Emergency Care of Urticaria

Urticaria, commonly referred to as hives, is a common dermatologic disorder seen in the emergency department (ED). It may be either acute (lasting < 6 wk) or chronic (lasting >6 wk). A large variety of urticaria variants exist, including acute immunoglobulin E (IgE)–mediated urticaria, chemical-induced urticaria (non-IgE-mediated), urticarial vasculitis, autoimmune urticaria, urticaria multiforme, neutrophilic urticaria, cholinergic urticaria, cold urticaria, mastocytosis, Muckle-Wells syndrome, and many others. ^{[1, 2, 3, 4]}

Urticaria appears as raised, well-circumscribed areas of erythema and edema, often with central pallor, that involve the dermis and epidermis and are usually very pruritic. It may be confused with a variety of other dermatologic diseases that are similar in appearance, including atopic dermatitis (eczema), maculopapular drug eruptions, contact dermatitis, insect bites, erythema multiforme, pityriasis rosea, and others. ^[5]

Usually, however, the experienced clinician is able to distinguish these other diseases from urticaria because of the latter’s distinctive appearance (see the images below), because it is intensely pruritic, and because it blanches completely with pressure. ^[5]

Acute IgE-mediated urticaria is the most benign form of anaphylaxis. It usually occurs independently, but it may be accompanied by the more serious clinical manifestations of anaphylaxis: angioedema and anaphylactic shock. Therefore, the clinician must rule out these more severe syndromes of anaphylaxis in patients presenting with urticaria. The lesions of IgE-mediated urticaria usually last less than 24 hours and are often migratory and leave no residual skin abnormalities. The lesions of urticarial vasculitis usually last longer than 24 hours, are both painful and pruritic, and often leave purpuric and hyperpigmented lesions. ^[6]

The etiologies of both acute and chronic urticaria are numerous. (See Etiology.) The etiologic agent is more likely to be identified in acute urticaria (40-60%) than in chronic urticaria (10-20%). In a survey of 250 patients treated in a Portuguese pediatric emergency department for acute urticaria, the most common etiologies were undetermined (44%), infections (22%), foods (12%), insect stings or bites (9%), and drugs (8%). ^[7]

For a general discussion of urticaria, see the overview topic Acute Urticaria.

Prognosis

The prognosis in acute urticaria is excellent. This condition is usually self-limited and commonly resolves within 24 hours, though it may last up to 6 weeks. The prognosis in chronic urticaria is more guarded and depends on the comorbid disease causing the urticaria, as well as on the response to therapy. It lasts more than 6 weeks and may continue for years, despite aggressive therapy.

Workup

For acute urticaria, laboratory studies generally are not indicated. The patient’s history and physical examination should direct any diagnostic studies. For chronic or recurrent urticaria, basic laboratory studies should include a complete blood count (CBC), erythrocyte sedimentation rate (ESR), thyroid-stimulating hormone (TSH) level, and an antinuclear antibody (ANA) test to look for possible causes of the urticaria. ^[8]

Imaging studies generally are not indicated. If, however, a specific finding on clinical examination or history suggests an underlying etiology that may warrant further diagnostic evaluation, imaging studies may be used. ^[9]

If urticarial vasculitis is suspected (urticaria lasting longer than 24 h; significant pain as well as pruritus), biopsy is warranted. A punch biopsy of the lesion should be performed and sent to the pathology laboratory to look for leukocytoclastic vasculitis. ^[6]

Consultations

Consultation with or referral to a dermatologist, allergist, immunologist, or rheumatologist may be appropriate in selected cases, particularly in cases of complicated, recurrent, refractory, severe, or chronic urticaria. Dermatology referral is mandatory if vasculitic urticaria is suspected.

Further inpatient care

In general, patients with urticaria do not require further inpatient care unless their urticaria is severe and does not respond to antihistamine therapy or unless they progress to laryngeal angioedema and/or anaphylactic shock or have comorbidities that necessitate inpatient therapy.

