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Make These Itchy Bumps Go Away!

Educational Objectives

 

After reading this article and answering the review questions, the reader will be able to:

  1. Recognize acute urticaria and angioedema
  2. Explain the pathophysiology and causes of acute urticaria and angioedema
  3. Describe the recommended tests and treatment strategies for acute urticaria and angioedema

Case

 

Samantha is an 8-year-old Caucasian girl with a history of seasonal allergic rhinitis to ragweed who presents to your clinic in September. She notes 14 days of purulent nasal discharge, headache and cough that is worse at night. Her symptoms are not improving. Her medications include fluticasone propionate nasal spray and nasal saline irrigations as needed from August through November yearly. She has no known medication allergies and is not taking NSAIDs. On examination, her vitals are as follows: temperature 99.6ºF, respirations 16, blood pressure 102/74, and pulse 88. Significant physical exam findings include: bilateral tympanic membrane retraction, moderate nasal turbinate edema, nasal congestion with thick, yellow mucoid rhinorrhea bilaterally, and postnasal drainage. Her skin, lung and heart examination are unremarkable. Samantha is diagnosed with acute rhinosinusitis and is prescribed amoxicillin 80 mg/kg/day in two divided doses for 10 days. She is told to perform nasal saline irrigation once to twice daily as tolerated.

 

After two days, Samantha’s sinus symptoms are improving; however, Samantha’s mother calls the clinic and states that Samantha woke up yesterday with an “itchy, bumpy rash” that seems to be “really bothering her” because she had a difficulty sleeping. Her mother gave her diphenhydramine for her rash. The clinic nurse confirms Samantha has no other symptoms, recommends that she stop the amoxicillin, and schedules a return clinic visit.

 

Samantha is seen in the clinic the next day. Her skin examination reveals multiple raised, erythematous, blanchable lesions scattered from head to foot measuring one to three cm with areas of confluence on her back, chest and thighs. She does not have any areas of swelling without erythema. There are no areas of hyperpigmentation. The remainder of her examination is unremarkable, including no evidence of mucosal lesions, joint swelling, or wheezing. Her last dose of diphenhydramine was two hours ago.

 

Samantha is diagnosed with acute urticaria, likely due to either amoxicillin allergy or infection. Samantha is advised to stop diphen- hydramine and start cetirizine 5 mg once daily. She is prescribed a course of azithromycin. An Allergy Clinic consultation is scheduled for evaluation of possible beta-lactam allergy. A week later, the hives are improved and she is not experiencing sleepiness with cetirizine. Cetirizine is discontinued and she does not have any recurrence.

 

Discussion

 

Urticaria and angioedema are common, and occur in up to 25% of the population. The most common causes of acute urticaria in children are foods, medications (most commonly NSAIDs and antibiotics), physical stimuli, and infections. For some cases of acute urticaria, no precipitating cause is identified (Table 1).

 

Table 1

 

Drug reactions

Foods

Exercise induced

Hormones (cyclic urticaria)

Transfusion reactions

Insects (papular urticaria)

Radioactive dye

Inhalation, ingestion of, or contact with antigens

Acute spontaneous (idiopathic)

Infections: bacterial; fungal; viral;
and helminthic

Physical urticaria: cold; heat; cholinergic; dermatographism; pressure; vibratory; solar; and aquagenic

 

Risk factors associated with a more severe initial episode of acute urticaria include: pre-school or adolescent age, association with infection and medications, and presentation with pyrexia and/or coexisting angioedema. Chronic urticaria is much less common, especially in children. Patients with chronic urticaria may require additional testing and/or treatment methods as discussed later in this article.

 

Pathophysiology

 

Urticaria and angioedema may occur separately or together. They are differentiated by the tissue in which the reactions occur (urticaria in the dermis, angioedema in the subcutaneous tissue), time to resolution, and associated symptoms. Urticaria and angioedema may occur as symptoms of anaphylaxis; however, anaphylaxis involves organs other than the skin and is generally considered to be a systemic allergic reaction.

