Drug Hypersensitivity Reactions Research Articles

Zanubrutinib, Alone and in Combination With Tislelizumab, for the Treatment of Richter Transformation of Chronic Lymphocytic Leukemia.

Zanubrutinib, Alone and in Combination With Tislelizumab, for the Treatment of Richter Transformation of Chronic Lymphocytic Leukemia.

Rare cas de syndrome de sweet bulleux induit par produit de contraste ionisé

To our knowledge, sweet bullous syndrome has been associated with contrast media only once in the literature, which makes our case very rare. Our patient developed, 48h after the realization of an injected scanner, a bullous eruption, cocardoides lesions and a fronto-malar erythema. The skin biopsy concluded to a bullous Sweet syndrome. The patient was treated with topical corticosteroids and the lesions disappeared after 7 days. Drug-induced sweet syndrome can mimic several other diagnoses. In our case, the malar erythema is reminiscent of lupus. Drug-induced sweet is a drug hypersensitivity reaction characterized by the following clinical signs: chronological development of a skin lesion following drug exposure, fever of 38.4°C, neutrophil infiltration in the dermis without vasculitis, and resolution of symptoms following steroid use, all of which were present in our case. We report a case of bullous sweet syndrome, an aggressive form which resolved with steroids. Key words: Delayed hypersensitivity; Sweet; Bullous sweet variant; Iodinated contrast media

In vitro diagnostic testing for drug allergy in children

Diagnosing Drug Hypersensitivity Reactions (DHRs) could be a complicated process especially in children, since allergic-like manifestation at this age is more often the expression of concomitant infections rather than a actual DHRs. In vivo tests are usually suggested as a first step; however, prick and intradermal tests could be painful and have shown different sensitivity and specificity among published studies. In some cases, in vivo tests such as Drug Provocation test (DPT) could be even contraindicated. Therefore, the need for in vitro testing is compelling, to add useful information along the diagnostic pathway and to limit the need of DPT. In this review, we analyze the different types of in vitro tests, focusing on those used more widely such as specific IgE and on those that are still for research settings, such as basophil activation test and lymphocyte transformation test, but that have shown some useful diagnostic potential.

Drug Hypersensitivity Reactions in Patients with Cystic Fibrosis: Potential Value of the Lymphocyte Toxicity Assay to Assess Risk.

Cystic fibrosis (CF) is a genetic disease characterized by multi-system dysfunction resulting in recurrent lung infections and progressive pulmonary disease. CF patients are at a higher risk for drug hypersensitivity reactions (DHRs) compared to the general population, which has been attributed to the recurrent need for antibiotics and the inflammation associated with CF disease. In vitro toxicity tests such as the lymphocyte toxicity assay (LTA) offer the potential for risk assessment for DHRs. In the current study, we investigated the utility of the LTA test for diagnosis of DHRs in a cohort of CF patients. Twenty CF patients with suspected DHRs to sulfamethoxazole, penicillins, cephalosporins, meropenem, vancomycin, rifampicin, and tobramycin were recruited to this study and tested using the LTA test along with 20 healthy control volunteers. Demographic data of the patients, including age, sex, and medical history, were obtained. Blood samples were withdrawn from patients and healthy volunteers, and the LTA test was performed on isolated peripheral blood monocytes (PBMCs) from those individuals. Cells from CF patients with DHRs displayed a significant (p < 0.0001) concentration-dependent enhanced cell death upon incubation with the culprit drug compared to cells from healthy volunteers. The positivity rate of the LTA test was over 80% in patients with a medical history and clinical presentation consistent with DHRs. This study is the first to evaluate the use of the LTA test for diagnosis of DHRs in CF patients. According to our results, the LTA test may be a useful tool for diagnosis and management of DHRs in CF patients. Identifying the culprit drug is essential for optimal healthcare for CF patients in the setting of a suspected DHR. The data also provide evidence that accumulation of toxic reactive metabolites could be an important component in the cascade of events leading to the development of DHRs in CF patients. A larger-scale study is needed to confirm the data.

