Comparison of three dosing intervals for the primary vaccination of the SARS-CoV-2 mRNA Vaccine (BNT162b2) on magnitude, neutralization capacity and durability of the humoral immune response in health care workers: A prospective cohort study.

OBJECTIVES: The dosing interval of a primary vaccination series can significantly impact on vaccine immunogenicity and efficacy. The current study compared 3 dosing intervals for the primary vaccination series of the BNT162b2 mRNA COVID-19 vaccine, on humoral immune response and durability against SARS-CoV-2 ancestral and Beta variants up to 9 months post immunization. METHODS: Three groups of age- and sex-matched healthcare workers (HCW) who received 2 primary doses of BNT162b2 separated by 35-days, 35-42 days or >42-days were enrolled. Vaccine induced antibody titers at 3 weeks, 3 and 6-9 months post-second dose were assessed. RESULTS: There were 309 age- and sex-matched HCW (mean age 43 [sd 13], 58% females) enrolled. Anti-SARS-CoV-2 binding (IgG, IgM, IgA) and neutralizing antibody titers showed significant waning in levels beyond 35 days post first dose. The second dose induced a significant rise in antibody titers, which peaked at 3 weeks and then declined at variable rates across groups. The magnitude, consistency and durability of response was greater for anti-Spike than anti-RBD antibodies; and for IgG than IgA or IgM. Compared to the shorter schedules, a longer interval of >42 days offered the highest binding and neutralizing antibody titers against SARS-CoV-2 ancestral and Beta (B1.351) variants beyond 3 months post-vaccination. CONCLUSIONS: This is the first comprehensive study to compare 3 dosing intervals for the primary vaccination of BNT162b2 mRNA COVID-19 vaccine implemented in the real world. These findings suggest that delaying the second dose beyond 42 days can potentiate and prolong the humoral response against ancestral and Beta variants of SARS-CoV-2 up to 9 months post-vaccination.

Hospitalised COVID-19 outcomes are predicted by hypoxaemia and pneumonia phenotype irrespective of the timing of their emergence.

Despite the known clinical importance of hypoxemia and pneumonia, there is a paucity of evidence for these variables with respect to risk of mortality and short-term outcomes among those hospitalised with COVID-19. OBJECTIVE: Describe the prevalence and clinical course of patients hospitalised with COVID-19 based on oxygenation and pneumonia status at presentation and determine the incidence of emergent hypoxaemia or radiographic pneumonia during admission. METHODS: A retrospective study was conducted using a Canadian regional registry. Patients were stratified according to hypoxaemia/pneumonia phenotype and prevalence. Clinical parameters were compared between phenotypes using χ2 and one-way Analysis of variance (ANOVA). Cox analysis estimated adjusted Hazard Ratios (HR) for associations between disease outcomes and phenotypes. RESULTS: At emergency department (ED) admission, the prevalence of pneumonia and hypoxaemia was 43% and 50%, respectively, and when stratified to phenotypes: 28.2% hypoxaemia+/pneumonia+, 22.2% hypoxaemia+/pneumonia-, 14.5% hypoxaemia-/pneumonia+ and 35.1% hypoxaemia-/pneumonia-. Mortality was 31.1% in the hypoxaemia+/pneumonia- group and 26.3% in the hypoxaemia+/pneumonia+ group. Hypoxaemia with pneumonia and without pneumonia predicted higher probability of death. Hypoxaemia either <24 hours or ≥24 hours after hospitalisation predicted higher mortality and need for home oxygen compared with those without hypoxaemia. Patients with early hypoxaemia had higher probability of Intensive care unit (ICU) admission compared with those with late hypoxaemia. CONCLUSION: Mortality in COVID-19 infection is predicted by hypoxaemia with or without pneumonia and was greatest in patients who initially presented with hypoxaemia. The emergence of hypoxaemia was predicted by radiographic pneumonia. Patients with early and emergent hypoxaemia had similar mortality but were less likely to be admitted to ICU. There may be delayed identification of hypoxaemia, which prevents timely escalation of care.

Functional recovery following hospitalisation of patients diagnosed with COVID-19: a protocol for a longitudinal cohort study.

INTRODUCTION: COVID-19 is an international public health crisis with more than 132 million infections worldwide. Beyond acute infection, emerging data indicate patients diagnosed with COVID-19 may experience persistent sequelae similar to survivors of sepsis or acute respiratory syndromes, including mobility limitations and fatigue. However, there is limited evidence on the trajectory of functional recovery in those hospitalised with COVID-19. The primary aim of the Coronavirus Registry Functional Recovery (COREG-FR) study is to understand the trajectory of functional recovery among individuals hospitalised for COVID-19 over the medium (up to 6 months) and longer term (6-12 months) that will guide clinical care and optimal management of serious COVID-19 illness and recovery. METHODS AND ANALYSIS: COREG-FR is a multicentre longitudinal cohort study. We will enrol a minimum of 211 adults age 18 years and older with COVID-19 from five hospitals. Participants will be followed from admission to hospital as an inpatient, to hospital discharge, and at 3-month, 6-month, 9-month and up to 12-month post-hospital discharge. We will conduct telephone interviews at ward admission and discharge, and telephone interviews plus in-person assessments of physical function and lung function at all remaining follow-ups. Our primary outcome is the Activity Measure for Post-Acute Care mobility scale measured at all time points. We will conduct linear mixed effects regression analyses to explore determinants of functional outcomes after COVID-19 illness. Subgroup analyses based on age (≤65 vs >65 years), frailty status (Clinical Frailty Scale score ≤4 vs >5) and variants of concern will be conducted. ETHICS AND DISSEMINATION: COREG-FR has been approved by Research Ethics Boards at participating sites. We will disseminate this work through peer-reviewed manuscripts, presentations at national and international meetings and through the established COREG website (www.coregontario.ca). COREG-FR is designed as a data platform for future studies evaluating COVID-19 recovery. TRIAL REGISTRATION NUMBER: NCT04602260; Pre-results.

