**10. Differential diagnosis**

urticaria, history taking and physical examination is sufficient for the diagnosis. Further investigations are generally not required in patients with acute urticaria except those with a clinical history or physical examination suggesting an underlying cause, such as upper respiratory tract infection, food- or drug-induced urticaria [8]. Skin prick tests and serumspecific IgE tests can be used to confirm allergic reaction to foods, latex and certain anti-

In chronic urticaria, complete blood count, liver enzymes, urinalysis and thyroid function tests can be checked; however, these laboratory tests are of minor significance, if there is not a

Skin testing to aeroallergens can be of value only if the patient has concomitant allergic rhinitis and/or asthma. If the patient reports a specific food to be strongly related with the attacks, a serologic test to the specific food can be performed. Serologic testing would be more reliable than skin testing as an interpretation of wheal and flare response would be misleading in

Autologous serum skin test is a practical clinical test to detect circulating functional autoantibodies in patients with chronic urticaria. The test is performed by intradermal injection of patient's own serum obtained while the patient is symptomatic and injection of 0.9% saline on volar aspect of the forearm. It is of importance to stop antihistamines 2 days before application. A positive autologous serum skin test is defined as a red serum-induced wheal having a diameter greater than 1.5 mm than the saline-induced wheal at 30 min. The test is performed when an immunomodulatory treatment is planned for patients with severe chronic urticaria. However, this is a controversial issue as the presence or absence of autoantibodies does not predict efficacy to most therapies [5, 16]. Basophil histamine release assays, western blot analysis or ELISA are also used to detect autoantibodies. However, these tests are sophisticated

Urticaria activity score (UAS) is commonly used to assess disease activity and treatment response in patients with chronic urticaria. UAS is calculated based on the daily number of wheals (1–3 points) and the intensity of pruritus (0–3 points) and ranges from 0 to 6 [23]. UAS7 is calculated by summing UAS recorded by the patient on 7 consecutive days. A UAS7 score of less than 7 indicates control of disease, whereas a score exceeding 28 indicates poorly

Skin biopsies of acute lesions demonstrate a minimal inflammatory infiltrate along with dilatation of small vessels, flattened rete pegs and swollen collagen fibers. Histology of chronic urticaria lesions reveals a perivascular cuffing by predominantly T lymphocytes and also

Observation of fragmentation of neutrophils, red cell extravasation and swelling of endothelial cells in persistent lesions points to the diagnosis of leukocytoclastic vasculitis [13].

suspected underlying etiology for persistent urticarial lesions [13, 21].

patients under recurrent bouts of urticaria [16].

16 A Comprehensive Review of Urticaria and Angioedema

tests not readily available to most clinicians [22].

monocytes, neutrophils, eosinophils and basophils [25].

controlled symptoms [24].

**9. Histopathology**

biotics [5].

Urticarial rash may be seen in the course of many diseases (**Table 1**). Urticaria and angioedema can be manifestations of underlying systemic diseases, such as collagenopathies, endocrinopathies, tumors and hemolytic diseases [1].

Urticarial vasculitis is a rare condition mainly affecting adult females in 4th decade of life. It may manifest with urticarial plaques, which generally persist for 48–72 hours. Pain and tenderness is a common complaint. The wheals may resolve leaving residual purpuric or hyperpigmented discoloration of the skin. Underlying pathogenesis is a type III hypersensitivity reaction mediated by immune complexes. It is mostly idiopathic, however cases associated with connective tissue diseases (systemic lupus erythematosus), infections (hepatitis B and hepatitis C), medications (diltiazem, fluoxetine, potassium iodide, etc.) and malignancies have been reported. In histopathology, leukocytoclastic vasculitis is seen with signs of vessel damage, such as leukocytoclasis and fibrinoid deposits around venules. In contrast to urticaria, immunofluorescence of the skin shows deposits of immunoglobulins and complement [26, 27].

Systemic mastocytosis is a rare disorder in which atypical mast cells proliferate in the liver, spleen, lymph nodes, bone marrow and other organs. Involvement of the skin manifests as wheals and itching [5].

Urticarial lesions that persist beyond 24 hours should warrant alternative diagnosis, such as erythema multiforme minor, morbilliform drug eruption, dermatitis herpetiformis and bullous pemphigoid [9]. Erythema multiforme minor is an acute condition that differs from urticaria with its persistent targetoid lesions, and is typically less pruritic than urticaria [13].

