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Proton pump inhibitors (PPIs) are invaluable therapeutic options in a variety of dyspeptic diseases. In addition to their well-known risk profile, PPI consumption is related to food and environmental allergies, dysbiosis, osteoporosis, as well as immediate and delayed hypersensitivity reactions (HSRs). The latter, although a rare event, around 1%-3%, due to the extraordinarily high rate of prescription and consumption of PPIs are related to a substantial risk. In this Position Paper, we provide clinicians with practical evidence-based recommendations for the diagnosis and management of HSRs to PPIs. Furthermore, the unmet needs proposed in the document aim to stimulate more in-depth investigations in the topic., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

In drug hypersensitivity, drug provocation testing (DPT), also called drug challenge, is the gold standard for investigation. In recent years, risk stratification has become an important tool for adjusting the diagnostic strategy to the perceived risk, whilst still maintaining a high level of safety for the patient. Skin tests are recommended before DPT but may be omitted in low-risk patients. The task force suggests a strict definition of such low-risk patients in children and adults. Based on experience and evidence from studies of allergy to beta-lactam antibiotics, an algorithm on how to adjust DPT to the risk, and when to omit skin tests before DPT, is presented. For other antibiotics, non-steroidal anti-inflammatory drugs and other drugs, skin tests are poorly validated and DPT is frequently necessary. We recommend performing DPT with chemotherapeutics and biologicals to avoid unnecessary desensitization procedures and DPT with skin tests negative contrast media. We suggest DPT with anesthetics only in highly specialized centers. Specifics of DPT to proton pump inhibitors, anticonvulsants and corticosteroids are discussed. This position paper provides general recommendations and guidance on optimizing use of DPT, whilst balancing benefits with patient safety and optimizing the use of the limited available resources., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Diagnosing immediate drug hypersensitivity reactions (IDHRs) can pose a significant challenge and there is an urgent need for safe and reliable tests. Evidence has emerged that the basophil activation test (BAT), an in vitro assay that mirrors the in vivo response, can be a complementary test for many drugs. In this position paper, members of Task Force (TF) "Basophil activation test in the evaluation of Drug Hypersensitivity Reactions" from the European Academy of Allergy and Clinical Immunology (EAACI) present the data from a survey about the use and utility of BAT in IDHRs in Europe. The survey results indicate that there is a great interest for using BAT especially for diagnosing IDHRs. However, there are still main needs, mainly in the standardization of the protocols. Subsequently consensus-based recommendations were formulated for: (i) Technical aspects of BAT in IDHRs including type of sample, management of drugs, flow cytometry protocols, interpretation of the results; and (ii) Drug-specific aspects that should be taken into account when performing BAT in relation to betalactams, neuromuscular blocking agents, fluoroquinolones, chlorhexidine, opioids, radio contrast media, chemotherapeutics, biological agents, nonsteroidal anti-inflammatory drugs, COVID vaccine, and excipients. Moreover, aspects in the evaluation of pediatric population have also been considered. All this indicates that BAT offers the clinician and laboratory a complementary tool for a safe diagnostic for IDHRs, although its place in the diagnostic algorithm depends on the drug class and patient population (phenotype, geography, and age). The standardization of BAT is important for generalizing this method beyond the individual laboratory., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Penicillin allergy is a significant burden on patient, prescribing and hospital outcomes. There has been increasing interest in the incorporation of penicillin allergy testing (i.e. delabelling) into antimicrobial stewardship (AMS) programmes to reduce the burden of penicillin allergy labels and improve prescribing. In particular, there has been a focus on point-of-care penicillin allergy assessment and direct oral challenge for low-risk phenotypes. The National Antibiotic Allergy Network has provided a guide to assist AMS clinicians with the incorporation of penicillin allergy programmes, in particular direct oral challenge, into Australian hospitals., (© 2024 The Author(s). Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Background: Anaphylaxis, which is rare, has been reported after COVID-19 vaccination, but its management is not standardized., Method: Members of the European Network for Drug Allergy and the European Academy of Allergy and Clinical Immunology interested in drug allergy participated in an online questionnaire on pre-vaccination screening and management of allergic reactions to COVID-19 vaccines, and literature was analysed., Results: No death due to anaphylaxis to COVID-19 vaccines has been confirmed in scientific literature. Potential allergens, polyethylene glycol (PEG), polysorbate and tromethamine are excipients. The authors propose allergy evaluation of persons with the following histories: 1-anaphylaxis to injectable drug or vaccine containing PEG or derivatives; 2-anaphylaxis to oral/topical PEG containing products; 3-recurrent anaphylaxis of unknown cause; 4-suspected or confirmed allergy to any mRNA vaccine; and 5-confirmed allergy to PEG or derivatives. We recommend a prick-to-prick skin test with the left-over solution in the suspected vaccine vial to avoid waste. Prick test panel should include PEG 4000 or 3500, PEG 2000 and polysorbate 80. The value of in vitro test is arguable., Conclusions: These recommendations will lead to a better knowledge of the management and mechanisms involved in anaphylaxis to COVID-19 vaccines and enable more people with history of allergy to be vaccinated., (© 2022 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Purpose of Review: Drug allergy is responsible for a huge burden on public healthcare systems, representing in some instances a threat for patient's life. Diagnosis is complex due to the heterogeneity of clinical phenotypes and mechanisms involved, the limitations of in vitro tests, and the associated risk to in vivo tests. Predictive models, including those using recent advances in artificial intelligence, may circumvent these drawbacks, leading to an appropriate classification of patients and improving their management in clinical settings., Recent Findings: Scores and predictive models to assess drug allergy development, including patient risk stratification, are