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.

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.

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.

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.

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.

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.

Hypersensitivity reactions to non-betalactam antibiotics in children: an extensive review.

In contrast to hypersensitivity reactions (HSRs) to ß-lactam antibiotics in children, studies about HSR to non-ß-lactam antibiotics (NBLAs) such as sulfonamides, macrolides, quinolones, and antituberculosis agents are scarce, and information is generally limited to case reports. The aim of this extensive review was to summarize our present knowledge on clinical characteristics, evaluation, and management of HSR to NBLAs in children based on the literature published between 1980 and 2013. NBLAs have been reported to induce a wide spectrum of HSRs from mild eruptions to severe, and sometimes fatal, systemic drug reactions, especially in some high-risk groups. The diagnosis relied upon history and remained unconfirmed by allergological tests in most of the cases. Obtaining a detailed history is valuable in the diagnosis of suspected reactions to NBLAs. Diagnostic in vivo and in vitro tests for NBLAs lack validation, which makes the diagnosis challenging. The definitive diagnosis of NBLA hypersensitivity frequently depends upon drug provocation tests. Studies including children showed that only 7.8 to 36% of suspected immediate and delayed HSRs to NBLAs could be confirmed by skin and/or provocation tests. Therefore, a standardized diagnostic approach and management strategy should be developed and employed for pediatric patients in the evaluation of suspected HSRs to NBLAs, some of which may be critical and unreplaceable in certain clinical situations.

Managing a child with possible allergy to vaccine.

Similarly to other medications, vaccines may be responsible for allergic reactions. Although IgE-mediated allergies to vaccine are extremely rare, they are clearly overdiagnosed. Indeed, accurate diagnosis of vaccine allergy is important not only to prevent serious or even life-threatening reactions, but also to avoid unnecessary vaccine restriction. Systematic approaches have been proposed and, if implemented, will likely reduce the number of children being inappropriately labeled as allergic to vaccine. In diagnosis of vaccine allergy, the patient's history is central although not sufficient. In case of suspicion of an allergy, the child should be referred to an allergist in order to perform a complete allergy workup, based primarily on skin tests and/or specific IgE. Highlighting the most recent literature, this article will address the management of children with a possible allergy to vaccine.

Inhibition of capsaicin-driven nasal hyper-reactivity by SB-705498, a TRPV1 antagonist.

AIMS: To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of intranasal SB-705498, a selective TRPV1 antagonist. METHODS: Two randomized, double-blind, placebo-controlled, clinical studies were performed: (i) an intranasal SB-705498 first time in human study to examine the safety and PK of five single escalating doses from 0.5 to 12 mg and of repeat dosing with 6 mg and 12 mg twice daily for 14 days and (ii) a PD efficacy study in subjects with non-allergic rhinitis (NAR) to evaluate the effect of 12 mg intranasal SB-705498 against nasal capsaicin challenge. RESULTS: Single and repeat dosing with intranasal SB-705498 was safe and well tolerated. The overall frequency of adverse events was similar for SB-705498 and placebo and no dose-dependent increase was observed. Administration of SB-705498 resulted in less than dose proportional AUC(0,12 h) and Cmax , while repeat dosing from day 1 to day 14 led to its accumulation. SB-705498 receptor occupancy in nasal tissue was estimated to be high (>80%). Administration of 12 mg SB-705498 to patients with NAR induced a marked reduction in total symptom scores triggered by nasal capsaicin challenge. Inhibition of rhinorrhoea, nasal congestion and burning sensation was associated with 2- to 4-fold shift in capsaicin potency. CONCLUSIONS: Intranasal SB-705498 has an appropriate safety and PK profile for development in humans and achieves clinically relevant attenuation of capsaicin-provoked rhinitis symptoms in patients with NAR. The potential impact intranasal SB-705498 may have in rhinitis treatment deserves further evaluation.

[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.

Current management of allergic rhinitis in children.

Over the last 20 years, there has been significant progress in our understanding of the pathophysiology of allergic rhinitis, including the discovery of new inflammatory mediators, the link between asthma and allergic rhinitis ('one airway-one disease' concept) and the introduction of novel therapeutic modalities. These new insights have been documented in the Allergic Rhinitis and its Impact on Asthma guidelines and have led to the creation of evidence-based management algorithms. We now understand the importance of a common strategy for treating allergic inflammation of the upper and lower airway as a way of improving outcome, reducing hospital admissions, providing better quality of life and perhaps, altering the natural course of the 'allergic march'. A therapeutic ladder is suggested: Whereas for mild intermittent allergic rhinitis, allergen avoidance should be the first line of treatment with subsequent addition of a second generation topical or oral antihistamine, nasal saline or cromoglycate, in cases of moderate to severe allergic rhinitis, a nasal steroid is the treatment of choice. If a patient with moderate/severe persistent allergic rhinitis fails to improve after 4 wk of adequate treatment, patient compliance or the diagnosis must be re-assessed. In such cases, when the diagnosis is in doubt, a careful clinical examination including nasal endoscopy is mandatory to assess for other potential causes of nasal obstruction. In children who suffer from concomitant allergic rhinitis and asthma, a management algorithm that addresses concurrently asthma and allergic rhinitis is vital, both from a theoretical and from a practical point of view: Parents overwhelmingly prefer a single strategy for the treatment of their child's upper and lower airway symptoms; however, the overall quality of life in children with severe asthma can be significantly improved if rhinitis is adequately addressed.