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1.
Res Pract Thromb Haemost ; 6(2): e12669, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1756641

ABSTRACT

Background: Few therapies exist to treat severe COVID-19 respiratory failure once it develops. Given known diffuse pulmonary microthrombi on autopsy studies of COVID-19 patients, we hypothesized that tissue plasminogen activator (tPA) may improve pulmonary function in COVID-19 respiratory failure. Methods: A multicenter, retrospective, observational study of patients with confirmed COVID-19 and severe respiratory failure who received systemic tPA (alteplase) was performed. Seventy-nine adults from seven medical centers were included in the final analysis after institutional review boards' approval; 23 were excluded from analysis because tPA was administered for pulmonary macroembolism or deep venous thrombosis. The primary outcome was improvement in the PaO2/FiO2 ratio from baseline to 48 h after tPA. Linear mixed modeling was used for analysis. Results: tPA was associated with significant PaO2/FiO2 improvement at 48 h (estimated paired difference = 23.1 ± 6.7), which was sustained at 72 h (interaction term p < 0.00). tPA administration was also associated with improved National Early Warning Score 2 scores at 24, 48, and 72 h after receiving tPA (interaction term p = 0.00). D-dimer was significantly elevated immediately after tPA, consistent with lysis of formed clot. Patients with declining respiratory status preceding tPA administration had more marked improvement in PaO2/FiO2 ratios than those who had poor but stable (not declining) respiratory status. There was one intracranial hemorrhage, which occurred within 24 h following tPA administration. Conclusions: These data suggest tPA is associated with significant improvement in pulmonary function in severe COVID-19 respiratory failure, especially in patients whose pulmonary function is in decline, and has an acceptable safety profile in this patient population.

2.
Am J Med Qual ; 2022 Mar 11.
Article in English | MEDLINE | ID: covidwho-1741052

ABSTRACT

Accurate determinations of the time of intubation (TOI) are critical for retrospective electronic health record (EHR) data analyses. In a retrospective study, the authors developed and validated an improved query (Ti) to identify TOI across numerous settings in a large health system, using EHR data, during the COVID-19 pandemic. Further, they evaluated the affect of Ti on peri-intubation patient parameters compared to a previous method-ventilator parameters (Tv). Ti identified an earlier TOI for 84.8% (n = 1666) of cases with a mean (SD) of 3.5 hours (15.5), resulting in alternate values for: partial pressure of arterial oxygen (PaO2) in 18.4% of patients (mean 43.95 mmHg [54.24]); PaO2/fractional inspired oxygen (FiO2) in 17.8% of patients (mean 48.29 [69.81]), and oxygen saturation/FiO2 in 62.7% (mean 16.75 [34.14]), using the absolute difference in mean values within the first 4 hours of intubation. Differences in PaO2/FiO2 using Ti versus Tv resulted in the reclassification of 7.3% of patients into different acute respiratory distress syndrome (ARDS) severity categories.

3.
Clin Infect Dis ; 2022 Feb 26.
Article in English | MEDLINE | ID: covidwho-1713627

ABSTRACT

BACKGROUND: Open-label platform trials and a prospective meta-analysis suggest efficacy of anti-IL-6R therapies in hospitalized patients with COVID-19 receiving corticosteroids. This study evaluated the efficacy and safety of sarilumab, an anti-IL-6R monoclonal antibody, in the treatment of hospitalized patients with COVID-19. METHODS: In this adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial, adults hospitalized with COVID-19 (ClinicalTrials.gov: NCT04315298) received intravenous sarilumab or placebo. The phase 3 primary analysis population included patients with critical COVID-19 receiving mechanical ventilation randomized to sarilumab 400 mg or placebo. The primary outcome was proportion of patients with ≥1-point improvement in clinical status from baseline to day 22. RESULTS: There were 457 and 1365 patients randomized and treated in phases 2 and 3, respectively. In phase 3, patients with critical COVID-19 receiving mechanical ventilation (n = 298; 28.2% on corticosteroids), the proportion with ≥1-point improvement in clinical status (alive, not receiving mechanical ventilation) at day 22 was 43.2% in sarilumab and 35.5% in placebo (risk difference +7.5%; 95% CI, -7.4 to 21.3; P = .3261), a relative risk improvement of 21.7%. In post-hoc analyses pooling phase 2 and 3 critical patients receiving mechanical ventilation, the hazard ratio for death in sarilumab versus placebo was 0.76 (95% CI, .51-1.13) overall and 0.49 (95% CI, .25-.94) in patients receiving corticosteroids at baseline. CONCLUSIONS: This study did not establish the efficacy of sarilumab in hospitalized patients with severe/critical COVID-19. Post-hoc analyses were consistent with other studies that found a benefit of sarilumab in patients receiving corticosteroids.

