Diagnosis Of Pediatric Tuberculosis Research Articles

Utility of GeneXpert in Diagnosis of Pediatric Tuberculosis and Detection of Rifampicin Resistance

Abstract Background: Tuberculosis (TB) remains a significant public health challenge in developing countries, including India, where children under 15 years account for 12% of all TB cases. The National Tuberculosis Elimination Programme (NTEP) recommends the use of GeneXpert/Cartridge-Based Nucleic Acid Amplification Test (CBNAAT) for TB diagnosis, followed by Line Probe Assay (LPA) for detecting drug resistance. This study aimed to determine the prevalence of TB and rifampicin resistance in pediatric patients and to evaluate the utility of CBNAAT in comparison with LPA and Ziehl-Neelsen staining. Methods: This retrospective study was conducted over one year, from 1st January 2022 to 31st December 2022, at a tertiary care hospital in western Maharashtra. A total of 528 samples from pediatric patients (aged <18 years) suspected of having TB were included. Samples underwent CBNAAT testing and Ziehl-Neelsen staining. Positive samples were further analyzed using LPA or Mycobacterial Growth Indicator Tube (MGIT) culture. Results: Among the 528 samples analyzed, gastric lavage accounted for 81.25% of the specimens. CBNAAT detected TB in 61 (11.55%) of the samples, with 15 (24.59%) of these showing rifampicin resistance. Samples with very low or low bacterial loads were often missed by Ziehl-Neelsen staining. Conclusion: Pediatric tuberculosis continues to be a public health concern in developing countries. The study found an 11.55% positivity rate in children under 18 years of age, with 24.59% of positive cases exhibiting rifampicin resistance. The findings underscore the importance of using advanced diagnostic techniques like CBNAAT and highlight the limitations of Ziehl-Neelsen staining in detecting low bacterial loads.

Chest X-Ray-Based Telemedicine Platform for Pediatric Tuberculosis Diagnosis in Low-Resource Settings: Development and Validation Study.

Tuberculosis (TB) remains a major cause of morbidity and death worldwide, with a significant impact on children, especially those under the age of 5 years. The complex diagnosis of pediatric TB, compounded by limited access to more accurate diagnostic tests, underscores the need for improved tools to enhance diagnosis and care in resource-limited settings. This study aims to present a telemedicine web platform, BITScreen PTB (Biomedical Image Technologies Screen for Pediatric Tuberculosis), aimed at improving the evaluation of pulmonary TB in children based on digital chest x-ray (CXR) imaging and clinical information in resource-limited settings. The platform was evaluated by 3 independent expert readers through a retrospective assessment of a data set with 218 imaging examinations of children under 3 years of age, selected from a previous study performed in Mozambique. The key aspects assessed were the usability through a standardized questionnaire, the time needed to complete the assessment through the platform, the performance of the readers to identify TB cases based on the CXR, the association between the TB features identified in the CXRs and the initial diagnostic classification, and the interreader agreement of the global assessment and the radiological findings. The platform's usability and user satisfaction were evaluated using a questionnaire, which received an average rating of 4.4 (SD 0.59) out of 5. The average examination completion time ranged from 35 to 110 seconds. In addition, the study on CXR showed low sensitivity (16.3%-28.2%) but high specificity (91.1%-98.2%) in the assessment of the consensus case definition of pediatric TB using the platform. The CXR finding having a stronger association with the initial diagnostic classification was air space opacification (χ21>20.38, P<.001). The study found varying levels of interreader agreement, with moderate/substantial agreement for air space opacification (κ=0.54-0.67) and pleural effusion (κ=0.43-0.72). Our findings support the promising role of telemedicine platforms such as BITScreen PTB in enhancing pediatric TB diagnosis access, particularly in resource-limited settings. Additionally, these platforms could facilitate the multireader and systematic assessment of CXR in pediatric TB clinical studies.

Novel RNA biomarkers improve discrimination of children with tuberculosis disease from those with non-TB pneumonia after in vitro stimulation.

