ABSTRACT
Virus neutralizing antibody (vnAb) titers are the strongest laboratory correlate of protection from SARS-CoV-2. Providing individuals with real-time measures of their vnAb titers is predicted to improve their ability to make personal wellness decisions. Yet, widespread commercial testing of SARS-CoV-2 vnAbs does not currently occur. Here, we examined whether knowing their vnAb titer impacted wellness decision-making among individuals. To this end, starting on January 1, 2021, we offered all employees from two companies free IMMUNO-COV testing and conducted a survey to assess their behaviors and decisions regarding booster vaccination. IMMUNO-COV is a clinically validated, surrogate virus assay that quantitates serum titers of SARS-CoV-2 vnAbs. To help participants gauge their level of protection based on their vnAb titer, we calibrated IMMUNO-COV titers to the World Health Organization (WHO) International Standard (IU/mL), making them comparable to published reports of correlates of protection, and we fit historical IMMUNO-COV vnAb titer values into predictive models of immune protection from COVID-19. As expected, data for the 56 program participants showed variability in vnAb titers post vaccination, rates vnAb decay, and fold-increases in vnAb titers after booster vaccination. Based on the participant survey, the majority (66%) of participants indicated that knowing their vnAb titer impacted their social behaviors and/or their decision on the timing of a booster vaccination. Several participants indicated that knowing their vnAb titer contributed to their peace of mind regarding their high level of protection from COVID-19. Together, these data demonstrate that regular determination of SARS-CoV-2 neutralizing antibody titers can significantly impact decisions regarding social interactions and timing of booster vaccinations.
Subject(s)
COVID-19 , Severe Acute Respiratory SyndromeABSTRACT
Background: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is Nafamostat Mesylate.Methods: We present the findings of a phase Ib/II open label, platform randomised controlled trial of intravenous Nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), Nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2mg/kg/hour for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC.Results: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous Nafamostat. 78% of Nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The Nafamostat group developed significantly higher plasma creatinine levels and had a lower number of oxygen free days (posterior mean difference 10.57 micromol/L, 95% HPD interval 2.43 - 18.92, rate ratio 0.55- 95% HPD interval 0.31- 0.99 respectively). There were no other statistically significant differences in endpoints between Nafamostat and SoC. PK data demonstrated that intravenous Nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. Participants in the Nafamostat group had higher D-Dimers.Interpretation: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous Nafamostat. Further evaluation of Nafamostat delivered via a different route may be warranted.Clinical Trial Registration Details: This trial has been registered on ISRCTN (https://www.isrctn.com/) ISRCTN14212905, and Clinicaltrials.gov (https://www.clinicaltrials.gov/) NCT04473053. Funding Information: DEFINE was funded by LifeArc (an independent medical research charity under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230).Declaration of Interests: The authors report no conflict of interests.Ethics Approval Statement: The DEFINE trial has received full ethical approval from Scotland A REC (20/SS/0066), the MHRA (EudraCT 2020-002230-32) and NHS Lothian. Written informed consent was taken by trial clinicians prior to any trial procedures being performed. If a patient lacked capacity, consent could be provided by their next of kin.
Subject(s)
COVID-19 , Pneumonia , White Coat HypertensionABSTRACT
Despite the success of vaccines and selected repurposed treatments, COVID-19 is likely to remain a global health problem and further chemotherapeutics are required. Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials without characterisation of Pharmacokinetics (PK)/Pharmacodynamics (PD) including safety in COVID-19. One such drug is Nafamostat Mesylate (Nafamostat), a synthetic serine protease inhibitor with anticoagulant and anti-inflammatory properties. Preclinical data has demonstrated that it is has potent antiviral activity against SARS-CoV-2 by directly inhibiting the transmembrane protease serine 2 (TMPRSS2) dependent stage of host cell entry. Methods: We present the findings of a phase Ib/II open label, platform randomised controlled trial (RCT), exploring the safety of intravenous Nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), Nafamostat or an alternative therapy. Secondary endpoints included clinical endpoints such as number of oxygen free days and clinical improvement/ deterioration, PK/PD, thromboelastometry, D Dimers, cytokines, immune cell flow cytometry and viral load. Results: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous Nafamostat. The Nafamostat group developed significantly higher plasma creatinine levels, more adverse events and a lower number of oxygen free days. There were no other statistically significant differences in the primary or secondary endpoints between Nafamostat and SoC. PK data demonstrated that intravenous Nafamostat was rapidly broken down to inactive metabolites. We observed an antifibrinolytic profile, and no significant anticoagulant effects in thromboelastometry. Participants in the Nafamostat group had higher D Dimers compared to SoC. There were no differences in cytokine profile and immune cell phenotype and viral loads between the groups. Conclusion In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous Nafamostat. Given the number of negative trials with repurposed drugs, our experimental medicine trial highlights the value of PK/PD studies prior to selecting drugs for efficacy trials. Given the mechanism of action, further evaluation of Nafamostat delivered via a different route may be warranted. This trial demonstrates the importance of experimental trials in new disease entities such as COVID-19 prior to selecting drugs for larger trials.
