Introduction: Anaphylaxis to carboplatin and paclitaxel are important and potentially life-threatening events that can disrupt chemotherapeutic treatment of gynecologic cancers. Using the FDA Adverse Event Report System (FAERS), we sought to establish the relative incidence of reports of anaphylactic reactions to these drugs compared to other drugs and identify potential associations with age and sex. Methods: Using the search terms "anaphylactic reaction", "anaphylactic shock", "anaphylactoid reaction", or "anaphylactoid shock", we searched FAERS for reports associated with carboplatin or paclitaxel from 1970 until October 2023. Fatal and non-fatal reactions were included. Linear regression evaluated trends in reported cases. Results: Of 84,702 anaphylactic events reported to the FDA during the study period, 4,988 (5.9%) were fatal. Carboplatin (1,245 reports) and paclitaxel (1,430 reports) ranked 14th and 9th among all drugs associated with anaphylaxis, and 10th and 3rd among those associated with fatal anaphylaxis (8.0% and 10.6% fatality, respectively). Most reactions occurred in adults aged 18-85 (carboplatin 79.0%; paclitaxel 83.7%), and the majority of affected patients were women (carboplatin 70.4%; paclitaxel 68.8%). From 2013 to 2022, yearly anaphylactic reaction means were 77.9 total and 6.6 fatal carboplatin reports (fatal ratio 0.08), and 84.4 total and 8.2 fatal paclitaxel reports (fatal ratio 0.10). Conclusion: The ratio of fatal to total anaphylactic events remained steady over the last decade, suggesting a fatality rate of 8-10% among reports. Additional research is needed to identify biomarkers and improve management of these reactions in gynecologic oncology patients.

Background HIV infection has long been associated with increased incidence of severe cutaneous adverse reactions (SCAR). It remains unknown whether this increased incidence is a direct biological result of HIV infection, differences in drug exposure, or other demographic factors. Objective To evaluate the association between HIV and SCAR and determine whether this relationship persists after adjusting for demographic factors and structured drug exposure. Methods We analyzed reports from the FDA Adverse Event Reporting System (FAERS) from 2013-2023. SCAR outcomes included Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and generalized bullous fixed drug eruption (GBFDE). HIV status was determined using antiretroviral exposure, indication text, and machine-learning imputation. Logistic regression models were constructed sequentially: unadjusted, demographic-adjusted, and fully adjusted with drug principal components to account for polypharmacy. Drug-level disproportionality and HIV-drug interaction analyses were also performed. Results In unadjusted models, HIV was strongly associated with SCAR (OR ∼2.0-2.7). Adjustment for demographics attenuated this association, and further adjustment for drug exposure reduced the effect to near null for overall SCAR and DRESS. A modest residual association persisted for SJS/TEN (OR ∼1.3). Disproportionality analyses demonstrated enrichment of specific high-risk drugs in PLWH. Interaction modeling revealed drug-specific amplification of SCAR risk in HIV, notably for carbamazepine and clarithromycin, whereas other drugs showed minimal interaction. Conclusion The association between HIV and SCAR is largely explained by differences in drug exposure and demographic factors. Residual risk is drug-specific rather than uniform, supporting a model in which HIV modifies susceptibility to select drug triggers rather than acting as a global risk factor. Further prospective and retrospective studies are required to quantify associations. Highlights Box What is already known about this topic? HIV infection is associated with increased risk of severe cutaneous adverse reactions, but the relative contributions of biological susceptibility and drug exposure remain unclear. What does this article add to our knowledge? This study demonstrates that much of the HIV-SCAR association is explained by drug exposure patterns, with residual risk limited to specific drugs and phenotypes. How does this study impact current management guidelines? These findings support focusing risk mitigation on specific high-risk drugs in HIV rather than assuming uniformly elevated SCAR risk across all medications.

