scholarly journals Potential of host serum protein biosignatures in the diagnosis of tuberculous meningitis in children

2019 ◽  
Author(s):  
Charles M Manyelo ◽  
Regan S Solomons ◽  
Candice I Snyders ◽  
Kim Stanley ◽  
Gerhard Walzl ◽  
...  
Keyword(s):  
Serum Protein ◽  
Tuberculous Meningitis ◽  
Diagnostic Delay ◽  
Final Diagnosis ◽  
Tertiary Hospital ◽  
Severe Form ◽  
Case Definition ◽  
High Morbidity ◽  
Serum Samples ◽  
Improved Performance

AbstractBackgroundTuberculous meningitis (TBM) is the most severe form of tuberculosis and results in high morbidity and mortality in children. Diagnostic delay contributes to the poor outcome. There is an urgent need for new tools for the rapid diagnosis of TBM, especially in children.MethodsWe collected serum samples from children in whom TBM was suspected at a tertiary hospital in Cape Town, South Africa. Children were subsequently classified as having TBM or no TBM using a published uniform research case-definition. Using a multiplex cytokine array platform, we investigated the concentrations of serum biomarkers comprising 7-markers that were previously found to be of value in the diagnosis of adult pulmonary TB (CRP, SAA, CFH, IFN-γ, IP-10, Apo-AI and transthyretin) plus other potentially useful host biomarkers as diagnostic candidates for TBM.FindingsOf 47 children included in the study, 23 (48.9%) had a final diagnosis of TBM of which six had HIV co-infection. A modified version of the adult 7-marker biosignature in which transthyretin was replaced by NCAM1, diagnosed TBM in children with AUC of 0.80 (95% CI, 0.67-0.92), sensitivity of 73.9% (95% CI, 51.6-89.8%) and specificity of 66.7% (95% CI, 44.7-84.4%). A new childhood TBM specific 3-marker biosignature (adipsin, Aβ42 and IL-10) showed potential in the diagnosis of TBM, with AUC of 0.84 (95% CI, 0.73-0.96), sensitivity of 82.6% (95 CI, 61.2-95.0%) and specificity of 75.0% (95% CI, 53.3-90.2%) after leave-one-out cross validation.ConclusionAn adult 7-marker serum protein biosignature showed potential in the diagnosis of TBM in children. However, a smaller childhood TBM-specific biosignature demonstrated improved performance characteristics. Our data indicates that blood-based biomarkers may be useful in the diagnosis of childhood TBM and require further investigation.

scholarly journals OC 8277 IDENTIFICATION OF NEW CEREBROSPINAL FLUID AND BLOOD-BASED BIOMARKERS FOR THE DIAGNOSIS OF TUBERCULOUS MENINGITIS IN CHILDREN

2019 ◽  
Vol 4 (Suppl 3) ◽  
pp. A3.2-A3
Author(s):  
Masilo Charles Manyelo ◽  
Regan S Solomons ◽  
Gerhard Walzl ◽  
Novel N Chegou
Keyword(s):  
Cerebrospinal Fluid ◽  
Tuberculous Meningitis ◽  
Point Of Care ◽  
Extrapulmonary Tuberculosis ◽  
Diagnostic Delay ◽  
Severe Form ◽  
High Morbidity ◽  
Serum Samples ◽  
Meningitis In Children ◽  
Study Participants

BackgroundTuberculous meningitis (TBM) is the most severe form of extrapulmonary tuberculosis (TB). It mostly affects young children and results in high morbidity and mortality, mainly due to diagnostic delay. There is an urgent need for new tests for the earlier and accurate diagnosis of the disease. We previously identified a 3-marker cerebrospinal fluid (CSF) biosignature (VEGF, IL-13, and LL-37) with potential to diagnose TBM. In the present study, we show that CSF and blood-based biosignatures may be useful in the diagnosis of TBM.MethodsCSF and serum samples were consecutively collected from 47 children that were admitted to the Tygerberg Academic Hospital in Cape Town, South Africa, on suspicion of having TBM. Using a multiplex platform, the concentrations of 69 host markers were evaluated in the CSF and serum samples from all the study participants, followed by statistical analysis to ascertain the usefulness of these biomarkers as diagnostic candidates for TBM disease.ResultsOut of the 47 study participants, 23 (48.9%) were finally diagnosed with TBM and 6 (12.8%) were infected with HIV. Several CSF and serum biomarkers showed potential individually as diagnostic candidates for TBM as ascertained by area under the receiver operator characteristics curve (AUC). However, the main findings of our study were the identification of a four-marker CSF biosignature which diagnosed TBM with an AUC of 0.97 (95% CI, 0.92–1.00), and a 3-marker serum biosignature which diagnosed TBM with an AUC of 0.84 (95% CI, 0.73–0.96). We also validated a previously identified 3-marker CSF biosignature (VEGF, IL13 and LL37) in the study.ConclusionCSF and serum biosignatures may be useful in the diagnosis of TBM in children. Our findings require further validation in larger, multi-site studies after which the biosignatures may be incorporated into point-of-care diagnostic tests for TBM.

