ARTICLE
5
Urticaria, Anaphylaxis Fred
S. Rosen,
FOCUS
Angioedema, MD*
QUESTIONS
1. DefIne urticaria, angioedema, and anaphylaxis. 2. What is the common pathophysioio2j’ of urticaria and angloedema? 3. How do the IgE and the IgG mechanisms for anaphylaxis differ? 4. What etiologic agents commonly cause urticaria, angloedema, and anaphylaxis? 5. What are the signs and symptoms of anaphylaxis? How is It treated?
Urticaria, angioedema, and anaphylaxis are different manifestations of immediate hypersensitivity. Immediate hypersensitivity is an untoward, immunologically mediated reaction that occurs within minutes to a few hours of the introduction of antigen into an immune individual and that is mediated by antibodies; thus, these
S
reactions also have been called antibody-mediated hypersensitivity. Approximately 20% of the population manifests these symptoms, particularly urticaria, at some time during life.
Definitions Urticaria (or hives) is an intensely itchy rash consisting of a raised, irregularly shaped wheal with a blanched center surrounded by a red flare. Urticaria is caused by histamine release from the mast cells of the dermis. Although chemical and physical agents such as detergents or ultraviolet light can release histamine from mast cells, histamine release is most commonly due to an immunologic reaction between antigens and IgE antibodies bound to the membranes of mast cells. The release of histamine-containing granules from mast cells is calcium-dependent and requires energy. In addition to histamine, other mediators, such as leukotrienes, prostaglandins, and platelet
*Ja,nes
L.
Gamble
Professor
Harvard Medical School, Research and Children’s MA 02115
Pediatrics in Review
and
of Pediatrics,
Center for Blood Hospital, Boston,
VoL
13
No. 10
activating factor, also are released from immunologically stimulated mast cells. The binding of histamine to Hi receptors causes smooth muscle contraction and increased vascular permeability. Angioedema is an area of circumscribed swelling of any part of the body. It may be caused by the same mechanisms that cause hives when the immunologic events occur deeper in the cutis or in submucosal tissue of the respiratory or gastrointestinal tract. One special form of angioedema that results from a genetically determined deficiency of the inhibitor of the first component of complement (Cl inhibitor) will be presented at the end of this discussion. Anaphylaxis is the acute reaction that occurs when antigen is introduced rapidly and systemically into an individual who has preexisting IgE antibodies fixed to mast cells and basophils. Sometimes the reaction is unanticipated. Within seconds to minutes (but almost certainly within 1 h), the patient has difficulty breathing due to constriction of the major airways and shock due to falling blood pressure. The symptoms are attributable to the same mechanisms that cause urticaria or angioedema in a localized site.
Anaphylaxis Anaphylaxis most commonly results from the binding of IgE antibodies to the high-affinity receptors for IgE found on mast cells and basophils. An individual with relevant IgE antibodies that are cell-bound will have a reaction when an antigen binds to cell-bound IgE, crosslinks the IgE molecules, and thereby induces degranulation of mast cells and basophils. Anaphylaxis also can be induced by complexes of antigen and IgG antibody. These complexes fix complement. Activation of the complement cascade results in the release of two peptides, C3a and C5a, cleaved from the amino-terminal ends of the alpha or heavy chains of C3 and C5, respectively. Because C3a and C5a degranulate mast cells and October
cause symptoms of anaphylaxis, they are called anaphylatoxins. An anaphylactoid reaction is similar to anaphylaxis but is not immunologically mediated. Certain chemicals, such as hyperosmolar solutions of mannitol or radiocontrast material, and certain drugs, such as opiates and vancomycm, may degranulate mast cells and basophils to cause what resembles anaphylaxis. CAUSES Among the common causes of IgEmediated anaphylaxis are: insect yenoms; airborne allergens; foods such as peanuts, eggs, milk, and seafood products; and food dyes and flavors. Fatal anaphylaxis has been observed following injection of rabbit antilymphocyte globulin prior to transplantation. Antitoxins to tetanus and other microbial products of animal origin may cause anaphylaxis. Chemicals of low molecular weight, such as drugs (particularly penicillins), are not in themselves immunogenic but may bind to host proteins and act as haptens in the production of IgE antibodies. Anaphylaxis caused by drug injections probably exceeds the rates of reaction to insect venoms as a cause of anaphylaxis. Severe and fatal anaphylaxis has been observed in immunodeficient patients who have IgE antibodies to IgA. Complement-mediated anaphylactic reactions may result from IgG antibodies to blood products such as factor VIII. Exposure of blood to membranes such as Cuprane during hemodialysis can result in massive generation of C3a and C5a, with consequent degranulation of mast cells. The symptoms of anaphylaxispruritus, injection of the mucous membranes, bronchospasm, and hypotension-can be attributed largely but not completely to histamine release. Other preformed mediators also must play a role in anaphylaxis, but they have not yet been defined completely. The roles of prostaglandin D2 and leukotrienes also have not been defined clearly.
