Impact case study database

Research by King’s academics has made significant contributions to the rise of robotic surgery, particularly in the field of urology. The first Da Vinci system was installed in the UK in 2001. Now they are distributed in more than 70 NHS hospitals across the country (A), with robotic assisted radical prostatectomy being its most common operation. Up to 5,000 radical prostatectomy operations are performed annually in the country, around 60% of which are executed with a robot (B).

King’s transformed urology surgery in the UK through national uptake and training of robotic surgery through The Urology Foundation (C). In the early 2000s, Professor Dasgupta was one of the only people in the UK to perform robotic surgery. Recognising his expertise, The Urology Foundation (TUF) – a charity created to provide more funding for urology research and training – funded Professor Dasgputa to travel around the UK to provide travel mentorship and training to urology surgeons.

Later in 2016, TUF made the decision to create a consortium of five TUF Centres of Robotic Training in the UK, of which King’s – under Prof Dasgputa – was one. As part of the TUF Centres of Training consortium, King’s trained 31 urologists in robotic surgery between 2016-2019, of which five completed ‘mini fellowships’ at Guy’s Hospital and many more benefiting from the cascade training effect, and transforming the urological surgery landscape (C). The CEO of TUF confirmed this work has been instrumental in transforming urological surgery in the UK: “In a relatively short space of time – and with relatively modest funding – the majority of urological patients on the NHS now have access to robotic surgery by skilled robotic surgeons. 92% of prostatectomies, 82% of partial nephrectomies and 52% of cystectomies are now done robotically, meaning that the public are benefiting from this form of minimally invasive surgery and the improved outcomes.”

“The benefit to the public of TUF’s robotic surgery training programme – and Prof Dasgupta’s and KCL’s role in this – is transformative and ground-breaking. In a relatively short space of time, we have opened access to the improved benefits of robotic urological surgery to the vast majority of NHS patients, and it is increasingly becoming the norm in many urological operations. The benefits to patients mean they recover faster and get back to their day-to-day lives quicker, and the economic benefit to the NHS of shorter bed stays in hospital are enormous.” (C)

King’s developed the first international curriculum for safe training in robotic surgery. Following publication in the British Journal of Urology International (6), King’s curriculum was validated in collaboration with the European Association of Urology Robotic Urology Section (ERUS) and has been adapted by a number of other surgical specialties as a gold standard training tool (D.1). The curriculum was also adopted as the official guideline for training by the British Association of Urological Surgeons (BAUS) and King’s researchers were invited to be part of its guideline panel members, essentially shaping the design of the document (D.2). BAUS states that the guideline is relevant to both experienced surgeons learning robotic skills and also to senior trainees learning robotic-assisted surgery anew. It reviews the skills required within robotics, discusses current training methods for robotic surgery and makes specific recommendations e.g. for modular training. The President of BAUS affirmed (D.2): “This paper is the first of its type and could be the model for training documents in other complex areas of urology." As of September 2019, there were a total of 1220 consultant urological surgeons and 337 trainees in the UK and Ireland (D.3). 87.5% of the substantive consultants in the UK are BAUS members (D.3).

King’s expertise enabled Guy’s Hospital (GSTT) to carry out most of the robotic surgery in the country, around 400 cases a year (B.3). The majority are prostate operations, but also include bladder and kidney surgery. The entire robotic programme carried out at GSTT was developed by Prof Dasgupta (B.1). It is now the largest programme in the UK, training two full-time surgical fellows and more than 50 visiting surgeons a year (B.4).

In July 2014, the success of Prof Dasgupta’s work was recognised and GSTT received an international award of GBP600,000 from the Vattikuti Foundation (VF) to set up the Institute of Robotic Surgery, the only of its kind in the UK (B.2). VF is a non-profit organisation committed to making robotic surgery cost effective and available to underprivileged communities. The CEO of VF said: “Guy’s and St Thomas’ is the epicentre for urology robotic surgery in the UK, and has strong research and teaching programmes thanks to its links with King’s College London and the Urology Foundation (B.3).”

Since then, the Institute has trained three international fellows a year, many of whom have gone on to become independent robotic surgeons. It has led to >700 publications, device development, and the evaluation of new technologies for use in surgery such as Google Glass, Hololens and 3D printing of organs to guide surgery (B.2).

King’s research showed better patient outcomes through robotic surgery. The CORAL trial demonstrated the benefits robotic surgery offers in comparison with traditional surgery, such as less blood loss, less pain and quicker recovery (5). This was further confirmed by the European Association of Urology (EAU) Robotic Urology Section Scientific Working Group in a consensus view document published in 2016 (E). These benefits were also recognised by patients, as corroborated by one who underwent a procedure performed by Prof Dasgupta: “It’s great that something like this can be used to give surgeons more detail and help them to carry out the surgery effectively, so it was very reassuring to know it would be part of my operation (B.2).” A 65-year-old patient who went through the same procedure (also carried out by Prof Dasgupta), was able to get out of bed and go for a walk just one day after his surgery (B.4).

King’s changed the programme of care for prostate cancer survivors to include support for the psychological effects of radical surgery (F). The procedure has a high risk of incontinence and impotence, so, GSTT implemented a pre- and post-operative counseling pathway in 2015 to help prepare patients for the psychological and physical effects of surgery ensuring they live a healthier and active life after treatment. Prof Dasgupta supported the pathway by reviewing and analysing patients’ feedback forms, which were key from a strategic point of view to improve patient care. He also assisted in the pathway design, streamlined and designed to be patient centered and efficient for both staff (the NHS) and patients.

Multiple seminars were conducted throughout the trial of the pathway with pre- and then post-operative counselling. All patients that attended seminar sessions were satisfied with the experience. Overall, 99% of patients felt more confident in coping with their recovery after they attended the different seminars and 100% of them felt more confident in coping and understanding the discharge process after they attend their discharge seminar.

The Project Manager of the pathway has said: “If this hadn’t been implemented, the situation would be ‘status-quo’, nothing would have changed for these patients and there would be long waiting lists to see multiple different members of the multidisciplinary team. Prokar’s help in implementing the pathway was extremely valuable and the work shows how important it is to address patients unmet needs to reduce ‘regret’, streamline services and overall improve patient experience (F).”

King’s demonstrated the cost effectiveness of robotic surgery, informing national guidelines in the UK and Canada. Despite improved clinical outcomes, the high cost of purchasing and maintaining the da Vinci system remained a concern for national health services. A systematic review by the King’s team demonstrated that shorter hospital stays alone were not enough to offset the cost of expensive disposables. This led to King’s researchers partnering with colleagues from the Henry Ford Institute in Detroit and Harvard Medical School to show that in order to be cost-effective, centres needed to perform at least 150 operations per year (G ). After proving the cost-effectiveness of robotic surgery, the concept of ‘minimum volume’ was featured in the NICE prostate cancer guidance in 2019, designating centres performing 150 procedures/year as cost-efficient ( H). This resulted in a spike in the use of the da Vinci system in high volume centres to 5-6 days per week ( G). In 2020, the Canadian Agency for Drugs and Technologies in Health (CADTH) also utilised the ‘minimum volume’ concept as a standard recommendation for Canadian health care decision-makers ( I).

Fewer people have acquired HIV as a result of introducing these new approaches to reduce transmission. There has been a striking overall reduction in new HIV cases in the UK [A1], with Public Health England (PHE) reporting in 2017 that new diagnoses decreased from 5,280 new cases in 2016 to 4,363 [A2]. Between October 2015 and September 2016, HIV diagnoses fell by 32% compared with the previous year, among MSM attending selected London sexual health clinics (from 880 to 595; p = 0.014 for test of linear trend in diagnoses by quarter) [A1, A3]. This decline has been attributed to a combination of introducing treatment as prevention (TASP) for HIV positive individuals, increased HIV testing and a rapid increase in PrEP uptake: King’s has made an important contribution to impactful research in all three areas, collaborating on two of the most globally important large-scale clinical trials and leading clinical studies on complementary questions relevant to implementation of these approaches.

Changing national and international guidelines to give more people access to PrEP in the UK and internationally. The PROUD study (1) is widely viewed as the most important real-life PrEP study globally; the clear results were a key piece of evidence leading to changes in official guidelines on reducing HIV transmission. In the UK, the British HIV Association (BHIVA) – responsible for national clinical guidance on HIV – produced a statement in 2016 endorsing the use of PrEP and subsequently developed NICE-approved guidelines published in 2018, which are now followed by all clinicians working in the UK [B1]. The European AIDS Clinical Society (EACS) 2018 treatment guidelines include updated guidance on PrEP [B2]. The World Health Organisation (WHO) early release (2015) and subsequent consolidated guidelines (2016) included recommendation for use of PrEP in a wider population, citing PROUD results amongst the body of evidence reviewed to formulate these recommendations [B3].