scholarly journals Evolving Stroke in Tuberculous Meningitis

2021 ◽  
Author(s):  
Seng Wee Cheo ◽  
Rosdina Zamrud Ahmad Akbar ◽  
Song Weng Ryan Khoo ◽  
Yee Ann Tan ◽  
Qin Jian Low
Keyword(s):  
Tuberculous Meningitis ◽  
Neurological Complication ◽  
Severe Form ◽  
High Morbidity ◽  
Timely Initiation ◽  
Extra Pulmonary Tuberculosis ◽  
Aggressive Disease ◽  
Ct Brain ◽  
The Brain

Tuberculous meningitis (TBM) is the most severe form of extra-pulmonary tuberculosis which carries high mortality with 100% mortality without treatment. A neurological complication of TBM includes hydrocephalus, brain abscess and stroke. In this report, we would like to illustrate a case of stroke in a patient with TBM. In this case, a 37-year old man initially presented with fever for 1 week associated with severe headache and occasional vomiting. Computed tomography (CT) of the brain showed leptomeningeal enhancement and lumbar puncture findings consistent with infective in nature. His MARAIS score was 13 and was treated as tuberculous meningitis with anti-tuberculous therapy. While in the ward, he developed right-sided body weakness with evolving CT brain findings. His condition then stabilized with anti-tuberculous treatment which consists of isoniazid, rifampicin, pyrazinamide and streptomycin. Dexamethasone was also initiated. On follow up, his condition further improves and is functionally independent. In conclusion, tuberculous meningitis is an aggressive disease with high morbidity. Stroke can occur as a result of TBM. Timely initiation of treatment is important in improving the outcome of the patients.

scholarly journals Tuberculous Meningitis: a case report of a late diagnosis

2013 ◽  
Vol 12 (1) ◽  
pp. 127
Author(s):  
Bruna Tassi Borille ◽  
Flávia Martinello ◽  
Andressa Verzeletti Rodrigues ◽  
Renata Gonçalves
Keyword(s):  
Tuberculous Meningitis ◽  
Late Onset ◽  
Delayed Diagnosis ◽  
Vascular Wall ◽  
Severe Form ◽  
Late Diagnosis ◽  
University Hospital ◽  
High Morbidity ◽  
Early Treatment Response ◽  
Previous Diagnosis

<div>Introduction: Tuberculous meningitis (TM) is the most severe form of tuberculosis, it has high morbidity and mortality. Once it is diagnosed early, treatment response is excellent. Objective: To report and discuss a case of delayed diagnosis of TM. Methodology: It was selected a case from University Hospital of Federal University of Santa Catarina, the analysis of medical records was performed and discussed based on the scientific literature. Results: It was reported the case of a patient that was diagnosed with leukocytoclastic</div><div>vasculitis (LV) for six months and was admitted presenting granulomatous lung injury, weight loss, fever and dry cough for eigth months. The delay in the diagnosis of tuberculosis (TB) allowed an evolution to TM and the late onset of treatment impaired the patient’s prognosis. It was discussed the vasculitis as a first symptom of tuberculosis, which can occur by deposition of immune complexes</div><div>formed by antibodies against antigens of bacilli in the vascular wall. Conclusions: Previous diagnosis of LV deviated the focus of the case for their cause, and suggested other pathologic conditions, which contributed to delay in the diagnosis of TB. Despite the late diagnosis and treatment, the therapeutic approaches used for vasculitis, TB and TM followed the protocols described in the literature.</div>

scholarly journals A Simple Microfluidic Assay for Diagnosing Tuberculous Meningitis in HIV-Uninfected Patients

