Unravelling the immune signature of herpes zoster: Insights into pathophysiology and the HLA risk profile.

The varicella-zoster virus (VZV) infects over 95% of the population. VZV reactivation causes herpes zoster (HZ), known as shingles, primarily affecting the elderly and immunocompromised individuals. However, HZ can also occur in otherwise healthy individuals. We analyzed the immune signature and risk profile in HZ patients using a genome-wide association study across different UK Biobank HZ cohorts. Additionally, we conducted one of the largest HZ HLA association studies to date, coupled with transcriptomic analysis of pathways underlying HZ susceptibility. Our findings highlight the significance of the MHC locus for HZ development, identifying five protective and four risk HLA alleles. This demonstrates that HZ susceptibility is largely governed by variations in the MHC. Furthermore, functional analyses revealed the upregulation of type I interferon and adaptive immune responses. These findings provide fresh molecular insights into the pathophysiology and the activation of innate and adaptive immune responses triggered by symptomatic VZV reactivation.

Differential diagnosis of contact dermatitis: A practical-approach review by the EADV Task Force on contact dermatitis.

The diagnosis of eczema ('dermatitis') is mostly clinical and depends on the clinical history and exploratory objective findings (primary lesions, patterns). Contact dermatitis remains as an important condition in the group of eczematous disorders, with important socioeconomic and occupational relevance. Although irritant and allergic contact dermatitis have a different pathogenesis, both are characterized by a rather typical morphology, are triggered by external factors and tend to occur primarily in the area of contact with the exogenous agent. In addition, allergic and irritant dermatitis may also co-exist. The importance of diagnosing contact dermatitis, especially when allergic in nature, is both due to the possibility of avoiding the trigger, and due to its role in aggravating other skin conditions. Nevertheless, the heterogeneity of clinical presentations in daily practice may pose an important challenge for the suspicion and correct diagnosis of contact dermatitis. Furthermore, other conditions, with different pathogenesis and treatment, may clinically simulate contact dermatitis. The Task Force aims to conduct a review of the unifying clinical features of contact dermatitis and characterize its main clinical phenotypes, and its simulators, in order to contribute to an early suspicion or recognition of contact dermatitis and enable a correct differential diagnosis.

Current frequency of contact allergy to isothiazolinones (methyl-, benz- and octylisothiazolinone) across Europe.

BACKGROUND: The use of methylisothiazolinone (MI) as a preservative in cosmetic products caused an alarming increase in MI contact allergy across Europe in the 2010s. This was followed by regulations of use with a total ban on leave-on (implemented in 2017) and reduced use concentrations in rinse-off cosmetics (2018). OBJECTIVE: To follow-up on the prevalence of contact allergy to MI and the related benzisothiazolinone (BIT) and octylisothiazolinone (OIT) in consecutively patch-tested patients in Europe. METHODS: A cross-sectional audit following the design of two previous audits on MI contact allergy from 1 May 2022 to 31 October 2022 included all patients patch tested with the European baseline series, including or supplemented with MI, BIT and OIT across 10 departments in eight European countries. RESULTS: A total of 2554 patients were consecutively patch tested with the three isothiazolinones during the study period. The prevalence of MI and BIT contact allergy was 2.9% (95% confidence interval [CI]: 2.3%-3.7%; range 1.1%-5.8%) and 3.1% (95% CI: 2.4%-3.9%; range 0.0%-6.6%), respectively; that of OIT was 0.7% (95% CI: 0.4%-1.1%; range 0%-3.2%). Rinse-off cosmetic (73.3%) and leave-on cosmetic products (13.3%) were still associated with eliciting allergic contact dermatitis to MI. CONCLUSION: We confirmed a positive impact of regulatory measures on the prevalence of MI contact allergy in Europe, which halved compared to 2015. However, our data suggest that consumers may still be exposed to older cosmetic products containing MI. BIT has superseded MI in causing contact allergy, despite not being allowed for use in cosmetic products.

Severely compromised supply of patch test allergens in Europe hampers adequate diagnosis of occupational and non-occupational contact allergy. A European Society of Contact Dermatitis (ESCD), European Academy of Allergy and Clinical Immunology (EAACI), European Academy of Dermatology and Venereology (EADV) task forces 'Contact Dermatitis' and 'Occupational Skin Disease' position paper.

Patch testing is the only clinically applicable diagnostic method for Type IV allergy. The availability of Type IV patch test (PT) allergens in Europe, however, is currently scarce. This severely compromises adequate diagnostics of contact allergy, leading to serious consequences for the affected patients. Against this background, the European Society of Contact Dermatitis (ESCD) has created a task force (TF) (i) to explore the current availability of PT substances in different member states, (ii) to highlight some of the unique characteristics of Type IV vs. other allergens and (iii) to suggest ways forward to promote and ensure availability of high-quality patch testing substances for the diagnosis of Type IV allergies throughout Europe. The suggestions of the TF on how to improve the availability of PT allergens are supported by the ESCD, the European Academy of Allergy and Clinical Immunology, and the European Academy of Dermatology and Venereology and intend to provide potential means to resolve the present medical crisis.