 

Urticaria is characterized by the sudden appearance of pruritic cutaneous lesions of variable size that are pale and raised (wheal) with surrounding erythema (flare), indicating the presence of dilated blood vessels and edema (Image 1). Common urticarial lesions should be fleeting, with skin returning to its normal appearance within 24 hours. Biopsy of acute urticarial lesions reveals dilation of small venules, capillaries and lymphatic vessels located in the superficial dermis with widening of the dermal papillae, flattening of the rete pegs, swelling of collagen fibers, and a mixed inflammatory perivascular infiltrate. Angioedema is caused by the same or similar pathologic alterations that occur in the deep dermis and subcutaneous tissue, lasting up to 72 hours. Angioedema is rarely pruritic. Patients more often describe a painful or burning sensation. For the remainder of this discussion urticaria and angioedema will simply be referred to as “urticaria.”

 

Image 1. Urticarial lesions with classical wheal (central pallor) and flare (peripheral erythema) appearance

 

Urticarial lesions with classical wheal (central pallor) and flare (peripheral erythema) appearance

 

Activation of cells (mast cells and basophils) or enzymatic pathways causes a release of multiple vasoactive mediators including histamine and lipid-derived vasoactive factors, such as arachidonic acid metabolites (Table 2). Although all these factors can contribute to hive formation in the skin, histamine is usually the most important; thus, antihistamines provide significant relief for most (but not all) individuals.

 

Table 2: Mediators of urticaria and angioedema

 

Mast Cells and Basophils

Histamine

Prostaglandin D

Leukotrienes C and D

Platelet-activating factor (PAF)

Complement System 

Anaphylatoxins: C3a; C4a; and C5a

Histamine  

Factor XII-Dependent Pathway  Bradykinin 
Mononuclear Cells  Histamine-releasing factors (chemokines)

 

 

In acute urticaria, the major non-cytotoxic mechanism by which histamine is released requires the combination of an antigen with IgE antibody bound to basophils or tissue mast cells. In chronic urticaria, approximately 30-45% of pediatric cases have a proposed autoimmune cause that may be due to autoantibodies produced to the alpha subunit of the high-affinity IgE receptor or, less commonly, to IgE antibody itself. Histamine is released from preformed granules as a consequence of these IgE-mediated reactions and is capable of eliciting the classic triple response consisting of vasodilation (erythema), increased vascular permeability (edema), and an axon reflex that amplifies the reaction. A second pathway leading to the non-cytotoxic release of histamine from basophils or mast cells involves the complement cascade. Three fragments of complement components (C3a, C4a, and C5a) act as anaphylatoxins, interacting directly with the cell surface in the absence of antibody to trigger histamine release. Factor XII activation results in the production of the vasoactive peptide bradykinin. Bradykinin is degraded by angiotensin-converting enzyme (ACE). Lastly, mononuclear cells (i.e., T lymphocytes, B lymphocytes and monocytes) produce histamine-releasing factors that may be responsible for non-IgE-dependent histamine release seen in late phase reactions.

 

Diagnosis

 

The diagnosis and classification of urticaria should involve history, physical examination, and limited testing as appropriate (Table 3).

 

Table 3: Patient history in diagnosis of urticaria

 

Questions to ask Patients with Urticaria and Angioedema 
Time of onset 
Frequency and duration of wheals  
Shape, size and distribution of wheals   
Associated symptoms   
Response to treatment   
Associated angioedema  
Allergies  
Recent food ingestion  
Medication ingestion  
Infections  
Temporal relation to exercise or physical exposure (e.g., temperature changes, water exposure, pressure)   
Recent insect stings or bites  
Systemic disease  
Personal and/or family history of urticaria   
Relationship to menstruation (cyclic urticaria)   
 Psychosocial stressors (as an exacerbating factor)  

 

Urticaria is classified as acute if the process lasts less than six weeks. However, if the individual urticarial lesions last more than 24 hours or have associated bruising, a biopsy should be considered to rule out other diseases that may resemble urticaria, including vasculitis. Testing for physical urticaria, including dermatographism, should be performed if needed.

