Patch test results with the European baseline series and additions thereof in the ESSCA network, 2015-2018

Background: Clinical surveillance of the prevalence of contact allergy in consecutively patch tested patients is a proven instrument to continually assess the importance of contact allergens (haptens) assembled in a baseline series. Objectives: To present current results from the European Surveillance System on Contact Allergies, including 13 countries represented by 1 to 11 departments. Methods: Anonymized or pseudonymized patch test and clinical data from various data capture systems used locally or nationally as transferred to the Erlangen data centre were pooled and descriptively analysed after quality control. Results: In the 4 years (2015-2018), data from 51 914 patients patch tested with the European baseline series (EBS) of contact allergens were analysed. Contact allergy to nickel was most frequent (17.6% positive), followed by contact allergy to fragrance mix I (6.9%), methylisothiazolinone (MI; 6.2%), and Myroxylon pereirae resin (balsam of Peru; 5.8%). Conclusions: While the prevalence of MI contact allergy decreased substantially following regulatory intervention, the persistently high levels of allergy to metals, fragrances, other preservatives, and rubber chemicals point to problems needing further research and, potentially, preventive efforts. Results with national additions to the baseline series provide important information on substances possibly to be considered for inclusion in the EBS.


| INTRODUCTION
The value of surveillance of contact allergy using scientific networks has been repeatedly illustrated (for example, see

| METHODS
The ESSCA is a working group of the ESCD (https://www.escd.org).
Its objective is the clinical surveillance of contact allergy. 1,5 To this end, contributing departments (Table S1) submit either all patch test results or just patch test results obtained with the EBS (or national or local adaptations thereof), obtained following ESCD standards, 6 to the data centre in Erlangen. This is accompanied by important demographic and clinical information, ranging from "MOAHLFA" characteristics to a wider range of information according to the ESSCA minimal dataset definition. 1,7 Data from contributing departments are delivered in an anonymous format or partly, following national network standards, in a pseudonymized format, where the pseudonym cannot be related to actual personal data except in the contributing department itself. This difference is of importance, as only with pseudonymized data can re-investigations of patients be identified and eliminated, to avoid duplication of entries.
For the purpose of the present analysis, a random selection among two or more consultations documented in the database, involving testing the baseline series, was made. Data were quality checked, providing an internal report for each contributing department for scrutiny and approval before pooling of the respective data. 5 Two departments contributed aggregated (ie, no individual) data on results, stratified for gender, namely, Gentofte/Denmark and Coimbra/Portugal. Test results with different preparations of the same allergen, for example, concerning methylisothiazolinone (MI), are presented separately. Concerning MI, 0.05% and 0.2% aqueous (aq.) had been tested most commonly. Following an overall decline of patient numbers patch tested from 2015 to 2018, patch testing with MI 0.05% aq. also decreased, by 37.7%, whereas patch testing with MI 0.2% aq. decreased by 29.1% (P < .0001, chi-square test). Data management and analysis were performed with the R software package (www.rproject.org; RRID:SCR_001905), version 3.6. For the calculation of 95% confidence intervals (CIs) to zero proportions an approximation to an exact CI was used. 8 Data from the subset of departments from Austria, Germany, and Switzerland participating in the Information Network of Departments of Dermatology (IVDK, https://ivdk.org/en) and in the ESSCA (these departments roughly cover one-third of all investigations included in the IVDK) were also included in the presentation of 2007 to 2018 IVDK results with the German baseline series recently published. 9

