Trends in Benzisothiazolinone Sensitization: A Retrospective Analysis From 2010 to 2022, in a Tertiary Belgian Hospital.

BACKGROUND AND OBJECTIVESContact allergy is associated with a significant morbidity all over the world. This study was performed to investigate the pattern of sensitization by contact allergens in the local population.DESIGN AND SETTINGRetrospective study to investigate patch test reactivity among patients with clinical diagnosis of contact dermatitis who were referred to the allergy clinic at the King Khalid University Hospital, Riyadh, between April 2008 and March 2010.PATIENTS AND METHODSOf the 196 patients referred to the allergy clinic over the 2-year period, 91 (46.4%) patients reacted to one or more patch test allergens, and these patients were included in this study. The study group included 82 (91.1%) of Saudi nationality and 9 (8.9%) patients of other nationalities. The patch test was performed using the T.R.U.E TEST, containing 24 allergens/allergen mixes.RESULTSOf the 91 cases who reacted positively to one or more allergens, 67 (73.6%) were females with a mean age of 37 (8.3 years) and 24 (26.4%) were males with a mean age of 34 (11.6 years). Thirty-three (36.2%) patients reacted to nickel sulfate, 14 (15.3%) to p-phenylenediamine, 13 (14.2%) to p-tert-butylphenol-formaldehyde resin, 13 (14.2%) to thimerosal, and 9 (9.8%) to colophony. Reactivity against the rest of the allergens was not remarkable. A significantly higher percentage of females reacted to nickel sulfate (84.8% vs 15.2% in males; P=.0001), p-tert-butylphenol-formaldehyde resin (92.3% vs 7.7%; P=.0001), and thimerosal (76.9% vs 23.1%; P=.03).CONCLUSIONSPatch test reactivity to nickel sulfate was high. The pattern of contact allergy observed in this study indicates the need for large-scale investigations to identify local allergens responsible for contact allergy and for formulation of policies directed towards avoidance of exposure.

In 2019, a number of allergens (haptens), henceforth, "the audit allergens," were considered as potential additions to the European Baseline Series (EBS), namely, sodium metabisulfite, 2-bromo-2-nitropropane-1,3-diol, diazolidinyl urea, imidazolidinyl urea, Compositae mix II (2.5% or 5% pet), linalool hydroperoxides (lin-OOH), limonene hydroperoxides (lim-OOH), benzisothiazolinone (BIT), octylisothiazolinone (OIT), decyl glucoside, and lauryl glucoside; Evernia furfuracea (tree moss), was additionally tested by some departments as well. To collect further data on patch test reactivity and clinical relevance of the audit allergens in consecutive patients across Europe. Patch test data covering the audit allergens in 2019 and 2020 were collected by those departments of the European Surveillance System on Contact Allergies testing these, as well as further collaborators from the EBS working group of the European Society of Contact Dermatitis (ESCD), and the Spanish Grupo Español de Investigación en Dermatitis de Contacto y Alergia Cutánea. As patch test outcome, reactions between day (D) 3 and D5 were considered. Altogether n= 12 403 patients were tested with any of the audit allergen. Positive reactions were most common to lin-OOH 1% pet. (8.74% [95%CI: 8.14-9.37%]), followed by lin-OOH 0.5% pet., and lim-OOH 0.3% pet (5.41% [95% CI: 4.95-5.89%]). Beyond these terpene hydroperoxides, BIT 0.1% pet. was the second most common allergen with 4.72% (95% CI: 4.2-5.28%), followed by sodium metabisulfite 1% pet. (3.75% [95%CI: 3.32-4.23%]) and Compositae mix 5% pet. (2.31% [95% CI: 1.84-2.87%]). For some allergens, clinical relevance was frequently difficult to ascertain. Despite many positive patch test reactions, it remains controversial whether lin- and lim-OOH should be tested routinely, while at least the two preservatives BIT and sodium metabisulfite appear suitable. The present results are a basis for further discussion and ultimately decision on their implementation into routine testing among the ESCD members.

Allergic skin diseases

In the 2010s an epidemic of allergic contact dermatitis to methylisothiazolinone (MI) occurred in Europe. European authorities banned the use of methylisothiazolinone in leave-on cosmetics in 2017 and limited its use in rinse-off products in 2018. To investigate the sensitization rate to MI in Belgium between January 2014 and December 2019, and to assess cosensitizations to octylisothiazolinone (OIT) and benzisothiazolinone (BIT) in MI-sensitized patients. A retrospective study of patch test results with MI, OIT, and BIT observed in patients attending five Belgian hospitals. Overall, 560 of 10 029 patients (5.58%) had a positive patch test reaction to MI, and its sensitization rate decreased from 7.9% in 2014 to 3.1% in 2019. Rinse-off cosmetics, paints, and detergents were the most prevalent sensitization sources in recent years. Simultaneous reactions readily occurred to OIT, and, surprisingly, and increasingly, also to BIT. Contact allergy to MI in Belgium has reached a pre-epidemic level, reflecting the impact of recent regulatory measures. Leave-on cosmetics, in contrast to rinse-off products, have almost disappeared as sensitization sources in Europe. Paints and detergents also remain problematic. The remarkably high number of patients (co)sensitized to BIT should be a focus of future research.

