Healthcare disparities among anticoagulation therapies for severe COVID-19 patients in the multi-site VIRUS registry

COVID-19 patients are at an increased risk of thrombosis and various anticoagulants are being used in patient management without an established standard-of-care. Here, we analyze hospitalized and ICU patient outcomes from the Viral Infection and Respiratory illness Universal Study (VIRUS) registry. We find that severe COVID patients administered unfractionated heparin but not enoxaparin have a higher mortality-rate (311 deceased patients out of 760 total patients = 41%) compared to patients administered enoxaparin but not unfractionated heparin (214 deceased patients out of 1,432 total patients = 15%), presenting a risk ratio of 2.74 (95% C.I.: [2.35, 3.18]; p-value: 1.4e-41). This difference persists even after balancing on a number of covariates including: demographics, comorbidities, admission diagnoses, and method of oxygenation, with an amplified mortality rate of 39% (215 of 555) for unfractionated heparin vs. 23% (119 of 522) for enoxaparin, presenting a risk ratio of 1.70 (95% C.I.: [1.40, 2.05]; p-value: 2.5e-7). In these balanced cohorts, a number of complications occurred at an elevated rate for patients administered unfractionated heparin compared to those administered enoxaparin, including acute kidney injury (227 of 642 [35%] vs. 156 of 608 [26%] respectively, adjusted p-value 0.0019), acute cardiac injury (40 of 642 [6.2%] vs. 15 of 608 [2.5%] respectively, adjusted p-value 0.01), septic shock (118 of 642 [18%] vs. 73 of 608 [12%] respectively, adjusted p-value 0.01), and anemia (81 of 642 [13%] vs. 46 of 608 [7.6%] respectively, adjusted p-value 0.02). Furthermore, a higher percentage of Black/African American COVID patients (375 of 1,203 [31%]) were noted to receive unfractionated heparin compared to White/Caucasian COVID patients (595 of 2,488 [24%]), for a risk ratio of 1.3 (95% C.I.: [1.17, 1.45], adjusted p-value: 1.6e-5). After balancing upon available clinical covariates, this difference in anticoagulant use remained statistically significant (272 of 959 [28%] for Black/African American vs. 213 of 959 [22%] for White/Caucasian, adjusted p-value: 0.01, relative risk: 1.28, 95% C.I.: [1.09, 1.49]). While retrospective studies cannot suggest any causality, these findings motivate the need for follow-up prospective research in order to elucidate potential socioeconomic, racial, or other disparities underlying the use of anticoagulants to treat severe COVID patients.

Pre-existing conditions are associated with long-COVID patients hospitalization, despite confirmed clearance of SARS-CoV-2 virus

The current diagnostic gold-standard for SARS-CoV-2 clearance from infected patients is two consecutive negative PCR test results. However, there are anecdotal reports of hospitalization from protracted COVID complications despite such confirmed viral clearance, presenting a clinical conundrum. We conducted a retrospective analysis of 266 COVID patients to compare those that were admitted/re-admitted post-viral clearance (hospitalized post-clearance cohort, n=93) with those that were hospitalized pre-clearance but were not re-admitted post-viral clearance (non-hospitalized post-clearance cohort, n=173). In order to differentiate these two cohorts, we used neural network models for the augmented curation of comorbidities and complications with positive sentiment in the EHR physician notes. In the year preceding COVID onset, acute kidney injury (n=15 (16.1%), p-value: 0.03), anemia (n=20 (21.5%), p-value: 0.02), and cardiac arrhythmia (n=21 (22.6%), p-value: 0.05) were significantly enriched in the physician notes of the hospitalized post-clearance cohort. This study highlights that these specific pre-existing conditions are associated with amplified hospitalization risk in COVID patients, despite their successful SARS-CoV-2 viral clearance. Our finding that pre-COVID anemia amplifies risk of post-COVID hospitalization is particularly concerning given the high prevalence and endemic nature of anemia in many low- and middle-income countries (per the World Bank definition; e.g. India, Brazil), which are unfortunately also seeing high rates of SARS-CoV-2 infection and COVID-induced mortality. This study motivates follow-up prospective research into the specific risk factors we have identified that appear to predispose some patients towards the after effects of COVID-19. Article summary - Strengths and limitations of this studyO_LIThis is the first study at a major healthcare center analyzing risk factors for post-viral clearance hospitalization of COVID-19 patients. C_LIO_LIThis analysis uses augmented curation methods to identify complications and comorbidities from the physician notes, rather than relying upon ICD codes. C_LIO_LIThe statistical analysis identifies specific comorbidities in the year preceding PCR diagnosis of SARS-CoV-2 which are associated with increased rates of post-viral clearance hospitalization. C_LIO_LIThe dataset used for this study is limited to a single healthcare system, so the underlying clinical characteristics of the study population are biased to reflect the clinical characteristics of individuals that receive medical treatment in certain regions of the United States (Arizona, Florida, Minnesota). C_LIO_LIIn this study, we use the first of two consecutive negative PCR tests to estimate the viral clearance date for each patient, however the true viral clearance date for each patient is unknown. C_LI