Oral immunotherapy (OIT) can be effective and relatively safe for the treatment of food allergies, especially when started early in life. Grocery store foods used in OIT protocols are often heterogeneous in allergen potency and display product-to-product, lot-to-lot, and unit-to-unit variations, due to raw material variability and processing. This variability complicates dosing and poses a potential risk of anaphylaxis and/or subtherapeutic efficacy for patients. To improve practice, a ‘gradient of standardization’ framework is proposed, comprising four product categories: products assumed to contain the allergens of interest, products known to contain the allergens but in unknown amounts, partially quantified products, and fully standardized preparations. Based on verified allergen content rather than protein amount, this classification would help clinicians weigh safety and efficacy against feasibility and move toward greater conformity and standardization, supporting evidence-based dosing and probably improving patient outcomes. Ideally, foods as medicines for OIT should be well-described, minimally processed, and, preferably, with defined allergen content. Precise dosing, consistent procedures, neutral vehicles, and validated allergen quantification tools could potentially ensure reproducibility, reduce risk, strengthen clinical effectiveness, and facilitate meaningful comparisons across clinical trials and research studies. We suggest that standardized “pharmaceutical grade” products, while not always a practical option, should be preferred when available.

BACKGROUND:Inaccurate multiple antibiotic allergy labels to first-line agents (penicillins, cephalosporins, and sulfonamides) restrict optimal therapy and often require sequential evaluations across multiple visits, delaying delabeling and increasing loss to follow-up. OBJECTIVE:To conduct a comparative effectiveness study of the Multiple Antibiotic Allergy Evaluation Strategy (MAAES), comparing its effectiveness, safety, and patient-reported outcomes (PRO) with traditional sequential evaluation (non-MAAES). METHODS:This retrospective cohort study (2014-2024) compared same-day multi-antibiotic testing (MAAES) with non-MAAES in patients with 2 or more low-risk labels. Multivariable regression adjusted for baseline differences and testing era. Inverse probability of treatment weighting (IPTW) and a restricted post-2020 subcohort analysis addressed selection bias and temporal shifts. Outcomes included delabeling efficacy, time to complete delabeling, loss to follow-up, relabeling, adverse events (AEs), and PRO. RESULTS:Baseline differences were present between the MAAES and non-MAAES groups, including penicillin anaphylaxis (1.4% vs 6.6%, P = .002), angioedema (12.4% vs 19.1%, P = .049), maculopapular rash (13.1% vs 24.3%, P = .002), and unknown sulfonamide history (9.5% vs 3.7%, P = .03). MAAES removed 97.4% of labels versus 79.6% for non-MAAES (adjusted odds ratio [aOR]: 9.41, 95% confidence interval [CI]: 5.22-16.95, P < .001). MAAES achieved faster complete delabeling (log-rank χ2 = 42.4, P < .001), with 84.9% versus 21.1% delabeled at the initial visit (restricted mean survival time difference: 2.1 months). Results remained robust in post-2020 and IPTW models. Loss to follow-up (1.3% vs 17.2%; aOR: 0.06, 95% CI: 0.03-0.13, P <.001) and AEs (<1% vs 2.8%; aOR: 0.26, 95% CI: 0.09-0.78, P = .02) were significantly lower with MAAES. Favorable PRO was sustained, with no significant differences between groups. CONCLUSIONS:A consolidated multidrug evaluation strategy substantially improves the effectiveness of first-line antibiotic allergy delabeling while maintaining excellent safety profiles and PRO.

