Real-time whole genome sequencing to guide patient-tailored therapy of SARS-CoV-2 infection.

The management of COVID-19 has become more complex due to the expansion of available therapies. The presence of SARS-CoV-2 variants and mutations further complicate treatment due to their differing susceptibilities to therapies. Here we outline the use of real-time whole genome sequencing to characterise infections and guide treatment decisions.

Child Mortality in England During the First 2 Years of the COVID-19 Pandemic.

Importance: During the first year of the COVID-19 pandemic, child mortality in England was the lowest on record, but if this trend will continue, or if unrecognized morbidity during the first year of the pandemic will manifest as increased deaths over the next few years is unclear. Objective: To examine the risks and patterns of childhood deaths before and during the COVID-19 pandemic. Design, Setting, and Participants: This population-based cohort study includes all child deaths in England from April 1, 2019, to March 31, 2022. Exposures: The year of death. Main Outcomes and Measures: The primary outcome measure is risk of death. Results: Of the 9983 child deaths reported during the study period, 9872 (98.8%) were linked to demographic and population data with 3409 deaths (34.5%) between April 2019 and March 2020, 3035 (30.7%) between April 2020 and March 2021, and 3428 (34.7%) between April 2021 and March 2022. Most deaths occurred in children who were younger than 1 year (6257 of 9872 [62.7%]), the majority were male (5534 of 9760 [56.7%]), and lived in an urban area (8766 of 9872 [88.8%]). The risk of death was lower between April 2020 and March 2021 (relative risk [RR], 0.89 [95% CI, 0.84-0.93]), but not between April 2021 and March 2022 (RR, 1.00 [95% CI, 0.95-1.05]) when compared with April 2019 to March 2020. A population attributable risk (PAF) of 4.0% (95% CI, 0.1%-6.8%) suggested fewer deaths occurred during the whole 3-year period than expected. Reductions were seen in risk of dying by infection (PAF, 22.8% [95% CI, 8.2%-37.0%]) and underlying disease (PAF, 13.3% [95% CI, 8.1%-18.8%]), but there was evidence of an increasing risk of death by trauma (PAF, 14.7% [95% CI, 2.9%-25.2%]). Any reduction in the risk of death was greater in rural areas than in urban areas (RR, 0.73 [95% CI, 0.63-0.85] vs RR, 0.91 [95% CI, 0.86-0.95]) and was not seen in children older than 9 years. Conclusions and Relevance: In this cohort study, there was a significant reduction in all-cause child mortality during the first year of the COVID-19 pandemic (2020-2021), which returned to close to prepandemic levels the following year (2021-2022). However, there was a net reduction in deaths despite this, with 4% fewer deaths during the 3-year period than would have been expected from the 2019 to 2020 risks. The reductions were largest in rural areas and in children younger than 10 years.

SARS-CoV-2: A Rapid Review Of The Transmission Risk From Vaccinated Populations

IntroductionSince the vaccine roll out, research has focused on vaccine safety and efficacy, with large clinical trials confirming that vaccines are generally effective against symptomatic COVID-19 infection. However, breakthrough infections can still occur, and the effectiveness of vaccines against transmission from infected vaccinated people to susceptible contacts is unclear.Health Technology Wales (HTW) collaborated with the Wales COVID-19 Evidence Centre to identify and examine evidence on the transmission risk of SARS-CoV-2 from vaccinated people to unvaccinated or vaccinated people.MethodsWe conducted a systematic literature search for evidence on vaccinated people exposed to SARS-CoV-2 in any setting. Outcome measures included transmission rate, cycle threshold (Ct) values and viral load. We identified a rapid review by the University of Calgary that was the main source of our outcome data. Nine studies published following the rapid review were also identified and included.ResultsIn total, 35 studies were included in this review: one randomized controlled trial (RCT), one post-hoc analysis of an RCT, 13 prospective cohort studies, 16 retrospective cohort studies and four case control studies.All studies reported a reduction in transmission of the B.1.1.7 (Alpha) variant from partial and fully vaccinated individuals. More recent evidence is uncertain on the effects of vaccination on transmission of the B.1.617.2 (Delta) variant. Overall, vaccine effectiveness in reducing transmission appears to increase with full vaccination, compared with partial vaccination. Most of the direct evidence is limited to transmission in household settings therefore, there is a gap in the evidence on risk of transmission in other settings. One UK study found protection against onward transmission waned within 3 months post second vaccination.ConclusionsEarly findings that focused on the alpha variant, showed a reduction in transmission from vaccinated people. There is limited evidence on the effectiveness of vaccination on transmission of the Delta variant, therefore alternative preventative measures to reduce transmission may still be required.

