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angioedema
Chronic recurrent urticaria/angioedema
P. McHenry
Urticaria is a common condition which affects all age groups. Up to 20% of the population will have at least one episode. The majority of cases in children are acute lasting from hours to a few weeks but a small proportion have recurrent or chronic urticaria which has been arbitrarily defined as urticaria lasting longer than 6-8 weeks. 1 Infections, particularly acute viral infections, are the most commonly recognised cause of acute urticaria in children. In approximately 70% of patients with chronic recurrent urticaria no cause is identified.
Fig. 2~Angioedema.
Clinical manifestations Clinically urticaria is characterised by the development of red itchy hives or wheals (Fig. 1). The appearance results from localised capillary vasodilatation, followed by transudation of protein rich fluid into the surrounding tissue. The wheals resolve when the fluid is reabsorbed, usually within 24 h. As individual lesions are fading new ones may be developing. When there is massive transudation of fluid into the dermis and the subcutaneous or submucosal tissue, this is referred to as angioedema. Angioedema may be evident on the skin as deep oedematous swellings which
Fig. 1-Urticaria: characterised by the development of red, itchy hives or wheals.
Pamela MeHenry, Consultant Dermatologist, department of Dermatology, Western Infirmary, Glasgow G11 6NT. Correspondence and requests for offprints to PM.
Current Paediatrics (1995)5, 258-261 © 1995PearsonProfessionalLtd
258
CHRONIC RECURRENT URTICARIA/ANGIOEDEMA 259
may persist for several days. It commonly involves the eyelids (Fig. 2) lips, larynx and gastrointestinal tract. Itching is usually absent and the main symptoms are of burning or pain. Symptoms due to systemic involvement include hoarseness, dysphagia, shortness of breath, wheezing, nausea, vomiting, abdominal pain, and diarrhoea. If symptoms of dyspnoea or dysphagia have not occurred within the first few hours of any one urticarial episode, they are not likely to develop subsequently during the course of that attack. Urticaria and angioedema commonly occur together and may show a familial tendency which is distinct from the hereditary angioedema due to C1 esterase inhibitor deficiency. In a study of 554 patients, 50% experienced both urticaria and angioedema, 40% only urticaria and 10% only angioedema. 2 Patients with urticaria alone are more likely to undergo spontaneous resolution than those with urticaria and angioedema.
Pathogenesis It is a common misconception that urticaria results solely from an allergic process. Many factors both immunological and non immunological may result in mast cell degranulation (Table 1). 3 Mast cell degranulation releases a number of vasoactive substances which include histamine, kinins, serotonin, leukotrienes and prostaglandins. Release of these mediators causes vasodilatation and enhances permeability of the capillaries. Some conditions such as stress, infection and body temperature may influence the ease with which mast cells degranulate.
Chronic idiopathic urticaria/angioedema The role of IgE mediated allergy and in particular the role of food allergies in chronic idiopathic urticaria/angioedema is unclear.4 The type 1 IgE mediated reaction
seems to be more important for the development of acute urticarias in which the allergens such as foods, drugs, or infectious agents are often easily identified. Penicillin and related antibiotics are common causes of acute urticaria and at one time it was considered that small amounts of penicillin contaminating foods such as dairy products were the cause of some cases of chronic urticaria. Nowadays the amount of penicillin in milk is negligible and it seems unlikely that this could cause chronic urticaria. Studies have shown that patients with chronic urticaria do not have an increased incidence of atopy and total serum IgE levels are generally normal. In chronic urticaria a number of factors may contribute to the development of urticaria but these may not be the main cause. Salicylates, azo dyes, benzoates and yeasts can increase the urticarial tendency and give rise to exacerbations. Recent studies in adults with chronic urticaria have identified a functional IgG autoantibody against the high affinity IgE receptor in the sermn of at least a third of patients with chronic idiopathic urticaria. 5
Physical urticarias Unrecognised physical urticarias account for about 10% of all cases of chronic urticaria. Physical urticarias may be produced by stroking the skin, by exercise, heat, cold, water, vibration, solar radiation or pressure. A helpful distinguishing feature is that, with the exception of pressure urticaria, attacks are brief, lasting only 30-60 min, compared to the non-physical urticaria in which the eruption may last from a few hours to several days. In children, the more common types of physical urticarias include dermographism, cholinergic urticaria and less frequently cold urticaria and pressure urticaria. 'skin writing': Linear itchy wheals develop at the site of scratching or friction from clothing. It may be preceded by infection, or antibiotic therapy but
