The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria

3.1 Definition

Urticaria is a condition characterized by the development of wheals (hives), angioedema or both. Urticaria needs to be differentiated from other medical conditions where wheals, angioedema or both can occur, for example anaphylaxis, auto-inflammatory syndromes, urticarial vasculitis or bradykinin-mediated angioedema including hereditary angioedema (HAE).

3.2 Classification of urticaria on the basis of its duration and the relevance of eliciting factors

The spectrum of clinical manifestations of different urticaria subtypes is very wide. Additionally, 2 or more different subtypes of urticaria can coexist in any given patient.

Acute spontaneous urticaria is defined as the occurrence of spontaneous wheals, angioedema or both for less than 6 weeks.

Table 4 presents a classification of chronic urticaria (CU) subtypes for clinical use. This classification has been maintained from the previous guideline by consensus (>90%) urticarial vasculitis, maculopapular cutaneous mastocytosis (formerly called urticaria pigmentosa), auto-inflammatory syndromes (eg, cryopyrin-associated periodic syndromes or Schnitzler's syndrome), nonmast cell mediator-mediated angioedema (eg, bradykinin-mediated angioedema) and other diseases such as syndromes that can manifest with wheals and/or angioedema are not considered to be subtypes of urticaria, due to their distinctly different pathophysiologic mechanisms (Table 5).

3.3 Pathophysiological aspects

Urticaria is a mast cell-driven disease. Histamine and other mediators, such as platelet-activating factor (PAF) and cytokines released from activated skin mast cells, result in sensory nerve activation, vasodilatation and plasma extravasation as well as cell recruitment to urticarial lesions. The mast cell-activating signals in urticaria are ill-defined and likely to be heterogeneous and diverse. Histologically, wheals are characterized by oedema of the upper and mid dermis, with dilatation and augmented permeability of the postcapillary venules, as well as lymphatic vessels of the upper dermis leading to leakage of serum into the tissue. In angioedema, similar changes occur primarily in the lower dermis and the subcutis. Skin affected by wheals virtually always exhibits upregulation of endothelial cell adhesion molecules, neuropeptides and growth factors and a mixed inflammatory perivascular infiltrate of variable intensity, consisting of neutrophils with or without eosinophils, basophils, macrophages and T cells but without vessel-wall necrosis, which is a hallmark of urticarial vasculitis.13-17 The nonlesional skin of chronic spontaneous urticaria (CSU) patients shows upregulation of adhesion molecules,18 infiltrating eosinophils and altered cytokine expression.19 A mild to moderate increase in mast cell numbers has also been reported by some authors. These findings underline the complex nature of the pathogenesis of urticaria, which has many features in addition to the release of histamine from dermal mast cells.20-22 Some of these features of urticaria are also seen in a wide variety of inflammatory conditions and are thus not specific or of diagnostic value. A search for more specific histological biomarkers for different subtypes of urticaria and for distinguishing urticaria from other conditions is desirable.23

3.4 Burden of disease

The burden of CU for patients, their family and friends, the healthcare system and society is substantial. The use of patient-reported outcome measures such as the urticaria activity score (UAS), the angioedema activity score (AAS), the CU quality of life questionnaire (CU-Q2oL), the angioedema quality of life questionnaire (AE-QoL) and the urticaria control test (UCT) in studies and clinical practice has helped to better define the effects and impact of CU on patients.24 The available data indicate that urticaria markedly affects both objective functioning and subjective well-being.25-27 Previously, O'Donnell et al showed that health status scores in CSU patients are comparable to those reported by patients with coronary artery disease.28 Furthermore, both health status and subjective satisfaction in patients with CSU are lower than in healthy subjects and in patients with respiratory allergy.29 CU also has considerable costs to patients and the society.30-32

4.1 Diagnostic work up in Acute Urticaria

Acute urticaria usually does not require a diagnostic workup, as it is usually self-limiting. The only exception is the suspicion of acute urticaria due to a type I food allergy in sensitized patients or the existence of other eliciting factors such as nonsteroidal anti-inflammatory drugs (NSAIDs). In this case, allergy tests as well as educating the patients may be useful to allow patients to avoid re-exposure to relevant causative factors.