4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-306383

ABSTRACT

Background: Pulmonary vascular microthrombi have been proposed as a mechanism of COVID19 respiratory failure. We hypothesized that early administration of tissue-plasminogen activator(tPA) followed by therapeutic heparin would improve pulmonary function in these patients.Methods: Adults with COVID-19-induced respiratory failure were randomized May14, 2020-March 3, 2021 in two phases: Phase-1(n=36): control (standard-of-care) vs tPA-Bolus (50mg tPA IV-bolus followed by 7 days of heparin (goal aPTT=60-80s);Phase-2(n=14): control vs tPA-Drip (50 mg of tPA IV-bolus, followed by tPA drip 2mg/hr plus heparin 500U/hour over 24 hours, then heparin to maintain aPTT 60-80s/7 days). The primary outcome was PaO2/FiO2 improvement at 48 hours post-randomization. Secondary outcomes included: PaO2/FiO2 improvement>50% or PaO2/FiO2>=200 at 48hrs(COMPOSITE), ventilator-free days(VFD) and mortality.Findings: Fifty patients were randomized: Phase 1:17 control, 19 tPA-Bolus;Phase 2: 8 control, 6 tPA-Drip. There were no severe bleeding events in intervention groups. In tPA-Bolus patients, PaO2/FiO2 was significantly(p<0.017) higher than baseline at 6 through 168 hours post-randomization;controls experienced no significant improvements. Compared to controls, tPA-Bolus patients showed larger, but non-significant, improvements in PaO2/FiO2 at 48hours[16.9%(-8.3–36.8) vs 29.8%(4.5–88.7),p=0.11], resulting in more patients reaching the COMPOSITE outcome (11.8% vs 47.4%,p=0.03). Controls had less VFD[0.0(0.0–9.0) vs 12.0(0.0–19.0),p=0.11] and higher mortality(41.2% vs 21.1%,p=0.19) than tPA-Bolus patients, although not significantly. tPA-Drip patients did not experience benefit compared to simultaneously enrolled controls.Interpretation: The combination tPA-Bolus+heparin is safe in severe COVID-19 respiratory failure. A Phase 3 study is warranted given promising improvements in oxygenation, VFD, and mortality.Trial Registration: The trial was performed according to the Food and Drug Administration (FDA) Investigational New Drug regulations (IND 149634) and registered with ClinicalTrials.gov (NCT04357730).Funding: This investigator-initiated trial (NCT04357730) was funded by Genentech, Inc.Declaration of Interests: CDB, HBM, EEM, and MBY have patents pending related to both coagulation/fibrinolysis diagnostics and therapeutic fibrinolytics, and are passive co-founders and holds stock options in Thrombo Therapeutics, Inc. HBM and EEM have received grant support from Haemonetics and Instrumentation Laboratories. MBY has previously received a gift of Alteplase (tPA) from Genentech, and owns stock options as a co-founder of Merrimack Pharmaceuticals. CDB, HBM, EEM, JW, NH, DST, AS, and MBY have received research grant funding from Genentech. JW receives consulting fees from Camurus A. B.. All other authors have nothing to disclose.Ethics Approval Statement: All participating trial sites had study approval and oversight from their respective Institutional Review Boards. Due to the nature of the study, which enrolled critically ill patients on mechanical ventilation, informed consent for trial participation was obtained from each patient’s Legally Authorized Representative. An independent Data Safety Monitoring Board (DSMB) oversaw the safety of the trial with mandatory reviews at each interim analysis and for all suspected serious adverse events. Data were stored in a REDCap instrument sponsored by NIH/NCATS Colorado CTSA Grant Number UL1 TR002535.

