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UK Study Suggests Need for Faster Viral Meningitis Diagnosis

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NEW YORK (GenomeWeb) – A new study in the UK has shown that viral meningitis has more severe consequences than previously thought, and that it may also be underdiagnosed due to both procedural flaws and diagnostic limitations.

As such, researchers and other experts suggest that speeding up diagnosis — through faster time to lumbar puncture and faster diagnostic testing — could potentially help identify more viral pathogens and improve patient care.

The observational study, published last week in The Lancet, was conducted by researchers based at the University of Liverpool. The study is among the first to try to determine the true burden of viral meningitis, which happens to be much less frequently studied than bacterial meningitis, according to Fiona McGill, an author on the study.

The Liverpool researchers started with the basics. "Our primary goal was initially to try and understand how common viral meningitis is, and what are the viruses causing meningitis in UK adults," McGill said in an email.

For this, McGill and her collaborators enrolled 1,126 patients from 42 hospitals across England over a three-year period who were initially suspected of having meningitis, an inflammation of the membranes that surround the brain and spinal cord.

The researchers examined the association between the time it took until a patient got a procedure called a lumbar puncture — to collect cerebrospinal fluid (CSF) for different kinds of testing — and when the patient received a diagnosis. The study also tracked quality of life and cognitive function for a year following hospitalization.

Nearly 60 percent of patients in the study with suspected meningitis were ultimately confirmed as having the illness. Among the diagnosed cases, 36 percent were determined to be caused by a virus and more than half of these were specifically enteroviruses, while only 16 percent were caused by bacteria. Importantly, for 42 percent of patients diagnosed with meningitis no cause could be determined.

Having an unknown cause could be a problem, since the study also showed that appropriate diagnosis reduced inappropriate treatment. For example, 21 percent of patients with lymphocytic meningitis of unknown cause received a course of the antiviral drugs acyclovir or valacyclovir, compared with 6 percent of all meningitis patients diagnosed with enteroviral meningitis, an infection for which these drugs are ineffective. And, approximately half of the patients in the study received antivirals, which resulted in longer hospital stays because the intravenous treatments necessitated inpatient care.

The study determined that from the time a patient entered an emergency room with suspected meningitis until the time lumbar puncture was performed there was a delay of up to 29 hours for a quarter of patients, with a mean time to lumbar puncture of 17 hours.

Although it has been shown previously for bacterial meningitis, the Liverpool research is the first study to show that delays to lumbar puncture can reduce the likelihood of identifying viral pathogens. Specifically, the chances of having a pathogen identified in viral meningitis was reduced by one percent for every hour of delay to lumbar puncture after hospital admission. The study also showed a trend toward a reduction in pathogen identification for bacterial cases correlated with delay, but this was not statistically significant.

The UL researchers undertook additional follow-up measurements to look at patient outcomes. "The impetus was patients telling us, repeatedly, that they had ongoing problems, yet viral meningitis is always quoted to be 'benign and self-limiting,'" said McGill. "We wanted to see what the longer-term outcomes were," she said, adding that this could help researchers know what outcomes might be useful to track in future treatment trials.

The study measured morbidity of infection three weeks after admission, and also sent patients follow-up questionnaires periodically to assess quality of life. The data revealed that viral meningitis led patients to experience increased pain, anxiety, and depression, as well as lower activity levels, for up to 48 weeks after hospitalization.

Speeding up diagnosis — through faster time to lumbar puncture, or, perhaps through faster diagnostic testing — could potentially help identify more viral pathogens, and improve patient care, the authors speculated.

In the UK, guidelines recommend CFS and blood of patients with suspected meningitis be tested using a number of serology and nucleic acid amplification tests.

However, according to an editorial article accompanying study, "There is a clear need to improve diagnostic tests for patients with suspected [central nervous system] infections because a substantial proportion of patients do not have a cause-specific diagnosis, which impedes early directed treatment and hinders trials of new treatments."

The Lancet study noted in particular that delays in diagnosis occur if CSF samples need to be sent to offsite laboratories for analysis. "Because of sample batching and transport, it can take several days from doing a lumbar puncture to receiving results, despite the rapidity of the test itself," they wrote. "If PCR is done locally, [seven] days a week, on receipt of a single CSF sample, the length of the hospital stay can be reduced to less than a day, resulting in substantial cost savings."

There are many assays for the different bacterial and viral pathogens that can cause meningitis. The study did not report which tests were used to identify pathogens, but McGill said she believes overall in the UK labs use a combination of commercial assays and lab-developed tests. For suspected viral cases, for example, smaller labs might use tests like the Cepheid enterovirus panel, she said, and then send samples to larger labs if they test negative for enterovirus.

In addition to traditional PCR-based approaches to pathogen identification, there are also panel-based tests, such as the BioFire FilmArray Meningitis/Encephalitis panel — which is CE marked and cleared by the US Food and Drug Administration to detect six bacteria, seven viruses, and one type of yeast from CSF samples in one hour. That near-patient test has been suggested to improve patient care for meningitis, particularly in cases caused by viruses.

And, the Hibergene HG Pneumo/Meningo Combo test detects meningococcal and pneumococcal bacterial meningitis using loop-mediated isothermal amplification in less than 50 minutes, and is CE-marked

A group at University of California, San Francisco is also exploring the use of metagenomic sequencing to detect pathogens in challenging cases.

Some of the researchers involved in the Lancet study are also currently collaborating with FastTrack Diagnostics, a firm acquired by Siemens Healthineers last year, to develop a host-response blood test for meningitis.

The test will potentially be able to tell if a case of meningitis is caused by bacteria or not, McGill said. The Lancet study "provides the building blocks for that test," she said, adding that many of the patients in the study have given samples for the research to develop the host-response test as well.

There are a handful of other companies developing host-response assays, but these tend to be focused on respiratory illness and sepsis, not meningitis.

Faster testing performed nearer to patients may make a difference, but McGill emphasized that the time to lumbar puncture is still a major limiting factor to detecting a pathogen in both viral and bacterial meningitis. And, in some cases the amount of pathogen in the CSF is so small that "alternative methods of diagnosis are also required," she said, which necessitates more research as well as cost-effectiveness studies. For example, in viral meningitis cases caused by enteroviruses, throat and rectal swab samples tend to test positive for a longer interval as compared to CSF, and could be a better sample type to test.

Overall, according to the editorial, "The current study should be a wake-up call for policy makers to improve care for patients with CNS infections. Methods like pathogen discovery sequencing, use of RNA biosignatures, or point-of-care PCR tests, might "improve the yield of CSF examination," the editorial noted, and these "should be tested in large prospective studies, including cost-effectiveness analyses," but the editorial also reiterated that the ability to quickly identify pathogens would be "of little use" if lumbar puncture continued to be delayed.

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