Assessment of urticaria

The right clinical information, right where it's needed

Last updated: Dec 05, 2018

 Table of Contents
Summary 3

Overview 4
Aetiology 4

Emergencies 8
Urgent considerations 8
Red flags 9

Diagnosis 10
Step-by-step diagnostic approach 10
Differential diagnosis overview 18
Differential diagnosis 19
Diagnostic guidelines 29

References 31

Images 34

Disclaimer 39
 Summary

◊ Urticaria, also known as welts, hives, or wheals, is characterised by the appearance of intensely
pruritic erythematous plaques.[1] It appears clinically as pruritic, pale, blanching swellings of the
superficial dermis that last for up to 24 hours. Lesions may be small, large, giant, oval, or annular.
[Fig-1]
[Fig-2]
[Fig-3]
Urticaria affects 10% to 25% of the population and can occur in any age group.[2] It is a mast cell
driven disease. The triggering mechanisms for mast-cell activation in urticaria are not well defined
but seem to be multiple and diverse.[3] Urticaria is classified according to duration of symptoms:
• Acute urticaria: the occurrence of spontaneous wheals, angio-oedema, or both for 6 weeks or
less[2] [3]
• Chronic urticaria: urticaria that has been continuously or intermittently present for >6 weeks.[3]
Chronic urticaria is classified into 2 subtypes:[3]
• Chronic spontaneous urticaria: spontaneous appearance of wheals, angio-oedema, or both ≥6
weeks due to known or unknown causes.
• Inducible urticaria, for example delayed pressure urticaria, heat urticaria, solar urticaria,
symptomatic dermatographism, vibratory angio-oedema, aquagenic urticaria, cholinergic
urticaria, and contact urticaria.
Some people have urticaria that is complicated by angio-oedema, a swelling of the deeper dermis
and tissues (e.g., mucosal surfaces), with laryngeal oedema potentially causing respiratory
distress and death.[3] Angio-oedema is commonly associated with urticaria and may occur at
any age.[4] It may not necessarily be seen at the first urticarial episode, and its risk increases
with greater exposure to the allergenic substance.[5] Symptoms are typically numbness, pain, or
paraesthesias.[6] Angio-oedema without urticaria should prompt further evaluation.
[Fig-4]
 Assessment of urticaria Overview

Aetiology
Urticaria/angio-oedema involves the release of mediators, predominantly by mast cells, but also by
basophils, in the epidermis (urticaria) and deeper dermis (angio-oedema). Although multiple mediators are
OVERVIEW

released, the majority are histamine-like and result in symptoms of:

• Swelling
• Vasodilation
• Pruritis.

The exact mechanism by which various factors cause mast cell degranulation is not completely understood
(with the exception of IgE-mediated allergen activation). While multiple diseases can cause acute and
chronic urticaria/angio-oedema, most cases of chronic urticaria are idiopathic and likely caused by an
autoimmune phenomena. People with acute urticaria/angio-oedema more frequently have associated
identifiable causes.

Acute urticaria/angio-oedema
Allergy:

Most allergic reactions resulting in urticaria/angio-oedema are the result of IgE-mediated type 1
hypersensitivity. Many agents are capable of eliciting urticaria/angio-oedema reactions via IgE-mediated and
direct mast cell activation, for example:

• Foods and food additives: children with food and food additive allergies associated with urticaria are
usually allergic to milk, egg, soy, wheat, peanuts, and tree nuts, while adults react to shellfish, fish, tree
nuts, and peanuts. However, almost every food has been implicated.
• Medications: antibiotics, such as penicillin, are the drugs most likely to cause mast cell mediator
release via an IgE-mediated mechanism. However, there are case reports of many other medications
being associated with type 1 mediated urticaria/angio-oedema, such as anaesthetics, muscle
relaxants, and anti-seizure agents.
• Stinging insects: these include members of the Hymenoptera family (including bees, wasps, hornets,
fire ants), and bed bugs.
• Latex: particularly among patients who are chronically exposed, such as those with spina bifida.

Direct mast cell activation:

Various agents are capable of causing mast cell and basophil mediator release in a direct and non-
immunological fashion. Examples include:

• Foods and food additives: young children often have urticarial reactions to fruits and vegetables, such
as strawberries and tomatoes. It must be noted that these foods may also cause reactions via an IgE-
mediated mechanism in some patients.
• Medications: agents typically capable of direct mast cell degranulation include opiates and opioid
derivatives, such as morphine, fentanyl, codeine, and dextromethorphan. Non-steroidal anti-
inflammatory medications (NSAIDS) inhibit COX-1, resulting in overproduction of leukotrienes, which
may cause urticaria in susceptible patients (pseudoallergic reactions).
• Radiocontrast media: older preparations with high osmotic loads are more likely to result in mast cell
mediator release.

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Assessment of urticaria Overview
Infection:

• Viral and bacterial infections are believed to be responsible for urticaria/angio-oedema in the majority
of children with acute urticaria.

OVERVIEW
• Viral: viruses causing upper respiratory tract infections and acute gastroenteritis in younger children
(e.g., respiratory syncytial virus [RSV], rhinovirus, rotavirus) have often been associated with urticaria/
angio-oedema. Urticaria may precede active disease caused by chronic and indolent viral entities,
such as hepatitis, cytomegalovirus (CMV), and Epstein-Barr virus (EBV).
• Bacterial: agents that cause respiratory infections and gastroenteritis, such as streptococcal agents
and Helicobacter pylori , have been implicated. Many other bacteria have been associated with
urticaria in case reports.
• Parasitic: various parasites have been associated with urticaria/angio-oedema, including
Strongyloides , Toxocara and Fasciola . Usually, these patients have a history of travel to endemic
areas.
Systemic disease:

In rarer instances urticaria/angio-oedema precedes development of systemic diseases. Examples include:

• Autoimmune diseases: rheumatoid arthritis, systemic lupus erythematosus (SLE), and Sjogren’s
syndrome have been associated with urticaria/angio-oedema. Although not well understood,
mechanisms may include complement-mediated pathways and direct mast cell activation. Patients
with vasculitis, either as a primary immune disease (e.g., idiopathic urticarial vasculitis) or as a
component of other autoimmune diseases (e.g., Sjogren’s syndrome), may present with urticaria as a
separate disease or a mixed picture, as in urticarial vasculitis (skin disease with elements of urticaria
and vasculitis).
• Malignancies: various malignancies have been associated with pathogenesis of urticaria/angio-
oedema, particularly those with dysregulated expression of antibodies, such as paraproteinaemias.
Others include lymphoreticular diseases, such as chronic lymphocytic leukaemia. Complement-
mediated pathways are likely to be involved, although exact mechanisms are unknown.
• Endocrinopathies: autoimmune thyroid disease has been most commonly associated with urticaria/
angio-oedema. Thyroid autoimmunity has been associated with acute urticaria and some small studies
suggest that treatment of thyroid disease results in resolution of the skin disease.[7]
• Autoinflammatory syndromes: genetic diseases, usually of childhood, wherein mutations of
inflammasome (a multimeric protein complex) response to perceived danger signals result in persistent
expression of inflammatory peptides, such as interleukin-1. Many of these children have cold-induced
urticaria in addition to arthralgias, and eye diseases; some have more severe systemic disease, such
as amyloidosis, sensorineural deafness, and central nervous system inflammation. This is likely a
spectrum of illness, with familial cold-induced urticaria being the least clinically severe to Muckle-Wells
syndrome, and neonatal onset multi inflammatory disease (NOMID) the most severe.
Physical causes (physical urticaria):

Various physical factors can cause mast cell and basophil mediator release. Examples include:

• Water (aquagenic)
• Increase in core body temperature, such as with exercise or emotion (cholinergic)
• Cold, such as from swimming in cold water or cold wind exposure
• Heat, such as from a hot bath

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 Assessment of urticaria Overview
• Pressure, such as from sitting, lying, tight clothing (delayed pressure)
• Pressure to skin or minor trauma (dermatographism)
• Exercise (cholinergic or exercise-induced)
• Sunlight (solar)
OVERVIEW

• Use of vibrating tools (vibratory).

