Incidence, healthcare resource utilisation and mortality of invasive fungal infections (IFI) in hospitalised paediatric patients with and without ever having had an IFI-related hospitalisation in England: a retrospective cohort study using HES data

Adelphi Group Limited and Pfizer Limited require access to NHS England data for the following research project:

"Incidence, healthcare resource utilisation and mortality of invasive fungal infections (IFI) in hospitalised paediatric patients with and without ever having had an IFI-related hospitalisation in England: a retrospective cohort study using HES data"

Pfizer Limited has commissioned Adelphi Group Limited to undertake this work and has determined the purpose of processing. Adelphi Group Limited, in the form of their subsidiary Adelphi Real World, will make decisions about the manner and means of processing and is therefore considered a joint controller with Pfizer.

This is a retrospective cohort study using HES and Civil Registrations of Death data. The Data will be used to investigate the incidence, healthcare resource utilisation, and mortality of invasive fungal infections (IFI) in hospitalised paediatric patients with and without ever having had an IFI-related hospitalisation in England.

Globally, it has been estimated that invasive fungal infections (IFIs) affect over 150 million people and ultimately result in 1.5 million deaths annually. IFIs are a type of systemic infection that are caused by yeasts and moulds in deep-seated tissue. The most common IFIs include Candida and Aspergillus species. In children, depending upon age, severity of infection, and its management, IFIs may lead to hospitalisation and death.

In October 2022, the World Health Organization (WHO) put forward fungal pathogens as a global research priority (by priority fungal pathogen group) for the first time due to the unmet research and development need, and perceived public health importance. However, research funding remains significantly lower compared to other pathogens with a similar rate of mortality.

The burden of IFIs is likely to vary based on a multitude of factors including climate, geography, and demographics, ultimately influencing global estimates. However, evidence of the overall burden of IFIs in the United Kingdom (UK) is limited as there is no active surveillance for all types of IFIs, aside from Candidemia. A study utilised a population-based estimate to calculate the incidence of IFIs in the UK and found an incidence of 14.1 per 100,000 patients.

The following is a summary of the aims of the research provided by Adelphi Group on behalf of Pfizer:

• Quantify the incidence of IFI-related hospitalisation among all hospitalised paediatric patients (aged 0-17 years) in England.

• Describe the baseline sociodemographic and clinical characteristics of hospitalised paediatric patients with and without ever having had an IFI-related hospitalisation.

• Describe healthcare resource use (HCRU) among paediatric patients with and without ever having had an IFI-related hospitalisation.

• Quantify the all-cause mortality rate among paediatric patients with and without ever having had an IFI-related hospitalisation and the risk of all-cause death adjusting for sociodemographic and clinical characteristics.

• Quantify the all-cause in-hospital mortality rate and estimate the adjusted risk of mortality among paediatric patients with ≥1 IFI-related hospitalisation.

Results will be stratified by age group, sex, geographic region (hospital provider region), time period of hospitalisation (i.e. prior to/ during/ post COVID-19 pandemic), specific diagnoses associated with immunosuppression, and socioeconomic status using the index of multiple deprivation (IMD).

The following NHS England Data will be accessed:

• Hospital Episode Statistics

- Admitted Patient Care (HES APC)

- Critical Care (HES CC)

• Civil Registrations of Death

HES APC data will be used to access information on all eligible inpatient hospitalisation episodes, define the population of interest, assess healthcare resource use (e.g. overall length of hospital stay) as well as other sociodemographic/clinical information. This data is needed to answer the study objectives.

HES CC data will be used to capture information on critical care admissions, information which is not fully available in the HES APC dataset and is an important measure of secondary healthcare resource use in this population.

Civil registrations of Death data will be utilised to capture mortality as information on death outside of the hospital setting and cause of death are not captured in the HES APC and CC datasets.

The Data will be triangulated to derive IFI-related hospitalisations observed to assess the associated disease and national health economic burden of IFIs among this particularly vulnerable population to identify their characteristics and further investigate potential risk factors for IFI-related mortality that can be used to inform future research targeting interventions to prevent IFIs and/or improve the disease management in paediatric patients.

The level of the Data will be Pseudonymised.

The Data will be minimised as follows:

• Limited to a study cohort identified by NHS England as meeting the following criteria:

- Patients aged 0-17 years at the time of the patient’s first observed all-cause hospitalisation.

- At least one inpatient all-cause hospitalisation at any time during the index period (i.e., 1st April 2008 – Latest Available)

• Limited to data between 1st April 2006 and latest available. This allows for a 24-month baseline look-back period.

• Limited to conditions relevant to the study identified by ICD-10 codes for common serious (severe) IFIs, which are defined as follows:

- Aspergillosis

- Pneumocystis pneumonia (Pneumocystis jirovecii, PJP)

- Candidemia and Invasive candidiasis

- Cryptococcosis

- Mucormycosis

- Other invasive fungal infections, which include:

- Scedosporium spp.

- Fusarium spp.