The diagnosis of pediatric tuberculosis (TB) poses a challenge for clinical teams worldwide. TB-mediated changes in the expression of host genes in the peripheral blood can serve as diagnostic biomarkers and can provide better insights into the host immune mechanisms of childhood TB. Peripheral blood mononuclear cells (PBMCs) from children (n=102) with microbiologically confirmed TB disease, TB infection (TBI), pneumonia, and healthy controls (HC) were stimulated with either the Purified Protein Derivative (PPD) or the Early Secretory Antigen 6kDa-Culture Filtrate Protein 10 (ESAT6-CFP10) complex of Mycobacterium tuberculosis (Mtb). RNA was extracted and quantified using gene expression microarrays. Differential expression analysis was performed comparing microbiologically confirmed TB to the other diagnostic groups for the stimulated and unstimulated samples. Using variable selection, we identified sparse diagnostic gene signatures; one gene (PID1) was able to distinguish TB from pneumonia after ESAT6-CFP10 stimulation with an AUC of 100% in the test set, while a combination of two genes (STAT1 and IFI44) achieved an AUC of 91.7% (CI95% 75.0%-100%) in the test set after PPD stimulation. The number of significantly differentially expressed (SDE) genes was higher when contrasting TB to pneumonia or HC in stimulated samples, compared to unstimulated ones, leading to a larger pool of candidate diagnostic biomarkers. Our approach provides enlightened aspects of peripheral TB-specific responses and can form the basis for a point of care test meeting the World Health Organization (WHO) Target Product Profile (TPP) for pediatric TB.

CLINICAL PROFILE AND OUTCOME OF PEDIATRIC TUBERCULOSIS IN A TERTIARY CARE SETTING IN CENTRAL INDIA

Objective: To study the clinical profile and outcome of tuberculosis (TB) in children under 14 years of age. Methods: It is a hospital-based cross-sectional study done in a tertiary referral center in Central India from July 2017 to June 2019. After ethical approval, 80 children (under 14 years of age) diagnosed with presumptive TB were enrolled. Those already on TB treatment or prophylaxis for more than 7 days were excluded from the study. Relevant patient details were noted on a predesigned pro forma. Routine first-line investigations for TB were done in all cases. Histopathological and specific radiology tests were done as per the site involved. Microbiological confirmation was done using microscopy, and molecular diagnosis was done by a cartridge-based nucleic acid amplification test (CBNAAT). Results: Overall mortality was 13.8%, and 82% of them were children below 5 years of age. As per WHO criteria, 52.5% and 20% of children below 5 years of age were severely and moderately undernourished, respectively. History of contact was present in 66%; BCG scar in 91.3%; and tuberculin sensitivity test positivity in 56% of cases. Fever, cough, and weight loss were the most common presenting complaints. The majority had extrapulmonary involvement (75%), with neurotuberculosis being the most common and with the highest mortality (70%). Microbiological confirmation was possible in only 8.8% of cases. Conclusion: It is still challenging to diagnose pediatric TB. Though newer diagnostics are now available, clinical suspicion is a valuable tool. The diagnosis of pediatric TB should thus be based on a combination of epidemiological variables, clinical suspicion, and supported by various laboratory investigations.

Does multiple gastric aspirate collection increase sensitivity of M. tuberculosis detection in children with pulmonary tuberculosis?