Other aetiologies for urticaria include:

• Serum sickness: immune complex formation in response to exogenous antigens, such as medications
and antitoxins, may activate mast cells and basophils. Urticarial rashes may result, along with systemic
symptoms of fever, arthritis/arthalgias, and lymphadenopathy. Even though this condition is associated
with urticaria, it is generally not classified as a subtype of urticaria, rather a differential diagnosis to
consider.
• Progesterone-associated urticaria: women on hormone therapy may experience urticaria or
exacerbation of underlying urticaria. This may also occur in some patients during menstrual cycles.
• Mastocytosis: involves the presence of abnormally high numbers of mast cells in the skin and possibly
other organs. Perturbation of these may result in urticaria and flushing to varying degrees, including
anaphylaxis. There is persistence of hyper-pigmented areas after initial urticaria has resolved.

Chronic urticaria/angio-oedema
The only criteria for acute urticaria to become chronic urticaria is persistence of skin disease for more than
6 weeks. This means that any acute urticaria/angio-oedema aetiology that persists for 6 weeks can be an
aetiology for chronic urticaria.

• Infectious agents: hepatitis, EBV, and CMV may be associated with chronic urticaria. The majority of
bacterial and viral infections resolve within 6 weeks, with or without treatment, and are more likely to
be associated with acute urticaria/angio-oedema.
• Foods: most food allergies occur within minutes to hours of ingestion; therefore, patients know to avoid
them. In rare cases, food antigens may be hidden in processed foods (such as soy) and patients may
unknowingly continue to ingest them, resulting in chronic urticaria/angio-oedema.
• Medications: chronic urticaria/angio-oedema may, in rare cases, be caused unknowingly by continued
ingestion of certain medications/supplements, or may occur when there is no alternative treating
agent.
• Latex: used in many materials; in rare cases, chronic exposure to latex may result in chronic urticaria.
• Systemic diseases: may be indolent and subclinical for long periods of time. Chronic urticaria/angio-
oedema may be early manifestations of these illnesses.
• Physical urticarias: often aetiologies of both acute and chronic urticaria/angio-oedema.
• Mastocytosis: urticaria associated with mastocytosis is often chronic, as the underlying disease is
often persistent.
• Progesterone associated: urticaria may be chronic but symptoms will often wax and wane with
hormone fluctuations.

Chronic urticaria in people with good health and in the absence of

identifiable triggers
More than 90% of chronic urticaria/angio-oedema in patients with a normal clinical history and physical
examination (e.g., absence of signs or symptoms of infections or systemic disease) and no identifiable
triggers is idiopathic; this is termed chronic idiopathic urticaria (CIU). Of these, up to half may have an anti-

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Assessment of urticaria Overview
IgE receptor antibody resulting in chronic release of mast cell mediators.[8] [9] [10] This may be associated
with a family or personal history of autoimmunity (e.g., autoimmune thyroiditis, vitiligo, pernicious anaemia,
rheumatoid arthritis, insulin-dependent diabetes, alopecia areata), but can also occur in its absence.[11]
Whether these patients are at higher risk of developing autoimmune disease or malignant transformation is

OVERVIEW
yet to be determined, but seems unlikely.

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 Assessment of urticaria Emergencies

Urgent considerations
(See Differential diagnosis for more details)
Life-threatening conditions associated with urticaria that mandate immediate intervention, hospitalisation, or
prescription of rescue medication include anaphylaxis and airway obstruction.

Anaphylaxis
Anaphylaxis is a rapid systemic reaction that is usually diagnosed clinically. It presents as sudden onset of
respiratory or cardiovascular compromise, usually in sensitised people with a history of allergen exposure.
There may be skin rash, wheezing, inspiratory stridor, hypotension, anxiety, nausea, and vomiting. Urticaria
and angio-oedema may be part of the overall clinical presentation. Securing the airway and initiating
immediate treatment with intramuscular adrenaline (epinephrine) in the anterolateral thigh may save lives.
The comprehensive management of anaphylactic shock is beyond the scope of this topic and guidelines
should be consulted for more detail.[12] [13] [14]

Angio-oedema with airway compromise

EMERGENCIES

Episodes of urticaria with angio-oedema affecting the head and neck, which could potentially compromise
the airway, should be treated promptly with adrenaline (epinephrine). Stridor, odynophagia, dysphagia, or
respiratory distress may be signs of laryngeal oedema, which can lead to respiratory arrest. The status of the
airway should be assessed and closely monitored in all patients with angio-oedema, and all necessary steps
must be taken to ensure the airway is always secured. In severe cases, consultation with an anaesthetist
may be necessary.

Angio-oedema in the absence of urticaria

Angio-oedema that occurs in the absence of urticaria, especially when involving airway compromise,
mandates consideration for serious conditions, such as:

• Hereditary angio-oedema (HAE; due to inhibition of the complement/kinin metabolism):

• Typically lasts for a few days

• Often described as painful.[15]
• Acquired angio-oedema (with C1 inhibitor consumption from secondary causes, such as malignancy/
autoimmune disease):

• Patients may show signs and symptoms of malignancy/autoimmune disease pathologies.

• Angio-oedema with normal C1 inhibitor:

• May be drug-induced, e.g., due to angiotensin-converting-enzyme inhibitors. Often starts within

weeks of starting the drug, but a significant number of patients are asymptomatic for years
before the onset of swelling.

Recognition is paramount, as these patients are unlikely to respond to adrenaline (epinephrine) and require
C1 inhibitor replacement or bradykinin-blocking agents.[2] [15] Patients with HAE should, at a minimum, have
access to emergency rescue medication (dependent on local availability) in the event of attacks. Generally,
these patients should be managed by clinicians who are experienced with managing HAE.

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Assessment of urticaria Emergencies

Red flags
• Drug eruptions

• Insect bite

• Erythema multiforme

• Stevens-Johnson syndrome

• Bullous pemphigoid

• Mastocytosis

• Urticarial vasculitis

• Transfusion reactions

EMERGENCIES
• Serum sickness

• Cold-induced urticaria, Muckle-Wells syndrome, neonatal multi-system inflammatory disease

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 Assessment of urticaria Diagnosis

Step-by-step diagnostic approach

Following the exclusion of life-threatening conditions associated with urticaria (i.e., anaphylaxis and airway
obstruction), the evaluation of patients with urticaria/angio-oedema often proceeds as follows:

• Determine whether urticaria/angio-oedema is acute (6 weeks or less) or chronic (>6 weeks).

• Perform a comprehensive history and physical examination to determine the most likely aetiology. A
specific cause is more likely to be found in people with acute urticaria, while chronic urticaria is usually
idiopathic in people with a normal history and physical examination.
• Perform diagnostic testing, guided by abnormal/suspicious findings on history and physical
examination.

History: acute versus chronic

In the case of acute urticaria/angio-oedema, an aetiology is more likely to be found and treated (or self-
resolved in the case of viral infections) leading to resolution of disease within 6 weeks. If aetiology is missed
then urticaria/angio-oedema may persist and become chronic. Patients with chronic urticaria/angio-oedema
with a normal history and physical examination are likely to have idiopathic disease (more than 90% of
people with chronic urticaria/angio-oedema).

History: possible aetiology

Because almost every disease state, from infections to endocrinopathies, has been associated with the
pathogenesis of urticaria/angio-oedema, the initial history and physical examination should comprehensively
look for the presence of any disease. Specific signs and symptoms will help point towards the aetiology. For
instance, the aetiology for urticaria in patients with concomitant rhinorrhea and cough would likely be a viral
infection.

