Long COVID and the mental and physical health of children and young people: National matched cohort study protocol (the CLoCk study)

Introduction There is uncertainty surrounding the diagnosis, prevalence, phenotype, duration and treatment of Long COVID. This study aims to (A) describe the clinical phenotype of post-COVID symptomatology in children and young people (CYP) with laboratory-confirmed SARS-CoV-2 infection compared with test-negative controls, (B) produce an operational definition of Long COVID in CYP, and (C) establish its prevalence in CYP. Methods and analysis A cohort study of SARS-CoV-2-positive CYP aged 11-17 years compared with age, sex and geographically matched SARS-CoV-2 test-negative CYP. CYP aged 11-17 testing positive and negative for SARS-CoV-2 infection will be identified and contacted 3, 6, 12 and 24 months after the test date. Consenting CYP will complete an online questionnaire. We initially planned to recruit 3000 test positives and 3000 test negatives but have since extended our target. Data visualisation techniques will be used to examine trajectories over time for symptoms and variables measured repeatedly, separately by original test status. Summary measures of fatigue and mental health dimensions will be generated using dimension reduction methods such as latent variables/latent class/principal component analysis methods. Cross-tabulation of collected and derived variables against test status and discriminant analysis will help operationalise preliminary definitions of Long COVID. Ethics and dissemination Research Ethics Committee approval granted. Data will be stored in secure Public Health England servers or University College London's Data Safe Haven. Risks of harm will be minimised by providing information on where to seek support. Results will be published on a preprint server followed by journal publication, with reuse of articles under a CC BY licence. Data will be published with protection against identification when there are small frequencies involved. Trial registration number ISRCTN34804192; Pre-results

SARS-CoV-2-specific memory B cells can persist in the elderly who have lost detectable neutralising antibodies

Memory B cells (MBC) can provide a recall response able to supplement waning antibodies with an affinity-matured response better able to neutralise variant viruses. We studied a cohort of elderly care home residents and younger staff (median age 87yrs and 56yrs respectively) who had survived COVID-19 outbreaks with only mild/asymptomatic infection. The cohort was selected to enrich for a high proportion who had lost neutralising antibodies (nAb), to specifically investigate the reserve immunity from SARS-CoV-2-specific MBC in this setting. Class-switched spike and RBD-tetramer-binding MBC persisted five months post-mild/asymptomatic SARS-CoV-2 infection, irrespective of age. The majority of spike/RBD-specific MBC had a classical phenotype but activated memory B cells, that may indicate ongoing antigenic stimulation or inflammation, were expanded in the elderly. Spike/RBD-specific MBC remained detectable in the majority who had lost nAb, although at lower frequencies and with a reduced IgG/IgA isotype ratio. Functional spike/S1/RBD-specific recall was also detectable by ELISpot in some who had lost nAb, but was significantly impaired in the elderly. Our findings demonstrate a reserve of SARS-CoV-2-specific MBC persists beyond loss of nAb, but highlight the need for careful monitoring of functional defects in spike/RBD-specific B cell immunity in the elderly

Impact of the Coronavirus Disease 2019 (COVID-19) Pandemic on Invasive Pneumococcal Disease and Risk of Pneumococcal Coinfection With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): Prospective National Cohort Study, England.

