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19th December 2024
Daily monitoring of the blood biomarker procalcitonin (PCT) can pinpoint when to safely stop antibiotics in adults hospitalised for suspected sepsis, reducing the duration of therapy compared with standard care, a large study finds.
It was known that optimising duration of antibiotic therapy helped to reduce overtreatment, limit unwanted effects and preserve antibiotic effectiveness by minimising resistance, a team of UK-based researchers wrote in JAMA.
However, there was currently no agreed optimal duration for antibiotic therapy for sepsis.
Clinicians tended to use clinical judgment on when to cease antibiotics, with evidence remaining uncertain for the efficacy and safety of therapy guided by inflammatory biomarkers, such as PCT or C-reactive protein (CRP).
To close this evidence gap, the National Institute for Health and Care Research (NIHR) commissioned and funded a three-arm, randomised trial across 41 NHS intensive care units, which enrolled 2,760 adult patients requiring critical care for suspected sepsis.
Eligible patients, who had started intravenous antibiotics before study enrolment, were randomly assigned to either a daily PCT-protocol, a daily CRP-protocol or standard care.
Blood was drawn daily from all participants and sent for testing according to the treatment arm, but the results were concealed from the treating clinicians to minimise bias.
Instead, clinicians received daily written advice from their local clinical research team on either standard care or on PCT or CRP biomarker-guided antibiotic discontinuation.
From randomisation to 28 days, the PCT-guided protocol led to a significant reduction in antibiotic duration compared with standard care (mean duration, 10.7 days for standard care versus 9.8 days for PCT; mean difference, 0.88 days).
For all-cause mortality up to 28 days, the daily PCT-guided protocol was noninferior to standard care, where the noninferiority margin was set at 5.4%.
‘The duration reduction is in the order of 10% in antibiotic use for sepsis, which could provide significant cost and labour savings, and might also reduce the development of antimicrobial resistance,” the study authors wrote.
No difference was found in antibiotic duration for standard care compared with the daily CRP-guided protocol and the all-cause mortality for CRP compared with standard care was inconclusive.
The researchers from the University of Manchester, Northern Care Alliance NHS Foundation Trust and the Clinical Trials Unit of the University of Warwick’s Medical School also noted that the trial could not provide evidence for biomarker use in initiating antibiotic therapy as participants had commenced treatment before enrolling.
Chief investigator Professor Paul Dark, professor of critical care at the University of Manchester, said the simple protocol could significantly change the way sepsis is treated and combat antibiotic overuse and resistance.
‘It is also a powerful illustration of how precision medicine can make a real difference to patient care when treatment is tailored to individual test results of each patient,’ he said.
Professor Dark, who is also an NHS consultant in critical care medicine at Salford Royal, said sepsis had been at the forefront of UK policymaking since a 2013 Health Service Ombudsman report focusing on sepsis patients who were not treated urgently enough.
‘Ever since then, developing better diagnostics and treatment guidance for GPs and hospital clinicians to help them recognise sepsis at an early stage has been a national priority,’ he said.
Figures suggest there are at least 245,000 sepsis cases diagnosed in the UK every year.
In late 2023, research presented at the European Society of Emergency Medicine Congress suggested that two of the four internationally recommended sepsis screening tools are inadequate for recognising the condition.
Earlier this year, NICE released updated guidance on identifying and managing sepsis in over-16s recommending better targeting of antibiotics for suspected sepsis.
The updates specified that secondary care teams should target antibiotic use as more is learned about a patient’s condition to ensure the right people receive treatment as soon as possible but the medicines are not overused.
7th August 2024
Using one of the most detailed analyses ever undertaken into biological markers for tuberculosis (TB), researchers at the UK’s University of Southampton, working with colleagues from across the world, have identified a group of six biomarkers to help diagnose patients. Speaking to Katherine Price, lead author Dr Hannah Schiff shares her ambitions for these findings to pave the way for new lateral flow tests to diagnose more people with TB, diagnose them earlier and stop the infection from spreading.
Tuberculosis (TB) is the world’s deadliest infectious disease, killing more than one million people each year. An estimated 10.6 million people fell ill with TB in 2022, according to the World Health Organization (WHO). A disease often associated with health inequality, risk factors include smoking, alcohol abuse, HIV infection and malnourishment.
Europe accounted for 2% of all cases, according to the WHO data, and here it remains a public health issue despite most countries being low incidence. This is due to it predominantly affecting vulnerable populations such as migrants, prison inmates and people coinfected with HIV. In England, nearly 5,000 cases were recorded in 2023, with cases on the rise.
Closing diagnosis gaps is key in reducing incidence. However, in 2021, there were an estimated 3.7 million missed cases globally. Diagnostic delays, particularly in low- and middle-income countries, and funding for prevention, diagnostics and treatment fell far short of the globally estimated need and UN targets.
