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Purpose of Review: To understand the current global scale of drug hypersensitivity (DH) and drug allergy (DA), and to identify possible strategies to increase the accuracy of epidemiological data., Recent Findings: Global patterns of DH/DA seem to be changing and increasing worldwide, but there are still great challenges in capturing quality DH/DA mortality and morbidity statistics (MMS). DH/DA MMS may gain new perspectives with the global implementation of the International Classification of Diseases (ICD)-11. Improving the quality of epidemiological data related to DH/DA should clarify areas of uncertainty, which would lead to better strategies to reduce the burden of these conditions., Summary: DH/DA remains a complex and unaddressed problem globally that often deprives patients of optimal medication choices and places them at risk for life-threatening reactions. DH/DA labels should contribute to people well being, by protecting true allergic individuals from being re-exposed to their allergic drugs and providing needed medications to individuals wrongly labeled as allergic or who have lost allergic sensitivity. The true rate of DH/DA is in fact unknown due to a number of factors, such as misdiagnosis, miscoding and under- and over-notification, among others. Moreover, there is lack of data about DH/DA epidemiology in many countries. Difficulties on collecting accurate and comparable data should be acknowledged, with great impact in the correct labeling DH/DA in electronic health records and official statistics. More accurate definitions, classification and coding may contribute to a better-quality MMS thanks to the ICD-11, under implementation worldwide. Improving the quality of epidemiological data related to DH/DA should clarify areas of uncertainty, which would lead to better strategies to reduce the burden of these conditions. As knowledge derived from populations is key information for more realistic decision-making, the construction of the new section addressed to DH/DA in the ICD-11 will allow the collection of more accurate epidemiological data to support quality management of patients, and facilitate healthcare planning to implement public health measures to prevent and reduce the morbidity and mortality attributable to these conditions., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Perioperative anaphylaxis is rare but is associated with significant morbidity. This complication has been well described in France by the GERAP (Groupe d'Etude des Réactions Anaphylactiques Périopératoires), a network focused on its study. The epidemiology of perioperative anaphylaxis is evolving, influenced by environmental factors and clinical practice. The aim of this study was to update the epidemiology of perioperative anaphylaxis in France., Methods: This multicentre retrospective study was performed in 26 allergy clinics of the GERAP network in 2017-8., Results: There were 765 patients with perioperative anaphylaxis included. Most cases were severe, with 428 (56%) reactions graded as 3 or 4 according to the Ring and Messmer classification. Skin test results were available for 676 patients, with a culprit agent identified in 471 cases (70%). Neuromuscular blocking agents were the main cause of perioperative anaphylaxis (n=281; 60%), followed by antibiotics (n=118; 25%) and patent blue dye (n=11; 2%). Cefazolin was the main antibiotic responsible for perioperative anaphylaxis (52% of antibiotic-related reactions). Suxamethonium and rocuronium were the main neuromuscular blocking agents responsible for perioperative anaphylaxis with 7.1 (6.1-8.4) and 5.6 (4.2-7.4) reactions per 100,000 vials sold, respectively, whereas cefazolin-related cases were estimated at 0.7 (0.5-0.9) reactions per 100,000 vials sold., Conclusions: Our results confirm that most commonly identified triggering agents remain neuromuscular blocking agents. Reactions to antibiotics, particularly cefazolin, are becoming increasingly frequent. The origin of sensitisation to cefazolin is unknown, as no cross-sensitisation has been described, and it should be the subject of further study. Perioperative anaphylaxis should be followed over the years and understood given the changing triggers., Clinical Trial Registration: ClinicalTrials.gov (NCT04654923)., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Two-dimensional (2D) classifications of iodinated contrast media (ICM) are insufficient to explain the observed skin test (ST) reactivity patterns in patients with drug hypersensitivity reactions (DHRs) to ICM., Objective: To refine the current view on allergic DHRs to ICM by analyzing ST reactivity patterns in patients with previous reactions to ICM., Methods: Patients with a history of DHR to ICM and positive STs, who presented at the University Hospital of Montpellier between 2004 and 2022, were included in the study. The relative difference between every two ICM products was measured by Manhattan distance and odds ratios were computed for all pairs of products in the immediate reaction (IR) and non-immediate reaction (NIR) ST groups., Results: A total of 181 patients were included in the study. Odds ratio analysis identified significant associations between classical cross-reactive ICM, such as iohexol-ioversol, iohexol-iomeprol, iomeprol-ioversol, and iohexol-iodixanol in the IR ST group and iohexol-ioversol, iopromide-iohexol, and iomeprol-ioversol in the NIR ST group. We also identified uncommon associations, such as ioxitalamate-amidotrizoate in the IR ST group and amidotrizoate-iopamidol and amidotrizoate-ioxitalamate in the NIR ST group. The results were reflected by the Manhattan distance, which suggested the existence of clusters containing the same classically associated ICM as well as uncommon associations, which we hypothesize to be related to similarities in the 3D structure of the respective ICM., Conclusions: Current chemical (2D) classifications cannot explain all observed ST reactivity patterns. Whether the 3D structure can be integrated into the current classifications to interpret the observed ST reactivity patterns and predict tolerance to