Severely compromised supply of patch test allergens in Europe hampers adequate diagnosis of occupational and non-occupational contact allergy. A European Society of Contact Dermatitis (ESCD), European Academy of Allergy and Clinical Immunology (EAACI), European Academy of Dermatology and Venereology (EADV) task forces 'Contact Dermatitis' and 'Occupational Skin Disease' position paper.

Patch testing is the only clinically applicable diagnostic method for Type IV allergy. The availability of Type IV patch test (PT) allergens in Europe, however, is currently scarce. This severely compromises adequate diagnostics of contact allergy, leading to serious consequences for the affected patients. Against this background, the European Society of Contact Dermatitis (ESCD) has created a task force (TF) (i) to explore the current availability of PT substances in different member states, (ii) to highlight some of the unique characteristics of Type IV vs. other allergens and (iii) to suggest ways forward to promote and ensure availability of high-quality patch testing substances for the diagnosis of Type IV allergies throughout Europe. The suggestions of the TF on how to improve the availability of PT allergens are supported by the ESCD, the European Academy of Allergy and Clinical Immunology, and the European Academy of Dermatology and Venereology and intend to provide potential means to resolve the present medical crisis.

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.

Does treatment with antidepressants, antipsychotics, or benzodiazepines hamper allergy skin testing?

BACKGROUND: Treatment with commonly used drugs such as antidepressants (ADs), antipsychotics (APs), and benzodiazepines (BDs) may hamper the use of allergy skin testing due to possible antihistaminic effects. OBJECTIVE: To examine the antihistaminic effect of AD, AP, and BD as measured by the ability of these drugs to suppress the normal wheal reaction caused by skin prick test (SPT). METHODS: Skin prick test was performed in patients receiving treatment with AD, AP, and/or BD. Double SPT was performed with histamine solutions of 10, 30, and 100 mg/ml and mean wheal diameter calculated. RESULTS: A total of 313 patients were included. 236 (75%) patients were treated with one of the examined drugs and 77 (25%) patients with more than one of these drugs. Drugs most frequently used was sertraline (n = 65), citalopram (n = 63), mirtazapine (n = 36), venlafaxine (n = 33), and quetiapine (n = 32). Treatment with mirtazapine and/or quetiapine was associated with negative SPTs in 30/36 (83%) and 22/32 (69%), and the antihistaminic effect of these drugs was dose-dependent. For patients treated with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin norepinephrine reuptake inhibitors (SNRIs), or BD alone, almost all SPTs were positive (94%, 95%, 100%, and 100%, respectively). Negative SPTs in patients treated with SSRI, TCA, SNRI, or BD and ≥1 other of the examined drugs were associated with simultaneous treatment with mirtazapine or quetiapine in 39/44 (89%) patients. CONCLUSION: Skin testing has little meaning in patients treated with mirtazapine or quetiapine. Treatment with SSRI, SNRI, and BD does not seem to affect the results of SPTs, whereas skin tests in patients treated with TCA should be interpreted with caution.

Patients with suspected allergic reactions to COVID-19 vaccines can be safely revaccinated after diagnostic work-up.

BACKGROUND: When initiating the Danish vaccination program against COVID-19, the incidence of anaphylaxis was estimated to be 10 times higher compared to other virus-based vaccines. In this study, we present data on patients referred with suspected allergic reactions to COVID-19 vaccines. The main purpose of the study is to investigate the incidence and severity of the allergic reactions, and to evaluate the safety of revaccination. METHODS: All patients in the region of Southern Denmark with case histories of allergic reactions to COVID-19 vaccines in a defined period are included in this study. Diagnostic work up consisted of a detailed case history, evaluation of Brighton level of diagnostic certainty and World Allergy Organization grade of anaphylaxis and skin prick testing- and basophil histamine release testing with COVID-19 vaccines and relevant drug excipients. Patients were revaccinated at the Allergy Center when possible. RESULTS: Sixty-one patients are included in this study. In 199,377 doses administered, nine patients fulfilled the criteria of anaphylaxis when using the Brighton Criteria (incidence being 45 per million). Of 55 patients with reactions to the first dose, 52 patients were revaccinated without adverse reactions. We found no proven cases of immediate anaphylaxis due to COVID-19 vaccines. By skin prick test, we diagnosed three patients with drug excipient allergy and further a patient with mastocytosis was found. CONCLUSIONS: Anaphylactic reactions to COVID-19 vaccines are rare and the incidence is similar to what is seen with other virus-based vaccines. Revaccination is safe in the majority of patients; however, allergological evaluation is important since some prove to have drug excipient allergy.

