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Rebecca Pavlos, Elizabeth J PhillipsInstitute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, AustraliaAbstract: Antiretroviral therapy (ART) has evolved considerably over the last three decades. From the early days of monotherapy with high toxicities and pill burdens, through to larger pill burdens and more potent combination therapies, and finally, from 2005 and beyond where we now have the choice of low pill burdens and once-daily therapies. More convenient and less toxic regimens are also becoming available, even in resource-poor settings. An understanding of the individual variation in response to ART, both efficacy and toxicity, has evolved over this time. The strong association of the major histocompatibility class I allele HLA-B*5701 and abacavir hypersensitivity, and its translation and use in routine HIV clinical practice as a predictive marker with 100% negative predictive value, has been a success story and a notable example of the challenges and triumphs in bringing pharmacogenetics to the clinic. In real clinical practice, however, it is going to be the exception rather than the rule that individual biomarkers will definitively guide patient therapy. The need for individualized approaches to ART has been further increased by the importance of non-AIDS comorbidities in HIV clinical practice. In the future, the ideal utilization of the individualized approach to ART will likely consist of a combined approach using a combination of knowledge of drug, virus, and host (pharmacogenetic and pharmacoecologic [factors in the individual's environment that may be dynamic over time]) information to guide the truly personalized prescription. This review will focus on our knowledge of the pharmacogenetics of the efficacy and toxicity of currently available antiretroviral agents and the current and potential utility of such information and approaches in present and future HIV clinical care.Keywords: HIV, pharmacogenetics, pharmacogenomics, personalized medicine, antiretroviral

BackgroundLong-term sequelae are frequent and often disabling after epidermal necrolysis (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)). However, consensus on the modalities of management of these sequelae is lacking.ObjectivesWe conducted an international multicentric DELPHI exercise to establish a multidisciplinary expert consensus to standardize recommendations regarding management of SJS/TEN sequelae.MethodsParticipants were sent a survey via the online tool "Survey Monkey" consisting of 54 statements organized into 8 topics: general recommendations, professionals involved, skin, oral mucosa and teeth, eyes, genital area, mental health, and allergy workup. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). Results were analyzed according to the RAND/UCLA Appropriateness Method.ResultsFifty-two healthcare professionals participated. After the first round, a consensus was obtained for 100% of 54 initially proposed statements (disagreement index

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are the most severe cutaneous adverse reactions that are typically drug-induced in adults. Both SJS and TEN have high morbidity and mortality rates. SJS/TEN imposes clinical challenges for physicians managing patients suffering from this condition, both because it is rare and because it is a rapidly progressing systemic disease with severe cutaneous, mucosal, and systemic manifestations. Although many cases of SJS/TEN have been reported in the literature, there is no consensus regarding diagnostic criteria or treatment. Significant progress has been made in understanding its genetic predisposition and pathogenesis. This review is intended to provide physicians with a comprehensive but practical SJS/TEN roadmap to guide diagnosis and management. We review data on pathogenesis, reported precipitating factors, presentation, diagnosis, and management SJS/TEN focusing on what is new over the last 5 years., (© 2024. The Author(s).)