Contributing evidence that led to the UK Government PrEP implementation trial and investment in provision of PrEP through the NHS. So compelling were the results of the PROUD study (1) that, in 2016, the UK Government allocated £10 million to the large-scale PrEP Implementation Trial (citing PROUD), which ran from 2016-2019 and opened availability of PrEP through the NHS to 10,000 gay men [C1]. In January 2019, the Government announced their commitment to achieving zero HIV transmission by 2030 – setting out that reaching this goal would depend on continuing prevention efforts including making PrEP available to everyone who needs it [C2]. In March 2020 following the reporting of the PrEP Implementation Trial, the Government announced provision of a further £16 million to make PrEP available on the NHS [C3].

Influencing licensing decisions and recommendations on specific ARV drugs for PrEP. King’s research has influenced decisions on whether or not specific anti-retroviral (ARV) drugs were made available. The PROUD study was included in the 2016 NICE Evidence Review of Truvada [D1], and part of the evidence submitted leading to Truvada being licensed by the EMA in 2016 for use as PrEP [D2]. King’s research on Maraviroc (3) – another class of HIV prevention drug – demonstrated that this drug was not as effective as on demand PrEP. This prevented Maraviroc being investigated in a costly large phase 4 trial and prevented its recommendation for PrEP usage by regulators or national health services [D3].

Informing development of guidelines for use of PrEP drugs for Post-Exposure Prophylaxis (PEP). King’s research on HIV prevention (2,3) led to Dr Fox’s involvement in developing clinical guidance for the newer use of PrEP drugs for Post Exposure Prophylaxis (PEP), which involves treating someone recently exposed to HIV with a combination of ARV drugs that may prevent an infection developing. King’s co-authored the first clinical UK BHIVA PEP guidelines (2015, 2019) [E1,2] and led a PEP review for the BMJ (2017) [E3]. The BHIVA guidelines are now used by all sexual health institutions across the UK and recommended by the British Association for Sexual Health & HIV to healthcare professionals [E2].

Changing clinical practice to ensure that more people are getting tested for HIV, with focus on hard to reach populations. The estimated number of people with undiagnosed HIV infection in the UK reduced from 13,300 (CrI 10,600 to 18,200) in 2015 to 10,400 (CrI 8,400 to 15,700) in 2016, with most of the decline in London apparent in gay and bisexual men, and black African heterosexual women [F1]. King’s work contributed to the following efforts with continuing impact:

National reporting of missed diagnoses introduced: Following presentation of King’s findings on missed opportunities for diagnosing HIV in hospitals (4) at the 2010 British HIV conference, reporting in the Guardian newspaper raised the public profile of this issue. BHIVA subsequently carried out a national audit and produced guidance on recording later HIV diagnoses. Collectively this triggered NHS Trusts to start ensuring missed HIV diagnoses were formally reported as serious untoward incidents (SUIs) – serious clinical events that put lives at risk: these go to Trust leadership and must be acted on within 24 hours, meaning that root cause analysis is now carried out on each case [F2]. As well as introducing systematic data collection, this has reduced stigma by normalising HIV testing and helped increase testing in all healthcare settings as evidenced by the large number of hospitals adopting opt out HIV testing in A&E departments [F3].

Going Viral campaign: In 2017 King’s collaborated on the Going Viral campaign across 9 NHS Trusts across the UK to encourage opt-out HIV testing in A&E: Uptake of opt out testing services in A&E was >90% in these 9 NHS Trusts (GSTT, Royal London, Whipps Cross, Newham General, Homerton, King George, Queens Hospital, St James’ University Hospital and Gartnaval University Hospital [G]. King’s-GSTT was the first centre in the UK to adopt this approach as routine care. Local site information for GSTT shows that this represents a 95% increase in HIV tests carried out by A&E in a 12-month period [G].

Opt-out testing in A&E adopted by NHS Trusts around the UK: King’s research on the high levels of HIV infection in a general A&E population also provided data to support cost effectiveness of opt-out testing [4,5]. Guys and St Thomas’ NHS Trust was the first Trust in the UK to introduce opt-out HIV testing in A&E; this has since been introduced by Trusts throughout the UK in high HIV prevalence areas [F3]. As a result of the research on this subject, opt-out HIV testing in A&E is now recommended in high risk populations (all areas where the local rate of HIV infection is above a certain threshold) in the national BHIVA guidelines and thus been implemented UK wide [H1]. King’s A&E testing research [4,5] also led National British Association for Sexual Health (BASH) and the Royal Society of Emergency Medicine in 2020 to recommend that HIV testing be offered to millions of people living in areas of the UK with a high prevalence of HIV [H2, H3].

Supporting increased community testing: Community point of care (POCT) HIV testing has also increased, and King’s has supported this implementation process locally, evaluating POCT tests for their ability to detect early infection, providing guidance on which tests to use, and what to say or explain when using them in the community. For example, King’s worked with community healthcare providers to determine the social factors influencing uptake of HIV testing – whether people were willing to be tested, how they would feel most comfortable accessing tests; a recent survey in BAME London communities revealed interest in vending machine tests, particularly in specific places within the community such as hairdressers or barbers [I].

Service provision guidance on HIV testing: As a result of the work in this area, reviews of late HIV diagnosis were included in the 2018 BHIVA Standards of Care for People Living with HIV (which provides guidance of running HIV services) [J1] and in 2019, a King’s-led UK-wide audit of late HIV diagnoses was carried out by BHIVA [J2].

Providing expert advice to policy discussions and development. On the basis of her leadership in this area – combining expertise of lab-based drug trials with real-world implementation – King’s researcher Dr Fox has been asked to contribute to a number of policy and clinical discussions, including national committees for UK PEP and PrEP guidelines. Dr Fox is an advisor on WHO technical groups for HIV testing, PrEP (implementation, monitoring), HIV vaccine development and STI treatment; and on WHO guidelines for HIV testing in the presence of PrEP, the role of tenofovir monotherapy in PrEP and STI management in the era of PrEP [K].

Stigma surrounding HIV has reduced as a result of the term undetectable = uninfectious. King’s research on TASP, particularly collaboration on the PARTNER study showing that undetectable means uninfectious to transmit, has been especially influential in tackling stigma around HIV. This finding changed UK, EU and WHO HIV treatment guidelines so that TASP was an indication for starting ART, meaning HIV treatment is now offered to everyone irrespective of CD4 count, with accompanying mass public health campaigns [L]. The work also led to the coining of the U=U slogan (from undetectable= uninfectious), and the associated global campaign to raise public awareness; these efforts are reducing HIV stigma across all populations by reducing anxiety about transmission from HIV positive people, and the phrase U=U is now used globally by stakeholders to promote HIV awareness [L]. King’s researchers have been directly involved in shaping evidence-based public facing communication and advocacy to those living with HIV, advising the HIV treatment information base (i-base.info) and engaging research patient groups and HIV community organisations [L].

Research at King’s on the approach to management of lymphoma using PET scanning has led to the development of new international guidelines and shaped professional practice and treatment around the world. This work has ultimately improved patient diagnosis, management and outcomes nationally and internationally for those diagnosed with lymphomas.

King’s research has changed international guidelines. The methods developed in the King’s-led RATHL and RAPID trials (1-3) have contributed to the harmonisation of practices across PET imaging centres worldwide, stratification of patients and management of the disease. Specifically, King's research led to changes to international guidelines for management of lymphoma from the European Society of Medical Oncology (ESMO) and the US National Comprehensive Cancer Network (A, B); and contributed to European guidelines for performing quality-assured PET imaging from the European Association of Nuclear Medicine (EANM) (C). The 5-point scale developed at King’s (5) has become the international standard also known as the ‘Deauville criteria’ and has been adopted in multiple countries since 2014. Previously, there was no agreed common method to perform and report PET scans in lymphoma.

King’s research has influenced clinical practice and health services internationally. The approaches tested in these trials using PET have become the new standards-of-care amongst the haematology and oncology community and are widely used in the UK, USA, and parts of Europe and Australia. This is evidenced by professional material (H), and patient booklets (I). This is also confirmed by the Head of Department of Haematology at Concord Hospital, the University of Sydney ( Australia) and past Lymphoma Chair of the Australian Lymphoma and Leukaemia Group: *"*The PET guided approaches tested in RATHL and RAPID have shaped the management of patients treated in Australia, which is reflected in guidelines that will be published in Feb 2021 ” (J).

The continuous influence King’s researchers have had in professional practice can also be evidenced by (1) Prof Barrington’s Research Professorship flagship award from the National Institute for Health Research (NIHR) in 2017 and (2) her four-year membership of the European Lymphoma Institute’s scientific committee for international clinical workshops on PET and lymphoma (2010-2018) (D). The Scientific Advisor at Lymphoma Research Foundation ( USA) attested to the clinical significance of her work: “Dr. Barrington’s practice changing research now allows physicians to alter treatment in high risk patients resulting in improved outcomes, and reduce the amount of therapy for those at low risk, with a reduction in toxicities ” (E).