The influence of acetylsalicylic acid and alcohol on absorption kinetics of hen´s egg white in a human passive cutaneous anaphylaxis model.

Background: Despite the well-known fact that acetylsalicylic acid (ASA) can induce anaphylaxis in patients susceptible to wheat-dependent exercise-induced anaphylaxis, few studies have sought to investigate the effects of cofactors on type-1 food allergy and none with ASA and hen's egg and hen's egg and alcohol combined. Methods and results: We applied the experimental model of 'passive cutaneous anaphylaxis' in humans to study whether the absorption kinetics of egg white is altered while being treated with ASA or under the influence of alcohol. Donor sera from four egg allergic patients with specific immunoglobulin E (s-IgE) to ovalbumin (0.1-8.87-19.5-170 kUA/L) were injected intracutaneously into the forearm of 12 healthy volunteers who were then challenged separately to: 1) egg white 2) egg white + ASA and 3) egg white + alcohol. 'Time to wheal' and 'wheal size' were compared among the three experiments.We saw that 'time to wheal' with both ASA (P = 0.001) and alcohol (P = 0.019) added as cofactor significantly decreased compared with baseline. Conclusion: In this passive cutaneous anaphylaxis model, ASA and alcohol affected both reaction time and size of reactions elicited after egg ingestion. This suggests that patients with egg allergy could have faster and more severe reactions during ASA treatment or under alcohol influence.

Healthcare utilization in Danish children with atopic dermatitis and parental topical corticosteroid phobia.

BACKGROUND: Atopic dermatitis (AD) is a prevalent relapsing inflammatory skin disease. There is currently little knowledge about healthcare utilization and medication use along with parental corticosteroid phobia in relation to severity of pediatric AD. OBJECTIVES: To study the association between parental-reported healthcare utilization, medication use, and topical corticosteroid phobia and pediatric AD severity. METHODS: The study population included all children in Denmark with a diagnostic code of AD (ICD-10 code, group L20) given at a hospital department of dermatology between 2014 and 2018. A questionnaire containing 158 response items was sent to the legal parents. We surveyed disease severity, AD treatment, corticosteroid phobia, and healthcare use along with other variables. Disease severity was assessed using the Patient-Oriented Eczema Measure tool, and corticosteroid phobia was assessed using the Topical Corticosteroid Phobia (TOPICOP) score. RESULTS: In total, 1343 (39%) parents completed the questionnaire and 95.3% were completed by the biological mother. Children's mean age was 8.9 ± 4.5 years, and 52.8% were boys. Severe AD was associated with a higher number of healthcare visits to GPs, private dermatologists, and hospital departments. Mean global TOPICOP score was 38.27 ± 19.9%. There was a significant inverse linear trend between global TOPICOP score and parental educational level (Ptrend  < .0005). CONCLUSIONS: The significant association between high global TOPICOP score and low parental educational level, resulting in delayed treatment of AD flares, indicates that improved family education ultimately may reduce healthcare expenses and burden of disease.

The quest for ingested peanut protein in human serum.