Child mortality in England during the first year of the COVID-19 pandemic.

OBJECTIVES: To quantify the relative risk (RR) of childhood deaths across the whole of England during the first year of the COVID-19 pandemic, compared with a similar period of 2019. DESIGN: This work is based on data collected by the National Child Mortality Database (NCMD). Deaths from 1 April 2020 until 31 March 2021 (2020-2021) were compared with those from the same period of 2019-2020. RR and excess mortality were derived for deaths in 2020-2021 vs 2019-2020. SETTING: All deaths reported to NCMD in England of children under 18 years of age, between April 2019 and March 2021. PARTICIPANTS: 6490 deaths of children, under the age of 18 years, reported to the NCMD over the study period. RESULTS: Children had similar demographics in the 2 years. There were 356 (198-514) fewer deaths in 2020-2021 than in 2019-2020 (RR 0.90 (0.85 to 0.94), p<0.001). Deaths from infection (RR 0.49 (0.38 to 0.64)) and from other underlying medical conditions (RR 0.75 (0.68 to 0.82)) were lower in 2020-2021 than 2019-2020, and weak evidence (RR 0.50 (0.23 to 1.07), p=0.074) that this was also true of deaths from substance abuse. CONCLUSIONS: Childhood mortality in England during the first year of the SARS-CoV-2 pandemic was lower than expected, with over 300 fewer deaths than the preceding 12 months. The greatest reduction was in children less than 10 years old. It is important that we learn from this effect that potentially offers alternative ways to improve the outcome for the most vulnerable children in our society.

Evaluating the potential for respiratory metagenomics to improve treatment of secondary infection and detection of nosocomial transmission on expanded COVID-19 intensive care units.

BACKGROUND: Clinical metagenomics (CMg) has the potential to be translated from a research tool into routine service to improve antimicrobial treatment and infection control decisions. The SARS-CoV-2 pandemic provides added impetus to realise these benefits, given the increased risk of secondary infection and nosocomial transmission of multi-drug-resistant (MDR) pathogens linked with the expansion of critical care capacity. METHODS: CMg using nanopore sequencing was evaluated in a proof-of-concept study on 43 respiratory samples from 34 intubated patients across seven intensive care units (ICUs) over a 9-week period during the first COVID-19 pandemic wave. RESULTS: An 8-h CMg workflow was 92% sensitive (95% CI, 75-99%) and 82% specific (95% CI, 57-96%) for bacterial identification based on culture-positive and culture-negative samples, respectively. CMg sequencing reported the presence or absence of ß-lactam-resistant genes carried by Enterobacterales that would modify the initial guideline-recommended antibiotics in every case. CMg was also 100% concordant with quantitative PCR for detecting Aspergillus fumigatus from 4 positive and 39 negative samples. Molecular typing using 24-h sequencing data identified an MDR-K. pneumoniae ST307 outbreak involving 4 patients and an MDR-C. striatum outbreak involving 14 patients across three ICUs. CONCLUSION: CMg testing provides accurate pathogen detection and antibiotic resistance prediction in a same-day laboratory workflow, with assembled genomes available the next day for genomic surveillance. The provision of this technology in a service setting could fundamentally change the multi-disciplinary team approach to managing ICU infections. The potential to improve the initial targeted treatment and rapidly detect unsuspected outbreaks of MDR-pathogens justifies further expedited clinical assessment of CMg.

Child suicide rates during the COVID-19 pandemic in England.

