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Drug allergy (DA) remains a complex and unaddressed problem worldwide that often deprives patients of optimal medication choices and places them at risk for life-threatening reactions. Underdiagnosis and overdiagnosis are common and due to the lack of standardized definitions and biomarkers. The true burden of DA is unknown, and recent efforts in data gathering through electronic medical records are starting to provide emerging patterns around the world. Ten percent of the general population engaged in health care claim to have a DA, and the most common label is penicillin allergy. Up to 20% of emergency room visits for anaphylaxis are due to DA and 15%-20% of hospitalized patients report DA. It is estimated that DA will increase based on the availability and use of new and targeted antibiotics, vaccines, chemotherapies, biologicals, and small molecules, which are aimed at improving patient's options and quality of life. Global and regional variations in the prevalence of diseases such as human immunodeficiency virus and mycobacterial diseases, and the drugs used to treat these infections have an impact on DA. The aim of this review is to provide an update on the global impact of DA by presenting emerging data on drug epidemiology in adult and pediatric populations., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

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.)

Background: Drug hypersensitivity reactions (DHRs) to platinum-based drugs are heterogenous and restrict their access, and drug desensitization (DD) has provided a ground-breaking procedure for their re-introduction, although the response is heterogeneous. We aimed to identify the phenotypes, endotypes, and biomarkers of reactions to carboplatin and oxaliplatin and their response to DD., Methods: Seventy-nine patients presenting with DHRs to oxaliplatin (N = 46) and carboplatin (N = 33) were evaluated at the Allergy Departments of two tertiary care hospitals in Spain. Patient symptoms, skin testing, biomarkers, and outcomes of 267 DDs were retrospectively analyzed., Results: Oxaliplatin-reactive patients presented with type I (74%), cytokine release reaction (CRR) (11%), and mixed (Mx) (15%) phenotypes. In contrast, carboplatin reactive patients presented with predominantly type I (85%) and Mx (15%) but no CRRs. Out of 267 DDs, breakthrough reactions (BTRs) to oxaliplatin occurred twice as frequently as carboplatin (32% vs. 15%; p < .05). Phenotype switching from type I to another phenotype was observed in 46% of oxaliplatin DDs compared to 21% of carboplatin DDs. Tryptase was elevated in type I and Mx reactions, and IL-6 in CRR and Mx, indicating different mechanisms and endotypes., Conclusion: Carboplatin and oxaliplatin induced three different types of reactions with defined phenotypes and endotypes amendable to DD. Although most of the initial reactions for both were type I, oxaliplatin presented with unique CRR reactions. During DD, carboplatin reactive patients presented mostly type I BTR, while oxaliplatin-reactive patients frequently switched from type I to CRR, providing a critical difference and the need for personalized DD protocols., (© 2023 The Authors. Allergy published by 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.)

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.)