King’s research has improved outcomes for lymphoma patients. The adoption of international best-practice guidelines resulting from King's research has ensured that PET-CT is now the standard imaging test at diagnosis of HL worldwide (A, B), allowing patients to avoid painful and invasive bone marrow biopsies, as documented by patient-advocates in the UK charity Lymphoma Action Booklet (F).

Moreover, the quality assured PET reporting led to improved outcomes for HL patients treated with ABVD chemotherapy with inadequate early response to initial treatment in the RATHL trial. These patients received more intensive treatment following this PET assessment and as a result 67% of them were alive and free of lymphoma 3 years after treatment (2,3). This is in contrast to previous reports where only 20% of patients with adverse early PET scan findings survived using the then standard-of-care. More than 85% of patients in the RAPID and RATHL trials (1-3) who received less toxic treatment as a consequence of the quality-assured PET reporting were alive without lymphoma three years after treatment.

The Chair of the UK National Cancer Research Institute’s Hodgkin Lymphoma Research Group has said: “Professor Barrington has led the core PET laboratory at King’s which has resulted in practice changing research that has directly improved the care for patients with lymphoma. PET adapted therapy is [now] routinely practised worldwide for Hodgkin lymphoma and Professor Barrington pioneered this approach by leading the PET component of the RAPID and RATHL international studies. The resulting practice change has limited acute and late toxicities of treatments for patients and improved the cure rate for advanced stage disease ” (G).

Research by King’s has informed the work of cancer charities in the UK. Lymphoma Action is the UK's only charity dedicated to lymphoma and has provided in-depth, evidence-based information for over 30 years, helping thousands of people affected by lymphoma. In 2016, their website, which had over 1,000,000 unique website users, reported on the RATHL trial conducted on HL at King’s (K). In 2018, at their National Patient and Carer conference, they highlighted the benefits of using PET to guide treatment demonstrated in RAPID and RATHL (L, p.17-23).

Blood Cancer UK, a charity dedicated to beating blood cancer since 1960, reported how findings from the RAPID trial conducted on HL at King’s were changing practice worldwide “making Hodgkin lymphoma treatment kinder ” by offering less intensive treatment to patients with fewer side-effects which can include secondary cancer and heart disease (M).

OAB is not a normal part of ageing. It is a health problem that can persist for many years if it is not treated, and can negatively affect people’s lives. King’s research has enabled the treatment for OAB to progress substantially and, as a consequence, positively impact the lives of people who suffer from this condition.

King’s improved patient outcomes and quality of life through BTX-A administration using the Dasgupta technique: King’s research has involved 3000 patients over 20 years and has changed the way that OAB syndrome is managed. By using a less invasive BTX-A bladder-injection technique, that rapidly reduces overactive bladder symptoms and removes the need for major reconstructive surgery to increase bladder capacity, King’s work has provided measurable improvements to the lives of thousands of patients. Using validated patient reported experience measures (PREMs) such as Client Satisfaction Questionnaire-8, patients undergoing BTX-A treatment show significant improvements in their quality of life, such as overcoming negative emotions and social limitations and experiencing fewer physical symptoms associated with urinary incontinence (A). The beneficial effect can be maintained over 20 years without adversely affecting the bladder due to repeated injections. Evidenced by the PREMS, the BTX-A treatment received an overall patient satisfaction score of 28.3 out of 32 (A). In 2019, The Urology Foundation reported that the method developed by King’s researchers transformed the lives of patients through the UK’s first dedicated Botox clinic at Guy’s Hospital (B). The clinic currently injects close to 200 patients each year (B).

Enhanced cost effectiveness using BTX-A injections as a treatment for OAB syndrome:

A 2018 US study comparing different methods for treating OAB syndrome over a 10-year period demonstrated BTX-A to be the treatment that produced the largest gain in Quality Adjusted Life Years – QALYs (7.179) and lowest estimated incremental cost–effectiveness ratio (ICER) (USD32,680/QALY) of all assessed treatments compared with Best Supportive Care (BSC) (C). The Markov model used in the comparison study confirmed that the treatment with BTX-A 100 Units was the most cost-effective compared to BSC and all other methods (C). Given the minimally invasive nature of BTX-A therapy, these lower costs are often directly related to the decreased incidence of surgical complications (C).

Incorporation of King’s-developed BTX-A therapies into national and international clinical guidelines: King’s research has had a significant impact on informing the clinical management of OAB patients around the world. It has informed the treatment of lower urinary-tract disorders in NICE guidelines 2019 (D)**. This research has been further incorporated into international guidelines established by the European Association of Urology (EAU) 2019 (E) and the American Urological Association (AUA) 2019 (F).

International uptake of the Dasgupta surgical technique through King’s-based teaching & mentorship programmes: The King’s pioneered minimally invasive BTX-A injection technique has been taught by the King’s team to colleagues from around the world (2014-2015), including the UK, Italy, India, South Africa, the USA, Switzerland, the Netherlands and Belgium. A Consultant Neurologist at the National Hospital for Neurology and Neurosurgery, London (G) stated that Dasgupta has been “leading pioneering research into the overactive bladder for well over 25 years. His seminal contributions to the field include developing the technique of injecting botulinum toxin into the bladder wall under local anaesthesia. This minimally invasive "Dasgupta technique" has become an internationally accepted standard, and Prokar has personally trained 62 colleagues in the United Kingdom and overseas across the specialties of Urology and Urogynaecology […] The impact of his research has been substantial and has influenced the practice of Urology both nationally and world-wide .”

King’s COVID Symptom Study App-based research generated key evidence which widened the core symptoms for COVID-19 testing, enabling contact tracing of infectious individuals world-wide, and thus limiting spread and ultimately global deaths from the disease. Moreover, through providing critically early geographical data on predicted cases in the UK, the App enabled localised policies to reduce the spread of the virus, preventing health services from being overwhelmed.

King’s App data led the WHO and the UK Government to include anosmia in official COVID-19 symptoms lists. Data from our COVID-19 Symptom Tracking App confirmed, for the first time in non-clinical patients’, the loss of taste and smell as the most predictive symptom of COVID-19 - 10 times more so than the initial officially listed symptoms, fever or cough (2). As a result, the World Health Organisation (WHO) (E) and UK Government (F) added anosmia to the official list of COVID-19 symptoms. This increased the medical community’s diagnostic capability, and ensured the public recognised this symptom as a sign that they may have COVID and took appropriate action to protect themselves and their community. Professor Peter Byass, advisor to WHO, said (E.2): “Your [King’s] work, particularly in relation to anosmia, was really important in informing the discussions behind this and is much appreciated *.*” Sir Patrick Vallance, UK Government Chief Scientific Adviser (GCSA), confirmed that data from the App was one of the pieces of evidence reviewed which led to anosmia being added to the official case definition symptoms list for COVID-19 in May 2020. He added (F.2): “As estimated by NERVTAG at the time, this will have helped pick up 93% of symptomatic cases, up from 91% previously, which may have led to significant benefit over time.”

King’s App data led the UK Government to include delirium in the official COVID-19 symptoms list for the elderly. The COVID Symptom Study showed that delirium - a state of sudden confusion - is a key symptom of COVID-19 in older people (3). Public Health England’s (PHE) Chief Medical Officer, as a result, updated its guidance, outlining the addition of delirium to the UK’s official list of COVID-19 symptoms in the elderly, and advising doctors to test elderly people presenting with acute confusion for COVID-19 (F.2). This helped healthcare professionals in diagnosis, and increased awareness amongst the public and in care homes to recognise this symptom and take appropriate action to test and avoid spread.

Research by King’s allowed the UK government to identify hot spots across the nation. Thanks to the 4,200,000 people logging their symptoms and location in the App daily, the machine learning model algorithm provided information that was used by the different government bodies in England (F.2), Wales (A.3) and Scotland (B.1), to inform policies intended to slow rates of infection and allow health services to cope. The UK Government Chief Scientific Adviser stated (F.2): “(…) the App has been very useful in tracking the progress of the disease. Since March 2020, the data provided by the App has been informing SAGE advice to the UK government on COVID-19. Research by King’s helped the UK government to identify hot spots across the nation showing the rates of infection in real time all over the UK, allowing identification of areas where rates of infection were growing rapidly. These data have also contributed to increased public awareness and facilitated better management of the disease, which has had an impact on the UK population, the NHS and COVID-19 patients.”

