Tuberculosis Disease In Children Research Articles

Sex-specific blood-derived RNA biomarkers for childhood tuberculosis

Confirmatory diagnosis of childhood tuberculosis (TB) remains a challenge mainly due to its dependence on sputum samples and the paucibacillary nature of the disease. Thus, only ~ 30% of suspected cases in children are diagnosed and the need for minimally invasive, non-sputum-based biomarkers remains unmet. Understanding host molecular changes by measuring blood-based transcriptomic markers has shown promise as a diagnostic tool for TB. However, the implication of sex contributing to disease heterogeneity and therefore diagnosis remains to be understood. Using publicly available gene expression data (GSE39939, GSE39940; n = 370), we report a sex-specific RNA biomarker signature that could improve the diagnosis of TB disease in children. We found four gene biomarker signatures for male (SLAMF8, GBP2, WARS, and FCGR1C) and female pediatric patients (GBP6, CELSR3, ALDH1A1, and GBP4) from Kenya, South Africa, and Malawi. Both signatures achieved a sensitivity of 85% and a specificity of 70%, which approaches the WHO-recommended target product profile for a triage test. Our gene signatures outperform most other gene signatures reported previously for childhood TB diagnosis.

Parallel use of low-complexity automated nucleic acid amplification tests on respiratory samples and stool with or without lateral flow lipoarabinomannan assays to detect pulmonary tuberculosis disease in children

Parallel use of low-complexity automated nucleic acid amplification tests on respiratory samples and stool with or without lateral flow lipoarabinomannan assays to detect pulmonary tuberculosis disease in children

Analysis Of The Nutritional Status Of Pediatric Tuberculosis Patients After Treatment At The X General Hospital Center

Introduction: Indonesia is currently ranked 2nd in the country with the highest number of tuberculosis (TB) cases. TB disease in children cannot be separated from the role of nutritional status. Poor nutrition can cause immunological disorders and affect the disease healing process. Methodology: The research method used was cross-sectional which was carried out at Central General Hospital X in July 2019. A sample of 72 pediatric tuberculosis patients was taken using a simple random sampling technique. The data used is secondary data from medical records for the period January 2016-December 2018 to look at the characteristics of pediatric TB patients and analyze the evaluation of nutritional status after treatment. Data analysis used the non-parametric Wilcoxon test. Results: The highest age was in the 5-14 year category (51.4%). In the Wilcoxon test, a p-value of 0.000 (<0.05) was obtained, which stated that there was a significant difference between nutritional status before and after treatment. Conclusion: Compliance with pediatric TB patients in undergoing treatment will improve the patient’s nutritional status.

Pulmonary Tuberculosis and Rifampicin Resistant Mycobacterium Tuberculosis in Children and Adolescents using Gene Xpert MTB/RIF Assay in Tigray, Northern Ethiopia.

Tuberculosis (TB) continues to be a global health problem. While childhood TB contributes 10% to the global TB burden, the paucibacillary nature of TB disease in children and the absence of reliable diagnostic methods have made MTB diagnosis in children to be a great challenge. This study aimed to determine the prevalence of MTB and rifampicin-resistant MTB (RR-MTB) among children using Gene Xpert MTB/RIF Assay in Tigray, Ethiopia. A retrospective database study was conducted among children in ten governmental hospitals in the Tigray region. Gene Xpert MTB/RIF results of sputum/gastric lavage samples from children with presumptive TB from January 2016 to December 2019 were extracted using a data extraction sheet. Data were collected and analyzed using Statistical Package for the Social Sciences version 21. The prevalence of bacteriologically confirmed MTB by Gene-Xpert in children with presumptive TB was 7.3% (95% CI: 6.7%-7.9%) and the proportion of those that were Gene-Xpert MTB positive who also have rifampicin resistance was 10.9% (95% CI: 8.2-13.6%). Older children aged 11-15 years [AOR = 1.76; 95% CI = 1.33-2.33, p < 0.001] and adolescents 16-17 years [AOR = 2.18; 95% CI = 1.63-2.92, p < 0.001] were more likely to be MTB positive. Relapse cases [AOR = 1.66; 95% CI = 1.09-2.51, p = 0.017] and lost/failure cases [AOR = 8.82; 95% CI = 3.94-19.76, p < 0.001] were more likely to have MTB compared to the new cases. The proportion of MTB-positive among the TB presumptive patients was 7.3%. The proportion of rifampicin-resistant TB to all positive patients was 10.9%. Female participants had more MTB than males (or younger children). The result highlights the need for due attention in children because it is very helpful in determining the future control of the disease.