BACKGROUND: Streptococcus pneumoniae coinfection with influenza results in synergistic lethality, but there are limited data on pneumococcal coinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: Public Health England conducts invasive pneumococcal disease (IPD) and SARS-CoV-2 surveillance in England. IPD trends during 2000/2001-2019/2020 epidemiological years were analyzed and cases during February-June 2020 linked with laboratory-confirmed SARS-CoV-2 infections. Multivariable logistic regression was used to assess risk factors for death. RESULTS: IPD incidence in 2019/2020 (7.6/100 000; n = 3964) was 30% (IRR, .70; 95% CI, .18-2.67) lower compared with 2018/2019 (10.9/100 000; n = 5666), with large reductions observed across all age groups during March-June 2020. There were 160 886 SARS-CoV-2 and 1137 IPD cases during February-June 2020, including 40 IPD/coronavirus disease 2019 (COVID-19) co-infections (.025% [95% CI, .018-.034] of SARS-CoV-2 infections; 3.5% [2.5-4.8] of IPD cases), 21 with COVID-19 diagnosed 3-27 days after IPD, and 27 who developed COVID-19 ≥28 days after IPD. Case-fatality rates (CFRs) were 62.5 (25/40), 47.6% (10/21), and 33.3% (9/27), respectively (P < .001). In addition to an independent association with increasing age and serotype group, CFR was 7.8-fold (95% CI, 3.8-15.8) higher in those with IPD/COVID-19 coinfection and 3.9-fold (95% CI, 1.4-10.7) higher in patients who developed COVID-19 3-27 days after IPD compared with patients with IPD only. CONCLUSIONS: Large declines in IPD were observed following COVID-19 lockdown. IPD/COVID-19 coinfections were rare but associated with high CFR, mainly in older adults. The rarity, age and serotype distribution of IPD/COVID-19 coinfections do not support wider extension of pneumococcal vaccination

Feasibility and acceptability of SARS-CoV-2 testing and surveillance in primary school children in England: Prospective, cross-sectional study.

BACKGROUND: The reopening of schools during the COVID-19 pandemic has raised concerns about widespread infection and transmission of SARS-CoV-2 in educational settings. In June 2020, Public Health England (PHE) initiated prospective national surveillance of SARS-CoV-2 in primary schools across England (sKIDs). We used this opportunity to assess the feasibility and agreeability of large-scale surveillance and testing for SARS-CoV-2 infections in school among staff, parents and students. METHODS: Staff and students in 131 primary schools were asked to complete a questionnaire at recruitment and provide weekly nasal swabs for SARS-CoV-2 RT-PCR testing (n = 86) or swabs with blood samples for antibody testing (n = 45) at the beginning and end the summer half-term. In six blood sampling schools, students were asked to complete a pictorial questionnaire before and after their investigations. RESULTS: In total, 135 children aged 4-7 years (n = 40) or 8-11 years (n = 95) completed the pictorial questionnaire fully or partially. Prior to sampling, oral fluid sampling was the most acceptable test (107/132, 81%) followed by throat swabs (80/134, 59%), nose swabs (77/132, 58%), and blood tests (48/130, 37%). Younger students were more nervous about all tests than older students but, after completing their tests, most children reported a "better than expected" experience with all the investigations. Students were more likely to agree to additional testing for nose swabs (93/113, 82%) and oral fluid (93/114, 82%), followed by throat swabs (85/113, 75%) and blood tests (72/108, 67%). Parents (n = 3,994) and staff (n = 2,580) selected a preference for weekly testing with nose swabs, throat swabs or oral fluid sampling, although staff were more flexible about testing frequency. CONCLUSIONS: Primary school staff and parents were supportive of regular tests for SARS-CoV-2 and selected a preference for weekly testing. Children preferred nose swabs and oral fluids over throat swabs or blood sampling

Very low risk of monkeypox among staff and students after exposure to a confirmed case in educational settings, England, May to July 2022

We investigated a secondary school (11–16 year-olds), a primary school (5–11 year-olds), reception year (4–5 year-olds) and a nursery (2–5 year-olds) following confirmed monkeypox in an adult in each educational setting during June and July 2022. MVA-BN vaccine was offered up to 14 days post exposure to 186 children < 12 years and 21 were vaccinated. No secondary cases occurred among at least 340 exposed students and more than 100 exposed staff during the 28-day follow-up period

Implementation of preventive measures to prevent COVID-19: a national study of English primary schools in summer 2020.