4.2 The diagnostic work up in CU

The diagnostic work up of CSU has 3 major aims: (i) to exclude differential diagnoses, (ii) to assess disease activity, impact and control and (iii) to identify triggers of exacerbation or, where indicated, any underlying causes. Ad (1) Wheals or angioedema can be present in some other conditions, too. In patients who display only wheals (but no angioedema), urticarial vasculitis and auto-inflammatory disorders such as Schnitzler syndrome or cryopyrin-associated periodic syndromes (CAPS) need to be ruled out. On the other hand, in patients who suffer only from recurrent angioedema (but not from wheals), bradykinin-mediated angioedema-like angiotensin-converting enzyme (ACE) inhibitor-induced angioedema or other nonmast cell-related angioedema, that is HAE type 1-3, should be considered as differential diagnoses (Figure 1). Ad (2) Baseline assessment of disease activity (UAS, AAS), quality of life (CU-Q2oL, AE-QoL) and disease control (UCT) are indispensable for guiding treatment decisions, providing better insights into the patients’ disease burden, as well as facilitating, improving and standardizing the increasingly important documentation work (see also section on Assessment of disease activity, impact, and control). Ad (3) History taking is essential in patients with urticaria, as exacerbating triggers are variable. Further diagnostic procedures to reveal underlying causes in patients with long-standing and uncontrolled disease need to be determined carefully.

In the last decades, many advances have been made in identifying causes of different types and subtypes of urticaria, for example in CSU.33-35 Among others, autoimmunity mediated by functional auto-antibodies directed against the high-affinity IgE receptor or IgE-auto-antibodies to auto-antigens, pseudo-allergy (nonallergic hypersensitivity reactions) to foods or drugs, and acute or chronic infections (eg, Helicobacter pylori or Anisakis simplex) have been described as causes of CU (Table 6). However, there are considerable variations in the frequency of underlying causes in the different studies. This also reflects regional differences in the world, for example differences in diets and the prevalence of infections. Thus, it is important to remember that not all possible causative factors need to be investigated in all patients, and the first step in diagnosis is a thorough history, taking the following items into consideration:

The second step of the diagnosis is the physical examination of the patient. Where it is indicated by history and/or physical examination, further appropriate diagnostic tests should be performed. The selection of these diagnostic measures largely depends on the nature of the urticaria subtype, as summarized in Figure 1 and Table 6.

Intensive and costly general screening programs for causes of urticaria are strongly advised against. The factors named in Table 6 in the extended programme should only be investigated based on patient history. Type I allergy is an extremely rare cause of CSU. In contrast, pseudo-allergic (nonallergic hypersensitivity reactions) to NSAIDs or food may be more relevant for CSU. Diagnosis should be based on history of NSAID intake or a pseudo-allergic elimination diet protocol. Bacterial, viral, parasitic or fungal infections, for example with H. pylori, streptococci, staphylococci, Yersinia, Giardia lamblia, Mycoplasma pneumoniae, hepatitis viruses, norovirus, parvovirus B19, Anisakis simplex, Entamoeba spp, Blastocystis spp, have been implicated to be underlying causes of urticaria.36-38 The frequency and relevance of infectious diseases vary considerably between different patient groups and different geographical regions. For example, Anisakis simplex, a sea fish nematode, has only been discussed as a possible cause of recurrent acute spontaneous urticaria in areas of the world where uncooked fish is eaten frequently.39, 40 The relevance of H. pylori, dental or ear, nose and throat infections also appears to vary between patient groups.38, 41-44 More research is needed to make definitive recommendations regarding the role of infection in urticaria.

Routine screening for malignancies in the diagnosis of underlying causes for urticaria is not suggested. Although it is noted that a slightly increased prevalence has been reported in Taiwan,45 there is not sufficient evidence available for a causal correlation of urticaria with neoplastic diseases. Ruling out malignancies is, however, warranted if patient history (eg, sudden loss of weight) points to this.

Currently, the only generally available tests to screen for auto-antibodies against either IgE or FcεR1 (the high-affinity IgE receptor) are the autologous serum skin test (ASST) and basophil activation tests (BATs). The ASST is a nonspecific screening test that evaluates the presence of serum histamine-releasing factors of any type, not just histamine-releasing auto-antibodies. The ASST should be performed with utmost care as infections might be transmitted if, by mistake, patients were injected with someone else's serum. The subject is further elucidated in a separate EAACI/GA²LEN position paper.46, 47

BATs assess histamine release or upregulation of activation markers of donor basophils in response to stimulation with the serum of CSU patients. BATs can help to co-assess disease activity in patients with urticaria 48, 49 as well as to diagnose autoimmune urticaria.50 Furthermore, BAT can be used as a marker for responsiveness to ciclosporin A or omalizumab.51, 52

