Diagnosis and Treatment of Urticaria and Angioedema: A Worldwide Perspective

Contributing Regional Member Societies

American Academy of Allergy, Asthma and Immunology

American College of Allergy, Asthma and Immunology

Asia Pacific Association of Allergy, Asthma and Clinical Immunology

European Academy of Allergy and Clinical Immunology

Latin American Society of Allergy and Immunology

Classification

Urticaria can be classified on the basis of its duration and in the presence or absence of inducing factors (induced vs spontaneous).

Psychosomatic Factors

For decades, theories regarding etiology would appear and disappear, but none proved to be credible. In the 1950s and 1960s, many considered chronic spontaneous urticaria to be an anxiety disorder, and even now, there is some limited data to suggest worsening of symptoms with anxiety. It is now generally accepted that mental illnesses, such as depression and anxiety, influence the quality of life of chronic spontaneous urticaria patients and those are important comorbidities in such patients. However, it cannot be considered to be a cause, and a clear distinction between less tolerance of symptoms and actual worsening of skin inflammation has not been made.

Type 1 Food Allergy

The relation between food allergy/pseudoallergy and CU is controversial because some experts do not recommend elimination diets for such condition, whereas others have observed the improvement of symptoms by means of pseudoallergen-free diets in about one third of patients with chronic spontaneous urticaria [18].

Autoreactivity and Autoimmunity

Autoreactivity (see below) represents one major approach to elucidating the initiating stimulus for persisting hive formation. It is clear that cutaneous mast cell degranulation induces hive formation and on biopsy, a nonnecrotizing perivascular infiltration of cells is seen, which resembles a cutaneous late phase reaction [19–21]. There is infiltration with granulocytes (neutrophils, eosinophils, and basophils), although the magnitude can vary considerably. T cells are very prominent; most are CD4⁺ with a mixture of TH1 and TH2 subtypes [21]. There are also monocytes, but very few, if any B lymphocytes. A similar infiltration of cells can be seen when serum of patients is injected intradermally into their own skin, with a resultant wheal and flare reaction termed autoreactivity [22]. This is seen in 30% of patients and led to considerations of autoimmune (ie, immunoglobulin) mechanisms for the initiation of mast cell degranulation. At first, 5 to 10% of patients were found to have circulating IgG anti-IgE, which is functional,[23] and subsequently, 30 to 40% of patients were found to have IgG antibody to the α subunit of the IgE receptor [24]. The thesis is that cross-linking IgE receptors or occasionally IgE itself could activate skin mast cells in a selective fashion. Most commonly, human basophils were employed as an alternative to cutaneous mast cells and worked well to identify what has been termed chronic autoimmune urticaria. Serum-evoked basophil histamine release (HR), although time consuming, is the most quantitative assay, but upregulation of CD63 or CD203 assessed by fluorescence-activated cell sorter analysis can also be employed.

The remaining 55 to 60% of patients lacking such autoimmunity are considered to have chronic nonautoimmune or idiopathic (but nevertheless spontaneous) urticaria. In vitro studies support antireceptor antibody binding to the a subunit of the IgE receptor to activate the classical complement pathway with release of C5a, which further activates basophils and mast cells and contributes to recruitment of granulocytes and monocytes by its chemotactic activity [25]. Marked reduction in serum complement levels or complement deposition in lesion biopsies have not been demonstrated in subjects with serum autoimmunity.

The presence of these antibodies does not prove causality, although their role as a pathogenic mechanism is debated with evidence pro and con [26, 27]. Clearly, more than half of the patient population with chronic spontaneous urticaria lacks these anti-FceRI autoantibodies. However, in vitro HR can be blocked completely by saturating IgE receptors with an IgE myeloma protein so that antireceptor antibodies are sterically prevented from binding,[28] although an occasional exception is noted [29]. Soluble α subunit can be added to serum to bind the antireceptor antibody so that HR is prevented [24, 30]. In most cases studied, isolation of IgG has reproduced basophil activation based on HR, although the IgG depleted serum is negative.

There are also publications suggesting the presence of vasoactive factors in IgG-depleted serum of patients with CU,[31] but no factor has been isolated or identified, and the assay employed for detection is more typically the autologous skin test rather than basophil HR. Plasmapheresis can be used to stop the urticaria acutely indicating that removal of a critical plasma factor can potentially stop symptoms in select cases [32].

