Immune response to topical sodium lauryl sulfate differs from classical irritant and allergic contact dermatitis.

Sodium lauryl sulfate (SLS) is used as a control irritant in patch testing for allergic contact dermatitis (ACD). However, up to 20% of those tested react to SLS, whereby the pathophysiological basis of this reaction is still unclear. To mimic patch test reactions, we repeatedly applied SLS to the skin of wild-type mice. Reactions were compared with those in a classical ACD model induced by oxazolone and an irritant contact dermatitis (ICD) model induced by croton oil. Skin inflammation was assessed with ear thickness measurements, immunohistochemistry, qRT-PCR, and flow cytometry. Topical SLS treatment was further investigated in Flg/Hrnr-/-, Myd88/Tlr3-/-, and Rag1-/- mouse models. All three compounds caused ear swelling with different courses. Oxazolone treatment, compared with the ICD model, resulted in a greater influx of immune cells (CD4+, MHCII+, CD11b+). Similarly, SLS did not induce immune cell infiltration or expression of selected inflammatory and regulatory cytokines. SLS induced the most pronounced keratinocyte proliferation. Compared with wild-type mice, topical SLS application did not increase ear swelling in skin barrier deficient Flg/Hrnr-/- mice, but led to significantly delayed swelling in mice with defects in innate or adaptive immune functions (Myd88/Tlr3-/-, Rag1-/-). SLS-induced contact dermatitis differed from classical ACD and ICD, as it elicited less pronounced immune alterations. Skin barrier impairment does not affect SLS-induced contact dermatitis, whereas both innate and adaptive components are involved in SLS skin reactions.

Skin microdialysis detects distinct immunologic patterns in chronic inflammatory skin diseases.

BACKGROUND: Insight into the pathophysiology of inflammatory skin diseases, especially at the proteomic level, is severely hampered by the lack of adequate in situ data. OBJECTIVE: We characterized lesional and nonlesional skin of inflammatory skin diseases using skin microdialysis. METHODS: Skin microdialysis samples from patients with atopic dermatitis (AD, n = 6), psoriasis vulgaris (PSO, n = 7), or prurigo nodularis (PN, n = 6), as well as healthy controls (n = 7), were subjected to proteomic and multiplex cytokine analysis. Single-cell RNA sequencing of skin biopsy specimens was used to identify the cellular origin of cytokines. RESULTS: Among the top 20 enriched Gene Ontology (GO; geneontology.org) annotations, nicotinamide adenine dinucleotide metabolic process, regulation of secretion by cell, and pyruvate metabolic process were elevated in microdialysates from lesional AD skin compared with both nonlesional skin and controls. The top 20 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG; genome.jp/kegg) pathways in these 3 groups overlapped almost completely. In contrast, nonlesional skin from patients with PSO or PN and control skin showed no overlap with lesional skin in this KEGG pathway analysis. Lesional skin from patients with PSO, but not AD or PN, showed significantly elevated protein levels of MCP-1 compared with nonlesional skin. IL-8 was elevated in lesional versus nonlesional AD and PSO skin, whereas IL-12p40 and IL-22 were higher only in lesional PSO skin. Integrated single-cell RNA sequencing data revealed identical cellular sources of these cytokines in AD, PSO, and PN. CONCLUSION: On the basis of microdialysates, the proteomic data of lesional PSO and PN skin, but not lesional AD skin, differed significantly from those of nonlesional skin. IL-8, IL-22, MCP-1, and IL-12p40 might be suitable markers for minimally invasive molecular profiling.

Contact allergies to dental materials in patients.

