Advances in hypersensitivity drug reactions.

Immediate drug hypersensitivity reactions (DHRs) resemble typical immunoglobulin E (IgE)-mediated symptoms. Clinical manifestations range from local skin reactions, gastrointestinal and/or respiratory symptoms to severe systemic involvement with potential fatal outcome. Depending on the substance group of the eliciting drug the correct diagnosis is a major challenge. Skin testing and in vitro diagnostics are often unreliable and not reproducible. The involvement of drug-specific IgE is questionable in many cases. The culprit substance (parent drug or metabolite) and potential cross-reacting compounds are difficult to identify, patient history and drug provocation testing often remain the only means for diagnosis. Hence, several groups proposed basophil activation test (BAT) for the diagnosis of immediate DHRs as basophils are well-known effector cells in allergic reactions. However, the usefulness of BAT in immediate DHRs is highly variable and dependent on the drug itself plus its capacity to spontaneously conjugate to serum proteins. Stimulation with pure solutions of the parent drug or metabolites thereof vs. drug-protein conjugates may influence sensitivity and specificity of the test. We thus, reviewed the available literature about the use of BAT for diagnosing immediate DHRs against drug classes such as antibiotics, radio contrast media, neuromuscular blocking agents, non-steroidal anti-inflammatory drugs, and biologicals. Influencing factors like the selection of stimulants or of the identification and activation markers, the stimulation protocol, gating strategies, and cut-off definition are addressed in this overview on BAT performance. The overall aim is to evaluate the suitability of BAT as biomarker for the diagnosis of immediate drug-induced hypersensitivity reactions.

Multiple Non-steroidal anti-inflammatory drugs (NSAID)-induced urticaria/angioedema is the most common manifestation of hypersensitivity reactions to NSAIDs. Diagnostic evaluation is based on the clinical history and a drug provocation test. To evaluate the role of the clinical history in the diagnosis of multiple NSAID-induced urticaria/angioedema. We studied a group of patients with an unequivocal history of urticaria and/or angioedema after NSAID intake. Subjects had to have had at least two episodes of cutaneous symptoms with two different COX-1 inhibitors. The diagnosis was confirmed in all cases by a drug provocation test with acetyl salicylic acid (ASA). Multivariate analysis was done by analysing different variables, including number of drugs involved, episodes and time elapsed between drug intake and symptom onset. Of the total group of 75 cases with multiple NSAID-induced urticaria/angioedema diagnosed according to the clinical history, 76% developed a positive drug provocation test with ASA. The risk for having hypersensitivity was 17 times higher in patients who developed symptoms within the first 60 min after drug intake, 13 times higher in those who experienced reactions with more than two non-chemically related NSAIDs, and 10 times higher in women. Drug provocation testing with ASA confirms the diagnosis of multiple NSAID-induced urticaria/angioedema in up to 92% of cases with an unequivocal clinical history, when reactions occur within 1 h and more than two different NSAIDs are involved.

Beta-lactam allergy can be currently diagnosed based on positive skin testing, serum-specific IgE, or provocation challenge. In adults, sensitivity and specificity of skin testing and serum-specific IgE in the context of assessing distant reactions are poor. Paediatric data in this regard are missing. 135 children with a distant (over 6 months) reported beta-lactam allergy were assessed. Data collection included results of skin-prick testing, intradermal testing, oral provocation-challenge (1/10th and full dose), 5-day prolonged course (EC), serum specific IgE and Basophil Activation Testing (BAT). 135 children underwent oral provocation-challenges. Two (1.4 %) reacted immediately to 1/10th dose and 1 to the full dose. All children had skin testing. One had positive skin-prick testing and passed oral provocation-challenge. 3 had positive intradermal testing, 1 reacted immediately to a tenth dose, 2 passed oral provocation-challenge. 132 children went home on a 5-day EC with the challenge antibiotic, 10 (7.5%) reacting. All other children had negative testing. Ten children out of 135 had a positive serum-specific IgE for at least one beta-lactam, all of these children passed the oral provocation and EC challenge. Eighty children were tested by BAT, all were negative, including the 13 children with reactions to the oral provocation-testing. In our preliminary data set of children with distant antibiotic reactions, serum beta-lactam specific IgE, BAT testing and skin testing were poor predictors of positive reactions to provocation testing, mimicking recent observations in adults. For the 135 children challenged, the immediate reactions were urticarial rashes and no anaphylaxis; the non-immediate reactions during the prolonged course were rashes only. This further strengthens the data that oral provocation testing in children with distant reactions is safe and that skin testing, BAT and testing for specific IgE add very little to identify those with a true allergy.