It is not always chlorhexidine: Identification of benzoxonium chloride and lauramine oxide as culprit allergens in a popular antiseptic in Switzerland.

BACKGROUND: A popular antiseptic spray in Switzerland (Merfen spray), containing chlorhexidine digluconate, benzoxonium chloride and lauramine oxide, is frequently used to treat skin wounds. However, it is also increasingly reported as a major cause of adverse skin reactions, including allergic contact dermatitis (ACD). OBJECTIVES: To investigate the contact allergens responsible for ACD from this antiseptic. PATIENTS/METHODS: Patch tests were performed on seven patients with a clinical history compatible with contact dermatitis from this antiseptic mixture. RESULTS: All patients presented with acute eczematous reactions following contact with either Merfen spray alone, or with multiple products including this spray. Patients showed positive reactions to this product in both patch tests and repeated open application tests (ROATs). Four patients showed dose-dependent reactions to both benzoxonium chloride and lauramine oxide. One patient showed a dose-dependent reaction to the former and a non-dose-dependent reaction to the latter. Finally, two subjects showed responses only to lauramine oxide. One patient reacted to chlorhexidine digluconate 0.5% aq. in addition to both other allergens. CONCLUSIONS: Two commercially unavailable allergens, that is, benzoxonium chloride and/or lauramine oxide were identified as major causes of ACD from Merfen antiseptic spray, whereas chlorhexidine digluconate was a contributing culprit in only one patient.

The European baseline series and recommended additions: 2023.

The European baseline series was last updated in 2019. This article discusses the reasoning behind a further iteration of the series for 2023.

Contact allergy to and allergic contact dermatitis from formaldehyde and formaldehyde releasers: A clinical review and update.

This review aims to provide a clinically useful update regarding the role of formaldehyde (FA) and its five main releasers (FRs) quaternium-15, diazolidinyl urea, DMDM hydantoin, imidazolidinyl urea, and 2-bromo-2-nitropropane-1,3-diol (bronopol) in contact allergy and allergic contact dermatitis. These ubiquitous preservatives are still often present, and sometimes undeclared, in cosmetics, pharmaceuticals, medical devices, household detergents, and chemical (industrial) products. In Europe, the use of free FA and quaternium-15 in cosmetics is forbidden and contact allergy rates have been found to be stable to decreasing. However, FA/FRs still readily provoke localized (eg, facial/hand), airborne, and generalized dermatitis, and may also complicate atopic and stasis dermatitis, or result in nummular dermatitis. Seborrheic-, rosacea- and impetigo-like dermatitis have recently been reported. For a correct diagnosis, FA 2% aq. (0.60 mg/cm2 ) should be used, and particularly the FRs bronopol 0.5% pet. and diazolidinyl urea 2% pet. should be patch tested separately in a baseline series. If sensitization to FA occurs, both FA and FRs should preferably be avoided, except perhaps for bronopol in case it tests negatively. If a patient reacts to one or more FRs (such as bronopol or diazolidinyl/imidazolidinyl urea), but not to FA, then the specific FR(s) should be avoided.

Isocyanates may contribute to allergic contact dermatitis from diabetes devices and wound dressings.

BACKGROUND: Isocyanates are well-known occupational allergens, but can also be present in medical devices. OBJECTIVES: To highlight that contact sensitization to isocyanates might contribute to allergic contact dermatitis (ACD) from polyurethane (PU)-containing diabetes devices and wound dressings. PATIENTS AND METHODS: Nineteen patients with suspected ACD from diabetes devices and/or wound dressings were patch tested to an isocyanate series. Four wound dressings, six diabetes devices and four monomeric isocyanate patch test preparations were analysed with gas chromatography - mass spectrometry. RESULTS: Eight patients reacted to isocyanates and corresponding amines: 3 to isophorone diisocyanate (IPDI), 4 to 4,4'-diaminodiphenylmethane (MDA), 4 to 2,4-toluene diisocyanate (TDI) and 1 to polymeric methylene diphenyl diisocyanate (PMDI). Three of four wound dressings contained isocyanates (methylene diphenyl diisocyanate [MDI], TDI and/or IPDI), whereas five of six diabetes devices contained 4,4'-MDI, and one of them also IPDI. None of the medical devices contained 1,6-hexamethylene diisocyanate. Contrary to IPDI, and especially MDI, only the concentration of the TDI patch test preparation corresponded approximately (80%) to its label. CONCLUSION: Patch tests with isocyanates may be worth-while in patients with suspected ACD from PU-containing medical devices. Besides MDA, and PMDI, also TDI might potentially be a marker for MDI-sensitization.