alternative ICM requires further research., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: There is currently no standardized duration of drug provocation test (DPT) for confirming/delabeling beta-lactam hypersensitivity reaction (BL-HSR)., Objectives: This meta-analysis and systematic review aimed to investigate the added diagnostic value of extended-day over single-day DPT for confirming/delabeling BL-HSR in adults and children., Methods: The MEDLINE, EMBASE, Web of Science, and CINAHL online databases were searched from inception to March 15, 2023, for studies that performed extended-day DPT to confirm/delabel BL-HSR. Risk difference and risk ratio were used to compare the proportions of patients with confirmed BL-HSR by single-day or extended-day DPT., Results: A total of 10,371 DPTs from 42 studies were included. Extended-day DPTs ranged from 2 to 7 days, or as long as index reactions were reported (maximum 10 days). The overall prevalence of confirmed BL-HSR was 6.96% (3.31% during the first-day DPT, and 3.65% during extended-day DPT). Approximately half of the positive reactions during extended-day DPT occurred during the second/third day. The increased detected pool prevalence of confirmed BL-HSR yielded by extended-day DPT was 0.03 (95% CI, 0.02%-0.04%; I 2  = 57.69%; P < .001), and the risk ratio of positive reactions between extended-day and single-day DPT was 1.94 (95% CI, 1.62-2.33; I 2  = 36.26%; P < .001). The risk difference increased per 1% increase in prevalence of BL-HSR by 0.6% (95% CI, 0.4%-0.7%; P < .001). Twenty-three severe reactions occurred during DPT, and only 2 severe reactions (0.02%) occurred during extended-day DPT. An additional 28 extended-day DPTs were needed to identify 1 mild reaction., Conclusions: The increased prevalence of confirmed BL-HSR observed during extended-day DPT could be attributed to the first-day DPT. As a result, our findings do not conclusively support the use of extended-day DPT over single-day DPT. Further studies, incorporating a washout period, are required to comprehensively compare these 2 approaches., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: The aim of this study was to review the practice of general practitioners (GPs) in regard to the diagnosis and management of drug hypersensitivity reactions (DHRs) to identify major challenges and to facilitate the development of decision support tools to GPs confronted with DHRs patients., Recent Findings: DHRs are still a challenge in the GPs clinical practice, which implies difficulties in clinical decisions and referral to allergy specialists., Summary: DHRs can range from mild to severe and even life-threatening. Drugs are the main cause of anaphylaxis deaths in most countries. Most DHRs are firstly seen by GPs, paediatricians or emergency doctors. However, our systematic review demonstrated difficulties in differentiating DHRs from other drug side effects. Most DHRs epidemiological data are from hospital and emergency departments, which may not reflect the real-life experience in primary care. GPs should be aware of the alert signs of DHRs: the involvement of other systems beyond the skin and/or atypical skin/ mucosal involvement, which mandated immediate referral to an emergency department. Data still stress difficulties in the recognition of DHRs clinical manifestations and highlight the need for decision aids to support their management by GPs. Structured clinical history and clinical examination are key diagnostic tools. Reasons for referring to allergy specialists based on the literature are to investigate cause, to undergo specific procedure, such as desensitization and to identify well tolerated, alternative drugs., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Neuromuscular blocking agents (NMBAs) are among the leading cause of perioperative anaphylaxis, and most of these reactions are IgE mediated. Allergic sensitisation induced by environmental exposure to other quaternary ammonium-containing compounds, such as pholcodine, has been suggested. The aim of this study was to assess the relationship between pholcodine exposure and NMBA-related anaphylaxis., Methods: ALPHO was a multicentre case-control study, comparing pholcodine exposure within a year before anaesthesia between patients with NMBA-related perioperative anaphylaxis (cases) and control patients with uneventful anaesthesia in France. Each case was matched to two controls by age, sex, type of NMBA, geographic area, and season. Pholcodine exposure was assessed by a self-administered questionnaire and pharmaceutical history retrieved from pharmacy records. The diagnostic values of anti-pholcodine and anti-quaternary ammonium specific IgE (sIgE) were also evaluated., Results: Overall, 167 cases were matched with 334 controls. NMBA-related anaphylaxis was significantly associated with pholcodine consumption (odds ratio 4.2; 95% confidence interval 2.3-7.0) and occupational exposure to quaternary ammonium compounds (odds ratio 6.1; 95% confidence interval 2.7-13.6), suggesting that apart from pholcodine, other environmental factors can also lead to sensitisation to NMBAs. Pholcodine and quaternary ammonium sIgEs had a high negative predictive value (99.9%) but a very low positive predictive value (<3%) for identifying NMBA-related reactions., Conclusions: Patients exposed to pholcodine 12 months before NMBA exposure have a significantly higher risk of an NMBA-related anaphylaxis. The low positive predictive values of pholcodine and quaternary ammonium sIgEs precludes their use to identify a population with a high risk of NMBA-related anaphylaxis., Clinical Trial Registration: NCT02250729., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Over the last decade there have been key advances in understanding mechanisms, risk, and consequences of both true immunological drug hypersensitivity and unverified drug allergy labels that have changed clinical practice. This has been facilitated by the widespread adoption of electronic health records (EHRs). The vast majority of EHR drug allergy labels are unverified and cause significant morbidity from unnecessary avoidance of optimal drug therapy. There