A new-old allergen: propolis contact hypersensitivity 1992-2021 / Egy régi-új allergén - a propolisz szenzibilizáló hatásának vizsgálata 1992 és 2021 között

Introduction: Propolis is a resinous substance collected by bees. Its use is widespread in cosmetics and natural medi-cine because of variable beneficial effects. Local application and consumption may cause hypersensitivity.Objective: Aim of this study was to analyze the 30-year data of patients with propolis hypersensitivity.Method: 17 784 patients were patch tested between 1992 and 2021 in the Allergology Outpatient Unit of the De-partment of Dermatology, Venereology and Dermatooncology of the Semmelweis University. 464 patients (2.6%) had propolis sensibility. We present the annual changes in the frequency of propolis sensibility, the typical diagnoses, age groups, localizations most affected by clinical symptoms and the co-hypersensitivities according to propolis sen-sibility.Results: In the 30-year period, the sensitization frequency of propolis was on average 2.6%; in 2019-2021, we de-tected a sudden increase (6.2%, 8.4%, 6.9%). Female predominance was typical (70.7%). Most patients belonged to the age group 51-60 years (24.6%), the mean age was 52.5 years. Most skin symptoms appeared on hands (34.2%), legs (18.4%), and face (17.5%). Regarding co-hypersensitivities, fragrance mix I (27.7%), balsam of Peru (26.8%) and wood tar (23.0%) can be mentioned.Conclusion: The general need for biocosmetics, complementary and alternative medicine raises the exposure of propolis. The risk of contact hypersensitivity is increased because propolis products are used mostly on inflamed skin with higher allergen penetration. According to our results, propolis - beside its advantageous properties - is an important environ-mental allergen, especially among elderly women. Propolis sensibility, the possible cross-and co-hypersensitivities can cause contact dermatitis or may worsen different skin diseases. Propolis sensibility can be verified by patch testing.

Preservative Contact Hypersensitivity among Adult Atopic Dermatitis Patients.

Atopic dermatitis (AD) is a chronic inflammatory disease characterised by an impaired skin barrier. The prolonged use of topical preparations containing medications, emollients, fragrances and preservatives may increase the risk of contact hypersensitivity (CHS). In the Allergy Outpatient Unit of the Department of Dermatology, Venereology and Dermatooncology of Semmelweis University, 5790 adult patients were patch tested between 2007-2021 with the European Environmental Baseline Series according to international standards. Among all the tested adult patients, 723 had preservative CHS (PCHS) and 639 had AD. Among the 723 PCHS patients, 68 (9.4%) had AD; the female to male ratio was 3:1 in this group. Out of 639 AD patients, 68 had PCHS (10.6%). In the AD-PCHS group, 83.8% had CHS to methylisothiazolinone (MI) (tested from 2014), 36.8% to Kathon CG®, 16.2% to methyldibromo-glutaronitrile, 11.8% to paraben, 7.4% to formaldehyde, 4.4% to para-tert-butylphenol-formaldehyde resin and 1.5% to Quaternium-15. The most common concomitant PCHS combination was Kathon CG® + MI. Most patients (32.4%) belonged to the age group of 21-30, and skin symptoms affected mostly the limbs and face. The most common other concomitant allergens were nickel, lanolin alcohol and balsam of Peru. Preservatives (especially MI and Kathon CG®) are important contact allergens in adult AD, mostly among young women. The rate of AD in the PCHS group and the rate of PCHS in the AD group is remarkable; thus, the role of PCHS should be highlighted in the topical therapy and in the prevention of possible AD exacerbations.

Nickel sensitization: impact of the European Union Nickel Directives / A nikkelérzékenység jelentosége az Európai Unió direktíváinak tükrében.