Possible Role of Immunoglobulin E

Finally, it was theorized that anti-IgE therapy with omalizumab might be effective in patients with hives. The thesis was that as IgE levels decrease toward zero, IgE receptors are downregulated, and if the spacing and surface density is sufficiently low, the IgG anti-α subunit cannot cross-link receptors and activation of basophil and mast cell would not occur. In practice, the IgE receptor reduction via omalizumab occurs rapidly for blood basophils and much more slowly on skin mast cells, yet omalizumab does not eliminate either cell's capacity to respond to a cross-linking stimulus [33–35]. Thus far, therapy with this monoclonal antibody has been extremely successful,[36–38] and phase 3 studies of its efficacy and safety are ongoing currently. The mechanism of its effect is not clear because some patients respond dramatically in 2 to 3 days; so fast that receptors could not be significantly down-regulated, and there is evidence of efficacy even in the non-autoimmune urticaria population [39, 40]. Thus, it is likely that some unknown role for IgE is operative in all these patients, whereas receptor downregulation is superimposed some weeks later. There is precedent for synthesis of IgE that is either intrinsically abnormal or perhaps reactive with an unknown autoantigen; for example, it has been shown that isolated monomeric IgE of some patients with cold urticaria can passively transfer the disease,[41] that is, the IgE binds to normal mast cells of a recipient and renders them "cold sensitive" so that mast cells then degranulate upon a change in temperature. The abnormality resides with the IgE not the mast cell. There is also evidence for heightened skin mast cell release in active CU subjects [42–44]; furthermore, a recent publication reports the presence of a nonimmunoglobulin factor in patient's sera capable of activating cultured mast cells in vitro [45].

Additional Observations on the Pathogenesis of Urticaria

There are additional observations regarding chronic spontaneous urticaria possibly related to pathogenesis. Early on, an association with Hashimoto thyroiditis, and more specifically, with the presence of autoantibodies was reported,[46, 47] including antiperoxidase and antithyroglobulin antibodies. Although IgE antithyroid antibodies could have pathogenic significance, most patients have only IgG antibodies, and their presence is thought to represent a proclivity to autoimmune phenomena and a possible marker for the presence of anti-IgE receptor antibody [48]. C-reactive protein is elevated in the group when compared with normals, suggesting systemic recognition of cutaneous inflammation. Matrix metalloproteinase levels are increased in the blood plasma perhaps originating from skin inflammation [49]. The extrinsic coagulation cascade is activated based on elevated prothrombin fragments 1 and 2 and D-dimer levels but without any abnormal coagulopathy [50, 51]. Tissue factor, although produced by activated endothelial cells (stimulated, for example, by histamine or leukotriene C4), nevertheless seems to be secreted by eosinophils within the tissue [52]. It has been theorized that thrombin might activate mast cells; however, active thrombin has not been found; most demonstrations of thrombin-induced HR have employed rodent mast cells, and it is not clear that the thrombin dose needed is physiologic [53, 54]. Leukotriene C4, cytokines, and growth factors have also been found to be elevated in plasma of patients with CU, and cellular adhesion molecules are upregulated [55–57]. It is not clear whether these inflammatory stigmata are produced by activated cells in blood or these are found to having been produced in the skin.

Another approach to understanding chronic spontaneous urticaria, whether associated with autoantibodies, is to focus on possible abnormalities within the cell, and the basophil is a prime candidate. A hallmark of CU is the unique relationship of disease activity to altered blood basophil phenotypes [58]. Since the 1970s, many groups have found that blood basophils from active chronic spontaneous urticarial (CSU) subjects have reduced IgE receptor-mediated HR but not in the HR induced via IgE receptor-independent pathways (ionophore, 48/80, N-formyl-methionyl-leucin-phenylalanine (fMLP), bradykinin and monocyte chemoattractant protein 1 (MCP-1), indicating a specific defect in the FcεRI pathway [59–62]. CSU subjects can be segregated based on the bimodal distribution of their basophil FcεRI-induced HR profiles, a feature that is stable during active disease [60, 63]. Fifty percent of CSU subjects have significant reductions in their blood basophil IgE receptor-induced HR (< 10% of total histamine content) and are defined as nonresponders. The remaining CSU subjects have > 10% basophil FcεRI-induced HR and are called responders [64]. These basophil subgroups also have altered protein levels of signaling molecule expression that reflects their IgE receptor functional classification. Blood basopenia is also unique to CSU and is correlated with disease activity [65, 66]. Furthermore, basophils are found in both lesional and nonlesional skin biopsies of CSU subjects, suggesting that basopenia is related to the recruitment of basophils to skin tissues [67]. Systemic corticosteroid therapy, which leads to an increase in blood basophil numbers and reduces skin symptoms in CSU, is known to inhibit basophil recruitment to the skin [66, 68, 69]. In CSU subjects who enter remission, basophils shift toward normalization of basophil IgE receptor-mediated HR and correction of basopenia [60, 63].