Dermographism
Table 1 Typesof urticaria Idiopathic 70% cases of chronic urticaria/angioedemaare idiopathic. Immunological IgE- dependent mast cell degranulation
l. Specificantigen sensitivity:Usuallymanifestsas acute urticaria and the cause is often identifiablefrom the history.Typical allergens include some foods e.g. eggs, shellfish,strawberries,drugs e.g. penicillin,infectionse.g. helminth infestation.Atopic patients have an increasedincidenceof type 1 reactionsbut they also occur in non atopic individuals. 2. Physicalurticaria - Cholinergic,dermographism,pressure,vibration, cold, heat, solar. Complement mediated
Hereditary angioedema(C1 esteraseinhibitor deficiency) Type 1 (85%)C1 inhibitor absent Type2 (15%) C 1 inhibitor not functional. Acquired angioedema(functionalabnormality of C1 inhibitor in malignancyand autoimmune disease) Reaction to blood products, serum sickness. Non immunological Histamine releasing agents
Opiates, antibiotics,radiocontrast media, curare. Agents which alter arachidonic metabolism
Azo dyes,benzoates, salicylates.
260 CURRENTPAEDIATRICS in most cases there is no obvious cause. Treatment is not necessary unless the patient is extremely sensitive, and in these patients low dose non-sedating antihistamines usually provide adequate relief. Cold urticaria: This may be acquired or rarely is transmitted as an autosomal dominant trait. It is particularly likely to occur in children and young women. Like dermographism, cold urticaria may begin after infection, or drug therapy. Usually it is an IgE mediated response, but occasionally cryoproteins may be present in association with a connective tissue disease. The diagnosis of cold urticaria may be confirmed by inducing a wheal by the application of an ice cube against the skin. Anaphylactic reactions, particularly during swimming, may occur in those with acquired cold urticaria. Cholinergic urticaria: This occurs typically in adolescents. It has a very distinct clinical pattern. Small itchy papules 2-4 mm in diameter develop in response to an increase in body heat usually after exercising. Antihistamines taken before exercise may be of benefit in some cases. Pressure urticaria: This is uncommon in children. A deep itchy burning or painful swelling occurring 4-6 h after a pressure stimulus and lasting 8-72 h is characteristic. Antihistamines are not helpful and systemic steroids may be required if the disease is disabling. The vast majority of patients with treatment resistant chronic idiopathic urticaria probably have a component of pressure urticaria.
Hereditary angioedema Hereditary angioedema accounts for about 2% of all cases of angioedema. It is inherited as an autosomal dominant trait and is manifested by episodic bouts of subcutaneous and mucosal swelling. The erythematous lesions which accompany the angioedema are fiat reticulate patches rather than conventional urticarial wheals. The disease is due to low levels of functioning C1 esterase inhibitor. The disease usually becomes evident in late childhood or early adolescence. Angioedema can occur alone or with other systemic symptoms such as respiratory distress and hypotension. Abdominal pain is a prominent feature. Glottal oedema leading to laryngeal obstruction is a potentially fatal complication of hereditary angioedema. For acute life threatening attacks, purified C1 inhibitor concentrate or fresh frozen plasma are required. It is not responsive to steroids, adrenaline or antihistamines. Danazol and stanozolol increase serum levels of C1 inhibitor and may be used for short term and long term prophylaxis. Long term prophylaxis may cause androgenic problems in children.
reaction to bites from insects such as fleas and mites. They are often located on the lower extremities of children. The lesions are more persistent than ordinary urticaria. 3. Urticaria pigmentosa/mastocytosis: This condition is not uncommon in children and is due to collections of mast cells in the skin which appear as pigmented macules and papules which urticate when rubbed. These lesions tend to improve with time. 4. Erythema multiforme: Erythema multiforme may be urticarial in appearance but it characteristically has a marked acral distribution and classic cases have target lesions. In addition individual lesions are more persistent than those of urticaria. 5. Urticarial vasculitis: This is uncommon in children and the diagnosis is usually suggested from the history. Individual lesions may persist for 24-72 h and usually leave residual changes of purpura, scaling and hyperpigmentation. The lesions are burning and painful rather than itchy. The diagnosis is confirmed by a skin biopsy.