Összefoglaló. Bevezetés: A nikkel szélesköruen elterjedt fém és kontaktallergén. Megtalálható mindennapi használati tárgyainkban, feldolgozza az ipari termelés, és az egészségügyben is rendre bovül alkalmazási köre. Egyidejuleg a társadalom növekvo hányadánál fordul elo nikkel-kontaktszenzibilizáció. Célkituzés: Az epicutan tesztelt betegcsoport adatainak feldolgozása, kiemelve a nikkelpozitív betegek megoszlását nem, életkor, diagnózis, a klinikai tünetek lokalizációja és a társult fémérzékenység szerint, továbbá a 2004 óta érvényes európai uniós Nikkel Direktívák hatásainak tanulmányozása. Módszer: A közlemény a Semmelweis Egyetem Bor-, Nemikórtani és Boronkológiai Klinikájának Allergológia Laboratórium és Szakambulanciáján 1994-tol 2014-ig 13 693 fo (10-87 év közötti) standard környezeti epicutan sorral tesztelt beteg adatait vizsgálja retrospektív módon. Eredmények: Az összes vizsgált borbeteg nikkelszenzibilizációs aránya 1994-ben 13,1%, 2004-ben 11,5%, 2014-ben 19,1% volt. A nikkel-kontaktdermatitis foként nobetegeknél (93,0%) fordul elo. A klinikai tünetek elsosorban a karokra és az arcra lokalizálódnak. Nikkelérzékenyeknél az allergiás kontaktdermatitis diagnózisa 65,8%, atopiás dermatitis 9,7%-nál fordul elo. A nikkelérzékenységhez leggyakrabban társult fémallergének a kobalt és a króm. Az 1994-2004-es periódushoz képest az európai uniós Nikkel Direktívákat követo 10 évben a szenzibilizáció százalékos emelkedése szignifikáns volt, ugyanakkor a nikkelpozitívak évenkénti száma csökkent. 1994-ben a betegek legnagyobb hányada (26,5%) a 20-24 éves korcsoportba tartozott, 2004-ben szintén (20,8%), 2014-ben azonban a 35-39 éves korosztályhoz (15,1%). Következtetések: A nikkelszenzibilizáció korban eltolódást mutat az idosebb korosztály felé, a 35 évesnél fiatalabb betegek száma mérséklodött. A Nikkel Direktívák révén a fiatalabbak késobbi életkorban és kisebb mértéku nikkelexpozíciónak vannak kitéve. A vizsgált betegek nikkelérzékenységének százalékos emelkedése miatt azonban újabb szabályozások bevezetése és a hatályban lévok módosítása szükségszeru. Orv Hetil. 2021; 162(16): 629-637. INTRODUCTION: Nickel is a widely used metal and contact allergen. It can be found in our everyday objects and it is becoming more prevalent in healthcare. Simultaneously, nickel contact sensitization occurs more frequently. OBJECTIVE: Analysis of data of patch tested patients by gender, age, diagnosis, localization of skin lesions, and associated metal sensitivity. Furthermore, to study the effects of the European Nickel Directives in force since 2004. METHOD: Retrospective analysis of data of 13 693 patients (aged 10-87) tested with a standard series of contact allergens at the Allergy Outpatient Unit and Laboratory of the Department, Venereology and Dermatooncology, Semmelweis University. RESULT: Nickel sensitization of all examined patients was 13.1% in 1994, 11.5% in 2004, and 19.1% in 2014. Contact dermatitis occurred mainly in females (93.0%). Skin lesions are primarily localized to the arms and face. Diagnosis of allergic contact dermatitis occurred in 65.8%, and atopic dermatitis in 9.7% of tested patients. Commonly associated metal sensitivities were cobalt and chromium. In the 10 years following the Nickel Directives, the increase of the ratio of sensitized patients was significant while the number of nickel-positives per year decreased. Both in 1994 and 2004, the largest proportion of patients belonged to the 20-24 age group (26.5% and 20.8%, respectively), but in 2014, to the 35-39 age group (15.1%). CONCLUSION: Nickel sensitization shifts towards the older age group, with a decrease in young patients. Because of the Nickel Directives, people are exposed to nickel at a later age and to a lesser extent. Due to the increase of the ratio of nickel-sensitive patients, it is necessary to introduce new regulations and amend the existing ones. Orv Hetil. 2021; 162(16): 629-637.