This study aims to investigate the sensitivity of microscopy, culture and polymerase chain reaction on three gastric aspirates (GAs) in the microbiological confirmation of active pulmonary tuberculosis (TB) and to identify possible changes in sensitivity derived from the collection of a different number of aspirates. Children with clinical and radiological diagnoses of active pulmonary TB who underwent three GAs between March 2007 and June 2019 were retrospectively evaluated. Clinical, radiological, and microbiological data were collected. The sensitivity of microbiological tests on GAs was calculated. Moreover, differences in sensitivity according to age and radiological pattern were investigated. Overall, 156 children with active pulmonary TB were enrolled with a median age of 51.5 (IQR: 25.2–113.2) months. Microbiological investigations on the first GA showed a sensitivity of 34% (95%CI 26.7, 42), the cumulative sensitivity of first and second GAs was 40.4% (95%CI 32.7, 48.5) and of the three GAs was 47.4% (95%CI 39.8, 55.2). The collection of three GAs leads to an overall increase in sensitivity of the first GA by 13.4% (95%CI 2.8, 24.1%; p=0.014). Moreover, the increase in sensitivity was significantly higher in children ≤ 4 years of age and in those with uncomplicated TB (p=0.008).Conclusions: Performing a higher number of GAs increases the sensitivity of microbiological confirmation of active pulmonary TB, particularly in children ≤ 4 years and with an uncomplicated radiological pattern.What is known:• The diagnosis of paediatric tuberculosis is a challenge for paediatricians• Despite their low sensitivity gastric aspirates represent the standard sample for microbiological confirmation of active pulmonary tuberculosis in children• Most international guidelines recommend performing three sequential gastric aspirates on three consecutive daysWhat is new:• A significant increase in global sensitivity by 13.4% was found by the collection of three gastric aspirates compared to the first one• Performing a higher number of gastric aspirates increases the sensitivity of microbiological confirmation, particularly in children ≤ 4 years and with an uncomplicated radiological pattern

Small molecule bio-signature in childhood intra-thoracic tuberculosis identified by metabolomics.

The diagnosis of pediatric tuberculosis (TB) remains a major challenge, hence the evaluation of new tools for improved diagnostics is urgently required. We investigated the serum metabolic profile of children with culture-confirmed intra-thoracic TB (ITTB) (n = 23) and compared it with those of non-TB controls (NTCs) (n = 13) using proton NMR spectroscopy-based targeted and untargeted metabolomics approaches. In targeted metabolic profiling, five metabolites (histidine, glycerophosphocholine, creatine/phosphocreatine, acetate, and choline) differentiated TB children from NTCs. Additionally, seven discriminatory metabolites (N-α-acetyl-lysine, polyunsaturated fatty acids, phenylalanine, lysine, lipids, glutamate + glutamine, and dimethylglycine) were identified in untargeted metabolic profiling. The pathway analysis revealed alterations in six metabolic pathways. The altered metabolites were associated with impaired protein synthesis, hindered anti-inflammatory and cytoprotective mechanisms, abnormalities in energy generation processes and membrane metabolism, and deregulated fatty acid and lipid metabolisms in children with ITTB. The diagnostic significance of the classification models obtained from significantly distinguishing metabolites showed sensitivity, specificity, and area under the curve of 78.2%, 84.6%, and 0.86, respectively, in the targeted profiling and 92.3%, 100%, and 0.99, respectively, in the untargeted profiling. Our findings highlight detectable metabolic changes in childhood ITTB; however, further validation is warranted in a large cohort of the pediatric population.

Monocyte, Lymphocyte and Neutrophil Ratios - Easy-to-Use Biomarkers for the Diagnosis of Pediatric Tuberculosis.

The neutrophil-to-lymphocyte-ratio (NLR), neutrophil-to-monocyte-plus-lymphocyte-ratio (NMLR) and monocyte-to-lymphocyte-ratio (MLR) may have diagnostic potential for tuberculosis (TB). Data of two prospective multicenter studies in Switzerland were used, which included children <18 years with TB exposure, infection or disease or with febrile non-TB lower-respiratory-tract infection (nTB-LRTI). Of the 389 children included 25 (6.4%) had TB disease, 12 (3.1%) TB infection, 28 (7.2%) were healthy TB exposed and 324 (83.3%) nTB-LRTI. Median (IQR) NLR was highest with 2.0 (1.2, 2.2) in children with TB disease compared to TB exposed [0.8 (0.6, 1.3); P = 0.002] and nTB-LRTI [0.3 (0.1, 1.0); P < 0.001]. Median (IQR) NMLR was highest with 1.4 (1.2, 1.7) in children with TB disease compared to healthy exposed [0.7 (0.6, 1.1); P = 0.003] and children with nTB-LRTI [0.2 (0.1, 0.6); P < 0.001). Receiver operating characteristic curves to detect TB disease compared to nTB-LRTI for NLR and NMLR had an area under the curve of 0.82 and 0.86, the sensitivity of 88% and 88%, and specificity of 71% and 76%, respectively. NLR and NMLR are promising, easy-to-obtain diagnostic biomarkers to differentiate children with TB disease from other lower respiratory tract infections. These results require validation in a larger study and in settings with high and low TB endemicity.