Background: Vancomycin infusion reaction (VIR), reportedly mediated through Mas-Related G Protein-Coupled Receptor-X2, is the primary vancomycin-induced immediate drug reaction. Clinically, distinguishing the underlying drug-induced immediate drug reaction mechanisms is crucial for future treatment strategies, including drug restriction, re-administration, and pretreatment considerations. However, the lack of validated diagnostic tests makes this challenging, often leading to unnecessary drug restriction., Objective: To determine whether intradermal tests (IDTs) and, separately, the basophil activation test (BAT) differentiate VIR from vancomycin-tolerant subjects., Methods: This was a cross-sectional study of vancomycin-exposed adults with and without a history of VIR. Data on demographics, allergy-related comorbidities, history of vancomycin exposures, and VIR characteristics were collected. IDT with vancomycin was performed. IDT dose-response EC 50 , IDT-related local symptoms, and BAT results were compared between groups., Results: A total of 11 VIR and 10 vancomycin-tolerant subjects were enrolled. The most reported VIR symptoms were pruritus (82%), flushing (82%), hives (46%), angioedema (27%), and dyspnea (19%). The IDT dose-response mean EC 50 was 328 μg/mL (95% CI, 296-367) in the VIR versus 1166 μg/mL (95% CI, 1029-1379) in the tolerant group (P < .0001). All VIR subjects reported IDT-related local pruritus compared with 60% of tolerant subjects (P = .0185). The %CD63 + basophils were consistently less than 2%, without significant differences between groups (P < .54)., Conclusions: Variations in skin test methodologies could help identify other immediate drug reaction mechanisms beyond IgE. This skin test protocol holds the potential for identifying VIR, particularly in cases where patients have received multiple drugs while BAT is insufficient. Future studies will validate and delineate its predictive value, assessing the risk of VIR., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objectives: To address the need for interactive visualization tools and databases in characterizing multimorbidity patterns across different populations, we developed the Phenome-wide Multi-Institutional Multimorbidity Explorer (PheMIME). This tool leverages three large-scale EHR systems to facilitate efficient analysis and visualization of disease multimorbidity, aiming to reveal both robust and novel disease associations that are consistent across different systems and to provide insight for enhancing personalized healthcare strategies., Materials and Methods: PheMIME integrates summary statistics from phenome-wide analyses of disease multimorbidities, utilizing data from Vanderbilt University Medical Center, Mass General Brigham, and the UK Biobank. It offers interactive and multifaceted visualizations for exploring multimorbidity. Incorporating an enhanced version of associationSubgraphs, PheMIME also enables dynamic analysis and inference of disease clusters, promoting the discovery of complex multimorbidity patterns. A case study on schizophrenia demonstrates its capability for generating interactive visualizations of multimorbidity networks within and across multiple systems. Additionally, PheMIME supports diverse multimorbidity-based discoveries, detailed further in online case studies., Results: The PheMIME is accessible at https://prod.tbilab.org/PheMIME/. A comprehensive tutorial and multiple case studies for demonstration are available at https://prod.tbilab.org/PheMIME&#95;supplementary&#95;materials/. The source code can be downloaded from https://github.com/tbilab/PheMIME., Discussion: PheMIME represents a significant advancement in medical informatics, offering an efficient solution for accessing, analyzing, and interpreting the complex and noisy real-world patient data in electronic health records., Conclusion: PheMIME provides an extensive multimorbidity knowledge base that consolidates data from three EHR systems, and it is a novel interactive tool designed to analyze and visualize multimorbidities across multiple EHR datasets. It stands out as the first of its kind to offer extensive multimorbidity knowledge integration with substantial support for efficient online analysis and interactive visualization., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Chronic inflammation contributes to the prevalence of cardiovascular disease in people living with HIV (PLWH). The immune mechanisms driving atherosclerosis progression in PLWH remain unclear. This study conducted comprehensive assessments of medium-sized coronary arteries and aorta from deceased PLWH and controls without HIV using DNA/RNA assays, spatial transcriptomics, and high-resolution mass spectrometry. Findings revealed more significant inflammation correlated with higher HIV copy numbers in late atheroma of PLWH. Enhanced CXCL12 and decreased ABCA1/ABCG1 expression in CD163 + macrophages were co-localized in coronaries of PLWH, suggesting a reduction in plasma lipoprotein clearance compared to controls. Spatial analyses identified potential therapeutic targets by revealing inflammatory changes in medium-sized arteries and the aorta. We examined the relationship between atherosclerotic phenotypes and inflammatory gene expression in Vanderbilts Biobank to study these findings in a larger clinical cohort. This established a significant association between ABCA1 and CXCL12 gene expressions with atherosclerosis, partly influenced by HIV.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is a rare but life-threatening cutaneous drug reaction mediated by human leukocyte antigen (HLA) class I-restricted CD8 + T cells. For unbiased assessment of cellular immunopathogenesis, here we perform single-cell (sc) transcriptome, surface proteome, and T cell receptor (TCR) sequencing on unaffected skin, affected skin, and blister fluid from 15 SJS/TEN patients. From 109,888 cells, we identify 15 scRNA-defined subsets. Keratinocytes express markers indicating HLA class I-restricted antigen presentation and appear to trigger the proliferation of and killing by cytotoxic CD8 + tissue-resident T cells that express granulysin, granzyme B, perforin, LAG3, CD27, and LINC01871, and signal through the PKM, MIF, TGFβ, and JAK-STAT pathways. In affected tissue, cytotoxic CD8 + T cells express private expanded and unexpanded TCRαβ that are absent or unexpanded in unaffected skin, and mixed populations of macrophages and fibroblasts express pro-inflammatory markers or those favoring repair. This data identifies putative cytotoxic TCRs and therapeutic targets., (© 2024. The Author(s).)