History should take into consideration the following:

• Medications and supplements:

DIAGNOSIS

• A major cause of urticaria/angio-oedema.

• Usually elicited via an extensive medical history; however, given patients may have poor
immediate recall, this may have to be elicited over several visits. Use of electronic medical
records may help.
• Ensure that questions cover health supplements, vitamins, and alternative medicine agents, as
patients often think these are not 'medications'.
• Food allergens:

• Usually, culprit foods are temporally related, with rashes occurring within minutes to hours of
ingestion. Therefore, clinicians should focus on foods eaten close to time of urticaria/angio-
oedema.
• Certain foods may be hidden, such as soy used as fillers.
• Food ingredients should be studied for a common agent present at the time of eruptions,
especially in highly-processed meals.
• A food and urticaria diary may help.
• Infections:

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Assessment of urticaria Diagnosis

• Viral infections are usually easily identified, especially in children.

• Because occult infections have been implicated in urticaria/angio-oedema, a comprehensive
screening history should be performed. Ask about dental, skin, gastrointestinal, and
genitourinary infections, including bacterial and fungal aetiologies.
• Asymptomatic infections, such as hepatitis, should be considered in people from high-risk
populations (e.g., people of Asian origin).
• Endocrinopathies:

• Any symptoms/signs of possible endocrine abnormalities, especially thyroid disease should be

considered.
• Malignancies:

• Any symptoms/signs of possible malignancy should be considered.

• If there are no overt symptoms or signs of malignant transformation, age-appropriate
malignancy screens should be performed (if not previously performed).
• Autoimmune diseases:

• Any typical symptoms and signs of collagen vascular disease should be considered.
• Autoimmune diseases often evolve over time.
• When there are incomplete or non-specific symptoms and signs of specific syndromes (e.g.,
fatigue or arthralgias), diagnostic testing may be warranted, such as erythrocyte sedimentation
rate, antinuclear antibodies, rheumatoid factor.
• Physical urticarias:

• Pressure, vibration, solar/heat/cold/water exposure, and exercise can elicit urticarias. The
history should be directed towards whether these physical factors seem to be associated with
the development of urticaria/angio-oedema.

These aetiologies are common to the development of urticaria/angio-oedema but by no means 100%

DIAGNOSIS
comprehensive. A full and comprehensive medical history is required, including thorough description of
the presenting complaint, past medical history, family history, social history, and systems enquiry, and
considering questions relating to quality of life and the emotional impact of the condition.[3]

There are also certain conditions that may present with urticaria/angio-oedema but are not classified
as subtypes of urticaria because they have quite different pathophysiological mechanisms.[3] Likewise,
several syndromes that may feature wheals are not considered a subtype of urticaria but related to it. These
conditions need to be considered in the differential diagnosis and include:

• Cutaneous mastocytosis (urticaria pigmentosa)

• Urticarial vasculitis
• Auto-inflammatory syndromes (e.g., cryopyrin-associated periodic syndromes or Schnitzler’s
syndrome)
• Bradykinin-mediated angio-oedema (e.g., HAE)
• Transfusion reactions
• Serum sickness.

Other skin conditions with rashes that may appear similar and need to be differentiated from urticaria include:

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 Assessment of urticaria Diagnosis

• Drug eruptions (note that drug allergy can result in urticaria but drug eruptions may present in
morbilliform and more persistent rashes)
• Insect bites (papular rash)
• Viral exanthems
• Atopic dermatitis
• Contact dermatitis
• Bullous pemphigoid
• Erythema multiforme
[Fig-5]
• Stevens Johnson syndrome
[Fig-6]
• Auriculotemporal syndrome.

Physical examination
As such a wide range of disease states are associated with urticaria/angio-oedema, the physical examination
should be complete and encompassing so as not to miss any signs of a potential aetiology. An extensive
discussion of such examinations is beyond the scope of this review, and current guidelines should be
consulted for more detail.[3] [16] Important considerations when performing a physical examination in a
patient with urticaria are as follows:

Skin examination:

• The characteristic skin lesions present as sudden onset pruritic whealing of the superficial dermis,
generally lasting well under 24 hours.[5] Typically, urticarial lesions blanche fully on pressure or
diascopy. No overlying flaking or scaling should be noted, as this is a dermal process. It is useful to
ask the patient if they have any photos of the lesions if they are not present at the time of evaluation.
Urticaria may be accompanied by angio-oedema, a swelling of the deeper dermis and tissues. This
can result in a colorless, non-pitting induration of the extremities, lips, and genitals.[17]
Differentiating urticarial vasculitis/mastocytosis:
DIAGNOSIS

• In a patient with typical urticaria, individual crops of urticaria should be pruritic, blanch, and resolve
within 24 hours. They may reappear in a different location soon but underlying skin should remain
normal after resolution. The diagnoses of urticarial vasculitis (a form of cutaneous vasculitis
characterised by inflammation of the small blood vessels) and mastocytosis (a disease involving
abnormally high numbers of mast cells in the skin and possibly other organs) should be considered if
the lesions have the following atypical features:

• Persist for longer than 24 hours

• Have more of a burning sensation
• Do not blanch
• Leave a pigmented area after resolution.
• In these instances, biopsy may be necessary and further diagnostic workup performed to detect
possible associated systemic disease, such as rheumatologic conditions and mastocytosis.
• It is important to note that differentiating urticarial swellings from mastocytosis may be difficult.
Early onset mastocytosis with localised areas of mast cell aggregates in the skin may present with
single urticarial lesions (mastocytomas), multiple lesions with overlying hyperpigmentation (urticaria

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Assessment of urticaria Diagnosis
pigmentosa), or diffuse mastocytosis. Darier sign (urtication after pressure) is common in mastocytosis
lesions. Blistering can accompany mastocytosis of childhood. In adults, lesions are usually red to
brown small papules or macules but can be accompanied by telangiectasias (e.g., telangiectasia
macularis eruptive persistens).
Dermatographism:

• This is whealing of skin minutes after a superficial sharp scratch. Dermatographism is found in 3% to
5% of the normal general population with no skin disease.
[Fig-7]

It is, however, associated with:

• Physical urticaria
• Atopic dermatitis
• Chronic idiopathic urticaria.

Investigations: acute urticaria

In most instances of acute urticaria/angio-oedema, a careful history and physical examination elicits
diagnosis such that routine diagnostic testing is not recommended.[3] For instance, if peanuts were
ingested 10 minutes before onset of rash and swelling, or a child develops signs and symptoms of an upper
respiratory infection followed shortly by an urticarial rash, the history points towards the likely aetiology. In
most of these patients, urticaria/angio-oedema resolves after resolution of the illness or avoidance of the
allergen.

Diagnostic evaluation should be ordered in a targeted fashion, guided by abnormalities found on history and
physical examination. For example, patients who have a suspected history of food-induced urticaria/angio-
oedema may benefit from specific in vitro IgE or skin testing with the suspected culprit foods.

In general, in vitro and skin testing for food allergies have excellent negative predictive value, and negative
tests generally exclude food allergy. Positive tests, unless extremely high in value, generally have 50% to

DIAGNOSIS
60% positive predictive value. They merely suggest the possibility of food allergy, which has to be confirmed
with elimination of the food followed by challenge, with resolution and reappearance of urticaria respectively.

There are no validated tests for drug allergies, except for penicillin, and elimination of the suspected drug is
often necessary for diagnosis of drug allergy.

Rapid streptococcal antigen testing may help in the evaluation of urticaria associated with symptoms of
pharyngitis.

Diagnostic testing is important in patients who have signs and symptoms suggestive of serious systemic
illness, such as endocrinopathies, malignancy, and autoimmune disease, and referral to relevant specialists
should be made. For instance, patients with urticaria as well as arthritis, oral sores, and alopecia should be
tested for systemic lupus erythematosus (antinuclear antibodies [ANA], erythrocyte sedimentation rate [ESR],
dsDNA etc), and referred to a rheumatologist. Routine testing for these pathologies among patients with
urticaria along with a normal history and physical examination usually has a very low yield.

