Validation of the German Pruritus Questionnaire for the systematic assessment of chronic pruritus.

BACKGROUND: Chronic pruritus is a clinically heterogeneous symptom that manifests itself with varying duration, intensity, or quality. To date, there is no validated German-language instrument that systematically assesses the relevant parameters. With the support of the Pruritus Research Working Group (Arbeitsgemeinschaft Pruritusforschung, AGP), a questionnaire for the assessment of chronic pruritus (AGP questionnaire) was developed in 2008. The subsequently revised instrument, now called the German Pruritus Questionnaire, records pruritus-specific parameters such as localization, course, intensity and quality, anamnestic data on the general state of health, sociodemographic data, quality of life, and coping methods. It is to be validated in the study presented here. PATIENTS AND METHODS: The questionnaire was used in 366 patients with chronic pruritus of different etiologies from Germany (University Hospitals Heidelberg, Münster, Mainz, Erlangen, Giessen, private practice Bad Bentheim, TU Munich, Wiesbaden Kidney Center), Austria (Graz University Hospital) and Switzerland (Aarau Cantonal Hospital). RESULTS: The reliability for repeated completion (retest reliability) with regard to localization, first occurrence, and concomitant diseases showed high values for Cohen's kappa (> 0.8). The data on the retest reliability of the pruritus characteristics showed lower values (< 0.7). With regard to the measurability of practically relevant changes (change sensitivity), medium to strong effect sizes were found (0.09-0.19). A statistically significant differentiation of the pruritus etiologies based on the recorded parameters was not possible. CONCLUSIONS: The German Pruritus Questionnaire allows a comprehensive and structured recording of patient- and clinician-reported, relevant dimensions of chronic pruritus of different etiologies. Further adaptation and development are planned.

Basophil activation in insect venom allergy: comparison of an established test using liquid reagents with a test using 5-color tubes with dried antibody reagents.

BACKGROUND: Flow cytometry-based basophil activation tests (BAT) have been performed with various modifications, differing in the use of distinct identification and activation markers. Established tests use liquid reagents while a new development involves the use of tubes with dried antibody reagents. The aim of this pilot study was to compare these two techniques in patients with insect venom allergy. METHODS: Seventeen patients with an insect venom allergy were included in the study. The established "BAT 1" utilizes conventional antibody solutions of anti-CCR3 for basophil identification and anti-CD63 to assess basophil activation, whereas "BAT 2" uses dried anti-CD45, anti-CD3, anti-CRTH2, anti-203c and anti-CD63 for identification and activation measurement of basophils. Negative and positive controls as well as incubations with honey bee venom and yellow jacket venom at three concentrations were performed. RESULTS: Seven patients had to be excluded due to low basophil counts, high values in negative controls or negative positive controls. For the remaining 10 patients the overall mean (± SD) difference in activated basophils between the two tests was 0.2 (± 12.2) %P. In a Bland-Altman plot, the limit of agreement (LoA) ranged from 24.0 to -23.7. In the qualitative evaluation (value below/above cut-off) Cohen's kappa was 0.77 indicating substantial agreement. BAT 2 took longer to perform than BAT 1 and was more expensive. CONCLUSION: The BAT 2 technique represents an interesting innovation, however, it was found to be less suitable compared to an established BAT for the routine diagnosis of insect venom allergies.

Allergy to PEG (polyethylene glycol) - sensitivity of basophil activation test with COVID-19 mRNA-vaccine BNT162B2.

Basophil activation test (BAT) with COVID-19 mRNA vaccine seems particularly suitable for detecting sensitization to polyethylene glycol (PEG) in patients with PEG allergy. It was the aim of this study to determine the cutoffs for BAT using BNT162B2 (Comirnaty®) in a larger group of PEG allergic patients and controls. 10 PEG allergic patients and 10 controls were studied. BAT was performed using anti-CCR3 for basophil identification and anti-CD63 to assess basophil activation. Incubations with BNT162B2 at four different concentrations were performed. Basophil activation was significantly higher in PEG allergic patients compared to controls at the higher concentrations used. ROC curves showed best results with a sensitivity of 60% and specificity of 100% with a cutoff of 5% CD63+ basophils at a concentration of 4.5 µg/ml. Controls showed no positive results. In our group of PEG allergic patients, a concentration of 4.5 µg/ml BNT162B2 with a cutoff of 5% CD63+ basophils was the most suitable condition for identifying patients with a sensitization to PEG. Allergological work-up of PEG allergic patients including BAT with PEGylated lipid nanoparticles might play a role in the future when these substances will be used for other vaccines and cancer immunotherapies.

