Drug-induced Hypersensitivity Research Articles

Non-IgE-Mediated Immediate Drug-Induced Hypersensitivity Reactions

Non-IgE-Mediated Immediate Drug-Induced Hypersensitivity Reactions

Risk Factors and Drugs Associated with the Development of Drug-Induced Hypersensitivity Syndrome (DIHS)/Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): A Population-Based Cohort Study Using the Shizuoka Kokuho Database

Risk Factors and Drugs Associated with the Development of Drug-Induced Hypersensitivity Syndrome (DIHS)/Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): A Population-Based Cohort Study Using the Shizuoka Kokuho Database

Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions (SCARs), which include Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (also known as drug-induced hypersensitivity syndrome), acute generalized exanthematous pustulosis, and generalized bullous fixed drug eruption, are life-threatening conditions. The pathogenesis of SCARs involves T cell receptors recognizing drug antigens presented by human leukocyte antigens, triggering the activation of distinct T cell subsets. These cells interact with keratinocytes and various immune cells, orchestrating cutaneous lesions and systemic manifestations. Genetic predisposition, impaired drug metabolism, viral reactivation or infections, and heterologous immunity influence SCAR development and clinical presentation. Specific genetic associations with distinct SCAR phenotypes have been identified, leading to the implementation of genetic screening before prescription in various countries to prevent SCARs. Whilst systemic corticosteroids and conventional immunomodulators have been the primary therapeutic agents, evolving strategies, including biologics and small molecules targeting tumour necrosis factor, different cytokines, or Janus kinase signalling pathways, signify a shift towards a precision management paradigm that considers individual clinical presentations.

Drug reaction with eosinophilia and systemic symptoms (DRESS) caused by sulfasalazine: a case report and literature review

Drug-induced hypersensitivity syndrome (DIHS) or drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, potentially fatal systemic reaction characterized by multiorgan damage involving the liver, hematopoietic system and skin, and heterogeneous manifestations of fever, rash, lymphadenopathy and eosinophilia with unpredictable course.We describe a 41-year-old female patient who developed DRESS syndrome after taking sulfasalazine prescribed for non-radiographic axial spondyloarthritis. Treatment with intravenous and then oral glucocorticoids was effective. A review of the literature on this topic is presented.

Frequencies of HLA-B alleles in Indonesian Malay Ethnic

BackgroundThe HLA-B alleles have been used as a marker to predict drug-induced adverse reactions and as a major contributor to hypersensitivity reactions. We examined the feasibility of HLA-B alleles as pharmacogenomic markers of drug-induced hypersensitivity in an Indonesian Malay Ethnic. MethodsFifty-eight Indonesian individuals of Malay ethnicity were enrolled in this study. HLA-B alleles were determined using reverse sequence-specific oligonucleotide probe coupled with xMAP technology. ResultsHLA-B*15:02 (15.52%), HLA-B*35:05 (9.48%), and HLA-B*07:05 (7.76%) were frequent alleles in the Indonesian Malay ethnic populations. We discovered at least eight pharmacogenomics markers of drug-induced hypersensitivity: HLA-B*15:02, HLA-B*15:21, HLA-B*13:01, HLA-B*35:05, HLA-B*38:02, HLA-B*51:01, HLA-B*57:01, and HLA-B*58:01. HLA-B*15:02 was in the same serotype group with HLA-B*15:21, which is a B-75 serotype associated with genetic predisposition for carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis. The Indonesian population, represented by Malay, Javanese, and Sundanese ethnicities, was similar to South East Asian, Han Chinese, and Taiwanese populations based on HLA-B*15:02 frequency as the most common allele found in Malay ethnics. ConclusionWe provided valuable information on the frequency of drug hypersensitivity-associated HLA-B alleles in Indonesian Malay ethnic population, which can improve treatment safety.