Diagnostic Approach for Patients With Acute Spontaneous Urticaria

Although both a detailed history and physical examination remain essential, the etiology of acute spontaneous urticaria can be suggested by a patient's history. Upper respiratory tract and viral infections are the most common etiology in children. Foods and drugs such as antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs)[71] can be considered for both adults and children. In general, diagnostic workup is indicated only when type I allergy is suspected to be the underlying cause of acute spontaneous urticaria.

Diagnostic Approach in Patients With CSU

In patients with CSU, it is necessary to obtain a thorough history, including all possible eliciting factors, and to identify the significant aspects of the disease. This initial assessment is helpful in the identification of the subtype of urticaria (acute vs chronic, spontaneous vs induced). The overall duration of CSU is likely to be longer in patients with high disease severity, angioedema, positive autologous serum skin test (ASST) results, or comorbidity with physical urticaria. Next, the impact of the disease on the patient and the disease activity should be evaluated using the urticaria activity score and the CU quality of life questionnaire (see Quality of Life and Patient-Reported Outcomes). The patient should be asked about the time of onset; frequency and duration of wheals; presence of diurnal variation; shape, size, and distribution of wheals; associated angioedema; family and personal history of urticaria; atopy; medications (NSAIDs, hormones, laxatives, immunizations); and observed correlation with food and stress. The first step is to exclude major comorbid disorders and physical urticaria, and the second step is to identify the underlying cause. Patient questioning together with physical examination and laboratory and provocation tests may be useful to identify associated diseases and comorbidities, and in some cases, the underlying cause. Routine laboratory testing in the absence of a clinical history is rarely helpful in determining an etiology for patients with CSU [72, 73]. Nevertheless, expert opinion differs in regards to the number and type of testing appropriate for patients with CSU.

Routine hematological tests, including complete blood count and liver function tests, the determination of erythrocyte sedimentation rate, and C-reactive protein levels may be considered. The role for infectious agents such as Helicobacter pylori in the causation of chronic urticarial is controversial, and the evidence is weak and conflicting [74]. Screening for thyroid autoimmunity may be considered. Although type I allergies are a very rare cause of CSU, the IgE-mediated mechanism may be considered in patients with intermittent symptoms. For differential diagnosis from patients with angioedema alone without wheals, the measurement of C4 and C1 esterase inhibitor levels may be necessary. About one third of CSU patients have aspirin/NSAID hypersensitivity, and oral provocation tests with aspirin are available to confirm this if needed [71]. Some CSU patients improve with a food-additive-free diet, and challenge tests with food additives may be necessary [18]. The ASST is the only generally available test to screen for autoantibodies against either IgE or the high-affinity IgE receptor. Autoimmune urticaria responds poorly to H1 antihistamines and often manifests as severe CSU. However, some studies have demonstrated low sensitivity of the ASST with a high false-positive rate. The basophil HR test is more refined but is also insufficiently sensitive to be applied routinely. The diagnostic workup should include physical stimulation tests if physical urticaria is suspected. Ice cube or cold water tests are used widely for cold urticaria, and exercise challenge tests are used for cholinergic and exercise-induced urticaria. To improve outcomes for CSU patients, quality of life and psychiatric comorbidity should be considered. A skin biopsy may be needed to confirm urticarial vasculitis and Schnitzler syndrome.

