Contact Urticaria Syndrome 

Updated: Dec 09, 2016
Author: Saqib Bashir, MBChB, MD, FRCP; Chief Editor: Dirk M Elston, MD 

Overview

Background

Maibach and Johnson[1] defined contact urticaria syndrome in 1975; since then, numerous reports of contact urticaria syndrome caused by a variety of compounds, such as foods, preservatives, fragrances, plant and animal products, and metals, have been made. Because exposure to causal agents for contact urticaria can be similar to exposure to contact irritants (eg, in healthcare workplaces), vigilance is required to ensure that the patient is properly investigated and diagnosed. (See Etiology, Presentation, and Workup.) See the image below.

Urticaria associated with a drug reaction. Urticaria associated with a drug reaction.

Contact urticaria syndrome can be divided in two broad categories: nonimmunologic contact urticaria and immunologic contact urticaria. The former does not require presensitization of the patient's immune system to an allergen, whereas the latter does. However, some contact urticaria reactions of unknown mechanism are unclassified and associated with generalized histamine-type reactions. (See Etiology.)

Staging

The following staging system for contact urticaria syndrome has been described by Amin and Maibach[2] (see Presentation and Workup):

  • Stage 1 - Localized urticaria (redness and swelling); dermatitis (eczema); nonspecific symptoms (eg, itching, tingling, burning sensation)

  • Stage 2 - Generalized urticaria

  • Stage 3 - Bronchial asthma (wheezing); rhinitis, conjunctivitis (eg, runny nose, watery eyes); orolaryngeal symptoms (eg, lip swelling, hoarseness, difficulty in swallowing); GI symptoms (eg, nausea, vomiting, diarrhea, cramps)

  • Stage 4 - Anaphylactoid reactions (shock)

Stages 1 and 2 are characterized only by cutaneous reactions, while stages 3 and 4 demonstrate extracutaneous and systemic reactions.

Pathophysiology

Immunologic contact urticaria reactions are considered immediate IgE-mediated reactions that may spread beyond the site of contact and progress to generalized urticaria. When more severe, immunologic contact urticaria may lead to anaphylactic shock. This can happen, for example, as a result of contact with natural rubber latex. Typically, latex gloves cause a wheal and flare reaction at the site of contact but can generalize to anaphylaxis. Nonimmunologic contact urticaria is thought to be caused by the direct release of vasoactive substances from cells or potentially other granulocytes. However, the precise mechanisms by which both immunologic and nonimmunologic urticaria are elicited remain poorly defined.

Etiology

Nonimmunologic contact urticaria[3]

Nonimmunologic contact urticaria is the most common immediate contact reaction and occurs without prior sensitization in most individuals who are exposed. The symptoms may vary according to the site of exposure, the concentration, the vehicle, the mode of exposure, and the substance itself.

The mechanism of nonimmunologic contact urticaria is incompletely understood. Previously, histamine was assumed to be released from mast cells in response to exposure to an eliciting substance. However, evidence suggests that nonimmunologic contact urticaria may also be mediated by prostaglandins.

Immunologic contact urticaria

Immunologic contact urticaria is less common in clinical practice than is nonimmunologic contact urticaria but is typically more severe and can result in anaphylaxis. Immunologic contact urticaria is a type 1 hypersensitivity reaction mediated by IgE antibodies specific to the eliciting substance or antigen. Therefore, prior immune (IgE) sensitization is presumed to be required for this type of contact urticaria. Sensitization can be at the cutaneous level, but it may also be via other mucosal sites such as in the respiratory or gastrointestinal (GI) tract. The latter 2 routes of sensitization have frequently been reported among patients with immunologic contact urticaria to latex.

Persons with atopic dermatitis are predisposed to immunologic contact urticaria.

Cross-sensitization can also induce immunologic contact urticaria–type reactions. The patient may be sensitized to one protein and cross-react to other proteins that contain the same or similar antigenic components. In the example of latex allergy, patients may experience symptoms from banana, chestnut, and avocado, as well as a number of other fruits, vegetables, and nuts.[4] This phenomenon places patients with immunologic contact urticaria at increased risk for allergy to multiple substances.

