Mycobacterium Tuberculosis Infection In Children Research Articles

Identification of cuproptosis-related molecular subtypes as a biomarker for differentiating active from latent tuberculosis in children

BackgroundCell death plays a crucial role in the progression of active tuberculosis (ATB) from latent infection (LTBI). Cuproptosis, a novel programmed cell death, has been reported to be associated with the pathology of various diseases. We aimed to identify cuproptosis-related molecular subtypes as biomarkers for distinguishing ATB from LTBI in pediatric patients.MethodThe expression profiles of cuproptosis regulators and immune characteristics in pediatric patients with ATB and LTBI were analyzed based on GSE39939 downloaded from the Gene Expression Omnibus. From the 52 ATB samples, we investigated the molecular subtypes based on differentially expressed cuproptosis-related genes (DE-CRGs) via consensus clustering and related immune cell infiltration. Subtype-specific differentially expressed genes (DEGs) were found using the weighted gene co-expression network analysis. The optimum machine model was then determined by comparing the performance of the eXtreme Gradient Boost (XGB), the random forest model (RF), the general linear model (GLM), and the support vector machine model (SVM). Nomogram and test datasets (GSE39940) were used to verify the prediction accuracy.ResultsNine DE-CRGs (NFE2L2, NLRP3, FDX1, LIPT1, PDHB, MTF1, GLS, DBT, and DLST) associated with active immune responses were ascertained between ATB and LTBI patients. Two cuproptosis-related molecular subtypes were defined in ATB pediatrics. Single sample gene set enrichment analysis suggested that compared with Subtype 2, Subtype 1 was characterized by decreased lymphocytes and increased inflammatory activation. Gene set variation analysis showed that cluster-specific DEGs in Subtype 1 were closely associated with immune and inflammation responses and energy and amino acids metabolism. The SVM model exhibited the best discriminative performance with a higher area under the curve (AUC = 0.983) and relatively lower root mean square and residual error. A final 5-gene-based (MAN1C1, DKFZP434N035, SIRT4, BPGM, and APBA2) SVM model was created, demonstrating satisfactory performance in the test datasets (AUC = 0.905). The decision curve analysis and nomogram calibration curve also revealed the accuracy of differentiating ATB from LTBI in children.ConclusionOur study suggested that cuproptosis might be associated with the immunopathology of Mycobacterium tuberculosis infection in children. Additionally, we built a satisfactory prediction model to assess the cuproptosis subtype risk in ATB, which can be used as a reliable biomarker for the distinguishment between pediatric ATB and LTBI.

Aberrant expression of long non-coding RNAs in peripheral blood mononuclear cells response to tuberculosis in children.

We aimed to identify long non-coding RNAs (lncRNAs) aberrantly expressed in peripheral blood mononuclear cells (PBMCs) triggered by active tuberculosis (ATB), latent tuberculosis infection (LTBI), and healthy controls (HC). We examined lncRNAs expression in PBMCs isolated from children with ATB and LTBI, and from HC using RNA sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were used to explore the biological processes and signaling pathways of aberrantly expressed mRNAs. A total of 348 and 205 lncRNAs were differentially expressed in the ATB and LTBI groups, respectively, compared to the HC group. Compared to the LTBI group, 125 lncRNAs were differentially expressed in the ATB group. Compared to the HC group, 2317 mRNAs were differentially expressed in the ATB group, and 1093 mRNAs were differentially expressed in the LTBI group. Compared to the LTBI group, 2328 mRNAs were differentially expressed in the ATB group. The upregulated mRNAs were mainly enriched in neutrophil activation, neutrophil-mediated biological processes, and positive regulation of immune response in tuberculosis (TB), whereas the downregulated mRNAs were enriched in signaling pathways and structural processes, such as the Wnt signaling pathway and rDNA heterochromatin assembly. This is the first study on the differential expression of lncRNAs in PBMCs of children with TB. We identified significant differences in the expression profiles of lncRNAs and mRNAs in the PBMCs of children with ATB, LTBI, and HC, which has important implications for exploring lncRNAs as novel biomarkers for the diagnosis of TB. In addition, further experimental identification and validation of lncRNA roles could help elucidate the underlying mechanisms of Mycobacterium tuberculosis infection in children.

