Ring-shaped positive allergic patch test reactions to allergens in liquid vehicles

In recent years, we have observed several "ring-shaped" positive allergic patch test reactions to allergens dissolved in a liquid vehicle, a more intense response at the periphery of the site of application than in the central part. The occurrence of such reactions was evaluated for formaldehyde, Kathon CG, hydrocortisone and hexamidine diisethionate. Possible explanations for such reactions include pressure and/or a capillary effect.     

Kathon® CG reactivity in 1396 consecutively patch tested patients in the Copenhagen area

In 1396 consecutively patch tested patients 18 (1.3%) reacted to Kathon CG. Relevance was established in 4 of the 18 patients. The frequency of positive reactions to Kathon CG in eczema patients seems to have been stable in Denmark during the period 1983 to 1988.     

The association between size of test chamber and patch test reaction: a statistical reanalysis

A recent study by Brasch and co-workers reported on the association between size of test chamber and patch test reaction. The investigators interpreted their data on 495 patients as having conclusively shown that standard preparations of fragrance mix, wool wax alcohols, Kathon CG and formaldehyde led to more positive test reactions when large Finn Chambers were used for patch testing. We have scrutinized the statistical aspects of this study and conclude that the authors should have adopted a statistical approach suitable to analyse dependent samples. After explaining the correct methodological way of dealing with quadratic contingency tables formed by 2 dependent samples, we reanalyze the data accordingly and compare the results to those of the original paper. Based on this reanalysis, the conclusions are more complex: the reaction pattern for the fragrance mix and wool wax alcohols is significantly different between small and large test chambers; however, this discrepancy arises primarily from changing weak positive reactions with small chambers to strong positive reactions with large chambers. For formaldehyde, no relationship between chamber size and patch test reaction was found in the data, while for Kathon CG, statistical evidence is borderline that more positive test reactions are yielded by large test chambers than by small ones.     

More positive patch test reactions with larger test chambers?

Test chambers of various sizes are commercially available for patch testing. Therefore, we asked the question whether the size of patch test chambers may affect allergic patch test reactions. A total of 495 patients were doubletested synchronously with small and large Finn Chambers containing standard preparations of fragrance mix, wool wax alcohols. Kathon CG and formaldehyde, Double tests in 217 patients who had reacted with at least 1 allergic, questionable, or irritant reaction to 1 of these allergens were statistically evaluated. For each of the 4 allergens, a significantly higher number of stronger reactions was seen with the large chambers as compared to the small ones. It is concluded that large test chambers may be useful for detection of weak sensitizations to particular contact allergens.     

Simultaneous sodium lauryl sulphate testing improves the diagnostic validity of allergic patch tests. Results from a prospective multicentre study of the German Contact Dermatitis Research Group (Deutsche Kontaktallergie-Gruppe, DKG)

Background There is evidence that a higher skin susceptibility may induce nonspecific erythematous or weak positive reactions to contact allergens in patch testing. Objectives To evaluate whether simultaneous application of sodium lauryl sulphate (SLS) along with diagnostic patch tests with contact allergens can provide information regarding skin irritability which may help to discriminate allergic from nonspecific irritant reactions to contact allergens. Methods Between July 2001 and June 2003, this prospective study collected patch test data of 5971 patients from 19 centres in Germany and Austria in the Information Network of Departments of Dermatology (IVDK). In addition to contact allergens (standard series and eight known ‘problematic’ allergens with a low reaction index and a high positivity ratio: 1,3‐diphenylguanidine, amerchol L‐101, benzalkonium chloride, benzoyl peroxide, cocamidopropyl betaine, octyl gallate, phenyl mercuric acetate and propylene glycol), patches with SLS 0·5% and 0·25% aq. were applied. Reactions to the allergens and to SLS were analysed at the IVDK data centre. The association between an erythematous or positive reaction to a certain allergen and an irritant reaction to SLS was assessed with logistic regression analysis, at the same time controlling for the influence of age and sex. Results Of the 29 allergens of the standard series, 23 and 21 gave a higher percentage of nonspecific erythematous reactions in patients with an irritant reaction to 0·25% and 0·5% SLS, respectively, in comparison with SLS‐negative patients. All eight ‘problematic’ allergens gave an increased percentage of nonspecific erythematous reactions. Similarly, 22 and 21 allergens of the standard series gave a higher percentage of positive allergic reactions in patients with an irritant reaction to 0·25% and 0·5% SLS, respectively, and seven of the eight ‘problematic’ allergens gave a higher percentage of positive allergic rections (exception: octyl gallate). For most allergens, the markers of skin reaction (reaction index and positivity ratio) were worse in SLS‐positive patients. Differences were more pronounced when testing with SLS 0·25% than with SLS 0·5%. Conclusions Because there is a convincing association between skin irritability (evaluated by SLS test) and the degree of skin reaction to contact allergens, the SLS test may help in deciding whether a doubtful erythematous or weakly ‘positive’ skin reaction should be interpreted as allergic or irritant.     