1992
Downloaded from http://pedsinreview.aappublications.org/ at UCSF Library & CKM on March 28, 2015
387
IMMUNOLOGY UrtIcaria PREVENTION
The best preventive measure for anaphylaxis is avoidance of the cause. However, anaphylaxis frequently is unanticipated, and individuals with a history of anaphylaxis should be provided with injectable epinephrine. Short-term and longterm desensitization have been successful and should be carried out under controlled conditions by physicians experienced with these techniques. For example, shortterm desensitization may be needed in a patient requiring antibiotic treatment. Over the course of 8 h, increasing doses of penicillin may be injected every 20 mm, starting with 10 units and rising to 1 000 000 units to effect desensitization
the course. has been
Long-term
by the end of
desensitization
carried out over
up to 3 y with
bee
venom
a period
of
or inhal-
phylline are secondary measures that also should be considered; dosages of these agents are age-dependent and require monitoring of aminophylline levels.
Urticaria The cause of both urticaria and angioedema is frequently obscure. Urticaria may be induced by physical agents. Prominent among these is exposure to cold, leading to “cold” urticaria. It may cause severe systemic symptoms such as hypotension from immersion in cold water. In children, cold urticaria seldom is caused by cryoglobulins. Challenge with an ice cube applied for a few minutes to the forearm will evoke a remarkable urticanal reaction within 4 to 8 mm, thereby establishing the diagnosis. Cyproheptadine in a total daily dose
SOLAR
OTHER
Among the common causes of IgEmediated anaphylaxis are: insect venoms; airborne allergens; foods such as peanuts, eggs, milk, and seafood products; and food dyes and flavors.
ants such
of 8 mg/m2
90%
as ragweed. More than rates have been reported in desensitization to bee venom and >85% success has been achieved in
the treatment
success
The
is very
wheals
TREATMENT The acute treatment rests primarily with
of anaphylaxis the use of epi-
nephrine. Epinephrine at a 1:1000 dilution should be injected at 10- to 20-mm intervals in a volume appropriate for the age of the child. Oxygen should be administered and the airway secured. Beta adrenergic amines, such as a 5% solution of metaproterenol in 2.5 mL of saline, should be administered through a nebulizer. Administration of antihistamines,
388
corticosteroids,
and
amino-
is considered
of choice
for cold
urticaria.
abolishing rhinitis due to inhalants. Desensitization to food allergens should not be undertaken because it hazardous.
generally
CHOLINERGIC appearance surrounded
URTICARIA
of small
punctate
by a prominent
erythematous flare is called cholinergic urticaria. This most frequently is associated with exercise, sweating, exposure to heat, and even anxiety. Like hives, these small papular urtications are pruritic and appear prominently on the neck and upper thorax. This type of urticaria is termed cholinergic because it is thought to be caused by stimulation of cholinergic fibers. Sometimes it can be induced in patients by using methacholine. This form of urticaria is best treated with hydroxyzine in a total daily dose of 50 to 100 mg. Pediatrics
URTICARIA
Solar urticaria is uncommon and may be caused by various wavelengths of light, from 280 to 500 nm. Some forms may be transferred passively, which suggests immunologic mediation, but the mediator has not been identified. Congenital ferrochelatase deficiency (erythropoietic protoporphyria) causes an accumulation of protoporphyrin IX, which can act as a photosensitizer through complement activation and the release of C5a. It can be treated with beta-carotene, which absorbs light at the same wavelength as protoporphyrin IX; the daily dose is 30 to 150 mg with meals. Capsules can be emptied into orange juice for small children. Sun screens are useful in the treatment of other forms of solar urticaria. FORMS
OF URTICARIA
The most common cause of hives results from ingestion of foods or food additives or drugs. These usually cause hive formation for only hours or a couple of days. Salicylates, which are widespread in natural food substances, frequently cause chronic urticaria because of repeated ingestion. Sensitivity to the food additive tartazine yellow No. 5 frequently is encountered in patients with salicylate sensitivity. Hives also may be associated with infections due to parasites or viruses such as hepatitis or infectious mononucleosis. They also may be associated with collagen vascular disease complicated by vasculitis, such as systemic lupus erythematosus. The deposition of immune complexes in and around inflamed blood vessels is observed in biopsies. Such forms of urticaria are usually chronic, in contrast to the acute selflimited reactions to ingestants. Chronic urticaria optimally is treated with corticosteroids. Hives and bronchospasm may be induced by exercise. Sometimes exercise in combination with the recent ingestion of an offending food will combine to cause symptoms of immediate hypersensitivity. FACTOR
DEFICIENCIES
A rare cause of urticaria is found in patients with genetic deficiencies of factor H or factor I of the complement system (Figure). In this alternain Review
Vol.
