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Atopic dermatitis (AD) is a common chronic skin disease. Although generally thought to be a disease of T-cell dysregulation, recent studies have suggested that immune dysregulation of NK cells is also important. Killer cell Ig-like receptors (KIRs) are involved with NK cell regulation. The Pediatric Eczema Elective Registry is a U.S. nationwide longitudinal cohort with up to 10 y of follow-up in which 655 children had DNA available for full allelic KIR sequencing. Every 6 mo, AD activity was reported by Pediatric Eczema Elective Registry children. Using generalized estimating equations, we evaluated the association of KIR allelic variation in concert with known HLA binding ligands and whether the child reported AD in “remission” (no skin lesions and not using AD medication). KIR2DS4*001:01 (odds ratio 0.53, 95% CI [0.32, 0.88]) and KIR2DL4*001:02 (0.54, [0.33, 0.89]) in the presence of C*04:01 had the largest effect on decreasing the likelihood of AD remission. The haplotype KIR 2DL4*001:02 ∼ 2DS4*001:01 ∼ 3DL2*002:01 (0.77, [0.60, 0.99]) was also associated with a decreased likelihood of AD remission. Our findings add to the general body of evidence of a growing literature on the importance of NK cells with respect to the immunopathogenesis and natural history of AD.

Just over 1 year following rollout of the first vaccines for coronavirus disease 2019, 572 million doses have been administered in the United States. Compared with the number of vaccines administered, adverse effects such as anaphylaxis have been rare, and seemingly, the more serious the effect, the rarer the occurrence. Despite these adverse effects, there are few, if any, true contraindications to coronavirus disease 2019 vaccination and most individuals recover without further sequelae. This review provides guidance for the allergist/immunologist regarding appropriate next steps based on patient's known allergy history or adverse reaction after receipt of coronavirus disease 2019 vaccine to assist in safe global immunization.

HLA (HLA) alleles are risk factors for CD8+ T-cell-mediated drug hypersensitivity reactions. However, as most HLA associations are incompletely predictive and/or involve risk alleles at low frequency, costly sequence-based typing can elude an economically productive cost: benefit ratio for clinical validation studies and diagnostic and/or preventative screening. Hence rapid and low-cost detection assays are now required, both for single alleles but also across risk loci associated with broader multi-disease risk; exemplified by associations with diverse alleles in HLA-B*35, including HLA-B*35:01 and green tea- or co-trimoxazole-induced liver injury. Here, we developed a cost-effective ($10USD) qPCR assay for rapid (2.5 h) clinical detection of HLA-B*35 alleles. The assay was validated using 430 DNA samples with previous American society for histocompatibility and immunogenetics-accredited sequence-based high-resolution HLA typing, positively detecting all HLA-B*35 allelic variants in our cohort, and as expected by primer design, the six samples that expressed low-frequency B*78:01. The assay did not result in positive detection for any negative control allele. With expected detection of B*35 and B*78, our assay sensitivity (95% CI, 95.07%-100.00%) and specificity (95% CI, 98.97%-100.00%) of 100% using as low as 10 ng of DNA provides a reliable HLA-B*35 screening tool for clinical validation and HLA-risk-based prevention and diagnostics.

Heparin, a widely used anticoagulant, carries the risk of an antibody-mediated adverse drug reaction, heparin-induced thrombocytopenia (HIT). A subset of heparin-treated patients produces detectable levels of antibodies against complexes of heparin bound to circulating platelet factor 4 (PF4). Using a genome-wide association study (GWAS) approach, we aimed to identify genetic variants associated with anti-PF4/heparin antibodies that account for the variable antibody response seen in HIT. We performed a GWAS on anti-PF4/heparin antibody levels determined via polyclonal enzyme-linked immunosorbent assays. Our discovery cohort (n = 4237) and replication cohort (n = 807) constituted patients with European ancestry and clinical suspicion of HIT, with cases confirmed via functional assay. Genome-wide significance was considered at α = 5 × 10−8. No variants were significantly associated with anti-PF4/heparin antibody levels in the discovery cohort at a genome-wide significant level. Secondary GWAS analyses included the identification of variants with suggestive associations in the discovery cohort (α = 1 × 10−4). The top variant in both cohorts was rs1555175145 (discovery β = −0.112 [0.018], P = 2.50 × 10−5; replication β = −0.104 [0.051], P = .041). In gene set enrichment analysis, 3 gene sets reached false discovery rate-adjusted significance (q < 0.05) in both discovery and replication cohorts: “Leukocyte Transendothelial Migration,” “Innate Immune Response,” and “Lyase Activity.” Our results indicate that genomic variation is not significantly associated with anti-PF4/heparin antibody levels. Given our power to identify variants with moderate frequencies and effect sizes, this evidence suggests genetic variation is not a primary driver of variable antibody response in heparin-treated patients with European ancestry.