Pearls for practice from the 2022 joint task force drug allergy practice parameter.

To review updated recommendations in the 2022 Drug Allergy Practice Parameters for the evaluation and management of drug hypersensitivity reactions. Adverse drug reactions have become increasingly prominent with the advent of new and emerging pharmacologic therapies. Hypersensitivity reactions encompass a significant proportion of adverse drug reactions and negatively impact both the individual patient and overall health system. Reactions are heterogeneous in presentation and may be immediate (onset of symptoms ≤6 h) or delayed (onset of symptoms >6 h to months) after drug exposure. The 2022 Drug Allergy Practice Parameter provides consensus-based statements for evaluation of hypersensitivity reactions to antibiotics, NSAIDs, cancer chemotherapies, immune checkpoint inhibitors, biologics, and excipients. In general, the guideline highlights the importance of patient history in elucidating the phenotype and severity of the index reaction. Drug challenge remains the gold standard for diagnosis and is increasingly favored over skin testing in patients with nonsevere, nonanaphylactic drug reaction histories. The 2022 Drug Allergy Practice Parameter provides an updated framework for physicians to reference in clinical practice when managing patients with drug hypersensitivity reactions.

Antibiotikaallergien – gezieltes Vorgehen bei vermeintlicher β‑Laktam-Allergie

Allergic reactions to antibiotics belong to hypersensitivity drug reactions and can trigger both immunoglobulinE-mediated symptoms and Tcell-mediated symptoms. Skin manifestations are the most common symptoms. Although reporting apenicillin allergy results in considerable restrictions in the treatment of acute infections, which may be associated with poor treatment outcomes, in most cases the label 'penicillin allergy' is not called into question or critically reviewed. However, in 85-90% of patients, 'penicillin allergy' constitutes amislabeling of anon-specific intolerance reaction that does not pose arisk to the patient when re-exposed to penicillins. Careful history taking, an evaluation of manifestations in the past, and easy-to-perform initial diagnostic steps are crucial in differentiating non-specific intolerance reactions from penicillin allergy sensu stricto. Thus, apenicillin de-labeling strategy allows for optimized antibiotic therapy in the event of afuture infection. Although allergic cross-reactivity between different β‑lactam antibiotics can occur, the risk for asevere cross-reactivity is dependent on chemical properties of the specific β‑lactam. Published cross-reactivity tables can help in risk stratification and choice of alternative β‑lactam agents.

The impact of a drug allergy label in an internal medicine ward.

Background. Drug hypersensitivity reactions are presumably immune-mediated reactions that cause reproducible signs and/or symptoms. Overdiagnosis of drug allergy, frequently self-reported, is common and carries significant limitations. We intended to analyze the frequency and impact of drug allergy in hospitalized patients. Methods. A retrospective study was conducted in an Internal Medicine ward at a tertiary hospital in Portugal. All patients with a drug allergy report admitted within a 3-year period were included. Data were collected from their electronic medical records. Results. We found that 15.4% of patients had a report of drug allergy, with antibiotics being the most common (56.4%), followed by non-steroidal anti-inflammatory drugs (21.7%) and radiocontrast media (7.0%). The allergy report affected the clinical approach of 14.5% of patients by motivating the use of second-line agents, or the eviction of necessary procedures. The usage of alternative antibiotics entailed a cost increase of 2.4 times. There were 14.7% of patients to whom the suspected drug was administered: 87.0% tolerated and 13.0% developed a reaction. Only 1.9% were referred to our Allergy and Clinical Immunology department and proceeded in their allergy study. Conclusions. In this study, a considerable number of patients had a drug allergy label on their records. This label contributed to an increase in the cost of treatment, or the avoidance of necessary exams. However, disregarding an allergy record may lead to potentially life-threatening reactions that proper risk assessment could avoid. Further investigation should always be part of the follow-up routine of these patients, and better articulation between departments should be encouraged.