Background: Drugs are a frequent cause of severe anaphylactic reactions. Here, we analyze a large dataset on drug induced anaphylaxis regarding elicitors, risk factors, symptoms, and treatment., Methods: Data from the European Anaphylaxis Registry (2007-2019) with 1815 reported cases of drug-induced anaphylaxis were studied accordingly., Results: Drugs are the third most frequent cause of anaphylaxis reported in the Anaphylaxis Registry. Among the eliciting groups of drugs analgesics and antibiotics were far most often reported. Female and senior patients were more frequently affected, while the number of children with DIA was low. DIA patients had symptoms affecting the skin and mucous membranes (n = 1525, 84.02%), the respiratory (n = 1300, 71.63%), the cardiovascular (n = 1251, 68.93%) and the gastrointestinal system (n = 549, 30.25%). Drugs caused significant more severe reactions, occurred more often in medical facilities and led to increased hospitalization rates in comparison to food and insect venom induced anaphylaxis. Adrenaline was used more often in patients with DIA than in anaphylaxis due to other causes. Patients with skin symptoms received more antihistamines and corticosteroids in the acute treatment, while gastrointestinal symptoms led to less adrenaline use., Conclusion: The study contributes to a better understanding of DIA, with a large number of cases from Europe supporting previous data, e.g., analgesics and antibiotics being the most frequent culprits for DIA. Female gender and higher age are relevant risk factors and despite clear recommendations, the emergency treatment of DIA is not administered according to the guidelines., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Evaluation of perioperative hypersensitivity (POH) is challenging, and accurate screening tools are needed to optimize the diagnostic process. We aimed to assess and validate the diagnostic value of a published algorithm (using tryptase and clinical presentation) to identify appropriate individuals for further testing for IgE-mediated POH., Methods: We analysed the clinical presentation (tryptase elevation, cardiovascular, respiratory, skin involvement) of patients proceeding to testing for possible IgE-mediated POH at a single tertiary referral centre, relative to subsequent skin testing and specific IgE results. Clinical presentations by drug class were also determined., Results: In 293 consecutive patients, the use of a published algorithm based on one or more of; (i) defined increase in serum tryptase, (ii) involvement of at least two-organ systems, or (iii) presentation with new urticaria and/or angioedema; was highly sensitive [98.8% (CI95: 95.7-99.9%)] but less specific [34.6% (CI95: 25.7-44.4%)] in identifying patients testing positive on skin testing and/or specific IgE. Presentation with cardiovascular symptoms was also sensitive [89.8%(CI95: 84.2-94.0%)], while the combination of respiratory symptoms and increased tryptase was most specific [85.9%(CI95:76.6-92.5%)]. Respiratory involvement was more common in neuromuscular blocking agent allergy, while urticaria/angioedema was more common in antibiotic allergy., Conclusion: The published algorithm (of tryptase rise, two-organ involvement or new urticaria/angioedema) is highly sensitive, and appropriate as a screening tool to identify patients suitable for testing for IgE-mediated POH., (© 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: The diagnosis of allergic reactions to penicillins (AR-PEN) is very complex as there is a loss of sensitization over time, which leads to negative skin tests (STs) and specific IgE in serum, and even to tolerance to the drug involved. However, STs may become positive after subsequent exposure to the culprit drug (resensitization), with the risk of inducing potentially severe reactions. The exact rate of resensitization to penicillins is unknown, ranging from 0% to 27.9% in published studies., Objectives: To analyze the rate of resensitization in patients with suggestive AR-PEN by repeating STs (retest) after an initial evaluation (IE)., Material and Methods: Patients with suspected AR-PEN were prospectively evaluated between 2017 and 2020. They underwent STs, and a randomized group also underwent a