Quality control in clinical raster-scan optoacoustic mesoscopy.

Optoacoustic (photoacoustic) mesoscopy bridges the gap between optoacoustic microscopy and macroscopy and enables high-resolution visualization deeper than optical microscopy. Nevertheless, as images may be affected by motion and noise, it is critical to develop methodologies that offer standardization and quality control to ensure that high-quality datasets are reproducibly obtained from patient scans. Such development is particularly important for ensuring reliability in applying machine learning methods or for reliably measuring disease biomarkers. We propose herein a quality control scheme to assess the quality of data collected. A reference scan of a suture phantom is performed to characterize the system noise level before each raster-scan optoacoustic mesoscopy (RSOM) measurement. Using the recorded RSOM data, we develop a method that estimates the amount of motion in the raw data. These motion metrics are employed to classify the quality of raw data collected and derive a quality assessment index (QASIN) for each raw measurement. Using simulations, we propose a selection criterion of images with sufficient QASIN, leading to the compilation of RSOM datasets with consistent quality. Using 160 RSOM measurements from healthy volunteers, we show that RSOM images that were selected using QASIN were of higher quality and fidelity compared to non-selected images. We discuss how this quality control scheme can enable the standardization of RSOM images for clinical and biomedical applications.

Machine Learning Analysis of Human Skin by Optoacoustic Mesoscopy for Automated Extraction of Psoriasis and Aging Biomarkers.

Ultra-wideband raster-scan optoacoustic mesoscopy (RSOM) is a novel modality that has demonstrated unprecedented ability to visualize epidermal and dermal structures in-vivo. However, an automatic and quantitative analysis of three-dimensional RSOM datasets remains unexplored. In this work we present our framework: Deep Learning RSOM Analysis Pipeline (DeepRAP), to analyze and quantify morphological skin features recorded by RSOM and extract imaging biomarkers for disease characterization. DeepRAP uses a multi-network segmentation strategy based on convolutional neural networks with transfer learning. This strategy enabled the automatic recognition of skin layers and subsequent segmentation of dermal microvasculature with an accuracy equivalent to human assessment. DeepRAP was validated against manual segmentation on 25 psoriasis patients under treatment and our biomarker extraction was shown to characterize disease severity and progression well with a strong correlation to physician evaluation and histology. In a unique validation experiment, we applied DeepRAP in a time series sequence of occlusion-induced hyperemia from 10 healthy volunteers. We observe how the biomarkers decrease and recover during the occlusion and release process, demonstrating accurate performance and reproducibility of DeepRAP. Furthermore, we analyzed a cohort of 75 volunteers and defined a relationship between aging and microvascular features in-vivo. More precisely, this study revealed that fine microvascular features in the dermal layer have the strongest correlation to age. The ability of our newly developed framework to enable the rapid study of human skin morphology and microvasculature in-vivo promises to replace biopsy studies, increasing the translational potential of RSOM.

Diagnosis and treatment of Hymenoptera venom allergy: S2k Guideline of the German Society of Allergology and Clinical Immunology (DGAKI) in collaboration with the Arbeitsgemeinschaft für Berufs- und Umweltdermatologie e.V. (ABD), the Medical Association of German Allergologists (AeDA), the German Society of Dermatology (DDG), the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (DGHNOKC), the German Society of Pediatrics and Adolescent Medicine (DGKJ), the Society for Pediatric Allergy and Environmental Medicine (GPA), German Respiratory Society (DGP), and the Austrian Society for Allergy and Immunology (ÖGAI).

