Nine years of patch testing with isocyanates in a clinic of occupational dermatology.

BACKGROUND: Isocyanates are used as starting materials of polyurethane (PU) products. They are relatively important occupational skin sensitizers. OBJECTIVES: To analyse results of a large isocyanate patch test series of 19 isocyanate test substances and 4,4'-diaminodiphenylmethane (MDA), a marker of 4,4'-diphenylmethane diisocyanate (MDI) hypersensitivity. METHODS: Test files were screened for positive reactions in the isocyanate series. Patients with positive reactions were analysed for occupation, exposure and diagnosis. RESULTS: In 2010-2019, 53 patients had positive reactions in the series (16% of 338 patients tested). MDA, the well-established screening substance for MDI allergy, was positive in 30 patients, an in-house monomeric MDI test substance in 23 patients and 3 different polymeric MDI test substances in 19-21 patients. We diagnosed 16 cases of occupational allergic contact dermatitis (OACD) from MDI including 3 pipe reliners. Hexamethylene-1,6-diisocyanate (HDI) oligomers in paint hardeners caused 5 cases of OACD, more cases than 2,4-toluene diisocyanate (TDI; n = 3) and isophorone diisocyanate (IPDI; n = 1) put together. CONCLUSIONS: In contrast to previous studies, polymeric MDI test substances were not superior to a monomeric MDI. Pipe reliners may get sensitised not only by epoxy products and acrylates but also by MDI in hardeners of PU pipe coatings. HDI oligomers were the second most important causes of OACD after MDI.

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.

Machine-learning-driven biomarker discovery for the discrimination between allergic and irritant contact dermatitis.

Contact dermatitis tremendously impacts the quality of life of suffering patients. Currently, diagnostic regimes rely on allergy testing, exposure specification, and follow-up visits; however, distinguishing the clinical phenotype of irritant and allergic contact dermatitis remains challenging. Employing integrative transcriptomic analysis and machine-learning approaches, we aimed to decipher disease-related signature genes to find suitable sets of biomarkers. A total of 89 positive patch-test reaction biopsies against four contact allergens and two irritants were analyzed via microarray. Coexpression network analysis and Random Forest classification were used to discover potential biomarkers and selected biomarker models were validated in an independent patient group. Differential gene-expression analysis identified major gene-expression changes depending on the stimulus. Random Forest classification identified CD47, BATF, FASLG, RGS16, SYNPO, SELE, PTPN7, WARS, PRC1, EXO1, RRM2, PBK, RAD54L, KIFC1, SPC25, PKMYT, HISTH1A, TPX2, DLGAP5, TPX2, CH25H, and IL37 as potential biomarkers to distinguish allergic and irritant contact dermatitis in human skin. Validation experiments and prediction performances on external testing datasets demonstrated potential applicability of the identified biomarker models in the clinic. Capitalizing on this knowledge, novel diagnostic tools can be developed to guide clinical diagnosis of contact allergies.

Characterization of patients with occupational allergy to two new epoxy hardener compounds.

BACKGROUND: The practical importance of two recently described epoxy hardener allergens-1,3-benzenedimethanamine, N-(2-phenylethyl) derivatives (1,3-BDMA-D) and hydrogenated formaldehyde benzenamine polymer (FBAP)-as occupational allergens remains to be defined. OBJECTIVES: To describe patients diagnosed at the Finnish Institute of Occupational Health (FIOH) with positive reactions to 1,3-BDMA-D or FBAP. METHODS: We searched FIOH's patch-test files from January 2017 to December 2020 for patients examined due to suspected occupational contact allergy to epoxy compounds. We analyzed the patch-test results and sources of exposure to various epoxy hardeners and focused on occupations, symptoms, and the sources of exposure to 1,3-BDMA-D and FBAP. RESULTS: During the study period, 102 patients were examined at FIOH for suspected occupational contact allergy to epoxy compounds. Of these, 19 (19%) were diagnosed with contact allergy to 1,3-BDMA-D (n = 10) or FBAP (n = 12). The largest occupational group was sewage pipe reliners (n = 8). Seven different hardener products contained FBAP, whereas 1,3-BDMA-D was present in only one hardener used by spray painters. CONCLUSIONS: A substantial number of patients with suspected occupational epoxy resin system allergy tested positive to in-house test substances of 1,3-BDMA-D and/or FBAP.

Occupational IgE-mediated psyllium allergy in contemporary gluten-free and vegan baking: A case of allergic rhinitis.

