Epidemiology and Prognosis in Acute Myocarditis

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[4 paragraphs unchanged] A further project extension has been requested due to ongoing analyses that have partly informed the recently updated 2025 European Society of Cardiology Guidelines on Myocarditis and Pericarditis. https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaf192/8234483?login=true. There is ongoing need to refine our understanding of myocarditis and pericarditis and related conditions to drive forward advances in the field to improve patient outcomes, including greater understanding on regional variation in the provision of clinical care.

Unchanged: Objective for processing, Processing activities, Expected output, Expected measurable benefits.

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Objective for processing

GLOSSARY of TERMS Guy’s and St Thomas’ NHS Foundation Trust requires access to NHS England data for the purpose of the following research project: • Myocarditis - inflammation of the heart muscle. Is known to predominantly affect young adults aged between 19-35 years. It is usually related to a recent viral infection. Epidemiology and Prognosis in Acute Myocarditis. • myocardial infarction – medical name for a heart attack The following is a summary of the aims of the research project provided Guy’s and St Thomas’ NHS Foundation Trust. • Epidemiology - the branch of medicine which deals with the incidence, distribution, and possible control of diseases and other factors relating to health. “Royal Brompton Hospital (a part of the Royal Brompton and Harefield Clinical Group clinical group within the Guy's and St Thomas' NHS Foundation Trust) aims to describe the longitudinal epidemiological trends of acute myocarditis and related conditions referring to pericarditis and cardiomyopathy to provide a contemporary, population-level assessment of the burden of disease and how this may have changed over the last 23 years. National data is therefore required over a total of a 23-year period under this agreement recognising changes and variation arising from medical, biological, geographical, and social factors. • Pericarditis - inflammation of the adjacent lining of the heart “Myocarditis means inflammation of the heart muscle and is known to predominantly affect young adults aged between 19- 35 years. It is usually related to a recent viral infection. Patients often present with severe, sudden-onset chest pain mimicking a heart attack, difficulty breathing due to weakened heart muscle, and/or palpitations due to electrical rhythm disturbances within the heart. However, myocarditis also affects infants and older adults where causative factors, and clinical outcomes are poorly characterised. In the long-term, up to one third of patients are at risk of developing heart failure, known as dilated cardiomyopathy, or experiencing a sudden cardiac arrest. • Myopericarditis – overlap of Myocarditis and Pericarditis “Few studies have investigated the epidemiology of myocarditis on a population level, and there is no data on the incidence and prevalence of myocarditis within the UK. Historical studies focused on small cohorts, such as Finnish military conscripts in Helsinki. The WHO Global Burden of Disease study was not directly relevant to the UK and provided no data on patient prognosis. Whilst there are a growing number of clinical research studies investigating new diagnostic tools and treatments in myocarditis, these small groups of recruited study participants represent the 'tip of an iceberg.' • Dilated cardiomyopathy - is a condition in which the heart muscle becomes weakened and enlarged. As a result, the heart cannot pump enough blood to the rest of the body. “Guy’s and St Thomas’ NHS Foundation Trust also aims to provide an understanding of the burden of acute COVID-19 infection at any given time point relative to acute myocarditis admissions and to specifically determine the prevalence of acute myocarditis within patients hospitalised due to COVID-19. Demographic and diagnostic information from laboratory test reports (via the Second Generation Surveillance System (SGSS)) will be used alongside comorbidity, treatment, and clinical outcome information for patients recorded in the COVID-19 Hospitalisations in England Surveillance System (CHESS). Whilst there are limitations with the data quality arising from the earlier phases of the pandemic, Guy’s and St Thomas’ NHS Foundation Trust intends to use the data available to provide greater context of the burden of acute myocarditis during the pandemic in relation to COVID-19 infection, thereby addressing a key unmet clinical need.” • Troponin assays - Troponin is a calcium-regulatory protein for the calcium regulation of contractile function in skeletal and cardiac muscles. The assay is the test used for measuring troponin in nanograms per milliliter of blood (ng/ml) Guy’s and St Thomas’ NHS Foundation Trust have access to the following NHS England data: • Echocardiography – is a diagnostic test which uses ultrasound waves to make images of the heart chambers, valves and surrounding structures. It can measure cardiac output and is a sensitive test for fluid around the heart (pericardial effusion). • Hospital Episode Statistics Admitted Patient Care – necessary because the data will allow Royal Brompton Hospital to estimate how many patients are readmitted and whether this typically occurs in the short or long-term. Such data would be useful from a healthcare economics perspective and again alleviate patient concerns if appropriate to do so. • Viral aetiology – The study of the causes of viruses • Civil Registrations of Death (Secondary Care Cut) – necessary to provide insights into clinical outcomes in a real-world setting. • Cardiac arrhythmia – is an abnormality of the heart's rhythm • COVID-19 SGSS First Positives (Second Generation Surveillance System) - necessary to link in with the study of the epidemiology of acute myocarditis and impact of COVID-19. • Thrombogenicity - the tendency of a material in contact with the blood to produce a thrombus, or clot. • COVID-19 Hospitalization in England Surveillance System (CHESS) – necessary to provide an understanding of the burden of acute COVID-19 infection in relation to trends in acute myocarditis on a national level before and during the pandemic, recognising that an important subset of patients hospitalised with COVID-19 infection have superadded acute myocardial injury. • Thrombi – a blood clot formed in situ within the vascular system of the body and impeding blood flow. • Emboli - a blood clot, air bubble, piece of fatty deposit, or other object which has been carried in the bloodstream to lodge in a vessel and cause an embolism. ______________________________________________________ *** This amendment (v3) requests missing data for 2017/18, cause and identified as a change in the methodology later in their agreement. [1 paragraph unchanged] The study team have identified during their analysis that they are missing data for the latter half of the 2017-2018 HES APC dataset from their original data request in 2018. For example, from the row counts below, one can see that there were fewer episodes in this financial year: Demographic and diagnostic information from laboratory test reports is requested via the Second-Generation Surveillance System (SGSS), alongside comorbidity, treatment, and clinical outcome information for patients recorded in the COVID-19 Hospitalisations in England Surveillance System (CHESS). NIC144568_HES_APC_201299 2012 - 2013 2,334,645 The level of the data will be pseudonymised. NIC144568_HES_APC_201399 2013 - 2014 2,356,175 The data will be minimised as follows: NIC144568_HES_APC_201499 2014 - 2015 2,355,019 • The HES data is limited to individuals with ‘myocarditis’, pericarditis, cardiomyopathy, cardiac arrest, or myocardial infarction from all ages (birth to death) across England. NIC144568_HES_APC_201599 2015 - 2016 2,359,378 • The mortality data is limited to the HES cohort as defined above. NIC144568_HES_APC_201699 2016 - 2017 2,276,248 For the SGSS and CHESS datasets, data on all individuals included in the respective datasets are required to help understand the impact of COVID-19 infection rates on myocarditis and associated conditions. NIC144568_HES_APC_201799 2017 - 2018 1,640,625 * National data was requested to remove geographical bias due to regional differences in viral aetiology and healthcare systems, ultimately informing changes to clinical guidelines and policies on a national level. In order to complete their analyses, the study team are submitting this amendment (v3) to obtain the complete 2017-2018 dataset. Guy's and St Thomas' NHS Foundation Trust is the research sponsor and the controller as the organisation responsible for ensuring that the data will only be processed for the purpose described above. In their original application, the data had been truncated to 0-80 years but this upper age cut-off was removed in the recent application to study the full impact of the COVID-19 pandemic. Therefore, the study team requires the complete 2017-2018 dataset without an age filter. As before, a linkage with the Mortality data is required. The lawful basis for processing personal data under the UK GDPR is: Additionally, the study team are also requesting additional data for the fixed HES APC file of 2021/22 data plus the four quarters of 2021/22 (April 2021 to March 2022) to fully examine the effect of COVID-19 infection on subsequent myocarditis, but also the impact of the vaccines which are now also increasingly linked with myocarditis. For this aspect of the project, the study team are also requesting pseudonymised record-level national data from the SGSS and CHESS datasets. 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. It is noted under this amendment (v3) that the Data Controller's legal entity has been amended to Guy's and St Thomas' NHS Foundation Trust, as Royal Brompton Hospital (previously Royal Brompton and Harefield Hospitals) no longer hold Foundation Trust status. The sole Data Controller and legal entity is therefore Guy's and St Thomas' NHS Foundation Trust. Royal Brompton Hospital is referenced in this agreement as they are part of the Royal Brompton and Harefield Clinical Group within the Guy's and St Thomas' NHS Foundation Trust, where all the study researchers are based. All those accessing NHS Digital data are substantive employees of Guy's and St Thomas' NHS Foundation Trust. ***** The lawful basis for processing special category data under the UK GDPR is: SUMMARY 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. Royal Brompton Hospital (a part of the Royal Brompton and Harefield Clinical Group clinical group within the Guy's and St Thomas' NHS Foundation Trust) aims to describe the longitudinal epidemiological trends of acute myocarditis to provide a contemporary, population-level assessment of the burden of disease and how this may have changed over the last 23 years. National data is therefore required over a total of a 23 year period under this agreement recognising changes and variation arising from medical, biological, geographical and social factors. This processing is in the public interest because it is hoped that the outputs of this research will be used to improve and standardise the diagnosis, treatment, and surveillance of patients with myocarditis. Myocarditis means inflammation of the heart muscle and is known to predominantly affect young adults aged between 19-35 years. It is usually related to a recent viral infection. Patients often present with severe, sudden-onset chest pain mimicking a heart attack, difficulty breathing due to weakened heart muscle, and/or palpitations due to electrical rhythm disturbances within the heart. However, myocarditis also affects infants and older adults where causative factors and clinical outcomes are poorly characterised. In the long-term, up to one third of patients are at risk of developing heart failure, known as dilated cardiomyopathy, or experiencing a sudden cardiac arrest. The funding comes from multiple sources. Current funders include Alexander Janson Foundation, Royal Brompton Hospital & British Heart Foundation. Funding to continue