| Tuberculosis (TB) is a major infectious disease threatening millions of livesworldwide. Tuberculous meningitis (TBM) is one of the most serious forms of TB,particularly in developing countries. It accounts for1%-2%of TB cases.Approximately40%of TBM patients die despite anti-tuberculosis chemotherapy.Delays in diagnosis and treatment are regarded as major contributing factors to thehigh mortality reported in many recent studies.Tuberculous meningitis is diagnosed based on clinical features, cerebrospinalfluid (CSF) studies and radiological findings. Due to the variable clinicalpresentations and CSF findings, which could be confused with other infections of thecentral nervous system, tuberculous meningitis is sometimes difficult to diagnosiswith certainty, especially in its early phase. An early, rapid, accurate diagnostic test isurgently needed for tuberculous meningitis.Interferon-gamma release assays (IGRAs) have been increasingly used to detectthe IFN-γ response to the Mycobacterium tuberculosis-specific antigens. Thisblood-based immunologic approach is suitable for the diagnosis of tuberculosisinfection. High latent tuberculosis infection rates will inevitably impact thediagnostic accuracy of peripheral blood (PB) IGRAs, and the usefulness of this assayis questionable in high TB burden countries. An alternative method is to quantify thefrequency of antigen-specific effector cells at the infection site of disease, whichmight have higher interferon response frequency. However, there are no data to dateregarding the CSF T-SPOT.TB for the diagnosis of tuberculous meningitis in China.Thwaites GE. in Vietnam create a simple diagnostic aid for tuberculousmeningitis in adults on the basis of clinical and basic laboratory features. Five features were predictive of a diagnosis of tuberculous meningitis in this model: age,length of history, white-blood-cell count, total cerebrospinal fluid white-cell count,and cerebrospinal fluid neutrophil proportion. The Vietnam rule has been tested indifferent populations, however, this model could not be suitable for China due to thedifferent status onset of meningitis.Our study included TBM (n=31) and non-TBM (n=40) in a high-TB prevalencesetting. The sensitivity of PB T-SPOT.TB and CSF T-SPOT.TB was93.6%(29/31,95%CI:79.3%-98.2%) and53.3%(16/30,95%CI:36.1%-70.0%) respectively, thespecificity was75.0%(30/40,95%CI:59.8%-85.8%) and94.8%(37/39,95%CI:83.1%-98.6%), the accurate rate was83.7%(59/71,95%CI:72.7%-90.1%) and76.8%(50/69,95%CI:65.6%-85.2%) respectively. Features independently predictive ofTBM including CSF T-SPOT.TB, PB T-SPOT.TB, length of history, CSF ADA andCSF protein were candidate diagnostic biomarkers. A supervised machine-learningapproach based on the support vector machine (SVM) was used to obtain the mostsignificant features from the above five features, and then CSF T-SPOT.TB and PBT-SPOT.TB were selected as the most significant features and were modelled by adecision tree method. The diagnostic model based classification tree showed that thesensitivity and specificity were90.0%(27/30,95%CI:74.4%-96.5%) and94.9%(37/39,95%CI:83.1%-98.6%)，the accuracy was92.8%(64/69,95%CI:84.8%-96.9%)respectively.Our research demonstrated that PB T-SPOT.TB could be a rule-out diagnosticassay and CSF T-SPOT.TB could be a rule-in diagnostic assay. The Vietnam rule wasnot suitable for China. The joint diagnostic model was of high value for the diagnosisof tuberculous meningitis, while its performance should be assessed by resubstitutionand prospective test data methods. Recently the function of miRNAs in post-transcriptomic regulation are highlybeen concemed. Many researches have shown that miRNAs are playing importantroles in cell proliferation，differentiation，apoptosis，development and metabolism.The clinical application of miRNAs as diagnostic or prognostic biomarkers hasalready been demonstrated in various types of cancers and autoimmune diseases.However, compared to their well-known role in cancer, the role of miRNAs ininfectious disease, especially in ATB or TBM, is still poorly understood.To study the role of miRNAs in TBM and to discover candidate biomarkers ofthis transition, we used human miRNA microarrays to probe the miRNAs inperipheral blood mononuclear cells (PBMCs) in patients with TBM (n=8) andnon-TBM (n=8).11miRNAs were differentially expressed,they werehsa-miR-126-3p/5p，hsa-miR-130a-3p， hsa-miR-151a-3p/5p，hsa-miR-199a-3p，hsa-miR-221-3p，hsa-miR-4291，hsa-miR-584-5p，hsa-miR-6127，hsa-miR-744-5p.A comprehensive functional annotation software DAVID was used to analyze theGene ontology BP(biological process) of target gens to differentially expressedmiRNAs．Analysis showed that these target genes in TBM are mainly involved intranscription, metabolism of DNA and RNA and so on. Then the signaling pathwayswere analyzed and found several genes that involved in the regulation of tumor,MAPK, Wnt signaling pathways. The significance of differentially expressedmiRNAs to diagnose TBM should be validated by real time PCR in further largerresearch. And the further studies should demonstrate that whether these miRNAscould modulate the immune responses to M.TB, and pathogenesis of ATB and TBM. |
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