Unconfirmed Tuberculosis Research Articles

Incident Tuberculosis Diagnoses in Children at High Risk for Disease.

We followed 35 children meeting a research definition for unconfirmed tuberculosis (TB) but in whom a pediatric pulmonologist did not diagnose or treat TB. After a median follow-up of 16.4 months, most children were not diagnosed with TB following a comprehensive evaluation. However, 2 were diagnosed with TB, demonstrating high TB risk (6%; exact 95% CI, 1%–19%). In some contexts, researchers may wish to supplement these research definitions with clinical decision data and longitudinal follow-up in order to improve specificity.

Breath can discriminate tuberculosis from other lower respiratory illness in children

Pediatric tuberculosis (TB) remains a global health crisis. Despite progress, pediatric patients remain difficult to diagnose, with approximately half of all childhood TB patients lacking bacterial confirmation. In this pilot study (n = 31), we identify a 4-compound breathprint and subsequent machine learning model that accurately classifies children with confirmed TB (n = 10) from children with another lower respiratory tract infection (LRTI) (n = 10) with a sensitivity of 80% and specificity of 100% observed across cross validation folds. Importantly, we demonstrate that the breathprint identified an additional nine of eleven patients who had unconfirmed clinical TB and whose symptoms improved while treated for TB. While more work is necessary to validate the utility of using patient breath to diagnose pediatric TB, it shows promise as a triage instrument or paired as part of an aggregate diagnostic scheme.

A Prospective Evaluation of Xpert MTB/RIF Ultra for Childhood Pulmonary Tuberculosis in Uganda

Xpert MTB/RIF Ultra (Xpert Ultra) has improved the sensitivity to detect pulmonary tuberculosis (TB) in adults. However, there have been limited prospective evaluations of its diagnostic accuracy in children. We enrolled children undergoing assessment for pulmonary TB in Kampala, Uganda, over a 12-month period. Children received a complete TB evaluation and were classified as Confirmed, Unconfirmed, or Unlikely TB. We calculated the sensitivity and specificity of Xpert Ultra among children with Confirmed vs Unlikely TB. We also determined the diagnostic accuracy with clinical, microbiological, and extended microbiological reference standards (MRSs). Of the 213 children included, 23 (10.8%) had Confirmed TB, 88 (41.3%) had Unconfirmed TB, and 102 (47.9%) had Unlikely TB. The median age was 3.9 years, 13% were HIV-positive, and 61.5% were underweight. Xpert Ultra sensitivity was 69.6% (95% confidence interval [CI]: 47.1-86.8) among children with Confirmed TB and decreased to 23.4% (95% CI: 15.9-32.4) with the clinical reference standard. Specificity was 100% (95% CI: 96.4-100) among children with Unlikely TB and decreased to 94.7% (95% CI: 90.5-97.4) with a MRS. Sensitivity was 52.9% (95% CI: 35.1-70.2) and specificity 95.5% (95% CI: 91.4-98.1) with the extended MRS. Of the 26 positive Xpert Ultra results, 6 (23.1%) were "Trace-positive," with most (5/6) occurring in children with Unconfirmed TB. Xpert Ultra is a useful tool for diagnosing pulmonary TB in children, but there remains a need for more sensitive tests to detect culture-negative TB.

Machine Learning Algorithms Evaluate Immune Response to Novel Mycobacterium tuberculosis Antigens for Diagnosis of Tuberculosis.