5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-313137

ABSTRACT

Background:  Understanding heterogeneity seen in patients with COVIDARDS and comparing to non-COVIDARDS may inform tailored treatments.  Methods:  A multidisciplinary team of frontline clinicians and data scientists worked to create the Northwell COVIDARDS dataset (NorthCARDS) leveraging over 11,542 COVID-19 hospital admissions. The data was then summarized to examine descriptive differences based on clinically meaningful categories of lung compliance, and to examine trends in oxygenation. Findings:  Of the 1595 COVIDARDS patients in the NorthCARDS dataset, there were 538 (34·6%) who had very low lung compliance (<20ml/cmH 2 O), 982 (63·2%) with low-normal compliance (20-50ml/cmH 2 O), and 34 (2·2%) with high lung compliance (>50ml/cmH 2 O). The very low compliance group had double the median time to intubation compared to the low-normal group (107 hours (IQR 26·3, 238·3) vs. 37·9 hours (IQR 4·8, 90·7)). Overall, 67·5% (n=1049) of the patients died during the hospitalization. In comparison to non-COVIDARDS reports, there were less patients in the high compliance category (2.2%vs.12%, compliance ≥50mL/cmH20), and more patients with P/F ≤ 150 (57·8% vs. 45.6%). No correlation was apparent between lung compliance and P/F ratio. The Oxygenation Index was similar, (11·12(SD 5·67) vs.12·8(SD 10·8)). 1  

6.
BMC Pulm Med ; 22(1): 51, 2022 Feb 04.
Article in English | MEDLINE | ID: covidwho-1666648

ABSTRACT

BACKGROUND: Understanding heterogeneity seen in patients with COVIDARDS and comparing to non-COVIDARDS may inform tailored treatments. METHODS: A multidisciplinary team of frontline clinicians and data scientists worked to create the Northwell COVIDARDS dataset (NorthCARDS) leveraging over 11,542 COVID-19 hospital admissions. The data was then summarized to examine descriptive differences based on clinically meaningful categories of lung compliance, and to examine trends in oxygenation. FINDINGS: Of the 1536 COVIDARDS patients in the NorthCARDS dataset, there were 531 (34.6%) who had very low lung compliance (< 20 ml/cmH2O), 970 (63.2%) with low-normal compliance (20-50 ml/cmH2O), and 35 (2.2%) with high lung compliance (> 50 ml/cmH2O). The very low compliance group had double the median time to intubation compared to the low-normal group (107.3 h (IQR 25.8, 239.2) vs. 39.5 h (IQR 5.4, 91.6)). Overall, 68.8% (n = 1057) of the patients died during hospitalization. In comparison to non-COVIDARDS reports, there were less patients in the high compliance category (2.2% vs. 12%, compliance ≥ 50 mL/cmH20), and more patients with P/F ≤ 150 (59.8% vs. 45.6%). There is a statistically significant correlation between compliance and P/F ratio. The Oxygenation Index is the highest in the very low compliance group (12.51, SD(6.15)), and lowest in high compliance group (8.78, SD(4.93)). CONCLUSIONS: The respiratory system compliance distribution of COVIDARDS is similar to non-COVIDARDS. In some patients, there may be a relation between time to intubation and duration of high levels of supplemental oxygen treatment on trajectory of lung compliance.


Subject(s)
COVID-19/physiopathology , Hypoxia/virology , Lung/physiopathology , Respiratory Distress Syndrome/virology , Adult , Aged , Aged, 80 and over , Biomechanical Phenomena , COVID-19/therapy , Case-Control Studies , Disease Progression , Female , Humans , Hypoxia/physiopathology , Hypoxia/therapy , Male , Middle Aged , Respiration, Artificial , Respiratory Distress Syndrome/physiopathology , Respiratory Distress Syndrome/therapy , Respiratory Function Tests , Retrospective Studies , Treatment Outcome
7.
Cureus ; 13(11): e19828, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1547691

ABSTRACT

Recent landmark trials have increased the use of sodium-glucose cotransporter 2 inhibitors (SGLT-2i) in patients with type 2 diabetes (T2D). A rare but serious side effect of SGLT-2i is euglycemic diabetic ketoacidosis (euDKA), which usually occurs in the setting of acute illness such as the coronavirus disease 2019 (COVID-19). We report a distinctive case of a patient with hyperlipidemia and T2D on SGLT-2i therapy who presented with hypertriglyceridemia-induced pancreatitis (HTGP) concurrently with euDKA and COVID-19. The patient's initial labs included venous blood gas pH of 7.27, a blood glucose level of 146 mg/dL, serum triglyceride (TG) greater than 8,300 mg/dL and lipase of 527 U/L. Viral polymerase chain reaction (PCR) result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was also positive. We suspect this patient has a primary disorder of lipoprotein metabolism which was exacerbated by stress from euDKA and COVID-19 infection. The patient was treated with intravenous fluids, fasting and intravenous insulin infusion. Resolution of euDKA and improvement of hypertriglyceridemia to less than 1,000 mg/dL occurred by day 6 and the patient was transitioned to subcutaneous basal-bolus insulin. On discharge, the SGLT-2i was discontinued and the patient was discharged on insulin, metformin, omega-3 fatty acids, and fenofibrate.

