Contact sensitization in patients with lower extremity dermatitis in the South Moravian region,Czech Republic

Introduction

Lower extremity eczema/dermatitis is a rather common diagnosis in everyday practice for both dermatologists and general practitioners. The differential diagnosis involves various diseases of the eczema/dermatitis group such as stasis dermatitis (varicose eczema), microbial eczema, asteatotic dermatitis and irritant dermatitis; less often lower leg dermatitis could be the manifestation of atopic dermatitis. In the broader differential diagnosis, it is sometimes necessary to exclude other dermatoses such as pretibial myxedema, vasculitis, lichen ruber planus, superficial thrombophlebitis, phyto-photodermatitis, etc. Moreover, on the feet (soles) the dermatologist should also exclude inflamed mycosis, plantar pustulosis, hyperkeratotic or dyshidrotic eczema and others.

In each case of lower extremity dermatitis, every dermatologist must think of the possibility of contact sensitization. The occurrence of primary allergic contact dermatitis in this body region is relatively low. More commonly contact sensitization arises in the terrain of varicose dermatitis, inflamed interdigital mycosis or chronic leg ulcer.

In these cases, the cause of sensitization is the topical medication used for the treatment of dermatitis, fungal or bacterial infection or applied to the ulcer. In both cases the chronicity of the disease (and therefore the prolonged application of topical medication) and the disturbance of the skin surface (in leg ulcers or interdigital mycosis) or the skin barrier (in varicose dermatitis) play an important role. Contact sensitization may be caused not only by the effectual component of topical medication but also by various adjuvant substances of these preparations.

Patients and methods

The study population included a total number of 462 patients (196 men and 266 women) with lower extremity dermatitis investigated in the dermatoallergological office of our department between the years 2001 and 2007. The mean age of these patients was 49.1 years.

The characteristics of the study population are given in Table 1. Besides anamnesis and clinical investigation, all these patients were investigated with epicutaneous tests of the European Standard Series (Chemotechnique Diagnostics Company, Vellinge, Sweden) and also with other special patch tests – preservatives, antioxidants, emulgators and some allergens of natural origin: benzalkonium chloride 0.1%; benzotriazole 1%; butylhydroxyanisole 2%; diazolidinyl urea (Germall II) 2%; dibromodicyanobutane/phenoxyethanol (1:4) 1%; diethanolamine 2%; dichlorophene 0.5%; dipentene (di-limonene) 2%; DMDM hydantoine (in water) 2%; dodecyl gallate (lauryl gallate) 0.3%; glutar(di)aldehyde 0.3%; chloroacetamide 0.2%; butylhydroxytoluene 2%; chlorhexidine digluconate (in water) 0.5%; chlorocresol 1%; propyl gallate 0.5%; arnica extr. 0.5%; imidazolidinyl urea (Germall 115) 2%; methylene-bis(methyloxazolidine) 1%; octylisothiazolinone 0.025%; phenoxyethanol 1%; propylene glycol 5%; sorbic acid 2%; triclosan 2%; trolamine (triethanolamine) 2.5%; calendula extr. 2.5%; tea tree 10%; propolis 10%; chamomile extr., cocamidopropyl betaine 1.0%. Some patients were also patch tested with additional special allergens according to their anamnesis (for example, topical anti-inflammatory drugs such as ketoprophene or topical antifungal preparations).

Patch testing was performed on the back skin of patients with readings at 48, 72 and 96 hours after application. The evaluation of the reactions in the patch tests was done according to the International Contact Dermatitis Research Group (ICDRG) criteria. Patients were excluded from the study if they were receiving any oral immunosuppressive treatment. Informed consent was obtained from all patients before patch testing.

Results

In 218 patients (47.2%) contact sensitization was detected. Of these 218 patients, 108 individuals were sensitized to one allergen and 110 patients to more than one allergen. In 244 patients (52.8%) the patch tests were negative. The most frequent allergens were (1) balsam of Peru, 44/462 (9.5%); (2) wool alcohols, 41/462 (8.9%); (3) nickel sulphate, 39/462 (8.4%); (4) propolis, 35/462 (7.6%); (5) fragrance mix, 34 (7.4%); (6) colophony, 29/462 (6.3%); (7) chamomile extr. and arnica extr., both 28 (6.1%); (8) dodecyl gallate, 26/462 (5.6%); (9) cobalt chloride, 22/462 (4.8%); and (10) tea tree, 21/462 (4.5%).

