Effect of a Co-Located Bridging Recovery Initiative on Hospital Length of Stay Among Patients With Opioid Use Disorder: The BRIDGE Randomized Clinical Trial.

Importance: Co-located bridge clinics aim to facilitate a timely transition to outpatient care for inpatients with opioid use disorder (OUD); however, their effect on hospital length of stay (LOS) and postdischarge outcomes remains unclear. Objective: To evaluate the effect of a co-located bridge clinic on hospital LOS among inpatients with OUD. Design, Setting, and Participants: This parallel-group randomized clinical trial recruited 335 adult inpatients with OUD seen by an addiction consultation service and without an existing outpatient clinician to provide medication for OUD (MOUD) between November 25, 2019, and September 28, 2021, at a tertiary care hospital affiliated with a large academic medical center and its bridge clinic. Intervention: The bridge clinic included enhanced case management before and after hospital discharge, MOUD prescription, and referral to a co-located bridge clinic. Usual care included MOUD prescription and referrals to community health care professionals who provided MOUD. Main Outcomes and Measures: The primary outcome was the index admission LOS. Secondary outcomes, assessed at 16 weeks, were linkage to health care professionals who provided MOUD, MOUD refills, same-center emergency department (ED) and hospital use, recurrent opioid use, quality of life (measured by the Schwartz Outcome Scale-10), overdose, mortality, and cost. Analysis was performed on an intent-to-treat basis. Results: Of 335 participants recruited (167 randomized to the bridge clinic and 168 to usual care), the median age was 38.0 years (IQR, 31.9-45.7 years), and 194 (57.9%) were male. The median LOS did not differ between arms (adjusted odds ratio [AOR], 0.94 [95% CI, 0.65-1.37]; P = .74). At the 16-week follow-up, participants referred to the bridge clinic had fewer hospital-free days (AOR, 0.54 [95% CI, 0.32-0.92]), more readmissions (AOR, 2.17 [95% CI, 1.25-3.76]), and higher care costs (AOR, 2.25 [95% CI, 1.51-3.35]), with no differences in ED visits (AOR, 1.15 [95% CI, 0.68-1.94]) or deaths (AOR, 0.48 [95% CI, 0.08-2.72]) compared with those receiving usual care. Follow-up calls were completed for 88 participants (26.3%). Participants referred to the bridge clinic were more likely to receive linkage to health care professionals who provided MOUD (AOR, 2.37 [95% CI, 1.32-4.26]) and have more MOUD refills (AOR, 6.17 [95% CI, 3.69-10.30]) and less likely to experience an overdose (AOR, 0.11 [95% CI, 0.03-0.41]). Conclusions and Relevance: This randomized clinical trial found that among inpatients with OUD, bridge clinic referrals did not improve hospital LOS. Referrals may improve outpatient metrics but with higher resource use and expenditure. Bending the cost curve may require broader community and regional partnerships. Trial Registration: ClinicalTrials.gov Identifier: NCT04084392.

Implementation of a hospital-based intervention for MOUD initiation and referral to a Bridge Clinic for opioid use disorder.

INTRODUCTION: Individuals struggling with opioid use disorder (OUD) utilize the adult emergency department (ED) and psychiatric emergency department at high rates. In 2019, Vanderbilt University Medical Center created a system for individuals identified in the emergency department with OUD to transition care to a Bridge Clinic for up to three months of comprehensive behavioral health treatment, alongside primary care, infectious diseases, and pain management, regardless of their insurance status. METHODS: We conducted 20 interviews with patients enrolled in treatment in our Bridge Clinic and 13 providers in the psychiatric emergency department and emergency department. Our provider interviews focused on understanding experiences identifying people with OUD and referring them to care at the Bridge Clinic. Our patient interviews focused on understanding their experiences of care-seeking, the referral process, and their satisfaction with treatment at the Bridge Clinic. RESULTS: Our analysis generated 3 major themes around patient identification, referral, and quality of care from providers and patients. The study found general agreement between both groups around the high quality of care delivered in the Bridge Clinic compared with OUD treatment at nearby treatment facilities, specifically because it offered a stigma-free environment for the delivery of medication for addiction therapy and psychosocial support. Providers highlighted the lack of a systematic strategy for identifying people with OUD in an ED setting. They also found the referral process cumbersome because it could not be done through EPIC and there were limited patient slots available. In contrast, patients reported a smooth and simple referral from the ED to the Bridge Clinic. CONCLUSIONS: Creating a Bridge Clinic for comprehensive OUD treatment at a large university medical center has been challenging but has resulted in the creation of a comprehensive care system that prioritizes quality care. Funding to increase the number of patient slots available, coupled with an electronic system of patient referral, will increase the reach of the program to some of Nashville's most vulnerable constituents.

