Urticaria and angioedema ANDREW E. DAVIDSON, MD; S. DAVID MILLER, MD; GUY SETTIPANE, MD; DONALD KLEIN, MD • Urticaria and angioedema are commonly seen in the outpatient setting. Their pathogenesis involves complex cellular and humoral factors. Diagnosis depends on historical information such as duration of symptoms, exacerbating factors, and atopy. While many etiologic factors have been implicated, in most chronic cases no specific etiology is found. This article reviews physical and hereditary syndromes and discusses therapeutic regimens based on the duration and severity of symptoms. • INDEX TERMS: URTICARIA; ANGIONEUROTIC EDEMA • CLEVE CLIN J MED 1992; 59:529-534 HE RELATIVELY COMMON clinical mediated histamine release from cutaneous mast cells syndromes of urticaria and angioedema and basophils is thought to be the primary event in present challenging problems for the prac- allergic urticaria (as seen in food allergies and IgE- ticing physician. Although a spectrum of mediated drug reactions).4,6 In response to specific an- Tdiverse factors has been implicated in their etiology, in tigens or nonspecific stimuli, mast cells release pros- most chronic cases no specific etiologic factor is found. taglandin D2, leukotrienes C4 and D4, and The resulting diagnosis is "idiopathic urticaria." platelet-activating factor, which cause vasodilation and Urticaria is characterized by erythematous, pruritic, increased vascular permeability.4,7 Increased vascular cutaneous elevations that blanch with pressure. The permeability then leads to plasma kinin generation via lesions may occur anywhere on the body. Biopsy of Hageman factor autoactivation.2,8 Mast cells also acute lesions reveals dilated small venules and capil- release enzymes capable of generating and releasing laries in the superficial dermis. Chronic lesions contain bradykinin and kallikrein.2,9 non-necrotizing perivascular mononuclear cell in- Complement components C3a, C4a, and C5a are filtrates, including T cells, monocytes, and mast cells.1 nonspecific factors causing basophil and mast cell his- Clinically, urticaria and angioedema are not dis- tamine release.6 C5a is a chemotactic factor for tinct: they frequently occur together.2,3 Angioedema of eosinophils, monocytes, and neutrophils.2 CI esterase the deep dermal and subcutaneous tissues frequently inhibitor inhibits kinin formation and digestion of C2 involves the face, tongue, extremities, and genitals. and C4.10 These factors may play an important role in Laryngeal edema may be life-threatening. hereditary and acquired angioedema with CI esterase inhibitor deficiency (formerly "hereditary an- PATHOGENESIS gioedema"). Factors released from T lymphocytes and macro- Antibodies, inflammatory cells, complement, his- phages also cause histamine release from mast cells. tamine, kinins, cytokines, and prostaglandins have all Interleukin 3 and granulocyte macrophage colony been implicated in the pathogenesis of urticaria and stimulating factor have been implicated.11 2,4,5 angioedema (Figure): Immunoglobulin E (IgE)- A syndrome of urticaria and angioedema with From the Department of Pediatrics and Medicine, Rhode Island aspirin sensitivity has been described6 which may in- Hospital, Providence. volve increased production of leukotrienes secondary Address reprints requests to A.E.D., Rhode Island Hospital, Department of Pediatrics and Medicine, Division of Allergy, APC to decreased cyclooxygenase activity with shunting of 2 6, 593 Eddy Street, Providence, RI 02903. metabolites into the lipoxygenase pathway. SEPTEMBER • OCTOBER 1992 CLEVELAND CLINIC JOURNAL OF MEDICINE 529 Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. URI ICARIA AND ANGIOEDEMA • DAVIDSON AND ASSOCIATES implicated. Reactions to penicillins, sulfonamides, analgesics, contrast dye, Nonspecific stimuli sedatives, and diuretics are common (Table 1 ).2,12,13 An- C3a, C4a, C5a giotensin-converting en- Interleukin 3 zyme inhibitors have been Granulocyte macrophage associated with angio- colony activating factor edema, with increased kinin production as a postu- \ lated mechanism.14 Patients Histamine with urticaria and aspirin sensitivity may also react to Prostaglandin D2 other nonsteroidal anti-in- Kinin generation Leukotrienes C,D,E flammatory drugs (in- domethacin, ibuprofen) Platelet activating factor and tartrazine dye.15 These Hageman factor activation patients may tolerate salsa- late or choline magnesium trisalicylate, but some I cross-reactivity has been Increased vascular permeability reported.16 Patients with potentially life-threatening Vasodilation reactions of angioedema FIGURE. Pathogenesis of urticaria and angioedema. and anaphylaxis should avoid all nonsteroidal anti- inflammatory