MICA: Development of a novel host blood test using TRanscripts to Identify bacterial Meningitis - TRIM test study

Brain infections, such as bacterial meningitis, still cause death and disability in the UK and worldwide.

The key decision for a doctor is to decide whether a patient has bacterial meningitis, or whether they have a similar condition (a clinical mimic), such as viral meningitis. In both cases the patient often looks the same. However, bacterial infection needs immediate treatment with antibiotics whereas a mimic does not.

The essential test for distinguishing between the two is the lumbar puncture (a needle passing between the bones in the spine). The lumbar puncture is often delayed, or not performed at all. This can result in delayed antibiotic treatment for those who need it, or unnecessary antibiotics in those who do not, as well as a patient not receiving a diagnosis.

We offer a novel test measuring the body's response to bacterial infection in the blood. This means patients can be tested without having to wait for the lumbar puncture. We believe this test will help doctors to more accurately decide which patients do or do not need antibiotics. This will promote appropriate treatment, reduce unnecessary antibiotics, reduce in-patient stay, improve patient care and reduce the burden on health staff and hospitals.

We are working with an industrial company who are experts in developing diagnostic tests, to develop our test for clinical use. We are also linking with many expert clinical teams in the UK, Europe, Brazil and Africa to assess our test on a large number of patients to ensure it is accurate.

Through this project we will confirm the test is accurate and refine the test so that it can be used in hospitals in under the next 5 years.

Bacterial meningitis remains a significant cause of morbidity and mortality in the UK and worldwide, with considerable costs.

The key step in early patient management is to distinguish bacterial meningitis, which needs immediate antibiotic treatment, from the many mimics, such as viral meningitis, which do not. The essential test for distinguishing the two is the lumbar puncture, but this is often delayed, or not performed at all. Many patients are therefore treated with unnecessary antibiotics until a diagnosis of bacterial meningitis is excluded, contributing greatly to the burden of antimicrobial resistance.

A novel, rapid blood test measuring TRanscripts to Identify bacterial Meningitis (TRIM test) will improve management and reduce unnecessary antimicrobials.

Using samples from our multicentre observational UK Meningitis Study, funded by the National Institute for Health Research and the Meningitis Research Foundation, we have identified 5 highly discriminatory host transcripts in the blood of adults with bacterial meningitis. The markers exhibit high sensitivity (100%), specificity (90%) and negative predictive value (100%) in distinguishing patients with bacterial meningitis from the mimics

Working with Fast-Track Diagnostics Ltd, we have developed the TRIM test, a real-time PCR multiplex assay. We will validate it in an independent set of samples recruited through our UK and European clinical networks (France, Denmark and Holland). We will also begin to assess test accuracy in lower-middle income populations in Brazil and Malawi.

This work builds on the Liverpool Brain Infection Group's experience for delivering diagnostic tests for brain infections, for example, tests for Japanese encephalitis, now used across Asia.

The results will be used to produce the TRIM test system as a commercial diagnostic, and apply for subsequent funding, through the National Institute for Health Research, to assess its impact and health economic benefits.

Bacterial meningitis is a devastating disease. Delays in antibiotic treatment can have life-altering and life-limiting consequences. Conversely, overuse of antibiotics in patients who do not have bacterial meningitis may contribute to increasing antibiotic resistance.

Once established, the TRIM test will guide treatment rationalisation. It will prompt provision of antibiotics where bacterial infection was clinically regarded as improbable, reducing the patient's risk of disability or even death. Alternatively, it can trigger stopping antibiotics where the test indicates bacterial infection is unlikely, reducing the patient's risk of adverse drug reactions, and lowering the risk of hospitals' harboring bacteria resistant to antibiotics.

Reducing unnecessary courses of antibiotics, will shorten in-patient stay, ultimately reduce hospital costs and improve overall patient care. We estimate the TRIM test could save NHS hospitals up to £21.9M per year, by stopping antibiotics and the extended in-patients stay associated with unnecessary treatment with antibiotics.

The TRIM blood test also has potential to reduce the need for urgent lumbar puncture (LP). This is particularly useful in clinically unstable patients. It will free up medical staff and negate additional investigations (imaging, coagulation screen) to confirm the LP can be performed safely in a busy department.

The TRIM test will reduce the burden of suspected meningitis on hospital staff involved in diagnosis and treatment of adults with suspected meningitis in Europe, including staff in emergency, medical admissions unit, intensive care, infectious disease, neurology, microbiology and virology departments, as well as laboratory staff performing diagnostics.

The Hospital Episodes and Statistics database reports over 17,500 finished consultant episodes; 10,600 admissions; an average stay of 17.6 days; totaling over 140,200 bed-days from meningitis or mimics per year. The TRIM test could reduce unnecessary bed days, in turn reducing the burden on staff.

As part of this project, we will begin to gauge the test's global utility, potentially expanding end-users to health-care staff in Brazil, Malawi and beyond. Streamlining the TRIM test for use on a point-of-care (POC) device would be particularly useful for LMIC patients, where hospitals often do not have adequate infrastructure or funding to maintain high-quality microbiology or diagnostic laboratories. Furthermore, POC devices would enable patient testing at district hospitals or even health-care centers remote from microbiology or diagnostic laboratories.

Beyond meningitis, we have observed the test exhibits high accuracy in distinguishing bacterial from viral infection in adults in a range of clinical syndromes; including pneumonia, urinary tract infection, sepsis. Again, for suspected pneumonia patients the test could potentially be deployed as a POC test in GP surgeries.