- Histoplasma spp.

- Lomentospora prolificans

Groups may differ based on sample size, e.g. specific IFIs may be grouped with 'other IFIs' if there are too few cases.

The estimated study population is 250,000-500,000 patients per year. The estimate is based upon NHS England estimates (annual paediatric inpatient admissions in excess of 500,000+ in 2014/15 and 250,000+ in 2022/23).

This research focuses on patients aged 0-17 years because there is an overall scarcity of evidence regarding the impact of invasive fungal infections (IFIs) in the paediatric population in the UK. This is important to consider given that the neurodevelopmental and immunological response system of children varies when compared to adults. In the context of IFIs, this variability in response also means possible variation in healthcare resource use (HCRU) and mortality due to IFIs, which are under-reported in the literature for the paediatric population in the UK.

Since the clinical presentation of IFIs in children may also exhibit differently as compared to adults, it leads to further challenges in diagnosis and management, and therefore poor patient outcomes in the paediatric population. A survey from clinicians highlighted the variation in the treatment of paediatric and neonatal fungal infections across the leading hospitals in the UK. This results in adding uncertainty to the patient outcomes, hence necessitating the need to understand the HCRU burden on the health system in children and explains why previous research in the adult population cannot be extrapolated to this age group.

This methodological consideration also applies to the paediatric population in the study itself, as outcomes are likely to be different based on certain vulnerable population characteristics for example various age groups of children, immunocompromised conditions, and socio-economic status. Hence, informed by an extensive literature search Adelphi will further stratify our analysis to observe the study outcomes across age groups, sex, geographical regions of hospital, pre-, peri- and post-pandemic periods, specific diagnoses associated with immunosuppression and indices of multiple deprivation. In particular, for age, Adelphi will be reporting overall characteristics but also by <3 months as subgroup analysis, considering newborn and late postnatal stage is a high-risk period for acquiring infection, healthcare resource use and adverse outcomes. In addition to the above, Adelphi will also be reporting premature birth as a stratification in patients aged <3 months old, as this is another high-risk factor for poor outcomes in paediatric patients who acquire invasive fungal infection(s).

Pfizer Limited 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.

Pfizer Limited has commissioned Adelphi Group Limited to undertake the work. Adelphi is involved in decisions regarding the manner and means of processing the data and is therefore a joint controller who will also process the data.

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

Article 6(1)(f) - processing is necessary for the purposes of the legitimate interests pursued by the joint controllers:

- Public health research: the study aims to improve the understanding of the incidence of IFI- related hospitalisations and how this may differ based on important characteristics among paediatric patients, as well as the associated healthcare resource use. This research has clear public health benefits, particularly as little is currently known in this area. It is in Adelphi Real World’s legitimate interest to add value to data through the application of research methods and expertise. Adelphi Real World will provide Pfizer Limited with aggregated data, with small numbers suppressed according to NHS guidelines and will help them to interpret these outputs as outlined in the study outputs.

- Scientific research: the study is a retrospective observational real-world secondary data study that aims to generate new knowledge and insights into the incidence of and factors related to IFI-related hospitalisations. This is a legitimate interest to Pfizer Limited as outputs could indicate there is scope for further research into development of innovative treatments and/or preventative care.

- Health service planning: The study aims to investigate which paediatric patients may be at higher risk of IFI-related hospitalisations, and further, identify the groups of patients that may have a higher burden on the NHS. Such findings could inform future research which targets healthcare service planning and resource allocation. This is a legitimate interest to Pfizer Limited as outputs could indicate target groups for development of innovative treatments and/or preventative care.

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

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

This processing is in the public interest because it adheres to the UK Policy Framework for Health and Social Care Research, which protects and promotes the interests of patients, service users and the public, and aims to produce generalisable and publicly available information to inform future decisions over patients’ treatments or care.

The study is funded by Pfizer. The funding is specifically for the study described. Funding is in place for the duration of the study.

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

Prior to external release of results into the public domain, outputs will be reviewed by a key opinion leader from Great Ormond Street Hospital London who is a Professor and Paediatric Infectious Disease Specialist.

Data will be accessed by substantive employees of Adelphi Group Limited only.

Adelphi Group Limited did not engage a Public and Patient Involvement and Engagement group to refine the purpose of the research, but will engage PPIE during the interpretation of the results phase of the project to better understand/explain the findings that are observed in the study. Discussions with the PPIE group will feed into the report and publication write-ups.

No data will flow to NHS England for the purposes of this Data Sharing Agreement (DSA).

NHS England will provide the relevant records from the HES APC, HES CC, and Civil Registrations of Death datasets to Adelphi Group Limited. The Data will contain no direct identifying data items. The Data will be pseudonymised and individuals cannot be reidentified through linkage with other data in the possession of the recipient.

The Data will not be transferred to any other location.

The Data will be stored on servers at Adelphi Group Limited.

The Data will be accessed by authorised personnel via remote access.

