Optimising the impact of COVID-19 vaccination on mortality and hospitalisations using an individual additive risk measuring approach based on a risk adjustment scheme.

In this population-based cohort study, billing data from German statutory health insurance (BARMER, 10% of population) are used to develop a prioritisation model for COVID-19 vaccinations based on cumulative underlying conditions. Using a morbidity-based classification system, prevalence and risks for COVID-19-related hospitalisations, ventilations and deaths are estimated. Trisomies, behavioural and developmental disorders (relative risk: 2.09), dementia and organic psychoorganic syndromes (POS) (2.23) and (metastasised) malignant neoplasms (1.99) were identified as the most important conditions for escalations of COVID-19 infection. Moreover, optimal vaccination priority schedules for participants are established on the basis of individual cumulative escalation risk and are compared to the prioritisation scheme chosen by the German Government. We estimate how many people would have already received a vaccination prior to escalation. Vaccination schedules based on individual cumulative risk are shown to be 85% faster than random schedules in preventing deaths, and as much as 57% faster than the German approach, which was based primarily on age and specific diseases. In terms of hospitalisation avoidance, the individual cumulative risk approach was 51% and 28% faster. On this basis, it is concluded that using individual cumulative risk-based vaccination schedules, healthcare systems can be relieved and escalations more optimally avoided.

Urgent Guidance for Navigating and Circumventing the QTc-Prolonging and Torsadogenic Potential of Possible Pharmacotherapies for Coronavirus Disease 19 (COVID-19).

As the coronavirus disease 19 (COVID-19) global pandemic rages across the globe, the race to prevent and treat this deadly disease has led to the "off-label" repurposing of drugs such as hydroxychloroquine and lopinavir/ritonavir, which have the potential for unwanted QT-interval prolongation and a risk of drug-induced sudden cardiac death. With the possibility that a considerable proportion of the world's population soon could receive COVID-19 pharmacotherapies with torsadogenic potential for therapy or postexposure prophylaxis, this document serves to help health care professionals mitigate the risk of drug-induced ventricular arrhythmias while minimizing risk of COVID-19 exposure to personnel and conserving the limited supply of personal protective equipment.

A systematic review of long-term care facility characteristics associated with COVID-19 outcomes.

BACKGROUND/OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has taken a disproportionate toll on long-term care facility residents and staff. Our objective was to review the empirical evidence on facility characteristics associated with COVID-19 cases and deaths. DESIGN: Systematic review. SETTING: Long-term care facilities (nursing homes and assisted living communities). PARTICIPANTS: Thirty-six empirical studies of factors associated with COVID-19 cases and deaths in long-term care facilities published between January 1, 2020 and June 15, 2021. MEASUREMENTS: Outcomes included the probability of at least one case or death (or other defined threshold); numbers of cases and deaths, measured variably. RESULTS: Larger, more rigorous studies were fairly consistent in their assessment of risk factors for COVID-19 outcomes in long-term care facilities. Larger bed size and location in an area with high COVID-19 prevalence were the strongest and most consistent predictors of facilities having more COVID-19 cases and deaths. Outcomes varied by facility racial composition, differences that were partially explained by facility size and community COVID-19 prevalence. More staff members were associated with a higher probability of any outbreak; however, in facilities with known cases, higher staffing was associated with fewer deaths. Other characteristics, such as Nursing Home Compare 5-star ratings, ownership, and prior infection control citations, did not have consistent associations with COVID-19 outcomes. CONCLUSION: Given the importance of community COVID-19 prevalence and facility size, studies that failed to control for these factors were likely confounded. Better control of community COVID-19 spread would have been critical for mitigating much of the morbidity and mortality long-term care residents and staff experienced during the pandemic. Traditional quality measures such as Nursing Home Compare 5-Star ratings and past deficiencies were not consistent indicators of pandemic preparedness, likely because COVID-19 presented a novel problem requiring extensive adaptation by both long-term care providers and policymakers.

