The importance of context information in the diagnostic rating of digital images of patch test reactions.

BACKGROUND: Patch test (PT) guidelines recommend classifying PT reactions based on morphological criteria only, i.e. irrespective of context information such as substance, concentration and vehicle. OBJECTIVES: To analyse reclassification of PT reactions after revelation of context information subsequent to an initial blinded reading. METHODS: One hundred and twenty-two participants (experienced dermatologists and researchers) rated 20 digital images of different PT reactions twice, first blinded, then unblinded regarding substance, concentration and vehicle. Agreement between both ratings was quantified with Cohen's kappa, and systematic differences statistically examined with tests for marginal homogeneity. RESULTS: Mostly, ratings remained stable, e.g. in > 90% of cases of images showing typical strong or extreme positive PT reactions. Reclassification was comparatively often observed in images depicting irritant reactions. Conversely, 16 of 122 participants re-rated doubtful reactions to thiuram mix and dichromate, respectively, as 'allergic' (weak or strong positive) after knowing the substance. CONCLUSIONS: The considerable proportion of participants who choose an 'allergic' rating, despite a morphological presentation definitely not justifying this, points to a conceptual problem of the PT reading scale: the mixing up of morphological classification and interpretation. We therefore suggest amending the scale. Moreover, standardization of PT reading can be improved by continual PT training sessions.

para-Phenylenediamine: the profile of an important allergen. Results of the IVDK.

BACKGROUND: para-Phenylenediamine (PPD) is an important contact allergen and primarily used in hair dyeing. OBJECTIVES: To quantify cases of contact allergy (CA) to PPD attributed to sources of exposure. METHODS: Patients with PPD CA, diagnosed by the Information Network of Departments of Dermatology (IVDK; n = 3307 of 83 030 patients tested), were divided into five subgroups of exposure. Demographic variables and pattern of concomitant reactions were used to characterize the subgroups further. The impact of individual factors on the risk of PPD CA was examined with a logistic regression analysis. Clinical epidemiology and drug utilization research (CE-DUR) methods were employed to estimate the 10-year prevalence of PPD CA in the general population. RESULTS: The 4% prevalence of PPD CA in patients was extrapolated to a prevalence of 0.96% in the general population. The defined profiles were found to 'explain' the following percentages of PPD CA: (i) hair dyeing in clients 22% (0.2% of the general population); (ii) different occupational exposures, namely hair dyeing by hairdressers, paint- and rubber-associated exposures 23% (0.22% of the general population); (iii) clothing/shoes 12% (0.12% of the general population). A probable causal exposure to PPD could not be identified in about 44% of patients with PPD CA. CONCLUSIONS: In more than 50% of cases of PPD CA, a (very) probable causal exposure was identified. In the large remainder (44%) this was not possible. 'Historical' CA without current relevance and active sensitization through patch testing (a further important exposure to PPD) must be considered in these patients.

Patch test results with patients' own perfumes, deodorants and shaving lotions: results of the IVDK 1998-2002.

OBJECTIVE: Assessment of the value of patch testing patients' own perfumes, eau de toilette, deodorants and shaving lotions with regard to diagnosing contact allergy to fragrances, and an analysis of the spectrum of concurrent patch test reactions to single fragrance allergens. STUDY DESIGN: Data of the Information Network of Departments of Dermatology (IVDK; http://www.ivdk.org) regarding patch test results with above products brought in by the patient, considered as possible cause of contact dermatitis, were retrospectively analysed. Between 1998 and 2002, 1468 patients were patch tested with 2557 single products (deodorants, n = 1094; eau de toilette, n = 598; perfume, n = 530; and pre- or after-shave, n = 325; remainder not classifiable), mostly 'as is'. RESULTS: Positive reactions were observed in 129 patients (to 191 products). In 58 of these patients, no further patch test reactions to the fragrance mix (FM-I), Myroxylon pereirae resin (balsam of Peru) or 4-(4-hydroxy-4-methyl-pentyl)-3-cyclohexencarboxaldehyde (e.g. Lyral(R)) were found. A strong association between contact sensitivity to the above commercial allergens and positive reactions to products was observed. Some single compounds such as ylang-ylang oil, propolis and especially oak moss absolute are important allergens in the 'perfume-positive' subgroup, but less in a subgroup positive to own deodorants. DISCUSSION: Patch testing this scope of products, brought in by the patient, can be regarded as a simple, safe and effective method to diagnose clinically relevant contact sensitization - the more so, as the composition of such products is ever-changing, and the sensitivity of established 'screening allergens' is thus insufficient.

