Cutaneous Anaphylaxis

Malcolm HA Rustin and Catherine H Orteu, Department of Dermatology, The Royal Free Hospital, London, UK

Copyright © 1998 Elsevier Ltd. All Rights Reserved.

In 1902, Portier and Richet injectcd foreign protein into animals without incident, but found that when injected a second time a fatal systemic reaction was induced. The phenomenon was called anaphylaxis and may be defined as a specific immunoglobulin K (IgE)-mediated antigen-induced reaction by mast cells and basophils, the type 1 immediate hypersensitivity reaction of Gell and Coombs. Clinically, the term anaphylaxis is used to describe a syndrome resulting from the release of a variety of preformed and newly generated, mast cell-derived chemical mediators (Table 1). The trigger may be mediated by specific antibodies such as IgE, or by nonimmuno-logic mechanisms. The hallmarks of a cutancous anaphylactic reaction are urticaria and angioedema and such a reaction may remain localized to the skin, or become generalized, causing pruritus, diffuse erythema, urticaria, angioedema, laryngeal edema, bronchoconstriction, hypotension and cardiac arrhythmias. In addition, the skin may either be the source of an anaphylactic reaction, or be a target organ in a systemic reaction. Causes of systemic anaphylaxis in which the skin is the origin of the reaction are listed in Table 2.

Table 1 Mediators released from activated mast cells

Preformed mediators Histamine, heparin, tryptase, kininogenase, carboxypeptidase A Proteoglycans, eosinophil and neutrophil chemotactic factors

Newly generated mediators Prostaglandin D2, thromboxane A2 Leukotriene B4, C4, D4 and E„ Platelet-activating factor Cytokines Interleukin 3,4,5,6

Granulocyte-macrophage colony-stimulating factor

Table 2 Causes of cutaneous anaphylaxis

Immediate wheal and flare prick test responses Insect stings or bites Immunologic contact urticaria Physical urticaria: cold, aquagenic, solar, cholinergic, delayed pressure


Data on the prevalence of urticaria are few, but it is thought to affect 15-23% of the general population. It is an eruption caused by exudation of fluid into the dermis which presents as itchy, erythematous or edematous swellings known as wheals, surrounded by a bright red flare (Figure 1). Clearing of the central area may result in an annular pattern and lesions vary in size from 2-5 mm up to several centimeters in diameter (Figure 2). They may occur anywhere on the skin and usually last between 12 and 24 h. In angioedema the edema extends subcutaneouslv or submucosally and swellings are larger, usually nor itchy and may last up to 72 h. It most commonly affects the eyelids, lips and tongue, but any part of the body may be affected. Urticaria and angioedema occur together in nearly 50% of patients and both fade, leaving completely normal skin. There are many causes of urticaria (Table 3) but the end-result is a release of mediators that cause increased permeability of capillaries and small venules.

Urticaria is traditionally divided into acute and chronic forms (Table 4). Acute urticaria may be idiopathic, IgE mediated, or result from nonimmunolo-gically mediated reactions. The latter may be anaphylactoid reactions, or be due to direct mast cell activation or to altered arachidonic acid or kinin metabolism.

Chronic urticaria is arbitrarily defined as the occurrence of widespread wheals daily, or almost daily, for at least 6 weeks. It is idiopathic in approxi-

Figure 1 Acute urticaria with marked erythema and whealing. (See also color Plate 7A.)

Figure 2 Urticaria showing central clearing and an annular pattern. (See also color Plate 7B.)

matcly 75% of patients, and caused by physical stimuli in a further 15% of patients. In the past, it was suggested that up to 30% of patients with chronic urticaria reacted to food additives such as benzoic acid compounds, azo dyes and penicillins; more recently, in a placebo-controlled oral challenge study, Kobza Black and colleagues found an incidence of no more than 10%. Such reactions may be more common in children and, if the history is suggestive, appropriate challenge testing is justified. Other exacerbating factors include aspirin (in 30%), psychological stress, intercurrent febrile illness and, more rarely, parasitic infestations. Urticarial vasculitis is an important differential diagnosis and, if suspected, a skin biopsy should be performed. A prolonged history of repeated cutaneous or mucosal angioedema should prompt screening for hereditary or acquired CI esterase deficiency by measuring plasma complement C4 levels.