BACKGROUND: There is mounting evidence that systemic uptake of food allergens is key to triggering anaphylaxis. However, direct proof for this theory is still lacking. The purpose of this study was to quantify the absorption and to determine the absorption kinetics of immunoreactive peanut protein in relation to the allergic response in human. METHODS: Quantitative protein assays including mass spectrometry, dot blots and Western blotting were developed to determine the level of Ara h 2 absorption in human serum. The double monoclonal sandwich ELISA was applied to quantify absorbed Ara h 2 and 6, and the basophil histamine release assay and the human passive cutaneous anaphylaxis test were utilized to study the absorption kinetics of immunologically intact peanut proteins. RESULTS: The protein assays worked but were not sensitive enough to trace the minute amounts of absorbed Ara h 2 in human serum. The level of Ara h 6 in serum was found to be up to 0.2 ng/mL, but Ara h 2 could not be detected with the ELISA. Both the in vivo and the in vitro methods were successful in demonstrating that: immunoreactive peanut protein was absorbed shortly after ingestion (≤5 minutes); the peanut protein concentration peaks between 1 and 4 hours; and peanut proteins can circulate for at least 48 hours in the bloodstream. CONCLUSION: Ingested peanut protein is absorbed systemically and retains its immunoreactive capacity in human serum. However, the precise quantities and the implication for the elicitation of anaphylaxis remains to be elucidated.

Insulin allergy can be successfully managed by a systematic approach.

BACKGROUND: Type I insulin allergy can be a challenging condition, and there is no international consensus on how to establish the diagnosis. Measurement of specific IgE and skin testing have been cornerstones in the diagnostic work-up. However, these tests have limitations, mainly lack of correlation between test results and clinical findings. At the Allergy Centre, Odense University Hospital, patients with suspected insulin allergy have been evaluated since 2003. The aim of this study was to establish a systematic approach to diagnose and treat patients with insulin allergy. METHODS: The study was conducted retrospectively by retrieving data from the Allergy Centre database on patients with suspected insulin allergy evaluated from 2003 to 2017. The examination comprised a comprehensive medical history, specific IgE against insulin and intracutaneous tests (ICT) with different insulins. RESULTS: A total of 144 patients were examined on suspicion of insulin allergy of which 110 had negative specific IgE in serum. Of the remaining 34 patients, 33 had ICT performed; 2 had negative ICTs, while 31 had one or more positive ICT. All 34 patients had mild symptoms, and 4 could obtain symptom relief with antihistamines or local steroids, 9 could be managed with oral antidiabetics, and 7 were switched to other insulins. The final 14 patients were offered an insulin pump because of reactions to many different insulins, many positive ICTs, unmanageable diabetes, young age and compliance, or convenience. CONCLUSION: Insulin allergy can be managed by a systematic approach, and symptom relief is obtainable in most patients.

Assessing severity of anaphylaxis: a data-driven comparison of 23 instruments.

BACKGROUD: The severity of an allergic reaction can range from mild local symptoms to anaphylactic shock. To score this, a number of instruments have been developed, although heterogeneous in design and purpose. Severity scoring algorithms are therefore difficult to compare, but are frequently used beyond their initial purpose. Our objective was to compare the most used severity scoring instruments by a data-driven approach on both milder reactions and anaphylaxis. METHODS: All positive challenges to foods or drugs (n = 2828) including anaphylaxis (n = 616) at Odense University Hospital, Denmark from 1998 to 2016 were included and severity was scored according to Sampson5. Based on recommendations from an expert group, the symptoms and values from Sampson5 were for all reactions and anaphylaxis only translated and compared by kappa statistics with 22 instruments, ranging from 3 to 6 steps. RESULTS: For milder reactions, there was a significant correlation between the number of steps in an instrument and the number of challenges that could be translated, whereas all instruments were good to identify food anaphylaxis. Some instruments scored reactions more severely than Sampson5, other scored them milder and some scored food and drug challenges differently. Instruments for hymenoptera reactions were difficult to apply on food and drug reactions, and thus distributed severity differently. Algorithms hampered the translation between instruments, and 7 instruments were poor concerning drug anaphylaxis, including the only instrument developed specifically for drug reactions. CONCLUSION: The distributions of severity differed between the 23 instruments in both food and drug allergy, and thus rendering translation especially between scoring systems with 3 and 5 grades difficult. Fine-graded and simple instruments are preferred for comparison especially among milder reactions, and instruments applied to non-intended situations may not reflect a true severity picture.