2019 ◽  
Vol 57 (5) ◽  
Author(s):  
Joung Ha Park ◽  
Choong Eun Jin ◽  
Bonhan Koo ◽  
Ji-Soo Kwon ◽  
Hye Hee Cha ◽  
...  
Keyword(s):  
Tuberculous Meningitis ◽  
High Sensitivity ◽  
Tertiary Hospital ◽  
Case Definition ◽  
Reference Standards ◽  
Small Samples ◽  
Mycobacterial Culture ◽  
Immunodeficiency Virus ◽  
Uniform Case ◽  
Positive Results

ABSTRACTWe evaluated the diagnostic performance of asimple andlabel-free pathogen enrichment method using homobifunctionalimidoesters (HI) and amicrofluidic system, called the SLIM assay, followed by real-time PCR from cerebrospinal fluid (CSF) in human immunodeficiency virus (HIV)-uninfected patients with suspected tuberculous meningitis (TBM). Patients with suspected TBM were prospectively enrolled in a tertiary hospital in an intermediate tuberculosis (TB)-burden country during a 30-month period. TBM was classified according to the uniform case definition. Definite and probable TBM were regarded as the reference standards for TBM, and possible TBM and not-TBM as the reference standards for not-TBM. Of 72 HIV-uninfected patients with suspected TBM, 10 were diagnosed with definite (n = 2) and probable (n = 8) TBM by the uniform case definition. The sensitivity of the SLIM assay was 100% (95% confidence interval [CI], 69 to 100%) compared with definite or probable TBM, and it was superior to those of mycobacterial culture (20% [95% CI, 3 to 56%]) and the Xpert MTB/RIF assay (0% [95% CI, 0 to 31%]). Of 21 possible TBM and 41 not-TBM patients by the uniform case definition, 5 possible TBM and no not-TBM patients gave positive results in the SLIM assay. The specificity of the SLIM assay was 92% (95% CI, 82 to 97%; 5/62). We demonstrated that the SLIM assay had a very high sensitivity and specificity with small samples of 10 cases of definite or probable TBM. Further studies are needed to confirm this finding and to compare the SLIM assay with mycobacterial culture, Xpert MTB/RIF, and Xpert MTB/RIF Ultra assays in a larger prospective cohort of patients with suspected TBM, including both HIV-infected and HIV-uninfected cases.

scholarly journals Candidate Biomarkers to Distinguish Spinal Tuberculosis From Mechanical Back Pain in a Tuberculosis Endemic Setting

2021 ◽  
Vol 12 ◽  
Author(s):  
Theresa N. Mann ◽  
Johan H. Davis ◽  
Gerhard Walzl ◽  
Caroline G. Beltran ◽  
Jacques du Toit ◽  
...  
Keyword(s):  
Back Pain ◽  
Spinal Tuberculosis ◽  
Roc Curves ◽  
Tertiary Hospital ◽  
Severe Form ◽  
Serum Biomarkers ◽  
Western Cape ◽  
Serum Samples ◽  
Biomarker Analysis ◽  
Mechanical Back Pain

BackgroundSpinal tuberculosis (TB) may have a variable, non-specific presentation including back pain with- or without- constitutional symptoms. Further tools are needed to aid early diagnosis of this potentially severe form of TB and immunological biomarkers may show potential in this regard. The aim of this study was to investigate the utility of host serum biomarkers to distinguish spinal TB from mechanical back pain.MethodsPatients with suspected spinal TB or suspected mechanical back pain were recruited from a tertiary hospital in the Western Cape, South Africa, and provided a blood sample for biomarker analysis. Diagnosis was subsequently confirmed using bacteriological testing, advanced imaging and/or clinical evaluation, as appropriate. The concentrations of 19 host biomarkers were evaluated in serum samples using the Luminex platform. Receiver Operating Characteristic (ROC) curves and General Discriminant Analysis were used to identify biomarkers with the potential to distinguish spinal TB from mechanical back pain.ResultsTwenty-six patients with spinal TB and 17 with mechanical back pain were recruited. Seven out of 19 biomarkers were significantly different between groups, of which Fibrinogen, CRP, IFN-γ and NCAM were the individual markers with the highest discrimination utility (Area Under Curve ROC plot 0.88-0.99). A five-marker biosignature (CRP, NCAM, Ferritin, CXCL8 and GDF-15) correctly classified all study participants after leave-one-out cross-validation.ConclusionThis study identified host serum biomarkers with the potential to diagnose spinal TB, including a five-marker biosignature. These preliminary findings require validation in larger studies.

