Immediate Reactions Research Articles

Skin Test Reactivity Patterns in Patients Allergic to Iodinated Contrast Media: A Refined View

Two-dimensional (2D) classifications of iodinated contrast media (ICM) are insufficient to explain the observed skin test (ST) reactivity patterns in patients with drug hypersensitivity reactions (DHRs) to ICM. To refine the current view on allergic DHRs to ICM by analyzing ST reactivity patterns in patients with previous reactions to ICM. Patients with a history of DHR to ICM and positive STs, who presented at the University Hospital of Montpellier between 2004 and 2022, were included in the study. The relative difference between every two ICM products was measured by Manhattan distance and odds ratios were computed for all pairs of products in the immediate reaction (IR) and non-immediate reaction (NIR) ST groups. A total of 181 patients were included in the study. Odds ratio analysis identified significant associations between classical cross-reactive ICM, such as iohexol-ioversol, iohexol-iomeprol, iomeprol-ioversol, and iohexol-iodixanol in the IR ST group and iohexol-ioversol, iopromide-iohexol, and iomeprol-ioversol in the NIR ST group. We also identified uncommon associations, such as ioxitalamate-amidotrizoate in the IR ST group and amidotrizoate-iopamidol and amidotrizoate-ioxitalamate in the NIR ST group. The results were reflected by the Manhattan distance, which suggested the existence of clusters containing the same classically associated ICM as well as uncommon associations, which we hypothesize to be related to similarities in the 3D structure of the respective ICM. Current chemical (2D) classifications cannot explain all observed ST reactivity patterns. Whether the 3D structure can be integrated into the current classifications to interpret the observed ST reactivity patterns and predict tolerance to alternative ICM requires further research.

Resensitization in suspected penicillin allergy.

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. To analyze the rate of resensitization in patients with suggestive AR-PEN by repeating STs (retest) after an initial evaluation (IE). 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. 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). 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.

THE ROLE OF CLAVULANIC ACID IN IMMEDIATE ALERGIC REACTIONS TO BETA-LACTAMS

Among betalactams-antibiotics(BLs), the combination amoxicillin-clavulanic(AX-CLAV) is being increasingly prescribed in patients of all ages, involved in up to 80% of BL allergy reactions. Our aim was to evaluate the role of Clavulanic acid (CLAV) in this type of drug-allergy, with special attention on selective immediate-reactions(IRs).

Drug Allergy in Children: What is the Actual Frequency of Drug Allergies?

Drug hypersensitivity reactions are immunologically mediated reactions resulting in the production of drug-specific antibodies and/or T-cells and constituting only <15% of all drug reactions. Based on the clinical observations, both patients and their parents refer to any undesirable drug reactions as drug allergy, regardless of whether the underlying mechanism is immunological or not. After allergy examinations, only a small percentage of the patients who were reported positive for drug reactions based on their clinical history are actually confirmed to have hypersensitivity. This study aims to determine the actual frequency of drug allergies in children, the drugs that cause the most common allergies in patients with a complaint of drug allergy and evaluate the accompanying demographic and clinical features. The study evaluated data from a total of 266 patients (ages of 0-18) with suspected drug allergy during a 3-year period. Twenty-four patients with doctor-diagnosed drug-related anaphylaxis and 85 patients who did not accept diagnostic tests were excluded from the study and the study continued with a total of 157 patients. The allergy work-up consisted of in vivo and in vitro tests, in accordance with the recommendations of the ENDA/EAACI guidelines. Data from a group of 157 patients (M [54.6%]; F [45.4%]) were retrospectively analyzed. Beta-lactams (BLs) were the most common drugs involved in the reported clinical history followed by non-steroidal antiinflammatory drugs (NSAIDs). Allergic reactions occurred on the median 1st day (min: 1-max: 8) after drug intake and were most frequently observed as urticaria (55.3%). Immediate reactions (IRs) were observed in 53.5% and non-IRs in 46.5% of the patients. Our data demonstrated that only 15.5% of patients confirmed to be positive to allergy during testing which is in line with the data in the literature. An allergy work-up is mandatory for excluding suspected hypersensitivity.