Allergic contact dermatitis from ("hypoallergenic") adhesives containing D-limonene.

BACKGROUND: Besides being a potential component of (some species of) colophonium, D-limonene is also used as a tackifier in the production of adhesives. Hydroperoxides of limonene are well-known skin sensitizers. OBJECTIVES: To show that D-limonene may be present in colophonium-containing but also colophonium-free ("hypoallergenic") adhesives, and that patients suffering from allergic contact dermatitis (ACD) from both types of adhesives might display positive patch test reactions to limonene hydroperoxides in this regard. METHODS: Five patients with suspected ACD from adhesives were patch tested to the baseline series (containing limonene hydroperoxides 0.3 and 0.2% pet.), additional series and, if available, to the culprit adhesives. The adhesives labelled as containing colophonium (n = 3) or free from it (n = 2) were analysed with gas chromatography - mass spectrometry (GC-MS) for the presence of D-limonene. RESULTS: All five patients sensitised to adhesives had (strong) positive patch test reactions to limonene hydroperoxides. The presence of D-limonene, and/or related components, could be demonstrated in all three colophonium-containing and, surprisingly, also in two colophonium-free ("hypoallergenic") tapes. CONCLUSIONS: D-limonene may be present in both regular and "hypoallergenic" adhesives, with limonene hydroperoxides potentially contributing to ACD from such medical devices. The use of fragrance chemicals in adhesives deserves further research.

Limonene and linalool hydroperoxides review: Pros and cons for routine patch testing.

Limonene and linalool are among the most common fragrance terpenes used in everyday products. They are pre-haptens, forming hydroperoxides (Lim-OOHs, Lin-OOHs) upon oxidation and inducing frequent positive patch test reactions in patients with dermatitis, and yet they are not routinely tested in Europe. This review evaluates current patch testing with Lim-OOHs and Lin-OOHs by asking whether hydroperoxide patch testing is warranted, examining the difficulties or challenges related to reading and interpreting hydroperoxide patch test results with currently available material, and assessing their relevance. Studies are increasingly pointing to high percentages of positive reactions in patients consecutively patch tested with these oxidized products. An association between a positive clinical history and a strong patch test reaction has been described, but problems with doubtful/irritant reactions have also been reported. Considering the high frequency of relevant positive reactions, the incorporation of Lim-OOHs 0.3% and Lin-OOHs 1% in the baseline series may be justified. Since exposure, sensitization, and elicitation limits of Lim-OOHs and Lin-OOHs in the products still need to be better determined, an assessment of previous exposure, possible sensitizations, and reactions may help to improve the clinical assessment.

European patch test results with audit allergens as candidates for inclusion in the European Baseline Series, 2019/20: Joint results of the ESSCAA and the EBSB working groups of the ESCD, and the GEIDACC.

BACKGROUND: 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. OBJECTIVES: To collect further data on patch test reactivity and clinical relevance of the audit allergens in consecutive patients across Europe. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Patch test results with the European baseline series, 2019/20-Joint European results of the ESSCA and the EBS working groups of the ESCD, and the GEIDAC.

BACKGROUND: Continual analyses of patch test results with the European baseline series (EBS) serve both contact allergy surveillance and auditing the value of included allergens. OBJECTIVES: To present results of current EBS patch testing, obtained in 53 departments in 13 European countries during 2019 and 2020. METHODS: Anonymised or pseudonymised individual data and partly aggregated data on demographic/clinical characteristics and patch test rest results with the EBS were prospectively collected and centrally pooled and analysed. RESULTS: In 2019 and 2020, 22 581 patients were patch tested with the EBS. Sensitization to nickel remained most common (19.8 [19.2-20.4]% positivity [95% confidence interval]). Fragrance mix I and Myroxylon pereirae yielded very similar results with 6.80 (6.43-7.19)% and 6.62 (6.25-7.00)% positivity, respectively. Formaldehyde at 2% aq. yielded almost one percentage point more positive reactions than 1% concentration (2.49 [2.16-2.85]% vs. 1.59 [1.33-1.88]); methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) and MI alone up to around 5% positives. Among the new additions, propolis was most commonly positive (3.48 [3.16-3.82]%), followed by 2-hydroxyethyl methacrylate (2.32 [2.0-2.68]%). CONCLUSION: Ongoing surveillance on the prevalence of contact sensitization contributes to an up-to-date baseline series containing the most frequent and/or relevant contact sensitizers for routine patch testing in Europe.

Evolution of methylisothiazolinone sensitization: A Belgian multicentric study from 2014 to 2019.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: A retrospective study of patch test results with MI, OIT, and BIT observed in patients attending five Belgian hospitals. RESULTS: 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. CONCLUSIONS: 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.