Further outpatient care

Most patients with urticaria can be treated at home on nonsedating H1 antihistamines (ie, cetirizine, levocetirizine, loratadine, desloratadine, fexofenadine). If these drugs are not effective, the sedating antihistamines diphenhydramine (50 mg q6h) or hydroxyzine (50 mg q6h for 24-48 h) may be used or, in refractory cases, use a combination of H1 and H2 antihistamines plus oral glucocorticoids. If these therapies are not effective, consultation should be obtained.

If the patient has angioedema that is treated successfully in the ED, the patient should be sent home with an EpiPen prescription and told to keep it with him or her at all times and to use it if swelling of the lips, tongue, face develops or if his or her voice acutely become hoarse.

Consultation with or referral to a dermatologist, allergist, immunologist, or rheumatologist may be appropriate in cases of suspected urticarial vasculitis and in cases of refractory chronic or recurrent urticaria.

Patient education

Education regarding avoidance of the suspected offending allergen is essential.

For patient information, see the Allergy Center and Skin, Hair, and Nails Center, as well as Hives and Angioedema.

Urticaria results from the release of histamine, bradykinin, leukotriene C4, prostaglandin D2, and other vasoactive substances from mast cells and basophils in the dermis. These substances cause extravasation of fluid into the dermis, leading to the urticarial lesion.

The intense pruritus of urticaria is a result of histamine released into the dermis. Histamine is the ligand for 2 membrane-bound receptors, the H1 and H2 receptors, which are present on many cell types. The activation of the H1 histamine receptors on endothelial and smooth muscle cells leads to increased capillary permeability. The activation of the H2 histamine receptors leads to arteriolar and venule vasodilation that contribute to the swelling. ^[10]  Urticarial lesions are usually transient and rapidly enlarge over the course of an hour or so and resolve within 24 hours. Any area of the skin may be affected. 

This process is caused by several mechanisms:

• The type I allergic immunoglobulin E (IgE) response is initiated by antigen-mediated IgE immune complexes that bind and cross-link Fc receptors on the surface of mast cells and basophils, thus causing degranulation with histamine release.

• The type II allergic response is mediated by cytotoxic T cells, causing deposits of immunoglobulins, complement, and fibrin around blood vessels. This leads to urticarial vasculitis.

• The type III immune-complex disease is associated with systemic lupus erythematosus and other autoimmune diseases that cause urticaria. ^[11]

Complement-mediated urticarias include viral and bacterial infections, serum sickness, and transfusion reactions. Urticarial transfusion reactions occur when allergenic substances in the plasma of the donated blood product react with preexisting IgE antibodies in the recipient.

Certain drugs (opioids, vecuronium, succinylcholine, vancomycin, and others) as well as radiocontrast agents cause urticaria due to mast cell degranulation through a non-IgE-mediated mechanism. Urticaria from nonsteroidal anti-inflammatory drugs (NSAIDs) may be IgE-mediated or due to mast cell degranulation, and there may be significant cross-reactivity among the NSAIDs in causing urticaria and anaphylaxis. ^[12]

The physical urticarias in which some physical stimulus causes urticaria include immediate pressure urticaria, delayed pressure urticaria, cold urticaria, and cholinergic urticaria. ^[13]  Cold urticaria may produce severe symptoms, including anaphylaxis. ^[14]

For some urticarias, especially chronic urticarias, no cause can be found, despite exhaustive efforts. These are the so-called idiopathic urticarias, although most of these are chronic autoimmune urticaria as defined by a positive autologous serum skin test (ASST). ^[15] This test is not specific for autoantibodies against a specific antigen or diagnostic of a specific disease state. ^[16] To date, no reliable test exists to identify with certainty if chronic urticaria is autoimmune or nonautoimmune in the specific patient. ^[17]

Coronavirus disease 2019 (COVID-19) vaccination

Type I IgE-mediated allergic reactions to COVID-19 vaccines are a response to ancillary vaccine ingredients rather than the active ingredients. Polyethylene glycols and cross‐reactive polysorbate 80 have been named as specific culprits. Severe reactions that include anaphylaxis are quite rare, in the range of 2.5-11.1 per million. Allergy testing should be performed in patients with severe allergies to the initial vaccination dosage or with a documented history of severe allergies to vaccine ingredients. ^[18]

The cause of acute generalized urticaria often is undetermined (some sources report that the cause is undetermined in more than 60% of cases). Known causes include the following:

• Infections, such as pharyngitis, gastrointestinal infections, genitourinary infections, respiratory infections, fungal infections (eg, dermatophytosis), malaria, amebiasis, hepatitis, mononucleosis, coxsackievirus, mycoplasmal infections, infestations (eg, scabies), coronavirus disease 2019 (COVID-19), HIV, and parasitic infections (eg, ascariasis, strongyloidiasis, schistosomiasis, trichinosis)

• Caterpillars and moths ^[19]

• Foods (particularly shellfish, fish, eggs, cheese, chocolate, nuts, berries, tomatoes)

• Drugs (eg, penicillins, sulfonamides, salicylates, nonsteroidal anti-inflammatory drugs [NSAIDs], morphine, codeine, antihistamines, vancomycin, insulin ^[20] , anesthesia muscle relaxants, COVID-19 vaccination)

• Environmental factors (eg, pollens, chemicals, plants, danders, dust, mold)

• Exposure to latex

• Exposure to undue skin pressure, cold, or heat

• Insect stings (eg, bees, wasps, hornets, fire ants)

• Emotional stress

• Exercise

• Blood and blood product transfusions

• Pregnancy (ie, pruritic urticarial papules and plaques of pregnancy [PUPPP])

Chronic urticaria can be related to all of the above as well as to the following:

• Autoimmune disorders (systemic lupus erythematosus [SLE], rheumatoid arthritis, polymyositis, thyroid autoimmunity, and other connective tissue diseases); probably up to 50% of chronic urticaria is autoimmune ^{[15, 17, 21, 22]}

• Cholinergic urticaria induced by emotional stress, heat, or exercise; examine for other signs of cholinergic stimulation including lacrimation, salivation, and diarrhea. ^[13]

• Chronic medical illness, such as hyperthyroidism, amyloidosis, polycythemia vera, malignant neoplasms, lupus, lymphoma, and many others ^[23]

• Cold urticaria, cryoglobulinemia, cryofibrinogenemia, or syphilis ^[13]

• Mastocytosis ^[24]

• Inherited autoinflammatory syndromes ^[25]

• The etiology of chronic urticaria is undetermined in at least 80-90% of patients. ^[26]

Urticaria pigmentosa is a familial dermatologic disorder characterized by hyperpigmented (yellow, tan, or brown) papules or plaques that may be associated with lymphoproliferative disorders. These lesions are composed of mast cells. When the skin overlying an individual lesion of urticaria pigmentosa is stroked, a linear wheal is formed; this characteristic and diagnostic sign is known as the Darier sign. ^[27]   Wheals present with angioedema in 40% of pediatric urticaria cases. ^[28]  

Recurrent urticaria can be related to the following:

• Sun exposure -Solar urticaria, occurring only on skin exposed to the sun ^[29]

• Exercise (cholinergic urticaria)

• Emotional or physical stress

• Water (aquagenic urticaria)

In the United States, acute urticaria affects 15-20% of the general population at some time during their lifetime. The frequency of urticaria internationally is similar to that in the United States.

Urticaria can occur in any age group, although chronic urticaria is more common in the fourth and fifth decades. Incidence rates for acute urticaria are similar for men and women; chronic urticaria occurs more frequently in women (60%). No race-related variation in incidence is noted.

An Italian study of 314 pediatric patients admitted to the emergency department with acute urticaria found that there was a significant predilection for male sex in this patient population. ^[30]

Pruritus (itching) and rash are the primary manifestations of urticaria, and permanent hyperpigmentation or hypopigmentation are rare. Neither acute nor chronic urticaria results in long-term consequences other than anxiety and depression. The depression can be severe enough to lead to suicide in rare cases. In addition, many of the diseases associated with chronic urticaria may cause very significant morbidity and mortality (eg, malignancies, systemic lupus erythematosus).

Patient history

Information regarding history of previous urticaria and duration of rash and itching is useful for categorizing urticaria as acute, recurrent, or chronic. For chronic or recurrent urticaria, important considerations include previous causative factors and the effectiveness of various treatments. ^[2]

Ask about precipitants, such as heat, cold, pressure, exercise, sunlight, emotional stress, or chronic medical conditions (eg, hyperthyroidism, systemic lupus erythematosus [SLE], rheumatoid arthritis, polymyositis, amyloidosis, polycythemia vera, lymphoma and other malignant neoplasms).