BACKGROUND: Concerns regarding contact allergies and intolerance reactions to dental materials are widespread among patients. Development of novel dental materials and less frequent amalgam use may alter sensitization profiles in patients with possible contact allergy. OBJECTIVES: To analyse current sensitization patterns to dental materials in patients with suspected contact allergy. METHODS: This retrospective, multicentre analysis from the Information Network of Departments of Dermatology (IVDK) selected participants from 169 834 people tested in 2005-2019 and registered with (i) an affected area of 'mouth' (and 'lips'/'perioral'), (ii) with the dental material in question belonging to one of three groups (dental filling materials, oral implants or dentures or equivalents) and (iii) with patch-testing done in parallel with the German baseline series, (dental) metal series and dental technician series. RESULTS: A total of 2730 of 169 834 tested patients met the inclusion criteria. The patients were predominantly women (81.2%) aged ≥ 40 years (92.8%). The sensitization rates with confirmed allergic contact stomatitis in women (n = 444) were highest for metals (nickel 28.6%, palladium 21.4%, amalgam 10.9%), (meth)acrylates [2-hydroxyethyl methacrylate (HEMA) 4.8%] and the substances propolis (6.8%) and 'balsam of Peru' (11.4%). The most relevant acrylates were HEMA, 2-hydroxypropyl methacrylate, methyl methacrylate, ethylene glycol dimethacrylate and pentaerythritol triacrylate. Few men were diagnosed with allergic contact stomatitis (n = 68); sensitization rates in men were highest for propolis (14.9%) and amalgam (13.6%). CONCLUSIONS: Allergic contact stomatitis to dental materials is rare. Patch testing should not only focus on metals such as nickel, palladium, amalgam and gold, but also (meth)acrylates and the natural substances propolis and 'balsam of Peru'.

Inconsistent Skin Prick Tests for Allergy to Birch Homologous Trees May Result from Cross-Reacting Allergens or Technical Errors.

INTRODUCTION: Skin prick tests (SPTs) are the gold standard for diagnosis of allergic rhinitis (AR). A decrease in the number of allergens included in standard SPT panels has recently been debated - particularly regarding the cross-reacting homologous pollen from birch, alder, and hazel trees - but has not yet been implemented in clinical guidelines. METHODS: A subgroup of patients with AR (n = 69) who showed inconsistent SPT results among birch, alder, and hazel was investigated in detail. Beyond SPT, patient workup included assessment of clinical relevance and various serological parameters (total IgE, and specific IgE to birch, alder, and hazel and to Bet v 1, Bet v 2, and Bet v 4). RESULTS: More than half the study group had negative SPT results for birch but positive results for alder and/or hazel, and 87% of the study group was polysensitized, showing at least one more positive SPT result for other plants. Whereas 30.4% of patients showed serological sensitization to birch pollen extract, only 18.8% displayed positive specific IgE to Bet v 1. Clinical assessment revealed that most patients with AR were polysensitized and had perennial symptoms or symptoms also occurring during times other than tree flowering times. If the SPT panel is limited to testing birch only, 52.2% of patients in this subgroup would have been overlooked. CONCLUSION: Inconsistent SPT results in the birch homologous group may result from cross-reacting allergens or technical errors. If patients report convincing clinical symptoms despite negative results from a reduced SPT panel or inconsistent results for homologous allergens, SPT should be repeated, and molecular markers should be added to achieve a correct diagnosis.

Skin Tests versus Serology: Specific IgE May Suffice for Diagnosis of Vespid Venom Allergy and Follow-Up of Allergen Immunotherapy.