RationaleTuberculosis diagnosis in children remains challenging. Microbiological confirmation of tuberculosis disease is often lacking, and standard immunodiagnostic including the tuberculin skin test and interferon-γ release assay for tuberculosis infection has limited sensitivity. Recent research suggests that inclusion of novel Mycobacterium tuberculosis antigens has the potential to improve standard immunodiagnostic tests for tuberculosis.ObjectiveTo identify optimal antigen–cytokine combinations using novel Mycobacterium tuberculosis antigens and cytokine read-outs by machine learning algorithms to improve immunodiagnostic assays for tuberculosis.MethodsA total of 80 children undergoing investigation of tuberculosis were included (15 confirmed tuberculosis disease, five unconfirmed tuberculosis disease, 28 tuberculosis infection and 32 unlikely tuberculosis). Whole blood was stimulated with 10 novel Mycobacterium tuberculosis antigens and a fusion protein of early secretory antigenic target (ESAT)-6 and culture filtrate protein (CFP) 10. Cytokines were measured using xMAP multiplex assays. Machine learning algorithms defined a discriminative classifier with performance measured using area under the receiver operating characteristics.Measurements and main resultsWe found the following four antigen–cytokine pairs had a higher weight in the discriminative classifier compared to the standard ESAT-6/CFP-10-induced interferon-γ: Rv2346/47c- and Rv3614/15c-induced interferon-gamma inducible protein-10; Rv2031c-induced granulocyte-macrophage colony-stimulating factor and ESAT-6/CFP-10-induced tumor necrosis factor-α. A combination of the 10 best antigen–cytokine pairs resulted in area under the curve of 0.92 ± 0.04.ConclusionWe exploited the use of machine learning algorithms as a key tool to evaluate large immunological datasets. This identified several antigen–cytokine pairs with the potential to improve immunodiagnostic tests for tuberculosis in children.

Comparing accuracy of lipoarabinomannan urine tests for diagnosis of pulmonary tuberculosis in children from four African countries: a cross-sectional study

A sensitive and specific non-sputum-based test would be groundbreaking for the diagnosis of childhood tuberculosis. We assessed side by side the diagnostic accuracy of the urine-based lipoarabinomannan assays Fujifilm SILVAMP TB LAM (FujiLAM) and Alere Determine TB LAM Ag (AlereLAM) for detection of childhood tuberculosis. In this cross-sectional study, we tested urine samples from children younger than 15 years with presumed pulmonary tuberculosis. Children were consecutively recruited from four dedicated outpatient childhood tuberculosis clinics in The Gambia, Mali, Nigeria, and Tanzania. Biobanked urine samples were thawed and tested using FujiLAM and AlereLAM assays. We measured diagnostic performance against a microbiological reference standard (confirmed tuberculosis) and a composite reference standard (confirmed and unconfirmed tuberculosis). Sensitivity and specificity were estimated with bivariate random-effects meta-analyses. Between July 1, 2017, and Dec 1, 2018, we obtained and stored urine samples from 415 children. 63 (15%) children had confirmed tuberculosis, 113 (27%) had unconfirmed tuberculosis, and 239 (58%) were unlikely to have tuberculosis. 61 children were HIV-positive (prevalence 15%). Using the microbiological reference standard, the sensitivity of FujiLAM was 64·9% (95% CI 43·7-85·2; positive in 40 of 63 confirmed samples) and the sensitivity of AlereLAM was 30·7% (8·6-61·6; 19 of 63). The specificity of FujiLAM was 83·8% (95% CI 76·5-89·4; negative in 297 of 352 unconfirmed and unlikely samples) and the specificity of AlereLAM was 87·8% (79·0-93·7; 312 of 352). Against the composite reference standard, both assays had decreased sensitivity; the sensitivity of FujiLAM was 32·9% (95% CI 24·6-41·9; positive in 58 of 176 confirmed and unconfirmed samples) and the sensitivity of AlereLAM was 20·2% (12·3-29·4; 36 of 176). The specificity of FujiLAM was 83·3% (95% CI 71·8-91·7; negative in 202 of 239 unlikely samples) and the specificity of AlereLAM was 90·0% (81·6-95·6; 216 of 239). By comparison with AlereLAM, FujiLAM showed higher sensitivity and similar specificity. FujiLAM could potentially add value to the rapid diagnosis of tuberculosis in children. German Federal Ministry of Education and Research, the Global Health Innovative Technology Fund, the UK Research and Innovation Global Challenges Research Fund, and the UK Medical Research Council.

