Risk Factors for New Neurologic Diagnoses in Hospitalized Patients With COVID-19: A Case-Control Study in New York City.

Background and Objectives: There have been numerous reports of neurologic manifestations identified in hospitalized patients infected with SARS-CoV-2, the virus that causes COVID-19. Here, we identify the spectrum of associated neurologic symptoms and diagnoses, define the time course of their development, and examine readmission rates and mortality risk posthospitalization in a multiethnic urban cohort. Methods: We identify the occurrence of new neurologic diagnoses among patients with laboratory-confirmed SARS-CoV-2 infection in New York City. A retrospective cohort study was performed on 532 cases (hospitalized patients with new neurologic diagnoses within 6 weeks of positive SARS-CoV-2 laboratory results between March 1, 2020, and August 31, 2020). We compare demographic and clinical features of the 532 cases with 532 controls (hospitalized COVID-19 patients without neurologic diagnoses) in a case-control study with one-to-one matching and examine hospital-related data and outcomes of death and readmission up to 6 months after acute hospitalization in a secondary case-only analysis. Results: Among the 532 cases, the most common new neurologic diagnoses included encephalopathy (478, 89.8%), stroke (66, 12.4%), and seizures (38, 7.1%). In the case-control study, cases were more likely than controls to be male (58.6% vs 52.8%, p = 0.05), had baseline neurologic comorbidities (36.3% vs 13.0%, p < 0.0001), and were to be treated in an intensive care unit (62.0% vs 9.6%, p < 0.0001). Of the 394 (74.1%) cases who survived acute hospitalization, more than half (220 of 394, 55.8%) were readmitted within 6 months, with a mortality rate of 23.2% during readmission. Discussion: Hospitalized patients with SARS-CoV-2 and new neurologic diagnoses have significant morbidity and mortality postdischarge. Further research is needed to define the effect of neurologic diagnoses during acute hospitalization on longitudinal post-COVID-19-related symptoms including neurocognitive impairment.

Prolonged Unconsciousness is Common in COVID-19 and Associated with Hypoxemia.

OBJECTIVE: The purpose of this study was to estimate the time to recovery of command-following and associations between hypoxemia with time to recovery of command-following. METHODS: In this multicenter, retrospective, cohort study during the initial surge of the United States' pandemic (March-July 2020) we estimate the time from intubation to recovery of command-following, using Kaplan Meier cumulative-incidence curves and Cox proportional hazard models. Patients were included if they were admitted to 1 of 3 hospitals because of severe coronavirus disease 2019 (COVID-19), required endotracheal intubation for at least 7 days, and experienced impairment of consciousness (Glasgow Coma Scale motor score <6). RESULTS: Five hundred seventy-one patients of the 795 patients recovered command-following. The median time to recovery of command-following was 30 days (95% confidence interval [CI] = 27-32 days). Median time to recovery of command-following increased by 16 days for patients with at least one episode of an arterial partial pressure of oxygen (PaO2 ) value ≤55 mmHg (p < 0.001), and 25% recovered ≥10 days after cessation of mechanical ventilation. The time to recovery of command-following  was associated with hypoxemia (PaO2 ≤55 mmHg hazard ratio [HR] = 0.56, 95% CI = 0.46-0.68; PaO2 ≤70 HR = 0.88, 95% CI = 0.85-0.91), and each additional day of hypoxemia decreased the likelihood of recovery, accounting for confounders including sedation. These findings were confirmed among patients without any imagining evidence of structural brain injury (n = 199), and in a non-overlapping second surge cohort (N = 427, October 2020 to April 2021). INTERPRETATION: Survivors of severe COVID-19 commonly recover consciousness weeks after cessation of mechanical ventilation. Long recovery periods are associated with more severe hypoxemia. This relationship is not explained by sedation or brain injury identified on clinical imaging and should inform decisions about life-sustaining therapies. ANN NEUROL 2022;91:740-755.

The Impact of Age and BMI on the VWF/ADAMTS13 Axis and Simultaneous Thrombin and Plasmin Generation in Hospitalized COVID-19 Patients