Allergic contact dermatitis from potassium sorbate and sorbic acid in topical pharmaceuticals and medical devices.

BACKGROUND: The preservatives sorbic acid (SA) and potassium sorbate (PS) are considered rare skin sensitizers. PS-containing products always contain SA to a certain extent, and positivity to PS may reflect sensitization to SA. Their optimal patch-test conditions are unknown. OBJECTIVES: To report on the outcome of testing with SA and PS in various concentrations and/or vehicles. PATIENTS AND METHODS: Seventeen patients with allergic contact dermatitis from PS/SA-containing topical pharmaceuticals and medical devices were patch tested to SA 2% and 5% pet.; SA 1%, 2%, 3%, 5%. eth.; and/or SA 2% aq., whereas PS was patch tested 5% pet. and/or 5% aq. RESULTS: Only one patient, not tested to the ethanol preparations, presented with a (doubtful) positive reaction to SA 2% pet., while this remained negative in 13 patients who reacted to SA 2% eth. The preparations containing SA 5% pet.; 1%, 3%, and 5% eth.; and SA 2% aq. had little or no additional value. PS 5% pet. performed better than 5% aq., and always mirrored SA sensitization. CONCLUSIONS: Sensitization to SA and PS is probably underestimated. SA 2% eth. and PS 5% pet. are preferred for patch testing, and patients sensitized to SA should avoid PS-containing products. HIGHLIGHTS: Potassium sorbate (PS) and sorbic acid (SA) are widely used preservatives. PS-containing products always contain some SA. Both are considered rare skin sensitizers, but contact allergy in response to them might be underestimated. SA 2% eth. and PS 5% pet., rather than SA 2% pet. and PS 5% aq., respectively, may be required to diagnose contact allergy from PS/SA-containing topical pharmaceuticals and medical devices. A positive patch test to PS reflects sensitization to SA, and patients sensitized to SA should also avoid PS-containing products.

Concomitant positive patch test reactions in FreeStyle-allergic patients sensitized to isobornyl acrylate.

BACKGROUND: Concomitant positive patch test reactions in patients sensitized to isobornyl acrylate (IBOA) have rarely been documented. OBJECTIVES: To report concomitant sensitizations in patients with allergic contact dermatitis (ACD) from the glucose sensor FreeStyle Libre and sensitized to IBOA. METHODS: In 2019, 26 patients with suspected ACD from FreeStyle Libre were patch tested to a baseline series and to a (meth) acrylate series containing IBOA and 2-phenoxyethyl acrylate (PEA) 0.1% pet. Diabetes devices and patch test preparations were analyzed with gas chromatography - mass spectrometry (GC-MS) for the presence of IBOA and PEA. RESULTS: Of the 26 patients, 18 (69%) were sensitized to IBOA, and eight (44%) and 11 (61%) of these were co-sensitized to sesquiterpene lactones and fragrances, respectively. Ten patients (56%) were co-sensitized to PEA, which, contrary to IBOA, could not be detected in any device. The PEA test material was shown to be contaminated with IBOA. CONCLUSIONS: Contact allergy to IBOA appears to be declining and IBOA-sensitized patients are most often co-sensitized to sesquiterpene lactones and fragrances. Vigilance is required when patch testing (acrylate) materials obtained from industry, as these might be contaminated and, hence, alter the results and their interpretation.

The presence of benzophenone in sunscreens and cosmetics containing the organic UV filter octocrylene: A laboratory study.

BACKGROUND: The reason why patients photosensitized to the drug ketoprofen (KP) may develop severe photoallergic skin reactions to octocrylene (OCT), an organic ultraviolet filter in sunscreens and cosmetics, remains largely unknown. OCT can be synthesized by using unsubstituted benzophenone (BP), a possible human carcinogen. OBJECTIVES: To verify if, and to what extent, BP residues are present in OCT-containing consumer products. METHODS: The raw material of OCT and 39 skincare products, of which 28 contain OCT, were chemically analysed for the presence of BP by means of liquid chromatography. RESULTS: In the OCT raw material and in all 28 OCT-containing products the presence of BP could be demonstrated, mostly in concentrations above 10 ppm (0.001%), whereas a majority of OCT-free products (8/11, 73%) did not contain BP. Moreover, BP concentrations significantly increased, in a time- and temperature-dependent manner, likely due to the additional degradation of OCT. CONCLUSIONS: Photoallergic contact dermatitis from OCT in patients photosensitized to KP might rely on residual BP impurities. Toxicological and ecological studies that evaluate the safety of OCT might also need to consider the concomitant presence of BP.

In vivo demonstration of immunologic cross-reactivity to octylisothiazolinone in patients primarily and strongly sensitized to methylisothiazolinone.

BACKGROUND: 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). OBJECTIVE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.