Investigations A thorough history and examination is most important in the evaluation of patients with chronic urticaria/angioedema. The type of urticaria can usually be diagnosed from a thorough history. When physical urticarias are suspected these can be confirmed by simple tests such as application of an ice cube to the skin to confirm cold urticaria, asking the patient to exercise to produce cholinergic urticaria or simply by a brisk stroke on the skin to produce the linear urticaria of dermographism. Routine laboratory tests are of minimal value in patients with chronic idiopathic urticaria and the yield is low unless there is some lead from the history. In unremitting urticaria, a full blood count, ESR and urinalysis may be appropriate. 6 An elevated ESR is suggestive of complement associated reactions. The role of foods and the question as to whether oral challenge tests are useful in urticaria remains unresolved.7,s It may be useful to ask the patient to keep a food diary, and a diet avoiding food additives may be undertaken for 3-4 weeks. There is no indication for routinely carrying out investigations such as skin tests; total IgE; RASTs; connective tissue screens, thyroid function tests or a skin biopsy. Similarly, investigations for infections, focal sepsis and intestinal parasites are considered to give such a low yield of clinically useful results that their routine use is not recommended.6
Treatment Differential diagnosis of urticaria 1. Scabies: Scabies may present with an urticarial eruption and can cause dermographism. 2. Insect bites: Papular urticaria is a hypersensitivity
In the absence of specific reliable antagonists of the other vasoactive mediators released following mast cell degranulation, antihistamines remain the mainstay in the management of urticaria/angioedema.
CHRONIC RECURRENT URTICARIA/ANGIOEDEMA 261
Antihistamines do n o t block the release o f histamine but compete with histamine for the same receptor site. Sometimes combinations o f antihistamines are m o r e effective than a single agent. The newer antihistamines such as terfenadine (triludan), astemizole (hismanal), loratadine (clarityn), acrivastine (semprex) and cetirizine (zirtek) penetrate poorly across the b l o o d brain barrier and thereby cause less sedation than the older antihistamines. T h e y are similar in p o t e n c y but differ in dosage schedules, onset and duration o f action, side effects a n d interactions. Tachyarrhythmias with prolongation o f the Q - T interval have been reported when terfenadine or astemizole have been given in doses above those r e c o m m e n d e d or the antihistamine was taken in conjunction with a macrolide antibiotic such as erythromycin or oral imidazole antifungal preparations? The addition o f a H2 antagonist m a y be helpful in resistant cases.
Conclusion Urticaria and angioedema m a y be due to various immunological and inflammatory mechanisms. Regardless o f the initiating process, the final c o m m o n
pathway is that o f mast cell degranulation. M o s t cases o f chronic urticaria/angioedema are idiopathic. A detailed history is most i m p o r t a n t in the evaluation o f patients and further investigations are rarely indicated. Antihistamines are the mainstay o f management.
References 1. Harris A, Twarog F J, Geha R S. Chronic urticaria in childhood: natural course and etiology. Ann Allergy 1983; 51: 161-165. 2. Champion R H, Roberts S O B, Carpenter R Get al. Urticaria and angioedema: a review of 554 patients. Br J Dermatol 1969;81: 588-597. 3. Munroe E W, Jones H E. Urticaria - - An updated review. Arch Dermatol 1977; 113: 80-90. 4. Soter N A. Acute and chronic urticaria and angioedema. J Am Acad Dermatol 1991;25: t46-154. 5. Hide M, Francis D M, Grattan C E H et al. Autoantibodies against the high affinity IgE receptor as a cause of histamine release in chronic urticaria. N Engl J Med 1993; 328: 1599-1604. 6. Kobza Black A, Greaves M W, Champion R H, Pye R J. The urticarias 1990. Br J Dermatol 1991; 124: 100--108. 7. Smith R J, Burton J L. Oral challenge tests for urticaria - an ethical dilemma. Br J Dermatol 1994; 131: 583. 8. Cooper K D. Urticaria and angioedema: Diagnosis and evaluation. J Am Acad Dermatol 1992;25: 166-176. 9. Simons F E R, Simons K J. The pharmacology and use of H1 - receptor antagonists. N Engl J Med 1994; 23: 1663-1670.
