Updated: July 2019
Updated: February 2014
Originally posted: September 2004
Allen P. Kaplan, MD
Medical University of South Carolina
Dept. of Medicine: Pulmonary 96 Jonathan Lucas Street
Charleston, SC 29425
Urticaria is a transient erythematous swelling of the skin, associated with itching, which usually resolves within 24 hours. It is caused by degranulation of histamine containing cells (mast cells) in the superficial dermis.
Urticarial lesions itch, have a central white wheal that is elevated, and are surrounded by an erythematous halo. The lesions are typically rounded and circumscribed. Characteristically, hives should blanch with pressure; they generally resolve within 24 hours, and leave no residual scar or changes to the skin. The redness is due to dilated blood vessels in the superficial layers of the skin which have responded to histamine and is then augmented by a local neural reflex (axon reflex) initiated by the same nerve fibers that mediate itch. The wheal is due to leakage of these vessels and as fluid extravasates, compresses the vessels beneath so that the central area appears clear.
Angioedema often accompanies urticaria as the swelling results from the same processes that cause hives but involves small blood vessels (venules) in deeper layers of the skin.
Urticaria is commonly classified by duration. If hives are present for less than six weeks, the process is considered “acute”. If urticaria persists beyond 6 weeks, it is designated “chronic”. The causes and mechanisms of hive formation are different in each instance, as is the prognosis and approaches to treatment.
Acute urticaria can be divided into two general types, depending on the rate at which hive formation occurs and the length of time it is evident. One type produces lesions that last 1-2 hours and is typically encountered in physically induced hives. The inciting stimulus is present only briefly, and there is prompt mast cell degranulation. Biopsy of such lesions reveals little or no cellular infiltrate. The second type produces a prominent cellular infiltrate, and individual lesions can last as long as 36 hours. This type is encountered with food or drug reactions, delayed pressure urticaria, chronic spontaneous urticaria, and urticarial vasculitis.
Chronic spontaneous urticaria is characterized by a non-necrotizing perivascular mononuclear-cell infiltrate (CD4 positive T lymphocytes and monocytes) with variable accumulation of eosinophils, neutrophils, and mast cells. Patients with vasculitis and urticaria appear to be a separate sub-population in whom the cause and pathogenesis of hive formation probably involves immune complexes, complement activation, anaphylatoxin formation, histamine release, and neutrophil accumulation, activation, and degranulation.
Acute urticaria, which is an allergic (IgE-mediated) reaction, is common in both children and adults. This type of urticaria is a self-limiting process that occurs when mast cells in the skin are activated, degranulate, and secrete histamine, leukotrienes, platelet activating factor (PAF), enzymes such as tryptase and chymase, cytokines, and chemotactic cytokines (chemokines). When an allergen (for example, a food) to which the person is allergic arrives via the bloodstream to mast cells in the skin, it binds to the IgE, and the mast cells become activated, and degranulate. Allergens that can result in acute urticaria include foods, drugs (particularly antibiotics such as penicillin), and venoms from bee, wasp, yellow jacket, hornet, or fire ants. Virtually any allergen that can be disseminated throughout the body, and to which there is an IgE response, has the potential to cause generalized urticaria.
If an allergic reaction causes hives or swelling, it is usually ingested (food, oral drug) or injected (drugs, stings). If an allergen can penetrate the skin locally, hives will develop at the site of exposure. For example, contact urticaria may occur following exposure to latex gloves if sufficient latex penetrates through the skin.
Acute urticaria can result from "non-specific" stimulation of mast cells, when there is degranulation of mast cells in the absence of a defined allergen. An example is exposure to certain radiocontrast media which changes the osmolality of the environment in which the mast cell resides and can result in degranulation. Patients who develop acute urticarial eruptions can have other accompanying manifestations of a systemic anaphylactic reaction such as wheezing, laryngeal edema, cramps, diarrhea, and hypotension.