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 Assessment of urticaria Diagnosis
Referral to a dermatologist for skin biopsy is recommended for patients in whom lesions have abnormal
characteristics (e.g., those that persist for longer than 24 hours, have a burning sensation, and leave
pigmented areas) to include or exclude urticarial vasculitis or mastocytosis.

Investigations: chronic urticaria

Similar to acute urticaria, any diagnostic studies performed should be targeted to help confirm aetiology
dependent upon findings on history and physical examination. Biopsy should be considered if urticaria
lesions are atypical.

Up to 90% of patients with chronic urticaria accompanied by a normal comprehensive history and physical
examination have chronic idiopathic urticaria (CIU). Of these, up to half may have an anti-IgE receptor
antibody resulting in chronic release of mast cell mediators. Therefore, a thorough history and physical
examination may be sufficient to rule out exogenous aetiologies.

Only very limited routine diagnostic measures are recommended in chronic spontaneous urticaria.[3] These
measures may not be necessary in some patients, but can be used to exclude underlying causes.[16]

At the authors’ institution, these initial routine tests may include:

• Complete blood count with differential

• Serum chemistry, including liver function testing
• ESR
• Urinalysis
• Thyroid studies.
Other institutions may perform fewer investigations. Although these tests do not completely rule out all
serious disease, they are a screen for chronic infection, parasites, endocrinopathies, autoimmune disease,
and some malignancies, especially when they are used in conjunction with a thorough history and physical
examination. Normal results will also provide reassurance to the patient who may require significant amounts
of medication to suppress skin disease.
DIAGNOSIS

Physical (inducible) urticaria

Diagnostic tests are usually not needed for urticaria patients in which physical stimuli reliably elicit skin
disease. Sometimes, when diagnosis is not apparent or response to treatment is inadequate, physical
challenges may be performed. These are best performed by clinicians or centers with expertise.

• Pressure urticaria: eliciting urticaria in response to pressure after weight placement.

• Solar urticaria: eliciting urticaria after exposure to light of various wavelengths and natural sunlight.
• Vibratory urticaria: eliciting urticaria after exposure to a laboratory vortex mixer.
• Aquagenic urticaria: eliciting urticaria after application of wet compress.
• Cold-induced urticaria: eliciting urticaria after placement of ice cube.
• Cholinergic urticaria: eliciting urticaria after raising core temperature and/or after intradermal injection
of methacholine (high false negative rate).
• Dermatographism: eliciting urticaria after scratching skin.

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Assessment of urticaria Diagnosis

Special consideration of patients with angio-oedema without

urticaria
Patients with angio-oedema without urticaria need to be screened for hereditary angio-oedema. This is
cheaply and effectively undertaken by measuring complement 4 (C4) levels. Patients with hereditary and
acquired forms of angio-oedema, including consumption of C1 inhibitor from malignancy and autoimmune
disease, universally have low C4 levels. Further measurement of C1 inhibitor quantity and function can be
obtained if C4 is low. Acquired hereditary angio-oedema from a paraneoplastic process results in abnormal
C1q levels. There are other forms of angio-oedema with absent urticaria with normal C1 inhibitor quality/
function and normal C4 caused by over-expression of bradykinin. There are no specific tests for these
patients, and diagnosis is usually confirmed with a trial of bradykinin inhibitor, such as icatibant. In general,
these patients, especially those in whom swelling is severe or involving the airway, should be managed by
clinicians with experience in this area.

European guideline approach to assessment of urticaria and angio-

oedema
The following algorithm for patients presenting with urticaria, angio-oedema, or both is derived from the 2017
guideline from the European Academy of Allergy and Clinical Immunology (EAACI), the EU-funded network
of excellence, the Global Allergy and Asthma European Network (GA2 LEN), the European Dermatology
Forum (EDF), and the World Allergy Organization (WAO). Healthcare professionals should elicit a thorough
history, perform a physical examination, and conduct provocation tests (including for drugs, food) and
physical tests as indicated by the history.[3]

DIAGNOSIS

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 Assessment of urticaria Diagnosis

EAACI/GA2LEN/EDF/WAO recommended algorithm for chronic urticaria. Diagnostic algorithm for

DIAGNOSIS

patients presenting with wheals, angio-oedema, or both. AAE - acquired angio-oedema due to C1-
inhibitor deficiency; ACE-Inh - angiotensin-converting enzyme inhibitor; AE - angio-oedema; AID
- autoinflammatory disease; HAE - hereditary angio-oedema; RAS - renin angiotensin system
Reproduced from Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA2LEN/EDF/WAO guideline for the definition,
classification, diagnosis and management of urticaria. Allergy. 2018 Jul;73(7):1393-414. Used with permission

Key:

1. Apart from ACE-inhibitors other renin inhibitors and sartans have been described to induce angio-
oedema but much less frequently.
2. Patients should be asked for a detailed family history and age of disease onset.
3. Test for elevated inflammation markers (C-reactive protein, erythrocyte sedimentation rate), test
for paraproteinaemia in adults, look for signs of neutrophil-rich infiltrates in skin biopsy; perform
gene mutation analysis of hereditary periodic fever syndromes (e.g., cryopyrin-associated periodic
syndrome), if strongly suspected.
4. Patients should be asked: "How long does each individual wheal last?"

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Assessment of urticaria Diagnosis
5. Test for complement C4, C1-INH levels and function; in addition, test for C1q and C1-INH antibodies,
if AAE is suspected; do gene mutation analysis if former tests are unremarkable but patient's history
suggests hereditary angio-oedema.
6. If there is no remission after 6 months of ACE-inhibitor discontinuation, C1-inhibitor deficiency should
be tested for.
7. Does the biopsy of lesional skin show damage of the small vessels in the papillary and reticular dermis
and/or fibrinoid deposits in perivascular and interstitial locations suggestive of urticarial vasculitis?
8. Patients should be asked: "Can you make your wheals come? Can you bring out your wheals?"
9. In patients with a history suggestive of inducible urticaria, standardised provocation testing according
to international consensus recommendations should be performed.
10. Acquired autoinflammatory syndromes include Schnitzler syndrome as well as systemic-onset
juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD); hereditary autoinflammatory
syndromes include cryopyrin-associated periodic syndromes (CAPS) such as familial cold auto-
inflammatory syndromes (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multisystem
inflammatory disease (NOMID); more rarely, hyper-IgD syndrome (HIDS) and tumour necrosis factor
receptor alpha-associated periodic syndrome (TRAPS).
11. In some rare cases, recurrent angio-oedema is neither mast cell mediator-mediated nor bradykinin-
mediated, and the underlying pathomechanisms remain unknown. These rare cases are referred to as
"idiopathic angio-oedema" by some authors.

