BSACI guideline for the management of chronic urticaria and angioedema

doi: 10.1111/cea.12494 Clinical & Experimental Allergy, 45, 547–565

BSACI GUIDELINE

R. J. Powell

, S. C. Leech

, S. Till

, P. A. J. Huber

, S. M. Nasser

and A. T. Clark

Department of Clinical Immunology and Allergy, Nottingham University, Nottingham, UK,

Department of Child Health, Kings College Hospital, London,

UK,

Division of Asthma, Allergy and Lung Biology, Kings College London, London, UK,

BSACI, British Society for Allergy & Clinical Immunology, London,

UK,

Department of Allergy & Clinical Immunology, Addenbrooke’s NHS Trust, Cambridge, UK and

Department of Allergy, Addenbrookes NHS Trust,

Cambridge, UK

Clinical

Experimental

Allergy

Correspondence:

Dr A. T. Clark, Allergy Clinic,

Cambridge University Hospitals NHS

Foundation Trust, Box 40, Cambridge

CB2 2QQ, UK.

E-mail: [email protected]

Cite this as: R. J. Powell, S. C. Leech,

S. Till, P. A. J. Huber, S. M. Nasser and

A. T. Clark, Clinical & Experimental

Allergy, 2015 (45) 547–565.

Summary

This guidance for the management of patients with chronic urticaria and angioedema has

been prepared by the Standards of Care Committee of the British Society for Allergy and

Clinical Immunology (BSACI). The guideline is based on evidence as well as on expert

opinion and is aimed at both adult physicians and paediatricians practising in allergy.

The recommendations are evidence graded. During the development of these guidelines,

all BSACI members were included in the consultation process using a Web-based system.

Their comments and suggestions were carefully considered by the Standards of Care

Committee. Where evidence was lacking, a consensus was reached by the experts on the

committee. Included in this management guideline are clinical classiﬁcation, aetiology,

diagnosis, investigations, treatment guidance with special sections on children with urti-

caria and the use of antihistamines in women who are pregnant or breastfeeding. Finally,

we have made recommendations for potential areas of future research.

Keywords adult, allergy, angioedema, antihistamine, anti-IgE, auto-antibody, autoimmune,

breastfeeding, BSACI, child, epidemiology, guideline, hypothyroidism, IgE, management,

paraprotein, pregnancy, pregnancy, Urticaria

Submitted 6 October 2014; revised 11 December 2014; accepted 9 January 2015

Introduction

This guidance for the management of patients with

chronic urticaria/angioedema is intended for use by

physicians treating allergic conditions. It should be rec-

ognized that patients referred to an allergy clinic often

have a different pattern of presentation (e.g. intermit-

tent acute) from those referred elsewhere and both the

patient and referring practitioners often wish to deter-

mine whether allergy is involved.

Evidence for the recommendations was collected by

electronic literature searches of MEDLINE and EMBASE

using these primary key words: urticaria, angioedema,

angioneurotic oedema, allergy, allergic, antihistamines,

auto-antibody, autoimmune, hypothyroidism, IgE,

paraprotein, pregnancy, breastfeeding, child, epidemiol-

ogy, management, psychology. In addition, hand

searches were performed and the Cochrane library and

NHS evidence were also searched. Each article was

reviewed for suitability by the ﬁrst and second author

of this guideline. The recommendations were evidence

graded at the time of preparation of these guidelines

(Appendix Tables B1 and B2). During the development

of these guidelines, all BSACI members were consulted

using a Web-based system and their comments and

suggestions were carefully considered by the Standards

of Care Committee (SOCC). Where evidence was

lacking, a consensus was reached among the experts

on the committee. Conﬂict of interests were recorded

by the SOCC. None jeopardized unbiased guideline

development.

Executive summary and recommendations

(Grades of recommendations are described in Appendix

Tables B1 and B2)

•

Chronic urticaria/angioedema has traditionally been

deﬁned as weals, angioedema or both with daily or

almost daily symptoms lasting for m ore than 6 weeks.

In these guidelines, we have also included patients with

episodic acute intermittent urticaria/angioedema lasting

for hours or days and recurring over months or years.

•

Weals and angioedema commonly occur together,

but may also occur separately.

•

Chronic urticaria affects 2–3% of individuals (lifetime

prevalence) and signiﬁcantly reduces quality of life (QoL).

•

There are important differences in aetiology and

management in children compared to adults.

•

The diagnosis is based primarily on the clinical his-

tory. Investigations are determined by the clinical his-

tory and presentation, but may not be necessary.

•

Management must include the identiﬁcation and/or

exclusion of possible triggers, patient education and a

personalized management plan (grade of recommenda-

tion = D).

•

Food allergy can usually be excluded as a cause of urti-

caria/angioedema if there is no temporal relationship to a

particular food trigger, by either ingestion or contact. Food

additives rarely cause chronic urticaria and angioedema.

•

Certain drugs can cause or aggravate chronic urti-

caria and/or angioedema, and hence, a detailed drug

history is mandatory.

•

Autoimmune urticaria/angioedema in older children

and adults is reported to account for up to 50% of

chronic urticaria and may be associated with other

autoimmune conditions such as thyroiditis.

•

Autoimmune and some inducible weals can be more

resistant to treatment and follow a protracted course.

•

The commonest type of angioedema without weals is

histaminergic.

•

Angioedema without weals is a cardinal feature of

hereditary angioedema (HAE) and typically involves

subcutaneous sites, gut and larynx. In Types I and II

HAE, levels of C4 and C1 inhibitor (functional and/or

antigenic) are low.

•

Angiotensin converting enzyme (ACE) inhibitors can

cause angioedema without weals resulting in airway

compromise. They should be withdrawn in subjects with

a history of angioedema (grade of recommendation = C).

ACE inhibitors are contraindicated in individuals with a

history of angioedema with or without weals.

•

Pharmacological treatment should be started with a

standard dose of a non-sedating H1-antihistamine

(grade of recommendation = A).

•

The treatment regime should be modiﬁed according

to treatment response and development of side-effects.

•

Higher than normal doses of antihistamines may be

required to control severe urticaria/angioedema (grade of

recommendation = B). Updosing with a single antihista-

mine is preferable to mixing different antihistamines.

•

If an antihistamine is required in pregnancy, the

lowest dose of chlorphenamine, cetirizine or loratadine

should be used (grade of recommendation = C).

•

If an antihistamine is required during breastfeeding,

it is recommended that either cetirizine or loratadine

are taken at the lowest dose. Whenever possible, chlor-

phenamine should be avoided during breastfeeding

(grade of recommendation = C).

Deﬁnition

Chronic urticaria/angioedema (CU) has traditionally

been deﬁned as weals, angioedema or both lasting for

more than 6 weeks [1, 2]. Acute urticaria is an episode

of spontaneous weals lasting for <6 weeks and is not

considered further in this guideline. However, we have

included patients with episodic urticaria/angioedema

lasting for hours or days and recurring over months or

years. Although rarely life-threatening, chronic urti-

caria/angioedema lead s to both misery and embarrass-

ment and has a signiﬁcant impact on an individual’s

quality of life [3–5]. Regrettably, this troublesome con-

dition is often trivialized. Box 1 lists the terminology

pertaining to urticaria referred to in this guideline.

Urticaria (‘hives’ or ‘nettle rash’) is characterized by a

red (initially with a pale centre), raised, itchy rash

resulting from vasodilatation, increased blood ﬂow and

increased vascular permeability. Weals can vary in size

from a few millimetres to hand-sized lesions which

may be single or numerous. The major feature of urti-

caria is mast cell activation that results in the release of

histamine (and other inﬂammatory mediators); that in

turn accounts for the raised, superﬁcial, erythematous

weals and accompanying intense pruritus. Angioedema

(tissue swelling) is the result of a local increase in vas-

cular permeability, often notable in the face, orophar-

ynx, genitalia and less frequently in the gastrointestinal

tract. These swellings can be painful rather than itchy.

