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Background and Objective: Amoxicillin-clavulanic acid (AX-CL) is the most consumed ß-lactam antibiotic worldwide. We aimed to establish the different phenotypes of ß-lactam allergy in patients reporting a reaction to AX-CL and to investigate the differences between immediate and nonimmediate onset., Methods: We performed a cross-sectional retrospective study at Hospital Clínico San Carlos (HCSC), Madrid and Hospital Regional Universitario de Málaga (HRUM), Málaga, Spain. We included patients reporting reactions with AX-CL who underwent the allergy workup between 2017 and 2019. Data on the reported reaction and allergy work-up were collected. Reactions were classified as immediate and nonimmediate with a 1-hour cut-off., Results: The study population comprised 372 patients (HCSC 208, HRUM 164). There were 90 immediate reactions (24.2%), 252 nonimmediate reactions (67.7%), and 30 reactions with unknown latency (8.1%). Allergy to ß-lactams was ruled out in 266 patients (71.5%) and confirmed in 106 patients (28.5%). The final main diagnosis in the overall population was allergy to aminopenicillins (7.3%), to CL (7%), to penicillin (6.5%), and to ß-lactams (5.9%). Allergy was confirmed in 77.2% and 14.3% of immediate and nonimmediate reactions, respectively, with a relative risk of 5.06 (95%CI, 3.64-7.02) for an allergy diagnosis in those reporting immediate reactions. Only 2/54 patients with a late-positive intradermal test (IDT) result for CL were diagnosed with CL allergy., Conclusion: Allergy was diagnosed in a minority of the study population. However, given that it was diagnosed 5 times more frequently in patients reporting immediate reactions, this classification proved useful for risk stratification. Late-positive IDT results for CL have no diagnostic value. Therefore, the late IDT reading for CL could be removed from the diagnostic work-up.

Rapid drug desensitization has enabled first-line therapies in patients with drug hypersensitivity reactions to chemotherapeutic drugs including monoclonal antibodies. Desensitization is a safe and highly effective procedure, not only for IgE-mediated reactions, but also for those mediated by non-IgE mechanisms. The likelihood of breakthrough reactions during desensitization is low, and most are mild; in fact, moderate-to-severe reactions are infrequent. In this document, 16 allergy departments belonging to the Spanish research network ARADyAL present a review of the available scientific evidence and provide general guidelines for the diagnosis and management of drug hypersensitivity reactions to chemotherapeutic drugs and monoclonal antibodies. Emphasis is placed on the desensitization procedure.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used throughout the world. They are frequently involved in hypersensitivity reactions, which range from local or mild reactions to systemic and severe reactions. Consequently, it is necessary to perform an exhaustive study of patients in order to make an accurate diagnosis, search for safe procedures in the case of severe reactions, and identify alternative treatment options. Various guidelines and protocols address the management of hypersensitivity to NSAIDs, although these vary widely from country to country. The Committees of Asthma, Rhinoconjunctivitis, and Drug Allergy of the Spanish Society of Allergy and Clinical Immunology (SEAIC) propose the present position statement on available options for provocation testing with aspirin/NSAIDs. This document is the fruit of an exhaustive review of current evidence and is based on recent publications addressing the diagnosis of patients with hypersensitivity to NSAIDs and on a consensus-oriented discussion among a group of experts from the SEAIC. The main objective was to draft an easy-toread, practical guideline for health care professionals in specialist areas who assess and manage patients with suspected hypersensitivity to NSAIDs. Furthermore, indications, contraindications, and procedures for oral, bronchial, and nasal provocation tests with aspirin/NSAIDs have been updated.

Perioperative hypersensitivity reactions constitute a first-line problem for anesthesiologists and allergists. Therefore, hospitals should have a consensus protocol for the diagnosis and management of these reactions. However, this kind of protocol is not present in many hospitals, leading to problems with treatment, reporting of incidents, and subsequent etiological diagnosis. In this document, we present a systematic review of the available scientific evidence and provide general guidelines for the management of acute episodes and for referral of patients with perioperative hypersensitivity reactions to allergy units. Members of the Drug Allergy Committee of the Spanish Society of Allergy and Clinical Immunology (SEAIC) have created this document in collaboration with members of the Spanish Anesthesia Society (SEDAR). A practical algorithm is proposed for the etiologic diagnosis, and recommendations are provided for the management of hypersensitive patients.