Late reactions to the patch-test preparations para-phenylenediamine and epoxy resin: a prospective multicentre investigation of the German Contact Dermatitis Research Group.

BACKGROUND: Late patch-test reactions, developing at day (D) 7 or later have been described for several allergens. Late reactions may reflect patch-test sensitization. Para-phenylenediamine (PPD) and epoxy resins (ER) are potent allergens and therefore may potentially induce patch-test sensitization. Up to now, there has been no prospective study on the frequency of late reactions in routine patch testing with these allergens. OBJECTIVES: To assess the frequency of late reactions to PPD and ER. PATIENTS/METHODS: In 1748 patients PPD (PPD-base, 1% pet.) and ER [based on diglycidylether of bisphenol A (DGEBA, 1% pet.)], and in 812 patients, nickel sulphate (5% pet.) were removed from the test panel of the standard series and applied on the medial side of the upper arm. Patch-test occlusion time was 24 h in 588 (PPD and ER) and 241 patients (nickel sulphate), respectively, and 48 h in 1160 (PPD and ER) and 571 (nickel sulphate) patients, respectively. Patch tests were read on D1-3 and D2-3, respectively; additional late readings were performed on D7, D14 and D21 after patch-test application. Patients who were not able to return for all scheduled late readings were telephoned on D7, D14 or D21, and questioned about a reaction at the test sites. Patients were instructed to perform daily self-examination from D4 onwards and to return immediately to the clinic if a reaction at the upper arm became visible. RESULTS: Data of 1428 patients (ER and PPD) and 638 patients (nickel) were evaluable. In 25 patients (1.8%), patch tests became positive not before D7, among them 21 reactions to PPD (1.5%) and four reactions to ER (0.3%). In five of seven patients, repeated patch tests with PPD disclosed patch-test sensitization as the cause of the late reaction. All late reactions, except for one, occurred in patients in whom patch tests were applied for 48 h. No late reactions were seen with nickel sulphate. CONCLUSIONS: PPD (1% pet.) elicited late reactions in 1.5% of routine patch tests, the majority of them probably being caused by patch-test sensitization. Therefore, the German Contact Dermatitis Research Group decided to remove PPD 1% pet. from the German standard series and to take efforts to optimize the patch-test conditions of PPD. One way to optimize PPD testing could be to reduce the exposure of PPD 1% to 24 h. Alternatively the patch-test concentration of PPD might be reduced.

The European standard series in 9 European countries, 2002/2003 -- first results of the European Surveillance System on Contact Allergies.

Since January 2001, the European Surveillance System on Contact Allergies (ESSCA), supported by European Union funding (contract QLK4-CT-2001-00343), has started to collect patch-test data. This comprises a standardized clinical history and the patch-test results using the European standard series, from 17 centres in 9 European countries listed above. In 2002 and 2003, 10 511 patients' test results have been pooled and analysed. The anamnestic data partly reflect the subspecialties of some centres. The most common allergen was nickel sulfate (17.3%); however, large international variations were observed. The prevalence of contact allergy to Myroxylon pereirae resin (balsam of Peru) (5.8%) is coming close to the frequency found with the fragrance mix (6.4%). Regarding contact allergy to chromium compounds, different frequencies were noted in the 2 centres focused on occupational dermatitis (2.3% in the FIOH versus 7.4% in the Nofer Institute). These most likely reflect the beneficial effect of addition of ferrous sulfate in one, but not the other country. As differences may partly be due to different patch-test reading, standardization may need to be refined further. By providing post-marketing surveillance in the field of contact allergy, ESSCA will meet its objective of increased consumer safety across Europe.

Monitoring the European standard series in 10 centres 1996-2000.

A 5-year retrospective study of the frequency of sensitization to the 25 allergens of the European standard series (ESS) was conducted in 10 centres in 8 European countries. Included were the results of 26 210 patients. The range in sensitivities differed moderately between the centres. Combining results of different centres and drawing conclusions on incidences can be done only with great care. The information on the ranking of the allergens and their sensitization incidence in the clinics are useful for decisions on the future composition of the standard series. The ESS is still a valid screening tool, and no substances should be deleted.