Gram stain to the rescue: a case report of cerebral phaeohyphomycosis by Cladophialophora bantiana in an immunocompetent 24-year-old.

BACKGROUND: Fungal brain abscesses in immunocompetent patients are exceedingly rare. Cladophialophora bantiana is the most common cause of cerebral phaeohyphomycosis, a dematiaceous mold. Radiological presentation can mimic other disease states, with diagnosis through surgical aspiration and growth of melanized fungi in culture. Exposure is often unknown, with delayed presentation and diagnosis. CASE PRESENTATION: We present a case of cerebral phaeohyphomycosis in a 24-year-old with no underlying conditions or risk factors for disease. He developed upper respiratory symptoms, fevers, and headaches over the course of 2 months. On admission, he underwent brain MRI which demonstrated three parietotemporal rim-enhancing lesions. Stereotactic aspiration revealed a dematiaceous mold on staining and the patient was treated with liposomal amphotericin B, 5-flucytosine, and posaconazole prior to culture confirmation. He ultimately required surgical excision of the brain abscesses and prolonged course of antifungal therapy, with clinical improvement. CONCLUSIONS: Culture remains the gold standard for diagnosis of infection. Distinct microbiologic findings can aid in identification and guide antimicrobial therapy. While little guidance exists on treatment, patients have had favorable outcomes with surgery and combination antifungal therapy. In improving awareness, clinicians may accurately diagnose disease and initiate appropriate therapy in a more timely manner.

Bridging Recovery Initiative Despite Gaps in Entry (BRIDGE): study protocol for a randomized controlled trial of a bridge clinic compared with usual care for patients with opioid use disorder.

BACKGROUND: Patients with substance use disorders are overrepresented among general hospital inpatients, and their admissions are associated with longer lengths of stay and increased readmission rates. Amid the national opioid crisis, increased attention has been given to the integration of addiction with routine medical care in order to better engage such patients and minimize fragmentation of care. General hospital addiction consultation services and transitional, hospital-based "bridge" clinics have emerged as potential solutions. We designed the Bridging Recovery Initiative Despite Gaps in Entry (BRIDGE) trial to determine if these clinics are superior to usual care for these patients. METHODS: This single-center, pragmatic, randomized controlled clinical trial is enrolling hospitalized patients with opioid use disorder (OUD) who are initiating medication for OUD (MOUD) in consultation with the addiction consult service. Patients are randomized for referral to a co-located, transitional, multidisciplinary bridge clinic or to usual care, with the assignment probability being determined by clinic capacity. The primary endpoint is hospital length of stay. Secondary endpoints include quality of life, linkage to care, self-reported buprenorphine or naltrexone fills, rate of known recurrent opioid use, readmission rates, and costs. Implementation endpoints include willingness to be referred to the bridge clinic, attendance rates among those referred, and reasons why patients were not eligible for referral. The main analysis will use an intent-to-treat approach with full covariate adjustment. DISCUSSION: This ongoing pragmatic trial will provide evidence on the effectiveness of proactive linkage to a bridge clinic intervention for hospitalized patients with OUD initiating evidence-based pharmacotherapy in consultation with the addiction consult service. TRIAL REGISTRATION: ClinicalTrials.gov NCT04084392 . Registered on 10 September 2019. The study has been approved by the Vanderbilt Institutional Review Board. The current approved protocol is dated version May 12, 2021.