Delayed drug hypersensitivities are CD8+ T-cell mediated reactions associated with up to 50% mortality. Human leukocyte antigen (HLA) alleles are known to predispose disease, specific to drug, reaction, and patient ethnicity, with pre-treatment screening recommended for a handful of the strongest associations to identify and prevent drug use in high-risk patients. However, an incomplete predictive value implicates other HLA-imposed risk factors, and low carriage of many identified HLA-risk alleles combined with the high cost of sequence-based typing has limited economic viability for similar recommendation of screening across drugs and healthcare systems. To mitigate, an expanding armoury of low-cost polymerase chain reaction-based screens is being developed, and HLA-imposed risk factors are being discovered. These include (1) polymorphic variants of metabolic and endoplasmic reticulum aminopeptidase enzymes, towards multi-allelic screening with increased predictivity, (2) regulation by immune checkpoint inhibitors, enabling de-tolerised animal models of human disease, and (3) immunodominant T-cell receptors (TCR) on clonally expanded CD8+ T-cells. For the latter, HLA-risk restricted TCR provides immunogenomic strategies and samples from a single patient to identify novel HLA-risk associations in underserved minority populations, tissue-relevant effector biomarkers towards earlier diagnosis and treatment, and HLA-TCR-presented immunogenic structures to aid future drug development.

BACKGROUND: Garcinia cambogia, either alone or with green tea, is commonly promoted for weight loss. Sporadic cases of liver failure from G. cambogia have been reported, but its role in liver injury is controversial. METHODS: Among 1418 patients enrolled in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2018, we identified 22 cases (adjudicated with high confidence) of liver injury from G. cambogia either alone (n=5) or in combination with green tea (n=16) or Ashwagandha (n=1). Control groups consisted of 57 patients with liver injury from herbal and dietary supplements (HDS) containing green tea without G. cambogia and 103 patients from other HDS. RESULTS: Patients who took G. cambogia were between 17 to 54 years, with liver injury arising 13 to 223 days (median = 51) after the start. One patient died, one required liver transplantation, and 91% were hospitalized. The liver injury was hepatocellular with jaundice. Although the peak values of aminotransferases were significantly higher (2001 ± 1386 U/L) in G. cambogia group (p

SummaryPersistent systemic inflammation in persons with HIV (PWH) is accompanied by an increased risk of metabolic disease. Yet, changes in the innate and adaptive immune system in PWH who develop metabolic disease remain poorly defined. Using unbiased approaches, we show that PWH with prediabetes/diabetes have a significantly higher proportion of circulating CD14+monocytes complexed to T cells. The complexed CD3+T cells and CD14+monocytes demonstrate functional immune synapses, increased expression of proinflammatory cytokines, and greater glucose utilization. Furthermore, these complexes harbor more latent HIV DNA compared to CD14+monocytes or CD4+T cells. Our results demonstrate that circulating CD3+CD14+T cell-monocyte pairs represent functional dynamic cellular interactions that likely contribute to inflammation and, in light of their increased proportion, may have a role in metabolic disease pathogenesis. These findings provide an incentive for future studies to investigate T cell-monocyte immune complexes as mechanistic in HIV cure and diseases of aging.Graphical AbstractHighlightsPersons with HIV and diabetes have increased circulating CD3+CD14+T cell-monocyte complexes.CD3+CD14+T cell-monocytes are a heterogenous group of functional and dynamic complexes.We can detect HIV in T cell-monocyte complexes.The proportion of CD3+CD14+T cell-monocyte complexes is positively associated with blood glucose levels and negatively with plasma IL-10 and CD4+T regulatory cells.

Beta-lactam antibiotics are the most commonly reported drug allergy in adults and children. More than 95% of those with reported allergy labels to beta lactams are not confirmed when subjected to allergy testing. Beta lactam antibiotics are associated with a wide spectrum of immediate and delayed drug hypersensitivity reactions. The latency period to symptoms and clinical presentation aids in the causality assessment. Risk stratification based on diagnosis and timing then allows for appropriate management and evaluation. Skin prick testing, intradermal testing and oral challenge are well established for evaluation of immediate reactions. Delayed intradermal testing, patch testing and oral challenge can also be considered for evaluation of mild to moderate delayed reactions. Cross-reactivity between beta-lactams appears to be driven most commonly by a shared R1 side-chain. Standardized algorithms, protocols and pathways are needed for widespread implementation of a pragmatic and effective approach to patients reporting beta lactam allergy.

Natural killer cells (NK) have been associated with the pathophysiology of atopic dermatitis (AD). NK function is regulated by killer cell Ig-like receptor family (KIR) receptors that interact with HLA ligands. The goal of this study was to focus on allelic variation in genes KIR2DL5, KIR2DS5, and KIR2DS1 with respect to AD. This was a case-control study of individuals with (n = 313) and without (n = 176) AD. Associations were estimated using logistic regression. Evaluations included interactions between KIR and known HLA ligand pairs. The prevalence of KIR2DL5 was 52.5% (95% CI: 48.0,57.0), KIR2DS5 was 33.0% (28.8,37.3), and KIR2DS1 was 33.6% (29.4,38.0). When compared to those who did not have KIR2DL5, homozygote individuals for KIR2DL5*001:01 were more likely to have AD (OR: 2.16 (95% CI:1.31,3.53) p = 0.0023). The effect of KIR2DL5*001:01 was similar in Whites and Blacks. The alleles from the other KIR genes of interest were not associated with AD. There is no known HLA ligand for KIR2DL5. However, the effect of KIR2DL5*001:01 increases in the presence of HLA-B *-21TT leader sequence (2.46(1.37,4.41) p = 0.0025) and HLA-C2 ligand (2.07 (1.37,4.41, p = 0.000002). This is the first study to explore KIR allelic variation in AD. KIR2DL5*001:01 allele is independently associated with an increased risk of AD.