drug provocation test (DPT) with the culprit. Only patients with negative STs and/or DPT were included. All included cases were retested by STs at 2-8 weeks., Results: A total of 545 patients were included: 296 reporting immediate reactions (IRs) and 249 non-immediate reactions (NIRs). Eighty (14.7%) cases had positive results in retest (RT+): 63 (21.3%) IRs and 17 (6.8%) NIRs (p < 0.0001). The rate of RT+ was higher in anaphylaxis compared with all other reactions (45.8% vs 9.1%, p < 0.0001). The risk of RT+ was higher from the fifth week after IE (OR: 4.64, CI: 2.1-11.6; p < 0.001) and increased with the patient's age (OR: 1.02; CI: 1.01-1.04; p = 0.009)., Conclusions: Due to the high rate of resensitization, retest should be included in the diagnostic algorithm of IRs to penicillins after an initial negative study, especially in anaphylaxis, to avoid potentially severe reactions after subsequent prescriptions of these drugs., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Virus infections and T-cell-mediated drug hypersensitivity reactions (DHR) can influence each other. In most instances, systemic virus infections appear first. They may prime the reactivity to drugs in two ways: First, by virus-induced second signals: certain drugs like β-lactam antibiotics are haptens and covalently bind to various soluble and tissue proteins, thereby forming novel antigens. Under homeostatic conditions, these neo-antigens do not induce an immune reaction, probably because co-stimulation is missing. During a virus infection, the hapten-modified peptides are presented in an immune-stimulatory environment with co-stimulation. A drug-specific immune reaction may develop and manifest as exanthema. Second, by increased pharmacological interactions with immune receptors (p-i): drugs tend to bind to proteins and may even bind to immune receptors. Without viral infections, this low affine binding may be insufficient to elicit T-cell activation. During a viral infection, immune receptors are more abundantly expressed and allow more interactions to occur. This increases the overall avidity of p-i reactions and may even be sufficient for T-cell activation and symptoms. There is a situation where the virus-DHR sequence of events is inversed: in drug reaction with eosinophilia and systemic symptoms (DRESS), a severe DHR can precede reactivation and viremia of various herpes viruses. One could explain this phenomenon by the massive p-i mediated immune stimulation during acute DRESS, which coincidentally activates many herpes virus-specific T cells. Through p-i stimulation, they develop a cytotoxic activity by killing herpes peptide-expressing cells and releasing herpes viruses. These concepts could explain the often transient nature of DHR occurring during viral infections and the often asymptomatic herpes-virus viraemia after DRESS., (© 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Hypersensitivity reactions to drugs are increasing worldwide. They display a large degree of variability in the immunological mechanisms involved, which impacts both disease severity and the optimal diagnostic procedure. Therefore, drug hypersensitivity diagnosis relies on both in vitro and in vivo assessments, although most of the methods are not well standardized. Moreover, several biomarkers can be used as valuable parameters for precision medicine that provide information on the endotypes, diagnosis, prognosis, and prediction of drug hypersensitivity development, as well on the identification of therapeutic targets and treatment efficacy monitoring. Furthermore, in the last 2 years, the SARS-CoV-2 (severe acute respiratory syndrome-coronavirus) pandemic has had an important impact on health system, leading us to update approaches on how to manage hypersensitivity reactions to drugs used for its treatment and on COVID-19 (Coronavirus disease) vaccines used for its prevention. This article reviews recent advances in these 3 areas regarding drug hypersensitivity: in vitro tools for drug hypersensitivity diagnosis, recently identified biomarkers that could guide clinical decision making and management of hypersensitivity reactions to drugs and vaccines used for COVID-19., (© 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