Urticarial rash in a young child accompanied by fever, edema of hands and feet and arthralgias should prompt a diagnosis of serum sickness-like reaction. In this condition, urticarial plaques usually have an associated ecchymotic pattern. Serum sickness-like reaction is a hypersensitivity reaction that is often due to medications or infections. It develops 1–3 weeks


**Table 1.** Differential diagnosis of urticaria.

after the initial antigen exposure and has a self-limited course. Urticaria multiforme is also a hypersensitivity reaction marked with annular urticarial plaques and bruise-like areas similar to that seen in serum sickness-like reaction. The triggering factor is often a viral infection; urticarial lesions are preceded by 1–3 days of fever [28].

Cryopyrin-associated periodic syndromes are autoinflammatory diseases including familial cold autoinflammatory syndrome, Muckle-Wells syndrome and the neonatal onset multisystem inflammatory disease. They present often early in infancy with a variable severity of clinical manifestations. Main symptoms are fever, arthralgias and skin involvement with urticaria-like nonpruritic lesions. Histopathologically, the perivascular infiltration is composed of polymorphonuclear cells in contrast with classical urticaria [29].

### **11. Management**

Management of acute urticaria should initially focus on avoidance of any triggering factors, such as foods, drugs, insect venoms and latex. First-line treatment agents are antihistamines, corticosteroids and immunomodulatory agents are reserved for patients resistant to antihistamines [5].

#### **11.1. Antihistamines**

For the first-line management of acute or chronic urticaria, second-generation H<sup>1</sup> antihistamines are used. Fexofenadine, desloratadine, loratadine, cetirizine and levocetirizine are the most commonly prescribed agents [5, 10]. Symptomatic relief with suppression of the pruritus and reduction of the number and size of wheals is the main goal of treatment. Loratadine and cetirizine can be used starting from 6 months of age and are also safe during pregnancy [9, 10]. Efficacy of antihistamines is often patient specific and none are consistently superior [16].

Antihistamines target H<sup>1</sup> receptors located on endothelial cells and sensory nerves. Firstgeneration antihistamines (hydroxyzine, diphenhydramine and chlorpheniramine) can penetrate central nervous system and thus have sedating effects lasting longer than 12 hours. However relief of pruritus is much short-lived and lasts only up to 6 hours. Older first-generation antihistamines are not recommended for the management of chronic urticaria in the European Guidelines because they place patients at risk for serious side-effects and drug interactions. In contrast to first-generation antihistamines, the second-generation antihistamines are devoid of sedating and anticholinergic effects [30]. Similar to first-generation H<sup>1</sup> antihistamines, the use of H<sup>2</sup> receptor blockers (cimetidine and ranitidine) are not recommended in European Guidelines.

Updosing of antihistamines is safe in therapy resistant patients. Fourfold higher doses of licensed doses of antihistamines should be used before considering other treatments [30]. However, according to US guidelines treatment by updosing second-generation H<sup>1</sup> antihistamines can substituted with an add-on treatment with other second-generation H<sup>1</sup> antihistamines, H<sup>2</sup> antagonists, leukotriene receptor antagonists or first-generation H<sup>1</sup> antihistamines as alternative second step treatment options [31].

#### **11.2. Corticosteroids**

after the initial antigen exposure and has a self-limited course. Urticaria multiforme is also a hypersensitivity reaction marked with annular urticarial plaques and bruise-like areas similar to that seen in serum sickness-like reaction. The triggering factor is often a viral infection;

Cryopyrin-associated periodic syndromes are autoinflammatory diseases including familial cold autoinflammatory syndrome, Muckle-Wells syndrome and the neonatal onset multisystem inflammatory disease. They present often early in infancy with a variable severity of clinical manifestations. Main symptoms are fever, arthralgias and skin involvement with urticaria-like nonpruritic lesions. Histopathologically, the perivascular infiltration is composed of