We examined the feasibility of implementing preventive measures to prevent SARS-CoV-2 transmission across 105 English primary schools in summer 2020 via a survey and interviews with headteachers. High rates of implementation of most recommended measures were noted with the exception of requiring 2 m distance for students, fitting hand sanitizers in classrooms and introducing one-way systems in school corridors. Measures such as regular handwashing and stopping assemblies were considered easy to implement. Majorly challenging measures included distancing between individuals (for students: 51%, N = 99; for staff: 34%; N = 98; for parents: 26%, N = 100), spacing out desks (34%, N = 99), keeping same staff assigned to each student group (33%, N = 97) and staggering break times (25%, N = 99). Rapid implementation was facilitated by staff commitment and communication among stakeholders, but hampered by limitations with guidance received, physical environments, resources, parental adherence and balancing preventive measures with learning. Difficulties with distancing for younger children suggest that smaller bubbles with fewer distancing requirements within these may be a policy option. Schools require further financial, human resource and other support for effective implementation of preventive measures

Cross sectional investigation of a COVID-19 outbreak at a London Army barracks: Neutralising antibodies and virus isolation.

Background: Military personnel in enclosed societies are at increased risk of respiratory infections. We investigated an outbreak of Coronavirus Disease 2019 in a London Army barracks early in the pandemic. Methods: Army personnel, their families and civilians had nasal and throat swabs for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by reverse transcriptase -polymerase chain reaction (RT-PCR), virus isolation and whole genome sequencing, along with blood samples for SARS-CoV-2 antibodies. All tests were repeated 36 days later. Findings: During the first visit, 304 (254 Army personnel, 10 family members, 36 civilians, 4 not stated) participated and 24/304 (8%) were SARS-CoV-2 RT-PCR positive. Infectious virus was isolated from 7/24 (29%). Of the 285 who provided a blood sample, 7% (19/285) were antibody positive and 63% (12/19) had neutralising antibodies. Twenty-two (22/34, 64%) individuals with laboratory-confirmed infection were asymptomatic. Nine SARS-CoV-2 RT-PCR positive participants were also antibody positive but those who had neutralising antibodies did not have infectious virus. At the second visit, no new infections were detected, and 13% (25/193) were seropositive, including 52% (13/25) with neutralising antibodies. Risk factors for SARS-CoV-2 antibody positivity included contact with a confirmed case (RR 25.2; 95% CI 14-45), being female (RR 2.5; 95% CI 1.0-6.0) and two-person shared bathroom (RR 2.6; 95% CI 1.1-6.4). Interpretation: We identified high rates of asymptomatic SARS-CoV-2 infection. Public Health control measures can mitigate spread but virus re-introduction from asymptomatic individuals remains a risk. Most seropositive individuals had neutralising antibodies and infectious virus was not recovered from anyone with neutralising antibodies. Funding: PHE

Parents' and teachers' attitudes to and experiences of the implementation of COVID-19 preventive measures in primary and secondary schools following reopening of schools in autumn 2020: a descriptive cross-sectional survey.

OBJECTIVE: To assess implementation and ease of implementation of control measures in schools as reported by staff and parents. DESIGN: A descriptive cross-sectional survey. SETTING: Staff and parents/guardians of the 132 primary schools and 19 secondary schools participating in COVID-19 surveillance in school kids (sKIDs and sKIDsPLUS Studies). MAIN OUTCOME MEASURE: Prevalence of control measures implemented in schools in autumn 2020, parental and staff perception of ease of implementation. RESULTS: In total, 56 of 151 (37%) schools participated in this study, with 1953 parents and 986 staff members completing the questionnaire. Most common measures implemented by schools included regular hand cleaning for students (52 of 56, 93%) and staff (70 of 73, 96%), as reported by parents and staff, respectively, and was among the easiest to implement at all times for students (57%) and even more so, for staff (78%). Maintaining 2-metre distancing was less commonly reported for students (24%-51%) as it was for staff (81%-84%), but was one of the most difficult to follow at all times for students (25%) and staff (16%) alike. Some measures were more commonly reported by primary school compared to secondary school parents, including keeping students within the same small groups (28 of 41, 68% vs 8 of 15, 53%), ensuring the same teacher for classes (29 of 41, 71% vs 6 of 15, 40%). On the other hand, wearing a face covering while at school was reported by three-quarters of secondary school parents compared with only parents of 4 of 41 (10%) primary schools. Other measures such as student temperature checks (5%-13%) and advising staff work from home if otherwise healthy (7%-15%) were rarely reported. CONCLUSIONS: Variable implementation of infection control measures was reported, with some easier to implement (hand hygiene) than others (physical distancing)

Reinfection with new variants of SARS-CoV-2 after natural infection: a prospective observational cohort in 13 care homes in England.