Contact hypersensitivity in adolescents.

BACKGROUND: Contact hypersensitivity is common in adolescents, but data in the literature are limited. Adolescents often use cosmetics, wear jewelry, and obtain tattoos, which can be sources of allergens. METHODS: This was a retrospective, noninterventional cohort study of 100 adolescents (aged 13-18; 74 girls, 26 boys) who were consecutively patch tested. RESULTS: We detected contact hypersensitivity in 51 of the 100 patch-tested patients (51%): 52.7% of the girls and 46.2% of the boys were sensitized. The most common allergens were nickel (17%), thimerosal (12%), para-phenylenediamine (8%), cobalt (7%), and fragrance mix I (6%). Thirteen percent of the reactions did not appear until the seventh day. The majority of clinical lesions affected the hands and face. The most common contact allergens were mercury derivatives, lanolin, and para-phenylenediamine in boys and nickel, thimerosal, para-phenylenediamine, cobalt, and fragrance mix I in girls. Of the 47 adolescents with atopic dermatitis 51.1% had contact hypersensitivity. In this group, skin care product ingredients were the typical allergens (25.5%). The most common contact allergens of those with atopic dermatitis were nickel (12.8%), lanolin (10.6%), and thimerosal (8.5%). CONCLUSION: Contact hypersensitivity is common in adolescents. For patients with therapy-resistant skin lesions affecting the face and hands, patch testing with an evaluation for 7 days is recommended. Our results provide the first data on frequency of contact hypersensitivity in this age group in Hungary. Metals, fragrances, mercuric derivatives, dyeing materials, and skin care products were the most common allergens.

para-Phenylenediamine Hypersensitivity: A Report From Budapest, Hungary, 2007-2014.

BACKGROUND: para-Phenylenediamine (PPD) is a potent allergen with frequent exposure through use of hair dyes or henna tattoos. OBJECTIVES: We wished to determine if prevalence of PPD sensitivity is changing through time as trends in its use change. PATIENTS: A total of 3631 patients were patch tested consecutively with the environmental standard series between 2007 and 2014 to map the prevalence of PPD sensitivity and its distribution according to age, sex, and diagnosis. RESULTS: Two hundred nine patients (5.75%) were proven to be PPD sensitive. Most PPD-sensitive patients were approximately in their 60s in 2007, whereas in 2014, they were in their 20s and 30s. In 2014, 61.1% of the patients were younger than 35 years and 50% were younger than 25 years. Of 209 PPD-sensitive patients, 32.5% had present relevance related to hair dyeing and eyebrow or eyelash coloring procedures. All affected male patients were hairdressers. Adverse reaction to henna was detected in only 1 case after henna hair dye use. CONCLUSIONS: The 5.75% prevalence of PPD sensitization in our study was higher compared with that in the European data. It is alarming that PPD hypersensitivity occurred even among teenagers. This may be mainly explained by hair dyeing at an early age.

Methylchloroisothiazolinone/Methylisothiazolinone and Methylisothiazolinone Sensitivity in Hungary.

Background. Due to allowing of methylisothiazolinone (MI) in cosmetics, cleaning products, and paints, an epidemic of MI-hypersensitivity emerged. Patch testing Kathon CG® (3:1 mixture of methylchloroisothiazolinone and methylisothiazolinone, MCI/MI) does not correctly detect MI contact allergy, due to the low concentration of MI in the test material. Methods. A retrospective survey was performed to estimate the prevalence of MCI/MI hypersensitivity in 14693 patients tested consecutively between 1993 and 2014. Moreover, currently 314 patients were prospectively tested with the allergens MCI/MI and with MI during one year. Results. MCI/MI hypersensitivity increased retrospectively from 0.5% to 6.0%. By current prospective testing we detected 25 patients (8%) with MCI/MI and/or MI positive reactions. Out of the 25 patients 10 were only MCI/MI positive, 9 were only MI positive, and 6 were MCI/MI and MI positive. If MI had not been tested separately, MI contact allergy would have missed in 36% of all detected cases and in 2.8% of the total 314 patients. Conclusions. The frequency of MCI/MI hypersensitivity is increasing also in Hungary. We confirm that, in order to detect MI contact allergy, it needs to be tested separately. A further increase of MI hypersensitivity might be expected in the future as products containing MI are still widely available.