Long-lasting allergic patch test reactions to nickel sulfate: analysis by nickel quantification and immunocytochemistry

We previously showed the median duration of positive patch test reactions to nickel sulfate(5% pet) was 9 days, and defined as long-lasting (LLAPTR) the 14.3% of reactions that persisted for 17 Days or longer. The pathomechanisms of LLAPTR are unclear, but may involve either localized antigen persistence or abnormal down regulation of the cellular immune response. In this study, we compared (a) the nickel concentration and (b) the immunocytochemical nature of the local immune reaction, between biopsies from LLAPTR ( n = 8) and normally resolving allergic patch lest reactions (NRAPTR) ( n = 8) to nickel sulfate. The concentration of nickel in LLAPTR (median 0.8μg/g, μg/g, range 0.25–3.87 μg/g, mean 0.83μg/g, 95% CI 0 35–1.31) and NRAPTR (median 0.58 μg/g, range 0.2 1.85 μg/g, mean 0.88 μg/g, 95% CI 0.02 1.74) was similar. Activated T lymphocytes, expressing surface IL-2 receptor, HLA DR, DR alpha 1, DP, DQ, and CD2>CD8>CD4 antigens, were seen throughout the dermis and occasionally infiltrating the suprabasal layer of the epidermis in all biopsies. CDI and HLA DR, DR alpha 1, DP, and DQ-expressing Langerhans cells were present throughout the epidermis and occasionally seen in the papillary dermis. HLA DR, DR alpha 1, DP, and DQ antigen expression were also seen on the surface of non-dendritic cells in the epidermis (probably either keratinocytes or T lymphocytes) and vascular endothelial cells in the papillary dermis. There were no significant qualitative or quantitative differences in the immuno-cytochemical nature of the localized immune reaction between LLAPTR and NRAPTR. These findings suggest that the pathomechanism of LLAPTR to nickel sulfate is unlikely to be explained simply on the basis of nickel concentration or the nature of the localized immune reaction at the patch test site.     

The reproducibility of patch tests

There is conflicting evidence regarding the reproducibility of patch testing. Discordant results have been reported in up to 44% of cases. The clinical relevance of these discordant patch tests has not been previously assessed. We studied 383 consecutive patients receiving simultaneous duplicate patch testing on opposite sides of the upper back with 10 allergens from the European standard series. Completely discordant patch tests-a negative test on one side with a positive test on the opposite side-were recorded in 30 (8%) patients. Two patients had discordant tests to two of the allergens; 28 had discordant reactions to one allergen. Completely discordant tests were recorded for nickel in 10 (3%) patients, balsam of Peru in two (0.5%), thiomersal in one (0.3%), cobalt in four (1%), paraphenylenediamine in three (0.8%), fragrance mix in two (0.5%), formaldehyde in four (1%), potassium dichromate in two (0.5%), lanolin in three (0.8%) and Kathon CG in one (0.3%). Of those patients with completely discordant patch tests, the allergen was deemed to be a true positive in 11 (3% of total) cases and of possible relevance in a further three. The allergen was felt to be relevant to the presenting complaint in seven (2% of total) patients.     