Background: Understanding the duration of protection and risk of reinfection after natural infection is crucial to planning COVID-19 vaccination for at-risk groups, including care home residents, particularly with the emergence of more transmissible variants. We report on the duration, neutralising activity, and protection against the alpha variant of previous SARS-CoV-2 infection in care home residents and staff infected more than 6 months previously. Methods: We did this prospective observational cohort surveillance in 13 care homes in Greater London, England. All staff and residents were included. Staff and residents had regular nose and throat screening for SARS-CoV-2 by RT-PCR according to national guidelines, with ad hoc testing of symptomatic individuals. From January, 2021, antigen lateral flow devices were also used, but positive tests still required RT-PCR confirmation. Staff members took the swab samples for themselves and the residents. The primary outcome was SARS-CoV-2 RT-PCR positive primary infection or reinfection in previously infected individuals, as determined by previous serological testing and screening or diagnostic RT-PCR results. Poisson regression and Cox proportional hazards models were used to estimate protective effectiveness of previous exposure. SARS-CoV-2 spike, nucleoprotein, and neutralising antibodies were assessed at multiple timepoints as part of the longitudinal follow-up. Findings: Between April 10 and Aug 3, 2020, we recruited and tested 1625 individuals (933 staff and 692 residents). 248 participants were lost to follow-up (123 staff and 125 residents) and 1377 participants were included in the follow-up period to Jan 31, 2021 (810 staff and 567 residents). There were 23 reinfections (ten confirmed, eight probable, five possible) in 656 previously infected individuals (366 staff and 290 residents), compared with 165 primary infections in 721 susceptible individuals (444 staff and 277 residents). Those with confirmed reinfections had no or low neutralising antibody concentration before reinfection, with boosting of titres after reinfection. Kinetics of binding and neutralising antibodies were similar in older residents and younger staff. Interpretation: SARS-CoV-2 reinfections were rare in older residents and younger staff. Protection from SARS-CoV-2 was sustained for longer than 9 months, including against the alpha variant. Reinfection was associated with no or low neutralising antibody before reinfection, but significant boosting occurred on reinfection. Funding: Public Health England

COVID-19 outbreaks following full reopening of primary and secondary schools in England: Cross-sectional national surveillance, November 2020.

Background: The full reopening of schools in September 2020 was associated with an increase in COVID-19 cases and outbreaks in educational settings across England. Methods: Primary and secondary schools reporting an outbreak (≥2 laboratory-confirmed cases within 14 days) to Public Health England (PHE) between 31 August and 18 October 2020 were contacted in November 2020 to complete an online questionnaire. Interpretation: There were 969 school outbreaks reported to PHE, comprising 2% (n = 450) of primary schools and 10% (n = 519) of secondary schools in England. Of the 369 geographically-representative schools contacted, 179 completed the questionnaire (100 primary schools, 79 secondary schools) and 2,314 cases were reported. Outbreaks were larger and across more year groups in secondary schools than in primary schools. Teaching staff were more likely to be the index case in primary (48/100, 48%) than secondary (25/79, 32%) school outbreaks (P = 0.027). When an outbreak occurred, attack rates were higher in staff (881/17,362; 5.07; 95%CI, 4.75-5.41) than students, especially primary school teaching staff (378/3852; 9.81%; 95%CI, 8.90-10.82%) compared to secondary school teaching staff (284/7146; 3.97%; 95%CI, 3.79-5.69%). Secondary school students (1105/91,919; 1.20%; 95%CI, 1.13-1.28%) had higher attack rates than primary school students (328/39,027; 0.84%; 95%CI, 0.75-0.94%). Conclusions: A higher proportion of secondary schools than primary schools reported a COVID-19 outbreak and experienced larger outbreaks across multiple school year groups. The higher attack rate among teaching staff during an outbreak, especially in primary schools, suggests that additional protective measures may be needed. Funding: PHE