Accuracy of a Novel Urine Test, Fujifilm SILVAMP Tuberculosis Lipoarabinomannan, for the Diagnosis of Pulmonary Tuberculosis in Children.

An accurate point-of-care test for tuberculosis (TB) in children remains an elusive goal. Recent evaluation of a novel point-of-care urinary lipoarabinomannan test, Fujifilm SILVAMP Tuberculosis Lipoarabinomannan (FujiLAM), in adults living with human immunodeficiency virus (HIV) showed significantly superior sensitivity than the current Alere Determine Tuberculosis Lipoarabinomannan test (AlereLAM). We therefore compared the accuracy of FujiLAM and AlereLAM in children with suspected TB. Children hospitalized with suspected TB in Cape Town, South Africa, were enrolled (consecutive admissions plus enrichment for a group of children living with HIV and with TB), their urine was collected and biobanked, and their sputum was tested with mycobacterial culture and Xpert MTB/RIF or Xpert MTB/RIF Ultra. Biobanked urine was subsequently batch tested with FujiLAM and AlereLAM. Children were categorized as having microbiologically confirmed TB, unconfirmed TB (clinically diagnosed), or unlikely TB. A total of 204 children were enrolled and had valid results from both index tests, as well as sputum microbiological testing. Compared to a microbiological reference standard, the sensitivity of FujiLAM and AlereLAM was similar (42% and 50%, respectively), but lower than that of Xpert MTB/RIF of sputum (74%). The sensitivity of FujiLAM was higher in children living with HIV (60%) and malnourished children (62%). The specificity of FujiLAM was substantially higher than that of AlereLAM (92% vs 66%, respectively). The specificity of both tests was higher in children 2 years or older (FujiLAM, 96%; AlereLAM, 72%). The high specificity of FujiLAM suggests utility as a "rule-in" test for children with a high pretest probability of TB, including hospitalized children living with HIV or with malnutrition.

Use of Xpert Contributes to Accurate Diagnosis, Timely Initiation, and Rational Use of Anti-TB Treatment Among Childhood Tuberculosis Cases in South Central Ethiopia.

BackgroundChildhood tuberculosis (TB) was under-prioritized, and only 15% of childhood TB cases are microbiologically confirmed. Hence, most childhood TB diagnoses are made on a clinical basis and prone to over- or under-treatment. Xpert is a rapid method for the diagnosis of childhood TB with high sensitivity.ObjectiveTo assess the use of Xpert for accurate diagnosis, timely initiation, and rational use of anti-TB treatment among childhood TB.MethodsIn 2016, the hospital facilitated the installation of the Xpert machine. We reviewed data trends over four consecutive years; two years before the arrival of the machine and two years following the implementation of Xpert. Data were extracted retrospectively from electronically stored databases and medical records and entered to SPSS 21 for analysis.ResultsIn the pre-intervention period (2014–2015), 404 cases of children presenting with symptoms or signs suggestive of TB (“presumptive TB”) were evaluated using AFB microscopy. A total of 254 (62.8%) TB diagnoses were made, of which 54 (21.3%) were confirmed by smear AFB while 200 (78.7%) were treated as smear-negative TB cases. The mean waiting time to start anti-TB treatment was 6.95 days [95% CI (3.71–10.90)]. During the intervention period (2016–2017), 371 children with presumptive TB were evaluated using Xpert. A total of 199 (53.6%) childhood TB cases were notified, of which 88 (44.2%) were Xpert positive and 111 (55.8%) were treated as Xpert-negative probable TB cases. The tendency to initiate anti-TB treatment for unconfirmed TB cases was reduced by a third. Compared with smear AFB, Xpert improved accuracy of diagnosing pediatric TB cases two-fold. The average waiting time to start anti-TB treatment was 1.33 days [95% CI (0.95–1.71)]. There was a significant reduction in the waiting time to start anti-TB treatment, with a mean time difference before and during intervention of 5.62 days [95% CI (1.68–9.56)].ConclusionXpert use was associated with a significant increase in the accuracy of identifying confirmed TB cases, reduced unnecessary anti-TB prescription, and shortened the time taken to start TB treatment.

