[The correct and incorrect registration of drug allergies]. / Juiste en onjuiste registratie van medicatie-allergieën.

Drug reactions are common and have a major impact on prescribing behaviour in the Netherlands. An adequate allergy registration is essential both to avoid re-exposition and to prevent unnecessary avoidance. An incomplete or incorrect registration of allergies is a threat to good medical practice, unnecessarily leading to sub-optimal treatment. National registries such as the Dutch 'LandelijkSchakelpunt' (LSP), must be easily accessible to all care providers and kept up-to-date. Healthcare providers should be properly trained in recognizing allergies as well as correct allergy registration. Additionally, healthcare providers must be given the opportunity to register as well as delete allergies from registry systems.

Allergy-Test-Based Elimination Diets for the Treatment of Eosinophilic Esophagitis: A Systematic Review of Their Efficacy.

Eosinophilic esophagitis (EoE) is an immune-mediated esophageal disorder, linked with sensitization to food and airborne allergens. Dietary manipulations are proposed for the management of EoE inflammation and are often successful, confirming the etiological role of food allergens. Three different dietary approaches are widely used: the elemental, the empirical, and the allergy-test-driven approach. We performed a systematic review to assess the evidence on the association of allergens, detected by allergy tests, with clinically confirmed triggers of EoE. We systematically searched PubMed, Scopus, Embase, and the Cochrane Library, through 1 June 2021. We sought studies examining the correlation of skin-prick tests (SPT), atopy patch tests (APT), specific IgE, and serum-specific IgG4, with confirmed triggers of EoE. Data on the use of prick-prick tests were also extracted. Evidence was independently screened by two authors against predefined eligibility criteria. Risk of bias was assessed with the ROBINS-I tool. Of 52 potentially eligible studies, 16 studies fulfilling quality criteria were included. These studies used one to three different allergy tests detecting food sensitization. The positive predictive value was generally low to moderate but higher when a combination of tests was used than single-test evaluations. None of the selected studies used serum-specific IgG4. Although an extreme methodological variability was noticed in the studies, allergy-based elimination diets were estimated to be efficient in 66.7% of the cases. The efficacy of targeted elimination diets, guided by SPT, sIgE, and/or APT allergy tests, does not appear superior to empirical ones. In the future, tests using esophageal prick testing or ex vivo food antigen stimulation may prove more efficient to guide elimination diets.

Perioperative approach of allergic patients.

Perioperative allergic reactions are rare, yet important complications of anesthesia. Severe, generalized allergic reactions called anaphylaxis are estimated to have a mortality of 3.5-4.8%. Adequate recognition and handling of a severe perioperative anaphylactic reaction result in better outcomes, including less hypoxic-ischemic encephalopathy and death. The diagnosis of a perioperative allergic reaction can be difficult as the list of possible culprits of a perioperative allergic reaction is extensive. Making an informed guess on the causative agent and avoiding this agent in future anesthesia procedures is undesirable and unsafe. Therefore, to ensure future patient safety, a thorough investigation following a perioperative allergic reaction is mandatory. A collaborate approach by allergists and anesthesiologists is advised. In this article, we discuss the basic approach of the allergic patient and of patients with a suspected allergy to perioperatively administered medication.

Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment.

Angioedema in the mouth or upper airways is a feared adverse reaction to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, which is used for hypertension, heart failure and diabetes complications. This candidate gene and genome-wide association study aimed to identify genetic variants predisposing to angioedema induced by these drugs. The discovery cohort consisted of 173 cases and 4890 controls recruited in Sweden. In the candidate gene analysis, ETV6, BDKRB2, MME, and PRKCQ were nominally associated with angioedema (p < 0.05), but did not pass Bonferroni correction for multiple testing (p < 2.89 × 10-5). In the genome-wide analysis, intronic variants in the calcium-activated potassium channel subunit alpha-1 (KCNMA1) gene on chromosome 10 were significantly associated with angioedema (p < 5 × 10-8). Whilst the top KCNMA1 hit was not significant in the replication cohort (413 cases and 599 ACEi-exposed controls from the US and Northern Europe), a meta-analysis of the replication and discovery cohorts (in total 586 cases and 1944 ACEi-exposed controls) revealed that each variant allele increased the odds of experiencing angioedema 1.62 times (95% confidence interval 1.05-2.50, p = 0.030). Associated KCNMA1 variants are not known to be functional, but are in linkage disequilibrium with variants in transcription factor binding sites active in relevant tissues. In summary, our data suggest that common variation in KCNMA1 is associated with risk of angioedema induced by ACEi or ARB treatment. Future whole exome or genome sequencing studies will show whether rare variants in KCNMA1 or other genes contribute to the risk of ACEi- and ARB-induced angioedema.