Weals affect the superﬁcial skin layers (papillary der-

mis), whereas angioedema can involve the submucosa,

the deeper reticular dermis and subcutaneous tissues.

Weals and angioedema often coexist, but either can

occur separately. Characteristically the weals arise

spontaneously and each lesion re solves within 24 h.

This contrasts with angioedematous swellings that can

persist for a few days.

When functional antibodies are demonstrated, this

suggests an autoimmune basis. In the commonest form

Box 1. Terminology dependent on how study popula-

tion was characterized

Term Abbreviation Deﬁnition

Chronic urticaria CU Encompasses CsU and CaU

Chronic spontaneous

urticaria (previously

called CiU – chronic

idiopathic urticaria)

CsU Not associated with

auto-antibodies

Chronic autoimmune

urticaria

CaU Associated with antibodies

to IgE/IgE receptor

Hereditary Angioedema HAE Typically associated with

C1 inhibitor deﬁciency

548 R. J. Powell et al

of the disease (chronic spontaneous urticaria – CsU),

there appears to be persistent activation of mast cells in

the skin, but the precise mechanism of mast cell trig-

gering in CsU is unknown. Functional auto-antibodies

against the high-afﬁnity IgE receptor (FceR1) have been

demonstrated in 30–40% of patients with CU suggesting

an autoimmune basis (CaU) [6–8].

Urticaria and angioedema in adults

Prevalence

The lifetime prevalence for all types of urticaria is

8.8%, but CU only develops in 30–45% of these indi-

viduals [8–10].

Clinical classiﬁcation

Urticaria may occur alone in about 50% of cases,

urticaria with angioedema in 40%, and angioedema

without weals in 10% [11, 12]. However, a study by

Sabroe et al. [13] found a much higher percentage

(85%) of patients with urticaria and angioedema.

Table 1 lists the clinical classiﬁcation of chronic urti-

caria/angioedema.

Aetiology

Optimal management of chronic and acute intermittent

urticaria depends on a thorough understanding of clini-

cal presentation, aetiology, triggers and aggravating fac-

tors. Patients with chronic urticaria are often referred to

allergy clinics as cases of possible food allergy – ‘to ﬁnd

out what they are allergic to’. Rarely is food allergy the

cause of chronic urticaria and can typically be excluded

on the basis of clinical history. Common triggers/aggra-

vating factors/associations for exacerbations of chronic

urticaria are intercurrent viral infections [14] and psy-

chological factors [15]. The aetiological classiﬁcation of

chronic urticaria/angioedema is given in Table 2.

Mechanisms

The central effector cell is the dermal/submucosal mast

cell, which on degranulation releases preformed vasoac-

tive mediators such as histamine, a major mediator of

urticaria and angioedema. Subseq uently cytokines,

chemokines and membrane-derived mediators (leukotri-

enes and prostaglandins) are released, contributing to

both the early- and late-phase responses with extrava-

sation of ﬂuid into the superﬁcial tissues.

Table 1. Clinical classiﬁcation of chronic

urticaria/angioedema

Description Type Examples of triggers

Spontaneous urticaria Spontaneous Stress, infection, drugs (e.g. NSAIDs)

Autoimmune urticaria Autoimmune None known

Inducible urticaria Aquagenic Contact with hot or cold water

Cholinergic Exercise, emotion

Cold Swimming in cold water, cold wind

Delayed pressure Sitting, lying, tight clothing

Dermographism Minor trauma

Exercise Physical exertion

Heat Hot bath/shower

Solar Sunshine

Vibratory Use of vibrating tools

Angioedema

without weals

Spontaneous Stress, infection, drugs (e.g. NSAIDs)

C1 inhibitor deﬁciency Trauma, surgical procedures, stress,

infection

C1 inhibitor

deﬁciency related to

paraproteinaemia

Trauma, surgical procedures, stress,

infection

Drugs ACE inhibitors, oestrogens, antipsychotic

drugs, statins, NSAIDs

Vasculitis* Urticarial vasculitis Infection, e.g. with hepatitis B/C or

streptococcus; drugs, e.g. penicillins,

allopurinol, quinolones or

carbamazepine; autoimmune diseases;

paraproteinaemia; malignancy

Rare syndromes* Cryopyrin-associated

periodic syndrome (CAPS)

Cold

Schnitzler syndrome

*Vasculitis and rare syndromes are differential diagnoses of chronic urticaria and angioedema.

Urticaria and Angioedema BSACI guideline 549

Whereas the mast cell component of urticaria is easily

recognized (itching and wealing) and usually responds to

antihistamines, swelling in the deeper layers of the skin

is more difﬁcult to quantify and additional mechanisms

are probably involved. Several inﬂammatory mediators

increase microvascular permeability leading to plasma

leakage and oedema formation. Animal experiments

have shown that certain mediators, for instance LTB4

and C5a, cause plasma leakage via neutrophil-dependent

pathways in a manner that does not require the neutro-

phil to trav erse the vascular endothelium, i.e. adhesion of

neutrophils to the vessel wall is sufﬁcient to initiate

plasma leakage [16, 17]. Hence antihistamines are less

effective in contro lling the angioedema probably due to

their inability to affect consequent non-histamine-

related tissue oedema.

An examination of lesional skin biopsies from both

chronic spontaneous and autoimmune urticaria reveals

perivascular inﬁltrates of CD4+ lymphocytes, mono-

cytes and granulocytes (neutrophils, basophils and eo-

sinophils). This contrasts with biopsies from patients

with urticarial vasculitis (~1% ca ses of urticaria) in

which there is typically a small vessel vasculitis often

with deposition of immunoglobulin and complement

[11]. However, some patients with vasculitis exhibit

only subtle changes with endothelial cell swelling, red

cell extravasation and possibly leukocytoclasia.

Autoimmune urticaria (CaU). IgG antibodies to the

alpha subunit of the IgE receptor on mast cells or less

commonly IgG antibodies to IgE have been documented

in approximately one-third of individuals with chronic

urticaria [7, 18–20]. These antibodies are disease spe-

ciﬁc with some studies suggesting that this subgroup of

patients experiences a more intense and protracted dis-

ease course [13]. The mechanism has been reviewed in

the EACCI task force position paper [21].

However, sera from subjects wi th chronic urticaria are

also able to degranulate mast cells through mechanisms

independent of both IgE and IgG although the precise

nature of these histamine-releasing factors remains

unknown [22], but in vitro studies have suggested activa-

tion of the classical complement pathway [23, 24].