INTRODUCTION: In adults, allergic reactions to insect stings are among the most frequent causes of anaphylaxis, a potentially life-threatening condition. Recurrent anaphylaxis following vespid stings may be prevented by allergen immunotherapy (AIT). The aim of this study was to evaluate the benefit of measuring venom-induced wheal area in intracutaneous skin tests (ICT), in comparison to various serological and clinical parameters, for the diagnosis of severe vespid venom allergy and during follow-up of AIT. METHODS: We conducted a monocentric, retrospective evaluation of 170 patients undergoing AIT against vespid venoms. We scanned ICT wheals at baseline and at three time points after AIT initiation and measured wheal area using objective data analysis software. RESULTS: We found that ICT histamine-induced and venom-induced wheal areas did not correlate. In addition, the venom-induced wheal area was independent from the minimal venom concentration required to elicit a wheal in an ICT and all other parameters. No correlation was found between wheal area and the severity of anaphylaxis. Wheal area standardized to the application of 0.1 µg/mL venom inversely correlated with anaphylaxis severity and positively correlated with venom-specific IgE levels. During AIT, mean areas of venom-induced wheals did not change. In contrast, venom-specific IgG and IgG4 levels, and the minimal venom concentration required to induce a positive ICT result increased, while the venom wheal area standardized to 0.1 µg/mL venom application and specific IgE levels decreased over time. CONCLUSION: Wheal area evaluation did not provide additional information over specific IgE analysis. We therefore recommend that ICTs are used only as a secondary measure for confirming serological test results.

Full-body blue light irradiation as treatment for atopic dermatitis: a randomized sham-controlled clinical trial (AD-Blue).

BACKGROUND: Visible blue light (wavelength 400-495 nm) is a promising new treatment option for both psoriasis and atopic dermatitis (AD). Whilst previous clinical trials featured various devices and blue light at a variety of wavelengths, none of these interventions were challenged in objective clinical criteria. PATIENTS AND METHODS: Eighty-seven patients diagnosed with AD were enrolled in AD-Blue, an international, prospective, double-blinded, three-armed (415 nm vs. 450 nm vs. sham control), randomized trial designed to investigate the safety and efficacy of prototype full-body blue light devices. RESULTS: Full-body irradiation with 450 nm blue light but not 415 nm had a significant impact on itch (Itch-VAS, -1.6 ± 2.3; p  =  0.023 vs. sham irradiation). PO-SCORAD values also decreased significantly in response to irradiation at 415 nm (-11.5 ± 18.4; p = 0.028 vs. sham irradiation). None of the other outcome measures (EASI, SCORAD, IGA, DLQI) changed significantly. No safety signals were observed. Evaluation of skin transcriptomes, cytokine levels in serum, and ELISpots from peripheral blood mononuclear cells isolated from a subset of patients revealed moderate decreases in IL-31 in response to irradiation with blue light. CONCLUSIONS: Despite its favorable safety profile and moderate reductions in itch and IL-31 levels, full-body blue light irradiation did not lead to an amelioration of any of the objective measures of AD.

The benefit of late readings in patch testing depends both on allergen and patient characteristics.

BACKGROUND: Patch test (PT) readings are recommended after 48 h and 72 h (D3). An additional day 7 (D7) reading has been suggested by some, although data on efficient patient selection are scarce. We investigated positive D7 reactions regarding (i) allergens in the baseline series and additional PT series of the German Contact Dermatitis Research Group (DKG) and (ii) characteristics of the patients tested. METHODS: Retrospective, multicentre analysis of 190 allergens derived from 17 DKG test series in 4687 patients with an additional D7 reading. Patients were patch tested with the baseline series and additional series, if required. Occurrence of novel D7 reactions as well as increasing skin reactions from D3 to D7 was analysed separately. RESULTS: Depending on the allergen tested, waiving D7 readings would have missed 4.4-26.8% of positive PT results. Patch test series with the highest number of novel D7 reactions were baseline series, metal series, and leather/shoe series. New positive reactions on D7 were associated with age over 50 years and with a negative irritant control containing sodium lauryl sulphate. Of note, application of the PT allergens for 48 h instead of 24 h was positively associated with late PT reactions. CONCLUSION: Within the most frequently tested allergens, without late readings, on average 11.7% of sensitizations would have been missed. Novel late reacting allergens were identified. This study comprehensively dissects patient-, allergen- and test-dependent parameters in support for D7 readings. We propose to always consider late readings individually based on effort-benefit considerations.