8.
Chest ; 161(3): 710-727, 2022 03.
Article in English | MEDLINE | ID: covidwho-1491838

ABSTRACT

BACKGROUND: Pulmonary vascular microthrombi are a proposed mechanism of COVID-19 respiratory failure. We hypothesized that early administration of tissue plasminogen activator (tPA) followed by therapeutic heparin would improve pulmonary function in these patients. RESEARCH QUESTION: Does tPA improve pulmonary function in severe COVID-19 respiratory failure, and is it safe? STUDY DESIGN AND METHODS: Adults with COVID-19-induced respiratory failure were randomized from May14, 2020 through March 3, 2021, in two phases. Phase 1 (n = 36) comprised a control group (standard-of-care treatment) vs a tPA bolus (50-mg tPA IV bolus followed by 7 days of heparin; goal activated partial thromboplastin time [aPTT], 60-80 s) group. Phase 2 (n = 14) comprised a control group vs a tPA drip (50-mg tPA IV bolus, followed by tPA drip 2 mg/h plus heparin 500 units/h over 24 h, then heparin to maintain aPTT of 60-80 s for 7 days) group. Patients were excluded from enrollment if they had not undergone a neurologic examination or cross-sectional brain imaging within the previous 4.5 h to rule out stroke and potential for hemorrhagic conversion. The primary outcome was Pao2 to Fio2 ratio improvement from baseline at 48 h after randomization. Secondary outcomes included Pao2 to Fio2 ratio improvement of > 50% or Pao2 to Fio2 ratio of ≥ 200 at 48 h (composite outcome), ventilator-free days (VFD), and mortality. RESULTS: Fifty patients were randomized: 17 in the control group and 19 in the tPA bolus group in phase 1 and eight in the control group and six in the tPA drip group in phase 2. No severe bleeding events occurred. In the tPA bolus group, the Pao2 to Fio2 ratio values were significantly (P < .017) higher than baseline at 6 through 168 h after randomization; the control group showed no significant improvements. Among patients receiving a tPA bolus, the percent change of Pao2 to Fio2 ratio at 48 h (16.9% control [interquartile range (IQR), -8.3% to 36.8%] vs 29.8% tPA bolus [IQR, 4.5%-88.7%]; P = .11), the composite outcome (11.8% vs 47.4%; P = .03), VFD (0.0 [IQR, 0.0-9.0] vs 12.0 [IQR, 0.0-19.0]; P = .11), and in-hospital mortality (41.2% vs 21.1%; P = .19) did not reach statistically significant differences when compared with those of control participants. The patients who received a tPA drip did not experience benefit. INTERPRETATION: The combination of tPA bolus plus heparin is safe in severe COVID-19 respiratory failure. A phase 3 study is warranted given the improvements in oxygenation and promising observations in VFD and mortality. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04357730; URL: www. CLINICALTRIALS: gov.


Subject(s)
COVID-19/complications , Pandemics , Respiratory Insufficiency/drug therapy , SARS-CoV-2 , Thrombosis/complications , Tissue Plasminogen Activator/administration & dosage , Adolescent , Adult , Aged , COVID-19/blood , COVID-19/epidemiology , Cross-Sectional Studies , Female , Fibrinolytic Agents/administration & dosage , Follow-Up Studies , Humans , Male , Middle Aged , Partial Thromboplastin Time , Respiratory Insufficiency/blood , Respiratory Insufficiency/etiology , Retrospective Studies , Thrombosis/blood , Thrombosis/drug therapy , Treatment Outcome , Young Adult
9.
J Cardiothorac Vasc Anesth ; 2021 Oct 16.
Article in English | MEDLINE | ID: covidwho-1467153