The complete frequency of sensitization is listed in Tables 2 (European Standard Series) and 3 (special tests).

According to clinical relevance (present or past), the most common allergens were wool alcohols, 27/462 (5.8%); balsam of Peru, 23/462 (5%); neomycin sulphate, propolis and chamomile extr., all three 9/462 (1.9%); and parabens, 8/462 (1.7%). The frequency of sensitization according to clinical relevance is listed in Table 4.

On the basis of patch test results and clinical relevance, the diagnosis was made as contact dermatitis in 138/462 cases (29.9%), microbial eczema/varicose dermatitis in 112/462 cases (24.2%), atopic dermatitis in 108/462 cases (23.4%), irritant dermatitis in 39 cases (8.4%), plantar keratoderma or hyperkeratotic eczema of unknown origin in 23/462 cases (5%) and other diagnoses were made in 42/462 cases (9.1%) (see also Table 5).

Discussion

It is known from clinical practice that patients with eczematous changes in the lower extremity region have a higher frequency of contact sensitization than other patients referred for patch testing. This clinical knowledge corresponds to literary data: the prevalence of contact sensitization in patients with lower extremity eczema varies between 50% and 85%, ^1–8 while the prevalence of contact sensitization in patients with dermatitis in other locations is around 35–49%. ^1,2,4,9,10 In our patients with lower extremity eczema, contact sensitization was detected in 47.2%. The most common contact allergen found in our patients was balsam of Peru (9.5%) and the sensitization was mostly clinically relevant (23 of 44); the source was mostly the topical preparations used for the treatment of wounds, including leg ulcers. In the literature, the frequency of sensitization to balsam of Peru in patients with leg ulcers or lower leg dermatitis varies according to the study population between 14.5% and 30% ^5,11–15 or even 38% ⁸ and 42%. ⁶ Contact sensitization to balsam of Peru may be related to some other substances of natural origin such as propolis, colophony or fragrances, because of the common contentual components (for example, derivatives of cinnamic acid).

The second most common allergen according to the frequency of sensitization in our patients was wool alcohol (8.9%). In 27 of 41 patients sensitized to wool alcohols, the sensitization was clinically relevant; the source was various ointments used for the treatment of leg ulcers or surrounding dermatitis or lower leg dermatitis without leg ulcer (including atopic dermatitis). Wool alcohols are often present as adjuvant substances (emulgators) mostly in ointment bases of topical preparations. In Europe, higher frequencies of sensitization to wool alcohols were reported: England – 16.5%, ⁴ France – 22% ⁶ and Poland – 30%. ⁷ Lower frequencies were found in North America – 9% ⁵ and Singapore – 6.8%. ⁸ In terms of other auxiliary contentual substances of medicinal topical preparations and cosmetic products, the most frequent according to sensitization in our study was dodecyl gallate (5.6%) – an antioxidant with synchronous preservative effect. Its relatively high frequency of sensitization in our study can be partially explained by its presence in the ointment containing kebuzone (Ketazon ung), which was often used for the treatment of joint inflammation, including those of lower legs. Another reason is the fact that dodecyl gallate is present in some cosmetic products and also serves as a preservative in some food products. One cannot also forget possible cross-reactivity within the gallates family. The source of sensitization of other adjuvants diethanolamine and chloroacetamide (both 4.3%) were mostly cosmetic products. The frequency of contact sensitization to parabens was only 3% in our patients in contrast to literary data, which report contact sensitization to parabens up to 20%. ⁷