scholarly journals Comparative evaluation of IS6110 and protein antigen b PCR in cerebrospinal fluid for rapid diagnosis of tuberculous meningitis in children

2020 ◽  
Vol 69 (7) ◽  
pp. 979-985
Author(s):  
Sikha Agarwal ◽  
Arushi Gahlot Saini ◽  
Sumeet Dhawan ◽  
Alka Khadwal ◽  
Kusum Sharma ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Tuberculous Meningitis ◽  
Severe Form ◽  
Rapid Diagnosis ◽  
Protein Antigen ◽  
High Morbidity ◽  
Antigen B ◽  
Significant Difference ◽  
Lowenstein Jensen ◽  
Meningitis In Children

Introduction. Childhood tuberculosis meningitis is a severe form of tuberculosis with high morbidity and mortality. The diagnosis is frequently missed and delayed due to lack of sensitive tests like acid-fast bacilli (AFB) smear and delayed results by culture. Aims. To compare the role of IS6110 and protein antigen b PCR in cerebrospinal fluid (CSF) for rapid diagnosis of tuberculous meningitis (TBM) in children. Methodology. Forty-five cases of TBM and 20 controls were enrolled in this prospective study. Results. The mean ages of cases and controls were 4.2±0.5 years and 4.5±0.7 years, respectively. In the TBM group, two-thirds of the children were <4 years of age, and 62 % were males. Sensitivities of AFB smear examination, Löwenstein–Jensen (LJ) medium and bactenecin (BACTEC) culture in cases were 4.4, 0 and 2.2%, respectively. The protein antigen b PCR was most sensitive as it was positive in 35 (77.8 %) of TBM patients; IS6110 PCR was positive in 27 (60 %) patients. Both PCR-based tests had higher positivity than conventional tests and BACTEC culture. No significant difference was seen between the PCR tests. Excellent agreement was observed between both PCR-based tests as they were concordant for 26 positive samples and 35 negative samples. Conclusion. Protein b PCR is a sensitive and rapid method for the diagnosis of TBM (sensitivity 77.8 %). Both PCRs were more sensitive than smear, LJ and BACTEC. The specificity of both PCR was 100 %.

CHILDHOOD TUBERCULOSIS: CLINICAL VALUE OF THE ELECTROPHORETIC PATTERN OF THE SERUM PROTEINS

PEDIATRICS ◽  
1961 ◽  
Vol 27 (1) ◽  
pp. 54-67
Author(s):  
Rosa Lee Nemir ◽  
Charlotte Marker Zitrin ◽  
Paraskevi Tsouros ◽  
Enriqueta Melly
Keyword(s):  
Serum Protein ◽  
Tuberculous Meningitis ◽  
Gamma Globulin ◽  
Serum Proteins ◽  
Electrophoretic Pattern ◽  
Miliary Tuberculosis ◽  
Protein Fractions ◽  
Reciprocal Relation ◽  
Tuberculous Infection ◽  
Tuberculous Disease

The blood serum protein fractions of 138 children with tuberculosis were analyzed by paper electrophoresis serially over a period of many months. Many manifestations of tuberculous infection were studied. The group was divided into 11 categories ranging from healed or arrested tuberculous disease to various stages of activity. The serum protein fractions were evaluated in terms of prognosis, type of tuberculous disease, effect of intercurrent infection and age of patient. It was found that the greatest changes occurred in the gamma-globulin and albumin fractions in reciprocal relation. With the exception of tuberculous meningitis, the increase in gamma-globulin usually corresponded to the severity of disease. Albumin was correspondingly decreased, and was low even in tuberculous meningitis. Both fractions approached normal levels as the patients improved. Relatively normal readings were found in patients with tuberculosis observation or arrested tuberculosis. The greatest deviation from normal was seen in patients with miliary tuberculosis and those with pleurisy with effusion. Here, the gamma and alpha2-globulins were very high and the serum albumin was low. The alpha2 fraction was elevated in the children with more severe disease, including tuberculous meningitis; with clinical improvement it returned to normal more rapidly than the gamma. A rise in the beta-globulin fraction suggests caseation. Confirmatory evidence was obtained in patients with endobronchial disease, tuberculous adenitis and from the only necropsy in the series. The significant changes in the various fractions are further described and discussed.