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.)

Background: mRNA-based COVID-19 vaccines have been reported to induce hypersensitivity reactions (HSR) in a small number of individuals. We aimed to evaluate the real-world incidence of the BNT162b2 mRNA COVID-19 vaccine HSR and to determine the value of the basophil activation test (BAT) in the allergological workup of patients reporting these reactions., Methods: We prospectively enrolled patients with a clinical history indicative of HSR to the BNT162b2 mRNA COVID-19 vaccine. The allergological workup included skin testing (STs) and BAT with polyethylene glycol (PEG) and the vaccine. In those with negative allergy assessments, the administration of the second dose of the BNT162b2 mRNA COVID-19 vaccine was offered., Results: Seventeen adults were included. Eleven cases (64.7%) tested negative in the allergological workup and tolerated the re-administration of the second dose of the vaccine and considered non-allergic. Six cases (35.3%) were considered allergic and classified into three groups: 2 subjects displayed positive STs and/or BAT to PEG (Group A), two individuals displayed positive BAT to the vaccine (Group B), and in 2 patients with moderate or severe reactions, the culprit was not identified, tested negative to STs and BAT to both PEG and vaccine (Group C). We further evaluated the value of BAT when the results were positive to the vaccine and negative to PEG by performing BAT in controls groups, finding positive BAT results in 50% of controls, all of them recovered from COVID-19 infection. In contrast, BAT was negative in patients who had not suffered from COVID-19 disease., Conclusions: BAT can be used as a potential diagnostic tool for confirming allergy to PEG excipient but not to the vaccine as a positive result in BAT may indicate a past COVID-19 infection instead of an allergy., (© 20221 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Chemotherapeutic drugs have been widely used in the treatment of cancer disease for about 70 years. The development of new treatments has not hindered their use, and oncologists still prescribe them routinely, alone or in combination with other antineoplastic agents. However, all chemotherapeutic agents can induce hypersensitivity reactions (HSRs), with different incidences depending on the culprit drug. These reactions are the third leading cause of fatal drug-induced anaphylaxis in the United States. In Europe, deaths related to chemotherapy have also been reported. In particular, most reactions are caused by platinum compounds, taxanes, epipodophyllotoxins and asparaginase. Despite their prevalence and relevance, the ideal pathways for diagnosis, treatment and prevention of these reactions are still unclear, and practice remains considerably heterogeneous with vast differences from center to center. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology organized a task force to provide data and recommendations regarding the allergological work-up in this field of drug hypersensitivity reactions. This position paper aims to provide consensus on the investigation of HSRs to chemotherapeutic drugs and give practical recommendations for clinicians that treat these patients, such as oncologists, allergologists and internists. Key sections cover risk factors, pathogenesis, symptoms, the role of skin tests, in vitro tests, indications and contraindications of drug provocation tests and desensitization of neoplastic patients with allergic reactions to chemotherapeutic drugs. Statements, recommendations and unmet needs were discussed and proposed at the end of each section., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Biologicals are crucial targeted therapeutic agents in oncological, immunological, and inflammatory diseases, and their use in clinical practice is broadening. In recent years, the spread of Personalized Precision Medicine has facilitated a proliferation of new treatment options, especially biologicals. Consequently, biologicals are now among the drugs that most frequently cause hypersensitivity reactions (HSRs). Patients can develop HSRs to these agents during the first-lifetime exposure or after repeated exposure, and these HSRs can be potentially life-threatening or limit therapeutic options. Despite the relatively high prevalence, the underlying mechanisms of these HSRs remain obscure, and the optimal management pathways are still a matter of discussion. In this Position Paper, the authors will provide evidence-based recommendations for diagnosing and managing HSRs to biologicals. Additionally, the document defines unmet needs as an opportunity to shape future research., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Amoxicillin (AX) is nowadays the β-lactam that more frequently induces immediate allergic reactions. Nevertheless, diagnosis of AX allergy is occasionally challenging due to risky in vivo tests and non-optimal sensitivity of in vitro tests. AX requires protein haptenation to form multivalent conjugates with increased size to be immunogenic. Knowing adduct structural features for promoting effector cell activation would help to improve in vitro tests. We aimed to identify the optimal structural requirement in specific cellular degranulation to AX using well-precised nanoarchitectures of different lengths., Method: We constructed eight Bidendron Antigens (BiAns) based on polyethylene glycol (PEG) linkers of different lengths (600-12,000 Da), end-coupled with polyamidoamine dendrons that were terminally multi-functionalized with amoxicilloyl (AXO). In vitro IgE recognition was studied by competitive radioallergosorbent test (RAST) and antibody-nanoarchitecture complexes by transmission electron microscopy (TEM). Their allergenic activity was evaluated using bone marrow-derived mast cells (MCs) passively sensitized with mouse monoclonal IgE against AX and humanized RBL-2H3 cells sensitized with polyclonal antibodies from sera of AX-allergic patients., Results: All BiAns were recognized by AX-sIgE. Dose-dependent activation responses were observed in both cellular assays, only with longer structures, containing spacers in the range of PEG 6000-12,000 Da. Consistently, greater proportion of immunocomplexes and number of antibodies per complex for longer BiAns were visualized by TEM., Conclusions: BiAns are valuable platforms to study the mechanism of effector cell activation. These nanomolecular tools have demonstrated the importance of the adduct size to promote effector cell activation in AX allergy, which will impact for improving in vitro diagnostics., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Introduction: Mild non-immediate reactions (NIRs) to beta-lactams (BLs) are the most frequent manifestation of drug allergy in children. The diagnostic approach is complex as the utility of skin tests (STs) and lymphocyte transformation tests (LTTs) is controversial. Drug provocation test (DPT) is the gold standard, although no standardized protocols exist. We aimed to investigate the utility of DPT in a unique dose without previous STs, and LTTs in the diagnosis of NIRs to BLs in children., Methods: We prospectively evaluated children 0-14 years old referred to the Regional University Hospital of Málaga during 2017-2020 reporting NIRs to BLs. We performed a DPT with a unique dose followed by regular treatment at home. If positive, STs and LTTs were done after the reaction had disappeared., Results: We included 194 children, having 24 (12.4%) a positive DPT. The main culprit was AX (70.1%) followed by AX-clavulanic acid (CLV) (26.8%) and the main symptoms maculopapular exanthema (MPE) (49.5%) and delayed-urticaria (48.5%). A decrease (p = 0.013) in the interval of days between drug administration and onset of symptoms was observed in positive DPT compared with the original reaction (3.5 vs 6 days), with no differences in the overall percentage of MPE and delayed-appearing urticaria (p = 0.551). No severe reactions occurred during DPT. Moreover, STs were positive in 13.33% and LTTs in 52.9%., Conclusions: Single-dose DPT without previous STs is a safe and useful way to assess NIRs to BLs in children. LTT has shown to be useful, confirming a T-cell mechanism involved in these reactions., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