Vasculitis/immune complex-associated urticaria. Com-

plement activation can media te or augment histamine

Table 2. Aetiological classiﬁcation of chronic urticaria/angioedema

Aetiology Mechanism Examples Investigations

Spontaneous

(40–50% cases)

Unknown Typically negative

Autoimmune IgG auto-antibody to mast cell

IgE receptor or to IgE bound

to mast cells

Associated with autoimmune thyroiditis ANA, thyroid auto-antibodies

Physical stimuli Direct mast cell mediator release Exercise, heat, cold, pressure, aquagenic,

solar, delayed pressure, vibration,

dermographism

Challenge testing with

appropriate stimuli, e.g. ice

cube, exercise. Cryoglobulins

Drug induced Reduced kinin metabolism; elevated

leukotriene levels

ACE inhibitors (angioedema alone)

NSAIDs

Response to avoidance (may

be delayed for weeks or months)

Infection Complement activation due to immune

complex formation

Parasites, EBV, hepatitis B and C,

viral exanthems

Serology directed by clinical

history

Allergic IgE-mediated allergic contact urticaria Latex, animals, grass, food Skin tests, speciﬁc IgE to

allergen

C1 inhibitor deﬁciency

Genetic (i) Enhanced kinin production HAE Types I and II C4, C1 inhibitor

Genetic (ii) Activation of complement, ﬁbrinolysis

and coagulation systems

HAE Type III C4, C1 inhibitor, Factor

XII studies may be useful

Acquired Binding of C1 inhibitor by paraprotein Associated with paraproteinaemia C4, C1 inhibitor, Paraprotein

in both blood & urine

Non-IgE-mediated mast

cell degranulation

Non-receptor-mediated Opiates, Adrenocorticotropic

Hormones (ACTH)

Response to avoidance

Vasculitis Small vessel vasculitis, deposition of

immunoglobulin and complement

Urticarial vasculitis FBC, ESR, renal function,

urinalysis, LFT, ASOT,

hepatitis B and C serology,

immunoglobulin electrophoresis,

autoimmune screen including

ANA, ANCA, C3, skin biopsy

Food constituent (rare) Unknown Salicylates/benzoates Response to exclusion and

subsequent reintroduction

550 R. J. Powell et al

release from mast cells via the anaphylatoxin C5a. This

inﬂammatory pathway is triggered by the interaction

between antibody and antigen to form immune com-

plexes for example in hepatitis C [25–27], hepatitis B

[28], EBV and possibly parasitic infections.

Inducible urticarias. Patients can have an inducible ele-

ment to their urticaria with triggering by heat, cold,

pressure, vibration, water, ultraviolet light, etc. These

urticarias are induced reproducibly after a speciﬁc

physical stimulus is applied [29]. Weals usually appear

immediately and characte ristically fade within 1 h.

However, delayed pressure urticaria develops more

slowly after physical pressure and lasts several hours or

days. Inducible urticarias may require higher dose anti-

histamine therapy and delayed pressure urticaria may

remain refractory.

Possible food triggers. Symptoms of chro nic urticaria/

angioedema are typically non-allergic with most

patients having spontaneous or autoimmune urticaria/

angioedema. Nevertheless, patients or their parents fre-

quently analyse foods and food additives eaten over the

previous 24 h or longer in the search for a connection

with the symptoms.

A detailed history us ually enables an IgE-mediated

food allergy to be excluded as a cause of urticaria/an-

gioedema. Speciﬁcally in IgE-mediated food allergy,

symptoms typically occur reproducibly within 60 min

of exposure to the offending food rather than coming

on overnight or being present ﬁrst thing in the morn-

ing. Furthermore, symptoms do not last several days.

Also urticaria and angioedema associated with IgE-

mediated food allergic reactions seldom occur in isola-

tion, i.e. additional symptoms are usually present such

as oropharyngeal itching and discomfort, wheezing,

vomiting or abdominal pain. Therefore, unless there is a

close temporal relationship to a particular food trigger,

by either ingestion or contact, an IgE-mediated food

allergy can be excluded.

Exceptions include allergic reactions to allergens,

such as omega-5 gliadin in wheat and lipid transfer

proteins in plant-derived foods, which may occasion-

ally present as intermittent spontaneous urticaria/exer-

cise-induced anaphylaxis. As exertion is frequently a

cofactor for reactions to these allergens, the temporal

relation to ingestion may not be immediately obvi-

ous.

Allergy to Crustacea may behave similarly, although

in practice these allergens are less ubiquitous and a

temporal relationship between ingestion and urticarial

episodes is usually apparent. Allergy to aGAL in red

meat may cause delayed reaction with urticaria,

although this is currently believed to be rare in the Uni-

ted Kingdom [30].

Stress. Urticaria and angioedema can lead to signiﬁcant

stress and the converse is also recognized, namely that

psychological stress can trigger or aggra vate urticaria.

Although psychological stress in isolation is unlikely

to be the sole trigger, a high frequency of patients with

CsU report a stressful event preceding the onset of CsU

[31] and the possibility of a causal inﬂuence of emo-

tional distress, especially of stressful life events, on the

course of skin diseases has long been postu lated [32].

Patients with CsU experience high rates of anxiety,

depression and somatoform disorders such as ﬁbrom-

yalgia, with half of subjects with CsU being affected by

at least one of these conditions [33, 34]. Psychiatric

comorbidity appears to signiﬁcantly increase QoL

impairment [35]. Compared to allergy patients, individ-

uals with CsU had more severe comorbidity and higher

levels of life event stress and perceived stress. Further-

more, an association between post-traumatic stress and

chronic spontaneous urticaria has also been reported

[36]. Psychological therapies could be considered in

addition to medical management.

Other putative causes. An underlying extraneous cause

for chronic urticaria cannot be identiﬁed in many

patients, but infections may play a role in certain cases.

When present, chronic infections such as dental sepsis,

sinusitis, urinary tract infections and cutaneous fungal

infections should be treated. However, exhaustive inves-

tigations sear ching for underlying infections are not

indicated. Candida colonization does not cause chronic

urticaria [37]. There is limited evidence that if Helicobact-

er pylori colonization is present, eradication may result

in an improvement in CU; hence, routine screening of

Helicobacter pylori is not recommended [38, 39].

Mechanisms speciﬁcally related to angioedema

occurring without weals

Angioedema without weals. Individuals with angioe-

dema without associated weals should speciﬁcally have

their medication and family history reviewed to identify

those on angiotensin converting enzyme (AC E) inhibi-

tors and those patients with hereditary ang ioedema

(HAE). NSAIDs and antibiotics can also induce angioe-

dema [40, 41]. Acquired forms of C1 inhibitor deﬁ-

ciency can result from serum paraproteins that have

auto-antibody activity against C1 inhibitor. Immune

complex formation by IgG with tumour surface anti-

gens may result in complement consumption. Invest iga-

tions typically show reduced levels of complement C4

and may reveal low levels of C1 inhibitor.

Angioedema with ACE inhibitors. The incidence of ACE

inhibitor-induced angioedema may be as high as 0.68%

[42] as most cases were initially thought to occur in the

Urticaria and Angioedema BSACI guideline 551

ﬁrst weeks of treatment, but it is now appreciated that

later onset angioedema, occurring after many years of

uneventful drug use, is quite common [42–44]. The

mechanism underlying the angioedema is likely to be

due to the reduced metabolism of bradykinin; this effect

may also aggravate angioedema associated with HAE.

Angioedema associated with angiotensin receptor

blockers (ARB’s) has been occasionally reported and

hence their use in individuals with ACE inhibitor-

related angioedema has been questioned but is not con-

tra-indicated [45]. The patient usually presents with

swelling of the tongue, but the lips, pharynx, larynx

and viscera may also be involved. Fatalities are

reported [46], and hence, it is mandatory to recommend

that the ACE inhibitor is withdrawn. The episodes of

angioedema may persist for several months after with-

drawal of the ACE inhibitor without undermining the

validity of the drug-related diagnosis [45]. Individuals

of Afro-Caribbean origin are at increased risk of ACE

inhibitor-induced angioedema. As this group of drugs

are less effective in such individuals, an alternative

choice of antihypertensive is prudent [42, 43, 47]. Anti-

histamines, corticosteroids and adrenaline have tradi-

tionally been used to treat these individuals although

their efﬁcacy remains unproven. However, bradykinin

antagonists, such as icatibant, may be effective. These

drugs are undergoing clinical trials and may prove use-

ful. C1 inhibitor concentrate is not beneﬁcial in patients

with acute angioedema associated with ACE inhibitors.