Hypersensibilités aux produits de contraste iodés : analyse en cluster

Introduction Cluster analysis refers to a broad set of unsupervised learning techniques used to discover distinct subgroups or clusters within a set of data. This study aimed to distinguish different clinical characteristics among patients with suspicions of drug hypersensitivity reactions (DHRs) to iodinated radiocontrast media (iRCM) based on a cluster analysis. Methodes A retrospective study was performed using data extraction from the Drug Allergy and Hypersensitivity Database (DAHD) at the Allergy Unit, University Hospital of Montpellier, France. All referred patients with suspicions of iRCM DHRs between February 2001 and December 2019 either with confirmed positive skin tests (ST)s or negative STs were included in the analysis. Resultats A total of 1439 patients with suspicion of a DHR to iRCM who underwent a drug allergy work-up were analysed. Positive STs were displayed in 153 patients (10.6 %). The solution proposed by the automatic cluster analysis categorized the 1439 patients into five clusters, with a fair quality of clustering and an optimal ratio (2.3) of the cluster sizes. Cluster 1 contained almost only patients with a non-immediate reaction. Cluster 2 comprised virtually only patients with immediate reactions (IR), all with known culprit iRCM. These were the best defined clusters. Cluster 4 and 5 were virtually identical, with one exception, namely the clinical manifestation. Where they both comprised IRs, with multiple episodes of DHR, induced by unknown culprits, tested two decades after the index reaction, cluster 5 contained virtually only anaphylactic events whereas cluster 4 included various reactions, but no anaphylaxis. Confirmed allergies were more frequent in cluster 1 (16.9 %) and 2 (16.5 %). Conclusion Five clinical phenotypes which make sense clinically were determined by cluster analysis. From a pragmatic point of view, this new knowledge can be integrated in the drug allergy work-up reasoning : patients with well-defined recent reactions are allergic in up to 17 % of cases, but the frequency of allergy is leveled down by two or more in reactions tested more than a decade after their occurrence, despite the clinical manifestation which can resemble anaphylaxis.

Epidemiology and drug allergy results in children investigated in allergy unit of a tertiary-care paediatric hospital setting

Background and objectiveDrug Hypersensitivity Reactions (DHRs) are considered adverse effects of medications that resemble allergy symptoms. The reported positive clinical history of pediatric drug reactions is about 10%, however, after allergy investigations, only a small percent is confirmed as hypersensitivity.The aim of this study was to analyze the clinical history, allergy work-up results and sensitization profile of children and adolescents referred to our Allergy Unit for suspected DHRs.MethodsThe study evaluated data related to a group of children with a positive history of drug reactions during a two-year period. The allergy work-up consisted of in vivo and in vitro tests, in accordance with the recommendations of the ENDA/EAACI guidelines.ResultsData from a group of 637 patients [348 M (54.6%); 289 F (45.4%)] were retrospectively analyzed. Beta lactams (BLs) were the most common drugs involved in the reported clinical history, followed by non-steroidal anti-inflammatory drugs (NSAIDs). Severe cutaneous adverse reactions (SCARs) were most frequently observed during BL treatment. The confirmation of BL hypersensitivity was higher for immediate reactions (IRs) [9.4%; 5.1% through positive skin tests (STs) and 5.5% through drug provocation test (DPT)] compared to non-immediate reactions (non-IRs) (8.1%; 2.2% through STs and 6.2% through DPT). A higher number of positive results was obtained for BLs and macrolides when the tests were performed within 12 months after the index reaction (p < 0.05). During DPTs with amoxicillin-clavulanic acid, four hypersensitivity reactions (including one anaphylaxis) occurred despite negative STs.ConclusionOur data demonstrated that only 9.1% of patients resulted in being positive to allergy tests which is in line with the data in literature. An allergy work-up is mandatory for excluding suspected hypersensitivity.

