Elizabeth Phillips

Background
Co-trimoxazole is a leading global cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Co-trimoxazole-induced SCAR are associated with HLA class I alleles including HLA-B*13:01 and HLA-B*38:02 in Southeast Asian (SEA) populations. However, the global generalizability of these associations is unknown but critical for population-appropriate risk stratification and diagnosis.

Objective
To determine HLA risk factors associated with co-trimoxazole-induced SJS/TEN and DRESS in populations from the United States (US) and South Africa (SA).

Methods
We performed high-resolution HLA typing on dermatologist-adjudicated co-trimoxazole-induced SCAR patients in the US (n=63) and SA (n=26) compared to population controls. Peptide binding and docking analyses were performed using MHCcluster2.0 and CB-Dock2.

Results
In a multiple logistic regression model, HLA-B*44:03 (Pc<0.001, OR: 4.08), HLA-B*38:01 (Pc<0.001, OR: 5.66), and HLA-C*04:01 (Pc=0.003, OR: 2.50) were independently associated with co-trimoxazole-induced SJS/TEN in the US. HLA-B* 44:03 was also associated with co-trimoxazole-induced DRESS in SA (Pc=0.019, OR: 10.69). Distinct HLA-B variants with shared peptide binding specificities (SPBS) and HLA-C*04:01 identified 94% and 78% of co-trimoxazole-induced SJS/TEN and DRESS in the US, respectively. The SEA risk allele HLA-B*13:01, with SPBS to HLA-B*44:03, was identified in just 1/63 US SCAR patient.

Conclusion
HLA alleles with SPBS to SEA-related risk alleles including HLA-B*44:03 (SPBS with HLA-B*13:01) and HLA-B*38:01 (SPBS with HLA-B*38:02) but also HLA-C*04:01 predisposed to co-trimoxazole-induced SCAR in the US and SA. These findings provide biological plausibility and strategies for global risk prediction and diagnosis of co-trimoxazole-induced SCAR.

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.
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.
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.
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.
Education and deployment of an inpatient EHR tool kit increased the rate of inpatient removal of inaccurate penicillin allergies before discharge.

Consensus guidelines outline the recommended management of delayed drug hypersensitivity reactions (DHRs), but clinical practices are largely expert-based and may vary significantly across populations and regions. This study evaluated the approach and management of health care specialists globally regarding DHRs, including severe cutaneous adverse reactions.
To assess the current practices, knowledge, and availability of allergy testing for DHRs, including severe cutaneous adverse reactions, among relevant health care professionals globally.
The Global AppRoAch for Severe Cutaneous Adverse Reactions Survey study is a prospective, web-based survey conducted using the Research Electronic Data Capture platform. The 10- to 15-minute survey was directed to 14 allergy/immunology and dermatology associations through international mailing lists across 48 countries.
Among the 8561 members contacted, answers from 130 health care providers practicing in all 6 continents were analyzed. Most respondents identified as White (88 of 130 [68%]) and female (79 of 130 [61%]), representing a range of age groups and clinical expertise. Most practiced in dermatology (69 of 130 [53%]), followed by allergy/immunology (46 of 130 [35.4%]), and were based in an urban setting (127 of 130 [98%]). Among the 45 respondents (34.6%) who managed severe cutaneous adverse reactions, 27 (60%) had access to multidisciplinary care. Practices varied widely by clinical phenotype; for example, for maculopapular exanthema, 63 respondents indicated treating through the reaction (63 of 130 [49%]), whereas 16 (16 of 130 [12%]) offered desensitization. Under patient education and follow-up, only 60 (60 of 130 [46.2%]) participants organized a follow-up with the implicated specialist.
Significant variability in the management of DHRs was observed among the respondents. The results highlight the need for evidence-based protocols to standardize guidelines for managing DHRs.

Importance Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) survivors experience substantial long-term sequelae. Research on physical symptoms experienced during acute hospitalization is well documented, but limited studies have been completed on the long-term biopsychosocial effects of SJS/TEN, particularly from the patient’s perspective.

Objective To increase the understanding of the long-term complications of SJS/TEN.

Design, Setting, and Participants This qualitative investigation was completed from within a community-based study, the SJS Survivors Study, using a semistructured, in-depth interview guide to query participants about their SJS/TEN experience postdischarge from the hospital. Interviews took place by phone from July 2021 through August 2023. This study included adults who experienced SJS/TEN within the United States.

Main Outcome and Measures A biopsychosocial theory-based framework and hierarchical coding system were utilized to understand the long-term life impacts of survivors of SJS/TEN.