Nonsedating H, antihistamines are the mainstay of treatment in urticaria. A number of drugs are available, namely terfenadine, cetirizine, astemizole, acrivastine and loratidine. Terfenadine and astemizole are extensively metabolized by cytochrome P450 and can produce elongation of the Q-T interval and arrhythmias in susceptible patients. In view of this, recommended doses should not be exceeded and they should never be prescribed together or in conjunction

Table 3 Classification of urticarias according to underlying mechanism

Immunologic IgE mediated

Foods: fish, shellfish, milk, eggs, nuts, fruit, vegetables, spices

Drugs: penicillin, porcine insulin, dextran Insect stings: bees, wasps, hornets, yellow jackets Inhalants: pollens, animal dander Contactants: latex

Physical: dermographism, cold, solar, cholinergic IgG autoantibodies to high-affinity IgE receptor or IgE or both

Immune complex/anaphylatoxin-mediated Urticarial vasculitis SLE, Sjögrens syndrome, hepatitis B or C, serum sickness, drugs, IgM gammopathy Blood products Radiocontrast media Haptens penicillins, cephalosporins, sulphonamides, tetracyclines, macrolides Non-immunologic Direct mast cell activators Opiates, tubocurarine, radiocontrast media, dextran, polymyxin Arachidonic acid metabolism

Aspirin, non steroidal anti-inflammatory drugs (NSAIDs) Kinin metabolism Angiotensin converting enzyme (ACE) inhibitors Idiopathic Miscellaneous Physical: heat, vibratory, delayed pressure, aquagenic Thyroid autoimmunity

Table 4 Classification of urticarias

Acute Idiopathic IgE mediated: Immediate wheal and flare prick test response Insect stings, penicillin, Transfusion of blood or blood products Fish, shellfish, milk, nuts, vegetables, fruit, spices Nonimmunologically mediated: Aspirin, NSAIDs, paracetamol, radiocontrast media, dextran, food dyes, preservatives, morphine, codeine, tubocurarine Chronic Idiopathic

IgG autoantibodies to high-affinity IgE receptor or IgE or both Contact urticaria Immunologic Nonimmunologic Physical urticaria Dermographism, delayed pressure urticaria, cholinergic urticaria, cold urticaria, aquagenic urticaria, solar urticaria Urticarial vasculitis with drugs such as cyclosporine, erythromycin or ketoconazole. With astemizole adequate contraception is essential during treatment and for up to 4 weeks afterwards. Older, more sedating H, antihistamines, such as chlorpheniramine or hydroxyzine, can be used concurrently and may be useful to alleviate pruritus at night. If one particular compound is not effective, others should be tried sequentially as there is a wide variation in response between patients. There is also a variability of response to different antihistamines over time, largely as a result of tachyphylaxis, and breaks from or changes in treatment may be beneficial. The role of H2 antihistamines is controversial. There is some evidence that in combination with H, antihistamines they are of benefit in some patients with symptomatic dermographism and chronic idiopathic urticaria. Ranitidine is the drug of choice as it does not inhibit cytochrome P450 or seem to have the pronounced antiandrogenic effects of cimetidine with long-term use.

Immediate wheal and flare prick test responses

Prick testing involves the application of commercially prepared diluted antigens as single drops on marked areas of skin on the forearm. The skin is gently pricked through the drop and the drop is then removed with a tissue wipe. The wheal starts within 10 min, reaches a peak within 20-30 min and resolves in 1-2 h. It depends upon the reaction and cross-linking of antigens with specific IgE antibody bound through its Fc to mast cells and basophils. Rarely, prick tests may precipitate a systemic anaphylactic reaction.