S
13
No.
10
Downloaded from http://pedsinreview.aappublications.org/ at UCSF Library & CKM on March 28, 2015
October
1992
S
5
IMMUNOLOGY Urticaria
5
5
tive pathway of complement activation, the active enzyme formed by this pathway, C3bBb, is degraded by the binding of factor H to C3b. This facilitates the cleavage of the heavy (alpha) chain of C3b by factor I to form C3bi, which is enzymatically inactive. In the absence of factor H or factor I, the alternative pathway cannot be inhibited and the degradation of C3 goes on unimpeded, generating large amounts of C3a and consequently histamine release. Patients who have these defects excrete huge amounts of histamine. They frequently develop severe hives, particularly upon exposure to cold or hot water or following alcohol ingestion. The defects are inherited as autosomal recessive traits. The diagnosis is made first by finding a low level of C3 in the serum of the patient. Further investigation reveals that the C3 present in the blood is mostly converted to C3b. The advent of newer, nonsedating antihistamines has been a valuable addition to the pharmacopoeia. Terfenadine (60 mg b.i.d. for children older than 12 y) and astemizole (10 mg 2 h before meals in children older than 12 y) have proved very useful in the control of urticaria.
Angioedema Angioedema is mechanistically similar to hives, but the reaction is deeper in the dermis; thus, more diffuse swelling is observed rather than a sharply demarcated wheal. One special form of angioedema is observed in an inherited disease known as hereditary angioneurotic edema (I-lANE), which deserves attention because it is treatable and, once recognized, saves the patient much anxiety and needless surgical interventions.
HEREDITARY
ANGIONEUROTIC
EDEMA
S
Hereditary angioneurotic edema is characterized by episodes of localized subcutaneous edema of any part of the body and by attacks of severe abdominal cramps and vomiting due to edema of the bowel wall. Parents invariably report that affected children had severe colic during infancy, and they are very accurate in distinguishing their affected from their unafPediatrics
in Review
VoL
13
No. 10
C3
C3a
aC3b+ +
Factor
B
C3bB
4,.” C3bBb Factor Factor
Factor +
Ba
H\..J I J C3bi
+
Bb
+
C3f
Figure. The alternative pathway of complement activation. Reprinted with permission from Rosen FS, Steiner LA, Unanue ER. Dictionary of Immunology. London, England: Macmillan; 1989:10.
fected offspring. Patients who have HANE also may develop laryngeal edema and die from the consequent pulmonary edema, resulting in total upper airway obstruction. Attacks of palatal and laryngeal edema usually follow trauma in the dentist’s office or occur during upper respiratory infections. Almost all patients manifest symptoms of the disease during the first decade of life, but the symptoms become dramatically worse during pubescence and finally abate late in life. In girls, the attacks of angioedema may occur around menstrual periods. Generally, the angioedema does not itch and is not red or painful; it only causes a sensation of pressure because vast amounts of fluid may accumulate rapidly in a limb or external genitalia. The attacks generally last 24 to 48 h. They are brought on by trauma, menstrual periods, extremes of temperature, fatigue, or stress. HANE is inherited as a Mendelian autosomal dominant disease. It never skips a generation. However, about 10% of patients are new spontaneous mutants who subsequently pass the disease on to their offspring. In 85% of patients, a deficiency of the Ci inhibitor can be found in the serum or plasma; this is called type I HANE. In 15% of patients, Ci inhibitor is present in normal amounts, as measured immunochemically, but is not functional; this is called type II HANE. Almost all type II HANE pa-
October
tients have a point mutation in the Ci .inhibitor gene that results in production of a faulty, nonfunctional molecule. In type I HANE, there are frequent gene deletions or premature stop codons in the Cl inhibitor gene that result in the production of mRNA that is degraded within the cell, and no translation product can be measured. Because the disease is transmitted as an autosomal dominant trait, every patient who has HANE is heterozygous, having both a normal and an abnormal gene. However, the product of the single normal gene is insufficient to maintain homeostasis of the complement and contact systems, and angioedema results. The Cl inhibitor inhibits the enzymatic activity of the first component of complement (Cl). The substrates of Cl are the second and fourth cornponents of complement (C2 and C4). Patients who have HANE have a low level of C4 in their serum. This should be measured, along with Cl inhibitor, in suspected cases to detect the 15% of patients with imrnunochemically normal amounts of Ci inhibitor. Cl inhibitor also inhibits kallikrein of the contact system and factors XI and XII and plasmin of the clotting system. Angioedema in these patients is thought to occur from the generation of bradykinin by the contact system and a peptide from C2, called “C2 kinin,” which enhance the permeability of postcapillary venules. Nearly complete prophylaxis against attacks of angioedema can be achieved in patients who have HANE by treating them with impeded androgens (androgens that do not have an oxygen atom attached to the third carbon of the steroid ring and are, therefore, only minimally virilizing). Stanozolol, at a dose of 2 mg/d, or danazol, at a daily oral dose of 50 to 300 mg, can prevent attacks of angioedema. Although these androgens are highly effective, they should be used in children with great care, and bone age and other untoward effects of androgen therapy must be monitored (liver function tests). They can be given in large doses for short periods (eg, 10 mg stanozolol daily for 5 d) to children with I-LANE about to sustain dental trauma or other surgical interventions. Preparations of Cl inhibitor pun-
1992
Downloaded from http://pedsinreview.aappublications.org/ at UCSF Library & CKM on March 28, 2015
389
I L
IMMUNOLOGY Urticaria
fied from human plasma have been used extensively in Europe and have proved safe and effective in halting the progress of attacks and providing immediate relief of severe abdominal symptoms. One such preparation now is undergoing testing in the United States and may be approved for use by the federal Food and Drug Administration in the near future.