Hymenoptera venom (HV) is injected into the skin during a sting by Hymenoptera such as bees or wasps. Some components of HV are potential allergens and can cause large local and/or systemic allergic reactions (SAR) in sensitized individuals. During their lifetime, ~ 3% of the general population will develop SAR following a Hymenoptera sting. This guideline presents the diagnostic and therapeutic approach to SAR following Hymenoptera stings. Symptomatic therapy is usually required after a severe local reaction, but specific diagnosis or allergen immunotherapy (AIT) with HV (VIT) is not necessary. When taking a patient's medical history after SAR, clinicians should discuss possible risk factors for more frequent stings and more severe anaphylactic reactions. The most important risk factors for more severe SAR are mast cell disease and, especially in children, uncontrolled asthma. Therefore, if the SAR extends beyond the skin (according to the Ring and Messmer classification: grade > I), the baseline serum tryptase concentration shall be measured and the skin shall be examined for possible mastocytosis. The medical history should also include questions specific to asthma symptoms. To demonstrate sensitization to HV, allergists shall determine concentrations of specific IgE antibodies (sIgE) to bee and/or vespid venoms, their constituents and other venoms as appropriate. If the results are negative less than 2 weeks after the sting, the tests shall be repeated (at least 4 - 6 weeks after the sting). If only sIgE to the total venom extracts have been determined, if there is double sensitization, or if the results are implausible, allergists shall determine sIgE to the different venom components. Skin testing may be omitted if in-vitro methods have provided a definitive diagnosis. If neither laboratory diagnosis nor skin testing has led to conclusive results, additional cellular testing can be performed. Therapy for HV allergy includes prophylaxis of reexposure, patient self treatment measures (including use of rescue medication) in the event of re-stings, and VIT. Following a grade I SAR and in the absence of other risk factors for repeated sting exposure or more severe anaphylaxis, it is not necessary to prescribe an adrenaline auto-injector (AAI) or to administer VIT. Under certain conditions, VIT can be administered even in the presence of previous grade I anaphylaxis, e.g., if there are additional risk factors or if quality of life would be reduced without VIT. Physicians should be aware of the contraindications to VIT, although they can be overridden in justified individual cases after weighing benefits and risks. The use of ß-blockers and ACE inhibitors is not a contraindication to VIT. Patients should be informed about possible interactions. For VIT, the venom extract shall be used that, according to the patient's history and the results of the allergy diagnostics, was the trigger of the disease. If, in the case of double sensitization and an unclear history regarding the trigger, it is not possible to determine the culprit venom even with additional diagnostic procedures, VIT shall be performed with both venom extracts. The standard maintenance dose of VIT is 100 µg HV. In adult patients with bee venom allergy and an increased risk of sting exposure or particularly severe anaphylaxis, a maintenance dose of 200 µg can be considered from the start of VIT. Administration of a non-sedating H1-blocking antihistamine can be considered to reduce side effects. The maintenance dose should be given at 4-weekly intervals during the first year and, following the manufacturer's instructions, every 5 - 6 weeks from the second year, depending on the preparation used; if a depot preparation is used, the interval can be extended to 8 weeks from the third year onwards. If significant recurrent systemic reactions occur during VIT, clinicians shall identify and as possible eliminate co-factors that promote these reactions. If this is not possible or if there are no such co-factors, if prophylactic administration of an H1-blocking antihistamine is not effective, and if a higher dose of VIT has not led to tolerability of VIT, physicians should should consider additional treatment with an anti IgE antibody such as omalizumab as off lable use. For practical reasons, only a small number of patients are able to undergo sting challenge tests to check the success of the therapy, which requires in-hospital monitoring and emergency standby. To perform such a provocation test, patients must have tolerated VIT at the planned maintenance dose. In the event of treatment failure while on treatment with an ACE inhibitor, physicians should consider discontinuing the ACE inhibitor. In the absence of tolerance induction, physicians shall increase the maintenance dose (200 µg to a maximum of 400 µg in adults, maximum of 200 µg HV in children). If increasing the maintenance dose does not provide adequate protection and there are risk factors for a severe anaphylactic reaction, physicians should consider a co-medication based on an anti-IgE antibody (omalizumab; off-label use) during the insect flight season. In patients without specific risk factors, VIT can be discontinued after 3 - 5 years if maintenance therapy has been tolerated without recurrent anaphylactic events. Prolonged or permanent VIT can be considered in patients with mastocytosis, a history of cardiovascular or respiratory arrest due to Hymenoptera sting (severity grade IV), or other specific constellations associated with an increased individual risk of recurrent and/or severe SAR (e.g., hereditary α-tryptasemia). In cases of strongly increased, unavoidable insect exposure, adults may receive VIT until the end of intense contact. The prescription of an AAI can be omitted in patients with a history of SAR grade I and II when the maintenance dose of VIT has been reached and tolerated, provided that there are no additional risk factors. The same holds true once the VIT has been terminated after the regular treatment period. Patients with a history of SAR grade ≥ III reaction, or grade II reaction combined with additional factors that increase the risk of non response or repeated severe sting reactions, should carry an emergency kit, including an AAI, during VIT and after regular termination of the VIT.