Causative agents

Some of the more commonly reported causes of nonimmunologic contact urticaria include the following[5, 6, 7] :

  • Benzoic acid

  • Dimethylsulfoxide (DMSO)

  • Cinnamic aldehyde

  • Sorbic acid

  • Cobalt chloride

  • Trafuril (Ciba)

  • Polyaminopropyl biguanide (in wet wipes)[8]

  • Melon peel[9]

  • Levofloxacin hydrate ophthalmic solution[10]

  • Animal hair (ferrets)[11]

In some patients, nonimmunologic contact urticaria may account for cosmetic intolerance syndrome.[12, 13]

Reported causes of immunologic contact urticaria include the following[5, 14, 6, 15] :

  • Natural rubber latex

  • Raw meat and fish

  • Potatoes

  • Phenylmercuric propionate

  • Hair dye (in a hairdresser)[16]

Foods

Food handlers can develop contact urticaria in response to vegetables, raw meats, and fish and shellfish.[6]

Airborne agents

Importantly, causative agents may be airborne (eg, in a manufacturing facility, plant/animal dander exposure).

For example, some caterpillars (eg, Thaumetopoea pityocampa) have fine hairs that can become scattered and airborne, leading to exposure among forestry workers and recreational visitors to endemic areas, including children.[17] Affected personnel in one study included pinecone or resin collectors, woodcutters, farmers, and stockbreeders.[18] The mechanism is an immunologic contact urticaria that can lead to severe reactions; in one cohort of 16 patients, 80% had angioedema and 14% had severe anaphylaxis. Wheals were seen primarily on the neck and forearms.[19]

Epidemiology

Occurrence in the United States

Much of the epidemiologic data regarding contact urticaria syndrome is from occupational studies, which may therefore skew the reported etiologies. Little data exist regarding contact urticaria syndrome in the general population. Extrapolation of occupational data is difficult because the demography of the occupations concerned may not reflect that of the general population.

Despite the well-known risks of latex allergy in health care workers, Suneja and Belsito suggest that the incidence of immunologic contact urticaria to latex in healthcare workers remains high in the United States, in comparison to falling rates worldwide.[20] In their study based on patch test clinic attendees, they found that 13% of healthcare workers were sensitized to latex.

Atopic individuals and healthcare workers who have a coexisting type IV allergy (allergic contact dermatitis) may be predisposed to latex type I allergic reactions, although the precise contribution of these risk factors is unclear and may be compounded by the presence of irritant dermatitis, which is widespread in healthcare workers.

In a study of volunteer blood donors in southeastern Michigan, none of whom was a medical or dental professional, Ownby et al found that 6.4% had IgE-mediated hypersensitivity to latex.[21]

International occurrence

An older Polish study of patients attending an urticaria clinic found that contact urticaria constituted an estimated 1.1% of all urticaria cases at the facility.

Occupational contact urticaria

Kanerva et al gathered statistical data on occupational contact urticaria in Finland and found that the incidence more than doubled between 1989 (89 cases reported) and 1994 (194 cases reported).[22] Between 1990 and 1994, 815 cases were reported. The most common causes (in decreasing order of frequency) were cow dander, natural rubber latex, and flour/grains/feed.

These causal agents accounted for 79% of all cases. Reflecting on this data, the most affected occupations (per 100,000 workers), in decreasing order of frequency, were bakers, preparers of processed food, and dental assistants.

A large, retrospective Australian study of patients attending an occupational dermatology clinic found healthcare workers to be particularly at risk for contact urticaria from natural rubber latex, but the study also highlighted chefs and hairdressers as being at risk of nonlatex-related contact urticaria. Although a wide variety of industries can be affected, the top 3 were health care, food service, and hairdressing/beauty salons.[23]

In Germany, powdered natural rubber latex gloves have been banned in the workplace since 1998. By 2002, an 80% decrease had occurred in occupational contact urticaria in German healthcare workers.[24]

A Singaporean study showed no difference in sensitization between operating staff and other healthcare workers (8-9% sensitized).[25] This contrasts with older Finnish data,[26] which reported that operating staff were more likely to be sensitized. The contrast may represent changing patterns of glove use in modern health care. However, Singaporean hospital workers with no occupational exposure to latex had a latex sensitization prevalence of 3%.

