ELUCIDate: “ELUcidate long-term consequences of Childhood Infections using administrative and research Data”

The University of Bristol and the London School of Hygiene & Tropical Medicine (LSHTM) require access to NHS England Data for the purpose of the following two research themes (RTs):

• RT1: Which groups of children and adolescents experience long-COVID, how is this characterized in terms of symptoms and new diagnoses, and what are their healthcare and prescription needs?

• RT2: Do long-term health outcomes differ in children and adolescents who experienced SARS-CoV-2 infection with symptoms, compared to those who experienced infection without symptoms?

The following is a summary of the aims of the research provided by the University of Bristol and LSHTM.

“Our study is called “ELUCIDate”, which stands for, “ELUcidate long-term consequences of Childhood Infections using administrative and research Data”.

“COVID-19” is caused by severe acute respiratory syndrome coronavirus, SARS-CoV-2. Several aspects of the disease remain unclear, including the symptom profile and the determinants of symptomatic disease following infections in children and young people (CYP).

The Schools Infection Survey (SIS)-1 – jointly run by ONS, the UK Health Security Agency (UKHSA) and LSHTM – systematically tested a large random sample of school children for SARS-CoV-2 roughly twice every term over the school year 2020/2021 and collected data on symptoms and other characteristics using electronic questionnaires. The purpose of this Agreement is to link NHS England Data to data from the SIS-1 in order to investigate the above RTs. SIS-1, enriched by the requested linkages, provides a unique and convenient opportunity to examine these important research questions and provide further insight into the COVID-19 pandemic.

Little is known about the long-term consequences of SARS-CoV-2 infection and COVID-19 disease among CYP. Uncertainty in the diagnosis and presentation of what is colloquially known as long-COVID, means that even a basic understanding of the incidence and prevalence of the condition is lacking. In adults, the REal-time Assessment of Community Transmission 2 (REACT-2) study found that one in three individuals with SARS-CoV-2 infection had at least one of 29 symptoms persistent after 12 weeks since infection. Acute COVID-19 illness is milder among CYP, but this doesn’t mean that long-term consequences of infection do not impact this age group. As the infection impacts differently on CYP compared to adults, it is likely that the clinical presentation, those most at risk and the illness trajectory of long-COVID also vary.

The National Institute for Health and Care Excellence (NICE) currently uses the following definitions:

• Acute COVID-19: signs and symptoms of COVID-19 for up to 4 weeks.

• Ongoing symptomatic COVID-19: signs and symptoms of COVID-19 from 4 to 12 weeks.

• Post-COVID-19 syndrome: signs and symptoms that develop during or after an infection consistent with COVID-19, continue for more than 12 weeks and are not explained by an alternative diagnosis.

NICE also defines long-COVID as, “signs and symptoms that continue or develop after acute COVID-19”, i.e., including both ongoing symptomatic COVID-19 and post-COVID-19 syndrome. Studies in CYP have looked at ongoing symptomatic COVID-19 with estimates of long-lasting symptoms attributable to SARS-CoV-2 ranging between 3-14%. For example, in a cohort study of UK CYP aged 5-17 years, 4.4% who tested positive for SARS-CoV-2 infection experienced symptoms for at least 28 days, compared to 0.9% of matched negative controls (suggesting ~3% had SARS-CoV-2-attributable symptoms). A similar study found that 30% of CYP positive for SARS-CoV-2 had at least three symptoms 15 weeks later, compared to 16% of CYP who tested negative (suggesting 14% had SARS-CoV-2-attributable symptoms). No studies of CYP have yet to investigate the longer-term health outcomes associated with SARS-CoV-2, meaning the risk of post-COVID-19 syndrome is particularly poorly understood in this population.

A lack of consensus on the symptoms which constitute ongoing symptomatic COVID-19 and long-COVID, especially in CYP, means that identifying the scale of the problem has been challenging. Different studies have looked at different symptoms, although some commonalities between the most frequently-reported symptoms (e.g., headache, fatigue) have been found. Furthermore, many of the reported long-COVID symptoms are non-specific, and therefore differentiating between those caused by SARS-CoV-2 and other conditions is difficult, especially when an adequate control group is lacking. Looking more widely at symptoms, and incorporating other sources of data such as health service utilisation, new prescriptions and new diagnoses, would give a more complete picture of how the COVID-19 pandemic has affected the long-term health of CYP.