A Multicenter Retrospective Study on Hypersensitivity Reactions to Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in Children: A Report from the European Network on Drug Allergy (ENDA) Group

Drug hypersensitivity reactions (DHRs) represent an important public health problem. Knowledge of their clinical characteristics will provide improved diagnostic approaches to this topic. The aim of the present study was to describe the clinical characteristics of patients with suspected DHRs. The medical records of 206 outpatients with suspected DHRs, who consulted a Norwegian allergy centre from January 2005 to December 2009, were investigated in a retrospective study. Mean age (range) was 44.3 (11-84) years, and 72% of the patients were women. The most common underlying diseases justifying the use of drugs were infections (49%) and pain-related diseases (23%). Antibiotics (53%), non-steroidal anti-inflammatory drugs (NSAIDs) (32%), paracetamol (15%) and other drugs (46%), used as monotherapy or combinations, were the most often suspected drugs. Cutaneous symptoms were the most frequently reported symptoms (83%). Hospitalisation or prolonged hospitalisation was needed in 38% of the cases, and anaphylaxis was reported in 28% of all the patients. Skin prick tests were performed in 185 patients, of which 14 patients had positive test results. Drug provocation tests (DPTs) were performed in only 86 patients, six of which had positive reactions. DHRs were confirmed in 24 and rejected in 81 patients. Unsettled cases (39%) were mainly due to not performing DPTs. Suspected DHRs occur predominantly in women. The most common manifestations are cutaneous symptoms, but life-threatening reactions justifying hospitalisation may occur. Antibiotics and NSAIDs are the two drug families most frequently suspected. DPTs need to be included in diagnostic protocols in order to evaluate suspected DHRs.

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 describe the most common drugs associated with clinical reactions, diagnostic methods used, and outcomes of allergic evaluations of a national drug allergy registry over a 12-year period were used.Methods: An observational, prospective, patient’s data registry-based study was conducted to analyze all referrals to the drug allergy outpatient clinics at Al-Rashed Allergy Center, Kuwait, between 2007 and 2019. Demographics, description of DHRs, and results of allergy tests to potential causative medications were reviewed. Diagnostic methods were focused mainly on skin tests (STs) and drug provocation test (DPT), when indicated.Results: We evaluated 1,553 patients with reported DHRs. The mean age of the population was 41.52 ± 16.93 years, and the study population consisted of 63.7% female patients. Hypersensitivity was finally confirmed in 645 (41.5%) of patients, probable in 199 (12.8%), and not confirmed/nonallergic in 709 (45.6%) patients. Anti-inflammatory drugs and analgesics contributed to 39.22% of all confirmed drug allergies, followed by antibiotics 38.1% (β-lactam antibiotics (BLs) constituted 73.98% of all antibiotics and 28.21% of all drugs), anesthetics 1.8%, and radio-contrast media 0.31%. The majority of reactions were non-immediate 51.44%. The most commonly presenting symptoms among confirmed patients were urticaria 57.80%, angioedema 42.50%, respiratory symptoms 47.60%, and erythema 33.60%. Symptoms of anaphylaxis/anaphylactic shock were reported by 284 patients (44.00%) among confirmed cases. The most common method of diagnosis was a positive clinical history (54.4% in BLs and 90.45% in nonsteroidal anti-inflammatory drugs (NSAIDs). Among confirmed allergy to BLs, a positive ST was obtained in 31.9% of patients and positive DPT in 13.7%.Conclusion: NSAIDs and antibiotics, mainly BLs, are the most commonly implicated in confirmed allergy. In both confirmed and not confirmed/nonallergic cases, BLs are the most frequently involved DHRs which are mainly immediate, and the most commonly presenting symptoms were urticaria, angioedema, and respiratory symptoms. Diagnosis was confirmed mainly by a positive clinical history and when indicated, by positive STs or a DPT.