Cytokine Biosignature of Active and Latent Mycobacterium Tuberculosis Infection in Children.

None of the currently used diagnostic tools are efficient enough in diagnosing Mycobacterium tuberculosis (M.tb) infection in children. The study was aimed to identify cytokine biosignatures characterizing active and latent tuberculosis (TB) in children. Using a multiplex bead-based technology, we analyzed the levels of 53 Th17-related cytokines and inflammatory mediators in sera from 216 BCG-vaccinated children diagnosed with active TB (TB) or latent TB (LTBI) as well as uninfected controls (HC). Children with active TB, compared to HC children, showed reduced serum levels of IL-17A, MMP-2, OPN, PTX-3, and markedly elevated concentrations of APRIL/TNFSF13. IL-21, sCD40L, MMP-2, and IL-8 were significantly differentially expressed in the comparisons between groups: (1) HC versus TB and LTBI (jointly), and (2) TB versus LTBI. The panel consisting of APRIL/TNFSF13, sCD30/TNFRSF8, IFN-α2, IFN-γ, IL-2, sIL-6Rα, IL-8, IL-11, IL-29/IFN-λ1, LIGHT/TNFSF14, MMP-1, MMP-2, MMP-3, osteocalcin, osteopontin, TSLP, and TWEAK/TNFSF12 possessed a discriminatory potential for the differentiation between TB and LTBI children. Serum-based host biosignatures carry the potential to aid the diagnosis of childhood M.tb infections. The proposed panels of markers allow distinguishing not only children infected with M.tb from uninfected individuals but also children with active TB from those with latent TB.

Clinical features of children with immunodeficiency and Mycobacterium tuberculosis infection

OBJECTIVE To study the clinical features of Mycobacterium tuberculosis infection in children with secondary immunodeficiency disease (SID) versus primary immunodeficiency disease (PID). METHODS A retrospective analysis was performed on the medical data of children with immunodeficiency and Mycobacterium tuberculosis infection (36 children with SID and 52 with PID) and 108 children with Mycobacterium tuberculosis infection but without immunodeficiency (control group). RESULTS The onset age in the PID group was significantly lower than those in the control and SID groups (P < 0.05), and the proportation of males in the PID group was significantly higher than those in the control and SID groups (P < 0.05). Compared with the control group, the SID and PID groups had significantly lower incidence rates of tuberculosis poisoning symptoms (night sweeting, weight loss, fatigue and loss of appetite) and positive rate of PPD test (P < 0.05), as well as a significantly higher incidence rate of the involvement of ≥ 3 pulmonary lobes (P < 0.05). The children with PID tended to have the involvement of multiple organs (P < 0.05). The SID group had a significantly higher incidence rate of miliary shadow on chest CT than the control and PID groups (P < 0.05). The PID group had a significantly lower positive rate of IFN-gamma release assay (IGRA) than the control and SID groups (P < 0.05). Mycobacterium tuberculosis infection manifested as latent tuberculosis infection (36.1%) and active tuberculosis (63.9%) in the SID group. The infection mainly manifested as bacille Calmette-Guerin disease in the PID group (90.4%), among whom 2 children (3.8%) also had tuberculosis. CONCLUSIONS Children with immunodeficiency and Mycobacterium tuberculosis infection have atypical clinical symptoms, with a high incidence rate of disseminated infection and low positive rates of PPD and IGRA tests, which may lead to misdiagnosis and missed diagnosis. Children with immunodeficiency should undergo regular tuberculosis screening for early identification and intervention.

Accuracy of QuantiFERON-TB Gold Plus Test for Diagnosis of Mycobacterium tuberculosis Infection in Children.