In chronic infection, HIV gag-specific CD4+ T cell receptor diversity is higher than CD8+ T cell receptor diversity and is associated with less HIV quasispecies diversity.

Cellular immune responses to Gag correlate with improved HIV viral control. The full extent of cellular immune responses comprise both the number of epitopes recognized by CD4+ and CD8+ T cells, as well as the diversity of the T cell receptor (TCR) repertoire directed against each epitope. The optimal diversity of the responsive TCR repertoire is unclear. Therefore, we evaluated the TCR diversity of CD4+ and CD8+ T cells responding to HIV-1 Gag to determine if TCR diversity correlates with clinical or virologic metrics. Previous studies of TCR repertoires have been limited primarily to CD8+ T cell responses directed against a small number of well-characterized T cell epitopes restricted by specific human leucocyte antigens. We stimulated peripheral blood mononuclear cells from 21chronic HIV-infected individuals overnight with a pool of HIV-1 Gag peptides, followed by sorting of activated CD4+ and CD8+ T cells and TCR deep sequencing. We found Gag-reactive CD8+ T cells to be more oligoclonal, with a few dominant TCRs comprising the bulk of the repertoire, compared to the highly diverse TCR repertoires of Gag-reactive CD4+ T cells. HIV viral sequencing of the same donors revealed that high CD4+ T cell TCR diversity was strongly associated with lower HIV Gag genetic diversity. We conclude that the TCR repertoire of Gag-reactive CD4+ T helper cells display substantial diversity without a clearly dominant circulating TCR clonotype, in contrast to a hierarchy of dominant TCR clonotypes in the Gag-reactive CD8+ T cells, and may serve to limit HIV diversity during chronic infection.IMPORTANCE Human T cells recognize portions of viral proteins bound to host molecules (human leucocyte antigens) on the surface of infected cells. T cells recognize these foreign proteins through their T cell receptors (TCRs), which are formed by the assortment of several available V, D and J genes to create millions of combinations of unique TCRs. We measured the diversity of T cells responding to the HIV Gag protein. We found the CD8+ T cell response is primarily made up of a few dominant unique TCRs whereas the CD4+ T cell subset has a much more diverse repertoire of TCRs. We also found there was less change in the virus sequences in subjects with more diverse TCR repertoires. HIV has a high mutation rate, which allows it to evade the immune response. Our findings describe the characteristics of a virus-specific T cell response that may allow it to limit viral evolution.

Identification of drug-specific public TCR driving severe cutaneous adverse reactions.

Drug hypersensitivity such as severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), could be life-threatening. Here, we enroll SCAR patients to investigate the T cell receptor (TCR) repertoire by next-generation sequencing. A public αßTCR is identified from the cytotoxic T lymphocytes of patients with carbamazepine-SJS/TEN, with its expression showing drug/phenotype-specificity and an bias for HLA-B*15:02. This public αßTCR has binding affinity for carbamazepine and its structural analogs, thereby mediating the immune response. Adoptive transfer of T cell expressing this public αßTCR to HLA-B*15:02 transgenic mice receiving oral administration of carbamazepine induces multi-organ injuries and symptoms mimicking SCAR, including hair loss, erythema, increase of inflammatory lymphocytes in the skin and blood, and liver and kidney dysfunction. Our results not only demonstrate an essential role of TCR in the immune synapse mediating SCAR, but also implicate potential clinical applications and development of therapeutics.

HLA-A*32:01 is strongly associated with vancomycin-induced drug reaction with eosinophilia and systemic symptoms.