DIAGNOSIS

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 Assessment of urticaria Diagnosis

Differential diagnosis overview

Common

Acute spontaneous urticaria

Chronic spontaneous urticaria

Chronic inducible (physical) urticaria

Drug eruptions

Insect bite

Viral exanthem

Atopic dermatitis

Allergic contact dermatitis

Irritant contact dermatitis

Uncommon

Erythema multiforme

Stevens-Johnson syndrome
DIAGNOSIS

Auriculotemporal syndrome

Bullous pemphigoid

Mastocytosis

Urticarial vasculitis

Transfusion reactions

Serum sickness

Cold-induced urticaria, Muckle-Wells syndrome, neonatal multi-system inflammatory disease

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Assessment of urticaria
Differential diagnosis
Common
◊ Acute spontaneous urticaria
History
sudden onset pruritic
rash for <6 weeks, with
unknown or suspected
precipitating factor
(e.g., associated with
ingesting a specific
food or medication,
preceding history of
upper respiratory tract
infection)
◊ Chronic spontaneous urticaria
History
sudden onset pruritic
rash for >6 weeks, with
unknown or suspected
precipitating factor
(e.g., associated with
ingesting a specific
food or medication,
preceding history of
upper respiratory tract
infection); no history
of inducibility; majority
have no history of any
underlying aetiology
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Exam
pruritic, pale, blanching
swellings of the
superficial dermis that
last for up to 24 hours,
lesions may be small,
large, giant, oval, or
annular, no overlying
flaking or scaling;
may be associated
features of angio-
oedema (swelling of
the deeper dermis and
tissues, e.g., mucosal
surfaces); may be signs
associated with an
aetiology
Exam
pruritic, pale, blanching
swellings of the
superficial dermis that
last for up to 24 hours,
lesions may be small,
large, giant, oval, or
annular, no overlying
flaking or scaling;
may be associated
features of angio-
oedema (swelling of
the deeper dermis
and tissues such as
mucosal surfaces); may
be signs associated
with an aetiology
1st Test
»no initial test:
clinical diagnosis
1st Test
»no initial test:
no testing may be
necessary in some
patients
Limited routine
laboratory testing
can be performed to
exclude underlying
causes.[3]
»serum electrolytes:
commonly normal but
may be abnormal with
underlying medical
condition
»serum liver
function tests
(LFTs): commonly
normal but may
be abnormal with
underlying medical
condition
»erythrocyte
sedimentation rate
Diagnosis
Other tests
»no initial test:
unless strongly
suggested by the
history (e.g., allergy,
systemic illness)
Other tests
»targeted diagnostic
studies: may be
considered dependent
upon findings on
DIAGNOSIS
history and physical
examination
These may include:
tests for specific
infectious diseases
(e.g., Helicobacter
pylori , hepatitis); for
type I allergy; functional
autoantibodies; skin
tests; physical tests;
pseudoallergen-free
diet for 3 weeks;
tryptase; autologous
serum skin test;
skin lesion biopsy (if
urticaria lesions are
atypical).
19
 Assessment of urticaria Diagnosis

Common

◊ Chronic spontaneous urticaria

History Exam 1st Test Other tests

(ESR): commonly
normal but may
be abnormal with
underlying medical
condition
»thyroid studies:
commonly normal but
may be abnormal with
underlying medical
condition
»urinalysis:
commonly normal but
may be abnormal with
underlying medical
condition

◊ Chronic inducible (physical) urticaria

History Exam 1st Test Other tests

sudden onset pruritic
rash for at least 6
weeks, may be history
of inducibility of the
rash by physical factors
such as heat, cold,
pressure, vibration,
DIAGNOSIS
pruritic, pale, blanching
swellings of the
superficial dermis
that last for up to 24
hours, lesions may
be small, large, giant,
oval, or annular, with
»no initial test: tests
often not required
Some clinicians
perform physical
maneuvers to induce
the rash, such as
»FBC including
differential cell
count: only perform
if warranted by
history and physical
examination: normal
results help to rule

water, and sunlight
no overlying flaking
or scaling; may be
dermatographism
(whealing of skin
minutes after superficial
sharp scratch)
application of weights,
ice cube, heated water,
vibration, and light.
out other diseases;
abnormal result may
indicate other disease
(e.g., infection)
»erythrocyte
sedimentation
rate (ESR): only
perform if warranted
by history and physical
examination: normal
results help to rule
out other diseases;
abnormal result may
indicate other disease
(e.g., infection)
»C-reactive protein
(CRP): only perform
if warranted by
history and physical
examination: normal
results help to rule
out other diseases;

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Assessment of urticaria
Common
◊ Chronic inducible (physical) urticaria
History
◊ Drug eruptions
History
mostly macules and
papules of trunk and
extremities, commonly
with centrifugal
spread;[18] onset 1
to 2 weeks after start
of new medication,
possibly sooner with
repeat challenges;
lesions do not resolve
with antihistamines
◊ Insect bite
History
localised lesions on
exposed areas of skin,
often after outdoor
exposure; recent insect
bites; often other family
members are also
affected
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Exam
Exam
lesions may not blanch
fully, post-inflammatory
discolorations
Exam
nodules of the lower
extremities in the
summer suggestive
of mosquito bites,
similar lesions after ant/
bedbug/scabies/flea
bites (type IV reaction);
accompanying angio-
oedema suggestive of
Hymenoptera allergy
(type I reaction)
1st Test
1st Test
»no initial test:
clinical diagnosis
1st Test
»no initial test:
clinical diagnosis
Diagnosis
Other tests
abnormal result may
indicate other disease
(e.g., infection)
»cryoproteins: only
perform if warranted
by history and physical
examination: normal
results help to rule
out other diseases;
abnormal result may
indicate other disease
Other tests
»skin biopsy:
generally non-specific:
signs of inflammation
with mononuclear/
lymphocytic cell
infiltrate, often with
mild perivascular
component and
occasional erythrocyte
extravasation
DIAGNOSIS
Other tests
»Hymenoptera
allergy RAST
testing: positive in
allergic urticaria (type I
reaction)
Skin testing may be
delayed 4 to 6 weeks
after reaction has
occurred. If negative
results are obtained
when performed in
the acute setting,
testing should be
repeated 6 weeks later.
21
 Assessment of urticaria
Common
◊ Insect bite
History
◊ Viral exanthem
History
rash occurs
concurrently with
symptoms of viral
infection but can
precede symptoms
or occur during the
resolution of the viral
illness
◊ Atopic dermatitis
History
DIAGNOSIS
presents with pruritus;
may have history of
concomitant allergic
rhinitis and/or asthma;
may have family history
of atopic dermatitis
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Exam
Exam
rash can present
in various forms
including urticarial,
maculopapular,
morbilliform,
scarlatiniform or
dermatomal; rash can
also be widespread or
localised
Exam
presents with xerosis
(dry skin), erythema,
scaling, vesicles,
papules, keratosis
pilaris, excoriations,
lichenification,
hypopigmentation; in
infants affects cheeks,
forehead, scalp, and
extensor surfaces;
in children involves
flexures, particularly
the wrists, ankles,
and antecubital and
popliteal fossae;[19]
[20] chronic atopic
dermatitis often affects
the neck, upper back,
and arms, as well as
the hands and feet;[21]
[22] [23] [24] may also
1st Test
1st Test
»no initial tests:
clinical diagnosis
1st Test
»no initial test:
clinical diagnosis
Diagnosis
Other tests
Hymenoptera skin
testing may yield false
negative results within
the first few weeks after
anaphylaxis. Retesting
will be positive in these
cases.
Other tests
»viral studies:
may be positive for a
specific virus
Only performed in
situations where the
clinical presentation
of a viral infection is in
doubt.
Other tests
»allergy testing:
reactivity to allergens
IgE levels: elevated IgE
blood levels
»skin biopsy: findings
consistent with atopic
dermatitis
Assessment of urticaria
Common
◊ Atopic dermatitis
History
◊ Allergic contact dermatitis
History
recurrent dermatitis
in areas of exposure
to potential allergens:
for example, skin care
products or substances
used for hobbies or
professional activities
◊ Irritant contact dermatitis
History
repeated irritant
exposure: for example,
diapers or chronic
handwashing
Uncommon
◊ Erythema multiforme
History
onset of rash usually
after infection with virus
(e.g., herpes), bacteria,
mycoplasma, or after
drugs (e.g., penicillin)
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Exam
have dermatographism
(whealing of skin
minutes after superficial
sharp scratch)
Exam
lesions at site of
jewelry/belt buckle/
button/watch (nickel
allergy), eyelid (nail
polish allergy),
forehead and both
eyelids (shampoo
allergy)[25]
Exam
eczematous
lesions: lichenified,
hyperkeratotic (scaly),
erythematous plaques;
patterns suggestive
of exposures (e.g.,
hands [detergents and
household cleansers]
or buttocks [diapers])
Exam
rash consisting of
erythematous papules
with central clearing
(target lesions)
1st Test
1st Test
»patch testing:
positive for allergens
Not highly sensitive
but can be helpful in
identifying or confirming
allergens if tailored to
the patient's lifestyle or
exposures.
1st Test
»patch testing: no
reaction
Can elicit low-grade
reactions due to skin
irritation.
1st Test
»no initial test:
clinical diagnosis
Diagnosis
Other tests
Other tests
»open application
testing: positive for
allergen
Twice-daily to forearm;
as 1 product tested
at a time, only helpful
when specific allergen
suspected.
Other tests
»skin biopsy: non-
specific perivascular
inflammation
DIAGNOSIS
accompanied by
hyperkeratosis
Other tests
»skin biopsy: satellite
cell necrosis, vacuolar
degeneration of the
basement membrane,
severe papillary
oedema; lymphocytic
infiltration and non-
23
 Assessment of urticaria Diagnosis