[New interdisciplinary teaching concept for the cross-sectional subject of allergology in human medicine studies]. / Interdisziplinäre Neukonzeption der Lehre im Querschnittsfach "Allergologie" im Studiengang Humanmedizin.

BACKGROUND: Although allergic diseases are among the most important health disorders, allergology is not anchored as an independent subject in the clinical part of medical studies in Germany. OBJECTIVE: As all universities and institutes face the same challenge, the aim of our project was to establish exemplary coordination and networking of education in allergology at one location in agreement with all involved departments and institutes. Particularly, Comprehensive Allergy Centers (CAC) offer an established infrastructure via which the revised allergology education program can be transferred to other universities. MATERIALS AND METHODS: After an extensive inventory of the current allergological curriculum at the University Medical Center Göttingen, a new teaching concept was developed in interdisciplinary consensus, supplemented by first-time provision of additional digital contents ("blended learning"), and finally evaluated. RESULTS: Initially, we observed a high level of fragmentation in the teaching of allergology in the clinical study sections of human medicine, with no coordination between the 12 clinical departments/institutes involved and no coherent framework for the specific learning content. Within the established structure of the interdisciplinary CAC, we revised, coordinated, and defined key areas for improved student education in clinical allergology. The allocation of new interactive learning elements as well as supplementary materials for self-studies was welcomed by the students and positively evaluated. A survey among students after completing the former vs. current curricula showed significant improvements in achieving the desired educational objectives.

Sensitization against Fungi in Patients with Airway Allergies over 20 Years in Germany.

BACKGROUND: Fungal spores are ubiquitous allergens. Severe forms of asthma are particularly highly associated with fungal sensitization. National and international asthma guidelines recommend the implementation of allergen immunotherapy if indicated. Thus, detection and treatment of relevant allergies are key components of primary care of these patients. OBJECTIVES: The aims of the study were (i) to investigate trends in the prevalence of sensitization to twelve fungi in central Germany over the last 20 years and (ii) to dissect specific sensitization patterns among the 3 most important fungi: Aspergillus, Alternaria, and Cladosporium. METHODS: This single-center study evaluated skin prick test (SPT) results of 3,358 patients with suspected airway allergies over a period of 20 years (1998-2017). RESULTS: While 19.2% of all study patients had positive test results to at least 1 of the 3 fungi (Alternaria, Aspergillus, or Cladosporium) in the first study decade, this rate increased to 22.5% in the second decade. Slight increases in sensitization rates to almost all fungi were observed over the 20-year period. In the last decade, polysensitization to Alternaria, Aspergillus, and Cladosporium increased significantly. Sensitization to fungi is age-dependent and peaks in the age-group of 21-40 years during the second decade. CONCLUSION: Fungi are relevant allergens for perennial and seasonal allergy symptoms. We currently recommend including Aspergillus, Alternaria, and Cladosporium in the standard series of SPTs for airway allergies.

Contact sensitizations to disinfectants containing alcohols or quaternary ammonium compounds are rarely of clinical relevance.

BACKGROUND: The use of disinfectants is part of the everyday life of people, especially in the medical profession. During the coronavirus disease 2019 (COVID-19) pandemic, the use of disinfectants continues to increase and is of fundamental importance in infection control. OBJECTIVES: To determine the frequency of sensitization and the value of patch testing to didecyldimethylammonium chloride (DDAC) and the alcohols ethanol, 1-propanol, and isopropanol. METHODS: Clinical patch test data of 145 patients with suspected contact allergy to disinfectants were retrospective analysed. RESULTS: Among the 145 patients patch tested with the different alcohols, only one nurse was detected with a possible allergy to 1-propanol. Additional patch testing in 84 patients with DDAC 0.05% resulted in five patients with weakly positive reactions only, without clinical relevance. Patch testing with DDAC 0.03% showed no positive reactions at all on day 3 readings. CONCLUSIONS: DDAC and alcohols are rarely responsible for allergic contact dermatitis. The accused products of the patients should be checked for other allergens and further additives with skin-irritating properties. Individual susceptibility and mishandling of the disinfectants should be considered.

