Dermatology

Contact Urticaria Syndrome (Contact Urticaria, Nonimmunologic Contact Urticaria, Immunologic Contact Urticaria, Protein Contact Dermatitis)

Are You Confident of the Diagnosis?

Contact urticaria syndrome (CUS) encompasses immediate contact inflammatory reactions that appear within minutes after contact with a substance.

What you should be alert for in the history

Contact urticaria refers to a wheal and flare reaction and/or eczema following external contact with a substance, usually appearing within 30 minutes and clearing completely within hours, typically without residual signs. CUS may be produced by nonimmunologic (irritant) or immunologic (allergic) mechanisms. Protein contact dermatitis (PCD) represents a subset of immunologic mechanisms, in which repeated exposure to the urticariant causes the urticarial lesions to transform into dermatitis (eczema).

These conditions should be distinguished from allergic contact dermatitis, which is a delayed type of induced sensitivity that develops hours to days after contact with the offending agent and manifests as varying degrees of erythema, edema, and vesiculation.

CUS can be described in two broad categories: nonimmunologic contact urticaria (NICU) and immunologic contact urticaria (ICU). NICU, the most common form of the disease, is due to vasogenic mediators and does not require presensitization of the patient's immune system to an allergen, whereas ICU does.

ICU reflects a type I hypersensitivity reaction, mediated by allergen-specific immunoglobulin E in a previously sensitized individual. Patients with atopic dermatitis are predisposed to ICU, but no other predisposing factors have been described. In addition, ICU may spread beyond the initial site of contact and progress to generalized urticaria or anaphylactic shock, which may be seen in ICU secondary to latex.

PCD is caused by recurrent exposure to high-molecular-weight proteins that eventually results in an eczematous dermatitis. It has been reported with increasing frequency, most commonly as occupational hand dermatitis in food handlers. Proteins that induce PCD are classified into four groups: 1) fruits, vegetables, spices, plants; 2) animal proteins; 3) grains; and 4) enzymes. As association between atopy and PCD occurs in approximately 50% of affected patients, PCD typically affects the hands, especially the fingertips, and may extend proximally to include the wrist and arms. Some cases of chronic paronychia are characterized by redness and swelling of the proximal nail folds and are considered to be a variety of PCD.

Characteristic findings on physical examination

Manifestations of ICU depend on the dose and exposure route of the responsible substance. Skin lesions include wheal and flare reactions as well as symptoms such as itching, tingling or burning. Wheals appear as the unique symptom in contact urticaria, and eczema can be the only symptom in PCD. ICU can be divided into four stages of progression: 1) localized reaction (redness and swelling) with nonspecific symptoms (itching, tingling, burning); 2) generalized reaction; 3) extracutaneous symptoms (respiratory or gastrointestinal tracts); and 4) anaphylactic shock and rarely, death.

Expected results of diagnostic studies

Diagnosis is based on a complete medical history and skin testing with suspected substances. Skin testing may not be necessary if the patient is able to correlate symptoms to exposure to a specific substance. Details with regards to the patient's employment and activities at the onset of symptoms may assist in targeting a specific substance. If skin testing is warranted, it should be gradated and carefully monitored to manage potential anaphylactic reactions. In vitro techniques are available for only a few allergens, including latex. A skin biopsy is usually not necessary in the routine management of CUS.

The simplest cutaneous provocation test for ICU, NICU and immediate contact dermatitis is the open test. The test substance is applied and gently rubbed on slightly affected skin or on a normal looking 3x3 cm area of the skin, either on the upper back or the flexor side of the upper arm. The reaction in measured at 20, 40, and 60 minutes to avoid missing a positive reaction, which is characterized by a wheal and flare response. A control is rarely required because a positive reaction signifies a NICU or ICU etiology. If most exposed subjects are positive on the first exposure, this defines NICU. Reactions typically appear within 15 to 20 minutes but can be delayed up to 45 to 60 minutes following application of the test substance.

If the open test results are negative, the next diagnostic method of choice for immediate contact reactions is the prick test. The test substance is applied to the flexor side of the forearm and pierced into the skin using a lancet. The reaction is usually measured at 30 minutes. If there is a positive reaction, a control is required. This is accomplished by using histamine hydrochloride as a positive control and physiologic saline as a negative reference. As only a small amount of test substance is introduced into the skin, there is a low risk of anaphylaxis.