Pediatric Expression of Mast Cell Activation Disorders.

Mast cell activation disorders is a term proposed to cover diseases and conditions related to activation of mast cells and effects of mast cell mediators. In its broadest sense, the term encompasses a wide range of diseases from allergic asthma to rhinoconjunctivitis, urticaria, food allergy, anaphylaxis, mastocytosis, and other conditions where MC activation is contributing to the pathogenesis. This article focuses on clinical presentations, challenges, and controversies in pediatric mastocytosis and gives an overview of current knowledge and areas in need of further research.

Cow's milk allergic children-Can component-resolved diagnostics predict duration and severity?

BACKGROUND: Cow's milk allergy (CMA) affects 2% of all children. This study investigatescomponent-resolved diagnostics(CRD) to cow's milk proteins in children suspected of CMA, by correlating the level of CRD with outcome of the oral challenge. Furthermore, we evaluate the ability of serial CRD measurements to distinguish children with persistent CMA from children developing tolerance. METHODS: We included data from 78 children referred to the Allergy Centre during a 13-year period. Results from oral food challenges including threshold, severity, and sensitization data (IgE antibodies to whole milk protein, IgE components toward milk and skin prick test (SPT)) were collected. The milk allergic children were re-evaluated with sensitization data and rechallenges regularly. RESULTS: Thirty-nine children had negative first challenges, and 39 had positive first challenges. The positive group was rechallenged and separated into 3 groups depending on time to remission. At inclusion, children with persistent CMA had significantly larger size of SPT and higher levels of s-IgE to milk and CRD compared to the other groups. SPT wheal size was significantly larger in children with persistent CMA compared to children outgrowing CMA. Furthermore, a correlation between s-IgE level to cow's milk and casein and the severity of the allergic reaction elicited by food challenges was found. CONCLUSION: Oral food challenge cannot be replaced by s-IgE to whole milk protein or milk components nor SPT in the diagnosis of CMA; however, high levels of milk components and s-IgE to milk increase the risk of a long-lasting or persisting CMA.

Early-life sensitization to hen's egg predicts asthma and rhinoconjunctivitis at 14 years of age.

BACKGROUND: Sensitization to both inhalant and food allergens has been shown to be risk factors for development of asthma and rhinoconjunctivitis (RC). However, few studies have addressed the role of transient or persistent IgE sensitization to specific allergens in early life for later development of allergic diseases. The aim of this study was to explore the association between transient and persistent sensitization in early life and the development of asthma and RC at 6 and 14 years. METHODS: The Danish Allergy Research Center (DARC) cohort is a prospective non-interventional birth cohort study comprising 562 children. For the purpose of this study, we examined a subgroup of the original cohort with specific IgE measured at, at least 3 of 4 follow-ups between 3 and 18 months of age (n = 366). Multiple logistic regression models were used to investigate the association between transient and persistent early-life sensitization to groups of and to individual allergens and asthma and RC at 6 and 14 years compared to a reference group with no sensitization. RESULTS: Both transient early-life sensitization and persistent early-life sensitization to cow's milk or hen's egg proteins were associated with asthma (aOR 3.99[1.41-11.32] and 5.95[1.78-19.92]) and RC (aOR 2.94[1.19-7.28] and 6.18[1.86-20.53]) at 14 years, this association being driven mainly by sensitization to hen's egg. Transient early-life sensitization to house dust mite (HDM) had increased risk of asthma (aOR 3.80[1.17-12.41]) at 14 years. CONCLUSIONS: Early transient IgE sensitization and persistent IgE sensitization to hen's egg were associated with asthma and RC at 14 years. Furthermore, sensitization to HDM was associated with asthma at 14 years.

