Longitudinal Lower Airway Microbial Signatures of Acute Cellular Rejection in Lung Transplantation.

Rationale: Acute cellular rejection (ACR) after lung transplant is a leading risk factor for chronic lung allograft dysfunction. Prior studies have demonstrated dynamic microbial changes occurring within the allograft and gut that influence local adaptive and innate immune responses. However, the lung microbiome's overall impact on ACR risk remains poorly understood. Objectives: To evaluate whether temporal changes in microbial signatures were associated with the development of ACR. Methods: We performed cross-sectional and longitudinal analyses (joint modeling of longitudinal and time-to-event data and trajectory comparisons) of 16S rRNA gene sequencing results derived from lung transplant recipient lower airway samples collected at multiple time points. Measurements and Main Results: Among 103 lung transplant recipients, 25 (24.3%) developed ACR. In comparing samples acquired 1 month after transplant, subjects who never developed ACR demonstrated lower airway enrichment with several oral commensals (e.g., Prevotella and Veillonella spp.) than those with current or future (beyond 1 mo) ACR. However, a subgroup analysis of those who developed ACR beyond 1 month revealed delayed enrichment with oral commensals occurring at the time of ACR diagnosis compared with baseline, when enrichment with more traditionally pathogenic taxa was present. In longitudinal models, dynamic changes in α-diversity (characterized by an initial decrease and a subsequent increase) and in the taxonomic trajectories of numerous oral commensals were more commonly observed in subjects with ACR. Conclusions: Dynamic changes in the lower airway microbiota are associated with the development of ACR, supporting its potential role as a useful biomarker or in ACR pathogenesis.

Lung microbial and host genomic signatures as predictors of prognosis in early-stage adenocarcinoma.

BACKGROUND: Risk of early-stage lung adenocarcinoma (LUAD) recurrence after surgical resection is significant, and post-recurrence median survival is approximately two years. Currently there are no commercially available biomarkers that predict recurrence. Here, we investigated whether microbial and host genomic signatures in the lung can predict recurrence. METHODS: In 91 early-stage (Stage IA/IB) LUAD-patients with extensive follow-up, we used 16s rRNA gene sequencing and host RNA-sequencing to map the microbial and host transcriptomic landscape in tumor and adjacent unaffected lung samples. RESULTS: 23 out of 91 subjects had tumor recurrence over 5-year period. In tumor samples, LUAD recurrence was associated with enrichment with Dialister, Prevotella, while in unaffected lung, recurrence was associated with enrichment with Sphyngomonas and Alloiococcus. The strengths of the associations between microbial and host genomic signatures with LUAD recurrence were greater in adjacent unaffected lung samples than in the primary tumor. Among microbial-host features in the unaffected lung samples associated with recurrence, enrichment with Stenotrophomonas geniculata and Chryseobacterium were positively correlated with upregulation of IL-2, IL-3, IL-17, EGFR, HIF-1 signaling pathways among the host transcriptome. In tumor samples, enrichment with Veillonellaceae Dialister, Ruminococcacea, Haemophilus Influenza, and Neisseria were positively correlated with upregulation of IL-1, IL-6, IL17, IFN, and Tryptophan metabolism pathways. CONCLUSIONS: Overall, modeling suggested that a combined microbial/transcriptome approach using unaffected lung samples had the best biomarker performance (AUC=0.83). IMPACT: This study suggests that LUAD recurrence is associated with distinct pathophysiological mechanisms of microbial-host interactions in the unaffected lung rather than those present in the resected tumor.

Correcting dysbiosis in the lungs of COPD, one pathogen at a time.

In this issue of Cell Host & Microbe, Liang et al. demonstrate through genomic analysis of the sputum microbiome from COPD patients and preclinical models that Staphylococcus aureus promotes lung function decline via regulation of homocysteine levels. Homocysteine can promote lung injury by promoting neutrophil apoptosis-to-NETosis shift via AKT1-S100A8/A9 axis.

Patterns of in-hospital mortality and bleeding complications following PCI for very elderly patients: insights from the Dartmouth Dynamic Registry.

BACKGROUND: Very elderly patients (age ≥ 85 years) are a rapidly increasing segment of the population. As a group, they experience high rates of in-hospital mortality and bleeding complications following percutaneous coronary intervention (PCI). However, the relationship between bleeding and mortality in the very elderly is unknown. METHODS: Retrospective review was performed on 17,378 consecutive PCI procedures from 2000 to 2015 at Dartmouth-Hitchcock Medical Center. Incidence of bleeding during the index PCI admission (bleeding requiring transfusion, access site hematoma > 5 cm, pseudoaneurysm, and retroperitoneal bleed) and in-hospital mortality were reported for four age groups (< 65 years, 65-74 years, 75-84 years, and ≥ 85 years). The mortality of patients who suffered bleeding complications and those who did not was calculated and multivariate analysis was performed for in-hospital mortality. Lastly, known predictors of bleeding were compared between patients age < 85 years and age ≥ 85 years. RESULTS: Of 17,378 patients studied, 1019 (5.9%) experienced bleeding and 369 (2.1%) died in-hospital following PCI. Incidence of bleeding and in-hospital mortality increased monotonically with increasing age (mortality: 0.94%, 2.27%, 4.24% and 4.58%; bleeding: 3.96%, 6.62%, 10.68% and 13.99% for ages < 65, 65-74, 75-84 and ≥ 85 years, respectively). On multivariate analysis, bleeding was associated with increased mortality for all age groups except patients age ≥ 85 years [odds ratio (95% CI): age < 65 years, 3.65 (1.99-6.74); age 65-74 years, 2.83 (1.62-4.94); age 75-84 years, 3.86 (2.56-5.82), age ≥ 85 years: 1.39 (0.49-3.95)]. CONCLUSIONS: Bleeding and mortality following PCI increase with increasing age. For the very elderly, despite high rates of bleeding, bleeding is no longer predictive of in-hospital mortality following PCI.