BACKGROUND:Reported adverse events (AEs) to the Food and Drug Administration Adverse Event Reporting System (FAERS) have suggested an increased rate of serious AEs (SAEs) during the COVID-19 pandemic, but the extent to which this may be related to overall changes in reporting during this time period is uncertain. Accordingly, we aimed to evaluate trends in SAE reporting across commercially available ultrasound enhancing agent (UEA) brands as a function of overall trends in AE reporting. METHODS:We retrospectively analyzed the FAERS public database, 2014-2024, to evaluate risks of UEAs overall and by brand, compared to similar contrast media. RESULTS:Between 2014 and 2024, 21,960,760 AEs were reported to FAERS, of which 11,450,891 (52.1%) were categorized as SAEs. Overall SAE reports to FAERS increased from 678,953 in 2014 to 1,368,393 in 2021 before subsequently declining to 1,065,845 in 2024 (-7.9% change from 2021 to 2024). During the same period, overall death reports to FAERS increased from 124,055 in 2014 to 195,207 in 2018 before declining to 147,046 in 2024. During this period of decline, there was a 23.9% relative increase in SAEs to UEAs which peaked in 2023 at 350 before declining to 326 in 2024. Deaths attributed to SAEs increased from 1 in 2014 to 19 in 2023 before declining to 9 in 2024. Overall, these data suggest that 11.2% of the observed increase in SAEs to UEAs can be attributed to reporting changes. Despite changes in relative risks for SAEs, absolute SAE rates remained small and lower than other types of contrast media. CONCLUSIONS:In this analysis of the FAERS dataset, 2014-2024, 11.2% of SAEs to UEAs were attributable to temporal changes in AE reporting. Absolute risks are small and declining, suggesting broad safety of UEAs as a class. Collectively, these results support continued use of UEAs, but motivate improved safety screening and preparedness to mitigate small but existing risks.

Background: Transfusion-related alpha-gal syndrome (TRAGS) has recently been proposed as a cause of allergic transfusion reactions (ATRs) in which alpha-gal-specific IgE in sensitized group O (or potentially group A) recipients reacts with epitopes on group B or AB plasma-containing components. Fewer than 10 cases have been reported, all from the Northeast and mid-Atlantic United States, and alpha-gal-specific ATR evaluation practices are unstudied. Study Design and Methods: Two patients with ATRs consistent with TRAGS at a large academic medical center in Nashville, Tennessee are reported alongside a 5-year retrospective cohort analysis of group O and A recipients experiencing ATRs following transfusion of group B or AB plasma-containing products. Alpha-gal IgE testing, AGS diagnosis documentation, and documented consideration of IgA deficiency were assessed for each qualifying reaction. Results: Both index patients had pre-existing AGS diagnoses unrecognized at component selection; one was a 42-year-old female and the second an 83-year-old male. Among 50 qualifying ATRs in 44 patients, including 13 severe or anaphylactic reactions, alpha-gal IgE testing was not performed for any event, and no patient had a documented AGS diagnosis. IgA deficiency was considered in eight patients (18%), yielding no diagnoses. Conclusion: TRAGS occurs in the tick-endemic southeastern United States across a broader demographic range than previously recognized. IgA deficiency, present in <0.3% of the population, was considered in 18% of qualifying patients while alpha-gal sensitization, affecting 20%-30% in this region, was investigated in none. Integration of AGS history into pre-transfusion risk assessment and ATR evaluation protocols is warranted.

Alpha-gal syndrome (AGS) is an immunoglobulin E (IgE)-mediated hypersensitivity to the oligosaccharide galactose-α-1,3-galactose, acquired through tick bites and increasingly recognized as a cause of allergic reactions to mammalian-derived medical products. Every major transplant modality creates distinct conditions under which sensitized patients may encounter alpha-gal, yet AGS knowledge has developed almost entirely outside the transplant literature. In conventional solid organ transplantation, risk arises primarily from perioperative exposures to porcine-derived heparin, gelatin-based hemostatic agents, and other mammalian-derived materials. In xenotransplantation, the well-characterized role of alpha-gal as the principal xenoantigen has driven the development of glycoprotein alpha-galactosyltransferase 1-knockout swine, but the distinct IgE-mediated pathway that defines AGS has received little attention. Hematopoietic stem cell transplantation introduces questions about conditioning-related immune remodeling of preexisting IgE sensitization, rabbit antithymocyte globulin as an underrecognized alpha-gal exposure, and transfusion-related alpha-gal syndrome when group B or AB plasma-containing blood products are transfused to susceptible patients. Cellular therapy manufacturing workflows that use animal-derived ancillary materials represent a further theoretical exposure pathway. Importantly, detectable anti-alpha-gal IgE does not invariably predict clinical reactivity, and the most appropriate clinical approach is risk stratification rather than reflexive exclusion. Generating the evidence base to support such stratification will require collaboration across allergy, transplant, and transfusion medicine.