Acute viral illnesses in children can be associated with urticarial eruptions which last a few weeks and then spontaneously subside. This typically accompanies symptoms of viral rhinitis, pharyngitis, or bronchitis. When such patients are given an antibiotic, the cause of the hives becomes less clear because a drug reaction becomes an alternative possibility. If penicillin or related antibiotics have been given it is worth performing skin testing for penicillin and/or cephalosporin allergy, rather than making an unsubstantiated assumption that the child is "penicillin allergic." Hepatitis B, infectious mononucleosis (EB virus) and a large number of helminthic parasites may be associated with hives in all age groups.
Codeine and other opiate-derived medications can cause degranulation of mast cells by stimulation of opiate receptors. Urticaria and angioedema can result from agents that alter the metabolism of arachidonic acid, such as aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). These responses to NSAIDs have the potential to be fulminant with generalized hives and swelling.
The Inducible Urticarias
Physically induced hives and/or swelling share the common property of being induced by environmental factors such as a change in temperature or by direct stimulation of the skin by pressure, stroking, vibration, or light. These hives are fleeting i.e. last less than two hours, the only exception being delayed pressure urticaria. The stimulus results in mast cell histamine release and is not followed by any cellular infiltration i.e. no late phase component.
The physical urticarias
Physically induced hives and/or swelling share the common property of being induced by environmental factors such as a change in temperature or by direct stimulation of the skin by pressure, stroking, vibration, or light.
Idiopathic cold urticaria is characterized by the rapid onset of pruritus, erythema, and swelling after exposure to a cold stimulus. The location of the swelling is confined to those parts of the body that have been exposed. When suspected, an ice-cube test can be performed in which an ice cube is placed on the subject's forearm for 4-5 minutes. A positive reaction leads to formation of a hive in the shape of the ice cube within 10 minutes after the stimulus is removed. The time course of this reaction (i.e., cold challenge followed by hive formation as the area returns to body temperature) demonstrates that a two-step reaction has occurred in which exposure to cold is a prerequisite, but hive formation actually occurs as the temperature increases.
One proposal to explain this phenomenon is that patients have an IgE autoantibody to a cold-induced skin antigen. Passive transfer (PK-testing) has been reported in which serum of the patient was injected into the forearm as one could to an intradermal skin test. After 48 hrs. an ice cube test is done at the site and a small wheal is a positive test. This was done in the pre-HIV era. Fractionation of sera revealed IgE to be the pathogenic antibody and is not an IgE cryoglobulin, i.e. does not aggregate in the cold. Thus, sensitization might occur in the cold, and release of mediators proceeds as the cells warm. Studies to test this hypothesis (i.e. to identify a cold-inducible skin antigen) have thus far been negative.
Localized cold urticaria, in which only certain areas of the body urticate with cold contact, has been reported after predisposing conditions such as cold injury; it has also been reported at sites of intracutaneous allergen injections, ragweed immunotherapy, or insect bites.
Systemic cold urticaria yields severe generalized hive formation resulting from systemic cold challenge occurring over covered or uncovered parts of the body. Symptoms are unrelated to exercise or other activities, and the ice-cube test is negative.
Cold-dependent dermatographism demonstrates prominent hive formation if the skin is scratched and then chilled.
Cholinergic or generalized heat urticaria is characterized by the onset of small (1 mm) punctate wheals surrounded by a prominent erythematous flare associated with exercise, hot showers, sweating, and anxiety. Typically, lesions first appear about the neck and upper thorax; when viewed from a distance, hives may not be perceived and the patient appears flushed. Pruritus is a prominent feature of the reaction. Gradually the lesions spread distally to involve the face, back and extremities, and the wheals increase in size. In some patients the hives become confluent and resemble angioedema. Although uncommon, symptoms of more generalized cholinergic stimulation such as lacrimation, salivation, and diarrhea may occasionally be seen. These various stimuli have the common feature of being mediated by cholinergic nerve fibers. Sweat glands are a paradox; they are innervated by sympathetic fibers that release acetylcholine. Cholinergic urticaria is the only form of hives in which emotional stimuli can, in some patients, initiate an urticarial reaction. One study suggests that a subpopulation of patients has IgE antibody to an antigen in sweat.