Motivation Making sense of networked multivariate association patterns is vitally important to many areas of high-dimensional analysis. Unfortunately, as the data-space dimensions grow, the number of association pairs increases in O(n2); this means that traditional visualizations such as heatmaps quickly become too complicated to parse effectively. Results Here, we present associationSubgraphs: a new interactive visualization method to quickly and intuitively explore high-dimensional association datasets using network percolation and clustering. The goal is to provide an efficient investigation of association subgraphs, each containing a subset of variables with stronger and more frequent associations among themselves than the remaining variables outside the subset, by showing the entire clustering dynamics and providing subgraphs under all possible cutoff values at once. Particularly, we apply associationSubgraphs to a phenome-wide multimorbidity association matrix generated from an electronic health record and provide an online, interactive demonstration for exploring multimorbidity subgraphs. Availability and implementation An R package implementing both the algorithm and visualization components of associationSubgraphs is available at https://github.com/tbilab/associationsubgraphs. Online documentation is available at https://prod.tbilab.org/associationsubgraphs_info/. A demo using a multimorbidity association matrix is available at https://prod.tbilab.org/associationsubgraphs-example/.

Background: Genetic variations across the SARS-CoV-2 genome may influence transmissibility of the virus and the host’s anti-viral immune response, in turn affecting the frequency of variants over time. In this study, we examined the adjacent amino acid polymorphisms in the nucleocapsid (R203K/G204R) of SARS-CoV-2 that arose on the background of the spike D614G change and describe how strains harboring these changes became dominant circulating strains globally. Methods: Deep-sequencing data of SARS-CoV-2 from public databases and from clinical samples were analyzed to identify and map genetic variants and sub-genomic RNA transcripts across the genome. Results: Sequence analysis suggests that the 3 adjacent nucleotide changes that result in the K203/R204 variant have arisen by homologous recombination from the core sequence of the leader transcription-regulating sequence (TRS) rather than by stepwise mutation. The resulting sequence changes generate a novel sub-genomic RNA transcript for the C-terminal dimerization domain of nucleocapsid. Deep-sequencing data from 981 clinical samples confirmed the presence of the novel TRS-CS-dimerization domain RNA in individuals with the K203/R204 variant. Quantification of sub-genomic RNA indicates that viruses with the K203/R204 variant may also have increased expression of sub-genomic RNA from other open reading frames. Conclusions: The finding that homologous recombination from the TRS may have occurred since the introduction of SARS-CoV-2 in humans, resulting in both coding changes and novel sub-genomic RNA transcripts, suggests this as a mechanism for diversification and adaptation within its new host.

IMPORTANCE: There is an unprecedented need to rapidly identify safe and effective treatments for the novel coronavirus disease 2019 (COVID-19). OBJECTIVE: To systematically investigate if any of the available drugs in Electronic Health Record (EHR), including prescription drugs and dietary supplements, can be repurposed as potential treatment for COVID-19. DESIGN, SETTING, AND PARTICIPANTS: Based on a retrospective cohort analysis of EHR data, drug-wide association studies (DrugWAS) were performed on COVID-19 patients at Vanderbilt University Medical Center (VUMC). For each drug study, multivariable logistic regression with overlap weighting using propensity score was applied to estimate the effect of drug exposure on COVID-19 disease outcomes. EXPOSURES: Patient exposure to a drug during 1-year prior to the pandemic and COVID-19 diagnosis was chosen as exposure of interest. Natural language processing was employed to extract drug information from clinical notes, in addition to the prescription drug data available in structured format. MAIN OUTCOMES AND MEASURES: All-cause of death was selected as primary outcome. Hospitalization, admission to the intensive care unit (ICU), and need for mechanical ventilation were identified as secondary outcomes. RESULTS: The study included 7,768 COVID-19 patients, of which 509 (6.55%) were hospitalized, 82 (1.06%) were admitted to ICU, 64 (0.82%) received mechanical ventilation, and 90 (1.16%) died. Overall, 15 drugs were significantly associated with decreased COVID-19 severity. Previous exposure to either Streptococcus pneumoniae vaccines (adjusted odds ratio [OR], 0.38; 95% CI, 0.14–0.98), diphtheria toxoid vaccine (OR, 0.39; 95% CI, 0.15–0.98), and tetanus toxoid vaccine (OR, 0.39; 95% CI, 0.15–0.98) were significantly associated with a decreased risk of death (primary outcome). Secondary analyses identified several other significant associations showing lower risk for COVID-19 outcomes: 2 vaccines (acellular pertussis, Streptococcus pneumoniae), 3 dietary supplements (turmeric extract, flaxseed extract, omega-3 fatty acids), methylprednisolone acetate, pseudoephedrine, ethinyl estradiol, estradiol, ibuprofen, and fluticasone. CONCLUSIONS AND RELEVANCE: This cohort study leveraged EHR data to identify a list of drugs that could be repurposed to improve COVID-19 outcomes. Further randomized clinical trials are needed to investigate the efficacy of the proposed drugs.

