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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Delayed reactions to iodine contrast media (CM) account for 1-3% of patients with adverse reactions to iodine CM. The cellular and molecular mechanisms of these reactions remain poorly documented. Although most of these reactions are T cell mediated, the involvement of dendritic cells (DC) has not been investigated sufficiently. To determine whether the T cell response to iodixanol requires DC as antigen-presenting cell and, more particularly, to evaluate the changes induced by iodixanol on DC maturation and in vitro production of cytokines after drug stimulation in patients with maculopapular exanthema. Peripheral blood lymphocytes, immature monocyte-derived DC (imDC) and skin biopsies were obtained from patients with delayed reactions to iodixanol and tolerant subjects. We studied the consequences of the interaction between DC, lymphocytes and iodixanol by phenotype analysis, proliferation and cytokine production. A T-cell-mediated reaction was evidenced in patient biopsies, with a lymphocyte-rich, peri-vascular infiltrate. Iodixanol induced maturation of imDC from patients but not from controls, with expression of the co-stimulatory markers CD83, CD86 and CD40 and an increase in mean fluorescence intensity of CD80, CD86 and HLA-DR. In the absence of DC, positive cell proliferation to iodixanol was detected in only one patient while the addition of DC produced a positive test in five of the six patients. Similarly, the increase in cytokines (IFN-γ, IL-2, IL-6, IL-1b and TNF-α) was higher when imDC were introduced into the culture together with the culprit drug. These results provide evidence for a DC-mediated mechanism in delayed allergic reactions to CM, influencing T cell proliferation and cytokine production. These new insights will be helpful for designing immunotherapeutic strategies and in vitro diagnostic tests of CM-delayed reactions. Cite this as: C. Antunez, A. Barbaud, E. Gomez, S. Audonnet, S. Lopez, R.-M. Guéant-Rodriguez, I. Aimone- Gastin, F. Gomez, M. Blanca and J.-L. Guéant, Clinical & Experimental Allergy, 2011 (41) 657-664. [ABSTRACT FROM AUTHOR]

Skin testing with a suspected drug has been reported to be helpful in determining the cause of cutaneous adverse drug reactions (CADR). Many isolated reports of positive drug skin tests are published, but without detailed information concerning the clinical features of the CADR and the method used in performing drug skin tests, such data are not very informative. A working party of the European Society of Contact Dermatitis (ESCD) for the study of skin testing in investigating cutaneous adverse drug reactions, has proposed the herein-reported guidelines for performing skin testing in CADR in order to standardize these procedures. In each reported case, the imputability of each drug taken at the onset of the CADR and a highly detailed description and characterization of the dermatitis need to be given. Drug skin tests are performed 6 weeks to 6 months after complete healing of the CADR. Drug patch tests are performed according to the methods used in patch testing in studying contact dermatitis. The commercialized form of the drug used by the patient is tested diluted at 30% pet. (pet.) and/or water (aq.). The pure drug is tested diluted at 10% in pet. or aq. In severe CADR, drug patch tests are performed at lower concentrations. It is also of value to test on the most affected site of the initial CADR. Drug prick tests are performed on the volar forearm skin with the commercialized form of the drug, but with sequential dilutions in cases of urticaria. Intradermal tests (IDT) are performed with sterile sequential dilutions (10–4, 10–3, 10–2, 10–1) of a pure sterile or an injectable form of the suspected drug with a small volume of 0.04 ml. Drug skin tests need to be read at 20 min and also later at D2 and D4 for patch tests, at D1 for prick tests and IDT. All these tests also need to be read at 1 week. The success of skin tests varies with the drug tested, with a high % of positive results, for example, with betalactam antibiotics,... [ABSTRACT FROM AUTHOR]