Management of acute urticaria should initially focus on avoidance of any triggering factors, such as foods, drugs, insect venoms and latex. First-line treatment agents are antihistamines, corticosteroids and immunomodulatory agents are reserved for patients resistant

tamines are used. Fexofenadine, desloratadine, loratadine, cetirizine and levocetirizine are the most commonly prescribed agents [5, 10]. Symptomatic relief with suppression of the pruritus and reduction of the number and size of wheals is the main goal of treatment. Loratadine and cetirizine can be used starting from 6 months of age and are also safe during pregnancy [9, 10]. Efficacy of antihistamines is often patient specific and none are

generation antihistamines (hydroxyzine, diphenhydramine and chlorpheniramine) can penetrate central nervous system and thus have sedating effects lasting longer than 12 hours. However relief of pruritus is much short-lived and lasts only up to 6 hours. Older first-generation antihistamines are not recommended for the management of chronic urticaria in the European Guidelines because they place patients at risk for serious side-effects and drug interactions. In contrast to first-generation antihistamines, the second-generation antihistamines

Updosing of antihistamines is safe in therapy resistant patients. Fourfold higher doses of licensed doses of antihistamines should be used before considering other treatments [30]. However,

are devoid of sedating and anticholinergic effects [30]. Similar to first-generation H<sup>1</sup>

according to US guidelines treatment by updosing second-generation H<sup>1</sup>

receptors located on endothelial cells and sensory nerves. First-

receptor blockers (cimetidine and ranitidine) are not recommended in

antihis-

antihis-

antihistamines can

For the first-line management of acute or chronic urticaria, second-generation H<sup>1</sup>

urticarial lesions are preceded by 1–3 days of fever [28].

18 A Comprehensive Review of Urticaria and Angioedema

**11. Management**

to antihistamines [5].

**11.1. Antihistamines**

consistently superior [16].

Antihistamines target H<sup>1</sup>

tamines, the use of H<sup>2</sup>

European Guidelines.

polymorphonuclear cells in contrast with classical urticaria [29].

Corticosteroids can be used in the management of antihistamine-resistant cases of acute urticaria and exacerbations of chronic spontaneous urticaria. Long-term therapy with corticosteroids is strictly dismissed because of the risk of side effects and development of tolerance. Oral corticosteroids such as 7 days of prednisone up to 40 mg/day are often used to alleviate symptoms unresponsive to antihistamines in chronic urticaria [5]. Likewise, addition of a brief course of prednisone to antihistamines in acute urticaria significantly improves symptom control [32].

#### **11.3. Leukotriene receptor antagonists**

Leukotriene receptor antagonists, such as montelukast and zafirlukast, may have a role in the management of chronic urticaria. According to European Guidelines, leukotriene receptor antagonists may be considered in patients who do not respond to updosing of H<sup>1</sup> antihistamines, although evidence is low as compared to cyclosporine or omalizumab [30, 33].

#### **11.4. Immunosuppressives**

Cyclosporine has been shown to be effective in the treatment of recalcitrant cases of chronic spontaneous urticaria in combination with second-generation antihistamines especially cetirizine. Its mechanism of action depends on the inhibition of anti-IgE–induced histamine release from basophils and skin mast cells. Cyclosporine at 3–5 mg/kg/day is administered with monitorization of diastolic blood pressure and levels of serum creatinine, serum potassium, serum bilirubin and liver enzymes at each visit [34, 35]. Common adverse effects of cyclosporine therapy include hypertension, fatigue, gastrointestinal problems and headache [33].

Immunosuppressive therapy with mycophenolate, tacrolimus and methotrexate can also be considered in recalcitrant cases [31].

#### **11.5. Omalizumab**

Omalizumab is a recombinant humanized monoclonal anti-immunoglobulin E antibody that prevents binding of IgE to the high-affinity IgE receptor and thus prevents urticaria and angioedema. This new biologic treatment, applied by monthly subcutaneous injections in a standardized protocol, provides a rapid and effective control of treatment-refractory urticaria patients. Omalizumab is generally well-tolerated and safe. Major risks of omalizumab treatment include anaphylaxis, increased risk of cardiac and neurovascular events, and a controversial increased risk of lymphoma [16, 36, 37].

#### **11.6. Phototherapy**

Efficacy of phototherapy, both narrowband UVB and PUVA, has been shown in several studies. Phototherapy is not recommended in urticaria guidelines; still it appears to be a safe and effective therapeutic modality for patients with refractory chronic urticaria [38–40].