Propolis is a natural product that consists of more than 100 compounds and shows great compositional variation depending on its origin.1 The most common poplar-type propolis is produced by honeybees in China, Europe, and North America, and is characterized by several caffeates as major allergens.2 The Information Network of Departments of Dermatology (IVDK) and others recently observed increasing rates of propolis sensitization.3, 4 We aimed to identify causes of increasing sensitization to propolis using IVDK and German trade data. From 2013 to 2019, 66 104 of 79 120 consecutive IVDK patients were patch tested with propolis (10% pet.) in the baseline series. According to information from Allmiral Hermal and SmartPractice Europe, patch test (PT) preparations contained the same or rather similar poplar-type propolis. PTs were performed following German and European guidelines and read on day 3 (day 4 in a few exceptional cases).5-8 Statistical significance on a 5% level was concluded from non-overlapping 95% confidence intervals (95% CIs) in corresponding comparisons. In the study period, 2598 patients (3.9%; 95% CI 3.8%-4.1%) showed positive PT reactions to propolis. Reaction frequencies in female (3.8%; 95% CI 3.6%-4.0%) and male (4.2%; 95% CI 3.9%-4.4%) patients did not differ significantly. Concerning population characteristics and PT results, Table 1 displays differences between 2598 propolis-positive patients and 61 032 propolis-negative patients. Patients with doubtful (n = 1883, 2.8%) or irritant reactions (n = 591, 0.9%) were excluded from this analysis. Among propolis-positive patients, there were significantly more patients aged 40 or older, males, and with leg or face dermatitis, whereas occupational and hand dermatitis were diagnosed less often (Table 1). As expected, patients sensitized to propolis reacted significantly more often to balsam of Peru (Myroxylon pereirae) and colophonium, most probably due to common ingredients, such as (aromatic) resin acids and monoterpenes.1 In addition, propolis-positive patients were significantly more often sensitized to other fragrances, essential oils, and compounds found in topical preparations (Table 1). The upward trend from 3.5% (95% CI 3.2%-3.9%) positive propolis reactions in 2013 to 4.7% (95% CI 4.2%-5.1%) in 2019 (Figure 1) was significant (asymptotic Cochran-Armitage trend test; P < .0001). If this trend was based on variations in allergen content or concentration in different types of propolis used in consumer products or PT preparations, one would expect that epidemiological (clinical) markers reflect such changes. However, items presented in Table 1 showed no substantial variation between the single years of the study period, and hence cannot explain this increase (data not shown in detail). An analysis of propolis import and export in Germany using tridge.com, an internet platform that connects suppliers and buyers,9 revealed that, from 2016 to 2019, propolis export decreased while its import increased dramatically (Figure 1). Imported propolis mainly originated from China (29.9%), Spain (11.2%), the USA (10.9%), Italy (8.1%), and Brazil (6.9%). According to de Groot's classification,1 poplar-type propolis dominated in Germany every single year. Propolis import from the USA peaked in 2014 (20.4%) and 2016/2017 (nearly 17%). Propolis from Brazil, which is chemically different from the poplar type,1 consistently had a relatively small market share (maximum 16.9% in 2015). Considering patient characteristics, suspected allergen sources, and concomitant PT reactions, sensitization to propolis shows an association with skin care and topical medical preparations (Table 1). Since 2016, increased import and decreased export of propolis to and from Germany, respectively, probably indicate increased propolis use and exposure, which most likely explains the upward trend of propolis sensitization. Nevertheless, one has to be aware that differences in propolis composition, even between poplar-type propolis species, and heterogeneity of the propolis used in PT preparations as well as in propolis on the (cosmetics) market do exist and affect diagnostic accuracy in patch tested patients, as recently demonstrated in a Swedish study.10 The compositional (chemical) heterogeneity of commercially available PT preparations year on year should be studied. Open Access funding enabled and organized by Projekt DEAL. The authors have no personal conflicts of interests. The IVDK, maintained by the IVDK e.V., of which J. Geier and S. Schubert are employees, is sponsored by the cosmetic and fragrance industry (associations) as well as by public funds. Steffen Schubert: Conceptualization (equal); software (equal); writing; original draft (equal). Johannes Geier: Conceptualization (equal); writing; review and editing (equal). Heinrich Dickel: Investigation (equal); methodology (equal); writing; review and editing (equal). Timo Buhl: Investigation (equal); methodology (equal); writing; review and editing (equal). Franziska Ruëff: Investigation (equal); methodology (equal); writing; review and editing (equal). Harald Löffler: Investigation (equal); methodology (equal); writing; review and editing (equal).