Enoxaparin is associated with lower rates of thrombosis, kidney injury, and mortality than Unfractionated Heparin in hospitalized COVID patients

Although anticoagulants such as unfractionated heparin and low molecular weight heparin (LMWH, e.g. enoxaparin) are both being used for therapeutic mitigation of COVID associated coagulopathy (CAC), differences in their clinical outcomes remain to be investigated. Here, we employ automated neural networks supplemented with expert curation ( augmented curation) for retrospectively analyzing the complete electronic health records (EHRs) of 671 hospitalized COVID-19 patients administered either enoxaparin or unfractionated heparin, but not both. We find that COVID-19 patients administered unfractionated heparin but not enoxaparin have higher rates of mortality (risk ratio: 2.6; 95% C.I.: [1.2-5.4]; p-value: 0.02; BH adjusted p-value: 0.09), thrombotic events (risk ratio: 5.7, 95% C.I.: [2.1, 33.9], p-value: 0.024), acute kidney injury (risk ratio: 5.5; 95% C.I.: [1.2-17.7]; p-value: 0.02; BH adjusted p-value: 0.10), and bacterial pneumonia (risk ratio undefined; 95% C.I.: [1.0, 292]; p-value:0.02; BH adjusted p-value:0.10), compared to patients administered enoxaparin but not unfractionated heparin. Notably, even after controlling for potential confounding factors such as demographics, comorbidities, admission diagnosis, initial ICU status, and initial level of oxygen support, the above differences between the enoxaparin and unfractionated heparin patient cohorts remain statistically significant. This study emphasizes the need for mechanistically investigating differential modulation of the COVID-associated coagulation cascades by enoxaparin versus unfractionated heparin.

Plasma IL-6 Levels following Corticosteroid Therapy as an Indicator of ICU Length of Stay in Critically ill COVID-19 Patients

Intensive Care Unit (ICU) admissions and mortality in severe COVID-19 patients are driven by "cytokine storms" and acute respiratory distress syndrome (ARDS). Interim clinical trial results suggest that the corticosteroid dexamethasone displays superior 28-day survival in severe COVID-19 patients requiring ventilation or oxygen. Among 16 patients with plasma IL-6 measurement post-corticosteroid administration, a higher proportion of patients with an IL-6 value over 10 pg/mL have worse outcomes (i.e. ICU Length of Stay > 15 days or death) when compared to 41 patients treated with non-corticosteroid drugs including antivirals, tocilizumab, azithromycin, and hydroxychloroquine (p-value = 0.0024). Given this unexpected clinical association between post-corticosteroid IL-6 levels and COVID-19 severity, we hypothesized that the Glucocorticoid Receptor (GR or NR3C1) may be coupled to IL-6 expression in specific cell types that govern cytokine release syndrome (CRS). Examining single cell RNA-seq data from bronchoalveolar lavage fluid of severe COVID-19 patients and nearly 2 million human cells from a pan-tissue scan shows that alveolar macrophages, smooth muscle cells, and endothelial cells co-express both NR3C1 and IL-6. The mechanism of Glucocorticoid Receptor (GR) agonists mitigating pulmonary and multi-organ inflammation in some COVID-19 patients with respiratory failure, may be in part due to their successful antagonism of IL-6 production within lung macrophages and vasculature.

Quantifying the prevalence of SARS-CoV-2 long-term shedding among non-hospitalized COVID-19 patients

Analysis of 851 COVID-19 patients with a SARS-CoV-2-positive PCR at follow-up shows 99 patients remained SARS-CoV-2-positive after four weeks from initial diagnosis. Surprisingly, a majority of these long-term viral RNA shedders were not hospitalized (61 of 99), with variable PCR Crossing point values over the month post diagnosis. For the 851-patient cohort, the mean lower bound of viral RNA shedding was 17.3 days (SD: 7.8), and the mean upper bound of viral RNA shedding from 668 patients transitioning to confirmed PCR-negative status was 22.7 days (SD: 11.8). Among 104 patients with an IgG test result, 90 patients were seropositive to date, with mean upper bound of time to seropositivity from initial diagnosis being 37.8 days (95%CI: 34.3-41.3). Juxtaposing IgG/PCR tests revealed that 14 of 90 patients are non-hospitalized and seropositive yet shed viral RNA. This study emphasizes the need for monitoring viral loads and neutralizing antibody titers in long-term shedders.