Bledsoe, Adam C

ABSTRACT Background Immune checkpoint inhibitors (ICIs) enhance anti‐tumour immunity by modulating immune pathways but can also trigger immune‐related adverse events. We aimed to evaluate the risk of developing coeliac disease (CeD) among patients with malignancy treated with ICIs. Methods Using the TriNetX US Collaborative Network, we identified adults (≥ 18 years) diagnosed with malignancies for which ICIs are routinely used between January 2010 and December 2024 and stratified them by exposure to immune checkpoint inhibitors (nivolumab, pembrolizumab, ipilimumab, atezolizumab, durvalumab, tremelimumab, or avelumab). Patients with pre‐existing celiac disease (CeD) were excluded. Cohorts were propensity score matched for demographics and autoimmune comorbidities. The primary outcome was incident CeD occurring ≥ 90 days after the index event. Adjusted hazard ratios (aHRs) were calculated, with subgroup analyses by age and sex. Statistical significance was defined as p < 0.05. Results After propensity score matching, 158,208 patients were included in each cohort. CeD was diagnosed more frequently among patients exposed to ICIs than among matched controls (0.152% vs. 0.071%; aHR 3.95, 95% CI 3.11–5.03; p < 0.001), corresponding to a number needed to harm (NNH) of 1235. The increased risk persisted across sex and age subgroups, including females (aHR 3.43, 95% CI 2.55–4.62), males (aHR 5.36, 95% CI 3.53–8.12), with the risk being highest among patients older than 60 years (0.14% vs. 0.06%; aHR 4.24, 95% CI 3.17–5.67; p < 0.001). Conclusion In this large real‐world cohort, ICI exposure was associated with nearly a fourfold increase in the risk of being diagnosed with CeD compared with matched controls.

Abstract Genome-resolved virome analysis remains inaccessible for many samples, including those with clinical relevance, because viral nucleic acid recovered after enrichment is often too scarce to support de novo genome assembly. As a result, many analyses are limited to sparse read-level detection, which cannot recover divergent viruses, resolve strains, or interpret gene-level variation. Here, we developed Low Biomass Viral Sequencing (LBV-Seq), a workflow that couples low-input viral sample handling with modified primary template-directed amplification and short- or long-read sequencing to enable de novo reconstruction of DNA and RNA viral genomes from sub-femtogram to nanogram inputs. LBV-Seq reproducibly captures the same relative community composition, amplifies diverse viruses, and achieved broad genome coverage across nearly all targets regardless of viral genome structure, Baltimore class, abundance, or input mass. Short-read assemblies recovered near-complete genomes from femtogram-scale inputs. Long-read sequencing provided orthogonal support for genome structure, with PacBio HiFi reads spanning large portions of viral genomes and, in some cases, complete small viral genomes. Applied to virus-enriched human duodenal biopsy eluates, LBV-Seq provided proof-of-feasibility for recovering both bacteriophage and eukaryotic viral genomes from low-input biopsy-derived material. In the eluates tested, LBV-Seq recovered co-occurring Alphatorquevirus and Betatorquevirus genomes estimated to be present at roughly 10 copies/µL and at viral masses below 0.1 fg/µL. LBV-Seq enables genome-resolved virome analysis in samples previously limited to detection-based viromics, supporting viral discovery and strain-resolved analyses in settings where viral mass is low, including viruses enriched from human tissue biopsies.

Abstract Immune effector cell–associated enterocolitis (IEC-EC) has been observed after ciltacabtagene autoleucel (cilta-cel [Carvykti]) chimeric antigen receptor T-cell (CAR-T) therapy. It is associated with dismal outcomes and is poorly characterized. Here, we examined its clinical features, risk factors, and proposed management strategies. Among the 229 consecutive patients who received cilta-cel at Mayo Clinic, 9 (3.9%) presented with a nonresolving, nonbloody, grade 3 diarrhea, often requiring prolonged total parenteral nutrition. Gastrointestinal coinfections were seen in most patients. Median time from CAR-T infusion to symptom onset was 85 days (range, 35-166), and there appeared to be a latency from symptom onset to endoscopic evaluation. Histopathology findings resembling a graft-versus-host disease pattern of mucosal injury were most seen on duodenal biopsies, whereas 2 cases had patterns akin to a T-cell lymphoproliferative disorder (1 CD4+ and 1 CD8+). Independent associated factors for IEC-EC included high-risk disease as defined by the International Myeloma Society and International Myeloma Working Group, prolonged cytokine release syndrome, and antecedent delayed neurotoxicity. Response to first-line therapy comprising IV or oral corticosteroids, bile acid sequestrants, IV immunoglobulin, and antimicrobial-directed therapy was poor, with no durable responses. Biologic therapy appeared to induce durable responses in 3 of the 5 patients (2/2 vedolizumab; 1/3 infliximab); none of the responders had gastrointestinal coinfection. Early gastroenterology input for endoscopic evaluation with the inclusion of duodenal biopsy is a key component for diagnosis. Early institution of biologic therapy after failure of a short course of corticosteroids should be considered.

Coeliac disease is characterised by immune-mediated damage to the small intestine in response to dietary gluten in genetically predisposed individuals. Increased intestinal permeability is a central component to its pathophysiology. This review explores the evidence for increased permeability in coeliac disease and the underlying mechanisms, including the roles of zonulin, inflammatory cytokines, microbial alterations and immune responses to gliadin peptides. We also review comprehensively the therapies targeting barrier integrity and normalising intestinal permeability, including particular diets and supplements, and experimental and improved medications including larazotide acetate and IMU-856. Finally, we highlight the need for reliable biomarkers for evaluating increased permeability in coeliac disease and advocate for further research on therapies which normalise barrier function, particularly as a strategy to maintain remission.