Uncommon

◊ Erythema multiforme

History Exam 1st Test Other tests

specific immune
deposits
»immunofluorescence
biopsy: IgM and
C3 at the basement
membrane and
perivascularly
May be performed
to rule out other skin
diseases.

◊ Stevens-Johnson syndrome

History Exam 1st Test Other tests

history of medication
use such as allopurinol
sulfa drugs and
non-steroidal anti-
inflammatory drugs
(NSAIDs)
DIAGNOSIS
initial skin lesions
similar to erythema
multiforme rash
(erythematous papules
with central clearing
[target lesions])
but progresses into
widespread areas of
erythema; bullous
formation and necrosis
of the epidermal
layer may occur, oral
»no initial test:
clinical diagnosis based
on presence of oral and
skin lesions
»skin biopsy:
keratinocyte apoptosis
with detachment of the
epidermal layer of the
skin from the dermal
layer
»immunofluorescence
biopsy: negative
May be performed
to rule out other skin
conditions.

mucosities usually
present and other
mucosal surfaces may
be involved; ocular
involvement usually
includes conjunctivitis

◊ Auriculotemporal syndrome

History Exam 1st Test Other tests

history of trauma
to sympathetic and
parasympathetic fibres
around parotid gland
such as from forceps
birth
swelling and erythema »no initial test: »CT scan parotid
in facial area after usually a clinical area: usually normal; to
eating spicy or sour diagnosis confirm diagnosis and
foods evaluate damage

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Assessment of urticaria
Uncommon
◊ Bullous pemphigoid
History
common age of onset
60-70 years, may
have prodromal non-
bullous phase of
pruritus and non-
bullous rash (may be
urticarial), subsequent
development of
blisters; rash affects
face, hands, feet
and genitalia; drugs
commonly implicated
(e.g., furosemide,
non-steroidal anti-
inflammatory drugs
[NSAIDs], captopril,
penicillamine, and
systemic antibiotics);
heals spontaneously
◊ Mastocytosis
History
50% of cases present
in first 2 years of life;
pruritic skin lesions,
lesion described as
‘burning’ sensation,
accompanied by
diarrhoea, wheezing,
bone pain (adults);
polymyxin B increases
swelling/localised
blistering of lesions;
occasionally in adults:
symptoms of mast
cell leukaemia (e.g.,
pruritus, fatigue,
wasting, fever, chills,
night sweats and
other influenza-like
symptoms, swollen/
bleeding gums, excess
bleeding/bruising,
headache, frequent
infections, swollen
tonsils)[26]
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Exam
large, tense, sub-
epidermal bullae in
groin, axillae, trunk,
thighs, and flexor
surfaces of forearms,
often erythematous
or urticarial plaques,
some with localised
disease on shins,
bullae and erosions
heal spontaneously,
absent Asboe-Hansen
sign (extension of a
blister to adjacent
unblistered skin when
pressure is put on the
top of the bulla)
Exam
single/multiple/diffuse
swellings/pigmented
papules urticating with
pressure (Darier sign)
and blistering; lesions
persist for longer
than 24 hours and do
not blanch, lesions
leave a pigmented
area after resolution;
in adults also small
tan/brown papules
with telangiectasias;
rarely, doughy skin;
lymphadenopathy,
hepatosplenomegaly
1st Test
»skin biopsy: sub-
epidermal blister
with eosinophil-rich
inflammatory infiltrate
Early urticarial lesions
may show epidermal
spongiosis with
eosinophils.
1st Test
»no initial test:
clinical diagnosis with
confirmatory tests
Diagnosis
Other tests
»skin biopsy direct
immunofluorescence:
linear deposition of
IgG and C3 at dermal-
epidermal junction
»skin biopsy
indirect
immunofluorescence:
anti-basement
membrane
zone antibodies
directed against 2
hemidesmosomal
antigens, bp230 and
bp180
»immunoblot assay:
target antigens BP Ag1
(230 kD) and BP Ag2
(180 kD)
Other tests
»skin biopsy with
Giemsa stains or
toluidine blue:
DIAGNOSIS
mononuclear cells with
typical granules
Unnecessary except
in rare childhood
cases, but commonly
performed in adults
for confirmation of
diagnosis.
»CD 117, CD 25
testing of skin
biopsy specimen:
positive in mastocytosis
Identify skin cells of
mast cell origin.
»c-kit codon 816
mutations testing
in blood: positive in
mastocytosis
25
 Assessment of urticaria Diagnosis

Uncommon

◊ Mastocytosis

History Exam 1st Test Other tests

Identifies patients with
urticaria pigmentosa.

»alpha and beta

tryptase in blood
and urine: elevated
if mast cell numbers
excessively increased;
total tryptase elevated
in direct correlation with
extent of disease
»histamine and 1,4-
methylimida zole
acetic acid levels
in urine: elevated in
direct correlation with
extent of disease
Certain foods, such as
strawberries, tomatoes,
spinach, aubergine,
shrimp/lobster, aged
cheese, and wine,
are known to elevate
histamine levels
artificially.

»bone marrow
DIAGNOSIS

biopsy: excess mast

cells in mast cell
proliferative disease,
including leukaemia
Performed in cases of
suspected mast cell
leukaemia (mainly in
adults).

◊ Urticarial vasculitis

History Exam 1st Test Other tests

often painful, recurrent crops of lesions, »skin biopsy of »Epstein-Barr virus

lesions lasting longer
than 24 hours; may
be recent ingestion
of drugs (e.g.,
potassium iodide,
incomplete blanching
on diascopy or
dermoscopy, post-
inflammatory
discolorations of
active lesions: signs
of leukocytoclastic
vasculitis: perivascular
lymphocytic infiltrate
with vascular damage
(EBV) titre: positive
in associated EBV
infection
»hepatitis B and
C titres: positive in

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Assessment of urticaria
Uncommon
◊ Urticarial vasculitis
History
fluoxetine, non-steroidal
anti-inflammatory
drugs);[27] arthralgias,
arthritis, and
constitutional
symptoms (e.g.,
malaise, fever,
Raynaud phenomenon,
abdominal pain,
diarrhoea, and
symptoms of
pulmonary obstructive
disease); symptoms of
associated systemic
disease
◊ Transfusion reactions
History
onset during or up
to 1 hour after blood
transfusion; usually
mild symptoms (e.g.,
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Diagnosis
Exam 1st Test Other tests
resolved lesions; joint and erythrocyte associated chronic
swellings; signs of extravasation hepatitis B or C
associated systemic 3 mm punch biopsy or »ANA, anti-Ro
disease larger antibody, anti-La
antibody, and anti-
Smith antibody:
positive in associated
lupus erythematosus
and Sjogren's
syndrome
»FBC: lymphocytosis
in associated viral
illnesses with atypical
lymphocytes in EBV
infection; anaemia
in associated colon
carcinoma
»liver function tests:
potentially elevated in
associated hepatitis B
or C
»gamma globulin
and protein
electrophoresis:
IgG spikes in
associated autoimmune
disease, IgM spikes
in gammopathy or
DIAGNOSIS
multiple myeloma
»carcinoembryonic
antigen (CEA):
elevated in associated
colon carcinoma
»colonoscopy:
screening for colon
carcinoma may identify
a tumour
Exam 1st Test Other tests
usually no »inspection »ABO typing: no
differentiating of plasma in discrepancy to blood
examination findings; centrifuged, used for transfusion
rarely, generalised anticoagulated »direct antiglobulin
venous blood (Coombs) test:
sample: clear
27
 Assessment of urticaria Diagnosis