BACKGROUND: There is concern about the impact of COVID-19, and the control measures to prevent the spread, on children's mental health. The aim of this work was to identify if there had been a rise of childhood suicide during the COVID pandemic. METHOD: Using data from England's National Child Mortality Database (NCMD) the characteristics and rates of children dying of suicide between April and December 2020 were compared with those in 2019. In a subset (1st January to 17th May 2020) further characteristics and possible contributing factors were obtained. RESULTS: A total of 193 likely childhood deaths by suicide were reported. There was no evidence overall suicide deaths were higher in 2020 than 2019 (RR 1.09 (0.80-1.48), p = 0.584) but weak evidence that the rate in the first lockdown period (April to May 2020) was higher than the corresponding period in 2019 (RR 1.56 (0.86-2.81), p = 0.144). Characteristics of individuals were similar between periods. Social restrictions (e.g. to education), disruption to care and support services, tensions at home and isolation appeared to be contributing factors. LIMITATIONS: As child suicides are fortunately rare, the analysis is based on small numbers of deaths with limited statistical power to detect anything but major increases in incidence. CONCLUSION: We found no consistent evidence that child suicide deaths increased during the COVID-19 pandemic although there was a possibility that they may have increased during the first UK lockdown. A similar peak was not seen during the following months, or the second lockdown.

Child mortality in England during the COVID-19 pandemic.

OBJECTIVES: Using the National Child Mortality Database (NCMD), this work aims to investigate and quantify the characteristics of children dying of COVID-19, and to identify any changes in rate of childhood mortality during the pandemic. DESIGN: We compared the characteristics of the children who died in 2020, split by SARS-CoV-2 status. A negative binomial regression model was used to compare mortality rates in lockdown (23 March-28 June), with those children who died in the preceding period (6 January-22 March), as well as a comparable period in 2019. SETTING: England. PARTICIPANTS: Children (0-17 years). MAIN OUTCOME MEASURES: Characteristics and number of the children who died in 2020, split by SARS-CoV-2 status. RESULTS: 1550 deaths of children between 6th of January and 28 June 2020 were notified to the NCMD; 437 of the deaths were linked to SARS-CoV-2 virology records, 25 (5.7%) had a positive PCR result. PCR-positive children were less likely to be white (37.5% vs 69.4%, p=0.003) and were older (12.2 vs 0.7 years, p<0.0006) compared with child deaths without evidence of the virus. All-cause mortality rates were similar during lockdown compared with both the period before lockdown in 2020 (rate ratio (RR) 0.93 (0.84 to 1.02)) and a similar period in 2019 (RR 1.02 (0.92 to 1.13)). CONCLUSIONS: There is little to suggest that there has been excess mortality during the period of lockdown. The apparent higher frequency of SARS-CoV-2-positive tests among children from black, Asian and minority ethnic groups is consistent with findings in adults. Ongoing surveillance is essential as the pandemic continues.

Co-infection in critically ill patients with COVID-19: an observational cohort study from England.

Introduction. During previous viral pandemics, reported co-infection rates and implicated pathogens have varied. In the 1918 influenza pandemic, a large proportion of severe illness and death was complicated by bacterial co-infection, predominantly Streptococcus pneumoniae and Staphylococcus aureus.Gap statement. A better understanding of the incidence of co-infection in patients with COVID-19 infection and the pathogens involved is necessary for effective antimicrobial stewardship.Aim. To describe the incidence and nature of co-infection in critically ill adults with COVID-19 infection in England.Methodology. A retrospective cohort study of adults with COVID-19 admitted to seven intensive care units (ICUs) in England up to 18 May 2020, was performed. Patients with completed ICU stays were included. The proportion and type of organisms were determined at <48 and >48 h following hospital admission, corresponding to community and hospital-acquired co-infections.Results. Of 254 patients studied (median age 59 years (IQR 49-69); 64.6 % male), 139 clinically significant organisms were identified from 83 (32.7 %) patients. Bacterial co-infections/ co-colonisation were identified within 48 h of admission in 14 (5.5 %) patients; the commonest pathogens were Staphylococcus aureus (four patients) and Streptococcus pneumoniae (two patients). The proportion of pathogens detected increased with duration of ICU stay, consisting largely of Gram-negative bacteria, particularly Klebsiella pneumoniae and Escherichia coli. The co-infection/ co-colonisation rate >48 h after admission was 27/1000 person-days (95 % CI 21.3-34.1). Patients with co-infections/ co-colonisation were more likely to die in ICU (crude OR 1.78,95 % CI 1.03-3.08, P=0.04) compared to those without co-infections/ co-colonisation.Conclusion. We found limited evidence for community-acquired bacterial co-infection in hospitalised adults with COVID-19, but a high rate of Gram-negative infection acquired during ICU stay.