Genetic variants associated with T cell-mediated cutaneous adverse drug reactions: A PRISMA-compliant systematic review-An EAACI position paper.

Drug hypersensitivity reactions (DHRs) are associated with high global morbidity and mortality. Cutaneous T cell-mediated reactions classically occur more than 6 hours after drug administration and include life-threatening conditions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and hypersensitivity syndrome. Over the last 20 years, significant advances have been made in our understanding of the pathogenesis of DHRs with the identification of human leukocyte antigens as predisposing factors. This has led to the development of pharmacogenetic screening tests, such as HLA-B*57:01 in abacavir therapy, which has successfully reduced the incidence of abacavir hypersensitivity reactions. We have completed a PRISMA-compliant systematic review to identify genetic associations that have been reported in DHRs. In total, 105 studies (5554 cases and 123 548 controls) have been included in the review reporting genetic associations with carbamazepine (n = 31), other aromatic antiepileptic drugs (n = 24), abacavir (n = 11), nevirapine (n = 14), trimethoprim-sulfamethoxazole (n = 11), dapsone (n = 4), allopurinol (n = 10), and other drugs (n = 5). The most commonly reported genetic variants associated with DHRs are located in human leukocyte antigen genes and genes involved in drug metabolism pathways. Increasing our understanding of genetic variants that contribute to DHRs will allow us to improve diagnosis, develop new treatments, and predict and prevent DHRs in the future.

An EAACI position paper on the investigation of perioperative immediate hypersensitivity reactions.

Perioperative immediate hypersensitivity reactions are rare. Subsequent allergy investigation is complicated by multiple simultaneous drug exposures, the use of drugs with potent effects and the many differential diagnoses to hypersensitivity in the perioperative setting. The approach to the investigation of these complex reactions is not standardized, and it is becoming increasingly apparent that collaboration between experts in the field of allergy/immunology/dermatology and anaesthesiology is needed to provide the best possible care for these patients. The EAACI task force behind this position paper has therefore combined the expertise of allergists, immunologists and anaesthesiologists. The aims of this position paper were to provide recommendations for the investigation of immediate-type perioperative hypersensitivity reactions and to provide practical information that can assist clinicians in planning and carrying out investigations.

Diagnosis and management of drug-induced anaphylaxis in children: An EAACI position paper.

Drug hypersensitivity reactions (DHR) constitute a major and common public health problem, particularly in children. One of the most severe manifestations of DHR is anaphylaxis, which might be associated with a life-threatening risk. During those past decades, anaphylaxis has received particularly a lot of attention and international consensus guidelines have been recently published. Whilst drug-induced anaphylaxis is more commonly reported in adulthood, less is known about the role of drugs in pediatric anaphylaxis. Betalactam antibiotics and non-steroidal anti-inflammatory drugs are the most commonly involved drugs, probably related to high prescription rates. Diagnosis relies on the recognition of symptoms pattern and is based on complete allergic workup, particularly including skin tests and/or specific IgE. However, the real diagnostic value of those tests to diagnose immediate reactions in children remains not well defined for a significant number of the drugs. Generally, a drug provocation test is discussed to confirm or exclude an immediate-onset drug-induced hypersensitivity. Although avoidance of the incriminated drug (and related drug) is the rule, rapid desensitization is useful in selected subgroups of patients. There is a need for large, multicentric studies, to evaluate the real diagnostic value of the currently available skin tests. Moreover there is also a need to develop new diagnostic tests in the future to improve the management of these children.

Controversies in Drug Allergy: Drug Allergy Pathways.