The WHO criteria for drug allergy can be adapted as guidelines for primary sensitisation from consumer products or occupational exposures. In case a person with a formerly healthy skin, develops allergic contact dermatitis after a specific exposure (a product or occupational exposure) has a positive patch test to specific chemical present in the product and ideally a positive either patch test or use test to the product during re‐exposure primary sensitisation is likely.Allergic contact sensitisation is a unique toxicological event (e.g. compared to cancer) as there is a direct (time and skin area) correlation between exposure and disease and the basic damage on the individual can be identified by the diagnostic patch test. Primary sensitisation may occur after single exposure to potent allergens, experimental from DNCB, in the US poison ivy, occupational accidental exposure to isothiazolones (in%) or from hair dying with PPD and its derivatives as a flare‐up reaction occurring 1–2 weeks after the original exposure.The ongoing epidemic caused by methyldibromo glutaronitrile (MDGN) provides unique options for studying primary sensitisation from consumer products as the clinical reactions are often very severe and patch test reaction with the products often exceeds the strength of the standard patch test response. Chemical analysis of the products involved uniformly illustrates the presence of MDGN within the legal permitted concentration. At the start of the epidemic, primary sensitisation was mostly seen from leave on products. After EU actions in 2002 against the use of MDGN in leave on products primary sensitisation from this preservative is now caused by wash off products. This observation is significant as it underscores the effect of specific exposures for primary sensitisation from consumer products but also the fact that primary sensitisation from a moderate to strong hapten is possible from wash off products. The MDGN story has illustrated that human data are pivotal for the current risk assessment – risk management. No new chemical should be permanently permitted in consumer products before significant post marketing data, collected after stringent criteria, are public available and scrutinised by an independent scientific committee.Human sensitisation data has successfully been used to introduce regulation of nickel exposure from consumer items. The year 2000 EU regulation has been in use in Denmark for more than 10 years. A significant decline in both induction and elicitation of dermatitis from nickel releasing items has been observed. Health economists have calculated that the direct savings from the regulation amount to 1.2 bill Euro over a 20‐year period in a population of 5.2. mio individuals.Translated to the whole EU‐region substantial gains can be achieved by improving the contact allergy risk assessment – risk management process.

More than just methylisothiazolinone: Retrospective analysis of patients with isothiazolinone allergy in North America, 2017-2020

North American Contact Dermatitis Group Patch Test Results: 2019-2020.

Notwithstanding that concomitant exposure to different isothiazolinone derivatives may result in concomitant sensitization, clinical and animal studies have suggested cross-reactivity between these derivatives, notably between methylisothiazolinone (MI) and octylisothiazolinone (OIT). To investigate if patients sensitized to MI show cross-reactions to OIT and/or to benzisothiazolinone (BIT) by applying the concept of the re-test method. From March to October 2019 consecutive patients were patch tested with MI 0.2% aqueous in duplicate at the two lower corners of both shoulder blades. Patients sensitized to MI, but not to OIT 0.1% petrolatum (pet.) nor to BIT 0.1% pet., were re-tested, 2 months later, with the latter two derivatives at the skin sites where the MI reactions had fully disappeared. Of 116 patients, 15 (13%) were sensitized to MI, eight of these not sensitized to BIT nor to OIT. Of these, seven patients, all (very) strongly sensitized to MI, were re-tested: five patients showed positive patch test reactions to OIT 0.1% pet.; one patient to OIT 0.1% pet. and BIT 0.1% pet.; and one other patient showed no reactions. This study suggests that patients primarily and strongly sensitized to MI may show immunologic cross-reactions to OIT, and to a far lesser extent to BIT.