the work described will be sought on an ongoing basis. Few studies have investigated the epidemiology of myocarditis on a population level, and there is no data on the incidence and prevalence of myocarditis within the UK. Historical studies focused on small cohorts, such as Finnish military conscripts in Helsinki. The WHO Global Burden of Disease study was not directly relevant to the UK and provided no data on patient prognosis. Whilst there are a growing number of clinical research studies investigating new diagnostic tools and treatments in myocarditis, these small groups of recruited study participants represent the 'tip of an iceberg.' This Agreement refers to Royal Brompton Hospital as the study team are based there, representing the Royal Brompton and Harefield Clinical Group within the Guy's and St Thomas' NHS Foundation Trust. Royal Brompton Hospital seeks to obtain all available data on hospital admissions specifically due to 'myocarditis' (I40, I51.4, I01.2, I09.0) in all age groups across England/Wales over the last 23 years. Data on age, sex, ethnicity, length of admission, method of admission, Intensive Therapy Unit (ITU) bed days and specific cardiac procedures (including cardiac catheterisation, endomyocardial biopsy, pacemaker/implantable cardioverter defibrillator (ICD)/ ventricular assist device (VAD) implantation and cardiac transplantation) would be important to record. Data on readmission would be useful to understand predictors of disease recurrence, and ultimately, linkage to mortality data with cause of death would provide new insights into clinical outcomes in a real-world setting. Geographical data may be helpful to understand whether social deprivation or pollution levels are implicated. The study team works in an established research centre within the hospital intrinsically linked with the National Heart and Lung Institute of Imperial College London. For this reason, and due to the longevity of this study, the data has not been obtained via the one of the several recently developed Trusted Research Environments. Whilst this collaborative approach is important for the long-term future of national cardiovascular research initiatives, the applicants intend to complete the existing study (with this COVID-19 extension) using their own established and trusted research environment. Royal Brompton Hospital also seeks to obtain the same depth of Hospital Episode Statistics (HES) Admitted Patient Care (APC) and linked mortality information on hospital admissions due to pericarditis and myocardial infarction. Myocarditis overlaps with pericarditis (inflammation of the adjacent lining of the heart; collectively referred to as myopericarditis) and again there are no data on the incidence, prevalence or prognosis of pericarditis within the UK. Myocardial infarction represents a distinct disease process due to restriction in coronary blood supply but also presents with sudden-onset, severe chest pain. There are many published studies and national audits on myocardial infarction within the UK. Within this application, data on myocardial infarction is requested to allow accurate understanding and comparison across the same HES data elements on the scale and scope of myocarditis. A Public and Patient Involvement and Engagement group helped refine the purpose of the research. The group supported the collection of the data for the purposes described above. The Trust arranged its 6th annual myocarditis patient and relatives' information evening on 16th November 2022 in partnership with Cardiomyopathy UK with the specific aim of providing support and education to individuals affected by myocarditis, these meetings continue annually. Up to one third of patients with myocarditis develop heart failure and dilated cardiomyopathy (DCM). DCM is the leading cause for needing a heart transplant in the UK (based on studies conducted prior to the COVID-19 pandemic which does not encompass DCM following infection with SARS-CoV-2). Royal Brompton Hospital seeks to obtain the same depth of HES APC and linked mortality information on these hospital admissions to allow epidemiological and prognostic assessment of myocarditis relative to heart failure and dilated cardiomyopathy overall. Furthermore, it is expected that myocarditis may be recorded as a secondary diagnosis in a significant but yet unknown number of these admissions. Failing to detect these cases would lead to underestimation of the burden of myocarditis. Based on extrapolation from published data the Royal Brompton Hospital estimates that myocarditis accounts for one sudden cardiac death each week in an individual aged <35 years of age in the UK. From a mechanistic perspective, this occurs due to electrical disturbances within the heart due to the initial myocardial injury. Royal Brompton Hospital seeks to obtain the same depth of HES and linked mortality information in order to understand the true burden of myocarditis resulting in sudden cardiac arrest with or without successful resuscitation. Data is requested over a total of a 23 year period to study the longitudinal epidemiological trends linked to medical (e.g. technological advances in troponin assays, echocardiography, cardiac MRI for improved detection), social (e.g. increasing population density, pollution levels, changing work patterns) and biological (e.g. viral aetiology, drug and toxin use) changes over this time period. Twenty years allows for optimal longitudinal assessment based on published literature although the applicant is aware of the reduced depth of data in the earlier years. Data is requested for all individuals from birth to death recognising that while myocarditis predominantly affects young adults, it remains an important cause for heart failure in young infants and older age groups due to altered immune responses and overlap with other systemic inflammatory conditions - the understanding of myocarditis in these groups is particularly limited. National data is requested in order to remove geographical bias due to regional differences in viral aetiology and healthcare systems, ultimately informing changes to clinical guidelines and policies on a national level. Readmission data is requested in order to understand the likelihood of myocarditis recurrence over the study period as it is recognised that a subset of patents will suffer a recurrence many years later. At present, there are few tools to identify such patients at the time of index presentation. Alternative diagnoses made at the time of readmission may also be due to complications, such as heart failure and cardiac arrhythmia as described above. To facilitate accurate comparisons with other conditions of overlapping biology (pericarditis), clinical presentation (myocardial infarction) and better understanding of long-term complications (sudden cardiac arrest and dilated cardiomyopathy), Royal Brompton Hospital seeks the same depth of HES APC and mortality linked data on these linked diagnoses: The diagnostic codes required relate to: (i) Myocarditis: (ii) Pericarditis (iii) Dilated cardiomyopathy and heart failure (iv) Cardiac arrest (v) Myocardial infarction. Given the growing public interest in sudden cardiac deaths and cardiac transplantation amongst young individuals, there is a pressing need to improve the understanding of the epidemiology and prognosis of myocarditis. Early detection through improved awareness would make a significant contribution to individual patient care in all age groups, including infants and elderly patients, where understanding is further limited. Looking back to understand unique features of patients that subsequently suffered disease recurrence or death will enable clinicians to better identify these high-risk individuals at initial presentation. In light of the current COVID-19 pandemic, there is pressing unmet need to improve the national understanding of the implications of this disease on the heart and cardiovascular system. There are several recent case reports from China and Italy that indicate that viral myocarditis appears to be particularly common and fulminant amongst affected individuals and represents a leading cause of death. There are also growing reports of increased thrombogenicity (the tendency of a material in contact with the blood to produce a thrombus, or clot. It not only refers to fixed thrombi but also to emboli, thrombi which have become detached and travel through the bloodstream) amongst affected individuals leading to micro-emboli throughout the body. It would be extremely informative to the global healthcare community to understand the prevalence of myocarditis with COVID-19 as well the downstream complications and survival rates. The NHS would be well placed to provide this contemporary information on a population level. Royal Brompton Hospital thus also seeks to obtain the CHESS and SGSS datasets to provide an understanding of the burden of acute COVID-19 infection at any given time point relative to acute myocarditis admissions, and to specifically determine the prevalence of acute myocarditis within patients hospitalised due to COVID-19. Demographic and diagnostic information from laboratory test reports is requested via the Second Generation Surveillance System (SGSS), alongside comorbidity, treatment, and clinical outcome information for patients recorded in the COVID-19 Hospitalisations in England Surveillance System (CHESS). Whilst there are limitations with the data quality arising from the earlier phases of the pandemic, Royal Brompton Hospital intends to use the data available to provide greater context of the burden of acute myocarditis during the pandemic in relation to COVID-19 infection, thereby addressing a key unmet clinical need. Royal Brompton Hospital would like pseudonymised data on all patients within the CHESS and SGSS datasets. This is an important aspect of the study in order to be able to generate meaningful estimates of the proportion of COVID-19 patients affected by myocarditis, pericarditis, cardiomyopathy and other cardiovascular diagnoses of interest; and importantly to discover which clinical features could be harnessed to identify such high-risk patients and thereby tailor their clinical management. Whilst the HES cohort is defined by a primary diagnosis of acute myocarditis, the COVID-19 datasets will look at myocarditis recorded in patients with a primary diagnosis of COVID-19. These two approaches provide a robust approach to study the inter-relationships between myocarditis and COVID-19. All age groups are required, recognising there is a high burden of acute myocarditis in infants, children and adults. In order to examine regional differences, it also not possible to minimise this cohort by geography. This agreement refers to Royal Brompton Hospital as the study team are based there, representing the Royal Brompton and Harefield Clinical Group within the Guy's and St Thomas' NHS Foundation Trust. However, the Sole Data Controller is Guy's and St Thomas' NHS Foundation Trust who also process the data in this agreement. The study team work in an established research centre within the hospital intrinsically linked with the National Heart and Lung Institute of Imperial College London. For this reason, and also due to the longevity of this study, the data has not been obtained via the one of the several recently developed Trusted Research Environments. Whilst this collaborative approach is important for the long-term future of national cardiovascular research initiatives, the applicants intend to complete the existing study (with this COVID-19 extension) using their own established and trusted research environment. LEGAL BASIS The General Data Protection Regulation Article 6 (1) (e) and Article 9 (2) (j) are the legal basis for the processing of the data. Article 6 (1) (e) states that processing is necessary for the public interest. It is hoped that the outputs of this research will be used to improve and standardise the diagnosis, treatment and surveillance of patients with myocarditis. This data will not be used for commercial purposes, will not be provided in record level form to any third party and will not be used for direct marketing. Only patients residing in England and Wales have been included in this study.