Aging and obesity independently contribute toward an endothelial dysfunction that results in an imbalanced VWF to ADAMTS13 ratio. In addition, plasma thrombin and plasmin generation are elevated and reduced, respectively, with increasing age and also with increasing body mass index (BMI). The severity risk of Corona Virus Disease 2019 (COVID-19) increases in adults older than 65 and in individuals with certain pre-existing health conditions, including obesity (>30 kg/m2). The present cross-sectional study focused on an analysis of the VWF/ADAMTS13 axis, including measurements of von Willebrand factor (VWF) antigen (VWF:AG), VWF collagen binding activity (VWF:CBA), Factor VIII antigen, ADAMTS13 antigen, and ADAMTS13 activity, in addition to thrombin and plasmin generation potential, in a demographically diverse population of COVID-19 negative (−) (n = 288) and COVID-19 positive (+) (n = 543) patient plasmas collected at the time of hospital presentation. Data were analyzed as a whole, and then after dividing patients by age (<65 and ≥65) and independently by BMI [<18.5, 18.5–24.9, 25–29.9, >30 (kg/m2)]. These analyses suggest that VWF parameters (i.e., the VWF/ADAMTS13 activity ratio) and thrombin and plasmin generation differed in COVID-19 (+), as compared to COVID-19 (−) patient plasma. Further, age (≥65) more than BMI contributed to aberrant plasma indicators of endothelial coagulopathy. Based on these findings, evaluating both the VWF/ADAMTS13 axis, along with thrombin and plasmin generation, could provide insight into the extent of endothelial dysfunction as well as the plasmatic imbalance in coagulation and fibrinolysis potential, particularly for at-risk patient populations.

Insights into Fibrinogen-Mediated COVID-19 Hypercoagubility in Critically Ill Patients.

Coronavirus disease-2019 (COVID-19) is associated with hypercoagulability that may cause thromobembolic complications. We describe our recent studies investigating the mechanisms of hypercoagulability in patients with severe COVID-19 requiring mechanical ventilation during the COVID-19 crisis in New York City in spring 2020. Using rotational thombelastometry we found that almost all patients with severe COVID-19 had signs of hypercoagulability compared with non-COVID-19 controls. Specifically, the maximal clot firmness in the fibrin-based extrinsically activated test was almost twice the upper limit of normal in COVID patients, indicating a fibrin-mediated cause for hypercoagulability. To better understand the mechanism of this hypercoagulability we measured the components of the fibrinolytic pathways. Fibrinogen, tissue plasminogen activator and plasminogen activator inhibitor-1, but not plasminogen levels were elevated in patients with severe COVID-19. Our studies indicate that hypercoagulability in COVID-19 may be because of decreased fibrinolysis resulting from inhibition of plasmin through high levels of plasminogen activator inhibitor-1. Clinicians creating treatment protocols for anticoagulation in critically ill COVID-19 patients should consider these potential mechanisms of hypercoaguability.

Biological and Clinical Factors Contributing to the Metabolic Heterogeneity of Hospitalized Patients with and without COVID-19.

The Corona Virus Disease 2019 (COVID-19) pandemic represents an ongoing worldwide challenge. The present large study sought to understand independent and overlapping metabolic features of samples from acutely ill patients (n = 831) that tested positive (n = 543) or negative (n = 288) for COVID-19. High-throughput metabolomics analyses were complemented with antigen and enzymatic activity assays on plasma from acutely ill patients collected while in the emergency department, at admission, or during hospitalization. Lipidomics analyses were also performed on COVID-19-positive or -negative subjects with the lowest and highest body mass index (n = 60/group). Significant changes in amino acid and fatty acid/acylcarnitine metabolism emerged as highly relevant markers of disease severity, progression, and prognosis as a function of biological and clinical variables in these patients. Further, machine learning models were trained by entering all metabolomics and clinical data from half of the COVID-19 patient cohort and then tested on the other half, yielding ~78% prediction accuracy. Finally, the extensive amount of information accumulated in this large, prospective, observational study provides a foundation for mechanistic follow-up studies and data sharing opportunities, which will advance our understanding of the characteristics of the plasma metabolism in COVID-19 and other acute critical illnesses.

Disorders of Consciousness in Hospitalized Patients with COVID-19: The Role of the Systemic Inflammatory Response Syndrome.

BACKGROUND: Prevalence and etiology of unconsciousness are uncertain in hospitalized patients with coronavirus disease 2019 (COVID-19). We tested the hypothesis that increased inflammation in COVID-19 precedes coma, independent of medications, hypotension, and hypoxia. METHODS: We retrospectively assessed 3203 hospitalized patients with COVID-19 from March 2 through July 30, 2020, in New York City with the Glasgow Coma Scale and systemic inflammatory response syndrome (SIRS) scores. We applied hazard ratio (HR) modeling and mediation analysis to determine the risk of SIRS score elevation to precede coma, accounting for confounders. RESULTS: We obtained behavioral assessments in 3203 of 10,797 patients admitted to the hospital who tested positive for SARS-CoV-2. Of those patients, 1054 (32.9%) were comatose, which first developed on median hospital day 2 (interquartile range [IQR] 1-9). During their hospital stay, 1538 (48%) had a SIRS score of 2 or above at least once, and the median maximum SIRS score was 2 (IQR 1-2). A fivefold increased risk of coma (HR 5.05, 95% confidence interval 4.27-5.98) was seen for each day that patients with COVID-19 had elevated SIRS scores, independent of medication effects, hypotension, and hypoxia. The overall mortality in this population was 13.8% (n = 441). Coma was associated with death (odds ratio 7.77, 95% confidence interval 6.29-9.65) and increased length of stay (13 days [IQR 11.9-14.1] vs. 11 [IQR 9.6-12.4]), accounting for demographics. CONCLUSIONS: Disorders of consciousness are common in hospitalized patients with severe COVID-19 and are associated with increased mortality and length of hospitalization. The underlying etiology of disorders of consciousness in this population is uncertain but, in addition to medication effects, may in part be linked to systemic inflammation.