P. McHenry
Urticaria is a common condition which affects all age groups. Up to 20% of the population will have at least one episode. The majority of cases in children are acute lasting from hours to a few weeks but a small proportion have recurrent or chronic urticaria which has been arbitrarily defined as urticaria lasting longer than 6-8 weeks. 1 Infections, particularly acute viral infections, are the most commonly recognised cause of acute urticaria in children. In approximately 70% of patients with chronic recurrent urticaria no cause is identified.
Fig. 2~Angioedema.
Clinical manifestations Clinically urticaria is characterised by the development of red itchy hives or wheals (Fig. 1). The appearance results from localised capillary vasodilatation, followed by transudation of protein rich fluid into the surrounding tissue. The wheals resolve when the fluid is reabsorbed, usually within 24 h. As individual lesions are fading new ones may be developing. When there is massive transudation of fluid into the dermis and the subcutaneous or submucosal tissue, this is referred to as angioedema. Angioedema may be evident on the skin as deep oedematous swellings which
Fig. 1-Urticaria: characterised by the development of red, itchy hives or wheals.
Pamela MeHenry, Consultant Dermatologist, department of Dermatology, Western Infirmary, Glasgow G11 6NT. Correspondence and requests for offprints to PM.
Current Paediatrics (1995)5, 258-261 © 1995PearsonProfessionalLtd
258
CHRONIC RECURRENT URTICARIA/ANGIOEDEMA 259
may persist for several days. It commonly involves the eyelids (Fig. 2) lips, larynx and gastrointestinal tract. Itching is usually absent and the main symptoms are of burning or pain. Symptoms due to systemic involvement include hoarseness, dysphagia, shortness of breath, wheezing, nausea, vomiting, abdominal pain, and diarrhoea. If symptoms of dyspnoea or dysphagia have not occurred within the first few hours of any one urticarial episode, they are not likely to develop subsequently during the course of that attack. Urticaria and angioedema commonly occur together and may show a familial tendency which is distinct from the hereditary angioedema due to C1 esterase inhibitor deficiency. In a study of 554 patients, 50% experienced both urticaria and angioedema, 40% only urticaria and 10% only angioedema. 2 Patients with urticaria alone are more likely to undergo spontaneous resolution than those with urticaria and angioedema.
Pathogenesis It is a common misconception that urticaria results solely from an allergic process. Many factors both immunological and non immunological may result in mast cell degranulation (Table 1). 3 Mast cell degranulation releases a number of vasoactive substances which include histamine, kinins, serotonin, leukotrienes and prostaglandins. Release of these mediators causes vasodilatation and enhances permeability of the capillaries. Some conditions such as stress, infection and body temperature may influence the ease with which mast cells degranulate.
Chronic idiopathic urticaria/angioedema The role of IgE mediated allergy and in particular the role of food allergies in chronic idiopathic urticaria/angioedema is unclear.4 The type 1 IgE mediated reaction
seems to be more important for the development of acute urticarias in which the allergens such as foods, drugs, or infectious agents are often easily identified. Penicillin and related antibiotics are common causes of acute urticaria and at one time it was considered that small amounts of penicillin contaminating foods such as dairy products were the cause of some cases of chronic urticaria. Nowadays the amount of penicillin in milk is negligible and it seems unlikely that this could cause chronic urticaria. Studies have shown that patients with chronic urticaria do not have an increased incidence of atopy and total serum IgE levels are generally normal. In chronic urticaria a number of factors may contribute to the development of urticaria but these may not be the main cause. Salicylates, azo dyes, benzoates and yeasts can increase the urticarial tendency and give rise to exacerbations. Recent studies in adults with chronic urticaria have identified a functional IgG autoantibody against the high affinity IgE receptor in the sermn of at least a third of patients with chronic idiopathic urticaria. 5
Physical urticarias Unrecognised physical urticarias account for about 10% of all cases of chronic urticaria. Physical urticarias may be produced by stroking the skin, by exercise, heat, cold, water, vibration, solar radiation or pressure. A helpful distinguishing feature is that, with the exception of pressure urticaria, attacks are brief, lasting only 30-60 min, compared to the non-physical urticaria in which the eruption may last from a few hours to several days. In children, the more common types of physical urticarias include dermographism, cholinergic urticaria and less frequently cold urticaria and pressure urticaria. 'skin writing': Linear itchy wheals develop at the site of scratching or friction from clothing. It may be preceded by infection, or antibiotic therapy but