King’s App data uncovered key information about Long COVID-19 informing the approaches of NICE and the UK government. Data from our COVID Symptom Study suggests that while most people recover from COVID-19 within two weeks, one in ten people will suffer symptoms after three weeks, and some may suffer for months (6). In December 2020, The National Institute for Health and Care Excellence (NICE) published guidelines on the management of long-term COVID (G.1) heavily informed by King’s research. The Programme Director for NICE’s Centre for Guidelines said: “COVID Symptom Study data was made available to NICE at a critical moment in the development of the guideline, allowing the advisory panel to consider it when making recommendations on the identification and management of post COVID-19 syndrome (G.2).”

Furthermore, the Secretary of State for Health and Social Care Matt Hancock confirmed: "The findings of the Covid Symptom Study are stark and this should be a sharp reminder to the public, including to young people, that COVID-19 is indiscriminate and can have long-term and potentially devastating effects (H)." The UK GCSA added that data from the App will continue to help track the symptoms of those suffering from Long COVID, to help understand more about its course and the long-term impact of this disease on people’s lives (F.2).

Data collected by the King’s App has continued to support the UK Government’s decision-making on the pandemic (D, F). The research conducted by King’s supported by the data from the App remains one of only ten studies that support the Government’s population surveillance programmes. These are essential to understand the rate of COVID-19 infection, and how the virus has spread across the country. They have helped the Government assess the impact of measures taken to contain the virus, to inform current and future actions, and to develop new tests and treatments. The insight generated from the App along with data from other studies made a significant contribution in helping strengthen the government’s scientific understanding of COVID-19, inform their policy decisions and work across the testing programme. In August 2020, the UK government further recognised the importance of the App by awarding ZOE Global a GBP2,000,000 grant (I). They said the App is “the largest public science project of its kind anywhere in the world” and that it “will help control the spread of the virus by providing vital new intelligence on the scale of local outbreaks, inform our understanding of the virus and how it affects different demographics. ”

The Scottish and Welsh Governments and prominent health charities have endorsed the COVID Symptoms Study App. The Welsh Government and NHS Wales (A) were the first to make an appeal for the public to download the App and log their data to help them understand and predict the developing situation of the disease in Wales. In April 2020, they released a press release where Welsh First Minister, Mark Drakeford, stated: “Having a range of evidence and data is crucial in helping us build a clear picture of how the virus is behaving and affecting everyone’s lives. Crucially this app can help us anticipate potential COVID hot spots and get our NHS services ready. I’m asking everyone in Wales to download the new COVID Symptom Tracker app, so you can help protect our workers and save lives (A.1) *.*” The Scottish Government also encouraged people to use the App in their official social media channels which in combination reach over 543,000 people. They stated: “The COVID Symptom Tracker is an app, approved by Scotland’s top clinicians, designed to study the symptoms of #coronavirus and track how it spreads. We need as many people as possible to take part including people who are feeling well (B) .” Several key health charities in the UK also urged members and the general public to use the King’s App such as the British Heart Foundation, British Lung Foundation, National Rheumatoid Arthritis Society, and Stand Up to Cancer (C).

Members of the public have also benefitted from using the App. The App is free of charge and has been available since March 2020. It doesn’t just collect data, it also provides freely-available, up to date information about COVID cases. It’s rated 4.7 out of 5 stars based on over 276,500 user ratings in the Apple (J.1) and Google Play App Store (J.2). Anonymous reviews illustrate how well the App has been received by the public and what difference it has made in their lives while living through a pandemic. An anonymous review from April 2020 revealed (J.2): “In our isolation feels like we are helping to stop the spread of COVID-19 and the research into its spread with this app.” Another from December 2020 stated: “I have used this app from the start and it's comforting to know that my entries are being recorded and used to advance the fight against COVID. It is continually developing as new information is recorded and I gain more insight from the app rather than the usual media sources (J.2).”

Reviews have also shown the difference the App has made in people with Long COVID symptoms (J.1): “This app is very welcome both for its potential to enable better understanding of the illness, and for the fact that it makes those of us isolating with long term symptoms feel less alone. ” (May 2020) “(…) for us the symptom tracker is very useful because it reveals the extent of the long-term suffering that even a mild case of COVID-19 can cause. Moreover in the absence of a proper response by the U.K. government this is much better than nothing.” (April 2020) “My youngest daughter is showing signs of long COVID like myself, so this app is great for me to keep track of my symptoms and hers. ” (November 2020).

King’s work has led to the development and widespread implementation of highly accurate prognostic tools for AML patients, allowing them to receive personalised molecularly guided treatment. This has translated into changes in clinical practice, improvement in quality of life and survival and NHS cost savings. It has also paved the way for new clinical trial designs that will evaluate the effectiveness of new treatments more quickly and more accurately.

King’s research changed national clinical practice and incorporated molecular MRD assessment into international AML treatment guidelines. Following publication of King’s landmark study in 2016 (2), molecular assessment of MRD status has now been adopted as standard of care for therapeutic decision making in patients with AML including those treated outside clinical trials. In collaboration with Guy’s and St Thomas’ NHS Trust, these tests have been made available for routine use in the NHS and in the past year, 5799 samples have been analysed from 1440 patients (A). This represents a paradigm shift in the treatment of AML away from a single treatment pathway towards a personalised approach in which therapy is tailored based on each individual’s response to initial therapy.

Beyond the UK this change in practice has been reflected in international guidelines, for example those produced by the European Leukaemia Network (B) and the US National Comprehensive Cancer Network (C). These guidelines are used by the majority of physicians treating leukaemia worldwide and NICE takes them into account as part of their decision-making process.

King’s molecularly guided therapy advances patient survival, quality of life and long-term side effects of treatment. Improvement in patient outcome stems from (a) the ability to rationally select patients for bone marrow transplantation (BMT) and therefore to reduce the number of patients exposed to the toxicity of this procedure and (b) the ability to pre-emptively diagnose and treat relapse.

BMT has powerful anti-leukaemia activity but is associated with significant mortality and morbidity. Transplant-related mortality occurs in >10% of patients and many survivors experience serious long-term health issues particularly as a result of graft-versus-host disease (GvHD) which affects ~30% of transplant recipients. Whether to perform BMT as part of primary treatment has been controversial for many years and the decision has been based principally on risk-factors present at the time of diagnosis and clinician preference. The molecular MRD tests developed at King’s have substantially refined outcome prediction and therefore allowed much more rational selection of patients for upfront BMT. Precise numbers on uptake have not yet been obtained since they are only published a few years after the treatment is finalised. However, the Chair of the National Cancer Research Institute (NCRI) Acute Myeloid Leukaemia (AML) working group estimated that ~100 patients per year can safely avoid upfront BMT in the UK alone based on King’s approach (D.1). Additionally, at least 5 patients per year would avoid transplant-related death and ~20 avoid the long-term morbidity associated with GvHD (D.1).

Using King’s serial MRD assessment approach after completion of treatment, patients destined to relapse can be reliably identified. Treating patients at “molecular relapse” rather than full-blown haematological relapse has major advantages (D.1):

• Rather than requiring salvage therapy, which is conducted after the patient does not respond to standard therapy, in molecular relapse this can be timed carefully or in some cases avoided altogether. An increasing proportion of patients can receive treatment for molecular relapse as an outpatient using novel therapies such as venetoclax + cytarabine or gilteritinib, resulting in major improvements in patient experience and quality of life.

• For those patients who are treated with salvage chemotherapy in hospital, those treated at molecular relapse require fewer cycles of treatment than those treated in frank haematological relapse. It is estimated that ~25 patients per year can avoid at least one cycle of salvage chemotherapy.

• The early detection of relapse provides extra time for the identification of optimal donors for BMT and allows patients to enter salvage treatment and BMT in much better physical condition.

King’s approach presents ongoing cost savings for the NHS. As well as being highly toxic, BMT is also a highly expensive procedure with NHS costs of approximately GBP100,000 per patient (D.1). A reduction of 100 procedures per year therefore results in cost savings to the NHS of ~GBP10,000,000 annually. Treatment at the time of molecular relapse also results in a substantial reduction in healthcare resource use compared to treatment at frank haematological relapse. It has been estimated that 25 cycles of salvage chemotherapy are avoided each year by exploiting molecular monitoring which results in a saving of 800 bed-days as well as the associated antibiotic and blood product usage (D.1).

King’s led the development of emergency national guidelines and temporary new drug commissioning during the COVID-19 pandemic. During the peak of the COVID-19 pandemic it was unsafe to treat AML patients with intensive chemotherapy due to the high rates of fatality following infection, and it was desirable to reduce pressure on NHS bed occupancy. Based on their knowledge of molecular responses to novel therapies in different patient subgroups, King’s researchers led the rapid development of national treatment guidelines based on the use of new drugs. This guideline was first published in late March 2020 and was updated every few weeks (E).