scarce and usually apply logistic regression analysis. Over recent years, different methods encompassed under the general umbrella of artificial intelligence, including machine and deep learning, and artificial neural networks, are emerging as powerful tools to provide reliable and optimal models for clinical diagnosis, prediction, and precision medicine in different types of drug allergy., Summary: This review provides general concepts and current evidence supporting the potential utility of predictive models and artificial intelligence branches in drug allergy diagnosis., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Patients with mast cell disorders frequently experience symptoms from excessive mediator release like histamine and tryptase, ranging from mild flushing to severe anaphylactic responses. Hypersensitivity reactions (HRs) to drugs are a major cause of anaphylaxis in these patients, who often worry about triggering mast cell degranulation when taking medications. The aim of this review is to explore the complex interactions between mast cell disorders and drug HRs, focusing on the clinical challenges of managing these conditions effectively to enhance understanding and guide safer clinical practices., Recent Findings: Among the drugs most commonly associated with hypersensitivity reactions in patients with mast cell disorders are non-steroidal anti-inflammatory drugs, antibiotics, and perioperative agents. Recent studies have highlighted the role of Mas-related G-protein coupled receptor member X2 (MRGPRX2) - a receptor involved in non-immunoglobulin E mediated mast cell degranulation - in exacerbating HRs. Investigations reveal varied drug tolerance among patients, underscoring the need for individual risk assessments., Summary: Tailored diagnostic approaches are crucial for confirming drug allergies and assessing tolerance in patients with mastocytosis, preventing unnecessary medication avoidance and ensuring safety before acute situations arise., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Immediate and nonimmediate hypersensitivity reactions to iodinated contrast media (ICM) have been reported to occur in a frequency of about 0.5%-3% of patients receiving nonionic ICM. The diagnosis and management of these patients vary among guidelines published by various national and international scientific societies, with recommendations ranging from avoidance or premedication to drug provocation test. This position paper aims to give recommendations for the management of patients with ICM hypersensitivity reactions and analyze controversies in this area. Skin tests are recommended as the initial step for diagnosing patients with immediate and nonimmediate hypersensitivity reactions; besides, they may also help guide on tolerability of alternatives. Re-exposition or drug provocation test should only be done with skin test-negative ICMs. The decision for performing either re-exposition or drug provocation test needs to be taken based on a risk-benefit analysis. The role of in vitro tests for diagnosis and pretreatment for preventing reactions remains controversial., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

In evaluating adverse drug reactions (ADRs), patch tests (PTs), skin prick tests (SPTs), and intradermal tests (IDTs) are useful tools for identifying responsible drugs and finding safe alternatives. Their diagnostic value depends on the clinical features of the ADR and on the drug tested. PTs have a good sensitivity in assessing acute generalized exanthematous pustulosis and drug rash with eosinophilia and systemic symptoms. SPTs done with all drugs except opiates are used for immediate hypersensitivity reactions. IDTs seem sensitive for immediate hypersensitivity reactions to beta-lactam antibiotics, iodinated contrast media, heparins, general anesthetics, and platinum salts., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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.)

Background: Furazolidone is a nitrofuran antimicrobial agent used in the treatment of bacterial and protozoal infections. Hypersensitivity to furazolidone is rarely reported and only eight cases have been documented in English since 1967., Objectives: To report a 24-year-old man who developed exanthematous drug eruptions in general and swelling sensation of the hands after first dose of oral administration of medicines for Helicobacter pylori infection 7 h later, who was finally confirmed with delayed-type IV allergic reaction to furazolidone by provocation tests. And to review the existing literature., Methods: Thorough clinical examination, prick, intradermal, and patch tests, drug provocation tests were performed in the patient., Results: Skin tests of all used drugs were negative. Drug provocation tests to furazolidone resulted to be positive., Conclusions: Clinicians should be aware that furazolidone may induce delayed-type allergic reactions; diagnostic approaches should be taken to identify the responsible drug when multiple medications were used concurrently., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The prevalence of allergies to beta-lactam antibiotics is significantly overestimated based on anamnestic data - with significant medical and economic consequences. The aim of the study was to determine the frequency of immediate and delayed type reactions to beta-lactam antibiotics in order to optimize diagnostics and therapy. One focus was on the time interval between reaction and testing., Patients and Methodology: Anamnestic and diagnostic data of patients with suspected allergy to beta-lactam antibiotics who were examined in our department between 2020 and 2022 were analyzed., Results: 27/116 (23%) patients reacted in the skin tests. Type I sensitizations were detected in 4/35 patients (11%), type IV sensitizations in 23/83 (28%). In the case of negative in vitro diagnostics and skin testing, inpatient provocation tests were performed in 41/89 (46%). Type I allergies were confirmed in two of the 13 provoked patients (15%) with immediate type reactions, type IV allergies in three of 29 (10%) with delayed type reactions. The results were clearly related to the time interval after reaction. At less than one year, 19% (22/116) reacted, whereas only 4% (5/116) reacted at more than one year (for type I reaction 9% vs. 3%; for type IV reaction 23% vs. 5%).  CONCLUSIONS: The importance of the time interval between clinical event and allergological testing supports the guideline recommendation for skin testing within one year. Guideline recommendations on the diagnostic procedure for unclear reactions that occurred in the more distant past are desirable in order to rule out allergies to beta-lactam antibiotics., (© 2024 The Author(s). Journal der Deutschen Dermatologischen Gesellschaft published by Wiley‐VCH GmbH on behalf of Deutsche Dermatologische Gesellschaft.)