In some subjects with active CSU, several groups have noted blood basopenia and that blood basophils exhibit suppressed IgE receptor-mediated histamine release to anti-IgE. Blood basophils are detected in skin lesions of CSU patients.19 CSU remission is associated with increases in blood basophil numbers and IgE receptor-triggered histamine response.53, 54 A rise in basophil number is also observed during anti-IgE treatment 55 This finding, however, needs to be examined in future research and currently does not lead to diagnostic recommendations. However, it should be noted that a low basophil blood count should not result in further diagnostic procedures. It is also known that levels of D-dimer are significantly higher in patients with active CSU and decrease according to the clinical response of the disease to omalizumab. The relevance of this finding is not yet clear, and currently, it is not recommended to measure D-dimer levels.56, 57

4.3 The diagnostic work up in CIndU

In CIndUs, the routine diagnostic work up should follow the consensus recommendations on the definition, diagnostic testing and management of CIndUs.69 Diagnostics in CIndU are used to identify the subtype of CIndU and to determine trigger thresholds.69 The latter is important as it allows for assessing disease activity and response to treatment. For most types of CIndU, validated tools for provocation testing are meanwhile available.69 Examples include cold and heat urticaria, where a Peltier element-based provocation device (TempTest^®) is available,70 symptomatic dermographism for which a dermographometer (FricTest^®) has been developed,71, 72 and delayed pressure urticaria. In cholinergic urticaria, a graded provocation test with office-based methods, for example pulse-controlled ergometry, is available.66, 73 Patients with contact urticaria or aquagenic urticaria should be assessed by appropriate cutaneous provocation tests.69

4.4 Diagnosis in children

Urticaria can occur in all age groups, including infants and young children. Although data for childhood CSU are still sparse, recent investigations indicate that the prevalence of CIndUs and CSU, and underlying causes of CSU are very similar to the prevalence and causes in adults, with some minor differences.74-77

Thus, the diagnostic approaches for children should be similar to those in adults.

The diagnostic work up of CSU in children has the same aims as in adults: (i) differential diagnoses should be excluded with a special focus on cryopyrin-associated periodic syndrome (CAPS). CAPS is a rare disease with a urticaria-like rash that manifests in childhood.78 (ii) If possible, that is depending on the age of the child, disease activity, impact and control should be assessed using assessment tools similar to those used in adults, although it has to be noted that no validated disease-specific tools for children are available as of now. (iii) Triggers of exacerbation should be identified and, where indicated, underlying causes, which appear to be similar to those in adults, should be searched for. In children with CIndU, similar tests for provocation and the determination of trigger thresholds should be performed.

5.1 Basic considerations

5.2 Identification and elimination of underlying causes and avoidance of eliciting factors

To eliminate an underlying cause, an exact diagnosis is a basic prerequisite. The identification of a cause in CU is, however, difficult in most cases, for example infections may be a cause, aggravating factor or unrelated. The only definite proof of a causative nature of a suspected agent or trigger is the remission of symptoms following elimination and recurrence of symptoms following re-challenge in a double-blind provocation test. Spontaneous remission of urticaria can occur any time, the elimination of a suspected cause or trigger can also occur coincidentally.

5.3 Inducing tolerance

Inducing tolerance can be useful in some subtypes of urticaria. Examples are cold urticaria, cholinergic urticaria and solar urticaria, where even a rush therapy with UV-A has been proven to be effective within 3 days.96 However, tolerance induction is only lasting for a few days, and thus, a consistent daily exposure to the stimulus just at threshold level is required. Tolerance induction and maintenance are often not accepted by patients, for example in the case of cold urticaria where daily cold baths/showers are needed to achieve this.

5.4 Symptomatic pharmacological treatment

A basic principle of the pharmacological treatment is to aim at complete symptom relief. Another general principle in pharmacotherapy is to use as much as needed and as little as possible. The extent and selection of medication may therefore vary in the course of the disease.

The main option in therapies aimed at symptomatic relief is to reduce the effect of mast cell mediators such as histamine, PAF and others on the target organs. Many symptoms of urticaria are mediated primarily by the actions of histamine on H₁-receptors located on endothelial cells (the wheal) and on sensory nerves (neurogenic flare and pruritus). Thus, continuous treatment with H₁-antihistamines is of eminent importance in the treatment of urticaria (safety data are available for use of several years continuously). Continuous use of H₁-antihistamines in CU is supported not only by the results of clinical trials97, 98 but also by the mechanism of action of these medications, that is that they are inverse agonists with preferential affinity for the inactive state of the histamine H₁-receptor and stabilize it in this conformation, shifting the equilibrium towards the inactive state.