The aim of this study was to examine the pathophysiological mechanisms, epidemiology, diagnostic strategies, and treatment approaches for non-steroidal anti-inflammatory drug (NSAID) allergy based on clinical data obtained in routine allergy practice. The study combined an analysis of the scientific literature with a retrospective clinical analysis of adult patients who presented to an allergy department with suspected NSAID hypersensitivity. Clinical data were derived from patient medical records and included documented reactions to NSAIDs, diagnostic procedures performed as part of standard care (medical history assessment, skin testing, laboratory investigations, basophil activation testing, and drug provocation tests), and applied therapeutic strategies. The clinical analysis identified two principal reaction mechanisms: immediate-type hypersensitivity mediated by IgE-dependent immune activation and immediate non-immunological hypersensitivity associated with cyclooxygenase-1 (COX-1) inhibition. Clinical manifestations ranged from cutaneous reactions to severe systemic responses, including anaphylaxis, as well as chronic conditions such as aspirin-exacerbated respiratory disease. The diagnostic value and practical limitations of the applied methods were evaluated in the clinical setting. Individualised management strategies, including avoidance of the causative NSAID, the use of alternative agents such as selective COX-2 inhibitors, pharmacological treatment of acute reactions, and desensitisation protocols, were summarised based on observed clinical practice. By integrating real-world clinical data with current scientific evidence, this study provides a clinically grounded overview of NSAID allergy and highlights the importance of personalised diagnostic and therapeutic approaches in everyday medical practice. The findings may be useful for allergists, immunologists, and general practitioners involved in the management of patients with suspected NSAID hypersensitivity.

Direct Challenges for the Evaluation of Beta-Lactam Allergy: Evidence and Conditions for Not Performing Skin Testing

Clinical Characterization and Diagnostic Approaches for Patients Reporting Hypersensitivity Reactions to Quinolones

A Quantitative Analysis of NSAID-Induced Small Bowel Pathology by Capsule Enteroscopy

To determine the association between human leukocyte antigen (HLA) alleles and migraine, migraine subtypes, and sex-specific factors. It has long been hypothesized that inflammation contributes to migraine pathophysiology. This study examined the association between migraine and alleles in the HLA system, a key player in immune response and genetic diversity. We performed a case-control study and included 13,210 individuals with migraine and 86,738 controls. All participants were part of the Danish Blood Donor Study Genomic Cohort. Participants were genotyped and 111 HLA alleles on 15 HLA genes were imputed. We examined the association between HLA alleles and migraine subtypes, considering sex-specific differences. We found no association between HLA alleles and migraine, neither overall, nor in the sex-specific analysis. In the migraine subtype analysis, three HLA alleles were associated with migraine without aura; however, these associations could not be replicated in an independent Icelandic cohort (2191 individuals with migraine without aura and 278,858 controls). Furthermore, we found no association between HLA alleles and migraine with aura or chronic migraine. We found no evidence of an association between the HLA system and migraine, suggesting that genetic factors related to the HLA system do not play a significant role in migraine susceptibility.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in allergic reactions of which two main types exist: IgE-mediated and crossintolerance. The diagnosis of crossintolerance reactions is often based on the drug provocation test. The potential value of the basophil activation test (BAT) was evaluated using different basophil markers in the diagnosis of patients with crossintolerance to NSAIDs and cutaneous symptoms. We studied 46 patients with crossintolerance to NSAIDs and 45 tolerant controls. BAT was performed with acetyl salicylic acid, paracetamol, diclofenac, dipyrone, naproxen, and ibuprofen at four different concentrations using CD193 and CD203c as basophil markers and CD63 as activation marker. We compared BAT results using CD193⁺ or CD193⁺ CD203c⁺ for basophil selection and found a significant increase in the stimulation index when using CD193⁺ CD203c⁺ in both patients and controls (P = 0.004 and P = 0.017, respectively). Selection of living cells only produced an increase in basophil stimulation in patients for both CD193⁺ and CD193⁺ CD203c⁺ (P < 0.001 for both), whereas in controls there was no change with CD193⁺ and a decrease with CD193⁺ CD203c⁺ (P = 0.001). We found that CD193⁺ CD203c⁺ increased the percentage of positive cases in patients and controls when compared with CD193⁺. When excluding dead cells, there was an increase of 21.7% in patients and 10% in controls. These results indicate that using CD193⁺ CD203⁺, excluding dead cells, is the best approach for BAT although this test is not recommended for the diagnosis of patients with crossintolerance to NSAIDs owing to its low sensitivity and specificity.

