AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Maibach and Johnson¹ defined contact urticaria syndrome (CUS) in 1975; since then, numerous reports of CUS caused by a variety of compounds, such as foods, preservatives, fragrances, plant and animal products, and metals, continue to be reported. Because the exposure to contact urticariants can be similar to contact irritants (eg, health care workplaces), vigilance is required to ensure that the patient is properly investigated and diagnosed because contact urticaria in the setting of hand eczema may be overlooked.

Pathophysiology

CUS can be described in 2 broad categories: nonimmunologic contact urticaria (NICU) and immunologic contact urticaria (ICU). 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, such as that for ammonium persulfate.

NICU is the most frequent 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 NICU is incompletely understood. Previously, histamine was assumed to be released from mast cells in response to exposure to an eliciting substance. However, evidence exists that NICU may be mediated by prostaglandins.

ICU is less frequent in clinical practice than NICU. ICU is a type 1 hypersensitivity reaction mediated by immunoglobulin E (IgE) antibodies specific to the eliciting substance. Therefore, prior immune (IgE) sensitization is required for this type of contact urticaria. Sensitization can be at the cutaneous level, but it may also be via the mucous membranes, such as in the respiratory or gastrointestinal tracts. The latter 2 routes of sensitization have frequently been reported among patients with ICU to latex.

Persons with atopic dermatitis are predisposed toward ICU. In addition, it has been shown for ICU to latex that exposure through mucosa or dermatitic skin enhances the risk of developing immediate hypersensitivity.

ICU reactions may spread beyond the site of contact and progress to generalized urticaria. When more severe, ICU may lead to anaphylactic shock. One such example is ICU from natural rubber latex. Typically, latex gloves cause a wheal and flare reaction at the site of contact. This reaction can affect either the person wearing the gloves or the person being touched by the person wearing the gloves. In addition to direct skin contact, allergy may be caused by airborne natural rubber latex. Thus, sensitized, yet undiagnosed, individuals are at risk when in contact with airborne ICU allergens.

Cross allergy can also induce ICU reactions. The patient may be sensitized to 1 protein and react to other proteins that contain the same or similar allergenic molecules. 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. This phenomenon places patients with ICU at further risk.

Both ICU and NICU can display site specificity; for example, the neck and perioral areas are more sensitive than the forearm. This finding can be important in diagnostic testing.

Frequency

United States

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

In a Hawaiian study, Elpern studied the relationship of CUS in regard to race, sex, and age; the results of the study are described in the relevant sections below.^{2, 3} He demonstrated that 46% of patients with CUS had a personal history of atopy, whereas 44% had a family history of atopy. Only 21% of patients without CUS had a personal history of atopy.

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 as determined by the AlaSTAT assay and confirmed by the CAP assay.⁴

International

Kanerva gathered statistical data on occupational contact urticaria in Finland.^{5, 6} The incidence more than doubled from 89 reported cases in 1989 to 194 cases in 1994. 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 3 groups comprised 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.

In Germany, powdered natural rubber latex gloves have been banned in the workplace since 1998, with an 80% decrease in occupation contact urticaria in health care workers by 2002.⁷ A Singaporean study has shown no difference in sensitization between operating staff and other health care workers (8-9% sensitized).⁸ This contrasts with older Finnish data,⁹ 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%.

An older Polish study of patients attending an urticaria clinic describes that contact urticaria constituted an estimated 1.1% of all urticaria cases seen at the clinic. In contrast to the Hawaiian study, in this study, only 1 out of 5 patients had a personal or family history of atopy.

Mortality/Morbidity

A delayed (48-72 h) allergic eczematous contact dermatitis can result from some compounds that produce ICU and, to a lesser extent, from compounds that produce NICU.

When this occurs in occupational CUS, debilitating hand dermatitis may ensue.

If immediate contact reactions are not specifically sought, routine patch testing may miss the diagnosis.

CUS 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 CUS 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).

Race

Elpern's studies^{2, 3} demonstrated no difference in racial predisposition. White, Asian Filipino, Asian Japanese, and Hawaiian/part Hawaiian were the major groups studied.

Sex

Occupational and nonoccupational studies have demonstrated a slightly increased incidence of CUS in female patients. However, this may reflect the exposure of females to urticariants in the groups studied.

Age

In the Hawaiian demographic study of CUS, the incidence was constant from the second to the eighth decade.

