Visceral adipose macrophage content does not associate with body mass index or systemic inflammation in COVID-19: an autopsy study (preprint)

Introduction: Adiposity, especially visceral adiposity with elevated body mass index (BMI), is associated with a hyperinflammatory syndrome and poor outcomes in patients with COVID-19. In other diseases such as obesity, type 2 diabetes, and rheumatoid arthritis, systemic inflammation is driven directly by visceral adipose macrophages which release pro-inflammatory cytokines. Currently it is unknown whether visceral adipose tissue macrophage content may similarly explain the observation that COVID-19 patients with elevated BMI are at risk for a hyperinflammatory syndrome and death. Methods: This was a retrospective study of hospitalized adults who died of COVID-19 between March 2020 and June 2020 and underwent autopsy. Visceral adipose tissue macrophage content was quantified by histological staining of visceral adipose tissue samples with CD68, using pericolic fat gathered at autopsy from each subject. Clinical data including inflammatory markers such as erythrocyte sedimentation rate (ESR), C-reactive Protein (CRP), Troponin, D-dimer, Interleukin-6 (IL-6), and ferritin as well as BMI were collected from electronic medical records. Results: A total of 39 subjects were included in this study. There was no association between BMI and visceral adipose tissue macrophage content (Spearman R=0.025, p=0.88). Additionally, there was no association between adipose tissue macrophage content and any of the systemic markers of inflammation measured including ESR, CRP, Troponin, D-dimer, IL-6, and Ferritin (p>0.05 for all markers). Conclusion: Unlike chronic diseases such as obesity, type 2 diabetes, and rheumatoid arthritis, elevated BMI is not associated with increased visceral adipose tissue macrophage content in patients who died of COVID-19. Additionally, among patients who died of COVID-19, visceral adipose tissue macrophage content is not associated with markers of systemic inflammation. These results suggest that the elevations in systemic markers of inflammation-and the hyperinflammatory syndrome often observed during acute COVID-19-does not directly originate from visceral adipose macrophages as it seems to in chronic disease states.

Rationing Scarce Healthcare Capacity: A Study Of The Ventilator Allocation Guidelines During The Covid-19 Pandemic (preprint)

In the United States, even though national guidelines for allocating scarce healthcare resources are lacking, 26 states have specific ventilator allocation guidelines to be invoked in case of a shortage. While several states developed their guidelines in response to the recent Covid-19 pandemic, NYS developed these guidelines in 2015 as "pandemic influenza is a foreseeable threat, one that we cannot ignore." The primary objective of this study is to assess the existing procedures and priority rules in place for allocating/rationing scarce ventilator capacity and propose alternative (and improved) priority schemes. We first build machine learning models using inpatient records of COVID-19 patients admitted to New York-Presbyterian/Columbia University Irving Medical Center and an affiliated community health center to predict survival probabilities as well as ventilator length-of-use. Then, we use the resulting point estimators and their uncertainties as inputs for a multi-class priority queueing model with abandonments to assess three priority schemes: (i) SOFA-P, which most closely mimics the existing practice by prioritizing patients with sufficiently low Sequential Organ Failure Assessment (SOFA) scores, (ii) ISP, which assigns priority based on patient-level survival predictions, and (iii) ISP-LU, which takes into account survival predictions and resource use duration. Our findings highlight that our proposed priority scheme, ISP-LU, achieves a demonstrable improvement over the other two alternatives. Specifically, the expected number of survivals increases and death risk while waiting for ventilator use decreases. We also show that ISP-LU is a robust priority scheme whose implementation yields a Pareto-improvement over both ISP and SOFA-P in terms of maximizing saved lives after mechanical ventilation while limiting racial disparity in access to the priority queue.

Hospital length of stay for severe COVID-19: implications for Remdesivir's value (preprint)

Remdesivir has been granted emergency use authorization for treatment of severe COVID-19. Remdesivir's pricing is based on a presumed reduction of hospital length of stay (LOS) by four days. But the Adaptive COVID-19 Treatment Trial (ACTT-1) that suggested this treatment benefit excluded patients who were expected to be discharged within 72 hours. Perhaps as a result, median time to recovery was unusually long in both arms of the study (15 days vs 11 days). Remdesivir requires a 5-day inpatient stay, so patients who would otherwise be discharged in fewer than 5 days may remain hospitalized to complete treatment while patients who would be discharged between 5 and 8 days, would only have potential reductions in their hospital LOS of 0-3 days. In a retrospective analysis of 1643 adults with severe COVID-19 admitted to Columbia University Medical Center and the Allen community hospital between March 9, 2020 and April 23, 2020, median hospital LOS was 7 (3-14) days. Five-hundred and eighty-six patients (36%) had a LOS of 1-4 days, 384 (23%) had a LOS of 5-8 days, and 673 (41%) were hospitalized for greater than or equal to 9 days. Remdesivir treatment may not provide the LOS reductions that the company relied on when pricing the therapy: 36% of the cohort would need to have LOS prolonged to receive a 5-day course, and only 41% of patients in our cohort had LOS of 9 days or more, meaning they could have their LOS shortened by 4 days and still receive a full Remdesivir course. Further investigation of shorter treatment courses and programs to facilitate outpatient intravenous Remdesivir administration are needed.