Uncommon

◊ Transfusion reactions

History Exam 1st Test Other tests

fever, hypotension,
wheezing, anxiety)
bleeding tendency as
late complication
and pink red within IgG anti-A, anti-B, or
first few hours of anti-AB detected on
haemoglobinaemia circulating red cells
»inspection
of centrifuged
urine: clear red in
haemoglobinaemia

◊ Serum sickness

History Exam 1st Test Other tests

onset 7 to 10 days urticaria of several »FBC: leukocytosis/ »C3, C4, CH50:

after injection of
protein or drug; earliest
symptoms: fever,
malaise, headache;
subsequently: rash
at site of injection
or symmetrically
spreading from
abdomen, joint pain,
oedema, GI symptoms
(nausea, vomiting,
abdominal pain)
DIAGNOSIS
weeks' duration, joint leukopenia, depressed complement
swellings (knees, eosinophilia, or mild levels due to
ankles, shoulders, thrombocytopenia complement
wrists, spine, »erythrocyte consumption
temporomandibular sedimentation rate »C1q binding or Raji
joint), lymphadenopathy (ESR): usually slightly cell assays: elevated
elevated levels of immune
complexes
»C-reactive protein
(CRP): usually slightly
elevated
»urinanalysis:
albuminuria,
haematuria, active

sediment
»blood urea:
transiently elevated
»serum creatinine:
transiently elevated

◊ Cold-induced urticaria, Muckle-Wells syndrome, neonatal multi-

system inflammatory disease

History Exam 1st Test Other tests

group of skin manifestations »C-reactive protein »genetic testing:

autoinflammatory
conditions: cold-
induced urticaria,
Muckle-Wells
syndrome, neonatal
multi-system
inflammatory disease,
with increasing severity,
usually include
urticarial eruptions that
may be cold-induced,
usually migratory and
widespread; signs
and severity depend
on specific condition
but may include fever,
(CRP): elevated detection of relevant
mutation
»Erythrocyte
Genetic testing is
sedimentation rate
important to confirm
(ESR): elevated
»serum amyloid A: clinical diagnosis. In
elevated general, these patients
should be managed

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BMJ Best Practice topics are regularly updated and the most recent version
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subject to our disclaimer. © BMJ Publishing Group Ltd 2018. All rights reserved.
Assessment of urticaria Diagnosis

Uncommon

◊ Cold-induced urticaria, Muckle-Wells syndrome, neonatal multi-

system inflammatory disease

History Exam 1st Test Other tests

with recurrent episodes joint tenderness and »Cerebrospinal at a tertiary care
of inflammation swelling (arthritis), fluid (CSF) analysis: centre with expertise in
over months/years red painful eyes normal
without infection and (conjunctivitis, targeted genetic testing
»skin biopsy:
malignancy; age of uveitis), abdominal and genome exome/
neutrophilic infiltration
onset usually by 6 tenderness, and genome sequencing
months, symptoms and features of meningitis, techniques.
severity depend on bony overgrowth
specific condition but particularly of knees
may include periodic (neonatal multi-system
fevers, rash, joint pain, inflammatory disease)
headache, nausea,
painful red eyes
(conjunctivitis, uveitis),
severe episodes of pain
at various anatomical
sites, e.g., abdomen,
chest (serositis),
episodes of headache,
photophobia, neck
stiffness (meningitis);
progressive deafness
(with Muckle-Wells
syndrome and
neonatal multi-system
inflammatory disease)
and subsequently
features of amyloidosis

DIAGNOSIS
Diagnostic guidelines

Europe

Guidelines for evaluation and management of urticaria in adults and children

Published by: British Association of Dermatologists Therapy Guidelines and Audit Subcommittee
Last published: 2007

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 Assessment of urticaria Diagnosis

International

EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification,

diagnosis and management of urticaria

Published by: European Academy of Allergy and Clinical Immunology; Global Allergy and Asthma
European Network; European Dermatology Forum; World Allergy Organization
Last published: 2017

North America

Consultation and referral guidelines citing the evidence: how the allergist/
immunologist can help

Published by: American Academy of Allergy Asthma and Immunology

Last published: 2018

The diagnosis and management of acute and chronic urticaria: 2014 update

Published by: American Academy of Allergy, Asthma and Immunology

Last published: 2014

A focused parameter update: hereditary angio-oedema, acquired C1 inhibitor

deficiency, and angiotensin-converting enzyme inhibitor-associated angio-
oedema

Published by: American Academy of Allergy, Asthma and Immunology; American College of Allergy,
Asthma and Immunology
Last published: 2013
DIAGNOSIS

Oceania

ASCIA position paper on hereditary angioedema

Published by: Australasian Society of Clinical Immunology and Allergy

Last published: 2017

30 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Dec 05, 2018.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
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Assessment of urticaria References

Key articles
• Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA(2)LEN/EDF/WAO guideline for the definition,

REFERENCES
classification, diagnosis and management of urticaria. Allergy. 2018 Jul;73(7):1393-414. Full text
Abstract

• Irinyi B, Szeles G, Gyimesi E, et al. Clinical and laboratory examinations in the subgroups of chronic
urticaria. Int Arch Allergy Immunol. 2007;144(3):217-25. Abstract

• Grattan CE, Humphreys F, British Association of Dermatologists Therapy Guidelines and Audit
Subcommittee. Guidelines for evaluation and management of urticaria in adults and children. Br J
Dermatol. 2007 Dec;157(6):1116-23. Abstract

• Zuraw BL, Bernstein JA, Lang DM, et al. A focused parameter update: hereditary angioedema,
acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema.
J Allergy Clin Immunol. 2013 Jun;131(6):1491-3. Full text Abstract

• Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and chronic
urticaria: 2014 update. J Allergy Clin Immunol. 2014 May;133(5):1270-7. Abstract

References
1. Schaefer P. Acute and chronic urticaria: evaluation and treatment. Am Fam Physician. 2017 Jun
1;95(11):717-24. Full text Abstract

2. Guldbakke KK, Khachemoune A. Etiology, classification, and treatment of urticaria. Cutis. 2007
Jan;79(1):41-9. Abstract

3. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA(2)LEN/EDF/WAO guideline for the definition,
classification, diagnosis and management of urticaria. Allergy. 2018 Jul;73(7):1393-414. Full text
Abstract

4. Katelaris CH, Peake JE. MJA practice essentials 5. Allergy and the skin: eczema and chronic urticaria.
Med J Aust. 2006 Nov 6;185(9):517-22. Full text Abstract

5. Grattan CEH, Black AK. Urticaria and angioedema. In: Bolognia JL, Jorizzo JL, Rapini RP ed.
Dermatology (volume one). London, UK: Mosby; 2003;287-302.