Compared to its predecessor QuantiFERON-TB Gold In Tube (QFT-IT), QuantiFERON-TB Gold Plus (QFT-Plus) contains an additional antigen tube (TB2), stimulating both CD4+ and CD8+ T cells. The ability to discriminate CD4+ and CD8+ responses is suggested to be useful in differentiating stages of Mycobacterium tuberculosis infection. While QFT-Plus has already been evaluated in adults, there are not enough data in children evaluated for suspected active tuberculosis (TB) or latent TB infection (LTBI). A prospective cross-sectional study was conducted among children aged 0 to 17 years who were evaluated for suspected active TB or screened for LTBI. All children underwent QFT-Plus and further clinical, radiological, and/or microbiological analyses according to clinical scenario. Of the 198 children enrolled, 43 (21.7%) were tested because of suspicion of active TB. A total of 12/43 (27.9%) were diagnosed with active TB, and among these, 10/12 (83.3%) had a positive QFT-Plus assay. Of the 155 children screened for LTBI, 18 (11.6%) had a positive QFT-Plus, and 5 (2.5%) had an indeterminate result. TB1 and TB2 quantitative responses were not able to discriminate active disease from latent infection. The percent agreement between TB1 and TB2 was 100%. QFT-Plus assay showed good sensitivity for active TB and was particularly useful for the evaluation of children with suspected LTBI, giving a low rate of indeterminate results in this group. More studies are needed to properly evaluate QFT-Plus ability in discriminating active disease from latent infection.

Quality assessment of guidelines for the management of Mycobacterium tuberculosis infection in children.

OBJECTIVE: The quality of paediatric clinical practice guidelines (CPGs) for the management of Mycobacterium tuberculosis infection is unclear. We aimed to comprehensively assess the quality of these CPGs and identify areas requiring improvement.DESIGN: CPGs were systematically searched and identified before being appraised by independent reviewers using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) and Reporting Items for Practice Guidelines in HealThcare (RIGHT) tools. Inter-rater reliability was assessed using intra-class correlation coefficient (ICC).RESULTS: Twenty-five CPGs were evaluated. All CPG agreements among four reviewers were good (ICC 0.753-0.939). The mean CPG score was 50.5% (23.5-78.4%), and seven CPGs were recommended for use. The mean scores of three domains were low: 38% for stakeholder involvement (5.6-93.1%), 38.4% for rigour of development (1-97.4%) and 36.3% for applicability (12.5-64.6%). The mean reporting rate of Reporting Items for Practice Guidelines in HealThcare fields was 41.8%, and the evidence field had the highest reporting rate (63.1%), while the review and quality assurance field had the lowest rate (15.4%) for CPGs that include methods.CONCLUSION: The methodological and reporting quality of the CPGs was variable and poor, respectively. More effort is needed in stakeholder involvement, rigour of development, applicability domains and reporting to produce higher-quality CPGs.

Antibody-Secreting Cells To Diagnose Mycobacterium tuberculosis Infection in Children in Pakistan

Reliance on microbiologic methods to diagnose Mycobacterium tuberculosis infection is a suboptimal approach for children due in part to the paucibacillary nature of the disease. A blood-based biomarker assay, such as the mycobacterial-antibody-secreting cell (MASC) assay, could be a major advance for the field of study of pediatric tuberculosis (TB). Children <15 years of age with clinical concern for TB and age-matched children with no concern for TB were enrolled from outpatient clinics in Karachi, Pakistan. MASC, ferritin, and C-reactive protein (CRP) assays were performed, and results were compared among cases and controls, as well as among children with a case definition of "confirmed TB," "probable TB," or "possible TB." MASC responses were significantly higher among children with TB than among controls (0.41 optical density [OD] versus 0.28 OD, respectively, P < 0.001), and the differences were largely driven by the data from children with confirmed TB (P = 0.002). Ferritin and CRP values were significantly higher among those with confirmed TB than among those with the other disease states and controls (P = 0.004 and P = 0.019, respectively). The use of the MASC assay as a blood-based biomarker for TB disease shows some promise among children with microbiologically confirmed disease; however, the performance characteristics for the majority of young children with unconfirmed TB were suboptimal in this cohort.IMPORTANCE Tuberculosis (TB) in children represents a missed opportunity for diagnosis and preventive therapy. The magnitude or burden of disease in children is not fully understood due to our limitations with respect to exploring sensitive diagnostic algorithms. In a setting of TB endemicity in Pakistan, we carried out a proof-of-concept study to evaluate for the first time the performance of B cell analyses by the use of well-defined diagnostic criteria and NIH consensus guidelines as "culture-confirmed," "probable," and "possible" TB groups. In contrast to detection of serum antibody, we focused on mycobacterial-antibody-secreting cell (MASC) detection as a marker of active disease in children with a strong suspicion of TB. Further work exploring a larger panel of inflammatory biomarkers and enrichment of B cells with the objective of increasing the sensitivity of the current MASC assay would lead to the development of a field-friendly assay for timely diagnosis of childhood TB.