Excipients are necessary as a support to the active ingredients in drugs, vaccines and other products and they contribute to their stability, preservation, pharmacokinetics, bioavailability, appearance and acceptability. For both drugs and vaccines these are rare reactions however for vaccines they are the primary cause of immediate hypersensitivity. Suspicion for these “hidden dangers” should be high in particular when anaphylaxis has occurred in association with multiple chemically distinct drugs. Common excipients implicated include gelatin, carboxymethylcellulose (CMC), polyethylene glycols (PEG) and products related to PEG in immediate hypersensitivity reactions (IHRs); and propylene glycol (PG), in delayed hypersensitivity reactions (DHRs). Complete evaluation of a suspected excipient reaction requires detailed information from the product monograph and package insert to identify all ingredients that are present and to understand the function and structure for these chemicals. This knowledge helps develop a management plan that may include allergy testing to identify the implicated component and to give patients detailed information for future avoidance of relevant foods, drugs and vaccines. Excipient reactions should be particularly considered for specific classes of drugs where they have been commonly found to be the culprit (e.g. corticosteroids, injectable hormones, immunotherapies, monoclonal antibodies, and vaccines). We provide a review of the evidence-based literature outlining epidemiology and mechanisms of excipient reactions and provide strategies for heightened recognition and allergy testing.

Introduction: Isolevuglandins (isoLGs) are peroxidized lipids that covalently bond lysine residues to modify self-antigens in hypertension. We hypothesized that isoLG-adduction restricts peptide presentation to specific class 1 major histocompatibility complexes (MHC) in mice and humans. Methods and Results: We developed 2 mouse strains expressing either his-tagged class 1 MHC-I H-2D b or H-2K b with truncated membrane binding domains. Shed MHC-I from cultured splenoctyes was adsorbed onto nickel-agarose beads and used to stimulate T cells. We found that CD8+ T cell proliferation is restricted to H-2D b and not H-2K b (Fig 1A) and occurs only if both T-cells and soluble H-2D b are from hypertensive (angiotensin II-treated) mice. Proliferation was blocked if donors received an isoLG-scavenger or by an isoLG specific antibody added during the proliferation assay (Fig 1B). Fluorescence resonance energy transfer (FRET) demonstrated that isoLG-adducts associate with MHC-1 H-2D b and not H-2K b . We transfected HLA-null K562 cells with 18 common human HLA subtypes, and induced isoLG formation with tert-butyl hydroperoxide. Using FRET we identified human HLAs that are high, intermediate and low presenters of isoLG adducts (Fig 1C). Unique modeling software identified candidate peptides and showed that structural characteristics of H-2D b cause lysines at positions 4-7 to project from the MHC groove and present isoLGs (Fig 1D-E). Conclusion: IsoLG adduct presentation is MHC-1 restricted. This may explain differences in the degree of inflammation and end-organ damage observed between populations with hypertension and provides a possible new approach to personalized care.

The purpose of this review is to identify recent advances in our understanding and management of immunoglobulin E (IgE)-mediated antibiotic allergy.Antibiotics remain a leading cause of fatal anaphylaxis reported to the FDA. However, recent advances have defined the features of adult and pediatric patients without true IgE-mediated allergy or any mechanism of anaphylaxis when tested. This has created opportunities to use direct challenges to disprove these allergies at the point-of-care and improves antibiotic stewardship. Additional advances have highlighted cross-reactive structural considerations within classes of drugs, in particular the R1 side-chain of cephalosporins, that appear to drive true immune-mediated cross-reactivity. Further advances in risk-based approaches to skin testing, phenotyping, and re-exposure challenges are needed to standardize antibiotic allergy evaluation.Recent advances in defining true IgE-mediated drug allergy have helped to identify patients unlikely to be skin-test positive. In turn, this has identified patients who can skip skin testing and proceed to direct ingestion challenge using history risk-based approaches. The ability to identify the small number of patients with true IgE-mediated allergy and study their natural history over time, as well as the vast majority without true allergy will facilitate important and novel mechanistic discoveries.

BackgroundStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, life-threatening immunologic reactions. Prior studies using electronic health records, registries or reporting databases are often limited in sample size or lack clinical details. We reviewed diverse detailed case reports published over four decades.MethodsStevens-Johnson syndrome and toxic epidermal necrolysis-related case reports were identified from the MEDLINE database between 1980 and 2020. Each report was classified by severity (i.e., SJS, TEN, or SJS-TEN overlap) after being considered a “probable” or “definite” SJS/TEN case. The demographics, preconditions, culprit agents, clinical course, and mortality of the cases were analyzed across the disease severity.ResultsAmong 1,059 “probable” or “definite” cases, there were 381 (36.0%) SJS, 602 (56.8%) TEN, and 76 (7.2%) SJS-TEN overlap cases, with a mortality rate of 6.3%, 24.4%, and 21.1%, respectively. Over one-third of cases had immunocompromised conditions preceding onset, including cancer (n = 194,18.3%), autoimmune diseases (n = 97, 9.2%), and human immunodeficiency virus (HIV) (n = 52, 4.9%). During the acute phase of the reaction, 843 (79.5%) cases reported mucous membrane involvement and 210 (19.8%) involved visceral organs. Most cases were drug-induced (n = 957, 90.3%). A total of 379 drug culprits were reported; the most frequently reported drug were antibiotics (n = 285, 26.9%), followed by anticonvulsants (n = 196, 18.5%), analgesics/anesthetics (n = 126, 11.9%), and antineoplastics (n = 120, 11.3%). 127 (12.0%) cases reported non-drug culprits, including infections (n = 68, 6.4%), of which 44 were associated with a mycoplasma pneumoniae infection and radiotherapy (n = 27, 2.5%).ConclusionAn expansive list of potential causative agents were identified from a large set of literature-reported SJS/TEN cases, which warrant future investigation to understand risk factors and clinical manifestations of SJS/TEN in different populations.