ABSTRACT

OBJECTIVE: To develop a practical thromboelastograph guided (TEG) anticoagulation protocol to guide the management of COVID-19 critically ill patients. DESIGN: An inter disciplinary team reviewed the current literature on hypercoagulability in critically ill COVID-19 patients, clinical management practices and challenges with high rates of thrombotic events despite anticoagulant therapies. SETTING: The largest tertiary care hospital within the Northwell Health System in New York. PATIENTS: COVID-19 invasively mechanically ventilated patients in Medical Intensive Care Unit Settings. METHODS: TEG was monitored in critically ill COVID-19 patients. Patterns were reviewed to guide the development of a treatment protocol leveraging TEG parameters to select anticoagulant therapy. Three patients are reported to highlight TEG profiles that led to the development of the algorithm. Clinical trajectory and treatment decisions were extracted retrospectively from the Electronic Health Record, with input from the intensivists. Anticoagulant use, laboratory and TEG values, and venous/arterial lower extremity (LE) ultrasound results were recorded. MAIN RESULTS: These patients demonstrated hypercoagulable TEG results despite prophylactic or therapeutic dosages of unfractionated heparin or low-molecular-weight heparin (LMHW). TEG surveillance identified functional fibrinogen and maximum amplitude in high-risk patients with hyper inflammatory markers. Anticoagulation assessment, TEG parameters, and LE ultrasound monitoring for venous and arterial thrombus were used to construct an algorithm to guide and escalate anticoagulant therapy. CONCLUSIONS: TEG provides patient-specific evidence for a hypercoagulable state in patients receiving all types of anticoagulant therapy. The proposed TEG algorithm guides anticoagulation management decisions to maintain or escalate anticoagulant dose and/or change choice of anticoagulant. A TEG algorithm may help negotiate the potential harm/benefit balance of full-dose anticoagulation in critically ill COVID-19 patients, by allowing for a more individualized approach that goes beyond the review of activated partial thromboplastin time (aPTT) levels.

10.
11.
J Thromb Haemost ; 18(7): 1752-1755, 2020 07.
Article in English | MEDLINE | ID: covidwho-1317980

ABSTRACT

A prothrombotic coagulopathy is commonly found in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS). A unique feature of COVID-19 respiratory failure is a relatively preserved lung compliance and high Alveolar-arterial oxygen gradient, with pathology reports consistently demonstrating diffuse pulmonary microthrombi on autopsy, all consistent with a vascular occlusive etiology of respiratory failure rather than the more classic findings of low-compliance in ARDS. The COVID-19 pandemic is overwhelming the world's medical care capacity with unprecedented needs for mechanical ventilators and high rates of mortality once patients progress to needing mechanical ventilation, and in many environments including in parts of the United States the medical capacity is being exhausted. Fibrinolytic therapy has previously been used in a Phase 1 clinical trial that led to reduced mortality and marked improvements in oxygenation. Here we report a series of three patients with severe COVID-19 respiratory failure who were treated with tissue plasminogen activator. All three patients had a temporally related improvement in their respiratory status, with one of them being a durable response.


Subject(s)
Betacoronavirus/pathogenicity , Blood Coagulation Disorders/drug therapy , Coronavirus Infections/drug therapy , Fibrinolysis/drug effects , Fibrinolytic Agents/administration & dosage , Pneumonia, Viral/drug therapy , Thrombolytic Therapy , Tissue Plasminogen Activator/administration & dosage , Aged , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/diagnosis , Blood Coagulation Disorders/virology , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Fatal Outcome , Female , Fibrinolytic Agents/adverse effects , Host-Pathogen Interactions , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Recovery of Function , SARS-CoV-2 , Thrombolytic Therapy/adverse effects , Tissue Plasminogen Activator/adverse effects , Treatment Outcome
12.
Res Pract Thromb Haemost ; 2020 May 21.
Article in English | MEDLINE | ID: covidwho-1184616

ABSTRACT

BACKGROUND: The COVID-19 pandemic has caused a large surge of acute respiratory distress syndrome (ARDS). Prior phase I trials (non COVID-19) demonstrated improvement in pulmonary function in ARDS patients using fibrinolytic therapy. A follow-up trial using the widely available tissue-plasminogen activator (alteplase) is now needed to assess optimal dosing and safety in this critically ill patient population. OBJECTIVE: To describe the design and rationale of a Phase IIa trial to evaluate the safety and efficacy of alteplase treatment for moderate/severe COVID-19-induced ARDS. PATIENTS/METHODS: A rapidly adaptive, pragmatic, open label, randomized, controlled, phase IIa clinical trial will be conducted with three groups: intravenous(IV) alteplase 50mg, IV alteplase 100mg, and control (standard-of-care). Inclusion criteria are known/suspected COVID-19 infection with PaO2/FiO2 ratio<150mmHg for >4 hours despite maximal mechanical ventilation management. Alteplase will be delivered through an initial bolus of 50mg or 100mg followed by heparin infusion for systemic anticoagulation, with alteplase re-dosing if there is a >20% PaO2/FiO2 improvement not sustained by 24 hours. RESULTS: The primary outcome is improvement in PaO2/FiO2 at 48 hours post-randomization. Other outcomes include: ventilator- and ICU-free-days, successful extubation (no reintubation ≤3 days after initial extubation), and mortality. Fifity eligible patients will be enrolled in a rapidly adaptive, modified stepped-wedge design with four looks at the data. CONCLUSION: Findings will provide timely information on the safety, efficacy and optimal dosing of tPA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial. (NCT04357730; FDA IND 149634).