Improving povidone-iodine and iodine preparations for patch testing.

BACKGROUND: Allergy evaluation by patch testing with povidone-iodine (PVP-I) or iodine remains challenging, because current patch test preparations frequently lead to false-positive or irritant skin reactions. OBJECTIVES: To investigate different preparations for iodine patch tests and to assess their clinical relevance with repeated open application tests (ROATs). METHODS: We monocentrically analyzed 95 patients with suspected allergy to disinfectants in retrospect who underwent parallel iodine patch testing with four preparations: PVP-I 2% aq., 5% aq., 10% aq., and iodine 0.5% pet. RESULTS: In 27 of 95 patients (28.4%), we found positive reactions to one of the four test preparations. After ROATs in 22 of these 27 positively tested individuals, only one patient was diagnosed with iodine allergy. In contrast, 31 of 95 patients (32.6%) showed irritant or questionable patch test reactions on day 2 (D2) and/or D3 and/or D7 to one or more test preparations. Testing with PVP-I 2% aq. resulted in the lowest number of doubtful skin reactions while detecting the single allergic patient. CONCLUSION: PVP-I 2% aq. was found to be the optimal patch test preparation. In general, iodine allergy appears to be substantially overestimated, and positive patch test responses to iodine should prompt an urgent ROAT for confirmation before diagnosing iodine allergy.

Sensitization rates to common inhaled allergens in Germany - increase and change patterns over the last 20 years.

BACKGROUND: Sensitization rates to aeroallergens are rising worldwide. The prevalence is increasing, especially in Western countries. We aimed to investigate (1) sensitization rates and (2) cross-sensitization patterns in skin prick tests (SPTs) for the most relevant inhaled allergens in central Germany over 20 years, adjusted for regional pollen counts. PATIENTS AND METHODS: This monocentric study evaluated SPTs for tree pollen, grass pollen and house dust mites (HDMs) in 4,315 patients (including children) with suspected airway allergies, from 1998-2017. RESULTS: Sensitization rates to almost all aeroallergens have increased significantly over time, without relevant changes in regional pollen counts. Current sensitization rates in all our symptomatic patients were highest for grass (55.3 %) and rye pollen (59.6 %), with most pronounced increases in HDM sensitization over time (from 37.8 % to the current figure of 50.1 %). However, a low but consistent proportion of tree-sensitized patients (3.6-7.8 %) showed isolated positive SPTs to alder and/or hazel pollen without sensitization to birch pollen. CONCLUSIONS: We demonstrate a significant rise in the total number of sensitized patients as well as increases in cross-sensitization between closely related allergens. Individuals with unusual mono-sensitization profiles to common inhaled allergens should be studied in more detail, since these patients are currently excluded from clinical trials for allergen immunotherapy.

Atopic skin diathesis rather than atopic dermatitis is associated with specific contact allergies.

BACKGROUND: The association of atopic dermatitis (AD) and allergic contact dermatitis has been a matter of considerable uncertainty. Study results range from lack of any association to increased sensitization for multiple allergens, but fail to identify consistent allergen associations. OBJECTIVE: We studied a large patch test cohort of patients stratified by their atopic skin diathesis using the Erlangen Atopy Score (EAS), independent of active skin disease. METHODS: Retrospective multi-center data analysis from five departments of dermatology in Germany with 4,509 patients. Patients were grouped as "no atopic skin diathesis" (n = 2,165) and "atopic skin diathesis" (n = 1,743), according to EAS. RESULTS: Significantly more individuals with atopic skin diathesis showed at least one positive patch test reaction to the baseline series compared to individuals without atopic skin diathesis (49.1 % vs. 38.3 %). In logistic regression analyses, atopic skin diathesis was associated with a significantly higher risk of sensitization to methylchloroisothiazolinone/methylisothiazolinone (OR 2.383) and methylisothiazolinone (OR 1.891), thiuram mix (OR 1.614), as well as nickel (OR 1.530), cobalt (OR 1.683), and chromium (OR 2.089). CONCLUSIONS: Atopic skin diathesis proved to be the most important intrinsic risk factor for contact sensitization to few, specific allergens. Past or present AD was a less relevant variable.