Background: Patients with a penicillin allergy label are at risk of an associated increase in adverse antibiotic events and hospitalization costs., Aim: We aimed to study the economic savings derived from the correct diagnosis and delabeling inpatients with suspected beta-lactam allergy, considering the acquisition cost of antimicrobials prescribed during a patient's hospital stay., Method: We prospectively evaluated patients admitted to the University Hospital of Salamanca who had been labeled as allergic to beta-lactams and performed a delabeling study. Subsequently, cost differences between antibiotics administered before and after the allergy study and those derived from those patients who received alternative antibiotics during admission and those who switched to beta-lactams after the allergy study were calculated., Results: One hundred seventy-seven inpatients labeled as allergic to beta-lactams underwent a delabeling study; 34 (19.2%) were confirmed to have allergy to beta-lactams. Of the total number of patients, 136 (76.8%) received antibiotics during their hospitalization, involving a mean (SD) cost of €203.07 (318.42) and a median (IQR) cost of €88.97 (48.86-233.56). After delabeling in 85 (62.5%) patients, the antibiotic treatment was changed to beta-lactams. In this group of patients, the mean cost (SD) decreased from €188.91 (351.09) before the change to 91.31 (136.07) afterward, and the median cost (IQR) decreased from €72.92 (45.82-211.99) to €19.24 (11.66-168). The reduction was significant compared to the median cost of patients whose treatment was not changed to beta-lactams (p<0.001)., Conclusion: Delabeling hospitalized patients represents a cost-saving measure for treating patients labeled as allergic to beta-lactams., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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.)

Coronavirus disease 2019 (COVID-19), a respiratory tract infection caused by a novel human coronavirus, the severe acute respiratory syndrome coronavirus 2, leads to a wide spectrum of clinical manifestations ranging from asymptomatic cases to patients with mild and severe symptoms, with or without pneumonia. Given the huge influence caused by the overwhelming COVID-19 pandemic affecting over three million people worldwide, a wide spectrum of drugs is considered for the treatment in the concept of repurposing and off-label use. There is no knowledge about the diagnosis and clinical management of the drug hypersensitivity reactions that can potentially occur during the disease. This review brings together all the published information about the diagnosis and management of drug hypersensitivity reactions due to current and candidate off-label drugs and highlights relevant recommendations. Furthermore, it gathers all the dermatologic manifestations reported during the disease for guiding the clinicians to establish a better differential diagnosis of drug hypersensitivity reactions in the course of the disease., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Intradermal testing (IDT) with iodinated contrast media (ICMs) is an established diagnostic tool in patients with ICM hypersensitivity. Currently, it is unclear which test concentration is the more useful one, up to pure or up to 1:10 diluted ICMs., Methods: We searched the literature database PubMed for eligible papers dealing with ICM allergy and their IDT results. We analyzed the data presented by the papers and compared the pooled groups tested with diluted and undiluted ICMs., Results: We identified 29 eligible original papers, and extracted data of 1137 patients that formed the study population. Although in the cohort tested with diluted ICMs the number of tested ICMs was greater, the percentage of positive tests was significantly less (9.0% vs. 24.7%; P < 0.0001; OR 0.30 [0.26-0.34]). The frequency of positive tested culprit ICMs was also lesser in the group tested with diluted ICMs (31.0% vs. 72.5%; P < 0.0001; OR 0.17 [0.12-0.23]). The number of drug provocation tests (DPTs) was greater in patients with diluted IDTs (374 vs. 89; P < 0.0001; OR 2.54 [1.93-3.36]). We detected an increased sensitivity in patients with undiluted tests (0.774 vs. 0.282) and a nearly identical specificity in both groups (1 vs. 0.983)., Conclusions: For the first time, we show that IDT up to pure ICM concentrations is superior to using diluted ICMs only. Possibly, we can reduce the number of DPTs when performing IDTs with pure ICMs. In the undiluted group, there were no hints for skin irritations or unspecific test reactions., (© 2024 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

Background: Cystic fibrosis (CF) is a genetic disease characterized by multi-system dysfunction resulting in recurrent lung infections and progressive pulmonary disease. CF patients are at a higher risk for drug hypersensitivity reactions (DHRs) compared to the general population, which has been attributed to the recurrent need for antibiotics and the inflammation associated with CF disease. In vitro toxicity tests such as the lymphocyte toxicity assay (LTA) offer the potential for risk assessment for DHRs. In the current study, we investigated the utility of the LTA test for diagnosis of DHRs in a cohort of CF patients., Method: Twenty CF patients with suspected DHRs to sulfamethoxazole, penicillins, cephalosporins, meropenem, vancomycin, rifampicin, and tobramycin were recruited to this study and tested using the LTA test along with 20 healthy control volunteers. Demographic data of the patients, including age, sex, and medical history, were obtained. Blood samples were withdrawn from patients and healthy volunteers, and the LTA test was performed on isolated peripheral blood monocytes (PBMCs) from those individuals., Results: Cells from CF patients with DHRs displayed a significant (p < 0.0001) concentration-dependent enhanced cell death upon incubation with the culprit drug compared to cells from healthy volunteers. The positivity rate of the LTA test was over 80% in patients with a medical history and clinical presentation consistent with DHRs., Conclusion: This study is the first to evaluate the use of the LTA test for diagnosis of DHRs in CF patients. According to our results, the LTA test may be a useful tool for diagnosis and management of DHRs in CF patients. Identifying the culprit drug is essential for optimal healthcare for CF patients in the setting of a suspected DHR. The data also provide evidence that accumulation of toxic reactive metabolites could be an important component in the cascade of events leading to the development of DHRs in CF patients. A larger-scale study is needed to confirm the data., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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.)