Prevalence of Tuberculosis in Children After Natural Disasters, Bohol, Philippines.

In 2013, a severe earthquake and typhoon affected Bohol, Philippines. To assess the postdisaster risk for emergence of Mycobacterium tuberculosis infection in children, we conducted a cross-sectional multistage cluster study to estimate the prevalence of tuberculin skin test (TST) positivity and tuberculosis (TB) in children from 200 villages in heavily affected and less affected disaster areas. Of the 5,476 children we enrolled, 355 were TST-positive (weighted prevalence 6.4%); 16 children had active TB. Fourteen (7%) villages had >20% TST-positive prevalence. Although prevalence did not differ significantly between heavily affected and less affected areas, living in a shelter with >25 persons approached significance. TST positivity was independently associated with older age, prior TB treatment, known contact with a person with TB, and living on a geographically isolated island. We found a high TST-positive prevalence, suggesting that national programs should consider the differential vulnerability of children and the role of geographically isolated communities in TB emergence.

Effectiveness of BCG Vaccination Against Mycobacterium tuberculosis Infection in Adults: A Cross-sectional Analysis of a UK-Based Cohort

BCG appears to reduce acquisition of Mycobacterium tuberculosis infection in children, measured using interferon-gamma release assays (IGRAs). We explored whether BCG vaccination continues to be associated with decreased prevalence of M. tuberculosis infection in adults. We conducted a cross-sectional analysis of data from adult contacts of tuberculosis cases participating in a UK cohort study. Vaccine effectiveness (VE) of BCG, ascertained based on presence of a scar or vaccination history, against latent tuberculosis infection (LTBI), measured via IGRA, was assessed using multivariable logistic regression. The effects of age at BCG and time since vaccination were also explored. Of 3453 recent tuberculosis contacts, 27.5% had LTBI. There was strong evidence of an association between BCG and LTBI (adjusted odds ratio = 0.70; 95% confidence interval, .56-.87; P = .0017) yielding a VE of 30%. VE declined with time since vaccination but there was evidence that LTBI prevalence was lower amongst vaccinated individuals even >20 years after vaccination, compared with nonvaccinated participants. BCG is associated with lower prevalence of LTBI in adult contacts of tuberculosis. These results contribute to growing evidence that suggests BCG may protect against M. tuberculosis infection as well as disease. This has implications for immunization programs, vaccine development, and tuberculosis control efforts worldwide. NCT01162265.

Characterization of plasma proteins in children of different Mycobacterium tuberculosis infection status using label-free quantitative proteomics.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is an infectious disease found worldwide. Children infected with MTB are more likely to progress to active TB (ATB); however, the molecular mechanism behind this process has long been a mystery. We employed the label-free quantitative proteomic technology to identify and characterize differences in plasma proteins between ATB and latent TB infection (LTBI) in children. To detect differences that are indicative of MTB infection, we first selected proteins whose expressions were markedly different between the ATB and LTBI groups and the control groups (inflammatory disease control (IDC) and healthy control (HC) groups). A total of 521 proteins differed (> 1.5-fold or < 0.6-fold) in the LTBI group, and 318 proteins in the ATB group when compared with the control groups. Of these, 49 overlapping proteins were differentially expressed between LTBI and ATB. Gene Ontology (GO) analysis revealed most proteins had a cellular and organelle distribution. The MTB infection status was mainly related to differences in binding, cellular and metabolic processes. XRCC4, PCF11, SEMA4A and ATP11A were selected and further verified by qPCR and western blot. At the mRNA level, the expression of XRCC4, PCF11and SEMA4A presented an increased trend in ATB group compare with LTBI. At the protein level, the expression of all these proteins by western blot in ATB/LTBI was consistent with the trends from proteomic detection. Our results provide important data for future mechanism studies and biomarker selection for MTB infection in children.

