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.

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.

Patch Testing With Formaldehyde 2.0% (0.60 mg/cm2) Detects More Contact Allergy to Formaldehyde Than 1.0.

BACKGROUND: The International Contact Dermatitis Research Group increased the patch test concentration of formaldehyde from 1.0% aqueous (aq) to 2.0% aq (in 2011). OBJECTIVE: This study was designed to investigate the outcome of the decision. METHODS: Consecutive dermatitis patients in 8 different clinics were patch tested with formaldehyde 1.0% aq and 2.0% aq. The test solutions were applied with a micropipette to the filter paper discs in the respective chamber. RESULTS: A total of 2778 patients were tested with 1.0% aq and 2766 to 2.0% aq. Sixty-five patients (2.3%, calculated from 2766 tested, to 2.0% aq) had positive patch test reactions interpreted as contact allergy to formaldehyde. This is a rather low frequency. Of these 65, 46 were women (46/1703 [2.7%]) and 19 were men (19/1063 [1.8%]). Thirty-six reacted only to 2.0% aq, 21 patients reacted to both concentrations, and 8 patients reacted only to 1.0% aq. Significantly, more patients reacted to 2.0% aq compared with 1.0% aq (P < 0.001). There was no significant sex difference. A total of 0.8% irritant reactions were recorded to formaldehyde 2.0% aq and 0.1% to 1.0% aq. CONCLUSIONS: The increased formaldehyde patch test concentration to 2.0% aq revealed more formaldehyde contact allergy.

Proposed ICDRG Classification of the Clinical Presentation of Contact Allergy.

The International Contact Dermatitis Research Group proposes a classification for the clinical presentation of contact allergy. The classification is based primarily on the mode of clinical presentation. The categories are direct exposure/contact dermatitis, mimicking or exacerbation of preexisting eczema, multifactorial dermatitis including allergic contact dermatitis, by proxy, mimicking angioedema, airborne contact dermatitis, photo-induced contact dermatitis, systemic contact dermatitis, noneczematous contact dermatitis, contact urticaria, protein contact dermatitis, respiratory/mucosal symptoms, oral contact dermatitis, erythroderma/exfoliative dermatitis, minor forms of presentation, and extracutaneous manifestations.

Multicenter Patch Testing With a Resol Resin Based on Phenol and Formaldehyde Within the International Contact Dermatitis Research Group.

BACKGROUND: Contact allergy to phenol-formaldehyde resins (PFRs) based on phenol and formaldehyde is not detected by a p-tertiary-butylphenol-formaldehyde resin included in most baseline patch test series. OBJECTIVE: The aims of this study were to investigate the contact allergy rate to PFR-2 in an international population and to investigate associated simultaneous allergic reactions. METHODS: Thirteen centers representing the International Contact Dermatitis Research Group included PFR-2 into their patch test baseline series during a period of 6 months in 2012. RESULTS: Of 2259 patients tested, 28 (1.2%) reacted to PFR-2. Of those 28 individuals, one had a positive reaction to formaldehyde and 2 to p-tertiary-butylphenol-formaldehyde resin. Simultaneous allergic reactions were noted to colophonium in 3, to Myroxylon pereirae in 5, and to fragrance mix I in 8. CONCLUSIONS: The contact allergy frequency in the tested population (1.2%) merits its inclusion into the international baseline series and possibly also into other baseline series after appropriate investigations. Significantly, overrepresented simultaneous allergic reactions were noted for M. pereirae and fragrance mix I.

Sensitization to palladium and nickel in Europe and the relationship with oral disease and dental alloys.

BACKGROUND: The role of palladium and nickel sensitization in oral disease and dermatitis is not fully understood. OBJECTIVES: To investigate whether sensitization to these metals was associated with exposure to dental alloys and oral and skin complaints/symptoms in a European multicentre study. METHODS: In six dermatology clinics, patch tests with palladium (3% Na2 PdCl4 ; Pd = 102.0 µmol/g) and nickel (5% NiSO4 .6H2 O; Ni = 190.2 µmol/g) were performed in consecutive patients, and patients' characteristics were collected with a questionnaire and a clinical investigation. RESULTS: In total, 906 patients were included, of whom 24.3% reacted to palladium and 25.2% to nickel. The rate of monosensitization was 6-7% for both metals. Palladium sensitization (as opposed to no sensitization to both metals) was associated with exposure to dental crowns [odds ratio (OR) 2.0], skin reactivity to metals (OR 2.8), oral lichenoid lesions (OR 4.7), xerostomia (OR 7.3), and metal taste (OR 20.7), but not with eczema, stomatitis, or oral burning sensation. Additionally, xerostomia (OR 8.7) and metal taste (OR 4.6) were associated with sensitization to both metals. CONCLUSIONS: Clinically, it is important for palladium-sensitized patients to undergo an oral examination, with particular attention to the presence of/exposure to dental crowns. In the case of metal contact allergy, exposure to dental crowns could play a role.