Drug hypersensitivity reactions (DHRs) are common, and the skin is by far the most frequently involved organ with a broad spectrum of reaction types. The diagnosis of cutaneous DHRs (CDHR) may be difficult because of multiple differential diagnoses. A correct classification is important for the correct diagnosis and management. With these guidelines, we aim to give precise definitions and provide the background needed for doctors to correctly classify CDHR., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Around 10% of people report a drug allergy and avoid some medications because of fear of allergic reactions. However, only after a proper diagnostic workup can some of these reactions be confirmed as allergic or nonallergic hypersensitivities. Beta-lactams (BLs) are the most common medication suspected of being involved in drug hypersensivity reactions (DHRs) in children. Recently, direct oral provocation tests (DPT) with BLs gained popularity within pediatric populations as a tool for delabeling children with suspected BL allergies. This study aimed to evaluate the safety of direct provocation tests in infants with mild cutaneous non-immediate reactions to BLs., Methods: The authors retrospectively analyzed the data of 151 infants between 2015 and 2022, referred for evaluating a suspected allergy to BLs that occurred before age 24 months., Results: The mean age of the children, including 55% male kids, at the suspected reaction was 15.9 months and the mean age at the time of the DPT was 39.6 months. In most cases, antibiotics were prescribed to treat common upper respiratory infections, such as acute otitis (54.3%) and acute tonsillitis (27.2%). Amoxicillin was considered the culprit drug in 62.9% of the cases, and the combination of amoxicillin-clavulanic acid in the case of 33.8% of children. The most frequent associated cutaneous clinical manifestations were maculopapular exanthema in 74.8% and delayed urticaria/angioedema in 25.2%. Of the 151 infants evaluated, parents of 149 infants agreed for a direct DPT, and only three had a positive test (2%). Symptoms resulting from the DPT were mild and easily treatable., Conclusions: A direct DPT without prior tests is a safe and effective procedure to delabel BL allergy, even in infants. The authors wish to emphasize the importance of properly validating BL allergy suspicions by promoting appropriate diagnostic procedures in infants as, in most cases, DHRs can be excluded and there is no need for further therapeutic restrictions., Competing Interests: The authors have no conflicts of interest to declare.

Background: Allergy to beta-lactam antibiotics (BLA) is frequently suspected in children, but a drug provocation test (DPT) rules it out in over 90% of cases. Direct oral DPT (DODPT), without skin or other previous tests, is increasingly been used to delabel non-immediate BLA reactions. This real-world study aimed to assess the safety and effectiveness of DODPT in children with immediate and non-immediate reactions to BLAs., Methods: Ambispective registry study in children (<15 years), attended between 2016 and 2023 for suspected BLA allergy in 15 hospitals in Spain that routinely perform DODPT., Results: The study included 2133 patients with generally mild reactions (anaphylaxis 0.7%). Drug provocation test with the implicated BLA was performed in 2014 patients (94.4%): 1854 underwent DODPT (86.9%, including 172 patients with immediate reactions). One hundred forty-five (7.2%) had symptoms associated with DPT, although only four reactions were severe: two episodes of anaphylaxis and two of drug-induced enterocolitis syndrome, which resolved rapidly with treatment. Of the 141 patients with mild reactions in the first DPT, a second DPT was considered in 87 and performed in 57, with 52 tolerating it without symptoms. Finally, BLA allergy was ruled out in 90.9% of the sample, confirmed in 3.4%, and remained unverified, usually due to loss to follow-up, in 5.8%., Conclusions: Direct oral DPT is a safe, effective procedure even in immediate mild reactions to BLA. Many reactions observed in DPT are doubtful and require confirmation. Severe reactions are exceptional and amenable to treatment. Direct oral DPT can be considered for BLA allergy delabeling in pediatric primary care., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Immediate drug hypersensitivity reactions (IDHRs) are a burden for patients and the health systems. This problem increases when taking into account that only a small proportion of patients initially labelled as allergic are finally confirmed after an allergological workup. The diverse nature of drugs involved will imply different interactions with the immunological system. Therefore, IDHRs can be produced by a wide array of mechanisms mediated by the drug interaction with specific antibodies or directly on effector target cells. These heterogeneous mechanisms imply an enhanced complexity for an accurate diagnosis and the identification of the phenotype and endotype at early stages of the reaction is of vital importance. Currently, several endophenotypic categories (type I IgE/non-IgE, cytokine release, Mast-related G-protein coupled receptor X2 (MRGPRX2) or Cyclooxygenase-1 (COX-1) inhibition and their associated biomarkers have been proposed. A precise knowledge of endotypes will permit to discriminate patients within the same phenotype, which is crucial in order to personalise diagnosis, future treatment and prevention to improve the patient's quality of life., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Drug provocation tests (DPTs) are considered the gold standard for diagnosing beta-lactam allergy. However, positive results tend to be mild and difficult to interpret. This study aimed to describe pediatric patients with a presumedly positive or inconclusive DPT, assess the decision to repeat the DPT, and describe its outcome., Methods: Retrospective review of all presumedly positive or inconclusive DPTs performed in six pediatric allergy clinics from 2017 to 2019. We describe the interpretation of results, focusing on the decision to repeat the DPT and its outcome., Results: Of 439 children challenged with a beta-lactam, 26 (5.9%) with a presumedly positive or inconclusive result were included in this study. Most were girls (n = 16, 61.5%), and the median age was 5 years (range 1-13). The initial DPT used amoxicillin (n = 13, 50.0%), amoxicillin-clavulanic acid (n = 12, 46.2%), or cefadroxil (n = 1, 3.8%). Reactions were early (n = 11, 42.3 %), delayed (n = 14, 53.8 %), or not registered (n = 1, 3.8 %), but mild in all cases. A second confirmatory DPT was proposed in 19 patients (73.1%) and performed in 17 patients (65.4%). Nine DPTs were performed from 1 day to 4 months after the first DPT, and the remaining eight took place 6 months to 2 years later. Fifteen children tolerated the drug in the second DPT: 88.2% of those reevaluated and 57.5% of the whole study group., Conclusion: The positive predictive value of DPT may be lower than expected. Given the mildness of observed reactions, a second confirmatory DPT is warranted within a few weeks or months., Competing Interests: The authors declare no potential conflicts of interest with respect to research, authorship, and/or publication of this article.