Processing activities

Royal Brompton Hospital is seeking HES APC and linked mortality data on a population level for acute myocarditis to investigate the changing epidemiological trends and long-term prognosis of this disease. Royal Brompton Hospital does not require patient identifiable information. No data will flow to NHS England for the purposes of this Agreement. Under the previous iterations of this agreement, Royal Brompton Hospital obtained all available pseudonymised record level data on hospital admissions (HES APC) specifically due to 'myocarditis', pericarditis, cardiomyopathy, cardiac arrest or myocardial infarction (I40, I51.4, I01.2, I09.0) in age groups from 0 to death across England from 1997/98 to 2017/18, linked with mortality data. Under agreement version 2.4, Royal Brompton Hospital obtained ongoing quarterly data releases linked to mortality data are requested from 2018/19 to the end of March 2021. NHS Digital previously provided the relevant records from the HES Admitted Patient Care, Civil Registration Mortality, COVID-19 SGSS First Positives (Second Generation Surveillance System) & COVID-19 Hospitalization in England Surveillance System datasets to Guy’s and St Thomas’ NHS Foundation Trust. The data contained no direct identifying data items. The data is pseudonymised and individuals cannot be reidentified through linkage with other data in the possession of the recipient. Under this agreement amendment (version 3), Royal Brompton Hospital wish to obtain a refresh of 2017/18 Hospital Episode Statistics (HES) Admitted Patient Care (APC) data linked to Civil Registrations (Deaths) - Summary Care Cut without the age filter applied. Royal Brompton Hospital also wish to obtain the annual refresh file of 2021/22 and the four quarter data files for 2021/22, linked to Civil Registrations (Deaths) - Summary Care Cut without the age filter applied and, to fully examine the effect of COVID-19 infection on subsequent myocarditis, the study team are also requesting pseudonymised record-level national data from the SGSS and CHESS datasets. The data will not be transferred to any other location. METHODOLOGY The data will be stored on servers at the Royal Brompton Hospital. - NHS Digital Data Production Team needs to maintain copy of HES cohort from previous quarter The data will be accessed by authorised personnel via remote access. The data will always remain on the servers at Royal Brompton Hospital. - Each quarter, NHS Digital Data Production Team create a HES APC cohort of patients diagnosed with myocarditis and other heart related conditions (see Diagnosis Codes.xlsx attached to holder) Personnel are prohibited from downloading or copying data to local devices. - NHS Digital Data Production Team extract all episodes for cohort from the earliest diagnosis date onwards. There is no upper age limit. For newly diagnosed cohort members supply historic episodes in each quarterly data drop. For existing cohort members supply additional episodes only. The data will not leave England at any time. - NHS Digital Data Production Team link and extract mortality records for the cohort up to the latest date available in the data at the point of extraction. Access is restricted to employees of Guy’s and St Thomas’ NHS Foundation Trust who have authorisation from the Principal Investigator. - NHS Digital Data Production Team send pseudonymised record-level output via Secure Electronic File Transfer Service (SEFT) to: Royal Brompton Hospital. MINIMISATION Royal Brompton Hospital is seeking pseudonymised record level data filtered to hospital admissions due primarily to ‘myocarditis’, pericarditis, cardiomyopathy, cardiac arrest or myocardial infarction. - Data is requested for a further 1 year period to study the longitudinal epidemiological trends linked to medical, social and biological changes over this time period. The total 24 years of data allows for optimal longitudinal assessment based on published literature. - Data in previous versions of this agreement were restricted to only individuals. However, the age profile and demographic of hospitalised COVID patients has had significant impact on adverse outcomes with the elderly being worst affected. Royal Brompton Hospital seeks to study to impact of COVID-19 on hospitalisation due to myocarditis and related conditions (heart failure, cardiomyopathy, pericarditis, acute myocardial infarction and sudden cardiac death). Given that COVID-19 has had a significant impact on hospitalisation and mortality amongst older groups, Royal Brompton Hospital has altered their request in this agreement and now seeks to remove the upper age cut-off and include patients of all age groups from birth to death. In doing so, changes in the trends of admissions related to myocarditis and its related conditions can be accurately assessed before, during and after the COVID-19 pandemic to assess its impact and guide clinical risk stratification and future service provision. Data is requested for all other age groups because while myocarditis predominantly affects young adults, it remains an important cause for heart failure in young infants and older age groups - the understanding of myocarditis in these groups is particularly limited. - National data is requested in order to remove geographical bias due to regional differences in viral aetiology and healthcare systems, ultimately informing changes to clinical guidelines and policies on a national level. Data on age, sex, ethnicity, length of admission, method of admission, ITU bed days, specific cardiac procedures (including cardiac catheterisation, endomyocardial biopsy, pacemaker/ICD/VAD implantation and cardiac transplantation) and discharge medication (if available) would be important to record. Geographical data may be helpful to understand whether social deprivation or pollution levels are implicated. Readmission data is requested in order to understand the likelihood of myocarditis recurrence over the study period as it is recognised that a subset of patents will suffer a recurrence many years later. At present, there are few tools to identify such patients at the time of index presentation. Alternative diagnoses made at the time of readmission may also be due to complications, such as heart failure and cardiac arrhythmia as described above. To facilitate accurate comparisons with other conditions of overlapping biology (pericarditis), clinical presentation (myocardial infarction) and better understanding of long-term complications (sudden cardiac arrest and dilated cardiomyopathy), the Trust seeks the same depth of HES APC and mortality linked data on these linked diagnoses. A full list of diagnosis codes have been provided to NHS Digital. To study the burden of acute COVID-19 infection at any given time point relative to acute myocarditis admissions, and to specifically determine the prevalence of acute myocarditis within patients hospitalised due to COVID-19, the study team seeks to obtain CHESS and SGSS data to provide an understanding of patient demographics, comorbidity, treatment, and clinical outcome information. Whilst the HES cohort is defined by a primary diagnosis of acute myocarditis, the COVID-19 datasets will address this from the opposite direction looking at myocarditis recorded in patients with a primary diagnosis of COVID-19. These two approaches are thereby complementary and provide a robust approach to study the inter-relationships between myocarditis and COVID-19. All data received would be subject to protection and storage within Royal Brompton Hospital's restricted swipe card access department on restricted file servers operating behind an NHS specification firewall. All data stored on or transmitted by a computer of any sort at any location will be encrypted with password protected, 256 bit AES standard encryption. The data will be analysed by the researcher and the chief/principal investigator, who are both substantive employees of Guy's and St Thomas' NHS Foundation Trust. Statistical data analysis will be carried out via hospital PCs/laptops connected to the Royal Brompton Hospital network either directly in person or remotely, using an appropriate statistical package. To remotely access the devices requires a secure 2-factor authenticator (VPN) and users are then able to securely access the secure server on the Trust’s IT framework. All data analysis will be conducted within the confines of the Trust’s secure server, and will not be downloaded to remote devices for storage or processing. The data will not be linked with any record level data other than that which is described in this agreement. There will be no requirement nor attempt to re-identify individuals from the data. The data will not be made available to any third parties except in the form of aggregated outputs with small numbers suppressed in line with the HES Analysis Guide. The diagnostic codes required relate to: (i) Myocarditis: (ii) Pericarditis (iii) Dilated cardiomyopathy and heart failure (iv) Cardiac arrest (v) Myocardial infarction. All organisations party to this agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract i.e.: employees, agents and contractors of the Data Recipient who may have access to that data). HES DISCLOSURE CONTROL / SMALL NUMBER SUPPRESSION In order to protect patient confidentiality, when presenting results calculated from HES record level data, outputs will contain only aggregate level data with small numbers suppressed in line with HES Analysis Guide. When publishing HES data, you must make sure that: · cell values from 1 to 7 are suppressed at a local level to prevent possible identification of individuals from small counts within the table. · Zeros (0) do not need to be suppressed. · All other counts will be rounded to the nearest 5. [1 paragraph unchanged] All personnel accessing the data have been appropriately trained in data protection and confidentiality. The data will not be linked with any other data. There will be no requirement and no attempt to reidentify individuals when using the data. Analysts/researchers from the Guy’s and St Thomas’ NHS Foundation Trust will process/analyse the data for the purposes described above.

Expected output

In this study, Royal Brompton Hospital aims to investigate the following features with definable outputs as detailed below: The expected outputs of the processing will be: 1. Incidence and prevalence of myocarditis– there are no studies published to date that have examined the incidence and prevalence of acute myocarditis (or myopericarditis) on a national level. Estimates from the WHO Global Burden of disease study of 2013 suggest myocarditis affects 23 out of 100,000 people. However, there is a wide spectrum of clinical presentation and disease detection. In the wake of a number of sudden cardiac deaths due to myocarditis (http://www.bbc.co.uk/news/health-40408536; http://www.bbc.co.uk/news/health-11542429; http://www.bbc.co.uk/news/entertainment-arts-39193367; http://www.bbc.co.uk/news/uk-england-birmingham-41988846), there is a need for improved understanding of disease epidemiology and in turn, awareness and recognition. At present, there is no understanding of whether the number of cases of myocarditis is increasing or decreasing within the UK. The Trust will analyse and write up this data for publication in a high-impact medical journal, such as the Lancet or British Medical Journal (BMJ). Data will also be circulated widely through our partners, the British Heart Foundation and Cardiomyopathy UK. • Submissions to peer reviewed journals at the end of the study. 2. Long-term complications and prognosis of myocarditis – published studies investigating long-term outcome are subject to bias amongst recruited individuals and provide a narrow window into possible outcomes. Most of these studies have been performed on patients with biopsy-proven myocarditis in Germany and study outcomes may not be reflective of UK practice given geographical variation, for example, in viral aetiology. Royal Brompton Hospital will analyse and write up this data for publication in a high-impact medical journal, such as the Lancet or BMJ. • Presentations at British cardiovascular society, American cardiovascular society & European meetings. 3. Sex differences – no studies have specifically investigated age and sex differences in patients affected by acute myocarditis. There is evidence that myocarditis typically affects young men from 19-35 years of age. By studying all age groups across the county, Royal Brompton Hospital will generate up-to-date knowledge of this within the NHS - this will improve treating clinicians’ understanding and awareness of who is typically affected by myocarditis. It will also help support translational mechanistic studies to understand why there should be such differences and support awareness campaigns across the NHS. 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. 4. Seasonal variation – from Royal Brompton Hospital's experience of recruiting patients from across South East England into a genetics myocarditis research study based within the Trust, the number of new cases appears to be greatest during the Winter months. Royal Brompton Hospital aims to explore this on a national level through the HES APC data set. This will again be published in a high-impact medical journal providing new insights into seasonal variation. This could have a significant impact on health-care resource utilisation. It would also help with the timing of awareness campaigns in primary care and potentially guide protection of at risk patients. The outputs will be communicated to relevant recipients through the following dissemination channels: 5. Geographical variation – Royal Brompton Hospital hypothesises that myocarditis is predominantly a disease of major towns and cities rather than rural or coastal areas. Given that viral infection remains the leading aetiology, geographical differences are likely, in addition to differences depending on socio-economic status. These findings will again be published and circulated widely through the BHF and Cardiomyopathy UK. • Journals 6. Diagnostic approaches – there are currently no clinical recommendations to guide patient diagnosis and management in the UK. Individual practice varies between clinicians and hospitals, which has again been clear from the researcher's myocarditis research experience. As a result, there appears to be a postcode lottery for length of hospital admissions, investigations and treatments. By studying the national trends in length of admission, diagnostic tests performed (cardiac MRI, coronary angiogram, cardiac biopsy) and treatments delivered (pacemaker/ICD implantation, cardiac transplantation), Royal Brompton Hospital aims to write-up and publish a Consensus statement paper supported by the BHF and co-authored by leading Cardiology consultants with expertise in myocarditis from across the country to unify and guide the way in which patients with myocarditis are diagnosed and treated in future. Such a UK-centric document is greatly needed. Improved diagnostic confidence and approaches to management will translate in improved patient experience and clinical outcomes, which can be reassured after an interval. • Public events - AHA Scientific Session oral presentation & Cardiomyopathy UK patient event 7. Recurrence rates and prognosis – there are no published studies that have examined the real-world risks of recurrence following an acute episode of myocarditis. This is one of the most common questions asked by patients, and at present, the Trust is unable to base a response on any published evidence. HES APC data will allow Royal Brompton Hospital to estimate how many patients are readmitted, and whether this typically occurs in the short or long-term. Such data would be useful from a healthcare economics perspective, and again alleviate patient concerns if appropriate to do so. • Posters displayed at the American Heart Association Annual Scientific Session 8. Mortality rate – the number of patients that die as a result of acute myocarditis or related complications within the UK remains unknown. Whilst clinical outcomes in patients suffering a heart attack have vastly been improved in recent years due to developments and advances in service provision and coronary angioplasty, Royal Brompton Hospital expects that the mortality rate from myocarditis is likely to be: (i) underestimated and (ii) unchanged over the last 20 years despite advances in other areas. Knowledge of this information once disseminated through high-impact publications, the BHF and Cardiomyopathy UK will likely spur further public interest, funding and research into the condition. Importantly, it will also spur translational projects to identify where gaps in treatment should focus their efforts. • Press/media engagement 9. Impact of COVID-19 – this is new disease with anecdotal reports of fulminant acute myocarditis due to COVID-19, which is mechanistically and biologically plausible. The latest evidence from cardiac MRI studies of patients that have recovered from COVID-19 has yielded conflicting findings. In one study, up to 60% of individuals with prior COVID-19 infection had undiagnosed features of ongoing inflammation within the heart consistent with myocarditis (https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916 ). This work has had major public health implications; for example, in the US all college sports were stopped for a period due to concern about myocarditis and high-level sports post-COVID (https://www.theatlantic.com/health/archive/2020/09/covid-19-heart-pandemic-coronavirus-myocarditis/616420/). However, subsequently there has been strong divergent opinion suggesting a much lower prevalence. In order that they firstly better assess the prevalence but also help guide national policy, better quality data from across England will be very important. There is a need for improved understanding of disease epidemiology and in turn, awareness and recognition. Royal Brompton Hospital will analyse and write up this data for publication in a high-impact medical journal within a rapid time-frame to make a meaningful contribution to patient care. Data will also be circulated widely through the Trust's partners, the British Heart Foundation and Cardiomyopathy UK. Target dates for production and dissemination of the outputs will be Spring 2024. Data generated through this application will be analysed within Royal Brompton Hospital and disseminated widely through a number of channels within the year. These will include scientific publication in high-impact medical journals, such as the Lancet and BMJ, as well as lay summaries for communication with patient and public groups through established links with the British Heart Foundation, Imperial College London, Cardiomyopathy UK and Alexander Jansons Fund. Of note, the Trust arranged its 4th annual myocarditis patient and relatives information evening on 14th November 2019 in partnership with Cardiomyopathy UK with the specific aim of providing support and education to individuals affected by myocarditis. Through the planned Consensus statement paper and other established links with guideline committees such as NICE, the Trust hopes to improve and standardise the diagnosis, treatment and surveillance of patients with myocarditis. Project milestones and expected target dates for proposed analyses: Jan 2019 Receipt of 20-year myocarditis dataset Mar 2019 Preliminary analyses completed as part of PhD Sep 2019 Scientific manuscript prepared for points 1,3,4, 5 & 6 Nov 2019 AHA Scientific Session oral presentation & Cardiomyopathy UK patient event Dec 2019 Further analyses addressing point 2,7 & 8 through linkage to ONS data Feb 2020 PhD submitted but manuscript held back Mar 2020 Initial queries raised regarding inclusion of additional COVID data Nov 2020 Expected receipt of additional COVID dataset Mar 2021 Actual date of receipt of additional COVID dataset May 2021 Data analysis and identification of missing data from early 2018 Jun 2021 Submission of preliminary analyses to AHA Scientific Session on COVID-19 myocarditis Jul 2021 Manuscript preparation for impact of COVID on cardiomyopathy for BMJ Aug 2021 AHA abstract accepted for oral presentation & Submission of data amendment Sep 2021 UK government website updated to reference the applicants study presented in 2019 to guide national policy on COVID-19 vaccination in relation to myocarditis (https://www.gov.uk/government/publications/covid-19-vaccination-myocarditis-and-pericarditis-information-for-healthcare-professionals/information-for-healthcare-professionals-on-myocarditis-and-pericarditis-following-covid-19-vaccination) Nov 2021 Oral and poster presentations at the American Heart Association Annual Scientific Session Dec 2021 Submission of landmark study on impact of COVID on myocarditis and pericarditis Jan 2022 Submission of similar studies on impact of COVID on cardiomyopathy and sudden cardiac death Early 2022 Following receipt of Q2 data drop, analyses of impact of COVID vaccination on myocarditis Early 2022 Following receipt of Q3 data drop, ongoing sub-studies depending on the nature of the pandemic at this point Mid 2022 Following receipt of Q4, analyses focusing on longer-term consequences and mortality of myocarditis post-COVID Jul 2022 Preparation of final manuscript and position statement paper to guide ongoing UK management of myocarditis Late 2022 Ongoing substudies to dissect specific areas of clinical uncertainty e.g. geographical variation in access to CMR