Patients at the extremes of age constituted a smaller proportion of persons with the condition.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Many agents are capable of causing CUS; therefore, a detailed history is essential in establishing the etiology.
• • Contact urticaria reactions appear within minutes to about 1 hour after exposure of the urticariant to the skin.
  • The patient may complain of a local burning sensation, tingling, or itching. Swelling and redness may be seen (wheal and flare).
  • 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.
  • The extent of extracutaneous involvement (eg, asthma, rhinitis, conjunctivitis, gastrointestinal upset) should be ascertained.
  • A history of previous anaphylaxis should be sought, as should a personal or family history of atopy.
• A staging system of CUS has been described by Amin and Maibach.¹⁰
  
  
  • Cutaneous reaction only (stages 1 and 2)
  • • Stage 1 - Localized urticaria (redness and swelling); dermatitis (eczema); nonspecific symptoms (eg, itching, tingling, burning sensation)
    • Stage 2 - Generalized urticaria
  • Extracutaneous reactions (stages 3 and 4)
    
    
    • Stage 3 - Bronchial asthma (wheezing); rhinitis, conjunctivitis (eg, runny nose, watery eyes); orolaryngeal symptoms (eg, lip swelling, hoarseness, difficulty in swallowing); gastrointestinal symptoms (eg, nausea, vomiting, diarrhea, cramps)
    • Stage 4 - Anaphylactoid reactions (shock)

Physical

Signs on 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.

• Skin findings
• • Localized or generalized wheals may be present, especially on the hands, or eczematous skin may be observed if CUS has progressed to or developed in association with an eczematous dermatitis.
  • By definition, CUS lesions disappear within 24 hours of onset. Therefore, the skin may appear healthy, depending on when the patient presents to the physician.
    
    Table 1. Scale to Score Erythema¹¹
    

    Score	Description
    1+	Slight erythema, either spotty or diffuse
    2+	Moderate uniform erythema
    3+	Intense redness
    4+	Fiery redness with edema

    
    
    Table 2. Scale to Score Edema¹²
    

    Score	Description
    1	Slight edema, barely visible or palpable
    2	Unmistakable wheal, easily palpable
    3	Solid, tense wheal
    4	Tense wheal, extending beyond the test area

•  

• Respiratory findings
  
  
  • The patient may be in varying degrees of respiratory distress if a respiratory component to the CUS is involved.
  • Rhinitis may be present, and wheezing may be heard on auscultation.
  • However, the examination 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.

Causes

• Some of the more commonly reported causes of NICU include balsam of Peru, benzoic acid, cinnamic alcohol, cinnamic aldehyde, sorbic acid, and dimethylsulfoxide.¹³ In some patients, NICU may account for cosmetic intolerance syndrome.
• Reported causes of ICU include natural rubber latex, raw meat and fish, semen, many antibiotics, some metals (eg, platinum, nickel), acrylic monomers, short chain alcohols, benzoic and salicylic acids, parabens, polyethylene glycol, polysorbate, as well as other miscellaneous chemicals.¹³

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Aquagenic urticaria
Cold urticaria
Protein contact dermatitis
Asthma, allergic rhinitis, allergic conjunctivitis, and anaphylaxis (see History)

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab 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 ICU, the radioallergosorbent assay test (RAST) result (for allergen-specific IgE) may be positive for the offending substance. NICU cannot be diagnosed by the RAST test.

Imaging Studies

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

Other Tests

• Commonly used topical application techniques in both ICU and NICU 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, 1 mg/mL) and negative (normal sodium chloride solution) 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 ICU.
• The use test is a method in which 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 provokes latex ICU. A use test can provoke anaphylaxis in patients with ICU; therefore, clinicians should proceed cautiously with such testing. However, use testing can be especially helpful in patients with NICU. A positive reaction comprises 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 both NICU and ICU.
  • Repeated use of the same site may result in tachyphylaxis and can cause false-negative results.
• In the open test, 0.1 mL of the test substance is spread over a 3 X 3-cm area on the desired site.
• • Lahti¹⁴ suggests using alcoholic vehicles. 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.
  • ICU reactions typically appear within 15-20 minutes, whereas NICU reactions can be delayed up to 45-60 minutes following application.
• 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 as follows: Occlusion enhances percutaneous penetration; therefore, the sensitivity of the test is probably higher. A smaller area of the skin is required than in an open test.
  • For unexplained reasons, the chamber method may provide less responsiveness than the open test.
• The prick test, the scratch test, and the chamber prick test are the most commonly used in vivo techniques for detecting ICU. However, if these results are negative and ICU remains in the differential diagnosis, the chamber test, the open test, or the use test (as mentioned above) may be necessary. In vitro RAST may also be beneficial not only in establishing the diagnosis but also in determining the cross-reactivity (eg, latex and banana).
• In all 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 (see Tables 1 and 2 in Physical).
• NSAIDs, antihistamines, and exposure to UV light can cause false-negative results, as can tachyphylaxis.
• In testing for ICU 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.