Psyllium (from Plantago ovata; ispaghula) is used as a dietary supplement and is supplied in the form of husk, granules, capsules, or powder. Consumers using psyllium-containing laxatives, healthcare workers handling these, and pharmaceutical workers in laxative-manufacturing plants are known to be at risk of sensitization and subsequent rhinitis, asthma, contact urticaria, and even anaphylaxis. To our knowledge, the case we present here is the first of baker's immunoglobulin E (IgE)-mediated occupational allergy due to psyllium exposure. Our patient, a 24-year-old female baker with no previous allergies, was referred to our clinic with suspected occupational rhinitis. After 1 year of baking with cereal flour or gluten-free flour-mix, she began to suffer from rhino-conjunctival symptoms during workdays. Skin prick tests with agents from the patient's workplace revealed allergies not only to wheat and rye flours but also to psyllium, with a remarkable 10 mm wheal. Subsequently, nasal provocation tests confirmed occupational allergic rhinitis to psyllium. We also found work-related sensitization to buckwheat, which she used in gluten-free baking. Due to the increased prevalence of celiac disease and the popularity of gluten-free and vegan food, psyllium has recently become a common ingredient in baking, used as a substitute for gluten or eggs. Bakers handle allergens such as these in high concentrations and this may lie behind the emergence of respiratory and dermal symptoms. It is essential to consider new or recenlty introduced materials as possible allergens if it is suspected that a baker has work-related respiratory or allergic symptoms.

Allergic reactions to lower concentrations of nickel sulfate and formaldehyde often appear later than reactions to higher concentrations.

BACKGROUND: A late-appearing patch test reaction may be a sign of active sensitization or represent a delayed elicitation reaction. OBJECTIVES: To retrospectively study the effect of concentration on the time course of allergic reactions to routine concentration dilution series of formaldehyde and nickel sulfate. METHODS: We tested concentration dilution series of 2%, 1%, 0.32% and 0.1% formaldehyde and 5%, 1.6%, 0.5% and 0.16% nickel sulfate, respectively. The last readings were performed on day 4 to day 6. We included patients with allergic reactions to either of the two lowest concentrations in each dilution series and whose tests had been read three times. RESULTS: Forty-two nickel-allergic and 23 formaldehyde-allergic patients fulfilled the inclusion criteria. In 26 (62%) of the nickel-sensitive patients, reactions to lower concentrations appeared later than reactions to the highest concentration. Of the formaldehyde-sensitive patients, 17 (74%) developed one or two allergic reactions to lower concentrations later than reactions to the highest concentration, and one (4%) patient developed allergic reactions to lower concentrations sooner than a reaction to the highest concentration. The remaining patients showed all allergic reactions at the same reading. CONCLUSIONS: In these selected, relatively strongly sensitized patients, allergic reactions to lower concentrations quite regularly appeared later than reactions to higher concentrations.

Occupational allergic contact dermatitis caused by colophonium.

BACKGROUND: Colophonium is a common contact allergen that is present not only in household products but also in occupational settings. OBJECTIVES: To describe the sources of occupational exposure to colophonium and the occupations at risk of colophonium allergy. METHODS: We reviewed patch test files from the years 2002 to 2017 at the Finnish Institute of Occupational Health for patients with allergic reactions to colophonium and abietic acid. We analysed the patch test, occupation and exposure data of 39 patients diagnosed with occupational allergic contact dermatitis (OACD) caused by colophonium. RESULTS: Of the patients examined for suspected occupational dermatitis, 4.6% (n = 118) reacted positively to colophonium. The majority of the OACD patients worked in the wood industry, as machinists, or were involved in soldering or agriculture. The most common occupational sources of exposure were coniferous wood and wood-derived materials, followed by glues, metalworking fluids, and soldering materials. Colophonium is not always mentioned in safety data sheets (SDSs), and the sources of colophonium exposure are often materials for which there are no SDSs. CONCLUSION: OACD caused by colophonium is quite common and occurs in a variety of occupations. SDSs provide poor information for exposure assessment. Patch testing with the patient's own materials was often useful in establishing the diagnosis.

The Psoriasis Risk Allele HLA-C*06:02 Shows Evidence of Association with Chronic or Recurrent Streptococcal Tonsillitis.