PIR QUIZ
ing granules. c. Immunologic interaction between antigen and IgE antibodies bound to mast cells. d. Binding of histamine to Hi receptors.
SUGGESTED
READING BS, Lichtenstein LM. Anaphylaxis. N EnglJ Med. 1991;324:1785-1790 Donaldson VH, Rosen FS. Hereditary angioneurotic edema: A clinical survey. Pediatrics. 1966;37: 1017-1027 Elias J, Boss E, Kaplan AP. Studies of the cellular infiltrate of chronic idiopathic urticaria. Prominence of I lymphocytes, monocytes and mast cells. J Allergy Clin Immunol. 1986;78:914-918 Gigli I, Schothorst AA, Sote NA, Pathak MA. Erythropoietic protoporphyria: Photoactivation of the complement system. J Clin Invest. 1980;66:517-522 Kaplan AP. Urticaria and angioedema. In: Middleton E Jr, Reed CE, Ellis EF, Actkinson NF Jr, Yunginger JW, eds. Allergy, Principles and Practices. 4th ed. St. Louis, MO: Mosby Yearbook; in press.
S
18. The following events result in the clinical picture of urticania (hives): a. Smooth muscle contraction and increased vascular permeability. b. Release of histamine-contain-
Bochner
The correct
sequence
of these
events is: A. d, C, b, a. B. a, c, b, d. C. b, a, d, c. D. c, b, d, a. 19.
Each of the following is a true statement regarding urticaria,
except: A. Salicylates naturally present in foods can be causative. B. Terfenadine is useful in treatment. C. Anaphylaxis is a systemic response to the same mechanism causing urticania at local sites.
D. Gluten
protein
of wheat
is
frequently causative. E. A recognized chemical cause is yellow food dye with the tartazine structure. 20.
S
Each of the following is a wellrecognized cause of anaphylaxis,
except: A. Antitoxin of animal origin. B. Peanut-containing foods.
C. Amanita mushrooms. D. Penicillin. E. Insect venom.
21. Symptoms and clinical findings of anaphylaxis include all of the following, except: A. Hypertensive encephalopathy. B. Acute diarrhea.
C. Inspiratory
stnidor.
D. Urticania. E. Itching of the eyes.
22. Each of the following
is a correct procedure in the management of anaphylaxis, except: A. Acute desensitization to penicillin can be completed in less than 12 h.
B. Sensitized carry
individuals
ampules
roids for emergent C. Epinephrine
should
of corticoste-
use.
is the principal
drug for acute treatment. D.
390
Desensitization to food allergens is too hazardous for routine application.
Pediatrics
S in Review
VoL
13
No.
10
Downloaded from http://pedsinreview.aappublications.org/ at UCSF Library & CKM on March 28, 2015
October
1992
Urticaria, Angioedema, and Anaphylaxis Fred S. Rosen Pediatrics in Review 1992;13;387 DOI: 10.1542/pir.13-10-387
Updated Information & Services
including high resolution figures, can be found at: http://pedsinreview.aappublications.org/content/13/10/387
Permissions & Licensing
Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pedsinreview.aappublications.org/site/misc/Permissions.xhtml
Reprints
Information about ordering reprints can be found online: http://pedsinreview.aappublications.org/site/misc/reprints.xhtml
Downloaded from http://pedsinreview.aappublications.org/ at UCSF Library & CKM on March 28, 2015
Urticaria, Angioedema, and Anaphylaxis Fred S. Rosen Pediatrics in Review 1992;13;387 DOI: 10.1542/pir.13-10-387
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/content/13/10/387
Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 1992 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.