Insect bites and stings

Allergic reactions to insect stings may occur as extensive localized swelling (>10 cm in diameter) lasting at least 24 h, immediate IgE-mediated systemic reactions (urticaria, angioedema, bronchospasm and anaphylactic shock) or more rarely as delayed systemic reactions (vasculitis, polyradiculitis, glomerulonephritis). The prevalence of such reactions varies from 3.1-17% for extensive localized to 0.15-3.3% for systemic reactions. The diagnosis is suggested by the history and the Hymenoptera most often implicated include Apidae (the honeybee and bumblebee), Vespidae (wasps, hornets and yellow jackets) and Myrmicidae (stinging ants). The major allergens in venom are different forms of phospholipase A. In addition, bee venom contains enzymes (acid phosphatase and hyaluronidase), mediators (dopamine and norepinephrine) and peptide 401, which causes mast cell degranulation. Similar toxins are present in wasp venoms. The most sensitive techniques for determining the presence of venom-specific IgE antibody (i.e. sensitization) are the radioallergosorbent test (RAST) and skin testing with venoms. Such tests are positive in 15-25% of the general population, presumably reflecting normal IgE responses to insect stings in nonallergic subjects. A positive RAST does not discriminate between those patients who develop a local rather than a systemic anaphylactic reaction, and up to 2% of patients with anaphylactic reactions may have negative tests. A majority of patients with large local reactions will continue to have localized reactions regard less of their IgE status, although 5-10% of adults and 2% of children may have systemic reactions following a subsequent sting. The risk of systemic reactions on re-sting in patients with a previous systemic reaction is 29% and is usually of similar severity to the previous systemic reaction in adults and similar or less severe in children. Systemic reactions are more likely to be severe following bee stings (which contain a larger dose of venom than wasp stings), or if re-sting occurs >2-3 weeks and <10 years after a previous sting. Immunization with venom is a safe, extremely effective treatment for preventing future systemic reactions and the aim of such immunization is to increase venom-specific IgG levels and to produce negative skin tests and RAST. Such treatment is mandatory in patients with a history of severe systemic reactions and can be undertaken for milder systemic reactions in adults and children if appropriate. It is not recommended for large local reactions which respond to treatment with nonsedating H, antihistamines. In the event of a severe systemic reaction, treatment should be with epinephrine and antihistamines, as for systemic anaphylaxis (see below).

Contact urticaria

This is a localized wheal and flare response, usually occurring within minutes and provoked by the application of a wide range of rapidly absorbable agents to the skin, lips and buccal mucosa. Contact urticaria may occur through immunologic or nonimmuno-logic mechanisms.

Immunologic contact urticaria Immunologic contact urticaria is distinguishable by its ability to involve other organ systems and its increased prevalence in atopic individuals. It is due to a type I IgE-mediated hypersensitivity and so patients have positive RAST and skin prick tests to the contactant allergen, most of which are proteins or protein complexes. As systemic reactions can occur with skin prick testing in such patients, other tests are often undertaken: casual handling of the suspected provoking agent in exactly the same way as when the symptoms appear and open or occlusive patch testing

(in which the substance is applied to uninvolved skin for 15 minutes either with or without occlusion).

Foods Foodstuffs are common causes, and this type of reaction is common in food handlers who may present with a true contact urticaria or recalcitrant hand eczema (with immediate exacerbations when affected skin is exposed to the responsible food proteins). Common allergens include wheat flour, chicken, turkey, lamb, fish, shellfish, garlic, onions, chives, cucumber, horseradish, leek, parsley, tomato, lettuce, endive, apple and potato.

Some patients experience itching, tingling and/or edema of the lips and tongue and hoarseness, occasionally progressing to systemic symptoms following contact of fruit and vegetables, particularly apple, carrot, parsnip and potato, with the orolaryn-geal area. This is particularly common in atopics with hypersensitivity to birch pollen and, in such cases, is thought to be due to cross-reactivity of polypeptide fruit and vegetable allergens with birch allergens.