Antihistamines

Leukotriene Receptor Antagonists

The effectiveness of these drugs has been reported in several relatively small, randomized, double-blind studies,[108–112] but the results have been inconsistent [113]. A recent review on this issue concluded that leukotriene receptor antagonists might be effective in subsets of patients with CSU associated with aspirin or food additive intolerance or positive on ASST but not in other patients with chronic spontaneous urticaria,[114] although other studies do not seem to support this view [115]. Altogether, existing evidence of their effectiveness is limited, and the grade of recommendation for their use is low. Nonetheless, these drugs may be tried in patients unresponsive to antihistamines in view of their excellent safety profile.

Corticosteroids

Although it is clinically recognized that oral corticosteroids are effective for H1-antihistamine-resistant CU, controlled studies are lacking [117]. In view of the potentially severe side effects associated with long-term treatment, oral corticosteroids should be used for short periods and at the minimally effective dose necessary to achieve control. There is no consensus on the dose and duration of oral corticosteroids for the management of CU, but some recommended approaches about short-term therapy have been published [117]. Attempts should be made to find alternative agents to control urticaria to avoid long-term corticosteroid use. In rare patients, long-term corticosteroid use may be justified; however, patients should be monitored closely for adverse effects of corticosteroid therapy.

One published protocol suggests using prednisone 15 mg daily (preferably 10 mg) and decrease by 1 mg (using 1-mg tablets) each week. Considerable efficacy can be achieved, and subsequent responsiveness to other modalities can be enhanced. If higher doses are needed to significantly lessen symptoms, the drug should not be used [15, 117]. In conclusion, corticosteroids should be used sparingly only when all other therapies failed, until other controller therapies can be found that control the hives.

Anti-Inflammatory Agents

Although the evidence for efficacy in the treatment of CU for many of the following anti-inflammatory agents is limited, the favorable cost and relatively safe side effect profiles warrant their consideration before using more expensive or more toxic agents.

Immunosuppressive Agents

Biological Agents

Other Therapies

Anticoagulants have recently been found to be effective in patients with refractory CU [50–52, 177–180]. One recent study reported that low-molecular weight heparin was effective in a subset of refractory CU patients with elevated D-dimer levels [181]. Despite this increasing evidence, anticoagulant therapy cannot be presently recommended as a routine treatment for CU.

Other therapies have been reported as cases or case series for the treatment of CU, and very little information is known about their effectiveness and therefore is not recommended for routine use. These treatments include theophylline, androgens, β-agonists, nonsteroidal antinflammatory drugs, tumor necrosis factor-α inhibitors, calcium channel blockers, gold, plasmapheresis,[32] phototherapy, and autohemotherapy.

Acute urticaria

Few studies are available on the prognosis of AU [183, 184]. Two studies indicated that 20 to 30% of young children with AU are at the risk of chronic or recurrent urticaria [185–187]. More concerning than repeated episodes of AU is the progression of the disease to CU [188, 189].

Hospital admissions for urticaria were approximately 3 times higher in children aged 0 to 4 years than for other ages. Between 1993-1994 and 2004-2005, there were significant increases in the rate of hospital admissions for urticaria in all ages [1].

In adults, longer disease duration is an important risk for poorer prognosis [190]. AU causes discomfort, but not mortality, unless associated with angioedema of the upper airways [191–193]. Morbidity depends on severity and duration. One study found urticaria patients can have as much psychological, social, and occupational distress as patients awaiting triple coronary artery bypass surgery [194]. If a patient continues to be exposed to a trigger, urticaria may become chronic.

Chronic Urticaria

Studies in multiple countries report complete resolution in approximately one third of patients with idiopathic CU for more than 1 to 5 years and partial improvement in another third [195].

Spontaneous remission occurs in 30 to 50% of patients within 1 year, and another 20% within 5 years. Nearly 20% of patients still have symptoms after 5 years. Almost half of patients with CU lasting 6 months are likely to have wheals 10 years later [196]. Those with more severe symptoms may have longer lasting disease. A retrospective study of 372 patients with severe urticaria described resolution of symptoms in 29% of patients after 5 years and 44% after 10 years [197, 198].

Patients younger than 30 years with more severe symptoms, or symptoms with physical causes, fared less well [195]. For those with physical urticarias, their condition may be better measured in decades, rather than years, but can typically be controlled [199].

