Shift of lung macrophage composition is associated with COVID-19 disease severity and recovery (preprint)

Though it has been 2 years since the start of the Coronavirus Disease 19 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, very little progress has been made to identify curative therapies to treat COVID-19 and other inflammatory diseases which remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and death to develop tailored immunotherapy strategies to halt disease progression. Here we assembled the Mount Sinai COVID-19 Biobank which was comprised of ~600 hospitalized patients followed longitudinally during the peak of the pandemic. Moderate disease and survival were associated with a stronger antigen (Ag) presentation and effector T cell signature, while severe disease and death were associated with an altered Ag presentation signature, increased numbers of circulating inflammatory, immature myeloid cells, and extrafollicular activated B cells associated with autoantibody formation. Strikingly, we found that in severe COVID-19 patients, lung tissue resident alveolar macrophages (AM) were not only severely depleted, but also had an altered Ag presentation signature, and were replaced by inflammatory monocytes and monocyte-derived macrophages (MoM{phi}). Notably, the size of the AM pool correlated with recovery or death, while AM loss and functionality were restored in patients that recovered. These data therefore suggest that local and systemic myeloid cell dysregulation is a driver of COVID-19 severity and that modulation of AM numbers and functionality in the lung may be a viable therapeutic strategy for the treatment of critical lung inflammatory illnesses.

Cardiovascular disease and severe hypoxemia associated with higher rates of non-invasive respiratory support failure in COVID-19 (preprint)

RationaleAcute hypoxemic respiratory failure (AHRF) is the major complication of coronavirus disease 2019 (COVID-19), yet optimal respiratory support strategies are uncertain. ObjectivesTo describe outcomes with high-flow oxygen delivered through nasal cannula (HFNC) and non-invasive positive pressure ventilation (NIPPV) in COVID-19 AHRF and identify individual factors associated with failure. MethodsWe performed a retrospective cohort study of hospitalized adults with COVID-19 treated with HFNC and/or NIPPV to describe rates of success (live discharge without endotracheal intubation (ETI)), and identify characteristics associated with failure (ETI and/or in-hospital mortality) using Fine-Gray sub-distribution hazard models. ResultsA total of 331 and 747 patients received HFNC and NIPPV as the highest level of non-invasive respiratory support, respectively; 154 (46.5%) in the HFNC cohort and 167 (22.4%) in the NIPPV cohort were successfully discharged without requiring ETI. In adjusted models, significantly increased risk of HFNC and NIPPV failure was seen among patients with cardiovascular disease (subdistribution hazard ratio (sHR) 1.82; 95% confidence interval (CI), 1.17-2.83 and sHR 1.40; 95% CI 1.06-1.84), respectively, and among those with lower oxygen saturation to fraction of inspired oxygen (SpO2/FiO2) ratio at HFNC and NIPPV initiation (sHR, 0.32; 95% CI 0.19-0.54, and sHR 0.34; 95% CI 0.21-0.55, respectively). ConclusionsA significant proportion of patients receiving non-invasive respiratory modalities for COVID-19 AHRF achieved successful discharge without requiring ETI, with lower success rates among those with cardiovascular disease or more severe hypoxemia. The role of non-invasive respiratory modalities in COVID-19 related AHRF requires further consideration.