Evidence
Alert

A combination of tests is needed to diagnose a dangerous type of meningitis in children

Meningitis caused by tuberculosis (TB) is rare in the UK, but it is a dangerous disease which can be fatal or leave people with disabilities. Children are particularly vulnerable to poor outcomes.

TB is better known for causing lung disease, but the bacteria can also infect the brain, causing TB meningitis. The disease is often difficult to diagnose in children. They become unwell gradually and symptoms may initially be non-specific (vomiting, for example) and less obvious than in children with other types of meningitis (such as that caused by meningococcal bacteria and a range of viruses). Blood tests, brain scans and other investigations do not always detect the disease.

There is effective treatment for TB meningitis, but it needs to be started promptly. Delays to diagnosis also delay treatment and this can cost lives.

New research looked in detail at the tests used to diagnose TB meningitis. A review of records from children with TB meningitis in Europe found that none of the routinely-used tests were positive in all cases. Each showed some ‘false-negative’ results (a negative result in a patient who does have TB). However, most children (84%) who had four types of TB tests had at least one positive test result which would have helped lead to the correct diagnosis.

The researchers concluded that doctors need to be alert to the possibility of the disease, order multiple appropriate investigations, and interpret results with caution. They suggest that the combination of immune-based tests (which show whether someone has previously come into contact with TB) with microbiology tests (to find TB bacteria or its DNA) are needed to detect more cases of TB meningitis. Chest imaging and samples from lung or stomach may also be helpful to find evidence of TB elsewhere in the body in children who might have TB meningitis.

What’s the issue?

In Europe, TB accounts for one in forty of the world’s cases and is no longer as widespread as it is elsewhere. However, it can sometimes cause TB meningitis, especially in young children who have been exposed to TB in their communities or in parts of the world in which TB is more common.

Partly because of the rarity of TB meningitis, and partly because of its non-specific symptoms, it is easy for clinicians to miss. Delayed or missed diagnoses can cost lives. Around one in five children with TB meningitis die, and half of those who survive have disabilities as a result.

Existing tests include brain scans and chest X-rays, tests of fluid taken from around the spinal cord (cerebrospinal fluid, or CSF), and blood tests to look for the TB bacteria and an immune response to it. The tests have varying levels of accuracy and do not pick up all cases of TB meningitis when used individually. There has been little research looking at how useful newer tests are, especially in Europe where TB rates are lower.

What’s new?

A network of researchers asked paediatricians across Europe to submit information about children aged 16 or under, who had been treated for TB meningitis at their hospital or clinic. They received reports from 27 hospitals, including three in the UK, and they included 118 children in their study.

The children’s average age was just under three years, and half had parents who had been born in a country with high rates of TB. The most common symptoms were fever, vomiting, headache and drowsiness.

The children had undergone a range of tests and the researchers looked at how accurate the tests were:

  • Chest x-ray: 81 of 112 (72%) children tested had signs of TB disease in their lungs
  • CT scan or MRI scan of the brain: 90 of 108 (83%) children tested had abnormal findings in line with a diagnosis of TB meningitis
  • Two tests for an immune response to TB (the older tuberculin skin test; a newer blood test called IGRA): Most children, 43 of 54 (79%) who had both immune tests had at least one positive result. The newer IGRA test was only slightly more accurate than the skin test. Children with more severe TB meningitis were less likely to have a positive skin test.
  • Three tests for TB bacteria in CSF (looking for TB bacteria with a microscope; growing TB bacteria in culture; a test for genetic material from TB bacteria called PCR or polymerase chain reaction):
      • microscopy picked up only 4% cases
      • culture test picked up 50% cases
      • PCR test picked up 35% cases
      • combining the culture test and PCR test picked up 58% of cases
  • Combination of tests for bacteria and for immune response: in the group of 32 children who had all four key TB tests (tuberculin skin test and IGRA for immune response; and both culture and PCR tests for TB bacteria in CSF) most (84%) had at least one positive result.

The researchers also looked at a clinical scoring system currently used in TB meningitis research. The Uniform TB Research Case Definition score combines test results and symptoms. In this study, one in three (32%) children with confirmed TB meningitis had scores of below 12, which would have put them in the ‘possible’ category rather than ‘probable’ or ‘definite’. This suggests that the score has limitations in clinical practice, although full data were not available for every child in the study.

