Urticaria and angioedema


Urticaria and angioedema




Urticaria: introduction and pathogenesis



Urticaria is a term describing erythematous or oedematous swellings of the dermis or subcutaneous tissues. The defining characteristic of urticaria is the transient nature of the lesions, which persist only for minutes up to 24 hours.

Superficial swellings tend to be itchy, whereas deeper swellings are painful and are often described as angioedema.

Lesions are frequently more irregular or bizarre in outline in children than in adults, but diagnosis is rarely possible based on the appearance of the lesion alone.

In a minority of instances, the clinical phenomenon of urticaria is associated with identifiable physical causes, and these are often termed physical urticarias


In the majority of patients with urticaria, no such factors appear to be involved. The cause in such cases may be immunological, due to an IgE antibody directed against proven or putative antigens. Nonimmunological mechanisms of mast cell activation can also lead to the clinical phenomenon. The presentation may be acute and may be associated with anaphylaxis. Continued appearance of lesions for greater than 6 weeks is arbitrarily defined as chronic urticaria.

In the following discussion, the management of the more common group will be dealt with first and that of the less frequent physical urticarias subsequently.

Is it really urticaria?

Erythematous and oedematous lesions or painful subcutaneous swellings, which are not transient, are frequently seen in drug eruptions, erythema multiforme, erythema nodosum and vasculitis. The overlap syndrome, urticarial vasculitis, is discussed separately.


Essentially, mast cell activation by whatever mechanism is seen in all forms of urticaria. Mast cell activation leads to histamine release, which is important in the early phase of most types of urticaria, but it is clear that other inflammatory mediators, including prostaglandins, leukotrienes, neural cytokines and serotonin play a part, probably in the later phase of the reaction. Urticaria may be allergic or nonallergic. A lowered threshold for mast cell activation may be important, particularly in chronic urticaria, and the incidence is higher in atopic patients. Chronic urticaria is also more likely to involve mediators other than histamine and to demonstrate perivascular cellular infiltrate.

Acute urticaria


Many patients will undergo spontaneous remission within hours and may not need active treatment.

Removal of the cause

This is an obvious solution where a drug or food is clearly established as the cause, but even when this is done, cessation of the urticaria may not be immediate. Removing possible contactants should always be considered, eg latex rubber gloves, some foods.


Treat the urticaria, dependent on the severity.

In most situations, initially use

an oral antihistamine, see below.


In cases of extensive urticaria, or urticaria involving eyelids and lips, use

promethazine 25 to 50mg IM, as a single dose.


If there is not an immediate response to intramuscular antihistamine, use

prednisolone 25 to 50mg orally as a single dose.


Maintenance treatment is entirely symptomatic and is intended to provide relief until resolution of the initial process occurs. Although topical therapies are of limited benefit because of the depth and extent of involvement, the addition of cold packs and cooling agents, such as calamine lotion with menthol 0.25%, may be helpful where control is not satisfactorily achieved by systemic measures. Topical corticosteroids are rarely helpful.

If there is associated hypotension and evidence of anaphylactic shock then adrenaline should be administered intramuscularly, subcutaneously or slowly intravenously as the severity of the clinical state dictates. In addition to supportive measures, recommended treatment is with

adrenaline 1 in 1000 solution 0.3 to 1mL IM or SC, repeated every 10 to 15 minutes as required.


1 in 10 000 solution [Note 1] 1 to 2.5mL IV over 5 to 10 minutes, repeated every 10 to 15 minutes as required.


promethazine 50mg IM.


Oral antihistamines - The advent of nonsedating antihistamines such as loratadine], cetirizine and fexofenadine provides a variety of options for once or twice daily therapy with marked reduction of adverse effects. However, often in the acute phase of urticaria the induction of drowsiness is not a problem and older antihistamines such as promethazine and diphenhydramine,Table 1, may have a role to play. A current disadvantage of the newer antihistamines is a lack of flexibility in the recommended safe dosages. Therefore, first-line therapy is

cetirizine 10mg orally, once or twice daily OR loratadine 10mg orally, daily OR fexofenadine 180mg orally, daily.


If no response, add a second antihistamine with more sedating activity

promethazine 25mg OR hydroxyzine [Note 2] 25mg OR doxepin 10 to 75mg orally, at night.


Doxepin is an antidepressant that has very strong antihistaminic properties. It is both an H1-and an H2-receptor antagonist.