In an Amsterdam prospective study of 220 patients with CU and angioedema,[200] 35% of patients had complete resolution of symptoms 1 year after enrollment. Resolution rates ranged from a high of 59.6% in patients with idiopathic urticaria-angioedema to a low of 16.4% in patients who had urticaria with a physical cause [195]. In a Netherlands retrospective study, 544 cases with CU and angioedema identified the mean age at presentation to be 35 years, and patients had been symptomatic an average of 5 years [201].

A prospective study published in 2004 found that duration of urticaria was longer in patients who had associated angioedema or positive anti-IgE receptor antibody [202]. Disease duration is likely to be longer in cases of angioedema, a combination with physical urticaria, positivity in the ASST (autoreactivity), and a high disease severity [6, 203].

Malignancy has been linked with urticaria and may suggest a relapse of the malignancy. There is no strong evidence to confirm an association between malignancy and uncomplicated CU, except occasionally in urticarial vasculitis and, more frequently, in acquired C1 esterase inhibitor deficiency [204, 205]. Although mortality may occur because of laryngeal edema, death is more likely due to complications of the associated disorder [206].

Angioedema

In cases involving recurrent angioedema without urticaria, hereditary and acquired angioedema must be differentiated. Acquired angioedema includes, among other etiologies, ACE inhibitor-induced angioedema and angioedema due to acquired C1-inhibitor deficiency. Much like CU, the majority of cases involving acquired angioedema, with some exceptions such as ACE-inhibitor angioedema, can be adequately controlled with daily doses of nonsedating antihistamines [207]. Angioedema of the upper airway can be life threatening. In rare cases, angioedema may develop into anaphylaxis [208].

In Australia, over an 8-year period, there were 106 deaths associated with anaphylaxis or angioedema. According to this study, there was a continuous increase in the rate of hospital admissions for angioedema (3.0% per year) and urticaria (5.7% per year). The rate of hospitalization for angioedema was highest in persons aged 65 years and older and lowest in children between 5 and 14 years. Although the rate of hospital admissions for angioedema remained relatively constant for most age groups between 1993-1994 and 2004-2005, the rate in persons aged 65 years and older doubled from 10 to 20 per 100,000 population. This represented an average annual increase of 5.6% in the rate of admissions for angioedema in this older age group. For those aged 15 to 34 years, the average annual increase was 4.3%. There was no significant change in the rate of hospital admissions for angioedema in those younger than 15 years or from 35 to 64 years. Among older persons, angioedema is becoming an increasing problem [1].

The prognosis for patients with acquired angioedema associated with C1 inhibitor deficiency is variable and depends on control of the underlying disorder. Even with appropriate treatment of the underlying disease, patients may only temporarily be free of symptoms. In several small studies, patients with acquired angioedema associated with C1 inhibitor deficiency had approximately 20% incidence of non-Hodgkin lymphoma [206].

In summary, the prognosis of urticaria and angioedema is improved with prompt and proper treatment. Using available medications, the condition is usually manageable.

Prevalence

There is little published information on the prevalence, diagnosis, or management of urticaria in children. Even in the current EAACI/GA2LEN/EDF/WAO and BSACI guidelines on the diagnosis and management of urticaria,[3, 4] the section on paediatrics is small.

A very recent review on urticaria in children was published by Church et al,[209] which compared published studies of prevalence of urticaria in adults and in children and noted that CU in children appears to be less common [210]. In the United Kingdom, the incidence of childhood urticaria was around 3.4%,[188] in Germany 4.4%,[147] and in Denmark about 5.4% [211]. In children, most episodes of urticaria appear to be acute, and CU has been reported to affect only 0.1 to 0.3% of children in the United Kingdom [212]. By comparison, 13% of Thai children with a diagnosis of urticaria have been reported to have CU [213].

Etiology

For AU, infections appear to play a more significant role in infants [214] and children [215].

Natural History of the Disease

In the cohort of pediatric patients with chronic spontaneous urticaria followed for 3 years by Du Toit et al,[216] no clear predictions of disease remission were established; 25% experienced remission in the 3-year period, and this was unrelated to the presence or absence of associated autoimmunity to the IgE Fcε receptor.

By contrast, 58% of children became free of urticarial symptoms in a study of 94 children, of whom 29 were considered "idiopathic" after 16 months, whereas the remaining 42% continued to have recurrent symptoms [224]. A very recent study by Sahiner et al [225] in 2011 found that recovery was observed in 50% of children at 60 months.

