James M. Walter

Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span.

Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution. During the fibrotic phase, monocyte-derived alveolar macrophages differ significantly from tissue-resident alveolar macrophages in their expression of profibrotic genes. A population of monocyte-derived alveolar macrophages persisted in the lung for one year after the resolution of fibrosis, where they became increasingly similar to tissue-resident alveolar macrophages. Human homologues of profibrotic genes expressed by mouse monocyte-derived alveolar macrophages during fibrosis were up-regulated in human alveolar macrophages from fibrotic compared with normal lungs. Our findings suggest that selectively targeting alveolar macrophage differentiation within the lung may ameliorate fibrosis without the adverse consequences associated with global monocyte or tissue-resident alveolar macrophage depletion.

Complications of thoracentesis: incidence, risk factors, and strategies for prevention.

Purpose of review Although thoracentesis is generally considered safe, procedural complications are associated with increased morbidity, mortality, and healthcare costs. In this article, we review the risk factors and prevention of the most common complications of thoracentesis including pneumothorax, bleeding (chest wall hematoma and hemothorax), and re-expansion pulmonary edema. Recent findings Recent data support the importance of operator expertise and the use of ultrasound in reducing the risk of iatrogenic pneumothorax. Although coagulopathy or thrombocytopenia and the use of anticoagulant or antiplatelet medications have traditionally been viewed as contraindications to thoracentesis, new evidence suggests that patients may be able to safely undergo thoracentesis without treating their bleeding risk. Re-expansion pulmonary edema, a rare complication of thoracentesis, is felt to result in part from the generation of excessively negative pleural pressure. When and how to monitor changes in pleural pressure during thoracentesis remains a focus of ongoing study. Summary Major complications of thoracentesis are uncommon. Clinician awareness of risk factors for procedural complications and familiarity with strategies that improve outcomes are essential components for safely performing thoracentesis.

Severe Respiratory Viral Infections: New Evidence and Changing Paradigms

Lower respiratory tract infection is a leading cause of death in the United States. Advances in diagnostic testing have improved our ability to detect pathogens. Viral pathogens are important causal pathogens in immunocompetent patients. As the number of elderly adults and those with chronic medical conditions increases, the burden of viral respiratory infections will increase. Clinicians must be familiar with the characteristics of rhinovirus, human adenoviruses, respiratory syncytial virus, and human metapneumovirus. Major challenges include distinguishing true infection from asymptomatic carriage and characterizing patients admitted with severe lower respiratory tract infection who do not have a causative pathogen identified.

Metastatic pulmonary calcification and end-stage renal disease

CT may show diffusely calcified nodules, high-attenuation areas of consolidation, or fluffy ground-glass nodules.

Vitamin C and Sepsis: Framing the Postpublication Discussion

The Nevada Supreme Court casts doubt on the standard for brain death diagnosis. Med Sci Law. 2017;57(2): 100-102. 4. Machado C, Perez-Nellar J, Estevez M, et al. Evidence-based guideline update: determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2011;76(3):307-309. 5. Wijdicks EF. The case against confirmatory tests for determining brain death in adults. Neurology. 2010;75(1):77-83.

Single-Cell Transcriptomic Analysis of Human Lung Reveals Complex Multicellular Changes During Pulmonary Fibrosis

Pulmonary fibrosis is a devastating disorder that results in the progressive replacement of normal lung tissue with fibrotic scar. Available therapies slow disease progression, but most patients go on to die or require lung transplantation. Single-cell RNA-seq is a powerful tool that can reveal cellular identity via analysis of the transcriptome, but its ability to provide biologically or clinically meaningful insights in a disease context is largely unexplored. Accordingly, we performed single-cell RNA-seq on lung tissue obtained from eight transplant donors and eight recipients with pulmonary fibrosis and one bronchoscopic cryobiospy sample. Integrated single-cell transcriptomic analysis of donors and patients with pulmonary fibrosis identified the emergence of distinct populations of epithelial cells and macrophages that were common to all patients with lung fibrosis. Analysis of transcripts in the Wnt pathway suggested that within the same cell type, Wnt secretion and response are restricted to distinct non-overlapping cells, which was confirmed using in situ RNA hybridization. Single-cell RNA-seq revealed heterogeneity within alveolar macrophages from individual patients, which was confirmed by immunohistochemistry. These results support the feasibility of discovery-based approaches applying next generation sequencing technologies to clinically obtained samples with a goal of developing personalized therapies. One Sentence Summary Single-cell RNA-seq applied to tissue from diseased and donor lungs and a living patient with pulmonary fibrosis identifies cell type-specific disease-associated molecular pathways.