Sensitizations to allergens of TRUE test in 864 consecutive eczema patients in Israel

The TRUE test is a widespread diagnostic tool for initial patch testing of patients with contact dermatitis (CD). From 2002 to 2005, 864 patients with eczema were patch-tested using TRUE test in one Israeli allergology clinic. 547 (63.3%) patients were female and 317 (36.7%) were male. 346 (40%) patients had > or =1 positive patch test reactions. The most common allergens were nickel sulfate for 114 (13.2%) patients, potassium dichromate 111 (12.8%), fragrance mix 59 (6.8%), cobalt chloride 12 (1.4%), ethylenediamine dihydrochloride 11 (1.3%), epoxy resin 11 (1.3%), balsam of Peru 9 (1.0%), carba mix 7 (0.8%), thiomersal 6 (0.7%), wool alcohol 5 (0.6%), black rubber (PPD) mix 5 (0.6%), neomycin 4 (0.5%); Kathon CG, Colophony and Quaternium 15 - each 2 (0.2%), other allergens - each 1 (0.1%). In male patients, carba mix, black rubber (PPD) mix and epoxy resin sensitivity was more frequent, whereas nickel sulfate, fragrance mix, ethylenediamine dihydrochloride and cobalt chloride sensitivity was significantly more frequent in female patients. Our results are in general agreement with previously published reports, excluding the low sensitivity rates to cobalt, which maybe is missed by TRUE test.     

Standard patch test results in patients with contact dermatitis in Israel: age and sex differences

Previous studies have shown that the prevalence of specific allergens varies by geographic area, population, age and sex. The objective of the present study was to determine the relative frequency of positive reactions to different sensitizers in Israeli patients with clinically suspected contact dermatitis (CD) and to identify possible sex and age differences. A total of 943 consecutive patients were tested for CD using the European standard patch test series. The most frequent allergen was nickel sulfate followed by potassium dichromate and fragrance mix. Positive reactions to nickel sulfate were more common among women, especially those in the younger age group (younger than 40 years). Positive reactions to balsam of Peru were more common among men, especially those in the older age group (40 years or older). This study presents the result of the standard patch test in Israel with stratification according to age and sex. The findings of the present study, combined with reports on geographic/population differences in the prevalence of specific allergens in CD, indicate the need for further investigations to identify prominent local allergens for better adaptation of the standard patch test to local needs.     

Human safety study of body lotion containing Kathon® CG

The safety of Kathon CG biocide as a preservative in leave-on body lotions was assessed by 2 double-blind studies, using similar protocols. A total of 209 healthy male and female subjects aged 18 to 65 years, 100 in California (72 test subjects, 28 controls) and 109 in Florida (88 test subjects, 21 controls) completed the studies which included pre- and post-use phase diagnostic patch testing with Kathon CG 100 ppm active ingredient, and 13 weeks daily applications of either a test lotion containing Kathon CG 15 ppm active ingredient or a control lotion without Kathon CG. No evidence of irritation or sensitization attributable to use of the biocide was found during regular dermatological examinations during the use phase. Post-use phase patch testing produced negative results in all subjects with the exception of 1 control subject in Florida who had positive readings at the 2- and 4-week post-use phase patch testing. Overall, these studies show there is minimal, if any, risk of adverse effects associated with the use of Kathon CG 15 ppm active ingredient in a leave-on application.     

The "edge effect" with patch test materials

A positive "edge effect", i.e., the accumulation on the skin of a chemical solution (such as fluorescein 0.01% in a 50/50 water-ethanol solution) at the periphery of the patch test sites has been demonstrated. It occurs with different test materials (Finn Chamber; Silver Patch Test; Patch Test Chamber). Practical implications are discussed: this observation could be important when discussing results of laboratory investigations. In clinical practice, it could explain the occurrence of "ring-shaped" positive allergic patch test reactions to chemicals used in solution, i.e., Kathon CG or hydrocortisone.     