The first research theme aims to investigate the acute and long-term health consequences of SARS-CoV-2 infection in CYP using SIS-1. Data will be used on reported symptoms and school absences, and information on clinical diagnoses, prescriptions and health service utilisation during 2019 (to generate risk factor data) and since the start of 2020 (to use as outcome data), obtained from linking SIS-1 to data from electronic health records (EHRs). The analysis will use a novel approach of investigating the association of SARS-CoV-2 infection with each of the chapters of diagnoses from the 10th revision (2019 version) of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) that relate to all and any respiratory, cardiovascular, gastrointestinal, psychological/psychiatric, and nervous system diseases, as well as with signs and symptoms not elsewhere classified (which includes fever, headache, fatigue and pain), and with selected chapters of the British National Formulary for Children (BNFC) that relate to the same conditions, thereby covering all possible outcomes of SARS-CoV-2 infection, insofar as the outcomes considered are those that have most clinical relevance for CYP, and avoiding assumptions about the nature of long-COVID in children. These outcomes will be investigated for (1) between 4-12 weeks and (2) more than 12 weeks following (first) SARS-CoV-2 infection), where possible, in line with NICE’s definitions for ongoing symptomatic COVID-19 and post-COVID-19 syndrome, respectively, thereby generating some of the first evidence of the risk and nature of long-COVID in children. In summary, the first research theme will:

1. Examine whether SARS-CoV-2 infection (versus no SARS-CoV-2 infection) increases the risk of adverse health outcomes, and the predisposing socio-demographic and clinical factors for adverse health outcomes, as defined by:

a. reported survey symptoms persisting for (1) 4-12 weeks and (2) more than 12 weeks;

b. any diagnosis of a symptom/condition from selected ICD-10 chapters for (1) 4-12 weeks and (2) after 12 weeks since (first) SARS-CoV-2 infection;

c. any pharmacological product prescribed in primary care for selected BNF chapters for (1) 4-12 weeks and (2) after 12 weeks since (first) SARS-CoV-2 infection;

d. health service utilisation: (a) primary care visit (b) A&E visit; (c) hospital admission; (d) outpatient visit, for (1) 4-12 weeks and (2) after 12 weeks since (first) SARS-CoV-2 infection;

e. number of school absences due to illness (as a proxy measure of illness).

2. Investigate the predisposing socio-demographic and clinical factors associated with an increased risk of the adverse health outcomes following a SARS-CoV-2 infection

3. Explore the use of time-varying clustering to group self-reported symptoms and diagnoses and identify common post infection sequalae in CYP.

At present, it is very difficult to know whether long-COVID is different to the long-lasting effects of other infections in CYP, as these were not well understood even before the SARS-CoV-2 pandemic. Co-infections may be an important influencing factor on the development of long-COVID; however these are particularly poorly understood. The health consequences of SARS-CoV-2 infection in CYP will be compared to those following other infections, using acute fever (reported in SIS-1) as a marker, and again, exploring the influencing clinical and socio-demographic characteristics. Since fever is a specific, but not sensitive, marker for infection, as a first step, patterns of fever and other symptoms will be described. The marker for infection may be widened to consider other symptoms. The study team will examine the modifying effect of infectious agent in the analyses, where possible (including exploring co-infections), since acute fever has multiple possible infectious causes.

This research is hoped to generate an understanding of how long-COVID compares to long-term outcomes of other infections in children. The additional knowledge and understanding gained about the long-term outcomes of SARS-CoV-2 infection will generate additional value from the linked SIS-1 dataset, and is expected to increase the clinical relevance of the research.

The second research theme as part of this study will aim to characterise acute symptomatic SARS-CoV-2 infection in school-aged children in England and investigate determinants for symptomatic compared with asymptomatic infection in this population, including socio-demographics, virological, clinical and pharmacological characteristics. There remains a paucity of research characterising the symptom profile and determinants of acute SARS-CoV-2 infection and symptomatic COVID-19 disease among school-aged CYP. Additionally, there is limited evidence about how new variants of SARS-CoV-2 have contributed to a changing symptom profile in CYP. Available reports indicate that some of the new variants have changes that allow them to spread more easily in both children and the general population, but with no evidence of increased susceptibility compared to adults. However, due to some groups of CYP remaining largely unvaccinated it is useful to understand the symptom profile of COVID-19 in this group, as well as to elucidate who is most at risk of symptomatic infection and if they are at higher risk of subsequent clinical progression of disease. In addition, understanding who gets asymptomatic infection may help in exploring the role of CYP as transmitters.

