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Urticaria and angio-oedema
Executive Editor, InnovAiT E-mail: chantal.simon{at}oxfordjournals.org
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Abstract |
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 TOP Abstract The GP curriculum, urticaria...UrticariaManagement of urticariaUrticarial vasculitisAngio-oedemaC1 esterase inhibitor deficiencyReferences |
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The term urticaria (also known as ‘hives’ or ‘nettle rash’) is widely used to describe a superficial swelling of the epidermis and mucous membranes that results in a red, raised, itchy rash that can be localized or generalized. This rash is described as weals. The rash may be localized or generalized and acute or chronic. Most patients with urticaria do not have systemic reactions, but allergic urticaria and some physical urticarias may occasionally progress to anaphylaxis. However, urticaria is often a feature of anaphylactic reactions. Angio-oedema is a deeper form of urticaria with swelling in the dermis and submucosal or subcutaneous tissues. It may occur alone, or concurrently with urticaria, affecting up to 50% of patients with chronic urticaria.
Urticaria is listed as a common and important condition forming part of the knowledge base of curriculum statement 15.10: Skin problems. GPs in training should be able to:
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Urticaria |
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TOPAbstractThe GP curriculum, urticaria...UrticariaManagement of urticariaUrticarial vasculitisAngio-oedemaC1 esterase inhibitor deficiencyReferences |
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The skin changes of urticaria are caused by local vasodilation of capillaries and activation of mast cells which release histamine, resulting in plasma leaking from small blood vessels into the skin. Diagnosis is made from the history and by examination of the characteristic rash. It may also be possible to identify the underlying cause from the history (Fig. 2). It is unusual for the patient to feel unwell with urticaria. If the patient does feel unwell, consider another diagnosis, for example angio-oedema and/or anaphylaxis.
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Characteristics of an urticarial rash (Fig. 1) include:
- Small raised areas (1–2 cm) of the skin (weals) that develop suddenly
- Weals can be red or white and are itchy and surrounded by an area of redness (flare)
- Usually, individual weals last less than 24 hours (physical urticaria weals may only last 1–2 hours) and fade before the surrounding flare, making the skin look blotchy
- The rash may disappear completely but may reappear in hours or days
- Weals may coalesce with others making the rash look extensive and map-like (geographic rash)
- As weals disappear, others may appear elsewhere
- If the weals remain for longer than 24 hours and are painful and dark, leaving a residual pigmented lesion such as petechial haemorrhage, purpura or bruising, consider a diagnosis of ‘urticarial vasculitis’. The person may also have systemic symptoms, such as fever, malaise and arthralgia.
Clinical classification
Several clinical classifications of urticaria are in common usage and terminology can be confusing. The simplest classification is based on duration of symptoms.
Although most acute urticarial rashes last 24–48 hours and then disappear spontaneously, acute urticaria is defined as an urticarial rash and/or angio-oedema lasting for less than 6 weeks. Acute urticaria is much more common than chronic urticaria, affecting 1 in 6 people at some point in their lives. It is more common in children, in women aged 30–60 and in people with atopy.
Chronic urticaria is urticaria on a daily or almost daily basis lasting for longer than 6 weeks. Chronic urticaria is usually classified together with ‘episodic acute intermittent’ urticaria in which symptoms last for hours or days but recur over months or years. Prevalence rates vary from 1–5 in every 1000 people. Chronic urticaria may remit and relapse with relapses triggered by illness, stress, drugs or alcohol and hormonal changes such as menstruation. Duration of symptoms is very variable. Half of all cases resolve in 3–5 years, but one in five cases persists for more than 10 years. People with physical urticaria and those with severe episodes tend to have a longer duration of urticaria.
Chronic urticaria has a severe impact on the quality of life of the patient. The itching and rash causes distress, poor self-image and social isolation. Poor sleep may affect work or school performance and impact on personal relationships. It is thought that up to 14% of patients with chronic urticaria develop depression as a result of their illness.