A Randomized Open label Phase-II Clinical Trial with or without Infusion of Plasma from Subjects after Convalescence of SARS-CoV-2 Infection in High-Risk Patients with Confirmed Severe SARS-CoV-2 Disease (RECOVER): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Primary objectives • To assess the time from randomisation until an improvement within 84 days defined as two points on a seven point ordinal scale or live discharge from the hospital in high-risk patients (group 1 to group 4) with SARS-CoV-2 infection requiring hospital admission by infusion of plasma from subjects after convalescence of SARS-CoV-2 infection or standard of care. Secondary objectives • To assess overall survival, and the overall survival rate at 28 56 and 84 days. • To assess SARS-CoV-2 viral clearance and load as well as antibody titres. • To assess the percentage of patients that required mechanical ventilation. • To assess time from randomisation until discharge. TRIAL DESIGN: Randomised, open-label, multicenter phase II trial, designed to assess the clinical outcome of SARS-CoV-2 disease in high-risk patients (group 1 to group 4) following treatment with anti-SARS-CoV-2 convalescent plasma or standard of care. PARTICIPANTS: High-risk patients >18 years of age hospitalized with SARS-CoV-2 infection in 10-15 university medical centres will be included. High-risk is defined as SARS-CoV-2 positive infection with Oxygen saturation at ≤ 94% at ambient air with additional risk features as categorised in 4 groups: • Group 1, pre-existing or concurrent hematological malignancy and/or active cancer therapy (incl. chemotherapy, radiotherapy, surgery) within the last 24 months or less. • Group 2, chronic immunosuppression not meeting the criteria of group 1. • Group 3, age ≥ 50 - 75 years meeting neither the criteria of group 1 nor group 2 and at least one of these criteria: Lymphopenia < 0.8 x G/l and/or D-dimer > 1µg/mL. • Group 4, age ≥ 75 years meeting neither the criteria of group 1 nor group 2. Observation time for all patients is expected to be at least 3 months after entry into the study. Patients receive convalescent plasma for two days (day 1 and day 2) or standard of care. For patients in the standard arm, cross over is allowed from day 10 in case of not improving or worsening clinical condition. Nose/throat swabs for determination of viral load are collected at day 0 and day 1 (before first CP administration) and subsequently at day 2, 3, 5, 7, 10, 14, 28 or until discharge. Serum for SARS-Cov-2 diagnostic is collected at baseline and subsequently at day 3, 7, 14 and once during the follow-up period (between day 35 and day 84). There is a regular follow-up of 3 months. All discharged patients are followed by regular phone calls. All visits, time points and study assessments are summarized in the Trial Schedule (see full protocol Table 1). All participating trial sites will be supplied with study specific visit worksheets that list all assessments and procedures to be completed at each visit. All findings including clinical and laboratory data are documented by the investigator or an authorized member of the study team in the patient's medical record and in the electronic case report forms (eCRFs). INTERVENTION AND COMPARATOR: This trial will analyze the effects of convalescent plasma from recovered subjects with SARS-CoV-2 antibodies in high-risk patients with SARS-CoV-2 infection. Patients at high risk for a poor outcome due to underlying disease, age or condition as listed above are eligible for enrollment. In addition, eligible patients have a confirmed SARS-CoV-2 infection and O2 saturation ≤ 94% while breathing ambient air. Patients are randomised to receive (experimental arm) or not receive (standard arm) convalescent plasma in two bags (238 - 337 ml plasma each) from different donors (day 1, day 2). A cross over from the standard arm into the experimental arm is possible after day 10 in case of not improving or worsening clinical condition. MAIN OUTCOMES: Primary endpoints: The main purpose of the study is to assess the time from randomisation until an improvement within 84 days defined as two points on a seven-point ordinal scale or live discharge from the hospital in high-risk patients (group 1 to group 4) with SARS-CoV-2 infection requiring hospital admission by infusion of plasma from subjects after convalescence of a SARS-CoV-2 infection or standard of care. Secondary endpoints: • Overall survival, defined as the time from randomisation until death from any cause 28-day, 56-day and 84-day overall survival rates. • SARS-CoV-2 viral clearance and load as well as antibody titres. • Requirement mechanical ventilation at any time during hospital stay (yes/no). • Time until discharge from randomisation. • Viral load, changes in antibody titers and cytokine profiles are analysed in an exploratory manner using paired non-parametric tests (before - after treatment). RANDOMISATION: Upon confirmation of eligibility (patients must meet all inclusion criteria and must not meet exclusion criteria described in section 5.3 and 5.4 of the full protocol), the clinical site must contact a centralized internet randomization system ( https://randomizer.at/ ). Patients are randomized using block randomisation to one of the two arms, experimental arm or standard arm, in a 1:1 ratio considering a stratification according to the 4 risk groups (see Participants). BLINDING (MASKING): The study is open-label, no blinding will be performed. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total number of 174 patients is required for the entire trial, n=87 per group. TRIAL STATUS: Protocol version 1.2 dated 09/07/2020. A recruitment period of approximately 9 months and an overall study duration of approximately 12 months is anticipated. Recruitment of patients starts in the third quarter of 2020. The study duration of an individual patient is planned to be 3 months. After finishing all study-relevant procedures, therapy, and follow-up period, the patient is followed in terms of routine care and treated if necessary. Total trial duration: 18 months Duration of the clinical phase: 12 months First patient first visit (FPFV): 3rd Quarter 2020 Last patient first visit (LPFV): 2nd Quarter 2021 Last patient last visit (LPLV): 3rd Quarter 2021 Trial Report completed: 4th Quarter 2021 TRIAL REGISTRATION: EudraCT Number: 2020-001632-10, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001632-10/DE , registered on 04/04/2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2). The eCRF is attached (Additional file 3).