The following NHS England Data will be accessed:

• Hospital Episode Statistics Admitted Patient Care, Critical Care, Outpatients, and Accident & Emergency Data and the Emergency Care Data Set (ECDS) – necessary to capture secondary care data on demographics, healthcare utilisation, symptom reporting, diagnoses and comorbidities

• General Practice Extraction Service (GPES) Data for Pandemic Planning and Research (GDPPR) – necessary to capture primary care data on demographics, symptom reporting, healthcare utilisation, diagnoses and comorbidities

• COVID-19 Second Generation Surveillance Systems (SGSS) – necessary to capture data on SARS-CoV-2 infection

• Medicines dispensed in Primary Care NHS Business Services Authority (NHSBSA) – The NHSBSA Medicines Data Directions 2019 drives the linkage of medicines Data with other datasets to provide intelligence about the safety and effectiveness of medicines. This hypothesis-generating study aims to produce intelligence about the medicines that are prescribed following the development of long-COVID, which will be able to inform subsequent studies of the safety and efficacy of these medicines in CYP with long-COVID.

The linked dataset will greatly enrich the capability to find records within the SIS-1 cohort with symptoms as a result of SARS-CoV-2 infection, as well as other Data to explore for potential association with the risk of developing symptomatic COVID-19. As SARS-CoV-2 is a relatively new infection, new findings are being generated about the long-term implications of infection, and the study team require all of the described Data in order to respond to new findings and investigate these areas.

The level of the Data will be pseudonymised.

The Data will be minimised as follows:

• Limited to a study cohort identified by the Office for National Statistics (ONS) – including only pupils involved in the SIS-1;

• Limited to Data between 2019 and 2023

The University of Bristol as research sponsor, and LSHTM as the main collaborator, are joint controllers as the organisations responsible for ensuring that the Data will only be processed for the purpose described above.

The lawful basis for processing personal data under the UK GDPR is:

Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller.

The lawful basis for processing special category data under the UK GDPR is:

Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

This research is in the public interest because it is expected to:

1. Produce a definition or definition(s) of long-COVID in CYP

2. Identify which CYP are at greatest risk of acute SARS-CoV-2 symptoms and of long-COVID

3. Identify the socio-demographic and clinical characteristics of those children and young people with symptoms who attend primary care and those who do not

4. Characterise the healthcare needs, new prescriptions and new diagnoses CYP with long-COVID may have, thereby informing the clinical management of long-COVID, resource allocation, and subsequent studies of the safety and efficacy of new prescriptions in CYP with long-COVID

5. Characterise the ways in which long-COVID is different to the long-term effects possible from other infections among CYP.

This project will inform and support the clinical management of adverse SARS-CoV-2 related outcomes in children and young people through the following outputs:

Output 1: Generating a definition(s) of long-COVID in CYP for the better identification of this condition

Output 2: Identifying which groups of CYP are most at risk of long- and short-term effects of SARS-CoV-2 to inform clinical management and prevention strategies

Output 3: Informing the extent to which children and young people with long-COVID attend primary care (and hence the potential unmet need for care), and the influencing socio-demographic and clinical characteristics

Output 4: Informing the trajectory of long-COVID in CYP in terms of healthcare needs, new prescriptions and new diagnoses, and how this compares to that associated with long-term effects from other infections

Output 5: Producing appropriate information and messaging for the support of children and young people and their families.

The funding comes from multiple sources. Current funders include:

• National Institute for Health Research (NIHR) School of Primary Care Research (SPCR) – Funding is in place until 30/06/2024 (NCE to 31/12/2024).

• HDR UK - Funding has been provided to set up the study and carry out some preliminary analysis.

• NIHR Advanced Fellowship – Funding is in place until 31/07/2027.

Funding to continue the work described will be sought on an ongoing basis.

The funders will have no ability to suppress or otherwise limit the publication of findings.

ONS is a processor acting under the instructions of the University of Bristol and LSHTM. ONS’s role is limited to providing the study cohort to NHS England and providing access to the linked SIS-1 and NHS England Data in the Secure Research Service (SRS).

Crown Hosting Data Centres provide cloud-based infrastructure to ONS and will store the Data as contracted by ONS.

iTS Computing Group (formerly known as Equiniti) provide implementation and maintenance services for ONS SRS’s Crown Hosting Data Centres infrastructure.

UKHSA are collaborators on SIS but are not responsible for designing the research of this current study and are not accessing the NHS England Data.