Incidence of drug-induced hypersensitivity syndrome associated with levetiracetam and clobazam is likely underreported

Incidence of drug-induced hypersensitivity syndrome associated with levetiracetam and clobazam is likely underreported

Non–IgE-Mediated Immediate Drug-Induced Hypersensitivity Reactions

Immediate drug-induced hypersensitivity reactions (IDHSRs) have conventionally been attributed to an immunoglobulin E (IgE)-mediated mechanism. Nevertheless, it has now been acknowledged that IDHSRs can also occur independently of IgE involvement. Non-IgE-mediated IDHSRs encompass the activation of effector cells, both mast cell-dependent and -independent and the initiation of inflammatory pathways through immunogenic and nonimmunogenic mechanisms. The IDHSRs involve inflammatory mediators beyond histamine, including the platelet-activating factor, which activates multiple cell types, including smooth muscle, endothelium, and MC, and evidence supports its importance in IgE-mediated reactions in humans. Clinically, distinguishing IgE from non-IgE mechanisms is crucial for future treatment strategies, including drug(s) restriction, readministration approaches, and pretreatment considerations. However, this presents significant challenges because certain drugs can trigger both mechanisms, and their presentations can appear similarly, ranging from mild to life-threatening symptoms. Thus, history alone is often inadequate for differentiation, and skin tests lack a standardized approach. Moreover, drug-specific IgE immunoassays have favorable specificity but low sensitivity, and the usefulness of the basophil activation test remains debatable. Lastly, no biomarker reliably differentiates between both mechanisms. Whereas non-IgE-mediated mechanisms likely predominate in IDHSRs, reclassifying most drug-related IDHSRs as non-IgE-mediated, with suggested prevention through dose administration adjustments, is premature and risky. Therefore, continued research and validated diagnostic tests are crucial to improving our capacity to distinguish between these mechanisms, ultimately enhancing patient care.

Fulminant type 1 diabetes caused by DIHS could be affected by the reactivation of HHV-6.

In the previous issue of this journal, we reported that the incidence of fulminant type 1 diabetes (FT1D) due to the drug-induced hypersensitivity syndrome (DIHS) in Japan is higher than that in the general population and is associated with HLAB62. On the other hand, the reactivation of human herpesvirus 6 (HHV-6), which has been reported to be associated with DIHS, was observed at a higher frequency, but its association with the development of FT1D was unclear. We aimed to clarify the relationship between the onset of FT1D and the reactivation of HHV-6. We conducted a literature search for cases of DIHS-induced FT1D in addition to previously reported cases, and investigated the changes in the HHV-6 antibody titer before and after the onset of FT1D. The HHV-6 antibody titer was increased just before or after the onset of FT1D in all 8 cases. In one case, HHV-6 DNA was also identified shortly before the onset of FT1D. These results indicate for the first time that the reactivation of HHV-6 is associated with the onset of FT1D caused by DIHS. .

Circulating microbiome analysis in patients with perioperative anaphylaxis.

Perioperative anaphylaxis is a rare and acute systemic manifestation of drug-induced hypersensitivity reactions that occurs following anesthesia induction; the two main classes of drugs responsible for these reactions being neuromuscular blocking agents (NMBA) and antibiotics. The sensitization mechanisms to the drugs are not precisely known, and few risk factors have been described. A growing body of evidence underlines a link between occurrence of allergy and microbiota composition. However, no data exist on microbiota in perioperative anaphylaxis. The aim of this study was to compare circulating microbiota richness and composition between perioperative anaphylaxis patients and matched controls. Circulating 16s rDNA was quantified and sequenced in serum samples from 20 individuals with fully characterized IgE-mediated NMBA-related anaphylaxis and 20 controls matched on sex, age, NMBA received, type of surgery and infectious status. Microbiota composition was analyzed with a published bioinformatic pipeline and links with patients clinical and biological data investigated. Analysis of microbiota diversity showed that anaphylaxis patients seem to have a richer circulating microbiota than controls, but no major differences of composition could be detected with global diversity indexes. Pairwise comparison showed a difference in relative abundance between patients and controls for Saprospiraceae, Enterobacteriaceae, Veillonellaceae, Escherichia-Shigella, Pseudarcicella, Rhodoferax, and Lewinella. Some taxa were associated with concentrations of mast cell tryptase and specific IgE. We did not find a global difference in terms of microbiota composition between anaphylaxis patient and controls. However, several taxa were associated with anaphylaxis patients and with their biological data. These findings must be further confirmed in different settings to broaden our understanding of drug anaphylaxis pathophysiology and identify predisposition markers.