BACKGROUND: Vancomycin is a prevalent cause of the severe hypersensitivity syndrome drug reaction with eosinophilia and systemic symptoms (DRESS), which leads to significant morbidity and mortality and commonly occurs in the setting of combination antibiotic therapy, affecting future treatment choices. Variations in HLA class I in particular have been associated with serious T cell-mediated adverse drug reactions, which has led to preventive screening strategies for some drugs. OBJECTIVE: We sought to determine whether variation in the HLA region is associated with vancomycin-induced DRESS. METHODS: Probable vancomycin-induced DRESS cases were matched 1:2 with tolerant control subjects based on sex, race, and age by using BioVU, Vanderbilt's deidentified electronic health record database. Associations between DRESS and carriage of HLA class I and II alleles were assessed by means of conditional logistic regression. An extended sample set from BioVU was used to conduct a time-to-event analysis of those exposed to vancomycin with and without the identified HLA risk allele. RESULTS: Twenty-three subjects met the inclusion criteria for vancomycin-associated DRESS. Nineteen (82.6%) of 23 cases carried HLA-A*32:01 compared with 0 (0%) of 46 of the matched vancomycin-tolerant control subjects (P = 1 × 10-8) and 6.3% of the BioVU population (n = 54,249, P = 2 × 10-16). Time-to-event analysis of DRESS development during vancomycin treatment among the HLA-A*32:01-positive group indicated that 19.2% had DRESS and did so within 4 weeks. CONCLUSIONS: HLA-A*32:01 is strongly associated with vancomycin-induced DRESS in a population of predominantly European ancestry. HLA-A*32:01 testing could improve antibiotic safety, help implicate vancomycin as the causal drug, and preserve future treatment options with coadministered antibiotics.

Applications of Immunopharmacogenomics: Predicting, Preventing, and Understanding Immune-Mediated Adverse Drug Reactions.

Adverse drug reactions (ADRs) are a significant health care burden. Immune-mediated adverse drug reactions (IM-ADRs) are responsible for one-fifth of ADRs but contribute a disproportionately high amount of that burden due to their severity. Variation in human leukocyte antigen ( HLA) genes has emerged as a potential preprescription screening strategy for the prevention of previously unpredictable IM-ADRs. Immunopharmacogenomics combines the disciplines of immunogenomics and pharmacogenomics and focuses on the effects of immune-specific variation on drug disposition and IM-ADRs. In this review, we present the latest evidence for HLA associations with IM-ADRs, ongoing research into biological mechanisms of IM-ADRs, and the translation of clinical actionable biomarkers for IM-ADRs, with a focus on T cell-mediated ADRs.

SJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation.

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a life-threatening, immunologically mediated, and usually drug-induced disease with a high burden to individuals, their families, and society with an annual incidence of 1 to 5 per 1,000,000. To effect significant reduction in short- and long-term morbidity and mortality, and advance clinical care and research, coordination of multiple medical, surgical, behavioral, and basic scientific disciplines is required. On March 2, 2017, an investigator-driven meeting was held immediately before the American Academy of Dermatology Annual meeting for the central purpose of assembling, for the first time in the United States, clinicians and scientists from multiple disciplines involved in SJS/TEN clinical care and basic science research. As a product of this meeting, this article summarizes the current state of knowledge and expert opinion related to SJS/TEN covering a broad spectrum of topics including epidemiology and pharmacogenomic networks; clinical management and complications; special populations such as pediatrics, the elderly, and pregnant women; regulatory issues and the electronic health record; new agents that cause SJS/TEN; pharmacogenomics and immunopathogenesis; and the patient perspective. Goals include the maintenance of a durable and productive multidisciplinary network that will significantly further scientific progress and translation into prevention, early diagnosis, and management of SJS/TEN.

Severe Delayed Drug Reactions: Role of Genetics and Viral Infections.

Adverse drug reactions (ADRs) are a significant source of patient morbidity and mortality and represent a major burden to health care systems and drug development. Up to 50% of such reactions are preventable. Although many ADRs can be predicted based on the on-target pharmacologic activity, ADRs arising from drug interactions with off-target receptors are recognized. Off-target ADRs include the immune-mediated ADRs (IM-ADRs) and pharmacologic drug effects. In this review, we discuss what is known about the immunogenetics and pathogenesis of IM-ADRs and the hypothesized role of heterologous immunity in the development of IM-ADRs.

Severe Delayed Cutaneous and Systemic Reactions to Drugs: A Global Perspective on the Science and Art of Current Practice.