Quantitative patch and repeated open application testing in methyldibromo glutaronitrile-sensitive patients.

Contact allergy to methyldibromo glutaronitrile (MDBGN), often combined with phenoxyethanol (PE) (e.g., Euxyl K 400), increased throughout the 1990s in Europe. Consequently, in 2003, the European Commission banned its use in leave-on products, where its use concentration was considered too high and the non-sensitizing use concentration as yet unknown. The 2 objectives of the study are (a) to find a maximum non-eliciting concentration in a leave-on product in MDBGN/PE-sensitized patients, which could possibly also be considered safe regarding induction and (b) to find the best patch test concentration for MDBGN. We, therefore, performed a use-related test (ROAT) in patients sensitized to MDBGN/PE (n = 39) with 3 concentrations of MDBGN/PE (50, 100 and 250 p.p.m. MDBGN, respectively). A subset of these patients (n = 24) was later patch-tested with various concentrations (0.1, 0.2, 0.3 and 0.5% MDBGN, respectively). 15 patients (38%, 95% confidence interval (CI) = 23-55%) had a negative and 24 (62%; 95% CI = 45-77%) a positive overall repeated open application test (ROAT) result. 13 reacted to the lowest (50 p.p.m.), 8 to the middle (100 p.p.m.) and 3 to the highest concentration (250 p.p.m.) only. In those 13 reacting to the lowest ROAT concentration, dermatitis developed within a few days (1-7). The strength of the initial and the confirmatory patch test result, respectively, and the outcome of the ROAT were positively associated. Of the 24 patients with a use and confirmatory patch test, 15 reacted to 0.1% MDBGN, 16 to 0.2%, 17 to 0.3% and 22 to 0.5%. With the patch test concentration of 0.5%, the number of ROAT-negative patients but patch-test-positive patients increases considerably, particularly due to + reactions. A maximum sensitivity of 94% (95% CI = 70-100%) is reached with a patch test concentration of 0.2%, and is not further improved by increasing the concentration. However, the specificity decreases dramatically from 88 (95% CI = 47-100%) with 0.2% to a mere 12.5% (95% CI = 0-53%) with 0.5%. It can be concluded (a) that for MDBGN 0.2% is very likely the best patch test concentration and (b) that 50 p.p.m. in a leave-on product can elicit contact dermatitis in sensitized persons. We were, therefore, unable to find a safe, still microbicidal, concentration for leave-on products. By contrast, with other contact allergens, dose-response use tests may be able to identify a non-eliciting concentration, which could give valuable clues to a non-inducing (i.e., safe) concentration in products.

Patch testing with methyldibromo glutaronitrile, a multicentre study within the EECDRG.

Contact allergy to and allergic contact dermatitis from methyldibromo glutaronitrile (MDBGN) have frequently been reported. As there has been no agreement on which MDBGN test preparation to use, a study was initiated to help determine the optimal patch test preparation for MDBGN. 2661 consecutively patch tested patients at 11 test clinics representing 9 European countries participated. Petrolatum preparations with MDBGN at 1.0%, 0.5%, 0.3% and 0.1% were inserted in the standard series. Contact allergy rates were noted in the range 4.4-1.1% following decreasing test concentrations. Reactions not fulfilling all criteria to be classified as allergic reactions could represent either weak allergic or irritant reactions, and such reactions were noted in the range 8.2-0.5% with decreasing concentrations. A significant number of these reactions represented weak allergic reactions, as allergic reactions were obtained to higher patch test concentrations in the same individual. Morphologically irritant reactions were noted only for the highest test concentrations. In summary, the contact allergy rates and frequencies of doubtful and irritant reactions vary with the patch test concentration. The final decision on patch test concentration for MDBGN should not only rely on these factors but also include information on patch test concentrations required to diagnose individual cases with allergic contact dermatitis from MDBGN as well as results of repeated open application tests.

Repeated open application test with methyldibromo glutaronitrile, a multicentre study within the EECDRG.