Pharyngeal tonsillitis is one of the most common upper respiratory tract infections, and group A streptococcus is the most important bacterial pathogen causing it. While most patients experience tonsillitis only rarely, a subset of patients suffers from recurrent or chronic tonsillitis or pharyngitis. The predisposing factors for recurring or chronic forms of this disease are not yet fully understood, but genetic predisposition has been suggested. A genetic association study using Illumina's Immunochip single-nucleotide polymorphism (SNP) array was performed to search for new genetic biomarkers in pharyngeal tonsillitis. More than 100,000 SNPs relevant to immune-mediated diseases were analyzed in a cohort of 95 patients subjected to tonsillectomy due to recurrent/chronic tonsillitis and 504 controls. Genetic association between the cases and controls showed strongest association with two peaks in the HLA locus (odds ratio [OR], 3.7 to 4.7; P = 4.9 × 10-6 to 5.7 × 10-6). Further analysis with imputed classical HLA alleles suggested the known psoriasis risk allele HLA-C*06:02 as a risk factor for tonsillitis (P = 4.8 × 10-4; OR, 2.3). In addition, the imputed HLA haplotype HLA-C*06:02/HLA-B*57:01, a reported risk haplotype in psoriasis, had the strongest risk for tonsillitis (P = 3.2 × 10-4; OR, 6.5). These findings further support the previously reported link between streptococcal throat infections and psoriasis.

Intracellular signalling pathways and cytoskeletal functions converge on the psoriasis candidate gene CCHCR1 expressed at P-bodies and centrosomes.

BACKGROUND: CCHCR1 (Coiled-Coil α-Helical Rod protein 1) is a putative psoriasis candidate gene with the risk alleles CCHCR1*WWCC and *Iso3, the latter inhibiting the translation of isoform 1. CCHCR1 was recently shown to be a centrosomal protein, as well as a component of cytoplasmic processing bodies (P-bodies) that regulate mRNA turnover. The function of CCHCR1 has remained unsettled, partly because of the inconsistent findings; it has been shown to play a wide variety of roles in divergent processes, e.g., cell proliferation and steroidogenesis. Here we utilized RNA sequencing (RNAseq) using HEK293 cells overexpressing isoforms 1 or 3 (Iso1, Iso3 cells), in combination with the coding non-risk or risk (*WWCC) haplotype of CCHCR1. Our aim was to study the overall role of CCHCR1 and the effects of its variants. RESULTS: The overexpression of CCHCR1 variants in HEK293 cells resulted in cell line-specific expression profiles though several similarities were observable. Overall the Iso1 and Iso3 cells showed a clear isoform-specific clustering as two separate groups, and the Non-risk and Risk cells often exhibited opposite effects. The RNAseq supported a role for CCHCR1 in the centrosomes and P-bodies; the most highlighted pathways included regulation of cytoskeleton, adherens and tight junctions, mRNA surveillance and RNA transport. Interestingly, both the RNAseq and immunofluorescent localization revealed variant-specific differences for CCHCR1 within the P-bodies. CONCLUSIONS: CCHCR1 influenced a wide variety of signaling pathways, which could reflect its active role in the P-bodies and centrosomes that both are linked to the cytoskeleton; as a centrosomal P-body protein CCHCR1 may regulate diverse cytoskeleton-mediated functions, such as cell adhesion and -division. The present findings may explain the previous inconsistent observations about the functions of CCHCR1.

3-(Bromomethyl)-2-chloro-4-(methylsulfonyl)- benzoic acid: a new cause of sensitiser induced occupational asthma, rhinitis and urticaria.

OBJECTIVES: 3-(Bromomethyl)-2-chloro-4-(methylsulfonyl)-benzoic acid (BCMBA) has not previously been identified as a respiratory sensitiser. We detected two cases who presented respiratory and urticaria symptoms related to BCMBA and had positive skin prick tests to the agent. Subsequently, we conducted outbreak investigations at the BCMBA-producing factory and performed clinical examinations to confirm occupational diseases. METHODS: The outbreak investigations included observations of work processes, assessment of exposure, a medical survey with a questionnaire and skin prick tests with 0.5% BCMBA water solution on 85 exposed workers and 9 unexposed workers. We used specific inhalation or nasal challenge and open skin application test to investigate BCMBA-related occupational asthma, rhinitis and contact urticaria. RESULTS: We identified nine workers with respiratory and/or skin symptoms and positive skin prick tests to BCMBA in a chemical factory. A survey among chemical factory workers indicated a BCMBA-related sensitisation rate of 8% among all exposed workers; the rate was highest (25%) among production workers in the production hall. Sensitisation was detected only in workers with the estimated highest exposure levels. Six cases of occupational asthma, rhinitis and/or contact urticaria caused by BCMBA were confirmed with challenge tests. Asthma-provoking doses in specific inhalation challenges were very low (0.03% or 0.3% BCMBA in lactose). CONCLUSIONS: We identified a new low molecular weight agent causing occupational asthma, rhinitis and contact urticaria. A typical clinical picture of allergic diseases and positive skin prick tests suggest underlying IgE-mediated disease mechanisms. Stringent exposure control measures are needed in order to prevent BCMBA-related diseases.

Current knowledge on biomarkers for contact sensitization and allergic contact dermatitis.