| RESULTS
In total, data of 51 914 patients patch tested with the EBS from 2015 to 2018 (inclusive) were analysed. The individual contribution by country and department is shown in Table S1. Population characteristics according to the MOAHLFA index, 10 extended by the P-measure, that is, the proportion of patients positive to at least one allergen from the baseline series, 11 are illustrated in Table 1. The share of patients with one, two, and three or more positive reactions to unrelated allergens 12 applied in the baseline series was 23.3%, 12%, and 16.8%, respectively. A considerable variation of all MOAHLFA factors is evident. In the present data, the share of patients aged 40 or older is just slightly higher in males (62.9%) than in females (61.6%, P = .005). The overall share of patients with trunk or generalized dermatitis was 5% and 5.6%, respectively.
Patch test results with the EBS, in the version valid at the time, 13,14 are shown in Table 2 as crude overall prevalence and sexstratified prevalences, respectively. A supplemental analysis stratified for three age groups is presented in Table S2 for the EBS and in supplemental Table S3 for additions thereof. A further analysis presenting age-and sex-standardized, instead of age-and sex-stratified, results is presented in Table S4, for direct comparison with previous ESSCA analyses using the same standardization. 15 Patch testing results to the three metals, the four fragrance allergens, and the preservatives shown in Table 2 are as follows: 21.9% were positive to at least one metal, 12.1% to at least one of the fragrance markers, and 11.1% to at least one of the preservatives listed.
The currently used textile dye mix (TDM) 6.6% petrolatum (pet.) contains Disperse Orange 3 1%, which strongly cross-reacts with p-phenylenediamine (PPD). The cross-reactivity between TDM and PPD was thus assessed: Of the 11 996 patients tested with both TDM and PPD, 184 (1.5%) reacted to TDM and PPD, 152 (1.3%) only to TDM, and 209 (1.7%) only to PPD. An odds ratio (OR) of 66.3 indicates very marked cross-reactivity. In many departments temporary or long-term additions were tested along with the EBS in consecutive patients; these results are shown in Table 3 in a format identical to Table 2. "Carba mix" contains not only two dithiocarbamates (zinc dibutyldithiocarbamate and zinc diethyldithiocarbamate [ZDEC]) but also 1,3-diphenylguanidine. Of 18 796 patients patch tested with both thiuram and carba mix, 111 (0.59%) reacted to both, whereas 388 (2.06%) were positive only to carba mix and 188 (1%) only to thiuram mix. Of all 500 positive reactions to carba mix, 86.6% were weak positive, with the remainder either strong (12.4%) or extreme (1%) positive. None of the patients T A B L E 1 Demographic and clinical characteristics according to the MOAHLFA index 10 with "P-measure," 11 that is, the proportion of patients with at least one positive reaction to a baseline series allergen, excluding one purely paediatric department (Padova Paediatric Department)

Propolis is a long-standing constituent of the baseline series in
German-speaking countries. The prevalence of positive reactions was 4% in the participating departments of the three countries (Austria, Germany, and Switzerland) which are also members of the IVDK, and 1% in the others testing it, namely, departments from Italy, Lithuania, UK, and, to a limited extent, The Netherlands and Poland, P < .0001.
While propolis is not a fragrance allergen, cross-reactivity to FM I (OR 5.6) and M pereirae (OR 7.5) was substantial (both P < .0001).
Finally, patch test results with the TRUE Test are shown in Table 4; the departments using this test system as a part of their baseline patch test work-up supplemented this with investigator-loaded test allergens to (mostly) conform with the EBS. These latter results are included in Table 2, for example, concerning MI.

| DISCUSSION
The present analysis of routine surveillance data collected by the ESSCA follows up on previous reports and is a continuation of a series of similar reports on data from 2002/2003, 16 2004, 17 2005/2006, 18 2007/2008, 19 2009 to 2012, 20-25 and lastly, 2013/2014. 3 The changing patterns of contact allergy can therefore be observed and interpreted, albeit from the background of a partly changing contribution to the network, which needs to be considered. may be due to a change of treatment paradigms, with less allergenic products used in more recent times. 27 The increase in face dermatitis can, at least partly, be attributed to the recent epidemic of MI sensitization with many cosmetic-related cases of face dermatitis. 28 The overall yield of the baseline series, in terms of at least one positive reaction to one of its allergens, had been suggested as another descriptor of a patch tested patient population. 11 However, as this measure summarizes rather complex effects, as more extensively discussed in Uter et al, 20 its interpretation is not straightforward; notwithstanding, the broad range of positivity does stimulate speculation.