Multidimensional assessment of alveolar T cells in critically ill patients

Pneumonia represents the leading infectious cause of death in the United States. Foxp3+ regulatory T cells promote recovery from severe pneumonia in mice, but T cell responses in patients with pneumonia remain incompletely characterized because of the limited ability to serially sample the distal airspaces and perform multidimensional molecular assessments on the small numbers of recovered cells. As T cell function is governed by their transcriptional and epigenetic landscape, we developed a method to safely perform high-resolution transcriptional and DNA methylation profiling of T cell subsets from the alveoli of critically ill patients. Our method involves nonbronchoscopic bronchoalveolar lavage combined with multiparameter fluorescence-activated cell sorting, unsupervised low-input RNA-sequencing, and a modified reduced-representation bisulfite sequencing protocol. Here, we demonstrate the safety and feasibility of our method and use it to validate functional genomic elements that were predicted by mouse models. Because of its potential for widespread application, our techniques allow unprecedented insights into the biology of human pneumonia.

Chugging in patients on veno-venous extracorporeal membrane oxygenation: An under-recognized driver of intravenous fluid administration in patients with acute respiratory distress syndrome?

Background: Veno‐venous extracorporeal membrane oxygenation (VV‐ECMO) is increasingly utilized in the management of severe acute respiratory distress syndrome (ARDS). Providers who care for patients on VV‐ECMO should be familiar with common circuit complications. Objectives: To provide an example of a common complication, circuit “chugging,” and suggest a management algorithm which aims to avoid excessive fluid administration to patients with ARDS. Methods: We use a clinical case to illustrate chugging and discuss potential management strategies. Results: Our patient received frequent boluses of albumin for intermittent circuit chugging contributing to a net positive fluid balance of roughly 6 liters 4 days after cannulation. Conclusions: Chugging is a common complication for patients on VV ECMO. A thoughtful approach to management may help limit potentially harmful fluid administration for patients with ARDS.

Testing for Respiratory Viruses in Adults With Severe Lower Respiratory Infection

&NA; Viral pathogens are a common cause of severe lower respiratory tract infection in adults. Our ability to rapidly and accurately identify viral infections has dramatically improved as slow culture‐based techniques have been largely replaced by multiplex high‐throughput systems. Given these advances, reevaluation of the role of respiratory viral testing in adults presenting with lower respiratory tract infection is important. This article reviews the potential benefits of testing, provides an overview of the most commonly used diagnostic techniques, and considers whether current evidence supports routine testing.

Metformin Targets Mitochondrial Electron Transport to Reduce Air-Pollution-Induced Thrombosis.

Urban particulate matter air pollution induces the release of pro-inflammatory cytokines including interleukin-6 (IL-6) from alveolar macrophages, resulting in an increase in thrombosis. Here, we report that metformin provides protection in this murine model. Treatment of mice with metformin or exposure of murine or human alveolar macrophages to metformin prevented the particulate matter-induced generation of complex III mitochondrial reactive oxygen species, which were necessary for the opening of calcium release-activated channels (CRAC) and release of IL-6. Targeted genetic deletion of electron transport or CRAC channels in alveolar macrophages in mice prevented particulate matter-induced acceleration of arterial thrombosis. These findings suggest metformin as a potential therapy to prevent some of the premature deaths attributable to air pollution exposure worldwide.