Inconsistent directions of change in case severity across successive SARS-CoV-2 variant waves suggests an unpredictable future (preprint)

ObjectiveTo determine how the severity of successively dominant SARS-CoV-2 variants changed over the course of the COVID-19 pandemic. DesignRetrospective cohort analysis. SettingCommunity- and hospital-sequenced COVID-19 cases in the NHS Greater Glasgow and Clyde (NHS GG&C) Health Board. ParticipantsAll sequenced non-nosocomial adult COVID-19 cases in NHS GG&C infected with the relevant SARS-CoV-2 lineages during analysis periods. B.1.177/Alpha: 1st November 2020 - 30th January 2021 (n = 1640). Alpha/Delta: 1st April - 30th June 2021 (n = 5552). AY.4.2 Delta/non-AY.4.2 Delta: 1st July - 31st October 2021 (n = 9613). Non-AY.4.2 Delta/Omicron: 1st - 31st December 2021 (n = 3858). Main outcome measuresAdmission to hospital, ICU, or death within 28 days of positive COVID-19 test ResultsFor B.1.177/Alpha, 300 of 807 B.1.177 cases were recorded as hospitalised or worse, compared to 232 of 833 Alpha cases. After adjustment, the cumulative odds ratio was 1.51 (95% CI: 1.08-2.11) for Alpha versus B.1.177. For Alpha/Delta, 113 of 2104 Alpha cases were recorded as hospitalised or worse, compared to 230 of 3448 Delta cases. After adjustment, the cumulative odds ratio was 2.09 (95% CI: 1.42-3.08) for Delta versus Alpha. For non-AY.4.2 Delta/AY.4.2 Delta, 845 of 8644 non-AY.4.2 Delta cases were recorded as hospitalised or worse, compared to 101 of 969 AY.4.2 Delta cases. After adjustment, the cumulative odds ratio was 0.99 (95% CI: 0.76-1.27) for AY.4.2 Delta versus non-AY.4.2 Delta. For non-AY.4.2 Delta/Omicron, 30 of 1164 non-AY.4.2 Delta cases were recorded as hospitalised or worse, compared to 26 of 2694 Omicron cases. After adjustment, the median cumulative odds ratio was 0.49 (95% CI: 0.22-1.06) for Omicron versus non-AY.4.2 Delta. ConclusionsThe direction of change in disease severity between successively emerging SARS-CoV-2 variants of concern was inconsistent. This heterogeneity demonstrates that severity associated with future SARS-CoV-2 variants is unpredictable.

Comparison of children and young people admitted with SARS-CoV-2 across the UK in the first and second pandemic waves: prospective multicentre observational cohort study (preprint)

