Contact allergy in the anogenital region

Allergic contact dermatitis is a common anogenital disease. The predominant complaints are itching and burning. Scratching, mainly at night, and lichenification can lead to painful erosions. Topical medicaments, body care products, popular remedies, and sanitary products are the main sources of contact allergens in the anogenital area.

Epidemiology

During 1992-1997, 1008 patients with anogenital complaints (2% of the whole test population of 54 500 patients) were patch-tested in the Departments of Dermatology of the Information Network of Dermatological Clinics (IVDK). The standard series recommended by the German Contact Dermatitis Research Group (DKG) was tested in 978 of these patients. Other specific allergens were tested according to each patient's history. In most cases topical drugs, ointment bases, and preservatives were included, and in 466 cases patients' own products were also patch-tested. In 351 patients (35%), the final diagnosis of allergic contact dermatitis was confirmed (15). Similar numbers were reported from the UK, where anogenital dermatosis was diagnosed in 201 women in a contact dermatitis clinic over 14 years. In 79 cases (39%) the diagnosis of allergic contact dermatitis was confirmed by patch tests with the European standard series, a medicament series, a glucocorticoid series, and the patients' own medicaments, if necessary. In another UK study, 39 of 135 patients tested (29%) with persisting vulval symptoms had contact hypersensitivity (16). There is evidence that the vulval region and the perianal region should be considered separately, since patients with dermatosis that only involves the vulva have positive patch tests less often than patients with dermatosis of the vulva and the perianal area or patients who have only perianal involvement (17).

Allergens and sources

The most frequent allergens in the study of the IVDK are listed in Table 2, and Table 3 gives information about the patch test results obtained with topical drugs, ointment bases, and preservatives.

All allergens that led to positive reactions in at least 1% of the patients tested are listed (15).

Although the spectrum is comparable to that of all patients tested between 1992 and 1997, there are some allergens of pronounced significance for the anogenital region. Cinchocaine HCl ranked fourth among contact allergens

Table 2 The most frequent allergens among patients with anogenital complaints

Allergen

Number tested

Number with a

Number with a

IVDK

positive reaction (%)1

positive reaction (%)2

total 1992-7 (%)3

Nickel sulfate

962

86 (8.9)

12.6

16-17

Balsam of Peru

962

74 (7.7)

6.6

6.5-8

Fragrance mix

960

71 (4.7)

7.2

10-13

Cinchocaine HCl (dibucaine HCl)

592

50 (4.8)

7.4

*

Thiomersal

961

48 (5.0)

5.6

5-7

Methyldibromoglutaronitrile/

958

39 (1.4)

3.1

2-3

2-phenoxyethanol

Paraphenylenediamine

959

39 (1.4)

3.7

4-5.5

(Chloro)methylisothiazolinone (CMI/MI)

951

32 (3.4)

3.7

~2.5

Benzocaine

962

31 (2.3)

2.7

~1.5

Phenylmercuric acetate

736

28 (3.8)

4.0

4-8

Neomycin sulfate

962

23 (2.4)

2.1

~2.5

Wool wax alcohol

962

22 (2.3)

2.1

2.5-4

Amerchol L-101

561

21 (3.7)

2.9

*

Colophony (rosin)

961

19 (2.0)

2.3

2.5-3.5

Mercury amide chloride

962

19 (2.0)

1.7

~2.5

(ammoniated mercury)

Propolis

598

17 (2.8)

2.5

*

Parabens mix

962

17(1.8)

1.6

~1.5

Benzoylperoxide

218

15 (6.9)

7.6

*

Octylgallate

560

15(2.7)

2.8

*

Methyldibromoglutaronitrile

508

14 (2.8)

2.1

*

Cobalt chloride

960

13 (1.4)

2.0

4.5-5

Propylene glycol

744

12 (1.6)

1.5

*

Formaldehyde

961

12 (1.2)

1.5

Hexylresorcinol

476

11 (2.3)

2.1

*

Para-ferf-butylphenol

955

11 (1.2)

1.4

~1

Formaldehyde resin (PTBP-FR)

Thiuram mix

961

11 (1.1)

1.1

~2.5

'Percentage of positive reactions.