Downloaded from http://pedsinreview.aappublications.org/ at UCSF Library & CKM on March 28, 2015
5
Urticaria, Anaphylaxis Fred
S. Rosen,
FOCUS
Angioedema, MD*
QUESTIONS
1. DefIne urticaria, angioedema, and anaphylaxis. 2. What is the common pathophysioio2j’ of urticaria and angloedema? 3. How do the IgE and the IgG mechanisms for anaphylaxis differ? 4. What etiologic agents commonly cause urticaria, angloedema, and anaphylaxis? 5. What are the signs and symptoms of anaphylaxis? How is It treated?
Urticaria, angioedema, and anaphylaxis are different manifestations of immediate hypersensitivity. Immediate hypersensitivity is an untoward, immunologically mediated reaction that occurs within minutes to a few hours of the introduction of antigen into an immune individual and that is mediated by antibodies; thus, these
S
reactions also have been called antibody-mediated hypersensitivity. Approximately 20% of the population manifests these symptoms, particularly urticaria, at some time during life.
Definitions Urticaria (or hives) is an intensely itchy rash consisting of a raised, irregularly shaped wheal with a blanched center surrounded by a red flare. Urticaria is caused by histamine release from the mast cells of the dermis. Although chemical and physical agents such as detergents or ultraviolet light can release histamine from mast cells, histamine release is most commonly due to an immunologic reaction between antigens and IgE antibodies bound to the membranes of mast cells. The release of histamine-containing granules from mast cells is calcium-dependent and requires energy. In addition to histamine, other mediators, such as leukotrienes, prostaglandins, and platelet
*Ja,nes
L.
Gamble
Professor
Harvard Medical School, Research and Children’s MA 02115
Pediatrics in Review
and
of Pediatrics,
Center for Blood Hospital, Boston,
VoL
13
No. 10
activating factor, also are released from immunologically stimulated mast cells. The binding of histamine to Hi receptors causes smooth muscle contraction and increased vascular permeability. Angioedema is an area of circumscribed swelling of any part of the body. It may be caused by the same mechanisms that cause hives when the immunologic events occur deeper in the cutis or in submucosal tissue of the respiratory or gastrointestinal tract. One special form of angioedema that results from a genetically determined deficiency of the inhibitor of the first component of complement (Cl inhibitor) will be presented at the end of this discussion. Anaphylaxis is the acute reaction that occurs when antigen is introduced rapidly and systemically into an individual who has preexisting IgE antibodies fixed to mast cells and basophils. Sometimes the reaction is unanticipated. Within seconds to minutes (but almost certainly within 1 h), the patient has difficulty breathing due to constriction of the major airways and shock due to falling blood pressure. The symptoms are attributable to the same mechanisms that cause urticaria or angioedema in a localized site.
Anaphylaxis Anaphylaxis most commonly results from the binding of IgE antibodies to the high-affinity receptors for IgE found on mast cells and basophils. An individual with relevant IgE antibodies that are cell-bound will have a reaction when an antigen binds to cell-bound IgE, crosslinks the IgE molecules, and thereby induces degranulation of mast cells and basophils. Anaphylaxis also can be induced by complexes of antigen and IgG antibody. These complexes fix complement. Activation of the complement cascade results in the release of two peptides, C3a and C5a, cleaved from the amino-terminal ends of the alpha or heavy chains of C3 and C5, respectively. Because C3a and C5a degranulate mast cells and October
cause symptoms of anaphylaxis, they are called anaphylatoxins. An anaphylactoid reaction is similar to anaphylaxis but is not immunologically mediated. Certain chemicals, such as hyperosmolar solutions of mannitol or radiocontrast material, and certain drugs, such as opiates and vancomycm, may degranulate mast cells and basophils to cause what resembles anaphylaxis. CAUSES Among the common causes of IgEmediated anaphylaxis are: insect yenoms; airborne allergens; foods such as peanuts, eggs, milk, and seafood products; and food dyes and flavors. Fatal anaphylaxis has been observed following injection of rabbit antilymphocyte globulin prior to transplantation. Antitoxins to tetanus and other microbial products of animal origin may cause anaphylaxis. Chemicals of low molecular weight, such as drugs (particularly penicillins), are not in themselves immunogenic but may bind to host proteins and act as haptens in the production of IgE antibodies. Anaphylaxis caused by drug injections probably exceeds the rates of reaction to insect venoms as a cause of anaphylaxis. Severe and fatal anaphylaxis has been observed in immunodeficient patients who have IgE antibodies to IgA. Complement-mediated anaphylactic reactions may result from IgG antibodies to blood products such as factor VIII. Exposure of blood to membranes such as Cuprane during hemodialysis can result in massive generation of C3a and C5a, with consequent degranulation of mast cells. The symptoms of anaphylaxispruritus, injection of the mucous membranes, bronchospasm, and hypotension-can be attributed largely but not completely to histamine release. Other preformed mediators also must play a role in anaphylaxis, but they have not yet been defined completely. The roles of prostaglandin D2 and leukotrienes also have not been defined clearly.