Expected measurable benefits

Heart failure and sudden cardiac death are two separate but important worldwide health problems with high morbidity and mortality that can both arise from acute myocarditis at any age. Heart failure is reported to occur in up to one third of patients with acute myocarditis and has a major global economic burden through healthcare costs and lost productivity through heart failure hospitalisations. Based on published data from ONS, myocarditis is thought to account for approximately 1 sudden cardiac death under 35 years of age each week in the UK. Such events commonly feature in the media headlines and understandably generate considerable anxiety and questions. The findings of this research study are expected to contribute to evidence-based decision-making for policymakers, local decision-makers such as doctors, and patients to inform best practice to improve the care, treatment, and experience of health care users relevant to the subject matter of the study. By accruing data on the real-world burden of acute myocarditis resulting in hospital admission, relative to other similarly presenting conditions, and its downstream consequences in terms of recurrence, DCM and mortality, the Trust hopes to greatly enhance the understanding of this poorly characterised disease and dispel the old myth that myocarditis is; (i) rare and (ii) benign. Specific outputs and further details are include below: The use of the data could: 1. Accurate and contemporary data on incidence and prevalence within the UK would reveal health trends over time and support national service planning and provision. Early detection through improved recognition and awareness arsing from this study both amongst the public and medical staff would make a significant contribution to individual patient care and healthcare resource allocation. • help the system to better understand the health and care needs of populations. 2. Reductions in length of hospital admission due to defined diagnostic pathways from the Consensus pathway may both reduce hospital expenditure and employment productivity loss. Improved diagnostic confidence amongst clinicians with published data to support their clinical-decision making will improve the patient journey and outcome. • lead to the identification or improvement of treatments or interventions, or health and care system design to improve health and care outcomes or experience. 3. Better risk stratification of those patients at great risk of subsequent DCM and sudden cardiac arrest may provide a window to intervene at a much earlier stage in the disease where therapy is far more likely to make a difference. Once the disease has occurred and resulted in a complication, intervention is always more complicated, costly and less likely to deliver favourable results. • advance understanding of regional and national trends in health and social care needs. 4. The findings from this study will form the basis of the researcher's PhD and be published in high-impact medical journals with guidance from the Public Health Department at Imperial College London. This work is expected to be completed within 6-12 months of receiving the data within the time-scale of a higher research degree. The outputs will be supported and promoted through the British Heart Foundation Press Office, with whom the lead researcher has worked previously (https://www.bhf.org.uk/news-from-the-bhf/news-archive/2017/june/heart-scans-reveal-cause-of-sudden-cardiac-arrests-in-the-young), as well as Cardiomyopathy UK and the Alexander Janson Fund for publicising the results and conveying these findings to patients and their families. This is exemplified by the 3rd annual myocarditis patient and relatives evening due to be held at the Trust on 14th November 2018 (details of previous events found here: http://www.rbht.nhs.uk/research/research-news-2/patients-share-experiences-of-myocarditis-at-information-day/, https://www.cardiomyopathy.org/news--media/latest-news/post/268-myocarditis-patient-and-relatives-information-evening, http://www.rbht.nhs.uk/research/research-news-2/charity-funding-boosts-myocarditis-research-and-patient-support/, http://alexanderjansonsfund.org/wp-content/uploads/2017/01/patient-information-slides.pdf). • inform planning health services and programmes, for example to improve equity of access, experience, and outcomes. 5. Data generated from this study in all its forms (incidence, prevalence, age groups, sex differences, geographical variation, viral aetiology, social deprivation status, length of admission, investigations, treatments, recurrences, sudden death, heart failure and mortality) will be compiled into an epidemiological high-impact paper and a Consensus statement paper, both of which will be publicised and promoted through Imperial College, the BHF and Cardiomyopathy UK. Based on this evidence demonstrating the scope of the problem and the need for improved UK guideline support, the Trust intends to propose the development of NICE guidelines for managing patients with myocarditis. These will be proposed to the NICE Committee through established links within the Trust. • inform decisions on how to effectively allocate and evaluate funding according to health needs. 6. Ultimately, better evidence and information on the scale and scope of myocarditis will highlight and inform future directions for medical research, including the design of large multi-centre studies to evaluate new emerging immunological therapies. The overall aim is to improve patient outcomes. • provide a mechanism for checking the quality of care. This could include identifying areas of good practice to learn from, or areas of poorer practice which need to be addressed. 7. Answering the key question of what proportion of people with COVID-19 infection or vaccination subsequently develop an adverse reaction in the form of acute myocarditis. This is relevant across all age groups, especially in children and young adults. • support knowledge creation or exploratory research (and the innovations and developments that might result from that exploratory work). The study lead attended a number of training courses in statistical modelling and sought educational guidance and collaboration from a research group at the University of Leeds. Preliminary data was presented in a talk at the American Heart Association in November 2019, which has already formed the first reference on the current online UK government advice on COVID-19 and myocarditis (https://www.gov.uk/government/publications/covid-19-vaccination-myocarditis-and-pericarditis-information-for-healthcare-professionals/information-for-healthcare-professionals-on-myocarditis-and-pericarditis-following-covid-19-vaccination). By accruing data on the real-world burden of acute myocarditis resulting in hospital admission, relative to other similarly presenting conditions, and its downstream consequences in terms of recurrence, DCM and mortality, the Trust hopes to greatly enhance the understanding of this poorly characterised disease and dispel the old myth that myocarditis is (i) rare and (ii) benign. In light of Considering the COVID-19 pandemic, a much larger impact publication is planned to include [14 words unchanged] publications relating to specific aspects of myocarditis and related conditions. The project extension seeks to strengthen and build upon the initial research conducted by the [9 words unchanged] COVID-19 on myocarditis and its related conditions (heart failure, pericarditis, sudden cardiac death death, and myocardial infarction), both in the period before and during the initial peak and potentially any future surges over the next 12 months to improve understanding of disease trends, regional prevalence, severity severity, and clinical management. 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 for or within the NHS or treatment decisions in relation to specific patients.

Unchanged: Benefits reported.

Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.

Datasets: + COVID-19 Hospitalization in England Surveillance System; + COVID-19 SGSS First Positives (Second Generation Surveillance System); + HES-ID to MPS-ID HES Admitted Patient Care