Treatment success rates in Europe also remain far below regional targets, and have in fact decreased, indicating increasing challenges to delivery of care. Up to half of patients do not complete treatment courses, according to one US study, which often last several months or even years for multidrug-resistant TB, even if they do get a diagnosis.
‘That’s the driver, to try and close that case-diagnosis gap and finding the missing millions,’ says Dr Hannah Schiff, a National Institute for Health and Care Research (NIHR) academic clinical lecturer and speciality registrar in respiratory medicine at the University of Southampton. She is also the lead author on a new study that has identified tuberculosis-specific diagnostic biological markers.
Fascinated with the lungs, Dr Schiff trained at the John Radcliffe Hospital in Oxford and the Royal Berkshire Hospital in Reading, UK, before embarking on her specialist respiratory training at Southampton. ‘They’re just an amazing body organ to study,’ she says. ‘It’s such an interface for infection and I’ve always been interested in infections and the host and pathogen interaction. Why does the same bug cause slightly different disease in different people? And TB is a case in point for that – there are so many host factors that alter how lung disease manifests.’
Currently, TB diagnosis commonly relies on sputum samples, which not all patients can produce, as well as the necessary infrastructure and skilled operators for analysis. Patients with TB can also have a negative sputum smear microscopy and culture result – the latter of which can take several weeks to return, and these approaches haven’t changed for decades, says Dr Schiff.
While molecular testing for TB DNA has emerged over the last decade, this also relies on sputum samples and therefore suffers from the same limitations.
‘Making the diagnosis is the biggest block to the entire care cascade, and once a diagnosis is made, then you’re most of the way there,’ she explains.
Dr Schiff and her colleague, senior author Professor Paul Elkington, developed their research to address the urgent need for accurate point-of-care testing that doesn’t rely on sputum expectoration or specialist equipment.
Their latest study, supported by the NIHR and UK Medical Research Council and published in the Journal of Clinical Investigation Insight, shows the potential for host proteins to support diagnostics. It was a team effort drawing on global expertise.
From the NIHR Southampton Biomedical Research Centre, senior author Dr Diana Garay-Baquero, a chemist originally from Colombia, led the proteomics work under the supervision of US-based proteomics expert Dr Spiros Garbis.
Dr Naomi Walker, infectious disease specialist and a researcher at the Liverpool School of Tropical Medicine, contributed a cohort of South African samples, and Marc Tebruegge in Vienna contributed a UK-based cohort. Bioinformatics data collection was overseen by the University of Southampton’s Dr Andres Vallejo and US-based Dr Christopher Woelk, while the University of Oxford supported with the validation phase. The study was also undertaken with experts from South Africa’s University of Cape Town and Cayetano Heredia University in Peru.
‘It was really inspiring to work with people globally [who] just have such a variety of background experience and can bring so much to the project,’ says Dr Schiff.
The academics used a proteomics technique that doesn’t remove albumin, which Dr Schiff says can inadvertently remove proteins of biological interest. The team believes it’s one of the most detailed analyses ever undertaken of biomarkers for TB.
Proteins are excellent candidates for diagnostic biomarkers, being stable and utilisable for near-patient diagnostic tests. However, while several studies have explored the potential of host plasma protein biomarkers for TB diagnosis, and numerous candidate proteins have been detected, biomarkers or combinatorial biomarker signatures had not yet been found that could reliably differentiate TB from other respiratory diseases or predict progression.
Dr Schiff and her team of researchers applied a highly sensitive non-depletion tandem mass spectrometry discovery approach and bioinformatic analysis. Using linear modelling and network correlation analyses, they identified 118 differentially expressed proteins. These were then narrowed down to six that could distinguish contagious TB from healthy controls and other respiratory infections.
The researchers hope these six blood proteins will pave the way for the development of an affordable, sensitive, specific, user-friendly and rapid point-of-care test that could be used in resource-limited settings. Dr Schiff says this could be particularly helpful for case finding and reducing TB rates in communities of high disease instance.
However, next steps will be largely dependent on funding, and she says the next realistic milestone will probably be at least a few years down the line.
‘At the moment, measuring the markers needs sequencing and very highly specialised laboratory equipment,’ she explains. ‘We’re planning experiments to do it in a lower-level lab facility with more standard equipment… to try and get it onto a device that could be used at point-of-care.’
The idea is to leverage diagnostics innovation that emerged during the Covid-19 pandemic, such as at-home lateral flow testing. ‘The dream would be if you could get these markers onto a lateral flow test. That would be ideal, but you need a device that can measure several markers, not just one, and with enough sensitivity and a semi-quantitative readout, not just a yes/no answer,’ adds Dr Schiff. ‘But if we could translate this into use in the field, that’s where it would have the most benefit.’