Some of the recommended new treatments relied on the use of drugs which had not yet been approved for use in the NHS. Therefore in parallel to developing the treatment guideline, King’s played a pivotal role in urgent discussions with both pharmaceutical industry partners and NHS England which led to a rapid and major change in policy to supply two novel agents (gilteritinib and venetoclax) across the NHS from April 2020 for defined patient groups for the duration of the pandemic (D).

National guidelines and drug availability developed by King’s were highly valued by clinicians and patients throughout the UK. An example of this is confirmed by a Consultant Haematologist at Blackpool Victoria Hospital NHS Foundation Trust in charge of a patient with AML who had an early relapse three months after the end of treatment (F): “As we identified that he had low level disease, we did not feel the need to step in with intensive chemotherapy like Flag-Ida. He therefore was able to be started on molecularly targeted treatment in the form of gilteritinib, a novel FLT3 inhibitor that has recently been approved for use. (…) This is worlds apart from Flag-Ida chemotherapy which would have required intensive inpatient treatment, with significant immunosuppression and significant risk of developing COVID. This all occurred during the height of the pandemic. I am delighted to say that he went into a second molecular remission following treatment with gilteritinib. He therefore was entirely well going into an allogeneic transplant as result of this targeted therapy. All of this could not have been achieved without the help and dedication from yourself, your laboratory and your colleges. I feel this represents truly cutting-edge treatment for acute leukaemia that is unrivalled anywhere else in Europe or indeed the world. I feel myself very fortunate to have your support and expertise on the laboratory side to help and inform my clinical decision making .”

Another example of this is verified by a Consultant Haematologist at Leeds Teaching Hospital NHS Trust Foundation St James’s Institute of Oncology (G) who expressed how the guidelines during the COVID-19 pandemic have been extremely helpful to him and his colleagues: “Just writing to thank you for your help recently with the management of AML and MDS patients, specifically regarding the advised changes to management during the COVID-19 pandemic to try reduce the amount of time patients are both in hospital and neutropenic but at the same time balancing that with therapies that still provide excellent responses. (...) This has been very helpful in terms of treating patients who have molecular relapses before they get full blown relapses and for those with molecular persistence of disease markers and has also impacted in an extremely positive way the treatment pathways we are now able to offer patients.”

As of October 2020, over 350 patients have been treated using these drugs and King’s is leading the collection of real-world outcome data which will inform practice in the future, including in the event of further COVID-19 waves (H).

King’s research paved the way for the development of novel trial designs which evaluate new drugs more quickly and accurately. Incorporation of molecular MRD measurement has provided substantial added value to the UK national AML clinical trials, allowing better understanding of effects of new treatments (I). Molecular MRD status is now increasingly used as an endpoint for clinical trials because it provides a rapid read-out of treatment efficacy, while being highly correlated with traditional outcome measures such as relapse and death. King’s research on MRD assessments during and following therapy have become a key element of risk stratification in many other types of AML and have been integrated into the trials to guide therapy, predict outcome and monitor for relapse. The Chief Investigator of the NCRI AML17, AML18 and AML19 trials confirms that King’s “has been pivotal in pioneering this programme, its integration into the clinical trials and establishing MRD monitoring as a national standard of care. It is the only lab performing this work for the trials and provides a national clinical advisory service on the interpretation of the results (I).”

This has led to the development of new trial designs where patients with molecular evidence of treatment failure are pre-emptively switched to alternative therapy but still counted as a failure event for the trial endpoint. An example of this design is the VICTOR trial (Venetoclax or Intensive Chemotherapy for the Treatment Of favourable Risk AML, EudraCT 2020-000273-24) (D.1). This trial, which is being led by King’s, is testing an original outpatient-based non-intensive treatment against standard intensive chemotherapy. Molecular MRD status is used as the primary endpoint to assess efficacy of the new combination but is also used to switch patients failing this less intensive treatment back onto standard therapy thus allowing treatment de-escalation to be safely tested without putting patients at risk of relapse. This has substantial potential benefits to patients and the NHS in terms of quality of life and resource use.

A participant from the AML17 clinical trial and patient ambassador for Blood Cancer UK said: “I am particularly excited to be involved in the VICTOR trial which I think could offer real hope for older, less fit AML patients who might otherwise be only eligible for palliative care. Venetoclax really does seem to be offering hope for kinder, less damaging treatment. Although I remain in remission almost five years on from my transplant, I am still living with the side effects of my treatment. New drugs like Venetoclax offer real hope for successful treatment without resulting in long lasting side effects. I am very proud to be involved and support the work of Dr Dillon and his team and the AML working group (J). ”

Given the nature of this work, the research and impact described for this case study happened largely in parallel from 2018 onwards, with the evaluation of pilot data (1,2) happening hand in glove with the decision-making process around the implementation of HPV testing in England, the rollout itself, and the dissemination of results to healthcare professionals. Once King’s academics had completed the analysis and evaluation of the HPV testing pilot data (1, 2), they presented the findings of this PHE-commissioned project to UKNSC, PHE and NHSE in early 2018 (before publication of the academic papers describing the results). These heavily influenced and informed the English NHS Cervical Screening Programme, and in 2019, the national roll-out of HPV primary screening for women aged 25-64 was completed. King’s research was showcased by PHE as one of its flagship studies and King’s academics were invited to present the findings to hundreds of healthcare professionals at various scientific and educational events (A). King’s researchers were also invited to present the findings from the pilot to those involved in changing the cervical screening programme in Ireland (A.3). On behalf of the pilot group, King’s has communicated the benefits of these changes to the screening programme through various mass media outlets including BBC Radio 4, The Sun, and The Daily Mail to raise public awareness (B).

King’s researchers provided evidence that allowed the national roll-out of human papillomavirus (HPV) primary screening to go ahead (C). King’s analyses of the English pilot data (commissioned by PHE) contributed to the evidence which reassured decision makers of the effectiveness of HPV testing in preventing cervical cancer. On the back of this King’s-led research, the English Cervical Screening Programme proceeded with the planned national roll-out of HPV primary screening. The National Programme Manager for the National Cervical Screening Programme for England has said: “The evaluation [led by King’s] has proved to be pivotal in providing the data and evidence to inform the decision from the UKNSC to recommend to Ministers the implementation of HPV Primary screening in the wider screening programme (…) A subsequent Independent Cancer Taskforce Report, ‘Achieving world class outcomes’ stated that full national coverage for HPV primary testing would be achieved by 2020. This target was achieved, and HPV Primary screening was fully implemented across the nation in December 2019 (D).”

Kings helped NHSE choose which labs were the most appropriate to carry out the screening tests (and which tests were required) for the English programme. After King’s demonstrated 16/18 genotyping wasn’t sufficiently beneficial (2), the 2018 national tender to select the laboratories to provide HPV testing for the screening programme did not require them to be able to carry out genotyping tests. King’s work (2) was one of the crucial pieces of evidence that led UKNSC to recommend only cytology-based triage of women with HPV infections regardless of the infecting type (E), thus shaping the criteria of the tender process. This was confirmed by the Manager of the Screening Programme: “King’s analysis informed the UKNSC decision and showed that women with positive screening test results can be managed just as effectively without information on viral genotyping. This simplified the national guidelines on triage of human papillomavirus positive women. The simplification of the pathway provides a uniform approach that is clear for providers to adhere to and reduces risk in the programme (…) Every aspect of the planning and delivery of HPV primary screening has been informed by the evidence from Dr Rebolj and Mr Mathews (D).”

Furthermore, the decision not to require HPV typing as part of the triage testing of HPV-positive women, has beneficially impacted the potential cost savings for the NHS. Had typing been recommended for triage, all screening laboratories would have had to procure one of the HPV tests with typing; however, one of the few clinically validated HPV tests, associated with fewer false-positive tests and unnecessary colposcopy referrals, does not incorporate genotyping. As this was not required, several laboratories – processing more than half of all screening tests in the English programme collectively – have proceeded with procurement of this HPV test. A recent study estimated that, if all screening in the English Cervical Screening Programme were done with this HPV test, there is an additional cost saving to the NHS of several million GBP per year (F). These savings would not be achievable had typing tests been made a requirement in the tender for screening laboratories.

King’s researchers gave expert advice to commissioners and providers of cervical screening services that shaped operational delivery. Compared to a screening programme that is based on cytology, a programme based on HPV testing needs far fewer cytology workforce (lab professionals) but substantially more colposcopy capacity (specialised obstetrician-gynaecologists). King’s analyses estimated a reduction of cytology readers of about 85% and an increase of more than 50% in the colposcopy capacity in the first few years of the roll-out (1). These findings were presented to various professional groups within PHE, the UKNSC, and NHSE. These groups used King’s research as input for advance planning of the screening capacities needed across the NHS. As the Manager of the Screening programme explained: “The evidence from the epidemiological evaluation [provided by King’s] informed major service redesign of the operational delivery of the screening programme. An options appraisal to determine the best option for a reduced laboratory provision taking account of the wider footprint of the programme and quality aspects was informed by the data. These findings lead to rationalisation of the 49 cytology laboratories. The final outcome was that NHS England (NHSE) commissioned services for 9 laboratory lots, and 8 laboratories were successful in winning the contracts (D).”