Tuberculosis contact-tracing results in childhood: a retrospective study in a tertiary-care children’s hospital in Turkey

ABSTRACT Background Smear-positive adults with tuberculosis are the main source of childhood tuberculosis. The evaluation of children exposed to tuberculosis and determination of the disease stages are the cornerstones of managing childhood tuberculosis. Aim To determine the frequency of tuberculous contact, latent tuberculosis infection and tuberculosis disease in children who were in contact with smear-positive adults. Methods This is a single-centre, retrospective study. The medical records of children exposed to tuberculosis (<18 years old) between 2014 and 2018 were investigated. After diagnosing the index cases, the children were referred to the hospital. To identify the children in contact with adults with tuberculosis, a careful medical history, demographic features and physical examination, tuberculin skin test, postero-anterior and lateral chest radiographs, and, if necessary, chest computed tomography and microbiological tests were undertaken. The children’s final diagnosis, treatment regimens and follow-up were documented. The sensitivity, specificity and positive and negative predictive values, tuberculin skin test and chest radiograph imaging were assessed and compared with computed tomography results. Results A total of 150 paediatric patients were exposed to 88 index cases. These were fathers in 29.3% of cases and mothers in 10% of cases. Of the children, 131 (87.3%) were asymptomatic, and physical examination was normal in all children, apart from one who had respiratory symptoms. The tuberculin skin test results were positive in 60 (43%) patients and chest radiograph was abnormal in 100 (66%) children. Findings were consistent with tuberculosis in 34 (40%) of the 84 patients who underwent computed tomography. Fifty (38.5%) of the remaining children were defined as having been in contact with a case of tuberculosis, 41 (31.5%) had latent tuberculous infection and 39 (30%) had tuberculosis disease. Conclusion Pulmonary tuberculosis is asymptomatic in most children but with meticulous use of computed tomography it can be detected in asymptomatic children who have had close contact with tuberculosis. Abbreviation: AFB: acid-fast bacilli; AUC: area under the curve; BCG: bacillus Calmette-Guérin; CI: confidence interval; CT: computed tomography; CXR: chest radiograph; HIV: human immunodeficiency virus; ICD-10: International Classification of Diseases 10; LTBI: latent tuberculosis infection; MDR-TB: multi-drug-resistant tuberculosis; NPV: negative predictive value; PCR: polymerase chain reaction; PPV: positive predictive value; ROC: receiver operating characteristics; SD: standard deviation; TB: tuberculosis; TST: tuberculin skin test; XDR-TB: extensively drug-resistant tuberculosis.

Pediatric tuberculosis under six years old: an 18-year experience of a level II hospital

Background: Tuberculosis disease under six years is an indicator of recent transmission within the community. We aim to characterize tuberculosis disease in children under six years in a pediatric department of a level II hospital in the Lisbon metropolitan area, which serves a high percentage of immigrants from Portuguese-speaking African countries. Methods: Retrospective and descriptive study of tuberculosis disease cases treated in our Department between January 2004 and December 2021 (18 years). Descriptive analysis of the collected data was performed using SPSS Statistics® 25. Results: 25 patients were included, 60% diagnosed between 2016 and 2021. Five patients were born in countries with high TB incidence and 11 other patients had immigrant families from such countries. Ten out of 13 patients not immunized with BCG had the recommendation to do so. A close contact with tuberculosis was known in 15 patients, and in seven of those the system for TB prevention failed. At diagnosis: 4/25 patients had disseminated tuberculosis (three miliary and one congenital). Conclusions: The increase in tuberculosis disease cases under six years in the last three years points to some pitfalls in tuberculosis surveillance and transmission prevention. New studies and institutional protocols are needed to improve the effectiveness of the network involved in TB prevention and treatment.

Age-specific Clinical Presentation and Risk Factors for Extrapulmonary Tuberculosis Disease in Children.