BackgroundChildren and young people (CYP) were less affected than adults in the first wave of SARS-CoV-2 in the UK. We test the hypothesis that clinical characteristics of hospitalized CYP with SARS-CoV-2 in the UK second wave would differ from the first due to the combined impact of the alpha variant, school reopening and relaxation of shielding. MethodsPatients <19 years hospitalised in the UK with clinician-reported SARS-CoV-2 were enrolled in a prospective multicentre observational cohort study between 17th January 2020 and 31st January 2021. Minimum follow up time was two weeks. Clinical characteristics were compared between the first (W1) and second wave (W2) of infections. Findings2044 CYP aged <19 years were reported from 187 hospitals. 427/2044 (20.6%) had asymptomatic/incidental SARS-CoV-2 infection and were excluded from main analysis. 16.0% (248/1548) of symptomatic CYP were admitted to critical care and 0.8% (12/1504) died. 5.6% (91/1617) of symptomatic CYP had Multisystem Inflammatory Syndrome in Children (MIS-C). Patients in W2 were significantly older (median age 6.5 years, IQR 0.3-14.9) than W1 (4.0 (0.4-13.6, p 0.015). Fever was more common in W1, otherwise presenting symptoms and comorbidities were similar across waves. After excluding CYP with MIS-C, patients in W2 had lower PEWS at presentation, lower antibiotic use and less respiratory and cardiovascular support compared to W1. There was no change in the proportion of CYP admitted to critical care between W1 and W2. 58.0% (938/1617) of symptomatic CYP had no reported comorbidity. Patients without co-morbidities were younger (42.4%, 398/938, <1 year old), had lower Paediatric Early Warning Scores (PEWS) at presentation, shorter length of hospital stay and received less respiratory support. MIS-C was responsible for a large proportion of critical care admissions, invasive and non-invasive ventilatory support, inotrope and intravenous corticosteroid use in CYP without comorbidities. InterpretationSevere disease in CYP admitted with symptomatic SARS-CoV-2 in the UK remains rare. One in five CYP in this cohort had asymptomatic/incidental SARS-CoV-2 infection. We found no evidence of increased disease severity in W2 compared with W1. FundingShort form: National Institute for Health Research, UK Medical Research Council, Wellcome Trust, Department for International Development and the Bill and Melinda Gates Foundation. Long form: This work is supported by grants from the National Institute for Health Research (award CO-CIN-01) and the Medical Research Council (grant MC_PC_19059) and by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford (NIHR award 200907), Wellcome Trust and Department for International Development (215091/Z/18/Z), and the Bill and Melinda Gates Foundation (OPP1209135). Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research (grant reference: C18616/A25153). JSN-V-T is seconded to the Department of Health and Social Care, England (DHSC). The views expressed are those of the authors and not necessarily those of the DHSC, DID, NIHR, MRC, Wellcome Trust, or PHE.

Study Pre-protocol for 'BronchStart - The Impact of the COVID-19 Pandemic on the Timing, Age and Severity of Respiratory Syncytial Virus (RSV) Emergency Presentations; a Multi-Centre Prospective Observational Cohort Study' (preprint)

Background Bronchiolitis (most frequently caused by Respiratory Syncytial Virus; RSV) is a common winter disease predominantly affecting children under one year of age. It is a common reason for presentations to an Emergency Department (ED) and frequently results in hospital admission, contributing to paediatric units approaching or exceeding capacity each winter. During the SARS-CoV-2 pandemic, the circulation of RSV was dramatically reduced in the United Kingdom and Ireland. Evidence from the Southern Hemisphere and other European countries suggests that as social distancing restrictions for SARS-CoV-2 are relaxed, RSV infection returns, causing delayed or even summer epidemics, with different age distributions. Study question The ability to track, anticipate and respond to a surge in RSV cases is critical for planning acute care delivery. There is an urgent need to understand the onset of RSV spread at the earliest opportunity. This will influence service planning, to inform clinicians whether the population at risk is a wider age range than normal, and whether there are changes in disease severity. This information is also needed to inform decision on the timing of passive immunisation of children at higher risk of hospitalisation, intensive care admission or death with RSV infection, which is a public health priority. Methods and likely impact This multi-centre prospective observational cohort study will use a well-established research network (Paediatric Emergency Research in the UK and Ireland, PERUKI) to report in real time cases of RSV infection in children aged under two years, through the collection of essential, but non-identifying patient information. Forty centres will gather initial data on age, index of multiple deprivation quintile, clinical features on presentation, and co-morbidities. Each case will be followed up at 7 days to identify treatment, viral diagnosis and outcome. Information be released on a weekly basis and used to support clinical decision making.

Epidemic waves of COVID-19 in Scotland: a genomic perspective on the impact of the introduction and relaxation of lockdown on SARS-CoV-2 (preprint)

