Responses to a Neutralizing Monoclonal Antibody for Hospitalized Patients With COVID-19 According to Baseline Antibody and Antigen Levels : A Randomized Controlled Trial.

BACKGROUND: In a randomized, placebo-controlled, clinical trial, bamlanivimab, a SARS-CoV-2-neutralizing monoclonal antibody, given in combination with remdesivir, did not improve outcomes among hospitalized patients with COVID-19 based on an early futility assessment. OBJECTIVE: To evaluate the a priori hypothesis that bamlanivimab has greater benefit in patients without detectable levels of endogenous neutralizing antibody (nAb) at study entry than in those with antibodies, especially if viral levels are high. DESIGN: Randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04501978). SETTING: Multicenter trial. PATIENTS: Hospitalized patients with COVID-19 without end-organ failure. INTERVENTION: Bamlanivimab (7000 mg) or placebo. MEASUREMENTS: Antibody, antigen, and viral RNA levels were centrally measured on stored specimens collected at baseline. Patients were followed for 90 days for sustained recovery (defined as discharge to home and remaining home for 14 consecutive days) and a composite safety outcome (death, serious adverse events, organ failure, or serious infections). RESULTS: Among 314 participants (163 receiving bamlanivimab and 151 placebo), the median time to sustained recovery was 19 days and did not differ between the bamlanivimab and placebo groups (subhazard ratio [sHR], 0.99 [95% CI, 0.79 to 1.22]; sHR > 1 favors bamlanivimab). At entry, 50% evidenced production of anti-spike nAbs; 50% had SARS-CoV-2 nucleocapsid plasma antigen levels of at least 1000 ng/L. Among those without and with nAbs at study entry, the sHRs were 1.24 (CI, 0.90 to 1.70) and 0.74 (CI, 0.54 to 1.00), respectively (nominal P for interaction = 0.018). The sHR (bamlanivimab vs. placebo) was also more than 1 for those with plasma antigen or nasal viral RNA levels above median level at entry and was greatest for those without antibodies and with elevated levels of antigen (sHR, 1.48 [CI, 0.99 to 2.23]) or viral RNA (sHR, 1.89 [CI, 1.23 to 2.91]). Hazard ratios for the composite safety outcome (<1 favors bamlanivimab) also differed by serostatus at entry: 0.67 (CI, 0.37 to 1.20) for those without and 1.79 (CI, 0.92 to 3.48) for those with nAbs. LIMITATION: Subgroup analysis of a trial prematurely stopped because of futility; small sample size; multiple subgroups analyzed. CONCLUSION: Efficacy and safety of bamlanivimab may differ depending on whether an endogenous nAb response has been mounted. The limited sample size of the study does not allow firm conclusions based on these findings, and further independent trials are required that assess other types of passive immune therapies in the same patient setting. PRIMARY FUNDING SOURCE: U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.

Say No to This: Unilateral Do-Not-Resuscitate Orders for Patients with COVID-19.

In this article, we comment on Ciaffa's article 'The Ethics of Unilateral Do-Not-Resuscitate Orders for COVID-19 Patients.' We summarize his argument criticizing futility and utilitarianism as the key ethical justifications for unilateral do-not-resuscitate orders for patients with COVID-19.

Utility and futility of skin testing to address concerns surrounding messenger RNA coronavirus disease 2019 vaccine reactions.