Background:Clinical presentation for extrapulmonary tuberculosis (EPTB) in children can be variable and nonspecific, leading to delayed diagnosis, disease and death. We describe the age-specific clinical presentation and identify risk factors for EPTB among children in Pakistan.Methods:In 2015–2016 in 4 facilities in Sindh, Pakistan, children were diagnosed with TB either through bacteriologic confirmation or clinical-radiologic criteria. EPTB comprised any form of TB disease that did not involve the lungs. Among children with TB disease, we report demographics, clinical characteristics and symptoms, family medical history and diagnostic test results for children with and without EPTB. We conduct age-specific regression analyses to identify factors associated with an EPTB diagnosis among children age 0–4, 5–9 and 10–14 years.Results:A total of 1163 children were diagnosed with TB disease, of which 157 (13.5%) had EPTB. Of those, 46 (29.3%) were 0–4, 53 (33.8%) were 5–9 and 58 (36.9%) were 10–14 years old. Of children with EPTB, the most frequently reported sites were lymph node (113, 72.4%) and abdominal (31, 19.9%). Weight loss was associated with an increased risk of EPTB in the 0–4-year-old (adjusted odds ratio: 2.80, 95% confidence interval: 1.05–7.47) and 10–14-year-old (adjusted odds ratio: 2.79, 95% confidence interval: 1.28–6.07) groups, and the presence of cough was associated with a decreased risk of EPTB.Conclusions:This study provides new knowledge about age-specific clinical presentation and risk factors of EPTB in children in Pakistan. Our results can help to optimize clinical algorithms designed to achieve a timely diagnosis in children with EPTB along with improved treatment outcomes.

Towards Accurate Point-of-Care Tests for Tuberculosis in Children

In childhood tuberculosis (TB), with an estimated 69% of missed cases in children under 5 years of age, the case detection gap is larger than in other age groups, mainly due to its paucibacillary nature and children’s difficulties in delivering sputum specimens. Accurate and accessible point-of-care tests (POCTs) are needed to detect TB disease in children and, in turn, reduce TB-related morbidity and mortality in this vulnerable population. In recent years, several POCTs for TB have been developed. These include new tools to improve the detection of TB in respiratory and gastric samples, such as molecular detection of Mycobacterium tuberculosis using loop-mediated isothermal amplification (LAMP) and portable polymerase chain reaction (PCR)-based GeneXpert. In addition, the urine-based detection of lipoarabinomannan (LAM), as well as imaging modalities through point-of-care ultrasonography (POCUS), are currently the POCTs in use. Further to this, artificial intelligence-based interpretation of ultrasound imaging and radiography is now integrated into computer-aided detection products. In the future, portable radiography may become more widely available, and robotics-supported ultrasound imaging is currently being trialed. Finally, novel blood-based tests evaluating the immune response using “omic-“techniques are underway. This approach, including transcriptomics, metabolomic, proteomics, lipidomics and genomics, is still distant from being translated into POCT formats, but the digital development may rapidly enhance innovation in this field. Despite these significant advances, TB-POCT development and implementation remains challenged by the lack of standard ways to access non-sputum-based samples, the need to differentiate TB infection from disease and to gain acceptance for novel testing strategies specific to the conditions and settings of use.

Cytomegalovirus and tuberculosis disease in children

The risk of progressing from Mycobacterium tuberculosis infection to tuberculosis disease depends on the age at the time since infection. There is a complex relationship between tuberculosis and other infectious diseases; infections potentially alter the balance between immune responses that contain tuberculosis and those that allow disease progression. Understanding these associations provides potential insights into tuberculosis pathogenesis, can be used to assess progression risk in people with tuberculosis infection, and provides opportunities to prevent tuberculosis disease.