This could then help close the case-detection gap that fuels the global TB pandemic. ‘There shouldn’t be people in this world that are suffering from a disease that is curable and treatable, just for want of a diagnosis,’ says Dr Schiff.
Dr Schiff is currently working on further analysis of the proteomic datasets to explore variation of protein markers by host phenotypic characteristics and how these might be harnessed to improve diagnostic sensitivity.
Her colleague Dr Liku Tezera, who worked on the biomarker research, has developed a 3D TB infection cell culture model, which could be used to look at some of the identified biomarkers and explore their potential pathological role in TB infection, Dr Schiff explains. The TB clinic is also continuing to source samples from patients with active pulmonary disease, with help from a TB nursing team.
Wider developments in scaling up shorter treatment regimens, meanwhile, are believed to be behind the success rates for rifampicin-resistant TB that are slowly but consistently improving in Europe.
‘The key is having healthcare system support, your TB nursing team, and lines of communication and support open with the patients,’ says Dr Schiff. ‘We know what drugs work and we know the regimes. The challenges are getting people a timely diagnosis and successfully through the whole course of treatment.’
26th April 2024
A biomarker-based strategy is comparable to a magnetic resonance imaging (MRI)-enhanced approach for prostate cancer screening but results in more biopsies and increased detection of less aggressive cancers, a randomised trial has found.
Prostate cancer guidelines often recommended obtaining an MRI before a biopsy, yet MRI access was limited and using blood-based biomarkers with systematic biopsies could provide an alternative approach, Swedish researchers wrote in the journal JAMA Network Open.
In the open-label randomised trial, 12,743 men aged 50 to 74 with no previous cancer diagnosis underwent blood sampling for prostate specific antigen (PSA) levels and Stockholm3 tests to estimate their risk of clinically significant prostate cancer.
After the blood tests, men were randomly assigned in a 2:3 ratio to receive a Stockholm3 test with systematic biopsy (biomarker group) or a PSA test followed by MRI with systematic and targeted biopsy (MRI-enhanced group).
The Stockholm3 test, combines patient age, previous prostate biopsy results, family history of prostate cancer, single-nucleotide variations and levels of total PSA, free PSA, human kallikrein 2, β-microseminoprotein and growth differentiation factor 15 to estimate the risk of clinically significant cancer (Gleason score ≥ 3 + 4).
In the biomarker group (5,134 men), 8.0% of participants (413) had a Stockholm3 risk score of 0.15 or higher and underwent systematic biopsies, researchers said.
In the MRI-enhanced group (7,609 men), 12.2% participants (929) had a PSA level of 3ng/mL or higher and were referred for an MRI with biopsies if they had a Prostate Imaging-Reporting and Data System (PI-RADS) score of 3 or higher.
Detection rates of clinically significant prostate cancer were comparable between the two groups: 2.3% in the biomarker group and 2.5% in the MRI-enhanced group.
However, researchers reported more biopsies were performed in the biomarker group than in the MRI-enhanced group (326 of 5,134 [6.3%] vs 338 of 7,609 [4.4%]).
There were also more indolent cancers detected in the biomarker group (61 [1.2%] vs 41 [0.5%]).
Senior author Professor Anna Lantz, associate professor in urology at Karolinska Institute and consultant urologist at Karolinska University Hospital Solna in Stockholm, Sweden, noted that certain areas and healthcare systems lacked the capacity to implement the diagnostic chain required for MRI-based screening and the cost of MRI of the prostate varied by setting.
Given their findings, they concluded the Stockholm3 test could be a feasible alternative in regions with limited access to MRI.
‘Nevertheless, the biomarker-based approach comes at the expense of more biopsy procedures and increased detection of less aggressive cancers,’ Professor Lantz and colleagues said.
Strengths of the study included its randomised design, large-size and population-based screening setting.
Regarding limitations, the authors noted that optimal PSA cut-off values for triggering a Stockholm3 test and guiding biopsy decisions were undetermined.
‘Finally, we focused on detecting clinically significant prostate cancer, and long-term prostate cancer mortality implications remain uncertain,’ they wrote.
Last month, a Cancer Research UK study found fewer middle-aged people are dying of cancer in the UK than at any point over the last 25 years, despite a rise in cases of cancer, partly due to improvements in screening programmes.
Another recent artificial intelligence-based study found that prostate tumours evolve in two distinct disease types, which may lead to better diagnosis and tailored treatments in future.
31st January 2024
A simple blood test to diagnose Alzheimer’s disease could be as accurate as a lumbar puncture or expensive brain scans, according to a new study.
It raises the potential for early diagnosis to make best use of new medicines that slow the rate of cognitive decline but also could help doctors distinguish between different types of dementia in order to direct treatment.