Diagnostic accuracy of molecular detection of Mycobacterium tuberculosis in pediatric stool samples: A systematic review and meta-analysis

BackgroundStool is a promising specimen option to diagnose pediatric tuberculosis (TB), but studies have reported a wide range of test sensitivities. We conducted a meta-analysis to assess the accuracy of Xpert MTB/RIF or ‘in-house’ molecular tests on stool samples against culture or Xpert MTB/RIF on respiratory samples or clinically-diagnosed unconfirmed TB and aimed to identify factors that contribute to the heterogeneity of reported sensitivity. MethodsWe searched EMBASE and Pubmed databases and conference abstract books for studies reporting molecular stool testing against a clinical or microbiological reference standard among children. ResultsWe identified 16 studies that included 2,481 children in stool test analyses. Pooled specificity was 98% [95%CI: 96–99], pooled sensitivity was 57% [95%CI: 40–72] against culture and 3% [95%CI: 2–6] among children with clinically-diagnosed, unconfirmed TB. There was much heterogeneity. Sensitivity was higher among children with a smear-positive sputum test. Rifampin resistance in stool was reported in two studies and detected in 5/14 children (36%). ConclusionOur results suggest molecular stool tests have potential as diagnostic rule-in tests, but it is challenging to optimize sensitivity due to between-study variation in methodology and test procedures. Therefore, we recommend future research with rigorous study design and standardized results reporting.

The use of real-time polymerase chain reaction and an adenosine deaminase assay for diagnosing pleural tuberculosis.

BackgroundThe diagnosis of pleural tuberculosis remains a challenge, because the most widely used conventional diagnostic tools are unable to rapidly detect Mycobacterium tuberculosis in pleural fluid with sufficient sensitivity.ObjectivesThe aim of this study was to evaluate the usefulness of an adenosine deaminase assay and real-time polymerase chain reaction (qPCR) in diagnosing pleural tuberculosis.MethodsOne hundred and five consecutive pleural fluid specimens collected between August 2008 and March 2009 were assessed. Among the 105 specimens, 50 (48%) were unconfirmed tuberculosis cases, 21 (20%) were confirmed tuberculosis cases and 34 (32%) were non-tuberculosis cases (controls). Real-time PCR was performed using the Light Cycler Mycobacterium detection kit according to the manufacturer‘s instructions (Roche Diagnostics). An adenosine deaminase assay was carried out using a commercial colorimetric assay kit as a user-defined method on a Beckman DxC 600 Synchron analyser.ResultsThe sensitivity of the qPCR was 67% and specificity was 100%. The sensitivity of the adenosine deaminase assay was 80% and specificity was 94%.ConclusionThe findings show that the adenosine deaminase assay had higher sensitivity than qPCR. Real-time PCR had 100% specificity, thus a combination of the two methods may be useful for the diagnosis of pleural tuberculosis.

Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial

Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial

Microbiological diagnosis of pulmonary tuberculosis in children by oral swab polymerase chain reaction

Microbiological diagnosis of pediatric pulmonary tuberculosis (TB) is challenging due to the difficulty of collecting and testing sputum from children. We investigated whether easily-obtained oral swab samples are useful alternatives or supplements to sputum. Oral swabs and induced sputum (IS) were collected from 201 South African children with suspected pulmonary TB. IS samples were tested by mycobacterial culture and Xpert MTB/RIF. Oral swabs were tested by PCR targeting IS6110. Children were categorized as Confirmed TB (microbiologic confirmation on IS), Unconfirmed TB (clinical diagnosis only), or Unlikely TB (recovery without TB treatment). Relative to Confirmed TB, PCR on two oral swabs per child was 43% sensitive and 93% specific. This sensitivity fell below that of sputum Xpert (64%). Among children with either Confirmed or Unconfirmed TB, PCR on two oral swabs per child was 31% sensitive and 93% specific, which was more sensitive than sputum testing among this group (21%). Although oral swab analysis had low sensitivity in sputum-positive children, it detected TB in a significant proportion of sputum-negative children who were clinically diagnosed with TB. Specificity at 93% was suboptimal but may improve with the use of automated methods. With further development, oral swabs may become useful supplements to sputum as samples for diagnosis of pulmonary TB in children.