Pediatric Tuberculosis Disease during Years of High Refugee Arrivals: A 6-Year National Prospective Surveillance Study

Background: In Europe, surveillance and monitoring of pediatric tuberculosis (TB) remains important, particularly in the light of migration in recent years. The aim of the study was to evaluate incidence rates of childhood TB and detailed diagnostic pathways and treatment. Methods: Data were collected through the Swiss Pediatric Surveillance Unit (SPSU) from December 2013 to November 2019. Monthly ­notifications are obtained from the 33 pediatric hospitals in the SPSU, and a detailed questionnaire was sent out upon notification. Inclusion criteria were children and adolescents aged up to 15 years with culture- or molecular-confirmed TB disease or for whom a treatment with ≥3 antimycobacterial drugs had been initiated. Data were compared with age-matched notification data from the Swiss Federal Office of Public Health (FOPH). Results: Of the 172 cases notified to SPSU, a detailed questionnaire was returned for 161 (93%) children, of which 139 met the inclusion criteria. Reasons for exclusion were age >15 years, double reporting, and not fulfilling the criteria for TB disease. During the same time period, 172 pediatric TB cases were reported to the FOPH, resulting in an incidence of 2.1 per 100,000, ranging from 1.4 to 2.8 per year, without a clear trend over time. In the 64 (46.0%) foreign-born children, incidence rates were higher and peaked in 2016, with 13.7 per 100,000 (p = 0.018). The median interval between arrival in Switzerland and TB diagnosis was 5 (IQR 1–21) months, and 80% were diagnosed within 24 months of arrival. In 58% of the cases, TB disease was confirmed by culture or molecular assays. Age >10 years, presence of fever, or weight loss were independent factors associated with confirmed TB. Conclusion: The annual pediatric TB incidence rate only varied among foreign-born children and was highest in 2016 when refugee influx peaked in Europe. Importantly, most foreign-born children with TB were diagnosed within 2 years after arrival in Switzerland. Thus, the early period after arrival in Switzerland is associated with a higher risk of TB disease in children, and this should be considered for screening guidance in refugees.

The Magnitude of Interferon Gamma Release Assay Responses in Children With Household Tuberculosis Contact Is Associated With Tuberculosis Exposure and Disease Status.

The clinical utility of the magnitude of interferon gamma (IFNγ) in response to mycobacterial antigens is unknown. We assessed the association between quantitative IFNγ response and degree of Mycobacterium tuberculosis exposure, infection and tuberculosis (TB) disease status in children. We completed cross-sectional analysis of children (≤15 years) exposed to an adult with bacteriologically confirmed TB, 2007-2012 in Cape Town, South Africa. IFNγ values were reported as concentrations and spot forming units for the QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB, respectively. Random-effects linear regression was used to investigate the relation between the M. tuberculosis contact score, clinical phenotype (TB diseased, infected, uninfected) and IFNγ▪response as outcome, adjusted for relevant covariates. We analyzed data from 669 children (median age, 63 months; interquartile range, 33-108 months). A 1-unit increase in M. tuberculosis contact score was associated with an increase of IFNγ 0.60 international unit/mL (95% confidence interval [CI], 0.44-0.76 international unit/mL), and IFNγ spot forming unit 2 counts (95% CI, 1-3). IFNγ response was significantly lower among children with M. tuberculosis infection compared with children with TB disease (β = -1.42; 95% CI, -2.80 to -0.03) for the QFT-GIT, but not for the T-SPOT.TB. This association was strongest among children 2-5 years (β = -2.35 years; 95% CI, -4.28 to -0.42 years) and absent if <2 years. The magnitude of IFNγ response correlated with the degree of recent M. tuberculosis exposure, measured by QFT-GIT and T-SPOT.TB, and was correlated with clinically relevant TB phenotypes using the QFT-GIT. IFNγ values are not only useful in estimating the risk of M. tuberculosis infection but may also support the diagnosis of TB disease in children. The magnitude of IFNγ response correlated with the degree of recent M. tuberculosis exposure, measured by QFT-GIT and T-SPOT.TB, and was correlated with clinically relevant TB phenotypes using the QFT-GIT. IFNγ values are not only useful in estimating the risk of M. tuberculosis infection but may also support the diagnosis of TB disease in children.