Latex Although the predominant immunologic response (in 82% of cases) to natural rubber latex is a type IV delayed hypersensitivity to rubber additives which presents as contact dermatitis, IgE-mediated immunologic contact urticaria and anaphylactic reactions are well recognized. IgE antibody to residual rubber tree proteins in latex medical devices are present in 7-10% of nonatopic health care workers. Sensitization usually occurs as a result of regular latex exposure from wearing gloves or inhaling aerosolized latex in the workplace. In children with spina bifida the prevalence ranges from 28 to 67%, presumably as a result of mucosal absorption of latex allergens during multiple surgical procedures early in life. Exposure to latex gloves during surgery, gynecologic examination or dental procedures, and in men use of latex condoms, have also been implicated. Re-exposure of such individuals may lead to contact urticaria and/or systemic reactions such as allergic rhinoconjunctivitis, asthma or anaphylactic shock. Diagnosis is made on positive RAST or skin prick testing, however the latter appears to have an increased risk of anaphylactic reactions and should be performed with very dilute (1:1 million) doses of commercially available extracts. Treatment is by avoidance of latex-containing materials and, in particular, the complete removal of powdered latex gloves from the environment; this dramatically reduces the amount of aerosolized latex particles.

Many other agents are capable of producing immunologically mediated contact urticaria, including drugs; (particularly antibiotics, e.g. penicillin, cephalosporins, neomycin, chloramphenicol), metals (e.g. nickel), animal hair and dander, textiles and cosmetics.

Nonimmunologic contact urticaria This type of contact urticaria is much more common than the immunologic variety. Its mechanisms arc less well understood, although direct effects on vascular endothelium or non-antibody-mediated release of prostaglandins, leukotrienes and other inflammatory mediators have been suggested. Prior sensitization is not required. Common précipitants include salicylates, parabens, sulfites, benzoic acid, sorbic acid, cinnamic acid, cinnamic aldehyde and nicotinic acid esters present in foods, such as ice cream and chewing gum, shampoos, perfumes, mouthwashes, creams and ointments. Plants such as nettles, primula and seaweed, as well as moths, caterpillars, sea anemones, corals and jellyfish may also be responsible. Symptoms remain localized and include burning, stinging, itching, edema and erythema. Skin prick testing results often do not correlate with clinical findings and should be considered in conjunction with the history. Oral challenge testing is not performed routinely, but can be done on a placebo-controlled basis if the history is suggestive. It should not be undertaken in patients with a history of severe angioedema, asthma or systemic anaphylaxis. Sixteen different food additives, alternating with placebo, are administered on a daily basis. The patient keeps a daily diary of wheal counts and continues the usual dose of antihistamine if this has already been prescribed. If an exacerbation of urticaria occurs within 24 h of the ingestion of a numbered capsule, the potential culprit is administered once more to confirm the findings.

Chronic idiopathic urticaria

Up to 75% of patients seen with urticaria in dermatology clinics have chronic idiopathic urticaria, lasting more than 6 weeks. Clinically it resembles acute urticaria, usually occurs in adults and is twice as common in women. It frequently follows a relapsing-remitting course and up to 40% of patients who have chronic urticaria for over 6 months still have lesions 10 years later. It frequently occurs in association with physical urticarias, particularly symptomatic dermographism and delayed pressure urticaria. Appropriate challenge testing should be performed in such patients to assess the predominant cause of their symptoms. Autoimmune thyroid disease occurs in 14% of patients and rccent studies have suggested an autoimmune basis for chronic idiopathic urticaria. In up to 60% of patients an endogenous hista-mine-releasing factor has been identified. IgC auto-

antibodies causing mast cell degranulation have been found in nearly half of these patients: anti-IgE, anti-FceRIa (directed against the a subunit of the high-affinity IgE receptor expressed by basophils and mast cells) and a further antibody thought to interact with FceRI bur not FceRIa. These findings have therapeutic implications and in patients with autoantibodies and severe disease unresponsive to conventional therapy, plasmapheresis, intravenous immunoglobulin and cyclosporine have induced remissions. Nonsedating H, antihistamines remain the first-line treatment. Sedating antihistamines may be added if symptoms are troublesome at night. Doxepin (10 mg three times daily or 25 mg at night), which, in addition to its tricyclic antidepressant activity, is a potent H, antagonist, a weak H2 antagonist and a weak muscarinic agonist, is useful in patients with associated anxiety or depression. Doxepin should not be given with monoamine oxidase inhibitors or terfenadine. The addition of H2 antihistamines to H, antihistamines can produce additional benefit in some patients. Patients should avoid aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) and angiotensin-converting enzyme inhibitors, which may all aggravate symptoms. A salicy-late-free diet may be of benefit and a 4 week trial of a strict exclusion diet can be performed to assess this.