Contact allergy to and allergic contact dermatitis from methyldibromo glutaronitrile (MDBGN) have frequently been reported. This study was initiated to help determine the optimal patch test preparation for MDBGN. In 51 patients with a doubtful or a positive patch test reaction to at least 1 of 4 test preparations with MDBGN in petrolatum at 1.0% w/w, 0.5%, 0.3% and 0.1%, a repeated open application test (ROAT) with moisturizers with and without MDBGN at 0.03% w/w was performed on the upper arms for 2 weeks. 18 of the 51 (35.3%) patients developed a positive ROAT. In all patients, there was a positive ROAT only to the moisturizer with MDBGN (P < 0.001). A statistically significant association was also found between the patch test reactivity (PTRL) and the outcome of the ROAT (P < 0.001). If only considering those with a PTRL above 0.3%, thus with negative or doubtful test reactions to 0.1% and 0.3%, there were still statistically significantly more patients with a positive ROAT to the moisturizer with MDBGN than to the moisturizer without MDBGN. The study demonstrates that patch testing with MDBGN at 0.3% and 0.1% will miss clinically relevant patch test reactions to MDBGN.

Reactive perforating collagenosis associated with scabies in a diabetic.

Reactive perforating collagenosis (RPC) in adults commonly manifests in patients with diabetes mellitus. Pruritus and consequent induced scratching have been identified as the bases for the evolution of this skin disease. We present the unusual case of a 55-year-old female diabetic with characteristic umbilicated skin lesions and a long history of scabies. Histology from a crusty nodule revealed transepidermal elimination of collagen. Following antiscabietic treatment, two courses of oral doxycycline demonstrated beneficial effects in controlling the perforating skin disorder.

Allergic and non-allergic periorbital dermatitis: patch test results of the Information Network of the Departments of Dermatology during a 5-year period.

Periorbital dermatitis is common and can be due to the external use of ophthalmic drugs. We evaluated patch test results of the Information Network of the Departments of Dermatology. During a 5-year period (1995-99), of a total 49,256 patch-tested patients, 1053 (2.1%) were eventually diagnosed as allergic periorbital contact dermatitis (APD) and 588 (1.2%) as non-allergic periorbital dermatitis (NAPD). Patient characteristics between APD, NAPD and other cases (OCs) differed with respect to sex (19.7% male in both periorbital groups versus 36.3% in OCs), atopic dermatitis (10.4% in APD versus 60.2% in NAPD versus 16.9% in OCs) and age, APD being substantially more often (68.2%) aged 40 and above than NAPD (52.6%). Several of the top allergens in OCs [such as fragrance mix, Myroxylon pereirae resin (balsam of Peru), lanolin alcohol and potassium dichromate] caused significantly fewer positive test reactions in both periorbital groups. In contrast, thimerosal, phenylmercuric acetate, sodium disulfite, gentamicin sulfate, phenylephrine hydrochloride and benzalkonium chloride tested positively significantly more often in APD but not in NAPD, verifying them as true ophthalmic allergens. Finally, in 42 cases (4%) of APD patients, additional allergens were identified by testing of the patients' own substances (mostly beta-blockers, oxybuprocaine and dexpanthenol), supporting the necessity of testing with ophthalmic drugs as is where individual substances are not readily available.

[Condylomata acuminata gigantea. Surgical and combined immunomodulatory therapy]. / Condylomata acuminata gigantea. Chirurgische und kombinierte immunmodulierende Therapie.

A 50-year-old female developed extensive condylomata acuminata in the genitoanal region over a period of 12 years. She presented with multiple, verrucous lesions involving the whole genitoanal area plus the adjacent perineum and gluteal region which made it impossible to identify the anatomical structures. Proctoscopy was normal. Serology for infectious diseases was negative. Several biopsies showed no signs of malignant transformation. Tumor excision under general anaesthesia was incomplete. Therefore, adjunctive therapy with immunomodulatory agents was administered, utilizing local application of imiquimod cream (3 x weekly) for 3 months and subcutaneous injections of interferon-alpha-2a (3 million IU 3 x weekly) for 5 months. This treatment regimen resulted in complete remission of all skin lesions with only discrete superficial scarring but no significant loss of anatomical structures or functions. During a 1-year follow-up the patient showed no sign of relapse.

Angioedema and dysphagia caused by contact allergy to inhaled budesonide.