Background: Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (HR-NSAIDs) are common adverse events related to the widespread use of over-the-counter NSAIDs for the treatment of a variety of inflammatory conditions. Urticaria is the most commonly reported immediate cutaneous clinical sign of HR-NSAIDs, but it can be a manifestation of pathophysiologically different clinical entities that require different therapeutic strategies. The aim of this study is to ease the identification of the correct phenotype of HR-NSAIDs in patients reporting urticaria associated with the intake of NSAIDs and provide updated information about their diagnosis and management., Methods: The study is a narrative review conducted by collecting the most relevant and up-todate data related to the classification, pathophysiology, severity, and prognosis of NSAID hypersensitivity reactions. PubMed and Embase scientific databases were used as search engines to select relevant articles., Results: Patients developing HR-NSAIDs can be divided into two categories: selective responders (SR), who develop reactions after the administration of a single specific NSAID due to an underlying IgE or T-cell mediated hypersensitivity mechanism, or cross-intolerant (CI), who develop reactions to more than one chemically unrelated NSAIDs due to abnormalities in the biochemical pathways related with prostaglandin metabolism, independently from an underlying immunological mechanism. Five major different categories of HR-NSAIDs have been identified: NSAIDs-exacerbated cutaneous disease (NECD), NSAIDs-induced urticaria/angioedema with/without respiratory and systemic symptoms of anaphylaxis (NIUAA), and NSAIDsexacerbated respiratory disease (NERD), which are developed by CI patients, and single NSAIDs-induced urticaria, angioedema and/ or anaphylaxis (SNIUAA) and single NSAIDsinduced delayed hypersensitivity reactions (SNIDHR), which are developed by CI patients. In vivo and in vitro diagnostic tests have rarely been shown to be reliable in all these entities and therefore are not routinely used in clinical practice. The management in SR patients consists of strict avoidance of the culprit drug, while for cross-intolerance reactions oral tolerance tests with safe alternative drugs (e.g. weak COX-1 inhibitors or selective COX-2 inhibitors) can be performed., Conclusion: HR-NSAIDs are being observed with increasing frequency, however, the pathogenesis behind some NSAIDS-associated clinical entities is still unclear. Diagnosis is mostly based on a thorough clinical history and confirmed by a drug challenge test. Clinical management is based on strict avoidance and use of alternative tolerated medications. Overall, all therapeutic decisions depend on the correct identification of the type of reaction the patient experienced., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Beta-lactam antibiotics are the most commonly reported drug allergy in adults and children. More than 95% of those with reported allergy labels to beta lactams are not confirmed when subjected to allergy testing. Beta lactam antibiotics are associated with a wide spectrum of immediate and delayed drug hypersensitivity reactions. The latency period to symptoms and clinical presentation aids in the causality assessment. Risk stratification based on diagnosis and timing then allows for appropriate management and evaluation. Skin prick testing, intradermal testing and oral challenge are well established for evaluation of immediate reactions. Delayed intradermal testing, patch testing and oral challenge can also be considered for evaluation of mild to moderate delayed reactions. Cross-reactivity between beta-lactams appears to be driven most commonly by a shared R1 side-chain. Standardized algorithms, protocols and pathways are needed for widespread implementation of a pragmatic and effective approach to patients reporting beta lactam allergy., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Nonimmediate (delayed)-allergic reactions to penicillins are common and some of them can be life-threatening. The genetic factors influencing these reactions are unknown/poorly known/poorly understood. We assessed the genetic predictors of a delayed penicillin allergy that cover the HLA loci., Methods: Using next-generation sequencing (NGS), we genotyped the MHC region in 24 patients with delayed hypersensitivity compared with 20 patients with documented immediate hypersensitivity to penicillins recruited in Italy. Subsequently, we analyzed in silico Illumina Immunochip genotyping data that covered the HLA loci in 98 Spanish patients with delayed hypersensitivity and 315 with immediate hypersensitivity compared to 1,308 controls., Results: The two alleles DRB3*02:02:01:02 and DRB3*02:02:01:01 were reported in twenty cases with delayed reactions (83%) and ten cases with immediate reactions (50%), but not in the Allele Frequency Net Database. Bearing at least one of the two alleles increased the risk of delayed reactions compared to immediate reactions, with an OR of 8.88 (95% CI, 3.37-23.32; p < .0001). The haplotype (ACAA) from rs9268835, rs6923504, rs6903608, and rs9268838 genetic variants of the HLA-DRB3 genomic region was significantly associated with an increased risk of delayed hypersensitivity to penicillins (OR, 1.7; 95% CI: 1.06-1.92; p = .001), but not immediate hypersensitivity., Conclusion: We showed that the HLA-DRB3 locus is strongly associated with an increased risk of delayed penicillin hypersensitivity, at least in Southwestern Europe. The determination of HLA-DRB3*02:02 alleles in the risk management of severe delayed hypersensitivity to penicillins should be evaluated further in larger population samples of different origins., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Hypersensitivity to acetylsalicylic acid (ASA) constitutes a serious problem for subjects with coronary artery disease. In such subjects, physicians have to choose the more appropriate procedure between challenge and desensitization. As the literature on this issue is sparse, this study aimed to establish in these subjects clinical criteria for eligibility for an ASA challenge and/or desensitization., Methods: Collection and analysis of data