Urticarial vasculitis

This disorder presents clinically as urticaria but histopathologically the features are those of a cutaneous leukocytoclastic vasculitis of variable degree. It may be impossible, clinically, to differentiate ordinary urticaria from urticarial vasculitis but important pointers include a longer duration of lesions (up to 3-7 days), a burning or painful sensation at the site of lesions and the fact that lesions may resolve with residual purpura, bruising or scaling. Frankly vasculitic or bullous lesions may rarely occur. In addition, there may be evidence of a systemic vasculitis with fever, arthralgia and more rarely arthritis, glomerulonephritis, obstructive pulmonary disease or gastrointestinal, ophthalmic or central nervous system involvement. Many patients are hypocomplementemic and in some an IgG autoantibody to Clq has been demonstrated. In others, the pathogenesis is that of an immune-complex vasculitis resembling a type III hypersensitivity. The antigen involved is unknown in most cases, although patients with serum sickness, the collagen-vascular diseases systemic lupus erythematosus and Sjögrens syndrome, and infections such as hepatitis B and infectious mononucleosis may present with this clinical picture. Treatment with H, antihistamines alone or in combination with H2 antihistamines is only rarely of benefit. Additional therapy with dap-sonc, hydroxychloroquine, sulfasalazine, NSAIDs, systemic corticosteroids or azathioprine may be required.

Physical urticaria

In the physical urticarias, specific physical stimuli trigger mast cell degranulation, with the release of mediators. In some cases there is evidence of a passively transferable reactivity which is thought to involve IgE, or more rarely, IgM or IgA, recognizing a molecule released or conformational!}' altered b\ the physical stimulus. Often more than one type coexists in the same patient, suggesting abnormal tolerance of self antigens.

Dermographism Simple dermographism is a transi ent erythematous and whealing response which develops in 5% of the population after application of only a moderate pressure to the skin. It appears to represent a combined effect of pressure and shearing forces on the skin and is therefore an exaggerated triple response of Lewis. In symptomatic dermographism, the threshold to induce dermographism is lowered and there is marked pruritus (Figure 3). Lesions may be precipitated by the pressure caused by the elastic in underwear or from shower jets. Symptomatic dermographism is more common in young adults (mean age of onset 26 years) and is not associated with atopy. The diagnosis can be confirmed using a calibrated dermographometer. It may last for months or indefinitely. Treatment with the nonsedative H, antihistamines usually provides good symptomatic relief, cetirizine and astemizoie being the most effective. Addition of an H2 antihistamine may be of benefit in this group.

Delayed pressure urticaria This type of urticaria often occurs in association with chronic idiopathic

Figure 3 Symptomatic dermographism, marked linear whealing has occurred at sites of scratching. (See also color Plate 7C.)

urticaria. There is erythema, dermal and subcutaneous edema developing 4-6 hours after application of sustained pressure perpendicular to the skin. Lesions occur after activities such as climbing ladders, walking or sitting on a hard surface, carrying heavy items, wearing tight-fitting clothes, using a screwdriver or hammer or after kissing or sexual intercourse. Maximum swelling occurs after 10 h and the lesions may last up to 48 h. Patients often complain of itching and a painful or burning sensation in the lesions; generalized symptoms of malaise, fever, headache or generalized arthralgia occur in about 70% of patients. The diagnosis is confirmed using a calibrated dermographometer. Cetirizine (10 mg daily) is now the treatment of choice. It is the only FL antihistamine of any proven value, presumably because it also inhibits eosinophil and neutrophil chemotaxis. Stanazolol (2.5 mg daily) and dapsone (50-100 mg daily) are of benefit in some patients, although their mechanisms of action are unclear.