Discontinuation versus continuation of renin-angiotensin-system inhibitors in COVID-19 (ACEI-COVID): a prospective, parallel group, randomised, controlled, open-label trial.

BACKGROUND: SARS-CoV-2 entry in human cells depends on angiotensin-converting enzyme 2, which can be upregulated by inhibitors of the renin-angiotensin system (RAS). We aimed to test our hypothesis that discontinuation of chronic treatment with ACE-inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) mitigates the course o\f recent-onset COVID-19. METHODS: ACEI-COVID was a parallel group, randomised, controlled, open-label trial done at 35 centres in Austria and Germany. Patients aged 18 years and older were enrolled if they presented with recent symptomatic SARS-CoV-2 infection and were chronically treated with ACEIs or ARBs. Patients were randomly assigned 1:1 to discontinuation or continuation of RAS inhibition for 30 days. Primary outcome was the maximum sequential organ failure assessment (SOFA) score within 30 days, where death was scored with the maximum achievable SOFA score. Secondary endpoints were area under the death-adjusted SOFA score (AUCSOFA), mean SOFA score, admission to the intensive care unit, mechanical ventilation, and death. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT04353596. FINDINGS: Between April 20, 2020, and Jan 20, 2021, 204 patients (median age 75 years [IQR 66-80], 37% females) were randomly assigned to discontinue (n=104) or continue (n=100) RAS inhibition. Within 30 days, eight (8%) of 104 died in the discontinuation group and 12 (12%) of 100 patients died in the continuation group (p=0·42). There was no significant difference in the primary endpoint between the discontinuation and continuation group (median [IQR] maximum SOFA score 0·00 (0·00-2·00) vs 1·00 (0·00-3·00); p=0·12). Discontinuation was associated with a significantly lower AUCSOFA (0·00 [0·00-9·25] vs 3·50 [0·00-23·50]; p=0·040), mean SOFA score (0·00 [0·00-0·31] vs 0·12 [0·00-0·78]; p=0·040), and 30-day SOFA score (0·00 [10-90th percentile, 0·00-1·20] vs 0·00 [0·00-24·00]; p=0·023). At 30 days, 11 (11%) in the discontinuation group and 23 (23%) in the continuation group had signs of organ dysfunction (SOFA score ≥1) or were dead (p=0·017). There were no significant differences for mechanical ventilation (10 (10%) vs 8 (8%), p=0·87) and admission to intensive care unit (20 [19%] vs 18 [18%], p=0·96) between the discontinuation and continuation group. INTERPRETATION: Discontinuation of RAS-inhibition in COVID-19 had no significant effect on the maximum severity of COVID-19 but may lead to a faster and better recovery. The decision to continue or discontinue should be made on an individual basis, considering the risk profile, the indication for RAS inhibition, and the availability of alternative therapies and outpatient monitoring options. FUNDING: Austrian Science Fund and German Center for Cardiovascular Research.