The second SARS virus, SARS-CoV-2, emerged in December 2019, and within a month was globally distributed. It was first introduced into Scotland in February 2020 associated with returning travellers and visitors. By March it was circulating in communities across the UK, and to control COVID-19 cases, and prevent overwhelming of the National Health Service (NHS), a 'lockdown' was introduced on 23rd March 2020 with a restriction of people's movements. To augment the public health efforts a large-scale genome epidemiology effort (as part of the COVID-19 Genomics UK (COG-UK) consortium) resulted in the sequencing of over 5000 SARS-CoV-2 genomes by 18th August 2020 from Scottish cases, about a quarter of the estimated number of cases at that time. Here we quantify the geographical origins of the first wave introductions into Scotland from abroad and other UK regions, the spread of these SARS-CoV-2 lineages to different regions within Scotland (defined at the level of NHS Health Board) and the effect of lockdown on virus 'success'. We estimate that approximately 300 introductions seeded lineages in Scotland, with around 25% of these lineages composed of more than five viruses, but by June circulating lineages were reduced to low levels, in line with low numbers of recorded positive cases. Lockdown was, thus, associated with a dramatic reduction in infection numbers and the extinguishing of most virus lineages. Unfortunately since the summer cases have been rising in Scotland in a second wave, with >1000 people testing positive on a daily basis, and hospitalisation of COVID-19 cases on the rise again. Examining the available Scottish genome data from the second wave, and comparing it to the first wave, we find that while some UK lineages have persisted through the summer, the majority of lineages responsible for the second wave are new introductions from outside of Scotland and many from outside of the UK. This indicates that, while lockdown in Scotland is directly linked with the first wave case numbers being brought under control, travel-associated imports (mostly from Europe or other parts of the UK) following the easing of lockdown are responsible for seeding the current epidemic population. This demonstrates that the impact of stringent public health measures can be compromised if following this, movements from regions of high to low prevalence are not minimised.

Inactivated rabies virus vectored SARS-CoV-2 vaccine prevents disease in a Syrian hamster model. (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emergent coronavirus that has caused a worldwide pandemic. Although human disease is often asymptomatic, some develop severe illnesses such as pneumonia, respiratory failure, and death. There is an urgent need for a vaccine to prevent its rapid spread as asymptomatic infections accounting for up to 40% of transmission events. Here we further evaluated an inactivated rabies vectored SARS-CoV-2 S1 vaccine CORAVAX in a Syrian hamster model. CORAVAX adjuvanted with MPLA-AddaVax, a TRL4 agonist, induced high levels of neutralizing antibodies and generated a strong Th1-biased immune response. Vaccinated hamsters were protected from weight loss and viral replication in the lungs and nasal turbinates three days after challenge with SARS-CoV-2. CORAVAX also prevented lung disease, as indicated by the significant reduction in lung pathology. This study highlights CORAVAX as a safe, immunogenic, and efficacious vaccine that warrants further assessment in human trials.

Indirect effects of the COVID-19 pandemic on paediatric health-care use and severe disease: a retrospective national cohort study (preprint)