High-risk groups for alpha-gal sensitization.

BACKGROUND: Tick bite-induced IgE-mediated reactions to the oligosaccharide galactose α-1,3-galactose (alpha-gal) are increasingly recognized. This study investigated alpha-gal sensitization in three groups with different tick bite exposure. MATERIALS AND METHODS: Specific IgE antibodies to alpha-gal and total IgE were investigated in 485 patients with Lyme borreliosis with different disease manifestations and compared to a control group of 200 randomly selected patients without increased exposure to tick bites. A group of 232 hunters and forest workers served as a model for multiple tick bites. RESULTS: Specific IgE (sIgE) antibodies to alpha-gal (> 0.1 kU/L) were found in 12.6% of all borreliosis samples compared to the control group with 9% (relative risk 1.4; 95% CI 0.85 - 2.3; not significant (n.s.). The highest prevalence of sIgE to alpha-gal was observed in hunters and forest service employees (22.8%, relative risk 2.5; 95% CI 1.5 - 4.2; p < 0.001). Higher age and elevated total IgE were also associated with alpha-gal sensitization. CONCLUSION: IgE sensitization to alpha-gal tends to be more frequent in tick-exposed patients with borreliosis than in controls (n.s.). Moreover, hunters and forest workers show an even higher rate of elevated IgE to alpha-gal. Thus, frequent tick contact may result in alpha-gal sensitization. In the area of Munich, the prevalence of alpha-gal sensitization appears lower than in the state of Baden-Württemberg and lower than in the USA, which may be due to the difference in tick species or the frequency of tick exposure. This study could show that alpha-gal sensitization and presumably alpha-gal syndrome does not seem to be a modern problem but existed already more than 30 years ago.

A concept for integrated care pathways for atopic dermatitis-A GA2 LEN ADCARE initiative.

INTRODUCTION: The integrated care pathways for atopic dermatitis (AD-ICPs) aim to bridge the gap between existing AD treatment evidence-based guidelines and expert opinion based on daily practice by offering a structured multidisciplinary plan for patient management of AD. ICPs have the potential to enhance guideline recommendations by combining interventions and aspects from different guidelines, integrating quality assurance, and describing co-ordination of care. Most importantly, patients can enter the ICPs at any level depending on AD severity, resources available in their country, and economic factors such as differences in insurance reimbursement systems. METHODS: The GA2 LEN ADCARE network and partners as well as all stakeholders, abbreviated as the AD-ICPs working group, were involved in the discussion and preparation of the AD ICPs during a series of subgroup workshops and meetings in years 2020 and 2021, after which the document was circulated within all GAL2 EN ADCARE centres. RESULTS: The AD-ICPs outline the diagnostic procedures, possible co-morbidities, different available treatment options including differential approaches for the pediatric population, and the role of the pharmacists and other stakeholders, as well as remaining unmet needs in the management of AD. CONCLUSION: The AD-ICPs provide a multidisciplinary plan for improved diagnosis, treatment, and patient feedback in AD management, as well as addressing critical unmet needs, including improved access to care, training specialists, implementation of educational programs, assessment on the impact of climate change, and fostering a personalised treatment approach. By focusing on these key areas, the initiative aims to pave the way for a brighter future in the management of AD.

Placebo-Controlled Histamine Challenge Disproves Suspicion of Histamine Intolerance.