BACKGROUND: The mechanism of coronavirus disease 2019 (COVID-19) vaccine hypersensitivity reactions is unknown. COVID-19 vaccine excipient skin testing has been used in evaluation of these reactions, but its utility in predicting subsequent COVID-19 vaccine tolerance is also unknown. OBJECTIVE: To evaluate the utility of COVID-19 vaccine and vaccine excipient skin testing in both patients with an allergic reaction to their first messenger RNA COVID-19 vaccine dose and patients with a history of polyethylene glycol allergy who have not yet received a COVID-19 vaccine dose. METHODS: In this multicenter, retrospective review, COVID-19 vaccine and vaccine excipient skin testing was performed in patients referred to 1 of 3 large tertiary academic institutions. Patient medical records were reviewed after skin testing to determine subsequent COVID-19 vaccine tolerance. RESULTS: A total of 129 patients underwent skin testing, in whom 12 patients (9.3%) had positive results. There were 101 patients who received a COVID-19 vaccine after the skin testing, which was tolerated in 90 patients (89.1%) with no allergic symptoms, including 5 of 6 patients with positive skin testing results who received a COVID-19 vaccine after the skin testing. The remaining 11 patients experienced minor allergic symptoms after COVID-19 vaccination, none of whom required treatment beyond antihistamines. CONCLUSION: The low positivity rate of COVID-19 vaccine excipient skin testing and high rate of subsequent COVID-19 vaccine tolerance suggest a low utility of this method in evaluation of COVID-19 vaccine hypersensitivity reactions. Focus should shift to the use of existing vaccine allergy practice parameters, with consideration of graded dosing when necessary. On the basis of these results, strict avoidance of subsequent COVID-19 vaccination should be discouraged.

Considering Futility of Care Decisions in Neurosurgical Practice.

Neurosurgeons commonly encounter futility of care decisions in their practice. Are these decisions being made with adequate consideration? What is the preparation of neurosurgical trainees for making these decisions? The advent of the COVID-19 pandemic with its extreme pressure on resources and, in particular, intensive care unit beds, has prompted many health care providers including neurosurgeons to consider more fully the potentially futile nature of some treatments and how we might better manage limited resources for the future. We review the concept of futility in neurosurgery and suggest potential solutions to the multiple challenges that arise.

The role of cardiovascular magnetic resonance in the screening before the return-to-play of elite athletes after COVID-19: utility o futility?

Recent reports based on cardiovascular magnetic resonance (CMR) showed a wide range of prevalence of inflammatory heart diseases in COVID-19 convalescent athletes ranging from 0.4 up to 15%. These observations had an important impact in the field of sport cardiology opening an intense debate around the best possible screening strategy before the return-to-play. The diagnostic yield of CMR for detecting acute inflammatory disease is undebatable. However, the opportunity to use it in the screening protocol after COVID-19 has been questioned. Current evidence does not seem to support the routine use of CMR and the prescription of CMR should be based upon clinical indication.

COVID-19-Related Ethics Consultations at a Cancer Center in New York City: A Content Review of Ethics Consultations During the Early Stages of the Pandemic.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has raised a variety of ethical dilemmas for health care providers. Limited data are available on how a patient's concomitant cancer diagnosis affected ethical concerns raised during the early stages of the pandemic. METHODS: We performed a retrospective review of all COVID-related ethics consultations registered in a prospectively collected ethics database at a tertiary cancer center between March 14, 2020, and April 28, 2020. Primary and secondary ethical issues, as well as important contextual factors, were identified. RESULTS: Twenty-six clinical ethics consultations were performed on 24 patients with cancer (58.3% male; median age, 65.5 years). The most common primary ethical issues were code status (n = 11), obligation to provide nonbeneficial treatment (n = 3), patient autonomy (n = 3), resource allocation (n = 3), and delivery of care wherein the risk to staff might outweigh the potential benefit to the patient (n = 3). An additional nine consultations raised concerns about staff safety in the context of likely nonbeneficial treatment as a secondary issue. Unique contextual issues identified included concerns about public safety for patients requesting discharge against medical advice (n = 3) and difficulties around decision making, especially with regard to code status because of an inability to reach surrogates (n = 3). CONCLUSION: During the early pandemic, the care of patients with cancer and COVID-19 spurred a number of ethics consultations, which were largely focused on code status. Most cases also raised concerns about staff safety in the context of limited benefit to patients, a highly unusual scenario at our institution that may have been triggered by critical supply shortages.

