Attempting the Impossible: Keeping a Jail COVID-Free.

AbstractPrior to the COVID-19 pandemic, the United States housed 2.3 million inmates in 7,147 incarceration structures that, because of age, overcrowding, and poor ventilation, exacerbated the spread of airborne infections. The flow of individuals into and out of correctional facilities compounded the challenges in keeping them COVID-free. This article focuses on the work of the health and administrative leadership, in partnership with judicial and police personnel, to prevent COVID-19 inside the Albemarle-Charlottesville Regional Jail and to mitigate its spread when the jail population and/or its staff became infected. From the onset, implementing science-based policies and upholding the human right to health and healthcare for all were priorities.

Outcomes Associated with Asthma Exacerbations with Respiratory Failure Treated with Extracorporeal Membrane Oxygenation

Rationale: Asthma affects 20 million adults in the United States resulting in up to 500,000 hospitalizations each year. Patients admitted to the intensive care unit (ICU) for asthma exacerbations requiring invasive ventilation have a mortality of ∼7%. Extracorporeal membrane oxygenation (ECMO) is a salvage technique used in patients with respiratory failure to increase delivery of oxygen, remove CO2 and allow time for recovery. Case series and uncontrolled registry studies have examined benefits of ECMO for asthma exacerbations with respiratory failure, but no studies have examined outcomes associated with use of ECMO for asthma exacerbations compared to standard care. Objective: To assess outcomes associated with use of ECMO during asthma exacerbations requiring invasive ventilation compared to standard care. Methods: Patients were extracted from the Premier Database from 2010-2020 if they had a primary diagnosis of asthma, or a primary diagnosis of respiratory failure with a secondary diagnosis of asthma, and were treated with invasive ventilation. Patients were excluded for age < 18y, no ICU admission, chronic lung disease other than asthma, COVID-19, or if they were not treated with corticosteroids. Hospital mortality was the primary study outcome. Key secondary outcomes included ICU length of stay (LOS), hospital LOS, length of invasive ventilation and hospital costs. Differences in outcomes were assessed using propensity score matching at a 1:2 ratio of ECMO versus no ECMO, and by covariate adjustment of the entire study group. Results: A total of 20,494 patients with asthma exacerbations requiring invasive ventilation were included in the study, of which 130 were treated with ECMO and 20,364 were not. After propensity matching, ECMO (N=103) versus no ECMO (N=206) was associated with reduced mortality (11.4% vs. 23.3%, p = 0.017) and increased hospital costs, but no difference in ICU LOS, hospital LOS or length of mechanical ventilation (Table). The covariate-adjusted model replicated these findings (Table). When individual patients were assigned a probability of being treated with ECMO equal to the hospital rate where they were admitted, each 10% increase in the hospital rate of ECMO was associated with no change in the odds of mortality (OR, 1.12: 95% CI, 0.82-1.52), p=0.48). ECMO was also associated with increased renal replacement therapy (P = 0.02), shock (P=0.02) and 30-day all-cause readmission (P = 0.01). Conclusion: ECMO was associated with reduced mortality at the cost of increased morbidity in asthmatics requiring invasive ventilation, indicating that ECMO has the potential to save thousands of lives.

PTPα Is a Regulator of Fibroproliferation during ARDS

Rationale: Acute Respiratory Distress Syndrome (ARDS) is a major healthcare issue resulting in high morbidity and mortality. Up to 25% of patients with ARDS will develop pathological fibrosis, termed Fibroproliferative ARDS (FP-ARDS). In this subset of patients, ongoing injury and dysregulated repair results in persistence of inflammatory infiltrates, myofibroblast differentiation, and dysregulated deposition of extracellular matrix. The consequences of this pathologic fibroproliferation include increased mortality, prolonged ventilator dependence, and diminished quality of life for survivors. This is especially relevant in the context of the COVID-19 pandemic, during which fibroproliferation following ARDS is an increasingly recognized entity. We demonstrate that a tyrosine phosphatase, PTPα, plays an important role in promoting fibroproliferation following ARDS. Methods: Mice deficient in PTPα and littermate controls were treated with intratracheal hydrochloric acid;histological, biochemical, and gene expression endpoint analyses were performed. NIH 3T3 (murine) fibroblasts or normal human lung fibroblasts (NLHFs) were stimulated with BAL fluid from these mice, or from ARDS patients and healthy controls, respectively. Human lung fibroblasts in which PTPα was deleted via CRISPR-cas9 targeted guide RNA were treated with exogenous TGF-β. Analysis of gene expression by qPCR was performed. Results: Mice deficient in PTPα demonstrated reduced fibrotic outcomes after lung injury. A fibrosis-focused qPCR array showed significant attenuation of key pro-fibrotic genes in PTPα-null mice, even at early timepoints during which inflammatory outcomes were unchanged. BAL fluid from PTPα-null mice treated with HCl induced less fibroproliferative gene expression in murine fibroblasts than BAL fluid from littermate controls. Human fibroblasts lacking PTPα (generated via CRISPR-cas9 deletion) showed reduced pro-fibrotic gene expression responses following stimulation with exogenous TGF-β. NHLFs stimulated with ARDS patient BAL fluid demonstrated increased pro-fibrotic gene expression as compared to BAL fluid from control patients. Conclusions: We conclude that absence of PTPα is protective in a model of FP-ARDS, through mechanisms that result in reduced TGF-β-dependent gene expression. The alveolar milieu of mice lacking PTPα has reduced fibroproliferative potential than those that express PTPα. Similarly, human fibroblasts that have been genetically modified to delete PTPα are less responsive to stimulation with TGF-β, suggesting that this pathway is relevant to human pathology. Since human ARDS BAL fluid induces the same changes in normal human lung fibroblasts that are attenuated by the absence of PTPα in experimental models, this suggests that targeting of this protein could be a strategy to alleviate pathologic fibroproliferation following lung injury.