Recommendation to include formaldehyde 2.0% aqua in the European baseline patch test series.

BACKGROUND: The currently used patch test concentration of formaldehyde (1.0% aqua; 0.30 mg/cm(2)) has been shown to fail to detect ~ 50% of contact allergies to formaldehyde. OBJECTIVES: To justify the inclusion of formaldehyde 2.0% aqua (0.60 mg/cm(2)) in the European baseline patch test series. METHODS: A survey of the reported frequencies of contact allergy to formaldehyde found with formaldehyde 2.0% aqua as compared with 1.0% aqua was performed. Studies that describe a standardized patch test technique for obtaining a correct dose per unit area were included. Experimental provocation tests in patients with contact allergy to formaldehyde detected only with 2.0% aqua were also surveyed. RESULTS: In a multicentre study performed in 12 dermatology clinics among 3591 individuals, 3.4% reacted to 2.0%, and 1.8% reacted to 1.0% (p < 0.001). A randomized double-blind repeated open application test performed in individuals reacting only to 2.0% but not to 1.0% showed that 9 of 17 formaldehyde-allergic individuals reacted to a moisturizer that contained formaldehyde (p < 0.001). CONCLUSIONS: It is recommended that formaldehyde 2.0% aqua (0.60 mg/cm(2)) should replace formaldehyde 1.0% in the European baseline series from 2014. With the Finn Chamber(®) technique, a standardized amount of 15 µl of the solution obtained by using a micropipette should be used.

Characterization of the T cell response in allergic contact dermatitis caused by corticosteroids.

BACKGROUND: Delayed allergic hypersensitivity reactions have classically been described as type IV reactions, which are caused by T cells; however, the respective roles of CD4(+) and CD8(+) cells are yet to be defined. A central role for CD8(+) cytotoxic T cells as effector cells has been suggested. OBJECTIVES: To determine the type of T cell involved in corticosteroid allergy. METHODS: We analysed the kinetics of T cell recruitment and the cytokine production profile in positive patch tests of 27 corticosteroid-sensitized patients, as compared with control sites and control subjects. Skin biopsies, collected at 8, 24 and 48 hr following drug application, were embedded in paraffin for histological and immunohistological staining, and, in some cases, also deep-frozen for gene expression analyses. RESULTS: CD3(+) T cells were rapidly recruited in concert with the positivity of the patch test sites. High levels of interleukin (IL)-4, IL-5 and, to a lesser extent, interferon-γ suggested that both Th2 and Th1 cytokines were implicated. IL-4 was also produced by γδ T cell receptor (TCR) lymphocytes. CONCLUSIONS: This study showed that, in allergic contact dermatitis caused by corticosteroids, the inflammatory infiltrate is composed of CD3(+) T cells with a predominant Th2 cytokine profile, among which IL-4 is also produced by γδ TCR lymphocytes.

Patch testing with 2.0% (0.60 mg/cm 2) formaldehyde instead of 1.0% (0.30 mg/cm 2) detects significantly more contact allergy.

BACKGROUND: The currently used patch test concentration for formaldehyde is 1.0% (wt/vol) in water. However, clinical experience and previous studies suggest that 1.0% might be insufficient for detecting an optimized number of clinically relevant cases of contact allergy to formaldehyde. OBJECTIVES: To validate earlier patch test results for comparison of 1% (wt/vol) and 2% (wt/vol) formaldehyde in water, and to investigate co-reactivity with quaternium-15. MATERIALS AND METHODS: In 12 dermatology clinics, 3591 patients were routinely patch tested simultaneously with 2.0% (wt/vol) (0.60 mg/cm(2)) and 1.0% (wt/vol) (0.30 mg/cm(2)) formaldehyde. Micropipettes were used for delivering the exact dosage of the allergen. RESULTS: Significantly more patients reacted to 2.0% formaldehyde than to 1.0% (3.4% versus 1.8%, p < 0.001). Overall, there were no sex differences between those reacting positively to 2.0% and 1.0%. Of 25 quaternium-15-positive patients, 4 (0.1%) reacted positively without reacting to formaldehyde. CONCLUSION: On the basis of the results of this multicentre study, as well as of previous studies, it can be suggested that 2.0% (wt/vol) in water formaldehyde should be used in routine patch testing in the baseline series.