Follow-up studies on individuals with presumed ACE

inhibitor-related angioedema show that in the majority

symptoms disappear or are drastically reduced after

stopping the ACE inhibitor. Individuals who do not

improve even after several months of stopping the ACE

inhibitor are likely to have an alternative explanation

for their angioedema and were coincidentally taking an

ACE inhibitor. There are no routine investigations to

distinguish responders from non-responders to ACE

inhibitor withdrawal. If the ACE inhibitor is responsible

but is not withdrawn, the attacks may become more

severe and frequent. ACE inhibitors are contraindicated

in patients with a history of angioedema and an alter-

native antihypertensive should be substituted.

Hereditary angioedema (HAE). Angioedema occurs

without weals in HAE and typically involves cutaneous

sites, gut and larynx. A family history should be

sought. HAE can be subdivided into three types. Types I

and II are caused by mutations of the SERPING1 gene

and are associated with deﬁcient levels of C1 inhibitor

or a dysfunctional C1 inhibitor, respectively. Type III is

associated with mutations of Factor XII and the levels

of C1 inhibitor remain normal or only slightly reduced.

These mutations appear to be markers of enhanced ki-

nin production. Type III affec ts women more frequently

and more severely, probably related to the effect of oes-

trogen in promoting angioedema [48]. The beneﬁt of

progestin contraception rather than an oestrogen–pro-

gestin contraception in Type III is reported [49]. Com-

bined oral contraception should be avoided in all

women with HAE [50].

Prognosis

At least 20% of chronic urticaria patients with symp-

toms severe enough to warrant hospital referral remain

symptomatic 10 years after ﬁrst presentation and this

compares closely with a study published a decade ear-

lier [51, 52]. Increased duration of chronic urticaria cor-

relates with clinical severity, the presence of

angioedema and positive antithyroid antibodies [53]. A

positive autolo gous serum test has been correlated with

more severe symptoms but not prolong ed disease dura-

tion [7, 13].

Making the diagnosis

Clinical history and examination. A detailed history of

urticaria and angioedema is essential and should fully

document the frequency, circumstances of onset, trig-

gers, timin g, pattern of recurrence and duration of

attacks. The history and examination should also

include a description of the nature, site and duration of

individual lesions and whether they itch or are painful.

Photographs of urticaria and angioedema can be helpful

in conﬁrming the nature of the lesions. Detailed drug

and family history as well as response to treatment are

important. Important points to be considered when tak-

ing a clinical history are listed in Boxes 2 and 3. The

clinical history often identiﬁes triggers and is essential

to direct further investigation. Figure 1 shows an

algorithm for the diagnosis of chronic urticaria and/or

angioedema.

Box 2. Questions when considering an ‘allergic’ cause?

•

Could it be related to any drugs the patient has

taken (ACE inhibitor/aspirin/NSAID)?

•

Does it occur only and reproducibly within

60 min (usually within 20 min) of eating a particular

food? Exceptions meat and crustaceans (such as

prawn).

•

Does it occur only if a particular food (e.g. wheat)

has been eaten followed by exercise?

•

Does it occur after contact with an allergen to

which the patient is sensitized (animals, grass, food,

latex, etc.)?

552 R. J. Powell et al

Investigations

The diagnosis is based primarily on the clinical presen-

tation. The need for investigations to elucidate a possi-

ble underlying cause should be guided by the

presentation and response to antihistamines (Table 2)

[54].

Allergy testing. Patients are often referred to hosp ital in

the belief that foods are responsible for their chronic

urticaria. A practical approach could be to exclude an

atopic diathesis by skin prick testing (SPT) to a panel of

aeroallergens and suspect foods. The sight of negative

SPTs in certain patients helps to reassure the patient

that allergy is not the cause of their symptoms and may

contribute to improved adherence with long-term anti-

histamines.

When urticaria symptoms are linked to exertion or

exercise, there can be a role for limited speciﬁc IgE

testing to related food allergens, e.g. omega-5-gliadin

or lipid transfer proteins [55]. In certain Mediterranean

areas, Anisakis simplex hypersensitivity associated

with the consumption of raw ﬁsh should be considered

[56–58].

Full blood count (FBC)—The eosinophil count may be

elevated in parasitic infections and in some drug-

induced reactions. An elevated neutrophil count can be

associated with urticarial vasculitis.

Urinalysis—A screen for haematuria and proteinuria will

help to detect the presence of urinary tract infection

and renal involvement in vasculitis.

Acute phase response—An elevated ESR and/o r CRP

suggests an underlying systemic condition such as

chronic infection, vasculitis and a high ESR with nor-

mal CRP may indicate paraproteinaemia.

Thyroid function and auto-antibodies—The presence of

thyroid auto-antibodies is associated with chronic

URTICARIA

± ANGIOEDEMA

ANGIOEDEMA

Lesions last > 24 hours or

systemic features, e.g. arthralgia

Associated

autoimmune disorder

Exclusion of all known

precipitating factors

ACE

inhibitor

Low C4

± low or normal

C1 inhibitor

Low C4

with

paraprotein

Consider other tests

including skin biopsy

as clinically indicated

Urticarial

vasculitis

No vasculitis

Spontaneous

urticaria/angioedema

Consider

delayed-pressure

urticaria

Autoimmune urticaria

possible

Consistent with IgE mediated allergy

trigger, e.g. latex, animal, food

On a drug

known to cause or aggravate

urticaria +/– angioedema

Hereditary

angioedema

Acquired C1

esterase inhibitor

deficiency

(Acquired

angioedema)

Further appropriate tests

negative

Drug-induced urticaria

and/or angioedema

Probably drug

associated

STOP ACE inhibitor

Consider trial

off drug

Fig. 1. Algorithm for diagnosis of chronic urticaria and/or angioedema.

Box 3. Is there a vasculitic process?

•

Are the episodes of urticaria/angioedema persis-

tent rather than evanescent and self-limiting?

•

Do individual lesions last more than 24 h?

•

Are the urticarial lesions tender and painful

rather than itchy?

•

Does the skin sh ow evidence of residual petechial

haemorrhage, purpura or bruising?

•

Does the patient have any symptoms and signs of

underlying disease, e.g. fever, signiﬁcant malaise,

arthralgia, hypertension, and blood or protein in

urine?

Urticaria and Angioedema BSACI guideline 553

urticaria in both children and adults and suggests a

diagnosis of autoimmune urticaria. Such patients are

often euthyroid but require monitoring over time. Thy-

roxine treatment is not indicated in euthyroid individu-

als with CU and thyroid autoimmunity [59].

Approximately 20% of patients with chronic urticaria

have antithyroid antibodies [60–62] compared to 6% in

the general population [60].

Complement studies—C1 inhibitor deﬁciency is not asso-

ciated with urticaria, and hence, if urticaria is present,

measurement of C1 inhibitor is not required. Initial

complement investigations in patients with angioedema

without weals should include C4 and C1 inhibitor. The

C4 level will be low in most cases of Types I and II

HAE even between attacks. Functional C1 inhibitor

quantitation should be reserved for equivocal cases with

a suggestive history and low C4 but normal levels of

antigenic C1 inhibitor [63]. C3 and C4 should be mea-

sured in individuals with suspected urticarial vasculitis

[53], and if reduced, measurement of anti-C1q antibod-

ies may be useful.

Haematinics and vitamins—If clinically indicated, mea-

surement of serum iron [64] and vitamin B12 [65] lev-

els can be useful.

Immunoglobulins—Individuals, usually older than

40 years with CU and systemic symptoms such as one

of the following: malaise, fever, polyarthralgia, lymph-

adenopathy, leukocytosis, should have serum immuno-

globulins and electrophoresis undertaken to search for

an IgM paraprotein that may be ind icative of Schnitzler

syndrome [66]. Cryoglobulins can be associated with

secondary cold urticaria (requires a clotted sample col-

lected and transported to the laboratory at 37°C).

Acquired angioedema without urticaria can be associ-

ated with a B cell lymphoma and a search for a para-

protein may be indicated.