BACKGROUND: Histamine intolerance (HIT) is frequently diagnosed in patients with polysymptomatic otherwise unexplained symptoms. OBJECTIVES: To exclude HIT by a single-blind placebo-controlled histamine challenge (SBPCHC), to study clinical features of patients with positive challenge, and to examine the predictability of HIT by biomarkers. METHODS: SBPCHC was performed in 59 patients with suspected HIT. History and clinical data, including serum diamine oxidase (DAO) and histamine skin test wheal size of patients with positive versus negative SBPCHC, were compared. RESULTS: Patients were predominantly middle-aged women (84.7%). Three-quarters reported improvement but never resolution of symptoms during a histamine-low diet. Histamine provocation was safe; only 1 patient was treated with antihistamines. Thirty-seven patients (62.7%) displayed symptoms to placebo. HIT was excluded in 50 patients (84.7%). Objective symptoms occurred in 4 of 59 cases (6.8%) after histamine but not after placebo challenge. These were diagnosed with "plausible HIT" because reactions occurring by chance could not be excluded. Another 5 patients (8.5%) were diagnosed with "possible HIT" after case-dependent detailed analysis. Patients with plausible/possible HIT had reported more gastrointestinal symptoms (P = .01), but comparable diet response and equal histamine skin prick test wheal sizes to those without HIT. Serum DAO activity tended to be lower in patients with HIT (P = .08), but was highly variable in those without, limiting its value as a biomarker. CONCLUSIONS: SBPCHC disproves HIT in the majority of patients. Placebo-controlled challenges are needed as placebo reactions were frequent. Gastrointestinal symptoms after food intake and reduced DAO levels are markers for HIT; however, specificity is not sufficient enough for making the diagnosis.

Basophil Activation Test in Double-Sensitized Patients With Hymenoptera Venom Allergy: Additional Benefit of Component-Resolved Diagnostics.

BACKGROUND: In Hymenoptera venom allergy serologically double-sensitized patients, it is often difficult to identify the culprit insect for venom immunotherapy (VIT). OBJECTIVES: To evaluate if basophil activation tests (BATs) performed not only with venom extracts but additionally with single component-resolved diagnostics could differentiate between sensitized and allergic individuals and how the test results influenced the physicians' decision regarding VIT. METHODS: BATs were performed with bee and wasp venom extracts and with single components (Api m 1, Api m 10, Ves v 1, and Ves v 5) in 31 serologically double-sensitized patients. RESULTS: In 28 finally included individuals, 9 BATs were positive and 4 negative for both venoms. Fourteen of 28 BATs showed positive results for wasp venom alone. Two of 10 BATs positive for bee venom were only positive to Api m 1 and 1 of 28 BATs only to Api m 10, but not for whole bee venom extract. Five of 23 BATs positive for wasp venom were only positive for Ves v 5 but negative for wasp venom extract and Ves v 1. Finally, VIT with both insect venoms was recommended in 4 of 28 individuals, with wasp venom alone in 21 of 28 patients and with bee venom alone in 1 of 28. In 2 cases no VIT was recommended. CONCLUSIONS: BATs with Ves v 5, followed by Api m 1 and Api m 10, were helpful for the decision for VIT with the clinically relevant insect in 8 of 28 (28.6%) patients. A BAT with components should therefore be additionally carried out in cases with equivocal results.

SARS-CoV-2 and allergy - what have we learned after two and a half years?