Detection of Mycobacterium tuberculosis in pediatric stool samples using TruTip technology

BackgroundRapid and accurate diagnosis of childhood tuberculosis (TB) is challenging because children are often unable to produce the sputum sample required for conventional tests. Stool is an alternative sample type that is easy to collect from children, and studies investigating the use of stool for molecular detection of Mycobacterium tuberculosis (Mtb) have led to promising results. Our objective was to evaluate stool as an alternative specimen to sputum for Mtb detection in children. We did so using the TruTip workstation (Akonni Biosystems), a novel automated lysis and extraction platform.MethodsWe tested stool samples from 259 children aged 0–14 years old, in Lima, Peru who presented with TB symptoms. Following extraction with TruTip, we detected the presence of Mtb DNA by IS6110 real-time PCR. We calculated assay sensitivity in two groups: (1) children with culture confirmed TB (N = 22); and (2) children with clinically-diagnosed unconfirmed TB (N = 84). We calculated specificity among children in whom TB was ruled out (N = 153). Among children who were diagnosed with TB, we examined factors associated with a positive stool test.ResultsAssay sensitivity was 59% (95% confidence interval [CI]: 39–80%) and 1.2% (95% CI: 0.0–6.5%) in children with culture-confirmed and clinically-diagnosed unconfirmed TB, respectively, and specificity was 97% (95% CI: 93–99%). The assay detected Mtb in stool of 7/7 children with smear-positive TB (100% sensitivity; 95% CI: 59–100%), and in 6/15 of children with smear-negative, culture-confirmed TB (40% sensitivity; 95% CI: 16–68%). Older age, smear positivity, culture positivity, ability to produce sputum and cavitary disease were associated with a positive stool result.ConclusionTesting of stool samples with the TruTip workstation and IS6110 amplification yielded sensitivity and specificity estimates comparable to other tests such as Xpert. Future work should include detection of resistance using the TruTip closed amplification system and assay optimization to improve sensitivity in children with low bacillary loads.

Monocyte-to-Lymphocyte Ratio Is Associated With Tuberculosis Disease and Declines With Anti-TB Treatment in HIV-Infected Children.

The blood monocyte-to-lymphocyte ratio (MLR) is associated with active tuberculosis (TB) in adults but has not been evaluated as a TB diagnostic biomarker in HIV-infected children in whom respiratory sampling is difficult. In a cohort of HIV-infected hospitalized Kenyan children initiating antiretroviral therapy, absolute monocyte and lymphocyte counts were determined at enrollment and 4, 12, and 24 weeks thereafter. Children were classified as confirmed, unconfirmed, or unlikely pulmonary TB. Receiver operating characteristic curves of MLR cutoff values were generated to distinguish children with confirmed TB from those with unconfirmed and unlikely TB. General estimating equations were used to estimate change in the MLR over time by TB status. Of 160 children with median age 23 months, 13 (8.1%) had confirmed TB and 67 (41.9%) had unconfirmed TB. The median MLR among children with confirmed TB {0.407 [interquartile range (IQR) 0.378-0.675]} was higher than the MLR in children with unconfirmed [0.207 (IQR 0.148-0.348), P < 0.01] or unlikely [0.212 (IQR 0.138-0.391), P = 0.01] TB. The MLR above 0.378 identified children with confirmed TB with 77% sensitivity, 78% specificity, 24% positive predictive value, and 97% negative predictive value. After TB treatment, the median MLR declined in children with confirmed TB and levels were similar to children with unlikely TB after 12 weeks. The blood MLR distinguished HIV-infected children with confirmed TB from those with unlikely TB and declined with TB treatment. The MLR may be a useful diagnostic tool for TB in settings where respiratory-based microbiologic confirmation is inaccessible.