Clinical review of cerebral venous thrombosis in the context of COVID-19 vaccinations: Evaluation, management, and scientific questions.

BACKGROUND: Vaccine induced immune mediated thrombocytopenia or VITT, is a recent and rare phenomenon of thrombosis with thrombocytopenia, frequently including cerebral venous thromboses (CVT), that has been described following vaccination with adenovirus vaccines ChAdOx1 nCOV-19 (AstraZeneca) and Ad26.COV2·S Johnson and Johnson (Janssen/J&J). The evaluation and management of suspected cases of CVT post COVID-19 vaccination are critical skills for a broad range of healthcare providers. METHODS: A collaborative comprehensive review of literature was conducted among a global group of expert neurologists and hematologists. FINDINGS: Strategies for rapid evaluation and treatment of the CVT in the context of possible VITT exist, including inflammatory marker measurements, PF4 assays, and non-heparin anticoagulation.

Biological and Clinical Factors contributing to the Metabolic Heterogeneity of Hospitalized Patients with and without COVID-19.

The Corona Virus Disease 2019 (COVID-19) pandemic represents an ongoing worldwide challenge. Exploratory studies evaluating the impact of COVID-19 infection on the plasma metabolome have been performed, often with small numbers of patients, and with or without relevant control data; however, determining the impact of biological and clinical variables remains critical to understanding potential markers of disease severity and progression. The present large study, including relevant controls, sought to understand independent and overlapping metabolic features of samples from acutely ill patients (n = 831), testing positive (n = 543) or negative (n = 288) for COVID-19. High-throughput metabolomics analyses were complemented with antigen and enzymatic activity assays on 831 plasma samples from acutely ill patients while in the emergency department, at admission, and during hospitalization. We then performed additional lipidomics analyses of the 60 subjects with the lowest and highest body mass index, either COVID-19 positive or negative. Omics data were correlated to detailed data on patient characteristics and clinical laboratory assays measuring coagulation, hematology and chemistry analytes. Significant changes in arginine/proline/citrulline, tryptophan/indole/kynurenine, fatty acid and acyl-carnitine metabolism emerged as highly relevant markers of disease severity, progression and prognosis as a function of biological and clinical variables in these patients. Further, machine learning models were trained by entering all metabolomics and clinical data from half of the COVID-19 patient cohort and then tested on the other half yielding ~ 78% prediction accuracy. Finally, the extensive amount of information accumulated in this large, prospective, observational study provides a foundation for follow-up mechanistic studies and data sharing opportunities, which will advance our understanding of the characteristics of the plasma metabolism in COVID-19 and other acute critical illnesses.

Hypercoagulable viscoelastic blood clot characteristics in critically ill coronavirus disease 2019 patients and associations with thrombotic complications.