Further classification (Box 1) is made by presenting features and cause. In 40–50% of cases, cause is unclear. When the cause of the urticaria is unknown, it is classified as ‘ordinary’ or ‘idiopathic urticaria’. Patients present with spontaneous weals anywhere on the body with or without angio-oedema. Triggers may include viral infections (particularly in children), stress, overheating, drugs or alcohol.
| Box 1. Classification of urticaria and angio-oedema Ordinary or idiopathic—may be triggered by stress or viral infections
Physical—reproducibly induced by the same physical stimulus
Angio-oedema without weals
Contact—caused by contact with allergens (e.g. nuts, shellfish, milk, eggs, penicillin, insect stings and latex) or chemicals Urticarial vasculitis—defined by vasculitis on skin biopsy Autoinflammatory or autoimmune syndromes—patients develop spontaneous weals, pyrexia and malaise together with other features specific to their disease
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Physical urticarias are triggered reproducibly by one or more physical stimuli. Identifying the stimulus allows the patient to minimize or prevent urticaria through avoidance.
Contact urticaria occurs repeatably and reliably but only when the eliciting substance is absorbed into the body. This may be IgE-mediated ‘allergic urticaria’ resulting from exposure to or ingestion of an allergen (i.e. latex allergy, food allergy or allergy to an insect sting) or non-IgE mediated resulting from ingestion of certain other chemicals such as drugs or food additives. Implicated drugs include the opioids, aspirin, non-steroidal anti-inflammatories (NSAIDs) and radio-contrast media. Common food additives that cause urticaria include azo dyes, naturally occurring salicylates and food preservatives.
The duration that individual weals last can be helpful in distinguishing between clinical patterns:
- Vasculitic urticaria—weals last days
- Ordinary urticaria—weals typically last 2–24 hours
- Contact urticaria—weals last up to 2 hours
- Physical urticaria—weals last less than an hour (except weals in delayed pressure urticaria which take 2–6 hours to develop and up to 48 hours to fade)
Differential diagnosis
If the rash is not witnessed, for example if symptoms only occur at night, urticaria can be confused with any cause of chronic pruritus. Skin lesions of urticaria can be confused with erythema multiforme; however, the lesions of erythema multiforme are usually fixed and have a ‘target’ appearance and they may be associated with a prodromal illness. The early lesions of bullous pemphigoid and dermatitis herpetiformis also have a similar appearance to an urticarial rash.
In pregnancy, consider ‘pruritic urticarial papules and plaques of pregnancy’ (PUPPP—Fig. 3). PUPPP is associated with first and/or multiple pregnancies or excessive weight gain in pregnancy. It develops after 35 weeks gestation and appears as a rash usually confined to the lower abdomen and/or buttocks. It may appear in stretch marks. PUPPP usually clears spontaneously within 6 weeks and often just a few days after delivery. It does not recur in subsequent pregnancies.
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In small babies, erythema toxicum may have a similar appearance to urticaria. Skin lesions resolve spontaneously within the first few weeks of life. Urticaria pigmentosa, or cutaneous mastocytosis, appears in infancy and usually within the first 2 weeks of life. Dark, freckle-like lesions on the face, limbs or trunk become urticarial when the skin is rubbed (Derier's sign). No treatment is needed and the condition clears spontaneously in childhood.
Associations
Thyroid autoimmunity is roughly twice as prevalent among patients with chronic ordinary urticaria (COU) compared to population controls (14% as opposed to 6%). There is also a significantly higher prevalence of coeliac disease in children and adolescents with severe chronic urticaria than case-matched controls.
Other associations are disputed. For example, an association between chronic urticaria and chronic infection is often proposed. There is little evidence for this, but a meta-analysis of therapeutic trials for Helicobacter pylori eradication did show that resolution of chronic urticaria was more likely when antibiotic therapy was successful than when it failed.
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Management of urticaria |
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TOPAbstractThe GP curriculum, urticaria...UrticariaManagement of urticariaUrticarial vasculitisAngio-oedemaC1 esterase inhibitor deficiencyReferences |
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Acute urticaria
Patients presenting with acute urticaria may be having a completely new attack or a flare up of chronic urticaria. Anaphylaxis is likely when all of the following three criteria are met:
- Sudden onset and rapid progression of symptoms usually over a period of minutes
- Life-threatening Airway and/or Breathing and/or Circulation problems
- Skin and/or mucosal changes—flushing, erythema, urticaria and/or angio-oedema, rhinitis and/or conjunctivitis
However, skin and mucosal changes can be subtle or absent in up to one in five reactions. Indeed, some patients present with hypotension alone. Skin or mucosal changes on their own are ‘not’ a sign of an anaphylactic reaction, although they may develop into one. Other symptoms include abdominal symptoms such as abdominal pain, vomiting or incontinence. Often patients are also anxious and have a sense of impending doom.