BCG Vaccine Induced Tuberculous Osteomyelitis of Left Distal Femur in a Young Child: Case Report and Literature Review

Tuberculosis (TB) is an essential problem for healthcare systems especially in developing countries. TB continues to pose a significant global health burden [1]. Bacillus Calmette-Guérin (BCG) is an important vaccine used to prevent Tuberculosis (TB), especially meningeal TB and disseminated TB disease in children [2]. BCG is prepared from live bovine tuberculosis bacillus, and is given to protect against TB. Although vaccination against TB by means of BCG is widespread all over the world and is generally considered to be safe, but serious adverse reactions can occur. These may be minor such as abscess formation or skin ulceration at the site of vaccination to major adverse reaction such as fatal disseminated infection especially in patients with immune deficiency [3]. These adverse reactions after BCG vaccination depend on the BCG dose, vaccine strain, vaccine administration method, injection technique, and recipient’s underlying immune status [4]. The aim of this case report is to point out that clinical suspicion of BCG-induced osteomyelitis is warranted in pediatric patients with chronic symptoms of pain, limping, swelling and a limited ROM in the extremity. We also aimed to remind that imaging and culture studies may guide the clinician although tissue biopsies and genetic tests can confirm the histopathology and to review related articles.

ВОЗМОЖНЫЕ ПРИЧИНЫ ФОРМИРОВАНИЯ РЕЦИДИВОВ ТУБЕРКУЛЕЗА У ДЕТЕЙ В СОВРЕМЕННЫХ УСЛОВИЯХ: КЛИНИЧЕСКИЕ НАБЛЮДЕНИЯ

The epidemiological situation of tuberculosis (TB) has been improving steadily in recent years however, in the structure of TB patients, there is a high proportion of patients with multidrugresistant/extensively drug-resistant (XDR) pathogens and people with HIV and TB co-infection. As a result, cases of TB disease in children with many risk factors for unfavorable outcome of therapy are recorded, leading to subsequent relapse. the aim of the work was to analyze possible causes of formation and structure of clinical forms of recurrence of TB in children. A retrospective analysis of outpatient cards and medical records of children of residents of the Leningrad region, who had a TB relapse, was carried out. It has been established that in Leningrad Oblast, there were 3 cases of recidivism of TB among children registered from 2011 to 2020. The main risk factor for the development of primary TB was the lack of immunization against TB due to perinatal contact with an HIV-infected mother. The provoking factors of TB relapse were the occurrence of exogenous superinfection of TB, the presence of HIV infection in the child, the presence of large residual changes after primary TB, close contact with a TB patient with an XDR of the causative agent.

Association of Cartridge Based Nucleic Acid Amplification Test (CBNAAT) Grading on the Basis of Cycle Threshold Value with Conventional Microbiological Diagnosis in Pediatric Tuberculosis

Background: Microbiological confirmation of tuberculosis disease in children remains difficult due to paucibacillary disease and inability to obtain optimal samples. Recently introduced Cartridge based nucleic acid amplification test (CBNAAT) has improved microbiological diagnosis in pediatric tuberculosis.&#x0D; Objectives: We aimed to study association of CBNAAT grading based on cycle threshold value with conventional microbiological diagnosis.&#x0D; Methodology: This prospective study was conducted over a period from November 2016 to October 2017 in the Departments of Microbiology and Pediatrics, University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi. CBNAAT positive pediatric TB cases ≤12 years were recruited and subjected to Ziehl-Neelsen staining for acid fast bacilli (AFB) &amp; culture on Lowenstein Jensen medium. CBNAAT positivity was graded based on cycle threshold value: very low, low, medium and high.&#x0D; Results: Smear and culture positivity was highest (100%) among specimens with high positive CBNAAT result based on CT value. Time to culture positivity was inversely related to CBNAAT grading (p=0.000).&#x0D; Conclusion: CBNAAT grading has significant positive association with smear and culture positivity.&#x0D; Bangladesh Journal of Infectious Diseases 2020;7(2):72-77

Safety of the Polish BCG-10 Vaccine During a Period of BCG Vaccine Shortage: An Australian Experience.

Bacille Calmete-Guerin vaccine is widely administered to reduce the risk of severe tuberculosis disease in children. Recent global vaccine supply issues have led to the use of alternative products, which may vary in side effect profile. We report on the safety of the Polish (Moreau strain) "Bacille Calmete-Guerin-10" vaccine in an Australian cohort. Using active surveillance, we identified an adverse event rate of 54.6 per 10,000 doses (95% confidence interval: 38.5-75.2), which was comparable to that reported with the Danish Sanofi-Pasteur and Connaught strains.