scholarly journals Serum and cerebrospinal fluid host proteins indicate stroke in children with tuberculous meningitis

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0250944
Author(s):  
Charles M. Manyelo ◽  
Novel N. Chegou ◽  
James A. Seddon ◽  
Candice I. Snyders ◽  
Hygon Mutavhatsindi ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Tuberculous Meningitis ◽  
Multiple Testing ◽  
Serum Proteins ◽  
Lipocalin 2 ◽  
Host Proteins ◽  
Serum Samples ◽  
Csf Proteins ◽  
Study Participants

Introduction Stroke is a common complication in children with tuberculous meningitis (TBM). Host proteins may give us insight into the mechanisms of stroke in TBM and serve as biomarkers for detection of stroke, however, they have not been widely explored. In this study, we compared the concentrations of cerebrospinal fluid (CSF) and serum proteins between children who had TBM-related stroke and children with TBM without stroke. Methods We collected CSF and serum from 47 children consecutively admitted to the Tygerberg Academic Hospital in Cape Town, South Africa between November 2016, and November 2017, on suspicion of having TBM. A multiplex platform was used to measure the concentrations of 69 host proteins in CSF and serum from all study participants. Results After classification of study participants, 23 (48.9%) out of the 47 study participants were diagnosed with TBM, of which 14 (60.9%) demonstrated radiological arterial ischemic infarction. The levels of lipocalin-2, sRAGE, IP-10/ CXCL10, sVCAM-1, MMP-1, and PDGF-AA in CSF samples and the levels of D-dimer, ADAMTS13, SAA, ferritin, MCP-1/ CCL2, GDF-15 and IL-13 in serum samples were statistically different between children who had TBM-related stroke and children with TBM without stroke. After correcting for multiple testing, only the levels of sVCAM-1, MMP-1, sRAGE, and IP-10/ CXCL10 in CSF were statistically different between the two groups. CSF and serum protein biosignatures indicated stroke in children diagnosed with TBM with up to 100% sensitivity and 88.9% specificity. Conclusion Serum and CSF proteins may serve as biomarkers for identifying individuals with stroke amongst children diagnosed with TBM at admission and may guide us to understand the biology of stroke in TBM. This was a pilot study, and thus further investigations in larger studies are needed.

scholarly journals Circulating microRNA Expression in Cushing’s Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Sharmilee Vetrivel ◽  
Ru Zhang ◽  
Mareen Engel ◽  
Barbara Altieri ◽  
Leah Braun ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Validation Cohort ◽  
Cushing's Syndrome ◽  
Circulating Microrna ◽  
High Morbidity ◽  
Discovery Cohort ◽  
Serum Samples ◽  
Curative Surgery ◽  
Before And After ◽  
Diagnosis And Classification

ContextCushing’s syndrome (CS) is a rare disease of endogenous hypercortisolism associated with high morbidity and mortality. Diagnosis and classification of CS is still challenging.ObjectiveCirculating microRNAs (miRNAs) are minimally invasive diagnostic markers. Our aim was to characterize the circulating miRNA profiles of CS patients and to identify distinct profiles between the two major CS subtypes.MethodsWe included three groups of patients from the German Cushing’s registry: ACTH-independent CS (Cortisol-Producing-Adenoma; CPA), ACTH-dependent pituitary CS (Cushing’s Disease; CD), and patients in whom CS had been ruled out (controls). Profiling of miRNAs was performed by next-generation-sequencing (NGS) in serum samples of 15 CS patients (each before and after curative surgery) and 10 controls. Significant miRNAs were first validated by qPCR in the discovery cohort and then in an independent validation cohort of 20 CS patients and 11 controls.ResultsNGS identified 411 circulating miRNAs. Differential expression of 14 miRNAs were found in the pre- and postoperative groups. qPCR in the discovery cohort validated 5 of the significant miRNAs from the preoperative group analyses. Only, miR-182-5p was found to be significantly upregulated in the CD group of the validation cohort. Comparing all CS samples as a group with the controls did not reveal any significant differences in expression.OutcomeIn conclusion, our study identified miR-182-5p as a possible biomarker for CD, which has to be validated in a prospective cohort. Furthermore, our results suggest that presence or absence of ACTH might be at least as relevant for miRNA expression as hypercortisolism itself.

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