 

Diagnostic testing is not routinely recommended for acute or chronic urticaria unless a food or drug is temporally associated with symptoms. In younger children, egg, milk, soy, peanut, and wheat are the most common allergens. In older children, fish, shellfish, tree nuts, and peanuts are the most common offenders. The only available drug class that has standardized skin testing materials is beta lactam antibiotics. Skin testing of other drugs can be performed, but, in the absence of standardized reagents, the sensitivity and specificity are variable.

 

Additional testing may be necessary if the history and physical suggests an underlying disorder (Table 4), the patient is not responding to standard therapy, or urticaria persists beyond six weeks. If patients have systemic reactions, a serum tryptase level > 10 ng/ml measured within 4 hours of the reaction may help to diagnosis anaphylaxis (of note: tryptase may not always be elevated in food-related anaphylaxis). Recommended initial laboratory testing for chronic urticaria includes a CBC with differential and ESR or CRP to rule out inflammatory disorders. There are several tests that may indicate a higher possibility of autoimmune and/or more refractory urticaria, including autologous serum skin testing (not routinely performed) or chronic urticaria index (CU Index). The CU Index is an in vitro basophil histamine release assay in which the patient’s serum is mixed with donor basophils and released histamine is quantitatively measured. A higher CU Index suggests patients may be more refractory to standard therapy.

 

Table 4: Differential diagnosis of urticaria and angioedema

 

Heredity: hereditary angioedema (HAE); C3b inhibitor deficiency; autoinflammatory syndromes (e.g., NOMID, familial cold urticaria and Muckle-Wells syndrome)
Malignancy (angioedema secondary to acquired C1 esterase inhibitor deficiency)  
Systemic mastocytosis (urticarial pigmentosa)  
Erythema multiforme  
Rare syndromes: Schnitzler’s (monoclonal gammopathy, recurrent fever, arthritis); Gleich’s (episodic angioedema and eosinophilia); and Well’s (eosinophilic cellulitis)  
Connective tissue diseases including urticarial vasculitis  

 

Treatment

 

Complete symptom relief and maximizing performance of daily activities are the goals of urticaria treatment. If possible, underlying causes should be treated and triggers should be avoided. Symptomatic treatment works by inhibiting the release and/or effect of mast cell and other inflammatory mediators (Figure 1). Many, but not all, symptoms are mediated by the actions of histamine on tissue H1 receptors. As described above, other mediators of symptoms include arachidonic acid metabolites that may respond to leukotriene receptor antagonism (i.e., montelukast or zafirlukast) or 5-lipoxygenase inhibition (i.e., zileuton). Cellular infiltrates may respond to corticosteroids.

 

Figure 1: Acute urticaria treatment algorithm

 

 

 

There are multiple forms of antihistamines that are beneficial for patients with acute or chronic urticaria. First-generation H1-blocking antihistamines (e.g., diphenhydramine and hydroxyzine) work well for most individuals, but side effects, including anticholinergic actions and sedation, are potentially serious problems. Tricyclic antidepressants, with mixed H1 and H2 antagonism (e.g., doxepin), are effective but have a similar risk for side effects. The preferred first-line therapy for acute and chronic urticaria is a second-generation H1 antagonist (e.g., loratadine, desloratadine, cetirizine, levocetirizine, and fexofenadine). The second-generation H1 antagonists are unlikely to cause sedation and are FDA-approved in children six months of age or older.

 

If standard dosing of second-generation H1 antagonists does not relieve symptoms, there are several treatment options. Higher doses (up to four times standard dosing) of second-generation H1 antagonists can relieve cases of chronic urticaria that are refractory to standard doses. Another option may be to continue a second generation antihistamine during the daytime and dose a more sedating first-generation H1 antagonist, or mixed H1 and H2 antagonist, at bedtime for relief of nocturnal symptoms. If these do not fully relieve symptoms, the addition of a H2 antagonist (e.g., ranitidine, famotidine, or cimetidine) and/or leukotriene antagonist may be beneficial. A short course of an oral corticosteroid, such as prednisone 1 mg/kg (maximum 40 mg) daily for 3-7 days with or without a taper is usually effective in reducing urticaria severity.