Resuscitating Patient Rights during the Pandemic: COVID-19 and the Risk of Resurgent Paternalism.

The COVID-19 Pandemic a stress test for clinical medicine and medical ethics, with a confluence over questions of the proportionality of resuscitation. Drawing upon his experience as a clinical ethicist during the surge in New York City during the Spring of 2020, the author considers how attitudes regarding resuscitation have evolved since the inception of do-not-resuscitate (DNR) orders decades ago. Sharing a personal narrative about a DNR quandry he encountered as a medical intern, the author considers the balance of patient rights versus clinical discretion, warning about the risk of resurgent physician paternalism dressed up in the guise of a public health crisis.

Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial.

Importance: Data on the efficacy of hydroxychloroquine or lopinavir-ritonavir for the treatment of high-risk outpatients with COVID-19 in developing countries are needed. Objective: To determine whether hydroxychloroquine or lopinavir-ritonavir reduces hospitalization among high-risk patients with early symptomatic COVID-19 in an outpatient setting. Design, Setting, and Participants: This randomized clinical trial was conducted in Brazil. Recently symptomatic adults diagnosed with respiratory symptoms from SARS-CoV-2 infection were enrolled between June 2 and September 30, 2020. The planned sample size was 1476 patients, with interim analyses planned after 500 patients were enrolled. The trial was stopped after the interim analysis for futility with a sample size of 685 patients. Statistical analysis was performed in December 2020. Interventions: Patients were randomly assigned to hydroxychloroquine (800 mg loading dose, then 400 mg daily for 9 days), lopinavir-ritonavir (loading dose of 800 mg and 200 mg, respectively, every 12 hours followed by 400 mg and 100 mg, respectively, every 12 hours for the next 9 days), or placebo. Main Outcomes and Measures: The primary outcomes were COVID-19-associated hospitalization and death assessed at 90 days after randomization. COVID-19-associated hospitalization was analyzed with a Cox proportional hazards model. The trial included the following secondary outcomes: all-cause hospitalization, viral clearance, symptom resolution, and adverse events. Results: Of 685 participants, 632 (92.3%) self-identified as mixed-race, 377 (55.0%) were women, and the median (range) age was 53 (18-94) years. A total of 214 participants were randomized to hydroxychloroquine; 244, lopinavir-ritonavir; and 227, placebo. At first interim analysis, the data safety monitoring board recommended stopping enrollment of both hydroxychloroquine and lopinavir-ritonavir groups because of futility. The proportion of patients hospitalized for COVID-19 was 3.7% (8 participants) in the hydroxychloroquine group, 5.7% (14 participants) in the lopinavir-ritonavir group, and 4.8% (11 participants) in the placebo group. We found no significant differences between interventions for COVID-19-associated hospitalization (hydroxychloroquine: hazard ratio [HR], 0.76 [95% CI, 0.30-1.88]; lopinavir-ritonavir: HR, 1.16 [95% CI, 0.53-2.56] as well as for the secondary outcome of viral clearance through day 14 (hydroxychloroquine: odds ratio [OR], 0.91 [95% CI, 0.82-1.02]; lopinavir-ritonavir: OR, 1.04 [95% CI, 0.94-1.16]). At the end of the trial, there were 3 fatalities recorded, 1 in the placebo group and 2 in the lopinavir-ritonavir intervention group. Conclusions and Relevance: In this randomized clinical trial, neither hydroxychloroquine nor lopinavir-ritonavir showed any significant benefit for decreasing COVID-19-associated hospitalization or other secondary clinical outcomes. This trial suggests that expedient clinical trials can be implemented in low-income settings even during the COVID-19 pandemic. Trial Registration: ClinicalTrials.gov Identifier: NCT04403100.

Prioritising 'already-scarce' intensive care unit resources in the midst of COVID-19: a call for regional triage committees in South Africa.

