Residual endotoxin induces primary graft dysfunction through ischemia/reperfusion-primed alveolar macrophages.

Despite the widespread use of antibiotics, bacterial pneumonias in donors strongly predispose to the fatal syndrome of primary graft dysfunction (PGD) following lung transplantation. We report that bacterial endotoxin persists in human donor lungs after pathogen is cleared with antibiotics and is associated with neutrophil infiltration and PGD. In mouse models, depletion of tissue-resident alveolar macrophages (TRAMs) attenuated neutrophil recruitment in response to endotoxin as shown by compartmental staining and intravital imaging. Bone marrow chimeric mice revealed that neutrophils were recruited by TRAM through activation of TLR4 in a MyD88-dependent manner. Intriguingly, low levels of endotoxin, insufficient to cause donor lung injury, promoted TRAM-dependent production of CXCL2, increased neutrophil recruitment, and led to PGD, which was independent of donor NCMs. Reactive oxygen species (ROS) increased in human donor lungs starting from the warm-ischemia phase and were associated with increased transcription and translocation to the plasma membrane of TLR4 in donor TRAMs. Consistently, scavenging ROS or inhibiting their production to prevent TLR4 transcription/translocation or blockade of TLR4 or coreceptor CD14 on donor TRAMs prevented neutrophil recruitment in response to endotoxin and ameliorated PGD. Our studies demonstrate that residual endotoxin after successful treatment of donor bacterial pneumonia promotes PGD through ischemia/reperfusion-primed donor TRAMs.

Other Respiratory Viruses as a Cause of Community-Acquired Pneumonia.

Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality worldwide. There is growing appreciation of the burden of noninfluenza viral pathogens in CAP. Due to multiple factors including pneumococcal vaccination programs, declining rates of cigarette smoking, an aging population, and increasingly sensitive diagnostic tests, respiratory viruses are now the most common pathogens detected in CAP, outpacing Streptococcus pneumoniae. Noninfluenza respiratory pathogens are widely accepted as causal pathogens in CAP including in immunocompetent patients. This review provides an overview of five noninfluenza respiratory viral pathogens commonly implicated in CAP pathogenesis: rhinovirus, human metapneumovirus, respiratory syncytial virus, human parainfluenza virus, and human adenoviruses. Nucleic acid amplification testing platforms and their impact on antimicrobial stewardship efforts are also considered.

Pre-Intubation Veno-Venous Extracorporeal Membrane Oxygenation in Patients at Risk for Respiratory Decompensation.

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) has emerged as a potential life-saving treatment for patients with acute respiratory failure. Given the accumulating literature supporting the use of VV-ECMO without therapeutic levels of anticoagulation, it might be feasible to use it for planned intubation before surgical procedures. Here, we report consecutive series of patients who underwent planned initiation of VV-ECMO, without anticoagulation, before induction of general anesthesia for anticipated difficult airways or respiratory decompensation. We describe the approach to safely initiate VV-ECMO in an awake patient. We retrospectively identified patients in a prospectively maintained database who underwent planned initiation of VV-ECMO before intubation. Standard statistical methods were used to determine post-procedure outcomes. Patients included were three men and one woman, with a mean age of 34.3 ± 10.4 years. Indications included mediastinal lymphoma, foreign body obstruction, hemoptysis, and tracheo-esophageal fistula. VV-ECMO was initiated electively for all patients, and no anticoagulation was used. The median duration of VV-ECMO support was 2.5 days (1-11 days), the median length of ventilator dependence and intensive care unit stay was 1 day (1-23 days) and 5 days (4-31 days), respectively. The median length of stay was 18.5 days (8-39 days). There were no thrombotic complications and no mortality at 30 days. Initiation of awake VV-ECMO is feasible and is safe before intubation and induction of anesthesia in patients at high risk for respiratory decompensation.

Feasibility of Venovenous Extracorporeal Membrane Oxygenation Without Systemic Anticoagulation.

