Hand eczema in children referred for patch testing: North American Contact Dermatitis Group Data, 2000-2016.

BACKGROUND: Little is known about the aetiologies and relevant allergens in paediatric patients with hand eczema (HE). OBJECTIVES: To characterize the aetiologies and determine the proportion of positive and currently relevant allergens in children/adolescents (age < 18 years) with HE referred for patch testing. METHODS: A retrospective analysis (2000-2016) of North American Contact Dermatitis Group data was performed. RESULTS: Of 1634 paediatric patients, 237 (14·5%) had involvement of the hands. Final physician diagnoses included allergic contact dermatitis (49·4%), atopic dermatitis (37·1%) and irritant contact dermatitis (16·9%). In multivariable logistic regression models, employment was the only association with increased odds of any HE or primary HE. Children with HE vs. those without HE had similar proportions of positive patch tests (56·1% vs. 61·7%; χ2 -test, P = 0·11). The five most common currently relevant allergens were nickel, methylisothiazolinone, propylene glycol, decyl glucoside and lanolin. In multivariable logistic regression models of the top 20 relevant allergens, HE was associated with significantly higher odds of currently relevant reactions to lanolin, quaternium-15, Compositae mix, thiuram mix, 2-mercaptobenzathiazole and colophony. The allergens with the highest mean significance-prevalence index number were methylisothiazolinone, carba mix, thiuram mix, nickel and methylchloroisothiazolinone/methylisothiazolinone. CONCLUSIONS: Children with HE who were referred for patch testing had a high proportion of positive patch tests, which was similar to the proportion found in children without HE. Children with HE had a distinct and fairly narrow profile of currently relevant allergens.

Medical phototherapy in childhood skin diseases.

Phototherapy is used for the medical care of cutaneous conditions that do not respond to topical or systemic medical agents, and for conditions that require broad exposure to UV as a stabilizing agent for disease. Numerous wavelengths and delivery devices of ultraviolet light are used in childhood. This article is a brief overview of the medical usage of phototherapy in childhood. In the neonatal nursery blue light (459-460 nm) is used to reduce bilirubin levels and prevent kernicterus. While psoralens and UVA (PUVA) has been demonstrated to be efficacious in a variety of pediatric skin conditions, narrowband UVB therapy (311 nm) has largely replaced psoralens and UVA as initial choice in full-body phototherapy for children. The latter is easier to deliver, with less resultant erythema than systemic psoralens and UVA which requires strict use of 24 hour protective eyewear. Narrowband UVB is therefore preferred for stabilization and clearance of a variety of inflammatory and autoimmune conditions especially atopic dermatitis, psoriasis and vitiligo. Conditions with lymphocytic infiltration, including mycosis fungoides, alopecia areata and pityriasis lichenoides can improve with Narrowband UVB as well. Alternatively, localized delivery of Narrowband UVB can be performed using the excimer laser (308 nm), which has been described for the therapy of vitiligo and alopecia areata in childhood. Some diseases with dermal infiltration including morphea and mastocytosis may do better with Psoralens and UVA or UVA1. Delivery of psoralens can also be performed topically for said conditions and in the setting of alopecia areata, thereby limiting UVA exposure, while retaining efficacy. Phototherapy can be a helpful adjunct in pediatric skin disease, but is limited by compliance issues. Parents can act as partners in the safe and effective delivery of phototherapy by standing outside the booth or inside with the child to ensure lack of movement and to aid in maintenance of eyewear. Choice of type of phototherapy and close monitoring, with parental partnership, is the key to successful treatment.

Patch testing discordance alert: false-negative findings with rubber additives and fragrances.

From July 1996 through June 1998, the North American Contact Dermatitis Group evaluated 318 patients for suspected contact dermatitis by patch testing simultaneously with Finn Chambers and the T.R.U.E. Test allergen system. Discrepancies between the two systems were found in some of the results, particularly with fragrance and rubber allergens. These results suggest that positive reactions to fragrance, thiuram, and carba mix allergens may be missed if the T.R.U.E. Test is used alone.

A preliminary report of the occupation of patients evaluated in patch test clinics.

BACKGROUND: The interplay between the occupational environment and worker's skin can result in contact dermatitis of both irritant and allergic types. Other forms of dermatitis can also be influenced by occupational exposures. OBJECTIVE: The aim of this study is to compare the occupations and allergens of occupational contact dermatitis cases with nonoccupational contact dermatitis cases. METHODS: Diagnostic patch testing with allergens of the North American Contact Dermatitis Group and occupational coding by the National Institute for Occupational Safety and Health methods. RESULTS: Of 2,889 patients referred for evaluation of contact dermatitis, 839 patients (29%) were found to have occupational contact dermatitis. Of the 839 cases deemed occupational, 455 cases (54%) were primarily allergic in nature and 270 cases (32%) were primarily irritant in nature. The remaining 14% were diagnoses other than contact dermatitis, aggravated by work. The occupation most commonly found to have allergic contact dermatitis was nursing. Allergens strongly associated with occupational exposure were thiuram, carbamates, epoxy, and ethylenediamine. CONCLUSION: Some contact allergens are more commonly associated with occupational contact dermatitis. Nursing and nursing support are occupations most likely to be overrepresented in contact dermatitis clinics.

