initial treatment

  • Start loratadine 10 mg daily
  • Rapid throat culture for Group A streptococcus
  • Follow-up evaluation in 1 week

Follow-up evaluation at 1 week

  • Urticaria are improved, but ongoing
  • Rapid streptococcal throat culture result: positive
  • Antibiotics are given to treat the streptococcal pharyngitis
  • Escalate dose of loratadine
  • Follow-up evaluation in 2 weeks

Follow-up evaluation at 2 weeks

  • Patient reports intermittent urticaria with two episodes over the past 2 weeks
  • Switch to another non-sedating antihistamine, cetirizine 10 mg
  • Follow-up evaluation in 2 weeks (urticaria resolved)

Case 2

  • 14-year-old girl
  • 2-month history of intermittent pruritic urticarial lesions on back, chest, arms, occasionally on legs
  • Lesions are migratory, lasting 1 day
  • No associated symptoms of fever, arthralgias, shortness of breath
  • No significant past medical history or current disease
  • Detailed history and physical exam does not reveal signs of local disease
  • Takes occasional ibuprofen for headaches

Initial treatment

  • Start fexofenadine 15-180 mg daily
  • Discontinue ibuprofen
  • Follow-up evaluation at 2 weeks

Follow-up evaluation at 2 weeks

  • Patient reports slight improvement of intermittent urticaria but still having multiple episodes since last clinic visit
  • Escalate dose of fexofenadine
  • Blood test: complete blood count with differential, ESR
  • Follow-up evaluation at 4 weeks

Follow-up evaluation at 4 weeks

  • Patient reports ongoing improvement
  • Blood test results show slightly elevated ESR
  • Add montelukast 4-10 mg daily
  • Follow-up evaluation at 4 weeks (improved)

References

Khan DA. (2008) Chronic urticaria: diagnosis and management, Allergy Asthma Proc, 29: 439-446.

Peroni A et al. (2010) Urticarial lesions: If not urticaria, what else? The differential diagnosis of urticaria. Part I, II, J Am Acad Derm, 62:541-570.

Zuberbier T et al. (2009) Guideline: Management of urticaria, Allergy, 64:1427-1443.

Zuberbier T et al. (2009) Guideline: definition, classification and diagnosis of urticaria, Allergy, 64:1417-1426.