Parasitology—A clear association between parasitaemia

and CU has not been established.

Challenges—Cold-induced urticaria can usually be diag-

nosed by placing an ice cube in a sealed plastic bag

over the forearm for up to 10 min (allow skin to

rewarm subsequently). Dermographism is suspected at

the time of skin prick testing and conﬁrmed by lightly

scratching the skin with weals appearing within

10 min. The water test for aquagenic urticaria may be

applied by immersion of a body part into water (at

37°C) or by placing wet towels for a few minutes onto

the area of skin most affected. Cholinergic urticaria is

triggered by sweating due to heat, emotion or exercise

and can be provoked by exercising the patient in a

warm environment although this is not routinely under-

taken.

Skin biopsy—A lesional skin biopsy is appropriate when

there is an unusual pattern of presentation or in cases

of suspected vasculitis. Clinical clues include systemic

symptoms (fever and arthralgia or arthritis) and lesions

lasting for more than 24 h, or associated with tender-

ness, petechiae, purpura or skin staining as the lesions

fade. Linear bruising suggests excessive scratching

[11].

Autologous serum skin test and basophil release assay—

These both remain research tools. The autologous

serum skin test (ASST) involves intradermal injection

of the patient’s own serum. A positive weal and ﬂare

reaction is considered indicative of circulating auto-

antibodies to the high-afﬁnity IgE receptor on the mast

cell in CU patients [67]. The ASST is poorly tolerated

by younger children due to the discomfort associated

with intraderma l injections performed in the absence

of topical anaesthetic creams [18]. The role of the

basophil histamine release assay (BRA) in the clinical

management of CU remains unclear. The available

assays (BRA and ASST) for autoimmunity in CU do

not consistently assist clinicians in their understanding

of spontaneous CU pathogen esis [68] and remain

research tools.

Nasendoscopy—Nasendoscopy can be considered in an

individual with unexplained pharyngeal obstruction,

and this can be very useful during an attac k allowing

direct visualization of the pharynx/larynx to establish

or exclude the presence of angioedema of the throat.

Important differential diagnoses of ‘swelling, lump or

discomfort in the throat’ include globus, gastro-oesoph-

ageal reﬂux and vocal cord dysfunction.

Treatment in adults

Avoidance strategies. Symptom diaries can be useful as

an investigative tool to determine the frequency,

duration and severity of the urticarial episodes and

disease-speciﬁc QoL questionnaires /symptom scores are

available [69, 70]. Patients who fail to uncover a con-

sistent trigger are advised to discontinue the search for

an external cause.

If avoidable triggers (Table 1) are identiﬁed, the

patient should be given clear instructions on avoidance

strategies, for example avoiding cold or pressure. If the

patient is taking a drug associated with chronic urti-

caria or ang ioedema, for example a NSAID, it is pru-

dent for the patient to have a trial for at least several

weeks without this treatment. ACE inhibitors are con-

traindicated in angioedema regardless of the presence

554 R. J. Powell et al

or absence of weals. Treatment of underlying infections

and malignancies may lead to amelioration or resolu-

tion of symptoms. Alcohol can aggravate CU by its

effect of vasodilation [71].

Symptom control. In many cases, treatment of CSU is

predominantly directed towards symptom control and

therefore antihistamines active against the H1 receptor

remain the mainstay of treatment. Second-generation

antihistamines are commonly prescribed and are gener-

ally well tolerated with minimal sedation: many have a

once-daily dosage to improve adherence (see Table 4).

Pharmacokinetics suggest that to rapidly achieve opti-

mal blood levels and hence rapid relief of symptoms,

two tablets of the chosen antihistamine m ay be taken

as the ﬁrst dose, reverting to a single daily tablet there-

after. Studies of higher dose non-sedating antihista-

mines demonstrate efﬁcacy with up to 49 the

conventional dose using levocetirizine or desloratadine

[72]. Once symptom control has been accomplished,

daily treatment [73] is advised in m ost patients for 3–

6 months. For individuals with a long history at presen-

tation of urticaria with angioedema, treatment for 6 or

even 12 months is advised with gradual withdrawal

over a period of weeks. For patients with infrequent

symptoms, treatment may be taken as required or even

prophylactically (e.g. prior to occasions when symptoms

would be most unwelcome, such as business presenta-

tions). Figure 2 shows a step-up treatment plan for

chronic urticaria. A short course of corticosteroids may

be appropriate in severe episodes at any stage (e.g.

prednisolone up to 40 mg daily for 7 days) [74].

Patient-reported outcomes are available for the evalua-

tion of urticaria patie nts [75].

Standard treatment. Choice of H1-antihistamine—All

antihistamines are licensed for use in chronic urticaria,

but the chronic use of ﬁrst-generation antihistamines,

such as chlorphenamine, should be avoided where pos-

sible because of sedation and interference with psycho-

motor performance. Sedation and impaired

psychomotor function is reduced with seco nd-genera-

tion antihistamines, it but can still occur. Although a

sedating antihistamine at night can sometimes be use-

ful, the long half-life of hydroxyzine can cause day-

time somnolence [76]. Additional anti-inﬂammatory

effects as suggested by the various antihistamine man-

ufacturers may be relevant to the treatment of chronic

urticaria, but the impact on clinical practice has not

been quantiﬁed [77]. Table 3 lists the antihistamines

(H1-antihistamines) ind icated for use in chronic urti-

caria.

The efﬁcacy of the various antihistamines using sup-

pression of the weal and ﬂare response does not corre-

late with clinical urticarial responses and hence should

not be solely used to predict or compare clinical

responses in CU [78–80].

The absence of head to head comp arisons in clinical

trials prevents stratiﬁcation of efﬁcacy. Table 3 lists

the antihistamines (H1-antihistamines) indicated for

use in chronic urticaria. Individual patient responses

and side-effects to antihistamines vary and an

endorsement for a particular antihistamine cannot be

given. If higher than recomme nded doses of antihista-

mines are to be considered, incremental updosing is

advised.

Tranexamic acid—Tranexamic acid appears to beneﬁt

patients with angioedema particularly those without

weals and inhibits the conversion of plasminogen to

plasmin and consequently the production of bradykinin.

The evidence is anecdotal, but common usage recom-

mends consideration in problematic cases.

Refractory treatment. In cases of chronic urticaria and

angioedema, resistant to high-dose antihistamines, there

is no recommended second-line therapy, but the treat-

ment options given in Tables 4 and 5 and Fig. 2 may

be considered depending on the presenting clinical

symptoms, speciﬁc trigger factors and underlying

pathology.

Leukotriene receptor ant agonists—Leukotriene receptor

antagonists may be useful in combination with antihis-

tamines in a subgroup of patients with chronic urti-

caria, particularly those with adverse responses to

aspirin, NSAIDs and in those with delayed press ure urti -

IDENTIFICATION OF TRIGGERS

EDUCATION AND AVOIDANCE OF TRIGGERS

1) Standard dose non-sedating H1 antihistamine

2) Higher dose of H1-antihistamine up to four times

recommended dose or add in second antihistamine

3) Consider a second line agent, anti-leukotriene or, if

angioedema is present, use tranexamic acid

4) Consider an immunomodulant (e.g.

omalizumab, cyclosporine

Fig. 2. General management plan for chronic urticaria (Adults and

children). The starting point and the rate of progression between steps

depend on clinical severity and response. Short course of corticoster-

oids (e.g. 1 mg/kg prednisolone twice a day, up to 40 mg total per

day, for 3 days) may be used for severe exacerbations [74, 146], see

also section on rescue medication. The treatment should be stepped

down once control is achieved. Observations on the mechanism of

antihistamine action [147] suggest that it is probably sensible to with-

draw such therapy gradually, rather than stopping it abruptly.