Background and Objectives: Individuals who develop drug hypersensitivity reactions (DHRs) to chemically unrelated nonsteroidal anti-inflammatory drugs (NSAIDs) are considered cross-hypersensitive. The hallmark for this classification is that the patient presents a reaction after intake of or challenge with acetylsalicylic acid (ASA). Whether patients react to 2 or more NSAIDs while tolerating ASA remains to be studied (selective reactions, SRs). Objective: To identify patients with SRs to 2 or more NSAIDs including strong COX-1 inhibitors., Methods: Patients who attended the Allergy Service of Hospital Infanta Leonor, Madrid, Spain with DHRs to NSAIDs between January 2011 and December 2014 were evaluated. Those with 2 or more immediate reactions occurring in less than 1 hour after intake were included. After confirming tolerance to ASA, the selectivity of the response to 2 or more NSAIDs was demonstrated by in vivo and/or in vitro testing or by controlled administration., Results: From a total of 203 patients with immediate DHRs to NSAIDs, 16 (7.9%) met the inclusion criteria. The patients presented a total of 68 anaphylactic or cutaneous reactions (mean [SD], 4.2 [2.1]). Most reactions were to ibuprofen and other arylpropionic acid derivatives and to metamizole. Two different NSAIDs were involved in 11 patients and 3 in 5 patients., Conclusions: Patients with NSAID-induced anaphylaxis or urticaria/angioedema should not be considered cross-hypersensitive unless tolerance to ASA is verified.

Background: Amoxicillin (AX) is the ß-lactam most often involved in IgE-mediated reactions. Diagnosis is based mainly on skin testing, although sensitivity is not optimal. We produced a new AX derivative, amoxicilloyl-poly-L-lysine (APL), and analyzed its recognition of IgE using the passive histamine release test (pHRT)., Methods: The study population comprised patients (n=19) with confirmed AX allergy and specific IgE to AX and controls (n=10) with good tolerance to AX. pHRT was performed using "IgE-stripped" blood from a single donor that was sensitized in vitro by patient sera and incubated with AX or APL. Histamine release was determined and expressed as nanograms of histamine released per milliliter of blood., Results: The clinical symptoms were anaphylaxis (n=9), urticaria (n=7), erythema (n=2), and nondefined immediate reactions (n=1). The median (IQR) time interval between reaction and study was 90 (60-240) days and between drug intake and development of symptoms 24 (10-60) minutes. The median sIgE level was 3.37 (0.95-5.89) kUA/L. The sensitivity of pHRT to APL was 79% and the specificity 100%, which were higher than data obtained with pHRT to AX (63% sensitivity and 90% specificity). There was a positive correlation between maximal histamine release levels obtained with AX and APL (r=0.63)., Conclusions: In patients with immediate hypersensitivity reactions to AX, APL showed higher sensitivity and specificity than the culprit drug, AX, when tested in vitro by pHRT. This indicates that APL can improve the in vitro diagnostic accuracy of allergic reactions to AX. Further assessment of skin testing is necessary.

Drug hypersensitivity reactions (DHRs) are unpredictable, complex responses to medicines in predisposed individuals. They represent a major health problem owing to the number of patients affected and the severity of the clinical conditions they can induce. In addition to environmental factors, the underlying mechanisms of DHRs are also influenced by genetic factors, although considerable gaps remain in our knowledge. Therefore, further study of the genetics of DHRs is necessary to shed light on their underlying mechanisms. In this manuscript, we provide an update on the genetic basis of the most frequent types of DHRs, including those mediated by immunological and nonimmunological mechanisms. For the first group, we will focus on immediate reactions to β-lactam antibiotics, which are associated mainly with the IgE pathway (IL13, IL4R, LGALS3, and NOD2) and antigen presentation (HLA-DRA), and nonimmediate reactions to allopurinol, anticonvulsants, antibiotics, and antiretrovirals, which are often associated with polymorphisms in the HLA system. For the second group, we will focus on nonsteroidal anti-inflammatory drugs, which are mostly associated with genetic variants in enzymes and receptors from the arachidonic acid pathway (eg, ALOX5, ALOX5AP, PTGDR, and CYSLTR1). The information provided here will be of interest for medical practitioners from a range of disciplines who come across these reactions in their clinical practice, as well as for allergologists.