Contact sensitization is common and affects up to 20% of the general population. The clinical manifestation of contact sensitization is allergic contact dermatitis. This is a clinical expression that is sometimes difficult to distinguish from other types of dermatitis, for example irritant and atopic dermatitis. Several studies have examined the pathogenesis and severity of allergic contact dermatitis by measuring the absence or presence of various biomarkers. In this review, we provide a non-systematic overview of biomarkers that have been studied in allergic contact dermatitis. These include genetic variations and mutations, inflammatory mediators, alarmins, proteases, immunoproteomics, lipids, natural moisturizing factors, tight junctions, and antimicrobial peptides. We conclude that, despite the enormous amount of data, convincing specific biomarkers for allergic contact dermatitis are yet to be described.

Occupational contact dermatitis caused by 1,3-benzenedimethanamine, N-(2-phenylethyl) derivatives in hardeners for epoxy paints and coatings.

BACKGROUND: Amines in epoxy hardeners are significant causes of occupational allergic contact dermatitis among workers who use epoxy resin systems. OBJECTIVES: To describe a novel group of contact allergens: N-(2-phenylethyl) derivatives of the reactive amine 1,3-benzenedimethanamine (1,3-BDMA). METHODS: We describe the clinical examinations and exposure of 6 patients with occupational contact allergy to derivatives of 1,3-BDMA. RESULTS: Of the 6 patients, 4 were spray painters who used epoxy paints, 1 was a floor layer who handled a variety of epoxy coatings, and 1 was a worker in epoxy hardener manufacture. We were able to confirm exposure to epoxy hardeners that contained derivatives of 1,3-BDMA in 5 of the 6 sensitized patients. Despite the close structural resemblance between derivatives of 1,3-BDMA and m-xylylenediamine (MXDA), only 3 patients reacted positively to MXDA. Concomitant contact allergy to diglycidyl ether of bisphenol A resin was seen in 2 of the 6 patients. CONCLUSIONS: Because of the lack of a commercially available patch test substance, the diagnosis of contact allergy to derivatives of 1,3-BDMA requires patch testing with either the epoxy hardener product or a hardener ingredient that contains the derivatives of 1,3-BDMA.

Occupational contact allergy to methylchloroisothiazolinone/methylisothiazolinone and methylisothiazolinone.

BACKGROUND: Methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI) and MI are common preservatives in industrial and household products and in cosmetics. Occupational contact allergy to MCI/MI or MI has been reported among painters and paint factory workers in particular. OBJECTIVES: To retrospectively describe patients with occupational contact allergy to MCI/MI and MI at the Finnish Institute of Occupational Health (FIOH). METHODS: Patch test files and clinical records of patients examined at the FIOH between January 2002 and February 2013 were reviewed to identify the patients. RESULTS: Seventy-two of 1745 patients showed positive reactions to MCI/MI and/or MI. Of these, 36 were occupational cases, and 31 were diagnosed during the second half of the study period. Hairdressers and beauticians, mechanics and repairmen, and machinists were the most significant occupational groups, followed by painters and paint factory workers, and café and restaurant workers. CONCLUSIONS: We observed a sixfold increase in the number of occupational cases in the second half of the study period as compared with the first half. Liquid soaps and industrial hand cleansers were common sources of exposure to MCI/MI or MI. A total of 33% of the patients used products without any mention of MCI/MI or MI in safety data sheets or product declarations.

Occupational contact dermatitis caused by D-limonene.

BACKGROUND: Limonene is widely used as a fragrance substance and solvent in cleansing products. Oxidized limonene is a frequent contact allergen among consumers of cosmetics, personal care products, and scented household cleaning products. Less is known about the sources of occupational exposure and occupational contact dermatitis caused by limonene. OBJECTIVE: To report 14 patients with occupational contact allergy to limonene. METHODS: The patients were examined in 2008-2013. An in-house preparation of oxidized limonene was patch tested as 3% and 5% in petrolatum from 2008 to August 2010, and after this as 3%, 1% and 0.3% pet. From 2012 onwards, a commercial test substance of limonene hydroperoxides was also used. We assessed the patients' occupational and domestic exposure to limonene. RESULTS: Occupational limonene allergy was observed in workers who used limonene-containing machine-cleaning detergents and hand cleansers, and in workers who used limonene-containing surface cleaners and dishwashing liquids similar to those used by consumers. In 3 cases, the occupational limonene allergy resulted from work-related use of limonene-containing, leave-on cosmetic products. CONCLUSIONS: Limonene is a frequent occupational sensitizer in hand cleansers and cleaning products. Occupational limonene contact allergy may also be caused by exposure to cosmetic products scented with limonene.