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.)

Background: In up to 70%-80% of patients with a suspected non-steroidal anti-inflammatory drug hypersensitivity (NSAIDH), challenge tests with the culprit drug yield negative results. On the other hand, there could be a NSAIDH overdiagnosis when anaphylaxis is the clinical manifestation. We hypothesize that some negative NSAID challenge tests and an overdiagnosis of NSAIDH occur in patients with food-dependent NSAID-induced hypersensitivity (FDNIH)., Methods: We studied 328 patients with a suspected acute NSAIDH. FDNIH was diagnosed in patients meeting all the following: (1) tolerance to the food ingested more temporally closed before the reaction, later the episode, (2) respiratory or cutaneous symptoms or anaphylaxis related to NSAID, (3) positive skin prick test to foods and/or specific IgE to food allergens (Pru p 3, Tri a 19, Pen a 1) involved in the reaction, and (4) negative oral provocation test to the culprit NSAID., Results: 199 patients (60%) were diagnosed with NSAIDH and 52 (16%) with FDNIH. Pru p 3 was involved in 44 cases (84.6%) and Tri a 19 in 6 cases (11%). FDNIH subjects were younger (p < .001), with a higher prevalence of rhinitis (p < .001) and previous food allergy (p < .001), together with a higher proportion of subjects sensitized to pollens (p < .001) and foods (p < .001). Using just four variables (Pru p 3 sensitization, Tri a 19 sensitization, anaphylaxis, and any NSAID different from pyrazolones), 95.3% of cases were correctly classified, with a sensitivity of 92% and specificity of 96%., Conclusion: Evaluation of FDNIH should be included in the diagnostic workup of NSAIDH., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

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.)