1992
Downloaded from http://pedsinreview.aappublications.org/ at UCSF Library & CKM on March 28, 2015
387
IMMUNOLOGY UrtIcaria PREVENTION
The best preventive measure for anaphylaxis is avoidance of the cause. However, anaphylaxis frequently is unanticipated, and individuals with a history of anaphylaxis should be provided with injectable epinephrine. Short-term and longterm desensitization have been successful and should be carried out under controlled conditions by physicians experienced with these techniques. For example, shortterm desensitization may be needed in a patient requiring antibiotic treatment. Over the course of 8 h, increasing doses of penicillin may be injected every 20 mm, starting with 10 units and rising to 1 000 000 units to effect desensitization
the course. has been
Long-term
by the end of
desensitization
carried out over
up to 3 y with
bee
venom
a period
of
or inhal-
phylline are secondary measures that also should be considered; dosages of these agents are age-dependent and require monitoring of aminophylline levels.
Urticaria The cause of both urticaria and angioedema is frequently obscure. Urticaria may be induced by physical agents. Prominent among these is exposure to cold, leading to “cold” urticaria. It may cause severe systemic symptoms such as hypotension from immersion in cold water. In children, cold urticaria seldom is caused by cryoglobulins. Challenge with an ice cube applied for a few minutes to the forearm will evoke a remarkable urticanal reaction within 4 to 8 mm, thereby establishing the diagnosis. Cyproheptadine in a total daily dose
SOLAR
OTHER
Among the common causes of IgEmediated anaphylaxis are: insect venoms; airborne allergens; foods such as peanuts, eggs, milk, and seafood products; and food dyes and flavors.
ants such
of 8 mg/m2
90%
as ragweed. More than rates have been reported in desensitization to bee venom and >85% success has been achieved in
the treatment
success
The
is very
wheals
TREATMENT The acute treatment rests primarily with
of anaphylaxis the use of epi-
nephrine. Epinephrine at a 1:1000 dilution should be injected at 10- to 20-mm intervals in a volume appropriate for the age of the child. Oxygen should be administered and the airway secured. Beta adrenergic amines, such as a 5% solution of metaproterenol in 2.5 mL of saline, should be administered through a nebulizer. Administration of antihistamines,
388
corticosteroids,
and
amino-
is considered
of choice
for cold
urticaria.
abolishing rhinitis due to inhalants. Desensitization to food allergens should not be undertaken because it hazardous.
generally
CHOLINERGIC appearance surrounded
URTICARIA
of small
punctate
by a prominent
erythematous flare is called cholinergic urticaria. This most frequently is associated with exercise, sweating, exposure to heat, and even anxiety. Like hives, these small papular urtications are pruritic and appear prominently on the neck and upper thorax. This type of urticaria is termed cholinergic because it is thought to be caused by stimulation of cholinergic fibers. Sometimes it can be induced in patients by using methacholine. This form of urticaria is best treated with hydroxyzine in a total daily dose of 50 to 100 mg. Pediatrics
URTICARIA
Solar urticaria is uncommon and may be caused by various wavelengths of light, from 280 to 500 nm. Some forms may be transferred passively, which suggests immunologic mediation, but the mediator has not been identified. Congenital ferrochelatase deficiency (erythropoietic protoporphyria) causes an accumulation of protoporphyrin IX, which can act as a photosensitizer through complement activation and the release of C5a. It can be treated with beta-carotene, which absorbs light at the same wavelength as protoporphyrin IX; the daily dose is 30 to 150 mg with meals. Capsules can be emptied into orange juice for small children. Sun screens are useful in the treatment of other forms of solar urticaria. FORMS
OF URTICARIA
The most common cause of hives results from ingestion of foods or food additives or drugs. These usually cause hive formation for only hours or a couple of days. Salicylates, which are widespread in natural food substances, frequently cause chronic urticaria because of repeated ingestion. Sensitivity to the food additive tartazine yellow No. 5 frequently is encountered in patients with salicylate sensitivity. Hives also may be associated with infections due to parasites or viruses such as hepatitis or infectious mononucleosis. They also may be associated with collagen vascular disease complicated by vasculitis, such as systemic lupus erythematosus. The deposition of immune complexes in and around inflamed blood vessels is observed in biopsies. Such forms of urticaria are usually chronic, in contrast to the acute selflimited reactions to ingestants. Chronic urticaria optimally is treated with corticosteroids. Hives and bronchospasm may be induced by exercise. Sometimes exercise in combination with the recent ingestion of an offending food will combine to cause symptoms of immediate hypersensitivity. FACTOR
DEFICIENCIES
A rare cause of urticaria is found in patients with genetic deficiencies of factor H or factor I of the complement system (Figure). In this alternain Review
Vol.