Use Of PCR Amplification For The Evaluation Of TB Diagnosis In Children By Classic Methods

There have been few studies evaluating the efficacy of polymerase chain reaction (PCR) testing in Front other routine test for diagnosis of TB in children. The tuberculin skin test (TST) used to detect Mycobacterium tuberculosis infection in children has many drawbacks, and a new diagnostic test for has been introduced. We assessed the diagnostic yield of PCR prospectively in a blinded study of patients referred to Al-Nassyria center for chest diseases and other private laboratories from January to June 2008 and compared the results to the routine TST, smears with Ziehl-Neelsen staining and culture on Lo¨wenstein-Jensen medium which used as the “gold standard.”. Sputum specimens were collected from 108 TB suspects patients and analyzed for the presence of Mycobacterium tuberculosis..TST yielded 23 (21.3%) were positive for TB with 65.7 % sensitivity and 87% specificity in comparing with 35(32.4%) by culture which improved the presence of 3cases as false-positive and 15 cases as false-negative by TST . All smear positive specimens appeared culture positive, but showed 54.3 %sensitivity and 100 % specificity. PCR amplification results appeared less than culture and more than each of smear and TST with %88.6 sensitivity and 100% specificity .All the thirty one PCR positive samples showed culture positive. It is concluded that although both culture and PCR amplification method are Sensitive and specific for the detection of M. tuberculosis in respiratory specimens of children . Rapid PCR method appeared to be more suitable than other tests especially the routine TST which applied.

Challenges in the Estimation of the Annual Risk of Mycobacterium tuberculosis Infection in Children Aged Less Than 5 Years.

Accurate estimates of Mycobacterium tuberculosis infection in young children provide a critical indicator of ongoing community transmission of M. tuberculosis. Cross-reactions due to infection with environmental mycobacteria and/or bacille Calmette-Guérin (BCG) vaccination compromise the estimates derived from population-level tuberculin skin-test surveys using traditional cutoff methods. Newer statistical approaches are prone to failure of model convergence, especially in settings where the prevalence of M. tuberculosis infection is low and environmental sensitization is high. We conducted a tuberculin skin-test survey in 5,119 preschool children in the general population and among household contacts of tuberculosis cases in 2012–2014 in a district in northern Malawi where sensitization to environmental mycobacteria is common and almost all children are BCG-vaccinated. We compared different proposed methods of estimating M. tuberculosis prevalence, including a method described by Rust and Thomas more than 40 years ago. With the different methods, estimated prevalence in the general population was 0.7%–11.5% at ages <2 years and 0.8%–3.3% at ages 2–4 years. The Rust and Thomas method was the only method to give a lower estimate in the younger age group (0.7% vs 0.8%), suggesting that it was the only method that adjusted appropriately for the marked effect of BCG-attributable induration in the very young.

Risk factors for Mycobacterium tuberculosis infection in 2-4 year olds in a rural HIV-prevalent setting.

SUMMARYBACKGROUND: Mycobacterium tuberculosis infection in children acts as a sentinel for infectious tuberculosis.OBJECTIVE: To assess risk factors associated with tuberculous infection in pre-school children.METHOD: We conducted a population-wide tuberculin skin test (TST) survey from January to December 2012 in Malawi. All children aged 2–4 years residing in a demographic surveillance area were eligible. Detailed demographic data, including adult human immunodeficiency virus (HIV) status, and clinical and sociodemographic data on all diagnosed tuberculosis (TB) patients were available.RESULTS: The prevalence of M. tuberculosis infection was 1.1% using a TST induration cut-off of 15 mm (estimated annual risk of infection of 0.3%). The main identifiable risk factors were maternal HIV infection at birth (adjusted OR [aOR] 3.6, 95%CI 1.1–12.2), having three or more adult members in the household over a lifetime (aOR 2.4, 95%CI 1.2–4.8) and living in close proximity to a known case of infectious TB (aOR 1.6, 95%CI 1.1–2.4), modelled as a linear variable across categories (>200 m, 100–200 m, <100 m, within household). Less than 20% of the infected children lived within 200 m of a known diagnosed case.CONCLUSION: Household and community risk factors identified do not explain the majority of M. tuberculosis infections in children in our setting.