2Age- and sex-standardized frequency of sensitization.

3Range of the age- and sex-standardized frequency of sensitization in all patients tested (n = 54 500). 'Allergens were tested in selected patients only; so a comparison in this way makes no sense. All allergens that led to positive reactions in more than 1% of the total population (that is 10 patients) are listed. Source: IVDK 1992-1997 (n = 1008) (15).

Table 3 Patch test results obtained with topical drugs, ointment bases, and preservatives

Allergen

Test formulation

Number tested

Number with a positive reaction (%)

Bufexamac

5% petrolatum

534

9(1.7)

Framycetin sulfate

20% petrolatum

268

7 (2.6)

Lidocaine HCl

15% petrolatum

524

6(1.1)

Tincture of Arnica montana

20% petrolatum

241

5(1.2)

Clotrimazole

5% petrolatum

272

5(1.8)

Iodochlorhydroxyquin (clioquinol)

5% petrolatum

303

5(1.7)

Chamomile extract

2.5% petrolatum

173

5 (2.9)

Tetracaine HCl (amethocaine HCl)

1% petrolatum

306

4(1.3)

Panthenol

5% petrolatum

323

4(1.2)

Chloramphenicol

10% petrolatum

244

3(1.2)

Mafenide

10% petrolatum

299

3(1.0)

tert-Butyl hydroquinone

1% petrolatum

710

8(1.1)

Benzalkonium chloride

0.1% petrolatum

740

8(1.1)

Bronopol

0.5% petrolatum

728

7(1.0)

Chloroacetamide

0.2% petrolatum

743

7 (0.9)

in this region. Furthermore, there were more positive patch test results to (chloro)methylisothiazolinone (CMI/MI) and to benzocaine among patients with anogenital complaints compared with the whole test population (15).

Topical local anesthetics play an important role in anogenital contact allergy (15-19). Cinchocaine is commonly used in topical antihemorrhoidal formulations and is a well-known sensitizer (20). Although benzocaine is not as widely used in topical anesthetic formulations in Germany, patients with anogenital dermatitis were at higher risk of sensitization. Amide-type local anesthetics, like lidocaine HCl and tetracaine, are less potent sensitizers (21). Contact allergy to local anesthetics is more often observed among patients with perianal complaints than patients with perianal and vulval or only vulval dermatitis (17).

Topical antibiotics are often used in the treatment of dermatitis with bacterial superinfection. However, in Germany sensitization to the aminoglycoside antibiotic neomycin was less frequent in patients with anogenital dermatitis (15) compared with the UK, where 15 of 79 patients with positive patch tests and anogenital complaints were positive to neomycin (17). Framycetin contact sensitivity was frequent in the UK, partly through cross-reactivity with neomycin (16).

Another important substance in hemorrhoidal formulations is bufexamac, a non-steroidal anti-inflammatory drug that is a well-known sensitizer and sometimes elicits severe dermatitis (22). Bufexamac should therefore always be included in patch tests for anogenital dermatitis.

Glucocorticoid contact allergy is well known (SEDA-21, 158) and has to be particularly suspected in chronic conditions affecting the perianal area (17), after long-term topical medication, and in cases of failure to ameliorate dermatitis with corticosteroids. Patch tests should then be performed both with the recommended markers, budeso-nide (0.1% petrolatum) and tixocortol pivalate (1% petrolatum), and with the patient's own formulations.