Exercise-induced anaphylaxis was first described in a series of patients in whom combinations of pruritus, urticaria, angioedema, wheezing, and hypotension occurred as a result of exercise. The hives seen with exercise-induced anaphylaxis are large (10-15 mm), in contrast to the small punctate lesions characteristic of cholinergic urticaria. Subtypes of exercise-induced anaphylaxis have been described that are food-related. In one of these hives is seen only if exercise takes place within 5 hours after eating a food to which the patient is allergic. In a second subtype, hives occurs if exercise is within 5 hours of having eaten but the identity of the food is irrelevant.
Other physically induced forms of urticaria or angioedema
The remaining forms of physically induced hives or swelling are, with the exception of dermatographism, relatively rare disorders.
Dermatographism, the ability to write on the skin, can occur as an isolated disorder that often presents as traumatically induced urticaria. It can be diagnosed by observing the skin after stroking it with a tongue depressor or fingernail are more quantitatively employing a dermographometer where the level of stimulus can be controlled. A white line secondary to reflex vasoconstriction is followed by pruritus, erythema, and a linear wheal, as is seen in a classic wheal-and-flare reaction. It is often an isolated finding of little clinical significance. But symptomatic dermatographism can be very severe and debilitating. It can also be confused with chronic spontaneous urticaria if symptoms are on-going all of the time. Occasionally sensitivity is such that clothing rubbing along the skin during routine activites causes hive formation.
Pressure-induced urticaria typically occurs 4-6 hours after pressure has been applied. Patients may complain of swelling secondary to pressure with normal-appearing skin (i.e., no erythema or superficial infiltrating hive), so that the term angioedema is more appropriate. Others are predominantly urticarial and may or may not be associated with significant swelling. Symptoms occur about tight clothing; the hands may swell with activity such as hammering; foot swelling is common after walking in patients with normal heart function; and buttock swelling may be prominent after sitting for a few hours.
Solar urticaria is a rare disorder in which brief exposure to light causes the development of urticaria within 1-3 minutes. Typically, pruritus occurs first, in about 30 seconds, followed by edema confined to the light-exposed area and surrounded by a prominent erythematous zone caused by an axon reflex. The lesions usually disappear within 1-3 hours. Six subtypes can be defined based on the wave length of light that initiates a reaction. Type I solar urticaria and possibly type IV are IgE antibody dependent. Hereditary protporphyria is a photosensitive urticaria due to mutant protoporphyrin IX
Patients develop small wheals after contact with water, regardless of its temperature.
Chronic Spontaneous urticaria and angioedema (CSU)
CSU is diagnosed when urticaria is present for more than 6 weeks and when it has been determined that an apparent protracted episode of urticaria is not the result of recurrent episodes of acute urticaria. There typically is no identifiable food or medication causing it and the incidence of finding a food allergen as cause when urticaria persists for over six weeks, skin testing or RAST testing for food allergy is not recommended. The lesions can very greatly in shape or size but are roughly circular. They feel somewhat indurated (not flat) and individual lesions last 12-24 hrs. This latter characteristic also distinguishes it from inducible urticarias except for delayed pressure urticaria. Angioedema is present as well in about 40% of cases and may involve the lips, tongue, pharynx, extremities, but not the larynx, and asphyxiation is not a risk. The spontaneous remission rate is 65% within 3 years, 85% within 5 years, and 98% within 10 years.
CSU is not associated with atopy, i.e. there is an increased incidence of atopic dermatitis, allergic rhinitis, or asthma compared to the incidence of these disorders in the absence of chronic urticaria although their IgE level, as a group, is higher than normal. Some patients are dermatographic, although this is usually of milder degree than is seen with the IgE-dependent dermatographism described earlier. The dermatographism may wax and wane, and the urticaria may vary from severe to mild or may intermittently subside. These individuals have a normal white-blood-cell count and erythrocyte sedimentation rate (ESR) and have no evidence of systemic disease. CSU does not appear to be an allergic reaction in the classic sense, even though IgE antibody may be involved and no external allergen is needed to initiate or perpetuate the process. It differs from allergen-induced skin reactions or from physically induced urticaria (e.g., dermatographia or cold urticaria) in that histologic studies reveal a prominent cellular infiltrate around small venules, with an increased number of mast cells.