 

If a patient has an urticarial reaction in the physician’s office to medication or vaccination administration, the patient should be treated with an H1-antihistamine and observed for 4 hours for progression of symptoms that may require additional treatment (i.e., epinephrine). Patients with evidence of anaphylaxis should be treated immediately with intramuscular epinephrine 1:1000 solution 0.01 mg/kg (typical dose 0.1 mg-0.3 mg) and other medications as indicated.

 

Patients with acute or chronic urticaria not responding to the above treatments should be referred for specialist evaluation to perform additional testing, if appropriate, and discussion of additional treatment options. Additional treatments may include immunomodulators, especially for patients with evidence of an autoimmune chronic urticaria. Although many immunomodulators have been reportedly used for chronic urticaria treatment, cyclosporine, hydroxychloroquine, and mycophenolate mofetil are the most commonly used agents. More recently, a monoclonal antibody that binds IgE, omalizumab, has been shown to be beneficial in patients with chronic urticaria.

 

Conclusion

 

In the patient described in the case presentation, the acute urticaria may have been in response to either the amoxicillin or the infection itself. The prompt resolution after amoxicillin tilts the scales towards drug allergy. She did not have any symptoms to suggest serum sickness, which typically presents later in the treatment course. At the Allergy Clinic visit, penicillin skin testing confirmed a beta lactam allergy. It was recommended that she completely avoid beta lactam antibiotics, and this was noted in her medical record.

 

Summary

 

  • Acute urticaria is common and is often associated with infections, drugs, food, or other allergies.
  • A detailed patient history is the most important component of the patient encounter to help determine the cause of acute urticaria. 
  • Extensive testing is generally not needed for acute or chronic urticaria.
  • Treatment options for urticaria target products released by mast cells and basophils, including histamine and arachidonic acid metabolites, as well as cellular infiltrates. 
  • After elimination of triggers, the recommended initial acute urticaria treatment should be a second-generation H1-antihistamine.
  • Some patients with acute urticaria require additional medications such as H2 antagonists, leukotriene antagonists, or corticosteroids
  • Patients with urticaria in association with anaphylaxis, individual lesions lasting greater than 24 hours, evidence of underlying disease, or those who are refractory to standard therapy should be referred for specialty consultation.

CME Questions

 

Go to CME questions

 

References/Suggested Reading

 

  1. 1. Kaplan AP. Urticaria and angioedema. In: Adkinson NF, Bochner BS, Busse WW, Holgate ST, Lemanske RF, Simons FER, eds. Middleton’s Allergy: Principles and Practice. 7th Ed. Philadelphia, PA: Elsevier Inc; 2009:1063-1081.
  2. Zuberier T, et al. EAACI/GA2LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria. Allergy. 2009;64:1417-1476. 
  3. Zuberier T, et al. EAACI/GA2LEN/EDF/WAO guideline: management of urticaria. Allergy. 2009;64:1427-1443.
  4. Baxi S and Dinakar C. Urticaria and angioedema. Immunol Allergy Clin N Am. 2005;25:353-367.
  5. Kaplan AP. What the first 10,000 patients with chronic urticaria have taught me: a personal journey. J Allergy Clin Immunol. 2009;123(3):713-716.
  6. Bailey E and Shaker M. An update on childhood urticaria and angioedema. Curr Opin Pediatr. 2008;20:425-430. 7. Liu TH, et al. Significant factors associated with severity and outcome of an initial episode of acute urticaria in children. Pediatr Allergy Immunol. 2010;21:1043-1051.
  7. Boguniewicz M. The autoimmune nature of chronic urticaria. Allergy Asthma Proc. 2008;29(5):433-439.
  8. Biagtan M, et al. The clinical utility of the chronic urticaria index. J Allergy Clin Immunol. 2011;127(5):1626-1627.
  9. Saini S, et al. A randomized, placebo-controlled, dose-ranging study of single-dose omalizumab in patients with H1-antihistamine-refractory chronic idiopathic urticaria. J Allergy Clin Immunol. 2011;128(3):567-573.
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