The association between ambient air conditions (temperature and absolute humidity), irritant sodium lauryl sulfate patch test reactions and patch test reactivity to standard allergens

To support the decision as to whether erythematous patch test reactions to allergens are irritant or allergic, sodium lauryl sulfate (SLS, 0.5% in water) has been added to the standard patch tests since July 1996 in the Dortmund Department of Dermatology. Data on 1600 patients patch tested up until June 2001, as well as standardized data on ambient temperature and humidity obtained by the German Meteorological Service, were included in a logistic regression analysis taking age, sex and atopy as potential confounders into account. The pattern of association was heterogeneous: while doubtful reactions to nickel sulfate were significantly associated with dry/cold weather conditions, but not with SLS reactivity, the opposite was observed for lanolin alcohol, benzocaine and Myroxylon pereirae resin (balsam of Peru). Doubtful reactions to other allergens, namely formaldehyde, fragrance mix or p-phenylenediamine, were associated with both factors. For several other allergens of the standard series, no distinct, significant pattern could be discerned. In conclusion, meteorological conditions and SLS reactivity independently contribute information on individual irritability at the time of patch testing, and both should be considered.     

Kathon® CG: cosmetic allergy and patch test sensitization

Three cases of contact allergy to Kathon CG, a preservative for cosmetics and toiletries containing, as active ingredients, 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one are presented. In two patients, Kathon CG was contained in a moisturizing cream, and the third was sensitized by a diagnostic patch test. Although it has been used extensively in cosmetics and toiletries for 9 years in Europe and 4 years in the USA, these appear to be the first case reports of non-occupational sensitization to Kathon CG.     

Patch test reactions at D4, D5 and D6

In this retrospective study, patch test reactions in 3 groups of patients were analysed, in order to obtain information on the best day for the 2nd patch-test reading after day 2 (D2), on the usefulness of additional readings after D3, and on the dependence of patch-test reactions at D4, D5, or D6 on allergen and/or patient characteristics. In the years 1990 to 1995, patch tests were routinely read at D3 and D4 in 1096 patients, at D3 and D5 in 1243 patients, and at D3 and D6 in 1136 patients. In all of the 3 groups, significantly more positive reactions diminished than appeared de novo from D3 to the later reading. Virtually identical results were observed in subgroups of patients formed by sex, age or atopy. However, men might possibly react more slowly than women on patch testing, showing more increasing than diminishing reactions in the D3/D4- and the D3/D5-comparison. Reactions to individual allergens showed wide differences in this connection. Neomycin sulfate, cobalt salts, and p-phenylenediamine can be characterized as slow allergens, with more reactions increasing than diminishing from D3 to the later readings. With fragrance mix and balsam of Peru, the opposite pattern occurred. In all subgroups of patients, and with most allergens, the gain in positive reactions was biggest when an additional reading was performed at D5. We conclude that for a single 2nd patch test reading after D2, D3 is the best day, and especially better than D4. If a 3rd reading is performed, it should be done at D5 to get the maximum information out of patch testing. However, this extends the test procedure to at least 1 day of the weekend.     

Positive patch tests with a dermatophagoides mix relate to an increased responsiveness to standard patch test allergens

The diagnostic meaningfulness of patch tests with house dust mite allergens is still questionable. Our own impression has been that positive results with a dermatophagoides mix may occur preferentially in patients with a generally enhanced responsiveness to contact allergens. To check this, all of our patients allocated to patch testing with the standard series were additionally patch tested with a dermatophagoides mix by the same technique that was used for standard contact allergens. Out of 571 patients tested, 188 showed delayed responses to this mix that were indistinguishable from typical allergic patch test reactions but of no apparent clinical relevance. No relationship was found between positive dermatophagoides patch tests and an atopic disposition of the patients or characteristics of their eczema. However, 64.4% of the patients with a positive dermatophagoides patch test showed a response to at least 1 contact allergen of the standard series, compared to only 56.4% of the patients without a positive dermatophagoides reaction (p < 0.05). The reactivity to the mite mix was not related to the responsiveness towards any particular contact allergens. We suppose that some unidentified factors may contribute to positive reactions to the dermatophagoides mix that may also favour an enhanced general responsiveness to contact allergens.     