Drug allergy pathways are standardized approaches for patients reporting prior drug allergies with the aim of quality improvement and promotion of antibiotic stewardship. At the International Drug Allergy Symposium during the 2018 American Academy of Allergy, Asthma, and Immunology/World Allergy Organization Joint Congress in Orlando, Florida, drug allergy pathways were discussed from international perspectives with a focus on beta-lactam allergy pathways and pragmatic approaches for acute care hospitals. In this expert consensus document, we review current pathways, and detail important considerations in devising, implementing, and evaluating beta-lactam allergy pathways for hospitalized patients. We describe the key patient and institutional factors that must be considered in risk stratification, the central feature of pathway design. We detail shared obstacles to widespread beta-lactam allergy pathway implementation and identify potential solutions to address these challenges.

Endotyping of non-allergic, allergic and mixed rhinitis patients using a broad panel of biomarkers in nasal secretions.

BACKGROUND: Endotyping chronic rhinitis has proven hardest for the subgroup of non-allergic rhinitis (NAR) patients. While IgE-related inflammation is typical for allergic rhinitis (AR), no markers have been found that can be seen to positively identify NAR. A further complication is that AR and NAR might co-exist in patients with mixed rhinitis. As previous studies have considered only a limited number of inflammatory mediators, we wanted to explore whether a wider panel of mediators could help us refine the endotyping in chronic rhinitis patients. OBJECTIVE: To endotype chronic rhinitis, and non-allergic rhinitis in particular, with help of molecular or cellular markers. METHOD: In this study we included 23 NAR patients without allergen sensitizations and with persistent rhinitis symptoms, 22 pollen sensitized rhinitis patients with seasonal symptoms, 21 mixed rhinitis patients with pollen-related symptoms and persistent symptoms outside of the pollen season, and 23 healthy controls without any symptoms. Nasal secretions were collected outside of pollen season and differences between the endotypes were assessed for a broad range of inflammatory mediators and growths factors using a multiplex ELISA. RESULTS: Although we were able to identify two new nasal secretion makers (IL-12 and HGF) that were low in mixed and AR patients versus NAR and healthy controls, the most intriguing outcome is that despite investigating 29 general inflammatory mediators and growth factors no clear profile of non-allergic or mixed rhinitis could be found. CONCLUSION: Classical inflammatory markers are not able to differentiate between non-allergic or mixed rhinitis patients and healthy controls.

EAACI/ENDA Position Paper: Diagnosis and management of hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs) in children and adolescents.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in the pediatric population as antipyretics/analgesics and anti-inflammatory medications. Hypersensitivity (HS) reactions to NSAID in this age group, while similar to adults, have unique diagnostic and management issues. Although slowly accumulating, published data in this age group are still relatively rare and lacking a unifying consensus. This work is a summary of current knowledge and consensus recommendations utilizing both published data and expert opinion from the European Network of Drug Allergy (ENDA) and the Drug Hypersensitivity interest group in the European Academy of Allergy and Clinical Immunology (EAACI). This position paper summarizes diagnostic and management guidelines for children and adolescents with NSAIDs hypersensitivity.

Abnormal Responses to Local Esophageal Food Allergen Injections in Adult Patients With Eosinophilic Esophagitis.

Skin tests and measurement of serum levels of immunoglobulin E do not accurately identify foods for elimination from the diets of patients with eosinophilic esophagitis (EoE). We investigated whether an esophageal prick test, in which the esophageal mucosa is challenged by local injection of allergen extracts, could identify individuals with esophageal sensitization. During endoscopy, 6 allergens were injected in the esophagus of 8 patients with EoE and 3 patients without EoE (controls). A second endoscopy was performed after 24 hours to evaluate delayed responses. Five of the 8 patients with EoE had evidence for an acute response (luminal obstruction and mucosal blanching); 2 other patients had a delayed wheal or flare reaction. No responses were observed in controls. We conclude that esophageal mucosal food allergen injections induce acute and/or delayed responses in patients with EoE but not controls. The esophageal prick test deserves further exploration because it may guide elimination diets.

Vaccination and allergy: EAACI position paper, practical aspects.

