Differential presentation of hypersensitivity reactions to carboplatin and oxaliplatin: Phenotypes, endotypes, and management with desensitization.

BACKGROUND: Drug hypersensitivity reactions (DHRs) to platinum-based drugs are heterogenous and restrict their access, and drug desensitization (DD) has provided a ground-breaking procedure for their re-introduction, although the response is heterogeneous. We aimed to identify the phenotypes, endotypes, and biomarkers of reactions to carboplatin and oxaliplatin and their response to DD. METHODS: Seventy-nine patients presenting with DHRs to oxaliplatin (N = 46) and carboplatin (N = 33) were evaluated at the Allergy Departments of two tertiary care hospitals in Spain. Patient symptoms, skin testing, biomarkers, and outcomes of 267 DDs were retrospectively analyzed. RESULTS: Oxaliplatin-reactive patients presented with type I (74%), cytokine release reaction (CRR) (11%), and mixed (Mx) (15%) phenotypes. In contrast, carboplatin reactive patients presented with predominantly type I (85%) and Mx (15%) but no CRRs. Out of 267 DDs, breakthrough reactions (BTRs) to oxaliplatin occurred twice as frequently as carboplatin (32% vs. 15%; p < .05). Phenotype switching from type I to another phenotype was observed in 46% of oxaliplatin DDs compared to 21% of carboplatin DDs. Tryptase was elevated in type I and Mx reactions, and IL-6 in CRR and Mx, indicating different mechanisms and endotypes. CONCLUSION: Carboplatin and oxaliplatin induced three different types of reactions with defined phenotypes and endotypes amendable to DD. Although most of the initial reactions for both were type I, oxaliplatin presented with unique CRR reactions. During DD, carboplatin reactive patients presented mostly type I BTR, while oxaliplatin-reactive patients frequently switched from type I to CRR, providing a critical difference and the need for personalized DD protocols.

Development of a Pipeline for Removing Allergy Labels in Patients Undergoing Hematopoietic Stem Cell Transplantation.

Penicillin allergy is reported by 10% to 20 % of patients, but when evaluated only 1% to 2% may have a true allergy. Patients undergoing hematopoietic stem cell transplantation (HSCT) have a high likelihood of requiring beta-lactam antibiotics due to increased infection risk, which can be limited by a penicillin allergy label. When a penicillin allergy is recorded, alternatives are needed, including more expensive broader-spectrum antibiotics, with increases in drug-resistant bacteria, longer hospital stays, higher expenditures, and increases in nosocomial infections, such as Clostridium difficile colitis. This group of patients already undergoes extensive pretreatment testing and would especially benefit from allergy delabeling. This study aimed to develop a self-sustaining, low-cost pipeline between an HSCT clinic and an allergy clinic to identify and successfully delabel low-risk patients who endorse an allergy to penicillin, amoxicillin, amoxicillin-clavulanate, piperacillin-tazobactam, or ampicillin before admission to the hospital. We developed a survey to triage allergy risk, identified key stakeholders in building the pipeline, and underwent 4 plan, do, study, act (PDSA) cycles. Changes were made in each of the PDSA cycles to minimize cost and uncompensated provider time, as well as to increase patient retention throughout the pipeline by increasing appointment availability and decreasing reliance on patients to independently progress through the pathway. Of the 410 patients with planned HSCT who were screened over 11 months, 89 (21.7%) were listed as having a penicillin and/or beta lactam allergy. All but 1 (66 of 67; 98.5%) of the participants completed the survey accurately when confirmed by an allergist, and the survey was 100% accurate in predicting delabeling success in low-risk patients. Of eligible patients, 43.8% (n = 39) were successfully delabeled before their transplant date, and 97.4% of these (n = 38) have undergone HSCT to date. This pipeline is maintained by approximately 5 hours of work per week (1 hour of allergy physician time, 4 hours of nurse and/or clinical coordinator time), with no other direct costs. There is an estimated direct savings of at least $1914.93 per patient delabeled. We successfully designed and implemented a pipeline between the HSCT clinic and the allergy clinic as a quality improvement initiative to identify and address high rates of reported beta-lactam allergies. We identified and addressed patient-based factors, logistical, temporal, and financial barriers that impacted patient retention and sustainability. This model is expected to yield significant and sustained cost savings for the healthcare system as well as to improve patient outcomes, and this hypothesis is currently undergoing formal analysis. We anticipate that this model can be used to create a similar pipeline in other healthcare systems for HSCT recipients, as well as patients in other clinical settings, such as oncology and chimeric antigen receptor T cell therapy.