If anaphylaxis is suspected, start treatment with intramuscular adrenaline in accordance with the Resuscitation Council's anaphylaxis guideline. Admit the patient to hospital. In addition, admit any patient with urticaria and angio-oedema involving the airway as an emergency, even if anaphylaxis is not suspected.
For most patients, acute urticaria is not life threatening and attacks are normally self-limiting. Treatment is not needed if the episode is mild. Self-help measures include:
- Trying not to scratch—advise patients to rub their skin with the palms of their hands if they must itch and keep nails short and clean
- Choosing clothing that does not irritate the skin (such as cotton)
- Using lubricating, alcohol-free, hypoallergenic products on their skin
- Trying calamine lotion or cool baths to soothe the itch
If symptomatic treatment is needed, offer a non-sedating antihistamine to control daytime symptoms. Suitable choices include cetirizine, fexofenadine or loratadine. Response and tolerance to antihistamines does vary considerably between individuals, so if one antihistamine is not effective, try another. Consider adding a sedative antihistamine, such as chlorphenamine or hydroxyzine, at night if the itching interferes with sleep. Topical menthol 1% cream can be used as an alternative to, or in addition to, an oral antihistamine. Loratadine or chlorphenamine are thought to be safe antihistamines in pregnancy or for breast-feeding mothers.
For patients with severe symptoms, consider a short course of oral corticosteroids (such as prednisolone 40 mg daily for 3–5 days) in addition to the oral antihistamine. If rebound symptoms occur after a short course of corticosteroids seek specialist advice. Do not give repeat courses of steroids in primary care except with specialist advice.
Chronic urticaria
For all patients with chronic urticaria, assess severity of symptoms and their impact on the day-to-day life of the individual. Specifically, ask about problems with sleep and the psychological effects of the urticaria on the patient. It is not always possible to determine a cause for chronic urticaria, but if the cause of the urticaria is not known, try to identify any potential causes by taking a detailed history.
Clearly written information sheets (e.g. those available from websites www.bad.org.uk/public/leaflets/urticaria.asp, www.patient.co.uk/showdoc/23068988 or www.patient.co.uk/showdoc/27000970) can be very helpful to patients. Explain likely course and prognosis. Advise patients to avoid non-specific aggravating factors, such as overheating, stress, alcohol and drugs with the potential to worsen urticaria such as aspirin and codeine. NSAIDs should be avoided in aspirin-sensitive patients with urticaria.
The mainstay of medical management in primary care is with regular antihistamines. As for acute urticaria, use a non-sedating antihistamine to control daytime symptoms and consider adding a sedating antihistamine if sleep is disturbed. It may be necessary to try several antihistamines before one is found that suits the patient and works. If this does not control symptoms, then referral is indicated.
Specialist treatments include higher doses of antihistamines or a combination of non-sedative antihistamines. Other treatments frequently tried in addition to a regular antihistamine are H2-receptor antagonists, such as cimetidine or ranitidine (unlicensed indications) or antileukotrienes such as montelukast (unlicensed indication). Response to these agents is highly variable.
Investigation
Investigation is not usually necessary in primary care. For patients with chronic urticaria, consider checking a full blood count, ESR and thyroid function tests.
Referral
Depending on local policy, refer to an immunologist or dermatologist when there is:
- Urticaria with angio-oedema not involving the airway
- Acute urticaria which is severe and thought to be due to a food or latex allergy
- Chronic persistent urticaria (usually lasting beyond 6 weeks) which is troublesome despite the use of antihistamines and avoidance of known trigger factors
- Rebound urticaria following a course of steroids
- Vasculitic urticaria: suspect if lesions are painful and persistent
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Urticarial vasculitis |
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TOPAbstractThe GP curriculum, urticaria...UrticariaManagement of urticariaUrticarial vasculitisAngio-oedemaC1 esterase inhibitor deficiencyReferences |
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Urticarial vasculitis presents clinically with urticaria but small vessel vasculitis histologically. The clinical pictures may be indistinguishable from COU. Suspect if:
- Urticaria is relentless rather than transient and self-limiting
- Individual lesions last for more than 24 hours
- Lesions are burning or painful rather than itchy
- Lesions leave scaling, bruising, purpura or petechial haemorrhages
Other associated features may include joint pains, fever and/or malaise. In all cases, referral for specialist care is needed. Diagnosis is confirmed by skin biopsy. Specialist treatment is with steroids and/or other immunosuppressive agents.