IntroductionSevere cutaneous adverse reactions (SCAR) are a group of T cell-mediated hypersensitivities associated with significant morbidity, mortality and hospital costs. Clinical phenotypes include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP). In this Australasian, multicentre, prospective registry, we plan to examine the clinical presentation, drug causality, genomic predictors, potential diagnostic approaches, treatments and long-term outcomes of SCAR in Australia and New Zealand.Methods and analysisAdult and adolescent patients with SCAR including SJS, TEN, DRESS, AGEP and another T cell-mediated hypersensitivity, generalised bullous fixed drug eruption, will be prospectively recruited. A waiver of consent has been granted for some sites to retrospectively include cases which result in early mortality. DNA will be collected for all prospective cases. Blood, blister fluid and skin biopsy sampling is optional and subject to patient consent and site capacity. To develop culprit drug identification and prevention, genomic testing will be performed to confirm human leukocyte antigen (HLA) type and ex vivo testing will be performed via interferon-γ release enzyme linked immunospot assay using collected peripheral blood mononuclear cells. The long-term outcomes of SCAR will be investigated with a 12-month quality of life survey and examination of prescribing and mortality data.Ethics and disseminationThis study was reviewed and approved by the Austin Health Human Research Ethics Committee (HREC/50791/Austin-19). Results will be published in peer-reviewed journals and presented at relevant conferences.Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN12619000241134).

BACKGROUND AND AIMS Herbal supplements, and particularly multi-ingredient products, have become increasingly common causes of acute liver injury. Green tea is a frequent component in implicated products, but its role in liver injury is controversial. The aim of this study was to better characterize the clinical features, outcomes, and pathogenesis of green tea-associated liver injury. APPROACH AND RESULTS Among 1,414 patients enrolled in the U.S. Drug-Induced Liver Injury Network who underwent formal causality assessment, 40 cases (3%) were attributed to green tea, 202 to dietary supplements without green tea, and 1,142 to conventional drugs. The clinical features of green tea cases and representation of human leukocyte antigen (HLA) class I and II alleles in cases and control were analyzed in detail. Patients with green tea-associated liver injury ranged in age from 17 to 69 years (median = 40) and developed symptoms 15-448 days (median = 72) after starting the implicated agent. The liver injury was typically hepatocellular (95%) with marked serum aminotransferase elevations and only modest increases in alkaline phosphatase. Most patients were jaundiced (83%) and symptomatic (88%). The course was judged as severe in 14 patients (35%), necessitating liver transplantation in 3 (8%), but rarely resulting in chronic injury (3%). In three instances, injury recurred upon re-exposure to green tea with similar clinical features, but shorter time to onset. HLA typing revealed a high prevalence of HLA-B*35:01, found in 72% (95% confidence interval [CI], 58-87) of green tea cases, but only 15% (95% CI, 10-20) caused by other supplements and 12% (95% CI, 10-14) attributed to drugs, the latter rate being similar to population controls (11%; 95% CI, 10.5-11.5). CONCLUSIONS Green tea-related liver injury has distinctive clinical features and close association with HLA-B*35:01, suggesting that it is idiosyncratic and immune mediated.

Objective We developed and evaluated Drug-Drug Interaction Wide Association Study (DDIWAS). This novel method detects potential drug-drug interactions (DDIs) by leveraging data from the electronic health record (EHR) allergy list. Materials and Methods To identify potential DDIs, DDIWAS scans for drug pairs that are frequently documented together on the allergy list. Using deidentified medical records, we tested 616 drugs for potential DDIs with simvastatin (a common lipid-lowering drug) and amlodipine (a common blood-pressure lowering drug). We evaluated the performance to rediscover known DDIs using existing knowledge bases and domain expert review. To validate potential novel DDIs, we manually reviewed patient charts and searched the literature. Results DDIWAS replicated 34 known DDIs. The positive predictive value to detect known DDIs was 0.85 and 0.86 for simvastatin and amlodipine, respectively. DDIWAS also discovered potential novel interactions between simvastatin-hydrochlorothiazide, amlodipine-omeprazole, and amlodipine-valacyclovir. A software package to conduct DDIWAS is publicly available. Conclusions In this proof-of-concept study, we demonstrate the value of incorporating information mined from existing allergy lists to detect DDIs in a real-world clinical setting. Since allergy lists are routinely collected in EHRs, DDIWAS has the potential to detect and validate DDI signals across institutions.