Dermal Hypersensitivity Reaction to Semaglutide: Two Case Reports.

Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of antidiabetic agents that work by inducing insulin secretion and inhibiting release of glucagon in a glucose-dependent manner. They are especially promising given their long duration of action, decreased risk of hypoglycemia, and added benefit of weight loss. Semaglutide is a GLP-1 receptor agonist that has been approved for type II diabetes and chronic weight management in obese adults. Cases of hypersensitivity reactions have been previously reported in patients taking GLP-1 receptor agonists dulaglutide and liraglutide. However, to our knowledge, there have been no reports of hypersensitivity reactions to semaglutide. Here, we present two cases of dermal hypersensitivity reactions in patients taking semaglutide for type II diabetes. In the first case, a 75-year-old woman who had been taking semaglutide for 10 months presented with an eruption on her legs, back, and chest for 3 months duration. Histology showed a subepidermal blister with eosinophils, suggestive of a drug hypersensitivity reaction. In the second case, a 74-year-old white man who had been taking semaglutide for 1 month presented with an eruption on the bilateral flanks and lower abdomen for 3 weeks duration. Histology revealed perivascular inflammatory cell infiltrate with eosinophils, also suggestive of a drug hypersensitivity reaction. Both patients began experiencing resolution of their symptoms within 1 month of discontinuing semaglutide. J Drugs Dermatol. 2023;22(4): doi:10.36849/JDD.6550 Citation: Ouellette S, Frias G, Shah R, et al. Dermal hypersensitivity reaction to semaglutide: Two case reports. J Drugs Dermatol. 2023;22(4):413-415. doi:10.36849/JDD.6550.

Worldwide Prevalence of Antibiotic-Associated Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Antibiotics are an important risk for Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), which are the most severe types of drug hypersensitivity reaction with a mortality rate up to 50%. To our knowledge, no global systematic review has described antibiotic-associated SJS/TEN. To evaluate the prevalence of antibiotics associated with SJS/TEN worldwide. The MEDLINE and Embase databases were searched for experimental and observational studies that described SJS/TEN risks since database inception to February 22, 2022. Included studies adequately described SJS/TEN origins and specified the antibiotics associated with SJS/TEN. Two reviewers (E.Y.L. and C.K.) independently selected the studies, extracted the data, and assessed the risk of bias. A meta-analysis using a random-effects model was performed in the studies that described patient-level associations. Subgroup analyses were performed to explore the heterogeneity. The risk of bias was assessed using the Joanna Briggs Institute checklist, and the certainty of evidence was rated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Prevalence of antibiotic-associated SJS/TEN was presented as pooled proportions with 95% CIs. Among the 64 studies included in the systematic review, there were 38 studies that described patient-level associations; the meta-analysis included these 38 studies with 2917 patients to determine the prevalence of single antibiotics associated with SJS/TEN. The pooled proportion of antibiotics associated with SJS/TEN was 28% (95% CI, 24%-33%), with moderate certainty of evidence. Among antibiotic-associated SJS/TEN, the sulfonamide class was associated with 32% (95% CI, 22%-44%) of cases, followed by penicillins (22%; 95% CI, 17%-28%), cephalosporins (11%; 95% CI, 6%-17%), fluoroquinolones (4%; 95% CI, 1%-7%), and macrolides (2%; 95% CI, 1%-5%). There was a statistically significant heterogeneity in the meta-analysis, which could be partially explained in the subgroup analysis by continents. The overall risk of bias was low using the Joanna Briggs Institute checklist for case series. In this systematic review and meta-analysis of all case series, antibiotics were associated with more than one-quarter of SJS/TEN cases described worldwide, and sulfonamide antibiotics remained the most important association. These findings highlight the importance of antibiotic stewardship, clinician education and awareness, and weighing the risk-benefit assessment of antibiotic choice and duration.

