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Urticaria (Hives) and Angioedema
Urticaria and angioedema affect 20% of individuals at some point in their life. Episodes of hives that last for <6 wk are considered acute, whereas those that occur on most days of the week for >6 wk are designated chronic. The distinction is important, because the causes and mechanisms of urticaria formation and the therapeutic approaches are different in each instance.
Etiology and Pathogenesis
Acute urticaria and angioedema are often caused by an allergic IgE–mediated reaction ( Table 173.1 ). This form of urticaria is a self-limited process that occurs when an allergen activates mast cells in the skin. Common causes of acute generalized urticaria include foods, drugs (particularly antibiotics), and stinging-insect venoms. If an allergen (latex, animal dander) penetrates the skin locally, hives often can develop at the site of exposure. Acute urticaria can also result from non–IgE-mediated stimulation of mast cells, caused by radiocontrast agents, viral agents (including hepatitis B and Epstein-Barr virus), opiates, and nonsteroidal antiinflammatory drugs (NSAIDs). The diagnosis of chronic urticaria is established when lesions occur on most days of the week for >6 wk and are not physical urticaria or recurrent acute urticaria with repeated exposures to a specific agent ( Tables 173.2 and 173.3 ). In about half the cases, chronic urticaria is accompanied by angioedema. Rarely, angioedema occurs without urticaria. Angioedema without urticaria is often a result of allergy, but recurrent angioedema suggests other diagnoses.
Table 173.1
Etiology of Acute Urticaria
From Lasley MV, Kennedy MS, Altman LC: Urticaria and angioedema. In Altman LC, Becker JW, Williams PV, editors: Allergy in primary care , Philadelphia, 2000, Saunders, p 232.
| Foods | Egg, milk, wheat, peanuts, tree nuts, soy, shellfish, fish, (direct mast cell degranulation) |
| Medications | Suspect all medications, even nonprescription or homeopathic |
| Insect stings | Hymenoptera (honeybee, yellow jacket, hornets, wasp, fire ants), biting insects (papular urticaria) |
| Infections | Bacterial (streptococcal pharyngitis, Mycoplasma , sinusitis); viral (hepatitis, mononucleosis [Epstein-Barr virus], coxsackieviruses A and B); Parasitic (Ascaris, Ancylostoma, Echinococcus, Fasciola, Filaria, Schistosoma, Strongyloides, Toxocara, Trichinella); Fungal (dermatophytes, Candida ) |
| Contact allergy | Latex, pollen, animal saliva, nettle plants, caterpillars |
| Transfusion reactions | Blood, blood products, or IV immune globulin administration |
Table 173.2
Etiology of Chronic Urticaria
From Lasley MV, Kennedy MS, Altman LC: Urticaria and angioedema. In Altman LC, Becker JW, Williams PV, editors: Allergy in primary care , Philadelphia, 2000, Saunders, p 234.
| Idiopathic/autoimmune | Approximately 30% of chronic urticaria cases are physical urticaria, and 60–70% are idiopathic. Of the idiopathic cases approximately 35–40% have anti-IgE or anti-FcεRI (high-affinity IgE receptor α chain) autoantibodies (autoimmune chronic urticaria) |
| Physical | Dermatographism |
| Cholinergic urticaria | |
| Cold urticaria (see Table 173.5 ) | |
| Delayed pressure urticaria | |
| Solar urticaria | |
| Vibratory urticaria | |
| Aquagenic urticaria | |
| Autoimmune diseases | Systemic lupus erythematosus |
| Juvenile idiopathic arthritis | |
| Thyroid disease (Graves, Hashimoto) | |
| Celiac disease | |
| Inflammatory bowel disease | |
| Leukocytoclastic vasculitis | |
| Autoinflammatory/periodic fever syndromes | See Tables 173.3 and 173.5 . |
| Neoplastic | Lymphoma |
| Mastocytosis | |
| Leukemia | |
| Angioedema | Hereditary angioedema (autosomal dominant inherited deficiency of C1-esterase inhibitor) |
| Acquired angioedema | |
| Angiotensin-converting enzyme inhibitors |
Table 173.3
Febrile Autoinflammatory Diseases Causing Urticaria in Children
From Youseff MJ, Chiu YE: Eczema and urticaria as manifestations of undiagnosed and rare diseases, Pediatr Clin North Am 64:39–56, 2017 (Table 2, pp 49–50).