Comparative analysis of cartridge-based nucleic acid amplification test (CBNAAT) with conventional methods in the diagnosis of pediatric tuberculosis at a tertiary care center

BackgroundTuberculosis is an important cause of morbidity and mortality among children. Early diagnosis and treatment in children are challenging, more so in resource-limited, tuberculosis-endemic countries. In 2017, the WHO endorsed the use of CBNAAT for tuberculosis diagnosis. We have undertaken this study to evaluate the diagnostic value of CBNAAT in pediatric tuberculosis in comparison to other methods like microscopic detection of acid-fast bacilli and detection of mycobacteria-by-mycobacteria growth indicator tube (MGIT). Material and methodsThis hospital-based, cross-sectional, observational prospective study was conducted in the department of pediatrics, at a tertiary care center. A detailed history, general physical examination, and relevant physical examination were performed systematically and the findings were noted in the proforma. All necessary basic investigations like CBC, ESR, X-Ray, etc., and advanced investigations like MRI, CT, and FNAC were done as per the requirement of the subjects and the results were mentioned in the study proforma. Sensitivity, specificity, positive and negative predictive value, and diagnostic accuracy were calculated for various methods. A comparison between the two methods was done using the Mc Nemar test. p-value ≤0.05 was taken as statistically significant. All statistical analyses were done using Epi info version 7.2.1.0 statistical software. ResultsAmong 102 children suspected to be suffering from tuberculosis, the maximum number of TB cases were found in the age group of 11–16 years (43.2%), there were 58.2% of females, 58.8% belonged to the rural population, fever (78.4%) was the most common presenting symptom and 35.3% had a history of contact. In the present study, CBNAAT and ZN staining had equal sensitivity (60.8%) and specificity (100%) while the yield for MGIT culture was quite low (sensitivity 37.3%, specificity 100%). ConclusionsCBNAAT as a test was found to be useful, especially for early diagnosis and detection of rifampicin resistance in pediatric tuberculosis against MGIT culture. Since MGIT results become available only after 42 days and have a relatively lower yield so they can be utilized only in a selected clinical situation or in patients with high suspicion of tuberculosis where another test is not able to detect the organisms.

Cost-Effectiveness of Currently Available Diagnostic Tools for Diagnosis of Pediatric Tuberculosis Under National Tuberculosis Elimination Program.

In India, children do not get diagnosed with tuberculosis (TB) for reasons such as lack of screening modality at the health-care settings, inadequate sputum sample, and low detection rate. This study aims to assess various modalities for diagnosis of pediatric TB and their cost-effectiveness. Cost-effectiveness was found for various diagnostic modalities for TB diagnosis in children of India below 15 years of age. TrueNat MTB was the intervention being compared to GeneXpert MTB and sputum microscopy. Evidence pertinent to effectiveness and cost per test, and health benefits in terms of disability adjusted life years were researched and documented. Modeling a cohort of children through a decision tree and assimilating costs and disability-adjusted life years (DALYs) at each step gave results in the form of cost-effectiveness. Interventions were compared by calculating the cost-effectiveness ratio. The results revealed that TrueNat is more cost effective (Rs. 9450/DALY averted) compared to GeneXpert MTB/RIF (Rs. 9750/DALY averted). The incremental cost effectiveness ratio of TrueNat with respect to GeneXpert was found to be Rs. 5925 per DALY averted. Diagnosis through TrueNat point of care (POC) will avert 962 more DALYs compared to GeneXpert. As is evident from the results, TrueNat does alleviate disability caused by TB in children as more DALYs are averted. At an additional cost of Rs. 5925 to avert one DALY, which is below the gross domestic product (GDP) per capita for India (for 2021, it was $2277), TrueNat can have significant health benefits.