Diagnostic strategies for childhood tuberculosis in the context of primary care in a high burden setting: the value of alternative sampling methods

ABSTRACTBackground: Hospital studies have demonstrated the usefulness of alternative sampling strategies to expectorated sputum and new diagnostics for the diagnosis of childhood tuberculosis (TB) but there is limited evidence of how these approaches work in the primary-care setting.Aim: To assess the feasibility and yield of a variety of sample types and diagnostic tests for childhood TB at a primary-care clinic.Methods: A prospective cohort of children (<10 years) with signs and symptoms of TB was enrolled at a primary-care clinic in Johannesburg, South Africa. Tuberculin skin testing (TST) and chest X-ray (CXR) were performed in all. In those unable to expectorate, one induced sputum (IS), one ambulatory gastric aspirate (GA) and two nasopharyngeal aspirates (NPA) were collected. Stool was collected from all. Samples were processed for smear microscopy, liquid culture and Xpert MTB/RIF. The Determine TB LAM Ag (LAM) test was used for HIV-positive children.Results: From July 2013-December 2014, 119 children were enrolled, 21 (18%) of whom were HIV-positive. TST was positive in 25/105 (24%) and 70/116 (70%) had a positive CXR. Four (3%) had confirmed TB, 101 (85%) unconfirmed TB and 15 (13%) unlikely TB. Of the 469 samples collected, smear microscopy was positive in none, Xpert was positive in four (<1%) and culture was positive in two (<1%). Three of 11 (27%) HIV-positive patients were positive by LAM. Treatment was commenced in 48/119 (40%).Conclusions: At primary-care, alternative sampling strategies proved feasible but resulted in a low diagnostic yield. Extensive efforts to bacteriologically diagnose children did not contribute to clinical management.

Spectrum of Pediatric Tuberculosis in a Tertiary Care Setting in South India.

Pediatric tuberculosis (TB) is often underdiagnosed with poor estimate of its true burden. Availability of Xpert MTB/RIF assay enhances diagnostic capacity of pediatric TB. A 3-year retrospective review of hospital records was done for all children diagnosed with confirmed and unconfirmed TB. Comparison was made between intrathoracic, single-site extrathoracic and disseminated TB. In total, 274 children had TB with 130 (47.4%) having confirmed TB. Pulmonary (23.4%), lymph node (23%) and central nervous system (12.8%) TB were the three commonest forms. HIV TB coinfection was 2.9%. Mycobacterial culture was positive in 90 (32.8%) and XPert MTB/RIF in 85 patients (31%). Mycobacterial confirmation was obtained in 45 (56.3%) intrathoracic TB, 69 (45.4%) extrathoracic TB and 16 (38.1%) disseminated TB. Correlation between positive Xpert and mycobacterial culture was poor (kappa 0.38). Rifampicin resistance was present in 25 (19.2%) of the 130 microbiologically confirmed TB. Extrathoracic TB is common in children. Mycobacterial confirmation in pediatric TB is improved with use of Xpert.

Serologic Responses in Childhood Pulmonary Tuberculosis.