| DISEASE | GENE (PROTEIN) | INHERITANCE | ATTACK LENGTH | TIMING OF ONSET | CUTANEOUS FEATURES | EXTRACUTANEOUS CLINICAL FEATURES |
|---|---|---|---|---|---|---|
| FCAS | NLRP3 (cryopyrin) | AD | Brief; minutes to 3 days | Neonatal or infantile | Cold-induced urticaria | Arthralgia Conjunctivitis Headache |
| Muckle-Wells syndrome | NLRP3 (cryopyrin) | AD | 1-3 days | Neonatal, infantile, childhood (can be later) | Widespread urticaria | Arthralgia/arthritis Sensorineural hearing loss Conjunctivitis/episcleritis Headache Amyloidosis |
| Chronic infantile neurologic cutaneous articular syndrome; neonatal-onset multisystem inflammatory disease | NLRP3 (cryopyrin) | AD | Continuous flares | Neonatal or infantile | Widespread urticaria | Deforming osteoarthropathy, epiphyseal overgrowth Sensorineural hearing loss Dysmorphic facies Chronic aseptic meningitis, headaches, papilledema, seizures Conjunctivitis/uveitis, optic atrophy Growth retardation Developmental delay Amyloidosis |
| HIDS | MVK (mevalonate kinase) | AR | 3-7 days | Infancy (<2 yr) | Intermittent morbilliform or urticarial rash Aphthous mucosal ulcers Erythema nodosum |
Arthralgia/arthritis Cervical lymphadenopathy Severe abdominal pain Diarrhea/vomiting Headache Elevated IgD and IgA antibody levels Elevated urine mevalonic acid during attacks |
| Tumor necrosis factor receptor–associated periodic syndrome | TNFRSF1A (TNFR1) | AD | >7 days | Childhood | Intermittent migratory erythematous macules and edematous plaques overlying areas of myalgia, often on limbs Periorbital edema |
Migratory myalgia Conjunctivitis Serositis Amyloidosis |
| Systemic-onset juvenile idiopathic arthritis (SoJIA) | Polygenic | Varies | Daily (quotidian) | Peak onset at 1-6 yr | Nonfixed erythematous rash; may be urticarial With or without dermatographism With or without periorbital edema |
Polyarthritis Myalgia Hepatosplenomegaly Lymphadenopathy Serositis |
| PLAID | PLCG2 | AD | N/A | Infancy | Urticaria induced by evaporative cooling Ulcers in cold-exposed areas |
Allergies Autoimmune disease Recurrent sinopulmonary infections Elevated IgE antibody levels Decreased IgA and IgM antibody levels Often elevated antinuclear antibody titers |
AD, Autosomal dominant; AR, autosomal recessive; HIDS, hyperimmunoglobulinemia D syndrome; FCAS, familial cold-induced autoinflammatory syndrome; N/A, not available; PLAID, PLCγ2-associated antibody deficiency and immune dysregulation.
A typical hive is an erythematous, pruritic, raised wheal that blanches with pressure, is transient, and resolves without residual lesions, unless the area was intensely scratched. In contrast, urticaria associated with serum sickness reactions, systemic lupus erythematosus (SLE), or other vasculitides in which a skin biopsy reveals a small-vessel vasculitis, often have distinguishing clinical features. Lesions that burn more than itch, last >24 hr, do not blanch, blister, heal with scarring, or that are associated with bleeding into the skin (purpura) suggest urticarial vasculitis. Atypical aspects of the gross appearance of the hives or associated symptoms should heighten concern that the urticaria or angioedema may be the manifestation of a systemic disease process ( Table 173.4 ).