Genetic variants associated with drugs-induced immediate hypersensitivity reactions: a PRISMA-compliant systematic review.

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.

Diagnostic evaluation and risk factors for drug allergies in children: from clinical history to skin and challenge tests.

Parent or self-reported drug allergy claims frequently overestimate the real incidence of hypersensitivity reactions. A detailed and algorithmic diagnostic evaluation of drug reactions may allow a proper diagnosis. The aim of this study was to determine the confirmation rates and risk factors for confirmed allergic drug reactions in children. Mersin University Hospital in Turkey. The study consisted of children between ages of 8 months and 18 years with the history of suspected drug allergy as reported by the clinician or the patients. Parents were interviewed by a clinician to complete questionnaires that included questions about demographic data and characteristics of index drug reaction. Immediate reactions (IRs) were assessed with immediate-reading skin prick (SPT) and intradermal tests (IDT). Nonimmediate reactions (NIRs) were assessed with SPT, both early and delayed reading of IDT and patch tests. In case of negative skin tests, drug provocation tests were performed. The possible risk factors for confirmed drug allergy in univariate analysis (p < 0.1) were entered into the multivariate logistic regression analysis to determine independent predictors. (1) Confirmation rates of drug allergy (2) Risk factors related to confirmed drug allergy in children. We evaluated a total of 180 suspected drug allergy reactions in 97 children, mainly to antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs) and anticonvulsants. Among all suspected allergic drug reactions, 97 (53.9 %) were immediate type and 83 (46.1 %) were non-immediate type. The average time interval between the reaction and allergologic work-up was 5 months. Drug allergy confirmation rates were 30.1 % for beta-lactams, 27.2 % for non-betalactams, 21.1 % for NSAIDs and 30 % for anticonvulsants. Eight of 54 confirmed NIRs showed positivity on immediate skin tests. Regulatory T cells, TGF-β and IL-10 levels were not different between groups with and without confirmed drug allergy. A strong family and personal history of drug allergy were found to be significantly related to the confirmed allergic drug reactions. Parent or self-reported drug allergy should be evaluated with a standardized diagnostic work-up before strict prohibitions are made. In addition, family and personal histories of drug allergy were significant risk factors related to allergic drug reactions in children.

BLOOD DONORS AND BLOOD COLLECTION: Delayed adverse reactions to blood donation

BACKGROUND: Blood donation is safe, but a small proportion of donors have delayed and/or off‐site reactions that have the potential to lead to serious injury. This retrospective study sought to identify risk factors for delayed reactions (DRs).STUDY DESIGN AND METHODS: The records of 793,293 allogeneic whole blood and apheresis donations in 2007 were assessed for vasovagal reactions. Donor demographic, biometric, and clinical measurements were captured. Incidents related to needle insertion and mild reactions were excluded. Based on the reaction onset time relative to the procedure end time, reactions were classified as delayed (&gt;15 min) or immediate (≤15 min). Reactions were analyzed by multivariable logistic regression comparing donors with immediate reactions (IRs) or DRs to donors without reactions and comparing donors with DRs to IRs. The clinical consequences of off‐site and on‐site reactions are reported.RESULTS: The prevalence of reactions classified as moderate or severe was 41 in 10,000 donations; 24% of these reactions were delayed and 12% occurred off‐site. DRs were associated with female sex (odds ratio [OR], 2.96; 95% confidence interval [CI], 2.21‐3.96) and with low estimated blood volume (EBV; OR, 3.91; 96% CI, 2.84‐5.51). Off‐site reactions, particularly in female donors, were more likely to be associated with a fall, with head trauma, with other injury, and with the use of outside medical care.CONCLUSION: Low EBV, youth, and first‐time donor status are major risk factors for IRs and DRs. Women are more likely than men to report DRs. Delayed and off‐site reactions lead to potentially preventable morbidity. Understanding the physiologic basis of DRs may lead to the development of appropriate interventions to reduce their likelihood.