King’s research led to the change in the screening interval from 3 to 5 years. After the first results of King’s research were communicated in February 2018 (G), UKNSC opened a public consultation which reported no objections to extending the screening interval (E). The improved safety of HPV testing – reassured by King’s research (1,2) – requires fewer screens during a woman’s lifetime while maintaining the same level of protection from cervical cancer. In the UK, the extension of the screening interval from 3 to 5 years for women younger than 50 will reduce the lifetime number of screening invitations from 12 to 8. In the coming years, this will have a substantial effect on both the women and the NHS. Some women report feelings associated with cervical screening tests of embarrassment, inconvenience, pain, or discomfort during the screening procedure, which may last a few days; this is also known to prevent or delay some women from going for screening. With millions of women undergoing screening every year, tens of thousands will be able to avoid these short-term consequences of screening participation. Furthermore, a longer screening interval is expected to decrease NHSE healthcare costs and free up valuable time for primary care services. The Manager of the Screening Programme stated that “the implementation of the change to the screening intervals is currently in progress, so we cannot provide the exact extent of these savings but a 2019 study (H) predicted that £23 million per year would be saved under the new interval compared to keeping the 3-year interval **(D).**”

King’s research was used by European professional organisations to inform the internationally preferred approaches to screening and subsequent diagnostics of women (I). A joint position paper on the future of cervical screening was published by The European Society of Gynaecologic Oncology, Europe’s leading society for guidelines for treatment of gynaecological cancers with more than 3400 professional members, and the European Federation of Colposcopy, which includes 34 national colposcopy societies. Their aim is to set minimum standards for colposcopy and treatment of preinvasive cervical lesions in Europe. In this position paper, pilot data published by King’s researchers (2) was used to discuss the role of HPV typing and highlighted that, in contrast to what was previously thought, the use of typing should be dependent on the setting. These are two major international organisations in the field using King’s research to shed light on the use of genotyping and screening.

Public Health England invited King’s researchers to design a new national study and participate in advisory groups (D). Building on the evidence PHE has gained from the pilot and the data acquired, the UK screening programmes are now considering further opportunities that HPV primary screening provides, for example, self-sampling, where instead of going in for an appointment, the woman can take the sample herself, in the privacy of her own home and have it sent to the lab. In February 2020, they invited Dr Rebolj to help them design a new national clinical study to evaluate the impact self-sampling will have on the national screening programme in England. She has been a member of the Project Board, the highest level of governance for the study, and is also an active member of the Operational Steering Group. Dr Rebolj has also been asked to be one of only three authors to draft the first ever English guidelines on how to validate HPV self-sampling tests for future use in the English Cervical Screening Programme. The protocol and the ultimate list of approved technologies will be published by PHE and on the UK Government website – the first clinical validation study using these guidelines received ethics approval in Winter 2020 and is expected to be launched before end of April 2021.

The improvements that were made in the clinical management of suspected or confirmed cases of CDI in Guy’s and St Thomas’ NHS Trust (GSTT) resulted from research conducted by King’s academics. This work has been adopted by GSTT and cited in national CDI guidance. This has led to a dramatic and sustained improvement in care for patients with CDI on a local and national level.

King’s algorithm led to improvement in diagnosis and detection of cases locally and nationally. Accurate and timely laboratory diagnosis is critical to allowing any infection control interventions to be implemented. In 2010, GSTT introduced a new testing algorithm developed by King’s [1] that was able to more accurately (increased sensitivity and specificity) identify cases [A.1]. The Trust also implemented better infection control interventions based on King’s research [2, 3] including rapid isolation, adherence to personal protective equipment and improving hand hygiene; enhanced methods of environmental decontamination (including novel technologies such as sporicidal cleaning agents and automated cleaning technologies using vaporised hydrogen peroxide and UV light) [A]. This led to dramatic reduction in cases, hospital spread, rate of infection, in-hospital transmission and environmental contamination of the hospital environment. The Site General Manager at GSTT confirmed that the system has steadily helped to reduce the spread of infections, particularly CDI at GSTT [A.2].

Since 2007, PHE has carried out mandatory enhanced surveillance of CDI for NHS acute trusts, which includes GSTT. When the annual report was first introduced, GSTT had a hospital-onset CDI rate of 40.5 cases/100,000 Occupied Bed Days (OBDs). By the beginning of the impact assessment period this had already decreased to 13.5/100,000 OBDs and in 2019/2020 the rate decreased even further to 7.0 [B.1].

Source [B.1]

This has resulted in GSTT achieving the lowest CDI rate in the Shelford Group (of 10 leading academic NHS organisations), a position which it has held for the past three financial years. This rate is almost half that of the next best performing Shelford Group Trust (Sheffield Teaching Hospitals NHS Trust, with a rate of 15.2 cases/100,000 OBDs) [B.1]. This is further confirmed by GSTT’s Joint Director of Infection Prevention and Control [A.1]: “King’s research has significantly influenced hospital policy on control of this infection in the Trust. The introduction of many of the strategies outlined in King’s research has enabled rates of infection to be reduced to one of the lowest of any comparable NHS Trust *.*”

In March 2012, the Department of Health published updated guidance on the diagnosis and reporting of CDI [B.2] referencing King’s research [1]. When this national guidance was published, the hospital-onset CDI rate in England was 17.3/100,000 OBDs, by 2019/20 this had reduced to 13.6 [B.1]. The current protocol for testing and diagnosing remains unchanged and it’s based on the peer-reviewed, published research which includes King’s work [1] as outlined on an NHS Improvement 2019/20 document on CDI objectives for NHS organisations [B.3].

King’s research on fidaxomicin contributed to the growing evidence that it reduces recurrence rates and lowers mortality and provides cost savings for the treatment of potentially fatal CDI. Fidaxomicin (FDX) was approved for use in the UK in 2012. It is one of the only four drugs approved for CDI treatment. That same year, GSTT became one of the first hospitals in the country to routinely use this new drug for the treatment of adults. King’s research [4] showed that within the 1168 patients treated, there was a significant reduction in recurrence rates (from 16.3 to 3.1%) and lower all-cause mortality (from 17.3 to 6.3%). This was the first and only real-world evaluation of available antibiotics for CDI in the UK, that confirmed that first-line use of fidaxomicin could improve clinical outcomes in the treatment and management of CDI and its associated recurrences, resulting in an overall cost saving [4].

This work was awarded the Prix Galien award for Real World Evidence in 2016 [C]. Worldwide, the Prix Galien is regarded as the equivalent of the Nobel Prize in biopharmaceutical and medical technology research. Sir Michael Rawlins, chair of the UK Prix Galien judging panel, said: “A unique series of local service evaluations were conducted in 2013-2014 to evaluate the impact of Dificlir [trade name for fidaxomicin] introduction on the NHS. The evaluation, studied in real-world settings, included investigating its effects on service delivery, the management of CDI and its costs, primarily to inform local decision-making. Results indicated the very significant contribution that Dificlir’s use can make to tackling the major public health problems of antimicrobial resistance through targeted antibiotic therapy and infection control [C.2].”

Additionally, our work demonstrating the clinical benefits of using FDX [4] as well as its cost effectiveness [5,7,8], has enabled its inclusion in the list of NHS England high-cost drugs [D]. Drugs on this list are centrally funded by NHS England, which means it doesn’t come as a cost to individual NHS Trusts, thus making it more accessible for them to use.

Methods to combat CDI were further validated by King’s research. After GSTT introduced King’s algorithm and FDX, an analysis [3] was conducted to verify the effectiveness of these measures in comparison with other NHS Trusts (Leeds Teaching Hospitals, Calderdale and Huddersfield, City Hospitals Sunderland, St. Helens and Knowsley Teaching Hospitals and Great Western Hospitals). The data ranging from June 2013 to August 2014, revealed a low rate of in-hospital transmission at GSTT; only 7% of isolates could be potentially linked to a previous case at GSTT, compared with an average of 20% at the other NHS hospitals (range 7-24%) [3].

King’s research enabled expansion of FMT services with a regulated and licensed manufacturing facility. Although the initial treatment with anti-C. difficile antibiotics is generally effective, a significant proportion of patients (20-30%) suffer recurrent infection, which is associated with a disrupted/less diverse gut microbiota. Newer methods of manipulating the gut microbiota such Faecal Microbiota Transplant (FMT) are key to improving clinical outcomes. King’s research provided the evidence base [6] [E] for FMT to be introduced at GSTT in 2014.