Inhaled corticosteroids may cause various adverse effects ranging from irritation to severe anaphylactic reactions and systemic contact dermatitis. We report a 43-year-old woman who developed sore throat, swelling of the lips and oral cavity and dysphagia, 2 weeks after the use of budesonide spray (Budefat) for treatment of bronchial asthma. The symptoms occurred with a delay of 3-4 h after the treatment x2 daily. There were no immediate reactions on prick and intracutaneous testing with the commercial product used by the patient. However, marked pruritic infiltration developed within 24 h, progressing to coalescing eczematous lesions over the following 2 days. In addition, severe oedema of the right upper eyelid was observed. On patch testing, budesonide was strongly positive at day 2 and 3 in a concentration ranging from 1% to 10 p.p.m. (in petrolatum). Other corticosteroids of group A, B, C and D were completely negative. Repeated open application tests with amcinonide and triamcinolone acetonide cream on the ventral aspect of the upper arm were negative. Bronchial exposure to alternative sprays containing beclomethasone dipropionate (group D), fluticasone-17- propionate (D) and dexamethasone-21-isonicotinate (C) was well tolerated. In conclusion, this case is instructive, because the symptoms which developed after a short period of corticosteroid inhalation suggested a type I allergy. Testing proved a severe type IV contact allergy restricted to budesonide (group B), without cross-reactions to major corticosteroids of other groups.

Diagnostic and neural analysis of skin cancer (DANAOS). A multicentre study for collection and computer-aided analysis of data from pigmented skin lesions using digital dermoscopy.

BACKGROUND: Early detection of melanomas by means of diverse screening campaigns is an important step towards a reduction in mortality. Computer-aided analysis of digital images obtained by dermoscopy has been reported to be an accurate, practical and time-saving tool for the evaluation of pigmented skin lesions (PSLs). A prototype for the computer-aided diagnosis of PSLs using artificial neural networks (NNs) has recently been developed: diagnostic and neural analysis of skin cancer (DANAOS). OBJECTIVES: To demonstrate the accuracy of PSL diagnosis by the DANAOS expert system, a multicentre study on a diverse multinational population was conducted. METHODS: A calibrated camera system was developed and used to collect images of PSLs in a multicentre study in 13 dermatology centres in nine European countries. The dataset was used to train an NN expert system for the computer-aided diagnosis of melanoma. We analysed different aspects of the data collection and its influence on the performance of the expert system. The NN expert system was trained with a dataset of 2218 dermoscopic images of PSLs. RESULTS: The resulting expert system showed a performance similar to that of dermatologists as published in the literature. The performance depended on the size and quality of the database and its selection. CONCLUSIONS: The need for a large database, the usefulness of multicentre data collection, as well as the benefit of a representative collection of cases from clinical practice, were demonstrated in this trial. Images that were difficult to classify using the NN expert system were not identical to those found difficult to classify by clinicians. We suggest therefore that the combination of clinician and computer may potentially increase the accuracy of PSL diagnosis. This may result in improved detection of melanoma and a reduction in unnecessary excisions.

Hydroxyisohexyl 3-cyclohexene carboxaldehyde- known as Lyral: quantitative aspects and risk assessment of an important fragrance allergen.

Hydroxyisohexyl 3-cyclohexene carboxaldehyde, also known as Lyral, is a fragrance ingredient identified as the cause of contact allergic reactions in 2-3% of eczema patients undergoing patch testing. Lyral has been included in the standard patch test series in many clinics due to its importance as an allergen. It has been used without restrictions in cosmetic products, until now. In the present study, the dose-response relationship of Lyral contact allergy was studied with doses relevant for normal exposure in cosmetic products. 18 eczema patients, who previously had given a positive patch test to Lyral 5% petrolatum, were included along with 7 control subjects. All cases were tested with a serial dilution of Lyral in ethanol 6% to 6 p.p.m and subjected to a 2-week, repeated open application test with a low dose of Lyral in ethanol. In the case of no reaction, this was followed by another 2 weeks of testing with a higher dose. The test was performed at the volar aspect of the forearm. In 16 of 18 cases (89%), a positive use test developed, 11 reacting to the low and 5 to the high concentration. None reacted to the vehicle control of ethanol applied to the contralateral arm. All controls were negative to both the test solutions of Lyral and the ethanol control. The difference between the test and the control group was statistically significant (Fisher's test, P < 0.001). It is concluded that Lyral at the current usage levels is inducing sensitization in the community. The same levels were shown to elicit allergic contact dermatitis in almost all sensitized individuals. A significant reduction in usage concentrations is recommended to prevent contact allergic reactions.