Objective for processing

[14 paragraphs unchanged] ______________________________________________________ *** This amendment (v3) requests missing data for 2017/18, cause and identified as a change in the methodology later in their agreement. Myocarditis is increasingly identified as one of the sequalae of acute COVID-19 infection, and possibly COVID-19 vaccination, and therefore the need for accurate national epidemiological data in these specific areas continue to gain importance. The study team have identified during their analysis that they are missing data for the latter half of the 2017-2018 HES APC dataset from their original data request in 2018. For example, from the row counts below, one can see that there were fewer episodes in this financial year: NIC144568_HES_APC_201299 2012 - 2013 2,334,645 NIC144568_HES_APC_201399 2013 - 2014 2,356,175 NIC144568_HES_APC_201499 2014 - 2015 2,355,019 NIC144568_HES_APC_201599 2015 - 2016 2,359,378 NIC144568_HES_APC_201699 2016 - 2017 2,276,248 NIC144568_HES_APC_201799 2017 - 2018 1,640,625 * In order to complete their analyses, the study team are submitting this amendment (v3) to obtain the complete 2017-2018 dataset. In their original application, the data had been truncated to 0-80 years but this upper age cut-off was removed in the recent application to study the full impact of the COVID-19 pandemic. Therefore, the study team requires the complete 2017-2018 dataset without an age filter. As before, a linkage with the Mortality data is required. Additionally, the study team are also requesting additional data for the fixed HES APC file of 2021/22 data plus the four quarters of 2021/22 (April 2021 to March 2022) to fully examine the effect of COVID-19 infection on subsequent myocarditis, but also the impact of the vaccines which are now also increasingly linked with myocarditis. For this aspect of the project, the study team are also requesting pseudonymised record-level national data from the SGSS and CHESS datasets. It is noted under this amendment (v3) that the Data Controller's legal entity has been amended to Guy's and St Thomas' NHS Foundation Trust, as Royal Brompton Hospital (previously Royal Brompton and Harefield Hospitals) no longer hold Foundation Trust status. The sole Data Controller and legal entity is therefore Guy's and St Thomas' NHS Foundation Trust. Royal Brompton Hospital is referenced in this agreement as they are part of the Royal Brompton and Harefield Clinical Group within the Guy's and St Thomas' NHS Foundation Trust, where all the study researchers are based. All those accessing NHS Digital data are substantive employees of Guy's and St Thomas' NHS Foundation Trust. ***** [1 paragraph unchanged] Royal Brompton Hospital (a part of the Royal Brompton and Harefield Clinical Group clinical group within the Guy's and St Thomas' NHS Foundation Trust Trust) aims to describe the longitudinal epidemiological trends of acute myocarditis to provide [36 words unchanged] recognising changes and variation arising from medical, biological, geographical and social factors. [2 paragraphs unchanged] Royal Brompton and Harefield NHS Foundation Trust Hospital seeks to obtain all available data on hospital admissions specifically due to [7 words unchanged] age groups across England/Wales over the last 23 years. Data on age, gender, sex, ethnicity, length of admission, method of admission, Intensive Therapy Unit (ITU) bed [63 words unchanged] be helpful to understand whether social deprivation or pollution levels are implicated. Royal Brompton and Harefield NHS Foundation Trust Hospital also seeks to obtain the same depth of Hospital Episode Statistics (HES) [103 words unchanged] the same HES data elements on the scale and scope of myocarditis. Up to one third of patients with myocarditis develop heart failure and dilated cardiomyopathy (DCM). DCM is the leading cause for needing a heart transplant in the UK. UK (based on studies conducted prior to the COVID-19 pandemic which does not encompass DCM following infection with SARS-CoV-2). Royal Brompton and Harefield NHS Foundation Trust Hospital seeks to obtain the same depth of HES APC and linked mortality [46 words unchanged] detect these cases would lead to underestimation of the burden of myocarditis. Based on extrapolation from published data the Royal Brompton and Harefield NHS Foundations Trust Hospital estimates that myocarditis accounts for one sudden cardiac death each week in [19 words unchanged] disturbances within the heart due to the initial myocardial injury. Royal Brompton and Harefield NHS Foundation Trust Hospital seeks to obtain the same depth of HES and linked mortality information [7 words unchanged] of myocarditis resulting in sudden cardiac arrest with or without successful resuscitation. [2 paragraphs unchanged] To facilitate accurate comparisons with other conditions of overlapping biology (pericarditis), clinical [5 words unchanged] understanding of long-term complications (sudden cardiac arrest and dilated cardiomyopathy), Royal Brompton and Harefield NHS Foundation Trust Hospital seeks the same depth of HES APC and mortality linked data on these linked diagnoses: [7 paragraphs unchanged] ***In In light of the current COVID-19 pandemic, there is pressing unmet need to [131 words unchanged] be well placed to provide this contemporary information on a population level. Analyses of the original data set received data on 16th January 2019 were presented in a talk at the American Heart Association in November 2019 and a manuscript for scientific publication has been prepared. However, it is likely that additional data collected in 2019/2020 would be important to include as it would strengthen the impact of this publication.*** Royal Brompton Hospital thus also seeks to obtain the CHESS and SGSS datasets to provide an understanding of the burden of acute COVID-19 infection at any given time point relative to acute myocarditis admissions, and to specifically determine the prevalence of acute myocarditis within patients hospitalised due to COVID-19. Demographic and diagnostic information from laboratory test reports is requested via the Second Generation Surveillance System (SGSS), alongside comorbidity, treatment, and clinical outcome information for patients recorded in the COVID-19 Hospitalisations in England Surveillance System (CHESS). Whilst there are limitations with the data quality arising from the earlier phases of the pandemic, Royal Brompton Hospital intends to use the data available to provide greater context of the burden of acute myocarditis during the pandemic in relation to COVID-19 infection, thereby addressing a key unmet clinical need. Royal Brompton Hospital would like pseudonymised data on all patients within the CHESS and SGSS datasets. This is an important aspect of the study in order to be able to generate meaningful estimates of the proportion of COVID-19 patients affected by myocarditis, pericarditis, cardiomyopathy and other cardiovascular diagnoses of interest; and importantly to discover which clinical features could be harnessed to identify such high-risk patients and thereby tailor their clinical management. Whilst the HES cohort is defined by a primary diagnosis of acute myocarditis, the COVID-19 datasets will look at myocarditis recorded in patients with a primary diagnosis of COVID-19. These two approaches provide a robust approach to study the inter-relationships between myocarditis and COVID-19. All age groups are required, recognising there is a high burden of acute myocarditis in infants, children and adults. In order to examine regional differences, it also not possible to minimise this cohort by geography. This agreement refers to Royal Brompton Hospital as the study team are based there, representing the Royal Brompton and Harefield Clinical Group within the Guy's and St Thomas' NHS Foundation Trust. However, the Sole Data Controller is Guy's and St Thomas' NHS Foundation Trust who also process the data in this agreement. The study team work in an established research centre within the hospital intrinsically linked with the National Heart and Lung Institute of Imperial College London. For this reason, and also due to the longevity of this study, the data has not been obtained via the one of the several recently developed Trusted Research Environments. Whilst this collaborative approach is important for the long-term future of national cardiovascular research initiatives, the applicants intend to complete the existing study (with this COVID-19 extension) using their own established and trusted research environment. [3 paragraphs unchanged]

Processing activities

Royal Brompton and Harefield NHS Foundation Trust Hospital is seeking HES APC and linked mortality data on a population level [5 words unchanged] the changing epidemiological trends and long-term prognosis of this disease. Royal Brompton and Harefield NHS Foundation Trust Hospital does not require patient identifiable information. Under the previous iteration iterations of this agreement, Royal Brompton and Harefield NHS Foundation Trust Hospital obtained all available pseudonymised record level data on hospital admissions (HES APC) [20 words unchanged] to death across England from 1997/98 to 2017/18, linked with mortality data. Under agreement version 2.4, Royal Brompton Hospital obtained ongoing quarterly data releases linked to mortality data are requested from 2018/19 to the end of March 2021. Under this Agreement, ongoing quarterly data releases linked to mortality data are requested from 2018/19 to the end of this agreement, made up of: Under this agreement amendment (version 3), Royal Brompton Hospital wish to obtain a refresh of 2017/18 Hospital Episode Statistics (HES) Admitted Patient Care (APC) data linked to Civil Registrations (Deaths) - Summary Care Cut without the age filter applied. Royal Brompton Hospital also wish to obtain the annual refresh file of 2021/22 and the four quarter data files for 2021/22, linked to Civil Registrations (Deaths) - Summary Care Cut without the age filter applied and, to fully examine the effect of COVID-19 infection on subsequent myocarditis, the study team are also requesting pseudonymised record-level national data from the SGSS and CHESS datasets. - One drop of Pseudonymised record level HES APC Annual Refresh for 2018/19 and 2019/20, plus 2020/21 Q1, linked to Civil Registrations (Deaths) - Secondary Care Cut via a bridging file. - one drop of Pseudonymised record level HES APC 2020/21 Q2 in November 2020. - one drop of Pseudonymised record level HES APC 2020/21 Q3 in February 2021. - one drop of Pseudonymised record level HES APC 2020/21 Q4 in May 2021. [5 paragraphs unchanged] - NHS Digital Data Production Team send pseudonymised record-level output via Secure Electronic File Transfer Service (SEFT) to: Royal Brompton and Harefield NHS Foundation Trust. Hospital. [1 paragraph unchanged] Royal Brompton and Harefield NHS Foundation Trust Hospital is seeking pseudonymised record level data filtered to hospital admissions due primarily to ‘myocarditis’, pericarditis, cardiomyopathy, cardiac arrest or myocardial infarction. - Data is requested for a further 3 1 year period to study the longitudinal epidemiological trends linked to medical, social and biological changes over this time period. The total 23 24 years of data allows for optimal longitudinal assessment based on published literature. - Data in previous versions of this agreement were restricted to only [14 words unchanged] impact on adverse outcomes with the elderly being worst affected. Royal Brompton and Harefield NHS Foundation Trust Hospital seeks to study to impact of COVID-19 on hospitalisation due to myocarditis [19 words unchanged] a significant impact on hospitalisation and mortality amongst older groups, Royal Brompton and Harefield NHS Foundation Trust Hospital has altered their request in this agreement and now seeks to remove [84 words unchanged] groups - the understanding of myocarditis in these groups is particularly limited. [1 paragraph unchanged] Data on age, gender, sex, ethnicity, length of admission, method of admission, ITU bed days, specific cardiac [24 words unchanged] be helpful to understand whether social deprivation or pollution levels are implicated. [2 paragraphs unchanged] All data received would be subject to protection and storage within Royal Brompton Hospital's restricted swipe card access department on restricted file servers operating behind an NHS specification firewall. All data stored on or transmitted by a computer of any sort at any location will be encrypted with password protected, 256 bit AES standard encryption. The data will be analysed by the researcher and the chief/principal investigator, who are both substantive employees of Royal Brompton and Harefield NHS Foundation Trust. This analysis will only take place at the Royal Brompton Hospital and the applicant is aware of the security implications and limitations of this data processing methodology To study the burden of acute COVID-19 infection at any given time point relative to acute myocarditis admissions, and to specifically determine the prevalence of acute myocarditis within patients hospitalised due to COVID-19, the study team seeks to obtain CHESS and SGSS data to provide an understanding of patient demographics, comorbidity, treatment, and clinical outcome information. Whilst the HES cohort is defined by a primary diagnosis of acute myocarditis, the COVID-19 datasets will address this from the opposite direction looking at myocarditis recorded in patients with a primary diagnosis of COVID-19. These two approaches are thereby complementary and provide a robust approach to study the inter-relationships between myocarditis and COVID-19. All data received would be subject to protection and storage within Royal Brompton Hospital's restricted swipe card access department on restricted file servers operating behind an NHS specification firewall. All data stored on or transmitted by a computer of any sort at any location will be encrypted with password protected, 256 bit AES standard encryption. The data will be analysed by the researcher and the chief/principal investigator, who are both substantive employees of Guy's and St Thomas' NHS Foundation Trust. Statistical data analysis will be carried out via hospital PCs/laptops connected to the Royal Brompton Hospital network either directly in person or remotely, using an appropriate statistical package. To remotely access the devices requires a secure 2-factor authenticator (VPN) and users are then able to securely access the secure server on the Trust’s IT framework. All data analysis will be conducted within the confines of the Trust’s secure server, and will not be downloaded to remote devices for storage or processing. [14 paragraphs unchanged]