However, other mast cell mediators (PAF, leukotrienes, cytokines) can also be involved and a pronounced cellular infiltrate including basophils, lymphocytes and eosinophils may be observed.99 These may respond completely to a brief burst of corticosteroid and may be relatively refractory to antihistamines.

These general considerations on pharmacotherapy refer to all forms of acute and chronic urticaria. The difference between spontaneous urticaria and CIndU is, however, that in some forms of physical urticaria, for example cold urticaria instead of continuous treatment, on-demand treatment may be useful. In particular, if the patient knows of a planned trigger such as expected cold exposure, when going for a swim in summer, the intake of an antihistamine 2 hours prior to the activity may be sufficient.

Antihistamines have been available for the treatment of urticaria since the 1950s. The older first-generation antihistamines have pronounced anticholinergic effects and sedative actions on the central nervous system (CNS) and many interactions with alcohol and drugs affecting the CNS, such as analgesics, hypnotics, sedatives and mood elevating drugs, have been described. They can also interfere with rapid eye movement (REM) sleep and impact on learning and performance. Impairment is particularly prominent during multi-tasking and performance of complex sensorimotor tasks such as driving. In a GA²LEN position paper,100 it is strongly recommended not to use first-generation antihistamines any longer in allergy both for adults and especially in children. This view is shared by the WHO guideline ARIA.101 Based on strong evidence regarding potential serious side effects of old sedating antihistamines (lethal overdoses have been reported), we recommend against the use of these sedating antihistamines for the routine management of CU as first-line agents, except for the rare places worldwide in which modern 2^nd-generation antihistamines are not available. The side effects of first-generation H₁-antihistamines are most pronounced for promethazine, diphenhydramine, ketotifen and chlorphenamine and are well understood. They penetrate the blood-brain barrier, bind to H₁-receptors in the CNS and interfere with the neurotransmitter effects of histamine. Positron-emission tomography (PET) studies document their penetration into the human brain and provide a new standard whereby CNS H₁-receptor occupancy can be related directly to effects on CNS function.102

The development of modern 2^nd-generation antihistamines led to drugs which are minimally or nonsedating and free of anticholinergic effects. However, 2 of the earlier modern 2nd-generation drugs, astemizole and terfenadine, which were essentially pro-drugs requiring hepatic metabolism to become fully active, had cardiotoxic effects if this metabolism was blocked by concomitant administration of inhibitors of the cytochrome P450 (CYP) 3A4 isoenzyme, such as ketoconazole or erythromycin. These 2 drugs are no longer available in most countries, and we recommend that they are not used.

Further progress with regard to drug safety has been achieved in the last few decades with a considerable number of newer modern 2^nd-generation antihistamines.102 Not all antihistamines have been tested specifically in urticaria, but many nonsedating antihistamines studies are available, for example cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, ebastine, rupatadine and bilastine. Modern 2^nd-generation antihistamines should be considered as the first-line symptomatic treatment for urticaria because of their good safety profile. However, up to date, well-designed clinical trials comparing the efficacy and safety of modern 2^nd-generation H₁-antihistamines in urticaria are largely lacking.

There are studies showing the benefit of a higher dosage of 2^nd-generation antihistamines in individual patients103-105 corroborating earlier studies which came to the same conclusion employing first-generation antihistamines.106, 107 This has been verified in studies using up- to fourfold higher than recommended doses of bilastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine and rupatadine.103, 104, 108-111

In summary, these studies suggest that the majority of patients with urticaria not responding to standard doses will benefit from up-dosing of antihistamines. Modern 2^nd-generation antihistamines at licensed doses are first-line treatment in urticaria and up-dosing is second-line treatment (Figure 2).

5.5 Further therapeutic possibilities for antihistamines-refractory patients

Omalizumab (anti-IgE) has been shown to be very effective and safe in the treatment of CSU.112-117 Omalizumab has also been reported to be effective in CIndU118, 119 including cholinergic urticaria,120 cold urticaria,68, 121 solar urticaria,122 heat urticaria,123 symptomatic dermographism,67, 124 as well as delayed pressure urticaria.125 In CSU, omalizumab prevents angioedema development,126 markedly improves quality of life,9, 127 is suitable for long-term treatment128 and effectively treats relapse after discontinuation.128, 129 Omalizumab, in CU, is effective at doses from 150 to 300 mg per month. Dosing is independent of total serum IgE.112 The recommended dose in CSU is 300 mg every 4 weeks. The licensed doses and treatment duration vary between different countries.