Patient registries are a mechanism for collecting data on allergic and immunologic diseases that provide important information on epidemiology and outcomes that can ultimately improve patient care. Key criteria for establishing effective registries include the use of a clearly defined purpose, identifying the target population and ensuring consistent data collection. Registries in allergic diseases include those for diseases such as inborn errors of immunity (IEI), food allergy, asthma and anaphylaxis, pharmacological interventions in vulnerable populations, and adverse effects of pharmacologic interventions including hypersensitivity reactions to drugs and vaccines. Important insights gained from patient registries in our field include contributions in phenotype and outcomes in IEI, the risk for adverse reactions in food-allergic patients in multiple settings, the benefits and risk of biologic medications for asthma during pregnancy, vaccine safety, and the categorization and genetic determination of risk for severe cutaneous adverse reactions to medications. Impediments to the development of clinically meaningful patient registries include the lack of funding resources for registry establishment and the quality, quantity, and consistency of available data. Despite these drawbacks, high-quality and successful registries are invaluable in informing clinical practice and improving outcomes in patients with allergic and immunological diseases., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

A patient-reported outcome is directly reported by the patient without interpretation of the patient's response by anyone else. It refers to the patient's health (symptoms and feelings), quality of life, or functional status associated with health care or treatment. Patient-reported outcome measures (PROMs) are defined as the tools or instruments that are used to measure patient-reported outcomes. Health-related quality of life has been the most studied psychosocial PROM in food allergy, using validated questionnaires. In drug allergy, PROMs are useful in capturing patients' experiences of potential allergic reactions, including subjective symptoms such as headache, dizziness, or fatigue. Patient-reported outcome measures can also help differentiate true allergies from side effects or other nonallergic reactions and inform decisions about drug challenges and de-labeling strategies. Ensuring the chosen tool is validated for the specific allergy context is crucial for accurate data collection. Integrating patient-reported experiences alongside traditional methods can lead to more accurate assessments and personalized care., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: In high HIV prevalence settings, first-line antituberculosis drug (FLTD)-associated drug reaction with eosinophilia and systemic symptoms (DRESS) poses therapeutic challenges. A sequential and additive drug challenge (SADC) of FLTDs best identifies offending drug(s), avoids unnecessary exclusions, and optimizes reinitiation of nonoffending drugs. However, SADC-associated reaction complexities limit its utility., Objective: We aimed to describe the characteristics of patients with FLTD-associated DRESS, their treatment-limiting SADC reactions, and related outcomes., Methods: Patients hospitalized with FLTD-associated DRESS from 2013 to 2023 in a South African tertiary hospital and enrolled (retrospectively or prospectively) in an existing registry were eligible., Results: SADC was undertaken in 41 patients. Overall, 47 classifiable reactions occurred. 34/47 (72%) reactions in 29/41 (71%) patients were treatment-limiting and 12 of 41(29%) patients reinitiated FLTDs uneventfully. Fifteen single and 8 multiple drug reactors were identified. Rifampicin in 13 of 23(57%) reactors was the most common individual offender. Ethambutol was most frequently involved in multiple drug reactors. The median (interquartile range) time to a detectable reaction was 24(12-120) hours, 6 of 34(18%) being immediate (<6 hours). Itch (65%), eosinophilia (56%), fever (41%), atypical lymphocytosis (41%), rash (38%), transaminitis (32%), and facial edema (18%) singly or in combination were the most common features. Three reactions, 1 epidermal necrolysis and 2 liver derangements, were Common Terminology Criteria for Adverse Events grade 4 (life-threatening) events. No predictors of multiple drug reactivity were identified, but multiple reactors were hospitalized significantly longer, 125(100-134) days versus 60(45-80) days., Conclusions: SADC optimizes FLTD reinitiation. However, timing, clinical presentation, and severity of SADC-associated reactions after FLTD-associated DRESS are markedly heterogeneous. Additionally, multiple drug reactors are a complex group that require longer hospitalization. There are no routine biomarkers available to distinguish true multiple drug hypersensitivity from nonspecific flare-ups and to guide long-term drug avoidance strategies., (Copyright © 2024. Published by Elsevier Inc.)