Enhanced and durable protective immune responses induced by a cocktail of recombinant BCG strains expressing antigens of multistage of Mycobacterium tuberculosis

Although Bacillus Calmette-Guérin (BCG) vaccine confers protection from Mycobacterium tuberculosis infection in children, its immune protection gradually wanes over time, and consequently leads to an inability to prevent the reactivation of latent infection of M. tuberculosis. Therefore, improving BCG for better control of tuberculosis (TB) is urgently needed. We thus hypothesized that recombinant BCG overexpressing immunodominant antigens expressed at different growth stages of M. tuberculosis could provide a more comprehensive protection against primary and latent M. tuberculosis infection. Here, a novel cocktail of recombinant BCG (rBCG) strains, namely ABX, was produced by combining rBCG::85A, rBCG::85B, and rBCG::X, which overexpressed respective multistage antigens Ag85A, Ag85B, and HspX of M. tuberculosis. Our results showed that ABX was able to induce a stronger immune protection than individual rBCGs or BCG against primary TB infection in C57BL/6 mice. Mechanistically, the immune protection was attributed to stronger antigen-specific CD4+ Th1 responses, higher numbers of IFN-γ+ CD4+ TEM and IL-2+ CD8+ TCM cells elicited by ABX. These findings thus provide a novel strategy for the improvement of BCG efficacy and potentially a promising prophylactic TB vaccine candidate, warranting further investigation.

Association between passive smoking and Mycobacterium tuberculosis infection in children with household TB contact

Background Tuberculosis (TB) and cigarette consumption are relatively high in Indonesia. Passive smoking may increase the risk of infection and disease in adults and children exposed to TB. An association between passive smoking and Mycobacterium tuberculosis infection in children has not been well documented. Objective To assess for an association between passive smoking and M. tuberculosis infection in children who had household contact with a TB patient. Methods This cross-sectional study was conducted in February and March 2011. Children aged 5 to 18 years who had household contact with a TB patient underwent tuberculin testing for M. tuberculosis infection. Subjects were divided into two groups: those exposed to passive smoke and those not exposed to passive smoke. Chi-square test was used to assess for an association between passive smoking and M. tuberculosis infection. Results There were 140 children enrolled in this study, with 70 exposed to passive smoke and 70 not exposed to passive smoke. Prevalence of M. tuberculosis infection was significantly higher in the passive smoking group than in those not exposed to passive smoke [81.4% and 52.9%, respectively, (P= 0.0001)]. In the passive smoking group there were significant associations between nutritional state, paternal and maternal education, and M. tuberculosis infection. But no associations were found between M. tuberculosis infection and familial income or BCG vaccination. Conclusion Among children who had household contact with a TB patient, they who exposed to passive smoke are more likely to have M. tuberculosis infection compared to they who not exposed to passive smoke.

Association between passive smoking and Mycobacterium tuberculosis infection in children with household TB contact

Association between passive smoking and Mycobacterium tuberculosis infection in children with household TB contact

Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis

Objectives To determine whether BCG vaccination protects against Mycobacterium tuberculosis infection as assessed by interferon γ release assays (IGRA) in children.Design Systematic review and meta-analysis. Searches of electronic databases 1950...