Cholinergic urticaria This urticarial eruption occurs in situations where there is activation of cholinergic sympathetic autonomic nerve fibers supplying eccrine sweat glands, after exercising or hot baths, or during periods of mental stress or anxiety. The itchy lesions are 2-5 mm diameter monomorphic wheals surrounded by a bright red flare which lasts no more than 20 min to 1 h. In some cases angio-edema, flushing, faintness, bronchospasm or hypotension may occur. Cholinergic urticaria may be induced by intradermal injections of acetylcholine and can be abolished by local anesthetics and topical applications of atropine. The exact pathogenesis is unknown. The diagnosis is confirmed by reproduction of the eruption by exercising sufficiently to cause sweating or by immersion in bath water at 42°C for 10-15 min. Treatment with nonsedating H, antihistamines, either continuously or before an activity known to precipitate urticaria, is recommended. Danazol has also been reported to be effective. It raises protease inhibitor levels and clinical improvement can persist for several months after cessation of treatment. The condition may last for months or years and then spontaneously resolve.

Cold urticaria This urticaria develops after exposure of the skin to cold and may be idiopathic or secondary to serologic abnormalities. The majority of patients with the idiopathic form (over 90%) have the primary acquired form of cold urticaria.

A. Idiopathic cold urticaria

Primary acquired cold urticaria This occurs 5-30 min after exposure to cold and may be precipitated by wind, cold bathing, handling cold objects, immersion of the hands in cold water, and drinking cold foods or drinks. The urticaria may develop during the period of exposure but more often develops during rewarming. It lasts for about .30 min and resolves, to leave normal appearing skin. In up to 50% of patients systemic symptoms may occur, characterized by syncope, headache, palpitations and wheezing. Loss of consciousness and drowning may occur during swimming. The diagnosis can be confirmed by the induction of lesions by the application of a polythene-wrapped ice cube to the skin for 5-10 min with a 5 min period allowed for rewarming.

Rarer forms of primary acquired cold urticaria: 1) delayed cold urticaria - lesions occur several hours after exposure; 2) localized cold urticaria - lesions occur at sites of injections and bites; 3) reflex cold urticaria - widespread whealing occurs in response to a fall in core temperature.

Familial cold urticaria This is rare and is inherited as an autosomal dominant condition. It starts at an early age and is a lifelong problem. Urticaria develops 30 min after patients arc exposed to generalized cooling rather than local cold application, and lesions may persist for up to 48 h.

B. Secondary cold urticaria This type accounts for about 5% of all patients with cold urticaria and may occur in association with cryoglobulinemia, cryofibri-nogenemia and cold hemolysins. Other triggering factors such as viral infection, syphilis, infestations or allergies to drugs, such as penicillin, oral contraceptives and griseofulvin, can sometimes be identified.

The pathophysiology of cold urticaria is unclear but between 10 and 50% of patients with primary acquired cold urticaria demonstrate the phenomenon of passive transfer by a serum factor which may be either IgE or IgM. The mainstay of treatment is the avoidance of precipitating factors, but nonsedating H, antihistamines may be required. Ketotifen (2-4 mg daily), which is both an H, antihistamine and a mast cell stabilizer, and doxepin (10-25 mg three times daily) are both effective. Finally, induction of cold tolerance by repeated cold exposure may be attempted but this usually involves taking one or two cold showers or baths a day and requires that patients be strongly motivated.

Aquagenic urticaria Contact with water, irrespective of its temperature, may induce an urticarial eruption which looks very similar to cholinergic urticaria. The lesions are frequently confined to the neck, arms and upper trunk, develop within 5-30 min of exposure to water and resolve over the next hour. The condition is partly responsive to antihistamine therapy with terfenadine, cetirizine or loratidine (10 mg daily) and barrier preparations may be used for aquatic sports.