The third most common allergen to which contact sensitization was detected in our patients was nickel sulphate (8.4%); clinical relevance in the relationship with lower extremity dermatitis was however low (3 of 39 patients). In the literature, the data of contact sensitization to nickel vary greatly from 0% to 16.7% ^5,7,11,16,17 and even more. Contact sensitization to other metals such as cobalt chloride or potassium dichromate was lower than to nickel sulphate (4.8% and 3.2%, respectively). The frequency of sensitization to propolis was 7.6% in our patients. Propolis – a natural product – is a resinous mixture that honey bees collect from tree buds, sap flows or other botanical sources. The chemical composition of propolis varies, depending on season, bee species and geographic location. Propolis has approximately 50 constituents, primarily resins and vegetable balsams (50%), waxes (30%), essential oils (10%) and pollen (5%). Propolis has antibacterial, fungicidal, antipruritic and anti-inflammatory effects and promotes epithelization. It is therefore used in various indications, including treatment of leg ulcers especially in folk medicine. Propolis can also be the component of some cosmetic products. There is sparse information about the sensitization rate to propolis in the literature, because propolis is not commonly included while patch testing. Dastychová ¹⁸ reports the frequency of contact sensitization to propolis to be 14% of the patients who had been using this product. Similar frequency was detected by Ficova et al. – 13.9%. ⁴ Contact sensitization to fragrance mix was 7.4% in our patients. Literary data show a higher frequency of sensitization to fragrance mix in the group of patients with lower extremity dermatitis or leg ulcers ranging from 10–20%. ^5,7,12,15,16 The frequency of sensitization to colophony was 6.3% in our patients. Colophony – another natural substance obtained from Pinaceae plants – is a mixture of resin acids (the main allergens are oxidized acids of the abietic type). The most common source of sensitization to colophony in common population are the glues of adhesive plasters. Pentaentaerythriolester of hydrogenated resin, one of the contentual substances of hydrocolloid dressings, is a derivative of colophony. ^19,20 There may be cross-reactivity with turpentine, wood tars, balsam of Peru, fragrances and other natural resins. In the literature, the sensitization to colophony varies from 3% to 13.3%. ^{5,7,12,13,15,16} Other natural substances that caused contact sensitization in our patients with lower leg dermatitis were chamomile extract and arnica extract (both 6.1%) and tea tree oil (4.5%). The clinical relevance of contact sensitization of these three products was highest in chamomile extract (9/28) because it is still widely used in our country – mostly in folk medicine in the form of compresses on leg ulcers.

Rather surprising for us was the relatively low frequency of sensitization to neomycin sulphate (3.5%) in our patients, because in the literature sensitization is reported to be between 10% and 23.3%. ^5,7,12,16 Probable explanations are that: (1) most literature data regarded patients with leg ulcers only, who composed only a part of our cohort; and (2) there is a decrease in the use of neomycin for leg ulcer treatment. There is a possibility of cross-reactivity of neomycin with other aminoglycosidic antibiotics – for example with gentamycin. But in our patients we found only one sensitized to gentamycin. Also contact sensitization to topical corticosteroids is reported to be continually increasing. For example, Zmudzinska et al. ⁷ report contact sensitization to tixocortol pivalate to be 16% and to budesonide 20%. However, in our patients it was low (budesonide 0.9%, tixocortol pivalate 0%).

The spectrum of allergens in patients with lower leg dermatitis is quite similar worldwide: the most common allergens are balsam of Peru, wool alcohols, fragrance mix, colophony and neomycin sulphate. The comparison of the frequency of sensitization to the most common allergens detected by patch testing in patients with leg ulcers and lower leg dermatitis by various authors is given in Table 6.

Similar spectra of contact allergens were also detected in our study. Only the frequencies were generally lower, which can be explained by the rather wider spectrum of our patients including not only individuals with leg ulcers or varicose dermatitis, but also dermatitis of other origin on lower extremities such as atopic dermatitis, and also including patients with plantar location of dermatitis.

Conclusion

The spectrum of contact allergens causing lower extremity contact dermatitis has not changed dramatically during the last decades and the frequency of contact sensitization is still high. Top allergens remain those of natural origin (balsam of Peru, fragrance, colophony), antimicrobials (neomycin sulphate and recently gentamycin or fusidic acid) and adjuvants of topical preparations (preservatives, emulgators, etc.) – wool alcohols or parabens. An increasing frequency of contact sensitization to topical corticosteroids has been recently reported.

Dermatologists must be aware of the possibility of contact sensitization in this body region and conduct patch tests in these patients as early as possible. According to the results of the tests, the topical treatment can be modified to be effective. Even more important is primary prevention – substances with high sensitization potential like balsam of Peru or neomycin should be strictly avoided. Paying attention to the labelled ingredients of topical dermatological preparations and wound care products is necessary.