Detection of stool toxin A and/or B by EIA does not predict severe CDI or mortality. Infection with ribotype 027 independently predicts severe CDI and mortality. Use of concurrent antibiotics is a potentially modifiable risk factor for severe CDI.

Idiopathic pulmonary fibrosis (IPF) is the most common and devastating of the interstitial lung diseases. Epithelial dysfunction is thought to play a prominent role in disease pathology, and we sought to characterize secreted signals that may contribute to disease pathology. Transcriptional profiling of senescent type II alveolar epithelial cells from mice with epithelial-specific telomere dysfunction identified the transforming growth factor-β family member, growth and differentiation factor 15 (Gdf15), as the most significantly upregulated secreted protein. Gdf15 expression is induced in response to telomere dysfunction and bleomycin challenge in mice. Gdf15 mRNA is expressed by lung epithelial cells, and protein can be detected in peripheral blood and bronchoalveolar lavage following bleomycin challenge in mice. In patients with IPF, GDF15 mRNA expression in lung tissue is significantly increased and correlates with pulmonary function. Single-cell RNA sequencing of human lungs identifies epithelial cells as the primary source of GDF15, and circulating concentrations of GDF15 are markedly elevated and correlate with disease severity and survival in multiple independent cohorts. Our findings suggest that GDF15 is an epithelial-derived secreted protein that may be a useful biomarker of epithelial stress and identifies IPF patients with poor outcomes.

As the short telomere defect has been linked to the pathogenesis of IPF in some cases, our data indicate that impaired CMV immunity may be a systemic manifestation of telomere-mediated disease in these patients. Identifying this high-risk subset of lung transplant recipients has implications for risk assessment, management and potential strategies for averting posttransplant CMV morbidities.

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BackgroundLung microbiota profiles in patients with early idiopathic pulmonary fibrosis (IPF) have been associated with disease progression; however, the topographic heterogeneity of lung microbiota and their roles in advanced IPF are unknown.MethodsWe performed a retrospective, case-control study of explanted lung tissue obtained at the time of lung transplantation or rapid autopsy from patients with IPF and other chronic lung diseases (connective tissue disease-associated interstitial lung disease (CTD-ILD), cystic fibrosis (CF), COPD and donor lungs unsuitable for transplant from Center for Organ Recovery and Education (CORE)). We sampled subpleural tissue and airway-based specimens (bronchial washings and airway tissue) and quantified bacterial load and profiled communities by amplification and sequencing of the 16S rRNA gene.FindingsExplants from 62 patients with IPF, 15 patients with CTD-ILD, 20 patients with CF, 20 patients with COPD and 20 CORE patients were included. Airway-based samples had higher bacterial load compared with distal parenchymal tissue. IPF basilar tissue had much lower bacterial load compared with CF and CORE lungs (p<0.001). No microbial community differences were found between parenchymal tissue samples from different IPF lobes. Dirichlet multinomial models revealed an IPF cluster (29%) with distinct composition, high bacterial load and low alpha diversity, exhibiting higher odds for acute exacerbation or death.InterpretationIPF explants had low biomass in the distal parenchyma of all three lobes with higher bacterial load in the airways. The discovery of a distinct subgroup of patients with IPF with higher bacterial load and worse clinical outcomes supports investigation of personalised medicine approaches for microbiome-targeted interventions.

CMV remains an important opportunistic pathogen in high-risk lung transplant recipients. We characterized the phenotype and function of CD8 + T cells from acute/primary into chronic CMV infection in 23 (donor+/recipient2; D+R2) lung transplant recipients and found rapid induction of both KLRG1 + and/or CD57 + CMV-specific CD8 + T cells with unexpected coexpression of CD27. These cells demonstrated maturation from an acute effector T cell (T AEFF) to an effector memory T cell (T EM) phenotype with progressive enrichment of KLRG1 + CD57 + CD27 2 cells into memory. CMV-specific KLRG1 + T AEFF were capable of in vitro proliferation that diminished upon acquisition of CD57, whereas only KLRG1 + expression correlated with T-bet expression and effector function. In contrast to blood T AEFF , lung mucosal T AEFF demonstrated reduced KLRG1/T-bet expression but similar CD57 levels. Additionally, increased KLRG1 + T AEFF were associated with early immune viral control following primary infection. To our knowledge, our findings provide new insights into the roles of KLRG1 and CD57 expression in human T cells, forming the basis for a refined model of CD8 + T cell differentiation during CMV infection.

Background: The majority of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are triggered by nonbacterial causes, yet most patients receive antibiotics. Treatment guided by procalcitonin (PCT), a sensitive biomarker of bacterial infection, safely decreases antibiotic use in many controlled trials. We evaluated PCT implementation for inpatients with AECOPD at a large academic hospital. Methods: All patients admitted for AECOPD during the first 6 months of PCT-guided therapy were eligible for inclusion in this retrospective cohort study. Patients with PCT performed were compared with those without PCT. The primary outcome was antibiotic days of therapy (DOT). Secondary outcomes included 30-day readmission and mortality. Results: Of the 238 AECOPD admissions, 73 (31%) had PCT performed. Procalcitonin-tested patients were more likely to meet systemic inflammatory response syndrome (SIRS) criteria, require intensive care unit (ICU)-level care, and have a longer length of stay (LOS) compared with those without PCT. Even after adjustment for these factors, PCT-tested patients received more inpatient DOT and there was no difference in total DOT. However, a low PCT value (<0.25 ng/mL) was associated with a 25.5% ( P ⩽ .001) decrease in intravenous (IV) antibiotic DOT. Guideline-recommended follow-up testing was rare (12%). Procalcitonin measurement had no effect on 30-day readmission or mortality. Conclusions: In this real-world analysis of inpatients with AECOPD, PCT-guided therapy was poorly adopted by providers and was not associated with a decrease in total antibiotic DOT. However, a low PCT level was associated with a 25.5% decrease in IV antibiotic DOT, suggesting increased comfort stepping down from IV to PO therapy.

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder(EBV-PTLD) is a serious complication in lung transplant recipients (LTRs) associated with significant mortality. We performed a single-center retrospective study to evaluate the risks for PTLD in LTRs over a 7-year period. Of 611 evaluable LTRs, we identified 28 cases of PTLD, with an incidence of 4.6%. Kaplan-Meier analysis showed a decreased freedom from PTLD in idiopathic pulmonary fibrosis (IPF)-LTRs (P < .02). Using a multivariable Cox proportional hazards model, we found IPF (hazard ratio [HR] 3.51, 95% confidence interval [CI] 1.33-8.21, P = .01) and alemtuzumab induction therapy (HR 2.73, 95% CI 1.10-6.74, P = .03) as risk factors for PTLD, compared to EBV mismatch (HR: 34.43, 95% CI 15.57-76.09, P < .0001). Early PTLD (first year) was associated with alemtuzumab use (P = .04), whereas IPF was a predictor for late PTLD (after first year) (P = .002), after controlling for age and sex. Kaplan-Meier analysis revealed a shorter time to death from PTLD in IPF LTRs compared to other patients (P = .04). The use of alemtuzumab in EBV mismatch was found to particularly increase PTLD risk. Together, our findings identify IPF LTRs as a susceptible population for PTLD. Further studies are required to understand the mechanisms driving PTLD in IPF LTRs and develop strategies to mitigate risk. K E Y W O R D S clinical research/practice, hematology/oncology, immunosuppression/immune modulation, immunosuppressive regimens -induction, infection and infectious agents -viral: Epstein-Barr virus (EBV), lung disease, lung transplantation/pulmonology, posttransplant lymphoproliferative disorder (PTLD)