Ask about other medical conditions that can cause pruritus (usually without rash), such as diabetes mellitus, chronic renal insufficiency, primary biliary cirrhosis, or other nonurticarial dermatologic disorders (eg, eczema, contact dermatitis).

Ask about family and personal medical history of angioedema, which is urticaria of the deeper tissues and can be life threatening if it involves the larynx and vocal cords. Causes specific to angioedema include hereditary angioedema (a deficiency in C1-inhibitors) and acquired angioedema (associated with angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptor blockers [ARBs]). ^[31] Characteristics of angioedema include the following ^[5] :

• Vasodilation and exudation of plasma into deeper tissues than is seen in simple urticaria

• Swelling that is generally nonpitting and nonpruritic and usually occurs on the mucosal surfaces of the respiratory tract (lips, tongue, uvula, soft palate, and larynx) and gastrointestinal tract (swelling of the intestine leading to severe abdominal pain)

• Hoarseness, the earliest sign of laryngeal edema (ask the patient if he or she has had a voice change)

For acute urticaria, ask about possible precipitants, such as the following ^[10] :

• Recent illness (eg, fever, sore throat, cough, rhinorrhea, vomiting, diarrhea, headache, exposure to coronvirus disease 2019 [COVID-19])

• Medication use, including penicillins, cephalosporins, sulfas, diuretics, aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), iodides, bromides, quinidine, chloroquine, vancomycin, isoniazid, antiepileptic agents, and other agents

• Intravenous radiocontrast media

• Travel (amebiasis, ascariasis, strongyloidiasis, trichinosis, malaria)

• Foods (eg, shellfish, fish, eggs, cheese, chocolate, nuts, berries, tomatoes)

• New perfumes, hair dyes, detergents, lotions, creams, or clothes

• Exposure to new pets (dander), dust, mold, chemicals, or plants

• Pregnancy (usually occurs in last trimester and typically resolves spontaneously soon after delivery)

• Contact with nickel (eg, jewelry, jeans stud buttons), rubber (eg, gloves, elastic bands), latex, industrial chemicals, and nail polish

• Sun or cold exposure

• Exercise

Physical examination

Urticaria is characterized by blanching, raised, palpable wheals, which can be linear, annular (circular), or arcuate (serpiginous). These lesions occur on any skin area and are usually transient and migratory. These lesions are often separated by normal skin, but may coalesce rapidly to form large areas of erythematous, raised lesions that blanch with pressure. Dermographism may occur (urticarial lesions resulting from light scratching).

The physical examination should focus on conditions that might precipitate urticaria or could be potentially life threatening, as follows ^[5] :

• Angioedema of the lips, tongue, or larynx

• Individual urticarial lesions that are painful, long-lasting (longer than 36-48 h), or ecchymotic; also, urticarial lesions that leave residual hyperpigmentation or ecchymosis upon resolution (suggesting urticarial vasculitis)

• The presence of systemic signs or symptoms, particularly fever, arthralgias, arthritis, weight changes, bone pain, or lymphadenopathy

• Scleral icterus, hepatic enlargement, or tenderness that suggests hepatitis or cholestatic liver disease

• Thyromegaly suggesting autoimmune thyroid disease; joint examination for any evidence of connective tissue disease, rheumatoid arthritis, or systemic lupus erythematosus (SLE)

• Lungs for pneumonia or bronchospasm (asthma)

• Skin for evidence of bacterial or fungal infection

The differential diagnosis includes the following:

• Allergic Contact Dermatitis

• Atopic Dermatitis

• Drug Eruptions

• Erythema Multiforme

• Henoch-Schonlein Purpura (Anaphylactoid Purpura)

• Insect Bites

• Mastocytosis

• Pityriasis Rosea

• Scabies

• Urticarial Vasculitis

• Sweet syndrome

Other problems to consider include the following:

• Neurodermatitis

• Eczema

• Urticaria pigmentosa

Potential diagnostic pitfalls include the following:

• Missing the diagnosis of life-threatening laryngeal angioedema in a patient presenting with the primary complaint of urticaria (avoidable by always asking the patient if he or she has had a change in his or her voice or hoarseness)

• Missing the diagnosis of anaphylactic shock in a patient presenting with acute urticaria

• Missing the diagnosis of severe asthma in a patient presenting with acute urticaria

Prehospital care

Timely transport to the emergency department (ED) for any patient with signs or symptoms of an allergic reaction, including urticaria, angioedema, or anaphylactic shock is essential. Acute urticaria may progress to life-threatening angioedema and/or anaphylactic shock in a very short period, although it usually presents as rapid-onset shock with no urticaria or angioedema. ^[32] (See Anaphylaxis.)

If associated angioedema is present, especially if laryngeal angioedema (eg, hoarseness, stridor) is suspected, prehospital administration of 0.3-0.5 mg of intramuscular epinephrine may be warranted. If associated bronchospasm is present, prehospital nebulized albuterol may be warranted.

Other measures may be appropriate, such as continuous ECG monitoring, blood pressure and pulse oximetry monitoring, rapid infusion of intravenous (IV) crystalloids and intravenous epinephrine if the patient is hypotensive (anaphylactic shock), and administering oxygen. Diphenhydramine (25 mg IV or 50 mg intramuscularly [IM] or orally [PO]) or hydroxyzine (50 mg IM or PO) should be administered ^[9] if they are available.

Emergency department care

The management of urticaria is straightforward and typically is not altered by underlying etiology. The mainstay is avoidance of further exposure to the antigen (if known). Pharmacologic treatment also plays a role. In selecting medications for urticaria, it is important to avoid prescribing those that may have significant drug-drug interactions (especially true with ranitidine and cimetidine, which are both inhibitors of the P450 enzyme system in the liver).

Antihistamines are the first line of therapy for urticaria. ^[9] Most cases of mild-to-moderate acute urticaria can be treated with nonsedating H1 antihistamines. ^[33] These agents block the histamine response in sensory nerve endings and blood vessels through competitive inhibition of histamine at the H1 receptor, which mediates wheal and flare reactions, bronchial constriction, mucus secretion, smooth muscle contraction, and edema.

Diphenhydramine and hydroxyzine are the most commonly used H1-blocking antihistamines for urticaria. They act more rapidly than the minimally sedating H1-blocking antihistamines (see below). These medications are potentially sedating, and the patient should not be allowed to drive within 6 hours of their administration.

H1-blocking antihistamines are effective in relieving the pruritus and rash of acute urticaria in most cases. Their effects are dose related, but higher doses may cause excessive sedation, as well as serious anticholinergic side effects, such as hypotension, central nervous system (CNS) depression, urinary retention, and cardiac arrhythmias. ^[34]

Newer H1-blocking minimally sedating antihistamines are now available and include cetirizine (10 mg PO), levocetirizine (5 mg PO), loratadine (10 mg PO), desloratadine (5 mg PO), and fexofenadine (180 mg PO). In a phase III randomized, controlled trial among 262 patients, intravenous (IV) cetirizine was found to be as efficacious as IV diphenhydramine at improving 2-hour pruritus scores. Furthermore, the cetirizine group outperformed the diphenhydramine group for change from baseline sedation score at 2 hours (0.1 versus 0.5; P=.03), average time spent in treatment center (1.7 hours versus 2.1 hours; P=.005), return to treatment center (5.5% versus 14.1%; P=.02), and incidence of adverse events (3.9% versus 13.3%). ^[35]

If acute urticaria persists for more than 24-48 hours, the minimally sedating antihistamines should be prescribed, with supplementation with the sedating antihistamines if the pruritus and urticaria are refractory to the longer-acting, minimally sedating antihistamines. ^[5]

In cases of severe or persistent urticaria, H2 antihistamines, such as cimetidine, famotidine, and ranitidine, may be added. H2 antihistamines are reversible, competitive blockers of histamine at H2 receptors, particularly those in gastric parietal cells. These H2 antagonists are highly selective, do not affect H1 receptors, and are not anticholinergic agents. They block the vasodilation mediated by the H2 receptors in blood vessels, possibly leading to less edema formation in urticaria.