β-Lactams (BL) are the drugs most frequently involved in allergic reactions. They are classified according to their chemical structure as penicillins, cephalosporins, monobactams, carbapenems, and clavams. All BL antibiotics have a BL ring that is fused to a 5-member or 6-member ring (except in monobactams) and has 1, 2 or 3 side chains (except in clavams). Differences in chemical structure mean that a wide range of BLs are recognized by the immune system, and patients may experience clinical reactions to one BL while tolerating others. Diagnosis is based on skin and in vitro testing, although both display low sensitivity, possibly because they are based on drugs or drug conjugates that are not optimally recognized by the immune system. BLs are haptens that need to bind to proteins covalently to elicit an immune response. These drugs have a high capacity to form covalent adducts with proteins through nucleophilic attack of amino groups in proteins on the BL ring. Allergenic determinants have been described for all BLs, although benzylpenicillin is the most widely studied. Moreover, formation of BL-protein adducts is selective, as we recently demonstrated for amoxicillin, which mainly modifies albumin, transferrin, and immunoglobulin heavy and light chains in human serum. Given the complexity of BL allergy, understanding the immunological mechanisms involved and optimization of diagnostic methods require multidisciplinary approaches that take into account the chemical structures of the drugs and the carrier molecules, as well as the patient immune response.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used throughout the world to treat pain and inflammation; however, they can trigger several types of drug hypersensitivity reactions (DHRs) in all age groups. Although most such reactions occur through activation of the leukotriene pathway without specific immunological recognition (cross-intolerance), a significant number of DHRs to NSAIDs are due to immunological mechanisms (selective reactions [SRs]). SRs are thought to be induced by specific IgE antibodies or by T cells. In this manuscript, we focus on SRs, which are of great concern in children and adolescents and comprise a heterogeneous set of clinical pictures ranging from mild entities such as urticaria/angioedema to potentially life-threatening conditions such as Stevens-Johnson syndrome/toxic epidermal necrolysis. Paracetamol and ibuprofen are the most frequent elicitors of IgE-mediated SRs, although pyrazolones have also been implicated. T cell-mediated reactions are infrequent in children but have been associated with ibuprofen, naproxen, and dipyrone. In this review, we analyze the available literature on SRs in children and adolescents, with emphasis on epidemiological data, mechanisms, and drugs involved, as well as on diagnostic procedures.

Hypersensitivity drug reactions (HDRs) vary over time in frequency, drugs involved, and clinical entities. Specific reactions are mediated by IgE, other antibody isotypes (IgG or IgM), and T cells. Nonspecific HDRs include those caused by nonsteroidal anti-inflammatory drugs (NSAIDs). beta-Lactams--the most important of which are amoxicillin and clavulanic acid--are involved in specific immunological mechanisms. Fluoroquinolones (mainly moxifloxacin, followed by ciprofloxacin and levofloxacin) can also induce HDRs mediated by IgE and T cells. In the case of radio contrast media, immediate reactions have decreased, while nonimmediate reactions, mediated by T cells, have increased. There has been a substantial rise in hypersensitivity reactions to antibiotics and latex in perioperative allergic reactions to anesthetics. NSAIDs are the most frequent drugs involved in HDRs. Five well-defined clinical entities, the most common of which is NSAID-induced urticaria/angioedema, have been proposed in a new consensus classification. Biological agents are proteins including antibodies that have been humanized in order to avoid adverse reactions. Reactions can be mediated by IgE or T cells or they may be due to an immunological imbalance. Chimeric antibodies are still in use and may have epitopes that are recognized by the immune system, resulting in allergic reactions.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in hypersensitivity reactions. These reactions include various clinical entities with different mechanisms leading to the release of inflammatory mediators. Characterization of patients based on clinical manifestations and suspected underlying mechanisms is critical for implementation of adequate diagnostic procedures and patient management. Our objectives were to prepare a systematic review of available scientific evidence and to provide general guidelines for the diagnosis and management of patients with hypersensitivity reactions to NSAIDs. We also propose a practical algorithm for the diagnosis of specific types of hypersensitivity to NSAIDs and provide recommendations for the management of hypersensitive patients.