drugs.2 TABLE 1 Foods, including shellfish, nuts, eggs, and milk, are DRUGS IMPLICATED IN ACUTE URTICARIA AND ANGIOEDEMA common causes of acute urticaria and angioedema but only rarely cause chronic problems.2 Viral infections, Amphetamines Heterologous serum Phenylbutazone particularly in children, have been associated with Angiotensin-Converting Hydralazine Polymyxin acute urticaria.17 Seasonal allergen exposure in atopic enzyme inhibitors Insulin Probenecid 3,6 Aspirin Iodinated contrast dye Procaine patients occasionally results in urticaria. Allergic Atropine Isoniazid Protamine Sulfate reactions to Hymenoptera venom may result in ur- Barbiturates Narcotics Quinine 18,19 Cephalosporins Nitrofurantoin Streptokinase ticaria or angioedema. Transfusion reactions have Chymotrypsin Nonsteroidal Sulfonamides also been associated with acute onset of urticaria and Curare anti-inflammatory drugs Suxamethonium angioedema.2 Cyariocobalamin Pancreatin Tartrazine dye Deferoxamine Pancuronium Thiamine Dextran Papain Thiouracil Chronic urticaria Furosemide Penicillins d-Tubocurarine Gallamine Phenothiazines Urticaria of greater than 6 weeks' duration is chronic. In most cases no etiologic factor is found, despite investigation of the patient's history, physical examination, and laboratory evaluation.2,3 CLINICAL SYNDROMES An urticarial rash can develop in patients with sys- temic vasculitis in conjunction with Sjogren's Acute urticaria syndrome, systemic lupus erythematosus, polyarteritis Urticaria and angioedema are prevalent, affecting nodosa, rheumatoid arthritis, cryoglobulinemia, or 10% to 20% of the population at some time in their serum sickness. Untreated infections, particularly viral lives.2,3 The symptoms are transient in most patients hepatitis, infectious mononucleosis, and helminthic and resolve with symptomatic treatment. Drug reac- parasitic infections, have been associated with ur- tions, both IgE- and non-IgE-mediated, are frequently ticaria.6,20"22 Cases of urticaria with bacterial and fungal 530 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 59 NUMBER 5 Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. URTICARIA AND' ANGIO^^IIM TABLE 2 PHYSICAL SYNDROMES OF URTICARIA AND ANGIOEDEMA Disorder Symptoms Diagnosis Passive transfer Therapy Special characteristics Reference Acquired cold Localized wheal or Ice cube test Positive in Cyproheptadine :lv 2,6,26, urticaria systemic urticaria some cases cryoglobulins, 27,32 with or without cryofibrinogens, angioedema, paroxysmal cold hemoglobinuria, Donath-Landsteiner antibody Familial cold Erythematous History Negative Avoidance, Autosomal dominant 2,6 urticaria burning patches or responds poorly to inheritance papules with pyrexia, antihistamines leukocytosis, arthralgias Cholinergic Multiple 1-2 mm Exercise test, May respond to Overlap with syndromes of 3,6,27, urticaria wheals occur with mecholyl skin hydroxyzine exercise-induced 28,29, exertion, perspiration, test anaphylaxis and food- 30,32 anxiety related exercise-induced anaphylaxis Delayed pressure Local swelling, Sling test Avoidance, responds Occurs in patients with 6,30 urticaria erythema, and poorly to chronic idiopathic pain 4-6 hours antihistamines urticaria after pressure Symptomatic Stroking skin Dermographo- Positive Hydroxyzine, Can be seen in 6,31,32 dermographism produces wheal meter cyproheptadine, control subjects and flare teifenadine Solar urticaria Erythema, pruritus, Monochrometer Positive in Sunscreens, avoidance Different patients are 6,26, papules or wheals some patients sensitive to different 27, wavelengths of light, 32-34 erythropoietic protoporphyria should be excluded Vibratory Edema at site Vortex vibration Negative Avoidance Autosomal dominant 30,32 angioedema of vibration of forearm for response to hereditary form reported 5 minutes antihistamine is variable Aquagenic Pruritic wheals Water compress at — Terfenadine Other syndromes 30,32 urticaria on upper body body temperature hydroxyzine should be ruled out infections have been reported.23 Malignancies as- Hereditary syndromes sociated with urticaria include carcinoma of the colon, Several familial syndromes of urticaria or an- rectum, and lung, B-cell lymphoma, and Hodgkin's gioedema have been described. Familial cold urticaria lymphoma.2 Urticaria can occur with hyperthyroidism is an autosomal-dominant syndrome of cold in- and, rarely, with hypothyroidism.2'24 tolerance. Patients develop papular skin lesions, burn- In urticaria pigmentosa, brown cutaneous macules ing, fever, chills, arthralgias, myalgias, headache, and are present which urticate with stroking (Darier's leukocytosis approximately 30 minutes after cold ex- sign). This disease is primarily seen in children