has also been significant movement in our understanding of mechanisms of drug hypersensitivity that, in addition to advancing our understanding of the pathogenesis of immediate and delayed reactions, have guided preventive efforts, diagnostic procedures, and clinical management. More widespread adoption, including scale-up of "allergy" delabeling and appropriate management, specifically for antibiotics, opiates, radiocontrast, chemotherapeutics, biologics, and nonsteroidal anti-inflammatory medications, will be necessary to improve patient outcomes over the next decade. This will require further engagement and collaboration between primary care health care providers, allergists, and other specialists., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Most patients presenting with allergies are first seen by primary care health professionals. The perceived knowledge gaps and educational needs were recently assessed in response to which the LOGOGRAM Task Force was established with the remit of constructing pragmatic flow diagrams for common allergic conditions in line with an earlier EAACI proposal to develop simplified pathways for the diagnosis and management of allergic diseases in primary care. To address the lack of accessible and pragmatic guidance, we designed flow diagrams for five major clinical allergy conditions: asthma, anaphylaxis, food allergy, drug allergy, and urticaria. Existing established allergy guidelines were collected and iteratively distilled to produce five pragmatic and accessible tools to aid diagnosis and management of these common allergic problems. Ultimately, they should now be validated prospectively in primary care settings., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Purpose of Review: This systematic review evaluates published data related to the economic burden of drug-induced anaphylaxis (DIA) to understand preventive cost saving measures that could reduce the burden of these conditions., Recent Findings: Although DIA has a relevant societal impact, there are limited and heterogenous available data related to its cost. Direct costs related to the management of acute phase of DIA was estimated by $529.6 to $3125, depending on the number of emergency room visits/hospitalizations, emergency kits and transports in ambulance. Direct costs of investigations of DIA varied from $288 to $2292.95 and the desensitization was estimated by $6796. Main variables for this were: personnel, allergy screening procedures, medical consumables and space cost. The mean indirect cost was based on a mean absenteeism of 3 days per DIA corresponding to $381.2., Summary: More than reviewing the published data, we were able to identify variables that, if correctly managed, can reduce the economic burden of DIA, such as adjusting the timing of referral and etiological diagnosis, identification of potential risk and/or co-factors, correct written recommendations to patients. The evidence presented highlights the need of optimization of healthcare patients to patients suffering from DIA., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: To identify patterns and key issues though a systematic review in order to support prevention strategies and reduce avoidable deaths related to drug-induced anaphylaxis (DAF)., Recent Findings: DAF rate has been estimated by 0.13-0.53/106 population/year. General global trends of DAF are increasing over time, mostly occurring at healthcare settings (62%) with a similar gender distribution and an average age of 53 years. Antibiotics, anaesthetics, radio-contrast media and NSAIDs were the most frequently implicated agents. Main comorbidities were personal history of drug allergy, cardiovascular diseases and asthma. Main manifestations were cardiovascular and respiratory commitments. Use of adrenaline is mentioned in only 29% of the articles., Summary: DAF is increasing worldwide and most cases are iatrogenic. This first systematic review of DAF identified key gaps and served as a wake-up call to prevent avoidable deaths. Phenotype at risk for DAF was represented by patients aged more than 54 years, with personal history of drug allergy/hypersensitivity with no or incomplete allergological work-up, cardiovascular disease and/or asthma with need of hospitalization and/or frequent healthcare assistance. Additional risk for those who need frequent use of intravenous antibiotics and/or undergoing surgery or image investigation with radiocontrast media., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Serum total tryptase has been shown to increase during acute allergic reactions (acute tryptase, T A ); however, few studies have investigated the values of T A or a combination of T A and baseline tryptase (T B ) to discriminate positive from negative testing in perioperative hypersensitivity reaction (POH) allergy work-up. The aim of this study was to determine the diagnostic performance of T A in order to differentiate positive from negative allergy testing suspected POH and analyse the diagnostic performance of serial tryptase levels using several formulas., Methods: All patients from the University hospital of Montpellier and Strasbourg, France, who presented with suspected POH and underwent complete drug allergy work-up between March 2011 and December 2019 with available T A and T B were included. Four formulas, including a change in T A  > 11 (F1), or >2 + 1.2 × T B (F2), or >3 + T B (F3), or >120%T B (F4), were applied., Results: One hundred and sixty-two patients were included, and 131 of them (80.8%) had Grade III or IV reactions. Ninety patients had positive allergy testing. The optimal cut-off value of T A to distinguish positive from negative allergy testing patients was 9.8 μg/L with an AUC of 0.817 (95% CI: 0.752-0.882, p < .001). The 93% PPV threshold for T A was 33 μg/L (95.8% specificity). Paired tryptase levels according to formulas F2 and F3 yielded the highest Youden index (0.54 and 0.53, respectively)., Conclusion: The optimal cut-off point for T A for distinguishing positive from negative allergy testing suspected POH was 9.8 μg/L. T A value of 33 μg/L was required to achieve >90% PPV., (© 2021 John Wiley & Sons Ltd.)