A Three-Step Taxane Titration Protocol Decreases Hypersensitivity Reactions During First and Second Exposures.

INTRODUCTION: Patients receiving taxanes are at risk for developing hypersensitivity reactions (HSRs) primarily during first and second lifetime exposures. Immediate HSRs require emergency care and can interfere with the continuation of preferred treatment. Although different approaches to slow titration have been used successfully for desensitization after HSR occurrence, there are no standardized recommendations for taxane titration to prevent HSRs. PURPOSE: To determine if a gradual, three-step infusion rate titration decreases the rate and severity of immediate HSRs during first and second lifetime exposures to paclitaxel and docetaxel. METHODS: We used a prospective, interventional design with historical comparisons to evaluate a sample of 222 first and second lifetime exposure paclitaxel and docetaxel infusions. The intervention was a three-step infusion rate titration provided at the initiation of first and second lifetime exposures. Ninety-nine titrated infusions were compared with 123 historical records of nontitrated infusions. RESULTS: Compared with the nontitrated group (n = 123), the titrated group (n = 99) had significantly less HSRs (19% v 7%; P = .017). No significant difference in HSR severity was found between groups (P = 1.00). However, four nontitrated patients received epinephrine, and one required transfer to the emergency department (ED) because of reaction severity. In contrast, no titrated patients received epinephrine or required transfer to the ED. In the nontitrated group, seven patients did not complete their infusions versus one patient in the titrated group. CONCLUSION: A standardized, three-step infusion rate titration prevented HSR occurrence. Significant issues affecting practice feasibility and sustainability were addressed.

Basophil Activation Test as a Biomarker for Taxanes Anaphylaxis.

Introduction: Taxanes are widely used chemotherapy agents, and their administration, despite premedication, is associated with hypersensitivity reactions (HR) in up to 9% of patients, 1% of which are severe. The mechanisms of these reactions are not fully understood. Finding biomarkers for early diagnosis and better understanding the underlying mechanisms of these reactions are key to defining the best treatment strategy for patients. Methods: The purpose of this study was to evaluate the effectiveness of the basophil activation test (BAT) to diagnose patients with anaphylactic reactions to taxanes. Patients with anaphylaxis to taxane compounds (n = 15) were assessed through clinical history, skin testing (when possible), and BAT. BAT was performed immediately before rapid drug desensitization or before skin testing using anti-CD123 conjugated (APC-Biolegend), anti-HLADR conjugated (FITC-Biolegend) to gate Basophils and anti-CD63 conjugated (PE-Biolegend), and anti-CD203c conjugated (BV-Biolegend) to assess CD203c and CD63 expression on basophils under taxane stimulation. BAT was also performed in eight healthy volunteers. Results: BAT was positive for CD203c in eight out of 15 patients and for CD63 in four out of 15 patients and in two out of eight controls. The sensitivity for CD203c was 53%, the specificity was 87%, and the area under the curve was 0.66 (p = 0.19%). For CD63, these rates were 33%, 87%, and 0.6 (p = 0.4). In a subgroup analysis of patients with positive skin tests (11 patients), CD203c was positive in six patients (sensitivity of 54.5% and specificity of 87.5%), and CD63 was positive in five patients (sensitivity of 45% and specificity of 75%). Conclusions: BAT as a diagnostic tool for immediate hypersensitivity reactions to taxanes may be relevant in patients with selected phenotypes and endotypes, especially those with severe reactions or when the diagnosis cannot be established by the skin test. Increased expression of CD203c was more frequent than of CD63 in patients with positive results, and the sensitivity of this biomarker was higher in patient sub-group with positive skin tests, i.e., patients with IgE-mediated endotypes.

A Facility-Wide Plan to Increase Access to Medication for Opioid Use Disorder in Primary Care and General Mental Health Settings.