Reduced inflammatory threshold indicates skin barrier defect in transglutaminase 3 knockout mice.

Recently, a transglutaminase 3 knockout (TGM3/KO) mouse was generated that showed impaired hair development, but no gross defects in the epidermal barrier, although increased fragility of isolated corneocytes was demonstrated. Here we investigated the functionality of skin barrier in vivo by percutaneous sensitization to FITC in TGM3/KO (n=64) and C57BL/6 wild-type (WT) mice (n=36). Cutaneous inflammation was evaluated by mouse ear swelling test (MEST), histology, serum IgE levels, and by flow cytometry from draining lymph nodes. Inflammation-induced significant MEST difference (P<0.0001) was detected between KO and WT mice and was supported also by histopathology. A significant increase of CD4+ CD25+-activated T cells (P<0.01) and elevated serum IgE levels (P<0.05) in KO mice indicated more the development of FITC sensitization than an irritative reaction. Propionibacter acnes-induced intracutaneous inflammation showed no difference (P=0.2254) between the reactivity of WT and KO immune system. As in vivo tracer, FITC penetration from skin surface followed by two-photon microscopy demonstrated a more invasive percutaneous penetration in KO mice. The clinically uninvolved skin in TGM3/KO mice showed impaired barrier function and higher susceptibility to FITC sensitization indicating that TGM3 has a significant contribution to the functionally intact cutaneous barrier.

Patch tests with fragrance mix II and its components.

BACKGROUND: Fragrance mix II (FM II) was initiated to detect contact hypersenstitivity (CH) to fragrances that could not have been identified previously. OBJECTIVE: The aim of this multicenter study was to map the frequency of CH to FM II and its components in Hungary. METHODS: Six centers participated in the survey from 2009 to 2010. A total off 565 patients (434 women and 131 men) with former skin symptoms provoked by scented products were patch tested. The tests were performed with Brial GmbH D-Greven allergens. In the environmental patch test series, FM II, FM I, Myroxylon pereirae, colophonium, wood-tar mix, propolis, and sesquiterpene lactone mix were tested as fragrance allergens. The FM II components (citral, farnesol, coumarin, citronellol, α-hexyl-cinnamaldehyde, and hydroxy-isohexyl-3-cyclohexene-carboxaldehyde [Lyral]) were also tested. RESULTS: Contact hypersenstitivity to any fragrances was detected in 28.8%, to FM II in 17.2% of the patients. Contact hypersenstitivity to hydroxy-isohexyl-3-cyclohexene-carboxaldehyde was observed in 7.3%, to coumarin in 5.1%, to α-hexyl-cinnamaldehyde in 3.5%, to citral in 3.4%, to farnesol in 2.5%, and to citronellol in 1.2%. Of the FM II-positive cases, 48.4% showed isolated CH reaction. CONCLUSIONS: The frequency of CH to FM II is 17.2% in the tested, selected Hungarian population. The CH to FM II and its components could not have been revealed without the present test materials.

Association of collagenous colitis with prurigo nodularis.

