Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia.

Some patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop severe pneumonia and acute respiratory distress syndrome1 (ARDS). Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from that in other types of pneumonia2. Here we investigate SARS-CoV-2 pathobiology by characterizing the immune response in the alveoli of patients infected with the virus. We collected bronchoalveolar lavage fluid samples from 88 patients with SARS-CoV-2-induced respiratory failure and 211 patients with known or suspected pneumonia from other pathogens, and analysed them using flow cytometry and bulk transcriptomic profiling. We performed single-cell RNA sequencing on 10 bronchoalveolar lavage fluid samples collected from patients with severe coronavirus disease 2019 (COVID-19) within 48 h of intubation. In the majority of patients with SARS-CoV-2 infection, the alveolar space was persistently enriched in T cells and monocytes. Bulk and single-cell transcriptomic profiling suggested that SARS-CoV-2 infects alveolar macrophages, which in turn respond by producing T cell chemoattractants. These T cells produce interferon-γ to induce inflammatory cytokine release from alveolar macrophages and further promote T cell activation. Collectively, our results suggest that SARS-CoV-2 causes a slowly unfolding, spatially limited alveolitis in which alveolar macrophages containing SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation.

Diaphragm and Phrenic Nerve Ultrasound in COVID-19 Patients and Beyond: Imaging Technique, Findings, and Clinical Applications.

The diaphragm, the principle muscle of inspiration, is an under-recognized contributor to respiratory disease. Dysfunction of the diaphragm can occur secondary to lung disease, prolonged ventilation, phrenic nerve injury, neuromuscular disease, and central nervous system pathology. In light of the global pandemic of coronavirus disease 2019 (COVID-19), there has been growing interest in the utility of ultrasound for evaluation of respiratory symptoms including lung and diaphragm sonography. Diaphragm ultrasound can be utilized to diagnose diaphragm dysfunction, assess severity of dysfunction, and monitor disease progression. This article reviews diaphragm and phrenic nerve ultrasound and describes clinical applications in the context of COVID-19.

The distribution of acquired peripheral nerve injuries associated with severe COVID-19 implicate a mechanism of entrapment neuropathy: a multicenter case series and clinical feasibility study of a wearable, wireless pressure sensor.

We diagnosed 66 peripheral nerve injuries in 34 patients who survived severe coronavirus disease 2019 (COVID-19). We combine this new data with published case series re-analyzed here (117 nerve injuries; 58 patients) to provide a comprehensive accounting of lesion sites. The most common are ulnar (25.1%), common fibular (15.8%), sciatic (13.1%), median (9.8%), brachial plexus (8.7%) and radial (8.2%) nerves at sites known to be vulnerable to mechanical loading. Protection of peripheral nerves should be prioritized in the care of COVID-19 patients. To this end, we report proof of concept data of the feasibility for a wearable, wireless pressure sensor to provide real time monitoring in the intensive care unit setting.

Imaging Review of Peripheral Nerve Injuries in Patients with COVID-19.

With surging numbers of patients with coronavirus disease 2019 (COVID-19) throughout the world, neuromuscular complications and rehabilitation concerns are becoming more apparent. Peripheral nerve injury can occur in patients with COVID-19 secondary to postinfectious inflammatory neuropathy, prone positioning-related stretch and/or compression injury, systemic neuropathy, or nerve entrapment from hematoma. Imaging of peripheral nerves in patients with COVID-19 may help to characterize nerve abnormality, to identify site and severity of nerve damage, and to potentially elucidate mechanisms of injury, thereby aiding the medical diagnosis and decision-making process. This review article aims to provide a first comprehensive summary of the current knowledge of COVID-19 and peripheral nerve imaging.

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.

Multidimensional Assessment of the Host Response in Mechanically Ventilated Patients with Suspected Pneumonia.

Rationale: The identification of informative elements of the host response to infection may improve the diagnosis and management of bacterial pneumonia. Objectives: To determine whether the absence of alveolar neutrophilia can exclude bacterial pneumonia in critically ill patients with suspected infection and to test whether signatures of bacterial pneumonia can be identified in the alveolar macrophage transcriptome. Methods: We determined the test characteristics of alveolar neutrophilia for the diagnosis of bacterial pneumonia in three cohorts of mechanically ventilated patients. In one cohort, we also isolated macrophages from alveolar lavage fluid and used the transcriptome to identify signatures of bacterial pneumonia. Finally, we developed a humanized mouse model of Pseudomonas aeruginosa pneumonia to determine if pathogen-specific signatures can be identified in human alveolar macrophages. Measurements and Main Results: An alveolar neutrophil percentage less than 50% had a negative predictive value of greater than 90% for bacterial pneumonia in both the retrospective (n = 851) and validation cohorts (n = 76 and n = 79). A transcriptional signature of bacterial pneumonia was present in both resident and recruited macrophages. Gene signatures from both cell types identified patients with bacterial pneumonia with test characteristics similar to alveolar neutrophilia. Conclusions: The absence of alveolar neutrophilia has a high negative predictive value for bacterial pneumonia in critically ill patients with suspected infection. Macrophages can be isolated from alveolar lavage fluid obtained during routine care and used for RNA-Seq analysis. This novel approach may facilitate a longitudinal and multidimensional assessment of the host response to bacterial pneumonia.

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.

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.

Extracorporeal Membrane Oxygenation Can Successfully Support Patients With Severe Acute Respiratory Distress Syndrome in Lieu of Mechanical Ventilation.