Gold allergy in North America.

OBJECTIVE: To determine the prevalence of allergic reactions to gold among patients tested by the North American Contact Dermatitis Group (NACDG) from 1996 to 1998. METHODS: This is a prospective analysis of patch test results from the 12 centers that comprise the NACDG. Gold was tested as gold sodium thiosulfate (0.5% in petrolatum [pet]), along with 49 other screening allergens, in patients presenting with possible contact dermatitis. RESULTS: Of 4,101 patients tested, 388 (9.5%) had a positive patch test result to gold. Women accounted for 62.8% of the subjects tested and 90.2% of patients positive to gold (P < .0001). The most common sites of dermatitis in gold-allergic patients were the hands (29.6%), face (19.3%), and eyelids (7.5%). Nickel and cobalt allergies, respectively, also were present in 33.5% and 18.3% of gold allergic individuals, as compared with 14.2% and 9.0% of the total population. Gold was the only positive reaction in 15.2% of the 388 patients. CONCLUSION: Gold is a more common allergen than previously reported and might cause facial and eyelid dermatitis. Hypersensitivity to gold is statistically linked to female gender and to allergic reactions to nickel and cobalt.

Phototesting and photopatch testing: when to do it and when not to do it.

Phototesting and photopatch testing are among the most important tests in the evaluation of photodermatoses, yet their use has been restricted to specialized centers. To assist clinicians interested in conducting these procedures and in updating their techniques, we asked 4 experts to comment on these tests in the context of diagnostic approach to the photosensitive patient. A list of photoallergens and a protocol for their use is provided.

Photoprotective effect of black tea extracts against UVB-induced phototoxicity in skin.

In previous studies, we showed that green tea and black tea extracts and their major polyphenolic constituents protect against UVB light-induced carcinogenesis in murine skin. All of these studies required chronic administration of tea extracts or specific constituents either topically or orally. However, it is not known whether acute or subchronic administration of black tea extracts or constituents can ameliorate UVB-induced early effects in skin. In the present study, cultured keratinocytes and mouse and human skin were employed to assess the effect of both oral and topical administration of standardized black tea extract (SBTE) and its two major polyphenolic subfractions namely BTF1 and BTF2 against UVB-induced photodamage. In SKH-1 hairless mice, topical application of SBTE (0.2 mg/cm2) prior to UVB exposure (180 mJ/cm2) resulted in 40% reduced incidence and 64% reduced severity of erythema and 50% reduction in skinfold thickness by day 6 when compared to nontreated UVB-exposed animals. The SBTE was also effective in protecting against UVB-induced erythema in human volunteers. Administration of SBTE 5 min after UVB irradiation was similarly effective in reducing UVB-induced inflammation in both murine and human skin. The major polyphenolic subfractions, BTF1 and BTF2, were also effective in protecting in mouse skin. The SBTE subfractions inhibited UVB-induced tyrosine phosphorylation of epidermal growth factor receptor (EGFR). The UVB irradiation of human epidermoid carcinoma cells resulted in 3.3-fold induction of tyrosine phosphorylation of EGFR. Pretreatment with BTF1 and BTF2 reduced tyrosine phosphorylation of EGFR by 53% and 31%, respectively. The UVB-mediated enhanced expression of the early response genes, c-fos and c-jun in human epidermal keratinocytes was reduced in a dose-dependent manner by SBTE. Topical application of SBTE was also effective in reducing accumulation of c-fos and p53 proteins by 82% and 78%, respectively, in UVB-exposed mouse skin. These data provide evidence that constituents of black tea can abrogate UVB-induced erythema and associated early events in murine and human skin.

Haplotype analysis of families with erythropoietic protoporphyria and novel mutations of the ferrochelatase gene.