Association with autoimmune thyroid disease
Patients with CSU have an increased frequency of Hashimoto's thyroiditis. An association has been noted with the presence of antibodies to thyroglobulin, or a microsomal-derived antigen (peroxidase) even if patients are euthyroid. The incidence of thyroid autoantibodies in patients with chronic urticaria is approximately 24%. Thyroid function and thyroid antibodies should be checked in all patients with chronic urticaria. There are no data to suggest that either of these antibodies are pathogenic in terms of hive formation and it is believed that these are associated, parallel, autoimmune events.
There is an increased incidence of IgE antibodies to autoallergens that could have pathogenic significance. Besides the aforementioned IgG antibody to thyroperoxidase and to thyroglobulin, there is also a hgh incidence of IgE antiperioxidase antibody. Nevertheless to be pathogenically significant, thyroid antigen would need to be present in skin. When gene screening was done for any IgE antibody that is not present in normal controls that is directed to self-antigens, a very large number were identified. The most prominent was IgE anti-interleukin 27. Interleukin 27 has; however, been found in skin but is epidermal and the epidermis is normal in CSU. Examination in patients with atopic dermatitis would be of considerable interest.
Treatment of acute urticaria and angioedema
Identification of causative allergens, from the clinical history and blood testing or skin testing for specific IgE antibodies, will enable the individual with urticaria and angioedema to avoid pathogenic allergens. Where a reaction to medication has been implicated, for example, NSAID's or antibiotics, the physician should identify alternative drug groups for future treatment, and if possible perform skin testing with antibiotics to confirm or refute the diagnosis of specific antibiotic allergy. Acute attacks of urticaria or angioedema can be treated with H1 antihistamines. Treatment with 1% menthol in aqueous cream may suppress itching. As wheals can occur where tight clothing is in contact with the skin, loose clothing should be recommended. Itching is worse in warm conditions, and a cool temperature, particularly in the bedroom, is recommended. If urticaria and angioedema have occurred during a systemic anaphylaxis reaction, the patient should be prescribed an auto-injector of epinephrine to carry. Very often an episode of urticaria occurs without any explanation or lasting clinical significance, and without any risk of recurrence. Patients unresponsive to antihistamines can be treated with a tapering course of corticosteroid.
Disorders such as cold urticaria, cholinergic (generalised heat) urticaria, and dermatographism can be treated with antihistamines such as cetirizine or loratidine. If so severe that responsiveness to these is insufficient, higher than normal doses can be used (example loratidine or cetirizine 10 mg up to 4 times a day). In some instances, when severe, a particular drug can be tried, eg, cyproheptadine 4-8 mg, 3-4 times a day, to treat cold urticaria or hydroxyzine 50 mg four times a day for cholinergic urticaria. Solar urticaria (light-induced urticaria) is treated with antihistamines and sun-screens, if sensitivity is to u.v. wavelengths. Sensitivity to visible light wavelengths is particularly difficult since symptoms can occur indoors as well as outdoors. Delayed pressure urticaria is an exception where symptoms more closely resemble CSU (with which it is commonly associated) and responds poorly to antihistamines. It can be treated with omalizumab or cyclosporine. It does respond to corticosteroid, but chronic use is not recommended.
Chronic Spontaneous Urticaria
First generation antihistamines are no longer necessary since we have excellent alternatives when antihistamine resistance is encountered. The addition of 25-50 mg Hydroxamine or Diphendyramine at bedtime can help with sleeplessness or residual itch if urticaria is otherwise controlled such that additional agents are unnecessary. H-2 receptor antagonists and leucotriene antagonists are no longer recommended; there is no good evidence of efficacy beyond the placebo effect.