Dapsone-Induced DRESS Syndrome: A Case Report

Drug reaction with eosinophilia and systemic symptoms DRESS syndrome sometimes known as drug-induced hypersensitivity syndrome represents a unique and potentially life-threatening adverse response triggered by medications. It typically presents as a skin rash resembling measles affecting individuals of various age groups accompanied by symptoms like fever swollen lymph nodes irregular blood cell counts and a range of multiorgan issues. Its incidence is 11000 to 10000 exposures and its mortality is 10-20. We report a case of a patient diagnosed with DRESS syndrome secondary to Dapsone use. The main objective of this case report is to describe the characteristics complications and treatment of drug-induced DRESS syndrome. The presented case report of a 17-year-old female patient admitted to a tertiary care hospital in Bengaluru with a history of peeling skin all over the body for 10 days and was diagnosed with DRESS syndrome secondary to Dapsone use. During the admission she was prescribed Wysolone and Atarax Hydroxyzine. The patient was simultaneously treated with local ointments and her condition symptomatically improved. This case emphasizes the fatal and life-threatening adverse reactions of Dapsone and their management.

Detection of Intracellular Complement Activation by Nanoparticles in Human T Lymphocytes.

The complement system is complex and includes two main components: the systemic or plasma complement and the so-called intracellular complement or complosome. The complement proteins expressed by the liver and secreted into blood plasma compose the plasma complement system, whereas complement proteins expressed by and functioning inside the cell represent the intracellular complement. The complement system plays an essential role in host defense; however, complement activation may lead to pathologies when uncontrolled. When such undesirable activation of the plasma complement occurs in response to a drug product, it leads to immediate-type hypersensitivity reactions independent of immunoglobulin E. These reactions are often called complement activation-related pseudoallergy (CARPA). In addition to the blood plasma, the complement protein C3 is found in many cells, including lymphocytes, monocytes, endothelial, and even cancer cells. The activation of the intracellular complement generates split products, which are exported from the cell onto the membrane. Since the activation of the intracellular complement in T lymphocytes was found to correlate with autoimmune disorders, and growing evidence is available for the involvement of T lymphocytes in the development of drug-induced hypersensitivity reactions, understanding the ability of nanomaterials to activate intracellular complement may aid in establishing a long-term safety profile for these materials. This chapter describes a flow cytometry-based protocol for detecting intracellular complement activation by engineered nanomaterials.

Ciprofloxacin Ophthalmic DRESS Syndrome: Case Report

Introduction: Drug rash with eosinophilia and systemic symptoms (DRESS syndrome), also known as drug-induced hypersensitivity syndrome, is a rare severe systemic hypersensitivity drug reaction. Diagnosing DRESS syndrome is challenging due to non-specific manifestations that can make it difficult to recognize. Therefore, addressing and discussing this issue is extremely important, considering the potential lethality of a treatable syndrome. Clinical case: We describe the clinical characteristics of a 39-year-old female who presented with DRESS syndrome associated with the use of ciprofloxacin ophthalmic. The patient manifested a mild maculopapular rash located in the pelvic limbs with subsequent ascending distribution and generalized erythematoviolaceous affecting four extremities, trunk, facial region and scalp, together with fever and lymphadenopathy. Paraclinical tests revealed leukocytosis and eosinophilia. According to RegiScar's ranking, it scored 6 points, classifying it as the definitive case for DRESS. He concluded a schedule with prednisone 1 mg/kg/day with a slow reduction dose, obtaining a good response to treatment. Conclusions: DRESS syndrome should be suspected in a patient receiving medical treatment who presents with the following signs and symptoms: rash, fever (38°C), facial edema, and lymphadenopathy. Fortunately, this reaction is usually reversible, with a low incidence of residual damage or mortality, in the case of timely discontinuation of antibiotics and use of topical or systemic corticosteroids.