For the patient and public involvement and engagement (PPIE) activities, views about long-COVID were gathered from young people, parents and doctors between 9 March and 30 April 2021 to inform the research questions and methods through:

• an online meeting with seven young people aged 13-18 years from the NIHR Bristol Biomedical Research Centre Young People’s Advisory Group (YPAG);

• an online meeting with five families whose children, aged 10-16 years, have long-COVID or suspected long-COVID;

• a survey completed by four GPs and one paediatrician, and an online meeting with two paediatricians.

PPIE contributors said that:

1. The COVID-19 pandemic is ongoing and there are many knowledge gaps.

2. Clinical understanding of long-COVID in CYP is currently extremely limited. Long-COVID in CYP is not well defined, and it may be difficult for doctors to distinguish between long-COVID and other conditions. It still needs to be understood whether long-COVID is a new condition in itself, or a group of conditions like post viral fatigue.

3. For these reasons, long-COVID is likely to have been under-diagnosed to some extent to date, although it is still unclear what exactly long-COVID in CYP means.

4. Symptoms attributed to long-COVID varied between the families spoken to, and the symptoms their children had experienced were more wide-ranging than those listed on the NHS website. Not all had been tested at the time of their infection.

5. The families whose children have long-COVID or suspected long-COVID ranked extreme tiredness, shortness of breath, chest pain, heart palpitations, depression, anxiety, feeling sick or stomach pain, diarrhoea, headaches or fever, and allergies in the top 3 most harmful symptoms at least once.

6. Of the symptoms listed by the NHS for long-COVID, feeling sick or stomach pain, extreme tiredness, and headaches were the symptoms commonly ranked as most harmful by young people and by families whose children have long-COVID or long-COVID.

From this it was concluded that:

1. Considering a wider range of symptoms, and looking more broadly at things like GP and hospital visits, and school attendance, might be a better way at this time of assessing how COVID-19 has affected CYP. It is important to be aware of things like the extent to which healthcare is accessed according to need. The impact on CYP with milder symptoms may be missed if only EHR data are examined.

2. Feeling sick or stomach pain, extreme tiredness, and headaches will be important symptoms to consider in the study.

3. Some SARS-CoV-2 infections which occurred early in the pandemic will not have been recorded, affecting the measurement of long term health outcomes (e.g., misclassification of exposure bias).

These findings and conclusions have directly influenced the diagnoses/symptoms/prescriptions that will be looked at in the study (i.e., taking a broad, exploratory approach), what data will be used to investigate the long-term adverse effects SARS-CoV-2 has on CYP to include both EHR and research data, and consideration of potential biases such as those due to testing strategy leading to misclassification of exposure.

Under the previous iteration of this Data Sharing Agreement, the Office for National Statistics (ONS) transferred data to NHS England. The data consisted of identifying details (specifically NHS Number, Date of Birth and a unique person ID) for the cohort to be linked with NHS England Data. There are no plans for a further flow of data from ONS to NHS England.

NHS England will provide the relevant records from the General Practice Extraction Service (GPES) Data for Pandemic Planning and Research (GDPPR). The relevant records from the following NHS England data sets were supplied under the previous iteration of this Data Sharing Agreement: Emergency Care Data Set (ECDS); HES Admitted Patient Care, Critical Care, Outpatients, and Accident & Emergency; Medicines dispensed in Primary Care (NHSBSA), and COVID-19 Second Generation Surveillance Systems (SGSS) dataset to ONS.

The Data will contain no direct identifying data items but will contain a unique person ID which can be used to link the Data with other record level data already held by the recipient.

The Data will not be transferred to any other location.

The Data will be stored on servers at ONS.

ONS stores Data on the Cloud provided by Crown Hosting Data Centres.

The Data will be accessed by authorised personnel via remote access. The Data will remain on the servers at ONS at all times.

Personnel are not technically capable of downloading or copying data to local devices.

The Data will not leave the UK at any time.

Access is restricted to substantive employees of the University of Bristol and London School of Hygiene and Tropical Medicine (LSHTM) who are named ONS-accredited researchers, and substantive employees of ONS.

Access to confidential patient identifiable data is restricted to employees of ONS. The identifying details will be stored in a separate database to the linked dataset used for analysis. There would be no circumstances in which ONS would need to re-identify a study participant in relation to this study.

Employees of the University of Bristol and LSHTM are permitted to access pseudonymised Data only.

All personnel accessing the Data have been appropriately trained in data protection and confidentiality.

The Data will be linked at person record level with the Schools Infection Survey (SIS)-1 held by ONS.

There will be no requirement and no attempt to reidentify individuals when using the Data.

Researchers from the University of Bristol and LSHTM will analyse the Data with the support of ONS for the purposes described above.

