Post-Anticoagulant D-Dimer Is a Highly Prognostic Biomarker of COVID-19 Mortality (preprint)

Background: Clinical biomarkers that accurately predict mortality are needed for the effective management of patients with severe COVID-19 illness. Here, we determine whether changes in D-dimer levels after anticoagulation are predictive of in-hospital mortality.Methods: Adult patients hospitalized for severe COVID-19 who received therapeutic anticoagulation for thromboprophylaxis were identified from a large COVID-19 database of the Mount Sinai Health System in New York City. We studied the ability post-anticoagulant D-dimer levels to predict in-hospital mortality, while taking into consideration 65 other clinically important covariates including patient demographics, comorbidities, vital signs and laboratory tests at baseline.Findings: 1835 adult patients with PCR-confirmed COVID-19 who received therapeutic anticoagulation during hospitalization were included. Overall, 26% of patients died in the hospital. Significantly different in-hospital mortality rates were observed in patient groups based on the mean D-dimer levels and its trend following anticoagulation initiation: 49% for the high mean-increase trend (HI) group; 27% for the high-decrease (HD) group; 21% for the low-increase (LI) group; and 9% for the low-decrease (LD) group (p<0·001). Using penalized logistic regression models to simultaneously analyze 67 clinical variables, the HI (adjusted odds ratios [ORadj]: 6·58, 95% CI 3·81-11·16), LI (ORadj: 4·06, 95% CI 2·23-7·38) and HD (ORadj: 2·37; 95% CI 1·37-4·09) post-anticoagulant D-dimer groups had the highest odds for in-hospital mortality when compared to the LD group.Interpretation: D-dimer levels and its trend following anticoagulation are highly predictive of in-hospital mortality and may help guide resource allocation and identify candidates for studies of emerging treatments for severe COVID-19.Funding: NoneDeclaration of Interests: Authors have no competing interests to declare.Ethics Approval Statement: The Icahn School of Medicine at Mount Sinai Institutional Review Boardconsidered the study exempt.

Post-Anticoagulant D-dimer as a Highly Prognostic Biomarker of COVID-19 Mortality (preprint)

Importance: Clinical biomarkers that accurately predict mortality are needed for the effective management of patients with severe COVID-19 illness. Objective: To determine whether D-dimer levels after anticoagulation treatment is predictive of in-hospital mortality. Design: Retrospective study using electronic health record data. Setting: A large New York City hospital network serving a diverse, urban patient population. Participants: Adult patients hospitalized for severe COVID-19 infection who received therapeutic anticoagulation for thromboprophylaxis between February 25, 2020 and May 31, 2020. Exposures: Mean and trend of D-dimer levels in the 3 days following the first therapeutic dose of anticoagulation. Main Outcomes: In-hospital mortality versus discharge. Results: 1835 adult patients (median age, 67 years [interquartile range, 57-78]; 58% male) with PCR-confirmed COVID-19 who received therapeutic anticoagulation during hospitalization were included. 74% (1365) of patients were discharged and 26% (430) died in hospital. The study cohort was divided into four groups based on the mean D-dimer levels and its trend following anticoagulation initiation, with significantly different in-hospital mortality rates (p<0.001): 49% for the high mean-increase trend (HI) group; 27% for the high-decrease (HD) group; 21% for the low-increase (LI) group; and 9% for the low-decrease (LD) group. Using penalized logistic regression models to simultaneously analyze 67 variables (baseline demographics, comorbidities, vital signs, laboratory values, D-dimer levels), post-anticoagulant D-dimer groups had the highest adjusted odds ratios (ORadj) for predicting in-hospital mortality. The ORadj of in-hospital death among patients from the HI group was 6.58 folds (95% CI 3.81-11.16) higher compared to the LD group. The LI (ORadj: 4.06, 95% CI 2.23-7.38) and HD (ORadj: 2.37; 95% CI 1.37-4.09) groups were also associated with higher mortality compared to the LD group. Conclusions and Relevance: D-dimer levels and its trend following the initiation of anticoagulation have high and independent predictive value for in-hospital mortality. This novel prognostic biomarker should be incorporated into management protocols to guide resource allocation and prospective studies for emerging treatments in hospitalized COVID-19 patients.

An inflammatory cytokine signature helps predict COVID-19 severity and death (preprint)

The COVID-19 pandemic caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to more than 100,000 deaths in the United States. Several studies have revealed that the hyper-inflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death in infected patients. However, predictive biomarkers of pathogenic inflammation to help guide targetable immune pathways are critically lacking. We implemented a rapid multiplex cytokine assay to measure serum IL-6, IL-8, TNF-, and IL-1{beta} in hospitalized COVID-19 patients upon admission to the Mount Sinai Health System in New York. Patients (n=1484) were followed up to 41 days (median 8 days) and clinical information, laboratory test results and patient outcomes were collected. In 244 patients, cytokine measurements were repeated over time, and effect of drugs could be assessed. Kaplan-Meier methods were used to compare survival by cytokine strata, followed by Cox regression models to evaluate the independent predictive value of baseline cytokines. We found that high serum IL-6, IL-8, and TNF- levels at the time of hospitalization were strong and independent predictors of patient survival. Importantly, when adjusting for disease severity score, common laboratory inflammation markers, hypoxia and other vitals, demographics, and a range of comorbidities, IL-6 and TNF- serum levels remained independent and significant predictors of disease severity and death. We propose that serum IL-6 and TNF- levels should be considered in the management and treatment of COVID-19 patients to stratify prospective clinical trials, guide resource allocation and inform therapeutic options. We also propose that patients with high IL-6 and TNF- levels should be assessed for combinatorial blockade of pathogenic inflammation in this disease.