The drug allergy practice parameter was developed to provide guidance on the diagnosis and management of drug hypersensitivity reactions. It was last updated in 2010. With the growth of research and evidence-based data since then, experts came together to update the practice parameter with a focus on sections that the work group deemed to have significant changes (or were not addressed) in the previous practice parameter. This review is a focused update on aspects of the practice parameter deemed to have the greatest impact on clinical practice and includes significant updates on diagnosis of antibiotic allergy including penicillin, cephalosporin, sulfonamide, fluoroquinolone, and macrolide allergies. Other topics include the evolution in our management approach to patients with aspirin/nonsteroidal anti-inflammatory drug allergy, diagnostic testing for delayed drug hypersensitivity and allergy to chemotherapeutics and biologics, and the key consensus-based statements for clinical practice. Specifically, the updated practice parameter helps allergists understand the place of 1- or 2-step drug challenges that are valuable tools often without the need for skin testing in many clinical situations. A proactive approach to delabeling penicillin allergy as well as unnecessary avoidance of safe antibiotic alternatives for patients with proven penicillin allergy is emphasized. New guidance is provided on management of patients with different phenotypes of aspirin and nonsteroidal anti-inflammatory drug hypersensitivity reactions. Approaches to delayed drug hypersensitivity and use of delayed intradermal and patch testing for specific phenotypes are reviewed. Lastly, practical approaches to management of patients with reactions to chemotherapeutics and biologics are discussed.

The allergy section of the electronic health record (EHR) is ideally reviewed and updated by health care workers during routine outpatient visits, emergency room visits, inpatient hospitalizations, and surgical procedures. This EHR section has the potential to help proactively and comprehensively avoid exposures to drugs, contact irritants, foods, and other agents for which, based on an individual's medical history and/or genetics, there is increased risk for adverse outcomes with future exposures. Because clinical decisions are made and clinical decision support is triggered based on allergy details from the EHR, the allergy module needs to provide meaningful, accurate, timely, and comprehensive allergy information. Although the allergy section of the EHR must meet these requirements to guide appropriate clinical decisions and treatment plans, current EHR allergy modules have not achieved this standard. We urge EHR vendors to collaborate with allergists to optimize and modernize allergy documentation. A work group within the Adverse Reactions to Drugs, Biologicals, and Latex Committee of the American Academy of Allergy, AsthmaImmunology was formed to create recommendations for allergy documentation in the EHR. Whereas it is recognized that the term "allergy" is often used incorrectly because most adverse drug reactions (ADRs) are not true immune-mediated hypersensitivity reactions, "allergy" in this article includes allergies and hypersensitivities as well as side effects and intolerances. Our primary objective is to provide guidance for the current state of allergy documentation in the EHR. This guidance includes clarification of the definition of specific ADR types, reconciliation of confirmed ADRs, and removal of disproved or erroneous ADRs. This document includes a proposal for the creation, education, and implementation of a drug allergy labeling system that may allow for more accurate EHR documentation for improved patient safety.

Objective:To review the incidence, management, and current understanding of the pathophysiology of β-lactam–induced neutropenia and to critically evaluate the practicality and safety of direct substitution to an alternative β-lactam in the setting of this reaction.Data Sources:A literature analysis using the PubMed and Ovid search engines (July 1968 to October 2020) was performed using the search terms neutropenia, leukopenia, β-lactam, nonchemotherapy, agranulocytosis, and G-CSF (granulocyte colony-stimulating factor).Study Selection and Data Extraction:The included English-language studies evaluated the incidence, mechanism, and/or management of β-lactam–induced neutropenia in pediatric or adult patients.Data Synthesis:Drug-induced neutropenia is a well-documented adverse reaction of β-lactam antibiotics, with an incidence of approximately 10% following at least 2 weeks of intravenous therapy. However, multiple gaps in knowledge remain in the mechanism of pathophysiology and optimal management of this reaction. Both direct toxic and immune-mediated mechanisms have been implicated. Although the cornerstone of management includes cessation of the offending agent, controversy exists on the appropriateness of direct substitution or future use of an alternative β-lactam.Relevance to Patient Care and Clinical Practice:Given the frequency of use and superiority of β-lactams over alternative therapy for several infectious disease states, practical recommendations are needed on the management and safe use of β-lactams following β-lactam–induced neutropenia.Conclusion:Future use of β-lactams with differing R1 side chains, particularly those from a separate class, should not be deemed contraindicated following β-lactam–induced neutropenia and may be considered when indicated, with close laboratory monitoring.

Preexisting immune response to SARS-CoV-2 Robust T cell responses to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus occur in most individuals with coronavirus disease 2019 (COVID-19). Several studies have reported that some people who have not been exposed to SARS-CoV-2 have preexisting reactivity to SARS-CoV-2 sequences. The immunological mechanisms underlying this preexisting reactivity are not clear, but previous exposure to widely circulating common cold coronaviruses might be involved. Mateus et al. found that the preexisting reactivity against SARS-CoV-2 comes from memory T cells and that cross-reactive T cells can specifically recognize a SARS-CoV-2 epitope as well as the homologous epitope from a common cold coronavirus. These findings underline the importance of determining the impacts of preexisting immune memory in COVID-19 disease severity. Science , this issue p. 89

Hypersensitivity reactions to drugs are often unpredictable and can be life threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. We extracted data from the electronic health records of more than 600,000 participants from the UK, Estonian, and Vanderbilt University Medical Center's BioVU biobanks to study the role of genetic variation in the occurrence of self-reported penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from these cohorts to further fine map the human leukocyte antigen (HLA) association and replicated our results in 23andMe's research cohort involving a total of 1.12 million individuals. Genome-wide meta-analysis of penicillin allergy revealed two loci, including one located in the HLA region on chromosome 6. This signal was further fine-mapped to the HLA-B∗55:01 allele (OR 1.41 95% CI 1.33-1.49, p value 2.04 × 10-31) and confirmed by independent replication in 23andMe's research cohort (OR 1.30 95% CI 1.25-1.34, p value 1.00 × 10-47). The lead SNP was also associated with lower lymphocyte counts and in silico follow-up suggests a potential effect on T-lymphocytes at HLA-B∗55:01. We also observed a significant hit in PTPN22 and the GWAS results correlated with the genetics of rheumatoid arthritis and psoriasis. We present robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy.