Acute generalized exanthematous pustulosis (AGEP) is a rare, usually drug‐induced, acute pustular rash. Despite the lack of strong data supporting the effectiveness of topical or systemic corticosteroids in this drug reaction, they are widely used. More generally, there is no consensus on the diagnostic modalities and the management of patients with AGEP. We aimed to provide European expert recommendations for the diagnosis and management or patients with AGEP. Members of the ToxiTEN group of the European Reference Network (ERN)‐skin, all dermatologists and/or allergologists with expertise in drug reactions, elaborated these recommendations based on their own experience and on a review of the literature. Recommendations were separated into the following categories: professionals involved, assessment of the diagnosis of AGEP, management of the patient and allergological work‐up after the acute phase. Consensus was obtained among experts for the list of professionals involved for the diagnosis and management of AGEP, including the minimum diagnostic work‐up, the setting of management, the treatments, the modalities and the timing of allergological work‐up and follow‐up. European experts in drug allergies propose herein consensus on the diagnosis and management of patients with AGEP. A multidisciplinary approach is warranted, including dermatologists, allergologists and pharmacovigilance services. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity reactions (DHRs) affect an unknown proportion of the general population, and are an important public health problem due to their potential to cause life-threatening anaphylaxis and rare severe cutaneous allergic reactions. DHR evaluations are frequently needed in both ambulatory and hospital settings and have a complex diagnosis that requires a detailed clinical history and other tests that may include in vitro tests and in vivo procedures such as skin tests and drug provocation tests. Although over the years both European and U.S. experts have published statements on general procedures for evaluating DHRs, a substantial discordance in their daily management exists. In this review, we highlight both the differences and the similarities between the European and U.S. perspectives. While a general consensus exists on the importance of skin tests for evaluating DHRs, concordance between Americans and Europeans exists solely regarding their use in immediate reactions and the fact that a confirmation of a presumptive diagnosis by drug provocation tests is often the only reliable way to establish a diagnosis. Finally, great heterogeneity exists in the application of in vitro tests, which require further study to be well validated. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background. Drug patch tests (DPTs) with medicaments suspected of causing an allergic reaction represent a method of diagnostic testing that is low risk; DPTs can reproduce delayed hypersensitivity to drugs, and entail only a moderate re-exposure of patients to potential offending drugs. We assessed the non-irritating concentrations of DPTs and determined the amounts of active ingredient (AI) contained in the drugs used in the tests. Objectives. The objectives were to assess the non-irritating concentration of DPTs and determine the amounts of active ingredient (AI) contained in the drugs used in the tests. Methods. From a retrospective, single-centre study of all patients investigated during a 6-year period with a drug eruption, each potentially responsible drug was tested with the commercially available preparation diluted to 30% in water, petrolatum, or alcohol. Data collection was performed with a customized computer database. For each type of DPT studied, the numbers of positive and negative test results were recorded. The amount of AI contained in the DPT (as a percentage) was then calculated after weighing of each tablet. Results. Of the 5558 DPTs studied, all were non-irritant. The average concentration of AI was 9.8%; 25% of DPTs had an AI concentration of <2%, and 25% had an AI concentration of >16%. The AI concentration ranged from 0.05% (digoxin) to 30% (paracetamol lyophilisate). Conclusion. These data provide thresholds for the non-irritating concentration of AI of 68 different drugs, and thresholds for the non-irritating dilution for 82 drugs, and will help to standardize DPT methods. [ABSTRACT FROM AUTHOR]

Background We evaluated the value of skin tests and the efficacy of a 12-step desensitization protocol to pegylated interferon ( IFN) in patients with generalized drug eruptions due to IFNs. Methods A retrospective study (1998-2009) was followed by a cross-sectional clinical study conducted prospectively (2009-2011). All patients received a dermatological clinical examination and skin tests. Twelve-step IFN desensitization was proposed for patient with active hepatitis C and no alternative therapy. Results Twenty-six patients (13 males, mean age, 53.5 years) had generalized reactions to IFNs; 21 were treated with IFN-α and 5 with IFN-β. Moreover, 21 patients had skin tests. Intradermal tests ( IDTs) were positive after an average of 72 h. Cross-reactivity between peg- IFN-α2a and peg- IFN-α2b was observed in 5/10 cases in the prospective study. In 16 of 26 cases, IFN treatment was stopped. In 8 of 16 cases of diffuse eczematous drug eruption, treatment was continued. The corticosteroid and antihistamine were sufficient in 4/8 cases. In three other cases, topical tacrolimus was highly effective. In 3 of 16 cases in which treatment were stopped, patients underwent the early resumption of peg- IFN-α. These three patients had positive tests with peg- IFN-α2a and peg- IFN-α2b and successfully completed the tolerance induction protocol for peg- IFN-α2b. Tolerance induction involved a weekly dose of peg- IFN and a gradual increase in the recovery of an antiviral C. Clinical tolerance was excellent, and the patients' viral load C became negative. Conclusions Our study demonstrates the benefit of allergy testing in cases of generalized drug reactions to IFN, cross-reactivities in a single class of IFNs and the importance of delayed IDT reading. We report for the first time the effectiveness of 12-step desensitization with peg- IFN. [ABSTRACT FROM AUTHOR]