Antifungal drugs are comparatively rare contact allergens in the anogenital region in relation to their widespread use. Clotrimazole and nystatin are preferred. In the study of the IVDK, patch tests with clotrimazole were performed in only 272 patients, leading to five positive reactions (15). In the UK study on anogenital dermatosis, five women out of

201 patients tested had positive reactions to antifungal drugs, but was unfortunately not specified in the article (17). If sensitization to nystatin is suspected, polyethylene glycol should be used as a vehicle for patch-testing (23). Imidazoles can cross-react with one another (SEDA-20, 156). Most cases of contact allergy occurred with micona-zole, econazole, tioconazole, and isoconazole (24).

Moist toilet paper is a rare source of contact allergens. The most important allergens in moist toilet paper are preservatives, such as CMI/MI and dibromoglutaronitril + 2-phenoxyethanol (Euxyl K 400) (25-27). These substances were also incriminated in the study of the IVDK (15) and are also found in body care products. In Germany, when CMI/MI was replaced by iodopropyl butylcarbamate (IPBC) in moist toilet paper, one case of contact allergy to IPBC was soon described (28).

Other sources of preservatives are topical medicaments and body care products. Parabens, chloracetamide, and formaldehyde-releasing preservatives, like diazolidinyl urea, imidazolidinyl urea, bronopol, and quaternium 15, should also be considered (15).

Ointment bases do not seem to cause contact allergy in the anogenital region too often, despite wide use. Wool wax alcohol and amerchol L-101 are the most important (15,17). Contact sensitivity to balsam of Peru and fragrance mix is not infrequent and reflects the ubiquitous presence of these substances (16).

Topical remedies are very popular in self-treatment and patients will often not report this, since they do not regard them as medicaments. Furthermore, patients often do not suspect that "natural'' remedies cause adverse effects. Some substances lead to a considerable number of allergic reactions, for example chamomile extract and tincture of Arnica montana (15). Propolis also has pronounced sensitizing capacity (29), and sensitization to aged tea tree oil is being reported with increasing frequency (30).

Contact allergy from rubber additives in condoms is sometimes suspected, and there are anecdotal reports (31). However, in the study of the IVDK, condoms were patch-tested in 17 patients without positive results (15).

Although sensitization to nickel sulfate is common in patients with anogenital contact dermatitis and in patients with dermatitis in other body sites, the relevance to anogenital complaints of sensitization to nickel sulfate should always be doubted (15,16,32). However, direct transmission of nickel from the hands to the anogenital region has to be taken into account, and food can be a rare source of nickel contact in the anogenital area. In these cases relevance can be proved by oral nickel provocation and a nickel-restricted diet for a limited period may be justified (33).

Prediction of contact allergens

Certain chemical substructures, so-called toxophores, can be associated with an increased risk of skin sensitization. These have been codified in a set of 57 rules known as the DEREK (Deductive Estimation of Risk from Existing Knowledge) knowledge-based computer system (34). This rulebase has been subjected to extensive validation and continues to be refined. The predictive ability of the sensitization rule set was assessed by processing the structures of the first 84 chemical substances in the list of contact allergens issued by the German Federal Institute for Health Protection of Consumers (BgVV). The rules identified toxophores for skin sensitization in the structures of 71 of the 84 chemicals. After refinement, by extension of the scope of the existing rules and by generation of new rules with a sound mechanistic rationale for the biological activity, the rules identified toxophores for skin sensitization for 82 of the 84 chemicals.

Conclusions

Contact allergy should always be suspected in patients with anogenital dermatitis, especially if the perianal area is involved. In patients with other chronic inflammatory diseases of the anogenital region, for example lichen sclerosus, contact allergy should also be excluded, since long-term use of topical medicaments on compromised skin carries an increased risk of sensitization.

Patch tests in patients with anogenital eczema should include the standard series: cinchocaine HCl, propolis, bufexamac, and other ingredients of topical formulations according to the patient's history. In cases of doubt, the repeated open application test (ROAT) is recommended. Patients should be advised to apply the suspected product three times a day for 3 days to an area of healthy skin on measuring 5 cm x 5 cm the flexural site of the forearm (35).

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