Identification of the Mycobacterium tuberculosis immunoproteome and antigens associated with serologic responses in adults has renewed interest in developing a serologic test for childhood tuberculosis (TB). We investigated IgG antibody responses against M. tuberculosis antigens in children with well-characterized TB. We studied archived sera obtained from hospitalized children with suspected pulmonary TB, and classified as having confirmed TB (culture-confirmed), unlikely TB (clinical improvement without TB treatment), or unconfirmed TB (all others). A multiplexed bead-based assay for IgG antibodies against 119 M. tuberculosis antigens was developed, validated and used to test sera. The area under the curves (AUCs) of the empiric receiver-operator characteristic curves were generated as measures of predictive ability. A cross-validated generalized linear model was used to select the most predictive combinations of antigens. For the confirmed TB versus unlikely TB comparison, the maximal single antigen AUC was 0.63, corresponding to sensitivity 0.60 and specificity 0.60. Older (age: 60+ months old) children's responses were better predictive of TB status than younger (age: 12-59 months old) children's, with a maximal single antigen AUC of -0.76. For the confirmed TB versus unlikely TB groups, the most predictive combinations of antigens assigned TB risk probabilities of 0.33 and 0.33, respectively, when all ages were considered, and 0.57 (interquartile range: 0.48-0.64) and 0.35 (interquartile range: 0.32-0.40) when only older children were considered. An antigen-based IgG test is unlikely to meet the performance characteristics required of a TB detection test applicable to all age groups.

Mortality and its determinants in antiretroviral treatment-naive HIV-infected children with suspected tuberculosis: an observational cohort study

Tuberculosis is a major cause of morbidity and mortality in HIV-infected children, but is difficult to diagnose. We studied mortality and its determinants in antiretroviral treatment (ART)-naive HIV-infected children presenting with suspected tuberculosis. In this observational cohort study, HIV-infected children aged 13 years or younger with suspected tuberculosis were followed up for 6 months as part of the ANRS 12229 PAANTHER 01 cohort in eight hospitals in four countries (Burkina Faso, Cambodia, Cameroon, and Vietnam). Children started ART and antituberculosis treatment at the clinician's discretion and were retrospectively classified into one of three groups by tuberculosis documentation: confirmed by culture or Xpert MTB/RIF, unconfirmed, and unlikely. We assessed mortality and associated factors using Kaplan-Meier methods and Cox proportional hazard models. The ANRS 12229 PAANTHER 01 study is registered at ClinicalTrials.gov, number NCT01331811. 266 (61%) of 438 children enrolled in the study between April 27, 2011, and May 31, 2014, were ART-naive and included in the analysis (40 had confirmed tuberculosis, 119 unconfirmed tuberculosis, and 107 unlikely tuberculosis). 112·5 person-years of follow-up were available. 154 children (58%) started antituberculosis treatment and 212 (80%) started ART. 50 children (19%) died. Mortality by 6 months was higher in children with confirmed tuberculosis (14 deaths; 2 month survival probability 65·0% [95% CI 50·2-79·8]) compared with unconfirmed tuberculosis (19 deaths; 83·5% [76·8-90·3]) and unlikely tuberculosis (17 deaths; 83·5% [76·3-90·7]; log-rank p=0·0141) and was lower in children with confirmed or unconfirmed tuberculosis who started antituberculosis treatment (p<0·0001 for both). In a multivariate analysis, ART started during the first month of follow-up (hazard ratio 0·08; 95% CI 0·01-0·67), confirmed tuberculosis (6·33; 2·15-18·64), young age (5·90; 2·02-17·19), CD4 less than 10% (2·63; 1·25-5·53), miliary features (4·08; 1·56-10·66), and elevated serum transaminases (4·40; 1·82-10·65) were all independently associated with mortality. In our cohort, mortality was high in the first 6 months after suspicion of tuberculosis in ART-naive children. ART should be started early, particularly in children with factors associated with high mortality. Documented or empirical tuberculosis treatment decision should be accelerated to reduce mortality and allow early ART initiation. ANRS and Fondation Total.

Assessment of sputum smear-positive but culture-negative results among newly diagnosed pulmonary tuberculosis patients in Tanzania.