Table 173.4
Distinguishing Features Between Urticaria and Systemic Urticarial Syndromes
From Peroni A, Colato C, Zanoni G, Girolomoni G: Urticarial lesions: if not urticaria, what else? The differential diagnosis of urticaria, J Am Acad Dermatol 62(4):559, 2009.
| COMMON URTICARIA | URTICARIAL SYNDROMES (≥1 of following) |
|---|---|
| Only typical wheals: Erythematous edematous lesions Transient (<24-36 hr) Asymmetric distribution Resolution without signs No associated different elementary lesions (papules, vesicles, purpura, crustae) Pruritic (rarely stinging/burning) Possibly associated with angioedema No associated systemic symptoms |
Atypical “wheals”: Infiltrated plaques Persistent (>24-36 hr) Symmetric distribution Resolution with signs (hypo/hyperpigmentation, bruising, or scarring) Associated different elementary lesions (papules, vesicles, purpura, scaling, crustae) Not pruritic; rather painful or burning Usually no associated angioedema Often associated with systemic symptoms (fever, malaise, arthralgia, abdominal pain, weight loss, acral circulatory abnormalities, neurologic signs |
Physical Urticaria
Physically induced urticaria and angioedema share the common property of being induced by an environmental stimulus, such as a change in temperature or direct stimulation of the skin with pressure, stroking, vibration, or light (see Table 173.2 ).
Cold-Dependent Disorders
Cold urticaria is characterized by the development of localized pruritus, erythema, and urticaria/angioedema after exposure to a cold stimulus. Total body exposure, as seen with swimming in cold water, can cause massive release of vasoactive mediators, resulting in hypotension, loss of consciousness, and even death if not promptly treated. The diagnosis is confirmed by challenge testing for an isomorphic cold reaction by holding an ice cube in place on the patient's skin for 5 min. In patients with cold urticaria, an urticarial lesion develops about 10 min after removal of the ice cube and on rewarming of the chilled skin. Cold urticaria can be associated with the presence of cryoproteins such as cold agglutinins, cryoglobulins, cryofibrinogen, and the Donath-Landsteiner antibody seen in secondary syphilis (paroxysmal cold hemoglobinuria). In patients with cryoglobulins the isolated proteins appear to transfer cold sensitivity and activate the complement cascade on in vitro incubation with normal plasma. The term idiopathic cold urticaria generally applies to patients without abnormal circulating plasma proteins such as cryoglobulins. Cold urticaria has also been reported after viral infections. Cold urticaria must be distinguished from the familial cold autoinflammatory syndrome (see later, Diagnosis) ( Table 173.5 ; see also Table 173.3 and Chapter 188 ).
Table 173.5
Hereditary Diseases With Cold-Induced Urticaria
From Kanazawa N: Hereditary disorders presenting with urticaria, Immunol Allergy Clin NORTH Am 34:169–179, 2014 (Table 4, p 176).
| EPISODIC SYMPTOMS | SUSTAINED/PROGRESSIVE SYMPTOMS | ||
|---|---|---|---|
| CAPS | FCAS | Urticarial rash, arthralgia, myalgia, chills, fever, swelling of extremities | Renal amyloidosis |
| MWS | Urticarial rash, arthralgia, chills, fever | Sensorineural deafness, renal amyloidosis | |
| CINCA | Fever | Rash, arthritis, chronic meningitis, visual defect, deafness, growth retardation, renal amyloidosis | |
| NAPS12 (FCAS2) | Fever, arthralgia, myalgia, urticaria, abdominal pain, aphthous ulcers, lymphadenopathy | Sensorineural deafness | |
| PLAID (FCAS3) | Urticaria induced by evaporative cooling, sinopulmonary infections | Serum low IgM and IgA levels; high IgE levels; decreased B and NK cells; granulomata; antinuclear antibodies | |
CAPS, Cryopyrin-associated periodic syndromes; FCAS, familial cold-induced autoinflammatory syndrome; MWS, Muckle-Wells syndrome; CINCA, chronic infantile neurologic cutaneous articular syndrome; NAPS, NLRP-12–associated periodic syndrome; PLAID, PLCG2-associated antibody deficiency and immune dysregulation.
Cholinergic Urticaria
Cholinergic urticaria is characterized by the onset of small, punctate pruritic wheals surrounded by a prominent erythematous flare and associated with exercise, hot showers, and sweating. Once the patient cools down, the rash usually subsides in 30-60 min. Occasionally, symptoms of more generalized cholinergic stimulation, such as lacrimation, wheezing, salivation, and syncope, are observed. These symptoms are mediated by cholinergic nerve fibers that innervate the musculature via parasympathetic neurons and innervate the sweat glands by cholinergic fibers that travel with the sympathetic nerves. Elevated plasma histamine values parallel the onset of urticaria triggered by changes in body temperature.
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