Why is this important?

The research confirms that in high resource settings where TB meningitis is relatively rare in children that there is no single test that can be used to rule out the disease. Doctors seeing children with symptoms that may indicate meningitis need to consider the history of the child’s symptoms, the family and travel history, and use a range of tests to establish how likely their illness is to be TB meningitis.

NICE guidance recommends that people with suspected TB meningitis should have CT or MRI scans, and three tests for TB bacteria in CSF (microscope, culture and PCR). The guidance also says treatment should be started if symptoms and other findings suggest TB, even if some tests are negative.

This research extends the NICE recommendation for multiple tests, and it stresses that existing tests can miss TB meningitis. This means doctors should not dismiss the possibility of TB meningitis even when tests are negative.

The researchers recommend that all children with possible TB meningitis should have:

  • chest and brain imaging
  • two tests for an immune response to TB: tuberculin skin test and IGRA
  • two tests for TB bacteria: both culture and PCR CSF tests
  • tests to look for TB bacteria elsewhere in the body.

What’s next?

The research network is working on several studies that they hope will improve knowledge about diagnosis and treatment for TB meningitis, and other manifestations of TB. One study looks at treatments and outcomes for the same group of patients, which is expected to be published soon.

A clinical trial, led by the MRC Clinical Trials Unit at University College London (UCL), is to be carried out in Vietnam, India, Zambia, Uganda and Zimbabwe. It will compare standard 12-month four drug treatment for TB meningitis with 6-month treatment using higher doses and one different drug. A linked study will also recruit children with symptoms that look like TB meningitis but turn out to have a different illness. This will allow the researchers to look at how well new diagnostic tests are at distinguishing TB meningitis from other diseases that can look similar.

You may be interested to read

The full paper: Basu Roy R, and others. Performance of immune-based and microbiological tests in children with tuberculosis meningitis in Europe: a multicentre Paediatric Tuberculosis Network European Trials Group (ptbnet) study. Eur Respir J. 2020. doi: 10.1183/13993003.02004-2019

Chiang SS, and others. Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysisLancet Infect Dis. 2014;14:947-957

The Paediatric Tuberculosis Network Europe (PTBnet) website gives more information and contact details to join the group

A collection of recent open access articles on TB Meningitis research, published by Wellcome Open Research: Tuberculous Meningitis International Research Consortium

A clinical trial, led by the MRC Clinical Trials Unit at University College London (UCL)”: SURE: Short intensive treatment for children with tuberculous meningitis

NICE guidance: Tuberculosis [NG33] (2016, last updated 2019)

Funding

Author Robin Basu Roy is supported by an NIHR Academic Clinical Lectureship.

Commentaries

Study author

TB meningitis in children is often a devastating disease that causes many childhood deaths and significant disability worldwide.

It is difficult to diagnose because it can look similar to many other infections. There is no single test or clinical feature that is sensitive enough for us to say ‘this is definitely not TB meningitis’.

The main message for clinical practice is to have TB meningitis on your diagnostic radar, even in the UK where you don’t see it very often in children. If you don’t, you might not ask the right questions and request the right tests. Then there is the risk of missing the correct diagnosis and not starting the right treatment early.

TB meningitis is complex and often difficult to diagnose. Paediatricians should not be afraid to pick up the phone and ring a paediatric infectious disease specialist for advice.

Robin Basu Roy, NIHR Academic Clinical Lecturer in Paediatric Infectious Diseases, London School of Hygiene and Tropical Medicine

Researcher

Diagnosis of paediatric TB in general is complex; TB meningitis even more so. There is a great risk of underdiagnosis or late diagnosis. This study is interesting because it evaluates the properties of single diagnostic immunological and microbiological tests and the combination of these, all of which are feasible and routinely available in large centres in the UK and other high-income countries.

This is an important paper. TB meningitis in children is a rare disease and, while the study is small, it is likely to be one of the largest in this area. It certainly is an important stepping-stone to improved diagnosis and care for affected children and therefore clearly relevant for specialist doctors and health policy makers.

Dominik Zenner, Senior Clinical Lecturer in Infectious Disease Epidemiology, Queen Mary University London

Conflicts of Interest

Some authors have received fees and funding from pharmaceutical and diagnostics companies.