Clinical trial research on furagin-induced anaphylactic shock: assessing mechanisms and preventive strategies

Background. The study investigates the pressing issue of furagin-induced anaphylactic shock, addres-sing the immediate need to understand its mechanisms and create preventive strategies. Anaphylactic shock due to furagin, a widely used antimicrobial drug, has raised serious concerns. The goal is to elucidate the underlying mechanisms and risk factors of furagin-induced anaphylactic shock. Materials and methods. This research delves into this critical subject through a controlled longitudinal study on both humans and induced anaphylaxis in rats. Results. Using an advanced blind controlled longitudinal design, the study evaluates allergic reactions in humans and induced anaphylaxis in rats. It also explores the safety, tolerability, and pharmacokinetics of furagin over five days in adult patients. Moreover, the study assesses the efficacy of antihistamine pre-treatment in reducing allergic reactions. Results reveal a dose-dependent trend in allergic reactions in rats, demonstrating the effectiveness of antihistamine pre-treatment in reducing the severity of allergic symptoms. Patients with previous allergies, especially to medications, exhibited increased susceptibility to furagin-induced anaphylactic symptoms. The study underscores the potential for antihistamine pre-treatment as a preventive strategy and contributes to the understanding of allergic responses. This research informs clinical practice by providing insights into risk factors and preventive measures for furagin-induced hypersensitivity, ultimately enhancing patient safety. Conclusions. The study findings hold promise for personalized interventions and advance our understanding of drug-induced hypersensitivity reactions.

Drug-Induced Hypersensitivity Syndrome Combined with Hemophagocytic Lymphohistiocytosis related to Piperacillin-Tazobactam: A Case Report.

Drug-Induced Hypersensitivity Syndrome Combined with Hemophagocytic Lymphohistiocytosis related to Piperacillin-Tazobactam: A Case Report.

Atypical Intralymphatic T-Cell Proliferation during DRESS Mimicking Intravascular Lymphoma: Case Report

Drug-induced hypersensitivity syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug-induced reaction that represents a life-threatening condition. The histopathologic appearance of the skin biopsy is nonspecific but may exceptionally show an atypical intralymphatic lymphocytic infiltrate, and mimic an intravascular lymphoma. Through this article, we will report an exceptional case of a patient presenting with skin lesions pointing to a dress, but whose histological appearance, in the presence of adenopathy during physical examination, can lead, by mistake, to the diagnosis of an intralymphatic lymphoma. We aim to highlight the various diagnostic indices allowing the distinction between these two entities, including the immunohistochemical study, the search for the TcR clonal rearrangement and the anatomo-clinical correlation.

Flares in drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: a retrospective study.

Flares in drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: a retrospective study.

Fulminant type 1 diabetes: Focusing on triggering factors.

Fulminant type 1 diabetes (FT1D) is a novel type of type 1 diabetes that is caused by extremely rapid destruction of the pancreatic β cells. Early diagnosis or prediction of FT1D is critical for the prevention or timely treatment of diabetes ketoacidosis, which can be life-threatening. Understanding its triggers or promoting factors plays an important role in the prevention and treatment of FT1D. In this review, we summarised the various triggering factors of FT1D, including susceptibility genes, immunological factors (cellular and humoural immunity), immune checkpoint inhibitor therapies, drug reactions with eosinophilia and systemic symptoms or drug-induced hypersensitivity syndrome, pregnancy, viral infections, and vaccine inoculation. This review provides the basis for future research into the pathogenetic mechanisms that regulate FT1D development and progression to further improve the prognosis and clinical management of patients with FT1D.