The etiology and pathogenesis of collagenous colitis (CC) is poorly understood and probably multifactorial; many potential pathophysiological mechanisms have been described, although none have been conclusively proved. Circumstantial evidence suggests that CC appears as an autoimmune response to a luminal or epithelial antigen of unknown origin. Infections and certain drugs (e.g. NSAID, lansoprazole) may act as triggers for an immune-mediated process. CC is characterized clinically by chronic watery, nonbloody diarrhea with normal endoscopic appearance and without radiological abnormalities, but specific microscopic changes in the colon. Histopathology is featured by the presence of a thickened subepithelial collagen band adjacent to the basal membrane. Up to 40% of patients with CC have associated diseases of autoimmune or inflammatory origin, such as thyroid disease, coeliac disease, rheumatoid arthritis, diabetes mellitus, Sjögren's syndrome, CREST syndrome, scleroderma, pernicious anemia, and sarcoidosis. Prurigo nodularis is a chronic condition characterized by intensely pruritic, lichenified, or excoriated papules and nodules of unknown etiology. It is assumed to represent a cutaneous reaction pattern to repeated scrubbing or scratching caused by pruritus. We report a case of CC and prurigo nodularis. To our knowledge, this association has not been reported earlier.

[Adulthood atopic dermatitis: epidemiology, clinical symptoms, provoking and prognostic factors]. / Atópiás dermatitis felnottkorban: epidemiológia, klinikai jellemzok, provokáló és prognosztikai faktorok.

The prevalence of atopic diseases, including allergic rhinitis, asthma bronchiale and atopic dermatitis is increasing both in children and adults at different parts of the world. Atopic dermatitis is a chronic inflammatory skin disease affecting mostly children, but the atopic trait continues, not only for later respiratory allergies, but also for skin symptoms in adulthood. In this form dry skin, flexural lichenification, head and neck dermatitis, hand dermatitis are typical. The exact etiology of atopic dermatitis is unknown, in the background interactions of genetical predisposition, skin barrier defects and immunological and environmental factors can be verified. In the complex approach of atopic dermatitis, a pivotal role is ascribed to the evaluation and possibly the elimination of provoking factors, like gender, family structure, clothing, aero-, alimentary and contact allergens, psychosocial stress, migration, infections, and personal home environment. Authors review clinical manifestations, triggering and prognostic factors of the adulthood atopic dermatitis.

[Eczematous skin diseases]. / Ekzemás megbetegedések.

The skin, as one of the most important barriers of the human body, protects the inner homeostasis from the harmful environmental influences as well as physical, chemical and biological factors. When the impact of these factors exceeds the tolerance and reproducing capacity of the skin, pathological alterations will develop. If follows from this that dermatology can surely be considered to be a part of environmental medicine. Eczematous diseases are mostly pathological pictures of varied mechanisms developing as a result of environmental influences (irritants, contact allergens, microbes). Since their clinical appearance is similar, it is a serious professional challenge to diagnose them. In this article we present the clinical features, provoking factors of these skin diseases as well as therapeutical possibilities.

Age dependence of diphenylcyclopropenone sensitization in patients with alopecia areata.

Contact sensitization has been an accepted topical immunotherapy in the treatment of alopecia areata (1, 2). Whether the age of patients is a significant factor in the treatment results is a matter of controversy. In our study, we investigated the correlation between age of the patients and diphenylcyclopropen-one contact sensitization in vivo and in vitro (3, 4).

Correlation between T-cell and mast cell activity in patients with chronic urticaria.