In 2016, the success of FMT led to the creation of an MHRA licensed stool bank which has been used to treat over 250 patients from Guys and St Thomas. Owing to the current complexity of establishing an MHRA-accredited service for FMT, GSTT has become a centre of referral for other NHS providers in South East England with CDI and Ulcerative Colitis. This is one of only two licensed facilities in England and has facilitated two successful NIHR grant applications for randomised controlled trials of FMT in cirrhosis [F.1] and antibiotic resistant organisms [F.2]. Clinical success rates for patients treated with FMT have been over 95% and have improved quality of life as outlined in a patient’s testimonial [F.3]: “I have a Primary Immunodeficiency and get virtually continuous urinary infections and frequent chest infections, all requiring a large number of antibiotics. Several times I have ended up with CDI, a difficult and dangerous gut infection as a side effect of the antibiotics. These have been treated with vancomycin and metronidazole sadly without effect on both occasions. I was left wondering if I was going to die of this. I spent a considerable effort trying to locate someone doing faecal transplants and fortunately eventually found Dr Goldenberg at Guys and St Thomas’ NHS trust in 2018. He was a real lifesaver and arranged transplants promptly and on both occasions the CDI was cleared within a few days and my symptoms resolved. I remain eternally grateful to him and hope I don’t need to do this again but if I do, I know where great treatment can be found.”

King’s provide expert advice on treatment of CDI and guidelines for FMT. As a result of this research the case study author has been invited to participate on a number of national working groups/advisory committees. Goldenberg was invited to the Joint British Society of Gastroenterology/Healthcare Infection Society working group on the on the use of FMT to treat CDI. In 2018, the group published a set of UK guidelines for which Goldenberg was joint Chair and joint senior author [E.1]. The guidelines are used by both charities’ members which combined amounts to over 4,000 professionals in the UK [E.2].

In 2020, he joined the United European Gastroenterology (UEG) working group on FMT Banks and contributed to their European guidelines for processes involved with stool banking, such as handling of donor material, storage and donor screening and reviewed all of the evidence that the guidelines were based on [G.1]. UEG is a professional non-profit organisation recognised as the leading authority for digestive health.

Every year more than 15,000 babies in the UK will develop peanut allergy; King’s research has shown that at least 12,000 of these cases can be prevented. This fundamental shift in our understanding of childhood allergy has reversed infant weaning policy worldwide, and has directly led to new national and international guidelines recommending early peanut consumption for the prevention of peanut allergy. This impact case follows on from a REF2014 case covering the early impact of this research that led to a shift in the guidelines to withdraw the recommendation to actively avoid food allergens in the infants’ diet. Since 2014, King’s research has subsequently led international guidelines to be rewritten to recommend active introduction of allergenic foods, namely peanut and egg, in infants’ diet during weaning; a fundamental shift in the understanding of food allergy, and associated change in clinical practice; and direct benefit to children and families around the world

King’s trial results immediately reversed the global consensus on allergenic foods in infant diets. The LEAP findings were deemed so convincing that a statement was immediately published simultaneously (from August 2015) in eight journals recommending that the LEAP strategy should be put into practice, based on consensus among the 10 major international allergy specialist organisations: American Academy of Allergy, Asthma & Immunology (AAAAI), American Academy of Pediatrics (AAP), American College of Allergy, Asthma & Immunology (ACAAI), Australasian Society of Clinical Immunology and Allergy (ASCIA), Canadian Society of Allergy and Clinical Immunology (CSACI), European Academy of Allergy and Clinical Immunology (EAACI), Israel Association of Allergy and Clinical Immunology (ISACI), Japanese Society for Allergology (JSA), Society for Pediatric Dermatology (SPD), and World Allergy Organization (WAO). This was considered interim guidance whilst national and international guidelines were formalised [A].

New national clinical guidelines for the prevention of childhood peanut allergy are being developed around the world. In January 2017, the National Institute of Allergy and Infectious Diseases (USA) published new clinical practice guidelines for the prevention of peanut allergy which were endorsed by 26 federal agencies, professional societies, foundations, and advocacy groups [B]. In March 2019, the American Academy of Paediatrics updated its guidelines on how to prevent food allergies in children, saying there was not enough evidence to prove that delaying the exposure of children as young as four to six months old to allergenic foods helps keep them from developing food allergies. On the contrary, based on strong evidence from the LEAP study they endorsed the evidence showing that purposeful early introduction of peanuts may prevent peanut allergies in high-risk infants, resulting in the recommendation to introduce peanut protein as early as between four and six months [B]. Independently, scientific societies such as the Australasian Society of Clinical Immunology and Allergy have also produced their own guidelines [B]. As a result of these findings, the European Guidelines (from the European Academy of Allergy and Clinical Immunology, EAACI) have been re-written and are under submission for publication; these are followed by clinicians in the UK [B].

New clinical guidelines are already leading to a significant change in clinical practice. Implementation of the ASCIA guidelines in Australia has resulted in a dramatic shift in infant feeding, documented very rigorously: prior to 2011 fewer than 30% of 12-month-old infants were eating peanuts, whereas after the guidelines were introduced in 2017, almost 90% of infants were eating peanuts (of more than 6000 infants surveyed) [C].

Clinical programs are now being set up nationally and internationally to implement the findings of the LEAP study:

• The first NHS food allergy prevention clinic has been established. The research findings resulted in the first NHS food allergy prevention clinics being established at Guy’s & St. Thomas’ NHS Trust in 2018, with community liaison using Skype video consultations to promote early intervention in the first 12 months of life. In the last two years, more than 500 infants at risk of peanut allergy have been seen in this clinic and peanut has been introduced successfully in their diet in the vast majority, either at home or in hospital [D].

• Harvard clinicians Wayne Shreffler and colleagues at Massachussets General Hospital have instituted a similar programme in the Boston area. This focuses on identifying infants at risk of developing food allergies and facilitating early introduction of peanut and other allergenic foods, under medical supervision if needed. Since the establishment of the prevention programme in 2017, 862 new patient visits for evaluation of eczema or egg allergy in infants under one year of life have taken place. Over 616 food challenges have been conducted to a variety of foods, including 100 peanut challenges on patients under 18 months of life, where the allergenic food is introduced under medical supervision to assess for possible allergic reaction. 68 children did not react, allowing the incorporation of peanut in the diet [E].

King’s research has improved the lives of children at risk of food allergy, and their families. This patient-focused research has improved the lives of children worldwide by providing clear guidance on the age of dietary introduction of peanut to reduce allergies via simple, low-cost, safe, and practical means. Looking locally within our prevention clinic at who has been assessed and established on peanut consumption, this will have prevented more than 80 new cases in our community in the last couple of years [D]. This practice is now expanding to our Institutions in the four UK nations. The testimonials from parents of children identified as being at risk of peanut allergy who had the opportunity to attend our clinic and have medically supervised introduction of peanut into the diet have expressed how much difference it has made to their lives. For instance: “I am and will be forever grateful for the care you bestowed on baby (child’s name) when she was driven to madness by her eczema and the subsequent improvement in her health once she was found to be allergic to breast milk, eggs and wheat by your excellent team. Knowing now how lucky she is to hopefully be peanut tolerant for the rest of her life (she loved her Bamba) I feel so very grateful *.*” [F.1]. King’s has also improved the lives of children with allergies and their families through charities. The Anaphylaxis Campaign, for example, widely disseminated King’s papers on the LEAP and EAT studies. After that, they received feedback, via their helpline, from “parents who have changed their strategy for introducing solid food in order to ensure early introduction of allergenic foods that they would otherwise have avoided based on outdated advice” [F.2]. Additionally, the Head of Clinical Services at another organisation - Allergy UK - has said: “This is such important research and I have no doubt has given much more structure to our advice as a charity and helping parents make informed decisions.” [F.3]

The paradigm shift resulting from King’s RCTs is being transmitted to the medical community and trainees through teaching and professional development, transforming clinical practice and approach to treating and preventing childhood food allergy [G]:

• Medical students: Textbooks have been rewritten to include the new evidence and recommendations. Locally, at Kings the Paediatric Allergy Service has two medical students allocated per year who often focus their case study reports on early food introduction; and other groups of medical students covering paediatric specialties in their rotations (approximately eight students per week) who learn about food allergy prevention during their clinic placements.

• Paediatricians: There have been articles in general paediatrics journals about early introduction of allergenic foods in infants, which target a large and broad readership within the medical community. As part of the training in Paediatrics, the UK national curriculum now includes illustrations such that general paediatric trainees need to provide evidence of understanding of the principles of allergy prevention.