BACKGROUND: The opioid epidemic in the United States has generated a pressing need to enhance access to medications for opioid use disorder (MOUD). This program description illustrates a quality-improvement effort to extend MOUD to primary care and general mental health clinics within the US Department of Veterans Affairs (VA) Connecticut Healthcare system (VACHS), and to examine barriers and facilitators to implementation of MOUD in target clinics. OBSERVATIONS: As part of the national VA Stepped Care for Opioid Use Disorder Train the Trainer (SCOUTT) initiative to improve MOUD access, a VACHS team identified and resolved barriers to MOUD in target clinics. Key interventions were to obtain leadership support, increase waivered prescribers, and develop processes and tools to enhance prescribing. New initiatives included quarterly educational sessions, templated progress notes, and instant messaging for addiction specialist electronic consultations. MOUD receipt and prescriber characteristics were evaluated before and 1 year after implementation. There was a 4% increase in eligible patients receiving MOUD, from 552 (44%) to 582 (48%) (P = .04). The number of waivered prescribers increased from 67 to 131, and the number of buprenorphine prescribers increased from 35 to 52 over a 6-month span, and the percentage of health care practitioners capable of prescribing within the electronic health record increased from 75% to 89% (P = .01). CONCLUSIONS: An interdisciplinary team approach to identifying and overcoming barriers to MOUD target clinics expands access. Key interventions include interdisciplinary leadership engagement, proactive education and incentivization of target prescribers, removal of procedural barriers, and development of tools to facilitate and support prescribing. These concrete interventions can help inform other institutions interested in expanding MOUD access.

Application of a Rat Liver Drug Bioactivation Transcriptional Response Assay Early in Drug Development That Informs Chemically Reactive Metabolite Formation and Potential for Drug-induced Liver Injury.

Drug-induced liver injury is a major reason for drug candidate attrition from development, denied commercialization, market withdrawal, and restricted prescribing of pharmaceuticals. The metabolic bioactivation of drugs to chemically reactive metabolites (CRMs) contribute to liver-associated adverse drug reactions in humans that often goes undetected in conventional animal toxicology studies. A challenge for pharmaceutical drug discovery has been reliably selecting drug candidates with a low liability of forming CRM and reduced drug-induced liver injury potential, at projected therapeutic doses, without falsely restricting the development of safe drugs. We have developed an in vivo rat liver transcriptional signature biomarker reflecting the cellular response to drug bioactivation. Measurement of transcriptional activation of integrated nuclear factor erythroid 2-related factor 2 (NRF2)/Kelch-like ECH-associated protein 1 (KEAP1) electrophilic stress, and nuclear factor erythroid 2-related factor 1 (NRF1) proteasomal endoplasmic reticulum (ER) stress responses, is described for discerning estimated clinical doses of drugs with potential for bioactivation-mediated hepatotoxicity. The approach was established using well benchmarked CRM forming test agents from our company. This was subsequently tested using curated lists of commercial drugs and internal compounds, anchored in the clinical experience with human hepatotoxicity, while agnostic to mechanism. Based on results with 116 compounds in short-term rat studies, with consideration of the maximum recommended daily clinical dose, this CRM mechanism-based approach yielded 32% sensitivity and 92% specificity for discriminating safe from hepatotoxic drugs. The approach adds new information for guiding early candidate selection and informs structure activity relationships (SAR) thus enabling lead optimization and mechanistic problem solving. Additional refinement of the model is ongoing. Case examples are provided describing the strengths and limitations of the approach.

Endophenotyping Oxaliplatin Hypersensitivity: Personalizing Desensitization to the Atypical Platin.