Results The 29 participants, aged 26 to 76 years, were 66% female and 69% White and had experienced SJS/TEN from a wide range of drugs. Patients experienced support while in the hospital, but once discharged, felt isolated and without support to understand the potential sustained impacts of SJS/TEN in their lives and the lives of their family members. Patients experienced ongoing biological symptoms, such as skin issues, debilitating visual impairment, blindness, and lack of functional autonomy. Psychological impacts included symptoms of anxiety, obsessive thinking, flashbacks, and depression. Socially, some survivors expressed a sense of abandonment and described negative impacts on their careers. Survivors also expressed frustration and isolation with having to navigate posthospital care alone. There was a lack of preemptive discharge education and SJS/TEN-specific planning. Lack of physician knowledge about SJS/TEN was particularly noted and survivors turned to the internet for guidance instead of receiving direction from their physicians. Medical distrust among survivors was frequently noted.

Conclusions and Relevance The findings highlight the need for postdischarge care coordination among patients and their primary physicians, including mental health support. This care coordination should be arranged prior to discharge to ensure the availability of adequate support and optimal health outcomes. It is essential that clinicians and researchers prioritize the understanding of long-term sequelae of SJS/TEN and improve current discharge education and protocols for patients and their families.

Cytomegalovirus (CMV) establishes lifelong latency and is linked to immunosenescence in older and immunocompromised individuals. We hypothesize that CMV drives systemic and tissue-specific immune changes that may contribute to cardiovascular disease (CVD). Thoracic aorta, blood and perivascular mediastinal adipose tissue from cardiac surgery patients (n = 11) were processed within 30–60 min of excision. CMV IgG titres were quantified through ELISA to determine CMV status: CMV(−) (n = 4) and CMV(+) (n = 7). Immune profiling was performed using flow cytometry and single-cell RNA sequencing. Analyses included MiloR and differential gene expression. Participants (mean age 69.7 ± 8.4 years) were 80% male and 70% Caucasian. CMV(−) and CMV(+) participants had mean IgG titres of 0.038 and 13.55 IU ml−1, respectively. CD8+ T-cells expressing CD57+, GPR56+ and CX3CR1+ (CGC) were increased in the blood of CMV(+) participants. In the aorta of CMV(+) participants, CD8+ T cells and CD4+ T cells had decreased HLA-C expression and suppressed interferon-α pathways. In contrast, the TNF-α signalling pathway was increased. CMV infection shapes immune responses and in this pilot, we observed suppression of interferon-α signalling and increased TNF-α-associated pathways in the aorta. Larger studies are needed to define how CMV-driven immune remodelling contributes to CVD.

This article is part of the discussion meeting issue ‘The indirect effects of cytomegalovirus infection: mechanisms and consequences.’

The COVID-19 pandemic highlighted the critical need for vaccine strategies capable of addressing emerging viral threats. Betacoronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS), and SARS-CoV-2, present significant pandemic risks due to their zoonotic potential and genetic diversity. T cell-mediated immunity has demonstrated durable responses and strong cross-reactivity, offering a promising avenue for achieving broad immunity within a viral family. In this study, we combined comprehensive epitope mapping with sequence conservation analyses to identify conserved T cell epitope regions (CTERs), which constitute 12% of the complete SARS-CoV-2 proteome. We showed that SARS-CoV-2 CTER-specific T cells cross-reactively recognize sequences from multiple Betacoronavirus subgenera. Importantly, incorporating CTERs from non-spike proteins significantly enhanced T cell cross-reactivity potential and human leukocyte antigen (HLA) coverage compared with T cells targeting only spike proteins. Our findings lay the groundwork for a multi-antigen vaccine strategy that includes non-spike proteins to expand cross-reactive immunity across a broader spectrum of Betacoronaviruses.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive loss of motor neurons. Neuroinflammation is apparent in affected tissues, including increased T cell infiltration and activation of microglia, particularly in the spinal cord
. Autoimmune responses are thought to have a key role in ALS pathology, and it is hypothesized that T cells contribute to the rapid loss of neurons during disease progression
. However, until now there has been no reported target for such an autoimmune response. Here we show that ALS is associated with recognition of the C9orf72 antigen, and we map the specific epitopes that are recognized. We show that these responses are mediated by CD4
T cells that preferentially release IL-5 and IL-10, and that IL-10-mediated T cell responses are significantly greater in donors who have a longer predicted survival time. Our results reinforce the previous hypothesis that neuroinflammation has an important role in ALS disease progression, possibly because of a disrupted balance of inflammatory and counter-inflammatory T cell responses
. These findings highlight the potential of therapeutic strategies aimed at enhancing regulatory T cells
, and identify a key target for antigen-specific T cell responses that could enable precision therapeutics in ALS.

Background
There is a gap in knowledge regarding the contemporary epidemiology of penicillin-associated anaphylaxis.