• GPs and other health professionals: In the UK this work is being communicated to the medical community beyond the Allergy specialty through courses about prevention of food allergy run by the KCL Allergy Academy. This was set up by King’s researchers and is directed at GPs, general paediatricians, nurses and dietitians. The Children’s Allergy Service at the Evelina London also hosts international courses and two visiting professionals per year from around the world who come to learn about food allergy prevention, among other aspects of Paediatric Allergy. An allergy trainee from Portugal said: “I have had a wonderful experience at St Thomas’. I have learnt so much that I can take back into my own practice back home *.*” A visiting paediatrician commented: “I have gained so much from my year here and was exposed to so much, from so many different areas of allergy. I now feel confident to develop a service when I return to Greece” and a Clinical fellow from the Children's Hospital of Fudan University, China said: “The learning experience in St Thomas Hospital was very helpful for my professional career. I plan to do the skin prick test, food challenge and sublingual immunotherapy in our hospital in the future, which we do not do now. I think this work will benefit patients. ”

King’s raised public awareness on how to prevent childhood peanut allergy [H]. This work has been widely disseminated to the public through multiple national and international media outlets such as BBC, ITV, Sky, Channel 4, CNN, NHK, Al Jazeera, Canadian Broadcasting Corportation, ABC News, CBS, The Wall Street Journal, The New York Times, The Guardian, Daily Mail, The Times, and many more.

Following the publication of the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) in 2016 (1, 2), the major elements of international classification, policy and clinical guidance for sepsis which affect clinical care worldwide, have been changed. This has impacted national and international levels of healthcare policy and clinical management of sepsis.

Impact on international health policy and clinical management of sepsis

The revised sepsis definitions were adopted as the new International Classification of Diseases standard (ICD-11) [A]. The ICD coding system is used for classifying all diseases globally, overseen by the WHO, who describe the ICD as ‘the foundation for the identification of health trends and statistics globally, and the international standard for reporting diseases and health conditions. It is the diagnostic classification standard for all clinical and research purposes.’ In May 2019, the WHO’s World Health Assembly officially adopted ICD-11, directly drawn from King’s research (1,2). The ICD is used to underpin comparisons of health data (local, regional, national, international), in analysis that informs evidence-based decision making and policy development, and to monitor the incidence, prevalence and causes of disease. The ICD is also used to determine the Global Burden of Disease estimates of sepsis (a tool widely used by policymakers). WHO regulations ensure Member States use the most current ICD revision to record and report mortality and morbidity statistics, nationally and internationally: since the previous 1990 endorsed version, the system has been used by more than 150 countries and translated in over 40 languages.

The new definitions both support and help deliver on the WHO commitment to make sepsis a global health priority [B]. In 2017, the WHO highlighted the updated sepsis definitions as the diagnostic gold standard and recognised sepsis as a global health priority - a year after publication of pivotal research led by King’s researchers. Later that year the WHO Assembly adopted resolution WHA70.7 on ‘Improving the prevention, diagnosis and clinical management of sepsis’; this urged member states to ‘apply and improve the use of the International Classification of Diseases system to establish the prevalence and profile of sepsis’ [B.2]. In 2020, the progress report on this resolution specifically notes that the ‘WHO published the International Classification of Diseases, 11th Revision, allowing reporting of sepsis, in conjunction with the underlying infection’, as a milestone towards estimating the global burden of sepsis more accurately [B.3]. The WHO factsheet on sepsis also explicitly references King’s research (1, 2) [B.1].

The new definitions underpin the WHO’s first global epidemiological report on sepsis. In September 2020, the WHO published its first ‘Global report on the epidemiology and burden of sepsis’. When the report was launched the WHO Director-General said: “The world must urgently step up efforts to improve data about sepsis so all countries can detect and treat this terrible condition in time” [C.1]. This report enabled for the first time the gathering of global epidemiological data in sepsis incidence and outcome – and it noted that data was still incomplete and patchy, highlighting the need for more action. To address this, the WHO proposed using the ICD-11 going forwards to standardise diagnosis, treatment and reporting across regions in order to ‘Improve surveillance systems, starting at the primary care level, including the use of standardized and feasible definitions in accordance with the International Classification of Diseases (ICD-11), and leveraging existing programmes and disease networks ’ [C.2].

Impact of new ICD-11 definition for healthcare systems and professionals. The establishment of the ICD-11 definition of sepsis benefits national organisations that influence health policy to improve patient care. These definitions were endorsed by the UK’s Academy of Medical Royal Colleges and 30 equivalent national or regional societies from all WHO health regions (including the USA, Europe, Japan, China, Caribbean, Pan Arabic Critical Care Society, India) [D.1]. Following these endorsements, these Professional bodies and patient advocacy groups (for example the UK Sepsis Trust) have used the new sepsis definitions to lobby governments for improved management of sepsis patients [D.2]. These definitions are now used for diagnosing and treating sepsis patients in all these countries such that they have contributed to the quantitation of worldwide sepsis incidence and outcome statistics in the widely used WHO Global Burden of Disease [D.3]. The new definitions were also adopted by the International Surviving Sepsis Campaign (SSC) guidelines in 2016 [D.4]. The SSC is a global initiative of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM) at 200 sites internationally, to measure and compare changes in adherence to sepsis quality of care indicators, aiming to reduce mortality and morbidity from sepsis.

Impact on Sepsis patient management in the UK

The Intensive Care National Audit and Research Centre database ICNARC is the national audit for all 235 UK NHS Trusts (98% coverage of adult general critical care units in England, Wales and Northern Ireland), that assesses the outcome and care quality of adult critical care units in the UK every year. Shankar-Hari is a Senior Clinical Scientist at ICNARC and led the study that is currently used to benchmark sepsis between different intensive care units in England, Wales and Northern Ireland [E.1]. This King’s-led work described how to operationalise the international benchmarking of sepsis incidence and outcomes [E.2]. Since 2019, these methods are used for the national patient-centred safety and quality of care policy, funded by the UK Government (Getting It Right First Time) which expects hospitals to adapt their sepsis management procedures in line with the CQUIN report (NHS Commissioning for Quality and Innovation) [E.3, E.7]. This exemplifies a change of the implementation of national level benchmarking of critical care units to improve clinical care of sepsis patients (data on the effect of implementing this change in the UK is not yet available and will be highly skewed by COVID-19). In 2019, Shankar-Hari also collaborated with NHS Digital to extract all known sepsis events in the UK (2011-2017), in order to generate a measure of sepsis disease burden in the UK used to inform health policy [E.4-E.6].

Impact of King’s-led research on patient care and outcomes of sepsis

King’s expertise leads to the development of patient-centred clinical resources. The BMJ rapid practice recommendations provide guidance for clinicians on how best to treat patients with corticosteroids, based on critical appraisal of all available evidence (6). This coproduced research involved sepsis survivors and caregivers as well as healthcare professionals, and explicitly developed recommendations taking into account patient outcomes and patient preferences – for example, giving options which make a distinction between reducing the chance of death and quality of life. The resulting guidelines on corticosteroid therapy for sepsis patients are intended for use by clinicians, explicitly involving patients and carers in the decision-making process. BMJ guidelines – patient and practice-changing focused – are widely adopted, influencing patient care internationally [F.1]. Based on the findings on sepsis survivor care and prognosis (4), King’s developed a prognostic tool. This clinically-validated sepsis survivor score provides estimates of prognosis for the first year post-sepsis based on follow-up care, and can be used by clinicians/patients to anticipate risk and manage the follow-up care of sepsis survivors based on risk, for the first time. This open-access score has been endorsed by the UK Intensive Care Society for use by UK clinicians [F.2].

Raising awareness amongst clinicians, sepsis survivors and the public of health risks. In the UK, few patients who survive sepsis-related critical illness are given follow-up care, and King’s research highlighted that one in six sepsis survivors die in the first subsequent year (3,4). To increase public awareness and lobbying to address this at a national level, King’s have engaged extensively with the media on this important patient centred issue, with this specific study being covered by 86 National and International Newspapers and numerous blogs in 2019 [G.1]. Furthermore, focus groups of clinicians, sepsis survivors and their families revealed much greater awareness of the risk of future morbidity and mortality, and the need for close monitoring [G.2].

Using sepsis expertise to inform the clinical response to COVID-19. King’s research on the immunophenotyping of Sepsis and COVID-19 (5,7,8) has had several early impacts in 2020, with Professor Shankar-Hari taking leadership roles in the national response due to his expertise in the field of sepsis. Given his role in identifying long-term risk factors in sepsis survivors, his expertise was sought as part of the WHO international Long COVID Committee, which was tasked with the clinical characterisation of Long COVID and the ICD11 coding also directly informed WHO COVID information (2020) [H.1]. As a result of the COVID-IP and MIS-C studies, Professors Shankar-Hari and Hayday were invited to give evidence to the House of Lords Science & Technology Select Committee on the immunology of COVID-19 in June 2020 [H.2]. Furthermore, King’s work led to strategic investment of USD20 million by NIH to understand the pathology of MIS-C and pilot treatments [H.3].