Public Health Significance of Veterinary Drug Residue in Food Animal Products - A Review

The objective of this review paper was to investigate the public health significance of veterinary drug residues in food of animal origin. Data were collected by means of the search engine and all relevant journals published between 2019 and 2022 and stocked under Google Scholar were retrieved for analysis. The use of veterinary medications in animals that produce food has the potential to leave residues in animal-derived products (meat, milk, eggs and honey), which puts the consumer's health at risk. The inability to follow the withdrawal period and incorrect drug use are the most likely causes of drug residues. The development of antimicrobial drug resistance, hypersensitivity reaction, carcinogenicity, mutagenicity, teratogenicity and alteration of intestine natural flora are the main public health implications of drug residue. The frequent application of tandem or high-resolution mass spectrometry along with liquid chromatography has greatly enhanced analytical methods for residue analysis. This advancement made it possible to quickly conduct targeted searches for hundreds of target compounds in complicated matrices like milk, eggs, honey, or meat and organs after slaughter. Reduction of antimicrobial drug resistance problem has been indicated as one of the most challenging issues related to food safety in the forthcoming years. There is little data available on the extent of veterinary drug residue globally. Therefore, a significant amount of work must be done to assess the scope of the issue, prevent the occurrence of veterinary drug residues and to familiarize animal health professionals with the pharmacokinetics, pharmacodynamics and toxicological effects of veterinary drugs in order to reduce the potential public health risk posed by drug residues in food derived from animals.

Molecular profiling of skin test-induced inflammation to support the clinical diagnosis of delayed drug hypersensitivity reaction.

Molecular profiling of skin test-induced inflammation to support the clinical diagnosis of delayed drug hypersensitivity reaction.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Focus on the Pathophysiological and Diagnostic Role of Viruses

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a heterogeneous, multiorgan and potentially life-threatening drug-hypersensitivity reaction (DHR) that occurs several days or weeks after drug initiation or discontinuation. DHRs constitute an emerging issue for public health, due to population aging, growing multi-organ morbidity, and subsequent enhanced drug prescriptions. DRESS has more consistently been associated with anticonvulsants, allopurinol and antibiotics, such as sulphonamides and vancomycin, although new drugs are increasingly reported as culprit agents. Reactivation of latent infectious agents such as viruses (especially Herpesviridae) plays a key role in prompting and sustaining aberrant T-cell and eosinophil responses to drugs and pathogens, ultimately causing organ damage. However, the boundaries of the impact of viral agents in the pathophysiology of DRESS are still ill-defined. Along with growing awareness of the multifaceted aspects of immune perturbation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the ongoing SARS-CoV-2-related disease (COVID-19) pandemic, novel interest has been sparked towards DRESS and the potential interactions among antiviral and anti-drug inflammatory responses. In this review, we summarised the most recent evidence on pathophysiological mechanisms, diagnostic approaches, and clinical management of DRESS with the aim of increasing awareness on this syndrome and possibly suggesting clues for future research in this field.

Pathophysiology of drug hypersensitivity.

Drug hypersensitivity reactions (DHRs) are type B adverse drug reactions (ADRs) traditionally defined as unpredictable, dose independent and not related to the drug pharmacology. DHRs, also called drug allergy if the immune system involvement is confirmed, represent around one-sixth of all ADRs and can cause major clinical problems due to their vague clinical presentation and irregular time course. Understanding the underlying pathophysiology of DHRs is very important for their diagnosis and management. Multiple layers of evidence exist pointing to the involvement of the immune system in DHRs. Recent data have led to a paradigm shift in our understanding of the exact pathophysiology of these reactions. Numerous hypotheses proposing explanation on how a low molecular weight drug molecule can elicit an immune reaction have been proposed. In addition to the classical "hapten" hypothesis, the reactive metabolite hypothesis, the pharmacological interaction with the immune system (p-i) concept, the danger/injury hypothesis and the altered peptide repertoire hypothesis have been proposed. We here introduce the inflammasome activation hypothesis and the cross-reactivity hypothesis as additional models explaining the pathophysiology of DHRs. Available data supporting these hypotheses are briefly summarized and discussed. We also introduced the cross-reactivity model, which may provide a platform to appreciate the potential role played by other factors leading to the activation of the immune system. We believe that although the drug in question could be the trigger of the reaction, the components of the immune system mediating the reaction do not act in isolation but rather are affected by the proinflammatory milieu occurring at the time of the reaction. This review attempts to summarize the available evidence to further illustrate the pathophysiology of DHRs.