Objective
To assess whether penicillin antibiotics (PAs) had higher reporting odds of anaphylaxis compared with other medications, patterns of anaphylaxis reports attributed to specific PAs, and the frequency of reported mortality associated with anaphylaxis using pharmacovigilance methods using the Food and Drug Administration Adverse Event Reporting System database.

Methods
We included patients in the Food and Drug Administration Adverse Event Reporting System with reported anaphylaxis to PAs from 2013 to 2023 in this cross-sectional study. Reporting odds ratios and proportional reporting ratios were used to determine whether specific PAs had higher reporting odds of anaphylaxis.

Results
Among a total of 20,815,425 adverse events and 48,637 reports of anaphylaxis, there were 3,176 reports of anaphylaxis to PAs. Compared with other medications, all PAs had higher reporting odds of anaphylaxis. Compared with all other PAs, there were disproportionality signals for reported anaphylaxis to amoxicillin-containing medications (reporting odds ratio, 1.97; 95% CI, 1.82-2.14) and “unspecified” PAs (reporting odds ratio, 1.77; 95% CI, 1.44-2.19). We observed a higher proportion of anaphylaxis reports to all PAs (4.5%) from reports outside the United States (US) compared with reports from the US (2.3%, P < .0001). US reports demonstrated higher reporting odds for anaphylaxis to nonaminopenicillins and piperacillin-tazobactam, whereas non-US reports demonstrated higher reporting odds for amoxicillin-containing medications. There were 139 reports of anaphylaxis to PAs associated with death.

Conclusions
PAs had higher reporting odds of anaphylaxis compared with all other medications in the Food and Drug Administration Adverse Event Reporting System database. We observed regional differences in reporting odds to specific PAs when comparing US and non-US reports. Fatalities reported following anaphylaxis were rare.

Background
Diagnosis and management of intravenous iron reactions is often challenging as skin testing has unproven utility and most reactions are non-IgE-mediated.

Objective
We aimed to identify clinical patterns and tolerability predictors in patients with intravenous iron reactions.

Methods
We conducted a retrospective cohort study of intravenous iron reactions referred to Vanderbilt University Medical Center Drug Allergy Clinic from 04/2014-01/2025 and administered a follow-up survey via RedCap to evaluate patient outcomes with future intravenous iron administration.

Results
Among 51 patients presenting for intravenous iron adverse reactions, skin testing was deemed negative in all 48 (100%) tested. Notable labs within one year of reaction were low vitamin D (47%), high parathyroid hormone (46%), and low phosphorus (10%). Many patients (56%) were dermatographic and drug alert labels included opioids (31%), fluoroquinolones (14%), and radiocontrast dye (8%). Following assessment, 31 patients received intravenous iron (61%), using same (n=15, 48%) and/or different (n=17, 55%) formulations than initially implicated with various modifications including antihistamines, slower infusion rate, and intravenous fluid pretreatment. Of these 31 patients, 27 (87%) tolerated the infusions. Additionally, following evaluation, patients were surveyed regarding future intravenous iron administrations, with 29% response rate (n=15). Of responders, seven patients (47%) reported receiving intravenous iron after evaluation and all reported tolerance.

Conclusion
Most intravenous iron reactions are non-IgE-mediated; however, our study introduces two novel observations including a high frequency of dermatographism (56%) and common co-labeling of these patients with drug alerts to MRGPRX2-activating drugs suggesting a possible shared pathophysiologic mechanism.

Genetic associations within the human leukocyte antigen (HLA) gene complex and linked genes in TB-IRIS outcomes remains population specific and not well understood. Here, we conducted a study including well characterised HIV-TB coinfected patients with (n = 86) and without (n = 124) TB-IRIS from the randomized, double-blind, prophylactic prednisone trial (PredART study) with HLA, ERAP and KIR genotyping data. We confirmed the association of TB-IRIS with lower CD4 counts pre-ART initiation. We identified nine classical class I and II HLA alleles protective against TB-IRIS, while four alleles were linked to increased risk. Associations ranged from strongly protective (HLA-DQB1*05:01, OR: 0.07, 95%CI: 0.02-0.28, Pc < 0.001) to strongly risk associated (notably DRB1*01:02, OR: 5.92, 95%CI: 1.36-26.7, Pc = 0.028), with conflicting signals at the HLA-DRB1 locus. Conditional regression analysis revealed that residue E71 at the polymorphic position 71 within the HLA-DRB1 peptide-binding groove was critical, and grouping of HLA-DRB1 alleles by the residue at position 71 corresponded with differential TB-IRIS association. In conclusion, this study identifies population-specific genetic factors influencing TB-IRIS susceptibility and highlights a potential mechanistic role for specific HLA-DRB1 residues in modulating immune responses during ART.