Long-Incubation-Time Gamma Interferon Release Assays in Response to Purified Protein Derivative, ESAT-6, and/or CFP-10 for the Diagnosis of Mycobacterium tuberculosis Infection in Children

The diagnosis of childhood active tuberculosis (aTB) and latent Mycobacterium tuberculosis (M. tuberculosis) infection (LTBI) remains a challenge, and the replacement of tuberculin skin tests (TST) with commercialized gamma interferon (IFN-γ) release assays (IGRA) is not currently recommended. Two hundred sixty-six children between 1 month and 15 years of age, 214 of whom were at risk of recent M. tuberculosis infection and 51 who were included as controls, were prospectively enrolled in our study. According to the results of a clinical evaluation, TST, chest X ray, and microbiological assessment, each children was classified as noninfected, having LTBI, or having aTB. Long-incubation-time purified protein derivative (PPD), ESAT-6, and CFP-10 IGRA were performed and evaluated for their accuracy in correctly classifying the children. Whereas both TST and PPD IGRA were suboptimal for detecting aTB, combining the CFP-10 IGRA with a TST or with a PPD IGRA allowed us to detect all the children with aTB with a specificity of 96% for children who were positive for the CFP-10 IGRA. Moreover, the combination of the CFP-10 IGRA and PPD IGRA detected 96% of children who were eventually classified as having LTBI, but a strong IFN-γ response to CFP-10 (defined as >500 pg/ml) was highly suggestive of aTB, at least among the children who were <3 years old. The use of long-incubation-time CFP-10 IGRA and PPD IGRA should help clinicians to quickly identify aTB or LTBI in young children.

Helminths and skewed cytokine profiles increase tuberculin skin test positivity in Warao Amerindians

The immune regulatory mechanisms involved in the acquisition of Mycobacterium tuberculosis infection in children are largely unknown. We investigated the influence of parasitic infections, malnutrition and plasma cytokine profiles on tuberculin skin test (TST) positivity in Warao Amerindians in Venezuela. Pediatric household contacts of sputum smear-positive tuberculosis (TB) cases were enrolled for TST, chest radiograph, plasma cytokine analyses, QuantiFERON-TB Gold In-Tube (QFT-GIT) testing and stool examinations. Factors associated with TST positivity were studied using generalized estimation equations logistic regression models. Of the 141 asymptomatic contacts, 39% was TST-positive. After adjusting for age, gender and nutritional status, TST positivity was associated with Trichuris trichiura infections (OR 3.5, 95% CI 1.1-11.6) and low circulating levels of T helper 1 (Th1) cytokines (OR 0.51, 95% CI 0.33-0.79). Ascaris lumbricoides infections in interaction with Th2- and interleukin (IL)-10-dominated cytokine profiles were positively associated with TST positivity (OR 3.1, 95% CI 1.1-8.9 and OR 2.4, 95% CI 1.04-5.7, respectively). A negative correlation of QFT-GIT mitogen responses with Th1 and Th2 levels and a positive correlation with age were observed (all p < 0.01). We conclude that helminth infections and low Th1 cytokine plasma levels are significantly associated with TST positivity in indigenous Venezuelan pediatric TB contacts.

Environmental tobacco smoke exposure increases Mycobacterium tuberculosis infection risk in children

Data on the association between exposure to environmental tobacco smoke (ETS) and Mycobacterium tuberculosis infection in children are limited. To examine the dose-response effect of ETS exposure on the risk of M. tuberculosis infection in children in a high tuberculosis (TB) burden setting. This cross-sectional study included healthy South African children from impoverished urban communities. Data were collected on household ETS and M. tuberculosis exposure, demographics, socio-economic and anthropometric data, M. tuberculosis infection, human immunodeficiency virus and TB disease status. Among 196 children (median age 6.8 years, range 0.3-15.9), 97 (49.5%) were M. tuberculosis - i nfected (tuberculin skin test [TST] ≥ 10 mm) and 128 (65.3%) reported ETS exposure; of these, 81/128 (63.3%) were exposed to ≥ 2 household smokers. The presence of ≥ 2 household smokers was associated with M. tuberculosis infection in univariate analysis, irrespective of TST cut-off point. In analysis adjusting for M. tuberculosis exposure, socio-economic status, age and previous TB treatment, ETS exposure remained associated with M. tuberculosis infection. In univariate and multivariate analysis, pack-years of exposure were associated with risk of TB infection. Exposure to ETS is associated with M. tuberculosis infection in children after adjustment for multiple variables, with a dose-response relationship between the degree of ETS exposure and risk of infection. Public health interventions to reduce exposure to tobacco smoke among children in high TB burden settings are urgently needed.