Expected output

In this study, Royal Brompton and Harefield NHS Foundation Trust Hospital aims to investigate the following features with definable outputs as detailed below: [1 paragraph unchanged] 2. Long-term complications and prognosis of myocarditis – published studies investigating long-term [38 words unchanged] UK practice given geographical variation, for example, in viral aetiology. Royal Brompton and Harefield NHS Foundation Trust Hospital will analyse and write up this data for publication in a high-impact medical journal, such as the Lancet or BMJ. 3. Gender Sex differences – no studies have specifically investigated age and sex differences in [17 words unchanged] of age. By studying all age groups across the county, Royal Brompton and Harefield NHS Foundation Trust Hospital will generate up-to-date knowledge of this within the NHS - this will [24 words unchanged] there should be such differences and support awareness campaigns across the NHS. 4. Seasonal variation – from Royal Brompton and Harefield NHS Foundation Trust's Hospital's experience of recruiting patients from across South East England into a genetics [10 words unchanged] new cases appears to be greatest during the Winter months. Royal Brompton and Harefield NHS Foundation Trust Hospital aims to explore this on a national level through the HES APC [37 words unchanged] campaigns in primary care and potentially guide protection of at risk patients. 5. Geographical variation – Royal Brompton and Harefield NHS Foundation Trust Hospital hypothesises that myocarditis is predominantly a disease of major towns and cities [29 words unchanged] again be published and circulated widely through the BHF and Cardiomyopathy UK. 6. Diagnostic approaches – there are currently no clinical recommendations to guide [58 words unchanged] angiogram, cardiac biopsy) and treatments delivered (pacemaker/ICD implantation, cardiac transplantation), Royal Brompton and Harefield NHS Foundation Trust Hospital aims to write-up and publish a Consensus statement paper supported by the [50 words unchanged] patient experience and clinical outcomes, which can be reassured after an interval. 7. Recurrence rates and prognosis – there are no published studies that [34 words unchanged] response on any published evidence. HES APC data will allow Royal Brompton and Harefield NHS Foundation Trust Hospital to estimate how many patients are readmitted, and whether this typically occurs [13 words unchanged] economics perspective, and again alleviate patient concerns if appropriate to do so. 8. Mortality rate – the number of patients that die as a [29 words unchanged] to developments and advances in service provision and coronary angioplasty, Royal Brompton and Harefield NHS Foundation Trust Hospital expects that the mortality rate from myocarditis is likely to be: (i) [45 words unchanged] translational projects to identify where gaps in treatment should focus their efforts. *** 9. Impact of COVID-19 – this is new disease with anecdotal reports of fulminant acute myocarditis due to COVID-19, which is mechanistically and biologically plausible. The latest evidence from cardiac MRI studies of patients that have recovered from COVID-19 has yielded conflicting findings. In one study, up to 60% of individuals with prior COVID-19 infection had undiagnosed features of ongoing inflammation within the heart consistent with myocarditis (https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916 ). This work has had major public health implications; for example, in the US all college sports were stopped for a period due to concern about myocarditis and high-level sports post-COVID (https://www.theatlantic.com/health/archive/2020/09/covid-19-heart-pandemic-coronavirus-myocarditis/616420/). However, subsequently there has been strong divergent opinion suggesting a much lower prevalence. In order that they firstly better assess the prevalence but also help guide national policy, better quality data from across England will be very important. There is a need for improved understanding of disease epidemiology and in turn, awareness and recognition. Royal Brompton Hospital will analyse and write up this data for publication in a high-impact medical journal within a rapid time-frame to make a meaningful contribution to patient care. Data will also be circulated widely through the Trust's partners, the British Heart Foundation and Cardiomyopathy UK. 9. Impact of COVID-19 – this is new disease with anecdotal reports of fulminant acute myocarditis due to COVID-19, which is mechanistically and biologically plausible. The latest evidence from cardiac MRI studies of patients that have recovered from COVID-19 has yielded conflicting findings. In one study, up to 60% of individuals with prior COVID-19 infection had undiagnosed features of ongoing inflammation within the heart consistent with myocarditis (https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916 ). This work has had major public health implications; for example, in the US all college sports were stopped for a period due to concern about myocarditis and high-level sports post-COVID (https://www.theatlantic.com/health/archive/2020/09/covid-19-heart-pandemic-coronavirus-myocarditis/616420/). However, subsequently there has been strong divergent opinion suggesting a much lower prevalence. In order that we firstly better assess the prevalence but also help guide national policy, better quality data from across England will be very important. There is a need for improved understanding of disease epidemiology and in turn, awareness and recognition. Royal Brompton and Harefield NHS Foundation Trust will analyse and write up this data for publication in a high-impact medical journal within a rapid time-frame to make a meaningful contribution to patient care. Data will also be circulated widely through the Trust's partners, the British Heart Foundation and Cardiomyopathy UK. Data generated through this application will be analysed within Royal Brompton Hospital and disseminated widely through a number of channels within the year. These will include scientific publication in high-impact medical journals, such as the Lancet and BMJ, as well as lay summaries for communication with patient and public groups through established links with the British Heart Foundation, Imperial College London, Cardiomyopathy UK and Alexander Jansons Fund. Of note, the Trust arranged its 4th annual myocarditis patient and relatives information evening on 14th November 2019 in partnership with Cardiomyopathy UK with the specific aim of providing support and education to individuals affected by myocarditis. Through the planned Consensus statement paper and other established links with guideline committees such as NICE, the Trust hopes to improve and standardise the diagnosis, treatment and surveillance of patients with myocarditis. *** Data generated through this application will be analysed within Royal Brompton and Harefield NHS Foundation Trust and disseminated widely through a number of channels within the year. These will include scientific publication in high-impact medical journals, such as the Lancet and BMJ, as well as lay summaries for communication with patient and public groups through established links with the British Heart Foundation, Imperial College London, Cardiomyopathy UK and Alexander Jansons Fund. Of note, the Trust has arranged it's 3rd annual myocarditis patient and relatives information evening on 14th November 2018 in partnership with Cardiomyopathy UK with the specific aim of providing support and education to individuals affected by myocarditis. Through the planned Consensus statement paper and other established links with guideline committees such as NICE, the Trust hopes to improve and standardise the diagnosis, treatment and surveillance of patients with myocarditis. [9 paragraphs unchanged] Dec 2020 Further data analyses and manuscript preparation/revision Mar 2021 Actual date of receipt of additional COVID dataset Jan 2021 Submission of landmark study focusing on national myocarditis epidemiological trends over the last 20 years and the impact of COVID May 2021 Data analysis and identification of missing data from early 2018 Feb 2021 Submission of sub-studies focusing on changes in prevalence/outcomes linked to geographic variation and other confounding factors Jun 2021 Submission of preliminary analyses to AHA Scientific Session on COVID-19 myocarditis Mar 2021 Expected receipt of next quarterly dataset with analyses and manuscript preparation focusing on the 2nd surge Jul 2021 Manuscript preparation for impact of COVID on cardiomyopathy for BMJ Mid 2021 Ongoing updates to dataset with further quarterly data receipts and sub-studies depending on the nature of the pandemic at this point Aug 2021 AHA abstract accepted for oral presentation & Submission of data amendment Jun 2021 Presentation at BCS conference and other meeting over the year depending on the findings Sep 2021 UK government website updated to reference the applicants study presented in 2019 to guide national policy on COVID-19 vaccination in relation to myocarditis (https://www.gov.uk/government/publications/covid-19-vaccination-myocarditis-and-pericarditis-information-for-healthcare-professionals/information-for-healthcare-professionals-on-myocarditis-and-pericarditis-following-covid-19-vaccination) Nov 2021 Expect receipt of final quarterly data drop and analyses focusing on longer-term consequences and mortality of myocarditis post-COVID Nov 2021 Oral and poster presentations at the American Heart Association Annual Scientific Session Dec 2021 Preparation of final summary manuscript and position statement paper to guide ongoing UK management of myocarditis cases Dec 2021 Submission of landmark study on impact of COVID on myocarditis and pericarditis Jan 2022 Submission of similar studies on impact of COVID on cardiomyopathy and sudden cardiac death Early 2022 Following receipt of Q2 data drop, analyses of impact of COVID vaccination on myocarditis Early 2022 Following receipt of Q3 data drop, ongoing sub-studies depending on the nature of the pandemic at this point Mid 2022 Following receipt of Q4, analyses focusing on longer-term consequences and mortality of myocarditis post-COVID Jul 2022 Preparation of final manuscript and position statement paper to guide ongoing UK management of myocarditis Late 2022 Ongoing substudies to dissect specific areas of clinical uncertainty e.g. geographical variation in access to CMR

Expected measurable benefits

[5 paragraphs unchanged] 4. The findings from this study will form the basis of the [6 words unchanged] high-impact medical journals with guidance from the Public Health Department at Imperial College. College London. This work is expected to be completed within 6-12 months of receiving [77 words unchanged] November 2018 (details of previous events found here: http://www.rbht.nhs.uk/research/research-news-2/patients-share-experiences-of-myocarditis-at-information-day/, https://www.cardiomyopathy.org/news--media/latest-news/post/268-myocarditis-patient-and-relatives-information-evening, http://www.rbht.nhs.uk/research/research-news-2/charity-funding-boosts-myocarditis-research-and-patient-support/, http://alexanderjansonsfund.org/wp-content/uploads/2017/01/patient-information-slides.pdf). 5. Data generated from this study in all its forms (incidence, prevalence, age groups, gender sex differences, geographical variation, viral aetiology, social deprivation status, length of admission, investigations, [72 words unchanged] be proposed to the NICE Committee through established links within the Trust. [1 paragraph unchanged] The study lead attended a number of training courses in statistical modelling and sought educational guidance and collaboration from a research group at the University of Leeds. There is a strategy for further statistical modelling, which will then form the basis of a larger scientific publication, expected in 2020. Preliminary data was presented in a talk at the American Heart Association in November 2019 . In light of the COVID-19 pandemic, publication may be delayed to include this additional data, although the Trust may also generate a separate and more focused publication relating specifically to COVID-19 myocarditis in 2020. There is also an opportunity to generate an additional publication outlining the decline in general cardiology admissions during the pandemic, which is hypothesised to result in a surge later in the year. 7. Answering the key question of what proportion of people with COVID-19 infection or vaccination subsequently develop an adverse reaction in the form of acute myocarditis. This is relevant across all age groups, especially in children and young adults. The study lead attended a number of training courses in statistical modelling and sought educational guidance and collaboration from a research group at the University of Leeds. Preliminary data was presented in a talk at the American Heart Association in November 2019, which has already formed the first reference on the current online UK government advice on COVID-19 and myocarditis (https://www.gov.uk/government/publications/covid-19-vaccination-myocarditis-and-pericarditis-information-for-healthcare-professionals/information-for-healthcare-professionals-on-myocarditis-and-pericarditis-following-covid-19-vaccination). In light of the COVID-19 pandemic, a much larger impact publication is planned to include additional COVID-19 specific data, although the Trust may also generate separate and more focused publications relating to specific aspects of myocarditis and related conditions. The project extension seeks to strengthen and build upon the initial research conducted by the study team through the inclusion of the impact of COVID-19 on myocarditis and its related conditions (heart failure, pericarditis, sudden cardiac death and myocardial infarction), both in the period before and during the initial peak and potentially any future surges over the next 12 months to improve understanding of disease trends, regional prevalence, severity and clinical management.

Benefits reported

Analyses of epidemiological trends in myocarditis admissions and outcomes were presented by [25 words unchanged] This is available online to the public at the following address: https://www.ahajournals.org/doi/10.1161/circ.140.suppl_1.11463. This data is referenced on a key UK government website providing advice to patients and healthcare staff about the risks of incurring myocarditis following COVID-19 vaccination (https://www.gov.uk/government/publications/covid-19-vaccination-myocarditis-and-pericarditis-information-for-healthcare-professionals/information-for-healthcare-professionals-on-myocarditis-and-pericarditis-following-covid-19-vaccination). The yielded benefits are thus clear on a national level for this very topical and uncertain clinical area. This data has additionally been highlighted by Cardiomyopathy UK and the Janson’s Myocarditis Foundation (the two leading patient charitable organisations) to clinicians and patients across the UK. This data has been was presented to myocarditis patient groups hosted at the Royal Brompton Hospital and [113 words unchanged] undiagnosed features of ongoing inflammation within the heart consistent with myocarditis (https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916). This work has had major public health implications; for example, in the US all college sports were stopped for a period due to concern about myocarditis and high-level sports post-COVID (https://www.theatlantic.com/health/archive/2020/09/covid-19-heart-pandemic-coronavirus-myocarditis/616420/). However, subsequently there has been strong divergent opinion suggesting a much lower prevalence. In order that the study team firstly better assess the prevalence but also help guide national policy, better quality data from across England will be very important. This project extension seeks to strengthen and build upon the initial body of research epidemiology by including the impact of COVID-19 on myocarditis and its related conditions (heart failure, pericarditis, sudden cardiac death and myocardial infarction), both in the period before and during the initial peak and potentially any future surges over the next 12 months to improve understanding of disease trends, regional prevalence, severity and clinical management. This work has had major public health implications; for example, in the US all college sports were stopped for a period due to concern about myocarditis and high-level sports post-COVID (https://www.theatlantic.com/health/archive/2020/09/covid-19-heart-pandemic-coronavirus-myocarditis/616420/). However, subsequently there has been strong divergent opinion suggesting a much lower prevalence. In order that the study team firstly better assess the prevalence but also help guide national policy, better quality data from across England will be very important. This project extension seeks to strengthen and build upon the initial body of research epidemiology by including the impact of COVID-19 on myocarditis and its related conditions (heart failure, pericarditis, sudden cardiac death and myocardial infarction), both in the period before and during the initial peak and potentially any future surges over the next 12 months to improve understanding of disease trends, regional prevalence, severity and clinical management. The study has yielded significant benefit to patients and healthcare professionals both locally, nationally and internationally to provide greater contemporary understanding of the burden of acute myocarditis and early insights into the impact of COVID-19 infection.