Immunization is highly effective in preventing infectious diseases and therefore an indispensable public health measure. Allergic patients deserve access to the same publicly recommended immunizations as non-allergic patients unless risks associated with vaccination outweigh the gains. Whereas the number of reported possible allergic reactions to vaccines is high, confirmed vaccine-triggered allergic reactions are rare. Anaphylaxis following vaccination is rare, affecting <1/100 000, but can occur in any patient. Some patient groups, notably those with a previous allergic reaction to a vaccine or its components, are at heightened risk of allergic reaction and require special precautions. Allergic reactions, however, may occur in patients without known risk factors and cannot be predicted by currently available tools. Unwarranted fear and uncertainty can result in incomplete vaccination coverage for children and adults with or without allergy. In addition to concerns about an allergic reaction to the vaccine itself, there is fear that routine childhood immunization may promote the development of allergic sensitization and disease. Thus, although there is no evidence that routine childhood immunization increases the risk of allergy development, such risks need to be discussed.

Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.

INTRODUCTION: Eosinophilic esophagitis (EoE) is one of the most prevalent esophageal diseases and the leading cause of dysphagia and food impaction in children and young adults. This underlines the importance of optimizing diagnosys and treatment of the condition, especially after the increasing amount of knowledge on EoE recently published. Therefore, the UEG, EAACI ESPGHAN, and EUREOS deemed it necessary to update the current guidelines regarding conceptual and epidemiological aspects, diagnosis, and treatment of EoE. METHODS: General methodology according to the Appraisal of Guidelines for Research and Evaluation (AGREE) II and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used in order to comply with current standards of evidence assessment in formulation of recommendations. An extensive literature search was conducted up to August 2015 and periodically updated. The working group consisted of gastroenterologists, allergists, pediatricians, otolaryngologists, pathologists, and epidemiologists. Systematic evidence-based reviews were performed based upon relevant clinical questions with respect to patient-important outcomes. RESULTS: The guidelines include updated concept of EoE, evaluated information on disease epidemiology, risk factors, associated conditions, and natural history of EoE in children and adults. Diagnostic conditions and criteria, the yield of diagnostic and disease monitoring procedures, and evidence-based statements and recommendation on the utility of the several treatment options for patients EoE are provided. Recommendations on how to choose and implement treatment and long-term management are provided based on expert opinion and best clinical practice. CONCLUSION: Evidence-based recommendations for EoE diagnosis, treatment modalities, and patients' follow up are proposed in the guideline.

Association between atopic manifestations and eosinophilic esophagitis: A systematic review and meta-analysis.

BACKGROUND: Eosinophilic esophagitis (EoE) has repeatedly been associated with atopic manifestations, which are reported more frequently in these patients than in the general population. OBJECTIVE: To systematically assess the evidence and strength of the associations between EoE and atopy. METHODS: We performed a systematic search of the MEDLINE, EMBASE, and SCOPUS databases for case-control studies comparing the frequency of atopic diatheses among patients with EoE and control subjects representing the general population without EoE. Using random-effects meta-analyses, we calculated summary estimates, including 95% confidence intervals (CIs), for bronchial asthma, atopic rhinitis, and eczema. Publication bias risks were assessed by means of funnel plot analysis and specific statistical tests. RESULTS: Of the 2,954 references identified, data were collected from 21 studies, including a total of 53,542 patients with EoE and 54,759 controls. The criteria for defining a diagnosis of atopy in patients with EoE or controls was not structurally considered in most of the studies. Overall, allergic rhinitis was significantly more common among patients with EoE compared with control subjects (odds ratio [OR], 5.09; 95% CI, 2.91-8.90; I2 = 86.7%) as were bronchial asthma (OR, 3.01; 95% CI, 1.96-4.62; I2 = 84.5%) and eczema (OR, 2.85; 95% CI, 1.87-4.34; I2 = 57.1%). Food allergies and other atopic conditions were also assessed. No significant publication bias was found for studies dealing with allergic rhinitis and eczema in EoE. CONCLUSION: Despite pointing to a significant association between atopy and EoE, most of the studies provided no normalized diagnostic criteria for atopy. Further research should provide clear and standardized definitions of such conditions. TRIAL REGISTRATION: www.crd.york.ac.uk/PROSPERO Trial Identifier: CRD42016036161.