Background: β-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (type I) reactions mediated by antigen-specific IgE., Objective: We sought to identify genetic predisposing factors for immediate reactions to β-lactam antibiotics., Methods: Patients with a clinical history of immediate hypersensitivity reactions to either penicillins or cephalosporins, which were immunologically confirmed, were recruited from allergy clinics. A genome-wide association study was conducted on 662 patients (the discovery cohort) with a diagnosis of immediate hypersensitivity and the main finding was replicated in a cohort of 98 Spanish cases, recruited using the same diagnostic criteria as the discovery cohort., Results: Genome-wide association study identified rs71542416 within the Class II HLA region as the top hit (P = 2 × 10 -14 ); this was in linkage disequilibrium with HLA-DRB1∗10:01 (odds ratio, 2.93; P = 5.4 × 10 -7 ) and HLA-DQA1∗01:05 (odds ratio, 2.93, P = 5.4 × 10 -7 ). Haplotype analysis identified that HLA-DRB1∗10:01 was a risk factor even without the HLA-DQA1∗01:05 allele. The association with HLA-DRB1∗10:01 was replicated in another cohort, with the meta-analysis of the discovery and replication cohorts showing that HLA-DRB1∗10:01 increased the risk of immediate hypersensitivity at a genome-wide level (odds ratio, 2.96; P = 4.1 × 10 -9 ). No association with HLA-DRB1∗10:01 was identified in 268 patients with delayed hypersensitivity reactions to β-lactams., Conclusions: HLA-DRB1∗10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cephalosporins, which belong to the beta-lactam therapeutic class, are increasingly used throughout the world. Few large studies on this issue have been conducted, and most of them have been performed as part of penicillin hypersensitivity studies., Objective: We described our 26-year experience exploring cephalosporin drug hypersensitivity, from which we identified epidemiological and cross-reactivity data., Methods: We included 476 patients who reported drug hypersensitivity reaction (DHR) to cephalosporin and underwent an allergy workup between January 1992 and July 2018 in the Allergy Unit of the University Hospital of Montpellier (France). According to their structural side chain R1 homology, we worked with 4 classes of cephalosporins. Logistic regression analysis was used to search for risk factors for hypersensitivity to cephalosporin (positive skin test [ST] or drug provocation test [DPT] results)., Results: Cephalosporin hypersensitivity was proven in 22.3% of the patients referred in our Unit, according to positive ST (51.9%) or DPT to the culprit drug (48.1%). One in 5 patients were children, and cephalosporin hypersensitivity was confirmed in 15% (47.6% of them by means of ST). In the cephalosporin hypersensitive population, initial reactions were mostly immediate (68.9%) and anaphylactic (72.7%). Cross-reactivity with aminopenicillins was the most frequent pattern of cross-reactivity. In multivariate analysis, immediate reactions (odds ratio [OR] = 3, 95% confidence interval [CI] [1.6-5.5], P < .001), anaphylactic shock (OR = 6.5, 95% CI [3.3-13.1], P < .001) and anaphylaxis (OR = 3.1, 95% CI [1.6-6.1], P < .001), and multiple reactions to the same or several cephalosporins (OR = 2.0, 95% CI [1-3.5], P = .04) were statistically associated with confirmed DHR. DPT was generally safe, but elicited anaphylaxis in 20% of patients. Systemic reactions during skin testing occurred in 9.1% of positive patients, almost always related to anaphylactic index reactions. Nonimmediate confirmed DHR to cephalosporins were rare and occurred in less than 10% of the positive patients., Conclusion: Almost a quarter of the tested patients were confirmed as hypersensitive to cephalosporins; sensitivity of skin testing was 51.9%, and thus, half of the positive patients needed a DPT to prove the diagnosis., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Antiepileptic drugs (AEDs) are widely used for the treatment of epilepsy, but they can be associated with the development of mainly delayed/non-immediate hypersensitivity reactions (HRs). Although these reactions are usually cutaneous, self-limited, and spontaneously resolve within days after drug discontinuation, sometime HR reactions to AEDs can be severe and life-threatening., Aim: This paper seeks to show examples on practical management of AED HRs in children starting from a review of what it is already known in literature., Results: Risk factors include age, history of previous AEDs reactions, viral infections, concomitant medications, and genetic factors. The diagnostic workup consists of in vivo (intradermal testing and patch testing) and in vitro tests [serological investigation to exclude the role of viral infection, lymphocyte transformation test (LTT), cytokine detection in ELISpot assays, and granulysin (Grl) in flow cytometry. Treatment is based on a prompt drug discontinuation and mainly on the use of glucocorticoids., Conclusion: Dealing with AED HRs is challenging. The primary goal in the diagnosis and management of HRs to AEDs should be trying to accurately identify the causal trigger and simultaneously identify a safe and effective alternative anticonvulsant. There is therefore an ongoing need to improve our knowledge of HS reactions due to AED medications and in particular to improve our diagnostic capabilities., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

This paper presents the design and the users' perceptions of a Digital Allergy Card for recording, sharing and tracing information on drug allergies.