S
13
No.
10
Downloaded from http://pedsinreview.aappublications.org/ at UCSF Library & CKM on March 28, 2015
October
1992
S
5
IMMUNOLOGY Urticaria
5
5
tive pathway of complement activation, the active enzyme formed by this pathway, C3bBb, is degraded by the binding of factor H to C3b. This facilitates the cleavage of the heavy (alpha) chain of C3b by factor I to form C3bi, which is enzymatically inactive. In the absence of factor H or factor I, the alternative pathway cannot be inhibited and the degradation of C3 goes on unimpeded, generating large amounts of C3a and consequently histamine release. Patients who have these defects excrete huge amounts of histamine. They frequently develop severe hives, particularly upon exposure to cold or hot water or following alcohol ingestion. The defects are inherited as autosomal recessive traits. The diagnosis is made first by finding a low level of C3 in the serum of the patient. Further investigation reveals that the C3 present in the blood is mostly converted to C3b. The advent of newer, nonsedating antihistamines has been a valuable addition to the pharmacopoeia. Terfenadine (60 mg b.i.d. for children older than 12 y) and astemizole (10 mg 2 h before meals in children older than 12 y) have proved very useful in the control of urticaria.
Angioedema Angioedema is mechanistically similar to hives, but the reaction is deeper in the dermis; thus, more diffuse swelling is observed rather than a sharply demarcated wheal. One special form of angioedema is observed in an inherited disease known as hereditary angioneurotic edema (I-lANE), which deserves attention because it is treatable and, once recognized, saves the patient much anxiety and needless surgical interventions.
HEREDITARY
ANGIONEUROTIC
EDEMA
S
Hereditary angioneurotic edema is characterized by episodes of localized subcutaneous edema of any part of the body and by attacks of severe abdominal cramps and vomiting due to edema of the bowel wall. Parents invariably report that affected children had severe colic during infancy, and they are very accurate in distinguishing their affected from their unafPediatrics
in Review
VoL
13
No. 10
C3
C3a
aC3b+ +
Factor
B
C3bB
4,.” C3bBb Factor Factor
Factor +
Ba
H\..J I J C3bi
+
Bb
+
C3f
Figure. The alternative pathway of complement activation. Reprinted with permission from Rosen FS, Steiner LA, Unanue ER. Dictionary of Immunology. London, England: Macmillan; 1989:10.
fected offspring. Patients who have HANE also may develop laryngeal edema and die from the consequent pulmonary edema, resulting in total upper airway obstruction. Attacks of palatal and laryngeal edema usually follow trauma in the dentist’s office or occur during upper respiratory infections. Almost all patients manifest symptoms of the disease during the first decade of life, but the symptoms become dramatically worse during pubescence and finally abate late in life. In girls, the attacks of angioedema may occur around menstrual periods. Generally, the angioedema does not itch and is not red or painful; it only causes a sensation of pressure because vast amounts of fluid may accumulate rapidly in a limb or external genitalia. The attacks generally last 24 to 48 h. They are brought on by trauma, menstrual periods, extremes of temperature, fatigue, or stress. HANE is inherited as a Mendelian autosomal dominant disease. It never skips a generation. However, about 10% of patients are new spontaneous mutants who subsequently pass the disease on to their offspring. In 85% of patients, a deficiency of the Ci inhibitor can be found in the serum or plasma; this is called type I HANE. In 15% of patients, Ci inhibitor is present in normal amounts, as measured immunochemically, but is not functional; this is called type II HANE. Almost all type II HANE pa-
October
tients have a point mutation in the Ci .inhibitor gene that results in production of a faulty, nonfunctional molecule. In type I HANE, there are frequent gene deletions or premature stop codons in the Cl inhibitor gene that result in the production of mRNA that is degraded within the cell, and no translation product can be measured. Because the disease is transmitted as an autosomal dominant trait, every patient who has HANE is heterozygous, having both a normal and an abnormal gene. However, the product of the single normal gene is insufficient to maintain homeostasis of the complement and contact systems, and angioedema results. The Cl inhibitor inhibits the enzymatic activity of the first component of complement (Cl). The substrates of Cl are the second and fourth cornponents of complement (C2 and C4). Patients who have HANE have a low level of C4 in their serum. This should be measured, along with Cl inhibitor, in suspected cases to detect the 15% of patients with imrnunochemically normal amounts of Ci inhibitor. Cl inhibitor also inhibits kallikrein of the contact system and factors XI and XII and plasmin of the clotting system. Angioedema in these patients is thought to occur from the generation of bradykinin by the contact system and a peptide from C2, called “C2 kinin,” which enhance the permeability of postcapillary venules. Nearly complete prophylaxis against attacks of angioedema can be achieved in patients who have HANE by treating them with impeded androgens (androgens that do not have an oxygen atom attached to the third carbon of the steroid ring and are, therefore, only minimally virilizing). Stanozolol, at a dose of 2 mg/d, or danazol, at a daily oral dose of 50 to 300 mg, can prevent attacks of angioedema. Although these androgens are highly effective, they should be used in children with great care, and bone age and other untoward effects of androgen therapy must be monitored (liver function tests). They can be given in large doses for short periods (eg, 10 mg stanozolol daily for 5 d) to children with I-LANE about to sustain dental trauma or other surgical interventions. Preparations of Cl inhibitor pun-
1992
Downloaded from http://pedsinreview.aappublications.org/ at UCSF Library & CKM on March 28, 2015
389
I L
IMMUNOLOGY Urticaria
fied from human plasma have been used extensively in Europe and have proved safe and effective in halting the progress of attacks and providing immediate relief of severe abdominal symptoms. One such preparation now is undergoing testing in the United States and may be approved for use by the federal Food and Drug Administration in the near future.