Ferrochelatase, the enzyme that catalyzes the terminal step in the heme biosynthetic pathway, is the site of the defect in the human inherited disease erythropoietic protoporphyria. Molecular genetic studies have shown that the majority of erythropoietic protoporphyria cases are transmitted in dominant fashion and that mutations underlying erythropoietic protoporphyria are heterogeneous. We performed haplotype analysis of American families that shared recurrent ferrochelatase gene mutations yet had forbearers from several European countries. This was to gain insight into whether these mutations represent mutational hotspots at the ferrochelatase gene, or propagation of ancestral alleles bearing the mutations. Two recurrent mutations were found to occur on distinctive chromosome 18 haplotypes, consistent with being hotspot mutations. On the other hand, we found three sets of two unrelated families that shared the same haplotypes bearing these mutations, which could reflect geographic dispersion of ancestral mutant alleles. In addition, we report novel mutations associated with erythropoietic protoporphyria: g(+ 1)-->t transversion of the exon 4 donor site, g(+ 1)-->a transition of the exon 6 donor site, and t(+ 2)-->a substitution at the exon 9 donor site; these mutations are predicted to cause splicing defects of the associated exons. We also identified a g(+ 5)-->a transition of the exon 1 donor site in four unrelated families with erythropoietic protoporphyria, and a G(- 1)-->A substitution at the exon 9 donor site in an additional family. The probability that these sequence changes are normal polymorphisms was virtually excluded (p < 0.0001) by their absence in 120 ferrochelatase alleles from 30 normal subjects and 30 individuals with manifested erythropoietic protoporphyria with or without a known mutation.

North American Contact Dermatitis Group patch test results for the detection of delayed-type hypersensitivity to topical allergens.

BACKGROUND: Allergic contact dermatitis is a significant cause of cutaneous disease affecting many individuals. Patch testing, when used properly, often provides support for the diagnosis of allergic contact dermatitis. OBJECTIVE: This article reports patch testing results from July 1, 1994, to June 30, 1996, by the North American Contact Dermatitis Group (NACDG). METHODS: Patients evaluated in our patch test clinics were tested with the same screening series of allergens by the use of a standardized patch testing technique. The data from these patients were recorded on a standard computer entry form and analyzed. RESULTS: Forty-nine allergens were tested on 3120 patients. Budesonide was added to the series in July 1995 and tested on 1678 patients. Of these patients, 66.5% had positive allergic patch test reactions, and 57% had at least one allergic reaction that was felt to be clinically relevant to the present or past dermatitis. The 20 screening allergens commercially available to United States dermatologists in the Allergen Patch Test Kit, accounted for only 54.1% of the patients with positive allergic reactions. The additional 30 allergens on the NACDG screening series accounted for 47% of patients with positive allergic reactions. Had the Allergen Patch Test Kit alone been used, 12.4% of all patients tested may have had their disease misclassified as a nonallergic disorder, and an additional 34.4% of all tested patients would not have had their allergies fully defined. Among those patients with positive responses to the supplemental allergens, 81% of the responses were of present or past relevance. The 12 most frequent contact allergens were nickel sulfate, fragrance mix, thimerosal, quaternium-15, neomycin sulfate, formaldehyde, bacitracin, thiuram mix, balsam of Peru, cobalt chloride, para-phenylenediamine, and carba mix. The present relevance varied with the specific allergen from 10.7% (thimerosal) to 85.7% (quaternium-15). Among newer allergens, methyldibromoglutaronitrile/phenoxyethanol (cosmetic preservative) caused positive allergic reactions in 2% of the patients; tixocortol-21-pivalate and budesonide (corticosteroids), in 2.0% and 1.1% of the patients, respectively; and ethylene urea/melamine formaldehyde mix (textile resin), in 5% of the patients. CONCLUSION: The usefulness of patch testing is enhanced with the number of allergens tested, because allergens not found on the commercially available screening series in the United States frequently give relevant allergic reactions.

Inhibition of ultraviolet B (UVB)-induced c-fos and c-jun expression in vivo by a tyrosine kinase inhibitor genistein.

We reported the inhibitory effects of genistein, an inhibitor of tyrosine protein kinase (TPK), on ultraviolet B (UVB)-induced expression of c-fos and c-jun in SENCAR mouse skin. UVB irradiation substantially increased transcript levels of c-fos and c-jun mRNA in mouse skin. Topical application of genistein 60 min before UVB radiation reduced c-fos and c-jun expression in the mouse skin in dose-dependent manner. Inhibition was more pronounced in skin exposed to the low dose (5 kJ/m2) than to the high dose (15 kJ/m2) of UVB radiation. In addition, genistein exhibited more inhibition of c-fos than that of c-jun. Post-application of genistein after UVB exposure down-regulated the expressions of c-fos and c-jun, but to a lesser extent compared with pre-application. A431 human epidermoid carcinoma cells, which excessively express epidermal growth factor receptors (EGF-R), were used to investigate the possible mechanism of genistein's action. The results showed that genistein down-regulated the UVB-mediated phosphorylation of TPK-dependent EGF-R in a dose-dependent manner. We concluded that inhibition of UVB-induced c-fos and c-jun expression in mouse skin by genistein may, at least in part, result from the inhibition of TPK activities and down-regulation of EGF-R phosphorylation. Suppression of UVB-induced proto-oncogene expression in mouse skin suggests that genistein may serve as a potential preventative agent against photodamage and photocarcinogenesis.