Summary Paediatric penicillin allergy prevalence declined from 7.57% to 6.65% (2018–2024), especially in youngest children. An overall decrease in new PAL and an increase in institutional penicillin allergy delabelling was observed.

Abstract Importance Immune checkpoint inhibitors (ICIs) produce diverse immune toxicities, but whether checkpoint blockade also modifies associations between other drugs and adverse events is poorly understood. Objective To define ICI-associated toxicity organization and determine whether drug-associated adverse-event reporting and documented onset vary with ICI exposure and checkpoint pathway. Design and Setting Cross-sectional analysis of deduplicated FAERS reports from 2016 through 2025; analyses performed in 2026. Participants Among 13,701,106 deduplicated reports, 2,365,278 were associated with cancer and 256,940 contained an ICI. Median age among cancer reports with observed age was 66 years (IQR, 56-75 years). Exposures ICI exposure in any reported drug role, individual primary-suspect drugs, and checkpoint-pathway exposure. Main Outcomes and Measures Reporting odds ratios (ORs), cross-organ adverse-event communities, adjusted primary-suspect drug × ICI interaction ORs for Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), interstitial nephritis, drug-induced liver injury (DILI), anaphylaxis, and vomiting, and accelerated failure-time model time ratios for documented onset. Results Of 3001 eligible Preferred Terms in cancer-associated reports, 2091 differed at a false discovery rate (FDR) less than .05, and 4 cross-organ toxicity communities were identified. Of 147 eligible drug-phenotype pairs, 71 had FDR-significant interactions (56 amplification and 15 attenuation), including moxifloxacin–SJS/TEN amplification (interaction OR, 100.51; 95% CI, 38.58-261.84), enfortumab vedotin–SJS/TEN attenuation (interaction OR, 0.17; 95% CI, 0.13-0.23), and omeprazole–interstitial nephritis amplification (interaction OR, 10.33; 95% CI, 7.60-14.04). Among 64,593 reports in the 1-to 365-day temporal cohort, ICI exposure was associated with longer adjusted documented onset for 5 of 7 phenotypes (time ratios, 1.37-1.58); AGEP and anaphylaxis were not significant. Of 19 estimable checkpoint-phenotype coefficients, 10 remained FDR significant. Conclusions and Relevance ICIs were associated with a structured cross-organ toxicity landscape, phenotype-specific modification of drug-associated adverse-event reporting, and distinct temporal patterns across checkpoint pathways. These findings support checkpoint blockade as a modifier of drug-associated toxicity and motivate longitudinal and mechanistic validation. Key Points Question How does immune checkpoint inhibitor (ICI) exposure organize and modify drug-associated toxicity across phenotypes and time? Findings In this cross-sectional study of 13,701,106 deduplicated adverse-event reports, ICI exposure defined a broad toxicity landscape containing 4 cross-organ communities. Among 147 eligible primary-suspect drug-phenotype pairs across 7 focal phenotypes, 71 drug × ICI interactions were identified; documented time to onset also differed by phenotype and checkpoint pathway. Meaning Checkpoint blockade may create an altered treatment state in which the phenotype and timing of drug-associated toxicity depend on both the accompanying drug and the checkpoint pathway inhibited.

CLINICAL IMPLICATIONS:Penicillin G and aminopenicillins skin testing identified nearly 90% of penicillin allergic patients, suggesting PREPEN is not essential for most evaluations and can be reserved for high-risk patients during shortages. Current skin testing strategies remain clinically valuable even without PPL, while direct oral challenge stays preferred for low-risk patients.

