American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Apr 2024
Observational StudyHeterogeneity of Benefit from Earlier Time-to-Antibiotics for Sepsis.
Rationale: Shorter time-to-antibiotics improves survival from sepsis, particularly among patients in shock. There may be other subgroups for whom faster antibiotics are particularly beneficial. Objectives: Identify patient characteristics associated with greater benefit from shorter time-to-antibiotics. ⋯ Spline analysis confirmed differential nonlinear associations of time-to-antibiotics with mortality in patients with metastatic cancer and shock. Conclusions: In patients with community-onset sepsis, the mortality benefit of shorter time-to-antibiotics varied by patient characteristics. These findings suggest that shorter time-to-antibiotics for sepsis is particularly important among patients with cancer and/or shock.
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Am. J. Respir. Crit. Care Med. · Apr 2024
Host and Microbe Blood Metagenomics Reveals Key Pathways Characterizing Critical Illness Phenotypes.
Rationale: Two molecular phenotypes of sepsis and acute respiratory distress syndrome, termed hyperinflammatory and hypoinflammatory, have been consistently identified by latent class analysis in numerous cohorts, with widely divergent clinical outcomes and differential responses to some treatments; however, the key biological differences between these phenotypes remain poorly understood. Objectives: We used host and microbe metagenomic sequencing data from blood to deepen our understanding of biological differences between latent class analysis-derived phenotypes and to assess concordance between the latent class analysis-derived phenotypes and phenotypes reported by other investigative groups (e.g., Sepsis Response Signature [SRS1-2], molecular diagnosis and risk stratification of sepsis [MARS1-4], reactive and uninflamed). Methods: We analyzed data from 113 patients with hypoinflammatory sepsis and 76 patients with hyperinflammatory sepsis enrolled in a two-hospital prospective cohort study. ⋯ Significant overlap was observed between these phenotypes and previously identified transcriptional subtypes of acute respiratory distress syndrome (reactive and uninflamed) and sepsis (SRS1-2). Analysis of data from the VANISH trial indicated that corticosteroids might have a detrimental effect in patients with the hypoinflammatory phenotype. Conclusions: The hyperinflammatory and hypoinflammatory phenotypes have distinct transcriptional and metagenomic features that could be leveraged for precision treatment strategies.
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There is considerable interest in the potential for cell-based therapies, particularly mesenchymal stromal cells (MSCs) and their products, as a therapy for acute respiratory distress syndrome (ARDS). MSCs exert effects via diverse mechanisms including reducing excessive inflammation by modulating neutrophil, macrophage and T-cell function, decreasing pulmonary permeability and lung edema, and promoting tissue repair. ⋯ This perspective reassesses the therapeutic potential of MSC-based therapies for ARDS given insights from recent cell therapy trials in both COVID-19 and in 'classic' ARDS, and discusses studies in graft-vs.-host disease, one of the few licensed indications for MSC therapies. We identify important unknowns in the current literature, address challenges to clinical translation, and propose an approach to facilitate assessment of the therapeutic promise of MSC-based therapies for ARDS.
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Am. J. Respir. Crit. Care Med. · Apr 2024
Antimicrobial Drug Penetration is Enhanced by Lung Tissue Inflammation and Injury.
Rationale: Pneumonia is a frequent and feared complication in intubated critically ill patients. Tissue concentrations of antimicrobial drugs need to be sufficiently high to treat the infection and also prevent development of bacterial resistance. It is uncertain whether pulmonary inflammation and injury affect antimicrobial drug penetration into lung tissue. ⋯ Penetration into BAL fluid was excellent for both antimicrobials, but without left-to-right differences (ceftaroline fosamil, P = 0.78; linezolid, P = 1.00). Conclusions: Tissue penetration of two commonly used antimicrobial drugs for pneumonia is enhanced by early lung tissue inflammation and injury, resulting in longer times above the minimal inhibitory concentration. Thus, lung tissue inflammation ameliorates antimicrobial drug penetration during the acute phase.