Nonimmediate drug hypersensitivity reactions (DHRs) are difficult to manage in daily clinical practice, mainly owing to their heterogeneous clinical manifestations and the lack of selective biological markers. In vitro methods are necessaryto establish a diagnosis, especially given the low sensitivity of skin tests and the inherent risks of drug provocation testing. In vitro evaluation of nonimmediate DHRs must include approaches that can be applied during the different phases of the reaction. During the acute phase, monitoring markers in both skin and peripheral blood helps to discriminate between immediate and nonimmediate DHRs with cutaneous responses and to distinguish between reactions that, although they present similar clinical symptoms, are produced by different immunological mechanisms and therefore have a different treatment and prognosis. During the resolution phase, in vitro testing is used to detect the response of T cells to drug stimulation; however, this approach has certain limitations, such as the lack of validated studies assessing sensitivity. Moreover, in vitro tests indicate an immune response that is not always related to a DHR. In this review, members of the Immunology and Drug Allergy Committee of the Spanish Society of Allergy and Clinical Immunology (SEAIC) provide an overview of the most widely used in vitro tests for evaluating nonimmediate DHRs.

Background: Allergy to penicillin is the most commonly reported type of drug hypersensitivity. Diagnosis is currently confirmed using skin tests with benzylpenicillin reagents, ie, penicilloyl-polylysine (PPL) as the major determinant of benzylpenicillin and benzylpenicillin, benzylpenicilloate and benzylpenilloate as a minor determinant mixture (MDM)., Objective: To synthesize and assess the diagnostic capacity of 2 new benzylpenicillin reagents in patients with immediate hypersensitivity reactions to B-lactams: benzylpenicilloyl octa-L-lysine (BP-OL) as the major determinant and benzylpenilloate (penilloate) as the minor determinant., Methods: Prospective multicenter clinical trial performed in 18 Spanish centers. Efficacy was assessed by detection of positive skin test results in an allergic population and negative skin test results in a nonallergic, drug-exposed population. Sensitivity, specificity, and negative and positive predictive values were determined., Results: The study sample comprised 94 allergic patients: 31 (35.23%) presented anaphylaxis, 4 (4.55%) anaphylactic shock, 51 (58.04%) urticaria, and 2 (2.27%) no specific condition. The culprit 8-lactams were amoxicillin in 63 cases (71.60%), benzypencillin in 14 cases (15.89%), cephalosporins in 2 cases (2.27%), other drugs in 3 cases (3.42%), and unidentified agents in 6 cases (6.82%). The results of testing with BP-OL were positive in 46 cases (52.3%); the results of testing with penilloate were positive in 33 cases (37.5%). When both reagents were taken into consideration, sensitivity reached 61.36% and specificity 100%. Skin testing with penilloate was significantly more often negative when the interval between the reaction and the study was longer., Conclusions: The sensitivity of BP-OL and penilloate was 61%. Considering that amoxicillin was the culprit drug in 71% of reactions, these results indicate that most patients were allergic to the whole group of penicillins. These data support the use of benzylpenicillin determinants in the diagnosis of allergy to beta-lactams, even in predominantly amoxicillin-allergic populations.