BACKGROUND: Venovenous extracorporeal membrane oxygenation (ECMO) is increasingly being used for acute respiratory distress syndrome and as a bridge to lung transplantation. After initiation of venovenous ECMO, systemic anticoagulation therapy is traditionally administered and can cause bleeding diathesis. Here, we investigated whether venovenous ECMO can be administered without continuous systemic anticoagulation administration for patients with acute respiratory distress syndrome. METHODS: This is a retrospective review of an institutional ECMO database. We included consecutive patients from January 2015 through February 2019. Overall, 38 patients received low levels of continuous systemic anticoagulation (AC+) whereas the subsequent 36 patients received standard venous thromboprophylaxis (AC-). Published Extracorporeal Life Support Organization guidelines were used for the definition of outcomes and complications. RESULTS: Overall, survival was not different between the two groups (P = .58). However, patients in the AC+ group had higher rates of gastrointestinal bleeding (28.9%, vs AC- group 5.6%; P < .001). The events per patient-day of gastrointestinal bleeding was 0.00025 in the AC- group and 0.00064 in the AC+ group (P < .001). In addition, oxygenator dysfunction was increased in the AC+ group (28.9% and 0.00067 events per patient-day, vs AC- 11.1% and 0.00062 events per patient-day; P = .02). Furthermore, the AC+ group received more transfusions: packed red blood cells, AC+ group 94.7% vs AC- group 55.5% (P < .001); fresh frozen plasma, AC+ 60.5% vs AC- 16.6% (P = .001); and platelets, AC+ 84.2% vs AC- 27.7% (P < .001). There was no circuit thrombosis in either groups throughout the duration of ECMO support. CONCLUSIONS: Our results suggest that venovenous ECMO can be safely administered without continuous systemic anticoagulation therapy. This approach may be associated with reduced bleeding diathesis and need for blood transfusions.

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.

Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis.

Rationale: The contributions of diverse cell populations in the human lung to pulmonary fibrosis pathogenesis are poorly understood. Single-cell RNA sequencing can reveal changes within individual cell populations during pulmonary fibrosis that are important for disease pathogenesis. Objectives: To determine whether single-cell RNA sequencing can reveal disease-related heterogeneity within alveolar macrophages, epithelial cells, or other cell types in lung tissue from subjects with pulmonary fibrosis compared with control subjects. Methods: We performed single-cell RNA sequencing on lung tissue obtained from eight transplant donors and eight recipients with pulmonary fibrosis and on one bronchoscopic cryobiospy sample from a patient with idiopathic pulmonary fibrosis. We validated these data using in situ RNA hybridization, immunohistochemistry, and bulk RNA-sequencing on flow-sorted cells from 22 additional subjects. Measurements and Main Results: We identified a distinct, novel population of profibrotic alveolar macrophages exclusively in patients with fibrosis. Within epithelial cells, the expression of genes involved in Wnt secretion and response was restricted to nonoverlapping cells. We identified rare cell populations including airway stem cells and senescent cells emerging during pulmonary fibrosis. We developed a web-based tool to explore these data. Conclusions: We generated a single-cell atlas of pulmonary fibrosis. Using this atlas, we demonstrated heterogeneity within alveolar macrophages and epithelial cells from subjects with pulmonary fibrosis. These results support the feasibility of discovery-based approaches using next-generation sequencing technologies to identify signaling pathways for targeting in the development of personalized therapies for patients with pulmonary fibrosis.

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.

Smoking and mortality in stroke survivors: can we eliminate the paradox?

BACKGROUND: Many studies have suggested that smoking does not increase mortality in stroke survivors. Index event bias, a sample selection bias, potentially explains this paradoxical finding. Therefore, we compared all-cause, cardiovascular disease (CVD), and cancer mortality by cigarette smoking status among stroke survivors using methods to account for index event bias. METHODS: Among 5797 stroke survivors of 45 years or older who responded to the National Health Interview Survey years 1997-2004, an annual, population-based survey of community-dwelling US adults, linked to the National Death Index, we estimated all-cause, CVD, and cancer mortality by smoking status using Cox proportional regression and propensity score analysis to account for demographic, socioeconomic, and clinical factors. Mean follow-up was 4.5 years. RESULTS: From 1997 to 2004, 18.7% of stroke survivors smoked. There were 1988 deaths in this stroke survivor cohort, with 50% of deaths because of CVD and 15% because of cancer. Current smokers had an increased risk of all-cause mortality (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.14-1.63) and cancer mortality (HR, 3.83; 95% CI, 2.48-5.91) compared with never smokers, after controlling for demographic, socioeconomic, and clinical factors. Current smokers had an increased risk of CVD mortality controlling for age and sex (HR, 1.29; 95% CI, 1.01-1.64), but this risk did not persist after controlling for socioeconomic and clinical factors (HR, 1.15; 95% CI, .88-1.50). CONCLUSIONS: Stroke survivors who smoke have an increased risk of all-cause mortality, which is largely because of cancer mortality. Socioeconomic and clinical factors explain stroke survivors' higher risk of CVD mortality associated with smoking.