How the COVID-19 pandemic can distort risk adjustment of health plan payment.

The COVID-19 pandemic has led to disruptions in healthcare utilization and spending. While some changes might persist (e.g. substitution of specialist visits by online consultations), others will be transitory (e.g. fewer surgical procedures due to cancellation of treatments). This paper discusses the implications of transitory changes in healthcare utilization and spending for risk adjustment of health plan payment. In practice, risk adjustment methodologies typically consist of two steps: (1) calibration of payment weights for a given set of risk adjusters and (2) calculation of payments to insurers by combining the calibrated weights with enrollee characteristics. In this paper, we first introduce a simple conceptual framework for analyzing the (potential) distortions from the pandemic for both steps and then provide a hypothetical illustration of how these distortions can lead to under- or overpayment of insurers. The size of these under-/overpayments depends on (1) the impact of the pandemic on patterns in utilization and spending, (2) the distribution of risk types across insurers, (3) the extent to which insurers are disproportionately affected by the pandemic, and (4) features of the risk adjustment system.

Raising awareness about the unintended consequences of hand sanitiser in children.

The use of hand sanitisers is common practice to prevent the spread of coronavirus disease 2019 (COVID-19). However, the safety thereof requires consideration as this may be hazardous in children. Recent studies have shown that the misuse and increased unsupervised availability of alcohol-based hand sanitisers may result in adverse events in children such as skin irritation, dryness, cracking and peeling. Unintentional or intentional ingestion of hand sanitisers in children under the age of 12 years may occur because of the colour, smell and flavour added to it. Consumption of alcohol in children may result in hypoglycaemia, apnoea and acidosis. This allows the invasion of other bacterial and viral infections. Children may also rub their eyes with sanitised hands and cause ocular injury. Therefore, the use of hand sanitisers in general needs to be revised in both children and adults. Other interventions on lowering the risk of adverse events because of misuse of hand sanitiser should be practised more often. These include promoting washing of hands over sanitisers where possible, training children on how to use hand sanitisers and creating awareness of the dangers if ingested or in contact with the eyes.

Safety and Feasibility of a Protocolized Daily Assessment of Readiness for Liberation From Venovenous Extracorporeal Membrane Oxygenation.

BACKGROUND: Decannulation from venovenous extracorporeal membrane oxygenation (ECMO) at the earliest and safest possible time may improve outcomes and reduce cost. Yet, no prospective studies have compared weaning strategies for liberation from ECMO. RESEARCH QUESTION: Is a protocolized daily assessment of readiness to liberate from venovenous ECMO safe and feasible? STUDY DESIGN AND METHODS: We conducted a prospective, single-arm safety and feasibility study of a protocol for daily assessment of readiness to liberate from venovenous ECMO among consecutive adult patients receiving venovenous ECMO across four ICUs at a single center between June 20, 2020, and November 24, 2020. The ECMO-free protocol included three phases: (1) the safety screening, (2) non-ECMO Fio2 titration, and (3) the ECMO-free trial. Enrollment, interventions, and data collection were performed prospectively by trained study staff. RESULTS: Twenty-six patients received the ECMO-free protocol on 385 patient-days. The safety screening was passed during a total of 59 ECMO-free daily assessments (15.3%) among 20 patients. Every passed safety screening proceeded to an ECMO-free trial. Twenty-eight passed ECMO-free trials (47.5%) occurred among 16 patients (61.5%). No missed safety screenings, protocol deviations, or adverse events occurred. Of the 16 patients who passed an ECMO-free trial, 14 patients (87.5%) were decannulated. Among decannulated patients, 12 patients (85.7%) were decannulated on the same day as a passed ECMO-free trial, 6 patients (42.9%) were decannulated on the first day that they passed an ECMO-free trial, and 6 patients (42.9%) passed an ECMO-free trial at least twice consecutively before decannulation. The median time from first passed ECMO-free trial to decannulation was 2 days (interquartile range, 0-3 days). INTERPRETATION: The ECMO-free protocol is feasible and may identify patients for decannulation earlier than gradual approaches to weaning.