If internal organs have been involved in prior urticarial episodes, it is imperative to begin ICU testing with diluted allergen concentrations and to use serial dilutions to minimize allergen exposure. Trained personnel and resuscitation equipment should be readily available as life-threatening reactions have been documented during skin tests.

Open and prick tests are commonly used when testing for PCD. Patch-test results are usually negative unless there is a concomitant allergic contact dermatitis.

Scratch and intradermal testing are not routinely utilized unless open and patch testing are both negative. In the scratch test, an area of the skin is superficially scratched with needles after the test substance has been applied. The scratches are approximately 5mm, and there should be no bleeding. This test is also measured in 30 minutes. In the intradermal test, the test substance is injected strictly intradermally at a concentration of 1/100 of the prick test. The interpretation of intradermal test reactions is difficult and a positive reaction is characterized by a small wheal approximately 3mm in size. Normal controls are mandatory.

Diagnosis confirmation

The differential diagnosis of CUS includes the following entities:

  1. Acquired angioedema (painless, nonpruritic, nonpitting swelling of the skin classified into type I commonly associated with B-cell lymphoproliferative disorders and type II with an antibody directed against the C1 inhibitor molecule);

  2. Hereditary angioedema (painless, nonpruritic, nonpitting swelling of the skin secondary to C1-inhibitor molecule deficiency);

  3. Allergic contact dermatitis (delayed type of induced sensitivity that develops hours to days after contact with the offending agent and manifests as varying degrees of erythema, edema, and vesiculation);

  4. Irritant contact dermatitis (nonspecific response of skin to direct chemical damage that releases mediators of inflammation);

  5. Acute urticaria (one-time event of several hours' duration);

  6. Chronic urticaria (longer than 6 weeks);

  7. Cholinergic urticaria (precipitated by sweating secondary to heat);

  8. Dermographism urticaria (stroking of the skin produces an exaggerated tendency to wheal formation);

  9. Pressure urticaria (immediately or 4 to 6 hours after a pressure stimulus);

  10. Solar urticaria (pruritus, stinging, erythema, and wheal formation after exposure to natural sunlight or artificial light);

  11. Urticarial vasculitis (histologically shows changes of leukocytoclastic vasculitis).

Who is at Risk for Developing this Disease?

General population-based epidemiologic data is limited, and only occupational relevance has been evaluated in studies. Elpern's studies based in Hawaii demonstrated 46% of patients with contact urticaria had a personal history of atopy, whereas 44% had a family history of atopy. Only 21% of patients without contact urticaria had a personal history of atopy. There was no difference in racial predisposition, a slightly increased incidence in females, and a constant incidence from the second to eighth decades of life.

Workers in the food industries, agriculture, farming, floriculture, health care, plastics, pharmaceutical and other laboratories, as well as hunters, veterinarians, biologists or hairdressers are among those most frequently suffering from contact urticaria. Of note, spina bifida patients are at increased risk of latex sensitization because of early exposure to latex in the number of surgical procedures they endure.

What is the Cause of the Disease?

Etiology

Proteins and also chemicals are involved. More than 85,000 chemicals are currently in use. Low-molecular-weight molecules act as haptens and become antigens through covalent linkages with proteins or macromolecules. Some molecules, such as nickel and palladium, can react non-covalently. Commonly reported causes of NICU include basalm of Peru, benzoic acid, cinnamic alcohol, cinnamic aldehyde, sorbic acid, and dimethylsulfoxide.

ICU may be caused by natural rubber latex, raw meat and fish, semen, antibiotics, some metals (eg, platinum, nickel), acrylic monomers, short-chain alcohols, benzoic and salicylic acids, parabens, polyethylene glycol, polysorbate, and other miscellaneous chemicals.

While NICU is not responsive to antihistamines, it has a response to acetylsalicylic acid and non-steroidal anti-inflammatory drugs. As such, it has been proposed that the pathophysiology involves prostaglandin release from the epidermis rather than histamine release from the mast cells, as previously assumed. In contrast, a type I allergic skin reaction with the release of histamine is the major mechanism of action seen in ICU. Histamine is released after allergen-bound IgE binds to mast cells, basophils, Langerhans cells, and eosinophils, ultimately leading to mucous secretion, airway smooth muscle contraction and mucosal edema.

Pathophysiology

The pathogenesis of PCD is unclear and may involve type I and IV hypersensitivity reactions and/or a delayed reaction due to IgE-bearing Langerhans cells.