OBJECTIVES: Extracorporeal membrane oxygenation is increasingly used in the management of severe acute respiratory distress syndrome. With extracorporeal membrane oxygenation, select patients with acute respiratory distress syndrome can be managed without mechanical ventilation, sedation, or neuromuscular blockade. Published experience with this approach, specifically with attention to a patient's respiratory drive following cannulation, is limited. DESIGN: We describe our experience with three consecutive patients with severe acute respiratory distress syndrome supported with right jugular-femoral configuration of venovenous extracorporeal membrane oxygenation without therapeutic anticoagulation as an alternative to lung-protective mechanical ventilation. Outcomes are reported including daily respiratory rate, vital capacities, and follow-up pulmonary function testing. RESULTS: Following cannulation, patients were extubated within 24 hours. During extracorporeal membrane oxygenation support, all patients were able to maintain a normal respiratory rate and experienced steady improvements in vital capacities. Patients received oral nutrition and ambulated daily. At follow-up, no patients required supplemental oxygen. CONCLUSIONS: Our results suggest that venovenous extracorporeal membrane oxygenation can provide a safe and effective alternative to lung-protective mechanical ventilation in carefully selected patients. This approach facilitates participation in physical therapy and avoids complications associated with mechanical ventilation.

Alveolar Macrophages.

Alveolar macrophages are the most abundant innate immune cells in the distal lung parenchyma, located on the luminal surface of the alveolar space. They are the first to encounter incoming pathogens and pollutants and to help orchestrate the initiation and resolution of the immune response in the lung. Similar to other tissue-resident macrophages, alveolar macrophages also perform non-immune, tissue-specific, homeostatic functions, most notably clearance of surfactant. In this review we will discuss how ontogeny and local lung environment shape the role of alveolar macrophages in health and disease.

Invasive Mechanical Ventilation.

Invasive mechanical ventilation is a potentially lifesaving intervention for acutely ill patients. The goal of this review is to provide a concise, clinically focused overview of basic invasive mechanical ventilation for the many clinicians who care for mechanically ventilated patients. Attention is given to how common ventilator modes differ in delivering a mechanical breath, evaluation of respiratory system mechanics, how to approach acute changes in airway pressure, and the diagnosis of auto-positive end-expiratory pressure. Waveform interpretation is emphasized throughout the review.

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.

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.

Use of an Asynchronous Discussion Platform During the Pre-clerkship Curriculum: A Multiyear Retrospective Study.

Introduction: Asynchronous online message boards (OMBs) allow users to write questions or comments and share them with an online group. While the use of OMBs has been associated with positive outcomes in several educational settings, their use has not been studied in pre-clerkship undergraduate medical education (UME). Methods: This multiyear, observational, longitudinal study examined patterns of OMB use in pre-clerkship UME. Descriptive statistics were used to report the number of students and instructors who logged on and contributed, the number of posts, instructor answers, post views, and the average time to answer. Patterns of use by first- and second-year medical students as well as students undergoing remote versus in-person learning were compared using Wilcoxon signed-rank tests. Results: A total of 9870 posts were made to OMBs, initiated by 3869 student questions. There were 3078 total posts made by instructors and academic support staff and 1024 student answers to student questions. First-year medical students posted significantly more questions (149.83 vs. 83.7, p < 0.001), which resulted in significantly more instructor answers (125.0 vs. 59.1, p < 0.001). Modules during the remote learning period received more student questions (152.0 vs. 96.7, p < 0.001) and produced more instructor answers (123.8 vs. 74.7, p < 0.001) as compared to modules that took place during in-person learning. Discussion: Online message boards represent a readily available tool to stimulate asynchronous discussion in pre-clerkship UME. First-year medical students and students during remote learning were more active on OMBs.

Development of a Simulation-Based Mastery Learning Curriculum for Late Goals of Care Discussions.

INTRODUCTION: Fellows in critical care medicine (CCM) routinely help patients and families navigate complex decisions near the end of life. These "late goals of care" (LGOC) discussions require rigorous skills training and impact patient care. Innovation is needed to ensure that fellow training in leading these discussions is centered on reproducible competency-based standards. The aims of this study were to (1) describe the development of a simulation-based mastery learning (SBML) curriculum for LGOC discussions and (2) set a defensible minimum passing standard (MPS) to ensure uniform skill acquisition among learners. INNOVATION: We developed an SBML curriculum for CCM fellows structured around REMAP, a mnemonic outlining foundational components of effective communication around serious illness. A multidisciplinary expert panel iteratively created an LGOC discussion assessment tool. Pilot testing was completed to refine the checklist, set the MPS, and assess skill acquisition. OUTCOMES: The LGOC discussion assessment tool included an 18-item checklist and 6 scaled items. The tool produced reliable data (k ≥ 0.7 and ICC of ≥ 0.7). Using the Mastery Angoff method, the panel set the MPS at 87%. Ten CCM fellows participated in the pilot study. Performance on the checklist significantly improved from a median score of 52% (IQR 44%-72%) at pretest to 96% (IQR 82%-97%) at post-test (P = 0.005). The number of learners who met the MPS similarly improved from 10% during pre-testing to 70% during post-testing (P = 0.02). COMMENT: We describe the development of a LGOC SBML curriculum for CCM fellows which includes a robust communication skills assessment and the delineation of a defensible MPS.