BACKGROUND: Oxaliplatin causes a wider variety of immediate hypersensitivity reactions than do other platin-based chemotherapeutics. Some resemble type 1 reactions that respond to desensitization. Others are atypical, possibly mast cell-independent cytokine release reactions refractory to desensitization. Given this variability, clinicians need an evidence-based strategy to personalize therapy for oxaliplatin-hypersensitive patients. OBJECTIVE: To develop a data-driven algorithm to optimize treatment of oxaliplatin-hypersensitive patients. METHODS: We retrospectively analyzed the baseline clinical characteristics, biomarkers, and reactions of 48 oxaliplatin-hypersensitive patients who received a total of 266 oxaliplatin desensitizations. RESULTS: We characterized 4 endophenotypes: type 1, cytokine release, mixed, and either. A mean 40-fold increase in serum concentration of IL-6 helped define the cytokine release endophenotype. Younger patients were more likely to have a cytokine release endophenotype, whereas older patients were more likely to have a type 1 reaction. Skin testing was not informative for determining endophenotype or risk of reaction during desensitization, and did not associate with initial or desensitization grade of reaction. Patients with a history of atopy and an initial type 1 reaction responded to desensitization with antihistamine premedications, whereas nonatopic patients with the same initial reaction phenotype were more likely to convert to a cytokine release or mixed reaction during desensitization. We combined these reaction patterns with biomarker data and desensitization outcomes to construct an algorithm that helps tailor desensitization protocol design to meet individual patient needs. CONCLUSIONS: Endophenotyping oxaliplatin hypersensitivity reactions may help forecast desensitization outcomes and personalize treatment plans.

Use of a Bile Salt Export Pump Knockdown Rat Susceptibility Model to Interrogate Mechanism of Drug-Induced Liver Toxicity.

Inhibition of the bile salt export pump (BSEP) may be associated with clinical drug-induced liver injury, but is poorly predicted by preclinical animal models. Here we present the development of a novel rat model using siRNA knockdown (KD) of Bsep that displayed differentially enhanced hepatotoxicity to 8 Bsep inhibitors and not to 3 Bsep noninhibitors when administered at maximally tolerated doses for 7 days. Bsep KD alone resulted in 3- and 4.5-fold increases in liver and plasma levels, respectively, of the sum of the 3 most prevalent taurine conjugated bile acids (T3-BA), approximately 90% decrease in plasma and liver glycocholic acid, and a distinct bile acid regulating gene expression pattern, without resulting in hepatotoxicity. Among the Bsep inhibitors, only asunaprevir and TAK-875 resulted in serum transaminase and total bilirubin increases associated with increases in plasma T3-BA that were enhanced by Bsep KD. Benzbromarone, lopinavir, and simeprevir caused smaller increases in plasma T3-BA, but did not result in hepatotoxicity in Bsep KD rats. Bosentan, cyclosporine A, and ritonavir, however, showed no enhancement of T3-BA in plasma in Bsep KD rats, as well as Bsep noninhibitors acetaminophen, MK-0974, or clarithromycin. T3-BA findings were further strengthened through monitoring TCA-d4 converted from cholic acid-d4 overcoming interanimal variability in endogenous bile acids. Bsep KD also altered liver and/or plasma levels of asunaprevir, TAK-875, TAK-875 acyl-glucuronide, benzbromarone, and bosentan. The Bsep KD rat model has revealed differences in the effects on bile acid homeostasis among Bsep inhibitors that can best be monitored using measures of T3-BA and TCA-d4 in plasma. However, the phenotype caused by Bsep inhibition is complex due to the involvement of several compensatory mechanisms.

Hypersensitivity reactions to therapeutic monoclonal antibodies: Phenotypes and endotypes.

BACKGROUND: The increasing use of mAbs has led to a rise in hypersensitivity reactions (HSRs), which prevent their use as first-line therapy. HSRs' symptoms, diagnostic tools, and directed management approaches have not been standardized. OBJECTIVE: We propose a novel evidence-based classification of HSRs to mAbs, based on the clinical phenotypes, underlying endotypes and biomarkers, as well as their management with desensitization. METHODS: Phenotypes, endotypes, and biomarkers of HSRs to 16 mAbs for 104 patients were described and compared with the outcomes of 526 subcutaneous and intravenous desensitizations. RESULTS: Initial reactions presented with 4 patterns: type I-like reactions (63%), cytokine-release reactions (13%), mixed reactions (21%), and delayed type IV reactions (3%). In contrast, of the 23% breakthrough HSRs during desensitization, 52% were cytokine-release reactions, 32% were type 1, 12% were mixed, and 4% were type I with delayed type IV. Skin testing to 10 mAbs in 58 patients was positive in 41% of patients. Serum tryptase was elevated in 1 patient and IL-6 was elevated in 8 patients during desensitization and was associated with a cytokine-release phenotype. CONCLUSIONS: HSRs to mAbs can be defined as type I, cytokine-release, mixed (type I/cytokine-release), and type IV reactions, which are identified by biomarkers such as skin test, tryptase, and IL-6. These phenotypes can be used to improve personalized and precision medicine when diagnosing HSRs to mAbs and providing management recommendations with desensitization. Desensitization provides a safe and effective retreatment option to remain on culprit mAbs as first-line therapy.