The Controller(s) must confirm and provide evidence upon audit by NHS England that access via any remote device complies with the data security obligations within this DSA and the Data Sharing Framework Contract.

For remote access:

• Remote access will only be from secure locations situated within the territory of use (as further restricted elsewhere within the DSA if so done) stated within this DSA;

• Access controls granting users the minimum level of access required are in place;

• Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data;

• Multifactor authentication (MFA) is required for remote access;

• Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access;

• All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this DSA) and complies with the organisation’s remote access policy.

The above applies in addition to any condition set out elsewhere within the DSA (e.g. who may carry out processing, and for what purpose).

The Data will not leave England/Wales at any time.

Access is restricted to individuals within the study team at Adelphi Group Limited who have authorisation from the Study Team Lead. All such individuals are substantive employees of Adelphi Group Limited.

Employees of Pfizer Limited are only permitted to access anonymised data including information derived from NHS England Data. Such datasets will adhere to the relevant small number suppression rules to minimise the risk of individuals being identified.

Pfizer Limited is not permitted to access patient-level NHS England data, but they will be provided access to aggregated data outputs.

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

A Paediatric Infectious Diseases Specialist who is a Professor from the MRC Centre for Medical Mycology at Great Ormond Street Hospital London, will provide expert clinical and scientific opinion, and supporting the data controllers in interpreting the findings of the study. The individual will not have access to NHSE Data but will assist with analysis of aggregated outputs derived using the Data.

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 from Adelphi Group Limited will process the Data for the purposes described above.

The expected outputs of the processing will be:

• Reports of findings to Pfizer Limited. Regular descriptive preliminary summary snapshots throughout the analysis phase. A final results summary will be provided to Pfizer by mid- 2026.

• Submissions to peer reviewed journals by end of 2026. Examples of journals to be targeted are BMJ Open and the Pediatric Infectious Disease Journal.

• Presentations at appropriate conferences such as the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), and the European Society for Paediatric Infectious Diseases (ESPID) conferences.

These timelines are subject to change based on data delivery by NHS England.

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.

Where appropriate, the outputs will be communicated to relevant recipients through the following dissemination channels:

• Journals

• Posters displayed at conferences such as the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), and the European Society for Paediatric Infectious Diseases (ESPID) conferences.

• Reports aimed at the study sponsor Pfizer Limited.

• Direct bilateral engagement with patient advocacy groups, patient advisory committees, or other patient organisations.

All dates dependent on delivery of the data by NHS England. The target date for publication of outputs is December 2026.

The services provided to Pfizer Limited are expected to identify improvement opportunities which Pfizer may then utilise by making changes to systems, processes, resources or infrastructure in order to improve patient experience and patient care. For example, outputs might indicate there is scope for further research into development of innovative treatments and/or preventative care.

The use of the data could:

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

• Lead to the identification or improvement of treatments or interventions, or health and care system design to improve health and care outcomes or experience.

• Identify gaps in knowledge and areas for future research.

• Advance understanding of the need for, or effectiveness of, preventative health and care measures for particular populations or conditions such as IFI’s.

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

• Support knowledge creation or exploratory research (and the innovations and developments that might result from that exploratory work).

While the primary aim of the study is to generate new knowledge and insights into the incidence of and possible factors related to IFI-related hospitalisations, there are still some expected direct benefits to patients that could contribute to improved patient outcomes and healthcare quality; these may include:

• Improved knowledge about IFI-related hospitalisations: Patients may benefit from improved knowledge about the incidence and risk factors of IFI-related hospitalisations among paediatric patients. This could help patients to better understand their risk of IFI-related hospitalisations and take steps to prevent or manage these events.

• Improved awareness among healthcare staff, leading to improved diagnosis and treatment: By identifying factors that could contribute to the risk of IFI-related mortality, healthcare providers may be able to improve the diagnosis and treatment of IFI-related hospitalisations. This could lead to improved patient outcomes and reduced morbidity and mortality.

• Improved prevention strategies: By identifying subgroups of patients who are at higher risk of IFI-related hospitalisations, future research can focus on developing and testing IFI prevention strategies which healthcare providers could use to reduce the incidence of these events among paediatric patients. This could help to prevent unnecessary hospitalisations and reduce the burden on patients and healthcare systems.

• Improved communication with healthcare providers: Patients may benefit from improved communication with their healthcare providers about the risk of IFI-related hospitalisations, and patients at increased risk of death. This could help to improve patient engagement and involvement in their own care.

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.

Pfizer will need to take action based on the information provided to them in order to realise the potential improvement opportunities. For example, where there is an identified need for improved treatment or prevention of IFI’s, Pfizer Limited might commit resources to development of a new treatment or repurpose an existing treatment.

It should be noted that Pfizer might decide not to commit resources to development of improved treatment, or an innovate treatment might not be made available to patients or health & social care practitioners in England & Wales.

Pfizer plan to reach out to patient advocacy groups, patient advisory committees, or other patient organisations to identify potential patient partners who are interested in collaborating on the dissemination of research findings.

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