6. Kwong KY, Maalouf N, Jones CA. Urticaria and angioedema: pathophysiology, diagnosis, and
treatment. Pediatr Ann. 1998 Nov;27(11):719-24. Abstract

7. Kim DH, Sung NH, Lee AY. Effect of levothyroxine treatment on clinical symptoms in hypothyroid
patients with chronic urticaria and thyroid autoimmunity. Ann Dermatol. 2016 Apr;28(2):199-204. Full
text Abstract

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Dec 05, 2018.
BMJ Best Practice topics are regularly updated and the most recent version
31
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2018. All rights reserved.
 Assessment of urticaria References
8. Zuberbier T, Maurer M. Urticaria: current opinions about etiology, diagnosis and therapy. Acta Derm
Venereol. 2007;87(3):196-205. Abstract
REFERENCES

9. Irinyi B, Szeles G, Gyimesi E, et al. Clinical and laboratory examinations in the subgroups of chronic
urticaria. Int Arch Allergy Immunol. 2007;144(3):217-25. Abstract

10. Grattan CE, Humphreys F, British Association of Dermatologists Therapy Guidelines and Audit
Subcommittee. Guidelines for evaluation and management of urticaria in adults and children. Br J
Dermatol. 2007 Dec;157(6):1116-23. Abstract

11. Liu JB, Li M, Yang S, et al. Clinical profiles of vitiligo in China: an analysis of 3742 patients. Clin Exp
Dermatol. 2005 Jul;30(4):327-31. Abstract

12. Simons FE, Ardusso LR, Bilò MB, et al. 2012 Update: World Allergy Organization guidelines
for the assessment and management of anaphylaxis. Curr Opin Allergy Clin Immunol. 2012
Aug;12(4):389-99. Abstract

13. Resuscitation Council (UK). Emergency treatment of anaphylactic reactions: guidelines for healthcare
providers. July 2012 [internet publication]. Full text

14. Lieberman P, Nicklas RA, Randolph C, et al. Anaphylaxis - a practice parameter update 2015. Ann
Allergy Asthma Immunol. 2015 Nov;115(5):341-84. Abstract

15. Zuraw BL, Bernstein JA, Lang DM, et al. A focused parameter update: hereditary angioedema,
acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema.
J Allergy Clin Immunol. 2013 Jun;131(6):1491-3. Full text Abstract

16. Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and chronic
urticaria: 2014 update. J Allergy Clin Immunol. 2014 May;133(5):1270-7. Abstract

17. Muller BA. Urticaria and angioedema: a practical approach. Am Fam Physician. 2004 Mar
1;69(5):1123-8. Full text Abstract

18. Pudukadan D, Thappa DM. Adverse cutaneous drug reactions: clinical pattern and causative agents in
a tertiary care center in South India. Indian J Dermatol Venereol Leprol. 2004 Jan-Feb;70(1):20-4. Full
text Abstract

19. Williams H. Clinical practice. Atopic dermatitis. N Engl J Med. 2005 Jun 2;352(22):2314-24. Full text
Abstract

20. Morar N, Cookson W, Harper JI, et al. Filaggrin mutations in children with severe atopic dermatitis. J
Invest Dermatol. 2007 Jul;127(7):1667-72. Abstract

21. Spergel JM, Paller AS. Atopic dermatitis and the atopic march. J Allergy Clin Immunol. 2003
Dec;112(6 suppl):S118-27. Abstract

22. Leung D, Boguniewicz M, Howell MD, et al. New insights into atopic dermatitis. J Clin Invest. 2004
Mar;113(5):651-7. Full text Abstract

32 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Dec 05, 2018.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2018. All rights reserved.
Assessment of urticaria References
23. Hurwitz S, Paller AS, Mancini J. Hurwitz clinical pediatric dermatology: a textbook of skin disorders of
childhood and adolescence. 3rd ed. Philadelphia, PA; Edinburgh: Elsevier Saunders, 2006.

REFERENCES
24. Barnetson R, Rogers M. Childhood atopic eczema. BMJ. 2002 Jun 8;324(7350):1376-9. Abstract

25. Silverberg NB, Licht J, Friedler S, et al. Nickel contact hypersensitivity in children. Pediatr Dermatol.
2002 Mar-Apr;19(2):110-3. Abstract

26. Tharp MD. Mastocytosis. Adv Dermatol. 2003;19:207-36. Abstract

27. Hannon CH, Swerlick RA. Urticaria and angioedema. In: Bolognia JL, Jorizzo JL, Rapini RP ed.
Dermatology (Volume 1). London, UK: Mosby; 2003; 388-9.

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Dec 05, 2018.
BMJ Best Practice topics are regularly updated and the most recent version
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of the topics can be found on bestpractice.bmj.com . Use of this content is
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 Assessment of urticaria Images

Images
IMAGES

Figure 1: Acute urticaria: typical wheals

From the collection of Adam Reich, MD, PhD

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Assessment of urticaria Images
Figure 2: Typical lesions seen in acute or chronic urticaria
From the collection of Stephen Dreskin, MD, PhD

IMAGES

Figure 3: Urticaria: wheals

From the collection of Adam Reich, MD, PhD

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Dec 05, 2018.
BMJ Best Practice topics are regularly updated and the most recent version
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of the topics can be found on bestpractice.bmj.com . Use of this content is
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 Assessment of urticaria Images
Figure 4: Angio-oedema of the lips in a patient who also has urticaria
From the collection of Stephen Dreskin, MD, PhD
IMAGES

Figure 5: Palmar target lesions

From the personal collection of Nanette Silverberg, MD

Figure 6: Stevens-Johnson syndrome: targetoid lesion and epidermal loss

From the personal collection of Dr A. Kowal-Vern

36 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Dec 05, 2018.
BMJ Best Practice topics are regularly updated and the most recent version
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Assessment of urticaria Images

IMAGES
Figure 7: Dermatographism
Wikipedia Commons; by JAguayo18 (CC BY-SA 4.0)

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IMAGES Assessment of urticaria Images

Figure 8: EAACI/GA2LEN/EDF/WAO recommended algorithm for chronic urticaria. Diagnostic algorithm for
patients presenting with wheals, angio-oedema, or both. AAE - acquired angio-oedema due to C1-inhibitor
deficiency; ACE-Inh - angiotensin-converting enzyme inhibitor; AE - angio-oedema; AID - autoinflammatory
disease; HAE - hereditary angio-oedema; RAS - renin angiotensin system
Reproduced from Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA2LEN/EDF/WAO guideline for the
definition, classification, diagnosis and management of urticaria. Allergy. 2018 Jul;73(7):1393-414. Used with
permission

38 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Dec 05, 2018.
BMJ Best Practice topics are regularly updated and the most recent version
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Assessment of urticaria Disclaimer

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Contributors:

// Authors:

Marilyn Li, MD
Assistant Professor of Clinical Pediatrics, Clinician Educator
Director, Quality Improvement and Educational Activities For The Breathmobile Program, Keck School of
Medicine, USC, Los Angeles, CA
DISCLOSURES: ML was a speaker for MEDA Pharmaceuticals in 2016.

Kenny Y.C. Kwong, MD

Clinical Associate Professor of Pediatrics
Division of Allergy-Immunology, Los Angeles County+USC Medical Center, Los Angeles, CA
DISCLOSURES: KYCK has received grant support from and acts as a consultant and speaker for Thermo-
Fisher Scientific.

// Acknowledgements:
Dr Marilyn Li and Dr Kenny Y.C. Kwong would like to gratefully acknowledge Dr Nanette Silverberg, and
Dr Mary Lee-Wong, previous contributors to this topic. NS and MLW declare that they have no competing
interests.

// Peer Reviewers:

Christopher Parrish, MD
Assistant Professor
Pediatrics and Internal Medicine, Division of Allergy and Immunology, UT Southwestern, TX
DISCLOSURES: CP declares that he has no competing interests.

Amor Kachamoune, MD
Assistant Professor
New York University School of Medicine, New York, NY
DISCLOSURES: AK declares that he has no competing interests.

Bet tina Wedi, MD

Professor
Head of Allergy Division, Department of Dermatology and Allergy, Hannover Medical School, Hannover,
Germany
DISCLOSURES: BW declares that she has no competing interests.