Applicant organisation: Royal Brompton Hospital succeeded by Guy's and St Thomas' NHS Foundation Trust from 1 February 2021. NHS ODS records the succession, so this is not counted as a change.

Organisation type: NHS Trust Site succeeded by NHS Trust. Changed with the organisation, so not counted separately.

Data controllers: Royal Brompton Hospital succeeded by Guy's and St Thomas' NHS Foundation Trust from 1 February 2021. NHS ODS records the succession, so this is not counted as a change.

Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.

Objective for processing

Royal Brompton and Harefield NHS Trust aims to describe the longitudinal epidemiological trends of acute myocarditis to provide a contemporary, population-level assessment of the burden of disease and how this may have changed over the last 20 years. National data is therefore required over a 20 year period under this agreement recognising changes and variation arising from medical, biological, geographical and social factors. GLOSSARY of TERMS • Myocarditis - inflammation of the heart muscle. Is known to predominantly affect young adults aged between 19-35 years. It is usually related to a recent viral infection. • myocardial infarction – medical name for a heart attack • Epidemiology - the branch of medicine which deals with the incidence, distribution, and possible control of diseases and other factors relating to health. • Pericarditis - inflammation of the adjacent lining of the heart • Myopericarditis – overlap of Myocarditis and Pericarditis • Dilated cardiomyopathy - is a condition in which the heart muscle becomes weakened and enlarged. As a result, the heart cannot pump enough blood to the rest of the body. • Troponin assays - Troponin is a calcium-regulatory protein for the calcium regulation of contractile function in skeletal and cardiac muscles. The assay is the test used for measuring troponin in nanograms per milliliter of blood (ng/ml) • Echocardiography – is a diagnostic test which uses ultrasound waves to make images of the heart chambers, valves and surrounding structures. It can measure cardiac output and is a sensitive test for fluid around the heart (pericardial effusion). • Viral aetiology – The study of the causes of viruses • Cardiac arrhythmia – is an abnormality of the heart's rhythm • Thrombogenicity - the tendency of a material in contact with the blood to produce a thrombus, or clot. • Thrombi – a blood clot formed in situ within the vascular system of the body and impeding blood flow. • Emboli - a blood clot, air bubble, piece of fatty deposit, or other object which has been carried in the bloodstream to lodge in a vessel and cause an embolism. SUMMARY Royal Brompton and Harefield NHS Foundation Trust aims to describe the longitudinal epidemiological trends of acute myocarditis to provide a contemporary, population-level assessment of the burden of disease and how this may have changed over the last 23 years. National data is therefore required over a total of a 23 year period under this agreement recognising changes and variation arising from medical, biological, geographical and social factors. [2 paragraphs unchanged] The Royal Brompton and Harefield NHS Foundation Trust seeks to obtain all available data on hospital admissions specifically due to 'myocarditis' (I40, I51.4, I01.2, I09.0) in all age groups across England/Wales over the last 20 23 years. Data on age, sex, gender, ethnicity, length of admission, method of admission, Intensive Therapy Unit (ITU) bed [63 words unchanged] be helpful to understand whether social deprivation or pollution levels are implicated. The Royal Brompton and Harefield NHS Foundation Trust also seeks to obtain the same depth of HES Hospital Episode Statistics (HES) Admitted Patient Care (APC) and linked mortality information on hospital admissions due to pericarditis and myocardial [87 words unchanged] the same HES data elements on the scale and scope of myocarditis. Up to one third of patients with myocarditis develop heart failure and dilated cardiomyopathy (DCM). DCM is the leading cause for needing a heart transplant in the UK. The Royal Brompton and Harefield NHS Foundation Trust seeks to obtain the same depth of HES APC and linked mortality information on these hospital admissions to allow epidemiological and [37 words unchanged] detect these cases would lead to underestimation of the burden of myocarditis. Based on extrapolation from published data (Papadakis et al, 2009), the Royal Brompton and Harefield NHS Foundations Trust estimates that myocarditis accounts for one sudden cardiac death each week [18 words unchanged] to electrical disturbances within the heart due to the initial myocardial injury. The Royal Brompton and Harefield NHS Foundation Trust seeks to obtain the same depth of HES and linked mortality [8 words unchanged] of myocarditis resulting in sudden cardiac arrest with or without successful resuscitation. Data is requested over a 20 total of a 23 year period to study the longitudinal epidemiological trends linked to medical (e.g. [54 words unchanged] depth of data in the earlier years. Data is requested for all age groups individuals from birth to death recognising that while myocarditis predominantly affects young adults, it remains an important [54 words unchanged] ultimately informing changes to clinical guidelines and policies on a national level. Readmission data is requested in order to understand the likelihood of myocarditis recurrence over the study period as it is recognised that a subset of patents will suffer a recurrence many years later. At present, there are few tools to identify such patients at the time of index presentation. Alternative diagnoses made at the time of readmission may also be due to complications, such as heart failure and cardiac arrhythmia as described above. To facilitate accurate comparisons with other conditions of overlapping biology (pericarditis), clinical presentation (myocardial infarction) and better understanding of long-term complications (sudden cardiac arrest and dilated cardiomyopathy), Royal Brompton and Harefield NHS Foundation Trust seeks the same depth of HES APC and mortality linked data on these linked diagnoses: The diagnostic codes required relate to: (i) Myocarditis: (ii) Pericarditis (iii) Dilated cardiomyopathy and heart failure (iv) Cardiac arrest (v) Myocardial infarction. [1 paragraph unchanged] ***In light of the current COVID-19 pandemic, there is pressing unmet need to improve the national understanding of the implications of this disease on the heart and cardiovascular system. There are several recent case reports from China and Italy that indicate that viral myocarditis appears to be particularly common and fulminant amongst affected individuals and represents a leading cause of death. There are also growing reports of increased thrombogenicity (the tendency of a material in contact with the blood to produce a thrombus, or clot. It not only refers to fixed thrombi but also to emboli, thrombi which have become detached and travel through the bloodstream) amongst affected individuals leading to micro-emboli throughout the body. It would be extremely informative to the global healthcare community to understand the prevalence of myocarditis with COVID-19 as well the downstream complications and survival rates. The NHS would be well placed to provide this contemporary information on a population level. Analyses of the original data set received data on 16th January 2019 were presented in a talk at the American Heart Association in November 2019 and a manuscript for scientific publication has been prepared. However, it is likely that additional data collected in 2019/2020 would be important to include as it would strengthen the impact of this publication.*** LEGAL BASIS The General Data Protection Regulation Article 6 (1) (e) and Article 9 (2) (j) are the legal basis for the processing of the data. Article 6 (1) (e) states that processing is necessary for the public interest. It is hoped that the outputs of this research will be used to improve and standardise the diagnosis, treatment and surveillance of patients with myocarditis. This data will not be used for commercial purposes, will not be provided in record level form to any third party and will not be used for direct marketing. Only patients residing in England and Wales have been included in this study.

Processing activities

In summary, the Royal Brompton and Harefield NHS Foundation Trust is seeking HES APC and linked mortality data on a population level for acute myocarditis to investigate the changing epidemiological trends and long-term prognosis of this disease. The Royal Brompton and Harefield NHS Foundation Trust does NOT not require patient identifiable information. The Trust would like to obtain all available (pseudonymised) data on hospital admissions specifically due to 'myocarditis' (I40, I51.4, I01.2, I09.0 – full list of diagnostic codes copied below) in all age groups across England over the last 20 years. Data on age, sex, ethnicity, length of admission, method of admission, ITU bed days, specific cardiac procedures (including cardiac catheterisation, endomyocardial biopsy, pacemaker/ICD/VAD implantation and cardiac transplantation) and discharge medication (if available) would be important to record. Geographical data may be helpful to understand whether social deprivation or pollution levels are implicated. Under the previous iteration of this agreement, Royal Brompton and Harefield NHS Foundation Trust obtained all available pseudonymised record level data on hospital admissions (HES APC) specifically due to 'myocarditis', pericarditis, cardiomyopathy, cardiac arrest or myocardial infarction (I40, I51.4, I01.2, I09.0) in age groups from 0 to death across England from 1997/98 to 2017/18, linked with mortality data. Under this Agreement, ongoing quarterly data releases linked to mortality data are requested from 2018/19 to the end of this agreement, made up of: - One drop of Pseudonymised record level HES APC Annual Refresh for 2018/19 and 2019/20, plus 2020/21 Q1, linked to Civil Registrations (Deaths) - Secondary Care Cut via a bridging file. - one drop of Pseudonymised record level HES APC 2020/21 Q2 in November 2020. - one drop of Pseudonymised record level HES APC 2020/21 Q3 in February 2021. - one drop of Pseudonymised record level HES APC 2020/21 Q4 in May 2021. METHODOLOGY - NHS Digital Data Production Team needs to maintain copy of HES cohort from previous quarter - Each quarter, NHS Digital Data Production Team create a HES APC cohort of patients diagnosed with myocarditis and other heart related conditions (see Diagnosis Codes.xlsx attached to holder) - NHS Digital Data Production Team extract all episodes for cohort from the earliest diagnosis date onwards. There is no upper age limit. For newly diagnosed cohort members supply historic episodes in each quarterly data drop. For existing cohort members supply additional episodes only. - NHS Digital Data Production Team link and extract mortality records for the cohort up to the latest date available in the data at the point of extraction. - NHS Digital Data Production Team send pseudonymised record-level output via Secure Electronic File Transfer Service (SEFT) to: Royal Brompton and Harefield NHS Foundation Trust. MINIMISATION Royal Brompton and Harefield NHS Foundation Trust is seeking pseudonymised record level data filtered to hospital admissions due primarily to ‘myocarditis’, pericarditis, cardiomyopathy, cardiac arrest or myocardial infarction. - Data is requested for a further 3 year period to study the longitudinal epidemiological trends linked to medical, social and biological changes over this time period. The total 23 years of data allows for optimal longitudinal assessment based on published literature. - Data in previous versions of this agreement were restricted to only individuals. However, the age profile and demographic of hospitalised COVID patients has had significant impact on adverse outcomes with the elderly being worst affected. Royal Brompton and Harefield NHS Foundation Trust seeks to study to impact of COVID-19 on hospitalisation due to myocarditis and related conditions (heart failure, cardiomyopathy, pericarditis, acute myocardial infarction and sudden cardiac death). Given that COVID-19 has had a significant impact on hospitalisation and mortality amongst older groups, Royal Brompton and Harefield NHS Foundation Trust has altered their request in this agreement and now seeks to remove the upper age cut-off and include patients of all age groups from birth to death. In doing so, changes in the trends of admissions related to myocarditis and its related conditions can be accurately assessed before, during and after the COVID-19 pandemic to assess its impact and guide clinical risk stratification and future service provision. Data is requested for all other age groups because while myocarditis predominantly affects young adults, it remains an important cause for heart failure in young infants and older age groups - the understanding of myocarditis in these groups is particularly limited. - National data is requested in order to remove geographical bias due to regional differences in viral aetiology and healthcare systems, ultimately informing changes to clinical guidelines and policies on a national level. Data on age, gender, ethnicity, length of admission, method of admission, ITU bed days, specific cardiac procedures (including cardiac catheterisation, endomyocardial biopsy, pacemaker/ICD/VAD implantation and cardiac transplantation) and discharge medication (if available) would be important to record. Geographical data may be helpful to understand whether social deprivation or pollution levels are implicated. [1 paragraph unchanged] To facilitate accurate comparisons with other conditions of overlapping biology (pericarditis), clinical [11 words unchanged] arrest and dilated cardiomyopathy), the Trust seeks the same depth of HES APC and mortality linked data on these linked diagnoses (codes listed below). diagnoses. A full list of diagnosis codes have been provided to NHS Digital. All data received would be subject to protection and storage within Royal [46 words unchanged] be analysed by the researcher and the chief/principal investigator, who are both employed by substantive employees of Royal Brompton and Harefield NHS Foundation Trust. This analysis will only take place at the Royal Brompton Hospital. Hospital and the applicant is aware of the security implications and limitations of this data processing methodology [8 paragraphs unchanged] HES DISCLOSURE CONTROL / SMALL NUMBER SUPPRESSION In order to protect patient confidentiality, when presenting results calculated from HES record level data, outputs will contain only aggregate level data with small numbers suppressed in line with HES Analysis Guide. When publishing HES data, you must make sure that: · cell values from 1 to 7 are suppressed at a local level to prevent possible identification of individuals from small counts within the table. · Zeros (0) do not need to be suppressed. · All other counts will be rounded to the nearest 5. Data will not be made available to any third parties other than those specified except in the form of aggregated outputs with small numbers suppressed in line with the HES Analysis Guide.