Positive Skin Test or Specific IgE to Penicillin Does Not Reliably Predict Penicillin Allergy.

INTRODUCTION: According to guidelines, patients are diagnosed with penicillin allergy if skin test (ST) result or specific IgE (s-IgE) to penicillin is positive. However, the true sensitivity and specificity of these tests are presently not known. OBJECTIVE: To investigate the clinical relevance of a positive ST result and positive s-IgE and to study the reproducibility of ST and s-IgE. METHODS: A sample of convenience of 25 patients with positive penicillin ST results, antipenicillin s-IgE results, or both was challenged with their culprit penicillin. Further 19 patients were not challenged, but deemed allergic on the basis of a recent anaphylactic reaction or delayed reactions to skin testing. Another sample of convenience of 18 patients, 17 overlapping with the 25 challenged, with initial skin testing and s-IgE (median, 25; range, 3-121), months earlier (T-1), was repeat skin tested and had s-IgE measured (T0), and then skin tested and had s-IgE measured 4 weeks later (T1). RESULTS: Only 9 (36%) of 25 were challenge positive. There was an increased probability of being penicillin allergic if both ST result and s-IgE were positive at T0. Positive ST result or positive s-IgE alone did not predict penicillin allergy. Among the 18 patients repeatedly tested, 46.2% (12 of 25) of positive ST results at T-1 were reproducibly positive at T0. For s-IgE, 54.2% (14 of 24) positive measurements were still positive at T0 and 7 converted to positive at T1. CONCLUSIONS: The best predictor for a clinically significant (IgE-mediated) penicillin allergy is a combination of a positive case history with simultaneous positive ST result and s-IgE or a positive challenge result.

Early childhood risk factors for rhinoconjunctivitis in adolescence: a prospective birth cohort study.

BACKGROUND: Rhinoconjunctivitis is a global health problem and one of the most common chronic conditions in children. Development of rhinoconjunctivitis depends on both genetic and environmental factors. Many studies have investigated rhinoconjunctivitis, but only few studies have evaluated the risk factors for non-allergic rhinoconjunctivitis in children finding family history of atopic diseases and gender to be of importance. The aim of this study was to investigate possible risk factors in early life for rhinoconjunctivitis, allergic as well as non-allergic, in adolescence. METHODS: The children in the Danish Allergy Research Center cohort were examined eight times from birth to 14 years of age. Visits included questionnaire-based interview, clinical examination, skin prick test and specific IgE. We used univariate and multivariate logistic regression to investigate the relationship between early-life risk factors and the development of rhinoconjunctivitis, allergic as well as non-allergic, in adolescence. RESULTS: Follow-up rate at 14-years was 66.2%. The prevalence of rhinoconjunctivitis was 32.8%. Family history of atopic diseases (aOR 2.25), atopic dermatitis (aOR 3.24), food allergy (aOR 3.89), early sensitization to inhalant and food allergens (aOR 2.92 and aOR 3.13) and male gender (aOR 1.90) were associated with allergic rhinoconjunctivitis but not with non-allergic rhinoconjunctivitis. Early environmental tobacco exposure was inversely associated with rhinoconjunctivitis (aOR 0.42), allergic (aOR 0.47) as well as non-allergic (aOR 0.43). CONCLUSION: Different patterns of associations were revealed when stratifying rhinoconjunctivitis in allergic and non-allergic suggesting that allergic rhinoconjunctivitis and non-allergic-rhinoconjunctivitis are different phenotypes.

The prevalence of atopic diseases and the patterns of sensitization in adolescence.

