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1.
J Crit Care ; 71: 154114, 2022 Jul 18.
Article in English | MEDLINE | ID: covidwho-1936752

ABSTRACT

PURPOSE: To examine the association between a measure of heart rate variability and sudden cardiac death (SCD) in COVID-19 patients. METHODS: Patients with SARS-COV-2 infection admitted to Columbia University Irving Medical Center who died between 4/25/2020 and 7/14/2020 and had an autopsy were examined for root mean square of successive differences (RMSSD), organ weights, and evidence of SCD. RESULTS: Thirty COVID-19 patients were included and 12 had SCD. The RMSSD over 7 days without vs with SCD was median 0.0129 (IQR 0.0074-0.026) versus 0.0098 (IQR 0.0056-0.0197), p < 0.0001. The total adjusted adrenal weight of the non-SCD group was 0.40 g/kg (IQR 0.35-0.55) versus 0.25 g/kg (IQR 0.21-0.31) in the SCD group, p = 0.0007. CONCLUSIONS: Hospitalized patients with COVID-19 who experienced SCD had lower parasympathetic activity (RMSSD) and smaller sized adrenal glands. Further research is required to replicate these findings.

2.
Ann Neurol ; 91(6): 740-755, 2022 06.
Article in English | MEDLINE | ID: covidwho-1729093

ABSTRACT

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.


Subject(s)
Brain Injuries , COVID-19 , Brain Injuries/complications , COVID-19/complications , Cohort Studies , Humans , Hypoxia , Retrospective Studies , Unconsciousness/complications
3.
Front Med (Lausanne) ; 8: 770343, 2021.
Article in English | MEDLINE | ID: covidwho-1551517

ABSTRACT

Background: Characterization of coronavirus disease 2019 (COVID-19) endotypes may help explain variable clinical presentations and response to treatments. While risk factors for COVID-19 have been described, COVID-19 endotypes have not been elucidated. Objectives: We sought to identify and describe COVID-19 endotypes of hospitalized patients. Methods: Consensus clustering (using the ensemble method) of patient age and laboratory values during admission identified endotypes. We analyzed data from 528 patients with COVID-19 who were admitted to telemetry capable beds at Columbia University Irving Medical Center and discharged between March 12 to July 15, 2020. Results: Four unique endotypes were identified and described by laboratory values, demographics, outcomes, and treatments. Endotypes 1 and 2 were comprised of low numbers of intubated patients (1 and 6%) and exhibited low mortality (1 and 6%), whereas endotypes 3 and 4 included high numbers of intubated patients (72 and 85%) with elevated mortality (21 and 43%). Endotypes 2 and 4 had the most comorbidities. Endotype 1 patients had low levels of inflammatory markers (ferritin, IL-6, CRP, LDH), low infectious markers (WBC, procalcitonin), and low degree of coagulopathy (PTT, PT), while endotype 4 had higher levels of those markers. Conclusions: Four unique endotypes of hospitalized patients with COVID-19 were identified, which segregated patients based on inflammatory markers, infectious markers, evidence of end-organ dysfunction, comorbidities, and outcomes. High comorbidities did not associate with poor outcome endotypes. Further work is needed to validate these endotypes in other cohorts and to study endotype differences to treatment responses.

4.
Front Immunol ; 12: 754127, 2021.
Article in English | MEDLINE | ID: covidwho-1518487

ABSTRACT

COVID-19 presentations range from mild to moderate through severe disease but also manifest with persistent illness or viral recrudescence. We hypothesized that the spectrum of COVID-19 disease manifestations was a consequence of SARS-CoV-2-mediated delay in the pathogen-associated molecular pattern (PAMP) response, including dampened type I interferon signaling, thereby shifting the balance of the immune response to be dominated by damage-associated molecular pattern (DAMP) signaling. To test the hypothesis, we constructed a parsimonious mechanistic mathematical model. After calibration of the model for initial viral load and then by varying a few key parameters, we show that the core model generates four distinct viral load, immune response and associated disease trajectories termed "patient archetypes", whose temporal dynamics are reflected in clinical data from hospitalized COVID-19 patients. The model also accounts for responses to corticosteroid therapy and predicts that vaccine-induced neutralizing antibodies and cellular memory will be protective, including from severe COVID-19 disease. This generalizable modeling framework could be used to analyze protective and pathogenic immune responses to diverse viral infections.