Mas-related G protein-coupled receptor MRGPRX2 in human basophils: Expression and functional studies.

Occupancy of MRGPRX2 heralds a new era in our understandings of immediate drug hypersensitivity reactions (IDHRs), but a constitutive expression of this receptor by basophils is debated. To explore the expression and functionality of MRGPRX2 in and on basophils. Basophils from patients with birch pollen allergy, IDHRs to moxifloxacin, and healthy controls were studied in different conditions, that is, in rest, after stimulation with anti-IgE, recombinant major birch pollen allergen (rBet v 1), moxifloxacin, fMLP, substance P (SP), or other potential basophil secretagogues. In a separate set of experiments, basophils were studied after purification and resuspension in different media. Resting whole blood basophils barely express MRGPRX2 on their surface and are unresponsive to SP or moxifloxacin. However, surface MRGPRX2 is quickly upregulated upon incubation with anti-IgE or fMLP. Pre-stimulation with anti-IgE can induce a synergic effect on basophil degranulation in IgE-responsive subjects after incubation with SP or moxifloxacin, provided that basophils have been obtained from patients who experienced an IDHR to moxifloxacin. Cell purification can trigger a "spontaneous" and functional upregulation of MRGPRX2 on basophils, not seen in whole blood cells, and its surface density can be influenced by distinct culture media. Basophils barely express MRGPRX2 in resting conditions. However, the receptor can be quickly upregulated after stimulation with anti-IgE, fMLP, or after purification, making cells responsive to MRGPRX2 occupation. We anticipate that such "conditioned" basophils constitute a model to explore MRGPRX2 agonism or antagonism, including IDHRs originating from the occupation of this receptor.

Delayed Drug Hypersensitivity Reactions: Molecular Recognition, Genetic Susceptibility, and Immune Mediators.

Drug hypersensitivity reactions are classified into immediate and delayed types, according to the onset time. In contrast to the immediate type, delayed drug hypersensitivity mainly involves T lymphocyte recognition of the drug antigens and cell activation. The clinical presentations of such hypersensitivity are various and range from mild reactions (e.g., maculopapular exanthema (MPE) and fixed drug eruption (FDE)), to drug-induced liver injury (DILI) and severe cutaneous adverse reactions (SCARs) (e.g., Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP)). The common culprits of delayed drug hypersensitivity include anti-epileptics, antibiotics, anti-gout agents, anti-viral drugs, etc. Delayed drug hypersensitivity is proposed to be initiated by different models of molecular recognition, composed of drug/metabolite antigen and endogenous peptide, HLA presentation, and T cell receptor (TCR) interaction. Increasing the genetic variants of HLA loci and drug metabolic enzymes has been identified to be responsible for delayed drug hypersensitivity. Furthermore, preferential TCR clonotypes, and the activation of cytotoxic proteins/cytokines/chemokines, are also involved in the pathogenesis of delayed drug hypersensitivity. This review provides a summary of the current understanding of the molecular recognition, genetic susceptibility, and immune mediators of delayed drug hypersensitivity.

Celecoxib and Bullous Symmetrical Drug-Related Intertriginous and Flexural Exanthem (SDRIFE)

Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a nonimmediate, T-cell–mediated hypersensitivity drug reaction, characterized by symmetrical erythema involving the gluteal and intertriginous areas without systemic involvement. It occurs after systemic administration of a drug in an individual with/without prior sensitization.1 We report a case of celecoxib-induced bullous SDRIFE. Informed consent was obtained from the patient to publish the case report along with accompanying images.