Results of the performance of automated GeneXpert in childhood tuberculosis in Addis Ababa, Ethiopia: a retrospective cross-sectional study

Background: Approximately 81% of all childhood tuberculosis cases occur among 22 high-burden countries and Ethiopia ranks eighth among these high burden countries. The GeneXpert Mycobacterium tuberculosis DNA and resistance to rifampicin (MTB/RIF) test can detect pediatric tuberculosis and its multidrug-resistant form with very high sensitivity and specificity, but limited data exists on its use in our country. We aimed to evaluate the effectiveness of the GeneXpert assay in comparison to children with a clinical diagnosis of Tuberculosis. &#x0D; Methods: A descriptive retrospective study on 144 TB-diagnosed children younger than 15 years was conducted at Tikur-Anbessa specialized hospital and Yekatit 12-referral hospital, pediatrics departments, Addis Ababa, Ethiopia. The performance of the GeneXpert test was evaluated by re-vising the charts of patients who have begun anti-tuberculosis treatment. We extracted information from the chart review of 144 eligible children who were diagnosed with tuberculosis and began anti-TB treatment from February 2014 to July 2016. &#x0D; Result: In the study, 144 patients with clinical diagnosis of tuberculosis were included, and 23% of them also had concurrent HIV infection. Equal numbers of male and female were present; 48.6% were from Addis Ababa. Thirty-four patients (23.6%) were missing their childhood vaccinations. The GeneXpert assay detected disease in only 24 (16.7%) of clinically diagnosed pediatric tuberculosis patients.&#x0D; Conclusion: Although the GeneXpert assay is helpful in the diagnosis of pediatric tuberculosis, most patients were still receiving treatment even after a negative GeneXpert test, necessitating the need for a more sensitive test.

Clinical Presentation, Screening, and Diagnosis of Pediatric Tuberculosis

Tuberculosis (TB) remains a leading cause of illness and death throughout the world. Despite its high prevalence worldwide, a diagnosis of TB can be hampered by variable clinical presentation, differences in host response, and lack of clinician awareness. In addition to the lungs, TB can affect almost every organ system in the body. Importantly, the severity of the disease is influenced by the age and immune status of the patient. Because it is relatively rare in the United States and other high-income countries, pediatricians in those settings may be unfamiliar with this ancient disease and may omit it from their differential diagnosis. This article aims to bring general pediatricians up to date with the epidemiology of pediatric TB as well as common presentations and screening tests. Confirmatory testing and treatment of TB are out of the scope of this article. Consultation with the local health department is recommended for any patients in whom active TB is suspected or diagnosed. [Pediatr Ann. 2022;51(12):e461-e468.].

Pediatric tuberculosis outcomes and factors associated with unfavorable treatment outcomes in Botswana, 2008–2019: a retrospective analysis