We aim to bring awareness of allergies to excipients such as carboxymethylcellulose as "hidden dangers" that can be easily missed in diagnosis, leading to severe effects on patient health, and falsely limit the drug treatments that a patient can receive., Competing Interests: Supported by the 10.13039/100005276American Academy of Allergy, Asthma, & Immunology (10.13039/100019212AAAAI Foundation Faculty Development Award [to C.A.S.]). The funders played no role in any aspect of this article. Disclosure of potential conflict of interest: E. J. Phillips reports receiving grants and funding from the 10.13039/100000002National Institutes of Health (grants R01HG010863, R01AI152183, U01AI154659, R13AR078623, and UAI109565) and from the 10.13039/501100000925National Health and Medical Research Council of Australia; receiving royalties from UpToDate and consulting fees from Janssen, Vertex, Biocryst, Regeneron, and Verve; serving as codirector of IIID Pty Ltd, which holds a patent for HLA-B∗57:01 testing for abacavir hypersensitivity; and having a patent pending titled “Detection of Human Leukocyte Antigen-A∗32:01 in Connection with Diagnosing Drug Reaction with Eosinophilia and Systemic Symptoms” without any financial remuneration and not directly related to the submitted work. The rest of the authors declare that they have no relevant conflicts of interest., (© 2024 The Authors.)

Cutaneous adverse drug reactions collectively are delayed drug reactions such as morbilliform drug eruption and severe cutaneous adverse reactions (SCARs). Morbilliform drug eruption may wane over time, be the result of drug viral interactions, and be amenable to slow reintroduction or rechallenge, whereas SCARs are HLA class I restricted, T-cell-mediated reactions that demonstrate durable immunity and warrant lifelong avoidance. SCARs such as drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and generalized bullous fixed drug eruption often occur in the setting of multiple drugs dosed together. Collectively, they lead to significant morbidity, mortality, and drug safety concerns that could severely limit future treatment options. Currently, no single or combination of diagnostic tests for SCARs such as ex vivo or in vitro testing, in vivo (skin) testing, or other adjunctive tests such as HLA typing have 100% negative predictive value. In this "Controversies in Allergy Review" article, we review the current literature on delayed skin testing (patch and delayed prick/intradermal test) and critically assess the evidence base of its utility across different drugs and clinical phenotypes of delayed hypersensitivity reactions., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Dupilumab is a monoclonal antibody that targets the interleukin (IL)-4 receptor alpha subunit, thus blocking the effects of IL-4 and IL-13, and has shown efficacy in treating various conditions including asthma, atopic dermatitis, eosinophilic esophagitis, and others. Because of its immune modulatory effects, clinical trials that studied dupilumab did not allow patients to receive live vaccines during the clinical trials because of an abundance of caution, and thus package inserts recommend that patients who are being treated with dupilumab should avoid live vaccines. Because dupilumab is now approved for use in patients from 6 months of age for the treatment of atopic dermatitis, this reported contraindication is now posing a clinical dilemma for patients and clinicians., Objective: To perform a systematic review of literature on the safety and efficacy of vaccinations in patients who are receiving dupilumab and to provide expert guidance on the use of vaccines in patients who are receiving dupilumab., Methods: A systematic review of the literature was performed, and an expert Delphi Panel was assembled., Results: The available literature on patients who received vaccinations while using dupilumab overall suggests that live vaccines are safe and that the vaccine efficacy, in general, is not affected by dupilumab. The expert Delphi panel agreed that the use of vaccines in patients receiving dupilumab was likely safe and effective., Conclusion: Vaccines (including live vaccines) can be administered to patients receiving dupilumab in a shared decision-making capacity., Competing Interests: Disclosures J.A.L. served as consultant for ARS, Aquestive, Bryn, ALK, and Novartis and Co-Chair Joint Task Force for Practice Parameters; received research money to institution from DBV and adjudication for Abvie and Siolta. T.E.D. the project described was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH), under Award Number 2UL1TR001425 - 05A1; the content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. E.M.A. is and employee of Public Health Agency of