Urticaria and Angioedema BSACI guideline 555

caria or CaU [81–85]. See also evidence Table B3

(Appendix).

Anti-IgE therapy—Omalizumab is effective in random-

ized double-blind placebo-controlled trials in patients

with spontaneous and autoimmune CU who have per-

sistent symptoms despite high- dose antihistamines [86].

An EAACI position paper recommends omalizumab

when higher dose antihistamines have failed [74]. It

requires monthly injections and appears well tolerated.

It is effective in approximately 80% of individuals with

persistent/resistant symptoms leading to a rapid

improvement. Currently, treatment is recommended for

6 months, but typically relapses occur when treatment

is discontinued.

Ciclosporin—Low-dose ciclosporin may also be consid-

ered in patients with severe unremitting disease uncon-

trolled by antihistamines [87, 88]. A T cell-mediated

mechanism has been proposed, but ciclosporin also

Dose Licensed dose Other comments/side-effects References

Acrivastine 8 mg tds Second-generation antihistamine

Rapid onset of action, not long-lasting,

excreted unchanged in urine;

non-sedating; ‘on-demand’ therapy

[97]

Bilastine 20 mg Second-generation antihistamine [120]

Cetirizine 10 mg Second-generation antihistamine [84, 85, 87, 121]

Chlorphenamine 4 mg qds First-generation antihistamine

Not for long-term use; injectable;

short half-life; sedating

Desloratadine 5 mg Second-generation antihistamine [81, 82, 122]

Fexofenadine 120–180 mg Second-generation antihistamine [83, 101, 123]

Hydroxyzine 25 mg–100 mg

daily

First-generation antihistamine

Not for long-term use; sedating

Levocetirizine 5 mg Second-generation antihistamine [71]

Loratadine 10 mg Second-generation antihistamine [124, 125]

Mizolastine 10 mg Second-generation antihistamine [126]

Promethazine 10–20 mg tds First-generation antihistamine

Not for long-term use, injectable;

sedating

T. Dean, personal

communication

Rupatadine 10 mg Second-generation antihistamine [127]

None of the above second-generation antihistamines has demonstrated superiority over another

in licensed doses. The effectiveness of levocetirizine and desloratadine in up to four times the

conventional doses has been demonstrated in difﬁcult to treat urticaria [72].

Table 3. Antihistamine (H1-antihistamines)

licensed for CU

Table 4. Second-line pharmacotherapy

Drug (families) Grade Speciﬁc indication/comments/side-effects Reference

Omalizumab A Used for chronic urticaria failed on higher

dose antihistamines

[86]

Leukotriene receptor

antagonists (montelukast

zaﬁrlukast)

Most effective in combination with antihistamines

Autoimmune urticaria; chronic urticaria with

positive challenge to food, food additives or aspirin;

delayed pressure urticaria

[81–83, 122, 128]

Table B3 (Appendix)

Tranexamic acid D Showed reduced frequency of angioedema attacks. [129, 130]

Ciclosporin B Immunosuppresive, i.e. requires monitoring of blood

pressure, renal function and serum levels if indicated;

signiﬁcant side-effects

[87, 88]

Table B4 (Appendix)

Mycophenolate Mofetil D Used for chronic urticaria failed on

higher dose antihistamines

[89, 131]

Tacrolimus D Value in severe, steroid-dependent chronic urticaria

needs further randomized controlled studies

[132]

Grade = Grade of recommendation (Table B2) [133, 134]. B

= Grade only refers to montelukast, but not to zaﬁrlukast.

556 R. J. Powell et al

inhibits basophil and mast cell degranulation. See also

evidence Table B4 (Appendix).

Mycophenolate mofetil—Open-label studies suggest that

1000 mg twice daily is useful; however, its speed of

onset is slower than with both, omalizumab and ciclo-

sporin [89].

H2-Antihistamines—A recent review [90] concluded that

the evidence for the use of H2-antihistamines in urticaria

was weak. The combination of cimetidine with hydroxy-

zine results in an increased serum level of hydroxyzine

conﬁrming the rationale for its co-administration with

hydroxyzine in some patients with CU unresponsive to

hydroxyzine alone. There is no therapeutic rationale for

co-administration of cimetidine with cetirizine in CU

[91]. In CU, the combination of ranitidine with terfena-

dine was superior to terfenadine alone in terms of itch,

but there was no signiﬁcant effect on weals or swellings

[92]. There is no strong evidence to support the addition

of ranitidine to treatment regimes in CU.

Rescue medication. Corticosteroids—There are no con-

trolled studies on the use of corticosteroids in urticaria

and angioedema, but their effectiveness is general ly

accepted. Rarely, a short course of up to 40 mg pred-

nisolone may be prescribed for severe exacerbations of

chronic urticaria, especially when accompanied by an-

gioedema [74]. Corticosteroids may also be considered

when the symptoms remain uncontrolled by antihista-

mines alone or when rapid clinical relief is required.

Urticarial vasculitis is more likely to require corticoste-

roid treatment. Longer term corticosteroid usage should

be avoided whenever possible but if unavoidable, the

lowest dose should be adopted. Topical steroids have no

place in the treatment of chronic urticaria.

Intramuscular adrenaline—Self-administered intramus-

cular adrenaline may be indicated in patients with a his-

tory of severe angioedema affecting the upper airway or

urticaria with signiﬁcant cardiovascular symptoms. In

these individuals, all possible underlying causes should

be investigated and treated appropriately using the step-

up treat ment schedule (Fig. 2) in an attempt to suppress

the oropharyngeal swellings completely. Adrenaline is

not indicated in non-histaminergic angioedema as seen

in HAE and with ACE inhibitors.

Icatibant and CI inhibitor—The therapeutic beneﬁt of i-

catibant and C1 inhibitor in acute attacks of HAE is

recognized [93, 94]. It has been reported in a case series

that icatibant may have efﬁcacy in angioedema induced

by ACE inhibitors [95].

Others. Topical preparations—Cooling antipruritic

lotions such as 2% menthol in aqueous cream can be

soothing [71]. Topical steroids should not be used to

treat chronic urticaria.

Dietary advice—Diets low in salicyl ates and benzoates

have been anecdotally adopted in the management of

Table 5. Rarely used drugs

Drug (families) Grade Speciﬁc indication/comments/side-effects Reference

Bradykinin B2 receptor

antagonist (icatibant)

B Licensed for acute attacks of HAE [93, 95]

Dapsone D Several single-case reports of successful

treatments of urticarial vasculitis in resistant cases

Helped one patient with autoimmune thyroiditis

to stop oral steroid treatment

[135–137]

Hydroxy-chloroquine D Improvement of QoL, but no reduction in urticaria

scores or medication requirements

[138]

Methotrexate D Beneﬁcial for corticosteroid-dependent chronic

spontaneous urticaria (2 patients)

Efﬁcacy in urticarial vasculitis (one patient)

[139, 140]

Stanozolol (Danazol) C Beneﬁcial effects in patients with refractory CIU

(with simultaneous cetirizine dose); Long-term effects

unknown; drug currently not licensed, but available

on a named-patient basis as winstrol, 4 mg in the

United Kingdom. Danazol likely to have similar effects

[141]

Sulfasalazine D Successful in 2 patients with refractory delayed pressure

urticaria and angioedema. One was steroid-dependent

and managed to come off prednisolone

[142–144]

Warfarin C Improvement in 6 of 8 patients who were unresponsive

to antihistamines

[145]

Grade = Grade of recommendation (Table B2) [133, 134].

Urticaria and Angioedema BSACI guideline 557

urticaria. However, there is no evidence to support the

routine use of low salicylate diets [96]. Individuals with

chronic urticaria associated with salicylates may respond

to leukotriene receptor antagonists [82]. Suspected tartr-

azine-induced urticaria/angioedema is rarely reproduc-

ible by oral challenge, and hence, additive-free diets are

not justiﬁed in patien ts with CsU [97]. High-dose supple-

mental vitamin D

has been re ported to be beneﬁcial irre-

spective of a patient’s vitamin D status. [98].

