Direct capture of neutralized RBD enables rapid point-of-care assessment of SARS-CoV-2 neutralizing antibody titer.

Neutralizing antibody (NAb) titer is a key biomarker of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but point-of-care methods for assessing NAb titer are not widely available. Here, we present a lateral flow assay that captures SARS-CoV-2 receptor-binding domain (RBD) that has been neutralized from binding angiotensin-converting enzyme 2 (ACE2). Quantification of neutralized RBD in this assay correlates with NAb titer from vaccinated and convalescent patients. This methodology demonstrated superior performance in assessing NAb titer compared with either measurement of total anti-spike immunoglobulin G titer or quantification of the absolute reduction in binding between ACE2 and RBD. Our testing platform has the potential for mass deployment to aid in determining at population scale the degree of protective immunity individuals may have following SARS-CoV-2 vaccination or infection and can enable simple at-home assessment of NAb titer.

Study of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19: A Vanguard Multicenter, Rapidly Adaptive, Pragmatic, Randomized Controlled Trial.

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.

Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): A case series.

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.

Study of alteplase for respiratory failure in severe acute respiratory syndrome coronavirus 2/COVID-19: Study design of the phase IIa STARS trial.

Background: The coronavirus disease 2019 (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 patients ARDS using fibrinolytic therapy. A follow-up trial using the widely available tissue-type plasminogen activator (t-PA) 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 3 groups: intravenous alteplase 50 mg, intravenous alteplase 100 mg, and control (standard-of-care). Inclusion criteria are known/suspected COVID-19 infection with PaO2/FiO2 ratio <150 mm Hg for > 4 hours despite maximal mechanical ventilation management. Alteplase will be delivered through an initial bolus of 50 mg or 100 mg followed by heparin infusion for systemic anticoagulation, with alteplase redosing 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 after randomization. Other outcomes include ventilator- and intensive care unit-free days, successful extubation (no reintubation ≤3 days after initial extubation), and mortality. Fifty eligible patients will be enrolled in a rapidly adaptive, modified stepped-wedge design with 4 looks at the data. Conclusion: Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).

COVID-19: All the wrong moves in all the wrong places.

In this Editorial, Barrett and Yaffe highlight shortcomings in our collective response to the COVID-19 pandemic and underscore the need for more basic research into this new disease.

Development of Rapid Response Capabilities in a Large COVID-19 Alternate Care Site Using Failure Modes and Effect Analysis with In Situ Simulation.

Preparedness measures for the anticipated surge of coronavirus disease 2019 (COVID-19) cases within eastern Massachusetts included the establishment of alternate care sites (field hospitals). Boston Hope hospital was set up within the Boston Convention and Exhibition Center to provide low-acuity care for COVID-19 patients and to support local healthcare systems. However, early recognition of the need to provide higher levels of care, or critical care for the potential deterioration of patients recovering from COVID-19, prompted the development of a hybrid acute care-intensive care unit. We describe our experience of implementing rapid response capabilities of this innovative ad hoc unit. Combining quality improvement tools for hazards detection and testing through in situ simulation successfully identified several operational hurdles. Through rapid continuous analysis and iterative change, we implemented appropriate mitigation strategies and established rapid response and rescue capabilities. This study provides a framework for future planning of high-acuity services within a unique field hospital setting.

Fibrinolytic therapy for refractory COVID-19 acute respiratory distress syndrome: Scientific rationale and review.

The coronavirus disease 2019 (COVID-19) pandemic has caused respiratory failure and associated mortality in numbers that have overwhelmed global health systems. Thrombotic coagulopathy is present in nearly three quarters of patients with COVID-19 admitted to the intensive care unit, and both the clinical picture and pathologic findings are consistent with microvascular occlusive phenomena being a major contributor to their unique form of respiratory failure. Numerous studies are ongoing focusing on anticytokine therapies, antibiotics, and antiviral agents, but none to date have focused on treating the underlying thrombotic coagulopathy in an effort to improve respiratory failure in COVID-19. There are animal data and a previous human trial demonstrating a survival advantage with fibrinolytic therapy to treat acute respiratory distress syndrome. Here, we review the extant and emerging literature on the relationship between thrombotic coagulopathy and pulmonary failure in the context of COVID-19 and present the scientific rationale for consideration of targeting the coagulation and fibrinolytic systems to improve pulmonary function in these patients.

Salvage use of tissue plasminogen activator (tPA) in the setting of acute respiratory distress syndrome (ARDS) due to COVID-19 in the USA: a Markov decision analysis.

BACKGROUND: COVID-19 threatens to quickly overwhelm our existing critical care infrastructure in the USA. Systemic tissue plasminogen activator (tPA) has been previously demonstrated to improve PaO2/FiO2 (mmHg) when given to critically ill patients with acute respiratory distress syndrome (ARDS). It is unclear to what extent tPA may impact population-based survival during the current US COVID-19 pandemic. METHODS: A decision analytic Markov state transition model was created to simulate the life critically ill COVID-19 patients as they transitioned to either recovery or death. Two patient groups were simulated (50,000 patients in each group); (1) Patients received tPA immediately upon diagnosis of ARDS and (2) patients received standard therapy for ARDS. Base case critically ill COVID-19 patients were defined as having a refractory PaO2/FiO2 of < 60 mmHg (salvage use criteria). Transition from severe to moderate to mild ARDS, recovery, and death were estimated. Markov model parameters were extracted from existing ARDS/COVID-19 literature. RESULTS: The use of tPA was associated with reduced mortality (47.6% [tTPA] vs. 71.0% [no tPA]) for base case patients. When extrapolated to the projected COVID-19 eligible for salvage use tPA in the USA, peak mortality (deaths/100,000 patients) was reduced for both optimal social distancing (70.5 [tPA] vs. 75.0 [no tPA]) and no social distancing (158.7 [tPA] vs. 168.8 [no tPA]) scenarios. CONCLUSIONS: Salvage use of tPA may improve recovery of ARDS patients, thereby reducing COVID-19-related mortality and ensuring sufficient resources to manage this pandemic.