Improving early diagnosis of tuberculous meningitis in children

[摘要] ENGLISH SUMMARY: Due to the sub-optimal performance of definite diagnostic tests, the earlyidentification of paediatric TBM suspects relies on a thorough assessment of all theevidence derived from a careful history, clinical examination and relevantinvestigations. Rapid diagnosis is needed for early treatment initiation butmicrobiological confirmation is difficult at stage 1 disease because a lumbar punctureis generally only done once signs of meningitis have developed (stage 2 and 3 TBM).With this thesis, I aim to investigate mechanisms of improving the early and/or moreaccurate diagnosis of childhood TBM.PART IIn chapter 2 I provide an update on the diagnosis and management of TBM inchildren, based on local experience, which can be transposed to similar settings.Highlights include firstly that short (6 months) intensified therapy in children with drugsusceptible TBM is safe and effective, with a good outcome and low mortality.Secondly, home-based TBM treatment after initial in-hospital stabilization is feasiblein carefully selected patients under close supervision. Thirdly, treatment oftuberculous hydrocephalus depends on the level of cerebrospinal fluid (CSF)obstruction. Communicating hydrocephalus can be successfully treated with medicaltherapy with normalization of intracranial pressure occurring within days in themajority children and non-communicating hydrocephalus requires neurosurgicalintervention. Fourthly, thalidomide is the local drug of choice in children whodevelop life-threatening TB mass lesions (IRIS) despite corticosteroids.PART IIIn clinical practice, TBM diagnosis is most often based on a combination of clinical,laboratory and radiological findings. A uniform research case definition utilizing thesecriteria was proposed by an international panel of experts as a means of improvingdiagnostic standardization in order to answer critical research questions, categorizingpatients as definite, probable, or possible TBM. Part 2 of my thesis focuses on thediagnostic utility of the uniform research case definition criteria for TBM. In chapter 3.1 I retrospectively evaluate the diagnostic performance of probable and possibleTBM criteria in children with culture-confirmed TBM and culture-confirmed bacterialmeningitis. The proposed uniform research case definition provided excellentdiagnostic accuracy compared to microbiologically-confirmed TBM, when a'probable' TBM score was used. When a 'possible' TBM score was used, not a singleTBM case would have been missed, but clinical utility was minimal given the lowspecificity achieved. In order to strengthen my findings I prospectively assessed thediagnostic accuracy of the uniform TBM research case definition (see chapter 3.2).Excellent diagnostic accuracy was obtained for a diagnosis of TBM when compared tobacterial and viral meningitis controls. The high specificity of a probable TBM scorejustifies its use as an alternative reference standard to microbiological confirmation infuture studies. In both studies poor sensitivity was obtained when a probable TBMscore was used to diagnose early (stage 1) TBM, emphasizing a very high clinicalindex of suspicion of TBM in young children with recent TB exposure and persistentnon-specific signs.CSF findings are essential to early diagnosis of TBM. Cut-off values for CSF glucose inTBM lack evidence. A CSF protein cut-off of >1g/L (100mg/dL) differentiated betweencases of TBM and other forms of meningitis. My study on the diagnostic value ofcerebrospinal fluid chemistry results in childhood TBM found that the optimal lowerlimit of CSF glucose concentration as a diagnostic aid for TBM was 2.2 mmol/L (seechapter 3.3). Absolute CSF glucose differentiated non-TBM from TBM cases withsensitivity of 68% and specificity of 96%, excluding its use as a 'rule-out' test.Simultaneous determination of serum and CSF glucose was seldom performed but myfindings suggest that the CSF:serum glucose ratio may further improve diagnosticsensitivity.. CSF protein cut-off of >1g/L as well as CSF macroscopic appearance, cellcounts and the presence of lymphocyte predominance are required to assist thedistinction between TBM and bacterial meningitis.Previous studies suggest that chest X-ray findings consistent with active pulmonary TBare observed in 70% to 84% of children with TBM. In my study (chapter 3.4) only46% of cases with TBM had chest radiograph findings highly suggestive of pulmonary TB. A need to treat calculation showed that only 1 in 4.39 children ≤3 years of agewith TBM are likely to have 'certain TB' on chest X-ray.PART IIIMicrobiological confirmation of TBM remains the gold-standard of diagnosis, but ischallenging in young children due to the paucibacillary nature of disease, low CSFvolumes available for diagnostic analysis and sub-optimal sensitivity of directmicroscopy for acid-fast bacilli and M.tuberculosis culture on CSF. Several newcommercially available NAA tests have been developed for the rapid diagnosis of TB.In part III of the thesis my meta-analysis of newer commercial NAA tests found asummary sensitivity of 64% and specificity of 98%. Summary sensitivity ofcommercial NAA tests remains suboptimal and is unlikely to greatly enhance earlyaccurate diagnosis. However, the excellent specificity suggests that commercial NAAtests may be regarded as definitive in the correct clinical setting. In 2013, the WHOrecommended Xpert MTB/RIF® as the preferential initial investigation in all adults andpediatric TBM suspects. My sub-analysis of 5 studies reporting Xpert MTB/RIF® onCSF, found summary sensitivity of 70% and specificity of 97%.In chapter 4.2 I aim to assess the utility of MTBDRplus® and Xpert MTB/RIF® todiagnose TBM in a clinical setting, alone and/or in combination. The main finding wasthe incremental increase in diagnostic accuracy achieved with combined use of thesecommercial NAA tests performed on CSF. Although both NAA tests were superior toliquid culture, sensitivity remained low compared to a rigorous predefined clinicalcase definition. The MTBDRplus® assay performed with sensitivity of 33% (98%specificity), Xpert MTB/RIF® was 26% sensitive (100% specificity) and combiningpositive results from both these tests provided a sensitivity of 49% (98% specificity)against a TBM case definition. This is insufficient to serve as a rule-out test andprovides limited clinical guidance. However, microbiological confirmation providedby a positive test prevents unnecessary treatment delay and potential life-threateningconsequences. The additional advantage of a positive NAA test is that of earlydetection of mycobacterial resistance. A major limitation of this study was the failure to improve diagnosis of stage 1childhood TBM, mainly because it was hospital-based. Good surveillance at primaryhealthcare level, identifying children with poor weight-gain (or weight loss) andpersistent non-remitting cough for longer than 2 weeks, could improve the detectionof both childhood TB and early TBM. IMCI is potentially a valuable tool to increaseawareness of TBM among healthcare workers, and in detecting early TB and TBM, asit is practiced at the healthcare level of first contact. Household contact tracing andprophylaxis with isoniazid therapy, as well as more general measures such asimproving nutrition, housing and poverty relief, are valuable measures in preventingTBM in young children.

[发布机构] Stellenbosch University