Introduction: Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) is of great concern because they are frequently encountered in daily clinical practice. Drug provocation tests (DPTs) are particularly needed for NSAIDs., Methods: The aim of this retrospective study was to detect eliciting dose thresholds during NSAIDs DPT in order to suggest optimal step doses, using the survival analysis method. Our secondary objective was to describe subgroups at higher risk during DPT and evaluate the safety of our 30 minutes incremental 1-day protocol. The study comprised all the patients attended the Allergy of the University Hospital of Montpellier (France), between 1997 and 2017 for a suspicion of drug hypersensitivity reaction to NSAIDs., Results: Throughout the study period, 311 positive DPT were analyzed (accounting for 285 hypersensitive patients). We identified eliciting thresholds (dose and time), and we suggest the following steps for future DPT: for the rapid absorption group (acetylsalicylic acid, ibuprofen, ketoprofen, and tiaprofenic acid), every 30 minutes: 20%-30%-50% of daily therapeutic dose, for the moderate absorption group, every 30 minutes: for diclofenac 5%-15%-30%-50%, and for celecoxib, 20%-80%. For the slow absorption group, piroxicam, 25%-75%, was separated by a 3-hours interval. A surveillance period of 3 hours after the last dose is mandatory for patients., Conclusion: Drug provocation test protocols for NSAID are empirical, driven by the knowledge on patterns of DHR, cross-reactivity between NSAID and pharmacological effects of these all drugs. This is the second experience in improving DPT protocols, after BL (B-lactam) antibiotics., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

A recent survey of the European Academy of Allergy and Clinical Immunology (EAACI) Drug Allergy Interest Group (DAIG) on how European allergy specialists deal with beta-lactam (BL) hypersensitivity demonstrated a significant heterogeneity in current practice, suggesting the need to review and update existing EAACI guidelines in order to make the diagnostic procedures as safe and accurate, but also as cost-effective, as possible. For this purpose, a bibliographic search on large studies regarding BL hypersensitivity diagnosis was performed by an EAACI task force, which reviewed and evaluated the literature data using the GRADE system for quality of evidence and strength of recommendation. The updated guidelines provide a risk stratification in BL hypersensitivity according to index reaction(s), as well as an algorithmic approach, based on cross-reactivity studies, in patients with a suspicion of BL hypersensitivity and an immediate need for antibiotic therapy, when referral to an allergist is not feasible. Furthermore, the update addresses availability and concentrations of skin test (ST) reagents, ST and drug provocation test (DPT) protocols, and diagnostic algorithms and administration of alternative BL in allergic subjects. Specifically, distinct diagnostic algorithms are suggested depending on risk stratification of the patient into high and low risk based on the morphology and chronology of the reaction, immediate (ie, occurring within 1-6 hours after the last administered dose) or nonimmediate (ie, occurring more than 1 hour after the initial drug administration), and the reaction severity. Regarding the allergy workup, the main novelty of this document is the fact that in some low-risk nonimmediate reactions ST are not mandatory, especially in children. For DPT, further studies are necessary to provide data supporting the standardization of protocols, especially of those regarding nonimmediate reactions, for which there is currently no consensus., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

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., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Multiple drug hypersensitivity syndrome (MDHS) is defined as confirmed drug hypersensitivity (DH) to at least 2 chemically and pharmacologically unrelated drugs. Reports of MDHS are scarce and poorly specified, and studies that diagnose MDHS on the basis of positive allergy test results are lacking., Objective: To evaluate retrospectively the frequency and characteristics of patients with MDHS in a large database., Methods: We included all patients who consulted and were tested in our Allergy Unit between September 1996 and February 2018 for a suspicion of DH. Clinical history and allergy workup results compiled in our Drug Allergy and Hypersensitivity Database were reviewed, and data of patients with a diagnosis of MDHS were retrieved and analyzed., Results: During this period a total of 9250 patients were explored and 1819 tested positive for at least 1 drug. Forty-five cases, 30 female and 15 male patients cumulating 92 DHs, were confirmed as having MDHS. An immunologic mechanism, as demonstrated by positive skin testing, accounted for 59 DHs. Drug provocation tests were performed to confirm the diagnosis for the remaining 33 DHs. Of the 92 DHs in this series, 38 were