SAT440 DRESS/DHIS-associated Thyroiditis And Hypophysitis

Abstract Disclosure: I.R. Ranasinghe: None. M.S. Elston: None. V. Boyle: None. Introduction: Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DRESS/DIHS) is a severe life-threatening adverse reaction to specific drugs, including cephalosporin antibiotics (1). It is characterised by rash, fever, eosinophilia, lymphadenopathy, and inflammation of internal organs. Endocrine complications in the form of thyroid disease and Type 1 Diabetes have been reported following DRESS/DIHS (2). We report a case of thyroiditis and hypophysitis following cephalosporin-associated DRESS/DIHS. Case: A 21-year-old male farmer suffered a tractor crash accident resulting in hospitalization for bilateral compound distal femur fractures. He had no past medical history of note. One month later, he developed a maculopapular rash involving his limbs, mouth ulcers, fever, liver function derangement and eosinophilia. Punch biopsy was consistent with DRESS/DHIS. A 2- week tapering course of prednisone was initiated at 40mg daily in conjunction with a topical corticosteroid for 9 days with resolution of rash. Review of medication charts identified the most likely causative agent as cefazolin. An Endocrine consult was requested a month later due to new hypercalcemia. Investigations revealed new onset thyrotoxicosis and a decreasing morning cortisol over the following week despite having stopped all steroids one month earlier, normal ACTH, mildly elevated prolactin and secondary hypogonadism. Short Synacthen test showed suboptimal response. TRAb were negative and technetium thyroid scanning demonstrated a thyroiditis. MRI pituitary was unremarkable. He was commenced on hydrocortisone replacement for symptomatic cortisol deficiency. Biochemical abnormalities gradually normalized and his hydrocortisone ceased with symptomatic resolution. Endocrine involvement, particularly pancreas and thyroid has previously been reported in cases of DHIS/DRESS (3) (4). In this case, DHIS/DRESS-associated hypophysitis with thyroiditis may explain the clinical findings of pituitary dysfunction affecting multiple pituitary axes and the gradual recovery to normal pituitary function.

Drug-Induced Hypersensitivity Syndrome/Drug Reaction With Eosinophilia and Systemic Symptoms: Predictive Score and Outcomes.

We previously developed a drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) severity (DDS) score that may predict DIHS/DRESS-associated complications (DACs), including myocarditis, gastrointestinal bleeding, and autoimmune diseases. To externally confirm the predictive accuracy of the DDS score, clarify its ability to identify patients at high risk of DACs and fatal outcome, and determine which treatments might reduce or increase the risk. We conducted a nationwide multicenter retrospective study in which we followed 48 patients with DIHS/DRESS at 5 university hospitals in Japan for 1 year after onset. Patients were divided into mild, moderate, and severe DIHS/DRESS groups depending on their early DDS score. Eight cases had DACs in the severe group (n= 17); no DACs were observed in the mild group (n= 12). Receiver-operating characteristic curve analysis showed that a cutoff DDS score of ≥4.0 and ≤2.0 could differentiate patients who would and would not develop DACs, respectively. In the moderate-to-severe disease groups, DACs occurred only in patients who received corticosteroids and not in those who received supportive care. None of the patients who received early treatment for cytomegalovirus developed DACs. Autoimmune DACs were significantly more common in patients who received pulse corticosteroid therapy. Four deaths occurred within the 1-year follow-up; all were in patients with infectious DACs who received systemic corticosteroids. Our scoring system allows early identification of patients at increased risk for DACs. Risk factors for DACs include systemic or pulse corticosteroid therapy.

Drug-induced hypersensitivity reactions in a Lebanese outpatient population: A decade-long retrospective analysis (2012-2021)

Drug hypersensitivity reactions (DHRs) are becoming more common as a result of increasing prevalence and case complexity. Allergists and clinical immunologists worldwide are challenged daily to adequately diagnose and manage these reactions. Data in the literature regarding DHR outpatient consultations are scarce worldwide, limited in the Middle East, and currently unavailable in Lebanon. This retrospective study aimed to evaluate the characteristics of all reported DHRs over 10 years in a tertiary-care allergy clinic in Lebanon. We conducted a decade-long (2012-21) retrospective analysis of the archived medical records of patients with a history of DHRs. Demographics, clinical history, diagnostic tools, and characteristics of the DHRs were collected and analyzed. A total of 758 patients experienced DHRs to therapeutic molecules provided for ambulatory care. Our results identified 72 medications. The most frequently implicated drug classes included β-lactam antibiotics (53.8%), followed closely by nonsteroidal anti-inflammatory drugs (48.9%). Of the 758 patients, 32.6% reported DHRs to multiple molecules, and 11.8% reported concomitant DHRs to 1 or several molecules provided in the perioperative setting. Of those, opioids and neuromuscular blocking agents were the 2 most common therapeutic classes. Furthermore, we evaluated the cross-reactivity between molecules of the same class. In neuromuscular blocking agents, rocuronium and cisatracurium were the most commonly cross-reactive, and for opioids, the most common association we recorded was with morphine and pethidine. Our findings constitute the first step toward a more comprehensive evaluation of the clinical characteristics of DHRs in Lebanon.