BACKGROUND: Critically ill coronavirus disease 2019 (COVID-19) patients have frequent thrombotic complications and laboratory evidence of hypercoagulability. The relationship of coagulation tests and thrombosis requires investigation to identify best diagnostic and treatment approaches. We assessed for hypercoagulable characteristics in critically ill COVID-19 patients using rotational thromboelastometry (ROTEM) and explored relationships of D-dimer and ROTEM measurements with thrombotic complications. METHODS: Critically ill adult COVID-19 patients receiving ROTEM testing between March and April 2020 were analyzed. Patients receiving therapeutic anticoagulation before ROTEM were excluded. Rotational thromboelastometry measurements from COVID-19 patients were compared with non-COVID-19 patients matched by age, sex, and body mass index. Intergroup differences in ROTEM measurements were assessed using t tests. Correlations of D-dimer levels to ROTEM measurements were assessed in COVID-19 patients who had available concurrent testing. Intergroup differences of D-dimer and ROTEM measurements were explored in COVID-19 patients with and without thrombosis. RESULTS: Of 30 COVID-19 patients receiving ROTEM, we identified hypercoagulability from elevated fibrinogen compared with non-COVID-19 patients (fibrinogen assay maximum clot firmness [MCF], 47 ± 13 mm vs. 20 ± 7 mm; mean intergroup difference, 27.4 mm; 95% confidence interval [CI], 22.1-32.7 mm; p < 0.0001). In our COVID-19 cohort, thrombotic complications were identified in 33%. In COVID-19 patients developing thrombotic complications, we identified higher D-dimer levels (17.5 ± 4.3 µg/mL vs. 8.0 ± 6.3 µg/mL; mean difference, 9.5 µg/mL; 95% CI, 13.9-5.1; p < 0.0001) but lower fibrinogen assay MCF (39.7 ± 10.8 mm vs. 50.1 ± 12.0 mm; mean difference, -11.2 mm; 95% CI, -2.1 to -20.2; p = 0.02) compared with patients without thrombosis. We identified negative correlations of D-dimer levels and ROTEM MCF in these patients (r = -0.61; p = 0.001). CONCLUSION: We identified elevated D-dimer levels and hypercoagulable blood clot characteristics from increased fibrinogen on ROTEM testing in critically ill COVID-19 patients. However, we identified lower, albeit still hypercoagulable, ROTEM measurements of fibrinogen in COVID-19 patients with thrombotic complications compared with those without. Further work is required to externally validate these findings and to investigate the mechanistic drivers for these relationships to identify best diagnostic and treatment approaches for these patients. LEVEL OF EVIDENCE: Epidemiologic, level IV.

Frontotemporal EEG to guide sedation in COVID-19 related acute respiratory distress syndrome.

OBJECTIVE: To study if limited frontotemporal electroencephalogram (EEG) can guide sedation changes in highly infectious novel coronavirus disease 2019 (COVID-19) patients receiving neuromuscular blocking agent. METHODS: 98 days of continuous frontotemporal EEG from 11 consecutive patients was evaluated daily by an epileptologist to recommend reduction or maintenance of the sedative level. We evaluated the need to increase sedation in the 6 h following this recommendation. Post-hoc analysis of the quantitative EEG was correlated with the level of sedation using a machine learning algorithm. RESULTS: Eleven patients were studied for a total of ninety-eight sedation days. EEG was consistent with excessive sedation on 57 (58%) and adequate sedation on 41 days (42%). Recommendations were followed by the team on 59% (N = 58; 19 to reduce and 39 to keep the sedation level). In the 6 h following reduction in sedation, increases of sedation were needed in 7 (12%). Automatized classification of EEG sedation levels reached 80% (±17%) accuracy. CONCLUSIONS: Visual inspection of a limited EEG helped sedation depth guidance. In a secondary analysis, our data supported that this determination may be automated using quantitative EEG analysis. SIGNIFICANCE: Our results support the use of frontotemporal EEG for guiding sedation in patients with COVID-19.

Body Mass Index and Risk for Intubation or Death in SARS-CoV-2 Infection : A Retrospective Cohort Study.

BACKGROUND: Obesity is a risk factor for pneumonia and acute respiratory distress syndrome. OBJECTIVE: To determine whether obesity is associated with intubation or death, inflammation, cardiac injury, or fibrinolysis in coronavirus disease 2019 (COVID-19). DESIGN: Retrospective cohort study. SETTING: A quaternary academic medical center and community hospital in New York City. PARTICIPANTS: 2466 adults hospitalized with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection over a 45-day period with at least 47 days of in-hospital observation. MEASUREMENTS: Body mass index (BMI), admission biomarkers of inflammation (C-reactive protein [CRP] level and erythrocyte sedimentation rate [ESR]), cardiac injury (troponin level), and fibrinolysis (D-dimer level). The primary end point was a composite of intubation or death in time-to-event analysis. RESULTS: Over a median hospital length of stay of 7 days (interquartile range, 3 to 14 days), 533 patients (22%) were intubated, 627 (25%) died, and 59 (2%) remained hospitalized. Compared with overweight patients, patients with obesity had higher risk for intubation or death, with the highest risk among those with class 3 obesity (hazard ratio, 1.6 [95% CI, 1.1 to 2.1]). This association was primarily observed among patients younger than 65 years and not in older patients (P for interaction by age = 0.042). Body mass index was not associated with admission levels of biomarkers of inflammation, cardiac injury, or fibrinolysis. LIMITATIONS: Body mass index was missing for 28% of patients. The primary analyses were conducted with multiple imputation for missing BMI. Upper bounding factor analysis suggested that the results are robust to possible selection bias. CONCLUSION: Obesity is associated with increased risk for intubation or death from COVID-19 in adults younger than 65 years, but not in adults aged 65 years or older. PRIMARY FUNDING SOURCE: National Institutes of Health.