The dose of the antihistamine can be increased and midday doses included, dependent on an assessment of benefits and adverse effects

promethazine up to 75mg OR hydroxyzine [Note 2] up to 100mg orally, daily.


Warn patients about drowsiness associated with driving and operation of machinery with the sedating antihistamines. Hypnotics and alcohol will enhance this effect.

If terfenadine and astemizole are used, there is the potential for drug interactions with the azole antifungal agents (ketoconazole, itraconazole, fluconazole) and the macrolide antibiotics (erythromycin, roxithromycin, azithromycin, clarithromycin).


[Note 1]

If using adrenaline 1 in 1000 solution, dilute to 1 in 10 000 before IV administration.

[Note 2]

As hydroxyzine is the precursor of cetirizine, these antihistamines should not be combined.


Chronic urticaria



Urticaria persisting beyond 6 weeks is considered to be chronic and treatment is aimed at symptomatic relief. In 50% of patients, their chronic urticaria is still active at 12 months and in 10% at 10 years.

In the majority of cases persisting beyond 6 weeks where no obvious cause of the urticaria is found, extensive systemic investigation for urticaria is rarely justified. Radio-allergosorbent test (RAST) and patch testing, see Points on phototherapy, are rarely helpful. Full blood count, liver function test, antinuclear factor, total complement level, chest X-ray and mid-stream urine may be justified.

There is no evidence associating chronic urticaria with malignancy.

If abnormal findings on clinical examination suggest infection or connective tissue disease, further work up is justified, but this is unlikely to prove fruitful in the absence of such symptoms. Rarely, in longstanding urticaria without any systemic symptoms it may be decided to search for and exclude chronic infective foci including infections of sinuses or teeth or chronic yeast and fungal infections, or to conduct provocation tests with suspected allergens.

Even when the cause is known, eg a drug, its removal does not always lead to a spontaneous remission of the urticaria.

Removal of the cause

Salicylates should be avoided, both therapeutically and in food. Up to 50% of all patients with chronic urticaria have aspirin sensitivity, ie lesions are worsened by aspirin. In a smaller proportion of patients, the condition is aggravated by food dyes (eg tartrazine), preservatives (eg benzoates) and vasoactive amines. Mast cell degranulating agents such as codeine, morphine and curare should be avoided. Foods such as seafood act in the same way. Contrast media can cause degranulation by a complement-mediated mechanism.


First-line treatment is with oral antihistamines. As mentioned in the treatment of persistent acute urticaria, a combination of two antihistamines represents the best method of control if one is not successful alone, see Oral antihistamines. The natural history of chronic urticaria is a decrease in intensity of symptoms with time, and therefore a reduction in the suppressive dose of antihistamines should regularly be attempted.

A significant number of patients with chronic urticaria are unresponsive to antihistamines. If a combination of two antihistamines does not work then alternatives include the addition of a beta2-receptor agonist or a H2-receptor antagonist. This treatment has been quite disappointing but could be attempted as a relatively nontoxic option.

terbutaline 2.5 to 5mg orally, 3 times daily OR ranitidine 150mg orally, twice daily.


When angioedema is a feature of chronic urticaria and is not controlled by antihistamines, systemic corticosteroids can be used as an additional control measure. Use

prednisolone 25 to 50mg orally, daily for 1 week then reduce the dose gradually.


Up to 25% of patients with chronic idiopathic urticaria are thought to have a circulating IgG antibody binding to the IgE receptor on mast cells as the major factor contributing to chronicity, and they will respond well to immunosuppressive therapy, such as systemic corticosteroids, cyclosporin or azathioprine. Plasmapheresis is also temporarily effective in these patients and intravenous gamma globulin has induced permanent remission in some cases.

Some patients may be found to have depressed thyroid function and will respond to thyroxine.

Physical urticarias


Various forms of physically-induced urticaria exist, either alone or as a component of acute or chronic urticaria. They are summarised in Table 4.38 and discussed in more detail on the following pages. The causative mechanisms are less well understood, although histamine is a major effector in most forms. They are not IgE mediated.