classified as type IV and 21 as type I allergies; 33 remained of undetermined mechanism. Drug class occurrences seem to differ from those in monoallergic patients., Conclusions: Our data support the concept of MDHS as a distinct and rare subgroup of DH. The prevalence in our database was 2.5% in the total DH alleged patient population and 0.5% of the demonstrated DHs. Skin testing and drug provocation tests are mandatory for confirming the diagnosis., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: There is no perfect agreement on how to perform an allergy workup in suspected beta-lactam (BL)-allergic children, since skin test (ST)-induced pain is often a limitation. The aim of the study was to assess the possibility of reducing the number of ST in children when performing a complete allergy workup for BL hypersensitivity reactions., Methods: A retrospective analysis of all patients referring to the Allergy Unit of the University Hospital of Montpellier (France) with positive responses in immediateand non-immediate-reading ST to a BL over a 16-year period was performed, to determine the positive predictive value (PPV) of ST. All pediatric patients with a suspected BL hypersensitivity were skin-tested with the suspected drug only, during the following 54 months., Results: A total of 319 patients reporting 328 BL reactions were included in the retrospective study. The PPV of ST for the reported drug was of 99.4%. Based on the results, the number of patients to include in the prospective study was estimated to be 101. In the prospective study, 229 children were included. We diagnosed a BL hypersensitivity in 12 children (5.2%): Diagnosis was reached in 6 (50.0%) through ST (delayed reading for all) and in 6 through drug provocation test (DPT)., Conclusion: ST with BL should therefore be performed as a screening test, before DPT, and testing only the suspected drug may be sufficient when dealing with children., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

An accurate diagnosis of β-lactam (BL) allergy can reduce patient morbidity and mortality. Our aim was to investigate the availability of BL reagents, their use and test procedures in different parts of Europe, as well as any differences in the diagnostic workups for evaluating subjects with BL hypersensitivity. A survey was emailed to all members of the EAACI Drug Allergy Interest Group (DAIG) between February and April 2016, and the questionnaire was meant to study the management of suspected BL hypersensitivity. The questionnaire was emailed to 82 DAIG centres and answered by 57. Amoxicillin alone or combined to clavulanic acid were the most commonly involved BL except in the Danish centre, where penicillin V was the most frequently suspected BL. All centres performed an allergy workup in subjects with histories of hypersensitivity to BL: 53 centres (93%) followed DAIG guidelines, two national guidelines and two local guidelines. However, there were deviations from DAIG recommendations concerning allergy tests, especially drug provocation tests. A significant heterogeneity exists in current practice not only among countries, but also among centres within the same country. This suggests the need to re-evaluate, update and standardize protocols on the management of patients with suspected BL allergy., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Introduction and Objectives: Drug hypersensitivity reactions (DHRs) are the adverse effects of drugs that, when taken at doses generally tolerated by normal subjects, clinically resemble allergy. We aimed to assess the prevalence of self-reported DHRs among Lithuanian children and adults and to identify possible risk factors., Materials and Methods: A cross-sectional survey of a population visiting their general practitioners in Vilnius and Kaunas regions of Lithuania was performed. Thirty-five questions on drug allergy symptoms, in addition, food, pollen allergy and family history were included., Results: 3222 (60.0%) children and 2148 (40.0%) adults were included in the study. 7.9% of children and 13.8% of adults reported a DHR for at least one drug (p<0.001). 69.8% of children and 47.3% of adults, who indicated DHRs, had skin symptoms. Rate of anaphylaxis was similar in both groups (about 10%). 4.5% of children and 7.3% of adults had DHRs induced by antibiotics and this was the most implicated group of drugs. Significant self-reported risk factors for DHRs were family history of DHRs (OR=6.007, 95%CI 4.756-7.587), pollen allergy (OR=2.0, 95%CI 1.573-2.544), food allergy (OR=1.92, 95%CI 1.505-2.448), female gender (OR=1.439, 95%CI 1.187-1.744) and age (OR=1.017 in favour of adults, 95%CI 1.013-1.021)., Conclusions: The prevalence of self-reported DHRs in Lithuania is higher among adults than children. Drug-induced skin reactions were the predominant symptom in both groups. Besides female gender and age, a positive family history of DHR and presence of pollen or food allergy may be associated with DHR., (Copyright © 2018 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.)