Canada, but the views in any paper are her own and not those of Public Health Agency of Canada. Board member of the Canadian Society of Allergy and Clinical Immunology and Head of Allergy Section, Canadian Pediatric Society. A.A. received institutional funding (Novartis) and consultation/speaker fees (ALK, EPG Health, MJH, Adelphi, Genentech, FARE, and Medscape) and served as advisory board member (Ready, Set, Food; Novartis; and Genentech). K.G.B. received grants from NIH (R01AI150295), AHRQ (R01HS029319), and Thermo Fisher Scientific and royalties from UpToDate and is consulting for Denali Therapeutics. M.B. serves as investigator and advisory board member for Regeneron and Sanofi. N.M.C. serves as clinical investigator; received research support from AstraZeneca, Genentech, and Kenota Health; serves as advisor, consultant, and/or speaker for Amgen, ARS Pharma, AstraZeneca, Blueprint Medicines, Bryn Pharma LLC, Freed AI, Genentech, GSK, Hikma, Incyte, Novartis, Regeneron, and Sanofi. D.B.K.G. is a consultant for Novartis, Aquestive, CellDex, and Kokua; received clinical trials support from Genentech, Novartis, Pfizer, GSK, Merck, Regeneron, Allergy Therapeutics, Eli Lilly, and AstraZeneca and royalties from UpToDate. N.L.H. is a speaker for Adma Bio and Takeda; speaker and advisor for Pharming, Horizon/Amgen, Horizon; advisory board member and speaker for Pharmaceuticals/Amgen. M.G.L. received research money to institution from Regeneron. S.S.M. is speaker for Genentech, Regeneron/Sanofi, GSK, and AstraZeneca and received grant from Takeda. J.J.O. consultant/advisor: GSK, Aquestive, Amgen, and ARS; adjudication/DSMB: AZ, Novartis, GSK, Sanofi, and AbbVie; reviewer/editor and executive editor: Annals of Allergy, Asthma & Immunology; reviewer: UpToDate; executive editor: Medscape; research/grants: NIH. A.R. speakers bureau member for Sanofi/Regeneron, GSK, and AstraZeneca. N.L.R. received funding from the Jeffrey Modell Foundation (58293-I), the NIH (R21AI164100), and Takeda Pharmaceuticals; is consultant for Takeda, Pharming Healthcare, and CSL Behring; received royalties from Wolters Kluwer and UpToDate. L.S. is clinical investigator for Regeneron and DBV Technologies and advisor for Sanofi and Leo pharmaceuticals. M.S.S. is member and co-chair of the Joint Task Force on Practice Parameters; serves on the editorial board of The Journal of Allergy and Clinical Immunology In Practice; is an associate editor of Annals of Allergy, Asthma, and Immunology; serves on the board of directors of the American Academy of Allergy, Asthma, and Immunology (views expressed are his own); has participated in research that has received funding from DBV. J.M.S. received grant support from and is consultant for Regeneron/Sanofi. C.A.S. recipient of a AAAAI Foundation Faculty Development Award. The views expressed in this work are the responsibility of the authors and do not necessarily represent the official views of the AAAAI. D.R.S. is consultant to ARS. J.W. received research support from NIAID, Aimmune, DBV Technologies, and Siolta and consultancy fees from ALK Abello, DBV Technologies, and Novartis. M.J.G. is consultant for Aquestive; is a member of physician/medical advisory boards for DBV Technologies, Sanofi/Regeneron, Nutricia, Novartis, Acquestive, Allergy Therapeutics, AstraZeneca, ALK-Abello, Bryn, Genentech, and Prota; is an unpaid member of the scientific advisory council for the National Peanut Board and medical advisory board of the International Food Protein Induced Enterocolitis Syndrome Association; is a member of the Brighton Collaboration Criteria Vaccine Anaphylaxis 2.0 working group; is the senior associate editor for the Annals of Allergy, Asthma, and Immunology; is member of the Joint Taskforce on Allergy Practice Parameters; received honorarium for lectures from ImSci, Red Nucleus, Medscape, Paradigm Medical Communications, Kaplan, Food Allergy Research and Education, and multiple state/local allergy societies. The remaining authors have no conflicts of interest to report., (Copyright © 2024 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Azithromycin (AZ) is a widely used antibiotic. The aim of this study was to characterise the clinical features, outcomes, and HLA association in patients with drug-induced liver injury (DILI) due to AZ., Methods: The clinical characteristics of individuals with definite, highly likely, or probable AZ-DILI enrolled in the US Drug-Induced Liver Injury Network (DILIN) were reviewed. HLA typing was performed using an Illumina MiSeq platform. The allele frequency (AF) of AZ-DILI cases was compared to population controls, other DILI cases, and other antibiotic-associated DILI cases., Results: Thirty cases (4 definite, 14 highly likely, 12 probable) of