on ASA challenges and desensitizations from 10 allergy centers, as well as consensus among the related physicians and an expert panel., Results: Altogether, 310 subjects were assessed; 217 had histories of urticaria/angioedema, 50 of anaphylaxis, 26 of nonimmediate cutaneous eruptions, and 17 of bronchospasm related to ASA/nonsteroidal anti-inflammatory drugs (NSAID) intake. Specifically, 119 subjects had index reactions to ASA doses lower than 300 mg. Of the 310 subjects, 138 had an acute coronary syndrome (ACS), 101 of whom underwent desensitizations, whereas 172 suffered from a chronic ischemic heart disease (CIHD), 126 of whom underwent challenges. Overall, 163 subjects underwent challenges and 147 subjects underwent desensitizations; 86 of the latter had index reactions to ASA doses of 300 mg or less. Ten subjects reacted to challenges, seven at doses up to 500 mg, three at a cumulative dose of 110 mg. The desensitization failure rate was 1.4%., Conclusions: In patients with stable CIHD and histories of nonsevere hypersensitivity reactions to ASA/NSAIDs, an ASA challenge is advisable. Patients with an ACS and histories of hypersensitivity reactions to ASA, especially following doses lower than 100 mg, should directly undergo desensitization., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Allergy or hypersensitivity to drugs often affects the skin and sometimes also mucosa. While immediate type reactions show a rather homogeneous pattern, delayed type reactions reveal a high variability. In both cases it may not always be easy to differentiate drug reactions from non-drug-induced skin conditions. Furthermore, the different types of cutaneous adverse reactions may be difficult to distinguish in the beginning. This accounts predominately for delayed hypersensitivity reactions that can occur after a variety of medications and present with manifold lesions. Most of these cutaneous adverse reactions are mild, but some are severe with high morbidity and mortality. In the clinical setting, it is important to recognize the signs that point to a more severe condition early on in order to initiate appropriate management. In addition, it is crucial to identify the potentially culprit medication on the basis of a detailed medication history and by evaluating the relevant exposure times of certain drugs that differ substantially between the various reaction types. After the acute stage of the adverse reaction is managed successfully, further allergologic testing may be undertaken to confirm the offending drug., (© 2021. Springer Nature Switzerland AG.)

Background: Patch tests (PTs) with two readings have been used for decades to identify the culprit drug in nonimmediate cutaneous adverse drug reactions (NICADRs), followed more recently by late reading of intradermal tests (IDTs). Some teams tend to perform PTs with only one reading before IDTs or even directly perform IDTs., Objectives: To evaluate the relevance of a late PT reading on day 4 (D4) in NICADRs., Methods: We retrospectively selected patients who had a PT for an NICADR between July 2014 and March 2020., Results: During the study period, 328 patients had a PT with available results. Among the 75 positive-PT patients with available data for the two readings, 41 (54.7%) had positive results on D2 and D4 and 34 (45.3%) had negative results on D2 but positive results on D4. No patient had positive results on D2 and negative results on D4., Conclusion: This study shows that a D4 reading enhanced the PT-positive results. A positive PT result allows for reducing the number of IDTs, which are more difficult and costly to perform. Our series suggests that a late PT reading at D4 should be performed for exploring NICADRs., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Adverse drug reactions to iodinated contrast media (ICM) have risen due to their increasing use in x-ray-based imaging modalities. Delayed hypersensitivity reactions are mainly caused by nonionic monomeric compounds and represent an issue impacting the diagnostic-therapeutic pathways of cancer, cardiology and surgery patients., Objectives: To prospectively evaluate the usefulness of skin tests in delayed hypersensitivity reactions to ICM and to evaluate the tolerability of iobitridol, a monomeric nonionic low osmolality compound, as a possible safe alternative., Methods: Patients with delayed hypersensitivity reactions to ICM referred to us from 2020 to 2022 were prospectively enrolled in the study. All patients underwent patch test and, if negative, intradermal test with the culprit ICM and iobitridol as alternative., Results: A total of 37 patients (females 24, 64.9%) were enrolled in the study. Iodixanol and iomeprol were the most frequently involved ICM (48.5% and 35.2%, respectively); 62.2% of patients presented maculopapular eruption, while 37.8% reported delayed urticaria-like rash. Skin tests resulted positive to the culprit ICM in 19 patients (51.4%), 16 to patch test and 3 to intradermal test. Skin tests with iobitridol, tested as alternative, resulted positive in 3/19 patients (15.8%). All 16 patients with negative results to iobitridol were administered this ICM and tolerated it., Conclusions: In at least half of patients, delayed-type hypersensitivity was demonstrated by skin tests, particularly by patch test. This diagnostic approach resulted simple, cost-effective and safe, not only to confirm the culprit ICM but also to identify iobitridol as feasible alternative., (© 2023 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