Most immune-mediated adverse drug reactions (IM-ADRs) involve the skin, and many have additional systemic features. Severe cutaneous adverse drug reactions (SCARs) are an uncommon, potentially life-threatening, and challenging subgroup of IM-ADRs with diverse clinical phenotypes, mechanisms, and offending drugs. T-cell-mediated immunopathology is central to these severe delayed reactions, but effector cells and cytokines differ by clinical phenotype. Strong HLA-gene associations have been elucidated for specific drug-SCAR IM-ADRs such as Stevens-Johnson syndrome/toxic epidermal necrolysis, although the mechanisms by which carriage of a specific HLA allele is necessary but not sufficient for the development of many IM-ADRs is still being defined. SCAR management is complicated by substantial short- and long-term morbidity/mortality and the potential need to treat ongoing comorbid disease with related medications. Multidisciplinary specialist teams at experienced units should care for patients. In the setting of SCAR, patient outcomes as well as preventive, diagnostic, treatment, and management approaches are often not generalizable, but rather context specific, driven by population HLA-genetics, the pharmacology and genetic risk factors of the implicated drug, severity of underlying comorbid disease necessitating ongoing treatments, and cost considerations. In this review, we update the basic and clinical science of SCAR diagnosis and management.

Pharmacogenomics of off-target adverse drug reactions.

Off-target adverse drug reactions (ADRs) are associated with significant morbidity and costs to the healthcare system, and their occurrence is not predictable based on the known pharmacological action of the drug's therapeutic effect. Off-target ADRs may or may not be associated with immunological memory, although they can manifest with a variety of shared clinical features, including maculopapular exanthema, severe cutaneous adverse reactions (SCARs), angioedema, pruritus and bronchospasm. Discovery of specific genes associated with a particular ADR phenotype is a foundational component of clinical translation into screening programmes for their prevention. In this review, genetic associations of off-target drug-induced ADRs that have a clinical phenotype suggestive of an immunologically mediated process and their mechanisms are highlighted. A significant proportion of these reactions lack immunological memory and current data are informative for these ADRs with regard to disease pathophysiology, therapeutic targets and biomarkers which may identify patients at greatest risk. Although many serious delayed immune-mediated (IM)-ADRs show strong human leukocyte antigen associations, only a small subset have successfully been implemented in screening programmes. More recently, other factors, such as drug metabolism, have been shown to contribute to the risk of the IM-ADR. In the future, pharmacogenomic targets and an understanding of how they interact with drugs to cause ADRs will be applied to drug design and preclinical testing, and this will allow selection of optimal therapy to improve patient safety.

Old dog begging for new tricks: current practices and future directions in the diagnosis of delayed antimicrobial hypersensitivity.

PURPOSE OF REVIEW: Antimicrobials are a leading cause of severe T cell-mediated adverse drug reactions (ADRs). The purpose of this review is to address the current understanding of antimicrobial cross-reactivity and the ready availability of and evidence for in-vitro, in-vivo, and ex-vivo diagnostics for T cell-mediated ADRs. RECENT FINDINGS: Recent literature has evaluated the efficacy of traditional antibiotic allergy management, including patch testing, skin prick testing, intradermal testing, and oral challenge. Although patch and intradermal testing are specific for the diagnosis of immune-mediated ADRs, they suffer from drug-specific limitations in sensitivity. The use of ex-vivo diagnostics, especially enzyme-linked immunospot, has been highlighted as a promising new approach to assigning causality. Knowledge of true rates of antimicrobial cross-reactivity aids empirical antibiotic choice in the setting of previous immune-mediated ADRs. SUMMARY: In an era of increasing antimicrobial resistance and use of broad-spectrum antimicrobial therapy, ensuring patients are assigned the correct 'allergy label' is essential. Re-exposure to implicated antimicrobials, especially in the setting of severe adverse cutaneous reaction, is associated with significant morbidity and mortality. The process through which an antibiotic label gets assigned, acted on and maintained is still imprecise. Predicting T cell-mediated ADRs via personalized approaches, including human leukocyte antigen-typing, may pave future pathways to safer antimicrobial prescribing guidelines.

Extensive CD4 and CD8 T Cell Cross-Reactivity between Alphaherpesviruses.