Treatment

In view of the marked adverse effects on the quality of life, ability to play, and school attendance, treatment is necessary in nearly all children with chronic spontaneous urticaria. CU negatively affects school performance. First-generation antihistamines, although effective, are no longer recommended for the management of children with chronic spontaneous urticaria [209].

Second-generation antihistamines are the treatment of choice. In a study of antihistamine treatment given to infants with atopic dermatitis,[226] continuous treatment with levocetirizine significantly reduced exacerbations of concomitant urticaria in this cohort (5.8% vs 16.2% in a placebo group). A follow-up study with levocetirizine showed a 60% reduction in the number of urticarial episodes [227].

Pediatric suspensions of desloratadine, fexofenadine, rupatadine, and loratadine are available, but pediatric studies on these second-generation H1 antihistamines, which are effective in adult urticaria particularly at standard and higher than standard doses, are still to be performed.

In the follow-up study by Du Toit et al,[216] all children responded well to daily treatment with cetirizine, and very few required a short course of prednisone to control symptoms, irrespective of whether they had autoantibodies to the IgE receptor or not.

There are no pediatric studies on the use of leukotriene receptor antagonists, H2 antihistamines, cyclosporine, or omalizumab for the treatment of urticaria. Experience with cyclosporine in children with severe resistant chronic spontaneous urticaria is similar to that reported in adults. It has been found to be safe and highly effective when indicated [228].

There is no evidence in the literature that children with persistent spontaneous urticaria, who do not go into spontaneous remission within a few years, go on to develop other autoimmune diseases. Long-term follow-up studies (more than 10 years) of urticaria in children are awaited.

New-Onset Urticaria

Urticaria occurring only in pregnancy is rare, but when it occurs, it suggests that sensitivity to hormones may be the basis of the condition. It may recur with each pregnancy in a predisposed woman. Gestational urticaria must be distinguished from other pruritic dermatoses of pregnancy, such as prurigo of pregnancy, PUPPP, PEP, or autoimmune progesterone dermatitis of pregnancy.

Prurigo of Pregnancy (Prurigo Gestationis of Besnier)

This condition is relatively common occurring in approximately 1 in 300 pregnancies. Characteristically, it begins in the second or third trimester. Patients usually present with marked excoriations with erythematous nodules or papules on the extensor surfaces of the limbs and the trunk. Usually total remission occurs immediately postpartum. Management is usually with topical corticosteroids [230].

PUPPP (Pruritic Urticarial Plaques and Papules of Pregnancy) or PEP (Polymorphic Eruption of Pregnancy)

PUPPP occurs in 1 in 160 to 1 in 300 pregnancies and usually presents in the third trimester [231, 232]. It is seen most commonly in first pregnancies and with multiple births [233]. It presents typically with erythematous papules within the striae and these spread to extremities but spare the face, palms, and soles. Lesions may coalesce to form urticarial plaques. This condition causes extremely severe pruritus. Most commonly, it resolves within 2 weeks of delivery but may resolve beforehand. Occasionally, it may worsen postpartum. Management consists in relieving the distressing symptoms. Topical steroids and antihistamines are initially used; some patients require systemic corticosteroids because of severe pruritus.

Autoimmune Progesterone Dermatitis of Pregnancy

This condition is similar to the rare autoimmune progesterone urticaria that occurs in a cyclical pattern in nonpregnant women. In pregnancy, it is characterized by a papulopustular eruption, transient arthritis, eosinophilia, and delayed hypersensitivity to intradermal progesterone. It may be associated with spontaneous abortion [234–236].

Management

Pregnant women with urticaria should be treated with the least amount of medication possible. Most patients can be treated with H1 antihistamines alone, with occasional short courses of oral glucocorticosteroids (GCS) for severe flares.

Antihistamine treatment is the mainstay of management in urticaria. The intense itch experienced by patients demands relief, whereas soothing baths and emollients offer minor comfort; most patients require symptomatic relief with an antihistamine.

There are no oral antihistamines with a category A listing for pregnancy. Categories are based on the results of animal studies, human data, and whether the use of the drug has a positive risk-benefit ratio in pregnancy. Category "B" drugs possess reassuring animal data, but there are no controlled clinical human trials.

A number of studies [237–240] have evaluated the safety of antihistamines in pregnant women. Most women who require regular antihistamines for control of CU will prefer treatment with second generation, nonsedating drugs.