Dermographism
Table 1 Typesof urticaria Idiopathic 70% cases of chronic urticaria/angioedemaare idiopathic. Immunological IgE- dependent mast cell degranulation
l. Specificantigen sensitivity:Usuallymanifestsas acute urticaria and the cause is often identifiablefrom the history.Typical allergens include some foods e.g. eggs, shellfish,strawberries,drugs e.g. penicillin,infectionse.g. helminth infestation.Atopic patients have an increasedincidenceof type 1 reactionsbut they also occur in non atopic individuals. 2. Physicalurticaria - Cholinergic,dermographism,pressure,vibration, cold, heat, solar. Complement mediated
Hereditary angioedema(C1 esteraseinhibitor deficiency) Type 1 (85%)C1 inhibitor absent Type2 (15%) C 1 inhibitor not functional. Acquired angioedema(functionalabnormality of C1 inhibitor in malignancyand autoimmune disease) Reaction to blood products, serum sickness. Non immunological Histamine releasing agents
Opiates, antibiotics,radiocontrast media, curare. Agents which alter arachidonic metabolism
Azo dyes,benzoates, salicylates.
260 CURRENTPAEDIATRICS in most cases there is no obvious cause. Treatment is not necessary unless the patient is extremely sensitive, and in these patients low dose non-sedating antihistamines usually provide adequate relief. Cold urticaria: This may be acquired or rarely is transmitted as an autosomal dominant trait. It is particularly likely to occur in children and young women. Like dermographism, cold urticaria may begin after infection, or drug therapy. Usually it is an IgE mediated response, but occasionally cryoproteins may be present in association with a connective tissue disease. The diagnosis of cold urticaria may be confirmed by inducing a wheal by the application of an ice cube against the skin. Anaphylactic reactions, particularly during swimming, may occur in those with acquired cold urticaria. Cholinergic urticaria: This occurs typically in adolescents. It has a very distinct clinical pattern. Small itchy papules 2-4 mm in diameter develop in response to an increase in body heat usually after exercising. Antihistamines taken before exercise may be of benefit in some cases. Pressure urticaria: This is uncommon in children. A deep itchy burning or painful swelling occurring 4-6 h after a pressure stimulus and lasting 8-72 h is characteristic. Antihistamines are not helpful and systemic steroids may be required if the disease is disabling. The vast majority of patients with treatment resistant chronic idiopathic urticaria probably have a component of pressure urticaria.
Hereditary angioedema Hereditary angioedema accounts for about 2% of all cases of angioedema. It is inherited as an autosomal dominant trait and is manifested by episodic bouts of subcutaneous and mucosal swelling. The erythematous lesions which accompany the angioedema are fiat reticulate patches rather than conventional urticarial wheals. The disease is due to low levels of functioning C1 esterase inhibitor. The disease usually becomes evident in late childhood or early adolescence. Angioedema can occur alone or with other systemic symptoms such as respiratory distress and hypotension. Abdominal pain is a prominent feature. Glottal oedema leading to laryngeal obstruction is a potentially fatal complication of hereditary angioedema. For acute life threatening attacks, purified C1 inhibitor concentrate or fresh frozen plasma are required. It is not responsive to steroids, adrenaline or antihistamines. Danazol and stanozolol increase serum levels of C1 inhibitor and may be used for short term and long term prophylaxis. Long term prophylaxis may cause androgenic problems in children.
reaction to bites from insects such as fleas and mites. They are often located on the lower extremities of children. The lesions are more persistent than ordinary urticaria. 3. Urticaria pigmentosa/mastocytosis: This condition is not uncommon in children and is due to collections of mast cells in the skin which appear as pigmented macules and papules which urticate when rubbed. These lesions tend to improve with time. 4. Erythema multiforme: Erythema multiforme may be urticarial in appearance but it characteristically has a marked acral distribution and classic cases have target lesions. In addition individual lesions are more persistent than those of urticaria. 5. Urticarial vasculitis: This is uncommon in children and the diagnosis is usually suggested from the history. Individual lesions may persist for 24-72 h and usually leave residual changes of purpura, scaling and hyperpigmentation. The lesions are burning and painful rather than itchy. The diagnosis is confirmed by a skin biopsy.