Subject(s)
Alarmins/immunology , COVID-19 , Models, Biological , SARS-CoV-2 , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Anti-Inflammatory Agents/therapeutic use , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines , Humans , Middle Aged , Reproducibility of Results , Viral Load
5.
Non-conventional in English | [Unspecified Source], Grey literature | ID: grc-750479

ABSTRACT

Modified Vaccinia Ankara (MVA) is a highly attenuated poxvirus vector that is widely used to develop vaccines for infectious diseases and cancer. We developed a novel vaccine platform based on a unique three-plasmid system to efficiently generate recombinant MVA vectors from chemically synthesized DNA. In response to the ongoing global pandemic caused by SARS coronavirus-2 (SARS-CoV-2), we used this novel vaccine platform to rapidly produce fully synthetic MVA (sMVA) vectors co-expressing SARS-CoV-2 spike and nucleocapsid antigens, two immunodominant antigens implicated in protective immunity. Mice immunized with these sMVA vectors developed robust SARS-CoV-2 antigen-specific humoral and cellular immune responses, including potent neutralizing antibodies. These results demonstrate the potential of a novel vaccine platform based on synthetic DNA to efficiently generate recombinant MVA vectors and to rapidly develop a multi-antigenic poxvirus-based SARS-CoV-2 vaccine candidate.

6.
Neurocrit Care ; 36(1): 89-96, 2022 02.
Article in English | MEDLINE | ID: covidwho-1286190

ABSTRACT

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.


Subject(s)
COVID-19 , Consciousness , Hospitalization , Humans , Retrospective Studies , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/epidemiology
7.
J Trauma Acute Care Surg ; 90(1): e7-e12, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-1117212

ABSTRACT

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.


Subject(s)
COVID-19/physiopathology , Fibrin Fibrinogen Degradation Products/analysis , Thrombelastography/methods , Thrombophilia/blood , Thrombosis/etiology , Aged , COVID-19/blood , Case-Control Studies , Critical Illness , Female , Hemostasis , Humans , Male , Middle Aged , New York City , Partial Thromboplastin Time , SARS-CoV-2/isolation & purification , Thrombosis/diagnosis
8.
Clin Neurophysiol ; 132(3): 730-736, 2021 03.
Article in English | MEDLINE | ID: covidwho-1039319

ABSTRACT

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.


Subject(s)
COVID-19/drug therapy , Electroencephalography/methods , Frontal Lobe/physiology , Hypnotics and Sedatives/administration & dosage , Machine Learning , Temporal Lobe/physiology , Aged , Anesthesia/methods , COVID-19/diagnosis , COVID-19/physiopathology , Cohort Studies , Electroencephalography/drug effects , Female , Humans , Intensive Care Units , Male , Middle Aged
9.
bioRxiv ; 2020 Jul 02.
Article in English | MEDLINE | ID: covidwho-636653

ABSTRACT

Modified Vaccinia Ankara (MVA) is a highly attenuated poxvirus vector that is widely used to develop vaccines for infectious diseases and cancer. We developed a novel vaccine platform based on a unique three-plasmid system to efficiently generate recombinant MVA vectors from chemically synthesized DNA. In response to the ongoing global pandemic caused by SARS coronavirus-2 (SARS-CoV-2), we used this novel vaccine platform to rapidly produce fully synthetic MVA (sMVA) vectors co-expressing SARS-CoV-2 spike and nucleocapsid antigens, two immunodominant antigens implicated in protective immunity. Mice immunized with these sMVA vectors developed robust SARS-CoV-2 antigen-specific humoral and cellular immune responses, including potent neutralizing antibodies. These results demonstrate the potential of a novel vaccine platform based on synthetic DNA to efficiently generate recombinant MVA vectors and to rapidly develop a multi-antigenic poxvirus-based SARS-CoV-2 vaccine candidate.

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