BACKGROUND: The presence of autoantibodies reacting with the high affinity IgE receptor (FcepsilonRIalpha) usually indicates a more severe form of chronic urticaria (CU). Previously, we showed an increased lymphocyte reactivity in CU patients; however, the relation between enhanced cellular immunity and the presence of anti-FcepsilonRIalpha-specific autoantibodies has not been investigated. METHODS: Cellular and humoral immune reactivity of 50 CU patients and 28 healthy controls was studied. Serum sIL-2R, neopterin, and tryptase levels were measured to assess T-cell, monocyte/macrophage and mast cell activity, respectively. Helicobacter pylori (HP)-specific IgG antibody, and IgE levels were also tested. Anti-FcepsilonRIalpha-specific autoantibody was determined by Western blotting. In vivo histamine-releasing activity of patients' sera was assessed by the autologous serum skin test (AST). RESULTS: 17/50 CU patients, who both had IgG-type anti-FcepsilonRIalpha-antibodies by Western blotting and a positive AST response, were classified as autoimmune CU. All patients with CU had significantly higher serum sIL-2R and tryptase levels than healthy controls (p = 0.000257, p = 0.000166, respectively), indicating T-cell and mast cell activation. Patients with higher sIL-2R levels also had higher tryptase levels; the strongest correlation was shown in the autoimmune subgroup of patients (rho = 0.688, p = 0.002). There was a tendency towards higher tryptase levels in the autoimmune subgroup, as compared to the nonautoimmune CU patients. While the serum IgE was significantly lower in autoimmune than in nonautoimmune CU (p = 0.000836), there was no significant difference in their sIL-2R, neopterin and HP-specific IgG antibody levels. CU patients with a positive AST response (38/50) had significantly higher tryptase levels (p = 0.0107) when compared to the negative skin test group. CONCLUSIONS: The significant correlation between sIL-2R and tryptase levels in patients with CU indicates that T cell activation is proportional to mast cell degranulation in these patients. The increased level of tryptase in autoimmune CU may suggest more severe disease.

Multicentre study of fragrance allergy in Hungary. Immediate and late type reactions.

The authors followed the frequency of fragrance contact sensitization in Hungary in a multicentre study in the years 1998 and 1999. A total of 3,604 patients were tested with fragrance mix (FM), and positive reactions were observed in 294 (8.2%). In 160 FM hypersensitive patients, the study was continued with patch testing of the mix constituents (cinnamic alcohol, cinnamic aldehyde, eugenol, amyl cinnamic aldehyde, hydroxycitronellal, geraniol, isoeugenol, oak moss absolute). Of the patients tested, 70.6% produced positive reactions to the constituents. FM contact sensitization was mainly observed in female patients (74.4%). The incidence of contact urticaria in FM hypersensitive patients was 6.1%. Simultaneous patch test trials of other environmental contact allergens, in both early and late evaluations, mainly confirmed hypersensitivity reactions to balsams. Female dominance of hypersensitivity reactions observed during testing the individual components of the mix was striking (82.4%). In positive skin reactions, cinnamic alcohol, isoeugenol and oak moss provoked skin symptoms most frequently. We also tested the 104 patients who produced negative reactions to FM with the constituent individual allergens, with 11.9% positive incidence. The clinical symptoms of the patients were above all manifest in the form of contact eczema, located on the hands, face, eyelids and axillae. With this study, the authors, members of the Hungarian Contact Dermatitis Research Group, call attention to one of the most frequent allergens in the environment.

The Dominant T-Helper Lymphocyte Function of HIV Infected Patients.

In HIV infection, the decrease in the number and functional activity of lymphocytes is accompanied by atopia and an increased level of total IgE and some specific IgE antibodies. This could be explained by the Th2 dominance induced by HIV replication and so a Th1-Th2 switch could have prognostic value. We investigated the characteristic T-helper phenotype dominance and its relationship to cytokine expression and IgE immune response in the early stage of asymptomatic HIV infection. In the separated lymphocytes of i. asymptomatic HIV positive persons; ii. HIV negative homosexuals; iii. atopic patients; and iv. healthy controls, expression of mRNA for IFNg (Th1) and IL-10 (Th2) were determined by semiquantitative RT-PCR. The serum level of antibodies for HIV 1/2 and total/specific IgE were also determined. Transcription of mRNA of IFNg and IL-10 were more pronounced in HIV positive and atopic groups than in the healthy control, without lymphocyte phenotype dominance. In HIV negative persons, however, a significant Th2 dominance was detected. There was no significant difference in the IgE level between the 4 investigated groups. In the HIV positive cases, IL-10 expression and total serum IgE do not support a switch to Th2 dominance. In the atopic group, aside from the total IgE level, down regulation of IFNg was not observed. These results suggest a general activation of the immune system in the early stage of HIV infection.