Allergic Rhinitis to Weed Pollen in Germany: Dominance by Plantain, Rising Prevalence, and Polysensitization Rates over 20 Years.

BACKGROUND: In contrast to the 3 major aeroallergens tree pollen, grass pollen, and house dust mites, allergic rhinitis caused by herbal pollen has received comparatively little attention in recent clinical studies. Since various weeds flower during summer until fall, allergic rhinitis to weeds may be underdiagnosed and/or mistakenly diagnosed as grass pollen allergy. OBJECTIVE: To investigate (i) the currently most frequent weed allergy between mugwort, ragweed, plantain, chamomile, nettle, and oilseed rape and (ii) time trends in prevalence of sensitization to weed pollen in the middle of Germany over the last 20 years. METHODS: This study, the largest of its kind to date, monocentrically evaluated the prick test results of a total of 6,220 patients with suspected RCA over a period of 20 years (1998-2017). RESULTS: In the study cohort, sensitization rates to plantain almost doubled from 26.6% in the decade 1998-2007 to 50.5% in 2008-2017. Identical increases were observed for ragweed, while sensitization rates for mugwort stayed largely unchanged. The most prominent increase in positive skin prick tests to plantain and ragweed pollen was mainly observed in younger patients. Further, we identified a trend toward polysensitization, currently dominated by plantain and ragweed. Sensitization to weed pollen was found to be highly associated with additional sensitizations to grass and/or birch pollen. CONCLUSION: Plantain is currently the best choice to screen rhinitis patients for weed allergy which identifies 86% of all weed-sensitized individuals, at least in Germany. Over the last 20 years, we demonstrate a significant rise in the total number of weed pollen sensitization as well as increases in polysensitization, predominantly in younger patients.

Profile Shift in Latex Sensitization over the Last 20 Years.

BACKGROUND: Natural rubber latex (NRL) allergy is commonly diagnosed according to medical history, skin allergy tests, and serological analyses. However, skin tests are increasingly being abandoned because of (i) their time-consuming nature, (ii) latex preparations for skin tests being not commercially available, and (iii) the use of in-house prepared test solutions is becoming ever more difficult due to increasing regulatory hurdles. In this light, we have evaluated differences in the profiles of current and former patients with suspected latex allergy. METHODS: Sera of skin test-positive patients from a historic cohort (1995-2001, n = 149 patients) and currently (2014-2015, n = 48 patients) were simultaneously analyzed for specific IgE to latex by ImmunoCAP. If the serological screening was positive (≥0.35 kU/L), component-resolved diagnostics including profilins and cross-reactive carbohydrate determinants (CCDs) were performed. RESULTS: In contrast to 88% (131/149) of the skin test-positive patients from the 1990s, only 51.1% (24/47) of the current cohort were found positive for specific IgE to latex. While 48.3% (72/149) of the patients had a convincing positive history in the 1990s, current skin test-positive patients rarely reported a relevant medical history (8.5%, 4/47). Specific IgE levels to latex were significantly higher in former patients with suspected latex allergy (p < 0.001) than in former sensitized individuals without allergy. However, this significant difference was lost in current allergic and sensitized patients with positive skin tests. CONCLUSION: Sensitization profiles in patients with latex allergy have changed significantly over the last 2 decades. Discrimination between NRL sensitization and clinical allergy remains a diagnostic challenge. Our data highlight the need for a combination of all 3 criteria, i.e., patient history, skin test, and analysis of specific IgE, for a correct diagnosis of latex allergy.