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Angio-oedema |
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TOPAbstractThe GP curriculum, urticaria...UrticariaManagement of urticariaUrticarial vasculitisAngio-oedemaC1 esterase inhibitor deficiencyReferences |
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Angio-oedema is a swelling in the dermis, subcutaneous and submucosal tissues. One in 10 patients presenting with urticaria or angio-oedema present with angio-oedema alone, 4 in 10 present with a combination of urticaria and angio-oedema and the rest present with urticaria alone. Roughly, half of those with COU have episodes of angio-oedema too. Women are more frequently affected than men. Angio-oedema may be considered part of the continuum of anaphylaxis but, in isolation, without respiratory difficulty or hypotension, it is not anaphylaxis.
Skin swelling is less well defined than in urticaria. Swellings can occur anywhere on the body but most often involve the eyes, lips, genitalia and hands or feet (Fig. 4). The surface of the skin may appear normal. The swellings are often more painful than itchy and last longer than urticarial weals. Without treatment, angio-oedema may last up to 3 days. Systemic involvement can occur affecting the bowel and the airway. Bowel involvement may cause abdominal pain with or without nausea, vomiting or diarrhoea. Airway involvement may cause tongue swelling, shortness of breath and/or wheeze. If there is airway compromise, consider the possibility of anaphylaxis.
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Causes
The causes of angio-oedema are listed in Box 1 and Figure 2. Distinguish angio-oedema without weals from angio-oedema occurring with weals. Angio-oedema without weals is more commonly seen with hereditary angio-oedema, as a result of ACE inhibitors or NSAIDs, or as a result of physical causes of angio-oedema such as pressure.
Differential diagnosis
Skin infections such as cellulitis and erysipelas can present with localized skin swellings, though usually these are associated with fever, erythema and tenderness. Local skin reactions, such as contact dermatitis can also be confused with angio-oedema, but in these conditions there are usually changes to the overlying skin and the skin is intensely itchy. Lymphoedema may also present with localized swelling, but the swelling is usually chronic and the skin is often thickened and firm. Other rarer differential diagnoses include idiopathic scrotal oedema in children, in which the swelling is limited to the scrotum, and Rosenthal–Melkersson syndrome which causes recurrent non-resolving facial oedema, peripheral facial nerve palsy and fissuring of the tongue.
Management
If anaphylaxis is suspected, give adrenaline immediately and follow the Resuscitation Council algorithm for management of anaphylaxis. Admit immediately to hospital, even if the patient has seemingly recovered. If the patient has angio-oedema and any airway compromise, even if anaphylaxis is not suspected, refer the patient immediately to hospital.
If a decision is made not to admit the patient, confirm the diagnosis of angio-oedema and try to identify the underlying cause. Give an oral non-sedating antihistamine combined with an oral corticosteroid (e.g. prednisolone 40 mg once a day for 3–5 days).
Monitor the patient closely and at least daily until symptoms have resolved either by reviewing the patient by telephone, in the surgery or at home. Monitor patients who have poor social circumstances or are vulnerable due to their age or level of understanding more frequently. Give the patient verbal and written instructions about circumstances, such as worsening of symptoms or airway compromise, in which they should seek further help or go to A&E. Consider admission if there is no improvement after treatment in primary care or any worsening of symptoms while on treatment.
Investigations are not usually necessary in primary care. Refer all patients who have had an attack of angio-oedema to an immunologist or allergy clinic, except patients taking ACE inhibitors. For patients taking ACE inhibitors, stop the ACE inhibitor prior to referral. Only refer if the angio-oedema persists for longer than 3 months after stopping the ACE inhibitor or the patient has recurrent episodes of angio-oedema after stopping the ACE inhibitor. Long-term management is the same as for patients with chronic urticaria.