Procedures

• No invasive procedures are indicated in the routine management of CUS.
• Skin biopsy is not necessary in the routine management of CUS.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Patients need to be well versed in the nature of their urticarial reaction (ICU vs NICU), in avoidance techniques, and in suitable alternatives.
• Patients with ICU should purchase medic alert tags delineating their allergens, including potential cross-reacting substances.
• Depending on the degree of reactivity and the ubiquity of the allergen, patients with ICU may require antihistamines and self-administered epinephrine.

Diet

Other than avoidance of foods and food products that were found by clinical testing to induce urticaria, observing specific dietary guidelines is not necessary.

Activity

Other than avoiding exposure to known urticariants, physical activity is not restricted.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Depending on the ubiquity of the allergen, patients with ICU may be advised to carry antihistamines and self-administered epinephrine.

Drug Category: Antihistamines

These agents act by competitive inhibition of histamine at the H1 receptor.

Drug Name	Hydroxyzine (Atarax, Vistaril)
Description	Antagonizes H1 receptors in periphery. May suppress histamine activity in subcortical region of CNS.
Adult Dose	50-100 mg PO/IM qid
Pediatric Dose	0.6 mg/kg/dose PO q6h
Contraindications	Documented hypersensitivity
Interactions	CNS depression may increase with alcohol or other CNS depressants
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Associated with clinical exacerbations of porphyria (may not be safe for patients with porphyria); ECG abnormalities (alterations in T waves) may occur; may cause drowsiness

Drug Name	Loratadine (Claritin)
Description	Selectively inhibits peripheral histamine H1 receptors.
Adult Dose	10 mg/d PO on empty stomach
Pediatric Dose	<2 years: Not established 2-6 years: 5 mg/d PO on empty stomach >6 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Ketoconazole, erythromycin, procarbazine, and alcohol may increase levels
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Initiate therapy at lower dose in liver impairment

Drug Name	Desloratadine (Clarinex)
Description	Long-acting tricyclic histamine antagonist selective for H1 receptor. A major metabolite of loratadine, which after ingestion is extensively metabolized to active metabolite 3-hydroxydesloratadine.
Adult Dose	5 mg PO qd
Pediatric Dose	<12 years: Not established >12 years: Administer as in adults
Contraindications	Documented hypersensitivity to desloratadine or loratadine
Interactions	Limited data exist; erythromycin and ketoconazole increase desloratadine and 3-hydroxydesloratadine plasma concentrations, but no increase was observed in clinically relevant adverse effects, including QTc
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Decrease dose in hepatic impairment; rarely causes pharyngitis or dry mouth

Drug Category: Vasopressors

Epinephrine is the DOC for treating anaphylactoid reactions.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Routinely, admission for medical care is not indicated for CUS. Additional inpatient care is rarely indicated.

Further Outpatient Care

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

Transfer

• Transfer is rarely indicated.

Deterrence/Prevention

• CUS is treated by prevention. This highlights the importance of clinical testing to identify the causative substance. The patient should then be advised to avoid that substance or products containing that substance to prevent recurrence.

Complications

• A delayed allergic eczematous dermatitis reaction can occur (see Mortality/Morbidity). Extracutaneous CUS 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).

Prognosis

• The prognosis is entirely dependent on the ubiquity of the etiologic substance and the patient's ability to avoid contact with it. However, even in cases of severe ICU to latex, the long-term prognosis can be good if patients take an active role in controlling their environment by educating themselves and others.