The expected outputs of the processing will be:

• Submissions to peer reviewed journals – a minimum of 2 papers in high-impact open access journals are expected

• Presentations at key academic conferences such as the Royal College of Paediatrics and Child Health, the International Society for Infectious Diseases, and International Conference on Emerging Infectious Diseases conferences.

• Developed code shared via the HDR UK Innovation Gateway/ other appropriate information sharing platforms

The outputs will not contain NHS England Data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived.

The outputs will be communicated to relevant recipients through the following dissemination channels:

• Journals

• Social media

• Press/media engagement

• Blogs, press reports and news stories on the websites of the study team and funders

• Public reports

• Direct bilateral engagement with policy makers and the UK Health Security Agency

• Executive summaries for local and national policy makers

• ONS newsletters to key stakeholders including central Government

• Information sheets for patients and their families, clinicians, headteachers/schools and the public, as appropriate.

The target dates for production and dissemination of the outputs are Q2 2026 – Q2 2027.

It is expected that this research will help quantify the impact of adverse health outcomes of SARS-CoV-2 infection in children. It is also anticipated that this research will help determine the risk factors for developing symptomatic disease following infection, and long-term outcomes, such as age, gender, ethnicity and the nature of the SARS-CoV-2 infection itself.

By understanding the impact of the COVID-19 pandemic on children, healthcare services should be better placed to support children and young people (CYP). Understanding the impact of disease and who it most affects will inform the information, advice and care given to CYP with, or at risk of, long-COVID or long-term effects from other infections. It will help to enable the appropriate targeting of resources, e.g., to mental health services, or to chronic fatigue clinics, or to cardiac care. Understanding which medicines are newly prescribed to CYP with long-COVID will inform subsequent studies of the safety and efficacy of these medicines in CYP with long-COVID.

The COVID-19 pandemic has affected everyone. Public health policies on vaccination, testing, school closures and restriction of movement have widespread economic, health and social impact. Health resources are finite. It is in the public interest for there to be transparency in the underlying evidence supporting public health policies and resource distribution.

The use of the Data could:

• help the system to better understand the health and care needs of populations.

• lead to the identification or improvement of treatments or interventions, or health and care system design such as future vaccination and pandemic planning strategies

• advance understanding of regional and national trends in health and social care needs.

• advance understanding of the need for, or effectiveness of, preventative health and care measures for particular populations (here, CYP) or conditions (here, long-COVID)

• inform planning health services and programmes, for example to improve equity of access, experience and outcomes.

• inform decisions on how to effectively allocate and evaluate funding according to health needs.

It is hoped that through publication of findings in appropriate media, the findings of this research will add to the body of evidence that is considered by the bodies, organisations and individual care practitioners charged with making policy decisions concerning the management and support of children and young people’s recovery following the pandemic. The Schools Infection Survey (SIS) is a national study and it is anticipated that results from this project will influence national policy, with learnings generalisable to school settings internationally.

The study team recently produced a report of PPIE activities for the study. The report is entitled, “Long COVID in children: A report summarising the views of young people, parents and doctors.” This report was written for both an academic and public readership and was published on the COVID-19 Mapping and Mitigation in Schools (CoMMinS) website (https://commins.org.uk/news/july2021/). A press release was produced by the University of Bristol in collaboration with Health Data Research (HDR) UK, ONS, LSHTM and UKHSA, and the report was subsequently taken up by BBC Points West and BBC South Today. Key media outlets expressed a keen interest in doing features about the findings from the study when available, and contacts will be followed up with the findings. The report was featured in blogs and news stories on the CoMMinS website, IEUREKA website, University of Bristol news website and HDR UK website. HDR UK, the University of Bristol, ONS and LSHTM all tweeted about the report. The PPIE contributors were also contacted directly to share the published report with them. It is expected that a similar strategy will be taken when it comes to publicising the study findings. Since the start of the ELUCIDate study, a further 13 PPIE meetings have been held, reports for which are available on the ELUCIDate website https://elucidatestudy.blogs.bristol.ac.uk/public-involvement/.

The SIS and CoMMInS leadership teams, which include members of the Scientific Pandemic Influenza Group on Modelling and Joint Committee on Vaccination and Immunisation advisory groups, as well as national government bodies (ONS and UKHSA), will be utilised to disseminate findings to a wide audience.

NHSE supplied the relevant periods of data from the HES, ECDS, SGSS, and NHSBSA datasets by 20th December 2023. The Office for National Statistics stored these data in its secure environment ready for analysis by the Research Team. The Research Team await access to the GDPPR data necessary for the full analysis.