Investigations A thorough history and examination is most important in the evaluation of patients with chronic urticaria/angioedema. The type of urticaria can usually be diagnosed from a thorough history. When physical urticarias are suspected these can be confirmed by simple tests such as application of an ice cube to the skin to confirm cold urticaria, asking the patient to exercise to produce cholinergic urticaria or simply by a brisk stroke on the skin to produce the linear urticaria of dermographism. Routine laboratory tests are of minimal value in patients with chronic idiopathic urticaria and the yield is low unless there is some lead from the history. In unremitting urticaria, a full blood count, ESR and urinalysis may be appropriate. 6 An elevated ESR is suggestive of complement associated reactions. The role of foods and the question as to whether oral challenge tests are useful in urticaria remains unresolved.7,s It may be useful to ask the patient to keep a food diary, and a diet avoiding food additives may be undertaken for 3-4 weeks. There is no indication for routinely carrying out investigations such as skin tests; total IgE; RASTs; connective tissue screens, thyroid function tests or a skin biopsy. Similarly, investigations for infections, focal sepsis and intestinal parasites are considered to give such a low yield of clinically useful results that their routine use is not recommended.6
Treatment Differential diagnosis of urticaria 1. Scabies: Scabies may present with an urticarial eruption and can cause dermographism. 2. Insect bites: Papular urticaria is a hypersensitivity
In the absence of specific reliable antagonists of the other vasoactive mediators released following mast cell degranulation, antihistamines remain the mainstay in the management of urticaria/angioedema.
CHRONIC RECURRENT URTICARIA/ANGIOEDEMA 261
Antihistamines do n o t block the release o f histamine but compete with histamine for the same receptor site. Sometimes combinations o f antihistamines are m o r e effective than a single agent. The newer antihistamines such as terfenadine (triludan), astemizole (hismanal), loratadine (clarityn), acrivastine (semprex) and cetirizine (zirtek) penetrate poorly across the b l o o d brain barrier and thereby cause less sedation than the older antihistamines. T h e y are similar in p o t e n c y but differ in dosage schedules, onset and duration o f action, side effects a n d interactions. Tachyarrhythmias with prolongation o f the Q - T interval have been reported when terfenadine or astemizole have been given in doses above those r e c o m m e n d e d or the antihistamine was taken in conjunction with a macrolide antibiotic such as erythromycin or oral imidazole antifungal preparations? The addition o f a H2 antagonist m a y be helpful in resistant cases.
Conclusion Urticaria and angioedema m a y be due to various immunological and inflammatory mechanisms. Regardless o f the initiating process, the final c o m m o n
pathway is that o f mast cell degranulation. M o s t cases o f chronic urticaria/angioedema are idiopathic. A detailed history is most i m p o r t a n t in the evaluation o f patients and further investigations are rarely indicated. Antihistamines are the mainstay o f management.
References 1. Harris A, Twarog F J, Geha R S. Chronic urticaria in childhood: natural course and etiology. Ann Allergy 1983; 51: 161-165. 2. Champion R H, Roberts S O B, Carpenter R Get al. Urticaria and angioedema: a review of 554 patients. Br J Dermatol 1969;81: 588-597. 3. Munroe E W, Jones H E. Urticaria - - An updated review. Arch Dermatol 1977; 113: 80-90. 4. Soter N A. Acute and chronic urticaria and angioedema. J Am Acad Dermatol 1991;25: t46-154. 5. Hide M, Francis D M, Grattan C E H et al. Autoantibodies against the high affinity IgE receptor as a cause of histamine release in chronic urticaria. N Engl J Med 1993; 328: 1599-1604. 6. Kobza Black A, Greaves M W, Champion R H, Pye R J. The urticarias 1990. Br J Dermatol 1991; 124: 100--108. 7. Smith R J, Burton J L. Oral challenge tests for urticaria - an ethical dilemma. Br J Dermatol 1994; 131: 583. 8. Cooper K D. Urticaria and angioedema: Diagnosis and evaluation. J Am Acad Dermatol 1992;25: 166-176. 9. Simons F E R, Simons K J. The pharmacology and use of H1 - receptor antagonists. N Engl J Med 1994; 23: 1663-1670.