Latex sensitivity in surgical patients

Spina bifida patients are at increased risk of latex sensitization because of early exposure to latex and the number of surgical procedures to which they are exposed. An Italian study of 80 children with spina bifida found that 40% were radioallergosorbent test (RAST) ̶ positive for latex, although only approximately one third of those were actually symptomatic. Nevertheless, symptoms could be severe, including urticaria and angioedema. Those who were either sensitized or clinically affected were more likely to have had surgery on the first day of life and more likely to have had multiple surgical procedures.[27]

Adults undergoing surgery are also at risk of latex immunologic contact urticaria, with a high risk of systemic consequences, because of direct exposure of viscera to the latex-gloved hands of the surgeon. An Italian study of anaphylactic reactions in cesarean deliveries found an incidence of 1:310 (4 of 1240 cases). All were a result of latex sensitivity, with rash and facial edema developing within 30 minutes of skin incision.[28] Given the high volume of cesarean deliveries performed, obstetric and anesthetic staff must be vigilant for latex allergy, because early intervention can be lifesaving.

Race-, sex-, and age-related demographics

In a Hawaiian study, Elpern demonstrated no racial predisposition in contact urticaria syndrome. White, Asian Filipino, Asian Japanese, and Hawaiian/part Hawaiian were the major groups studied.[29, 30]

Occupational and nonoccupational studies have demonstrated a slightly increased incidence of contact urticaria syndrome in female patients. However, this may reflect the exposure of females to causative agents in the groups studied. Regarding age, Elpern found that the incidence of contact urticaria was constant from the second to the eighth decade. Patients at the extremes of age constituted a smaller proportion of persons with the condition.[30]

The aforementioned Australian study of occupational contact urticaria found a mean age of 31 years (range 15-79 y).[23] However, children with spina bifida are affected at a much younger age, showing evidence of latex sensitization/allergy at approximately age 12 years.[27]

Prognosis

The prognosis in contact urticaria syndrome is entirely dependent on the ability of the patient to avoid etiologic substances. However, even in cases of severe immunologic contact urticaria to latex, the long-term prognosis can be good if patients take an active role in controlling their environment by educating themselves and others and by taking all proper precautions.

Morbidity and mortality

A delayed (48-72 h) allergic eczematous contact dermatitis can result from some compounds that produce immunologic contact urticaria and, to a lesser extent, from compounds that produce the nonimmunologic form. When this occurs in occupational contact urticaria syndrome, debilitating hand dermatitis may ensue. If immediate contact reactions are not specifically sought, routine patch testing may miss the diagnosis.

Contact urticaria syndrome can also extend extracutaneously. In a study of 70 German patients with contact urticaria, 51% had rhinitis, 44% had conjunctivitis, 31% had dyspnea, 24% had systemic symptoms, and 6% had severe systemic reactions during surgery. Extracutaneous contact urticaria syndrome has led to anaphylaxis in severe cases and is believed to be a cause of death intraoperatively in some cases (due to allergy to latex). In fact, topical antibiotics such as bacitracin have also been associated with anaphylactic reactions.[31]

Patient Education

Patient education is critical to prevention. For ubiquitous allergens, such as latex, multiple consumer educational sites are available on the Internet. Most of these sites can be accessed from the US Department of Labor Occupational Safety and Health Administration.

For patient education information, see the Allergies Center and the Skin Conditions and Beauty Center, as well as Hives and Angioedema.

 

Presentation

History

Atopy

Many agents are capable of causing contact urticaria syndrome; therefore, a detailed history is essential in establishing the etiology. A history of previous anaphylaxis should be sought, as should a personal or family history of atopy.

In the aforementioned Hawaiian study, Elpern demonstrated that 46% of patients with contact urticaria syndrome had a personal history of atopy and that 44% had a family history of atopy. Only 21% of patients without contact urticaria syndrome had a personal history of atopy.[29, 30]

A Polish study found that among patients with contact urticaria attending an urticaria clinic, only 1 of 5 patients had a personal or family history of atopy, a lower percentage than in the Elpern study.