Solar urticaria This is an uncommon condition in which urticaria develops within 2-3 min of sun exposure and then fades within an hour or so. It occurs particularly in areas of exposed skin which are usually kept covered. All parts of the ultraviolet light spectrum may induce solar urticaria. Passive and reverse passive transfer tests have been demonstrated in such patients. A precursor is converted to an antigenic photoproduct which triggers an IgE-mediated response and the diagnosis is confirmed by monochromator or solar stimulator testing. Treatment is often disappointing as only in the mildest cases are sunscreens beneficial, and, with the exception of astemizole (a highly specific H, antagonist) antihistamine therapy is usually ineffective. Tolerance may be induced by the appropriate ultraviolet source and, as the condition is due to a circulating photoallergen, plasmapheresis can be used in severely affected patients during the desensitization phase. In combination, PUVA (psoralens and ultraviolet B) and plasmapheresis produce a more prolonged improvement than if used alone.

Hereditary angioedema

This is a rare disorder, inherited as an autosomal dominant trait in which there is a deficiency in the activity of CI esterase inhibitor, resulting in continued complement activation. There is usually a family history, although not invariably, and it usually presents in early childhood but may be delayed until late adult life. Patients present with nonitchy and sometimes painful swellings on the limbs or face, attacks of abdominal pain, vomiting and diarrhoea (which may be blood stained). The most serious manifestations are edema of the larynx, pharynx, trachea and bronchi, leading to respiratory obstruction and asphyxia in up to 30% of patients. Hypotension and urticaria are usually absent, helping to distinguish such attacks from acute, generalized anaphylaxis. Attacks may be precipitated by trauma, stress, infections or cold and usually last between 48 and 72 h, although lesions may not resolve for days or even weeks.

The diagnosis can be confirmed by the finding of low C4 and C2 levels in all patients. In type I heredi tary angioedema, which accounts for 85% of patients, low functional and antigenic levels (5-31% of normal) of the CI esterase inhibitor occur, due to decreased synthesis and increased metabolism. In the remaining 15% of patients, as a result of point mutations in the reactive center, the functional level is low but the antigenic level is within normal limits.

The treatment of choice in an acute attack is with intravenous purified CI esterase inhibitor (24 000-36 000 units). If this is unavailable, fresh frozen plasma may be used, although, because this contains more C4 and C2, patients may initially deteriorate before they improve. In the presence of laryngeal edema, epinephrine, oxygen, Hj antagonists and corticosteroids are also recommended (see treatment of anaphylaxis below). For prevention of recurrent attacks danazol (100^100 mg daily for 1 month, then 5 days on, 5 days off) or stanazolol (2.5-10 mg daily to control attacks then 2.5 mg three times a week), which increase hepatic synthesis of C1 esterase inhibitor, tranexamic acid (1-3 g daily), which carries a risk of thromboembolism, or epsilon amino-caproic acid may be prescribed. Patients should avoid taking angiotensin-converting enzyme inhibitors which alter kinin metabolism.

Acquired form of hereditary angioedema

In the nonhereditary form of angioedema, deficiency of the CI esterase inhibitor occurs either as an autoimmune process in systemic lupus erythematosus or in association with hematological malignancies such as lymphoma or myeloma. In the autoimmune variety, anti-Cl esterase inhibitor antibodies predispose it to cleavage. In lymphoproliferative disease there is a 2-3-fold increase in CI esterase inhibitor metabolism, possibly as a result of continuous activation of CI by anti-idiotype antibodies directed against surface immunoglobulin on the malignant B cells, leading to CI esterase inhibitor-complex formation and removal. Characteristically, in the acquired disease CI levels are very low, whereas in the hereditary form CI levels are normal. Treatment is aimed at the underlying cause.