AZ-DILI were enrolled between 2004 and 2022 with a median age of 46 years, 83% white, and 60% female. Median duration of AZ treatment was 5 days. Latency was 18.5 days. 73% were jaundiced at presentation. The injury pattern was hepatocellular in 60%, cholestatic in 27%, and mixed in 3%. Ten cases (33%) were severe or fatal; 90% of these were hepatocellular. Two patients required liver transplantation. One patient with chronic liver disease died of hepatic failure. Chronic liver injury developed in 17%, of which 80% had hepatocellular injury at onset. HLA-DQA1*03:01 was significantly more common in AZ-DILI versus population controls and amoxicillin-clavulanate DILI cases (AF: 0.29 vs. 0.11, p = 0.001 and 0.002, respectively)., Conclusion: Azithromycin therapy can lead to rapid onset of severe hepatic morbidity and mortality in adult and paediatric populations. Hepatocellular injury and younger age were associated with worse outcomes. HLA-DQA1*03:01 was significantly more common in AZ cases compared to controls., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Severe cutaneous adverse reactions (SCAR) are a group of delayed presumed T-cell mediated hypersensitivities associated with significant morbidity and mortality. Despite their shared global healthcare burden and impact, the clinical phenotypes, genomic predisposition, drug causality, and treatment outcomes may vary. We describe the establishment and results from the first Australasian registry for SCAR (AUS-SCAR), that via a collaborative network advances strategies for the prevention, diagnosis and treatment of SCAR., Methods: Prospective multi-center registry of SCAR in Australian adult and adolescents, with planned regional expansion. The registry collects externally verified phenotypic data drug causality, therapeutics and long-term patient outcomes. In addition, biorepository specimens and DNA are collected at participating sites., Results: we report on the first 100 patients enrolled in the AUS-SCAR database. DRESS (50%) is the most predominant phenotype followed by SJS/TEN (39%) and AGEP (10%), with median age of 52 years old (IQR 37.5, 66) with 1:1 male-to-female ratio. The median latency for all implicated drugs is highly variable but similar for DRESS (median 15 days IQR 5,25) and SJS/TEN (median 21 days, IQR 7,27), while lowest for AGEP (median 2.5 days, IQR 1,8). Antibiotics (54.5%) are more commonly listed as primary implicated drug compare with non-antibiotics agent (45.5%). Mortality rate at 90 days was highest in SJS/TEN at 23.1%, followed by DRESS (4%) and AGEP (0%)., Conclusion: In the first prospective national phenotypic and biorepository of SCAR in the southern hemisphere we demonstrate notable differences to other reported registries; including DRESS-predominant phenotype, varied antibiotic causality and low overall mortality rate. This study also highlights the lack of standardised preventative pharmacogenomic measures and in vitro / in vivo diagnostic strategies to ascertain drug causality., Trial Registration: ANZCTR ACTRN12619000241134. Registered 19 February 2019., Competing Interests: No relevant conflicts of interest to declare., (© 2024 The Author(s).)

An increased risk of cardiometabolic disease accompanies persistent systemic inflammation. Yet, the innate and adaptive immune system features in persons who develop these conditions remain poorly defined. Doublets, or cell-cell complexes, are routinely eliminated from flow cytometric and other immune phenotyping analyses, which limits our understanding of their relationship to disease states. Using well-characterized clinical cohorts, including participants with controlled HIV as a model for chronic inflammation and increased immune cell interactions, we show that circulating CD14 + monocytes complexed to CD3 + T cells are dynamic, biologically relevant, and increased in individuals with diabetes after adjusting for confounding factors. The complexes form functional immune synapses with increased expression of proinflammatory cytokines and greater glucose utilization. Furthermore, in persons with HIV, the CD3 + T-cell: CD14 + monocyte complexes had more HIV copies compared to matched CD14 + monocytes or CD4 + T cells alone. Our results demonstrate that circulating CD3 + T-cell:CD14 + monocyte pairs represent dynamic cellular interactions that may contribute to inflammation and cardiometabolic disease pathogenesis and may originate or be maintained, in part, by chronic viral infections. These findings provide a foundation for future studies investigating mechanisms linking T cellmonocyte cell-cell complexes to developing immune-mediated diseases, including HIV and diabetes., Competing Interests: Declaration of interests The authors have no competing interests.