Objective To review the relevant literature related to children with reported penicillin allergy and highlight the different ways in which children could be delabeled and to evaluate the public health impact that a penicillin allergy has for children. Data Sources Data for this review were obtained via PubMed searches and then retrieval of articles from their respective journals for further review. Study Selections Studies regarding the safety of different ways to evaluate penicillin allergy in children were identified via PubMed searches. Any study that reported different ways of testing (3-tier, direct oral challenge, 5-day oral challenges) were included. This same format was used when selecting relevant articg:les related to the costs, prescription patterns, and stewardship trends associated with a penicillin allergy label. Results This review found that penicillin allergy testing is a safe and effective way to delabel those with reported allergy. In children with low-risk allergy symptoms, a direct oral challenge approach may be optimal. In those children with a history of high-risk allergy symptoms, a 3-tiered approach is ideal. The review also found that there is a significant cost associated with reported penicillin allergy and that there are increased negative health benefits to those children with reported allergy. Conclusion Penicillin allergy is overdiagnosed, often incorrectly, and the label is frequently first applied during childhood. Targeting children for the removal of the incorrect penicillin allergy label provides a mechanism to reduce the use of broader-spectrum and less effective antibiotics.

Abacavir hypersensitivity syndrome (ABC HSS) is strongly associated with carriage of human leukocyte antigen (HLA)-B*57:01, which has a 100% negative predictive value for the development of ABC HSS. However, 45% of individuals who carry HLA-B*57:01 can tolerate ABC. We investigated immune and non-immune related genes in ABC HSS (n = 95) and ABC tolerant (n = 43) HLA-B*57:01 + patients to determine other factors required for the development of ABC HSS. Assignment of phenotype showed that ABC HSS subjects were significantly less likely than tolerants to carry only ERAP1 hypoactive trimming allotypes (p = 0.02). An altered self-peptide repertoire model by which abacavir activates T cells is in keeping with observation that endoplasmic reticulum aminopeptidase 1 (ERAP1) allotypes that favour efficient peptide trimming are more common in ABC HSS patients compared to patients who tolerate ABC. Independently, non-specific immune activation via soluble cluster of differentiation antigen 14 (sCD14) may also influence susceptibility to ABC HSS.

Self-reported antibiotic allergies, also known as antibiotic allergy labels, are common and may lead to worse patient outcomes. Within immunocompromized patients, antibiotic allergy labels can lead to inappropriate use of antimicrobials and may limit options for prophylactic and therapeutic options in the posttransplant period. While antibiotic allergy delabeling is considered an important aspect of antibiotic stewardship protocols, evidence and awareness of its application in transplant recipients is limited.We describe our experience with an antibiotic allergy delabeling intervention in the pretransplant evaluation period and its impact on posttransplant antimicrobial utilization. This was a retrospective analysis of patients with an antibiotic allergy label who underwent evaluation for solid organ or stem cell transplantation between 2015 and 2020. Patients included in this analysis were those who completed pretransplant antibiotic allergy delabeling through our Drug Allergy Clinic and were retained in care for 6 months after transplant.Twenty-six of 27 patients underwent pretransplant antibiotic allergy delabeling and safely received the delabeled antibiotic posttransplant. There were no reported side effects to the delabeled antibiotic within 6 months posttransplant. Specific examination of sulfonamide (sulfa)-antibiotic delabeling showed cost savings of $254 to $2910 per patient in the posttransplant period compared to the use of alternative antibiotics for prophylaxis protocol.Antibiotic allergy delabeling prior to transplant is safe, is of high value, and should be considered in the pretransplant evaluation period. More resources are needed for the development of delabeling guidelines and support for broad implementation of pretransplant antibiotic allergy delabeling programs.

The imagery of pigmented skin is underrepresented in teaching materials such as textbooks, journals, and online references, and this has resulted in poorer diagnostic and management outcomes of skin pathology, including delayed cutaneous drug hypersensitivity reactions. In this review, we use clinical images to highlight factors that impact clinical presentations and sequelae of drug hypersensitivity reactions in pigmented skin compared with nonpigmented skin. We describe clinical features in some anatomic sites that aid diagnosis or are associated with more severe sequelae. Finally, we discuss strategies that may aid the diagnosis and management of these reactions in pigmented skin.

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an effective strategy to prevent serious coronavirus disease 2019 (COVID-19) and is important for oncology patients. mRNA-based COVID-19 vaccines are contraindicated in those with a history of severe or immediate allergy to any vaccine component, including polyethylene glycol (PEG)2000. Patients with acute lymphoblastic leukemia/lymphoma receive asparaginase conjugated to PEG5000 (PEG-ASNase) and those with PEG-ASNase-associated hypersensitivity may be unnecessarily excluded from receiving mRNA COVID-19 vaccines. We, therefore, surveyed oncologists on COVID-19 vaccine counseling practice and vaccination outcomes in COVID-19 vaccination-eligible patients and show safe receipt of mRNA vaccines despite PEG-ASNase hypersensitivity.