13.
Arch Rehabil Res Clin Transl ; 3(2): 100113, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1086766

ABSTRACT

OBJECTIVE: To optimize the ability of hospitalized patients isolated because of coronavirus disease 2019 (COVID-19) to participate in physical therapy (PT). DESIGN: This was a prospective quality improvement trial of the feasibility and acceptability of a "hybrid" in-person and telerehabilitation platform to deliver PT to hospitalized adults. SETTING: Inpatient wards of a tertiary care, multispecialty academic medical center in the greater New York City metropolitan area. PARTICIPANTS: A convenience sample of 39 COVID-19-positive adults (mean age, 57.3y; 69% male) all previously community dwelling agreed to participate in a combination of in-person and telerehabilitation sessions (N=39). INTERVENTIONS: Initial in-person evaluation by physical therapist followed by twice daily PT sessions, 1 in-person and 1 via a telehealth platform meeting Health Insurance Portability and Accountability Act confidentiality requirements. The communication platform was downloaded to each participant's personal smart device to establish audiovisual contact with the physical therapist. MAIN OUTCOME MEASURES: We used the 6-clicks Activity Measure of Post-Acute Care (AM-PAC) to score self-reported functional status premorbidly and by the therapist at baseline and discharge. RESULTS: Functional status measured by AM-PAC 6-clicks demonstrated improvement from admission to discharge. Barriers to participation were identified and strategies were planned to facilitate use of the platform in the future. CONCLUSIONS: A consistent and structured protocol for engaging patient participation in PT delivered via a telehealth platform was successfully developed. A process was put in place to allow for further development, recruitment, and testing in a randomized trial.

14.
Chest ; 159(3): 933-948, 2021 03.
Article in English | MEDLINE | ID: covidwho-1064923

ABSTRACT

BACKGROUND: Cytokine storm is a marker of coronavirus disease 2019 (COVID-19) illness severity and increased mortality. Immunomodulatory treatments have been repurposed to improve mortality outcomes. RESEARCH QUESTION: Do immunomodulatory therapies improve survival in patients with COVID-19 cytokine storm (CCS)? STUDY DESIGN AND METHODS: We conducted a retrospective analysis of electronic health records across the Northwell Health system. COVID-19 patients hospitalized between March 1, 2020, and April 24, 2020, were included. CCS was defined by inflammatory markers: ferritin, > 700 ng/mL; C-reactive protein (CRP), > 30 mg/dL; or lactate dehydrogenase (LDH), > 300 U/L. Patients were subdivided into six groups: no immunomodulatory treatment (standard of care) and five groups that received either corticosteroids, anti-IL-6 antibody (tocilizumab), or anti-IL-1 therapy (anakinra) alone or in combination with corticosteroids. The primary outcome was hospital mortality. RESULTS: Five thousand seven hundred seventy-six patients met the inclusion criteria. The most common comorbidities were hypertension (44%-59%), diabetes (32%-46%), and cardiovascular disease (5%-14%). Patients most frequently met criteria with high LDH (76.2%) alone or in combination, followed by ferritin (63.2%) and CRP (8.4%). More than 80% of patients showed an elevated D-dimer. Patients treated with corticosteroids and tocilizumab combination showed lower mortality compared with patients receiving standard-of-care (SoC) treatment (hazard ratio [HR], 0.44; 95% CI, 0.35-0.55; P < .0001) and with patients treated with corticosteroids alone (HR, 0.66; 95% CI, 0.53-0.83; P = .004) or in combination with anakinra (HR, 0.64; 95% CI, 0.50-0.81; P = .003). Corticosteroids when administered alone (HR, 0.66; 95% CI, 0.57-0.76; P < .0001) or in combination with tocilizumab (HR, 0.43; 95% CI, 0.35-0.55; P < .0001) or anakinra (HR, 0.68; 95% CI, 0.57-0.81; P < .0001) improved hospital survival compared with SoC treatment. INTERPRETATION: The combination of corticosteroids with tocilizumab showed superior survival outcome when compared with SoC treatment as well as treatment with corticosteroids alone or in combination with anakinra. Furthermore, corticosteroid use either alone or in combination with tocilizumab or anakinra was associated with reduced hospital mortality for patients with CCS compared with patients receiving SoC treatment.