Psychological interventions—A recent meta-analysis

conﬁrmed the high prevalence of an association

between psychological factors and CU [15]. Even if psy-

chological symptoms develop subsequent to CU and

play little part in its pathogenesis, the positive correla-

tion between CU and markers of poor psy chological

wellness indicates that psychotherapeutic treatments

and behavioural interventions may prove beneﬁcial.

Patient leaﬂets—See appendices A1 (Adults) and A2

(children).

Chronic urticaria in childhood

Introduction

Chronic urticaria is less common in children than it is

in adults. Up to 40% of children with chronic urticaria

have autoreactive urticaria. There is no difference in

medication requirements or remission rates between

children who are ASST positive or negative. Cold and

pressure urticar ia are the most commonly diagnosed

induced urticarias in children. These may occur in com-

bination with dermographism or cholinergic urticaria.

Chronic spontaneous urticaria in childhood is rarely a

severe disease and usually remits over time. The major-

ity of children will respond to treatment with antihista-

mines and avoidance of triggers [99].

Box 4. Management of adult patients with weals

•

Check that symptomatic episodes have not fol-

lowed ingestion of a non-steroidal anti-inﬂammatory

drug such as aspirin or ibuprofen.

•

Give explanation of the symptoms and reassur-

ance that the histamine-induced chronic urticaria

symptoms do not involve the respiratory tract (upper

and/or lower) or cardiovascular system – as occurs

in anaphylaxis. There are, however, very rare excep-

tions to this rule.

•

Give a once-daily dose of a long acting, non-

sedating antihistamine (prn, if symptoms are infre-

quent).

•

If necessary, double the dose of antihistamine

(usually given at night), and/or add a second antihis-

tamine.

•

Consider further increase in dose of antihistamine

up to 49 recommended dose.

•

Consider adding one or more second-line drugs

(see Table 4 and Fig. 2).

•

Consider short-term oral corticosteroid rescue

treatment.

Box 6. Management plan for patients with angioedema

without weals in adults

1 Exclude C1 inhibitor deﬁciency – a norma l plasma

C4 during an attack, or normal C4, C1 inhibitor,

and C1 inhibitor function, between attacks, will

typically exclude this.

2 If the patient is taking an ACE inhibitor, this drug

should be stopped.

3 Even if the patient is not taking an ACE inhibitor,

these drugs should be avoided in the future.

4 Give a once-daily dose of a long acting, non-sedat-

ing antihistamine (prn, if symptoms are infrequent)

and consider higher doses of antihistamines.

5 Consider tranexamic acid in antihistamine-resis-

tant angioedema.

6 An adrenaline auto-injector and short-term oral

corticosteroids are unlikely to be beneﬁcial unless

an underlying histaminergic mechanism is consid-

ered to be responsible for the angioedema.

Box 5. Management plan for patients with angioedema

with weals in adults

In addition to instructions in ‘Box 4’ above, the

following steps should be considered:

1 If the patient is taking an ACE inhibitor, this drug

should be stopped.

2 Even if the patient is not taking an ACE inhibitor,

these drugs should be avoided in the future.

3 Consider addition of tranexamic acid for higher

dose antihistamine-resistant angioedema.

4 An adrenaline auto-injector is rarely required and

should only be considered if there is a history of

signiﬁcant angioedema affecting the upper airway

(rare in angioedema with urticaria). The patient

should then be shown how to use the device and

provided with a written self-management protocol.

5 Consider short-term oral corticosteroid rescue

treatment.

558 R. J. Powell et al

Acute spontaneous urticaria is not covered in this

guideline, although it remains the commonest form of

urticaria in childhood. In atopic children, acute urticaria

may occur as part of an allergic reaction, e.g. to food. If so,

it usually develops within an hour of eating the food and

resolves within 24 h. Acute spontaneous urticaria may

also occur in response to a viral infection, when it usually

persists for longer than 24 h and may last several days.

Epidemiology and clinical presentation

Urticaria (acute, intermittent and chronic ) affects

around 3.4% of British children. Only a small propor-

tion of these are chronic [100]. Approximately 50–80%

of children with chronic urticaria have associated an-

gioedema [11]. Chronic urticaria/angi oedema in child-

hood is usually not life-threatening. Concerns about the

physical appearance of weals and angioedema and

associated systemic symptoms may combine to impair

quality of life. It is not uncommon for children to have

missed signiﬁcant periods of school, due to a lay per-

ception that their appearance is infectious or allergic

and fear that the child is ‘unwell’.

Aetiology and mechani sms

Investigations are rarely required in children presenting

with chronic urticaria. A detailed clinical history and

physical examination usually establishes the diagnosis.

Most are spontaneous with physical factors such as

pressure or cold exposure being the most commonly

diagnosed precipitating factors. 31–47% of children

with CU have an autoimmune aetiolo gy with a positive

ASST [18, 19]. About 4% of children with CU have

positive antithyroid antibodies, the majority of these

are euthyroid [101 ] (Table 2).

Vasculitides and connective-tissue disorders. The com-

monest ca use of acute vasculitic urticaria in children is

Henoch–Schonlein purpura. This is a clinical diagnosis

presenting with a distinctive rash over the extensor sur-

faces of the legs and buttocks [102]. Rare causes of

chronic urticaria should be considered in patients with

other systemic symptoms or raised inﬂammatory mark-

ers [103]. A diagnostic lesional skin biopsy could be

considered if features such as fever, painful lesions,

arthralgia, raised ESR, lesions lasting 24 h or more or

lesions that resolve revealing purpura or petechiae.

Thyroid autoimmunity. An association between child-

hood chronic urticaria and thyroid autoimmunity has

been postulated [101, 104]. It is not clear whether the

association is causal, as the majority of children present

with hyper- or hypothyroid symptoms either before or

some time after the onset of chronic urticaria. The urti-

carial symptoms do not always improve with thyroxine

replacement therapy. Nonetheless, ongoing thyroid

function monitoring is encouraged for children with CU

and thyroid autoimmunity [18, 101].

Coeliac disease. There are case reports of an association

between chronic urticaria and coeliac disease, which

may improve on a gluten-free diet [105, 106].

Prognosis

Parents need reassurance that this is not a severe dis-

ease and that it remits over time. A quarter of children

with chronic spontaneous urticaria are disease-free

3 years after presentation [18], and 96% are asymptom-

atic after 7 years. Children with physical urticarias

should be advised to avoid triggers and the condition

usually regresses spontaneously after 2–3 years.

Investigations

A detailed clinical history is extremely important for

any decisions regarding further investigations. If the

clinical history and examination are typical of CsU,

then further laboratory investigations are rarely useful.

Chronic urticaria is commonly perceived by the parents

to be due to an allergic or idiosyncratic reaction to

foods or food additives, such as food preservatives or

food dyes. There is little published evidence to support

this. Families often ﬁnd it helpful to see a lack of atopy

demonstrated by negative skin tests.

Skin tests/speciﬁc IgE testing. If the clinical history

suggests a candidate allergen, then allergy tests (skin

testing or speciﬁc IgE tests) are warranted. The range of

allergens tested should be guided by the history to

avoid the need to explain any false-positive results.

Additional investigat ions if clinically indicated.