Timing

Contact urticaria reactions appear within minutes to approximately 1 hour after exposure of the urticarial causal agent to the skin. The patient may report a local burning sensation, tingling, or itching. Swelling and redness may be seen (wheal and flare).

Causal agents

The patient may be able to associate the symptoms to exposure to a specific substance. In some cases, this exposure may include the application of cosmetic products, especially to the face (cosmetic intolerance syndrome).

Details of the patient's employment provide insight into possible causes in the workplace, especially if the symptoms are temporally related to work.

The patient may be able to identify what he or she was doing at the onset of symptoms, again allowing the physician to narrow down the possible causes.

Extracutaneous symptoms

The extent of extracutaneous involvement (eg, asthma, rhinitis, conjunctivitis, GI upset) should be ascertained.

Physical Examination

Signs upon physical examination may be variable depending on when the patient presents to the clinic. At one extreme, the patient may be asymptomatic, while at the other extreme, the patient may have a generalized urticaria with extracutaneous symptoms.[32]

Immunologic and nonimmunologic contact urticaria can display site specificity; for example, the neck and perioral areas are more sensitive than the forearm.[33] This finding can be important in diagnostic testing.

Cutaneous findings

Localized or generalized wheals may be present, especially on the hands, or eczematous skin may be observed if contact urticaria syndrome has progressed to or developed in association with an eczematous dermatitis. (Contact urticaria in the setting of hand eczema may be overlooked.)

By definition, contact urticaria syndrome lesions disappear within 24 hours of onset. Therefore, the skin may appear healthy, depending on when the patient presents to the physician.

An ordinal scale for scoring erythema is as follows[34] :

  • Slight erythema, either spotty or diffuse - 1+

  • Moderate uniform erythema - 2+

  • Intense redness - 3+

  • Fiery redness with edema - 4+

An ordinal scale for scoring edema is as follows[35] :

  • Slight edema, barely visible or palpable - 1

  • Unmistakable wheal, easily palpable - 2

  • Solid, tense wheal - 3

  • Tense wheal, extending beyond the test area - 4

Respiratory findings

The patient may be in varying degrees of respiratory distress if a respiratory component to the contact urticaria syndrome is involved. Rhinitis may be present, and wheezing may be heard upon auscultation.

Results of the examination, however, may be normal if the disease is quiescent or if no extracutaneous expression is present.

Ocular findings

Conjunctivitis may be seen in active extracutaneous disease.

 

DDx

Diagnostic Considerations

Conditions to consider in the differential diagnosis of contact urticaria include the following:

  • Hereditary angioedema

  • Aquagenic urticaria

  • Cold urticaria

  • Protein contact dermatitis

  • Asthma, allergic rhinitis, allergic conjunctivitis, and anaphylaxis

Differential Diagnoses

 

Workup

Approach Considerations

Commonly used topical application techniques in immunologic and nonimmunologic contact urticaria are the prick test, the chamber prick test, the scratch test, the open test, and the chamber test. In any of the above in vivo tests, performing positive (histamine, 1mg/mL) and negative (normal saline) control tests is important.

Prick testing theoretically has the lowest risk of anaphylaxis, because only minute amounts of allergen are introduced into the skin. However, anaphylaxis is a risk in all of the above test methods if the patient has immunologic contact urticaria.

Laboratory studies

The total serum IgE level does not provide insight into the clinical contribution that an allergen is making to the patient's symptoms.

If the etiology is immunologic contact urticaria, the radioallergosorbent test (RAST) result (for allergen-specific IgE) may be positive for the offending substance. Nonimmunologic contact urticaria cannot be diagnosed by RAST.

Imaging studies

Radiologic imaging is not necessary in the dermatologic workup of contact urticaria syndrome. As a research tool, ultrasonography can be used to document the extent of edema.