BackgroundSevere disease directly associated with SARS-CoV-2 infection in children is rare. However, the indirect consequences of the COVID-19 pandemic on paediatric health have not been fully quantified. We examined paediatric health-care utilisation, incidence of severe disease, and mortality during the lockdown period in Scotland. MethodsThis national retrospective cohort study examined national data for emergency childhood primary and secondary care utilisation following national lockdown on March 23, 2020. To determine whether social distancing measures and caregiver behavioural changes were associated with delayed care-seeking and increased disease severity on presentation, unplanned, emergency admissions requiring invasive mechanical ventilation for the two national Paediatric Intensive Care Units (PICUs) were analysed. PICU admissions were grouped by diagnostic category, and disease severity on presentation calculated. National statutory death records were consulted to establish childhood mortality rates and causes of death. For all observations, the lockdown period was compared to equivalent dates in 2016-2019. FindingsWe identified 273,455 unscheduled primary care attendances; 462,437 emergency department attendances; 54,076 emergency hospital admissions; 413 PICU emergency admissions; and 415 deaths during the lockdown study period and equivalent dates in previous years. The rates of emergency presentations to primary and secondary care fell during lockdown in comparison to previous years. Emergency PICU admissions for children requiring invasive mechanical ventilation also fell, with an odds ratio of 0{middle dot}52 for chance of admission during lockdown (95% CI 0{middle dot}37-0{middle dot}73, p < 0{middle dot}001). Clinical severity scores did not suggest children were presenting with more advanced disease. The greatest reduction in PICU admissions was for diseases of the respiratory system; those for injury, poisoning or other external causes were equivalent to previous years. Mortality during lockdown did not change significantly compared to 2016-2019. InterpretationNational lockdown led a reduction in paediatric emergency care utilisation, without associated evidence of severe harm. FundingNone Research in contextO_ST_ABSEvidence before this studyC_ST_ABSData on the indirect effects of the COVID-19 pandemic on children at a population level are limited. We searched PubMed and medRxiv on October 13, 2020, for studies published from Jan 1, 2020 examining the indirect effects of non-pharmaceutical interventions (NPIs), and associated changes in caregiver health-care seeking behaviour, on the risk of severe paediatric disease and death. We used the search terms COVID-19, SARS-CoV-2, non-pharmaceutical interventions, indirect, and children, as well as manually searching references in other relevant papers. Terms were searched individually and in combination as necessary, with no language restrictions. We identified one study that modelled the indirect effects of the COVID-19 pandemic on child deaths in low- and middle-income countries. Other studies analysed in isolation the effects of NPIs and other behavioural changes on emergency department attendances, hospital admission rates, paediatric intensive care unit (PICU) admission rates, or the incidence of specific presentations, such as asthma exacerbations. Some case series described delayed care-seeking for children with non-SARS-CoV-2 disease. We did not identify any national studies examining the indirect effects of the COVID-19 pandemic on the incidence of severe paediatric disease and mortality. Added value of this studyThis national study quantified the changes following national lockdown in Scotland on March 23, 2020. We examined data for unscheduled primary care and emergency department attendances, emergency hospital admissions, emergency paediatric intensive care unit (PICU) admissions requiring invasive mechanical ventilation, and paediatric mortality. Rates were compared with previous years. We found a reduction in paediatric emergency care utilisation rates associated with national lockdown. This reduction is likely to be due to a combination of changes in health care seeking behavior, and a fall in overall burden of paediatric infectious disease. These measures did not appear to have been associated with evidence of severe harm to children in Scotland, as evidenced by severity scores on presentation to PICU or mortality. Implications of all the available evidenceThis is the first comprehensive population-based assessment at a national level of the indirect effects of the COVID-19 pandemic on severe paediatric morbidity and mortality. Despite a significant reduction in health-care utilisation rates, we did not find associated evidence of severe harm. This study will assist policy makers, health-care providers and the public in evaluating the effects of lockdown on the risk of severe paediatric disease at a population level.

Sensitivity of RT-PCR testing of upper respiratory tract samples for SARS-CoV-2 in hospitalised patients: a retrospective cohort study. (preprint)

ObjectivesTo determine the sensitivity and specificity of RT-PCR testing of upper respiratory tract (URT) samples from hospitalised patients with COVID-19, compared to the gold standard of a clinical diagnosis. MethodsAll URT RT-PCR testing for SARS-CoV-2 in NHS Lothian, Scotland, United Kingdom between the 7th of February and 19th April 2020 (inclusive) was reviewed, and hospitalised patients were identified. All URT RT-PCR tests were analysed for each patient to determine the sequence of negative and positive results. For those who were tested twice or more but never received a positive result, case records were reviewed, and a clinical diagnosis of COVID-19 allocated based on clinical features, discharge diagnosis, and radiology and haematology results. For those who had negative URT RT-PCR tests but a clinical diagnosis of COVID-19, respiratory samples were retested using a multiplex respiratory panel, a second SARS-CoV-2 RT-PCR assay, and a human RNase P control. ResultsCompared to the gold standard of a clinical diagnosis of COVID-19, the sensitivity of an initial URT RT-PCR for COVID-19 was 82.2% (95% confidence interval 79.0-85.1%). Two consecutive URT RT-PCR tests increased sensitivity to 90.6% (CI 88.0-92.7%). A further 2.2% and 0.9% of patients who received a clinical diagnosis of COVID-19 were positive on a third and fourth test. ConclusionsThe sensitivity of a single RT-PCR test of an URT sample in hospitalised patients is 82.2%. Sensitivity increases to 90.6% when patients are tested twice. A proportion of cases with clinically defined COVID-19 never test positive on URT RT-PCR despite repeated testing.