Background: The management of iodinated contrast medium (ICM) hypersensitivity has been a matter of debate. Skin testing to identify a subgroup of ICM allergic patients has been proposed, in addition to complete avoidance, provocation testing, or premedication., Objective: The objective of this study was to assess the negative predictive value (NPV) of skin testing for ICM., Methods: Patients with a hypersensitivity reaction to ICM who underwent skin testing during a 13.5-year period at a single center were evaluated for re-exposure to a negatively skin-tested ICM. Premedication, consisting of second-generation H1-antihistamines twice a day 48 hours before the examination, was advised only for patients with mast cell disorder or chronic urticaria who had negative skin tests., Results: A total of 597 patients tested for 423 (70.9%) immediate, 118 (19.7%) nonimmediate, and 56 (9.4%) hypersensitivity reactions with undetermined chronology were included. Eighty (13.4%) patients were skin test positive. Re-exposure to ICM occurred in 233 (39.0%) patients and was tolerated in 16 of 17 (94.1%) with at least 1 positive skin test and 201 of 216 (93.1%) with all negative skin tests. Reaction intensity was similar in 4, milder in 10, unknown in 1, and worse in 1 patient although this reaction was deemed to be nonallergic in hindsight. Premedication was administered in 20.7% of patients and associated with more reactions (19.4% vs 5.7%, P = .01). The overall NPV of skin testing for ICM was 93.1% (95% confidence interval [CI] 89.1% to 96.0%), and for immediate and nonimmediate hypersensitivity reactions 94.2% (95% CI 89.6% to 97.2%) and 86.1% (95% CI 72.1% to 94.7%), respectively. We cannot exclude some challenges occurred with a different than the initial culprit ICM, possibly overestimating the NPV., Conclusions: Skin testing for potential ICM hypersensitivity can identify safe alternative(s) for ICM re-exposure especially in patients with an immediate hypersensitivity reaction and/or skin test-proven ICM drug allergy. Reactions on re-exposure were infrequent, mostly milder, and occurred in some patients despite premedication., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Drug hypersensitivity reactions (DHRs) represent growing health problem worldwide, affecting more than 7% of the general population, and represent an important public health problem. However, knowledge in DHRs morbidity and mortality epidemiological data is still not optimal and international comparable standards remain poorly accessed. Institutional databases worldwide increasingly use the WHO International Classification of Diseases (ICD) system to classify diagnoses, health services utilization, and death data. The misclassification of disorders in the ICD system contributes to a lack of ascertainment and recognition of their importance for healthcare planning and resource allocation. It also hampers clinical practice and prevention actions. To further inform the allergy community and to ensure that the revision process is transparent as advised in the WHO ICD-11 revision agenda, we report the advances and use of the pioneering "Drug hypersensitivity" subsection of ICD-11 and implementation in the WHO International Classification of Health Interventions (ICHI). The new classification addressed to DHRs will enable the collection of more accurate epidemiological data to support quality management of patients with drug allergies and better facilitate healthcare planning and decision-making and public health measures to prevent and reduce the morbidity and mortality attributable to DHRs., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Beta-lactam antibiotics represent the main cause of allergic reactions to drugs, inducing both immediate and nonimmediate allergies. The diagnosis is well established, usually based on skin tests and drug provocation tests, but cumbersome., Objectives: To design predictive models for the diagnosis of beta-lactam allergy, based on the clinical history of patients with suspicions of allergic reactions to beta-lactams., Methods: The study included a retrospective phase, in which records of patients explored for a suspicion of beta-lactam allergy (in the Allergy Unit of the University Hospital of Montpellier between September 1996 and September 2012) were used to construct predictive models based on a logistic regression and decision tree method; a prospective phase, in which we performed an external validation of the chosen models in patients with suspicion of beta-lactam allergy recruited from 3 allergy centers (Montpellier, Nîmes, Narbonne) between March and November 2013. Data related to clinical history and allergy evaluation results were retrieved and analyzed., Results: The retrospective and prospective phases included 1991 and 200 patients, respectively, with a different prevalence of confirmed beta-lactam allergy (23.6% vs 31%, P = .02). For the logistic regression method, performances of the models were similar in both samples: sensitivity was 51% (vs 60%), specificity 75% (vs 80%), positive predictive value 40% (vs 57%), and negative predictive value 83% (vs 82%). The decision tree method reached a sensitivity of 29.5% (vs 43.5%), specificity of 96.4% (vs 94.9%), positive predictive value of 71.6% (vs 79.4%), and negative predictive value of 81.6% (vs 81.3%)., Conclusions: Two different independent methods using clinical history predictors were unable to accurately predict beta-lactam allergy and replace a conventional allergy evaluation for suspected beta-lactam allergy., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Drug provocation tests (DPT) are commonly performed as part of β-lactam (BL) allergy workup, in case of negative skin tests (ST) and in the absence of contraindications. The recommendations of learned societies have created a frame for DPT performance, but protocols vary widely between centres, generating various hypothesis-driven protocols (i.e. empirical dosing, driven by both safety concerns and practical aspects)., Methods: The primary objective of this retrospective analysis was to detect eliciting dose thresholds (reactive doses) during BL DPT, using the survival analysis method, in order to suggest optimal step doses. Our secondary objective was to evaluate the safety of our 30-min incremental 1-day protocol. The study included all the patients explored in the Allergy Unit of the University Hospital of Montpellier (France), between September 1996 and July 2015 for a suspicion of drug hypersensitivity reaction to BLs, with negative ST and positive DPT., Results: During the study period, 