Human leukocyte antigen association with azathioprine-induced drug hypersensitivity reactions in patients with anti-neutrophil cytoplasmic antibody associated vasculitis

Azathioprine (AZA) drug hypersensitivity reaction (DHR) is an uncommon yet potentially lethal condition that often goes unrecognised in patients with anti-Neutrophil Cytoplasmic Antibody (ANCA) associated vasculitis (AAV). We conducted a retrospective review of AAV patients on AZA maintenance therapy (N = 35). Participants were categorised into those who had experienced AZA-DHR (N = 15) and those who were AZA-tolerant (N = 20). Human leukocyte antigen (HLA) typing was performed in both groups. The primary endpoint was identification of a HLA gene association with AZA-DHR in the context of AAV. HLA-C*06:02, was solely expressed in AZA-DHR patients (33.3 %), whilst no patient who tolerated AZA carried this allele (0.0 %). This yielded a positive predictive value of 100 % for HLA-C*06:02 in predicting AZA-DHR in AAV patients, negative predictive value of 66.7 %, sensitivity of 33.3 % and specificity of 100 %. HLA-C*06:02 may predict the development of AZA-DHR in patients with AAV and inform safer therapeutic choice.

Drug-induced Anaphylaxis.

Drug hypersensitivity is increasing worldwide as the consumption of drug is increasing. Many clinical presentations of drug hypersensitivity are complex and take place in the setting of illness and/or polypharmacotherapy. To review the most recent findings in the diagnosis and management of immediate drug hypersensitivity reactions. Studies were selected based on their relevance, originality and date of publication. The understanding of endotypes, biomarkers and phenotypes has improved the categorization of immediate hypersensitivity reactions. In this review, we discussed the short- and long-term management of anaphylaxis with a special focus on in vivo and in vitro diagnostic methods. Moreover, the clinical management of drug-induced anaphylaxis, the role of hidden allergens and the importance of delabeling are discussed. Endophenotyping is crucial to correctly diagnose and treat patients with immediate drug hypersensitivity reactions, preventing future episodes through drug desensitization.

Incidence and Economic Burden of Adverse Drug Reactions in Hospitalization: A Prospective Study in Korea.

Adverse drug reactions (ADRs) are escalating, and their socioeconomic burden is increasing. However, large-scale prospective studies investigating ADRs during hospitalization are rare in Korea. We prospectively investigated the incidence, characteristics, and economic burden of ADRs in hospitalized patients based on electronic medical records (EMRs). Among patients admitted to three hospitals from October 2016 to October 2017, 5,000 patients were randomly selected and prospectively observed during hospitalization. Research nurses monitored and detected patients who had symptoms, signs, or laboratory findings suspicious for ADRs using an EMR-based detection protocol. Next, allergy and ADR specialists reviewed the medical records to determine the relationship between adverse reactions and drugs. Cases in which a causal relationship was certain, probable/likely, or possible were included in the ADR cases. Clinically meaningful ADR cases or those leading to prolonged hospitalization were defined as significant ADRs. ADRs occurred in 510 (10.2%) patients. The mean length of hospital stay was approximately 5 days longer in patients with ADRs. Opioids accounted for the highest percentage of total ADRs. Significant ADRs were observed in 148 (3.0%) patients. Antibiotics accounted for the highest percentage of significant ADRs. Drug hypersensitivity reactions (DHRs) occurred in 88 (1.8%) patients. Antibiotics accounted for the highest percentage of DHRs. The average medical expenses for one day of hospitalization per patient were highest in significant ADRs, followed by non-significant ADRs, and non-ADRs. ADRs in hospitalized patients are an important clinical issue, resulting in a substantial socioeconomic burden. EMR-based strategy could be a useful tool for ADR monitoring and early detection.

Guideline for allergological diagnosis of drug hypersensitivity reactions

Guideline for allergological diagnosis of drug hypersensitivity reactions