Drug-Induced Paradoxical Vocal Fold Motion.

Vocal cord dysfunction, also known as paradoxical vocal fold motion (PVFM), is a disorder characterized by abnormal vocal cord adduction during inspiration. PVFM is commonly misdiagnosed as asthma because of the similarity of symptoms: cough, wheezing, chest pain, and dyspnea. We present the clinical vignette of a 36-year-old woman with juvenile rheumatoid arthritis and multiple adverse drug reactions who presented with recurrent episodes of unrecognized PVFM during skin testing for drug allergy, omalizumab treatment, and tocilizumab desensitization. Before the diagnosis of PVFM, these episodes were treated as anaphylaxis, including the administration of epinephrine. Once diagnosed and treated for PVFM, the patient did not present any further events and continued treatment for drug allergy. PVFM may be underreported in hypersensitivity reactions because of the similarity to Type 1-mediated respiratory symptoms and comorbid asthma.

Progestogen Hypersensitivity in 24 Cases: Diagnosis, Management, and Proposed Renaming and Classification.

BACKGROUND: Autoimmune progesterone dermatitis is a poorly recognized syndrome associated with a hypersensitivity to progestogens. Symptoms present heterogeneously, which may complicate diagnosis. Management has generally centered on symptomatic control with medication. Recently, an increasing number of cases have been reported with in vitro fertilization (IVF). Desensitization to progestogens is suggested as an approach to tolerate fertility treatments and provide symptom control. OBJECTIVES: To describe the diagnosis and management of progestogen hypersensitivity (PH) and to detail the use of desensitization. We also propose a new terminology of progestogen hypersensitivity instead of autoimmune progesterone dermatitis, and a classification system based on exogenous and endogenous progestogen triggers to facilitate diagnosis and management. METHODS: Twenty-four cases of PH were evaluated retrospectively. Symptom presentation, diagnostic modalities, desensitization protocols, and outcomes were analyzed. RESULTS: Symptom onset was classified as a reaction to either endogenous progesterone (42%) or exogenous progestogens (58%). Symptoms were heterogeneous and included cyclical dermatitis, urticaria, angioedema, asthma, and anaphylaxis. Triggers were also heterogenous and included progesterone as well as progestins. Eleven patients underwent intramuscular (27%) or oral (73%) desensitization. Desensitization resulted in symptom control in 8 patients, IVF medication tolerance in 3 patients, and 2 pregnancies. CONCLUSIONS: This is the largest case series of patients with PH with successful treatment outcomes. The new terminology progestogen hypersensitivity more accurately represents the diversity of presentations to endogenous or exogenous progestogens. We demonstrate that progestogen desensitization is successful in multiple patients and can result in symptom control and fertility. Women with cyclical allergic symptoms, including those undergoing IVF, should be evaluated for PH.

Integrating DSM-IV factors to predict violence in high-risk psychiatric patients.

This study incorporated Axis-II and Axis-IV factors in DSM-IV to test the relationship between predicted risk for violence assessed in the psychiatric emergency room and actual violence during hospitalization. Psychiatric nurses lack an objective instrument to use during the acute psychiatric assessment. The retrospective study comprised consecutive psychiatric admissions (n = 161) in one tertiary veterans' hospital. Statistical testing for the predictive power of risk factors, relationships between variables, and violent events included nonparametric tests, factor analysis, and logistic regression. Of the 32 patients who committed violence during hospitalization, 12 had committed violence in the psychiatric emergency room. Statistical significance was shown for violent incidents and dementia, court-ordered admission, mood disorder, and for three or more risk factors. The 13-item Risk of Violence Assessment (ROVA) scale suggests validity and sensitivity for rating DSM-IV factors and psychosocial stressors to predict risk for violence during hospitalization. Replication studies are recommended to strengthen validity of the ROVA scale.