Ciclosporin A also has a moderate, direct effect on mast cell mediator release.130, 131 Efficacy of ciclosporin A in combination with a modern 2^nd-generation H₁-antihistamine has been shown in placebo-controlled trials 132-134 as well as open controlled trials 135 in CSU, but this drug cannot be recommended as standard treatment due to a higher incidence of adverse effects.133 Ciclosporin A is off-label for urticaria and is recommended only for patients with severe disease refractory to any dose of antihistamine and omalizumab in combination. However, ciclosporin A has a far better risk/benefit ratio compared with long-term use of steroids.

Some previous RCTs have assessed the use of leukotriene receptor antagonists. Studies are difficult to compare due to different populations studied, for example inclusion of only aspirin and food additive intolerant patients or exclusion of ASST-positive patients. In general, the level of evidence for the efficacy of leukotriene receptor antagonists in urticaria is low but best for montelukast.

At present, topical corticosteroids are frequently and successfully used in many allergic diseases, but in urticaria topical steroids are not helpful (with the possible exception of pressure urticaria on soles as alternative therapy with low evidence). If systemic corticosteroids are used, doses between 20 and 50 mg/day for prednisone are required with obligatory side effects on long-term use. There is a strong recommendation against the long-term use of corticosteroids outside specialist clinics. Depending on the country, it must be noted that steroids are also not licensed for CU (eg, in Germany prednisolone is only licensed for acute urticaria). For acute urticaria and acute exacerbations of CSU, a short course of oral corticosteroids, that is treatment of a maximum of up to 10 days, may, however, be helpful to reduce disease duration/activity.136, 137 Nevertheless, well-designed RCTs are lacking.

While antihistamines at up to quadruple the manufacturers’ recommended dosages will control symptoms in a large part of patients with urticaria in general practice, alternative treatments are needed for the remaining unresponsive patients. Before changing to an alternative therapy, it is recommended to wait for 1-4 weeks to allow full effectiveness.

As the severity of urticaria may fluctuate, and spontaneous remission may occur at any time, it is also recommended to re-evaluate the necessity for continued or alternative drug treatment every 3-6 months.

Except for omalizumab and ciclosporin A, which both have restrictions due to their high cost, many of the alternative methods of treatment, such as combinations of modern 2^nd-generation H₁-antihistamines with leukotriene receptor antagonists, are based on clinical trials with low levels of evidence (Table 9). Based on the level of evidence, the recommended third-line and fourth-line treatment options are thus limited (see algorithm figure 2).

H₂-antagonists and dapsone, recommended in the previous versions of the guideline, are now perceived to have little evidence to maintain them as recommendable in the algorithm but they may still have relevance as they are very affordable in some more restricted healthcare systems. Sulphasalazine, methotrexate, interferon, plasmapheresis, phototherapy, intravenous immunoglobulins (IVIG/IGIV) and other treatment options have low-quality evidence, or just case series have been published2 (Table 9). Despite the lack of published evidence, all these drugs may be of value to individual patients in the appropriate clinical context.138

Antagonists of tumour necrosis factor alpha (TNF-alpha)139 and IVIG/IGIV,140-143 which have been successfully used in case reports, are recommended currently only to be used in specialized centres as last option (ie, anti-TNF-alpha for delayed pressure urticaria and IVIG/IGIV for CSU).144, 145

For the treatment of CSU and symptomatic dermographism, UV-B (narrow-band UV-B, TL01), UV-A and PUVA treatment for 1-3 months can be added to antihistamine treatment.146-148

Some treatment alternatives formerly proposed have been shown to be ineffective in double-blind, placebo-controlled studies and should no longer be used as the grade of recommendation is low. These include tranexamic acid and sodium cromoglycate in CSU,149, 150 nifedipine in symptomatic dermographism/urticaria factitia 151 and colchicine and indomethacin in delayed pressure urticaria.152, 153 However, more research may be needed for patient subgroups, for example recently Ref.154 a pilot study of patients with elevated D-dimer levels showed heparin and tranexamic acid therapy may be effective.

5.6 Treatment of special populations