Systemic Implications and Complications

As described above, stages 1 and 2 of ICU are confined to the skin. However, the third and fourth stages progress to extracutaneous symptoms. Stage 3 can involve bronchial asthma, rhino-conjunctivitis, orolaryngeal symptoms, and gastrointestinal dysfunction. Stage 4 may ultimately progress to anaphylaxis or an anaphylactoid reaction, and epinephrine is the adrenergic drug of choice in treating these severe reactions.Treatment options are summarized in the Table.

Table 1.

Treatment options for contact urticaria syndrome
Medical Treatment Surgical Procedures Physical Modalities
H1 receptor antagonist None UV radiation/photochemotherapy
H2 receptor antagonist
Second generation antihistamine
Tricyclic antidepressants
Corticosteroids
Leukotriene receptor antagonists
Immunomodulatory agents (cyclosporine, methotrexate)

Treatment Options

Treatment options are summarized in the Table 1.

Optimal Therapeutic Approach for this Disease

- Emphasis should be placed on prevention, which is the ideal approach. A thorough history and appropriate clinical testing will help determine the responsible substances. Once the diagnosis is established, avoidance is almost always possible. Suitable alternatives, when available, should be discussed.

- However, contact with triggering substances may still occur. In these instances, first-line therapy includes the use of H1 receptor antihistamines (diphenhydramine, hydroxyzine), which can suppress the histamine-induced wheal and flare response. Diphenhydramine: 25 to 50mg orally every 6 to 8 hours; hydroxyzine: 10 to 50 mg orally 4 times daily

- H2 receptor antagonists (cimetidine, ranitidine, and famotidine) can be used concomitantly with H1 receptor antagonists, because 15% of skin receptors are of the H2 type. Cimetidine: 400 to 800mg orally twice daily; ranitidine: 150 to 300mg orally twice daily; famotidine: 20 to 40mg orally twice daily

- Nonsedating antihistamines (fexofenadine, loratadine, and cetirizine) have greater receptor specificity, lower penetration of the blood-brain barrier, and are less likely to cause drowsiness or psychomotor impairment. Fexofenadine: 180mg orally daily OR 180mg twice daily; loratadine: 10 to 20mg orally daily; cetirizine: 10mg orally daily

- If antihistamines fail, UV radiation and photochemotherapy may be beneficial as they have been used successfully in the treatment of chronic urticaria. UVA (above 340nm) and UVB (above 300nm) radiation may induce T-lymphocyte apoptosis and reduce mast cells and Langerhans cells in the dermis. Adverse effects include erythema, hyperpigmentation, polymorphic light eruption, and pruritus (due to radiation-induced dryness). Chronic side effects include photoaging and skin cancer.

- Tricyclic antidepressants (doxepin) have H1 and H2 receptor antagonist activity. Dosage is 10 to 25mg and may be gradually increased to 50mg at bedtime, which may reduce the sedating and anticholinergic effects.

- Systemic corticosteroids may be considered when rapid and complete disease control is necessary. Prednisone: 20mg every other day with gradual tapering (many other dose schedules); methylprednisolone: 16mg every other day with gradual tapering (many other dose schedules)

- Leukotriene receptor antagonists (montelukast, zafirlukast, and zileuton) can be effective by inhibiting potent inflammatory mediators.

Montelukast: 10mg orally at sleep; zafirlukast: 20mg orally; zileuton (extended release): 1200mg PO BID

- As a last resort, immunomodulatory agents such as cyclosporine (3 to 5mg/kg reduced over 3 to 4 months) and methotrexate (2.5 to 5 mg PO BID for 3 days of the week) may be utilized to ameliorate symptoms. Long-term therapy is limited due to adverse side effects, which include hypertension and renal toxicity secondary to cyclosporine and bone marrow suppression and hepatitis secondary to methotrexate.

- Patients with immunologic urticaria should purchase medic alert tags delineating their allergens, including potential cross-reacting substances.

- Note, as stated above, the primary goal in the management of patients with CUS is avoidance of the eliciting agent.

Patient Management

CUS is treated by prevention. If the culprit substance is identified, the patient should be advised to avoid that substance and potential cross-reacting substances. If a patient is diagnosed with ICU, a follow-up visit may be warranted to verify the patient understands the condition and its implications. The prognosis is completely dependent on the patient's ability to avoid contact with the substance. The therapeutic options discussed above are only employed if prevention has failed and symptomatic relief is necessary.