Subject(s)
Adrenal Cortex Hormones/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , COVID-19 , Cytokine Release Syndrome , Immunomodulation , Interleukin 1 Receptor Antagonist Protein/administration & dosage , COVID-19/immunology , COVID-19/mortality , COVID-19/therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/therapy , Cytokine Release Syndrome/virology , Drug Repositioning , Drug Therapy, Combination/methods , Electronic Health Records/statistics & numerical data , Humans , Immunosuppressive Agents/administration & dosage , Medication Therapy Management/statistics & numerical data , Middle Aged , Outcome and Process Assessment, Health Care , Retrospective Studies , SARS-CoV-2/immunology , Severity of Illness Index , Survival Analysis , United States/epidemiology
15.
Eur J Gastroenterol Hepatol ; 33(1S Suppl 1): e42-e49, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1010682

ABSTRACT

Liver dysfunction manifesting as elevated aminotransferase levels has been a common feature of coronavirus disease-2019 (COVID-19) infection. The mechanism of liver injury in COVID-19 infection is unclear. However, it has been hypothesized to be a result of direct cytopathic effects of the virus, immune dysfunction and cytokine storm-related multiorgan damage, hypoxia-reperfusion injury and idiosyncratic drug-induced liver injury due to medications used in the management of COVID-19. The favored hypothesis regarding the pathophysiology of liver injury in the setting of COVID-19 is cytokine storm, an aberrant and unabated inflammatory response leading to hyperproduction of cytokines. In the current review, we have summarized the potential pathophysiologic mechanisms of cytokine-induced liver injury based on the reported literature.


Subject(s)
COVID-19 , Cytokine Release Syndrome , Liver Diseases/virology , COVID-19/complications , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/virology , Cytokines , Humans
17.
Arthritis Rheumatol ; 73(1): 23-35, 2021 01.
Article in English | MEDLINE | ID: covidwho-757767

ABSTRACT

The clinical progression of the severe acute respiratory syndrome coronavirus 2 infection, coronavirus 2019 (COVID-19), to critical illness is associated with an exaggerated immune response, leading to magnified inflammation termed the "cytokine storm." This response is thought to contribute to the pathogenicity of severe COVID-19. There is an initial weak interferon response and macrophage activation that results in delayed neutrophil recruitment leading to impeded viral clearance. This causes prolonged immune stimulation and the release of proinflammatory cytokines. Elevated inflammatory markers in COVID-19 (e.g., d-dimer, C-reactive protein, lactate dehydrogenase, ferritin, and interleukin-6) are reminiscent of the cytokine storm seen in severe hyperinflammatory macrophage disorders. The dysfunctional immune response in COVID-19 also includes lymphopenia, reduced T cells, reduced natural killer cell maturation, and unmitigated plasmablast proliferation causing aberrant IgG levels. The progression to severe disease is accompanied by endotheliopathy, immunothrombosis, and hypercoagulability. Thus, both parts of the immune system-innate and adaptive-play a significant role in the cytokine storm, multiorgan dysfunction, and coagulopathy. This review highlights the importance of understanding the immunologic mechanisms of COVID-19 as they inform the clinical presentation and advise potential therapeutic targets.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , Cytokine Release Syndrome/immunology , Immunity, Innate/immunology , Respiratory Distress Syndrome/immunology , Antibody Formation , Antiviral Agents/therapeutic use , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/blood , COVID-19/drug therapy , COVID-19/physiopathology , Complement Inactivating Agents/therapeutic use , Cytokines/antagonists & inhibitors , Cytokines/immunology , Endothelium, Vascular/immunology , Endothelium, Vascular/physiopathology , Humans , Immunity, Humoral/immunology , Immunoglobulin G/immunology , Immunologic Factors/therapeutic use , Immunologic Memory , Immunosuppressive Agents/therapeutic use , Interferons/immunology , Killer Cells, Natural/immunology , Lymphopenia/immunology , Macrophage Activation/immunology , Neutrophil Infiltration/immunology , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/immunology , Thrombophilia/blood , Thrombophilia/immunology , Thrombosis/blood , Thrombosis/immunology
19.
Diagn Progn Res ; 4: 11, 2020.
Article in English | MEDLINE | ID: covidwho-324393