The test, which is commercially available, measures levels of p-tau217 in plasma samples – a biomarker that can be used to detect a build-up of amyloid and tau proteins in the brain.
Research done in three separate groups of patients over eight years found the precision of the blood test was comparable to cerebrospinal fluid biomarkers.
It was particularly effective in detecting longitudinal changes, even in preclinical stages of the disease, the researchers reported in the journal JAMA Neurology.
The test could also significantly reduce the need for additional confirmatory tests patients have to have to verify their diagnosis, the international team of researchers said.
Study author Dr Daniel Alcolea, researcher at the Dementia Neurobiology Group at the Sant Pau Research Institute in Barcelona and head of the biomarkers platform at Hospital Sant Pau’s Memory Unit, said: ‘This biomarker has shown very high performance in detecting Alzheimer’s in blood, with an accuracy between 90 and 95%.
‘Of all the biomarkers currently being studied for diagnosing Alzheimer’s disease, this one has shown the best results.’
Dr Richard Oakley, associate director of research and innovation at Alzheimer’s Society, said there were potentially ground-breaking new drugs which can slow the progression of early-stage Alzheimer’s disease in the development pipeline.
‘But for people to be eligible for them if they’re approved in the UK, they will need an early, accurate diagnosis. This study is a hugely welcome step in the right direction,’ he said.
Professor David Curtis, honorary professor at the UCL Genetics Institute, said the test potentially had huge implications for screening, diagnosis and developing better treatments.
‘When effective treatments to prevent the progression of Alzheimer’s disease become available it will be essential to be able to identify people who are at high risk before they begin to deteriorate.
‘This study shows that a simple blood test might be able to do this by measuring levels of tau protein in the blood which has been phosphorylated in a specific way.’
The only way to prove someone has a build-up of Alzheimer’s-related proteins in the brain currently is through a lumbar puncture or an amyloid PET scan, which are only available in around one in 20 memory clinics, said Professor Charles Marshall, professor of clinical neurology at Queen Mary University of London.
‘Before these tests become widely used in the NHS, we will need further evidence to show that the blood test can accurately diagnose who is in the process of developing dementia, and that it can identify who is likely to benefit from treatments to slow down the disease’, he said.
‘We will also need to ensure that the blood test performs equally well in more diverse populations, so that it does not worsen existing health inequalities in access to diagnosis and treatment for dementia.’
A version of this article was originally published by our sister publication Pulse.
17th July 2023
Diagnosing Alzheimer’s disease through the use of blood biomarkers could transform care for patients after new proposed guidelines were presented at the International Alzheimer’s Congress in Amsterdam.
Developed by clinicians and researchers from around the world, the proposed guidelines incorporate blood-based biomarkers, which offer a low cost and easily accessible alternative to more traditional routes of diagnosis.
A blood test has been developed for this purpose in recent years, which has shown good results, and this can be used outside of specialist clinics, meaning underserved and rural populations can also benefit.
Charlotte Teunissen, professor of neurochemistry at Amsterdam University Medical Centre, who was involved in drafting the new guidelines, said: ‘A new generation of biomarkers is now available to detect Alzheimer’s disease more and more effectively. We have already gained a lot of experience with this in our Alzheimer’s centre, but in the long term the test can also be successfully implemented after a GP’s referral.‘
Currently, Alzheimer’s is diagnosed through the analysis of cerebrospinal fluid, acquired through an invasive lumbar puncture, or via an expensive PET scan. The proposed diagnostic criteria would prove less stressful to patients as well as speeding up diagnosis, offering a gateway to earlier treatment and allowing patients to make more informed decisions about their treatment and disease management.
Defining neurodegenerative diseases biologically, rather than based on syndromic presentation, has become a unifying concept common to all neurodegenerative diseases, not just Alzheimer’s.
While many biomarkers have shown promise and performance in the ability to detect Alzheimer’s disease, some of the biomarkers described in the proposal have not yet been extensively tested in broadly representative populations, and further analysis in these groups is urgently needed, the Alzheimer’s Association said.
The draft proposal will be open for consultation for 30 days, and the working group invites comments from scientific and clinical audiences.
Maria C. Carrillo, chief science officer, Alzheimer’s Association, said: ‘Care has to evolve with the science. Our understanding of Alzheimer’s disease has advanced, in particular our understanding of biomarkers, and this needs to be reflected in how we describe and diagnose the disease.
‘We look forward to input from the scientific and clinical community on these proposed revisions. The Alzheimer’s Association is proud to lead this important effort, which will ultimately enable people to get a more accurate diagnosis earlier, as well as help those diagnosed enrol in research trials and, if appropriate, get access to approved treatments.‘
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