Diagnosis of pulmonary tuberculosis (TB) in technology-limited countries is widely achieved by smear microscopy, which has limited sensitivity and specificity. The frequency and clinical implication of smear-positive but culture-negative among presumptive TB patients remains unclear. A cross-sectional substudy was conducted which aimed to identify the proportion of nontuberculous mycobacteria (NTM) infections among 94 “smear-positive culture-negative” patients diagnosed between January 2013 and June 2016 in selected health facilities in Tanzania. Out of 94 sputa, 25 (26.60%) were GeneXpert® mycobacteria TB positive and 11/94 (11.70%) repeat-culture positive; 5 were Capilia TB-Neo positive and confirmed by GenoType MTBC to be Mycobacterium tuberculosis/Mycobacterium canettii. The remaining 6 Capilia TB-Neo negative samples were genotyped by GenoType® CM/AS, identifying 3 (3.19%) NTM, 2 Gram positive bacteria, and 1 isolate testing negative, together, making a total of 6/94 (6.38%) confirmed false smear-positives. Twenty-eight (29.79%) were confirmed TB cases, while 60 (63.83%) remained unconfirmed cases. Out of 6 (6.38%) patients who were HIV positive, 2 patients were possibly coinfected with mycobacteria. The isolation of NTM and other bacteria among smear-positive culture-negative samples and the presence of over two third of unconfirmed TB cases emphasize the need of both advanced differential TB diagnostic techniques and good clinical laboratory practices to avoid unnecessary administration of anti-TB drugs.

Role of laparoscopy in the diagnosis and management of abdominal tuberculosis

Background: Each year tuberculosis (TB) results in the death of 1.5 million people globally .The complexity of TB is clearly evident by noting that this disease primarily involved the lung now involves all organs and systems. Abdominal TB is one such complex presentation. The use of laparoscopy in the diagnostic work-up of suspected abdominal tuberculosis is underutilized in developing countries. Methods: The study of Role of laparoscopy in the diagnosis and management of abdominal tuberculosis was conducted in patients with clinically suspected abdominal tuberculosis but histologically or microbiologically unconfirmed tuberculosis at any other site. Patients satisfying inclusion criteria are subjected to diagnostic laparoscopy, biopsy of specimen from peritoneum , omentum, tissues, mesenteric lymph nodes for histopathological examination, AFB staining and cartridge based nucleic acid amplification test (CBNAAT) of peritoneal aspirates for confirmation of abdominal tuberculosis. Results: Total 38 cases were included in this study with a clinical and radiological diagnosis of suspected abdominal tuberculosis. All patients underwent diagnostic laparoscopy. Conclusions: Diagnostic laparoscopy avoids the morbidity and mortality of laparotomy in chronically ill patients, reduces the rate of misdiagnosis of other abdominal conditions and unnecessary long-term therapy. Diagnostic laparoscopy and tissue sampling is a viable and reliable strategy in patients with suspected abdominal tuberculosis.

A prospective audit of the use of diagnostic laparoscopy to establish the diagnosis of abdominal tuberculosis

The incidence of abdominal tuberculosis is much higher in an HIV-positive cohort. The use of laparoscopy in the diagnostic work-up of suspected abdominal tuberculosis is underutilized and its use and efficacy in the context of HIV co-infection has never been examined. A prospective clinical audit of the use of diagnostic laparoscopy was conducted in patients with clinically suspected abdominal tuberculosis but histologically or microbiologically unconfirmed tuberculosis at any site. From January 2008 to June 2010, 81 patients underwent diagnostic laparoscopy; 34 were male and 47 were female, with a mean age of 33years, and 77% were HIV-positive. Fifty-five patients (68%) had positive histology or culture for tuberculosis. In 15 patients (19%), histology revealed non-specific inflammation, no pathology was found in one patient, and no specimen was taken from one patient. Eighty percent of peritoneal deposits and 77% of lymph nodes were positive for tuberculosis, whereas 35% of ascitic fluid cultures were positive. In nine patients (11%) an alternative diagnosis was found; nine patients (11%) had conversion to laparotomy. There was no procedure-related death. Nine patients (11%) died during the 2-month follow-up period. Diagnostic laparoscopy avoids the morbidity and mortality of laparotomy in chronically ill patients, and reduces the rate of misdiagnosis of other abdominal conditions and unnecessary long-term therapy. Diagnostic laparoscopy and tissue sampling is a viable and reliable strategy in patients with suspected abdominal tuberculosis.