ABSTRACT

BACKGROUND: The need for life-saving interventions such as mechanical ventilation may threaten to outstrip resources during the Covid-19 pandemic. Allocation of these resources to those most likely to benefit can be supported by clinical prediction models. The ethical and practical considerations relevant to predictions supporting decisions about microallocation are distinct from those that inform shared decision-making in ways important for model design. MAIN BODY: We review three issues of importance for microallocation: (1) Prediction of benefit (or of medical futility) may be technically very challenging; (2) When resources are scarce, calibration is less important for microallocation than is ranking to prioritize patients, since capacity determines thresholds for resource utilization; (3) The concept of group fairness, which is not germane in shared decision-making, is of central importance in microallocation. Therefore, model transparency is important. CONCLUSION: Prediction supporting allocation of life-saving interventions should be explicit, data-driven, frequently updated and open to public scrutiny. This implies a preference for simple, easily understood and easily applied prognostic models.

20.
JAMA ; 323(20): 2052-2059, 2020 05 26.
Article in English | MEDLINE | ID: covidwho-101977

ABSTRACT

Importance: There is limited information describing the presenting characteristics and outcomes of US patients requiring hospitalization for coronavirus disease 2019 (COVID-19). Objective: To describe the clinical characteristics and outcomes of patients with COVID-19 hospitalized in a US health care system. Design, Setting, and Participants: Case series of patients with COVID-19 admitted to 12 hospitals in New York City, Long Island, and Westchester County, New York, within the Northwell Health system. The study included all sequentially hospitalized patients between March 1, 2020, and April 4, 2020, inclusive of these dates. Exposures: Confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by positive result on polymerase chain reaction testing of a nasopharyngeal sample among patients requiring admission. Main Outcomes and Measures: Clinical outcomes during hospitalization, such as invasive mechanical ventilation, kidney replacement therapy, and death. Demographics, baseline comorbidities, presenting vital signs, and test results were also collected. Results: A total of 5700 patients were included (median age, 63 years [interquartile range {IQR}, 52-75; range, 0-107 years]; 39.7% female). The most common comorbidities were hypertension (3026; 56.6%), obesity (1737; 41.7%), and diabetes (1808; 33.8%). At triage, 30.7% of patients were febrile, 17.3% had a respiratory rate greater than 24 breaths/min, and 27.8% received supplemental oxygen. The rate of respiratory virus co-infection was 2.1%. Outcomes were assessed for 2634 patients who were discharged or had died at the study end point. During hospitalization, 373 patients (14.2%) (median age, 68 years [IQR, 56-78]; 33.5% female) were treated in the intensive care unit care, 320 (12.2%) received invasive mechanical ventilation, 81 (3.2%) were treated with kidney replacement therapy, and 553 (21%) died. As of April 4, 2020, for patients requiring mechanical ventilation (n = 1151, 20.2%), 38 (3.3%) were discharged alive, 282 (24.5%) died, and 831 (72.2%) remained in hospital. The median postdischarge follow-up time was 4.4 days (IQR, 2.2-9.3). A total of 45 patients (2.2%) were readmitted during the study period. The median time to readmission was 3 days (IQR, 1.0-4.5) for readmitted patients. Among the 3066 patients who remained hospitalized at the final study follow-up date (median age, 65 years [IQR, 54-75]), the median follow-up at time of censoring was 4.5 days (IQR, 2.4-8.1). Conclusions and Relevance: This case series provides characteristics and early outcomes of sequentially hospitalized patients with confirmed COVID-19 in the New York City area.


Subject(s)
Betacoronavirus , Comorbidity , Coronavirus Infections/epidemiology , Pneumonia, Viral/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19 , Child , Child, Preschool , Coronavirus Infections/complications , Coronavirus Infections/mortality , Diabetes Complications , Female , Hospitalization , Humans , Hypertension/complications , Infant , Infant, Newborn , Male , Middle Aged , New York City/epidemiology , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/mortality , Risk Factors , SARS-CoV-2 , Treatment Outcome , Young Adult
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