Background: Hypersensitivity reactions (HSRs) to nonsteroidal anti-inflammatory drugs (NSAIDs) are a significant clinical issue. Several classifications have been proposed to categorize these reactions, including the current European Academy of Allergy and Clinical Immunology/European Network for Drug Allergy (EAACI/ENDA) classification. This study aimed to evaluate the applicability of this classification in a real-world clinical setting., Methods: We conducted a national multicenter study involving patients from nine hospitals in four major urban centers in Turkey. All patients had a suggestive clinical history of hypersensitivity reactions to NSAIDs. Researchers collected data using a structured form and classified reactions based on the EAACI/ENDA classification. Oral provocation tests with several NSAIDs were performed using a single-blind challenge per EAACI/ENDA guidelines., Results: Our retrospective study included 966 adult patients with a history of hypersensitivity to NSAIDs. The most common triggers were Acetylsalicylic Acid (ASA), paracetamol, and metamizole. The most prevalent acute NSAID hypersensitivity group was NSAID-induced urticaria/angioedema (NIUA) (34.3%). However, 17.3% of patients did not fit neatly into the current EAACI/ENDA classification. Notably, patients with underlying asthma or allergic rhinoconjunctivitis exhibited unusual reactions, such as urticaria and/or angioedema induced by multiple chemical groups of NSAIDs, blended mixed reactions, and isolated periorbital angioedema in response to multiple chemical groups of NSAIDs., Conclusions: While the EAACI/ENDA classification system stratifies NSAID-induced hypersensitivity reactions into five distinct endotypes or phenotypes, it may not fully capture the diversity of these reactions. Our findings suggest a need for further research to refine this classification system and better accommodate patients with atypical presentations.

Drug hypersensitivity includes allergic (AR) and nonallergic reactions (NARs) influenced by genetic predisposition. We performed a systematic review of genetic predictors of IgE-mediated AR and NAR with MEDLINE and PubMed search engine between January 1966 and December 2014. Among 3110 citations, the search selected 53 studies, 42 of which remained eligible. These eligible studies have evaluated genetic determinants of immediate reactions (IR) to beta-lactams (n = 19), NAR against aspirin (n = 12) and other nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 8), and IR to biologics (n = 3). We reported two genomewide association studies and four case-control studies on candidate genes validated by replication. Genes involved in IR to beta-lactams belonged to HLA type 2 antigen processing, IgE production, atopy, and inflammation, including 4 genes validated by replications, HLA-DRA, ILR4, NOD2, and LGALS3. Genes involved in NAR to aspirin belonged to arachidonic acid pathway, membrane-spanning 4A gene family, histamine production pathway, and pro-inflammatory cytokines, while those involved in NAR to all NSAIDs belonged to arachidonic acid pathway and HLA antigen processing pathway. ALOX5 was a common predictor of studies on NAR to both aspirin and NSAIDs. Although these first conclusions could be drawn, this review highlights also the lack of reliable data and the need for replicating studies in contrasted populations, taking into account worldwide allele frequencies, gene-gene interactions, and contrasted situations of environmental exposure., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Our knowledge of genetic predisposing factors of drug hypersensitivity reactions (DHRs) is still scarce. The analysis of the genetic basis of these reactions may contribute to dissect the underlying mechanisms. We will outline current knowledge of the genetic predictors of most common DHRs, including reactions to betalactam antibiotics (BLs), nonsteroidal anti-inflammatory drugs (NSAIDs) and biological agents. The predictors of DHRs to BLs are mostly linked to IgE-class switching, IgE pathway and atopy (IL4R, NOD2, LGALS3) in replicated candidate gene studies, and to antigen presentation (HLA-DRA) in the single replicated GWAS performed so far. The HLA-DRA variants are predictors of allergy to penicillins, but not to cephalosporins and they influence also the sensitization against prevalent allergens. The predictors of DHRs against NSAIDs are mostly linked to metabolism of eicosanoids (ALOX5, ALOX5AP, TBXAS1, PTGDR, CYSLTR1). Single nucleotide polymorphisms (SNPs) in genes involved in histamine biosynthesis and antigen presentation, HLA, could also have a role in DHRs against NSAIDs. The intriguing association of DHRs to NSAIDs with atopy should deserve further attention. Predictors of DHRs against asparaginase and other biological agents relate to antigen presentation (HLA-DRB1 and HLA-A alleles, respectively). The potential relationship of genetic predictors of DHRs with pathomechanisms also involved in environmental exposure and atopy highlights the need to perform GWAS in contrasted populations, taking into account world-wide variations of allele frequencies and contrasted situations of environmental exposure., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Beta-lactam (BL) allergy suspicion is common in children and constitutes a major public health problem, with an impact on patient's health and on medical costs. However, it has been found that most of these reactions are not confirmed by a complete allergic workup. The diagnostic value of the currently available allergy tests has been investigated intensively recently by different groups throughout the world. This has led to major changes in the management of children with a suspected BL allergy. Particularly, it is now well accepted that skin tests can be skipped before the drug provocation test in children with a benign non-immediate reaction to BL. However, there is still a debate on the optimal allergic workup to perform in children with a benign immediate reaction. In addition, management of children with severe cutaneous adverse drug reactions remains difficult. In this review, based on a selection of the most relevant studies found in the literature, we will review and discuss the diagnosis of different forms of BL allergy in children., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Purpose of Review: The true exanthematous reactions to drugs in children are rare and overdiagnosed. Drugs may cause exanthema either due to inducing an immune response or because of their interaction with viruses, if drugs are taken in the course of a viral infection. Also, viral infections are very often in children and they can provoke an exanthema which is difficult to differentiate from exanthematous reactions to drugs. Consequently, the majority of children are incorrectly labeled as 'allergic'., Recent Findings: The correct diagnosis of exanthematous drug