PIR QUIZ
ing granules. c. Immunologic interaction between antigen and IgE antibodies bound to mast cells. d. Binding of histamine to Hi receptors.
SUGGESTED
READING BS, Lichtenstein LM. Anaphylaxis. N EnglJ Med. 1991;324:1785-1790 Donaldson VH, Rosen FS. Hereditary angioneurotic edema: A clinical survey. Pediatrics. 1966;37: 1017-1027 Elias J, Boss E, Kaplan AP. Studies of the cellular infiltrate of chronic idiopathic urticaria. Prominence of I lymphocytes, monocytes and mast cells. J Allergy Clin Immunol. 1986;78:914-918 Gigli I, Schothorst AA, Sote NA, Pathak MA. Erythropoietic protoporphyria: Photoactivation of the complement system. J Clin Invest. 1980;66:517-522 Kaplan AP. Urticaria and angioedema. In: Middleton E Jr, Reed CE, Ellis EF, Actkinson NF Jr, Yunginger JW, eds. Allergy, Principles and Practices. 4th ed. St. Louis, MO: Mosby Yearbook; in press.
S
18. The following events result in the clinical picture of urticania (hives): a. Smooth muscle contraction and increased vascular permeability. b. Release of histamine-contain-
Bochner
The correct
sequence
of these
events is: A. d, C, b, a. B. a, c, b, d. C. b, a, d, c. D. c, b, d, a. 19.
Each of the following is a true statement regarding urticaria,
except: A. Salicylates naturally present in foods can be causative. B. Terfenadine is useful in treatment. C. Anaphylaxis is a systemic response to the same mechanism causing urticania at local sites.
D. Gluten
protein
of wheat
is
frequently causative. E. A recognized chemical cause is yellow food dye with the tartazine structure. 20.
S
Each of the following is a wellrecognized cause of anaphylaxis,
except: A. Antitoxin of animal origin. B. Peanut-containing foods.
C. Amanita mushrooms. D. Penicillin. E. Insect venom.
21. Symptoms and clinical findings of anaphylaxis include all of the following, except: A. Hypertensive encephalopathy. B. Acute diarrhea.
C. Inspiratory
stnidor.
D. Urticania. E. Itching of the eyes.
22. Each of the following
is a correct procedure in the management of anaphylaxis, except: A. Acute desensitization to penicillin can be completed in less than 12 h.
B. Sensitized carry
individuals
ampules
roids for emergent C. Epinephrine
should
of corticoste-
use.
is the principal
drug for acute treatment. D.
390
Desensitization to food allergens is too hazardous for routine application.
Pediatrics
S in Review
VoL
13
No.
10
Downloaded from http://pedsinreview.aappublications.org/ at UCSF Library & CKM on March 28, 2015
October
1992
Urticaria, Angioedema, and Anaphylaxis Fred S. Rosen Pediatrics in Review 1992;13;387 DOI: 10.1542/pir.13-10-387
Updated Information & Services
including high resolution figures, can be found at: http://pedsinreview.aappublications.org/content/13/10/387
Permissions & Licensing
Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pedsinreview.aappublications.org/site/misc/Permissions.xhtml
Reprints
Information about ordering reprints can be found online: http://pedsinreview.aappublications.org/site/misc/reprints.xhtml
Downloaded from http://pedsinreview.aappublications.org/ at UCSF Library & CKM on March 28, 2015
Urticaria, Angioedema, and Anaphylaxis Fred S. Rosen Pediatrics in Review 1992;13;387 DOI: 10.1542/pir.13-10-387
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/content/13/10/387
Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 1992 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.
Downloaded from http://pedsinreview.aappublications.org/ at UCSF Library & CKM on March 28, 2015