Allergic and immunologic skin disorders.

The skin represents a unique immunologic organ poised to protect the host from invading organisms and environmental antigens. The skin is also an important target for a variety of allergic and autoimmune responses. Mast cells are key to the pathogenesis of urticaria, angioedema, and mastocytosis. Atopic dermatitis is the consequence of an immunoregulatory abnormality resulting in a skin-directed T helper type 2 response. Allergic contact dermatitis is an example of classic delayed type hypersensitivity. Circulating autoantibodies against the epidermis are a key mechanism by which bullous skin diseases occur.

Photosensitivity in the pediatric patient.

Photosensitivity in the pediatric patient is caused by a diverse group of disorders. It may indicate a serious underlying systemic disease such as lupus erythematosus or dermatomyositis, or be an early symptom of a rare group of genetic disorders that includes the porphyrias, xeroderma pigmentosum, Cockayne syndrome, Bloom syndrome, and Rothmund-Thomson syndrome. Idiopathic disorders and ultraviolet light-induced reactions to topical or systemic agents may also cause photosensitivity in children. Early recognition and prompt diagnosis may prevent complications associated with prolonged unprotected exposure to sunlight and permit recognition of families at risk for rare heritable disorders associated with photosensitivity.

Ultraviolet radiation B induces differentiation and protein kinase C in normal human epidermal keratinocytes.

Mid-wave ultraviolet radiation (UVB, 280-320 nm) is highly efficient at inducing erythema, pyrimidine dimers in DNA, oncogene expression and initiation of cutaneous tumors. These UVB-induced responses of epidermal cells have been correlated with the direct effects of UVB on DNA. However, UVB has also been shown to have biologic effects at the cellular level that appear to mimic some of the membrane-associated effects produced by phorbol ester tumor promoters such as 12-O-tetradecanoyl phorbol-13-acetate (TPA). For example, we have previously shown that both UVB irradiation and TPA treatment are followed by release of arachidonic acid and a rapid, dose-dependent inhibition of epidermal growth factor (EGF) binding. TPA generates cellular responses through activation of a phospholipid-dependent, calcium-sensitive protein kinase, protein kinase C (PKC). The primary goal of the studies described here was to compare the cellular effects of TPA with those of UVB with special regard to PKC and keratinocyte growth control, using normal human epidermal keratinocytes. The results obtained showed that both TPA and UVB radiation induced differentiation in normal human keratinocytes. UVB radiation, however, increased both cytosolic and membrane-associated levels of PKC, in contrast to TPA, which increased PKC primarily in the membrane fraction. PKC is probably not the initial chromophore or target molecule of UVB, but because activation of PKC has been shown to be essential for keratinocyte differentiation, differentiation induced by UVB may be caused by activation of PKC by UVB-induced release of diacylglycerol or arachidonic acid.

Arachidonic acid release: an in vitro alternative for dermal irritancy testing.

Validated in vitro alternatives are being utilized extensively for mutagenicity and ocular irritancy testing. However, validation of alternative assays for dermal irritancy is progressing more slowly. As the irritant response in human skin is mediated, at least in part, by eicosanoids derived from arachidonic acid, the effect of relatively pure anionic surfactants (AS, n=8) and surfactant-containing finished products (FP, n=25) on the release of [3H]arachidonic acid from a prelabelled murine fibroblast cell line (C3H-10T1/2 cells) in vitro was examined. Test substances were administered at various non-lethal concentrations, in triplicate, to 12- and 24-well plates containing preconfluent monolayers (80-90% confluence) of C3H-10T1/2 cells. Because it is impossible to test all concentrations of each test substance in a single assay, statistical techniques were developed to 'standardize' in vitro assay results. In each assay, radiolabel release due to a positive control was also measured, using 0.04, 0.05 and 0.06 mM concentrations of sodium dodecyl sulfate (SDS). Test substance releases were then transformed into 'SDS equivalent' responses, significantly reducing both inter- and intra-assay variability. A straight line was fitted to the test substance responses and compared with that for SDS to calculate the relative potency in vitro for individual AS and FP. Relative potencies correlated with in vivo responses, that is primary dermal irritation indices obtained in rabbits, with Spearman p=0.408 (P<0.03) for 32 tested agents, and p=0.976 (P<0.001) for the eight AS. Exclusion of extremely alkaline or acidic FP (pH>11 or <2, n=4) and those which were insoluble in the aqueous cell culture media at the 1% stock dilution (n=5), improved the overall in vivo-in vitro correlation significantly (p=0.683, P<0.001, n=23) and produced a significant correlation for FP alone (p=0.539, P<0.05, n=15). These results suggest that release of [3H]arachidonic acid from cultured skin cells represents a novel, mechanistically based in vitro screen for dermal irritancy testing.