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 excellent patient education resources, visit eMedicine's Allergy Center and Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Hives and Angioedema.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• ICU can have significant medicolegal implications, as witnessed by the numerous suits engendered by the epidemic of ICU to latex.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Maibach HI, Johnson HL. Contact urticaria syndrome. Contact urticaria to diethyltoluamide(immediate-type hypersensitivity). Arch Dermatol. Jun 1975;111(6):726-30. [Medline].
2. Elpern DJ. The syndrome of immediate reactivities (contact urticaria syndrome). An historical study from a dermatology practice. II. The atopic diathesis and drug reactions. Hawaii Med J. Dec 1985;44(12):466-8. [Medline].
3. 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. Jan 1986;45(1):10-2. [Medline].
4. Ownby DR, Ownby HE, McCullough J, Shafer AW. The prevalence of anti-latex IgE antibodies in 1000 volunteer blooddonors. J Allergy Clin Immunol. Jun 1996;97(6):1188-92. [Medline].
5. Kanerva L, Toikkanen J, Jolanki R, Estlander T. Statistical data on occupational contact urticaria. Contact Dermatitis. Oct 1996;35(4):229-33. [Medline].
6. Kanerva L, Jolanki R, Toikkanen J, Estlander T. Statistics on occupational contact urticaria. In: Amin S, Lahti A, Maibach HI, eds. Contact Urticaria Syndrome. CRC Press;1997:57-70. [Medline].
7. Allmers H, Schmengler J, John SM. Decreasing incidence of occupational contact urticaria caused by natural rubber latex allergy in German health care workers. J Allergy Clin Immunol. Aug 2004;114(2):347-51. [Medline].
8. Tang MB, Leow YH, Ng V, Koh D, Goh CL. Latex sensitisation in healthcare workers in Singapore. Ann Acad Med Singapore. Jun 2005;34(5):376-82. [Medline].
9. Turjanmaa K. Incidence of immediate allergy to latex gloves in hospital personnel. Contact Dermatitis. Nov 1987;17(5):270-5. [Medline].
10. Amin S, Maibach HI. Immunologic contact urticaria - definition. In: Amin S, Lahti A, Maibach HI, eds. Contact Urticaria Syndrome. CRC Press;1997:chap 2.
11. Frosch PJ, Kligman AM. The soap chamber test. A new method for assessing the irritancy of soaps. J Am Acad Dermatol. Jul 1979;1(1):35-41. [Medline].
12. Gollhausen R, Kligman AM. Human assay for identifying substances which induce non-allergic contact urticaria: the NICU-test. Contact Dermatitis. Aug 1985;13(2):98-106. [Medline].
13. von Krogh G, Maibach HI. The Contact Urticaria Syndrome - 1982. Semin Dermatol. 1982;1:59-66.
14. Lahti A. Non-immunologic contact urticaria. Acta Derm Venereol Suppl (Stockh). 1980;Suppl 91:1-49. [Medline].
15. Bourrain JL. Occupational contact urticaria. Clin Rev Allergy Immunol. Feb 2006;30(1):39-46. [Medline].
16. Filon FL, Radman G. Latex allergy: a follow up study of 1040 healthcare workers. Occup Environ Med. Feb 2006;63(2):121-5. [Medline].
17. Hannuksela M. Mechanisms in contact urticaria. Clin Dermatol. Jul-Aug 1997;15(4):619-22. [Medline].
18. Jaeger D, Kleinhans D, Czuppon AB, Baur X. Latex-specific proteins causing immediate-type cutaneous, nasal,bronchial, and systemic reactions. J Allergy Clin Immunol. Mar 1992;89(3):759-68. [Medline].
19. Jovanovic M, Karadaglic E, Brkic S. Contact urticaria and allergic contact dermatitis to lidocaine in a patient sensitive to benzocaine and propolis. Contact Dermatitis. Feb 2006;54(2):124-126. [Medline].
20. Lahti A. Immediate contact reactions. In: Rycroft RJG, Menné T, Frosch PJ, eds. Textbook of Contact Dermatitis. 1995:chap 2.3.
21. Lahti A. Non-immunologic contact urticaria. In: Amin S, Lahti A, Maibach HI, eds. Contact Urticaria Syndrome. CRC Press;1997:chap 3. [Medline].
22. Majmudar V, Azam NA, Finch T. Contact urticaria to Cannabis sativa. Contact Dermatitis. Feb 2006;54(2):127. [Medline].
23. Rudzki E, Rebandel P, Grzywa Z. Incidence of contact urticaria. Contact Dermatitis. Oct 1985;13(4):279. [Medline].
24. Shriner DL, Maibach HI. Regional variation of nonimmunologic contact urticaria. Functional map of the human face. Skin Pharmacol. 1996;9(5):312-21. [Medline].
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Article Last Updated: May 25, 2006