In Vivo Tests

The prick test, the scratch test, and the chamber prick test are the most commonly used in vivo techniques for detecting immunologic contact urticaria. However, if these results are negative and immunologic contact urticaria remains in the differential diagnosis, the chamber test, the open test, or the use test may be necessary. An in vitro RAST may also be beneficial for establishing the diagnosis and determining the cross-reactivity (eg, latex and banana).

In all of the above referenced in vitro test methods, contact urticaria can be graded visually by marking the degree of erythema and edema on an ordinal scale.

Nonsteroidal anti-inflammatory drugs (NSAIDs), antihistamines, and exposure to UV light can cause false-negative results, as can tachyphylaxis.

In testing for immunologic contact urticaria in patients with a history of extracutaneous involvement, particular care must be taken to use low concentrations of test substances and to have resuscitation equipment immediately available in case of anaphylaxis.

Use test

In the use test, a research subject known to be affected uses the causative substance in the same way as when the symptoms first appeared; for example, wearing surgical gloves on wet hands to provoke latex immunologic contact urticaria.

Because a use test can provoke anaphylaxis in patients with immunologic contact urticaria, clinicians should proceed cautiously with such testing. However, use testing can be especially helpful in patients with nonimmunologic contact urticaria. A positive reaction appears as a wheal and flare and sometimes an eruption of vesicles.

Serial dilutions are useful in determining the test dose. Examples of concentrations that have been used in dilution series in alcohol vehicles are 250, 125, 62, and 31 mmol/L for benzoic acid and 50, 10, 2, and 0.5 mmol/L for methyl nicotinate.

Initially, the upper back, the flexor aspect of the upper arm, or the forearm is the site used. However, if the reaction is negative, previously or currently affected skin should be tested because site variability exists in the nonimmunologic and immunologic forms of contact urticaria. Repeated use of the same site may result in tachyphylaxis and can cause false-negative results.

Open test

In the open test, 0.1 mL of the test substance is spread over a 3 x 3-cm area on the desired site. Lahti suggests using alcoholic vehicles.[36] The addition of propylene glycol to a vehicle enhances the sensitivity of the test compared with previously used petrolatum and water vehicles.

The test sites are usually read at 20, 40, and 60 minutes to see the maximal response. Immunologic contact urticaria reactions typically appear within 15-20 minutes, whereas nonimmunologic contact urticaria reactions can be delayed up to 45-60 minutes following application.

Chamber test

The chamber test is an occlusive method of applying the substance to be tested. The substances to be tested are applied in small aluminum containers (Finn Chamber, Epitest Ltd; Hyryl, Finland) and attached to the skin via a porous tape. The chambers are applied for 15 minutes, and the results are read at 20, 40, and 60 minutes.

The advantages of this method are that occlusion enhances percutaneous penetration; therefore, the sensitivity of the test is probably higher. Additionally, a smaller area of the skin is required than in an open test. For unexplained reasons, however, the chamber method may provide less responsiveness than the open test.

 

Treatment

Approach Considerations

Patients need to be well versed in the nature of their urticarial reaction (immunologic vs nonimmunologic contact urticaria), in avoidance techniques, and in suitable alternatives.

Patients with immunologic contact urticaria should purchase medic alert tags delineating their allergies, including potential cross-reacting substances. Depending on the degree of reactivity and the ubiquity of the allergen, patients with immunologic contact urticaria may require antihistamines and self-administered epinephrine.

Diet

Affected individuals should avoid foods and food products that trigger their symptoms. One should be aware that food extracts are sometimes used in cosmetics, which may lead to unintended exposure. Additionally, cross-reactivity of latex to foods such as banana, kiwi, and avocado may require additional avoidance.[4]

However, advice regarding the avoidance of cross-reactive foods should be given after appropriate skin prick testing or a RAST because not all individuals are affected in this way.

Inpatient care

Admission for medical care is not routinely indicated for contact urticaria syndrome. Patient transfer is also rarely indicated.

Follow-up

If a patient has immunologic contact urticaria, a follow-up visit to verify the patient's understanding of the condition may be indicated.