IntroductionGlobally, the amount of research on the outcomes of pediatric tuberculosis (TB) is disproportionately less than that of adult TB. The diagnosis of paediatric TB is also problematic in developing countries. The aim of this study was to describe the outcomes of pediatric TB in Botswana and to identify the factors associated with unfavorable outcomes.MethodsThis was a retrospective analysis of pediatric TB outcomes in Botswana, over a 12-year period from January 2008 to December 2019. Treatment success (treatment completion or cured) was considered a favorable outcome, while death, loss to follow-up and treatment failure were considered unfavorable outcomes. Program data from drug-sensitive TB (DS-TB) cases under the age of 15 years were included. Sampling was exhaustive. Binary logistic regression was used to determine the factors associated with unfavorable outcomes during TB treatment. A p value of < 0.05 was considered a statistically significant association between the predictor variables and unfavorable outcomes.ResultsThe data of 6,004 paediatric TB cases were extracted from the Botswana National TB Program (BNTP) electronic registry and analyzed. Of these data, 2,948 (49.4%) were of female patients. Of the extracted data, 1,366 (22.8%) were of HIV positive patients and 2,966 (49.4%) were of HIV negative patients. The rest of the data were of patients with unknown HIV status. Pulmonary TB accounted for 4,701 (78.3%) of the cases. Overall, 5,591 (93.1%) of the paediatric TB patient data showed treatment success, 179 (3.0%) were lost to follow-up, 203 (3.4%) records were of patients who died, and 31 (0.5%) were of patients who experienced treatment failure. The factors associated with unfavorable outcomes were positive HIV status (AOR 2.71, 95% CI: 2.09–3.52), unknown HIV status (AOR 2.07, 95% CI: 1.60–2.69) and retreatment category (AOR 1.92, 95% CI: 1.30–2.85). Compared with the 0–4 years age category, the 5–9 years (AOR 0.62, 95% CI: 0.47–0.82) and 10–14 years (AOR 0.76, 95% CI: 0.60–0.98) age categories were less likely to experience the unfavorable outcomes.ConclusionThis study shows a high treatment success rate among paediatric TB cases in Botswana. The government under the National TB Program should maintain and consolidate the gains from this program. Public health interventions should particularly target children with a positive or unknown HIV status, those under 5 years, and those who have been previously treated for TB.

Accuracy of Xpert Ultra for the diagnosis of paediatric tuberculosis in a low TB burden country: a prospective multicentre study

IntroductionChildhood pulmonary tuberculosis (TB) remains a diagnostic challenge. This study aimed to evaluate the performance of Xpert Ultra for the diagnosis of pulmonary TB in children in a low TB...

Diagnosis of paediatric tuberculosis by optically detecting two virulence factors on extracellular vesicles in blood samples

Sensitive and specific blood-based assays for the detection of pulmonary and extrapulmonary tuberculosis would reduce mortality associated with missed diagnoses, particularly in children. Here we report a nanoparticle-enhanced immunoassay read by dark-field microscopy that detects two Mycobacterium tuberculosis virulence factors (the glycolipid lipoarabinomannan and its carrier protein) on the surface of circulating extracellular vesicles. In a cohort study of 147 hospitalized and severely immunosuppressed children living with HIV, the assay detected 58 of the 78 (74%) cases of paediatric tuberculosis, 48 of the 66 (73%) cases that were missed by microbiological assays, and 8 out of 10 (80%) cases undiagnosed during the study. It also distinguished tuberculosis from latent-tuberculosis infections in non-human primates. We adapted the assay to make it portable and operable by a smartphone. With further development, the assay may facilitate the detection of tuberculosis at the point of care, particularly in resource-limited settings.

Xpert Ultra stool testing to diagnose tuberculosis in children in Ethiopia and Indonesia: a model-based cost-effectiveness analysis

ObjectivesThe WHO currently recommends stool testing using GeneXpert MTB/Rif (Xpert) for the diagnosis of paediatric tuberculosis (TB). The simple one-step (SOS) stool method enables processing for Xpert testing at the...

The Kynurenine/Tryptophan Ratio Is a Sensitive Biomarker for the Diagnosis of Pediatric Tuberculosis Among Indian Children.