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C1 esterase inhibitor deficiency |
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TOPAbstractThe GP curriculum, urticaria...UrticariaManagement of urticariaUrticarial vasculitisAngio-oedemaC1 esterase inhibitor deficiencyReferences |
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C1 esterase inhibitor deficiency, often termed hereditary angio-oedema or HAE, is usually inherited as an autosomal dominant gene. Rarely, C1 esterase inhibitor deficiency may be acquired in association with lymphoma or connective tissue disorders such as systemic lupus erythematosus.
HAE is characterized by acute recurrent attacks of angio-oedema with more gradual onset than allergic angio-oedema. These attacks usually start after puberty. Attacks may be precipitated by stress, trauma, minor operations and dental surgery. Swellings most commonly affect the hands and the feet and are painless. However, up to one in four sufferers have airway involvement and gastrointestinal symptoms are common. Rarely, abdominal symptoms may mimic an acute abdomen.
Management
Refer any patient suspected of having C1 esterase inhibitor deficiency for further investigation via an immunology or allergy clinic. A reduced C4 level (less than 30% of expected levels) is strongly suggestive of the diagnosis and should prompt specialized assays of C1 esterase inhibitor.
Maintenance therapy is only necessary for patients with symptomatic recurring angio-oedema or related abdominal pain. Anabolic steroids are the treatment of choice for most adults but should be avoided in children. Virilizing side effects may occur even at low doses. Regular monitoring for hepatic inflammation and hepatocellular adenomas is essential. Alternatively, tranexamic acid may be used for maintenance but is contraindicated in patients with a history of thrombosis. Regular eye examinations and liver function tests are recommended. Prophylaxis before planned surgery or dental procedures includes taking tranexamic acid 2 days before and afterwards or increasing the dose of established maintenance therapies with tranexamic acid or anabolic steroids.
C1 esterase inhibitor concentrate is reserved for emergency treatment of serious angio-oedema attacks or as prophylaxis before surgery, especially when intubation or dental extractions are necessary. Fresh frozen plasma may be used as a substitute in an emergency if C1 esterase inhibitor concentrate is not available.
Key points
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TOPAbstractThe GP curriculum, urticaria...UrticariaManagement of urticariaUrticarial vasculitisAngio-oedemaC1 esterase inhibitor deficiencyReferences |
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Clinical Knowledge Summaries.
Angio-oedema and anaphylaxis. Accessed via cks.library.nhs.uk/angio_oedema_and_anaphylaxis [date last accessed 28.07.2008].
Urticaria. Accessed via cks.library.nhs.uk/urticaria [date last accessed 28.07.2008].
Federman DG, Kirsner RS, Moriarty JP, Concato J. The effect of antibiotic therapy for patients infected with Helicobacter pylori who have chronic urticaria. Journal of the American Academy of Dermatology (2003) 49:861–4.[CrossRef][Web of Science][Medline]
Grattan CEH, Humphreys F. Guidelines for evaluation and management of urticaria in adults and children. British Journal of Dermatology (2007) 157:1116–23. Accessed via www.bad.org.uk/healthcare/guidelines/Urticaria_and_Angiodema_(2007).pdf [date last accessed 24.06.2008].[CrossRef][Web of Science][Medline]
Powell RJ, et al. BSACI guidelines for the management of chronic urticaria and angio-oedema. Clinical and Experimental Allergy (2007) 37:631–50. Accessed via www.blackwell-synergy.com/action/showPdf?submitPDF=Full+Text+PDF+%28220+KB%29&;doi=10.1111%2Fj.1365-2222.2007.02678.x [date last accessed 24.06.2008].[CrossRef][Web of Science][Medline]
RCGP. Curriculum statement 15.10: Skin problems. Accessed via www.rcgp-curriculum.org.uk/PDF/curr_15_10_Skin_problems.pdf [date last accessed 24.06.2008].
Resuscitation Council UK. Emergency medical treatment of anaphylactic reactions: guidelines for healthcare providers (2008) Accessed via www.resus.org.uk/pages/reaction.pdf [date last accessed 24.06.2008].
Simon C. Oxford GP library. Dermatology. Oxford: Oxford University Press. In press.
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