Allergic contact dermatitis caused by isopropyl alcohol: a missed allergen?

BACKGROUND: Isopropyl alcohol is a secondary alcohol, a structural isomer of propanol, that is widely used as an industrial solvent and as a preservative and antiseptic in the clinical environment. It is known to be a mild irritant for the eyes and mucous membranes, but is considered to be a weak and infrequent sensitizer. OBJECTIVES: To show that isopropyl alcohol should be considered as a potential allergen in patients with eczema who have contact with this substance. MATERIALS AND METHODS: We present a series of 1450 patients patch tested with isopropyl alcohol during the period 1992-2011. RESULTS: Forty-four patients showed an allergic response to isopropyl alcohol. Four cases presented as occupational hand eczema. Fourteen cases were seen in patients with leg ulcers. Twenty-six patients presented with eczematous lesions following the use of products containing isopropyl alcohol to disinfect previous skin lesions. Eighty-four per cent of the patients showed sensitization to three or more allergens. Relevance was present in 84% of the patients. CONCLUSIONS: We report here the first large case series of contact allergy to isopropyl alcohol, which demonstrates that sensitization to this substance might not be as uncommon as previously thought.

Clinical and experimental studies of octocrylene's allergenic potency.

BACKGROUND: Reports of positive patch test and photopatch test reactions to the chemical ultraviolet filter octocrylene have increased during the last decade. Little is known about the reason for octocrylene's allergenic activity. OBJECTIVES: To present and discuss the results of patch tests and photopatch tests with octocrylene, and to investigate the possible cause of its allergenic properties. METHODS: Results of patch tests and photopatch tests with octocrylene in patients with adverse skin reactions to sunscreen products and/or ketoprofen were collected. The allergenic potency of octocrylene was investigated in the murine local lymph node assay (LLNA). Chemical reactivity assays were used to mimic octocrylene's interaction with biomolecules. RESULTS: We report 23 cases of positive test reactions to octocrylene (5 patch test and 18 photopatch). Notably, many of these patients also had positive photopatch test reactions to ketoprofen and benzophenone-3. Octocrylene was shown to be a moderate sensitizer in the LLNA, and it reacted with amines such as lysine, but not with thiols such as cysteine. CONCLUSIONS: The clinical studies show that octocrylene is both a photocontact allergen and a contact allergen. Octocrylene's ability to cause contact allergy is probably attributable to its reactivity towards lysine. To be able to understand why octocrylene causes photocontact allergy, further studies are needed.

Delayed hypersensitivity to corticosteroids in a series of 315 patients: clinical data and patch test results.

BACKGROUND: Corticosteroids may cause immediate or delayed hypersensitivity. In 1989, based on structural and clinical characteristics, we put forward a classification of corticosteroids into four cross-reacting groups, namely group A, B, C, and D, the latter later subdivided into two subgroups, i.e. D1 and D2. The constituents on the D-ring of the corticosteroid-molecule are considered to have a central role for binding to skin proteins and for cross-reactions patterns; however, halogenation of the molecules is also interfering. OBJECTIVE: To study the clinical data and analyse simultaneous positive reactions obtained in a large group of corticosteroid-allergic patients. METHODS: Patch tests were performed with the baseline series, to which hydrocortisone butyrate and prednisolone caproate were added, as well as with the corticosteroids to which the patients had been exposed. Three hundred and forty subjects with a presumed or proven corticosteroid allergy were further investigated with an extended series containing 72 molecules. RESULTS: Out of 11 596 patients investigated, 315 subjects reacted positively to at least 1 corticosteroid-molecule, with most of them presenting with multiple positive reactions. CONCLUSION: A prevalence of corticosteroid allergy of 2.7% was found. Despite validity of the ABCD (sub)classification in many cases, possible adjustments may have to be considered.

Granuloma possibly induced by palladium after ear piercing.

A case of sarcoidal-type allergic contact granuloma due to palladium is presented. The patient developed papulonodular lesions at the right earlobe after ear piercing, which after 3 to 4 years became more granulomatous and very resistant to treatment. Repeated intralesional injections with corticosteroids produced only a temporary regression of the lesions. Patch testing revealed a strong positive reaction to palladium (and nickel). Biopsy specimens taken from the persistent granulomatous lesion in the nodule at the earlobe, as well as from the site of the positive test reaction to palladium several weeks after patch testing, indicated epithelioid granulomas with some multinucleate histiocytes surrounded by a lymphocytic-histiocytic infiltrate. Similar cases (also with other metals) have been reported in the literature.