182 positive DPT (accounting for 171 hypersensitive patients) were analysed. We identified eliciting thresholds, and we suggest the following steps for DPT to BLs: 5-15-30-50% of daily therapeutic dose (with additional lower steps for index reactions of anaphylaxis). We confirm the safety of 1-day protocol for immediate and mild nonimmediate reactors, for both children and adults, with a surveillance period of 2 h after the last administered dose, and a prolonged surveillance after discharge of 48 h., Conclusion: This data-driven approach in designing DPT protocols is a step forward in improving DPT standardization, starting with the most frequently tested drugs, BL antibiotics., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Immediate hypersensitivity reactions during anaesthesia are rare but potentially life-threatening. The epidemiology changes with time and evolving professional practice, and hence needs to be monitored. Our objective was to follow this epidemiology., Methods: This was a retrospective, observational study in French hospital clinics, conducted by GERAP members (Groupe d'Étude des Réactions Anaphylactoïdes Périopératoires). Consecutive patients seen in allergo-anaesthesia outpatient clinics, who had experienced a hypersensitivity reaction during anaesthesia between 1 January 2011 and 31 December 2012, were included. Demographic data, allergy history, drugs received before the reaction, symptoms of the reaction, results of blood samples (histamine, tryptase, IgE-specific assays), and results of the allergy assessment were recorded., Results: The most common causes of allergic reactions were (Neuromuscular Blocking Agents) NMBAs (N = 302; 60.6%), antibiotics (N = 91, 18.2%, Cephalosporin N = 49, 10%) and dyes (N = 27; 5.4%). Latex as an allergic agent was involved in 26 cases (5.2%), hypnotics in 11 cases (2.2%) and opioids in seven cases (1.4%). Of the NMBAs, Rocuronium had the highest proportion of reactions (13.8 reactions/100,000 vials sold) followed by Suxamethonium (13.3/100,000 vials sold). Cisatracurium had the lowest proportion of reactions (0.4/100,000 vials sold). Patients were sensitized to two or more NMBAs in 48.9% of cases and without testing, cross-sensitivity cannot be predicted., Conclusions: When compared with the previous GERAP studies, NMBAs are still the most frequently triggering allergens, with marked differences between individual NMBAs, but they are now followed by antibiotics (of which greater than 50% were cephalosporins) and dyes. Anaesthetists must be aware of the differences between drugs and of the pattern of emerging allergens. For the future of safe anaesthesia, allergy assessment is essential., (© 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

The strongest and best-documented risk factor for drug hypersensitivity (DH) is the history of a previous reaction. Accidental exposures to drugs may lead to severe or even fatal reactions in sensitized patients. Preventable prescription errors are common. They are often due to inadequate medical history or poor risk assessment of recurrence of drug reaction. Proper documentation is essential information for the doctor to make sound therapeutic decision. The European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology have formed a task force and developed a drug allergy passport as well as general guidelines of drug allergy documentation. A drug allergy passport, a drug allergy alert card, a certificate, and a discharge letter after medical evaluation are adequate means to document DH in a patient. They are to be handed to the patient who is advised to carry the documentation at all times especially when away from home. A drug allergy passport should at least contain information on the culprit drug(s) including international nonproprietary name, clinical manifestations including severity, diagnostic measures, potential cross-reactivity, alternative drugs to prescribe, and where more detailed information can be obtained from the issuer. It should be given to patients only after full allergy workup. In the future, electronic prescription systems with alert functions will become more common and should include the same information as in paper-based documentation., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are the main cause of drug-induced hypersensitivity in children. Many classifications have been proposed, focusing on adults. So far, no large study has deeply investigated a pediatric cohort. The aim of the present study was to describe a population of NSAID hypersensitive patients reporting a reaction during their childhood and to verify whether it is possible to classify pediatric patients, following the EAACI/ENDA classification., Methods: We conducted a historical prospective study including patients evaluated from 1996 to 2015 in the allergy unit of the Montpellier University Hospital. We included 635 patients. For each patient, we recorded clinical manifestations and possible comorbidities and tried to identify possible risk factors., Results: NSAID hypersensitivity was diagnosed in 107 of 635 patients (16.9%). In this group, 43 patients (40.2%) could not be classified following the ENDA recommendations. The main discrepancies were on the patients' clinical manifestations and on their possible underlying diseases. We identified, on a multivariate analysis, some risk factors for NSAID hypersensitivity: chronic urticaria (OR 7.737, 3.375-18.296 95%CI), atopic status (OR 2.514, 1.504-4.364 95%CI), and allergic rhinoconjunctivitis (OR 1.799, 1.138-2.837 95%CI). On the basis of our results, we are proposing an adapted classification for NSAID hypersensitivity in children., Conclusions: The current ENDA classification does not seem to be adapted for pediatric patients; a modified version does. Our study could help allergists better understand the differences between adults and children in developing hypersensitivity reactions to NSAIDs, but further large-scale prospective longitudinal analyses are required to validate this new classification., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The incidence of allergic reactions to local anesthetics is low. Most cases involve a psychogenic reaction rather than an allergic reaction. Additives and preservatives added to local anesthetics may cause allergic reactions. Vascular resorption of epinephrine-containing local anesthetics may produce cardiovascular signs similar to an allergic reaction. Diagnosis of allergy to local anesthetics must be established by skin testing and provocative challenge., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)