Expected output

In this study, the Royal Brompton and Harefield NHS Foundation Trust aims to investigate the following features with definable outputs as detailed below: [1 paragraph unchanged] 2. Long-term complications and prognosis of myocarditis – published studies investigating long-term [36 words unchanged] reflective of UK practice given geographical variation, for example, in viral aetiology. The Royal Brompton and Harefield NHS Foundation Trust will analyse and write up this data for publication in a high-impact medical journal, such as the Lancet or BMJ. 3. Gender differences – no studies have specifically investigated age and sex [17 words unchanged] 19-35 years of age. By studying all age groups across the county, the Royal Brompton and Harefield NHS Foundation Trust will generate up-to-date knowledge of this within the NHS - this will improve treating clinicians’ understanding and awareness of who is typically affected by myocarditis. It will also help support translational mechanistic studies to understand why there should be such differences and support awareness campaigns across the NHS. 4. Seasonal variation – from the Royal Brompton and Harefield NHS Foundation Trust's experience of recruiting patients from across South East England into a [9 words unchanged] number of new cases appears to be greatest during the Winter months. The Royal Brompton and Harefield NHS Foundation Trust aims to explore this on a national level through the HES dataset. APC data set. This will again be published in a high-impact medical journal providing new insights into seasonal variation. This could have a significant impact on health-care resource utilisation. It would also help with the timing of awareness campaigns in primary care and potentially guide protection of at risk patients. 5. Geographical variation – the Royal Brompton and Harefield NHS Foundation Trust hypothesises that myocarditis is predominantly a disease of major towns and [30 words unchanged] again be published and circulated widely through the BHF and Cardiomyopathy UK. 6. Diagnostic approaches – there are currently no clinical recommendations to guide [56 words unchanged] MRI, coronary angiogram, cardiac biopsy) and treatments delivered (pacemaker/ICD implantation, cardiac transplantation), the Royal Brompton and Harefield NHS Foundation Trust aims to write-up and publish a Consensus statement paper supported by [51 words unchanged] patient experience and clinical outcomes, which can be reassured after an interval. 7. Recurrence rates and prognosis – there are no published studies that [28 words unchanged] Trust is unable to base a response on any published evidence. HES APC data will allow the Royal Brompton and Harefield NHS Foundation Trust to estimate how many patients are readmitted, and whether this typically [14 words unchanged] economics perspective, and again alleviate patient concerns if appropriate to do so. 8. Mortality rate – the number of patients that die as a [27 words unchanged] years due to developments and advances in service provision and coronary angioplasty, the Royal Brompton and Harefield NHS Foundation Trust expects that the mortality rate from myocarditis is likely to be: [29 words unchanged] will likely spur further public interest, funding and research into the condition. Importantly, it will also spur translational projects to identify where gaps in treatment should focus their efforts. Data generated through this application will be analysed within the Trust and disseminated widely through a number of channels within the year. These will include scientific publication in high-impact medical journals, such as the Lancet and BMJ, as well as lay summaries for communication with patient and public groups through established links with the British Heart Foundation, Imperial College London, Cardiomyopathy UK and Alexander Jansons Fund. Of note, the Trust has arranged it's 3rd annual myocarditis patient and relatives information evening on 14th November 2018 in partnership with Cardiomyopathy UK with the specific aim of providing support and education to individuals affected by myocarditis. Through the planned Consensus statement paper and other established links with guideline committees such as NICE, the Trust hopes to improve and standardise the diagnosis, treatment and surveillance of patients with myocarditis. *** 9. Impact of COVID-19 – this is new disease with anecdotal reports of fulminant acute myocarditis due to COVID-19, which is mechanistically and biologically plausible. The latest evidence from cardiac MRI studies of patients that have recovered from COVID-19 has yielded conflicting findings. In one study, up to 60% of individuals with prior COVID-19 infection had undiagnosed features of ongoing inflammation within the heart consistent with myocarditis (https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916 ). This work has had major public health implications; for example, in the US all college sports were stopped for a period due to concern about myocarditis and high-level sports post-COVID (https://www.theatlantic.com/health/archive/2020/09/covid-19-heart-pandemic-coronavirus-myocarditis/616420/). However, subsequently there has been strong divergent opinion suggesting a much lower prevalence. In order that we firstly better assess the prevalence but also help guide national policy, better quality data from across England will be very important. There is a need for improved understanding of disease epidemiology and in turn, awareness and recognition. Royal Brompton and Harefield NHS Foundation Trust will analyse and write up this data for publication in a high-impact medical journal within a rapid time-frame to make a meaningful contribution to patient care. Data will also be circulated widely through the Trust's partners, the British Heart Foundation and Cardiomyopathy UK. *** Data generated through this application will be analysed within Royal Brompton and Harefield NHS Foundation Trust and disseminated widely through a number of channels within the year. These will include scientific publication in high-impact medical journals, such as the Lancet and BMJ, as well as lay summaries for communication with patient and public groups through established links with the British Heart Foundation, Imperial College London, Cardiomyopathy UK and Alexander Jansons Fund. Of note, the Trust has arranged it's 3rd annual myocarditis patient and relatives information evening on 14th November 2018 in partnership with Cardiomyopathy UK with the specific aim of providing support and education to individuals affected by myocarditis. Through the planned Consensus statement paper and other established links with guideline committees such as NICE, the Trust hopes to improve and standardise the diagnosis, treatment and surveillance of patients with myocarditis. Project milestones and expected target dates for proposed analyses: Jan 2019 Receipt of 20-year myocarditis dataset Mar 2019 Preliminary analyses completed as part of PhD Sep 2019 Scientific manuscript prepared for points 1,3,4, 5 & 6 Nov 2019 AHA Scientific Session oral presentation & Cardiomyopathy UK patient event Dec 2019 Further analyses addressing point 2,7 & 8 through linkage to ONS data Feb 2020 PhD submitted but manuscript held back Mar 2020 Initial queries raised regarding inclusion of additional COVID data Nov 2020 Expected receipt of additional COVID dataset Dec 2020 Further data analyses and manuscript preparation/revision Jan 2021 Submission of landmark study focusing on national myocarditis epidemiological trends over the last 20 years and the impact of COVID Feb 2021 Submission of sub-studies focusing on changes in prevalence/outcomes linked to geographic variation and other confounding factors Mar 2021 Expected receipt of next quarterly dataset with analyses and manuscript preparation focusing on the 2nd surge Mid 2021 Ongoing updates to dataset with further quarterly data receipts and sub-studies depending on the nature of the pandemic at this point Jun 2021 Presentation at BCS conference and other meeting over the year depending on the findings Nov 2021 Expect receipt of final quarterly data drop and analyses focusing on longer-term consequences and mortality of myocarditis post-COVID Dec 2021 Preparation of final summary manuscript and position statement paper to guide ongoing UK management of myocarditis cases

Expected measurable benefits

[8 paragraphs unchanged] The study lead attended a number of training courses in statistical modelling and sought educational guidance and collaboration from a research group at the University of Leeds. There is a strategy for further statistical modelling, which will then form the basis of a larger scientific publication, expected in 2020. Preliminary data was presented in a talk at the American Heart Association in November 2019 . In light of the COVID-19 pandemic, publication may be delayed to include this additional data, although the Trust may also generate a separate and more focused publication relating specifically to COVID-19 myocarditis in 2020. There is also an opportunity to generate an additional publication outlining the decline in general cardiology admissions during the pandemic, which is hypothesised to result in a surge later in the year.

Benefits reported

Preliminary analyses Analyses of epidemiological trends in myocarditis admissions and outcomes have been accepted for oral presentation were presented by the Study Lead at the American Heart Association Annual Scientific Session in November 2019 in Philadelphia, USA (weblink: https://www.abstractsonline.com/pp8/#!/7891/presentation/29869). These findings have also been included as a chapter USA, and subsequently published in the PhD thesis of medical journal, ‘Circulation’. This is available online to the study lead Dr Amrit Lota, which is due for submission to Imperial College. public at the following address: https://www.ahajournals.org/doi/10.1161/circ.140.suppl_1.11463. This has been highlighted by Cardiomyopathy UK and the Janson’s Myocarditis Foundation (the two leading patient charitable organisations) to clinicians and patients across the UK. This data has been presented to myocarditis patient groups hosted at the Royal Brompton Hospital and organised by Cardiomyopathy UK (https://www.cardiomyopathy.org/information-events-myocarditis-information-evening/myocarditis-information-evening-for-parents-and-relatives-1). The project and findings have been made publicly available on a dedicated webpage (https://www.rbht.nhs.uk/research/our-research/active-research-studies/epidemiology-and-prognosis-acute-myocarditis). Further analyses were subsequently conducted by the Study Lead and presented in their PhD, which was recently awarded by Imperial College London on 1st October 2020. These findings were compiled into a scientific manuscript over the 2019 Winter period but this was not submitted for publication due to the emergence of the COVID-19 pandemic and ensuing rise in myocarditis cases earlier in 2020. The latest evidence from cardiac MRI studies of patients that have recovered from COVID-19 has yielded conflicting findings. In one study, up to 60% of individuals with prior COVID-19 infection had undiagnosed features of ongoing inflammation within the heart consistent with myocarditis (https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916). This work has had major public health implications; for example, in the US all college sports were stopped for a period due to concern about myocarditis and high-level sports post-COVID (https://www.theatlantic.com/health/archive/2020/09/covid-19-heart-pandemic-coronavirus-myocarditis/616420/). However, subsequently there has been strong divergent opinion suggesting a much lower prevalence. In order that the study team firstly better assess the prevalence but also help guide national policy, better quality data from across England will be very important. This project extension seeks to strengthen and build upon the initial body of research epidemiology by including the impact of COVID-19 on myocarditis and its related conditions (heart failure, pericarditis, sudden cardiac death and myocardial infarction), both in the period before and during the initial peak and potentially any future surges over the next 12 months to improve understanding of disease trends, regional prevalence, severity and clinical management.