How high-quality research saves many lives and millions of pounds
Wei Shen Lim, a consultant respiratory physician at Nottingham University Hospitals NHS Trust and an honorary professor at the University of Nottingham, has had an extraordinary impact on health.
Professor Wei Shen Lim, in his role as chair of Covid-19 Immunisation on the Joint Committee on Vaccination and Immunisation, delivers a briefing in 10 Downing Street.
In the UK, his research helped save the NHS around £233m by transforming policies for vaccination in the adult population against pneumococcal disease, which can lead to pneumonia, blood poisoning and meningitis. A further £34m a year was saved for informing a change in the childhood vaccination schedule.
Professor Lim and his colleagues went on to play a key role in the evaluation of dexamethasone in the RECOVERY trial, which demonstrated the steroid’s effectiveness in treating patients with severe respiratory complications due to Covid-19. Dexamethasone reduced death rates among ventilated patients with Covid by a third, which was estimated to have saved over one million lives across the world up from its introduction in June 2020.
Dexamethasone, inexpensive and widely available, was the first medicine to reduce mortality from Covid-19 and the UK Government’s Chief Scientific Adviser, Sir Patrick Vallance, said:
“This is a ground-breaking development in our fight against the disease, and the speed at which researchers have progressed finding an effective treatment is truly remarkable. It shows the importance of doing high quality clinical trials and basing decisions on the results of those trials.”
"The speed at which researchers have progressed finding an effective treatment is truly remarkable. It shows the importance of doing high quality clinical trials and basing decisions on the results of those trials"
Reducing the burden of pneumococcal disease
Until the early 2000s, pneumococcal infections placed a significant burden on the NHS, with groups such as babies, adults aged 65 and over and those with long-term health conditions, such as a serious heart or kidney condition, considered to be those at high-risk of the disease.
The introduction in 1992 of pneumococcal polysaccharide immunisation (PPV) - a pneumonia vaccine - for adults and the subsequent adoption of a pneumococcal conjugate vaccine (PCV) for at-risk children under two years of age helped lessen this burden. The PCV vaccine reduces pneumococcal carriage in children and, through herd protection, consequently reduces adult pneumococcal disease.
But routine blood testing of all patients admitted to hospital with pneumonia is only capable of picking up strains associated with the 10% of patients with pneumonia who also have a positive blood culture result. The strains associated with the other 90% of patients with pneumonia cannot be identified, making it difficult to measure the effectiveness of the PPV and PCV vaccines.
In 2008 Dr Robert George of Public Health England’s Colindale laboratory developed a urine test that had the potential to capture data on pneumococcal strains from 100% of patients with pneumonia.
This significant breakthrough led Dr George and Professor Lim to co-found a UK surveillance programme in the same year, assessing how the prevalence of pneumococcal strains were changed by the introduction of the childhood vaccination. The ongoing programme is thought to be the only and longest running longitudinal study of its kind on pneumococcal infections in the world.
By testing all adults admitted to Nottingham hospitals with community-acquired pneumonia (CAP), the study provides invaluable information on how the serotypes (strains) of pneumococcal pneumonia adapt over time, following changes in pneumococcal vaccination policy in the UK.
By 2015, data from the study identified that the incidence of adult pneumococcal pneumonia had declined from 2010, and that PCV infant vaccination had had an effect on herd protection on the adult population. Advances in the urine test’s ability to detect a wider range of pneumococcal strains, with contributions from Professor Lim’s clinical research team in Nottingham, further enhanced the richness of the data available to NHS policymakers.
This data informed the Joint Committee on Vaccination and Immunisation’s decision to not offer the PCV13 vaccine used in infants to adults over the age of 65 in the UK, as it was unlikely to have a big impact on CAP.
Professor Lim’s research was also cited in a decision in 2019 by the United States Advisory Committee on Immunization Practices to reverse its decision to recommend PCV13 to adults.
The data has been used by the JCVI to monitor the effectiveness of primary and booster doses for infants and inform childhood vaccination policies.
Such evidence-based decisions have enabled the NHS to make huge savings in procurement and delivery costs of pneumococcal immunisation, with ongoing monitoring of pneumonia patients in Nottingham by Professor Lim and his team providing valuable insights into population-level changes in case numbers.
Dexamethasone: the breakthrough Covid-19 treatment
Professor Lim was the co-lead investigator of the dexamethasone arm of the RECOVERY trial, the world’s largest clinical trial to discover drug treatments for Covid-19-19. Led by the University of Oxford and set up in March 2020, it involved more than 40,000 participants across 185 trial sites in the UK, including Nottingham University Hospitals NHS Trust
The trial determined that Dexamethasone, a low-cost steroid treatment, reduced deaths in patients hospitalised with severe respiratory complications from Covid-19 by up to one third.