Italian association for the study of the liver position statement on SARS-CoV2 vaccination.

The vaccination campaign against Sars-CoV-2 commenced in Italy at the end of December 2020. The first ones to receive the immunization against the virus were the health workers and the residents of nursing homes, following which the vaccine would be available for the entire population, beginning with the most vulnerable individuals. SARS-CoV2 vaccines have been demonstrated to be safe for the general population, although no data for patients with liver diseases or those having undergone liver transplantation are available so far. The present position statement AISF is an attempt to suggest, based on the published data on the impact of Sars-Cov-2 infection in patients with chronic liver disease, a possible priority for vaccination for this category of patients.

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.

Reintroduction of elective cardiac interventions in the era of COVID-19: the Barts experience.

BACKGROUND: The response to COVID-19 has required cancellation of all but the most urgent procedures; there is therefore a need for the reintroduction of a safe elective pathway. METHODS: This was a study of a pilot pathway performed at Barts Heart Centre for the admission of patients requiring elective coronary and structural procedures during the COVID-19 pandemic (April-June 2020). All patients on coronary and structural waiting lists were screened for procedural indications, urgency and adverse features for COVID-19 prognosis and discussed at dedicated multidisciplinary teams. Dedicated admission pathways involving preadmission isolation, additional consent, COVID-19 PCR testing and dedicated clean areas were used. RESULTS: 143 patients (101 coronary and 42 structural) underwent procedures (coronary angiography, percutaneous coronary intervention, transcatheter aortic valve intervention and MitralClip) during the study period. The average age was 68.2; 74% were male; and over 93% had one or more moderate COVID-19 risk factors. All patients were COVID-19 PCR negative on admission with (8.1%) COVID-19 antibody positive (swab negative). All procedures were performed successfully with low rates of procedural complications (9.8%). At 2-week follow-up, no patients had symptoms or confirmed COVID-19 infection with significant improvements in quality if life and symptoms. CONCLUSION: We demonstrated that patients undergoing coronary and structural procedures can be safely admitted during the COVID-19 pandemic, with no patients contracting COVID-19 during their admission. Reassuringly, patients reflective of typical practice, that is, those at moderate or higher risk, were treated successfully. This pilot provides important information applicable to other settings, specialties and areas to reintroduce services safely.

A review on medical management of inflammatory bowel disease during the coronavirus disease 2019 pandemic.

The coronavirus disease 2019 pandemic has engulfed the world and is the highlight of medical community at this time. As humanity fights the battle against this virus, questions are arising regarding the appropriate management of at risk patient populations. The immunocompromised cohort is particularly susceptible to this infection, and we have tried to explore the medical management of one such group, which is composed of individuals with inflammatory bowel disease (IBD). There is limited data on the management of IBD during the ongoing pandemic. Several medical societies have put forth suggestions on how to manage immunocompromised patients in order to minimize risk of developing coronavirus disease 2019. This review aims to present available recommendations from experts and provides an insight on preventive and therapeutic strategies that can be implemented for the medical management of patients with IBD. We anticipate that as more information arises, new guidelines will emerge.