Major features of physical urticaria (Table 1)



Associated features


stroking skin

common in acute and chronic urticaria


sweating caused by heat, emotion or food

small papule with flare





sustained pressure, eg feet and buttocks

delayed onset


cold water, winds

systemic disease, anaphylaxis


water, all temperatures



sunlight – long wave UV to visible

seen in erythropoietic protoporphyria


jack-hammers, vigorous towelling

extremely rare


localised >43°C




Dermographism is an exaggerated response to firm stroking of the skin, consisting of local erythema, oedema and a surrounding flare. It may be present alone or may complicate acute or chronic urticaria. When it is present as an isolated problem, patients should be told that the problem is often self-limiting. Occasionally symptomatic treatment is requested and antihistamines may be tried.

Cholinergic urticaria

This distinctive micropapular urticaria particularly affects the upper trunk, and is always initiated by sweating associated with heat, exertion or some types of food. Attacks last from a few minutes up to 2 hours. It is best treated by an antihistamine, either sedating or nonsedating, see Oral antihistamines. This may be necessary on a regular basis or intermittently as required for ‘major events’. Some patients with this condition notice that there is a refractory period for up to 24 hours after attacks. If so, the induction of a refractory period by deliberate initiation of the eruption 2 hours before the ‘major event’ works well.

Adrenergic urticaria

This condition has only recently been described but probably is more common than originally realised. The onset of urticaria and swelling is associated with a stressful event and can be prevented by the use of

propranolol 25mg orally, 3 times daily.


Pressure urticaria

This painful and distressing condition, in which swelling may not appear for some hours after the initiating event, seems to involve deeper vessels and different mediators. It responds poorly to antihistamines and, as the buttocks after sitting and the feet after prolonged periods of standing are often involved, systemic corticosteroids may be needed for control. Use

prednisolone 25 to 50mg orally daily, initially, then adjust to the lowest dose that provides a risk/benefit advantage.


Cold urticaria

This condition is uncommon and infrequently associated with blood abnormalities that may be corrected by treatment of the causative disease. Patients who suffer collapse or intraoral symptoms should avoid all water sports.

In other patients, antihistamines, eg cyproheptadine, can suppress the symptoms. Desensitisation by repeated exposure to cold has been achieved but is impracticable on a long-term basis.

Aquagenic urticaria

This form of urticaria simulates cholinergic urticaria in morphology but is induced by water of any temperature. Treatment is the same as for cholinergic urticaria.

Solar urticaria

This condition is rare and has quite a broad-spectrum of initiating wavelengths, so high protection sun screens are not particularly helpful. Sun avoidance and the use of protective clothing is more useful. Porphyria needs to be excluded (erythropoietic protoporphyria). Psoralen and ultraviolet A (PUVA) therapy, see Points on phototherapy, has been shown to be beneficial.

Vibratory urticaria

This is a rare form of urticaria, initiated by any vibratory stimulus, eg jogging, use of vibrating tools, lawn mowers. It usually presents as a red itchy swelling lasting up to 2 hours. Systemic symptoms and generalised erythema can occur. Management is by avoidance of precipitating factors.

Heat urticaria

This is a very rare condition. It responds poorly to antihistamines and is said to benefit by repeated exposure to heat, which may cause desensitisation.




Angioedematous lesions are common in acute and chronic forms of urticaria and may affect the face, periorbital region, lips, tongue, glottis, dorsa of feet and hands, and genitalia. Treatment is similar to that of urticaria and the use of systemic corticosteroids may be indicated. Use

prednisolone 25 to 50mg orally, daily for 1 week then taper the dose gradually.


Congenital angioedema is rare and not associated with urticaria. The life threatening involvement of mucous membranes and presence of laryngeal oedema may require emergency treatment with adrenaline and tracheostomy. Systemic corticosteroids are not helpful in this form of angioedema, but considerable benefit has been derived in recent years with the long-term use of stanozolol and danazol.

Acquired angioedema

This is seen particularly with B-cell lymphoma and systemic lupus erythematosus. Treatment with stanozolol or replacement therapy with complement C-1 esterase inhibitor has been used. Immunosuppressive therapy with prednisolone may help, particularly in the rare autoimmune form.

Angioedema associated with angiotensin converting enzyme (ACE) inhibitors responds well to cessation of the drug. Clinicians should exercise caution in prescribing ACE inhibitors for patients with prior idiopathic episodes of sudden swelling of the skin or mucous membranes.

When to use corticosteroids systemically

           In acute episodes of urticaria when there is not an immediate response to intramuscular antihistamine, particularly where swelling of the face and lips is associated.

           As an additional control measure in acute or chronic urticaria when angioedema is a feature and is not controlled by antihistamines.

           When there is persistent painful swelling associated with pressure urticaria.




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