| European baseline series (version 2015)
Taken together, and certainly dominated by nickel, the three metals included in the EBS most commonly cause contact allergies. Agestratified results indicate a lower prevalence of nickel allergy in the youngest age group, compared with the quite broadly defined middle age group. This may reflect to some extent a, albeit limited, decline of nickel contact allergy. 29 However, despite a considerable success of preventive efforts, nickel exposure prevention needs further improvement. 30 The prevalence of chromium contact allergy is lowest in the youngest age group; however, because chromium is a less ubiquitous allergen, the success of prevention (reduction of hexavalent chromium in cement and more recently, in leather) should best be reviewed in particularly exposed subgroups, for example, in the building industry 31 and in patients with shoe (foot) dermatitis. Cobalt, in contrast to the other two metals, does not display any age pattern. Given the general difficulty in identifying clinical relevance for sensitization to cobalt, 32 it is difficult to identify relevant exposures which need to be addressed by further research and, ultimately, prevented.
Fragrances are the next most common group of substances or mixtures causing contact allergy. Positive patch test reactions to FM I show a well-known age gradient, 33 possibly owing to the life-long cumulative exposure and steadily increasing risk of sensitization. It is unclear, at least by just looking at the FM I results, whether the lower prevalence in the younger patients also reflects self-regulatory concentration restrictions concerning FM I constituents in cosmetics taken in the past. A similar pattern is seen for FM II and its main allergenic constituent, hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC). In view of the recent ban of HICC, and the de facto ban of Evernia prunastri (oak moss) due to the restrictions on (chlor)atranol, 34 a re-design of the mixes could be considered in due time, to adapt these to the currently relevant exposure conditions in Europe. The age gradient of positive reactions to M. pereirae (balsam of Peru) is even more marked than that of FM I. This "ill-defined natural fragrance mix" is an apparently important, but also enigmatic allergen, concerning the consequences of a positive patch test for the patient, as recently reviewed by de Groot. 35 The dramatic increase of contact allergy prevalence to MI and, parallel to this, to the mixture methylchloroisothiazolinone (  allergy in about 40% of the patients in that study, which probably depends on country-or region-specific exposure/prescription. Of note, the Spanish study used a day 7 reading, which was mostly lacking in the present data, and in the outcome definition, which must be regarded as a shortcoming leading to underestimation of the sensitization prevalence particularly of the corticosteroids by up to 30%. 42 It is recommended to test with a full series of corticosteroids in case allergic contact dermatitis to these is suspected.
Clioquinol contact allergy has become a rarity, justifying its recent elimination from the EBS. 4 45 which has been found, at the same time, to be an important allergen in synthetic rubber gloves. 46 The sensitization prevalence of PPD is largely stable, with a preponderance of females (Table 2) and a weak variation across age groups (Table S2). Contact allergy to PPD is often related to exposure to oxidative hair dyes. 47 Hence, a much reduced share of PPDcontaining hair dye products and replacement with only partially cross-reacting PPD derivatives recently observed at least in Germany 48 could be expected to contribute to a lessening of sensitization and with just a slight increase with age, propolis seems indeed a worthwhile addition. Accordingly, propolis had been identified as an emerging allergen in a recent analysis of long-term data from the IVDK (of which the present data sample constitutes a fraction, see the "Methods" section). 9 A comparison between results from "IVDK countries" and the remaining countries testing with propolis shows a highly significant difference in prevalences, with a prevalence of 1% in the latter, illustrating the well-known geographical variation of contact allergy to this natural product. 19  Data suggest that SL mix alone is insufficient as a screen to diagnose Compositae allergy, but the ideal combination is not yet established.
Some suggest a combination with Compositae mix II 2.5% pet. and parthenolide 0.1% pet. 53 However, while the original Compositae mix I 5% pet. induced active sensitization, others feel that the 5% concentration of the Compositae mix II is not sensitizing and contains parthenolide 0.1% 54 rather than feverfew extract that was in the mix I.
The question as to whether different formaldehyde releasers, including quaternium-15, which is a longstanding constituent of the EBS, should be tested in addition to formaldehyde (ideally 2% aq.) has been addressed by another, dedicated analysis and shall not be discussed here. 55 The present results with the different formaldehyde releasers are largely similar to the more detailed, department-wise analysis of 2013/2014 data. 56 The mixture of MDBGN and 2-phenoxyethanol 1:4 (eg, Euxyl K 400 as trademark) is still tested to a limited extent by some departments. Iodopropynyl butylcarbamate (IPBC) 0.2% pet., tested in more than 20 000 consecutive patients, caused over 1% positive, mostly weak positive, reactions and about three times as many doubtful or irritant reactions. However, other studies found a lower sensitization prevalence (eg, 0.53%). 57 IPBC liberates iodine, which has also been supported by observing simultaneous contact allergy to IPBC and iodine. 58 Owing to possible endocrine interference, use concentrations are restricted to between 0.02% in rinse-off products and 0.0075% in deodorants/antiperspirants for many years (SCCNFP/0826/04, EU Cosmetics Regulation, Annex V/56). It would be of interest to further investigate IPBC regarding the clinical relevance of (weak) positive patch test reactions.
Similar to propolis, cetearyl alcohol also exhibits significant geographical differences, albeit on a much lower level, presently not justifying inclusion into the EBS. While sodium metabisulfite yields a considerable number of positive reactions (Table 3) and has thus been recommended to be added to the EBS, 4 fusidic acid seems to be a rare allergen not warranting consecutive testing.

ACKNOWLEDGEMENTS
This study was funded in part by the EADV Grant PPRC-2018-8.
Open access funding enabled and organized by Projekt DEAL.

CONFLICTS OF INTEREST
W.U. has accepted travel reimbursement and research funds from the cosmetic industry association IFRA and has received a lecture fee from dermatology-related sponsors for an educational lecture on contact allergy. The IVDK, maintained by the IVDK e.V., of which J.G. is an employee, is sponsored by the cosmetic and fragrance industry (associations) as well as by public funds. M.G. has received honoraria for advisory boards and lectures from Novartis and Sanofi-Genzyme.
M.W. has received travel reimbursement to attend meetings with the cosmetic industry. The other authors have no pertinent conflict of interests to declare.