The Alphaherpesvirinae subfamily includes HSV types 1 and 2 and the sequence-divergent pathogen varicella zoster virus (VZV). T cells, controlled by TCR and HLA molecules that tolerate limited epitope amino acid variation, might cross-react between these microbes. We show that memory PBMC expansion with either HSV or VZV enriches for CD4 T cell lines that recognize the other agent at the whole-virus, protein, and peptide levels, consistent with bidirectional cross-reactivity. HSV-specific CD4 T cells recovered from HSV-seronegative persons can be explained, in part, by such VZV cross-reactivity. HSV-1-reactive CD8 T cells also cross-react with VZV-infected cells, full-length VZV proteins, and VZV peptides, as well as kill VZV-infected dermal fibroblasts. Mono- and cross-reactive CD8 T cells use distinct TCRB CDR3 sequences. Cross-reactivity to VZV is reconstituted by cloning and expressing TCRA/TCRB receptors from T cells that are initially isolated using HSV reagents. Overall, we define 13 novel CD4 and CD8 HSV-VZV cross-reactive epitopes and strongly imply additional cross-reactive peptide sets. Viral proteins can harbor both CD4 and CD8 HSV/VZV cross-reactive epitopes. Quantitative estimates of HSV/VZV cross-reactivity for both CD4 and CD8 T cells vary from 10 to 50%. Based on these findings, we hypothesize that host herpesvirus immune history may influence the pathogenesis and clinical outcome of subsequent infections or vaccinations for related pathogens and that cross-reactive epitopes and TCRs may be useful for multi-alphaherpesvirus vaccine design and adoptive cellular therapy.

Evolving models of the immunopathogenesis of T cell-mediated drug allergy: The role of host, pathogens, and drug response.

Immune-mediated (IM) adverse drug reactions (ADRs) are an underrecognized source of preventable morbidity, mortality, and cost. Increasingly, genetic variation in the HLA loci is associated with risk of severe reactions, highlighting the importance of T-cell immune responses in the mechanisms of both B cell-mediated and primary T cell-mediated IM-ADRs. In this review we summarize the role of host genetics, microbes, and drugs in IM-ADR development; expand on the existing models of IM-ADR pathogenesis to address multiple unexplained observations; discuss the implications of this work in clinical practice today; and describe future applications for preclinical drug toxicity screening, drug design, and development.

Linezolid desensitization for a patient with multiple medication hypersensitivity reactions.

OBJECTIVE: To describe a case in which a linezolid desensitization protocol was successfully used for a polymicrobial surgical wound infection in a patient with multiple drug hypersensitivity reactions. CASE SUMMARY: A 24-year-old woman with vocal cord dysfunction requiring tracheostomy was admitted for a surgical wound infection following a tracheostomy fistula closure procedure. The patient reported multiple antibiotic allergies including penicillins (rash), sulfonamides (rash), vancomycin (anaphylaxis), azithromycin (rash), cephalosporins (anaphylaxis), levofloxacin (unspecified), clindamycin (unspecified), and carbapenems (unspecified). Gram stain of the purulent wound drainage demonstrated mixed gram-negative and gram-positive flora, and bacterial cultures were overgrown with Proteus mirabilis, which precluded identification of other pathogens. Following failed test doses of linezolid, tigecycline, and daptomycin, all of which resulted in hypersensitivity reactions, a 16-step linezolid desensitization protocol was developed and successfully implemented without adverse reactions. The patient completed a 2-week course of antibiotic therapy that included linezolid upon finishing the desensitization protocol. DISCUSSION: Linezolid is useful in treating complicated and uncomplicated skin and soft tissue infections caused by gram-positive bacteria. With precautions, including premedication, a monitored nursing unit, and immediate availability of an emergency anaphylaxis kit, drug desensitization allows patients the ability to safely use medications to which they may have an immediate hypersensitivity reaction. Minimal data exist on linezolid desensitization protocols. CONCLUSIONS: Linezolid desensitization can be a viable option in patients requiring antimicrobial therapy for complicated gram-positive skin infections.