ObjectivesPediatric tuberculosis (TB) remains difficult to diagnose. The plasma kynurenine to tryptophan ratio (K/T ratio) is a potential biomarker for TB diagnosis and treatment response but has not been assessed in children.MethodsWe performed a targeted diagnostic accuracy analysis of four biomarkers: kynurenine abundance, tryptophan abundance, the K/T ratio, and IDO-1 gene expression. Data were obtained from transcriptome and metabolome profiling of children with confirmed tuberculosis and age- and sex-matched uninfected household contacts of pulmonary tuberculosis patients. Each biomarker was assessed as a baseline diagnostic and in response to successful TB treatment.ResultsDespite non-significant between-group differences in unbiased analysis, the K/T ratio achieved an area under the receiver operator characteristic curve (AUC) of 0.667 and 81.5% sensitivity for TB diagnosis. Kynurenine, tryptophan, and IDO-1 demonstrated diagnostic AUCs of 0.667, 0.602, and 0.463, respectively. None of these biomarkers demonstrated high AUCs for treatment response. The AUC of the K/T ratio was lower than biomarkers identified in unbiased analysis, but improved sensitivity over existing commercial assays for pediatric TB diagnosis.ConclusionsPlasma kynurenine and the K/T ratio may be useful biomarkers for pediatric TB. Ongoing studies in geographically diverse populations will determine optimal use of these biomarkers worldwide.

The Diagnostic Accuracy of Chest Radiographic Features for Pediatric Intrathoracic Tuberculosis.

The chest radiograph (CR) remains a key tool in the diagnosis of pediatric tuberculosis (TB). In children with presumptive intrathoracic TB, we aimed to identify CR features that had high specificity for, and were strongly associated with, bacteriologically confirmed TB. We analyzed CR data from children with presumptive intrathoracic TB prospectively enrolled in a cohort study in a high-TB burden setting and who were classified using standard clinical case definitions as "confirmed," "unconfirmed," or "unlikely" TB. We report the CR features and inter-reader agreement between expert readers who interpreted the CRs. We calculated the sensitivity and specificity of the CR features with at least moderate inter-reader agreement and analyzed the relationship between these CR features and the classification of TB in a multivariable regression model. Of features with at least moderate inter-reader agreement, enlargement of perihilar and/or paratracheal lymph nodes, bronchial deviation/compression, cavities, expansile pneumonia, and pleural effusion had a specificity of > 90% for confirmed TB, compared with unlikely TB. Enlargement of perihilar (adjusted odds ratio [aOR]: 6.6; 95% confidence interval [CI], 3.80-11.72) and/or paratracheal lymph nodes (aOR: 5.14; 95% CI, 2.25-12.58), bronchial deviation/compression (aOR: 6.22; 95% CI, 2.70-15.69), pleural effusion (aOR: 2.27; 95% CI, 1.04-4.78), and cavities (aOR: 7.45; 95% CI, 3.38-17.45) were associated with confirmed TB in the multivariate regression model, whereas alveolar opacification (aOR: 1.16; 95% CI, .76-1.77) and expansile pneumonia (aOR: 4.16; 95% CI, .93-22.34) were not. In children investigated for intrathoracic TB enlargement of perihilar or paratracheal lymph nodes, bronchial compression/deviation, pleural effusion, or cavities on CR strongly support the diagnosis.

Paediatric tuberculosis diagnosis using Mycobacterium tuberculosis real-time polymerase chain reaction assay: a systematic review and meta-analysis

BackgroundRapid and accurate diagnosis of paediatric tuberculosis (TB) is key to manage the disease and to control and prevent its transmission. Collection of quality sputum samples without invasion methods from paediatrics (age < 16 years) with presumptive pulmonary tuberculosis (PTB) remains a challenge. Thus, the aim of this meta-analysis was to assess the overall accuracy of a real-time polymerase chain reaction (RT-PCR)-based assay, for routine diagnosis of MTB in different samples from paediatrics with active pulmonary and extra-pulmonary tuberculosis using mycobacterial culture as the gold standard in clinical microbiology laboratories.MethodsWe conducted a systematic review and meta-analysis to examine the diagnostic test accuracy of RT-PCR based assay for the detection of MTB in paediatric clinical samples.A systematic literature search was performed for publications in any language. MEDLINE via PubMed, EMBASE, and Web of Science were among 9 bibliographic databases searched from August 2019 until November 2020. Bivariate random-effects model of meta-analysis were performed to generate pooled summary estimates (95% CIs) for overall accuracy of RT-PCR based assay compared to mycobacterial culture as the reference standard.ResultsOf the 1592 candidate studies, twenty-one eligible studies met our inclusion criteria. In total, the review and meta-analysis included 5536 (3209 PTB and 2327 EPTB). Summary estimates for pulmonary TB (11 studies) were as follows: sensitivity 56 (95% CI 51–62), specificity 97 (95% CI 96–98) and summary estimates for extra-pulmonary TB (10 studies) were as follows: sensitivity 87 (95% CI 82-91)) specificity 100 (95% CI 99–100). There was significant heterogeneity in sensitivity and specificity among the enrolled studies (p < 0.001).ConclusionsOur results suggested that the RT-PCR based assay could be a useful test for the diagnosis of paediatrics TB with high sensitivity and specificity in low-income/high-burden and upper medium income/low-burden settings. From the study, RT-PCR assay demonstrated a high degree of sensitivity for extra-pulmonary TB and good sensitivity for pulmonary TB which is an important factor in achieving effective global control and for patient management in terms of initiating early and appropriate anti-tubercular therapy.Systematic review registrationPROSPERO CRD42018104052