Dexamethasone was the first drug found to be effective against Covid-19 and a landmark in the fight against the virus. But getting Dexamethasone to be assessed in a clinical trial in the first place was not straightforward.
“There was a lot of resistance because of scepticism about whether steroids would work as a treatment and even be harmful,” recalls Professor Lim.
But he was well-placed to run such a trial – following 2009’s H1N1 (swine flu) pandemic, Nottingham set up the ASAP Trial (Adjuvant Steroids in Adults admitted to hospital with Pandemic influenza) in 2012 to test whether dexamethasone would be an effective treatment for severe pandemic influenza.
The ASAP trial was put into ‘hibernation’ by Professor Lim and his colleagues including Claire Brittain, Professor Lelia Dudley and Professor Sir Jonathan Van-Tam, at the time a University of Nottingham Professor of Health Protection, who went on to become the UK’s Deputy Chief Medical Officer – meaning the trial, with researchers and clinicians signed up and ready to enrol patients, was ready to be kick-started to test treatments during any future pandemic.
This provided a strong basis for Professor Lim and fellow members of the New and Emerging Respiratory Viruses Threats Advisory Group (NERVTAG) to advise health chiefs regarding the evaluation of low-dose steroids in patients hospitalised with Covid-19.
He said: “The groundwork set by the ASAP Trial made an important difference in getting dexamethasone evaluated within the RECOVERY trial. Sites that had signed up to the ASAP Trial contributed towards a third of participants recruited to the dexamethasone evaluation in the RECOVERY Trial, with Nottingham one of the highest recruiting centres.”
Results from the trial led the World Health Organisation, European Medicines Agency and countries such as the UK, United States, Canada, Ireland, South Africa and Belgium to recommend the clinical use of dexamethasone to reduce death rates.
Before dexamethasone’s introduction as a therapy, the fatality rate of patients with Covid-19 admitted to hospital during the 2020 pandemic was approximately 26%, rising to more than 37% among patients who required invasive mechanical ventilation.
Dexamethasone reduced deaths by one-third in ventilated patients and by one fifth in other patients receiving oxygen only.
NHS chief executive Sir Simon Stevens said: “Thanks to the exceptional work of our researchers, NHS staff and patients, around one million lives may have been saved around the world. Research that would usually take years produced answers in record time – with results that have reverberated across the globe.”
"Thanks to the exceptional work of our researchers, NHS staff and patients, around one million lives may have been saved around the world. Research that would usually take years produced answers in record time – with results that have reverberated across the globe"
Professor Lim said: “To be involved in this work and have such a global impact is fantastic.”
He is also struck by how his research into pneumococcal pneumonia has influenced vaccination policies, allowing the NHS to make huge savings while ensuring the population is protected.
"To be involved in this work and have such a global impact is fantastic"
Another career highlight goes back to 1997, when he helped develop the CURB65 score; a severity assessment tool to identify patients who might be at higher risk of dying from pneumonia, which is used in guidelines across the world.
As chair of Covid-19 Immunisation on the Joint Committee on Vaccination and Immunisation, Professor Lim has acted as an independent advisor to the government regarding the vaccine programme.
“It’s a huge privilege to have been in the eye of the storm and to be involved in vaccine advice and policy development,” he said. “It is our responsibility to carry out our work with the public's interest and what is best for patients in mind.”
Professor Wei Shen Lim
Professor Wei Shen Lim is a consultant respiratory physician at Nottingham University Hospitals NHS Trust, a member of the NIHR Nottingham Biomedical Research Centre and honorary professor at the University of Nottingham.
In 2021 he was awarded the Moxon Medal by the Royal College of Physicians in recognition of his outstanding contribution to clinical medicine.
NIHR Health Technology Assessment 2015: Lim W, Brittain C, Duley L, et al Blinded randomised controlled trial of low-dose Adjuvant Steroids in Adults admitted to hospital with Pandemic influenza (ASAP): a trial ‘in hibernation’, ready for rapid activation.
The Lancet Infectious Diseases. 2020: Simpson, Lim, et al The UK hibernated Impact case study (REF3) Page 3 pandemic influenza research portfolio: triggered for COVID-19
Clin Vaccine Immunol 2017: Eletu, Lim et al Development of an extended specificity multiplex immunoassay for detection of Streptococcus pneumoniae serotype-specific antigen in urine using human monoclonal antibodies
Thorax. 2020: Pick, Lim et al: Pneumococcal serotype trends, surveillance and risk factors in UK adult pneumonia, 2013–18