When the response to antihistamines is unsatisfactory, the agent of choice is Omalizumab administered as a 150 mg or 300 mg subcutaneous injection monthly. The UAS-7 instrument measures itch and urticaria on a 0 – 3 scale and multiplies by 7 days/week. Thus a score of 42 is maximal (worst). It is a useful tool for following the clinical course of patients and was employed in three, phase 3 studies of over 300 patients each. A striking dimination of symptoms was observed in patients refractory to antihistaminics and leucotriene antagonists with a weekly score of 6 or less in about 60-70% of patients and complete control, i.e. a score of zero, in 40-50%.
Figure - Symptom score demonstrating response to 300 mg Omalizumab vs placebo during a 6 month trial.
When therapy was discontinued after a 6 months trial, symptoms recurred, and later studies suggest that even 1 yr. is not sufficient to be able to stop the drug and have a significant number who do not relapse. We do know that restarting omalizumab after a relapse has occurred leads to excellent disease control once again. Angioedema or symptoms of delayed pressure urticaria respond along with the urticaria.
The rate of response suggests two groups of patients. There are rapid responders i.e. with one week (i.e. one injection) while others show a slower, progressive diminution of symptoms over 16 weeks i.e. 4 injections. IgE levels drop towards zero soon after administration, bound IgE (to mast cells and basophils), appears to dissociate in the presence of omalizumab, and the IgE receptor is downregulated. Any or all of these may lead to mast cell desensitization accounting, depending on which effect predominates, for the rapid and slower responding subjects. When the response appears to be unsatisfactory after at least 4 doses, one may increase further to 450 mg or even 600 mg or decrease the interval of a 300 mg dose to every 2-3 weeks. This is based in part-marketing experience and has not been formally studied. Although the 150 to 300 mg doses are approved, all studies demonstrated superior efficacy at 300 mg.
If antihistamines treat 45% of patients, and omalizumab is successful in the remaining 55%, it is estimated that both drugs should be effective in about 83% of patients with CSU. When a response to omalizumab is not seen, the next drug of choice is cyclosporine. A typical adult dose is 200 mg and it is recommended that 3.5 mg/kg not be exceeded. Because of possible side effects on renal function and blood pressure; patients are checked every 4-6 weeks for BUN, creatinine, urine protein, and blood pressure. The drug can be safely employed and most patients are free of adverse effects. If cyclosporine is discontinued should an adverse effect on creatinine or blood pressure be encountered, it typically reverses within 3 weeks. Frequent monitoring is key. Its efficacy is also at least 70%, as is that of omalizumab and had previously been the medication of choice for anti-histamine resistant patients. The estimated success rate employing all three medications in sequence i.e. after failing antihistamines and Omalizumab is 93%.
Should failure with all three be encountered, there are no studies that recommend what to do. Agents tried previously that have not been clearly shown to have an effect on the disease beyond the 25-30% placebo effect include dapsone, sulfasalazine, hydroxychloroquin, IV gamma globulin, and methotrexate. Tacrolimas is in the same drug category as cyclosporine and might be an alternative. Corticosteroid can be used acutely, but not chronically, for particularly severe episodes. Forty mg/day for 3 doses (stop without a taper) will treat angioedema. A longer course that tapers by 5 mg/day (total of 10 days) can be ameliorative temporarily as one considers alternative agents. Small numbers of patients (anecdotally) have responded to omalizumab and low-dose cyclosporine used in combination.
Urticarial vasculitis can be treated similarly but other agents (that are typically less effective for CSU) may be tried, such as dapsone, hyroxychloroquine, or colchicine. Hydroxychloroquine can be particularly helpful for the treatment of the hypocomplementaemic urticarial vasculitis syndrome. The various types of urticarial vasculitis account for less than 1% of all chronic urticarias. Confirmation by skin biopsy is needed. Clues to its presence are fever, organ involvement other than skin, petechiae and/or pupura, or lesions that scar or last 36 hrs. or more.