Competing Interests: Matthew S. Krantz reports grants from the National Institutes of Health (T32, HL087738-17). Elizabeth J. Phillips reports grants from the National Institutes of Health (R01HG010863, R01AI152183, and U01AI154659) and from the National Health and Medical Research Council of Australia. She receives royalties from and consults for UpToDate. She consults for Janssen, Verve, Biocryst, Ramboll/Esperion, Lexicomp, Regeneron, AstraZeneca, and Novavax.

Objective: To describe patients with NSAID-DILI, including genetic factors associated with idiosyncratic DILI., Methods: In DILIN, subjects with presumed DILI are enrolled and followed for at least 6 months. Causality is adjudicated by a Delphic approach. HLA sequencing of multiethnic NSAID-DILI patients and HLA allele imputation of matching population controls were performed following overall, class and drug-based association analysis. Significant results were tested in a non-Hispanic White (NHW) case-control replication cohort., Results: Between September 2004 and March 2022, causality was adjudicated in 2498, and 55 (41 [75%] women) were assessed as likely due to NSAIDs. Median age at onset was 55 y (range 22-83 y). Diclofenac was the causative drug in 29, celecoxib in 7, ibuprofen in 5, etodolac and meloxicam each in 4. Except for meloxicam and oxaprozin (n = 2), the liver injury was hepatocellular with median R 15-25. HLA-DRB1*04:03 and HLA-B*35:03 were significantly more frequent in NSAID-DILI patients than in non-NSAID DILI controls. Interestingly, 85% of the HLA-DRB1*04:03 carriers developed DILI due to the use of acetic acid derivative NSAIDs, supporting the hypothesis that HLA-DRB1*04:03 could be a drug and/or class risk factor. HLA-B*35:03 but not HLA-DRB1*04:03 association was confirmed in the independent NHW replication cohort, which was largely driven by diclofenac., Conclusions: Despite prevalent use, NSAID-DILI is infrequent in the United States. Diclofenac is the most commonly implicated, and adherence to warnings of risk and close observation are recommended. The increased frequency of HLA-B*35:03 and DRB1*04:03, driven by diclofenac, suggests the importance of immune-mediated responses., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Drug-induced hypersensitivity syndrome (DiHS), also known as drug reaction with eosinophilia and systemic symptoms (DRESS), is a severe cutaneous adverse reaction (SCAR) characterized by an exanthem, fever, and hematologic and visceral organ involvement. Anticonvulsants, antibiotics, and allopurinol are the most common triggers. The pathogenesis involves a complex interplay between drugs, viruses, and the immune system primarily mediated by T-cells. DiHS/DRESS typically presents with a morbilliform eruption 2-6 weeks after drug exposure, and is associated with significant morbidity, mortality, and risk of relapse. Long-term sequelae primarily relate to organ dysfunction and autoimmune diseases. Part I of this continuing medical education activity on DiHS/DRESS provides an update on epidemiology, novel insights into pathogenesis, and a description of clinicopathological features and prognosis., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Drug-induced hypersensitivity syndrome, also known as drug reaction with eosinophilia and systemic symptoms, is a severe cutaneous adverse reaction characterized by an exanthem, fever, and hematologic and visceral organ involvement. The differential diagnosis includes other cutaneous adverse reactions, infections, inflammatory and autoimmune diseases, and neoplastic disorders. Three sets of diagnostic criteria have been proposed; however, consensus is lacking. The cornerstone of management is immediate discontinuation of the suspected drug culprit. Systemic corticosteroids remain first-line therapy, but the literature on steroid-sparing agents is expanding. Longitudinal evaluation for sequelae is recommended. Adjunctive tests for risk stratification and drug culprit identification remain under investigation. Part II of this continuing medical education activity begins by exploring the differential diagnosis and diagnosis of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms and concludes with an evidence-based overview of evaluation and treatment., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)