•

Urinalysis

•

Full blood count (FBC)

•

Erythrocyte sedimentation rate (ESR)

•

Liver function tests (add viral hepatitis screen if

transaminases are abnormal)

•

Coeliac screen: Tissue transglutaminase IgA antibod-

ies and/or endomysial IgA antibodies – if abnormal or

history suggestive, refer for intestinal biopsy. If the

patient is on a gluten-free diet or has IgA deﬁciency,

these tests may be misleading

•

Thyroid function and antithyroid antibodies

•

Cold, dermographism and pressure provocation tests

[107]

•

Elimination rechallenge diets: rarely, it may be nec-

essary to undertake carefully planned and dietician-

supervised elimination and rechallenge diets

Urticaria and Angioedema BSACI guideline 559

•

Antinuclear antibodies should only be measured if a

connective-tissue disorder is clinically suspected

•

A skin biopsy may be indicated if vasculitis is sus-

pected

•

C4 and C1 inhibitor quantitation to detect C1 inhibi-

tor deﬁciency are only indicated for children, typically

teenagers, presenting with angioedema without urticaria

to deﬁne the presence or absence of C1 inhibitor deﬁ-

ciency [108]

•

Tests for current or past viral, bacterial or parasitic

infections should be guided by the history, clinical

ﬁndings and initial screening tests, e.g. eosinophilia

Treatment in children

Management plan. Avoidance of known provoking

stimuli should be the primary strategy in any treatment.

Drug treatment is described in the management plan in

Fig. 2.

H1-antihistamines (grade of recommendation = B)—

Non-sedating antihistamines are the mainstay of treat-

ment for children with chronic urticaria. Up to four

times the recommended dose may be required to ade-

quately contro l symptoms. A lack of response to high-

dose antihistamine therapy should raise the possibility

of an underlying diagnosis such as vasculitis. Chronic

urticaria may present as early as the second year of

life and this can limit the choice of licensed antihista-

mine [18, 19]. Cetirizine and desloratadine are licensed

for the treatment of chronic urticaria in children from

1 year of age; loratadine and levocetirizine are

licensed for the treat ment of children of 2 years and

older. Acrivastine, bilastine, fexofenadine, mizolastine

and rupatadine are licensed for use in children over

12 years. Des loratadine, levocetirizine, loratadine and

cetirizine are available in syrup formulations. The

metabolism of cetirizine in children is different to that

in adults, and hence, this drug should be taken twice

daily.

First-generation sedating antihistamines. Children may

become accustomed to the sedating effects of ﬁrst-gen-

eration antihistamines; howeve r, the risk of psychomo-

tor impairment remains and this may impact on the

child’s safety and education. Those licensed for use in

childhood include diphenhydramine, hydroxyzine, pro-

methazine and chlorphenamine.

Leukotriene receptor antagonists (grade of recommenda-

tion = C)—Evidence for the effectiveness of leukotriene

receptor antagonists (LTRAs) as monotherapy is poor .

Patients not responding to antihistamines alone should

be offered a 1- to 4-week trial of the addition of a

LTRA, e.g. montelukast 4–10 mg nocte.

Corticosteroids (grade of recommendation = D)—Short-

term use of oral corticosteroids (3–5 days ) may be

required to gain control of symptoms. In inducible urti-

caria unresponsive to ﬁrst-line therapy, corticosteroids

are poorly effective. In patients with delayed pressure

urticaria, corticosteroids are more effective [100]. Pro-

longed use of oral corticosteroids produces unacc ept-

able/severe side-effects.

Tranexamic acid. Tranexamic acid can be effective in

the treatment of isolated angioedema [109]. A dose of

15–25 mg/kg (maximum 1.5 g) 2–3 times per day is

recommended.

Anti-IgE. There is increasing evidence for the efﬁcacy

and sa fety of Omalizumab in children ove r 7 years of

age with CU, resistant to ﬁrst-line treatment. Three to

six injections of 150–300 mg are administered monthly

[86, 110, 111]. The tre atment is well tolerated, but

should be restricted to specialist centres.

Other treatments. Other therapies such as ciclosporin

[100, 101] should be limited to use in difﬁcult cases

and only considered in specialist centres.

Chronic urticaria in pregnancy and breastfeeding

Pregnancy. Chronic urticaria often improves in preg-

nancy, reducing the need for antihistamine treatment,

although in some rare cases, urticaria deteriorates. It is

best practice to avoid taking drugs in pregnancy. There

is no evidence in humans that antihistamines are tera-

togenic, but in animal studies using high doses of

hydroxyzine and loratadine have led to embryotoxicity.

The data sheets for cetirizine, desloratadine, hydroxy-

zine and loratadine all advise avoidance in pregnancy.

Hydroxyzine is speciﬁcally contraindicated in early

pregnancy.

Pregnant women should be informed that no drug

can be considered absolutely safe, and the beneﬁts of

keeping the mother healthy have to be balanced against

the small risk to the foetus. The consequences of inade-

quately controlled disease should be discussed with the

patient and documented in the case notes.

There is considerable clinical experience with cetiri-

zine and loratadine in pregna ncy, with no increase in

the rate of congenital abnormalities [112–117].

Cetirizine and loratadine have been as signed a cate-

gory B by the US FDA. Hence, antihistamines should

only be used if clearly needed and when the potential

beneﬁts outweigh the unknown risks to the foetus.

560 R. J. Powell et al

Breastfeeding. Antihistamines should only be used dur-

ing lactation when the clinical imperative outweighs

the potential harm to the child. The lowest dose should

be used for the shortest duration. Signiﬁcant amounts

of antihistamines are excreted in breast milk and,

although not known to be harmful, the manufacturers

of most antihistamines advise avoidance whilst breast-

feeding. Chlorphenamine may cause drowsiness and

poor feeding. Both loratadine [118] and cetirizine

appear safer with only low levels found in breast milk

[119], and therefore, these drugs could be considered if

required.

Future research – key areas

•

Well-controlled clinical trials in chronic urticaria

that does not respond to standard therapy are required.

Such studies should have the appropriate statistical

power to clarify which drugs should be used, in what

dose and for how long. Studies to investigate whether

the presence of angioedema affects the prognosis of

disease.

•

Investigation of the role of exacerbating factors in

urticaria and angioedema, e.g. NSAIDs, stress.

•

Studies designed to correlate clinical presentation

with prognosis and response to treatment, e.g. the use

of tranexamic acid in spontaneous (idiopathic) angio e-

dema.

•

Studies designed to understand the clinico-patholog-

ical association of thyroid autoimmunity and autoim-

mune urticaria.

•

Development of reliable laboratory assays for identi-

ﬁcation of autoimmune urticaria.

•

Systematic review of psychological interventions in

CsU.

This guideline informs the management of urticaria

and angioedema. Adherence to this guideline does not

constitute an automatic defence for negligence and

conversely non-adherence is not indicative of negli-

gence. It is anticipated that this guideline will be

reviewed 5 yearly.

Acknowledgements

The preparation of this document has beneﬁted from

extensive discussions within the Standards of Ca re

Committee of the BSACI and we would like to acknowl-

edge all the members of this committee for their valu-

able contribution, namely Elizabeth Angier, Nicola

Brathwaite, Tina Dixon, Pamela Ewan, Sophie Farooque,

Thirumala Krishna, Rita Mirakian, Helen Smith and Ste-

phen Till. We give special thanks to Clive Grattan for

his invaluable advice. We would also like to thank our

lay advisor, Nicola Mundy, for her valuable comments.

She reviewed a draft of this guideline and her suggested

changes were incorporated into the ﬁnal document.

Finally, we would like to acknowledge the very valu-

able considerations and criticism we received from

many BSACI members during the consultation process.

Conﬂict of interests were recorded by the SOCC. None

jeopardized unbiased guideline development.

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Supporting Information

Additional Supporting Information may be found in

the online version of this article:

Appendix A1. Patient information sheet - chronic

urticaria and angioedema in adults.

Appendix A2. Patient information sheet - chronic

urticaria and angioedema in children.

Urticaria and Angioedema BSACI guideline 565