BACKGROUND: Coronavirus disease-2019 (COVID-19) has significantly hampered the regular workflow for allergists and allergy departments. MATERIALS AND METHODS: The purpose of this review is to highlight our own experiences on SARS-CoV-2 and allergy as well as to discuss findings from the literature. RESULTS: Vaccination against SARS-CoV-2 is needed for protection against severe infection. Skin reactions may arise with SARS-CoV-2 infections. Short-term general immune reactions and skin reactions are also possible upon SARS-CoV-2 vaccination; however, they recur in only a proportion of patients during follow-up vaccinations. Initial reports of anaphylaxis after vaccination fueled public fear. On the other hand, more recent epidemiologic data do not show a substantially increased anaphylaxis risk compared with other vaccines. Fear-related reactions may be essential for many "anaphylaxis" reports. In Germany, the flow chart developed by Paul-Ehrlich-Institut (PEI) and Robert-Koch-Institut (RKI) together with the allergological societies helps to care for patients with suspected "allergy history" safely and effectively. Through this, patients with increased risk of anaphylaxis to SARS-CoV-2 vaccines and their ingredients (e.g., polyethylene glycol (PEG), polysorbate 80) are identified. However, since only small amounts of these excipients are contained in mRNA vaccines, even some PEG-allergic patients can tolerate the vaccination. In Germany, an allergy test-guided procedure is recommended for high-risk patients, including an allergy history, prick tests, intradermal and basophil activation tests, and, if necessary, provocation tests. This also appears effective for anxiety reduction in patients with vaccination skepticism. To date, all of our patients have been able to be vaccinated with SARS-CoV-2 vaccines without the occurrence of significant reactions. CONCLUSION: Many initial concerns about unexpected side effects of SARS-CoV-2 vaccination have not been confirmed. The flowchart and, in the case of suspicion of hypersensitivity, an allergy test-guided risk assessment helps to reduce patients' fear of vaccination and enables safe vaccination.

S2k guideline: Diagnosis and treatment of chronic pruritus.

Pruritus is a cross-disciplinary leading symptom of numerous diseases and represents an interdisciplinary diagnostic and therapeutic challenge. In contrast to acute pruritus, chronic pruritus (CP) is a symptom of various diseases that is usually difficult to treat. Scratching and the development of scratch-associated skin lesions can alter the original skin status. In the presence of an itch-scratch-cycle, even secondary diseases such as chronic prurigo can develop. Chronic pruritus leads to considerable subjective suffering of those affected, which can result in restrictions on the health-related quality of life such as sleep disturbances, anxiety, depressiveness, experience of stigmatization and/or social withdrawal up to clinically relevant psychic comorbidities. Medical care of patients should therefore include (a) interdisciplinary diagnosis and therapy of the triggering underlying disease, (b) therapy of the secondary symptoms of pruritus (dermatological therapy, sleep promotion, in the case of an accompanying or underlying psychological or psychosomatic disease an appropriate psychological-psychotherapeutic treatment) and (c) symptomatic antipruritic therapy. The aim of this interdisciplinary guideline is to define and standardize the therapeutic procedure as well as the interdisciplinary diagnosis of CP. This is the short version of the updated S2k-guideline for chronic pruritus. The long version can be found at www.awmf.org.

Enabling precision monitoring of psoriasis treatment by optoacoustic mesoscopy.

Psoriasis is a widespread inflammatory skin disease affecting about 2% of the general population. Recently, treatments that specifically target key proinflammatory cytokines driving the disease have been developed to complement conventional therapies with unspecific antiproliferative or anti-inflammatory effects. Efficient monitoring of treatment efficacy in the context of precision medicine and the assessment of new therapeutics require accurate noninvasive readouts of disease progression. However, characterization of psoriasis treatment remains subjective based on visual and palpatory clinical assessment of features observed on the skin surface. We hypothesized that optoacoustic (photoacoustic) mesoscopy could offer label-free assessment of inflammation biomarkers, extracted from three-dimensional (3D) high-resolution images of the human skin, not attainable by other noninvasive methods. We developed a second-generation ultra-broadband optoacoustic mesoscopy system, featuring sub-10-µm resolution and advanced motion correction technology, and performed 80 longitudinal measurements of 20 psoriatic skin plaques in humans under conventional inpatient treatment or receiving biologics with concomitant topical corticosteroid treatment. Optoacoustic image analysis revealed inflammatory and morphological skin features that indicated treatment efficacy with sensitivity, accuracy, and precision that was not possible using clinical metrics. We identify 3D imaging biomarkers that reveal responses to treatment and offer the potential to facilitate disease and treatment characterization. Our findings suggest that optoacoustic mesoscopy may offer a method of choice for yielding both qualitative and quantitative evaluations of skin treatments that are inaccessible by other methods, potentially enabling optimized therapies and precision medicine in dermatology.

Fast raster-scan optoacoustic mesoscopy enables assessment of human melanoma microvasculature in vivo.