Background: Drug hypersensitivity reactions (DHRs) are among the most frequent reasons for consultation in allergy departments, and are becoming more common due to increasing prevalence and case complexity., Objective: To study the clinical characteristics, drugs involved, diagnostic methods, and temporal variation of DHRs in a large series of patients over a 6-year period., Methods: We included all patients attending our department between 2005 and 2010. The diagnosis was performed by in vivo and/or in vitro tests (basophil activation test and specific immunoglobulin [Ig] E in serum and drug provocation testing [DPT]) when indicated., Results: We evaluated 4460 patients who reported 4994 episodes (mean [SD] of 1.13 [0.36] [range, 1-3] episodes per patient). Based on clinical history, 37% of the episodes were attributed to nonsteroidal anti-inflammatory drugs (NSAIDs), 29.4% to beta-lactam antibiotics (BLs), 15% to non-BLs, and 18.4% to other drugs.Analysis of the 1683 patients (37.45%) finally confirmed as allergic showed the most frequent diagnosis to be hypersensitivity to multiple NSAIDs (47.29%), followed by immediate reactions to BLs (18.12%). There was an increase in reactions to non-BLs (from 21.2% to 31.9%; P < .03) over the study period, mainly due to an increase in allergy to quinolones (from 0.5% to 6.8%; P < .02); 44% of patients were diagnosed by clinical history, 14.6% by skin tests, 10.4% by in vitro tests, and 30.8% by DPT., Conclusions: NSAIDs were the drugs most frequently involved in DHRs and the most common diagnosis was urticaria/angioedema with cross intolerance. Reactions to emerging drugs such as quinolone derivatives and radiocontrast media are becoming more common.

Introduction: This multicenter study aimed to evaluate the diagnostic value of 2 cellular tests based on basophil reactivity--the basophil activation test (BAT, Flow-CAST) and the sulfidoleukotriene release assay (CAST-ELISA)--in immediate-type beta-lactam allergy, particularly in patients with a clinical history of allergy and a negative skin test result., Material and Methods: In a multicenter study encompassing 10 European centers, 181 patients with a history of immediate-type beta-lactam allergy, and 81 controls, we evaluated the diagnostic efficiency of specific IgE determinations and of 2 cellular tests based on basophil reactivity, the BAT and the sulfidoleukotriene release assay., Results: With Flow-CAST, sensitivity varied for individual beta-lactam allergens from 16% for penicilloyl-polylysine to 33% for amoxicillin, reaching 50% when all 5 allergens were considered. In beta-lactam-allergic patients with negative skin test results (22.8%), Flow-CAST showed positive results for at least 1 of the 5 allergens in 37%. Specificity varied from 89% to 97%, depending on the allergens used. In CAST-ELISA, the overall sensitivity in skin test-positive patients was 41.7%; in patients with negative skin test results it was 27.9%. Both tests were not absolutely correlated, so that when all the results were considered together, sensitivity increased to 64.3% and specificity varied for both tests combined from 73% to 92%. In contrast, specific IgE determinations in the same population yielded a lower sensitivity (28.3%)., Conclusions: A diagnostic algorithm including skin tests and specific IgE, followed by cellular tests in negative patients and controlled challenge enabled us to confirm beta-lactam allergy in 92% of cases. This procedure would also allow us to avoid two-thirds of the required controlled challenges.

Nonimmediate allergic reactions (NIRs) to drugs, which are the most common reactions induced by specific immunologic mechanisms, can be induced by all commercially available drugs. NIRs can appear hours, days, or even weeks after drug intake. They elicit a spectrum of manifestations, mostly affecting the skin, ranging from maculopapular exanthema and urticaria to other less common but more severe entities such as acute generalized exanthematic pustulosis, drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The main pathologic event involved in NIRs is a T-cell effector response and the wide heterogeneity of clinical symptoms may reflect differences in the underlying immunologic mechanisms. Despite their clinical heterogeneity, NIRs share certain aspects such as the activation of T cells with increased expression of CD25 and HLA-DR. NIRs are classified as type 1 helper (T(H)1) T-cell responses, characterized by the production of interferon-gamma, tumor necrosis factor-alpha, interleukin 2, T-bet, and the cytotoxic markers perforin and granzyme B. Diagnosis is often complicated because of the difficulty of obtaining a reliable clinical history, the important role played by cofactors such as viral diseases, and the low sensitivity of skin tests and in vitro tests. Further studies are thus required in order to improve our understanding of NIRs and refine our diagnostic criteria.