Unusual Clinical Scenarios to Consider in Patient Management

Even though a patient may have a history suggestive of a particular substance as the likely urticariant, it is essential to evaluate all possibilities before arriving at a final diagnosis. This is best illustrated with a patient that presented with lip swelling following the use of mouthwash. The patient had a history of ethyl alcohol-induced bronchospasm and ethyl alcohol was suspected as the substance eliciting contact urticaria. However, ethyl alcohol failed to produce any response and instead cinnamic aldehyde, another component of the mouthwash, was found to be the culprit substance. Because of the dramatic clinical manifestations, we question whether there may also have been an immunologic component.

What is the Evidence?

Agarwal, S, Gawkrodger, DJ. "Latex allergy: a health care problem of epidemic proportions". Eur J Dermatol . vol. 12. 2002. pp. 311-5.

(Latex is one of the most common causes of immunologic contact urticaria. This review outlines its pathogenesis, clinical manifestations, diagnosis, management, and prevention. It also delineates a list of medical devices that contain latex in the modern operating room, which may be of diagnostic use for both patients and health care providers suffering from this common allergy.)

Amaro, C, Goossens, A. "Immunological occupational contact urticaria and contact dermatitis from proteins: a review". Contact Dermatitis . vol. 58. 2008. pp. 67-75.

(This comprehensive review focuses on the pathogenesis, clinical picture, and literature on proteins that cause immunologic occupation-related skin problems. This is also illustrated with cases observed in a contact-allergy unit.)

Bhatia, R, Alikhan, A, Maibach, HI. "Contact urticaria: present scenario". Indian J Dermatol . vol. 54. 2009. pp. 264-8.

(This thorough review covers the classification, epidemiology, diagnosis, testing, and treatment options available to patients with contact urticaria.)

Doutre, MS. "Occupational contact urticaria and protein contact dermatitis". Eur J Dermatol . vol. 15. 2005. pp. 419-24.

(This concise and focused review serves as a useful foundation for core concepts on contact urticaria and protein contact dermatitis.)

Elpern, DJ. "The syndrome of immediate reactivities (contact urticaria syndrome). An historical study from a dermatology practice. III. General discussion and conclusions". Hawaii Med J . vol. 45. 1986. pp. 10-2.

(This is the last of three installments from a Hawaiian-based practice that attempts to gather more epidemiologic data with regard to contact urticaria syndrome. The first installment explores age, sex, race, and putative substances. The second installment discusses atopic diatheses and drug reactions and this third installment provides an informative summary.)

Gimenez-Arnau, A, Maurer, M, De La Cuadra, J, Maibach, HI. "Immediate contact skin reactions, an update of contact urticaria, contact urticaria syndrome and protein contact dermatitis- - “a never ending story.”". Eur J Dermatol . vol. 20. 2010. pp. 552-562.

(An excellent review of the classic concepts, introduces new compounds responsible for immediate skin reactions, and suggests routes of further investigation.)

Kanerva, L, Elsner, P, Wahlberg, JE, Maibach, HI. "Handbook of occupational dermatology". Springer-Verlag. 2000.

(A comprehensive review of the epidemiology, treatment, and prognosis of occupational diseases, including contact urticaria with a strong focus on the particular antigens and irritants frequently encountered in various work environments. There are also extensive tables of patch-test allergens that include information on concentration and vehicles for patch testing, chemical structure of allergens, sources of exposure, and the clinical presentation of allergic responses.)

Mathias, CGT, Chappler, RR, Maibach, HI. "Contact urticaria from cinnamic aldehyde". Arch Dermatol . vol. 116. 1980. pp. 74-6.

(An interesting case report of a patient presenting with lip swelling following the use of mouthwash. The patient had a history of ethyl alcohol-induced bronchospasm, and ethyl alcohol was suspected as the substance eliciting contact urticaria in the patient. However, ethyl alcohol failed to produce any response and instead cinnamic aldehyde was found to be the culprit substance.)

Tiles, SA. "Approach to therapy in chronic urticaria: when benadryl is not enough". Allergy Asthma Proc . vol. 26. 2005. pp. 9-12.

(This succinct review outlines the treatment options available for chronic urticaria when avoidance of the eliciting substance has failed.)

Warner, M, Taylor, JS, Leow, Yung-Hian. "Agents causing contact urticaria". Clin Dermatol . vol. 15. 1997. pp. 623-35.

(This excellent review focuses on more recently identified immunologic and nonimmunologic agents causing contact urticaria.)
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