Subject(s)
COVID-19 , PneumoniaABSTRACT
ObjectivesTo determine if there is an association between survival rates in intensive care units (ICU) and occupancy of the unit on the day of admission. DesignNational retrospective observational cohort study spanning the first wave of the Englands COVID-19 pandemic. Setting114 hospital trusts (groups of hospitals functioning as single operational units). Participants4,032 adults admitted to an ICU in England between 2nd April and 1st June, 2020, with presumed or confirmed COVID-19, for whom data was submitted to the national surveillance programme and met study inclusion criteria. InterventionsN/A Main Outcomes and MeasuresA Bayesian hierarchical approach was used to model the association between hospital trust level (mechanical ventilation compatible) bed occupancy, and in-hospital all-cause mortality. Results were adjusted for unit characteristics (pre-pandemic size), individual patient-level demographic characteristics (age, sex, ethnicity, time-to-ICU admission), and recorded chronic comorbidities (obesity, diabetes, respiratory disease, liver disease, heart disease, hypertension, immunosuppression, neurological disease, renal disease). Results79,793 patient-days were observed, with a mortality rate of 19.4 per 1,000 patient days. Adjusting for patient-level factors, mortality was higher for admissions during periods of high occupancy (>85% occupancy versus the baseline of 45 to 85%) [OR 1.19 (95% posterior credible interval (PCI): 1.00 to 1.44)]. In contrast, mortality was decreased for admissions during periods of low occupancy (<45% relative to the baseline) [OR 0.75 (95% PCI: 0.62 to 0.89)]. Conclusion and RelevanceIncreasing occupancy of beds compatible with mechanical ventilation, a proxy for operational strain, is associated with a higher mortality risk for individuals admitted to ICU. Public health interventions (such as expeditious vaccination programmes and non-pharmaceutical interventions) to control both incidence and prevalence of COVID-19, and therefore keep ICU occupancy low in the context of the pandemic, are necessary to mitigate the impact of this type of resource saturation. Trial RegistrationN/A O_TEXTBOXSummary Box What is already known on this topicPre-pandemic, higher occupancy of intensive care units was shown to be associated with increased mortality risk. However, there is limited data on the extent to which occupancy levels impacted patient outcomes during the first wave of COVID-19, especially in light of the mobilisation of significant additional resources. A recent study from Belgium reported a 42% higher mortality during periods of ICU surge capacity deployment, although in the analysis surge capacity was evaluated only as a binary variable. Although, this contradicts earlier results from smaller studies in Australia and Wales, where no association between ICU occupancy and mortality was identified. What this study addsThe results of this study suggest that survival rates for patients with COVID-19 in intensive care settings appears to deteriorate as the occupancy of (surge capacity) beds compatible with mechanical ventilation (a proxy for operational pressure), increases. Moreover, this risk doesnt occur above a specific threshold, but rather appears linear; whereby going from 0% occupancy to 100% occupancy increases risk of mortality by 92% (after adjusting for relevant individual-level factors). Furthermore, risk of mortality based on occupancy on the date of recorded outcome is even higher; OR 4.74 (95% posterior credible interval: 3.54 - 6.34). As such, this national-level cohort study of England provides compelling evidence for a relationship between occupancy and critical care mortality, and highlights the needs for decisive action to control the incidence and prevalence of COVID-19. C_TEXTBOX
Subject(s)
Respiratory Tract Diseases , Diabetes Mellitus , Heredodegenerative Disorders, Nervous System , Obesity , Kidney Diseases , Hypertension , COVID-19 , Heart Diseases , Liver DiseasesABSTRACT
Background: Non-pharmacological interventions were introduced based on modelling studies which suggested that the English National Health Service (NHS) would be overwhelmed by the COVID-19 pandemic. In this study, we describe the pattern of bed occupancy across England during the first wave of the pandemic, January 31st to June 5th 2020. Methods: Bed availability and occupancy data was extracted from daily reports submitted by all English secondary care providers, between 27-Mar and 5-June. Two thresholds (85% as per Royal College of Emergency Medicine and 92% as per NHS Improvement) were applied as thresholds for safe occupancy. Findings: At peak availability, there were 2711 additional beds compatible with mechanical ventilation across England, reflecting a 53% increase in capacity, and occupancy never exceeded 62%. A consequence of the repurposing of beds meant that at the trough, there were 8.7% (8,508) fewer general and acute (G&A) beds across England, but occupancy never exceeded 72%. The closest to (surge) capacity that any trust in England reached was 99.8% for general and acute beds. For beds compatible with mechanical ventilation there were 326 trust-days (3.7%) spent above 85% of surge capacity, and 154 trust-days (1.8%) spent above 92%. 23 trusts spent a cumulative 81 days at 100% saturation of their surge ventilator bed capacity (median number of days per trust = 1 [range: 1 to 17]). However, only 3 STPs (aggregates of geographically co-located trusts) reached 100% saturation of their mechanical ventilation beds. Interpretation: Throughout the first wave of the pandemic, an adequate supply of all bed-types existed at a national level. Due to an unequal distribution of bed utilization, many trusts spent a significant period operating above safe occupancy thresholds, despite substantial capacity in geographically co-located trusts; a key operational issue to address in preparing for a potential second wave. Funding: This study received no funding.