Chlorpheniramine, loratadine, cetirizine, and levocetirizine have all been assigned category B by the US Food and Drugs Administration. As with any medication use, antihistamines should only be used if clearly needed and when the benefits outweigh the potential risk to the fetus. Use of the lowest dose that gives relief is advisable. There are several thousand reports of chlorpheniramine use in pregnancy with no evidence of increased incidence of congenital abnormality. No rate of increased congenital defects was reported in prospectively collected data from 1769 women exposed to loratadine. Small sample size studies are available for cetirizine, and there is a meta-analysis available for loratadine [237, 238]. Hydroxyzine is the only antihistamine specifically contraindicated in pregnancy in the product literature.

The second-generation antihistamines of choice in pregnancy are loratadine 10 mg daily or cetirizine 10 mg daily because there is a body of evidence of their use in pregnancy with reassuring safety profiles [240].

In special cases where a sedative effect is required along with an antihistaminic effect, chlorpheniramine is the first-generation antihistamine of choice. Recommended dosing is 4 mg 3 to 4 times a day. Diphenhydramine shows higher efficacy and can be used as an alternative to chlorpheniramine if the use of a first-generation antihistamine is being considered.

Antihistamines and Breast-feeding

Significant amounts of some antihistamines are detected in breast milk. Again, antihistamines should only be used during lactation when the benefit outweighs the potential harm to the infant, and in this circumstance, use the lowest dose possible for the shortest duration to give relief from symptoms. Loratadine and cetirizine appear safer than others with very low levels recorded in breast milk [241, 242].

Corticosteroids

Systemic corticosteroids may be required periodically to gain temporary control of symptoms during severe exacerbations of urticaria that significantly impair the quality of life. These rescue courses are generally added to the medications the patient is already taking.

The optimal dose and duration of GCS used for urticarial exacerbations has not been systematically studied, and recommendations vary among specialists. In addition, patients differ in their responsiveness to GCS in both the dose and duration of treatment required to control symptoms. Because of their importance in the treatment of a variety of inflammatory conditions, systemic GCS have been used fairly extensively during pregnancy.

Three potential areas of concern have been raised: congenital malformations (primarily cleft palate), neonatal adrenal insufficiency, and low birth weight [243]. The combined results of 5 large studies (2 surveillance and 3 case-control studies) found that the risk of oral clefts is approximately doubled [244–248]. However, the absolute risk is low. Because palatal closure is usually complete by the 12th week of pregnancy, the risk is limited to administration during the first trimester.

Neonatal adrenal insufficiency following maternal administration of steroids is unusual. The rapid maternal metabolism of prednisolone binding to serum proteins and conversion to inactive metabolites by placental 11 beta-hydroxysteroid dehydrogenase results in relatively low fetal compared with maternal concentrations [249]. As a result, the fetal pituitary is rarely suppressed in mothers taking GCS [248]. However, long-term high doses will suppress the fetal adrenal glands.

Multiple studies have observed low birth weight in offspring of animals given GCS during pregnancy. However, this association has been rarely reported in humans [243]. It is difficult to draw conclusions regarding the effects of GCS on fetal growth because of variability in the dose, duration, and type of steroid and the confounding effects of the underlying maternal disease on the pregnancy. GCS have the potential for exacerbating pregnancy-induced hypertension, gestational diabetes, and preterm delivery from premature rupture of membranes [250]. Thus, women at risk should be appropriately monitored.

Corticosteroids and Breast-feeding

Low levels of prednisone and prednisolone can be measured in breast milk. A nursing infant of a mother consuming a daily dose of 80 mg of prednisolone would ingest < 0.1%, which is equivalent to < 10% of endogenous cortisol production [249]. As a result, although it may be reasonable to delay breast-feeding for several hours after ingesting prednisone, it appears to be safe during breast-feeding [251].