Treatment of anaphylaxis

The first-line treatment of systemic reactions, which may include bronchospasm, hypotension and angioedema, is an intramuscular injection of epinephrine in a dose of 10 /Agkg"1 up to 1 mg (1 ml of 1:1000 solution), which may need to be repeated every 10 min until improvement occurs. Epinephrine acts as a positive inotrope, blocks the end-organ effects of histamine, and inhibits release of histamine and leukotrienes from mast cells. Administration of high-dose oxygen is also of primary importance. Additional second-line treatment consists of H, antagonists, initially intravenously (chlorpheniramine 10-20 mg) and then orally (e.g. cetirizine 10 mg once daily or terfenadine 60 mg twice daily) for 24—48 h to prevent relapse, and corticosteroids (intravenous hydrocortisone 100-300 mg or 5 mg kg '), which may help suppress the late-phase and persistent responses. Continuing deterioration may necessitate treatment with bronchodilators, either nebulized or intravenous f32 agonists (nebulized salbutamol 2.5-5 mg four times daily, intravenous salbutamol 3-20 fig min"1) or intravenous aminophylline infused slowly over 10-15 min (up to a total dose of 500 mg or 4mgkg '). Occasionally, slow intravenous infusion of low dose adrenaline (5 ml of 1:10000 adrenaline at a rate of 1 ml = 100 ¡jig min-1 until improvement occurs) is required. Fluid replacement with colloids such as hemaccel, monitoring of central venous pressure (CVP) and/or pulmonary capillary wedge pressure (PCWP) and in the presence of a raised CVP or PCWP, inotropic support with dopamine (5 jug kg 1 min"') and occasionally norepinephrine may be necessary. The use of H2 antagonists is controversial, but it has been suggested that in combination with H| antagonists these agents suppress late-phase cutaneous responses.

For patients with previous or recurrent anaphylactic reactions, for example to bee stings, emergency self-treatment kits are available (e.g. Epipen which contains 300 jug epinephrine in a fully assembled syringe) and patients should be taught to give their own injections. Epinephrine inhalations (e.g. Medi-haler-Epi which contains 280 /i.g per metered inhalation - adults should take a minimum of 20 puffs) are much less effective but may be useful in patients without other symptoms who are beginning to develop bronchospasm or edema in the orolaryn-geal area.

See also: Allergens; Anaphylatoxins; Arachidonic acid and the leukotrienes; Atopic allergy; Autoanti-gens; Autoimmune disease, pathogenesis; Autoimmune diseases; Basophils; Blood transfusion reactions; Complement deficiencies; Contact hypersensitivity; Drugs, allergy to; Eczema; Eosinophil chemotactic factors; Exercise and the immune response; Food allergy; Granulocyte-macrophage colony stimulating factor (GM-CSF); Histamine; Hypersensitivity reactions; IgE; Interleukin 3; Interleukin 4; Interleukin 5 and its receptor; Interleukin 6; Kallikrein-Kinin system; Mast cells; Platelet-activating factor (PAF); Prostaglandins; Serum sickness; Venoms.

Further reading

Champion RH, Greaves MW, Black AK and Pye RJ (eds) (1985) The Urticarias. Edinburgh: Churchill Livingstone.

Charpin D, Birnbaum J and Vervloet D (1994) Epidemiology of hymenoptera allergy. Clinical and Experimental Allergy 24: 1010-1015. Greaves MW (1995) Chronic urticaria. New E.ngland

Journal of Medicine 332: 1767-1772. Harvell J, Bason M and Maibach H (1994) Contact urticaria and its mechanisms. Food and Chemical Toxicology 322: 103-112. Hide M, Francis DM, Grattan CEH, Barr RM, Winkleman RK and Greaves MW (1994) The pathogenesis of chronic idiopathic urticaria: new evidence suggests an auto-immune basis and implications for treatment. Clinical and Experimental Allergy 24: 624-627. Holgate ST and Church MK (eds) (1993) Allergy. London: Gower.

Kobza Black A, Greaves MW, Champion RH and Pye RJ (1991) The urticarias 1990. British Journal of Dermatology 124: 100-108. Muller U and Mosbech H (1993) Position paper: Immunotherapy with hymenoptera venoms. Allergy 48: 37-46. Ormerod AD (1994) Urticaria, recognition, causes and treatment. Drugs 485: 717-730. Simons FER and Simons KJ (1994) The pharmacology and use of H, receptor-antagonist drugs. New Fingland Journal of Medicine 33023: 1663-1670. Sussman GL and Beezhold DH (1995) Allergy to latex rubber. Annals of Internal Medicine 122: 43—46.

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