Prevention

Affected patients should avoid exposure to trigger substances. A large cohort study following nearly 1000 healthcare workers found that latex-sensitized healthcare workers can reduce or eliminate cutaneous symptoms by wearing nonlatex gloves themselves and ensuring that their coworkers wear nonpowdered latex gloves (or, ideally, nonlatex gloves).

A policy of minimizing glove use and using only powder-free gloves prevented any new sensitizations in the 3-year study period.[37] However, patients with respiratory or systemic features may have to work in a completely latex-free environment.

 

Medication

Medication Summary

Depending on the ubiquity of the allergen, patients with immunologic contact urticaria may be advised to carry antihistamines and self-administered epinephrine. Antihistamines used in the treatment of contact urticaria include the H1-receptor blockers diphenhydramine, hydroxyzine, loratadine, and desloratadine, a loratadine metabolite. Epinephrine, a vasopressor, is used in the treatment of anaphylactoid reactions (stage 4 contact urticaria syndrome).

Antihistamines, First Generation

Class Summary

First-generation antihistamines compete with histamine at the tissue-receptor level, preventing it from mediating its proinflammatory effects.

Diphenhydramine (Benadryl, Diphenhist, Allerdryl)

Diphenhydramine is for symptomatic relief of urticaria symptoms caused by the release of histamine in allergic reactions.

Hydroxyzine (Vistaril)

Hydroxyzine antagonizes H1 receptors in the periphery. It may suppress histamine activity in the subcortical region of the central nervous system.

Antihistamines, Second Generation

Class Summary

Second-generation antihistamines, also known as less-sedating or low-sedation antihistamines, produce less sedation than traditional H1 blockers because they are less lipid-soluble and only cross the blood-brain barrier in small amounts. They also have longer half-lives, allowing less frequent dosing.

Fexofenadine (Allegra)

Fexofenadine competes with histamine for H1 receptors in the GI tract, blood vessels, and the respiratory tract, reducing hypersensitivity reactions. It does not sedate. Fexofenadine is available as a 30-, 60-, or 180-mg tablet. The Allegra ODT tablet is formulated for disintegration in the mouth immediately after administration. Each orally disintegrating tablet contains 30 mg of fexofenadine hydrochloride. The Allegra oral suspension contains 6 mg/mL of fexofenadine hydrochloride (30 mg/5 mL).

Loratadine (Claritin)

Loratadine selectively inhibits peripheral histamine H1 receptors.

Desloratadine (Clarinex)

Desloratadine is a long-acting tricyclic histamine antagonist that is selective for H1 receptors. This agent is a major metabolite of loratadine, which after ingestion is extensively metabolized to active metabolite 3-hydroxydesloratadine.

Levocetirizine (Xyzal)

Levocetirizine is an H1-receptor antagonist, an active enantiomer of cetirizine. It is a second-generation prescription antihistamine.

Corticosteroids

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. These agents modify the body's immune response to diverse stimuli. In patients with generalized urticaria or asthma, systemic glucocorticoids can be highly effective. However, epinephrine and H1 antihistamines are the high-priority and first-line agents in anaphylaxis.

Methylprednisolone (Medrol, Medrol Dosepak, DepoMedrol, SoluMedrol)

Methylprednisolone may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. It is ndicated for severe, prolonged, or anaphylactic reactions. It decreases late immune-mediated complications.

Prednisone (Deltasone, Rayos, Prednisone Intensol, Sterapred, Sterapred DS)

Prednisone is indicated for severe, prolonged, or anaphylactic reactions. It decreases late immune-mediated complications. It must be metabolized to the active metabolite prednisolone for effect. Conversion may be impaired in liver disease.

Alpha/Beta Adrenergic Agonists

Class Summary

These agents are used in the emergency management of systemic allergic reactions or anaphylaxis (eg, urticaria, angioedema, bronchospasm, cardiovascular collapse). The effects are immediate and dramatic. The appropriate use of this class of medication can be lifesaving, especially in the emergency management of anaphylaxis.

Epinephrine (EpiPen, Adrenaline, Twinject)

Epinephrine has alpha-agonist effects that include increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. Beta-agonist effects of epinephrine include bronchodilatation, chronotropic cardiac activity, and positive inotropic effects.