Human leucocyte antigen (HLA) alleles may generate antibodies that are undetectable by routine single-antigen beads (SABs) assays if their unique epitopes are unrepresented. We aimed to describe the prevalence and explore the potential impact of unrepresented HLA alleles in standard SAB kits in our cohort. All individuals who had undergone two-field HLA typing (HLA-A/B/C/DRB1/DQA1/-DQB1/-DPA1/-DPB1) from February 2021 to July 2023 were included. Two-field HLA-DRB3/4/5 typing was imputed. Each unrepresented allele was compared with the most similar represented allele in the standard LABScreen, LABScreen ExPlex (One Lambda) and the LIFECODES (Immucor) SAB kits. Differences in eplet expression (HLA Eplet Registry) were identified. Differences in three-dimensional molecular structures were visualized using generated models (SWISS-MODEL). Two-field HLA typing was performed for 116 individuals. Overall, 16.7% of all HLA alleles, found in 36.2% of individuals, were unrepresented by all SAB test kits. Four eplets, found in 12.9% of individuals, were unrepresented in at least 1 SAB kit. Non-Chinese individuals were more likely to have unrepresented HLA alleles and eplets than Chinese individuals. There were differences in HLA allele and eplet representation amongst the different SAB test kits. Use of supplementary SAB test kits may improve HLA allele and eplet representation. Although some HLA alleles were unrepresented, most epitopes were represented in current SAB kits. However, some unrepresented alleles may contain epitopes which may generate undetectable antibodies. Further studies may be needed to investigate the potential clinical impact of these unrepresented alleles and eplets, especially in certain ethnic populations or at-risk individuals.

Multiple works have studied possible associations between human leukocyte antigen (HLA) alleles and end stage renal disease (ESRD) showing, however, contradictory and inconsistent results. Here, we revisit the association between ESRD and HLA antigens, comparing HLA polymorphism (at HLA-A, -B, -C, -DRB1, -DQB1 and DQA1 loci) in ESRD patients (n = 497) and controls (n = 672). Our data identified several HLA alleles that displayed a significant positive or negative association with ESRD. We also determined whether heterozygosity or homozygosity of the ESRD-associated HLA alleles at different loci could modify the prevalence of the disease. Few HLA allele combinations displayed significant associations with ESRD, among which A*3_26 combination showed the highest strength of association (OR = 4.488, P≤ 0.05) with ESRD. Interestingly, the age of ESRD onset was not affected by HLA allele combinations at different loci. We also performed an extensive literature analysis to determine whether the association of HLA to ESRD can be similar across different ethnic groups. Our analysis showed that at least certain HLA alleles, HLA-A*11, HLA-DRB1*11, and HLA-DRB1*4, display a significant association with ESRD in different ethnic groups. The findings of our study will help in determining possible protective or susceptible roles of various HLA alleles in ESRD.

Adolescence is critical in the habituation of diverse lifestyles and is a base for future physical well-being. Although gastrointestinal disorders are frequently reported in adolescents, studies related to GI drug use or related factors in Korean adolescents are rare. Thus, this study examined Korean adolescents for the use of GI drugs for abdominal symptoms and analyzed the associated factors. This cross-sectional study was done with a total of 2,416 students who completed a given questionnaire. The health-related questions included GI medication intake, smoking, alcohol, caffeine, regular exercise, self-cognitive health level, GI symptom, non-steroidal anti-inflammatory drugs (NSAIDs) intake, and sleep problems. In questions about GI medication intake, drugs included digestives and antacids. And the intake of GI drugs more than once during the past 1 month was regarded as taking GI drugs. The sociodemographic questions included age, gender, grade, number of close friends, extracurricular activities, and school performance. The overall prevalence for taking GI drugs, including antacids and digestives, was 17.4 %. When students taking GI drugs were compared with those not taking GI drugs, the former group showed higher rates of girls (P < 0.001) and participants in extracurricular activities (P < 0.05) than the latter group. Factors including alcohol, caffeine, self-cognitive health levels, and GI symptoms showed statistical significance with the rate of GI drug intake. The rate of GI drug intake in NSAID users was 2.7 times higher than that in non-users (P < 0.001). The prevalence rate of every sleep problem was higher in students taking GI medications except snoring, witnessed apnea, and teeth grinding. From the multiple regression, it was found that gender (female), extracurricular activities, alcohol intake, self-cognitive health levels, NSAIDs intake, and nightmares were related factors to GI drug intake. Based on the results, it was conclude that encouragement to build healthy lifestyle habits in adolescents is very important for their academic performances and health status in adulthood.