Multiple concomitant positive patch test reactions

Thirty-five patients who showed 90 one plus (+) patch test reactions to 28 patch test chemicals at Day 2 (D2) were retested to the chemicals at D7. On retesting, 60 % (54/90) reactions were positive but 42 % (38/90) were negative at D9, suggesting that false positive patch test reactions were common when more than one positive reaction was obtained by concomitant patch testing. On retesting, the total % positivity was reduced from 344 to 241 suggesting that the true index of sensitivity was falsely exaggerated by concomitant testing.     

Statistical evaluation of the persistence of acquired hypersensitivity by standardized patch tests

Numerous studies have focused attention on the influence of various biological and environmental factors on contact hypersensitivity. In order to evaluate the persistence and/or modification of allergic contact sensitivity 10 a number of common contact sensitizers, the same standardized patch tests were repeated on 174 subjects with contact sensitivity after a lime lapse of 5 years (1987–1992). In 18.4% of the cases, 1 or more sensitivities were lost: 28.7% of the patients had a higher number of positive patch tests after 5 years, while the remaining 52.9% of the patients showed no change in the number of positive patch tests. In 88%, the positive allergens were unchanged, whereas in the remaining 12% of the subjects, they showed 1 or more variations. The association between the allergens most often positive was calculated for both the 1st and the 2nd patch lest results. Moreover, to evaluate the frequency of an allergen's positivity. We studied the disappearance of old sensitivities and the appearance of new sensitivities by the McNemar test. Cobalt chloride was the only allergen with a significant frequency of new positivities over the period of observation ( p < 0.01). Logistic regression analysis was performed to evaluate the possible influence of positive tests to other allergens, and of some clinical findings associated with contact dermatitis, on the sensitivity to cobalt chloride in 1987 and in 1992.     

Frequency of contact allergy in German children and adolescents patch tested between 1995 and 2002: results from the Information Network of Departments of Dermatology and the German Contact Dermatitis Research Group

Allergic contact dermatitis (ACD) affects approximately 7% of the general population. To evaluate the frequency of ACD in children, we analysed patch test results collected by the Information Network of Departments of Dermatology between 1995 and 2002. Data of 285 children (6-12 year) and 2175 adolescent patients (13-18 year) were analysed to determine the frequency of sensitization to the 30 most common contact allergens, adjusting for age and sex. As control group, we defined adult patients (60-66 year, n = 7904). The top allergens in children were thimerosal, gentamicin sulphate, nickel-II-sulphate, ammoniated mercury, cobalt-II-chloride, fragrance mix, bufexamac, Compositae mix, propylene glycol and turpentine. The overall proportion of sensitized patients according to the patch test results was 52.6% in the children group compared to 49.7% in the adolescent group. These findings were similar in the adult group at 52.2%. The detailed analysis regarding sex, occupation, atopy, site of eczema and age showed distinct patterns in each group indicating age-specific exposures. Atopy-related diseases were more common in children compared to adults. On the basis of the data of this study, the relationship between atopy and the risk of development of ACD, at least in children, needs further investigation.     

Delayed patch test reactions at days 7 and 9

403 consecutive patients were examined on days 2, 4, 7, and 9 following application of patch tests. Late positive reactions, i.e., those which manifested after day 4, were seen in 29 patients (7.2%). The allergens which most commonly produced late positive reactions were neomycin (7), potassium dichromate (4), and cobalt (3). Paired patch test readings on days 4 and 7 were more reliable than those on days 2 and 4. If only 1 patch test reading were performed, a single reading on day 4 would have been most useful. The reading on day 9 proved to be of limited value. Of 11 patients who were retested after an interval of more than 6 months, 7 showed earlier eliciting reactions, which may have been due to active sensitization.     

Results of routine patch testing of 834 patients in Turin

834 consecutive patients (630 female), aged between 26 and 46 years, who were suspected of having allergic contact dermatitis were patch tested with the GIRDCA standard series during 1989-1990. The most frequent sensitizers observed included nickel sulphate, cobalt, Kathon CG, perfumes, potassium dichromate and balsam of Peru. We have evaluated the influence of individual factors such as sex, age and occupation on the patch test results, and the coexistence of 2 or more unrelated but statistically significant sensitivities.