BACKGROUND: The worsening COVID-19 pandemic in South Africa poses multiple challenges for clinical decision making in the context of already-scarce ICU resources. Data from national government and the last published national audit of ICU resources indicate gross shortages. While the Critical Care Society of Southern Africa (CCSSA) guidelines provide a comprehensive guideline for triage in the face of overwhelmed ICU resources, such decisions present massive ethical and moral dilemmas for triage teams. It is therefore important for the health system to provide clinicians and critical care facilities with as much support and resources as possible in the face of impending pandemic demand. Following a discussion of the ethical considerations and potential challenges in applying the CCSSA guidelines, the authors propose a framework for regional triage committees adapted to the South African context. DISCUSSION: Beyond the national CCSSA guidelines, the clinician has many additional ethical and clinical considerations. No single ethical approach to decision-making is sufficient, instead one which considers multiple contextual factors is necessary. Scores such as the Clinical Frailty Score and Sequential Organ Failure Assessment are of limited use in patients with COVID-19. Furthermore, the clinician is fully justified in withdrawing ICU care based on medical futility decisions and to reallocate this resource to a patient with a better prognosis. However, these decisions bear heavy emotional and moral burden compounded by the volume of clinical work and a fear of litigation. CONCLUSION: We propose the formation of Provincial multi-disciplinary Critical Care Triage Committees to alleviate the emotional, moral and legal burden on individual ICU teams and co-ordinate inter-facility collaboration using an adapted framework. The committee would provide an impartial, broader and ethically-sound viewpoint which has time to consider broader contextual factors such as adjusting rationing criteria according to different levels of pandemic demand and the latest clinical evidence. Their functioning will be strengthened by direct feedback to national level and accountability to a national monitoring committee. The potential applications of these committees are far-reaching and have the potential to enable a more effective COVID-19 health systems response in South Africa.

External validation of multimodal termination of resuscitation rules for out-of-hospital cardiac arrest patients in the COVID-19 era.

BACKGROUND: Futile resuscitation for out-of-hospital cardiac arrest (OHCA) patients in the coronavirus disease (COVID)-19 era can lead to risk of disease transmission and unnecessary transport. Various existing basic or advanced life support (BLS or ALS, respectively) rules for the termination of resuscitation (TOR) have been derived and validated in North America and Asian countries. This study aimed to evaluate the external validation of these rules in predicting the survival outcomes of OHCA patients in the COVID-19 era. METHODS: This was a multicenter observational study using the WinCOVID-19 Daegu registry data collected during February 18-March 31, 2020. The subjects were patients who showed cardiac arrest of presumed cardiac etiology. The outcomes of each rule were compared to the actual patient survival outcomes. The sensitivity, specificity, false positive value (FPV), and positive predictive value (PPV) of each TOR rule were evaluated. RESULTS: In total, 170 of the 184 OHCA patients were eligible and evaluated. TOR was recommended for 122 patients based on the international basic life support termination of resuscitation (BLS-TOR) rule, which showed 85% specificity, 74% sensitivity, 0.8% FPV, and 99% PPV for predicting unfavorable survival outcomes. When the traditional BLS-TOR rules and KoCARC TOR rule II were applied to our registry, one patient met the TOR criteria but survived at hospital discharge. With regard to the FPV (upper limit of 95% confidence interval < 5%), specificity (100%), and PPV (> 99%) criteria, only the KoCARC TOR rule I, which included a combination of three factors including not being witnessed by emergency medical technicians, presenting with an asystole at the scene, and not experiencing prehospital shock delivery or return of spontaneous circulation, was found to be superior to all other TOR rules. CONCLUSION: Among the previous nine BLS and ALS TOR rules, KoCARC TOR rule I was most suitable for predicting poor survival outcomes and showed improved diagnostic performance. Further research on variations in resources and treatment protocols among facilities, regions, and cultures will be useful in determining the feasibility of TOR rules for COVID-19 patients worldwide.