Background: Little is known about the diagnostic approaches for immediate hypersensitivity reactions (IHRs) due to 5-nitroimidazole antibiotics. The aim was to evaluate the usefulness of in vivo tests and basophil activation test (BAT) for the diagnosis of IHRs due to metronidazole and ornidazole and to determine possible cross-reactivity in between., Methods: Forty-nine patients with a clear history of IHRs due to these drugs and 20 healthy subjects who were known to tolerate these drugs were included. Skin tests (STs) and single-blind placebo-controlled drug provocation tests (SBPCDPTs) were performed with both drugs whereas BAT was applied only with the culprit drug., Results: The most and least common reaction types were urticaria/angioedema (34.7%) and anaphylaxis (14.3%), respectively. SBPCDPTs were positive in 15 out of 47 patients, and only 7 had positive STs. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of STs for metronidazole/ornidazole were 33.3%/16.6%, 94.2%/97.3%, 60%/50%, and 84.6%/88.1%, respectively. BAT was positive in 12 out of 15 patients and negative in 10 control subjects, giving a sensitivity rate of 71.4% (CI, 29.0%-96.3%) for metronidazole and 83.3% (CI, 35.8%-99.5%) for ornidazole. The optimal concentration of both drugs for BAT was determined as 5 mg/mL. No cross-reactivity among two drugs was observed according to in vivo tests., Conclusions: Our study showed that SBPCDPT and BAT are both useful diagnostic tools for IHRs due to 5-nitroimidazole antibiotics and can be used as supplementary to each other. No cross-reactivity between metronidazole and ornidazole in IHRs exists., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Penicillin refers to a group of beta-lactam antibiotics that are the first-line treatment for a range of infections. However, they also possess the ability to form novel antigens, or neoantigens, through haptenation of proteins and can stimulate a range of immune-mediated adverse reactions-collectively known as drug hypersensitivity reactions (DHRs). IgE-mediated reactions towards these neoantigens are well studied; however, IgE-independent reactions are less well understood. These reactions usually manifest in a delayed manner as different forms of cutaneous eruptions or liver injury consistent with priming of an immune response. Ex vivo studies have confirmed the infiltration of T cells into the site of inflammation, and the subsets of T cells involved appear dependent on the nature of the reaction. Here, we review the evidence that has led to our current understanding of these immune-mediated reactions, discussing the nature of the lesional T cells, the characterization of drug-responsive T cells isolated from patient blood, and the potential mechanisms by which penicillins enter the antigen processing and presentation pathway to stimulate these deleterious responses. Thus, we highlight the need for a more comprehensive understanding of the underlying genetic and molecular basis of penicillin-induced DHRs., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

A correct diagnosis of drug hypersensitivity reactions (DHRs) is very important for both the patient and health system. However, DHRs diagnosis is complex, time consuming, requires trained personnel, is not standardized for many drugs, involves procedures not exempt of risk, and in most cases lacks standardized in vivo and in vitro tests. Thus, there is an urgent need for improving the different approaches to diagnose patients with suspected DHRs. In this review, we have analyzed the advances performed in immediate and nonimmediate DHRs diagnosis during the last two years and obtained several conclusions: the significant heterogeneity in current practice among centers illustrates the need to re-evaluate, update, and standardize in vivo tests and protocols for the diagnosis and management of patients with suspected drug allergy. Regarding in vitro tests, the latest studies have focused on increasing their sensitivity or on establishing the sensitivity and specificity for the tests performed with new drugs. There seems to be a consensus about combining in vivo and in vitro tests as the best way to increase the diagnostic accuracy., (© 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: Betalactam (BL) antibiotics are the most common cause of drug hypersensitivity. Amoxicillin (AX), which is often prescribed alongside clavulanic acid (Clav), is the most common elicitor. The aim of this study was to determine whether AX and Clav-responsive T-cells are detectable in patients with immediate hypersensitivity to AX-Clav, to assess whether these T-cells display the same specificity as that detected in skin and provocation testing, and to explore T-cell activation pathways., Methods: Drug-specific T-cell clones were generated from immediate hypersensitive patients´ blood by serial dilution and repetitive mitogen stimulation. Antigen specificity was assessed by measurement of proliferation and cytokine release. CD4 + /CD8 + phenotype and chemokine receptor expression were analyzed by flow cytometry., Results: 110 AX-specific and 96 Clav-specific T-cell clones were generated from seven patients with positive skin test to either AX or Clav. Proliferation of AX- and Clav-specific clones was dose-dependent, and no cross-reactivity was observed. AX- and Clav-specific clones required antigen-presenting cells to proliferate, and drugs were presented to CD4 + and CD8 + T-cells by MHC class-II and I, respectively. A higher secretion of IL-13 and IL-5 was detected in presence of the culprit drug compared with the alternative drug. Clones expressed CD69, CCR4, CXCR3, and CCR10., Conclusions: Our study details the antigen specificity and phenotype of T-cell clones generated from patients with AX-Clav-induced immediate hypersensitivity diagnosed by positive skin test. AX- and Clav-specific clones were generated from patients irrespective of whether AX or Clav was the culprit, although differences in cytokine secretion were observed., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

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.)