HRQoL and CU

Actions To Be Taken

Although PROs evaluation is relevant for a more global comprehension of a disease and its treatment, the available literature on CU is still poor. The following unexplored areas should be further investigated:

Diagnosis in Physical Urticaria

Although the current international guidelines on the classification, definition, and diagnosis of urticaria give general recommendations, more detailed recommendations for diagnostic testing in physical urticaria are published in the "European guideline definition and diagnostic testing of physical and cholinergic urticariasd--EACCI/GA²LEN/EDF/UNEV consensus panel recommendations."[278]

A general principle in the diagnosis of physical urticaria is to mimic the physical stimulus, which leads to the formation of wheals and angioedema and at the same time if possible determine the threshold. Threshold measurements are important because they can help to give the patient practical advice on how to avoid or reduce above threshold stimulus exposure. Threshold testing also allows for the objective evaluation and monitoring of patients who receive treatment. Figure 1 and figure 2 show the recommended provocation tests for physical urticaria (modified from Magerl et al [278]).

When performing provocation tests in patients with physical urticaria, it is recommended to have the same standard of emergency treatment available as for other kinds of allergy skin testing because rare cases of systemic anaphylactic reactions, especially in cold urticaria, have been described.

Severity of Disease and PROs

Physical urticaria can vary considerably in severity between individuals. In a number of patients, signs of physical urticaria only occur with unusually strong external stimulation of the skin, for example, very cold, windy, winter days in cold urticaria, and depending on the usual geographic location and everyday living habits, the required strength of the stimulus to elicit symptoms is not usually reached. However, in other cold urticaria patients, the eliciting temperature of the skin can be as high as 28°C, a temperature which is easily reached in usual daily activities in moderate climates, and even in warm climates, if there is a mild wind because wind chill temperature increases the cooling effect on the skin. In cold urticaria, systemic reactions have been described in the case of a rapid change of skin temperature, for example, when patients jumped into cold water. Another risk factor in cold urticaria is the rapid ingestion of cold food such as ice cream or cold beverages, which may lead to swellings of the upper airways and in the esophagus and to systemic histamine liberation and subsequent anaphylactic reactions.

Physical urticaria can also have an impact on occupation. It has been recognized as an occupational disease (eg, vibratory urticaria/angioedema can be the reason for disability in construction workers).

Management of Physical Urticaria

A general principle of the international urticaria guidelines on the management of urticaria is the identification and elimination of the underlying cause and/or trigger [5]. Although in the majority of physical urticarias, the underlying cause is unknown and cannot, therefore, be eliminated, avoidance of a known trigger can be very useful.

With the exception of cold contact urticaria where in rare cases infectious diseases, such as hepatitis, have been described as an underlying cause, it is not recommended to invest too many resources into the investigation of causes. In physical urticaria, the routine diagnostic program should be limited at the most to differential blood count and the determination of erythrocyte sedimentation rate. However, with the identification of the eliciting trigger, it is in many cases easy to help the patient by in detail explanation of the possibilities for avoidance. For example, pressure is defined as force per area and simply increasing the size of a handle of a bag may help in patients with pressure urticaria to avoid symptoms.

The treatment in physical urticaria is aimed at the prevention and reduction of symptoms. This follows in general the algorithm, which has been published for urticaria in the international consensus guidelines (Figure 3).

The level of evidence for first-line treatment with nonsedating antihistamines is very good both in chronic spontaneous urticaria and physical urticaria. The updosing of nonsedating antihistamines has been widely studied in physical urticaria.

Thus, the level of evidence to use higher than standard doses as the preferred second-line treatment is very high in this group of urticarias. Siebenhaar et al [279] studied the impact of increasing the dose of desloratadine from 5 mg up to 20 mg in cold urticaria and showed a clear dose-dependent response, which supports the recommendation to increase the antihistamine dosage in those patients who do not show sufficient responses to standard doses.

In general, however, the level of antihistamine treatment required may be different from day to day depending on the strength of the external stimuli and patients' needs to be very thoroughly counseled on the daily use of the drug treatment.

Alternative treatments in physical urticaria have only been scarcely studied and knowledge needs to be extrapolated from what we know from chronic spontaneous urticaria. However, physical urticarias are distinct from other urticaria subtypes in that it is possible to achieve a reduction of repetitive mast cell responses to the specific physical stimulus by long-term controlled exposure to the stimulus. For example, in cold contact urticaria, the occurrence of symptoms can be prevented by administering daily cold baths, and for solar urticaria, UV light treatment can raise UV tolerance. However, this kind of treatment is time consuming for the patient and in the case of cold bath is not always very well liked. Furthermore, it is recommended to start at the threshold level and increase slowly the strength of the physical stimulus because generalized reactions may occur.