BACKGROUND: Atopic diseases are among the most common chronic diseases in adolescents, and it is uncertain whether the prevalence of atopic diseases has reached a plateau or is still increasing. The use of the ISAAC (International Study of Asthma and Allergy in Childhood) questionnaire has provided comparable prevalence rates from many countries, whereas studies including clinical examinations and strict diagnostic criteria are scarce. We aimed to investigate the prevalence of atopic diseases, the pattern of sensitization, and comorbidities at 14 years in a prospective birth cohort. METHODS: The children were examined eight times from birth to 14 years. Visits included questionnaire-based interviews, clinical examination, skin prick test, and specific IgE. RESULTS: Follow-up rate at 14 years was 66.2%. The 12-month prevalence of any atopic disease was high (40.3%) mostly due to a high prevalence of rhinoconjunctivitis (32.8%), whereas the prevalence of asthma was 12.9% and of atopic dermatitis 8.1%. In children with at least one atopic disease, 60% were sensitized, while only 16% of those without atopic diseases were sensitized. The frequency of sensitization depended on the phenotype. Among children with rhinoconjunctivitis only, rhinoconjunctivitis with concomitant asthma or atopic dermatitis or both 62.5%, 81.5%, 70%, and 100%, respectively, were sensitized, whereas it was 7.7% and 33.3% of children with only asthma or atopic dermatitis. CONCLUSION: The prevalence of rhinoconjunctivitis was high in adolescence. Children with rhinoconjunctivitis with and without comorbidities were frequently sensitized. Children with asthma without concomitant allergic rhinoconjunctivitis were rarely sensitized.

Risk of solid cancer, cardiovascular disease, anaphylaxis, osteoporosis and fractures in patients with systemic mastocytosis: A nationwide population-based study.

In patients with systemic mastocytosis (SM), several aspects of morbidity remain poorly understood. We assessed the risk of solid cancers, cardiovascular disease, anaphylaxis, osteoporosis, and fractures in SM patients. Using Danish medical registries, we conducted a nationwide population-based cohort study including 687 adult (≥15 years) SM patients diagnosed during 1997-2012. A comparison cohort of 68,700 subjects from the general Danish population who were alive and without SM at the given SM subject's diagnosis were age- and gender-matched. Outcomes were a new diagnosis of solid cancer, venous thromboembolism (VTE), myocardial infarction (MI), stroke, anaphylaxis, osteoporosis, or fracture. For solid cancers the hazard ratio (HR) was 2.4 (95% confidence interval [CI] 1.9-2.8) with a 10-year absolute risk (AR) in the SM-cohort of 12.6% (95% CI 9.4-16.3). Specifically, we found a HR of 7.5 (95% CI 4.4-13.0) for melanoma and a HR of 2.5 (95% CI 1.7-3.5) for non-melanoma skin cancers (NMSCs). For VTE we found a HR of 1.9 (95% CI 1.2-3.0), with a 10-year AR of 3.9% (95% CI 2.3-6.1); for MI a nonsignificant increased HR of 1.4 (95% CI 0.9-2.3), with a 10-year AR of 1.8% (95% CI 0.9-3.2); and for stroke a HR of 1.6 (95% CI 1.1-2.3) with a 10-year AR of 4.6% (95% CI 2.8-6.9). The HR for anaphylaxis was 7.2 (95% CI 5.3-9.9), and the 10-year AR was 3.1% (95% CI 1.9-4.9). For osteoporosis the HR was 3.6 (95% CI 2.7-4.6) with a 10-year AR of 7.2% (95% CI 5.2-9.8). For fractures the HR was 1.2 (95% CI 0.9-1.6) and the 10-year AR was 5.9% (95% CI 3.9-8.4). SM patients are at increased risk of solid cancers - especially melanoma and NMSC-and cardiovascular disease. The risk of anaphylaxis and osteoporosis is clearly increased in SM, though absolute risk was low in this population-based study. The fracture-risk was only slightly increased. Am. J. Hematol. 91:1069-1075, 2016. © 2016 Wiley Periodicals, Inc.