Pre-existing pathogen-specific memory T cell responses can contribute to multiple adverse outcomes including autoimmunity and drug hypersensitivity. How the specificity of the T cell receptor (TCR) is subverted or seconded in many of these diseases remains unclear. Here, we apply abacavir hypersensitivity (AHS) as a model to address this question because the disease is linked to memory T cell responses and the HLA risk allele, HLA-B*57:01, and the initiating insult, abacavir, are known. To investigate the role of pathogen-specific TCR specificity in mediating AHS we performed a genome-wide screen for HLA-B*57:01 restricted T cell responses to Epstein-Barr virus (EBV), one of the most prevalent human pathogens. T cell epitope mapping revealed HLA-B*57:01 restricted responses to 17 EBV open reading frames and identified an epitope encoded by EBNA3C. Using these data, we cloned the dominant TCR for EBNA3C and a previously defined epitope within EBNA3B. TCR specificity to each epitope was confirmed, however, cloned TCRs did not cross-react with abacavir plus self-peptide. Nevertheless, abacavir inhibited TCR interactions with their cognate ligands, demonstrating that TCR specificity may be subverted by a drug molecule. These results provide an experimental road map for future studies addressing the heterologous immune responses of TCRs including T cell mediated adverse drug reactions.

This Patient Page describes the symptoms, diagnosis, and treatment of drug reaction with eosinophilia and systemic symptoms.

Discovering novel uses for existing drugs, through drug repurposing, can reduce the time, costs, and risk of failure associated with new drug development. However, prioritizing drug repurposing candidates for downstream studies remains challenging. Here, we present a high-throughput approach to identify and validate drug repurposing candidates. This approach integrates human gene expression, drug perturbation, and clinical data from publicly available resources. We apply this approach to find drug repurposing candidates for two diseases, hyperlipidemia and hypertension. We screen >21,000 compounds and replicate ten approved drugs. We also identify 25 (seven for hyperlipidemia, eighteen for hypertension) drugs approved for other indications with therapeutic effects on clinically relevant biomarkers. For five of these drugs, the therapeutic effects are replicated in the All of Us Research Program database. We anticipate our approach will enable researchers to integrate multiple publicly available datasets to identify high priority drug repurposing opportunities for human diseases., Prioritizing drug repurposing candidates for downstream studies remains challenging. Here, the authors present a high-throughput approach to identify and validate drug repurposing candidates, integrating human gene expression, drug perturbation, and clinical data from publicly available resources.

PURPOSE OF REVIEW: The goal of this article is to provide an updated understanding and evidence-based approach where possible for antifungal hypersensitivity. This includes recognition of clinical phenotype, implications for cross-reactivity and diagnostic, and management strategy for immediate and delayed hypersensitivity reactions. RECENT FINDINGS: Antifungal hypersensitivity reactions can be classified according to their latency (immediate or delayed) and clinical phenotype. The majority of the cases described in the literature are delayed T-cell mediated reactions of various severities but immediate reactions consistent with non-Immunoglobulin E (IgE)-mediated mast cell activation and IgE-mediated reactions have also been described. Ancillary information such as skin testing, drug challenge and ex vivo experimental approaches can aid causality assessments and inform antifungal class cross-reactivity, which help optimize antifungal prescribing and stewardship. SUMMARY: This review will update the clinician on mechanisms of drug hypersensitivity as well as providing a structured approach to the recognition, diagnosis and management of antifungal hypersensitivity reaction.

Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. We performed a genome-wide association study (GWAS) with positive functional assay as the outcome in a large discovery cohort of patients divided into 3 groups: (1) functional assay-positive cases (n = 1269), (2) antibody-positive (functional assay-negative) controls (n = 1131), and (3) antibody-negative controls (n = 1766). Significant associations (α = 5 × 10−8) were investigated in a replication cohort (α = 0.05) of functional assay-confirmed HIT cases (n = 177), antibody-positive (function assay-negative) controls (n = 258), and antibody-negative controls (n = 351). We observed a strong association for positive functional assay with increasing PF4/heparin immunoglobulin-G (IgG) level (odds ratio [OR], 16.53; 95% confidence interval [CI], 13.83-19.74; P = 1.51 × 10−209) and female sex (OR, 1.15; 95% CI, 1.01-1.32; P = .034). The rs8176719 C insertion variant in ABO was significantly associated with positive functional assay status in the discovery cohort (frequency = 0.41; OR, 0.751; 95% CI, 0.682-0.828; P = 7.80 × 10−9) and in the replication cohort (OR, 0.467; 95% CI, 0.228-0.954; P = .0367). The rs8176719 C insertion, which encodes all non-O blood group alleles, had a protective effect, indicating that the rs8176719 C deletion and the O blood group were risk factors for HIT (O blood group OR, 1.42; 95% CI, 1.26-1.61; P = 3.09 × 10−8). Meta-analyses indicated that the ABO association was independent of PF4/heparin IgG levels and was stronger when functional assay-positive cases were compared with antibody-positive (functional assay-negative) controls than with antibody-negative controls. Sequencing and fine-mapping of ABO demonstrated that rs8176719 was the causal single nucleotide polymorphism (SNP). Our results clarify the biology underlying HIT pathogenesis with ramifications for prediction and may have important implications for related conditions, such as vaccine-induced thrombotic thrombocytopenia.