Plasma chemokines as immune biomarkers for diagnosis of pediatric tuberculosis

BackgroundDiagnosing tuberculosis (TB) in children is challenging due to paucibacillary disease, and lack of ability for microbiologic confirmation. Hence, we measured the plasma chemokines as biomarkers for diagnosis of pediatric tuberculosis.MethodsWe conducted a prospective case control study using children with confirmed, unconfirmed and unlikely TB. Multiplex assay was performed to examine the plasma CC and CXC levels of chemokines.ResultsBaseline levels of CCL1, CCL3, CXCL1, CXCL2 and CXCL10 were significantly higher in active TB (confirmed TB and unconfirmed TB) in comparison to unlikely TB children. Receiver operating characteristics curve analysis revealed that CCL1, CXCL1 and CXCL10 could act as biomarkers distinguishing confirmed or unconfirmed TB from unlikely TB with the sensitivity and specificity of more than 80%. In addition, combiROC exhibited more than 90% sensitivity and specificity in distinguishing confirmed and unconfirmed TB from unlikely TB. Finally, classification and regression tree models also offered more than 90% sensitivity and specificity for CCL1 with a cutoff value of 28 pg/ml, which clearly classify active TB from unlikely TB. The levels of CCL1, CXCL1, CXCL2 and CXCL10 exhibited a significant reduction following anti-TB treatment.ConclusionThus, a baseline chemokine signature of CCL1/CXCL1/CXCL10 could serve as an accurate biomarker for the diagnosis of pediatric tuberculosis.

Discovery and Validation of a Three-Cytokine Plasma Signature as a Biomarker for Diagnosis of Pediatric Tuberculosis.

Pediatric TB poses challenge in diagnosis due to the paucibacillary nature of the disease. We conducted a prospective diagnostic study to identify immune biomarkers of pediatric TB and controls (discovery cohort) and obtained a separate “validation” cohort of confirmed cases of pediatric TB and controls. Multiplex ELISA was performed to examine the plasma levels of cytokines. Discovery and validation cohorts revealed that baseline plasma levels of IFNγ, TNFα, IL-2, and IL-17A were significantly higher in active TB (confirmed TB and unconfirmed TB) in comparison to unlikely TB children. Receiver operating characteristics (ROC) curve analysis revealed that IFNγ, IL-2, TNFα, and IL-17A (in the discovery cohort) and TNFα and IL-17A (in the validation cohort) could act as biomarkers distinguishing confirmed or unconfirmed TB from unlikely TB with the sensitivity and specificity of more than 90%. In the discovery cohort, cytokines levels were significantly diminished following anti-tuberculosis treatment. In both the cohorts, combiROC models offered 100% sensitivity and 98% to 100% specificity for a three-cytokine signature of TNFα, IL-2, and IL-17A, which can distinguish confirmed or unconfirmed TB children from unlikely TB. Thus, a baseline cytokine signature of TNFα, IL-2, and IL-17A could serve as an accurate biomarker for the diagnosis of pediatric tuberculosis.