Differential cytokine and transcription factor expression in patients with allergic reactions to drugs

Allergic drug reactions (ADR) can be either immediate reaction (IR) (IgE mediated) or delayed reaction (DR) (T-cell mediated). They follow the Th1/Th2 paradigm, with DR expressing interferon-gamma (IFN-gamma) with down-regulation of interleukin-4 (IL-4) and IR expressing IL-4 with down-regulation of IFN-gamma. We studied the extension of this polarization in DR and IR by examining the cytokine and transcription factor profile in T-cell subpopulations during the acute phase of an ADR. Expressions of cytokines [IL-4, IFN-gamma and tumor necrosis factor-alpha (TNF-alpha)] and transcription factors (c-maf, GATA-3 and T-bet) were analysed by semi-quantitative real time-polymerase chain reaction in peripheral blood mononuclear cells and in CD4 and CD8 subpopulations from ADR patients. In DR, IFN-gamma, TNF-alpha and T-bet increased significantly in both CD4 and CD8 subpopulations, depending on the clinical severity. In IR, IL-4, c-Maf and GATA-3 were increased, but only significantly in CD4. A positive correlation existed between IFN-gamma and T-bet in DR and between IL-4 and c-Maf and GATA-3 in IR. In DR, IFN-gamma, TNF-alpha and T-bet were increased during the acute phase in CD4 and CD8. In IR, IL-4, c-Maf and GATA-3 were all increased in the acute phase, but only in CD4. These results support the Th1/Th2 paradigm in ADR, confirming previous findings that include the expression in both CD4 and CD8 T cells, and extending the observation to the transcription factors involved in the polarization of the immune response. Monitoring the reactions in the cell populations implicated, could be an important tool for assessing the mechanisms involved in ADR.

Pharmacological characterisation of a new model of antigen-induced pulmonary late-phase reaction in the conscious guinea pig which uses additional polymyxin B inhalation

The aim of the present study was to develop a new model of allergic late-phase reaction in the airways of concious guinea pigs (GPs) and to characterise it by pharmacological in tervention. GPs were pretreated with cyclophosphamide and sensitized with ovalbumin (OA) in Al(OH) 3. Weeklt inhalations of polymyxin B were performed before and during sensitization and continued throughout the study period. Under cover of 10 mg/kg i.p. mepyramine all GPs still exhibtied a pronounced immediate reaction (IR), peaking during the first 15 min after OA. Nine out of 15 GPs demonstrated, during screening, a reproducible (twice) second phase (late phase reaction (LPR) of decreased airflow and tidal volume (TV) peaking 4–8 h after OA. In a cross over study, methylprednisolone (MP) at 30 mg/kg p.o. (16 h and 1 h before OA) significantly inhibited the LPR at its peak (4–8 h) peak decrease of TV to % of basal; control 49.4 ± 3.7; MP 78.9 ± p < 0.01; n = 7). After another booster sensitization with 2 μg OA/GP under the same conditions, the Paf-antagonist WEB 2347 at 3 mg/kg p.o. (1 h before OA) inhibited the LPR at its peak agin (peak decrease of TV to % of basal: control 57.3 ± 3.5; WEB 2347 74.8 ± 7.6; p < 0.01; n = 6). In conclusion more than 50% of repeatedly ovalbumin sensitized (and polymyxin B-treated) unanaesthetized GPs developed a reproducible pulmonary late phase reaction (LPR). The LPR peaked at 4–8 h after antigen-exposure. The inhibitory effect by a glucocorticoid and the Paf-antagonist WEB 2347 suggests the inflammatory nature of the LPR and the involvement of platelet-activating factor (Paf) in this model.