Melanoma is associated with angiogenesis and vascular changes that may extend through the entire skin depth. Three-dimensional imaging of vascular characteristics in skin lesions could therefore allow diagnostic insights not available by conventional visual inspection. Raster-scan optoacoustic mesoscopy (RSOM) images microvasculature through the entire skin depth with resolutions of tens of micrometers; however, current RSOM implementations are too slow to overcome the strong breathing motions on the upper torso where melanoma lesions commonly occur. To enable high-resolution imaging of melanoma vasculature in humans, we accelerate RSOM scanning using an illumination scheme that is coaxial with a high-sensitivity ultrasound detector path, yielding 15 s single-breath-hold scans that minimize motion artifacts. We apply this Fast RSOM to image 10 melanomas and 10 benign nevi in vivo, showing marked differences between malignant and benign lesions, supporting the possibility to use biomarkers extracted from RSOM imaging of vasculature for lesion characterization to improve diagnostics.

Do basophil activation tests help elucidate allergic reactions to the ingredients in COVID-19 vaccines?

The worldwide use of COVID-19 vaccines has shown that immediate allergic reactions to the ingredients are rare but should be clarified by means of an allergological work-up. This review aims to highlight the current state of knowledge and possible pathogenesis based on the literature published to date. In addition to recording a detailed history and performing skin tests, cellular tests (basophil activation or basophil histamine release test) by using the vaccines or modified compounds containing polyethylene glycol (PEG), rather than unmodified PEGs, have proven to be particularly helpful. Negative results with vaccines seem to indicate tolerance. Details of the performance of these cellular tests with different vaccines, PEGs of different molecular weights, other ingredients of the vaccines, as well as other PEGylated drugs, and the results in the context of COVID-19 vaccination of various working groups worldwide are summarized.

Proposal of 0.5 mg of protein/100 g of processed food as threshold for voluntary declaration of food allergen traces in processed food-A first step in an initiative to better inform patients and avoid fatal allergic reactions: A GA²LEN position paper.

BACKGROUND: Food anaphylaxis is commonly elicited by unintentional ingestion of foods containing the allergen above the tolerance threshold level of the individual. While labeling the 14 main allergens used as ingredients in food products is mandatory in the EU, there is no legal definition of declaring potential contaminants. Precautionary allergen labeling such as "may contain traces of" is often used. However, this is unsatisfactory for consumers as they get no information if the contamination is below their personal threshold. In discussions with the food industry and technologists, it was suggested to use a voluntary declaration indicating that all declared contaminants are below a threshold of 0.5 mg protein per 100 g of food. This concentration is known to be below the threshold of most patients, and it can be technically guaranteed in most food production. However, it was also important to assess that in case of accidental ingestion of contaminants below this threshold by highly allergic patients, no fatal anaphylactic reaction could occur. Therefore, we performed a systematic review to assess whether a fatal reaction to 5mg of protein or less has been reported, assuming that a maximum portion size of 1kg of a processed food exceeds any meal and thus gives a sufficient safety margin. METHODS: MEDLINE and EMBASE were searched until 24 January 2021 for provocation studies and case reports in which one of the 14 major food allergens was reported to elicit fatal or life-threatening anaphylactic reactions and assessed if these occurred below the ingestion of 5mg of protein. A Delphi process was performed to obtain an expert consensus on the results. RESULTS: In the 210 studies included, in our search, no reports of fatal anaphylactic reactions reported below 5 mg protein ingested were identified. However, in provocation studies and case reports, severe reactions below 5 mg were reported for the following allergens: eggs, fish, lupin, milk, nuts, peanuts, soy, and sesame seeds. CONCLUSION: Based on the literature studied for this review, it can be stated that cross-contamination of the 14 major food allergens below 0.5 mg/100 g is likely not to endanger most food allergic patients when a standard portion of food is consumed. We propose to use the statement "this product contains the named allergens in the list of ingredients, it may contain traces of other contaminations (to be named, e.g. nut) at concentrations less than 0.5 mg per 100 g of this product" for a voluntary declaration on processed food packages. This level of avoidance of cross-contaminations can be achieved technically for most processed foods, and the statement would be a clear and helpful message to the consumers. However, it is clearly acknowledged that a voluntary declaration is only a first step to a legally binding solution. For this, further research on threshold levels is encouraged.