External validation of the 4C mortality score among COVID-19 patients admitted to hospital in Ontario, Canada: a retrospective study.

Risk prediction scores are important tools to support clinical decision-making for patients with coronavirus disease (COVID-19). The objective of this paper was to validate the 4C mortality score, originally developed in the United Kingdom, for a Canadian population, and to examine its performance over time. We conducted an external validation study within a registry of COVID-19 positive hospital admissions in the Kitchener-Waterloo and Hamilton regions of southern Ontario between March 4, 2020 and June 13, 2021. We examined the validity of the 4C score to prognosticate in-hospital mortality using the area under the receiver operating characteristic curve (AUC) with 95% confidence intervals calculated via bootstrapping. The study included 959 individuals, of whom 224 (23.4%) died in-hospital. Median age was 72 years and 524 individuals (55%) were male. The AUC of the 4C score was 0.77, 95% confidence interval 0.79-0.87. Overall mortality rates across the pre-defined risk groups were 0% (Low), 8.0% (Intermediate), 27.2% (High), and 54.2% (Very High). Wave 1, 2 and 3 values of the AUC were 0.81 (0.76, 0.86), 0.74 (0.69, 0.80), and 0.76 (0.69, 0.83) respectively. The 4C score is a valid tool to prognosticate mortality from COVID-19 in Canadian hospitals and can be used to prioritize care and resources for patients at greatest risk of death.

Incidence and Outcomes of Acute Kidney Injury in Patients Admitted to Hospital With COVID-19: A Retrospective Cohort Study.

BACKGROUND: The incidence of acute kidney injury (AKI) in patients with COVID-19 and its association with mortality and disease severity is understudied in the Canadian population. OBJECTIVE: To determine the incidence of AKI in a cohort of patients with COVID-19 admitted to medicine and intensive care unit (ICU) wards, its association with in-hospital mortality, and disease severity. Our aim was to stratify these outcomes by out-of-hospital AKI and in-hospital AKI. DESIGN: Retrospective cohort study from a registry of patients with COVID-19. SETTING: Three community and 3 academic hospitals. PATIENTS: A total of 815 patients admitted to hospital with COVID-19 between March 4, 2020, and April 23, 2021. MEASUREMENTS: Stage of AKI, ICU admission, mechanical ventilation, and in-hospital mortality. METHODS: We classified AKI by comparing highest to lowest recorded serum creatinine in hospital and staged AKI based on the Kidney Disease: Improving Global Outcomes (KDIGO) system. We calculated the unadjusted and adjusted odds ratio for the stage of AKI and the outcomes of ICU admission, mechanical ventilation, and in-hospital mortality. RESULTS: Of the 815 patients registered, 439 (53.9%) developed AKI, 253 (57.6%) presented with AKI, and 186 (42.4%) developed AKI in-hospital. The odds of ICU admission, mechanical ventilation, and death increased as the AKI stage worsened. Stage 3 AKI that occurred during hospitalization increased the odds of death (odds ratio [OR] = 7.87 [4.35, 14.23]). Stage 3 AKI that occurred prior to hospitalization carried an increased odds of death (OR = 5.28 [2.60, 10.73]). LIMITATIONS: Observational study with small sample size limits precision of estimates. Lack of nonhospitalized patients with COVID-19 and hospitalized patients without COVID-19 as controls limits causal inferences. CONCLUSIONS: Acute kidney injury, whether it occurs prior to or after hospitalization, is associated with a high risk of poor outcomes in patients with COVID-19. Routine assessment of kidney function in patients with COVID-19 may improve risk stratification. TRIAL REGISTRATION: The study was not registered on a publicly accessible registry because it did not involve any health care intervention on human participants.

Inflammatory biomarkers as independent prognosticators of 28-day mortality for COVID-19 patients admitted to general medicine or ICU wards: a retrospective cohort study.

Inflammatory biomarkers may be associated with disease severity and increased mortality in COVID-19 patients but have not been studied in North American populations. We sought to determine whether a set of commonly ordered inflammatory biomarkers can predict 28-day mortality. We analyzed a multi-centered (four) COVID-19 registry cohort from March 4th to December 7th, 2020. This cohort included COVID-19-positive patients admitted to medical wards or intensive care units. Patients presenting to the emergency department for COVID-19 symptoms and then subsequently discharged were also included. We performed Cox-regression analysis to measure whether commonly used biomarkers were associated with an increased 28-day mortality. Of 336 COVID-19-positive patients, 267 required hospital admission, and 69 were seen in the emergency room and discharged. The median age was 63 years (IQR 80-50) and the female-to-male ratio was 49:51. Derivation of internally validated cut-offs suggested that C-reactive protein ≥ 78.4 mg/L, neutrophil-to-lymphocyte ratio ≥ 6.1, lymphocyte-to-white blood cell ratio < 0.127, and a modified Glasgow prognostic score equal to 2 vs. 1 or 0 were associated with the highest increased risk of 28-day mortality. We provide early estimates of cut-off values for inflammatory biomarkers and indices measured at the time of admission that may be useful to clinicians for predicting 28-day mortality in North American COVID-19 patients.