reactions in children is still an important and hot topic. Most information about the approach and management of drug hypersensitivity in children is applied from available guidelines and consensus statement for adults. Recently, a systematic clinical approach for timely differential diagnosis and management of rashes in children who present a cutaneous exanthema while receiving a drug, is proposed., Summary: It is important to consider the detailed clinical history of appearing and developing exanthematous drug reaction, as well as physical examination which includes the description and the distribution of exanthema and at the end making the appropriate diagnosis. Thus, it could reduce overdiagnosis and promote appropriate procedures, that will prevent the overlabeling of drug hypersensitivity in children., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Lymphocyte transformation test (LTT) has been widely used to evaluate non-immediate drug hypersensitivity reactions (NIDHRs). However, the lack of standardization and the low sensitivity have limited its routine diagnostic use. The drug presentation by dendritic cells (DCs) and the assessment of proliferation on effector cells have shown promising results. Flow-cytometry-based methods can help apply these improvements. We aimed to assess the added value of using drug-primed-DCs and the determination of the proliferative response of different lymphocyte subpopulations in NIDHRs., Methods: Patients with confirmed NIDHR were evaluated by both conventional (C-LTT) and with drug-primed-DCs LTT (dDC-LTT)analysing the proliferative response in T cells and other effector cell subpopulations by using the fluorescent molecule, carboxyfluorescein diacetate succinimidyl ester (CFSE)., Results: The C-LTT showed a significantly lower sensitivity (29.4%) compared with dDC-LTT (61.8%), which was confirmed analysing each particular clinical entity: SJS-TEN (62.5% vs 87.5%), MPE (15% vs 47.4%) and AGEP (33% vs 80%). When including the effector cell subpopulations involved in each clinical entity, CD3 + +CD4 + T h 1 or CD3 + +NK cells in SJS-TEN, CD3 + +CD4 + T h 1+NK cells in MPE and CD3 + +NK cells in AGEP, we could significantly increase the sensitivity of the in vitro test to 100%, 68.4% and 100%, respectively, with an overall sensitivity of 87% and 85% of specificity in NIDHR., Conclusions: The use of a flow-cytometry-based test, DCs as drug presenting cells, and focusing on effector cell subpopulations for each clinical entity significantly improved the drug-specific proliferative response in NIDHRs with a unique cellular in vitro test., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Childhood rashes or exanthemas are common and are usually relatively benign. There are many causes of rash in children, including mainly viruses, and less often bacterial toxins, drugs, allergens and other diseases. Viral exanthema often appears while children are taking a medication in the course of a viral infection; it can mimic drug exanthema and is perceived as a drug allergy in 10% of cases. In the vast majority of cases, the distinction between virus-induced and drug-induced skin eruption during the acute phase is not possible. The drugs most commonly implicated are beta-lactams (BL) and non-steroidal anti-inflammatory drugs (NSAIDs). Viruses, commonly Epstein-Barr virus (EBV), human herpesvirus 6 (HHV6) and cytomegalovirus (CMV), and the bacterium, Mycoplasma pneumoniae, may cause exanthema either from the infection itself (active or latent) or because of interaction with drugs that are taken simultaneously. Determination of the exact diagnosis requires a careful clinical history and thorough physical examination. Haematological and biochemical investigations and histology are not always helpful in differentiating between the two types of exanthema. Serological and polymerase chain reaction (PCR) assays can be helpful, although a concomitant acute infection does not exclude drug hypersensitivity. A drug provocation test (DPT) is although considered the gold standard for the diagnosis and is not preferred by the patients. Skin tests are not well tolerated, and in vitro tests, such as the basophil activation test and lymphocyte transformation, are of low sensitivity and specificity and their relevance is debatable. Based on current evidence, we propose a systematic clinical approach for timely differential diagnosis and management of rashes in children who present a cutaneous eruption while receiving a drug., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

A proper allergy work-up, based on the gold standard drug provocation test (DPT), usually rules out suspected drug hypersensitivity in children. These tests are generally open, given their high efficiency compared with double-blind placebo-controlled DPTs. Although their negative predictive value is excellent, no studies have calculated their positive predictive value, highly dependent on the prevalence of the disease. Most studies have found a rate of <5%-10% of true beta-lactam hypersensitivity in children. Given this low prevalence (pre-test probability), a few false-positive results can significantly reduce the estimated positive predictive value. False positives may arise from the nocebo effect during the test, including nocebo by proxy, or from observer bias, which depends on professional expertise and organizational circumstances. Some studies have found a high rate of tolerance on a second DPT in children who failed the first, but these results may be affected by the interval between the two tests, of a year or more in most cases, reflecting a loss of hypersensitivity over time. Taking into account the low rate of positive DPTs, with commonly mild reactions, we suggest confirming nonsevere positive DPTs with a second provocation performed soon after the first, especially in the case of beta-lactam antibiotics, in order to improve the diagnostic accuracy, de-label more patients, and achieve a better estimation of true drug hypersensitivity prevalence. In case of mild immediate reactions, the potential benefits of a second DPT should be carefully weighed against the risk of anaphylaxis., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)