Immune checkpoint inhibitors (ICIs) are transformative cancer therapies but have been implicated in rare, life-threatening cutaneous adverse reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN). Whether ICIs serve as independent causative agents or amplify risk from other drugs remains incompletely understood. METHODS:We analyzed 13.9 million deduplicated reports from the FDA Adverse Event Reporting System (FAERS) between 2013 and 2023, including 17,495 cases of SJS/TEN. We conducted multivariable logistic regression to assess the independent effects of ICIs, high-risk ("strong") and moderate-risk ("weak") culprit drugs, as well as their interactions. Age was modeled using natural splines. Additive interaction was assessed using the relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S). We also performed Cox regression analyses using time-to-event (TTE) data to evaluate latency patterns associated with different ICI classes. RESULTS:ICI exposure was independently associated with increased risk of SJS/TEN (adjusted OR 9.14, 95% CI 8.42-9.93). Strong culprit drugs (e.g., allopurinol, TMP-SMX) and weak culprits (e.g., fluoroquinolones, macrolides) also conferred elevated risk. Notably, we observed significant additive interaction between ICIs and both strong (RERI 13.69, AP 0.38) and weak culprits (RERI 12.92, AP 0.52), indicating synergistic risk amplification. In time-to-event analyses of 4,086 cases with latency data, PD-1 inhibitors were consistently associated with delayed onset of SJS/TEN compared to non-ICI triggers (HR 0.71-0.82), with median latency nearly doubled. CONCLUSIONS:Our findings support a two-hit immunopathogenic model in which ICIs lower the activation threshold for drug-specific T-cell responses, enabling otherwise tolerated medications to trigger severe cutaneous reactions. These results have critical implications for the co-prescription of high-risk drugs in patients receiving ICIs and underscore the need for enhanced pharmacovigilance and risk mitigation in cancer immunotherapy.

BACKGROUND:Inaccurate penicillin allergy labels (PALs) affect antimicrobial stewardship, health outcomes, and costs. More than 95% of PALs can be de-labeled when tested, but this rarely happens. OBJECTIVE:We sought to determine whether education and an electronic health record (EHR) tool kit to identify low-risk PALs would facilitate inpatient penicillin allergy de-labeling by pharmacists. METHODS:Pragmatic Removal of Penicillin Allergy Electronic Health Record Labels was a stepped-wedge, nonblinded, randomized, controlled, pragmatic clinical trial including 12 inpatient medical units. From November 2020 to November 2021, units entered intervention at 1-month stepped intervals in random order. Medically stable, nonpregnant adults with an her-documented PAL who were hospitalized on intervention units for 24 hours were included. The intervention included pharmacist and nursing education, a patient list for systematic identification of PALs, presentation of a risk-assessment tool, and an oral amoxicillin challenge order set. The primary outcome was removal of PAL by hospital discharge. Secondary outcomes included safety and implementation measures, longer-term continued label removal, and antibiotic use. RESULTS:On 12 randomized units, 2,052 patients with a PAL presented during the 1-year trial. More intervention-exposed patients had EHR-documented penicillin allergy removal compared with controls (45 of 1,018 [4.4%] vs 31 of 1,034 [3%], respectively; adjusted odds ratio = 2.05; 95% CI, 1.08-3.91). More intervention-exposed patients received an EHR-documented penicillin allergy risk assessment than did controls (86 of 1,018 [8.4%] vs 27 of 1,034 [2.6%]; adjusted odds ratio = 6.42; 95% CI, 3.08-13.38). Moreover, 27 of 1,018 intervention patients (2.7%) received amoxicillin challenge compared with 21 of 1,034 control patients (2.0%). All amoxicillin challenges were tolerated. CONCLUSION:Education and deployment of an inpatient EHR tool kit increased the rate of inpatient removal of inaccurate penicillin allergies before discharge.