Skin tests are of paramount importance for the evaluation of drug hypersensitivity reactions. Drug skin tests are often not carried out because of lack of concise information on specific test concentrations. The diagnosis of drug allergy is often based on history alone, which is an unreliable indicator of true hypersensitivity.To promote and standardize reproducible skin testing with safe and nonirritant drug concentrations in the clinical practice, the European Network and European Academy of Allergy and Clinical Immunology ( EAACI) Interest Group on Drug Allergy has performed a literature search on skin test drug concentration in MEDLINE and EMBASE, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation. Where the literature is poor, we have taken into consideration the collective experience of the group.We recommend drug concentration for skin testing aiming to achieve a specificity of at least 95%. It has been possible to recommend specific drug concentration for betalactam antibiotics, perioperative drugs, heparins, platinum salts and radiocontrast media. For many other drugs, there is insufficient evidence to recommend appropriate drug concentration. There is urgent need for multicentre studies designed to establish and validate drug skin test concentration using standard protocols. For most drugs, sensitivity of skin testing is higher in immediate hypersensitivity compared to nonimmediate hypersensitivity. [ABSTRACT FROM AUTHOR]

Background: In patients with cutaneous adverse drug reactions (CADR), drug skin tests and re-challenge under hospital surveillance (RCH) are helpful. The aim of this study was to determine if patients with negative drug RCH can tolerate subsequent treatments with the same drugs. Patients and Methods: Patients with a negative RCH in the last 10 years answered a telephone questionnaire which was delivered by the same investigator in order to determine if subsequently the patients were able to tolerate the drug with which they had a negative RCH and also to study the reasons why the drugs were not taken again. Results: Six hundred and thirty-seven RCH were analyzed (349 patients, mean age 47 years), 134 drugs were taken again (group A) and 359 were not (group B). In group A, 12 reactions occurred in 10 patients (9%). In group B, drugs were not taken again because 76% of the patients evaluated for an intolerance to antibiotics or radiocontrast media did not require a new course of these products or because their general practitioner (GP) did not want to prescribe these drugs. Discussion: Ninety percent of the RCH (88.5% of the patients) with a CADR followed by investigations and a RCH have a good tolerance to subsequent treatment with the RC drug. The mechanisms involved in this intolerance despite negative RCH are discussed. Conclusion: The provocation test procedure, considered as useful by 88% of the patients, has a good negative predictive value. Furthermore, these investigations need to be accompanied by clear information on the patient and his GP. [ABSTRACT FROM AUTHOR]

Nonallergic hypersensitivity and allergic reactions are part of the many different types of adverse drug reactions (ADRs). Databases exist for the collection of ADRs. Spontaneous reporting makes up the core data-generating system of pharmacovigilance, but there is a large under-estimation of allergy/hypersensitivity drug reactions. A specific database is therefore required for drug allergy and hypersensitivity using standard operating procedures (SOPs), as the diagnosis of drug allergy/hypersensitivity is difficult and current pharmacovigilance algorithms are insufficient. Although difficult, the diagnosis of drug allergy/hypersensitivity has been standardized by the European Network for Drug Allergy (ENDA) under the aegis of the European Academy of Allergology and Clinical Immunology and SOPs have been published. Based on ENDA and Global Allergy and Asthma European Network (GA2LEN, EU Framework Programme 6) SOPs, a Drug Allergy and Hypersensitivity Database (DAHD®) has been established under FileMaker® Pro 9. It is already available online in many different languages and can be accessed using a personal login. GA2LEN is a European network of 27 partners (16 countries) and 59 collaborating centres (26 countries), which can coordinate and implement the DAHD across Europe. The GA2LEN–ENDA–DAHD platform interacting with a pharmacovigilance network appears to be of great interest for the reporting of allergy/hypersensitivity ADRs in conjunction with other pharmacovigilance instruments. [ABSTRACT FROM AUTHOR]