Due to an increasing occupational usage of isothiazolinone (IT)-containing preservatives, and their potential to cause skin sensitization and allergic contact dermatitis, that is, chronic disease, there is a need for more knowledge on how highly exposed workers are affected. The overall objective was to explore dermatological symptoms of potentially long-lasting or chronic character in Swedish painters. Building painters from western and southern Sweden were initially invited to perform a questionnaire on occurrence of skin symptoms. Participants with affirmative responses, and the right inclusion criteria, were further invited to patch testing with four different ITs: benzisothiazolinone (BIT), methylisothiazolinone, methylchloroisothiazolinone and octylisothiazolinone. There was a tendency towards higher occurrence of positive patch test reactions among the painters compared with occupationally unexposed registry patients; however, not statistically significant differences. BIT was the substance most frequently causing positive test results in both groups. The occurrence of adult-onset eczema was higher in painters than in the control group of electricians, and just shy of statistical significance concerning any of several skin locations (face/legs/arms/hands). Building painters present with positive patch test reactions to common paint preservatives (ITs), and they report adult-onset eczema more often than do less occupationally exposed groups.

Allergic contact dermatitis in the pediatric population is more common than previously recognized, with recent prevalence estimates of positive patch test reactions in the range of 14-70% of children patch tested. The aim of this study was to confirm the prevalence of clinically relevant allergic contact dermatitis in children at two referral centers and determine the most common contact allergens. We performed a retrospective case series analysis of 65 symptomatic children (35 girls and 30 boys) aged 1-18 years old who were patch tested over a 5-year period for recalcitrant dermatitis. Positive patch test reactions were noted in 54 of the 65 children (prevalence rate of 83%) to 80 different allergens. Fifty children (77%) had positive reactions which were determined to be of "definite" or "probable" current clinical relevance. We conclude that the diagnosis of allergic contact dermatitis to specific relevant allergens is common in children referred for patch testing and that contact allergy should be considered in all children with recalcitrant dermatitis. With this article, we review the literature and present a US based study regarding the clinical relevance of positive patch test reactions in children.

BackgroundOften concomitant patch test (PT) reactivity to palladium (Pd) and nickel (Ni) is found.ObjectivesTo determine whether lymphocyte transformation test (LTT) could be useful in discrimination between cross‐reacting or distinct PT results, and to compare the results with in vitro cytokine production upon Pd or Ni stimulation.Materials and MethodsThe study population consisted of two groups: 13 individuals with Pd PT reactions (10 with concomitant Ni PT reaction, 3 individuals with only Pd PT reactivity) and 10 Ni/Pd PT negative individuals. LTT and assessment of cytokine release (interferon‐gamma, interleukin‐5 [IL‐5], IL‐8, IL‐17A, tumor necrosis factor alpha) by cytometric bead assay were performed.ResultsAll 10 patients with positive PT to Ni and Pd showed positive LTT to Ni (P < .05) as compared with the 10 Pd/Ni PT negative patients—but had no significant LTT reaction to Pd. In all, 9 out of 10 Pd/Ni PT negative patients were also LTT negative to Ni and 10 out of 10 to Pd. In the 3 only Pd PT reactors 2 out of 3 remained LTT negative to Ni and 0 out of 3 to Pd. As a major finding, cytokine production gave clearly enhanced IL‐5 response to Ni in Ni PT positive individuals (P < .05), whereas Pd PT reactivity was not linked with such enhanced IL‐5 production in vitro to Pd.ConclusionsPd and Ni sensitization are mostly found concomitantly, and cross‐reactivity is questioned. By different LTT reactions and particularly IL‐5 production in vitro, predominant Ni sensitization becomes more evident.

Patch test (PT) reactions to thiuram mix (TM) and fragrance mix (FM) I or II without concomitant reactions to their single constituents are potentially caused by the irritant properties of the mixes. Comparing inflammatory profiles of PT reactions to TM, FM I, FM II, and their constituents and assessing their potential in discrimination of irritant and allergic reactions. Levels of 14 cytokines and natural moisturizing factor (NMF) were determined in stratum corneum samples collected from PT reactions to TM, FM I or II, their constituents, and petrolatum (pet.) control sites in 36 individuals. Levels of interleukin (IL)-16, chemokine (CXC motif) ligand (CXCL) 8, CXCL10, chemokine (CC motif) ligand (CCL) 17, and CCL22 were significantly increased in reactions (+, ++) to thiurams and fragrances compared to their petrolatum. controls, except for PT reactions to FM I/II with negative breakdown testing in which, however, decreased levels of NMF were observed. In doubtful reactions to FM I/II with negative breakdown testing, NMF was significantly lower than in petrolatum controls. PT reactions to thiurams and fragrances indicate a Th2-skewed inflammation. The inflammatory profiles suggest that weak or doubtful FM I/II reactions without accompanying reaction to a constituent were irritant. IL-16 might be suitable to distinguish irritant from allergic reaction.

Positive patch test reactions in older individuals: Retrospective analysis from the North American Contact Dermatitis Group, 1994-2008

Atopy patch testing--a diagnostic tool?