H1 and H2 antihistamines are thought to have a synergistic effect and often result in a more rapid and complete resolution of urticaria than H1 antihistamines alone, especially if given simultaneously IV. ^[36] The combination of H1 and H2 antagonists may be useful in acute urticaria as well as chronic idiopathic urticaria not responding to H1 antagonists alone. ^{[37, 38]} This combination of H1 and H2 blockers in IV form also may be useful for itching and flushing in anaphylaxis, pruritus, urticaria, and contact dermatitis.

If a patient with chronic urticaria is refractory to nonsedating antihistamines, doses up to 4 times the recommended maximal dose may be effective. ^[9] If maximum doses of nonsedating antihistamines are not effective, other therapies should be tried. ^{[37, 39]}

Tricyclic antidepressants are a complex group of drugs that have central and peripheral anticholinergic effects, as well as sedative effects, and block the active reuptake of norepinephrine and serotonin. Some, such as doxepin, have antihistamine effects, blocking both the H1 and H2 receptors, and have been used in the treatment of allergic reactions, especially urticaria. Doxepin may be effective in refractory cases of urticaria in doses of 25-50 mg at bedtime or 10-25 mg 3-4 times a day. ^[40]

Glucocorticoids stabilize mast cell membranes and inhibit further histamine release. They also reduce the inflammatory effect of histamine and other mediators. In particular, they decrease the inflammation associated with urticaria resistant to H1- and H2-receptor antihistamine therapy. They do not inhibit mast cell degranulation.

The efficacy of glucocorticoids in acute urticaria remains controversial. In one study, acute urticaria improved more quickly in a prednisone-treated group than in the placebo group. ^[41] In adults, prednisone 40-60 mg/d for 5 days is a reasonable regimen. In children, the treatment is 1 mg/kg/d for 5 days. Tapering of the corticosteroid dose is not necessary in most cases of acute urticaria. ^[5] In chronic urticaria, glucocorticoids are often effective, but they should be tapered to the lowest effective dose to prevent long-term complications.

The efficacy of epinephrine in acute urticaria is controversial. ^[9] If angioedema is present with urticaria, 0.3-0.5 mg of epinephrine should be administered intramuscularly. Remember that ACE-inhibitor–induced angioedema usually does not respond to epinephrine or most other common therapies, since it is not an IgE-mediated process. ^{[42, 43]}

The use of methotrexate, colchicine, dapsone, indomethacin, and hydroxychloroquine may be effective in the management of vasculitic urticaria. ^[6]

Urticaria in the setting of coronavirus disease 2019 (COVID-19)

A systematic review of urticaria in COVID-19 patients up to August 1, 2020, reported 26 patients with COVID-19 infection and concomitant urticaria and/or angioedema. While the majority (69%) of patients were over the age of 50 years, the youngest patient was 2 months old. All urticaria cases resolved with antihistamine and/or steroid treatment. No cases recurred or were unresponsive to steroids. The authors recommend considering prednisone treatment on a case-by-case basis. ^[44]

In a COVID-19 case in France, a 27-year-old female medical resident presented with common COVID-19 symptoms and urticaria. COVID-19 testing was positive, and urticaria was confirmed by a dermatologist. Treatment was acetaminophen and antihistamines, with slow resolution of symptoms. ^[45]

Chronic or recurrent urticaria

Refractory cases of chronic urticaria may improve with glucocorticosteroids. Chronic urticaria may benefit from treatment with doxepin. Because of its significant sedative properties, it should be given at bedtime. Topical therapy with 5% doxepin cream or capsaicin may also be used in refractory cases. Cyproheptadine may be useful to suppress recurrent cold urticaria.

One study showed that the combination of a leukotriene receptor antagonist and a nonsedating antihistamine was superior to the antihistamine alone in treating chronic idiopathic urticaria. ^[46]  Cyclosporine and omalizumab have been shown to be effective in cases of refractory chronic urticaria. ^{[38, 47, 48]}  Additionally, omalizumab has been found to be useful in the treatment of chronic inducible urticaria and safe in extended dosing. ^[49]  

Patients with chronic or recurrent urticaria should be referred to a dermatologist for further evaluation and management.