Tuberculosis Disease in Children and Adolescents on Therapy With Antitumor Necrosis Factor-ɑ Agents: A Collaborative, Multicenter Paediatric Tuberculosis Network European Trials Group (ptbnet) Study.

In adults, anti-tumor necrosis factor-α (TNF-α) therapy is associated with progression of latent tuberculosis (TB) infection (LTBI) to TB disease, but pediatric data are limited. Retrospective multicenter study within the Paediatric Tuberculosis Network European Trials Group, capturing patients <18 years who developed TB disease during anti-TNF-α therapy. Sixty-six tertiary healthcare institutions providing care for children with TB participated. Nineteen cases were identified: Crohn's disease (n = 8; 42%) and juvenile idiopathic arthritis (n = 6; 32%) were the commonest underlying conditions. Immune-based TB screening (tuberculin skin test and/or interferon-γ release assay) was performed in 15 patients before commencing anti-TNF-α therapy but only identified 1 LTBI case; 13 patients were already receiving immunosuppressants at the time of screening. The median interval between starting anti-TNF-α therapy and TB diagnosis was 13.1 (IQR, 7.1-20.3) months. All cases presented with severe disease, predominantly miliary TB (n = 14; 78%). One case was diagnosed postmortem. TB was microbiologically confirmed in 15 cases (79%). The median duration of anti-TB treatment was 50 (IQR, 46-66) weeks. Five of 15 (33%) cases who had completed TB treatment had long-term sequelae. LTBI screening is frequently false-negative in this patient population, likely due to immunosuppressants impairing test performance. Therefore, patients with immune-mediated diseases should be screened for LTBI at the point of diagnosis, before commencing immunosuppressive medication. Children on anti-TNF-α therapy are prone to severe TB disease and significant long-term morbidity. Those observations underscore the need for robust LTBI screening programs in this high-risk patient population, even in low-TB-prevalence settings.

Factors associated with tuberculosis disease among children who are household contacts of tuberculosis cases in an urban setting in Malaysia

BackgroundWith the rise in prevalence of childhood tuberculosis (TB) globally, contact tracing should be a powerful strategy for early diagnosis and management, especially in children who are household contacts of active TB cases. Here, we aimed to determine the prevalence and factors associated with TB disease in children who are household contacts of TB cases.MethodsWe used a cross-sectional study with data from the Malaysian TB Information System (TBIS) recorded from 1 January 2014 to 31 December 2017. All children aged 0–14 years who were registered in the TBIS with at least one household contact of TB cases were included in the study. Multiple logistic regression analysis was performed to calculate the adjusted odds ratio (adj. OR) and for adjusting the confounding factors.ResultsA total of 2793 children were included in the study. The prevalence of active TB was 1.5% (95% confidence interval [CI]: 1.31, 1.77%). Children aged < 5 years [adj. OR 9.48 (95% CI: 3.41, 26.36) p < 0.001] with positive tuberculin skin test [adj. OR 395.73 (95% CI: 134.17, 1167.13), p < 0.001] and investigation period of > 6 weeks [adj. OR 7.48 (95% CI: 2.88, 19.43), p < 0.001] had significantly higher odds for TB disease.ConclusionsThe prevalence of TB disease in children who were household contacts of TB cases is relatively low. However, contact tracing programmes should not only focus on children aged < 5 years and with positive tuberculin skin test results, but also be empowered to reduce the investigation period.

Vitamin D and LL-37 Levels in Childhood Tuberculosis Disease and Latent Tuberculosis Infection

Vitamin D and LL-37 Levels in Childhood Tuberculosis Disease and Latent Tuberculosis Infection

Biomarkers for diagnosis of childhood tuberculosis: A systematic review.

IntroductionAs studies of biomarkers of tuberculosis (TB) disease provide hope for a simple, point-of-care test, we aimed to synthesize evidence on biomarkers for diagnosis of TB in children and compare their accuracy to published target product profiles (TPP).MethodsWe conducted a systematic review of biomarkers for diagnosis of pulmonary TB in exclusively paediatric populations, defined as age less than 15 years. PubMed, EMBASE and Web of Science were searched for relevant publications from January 1, 2000 to November 27, 2017. Studies using mixed adult and paediatric populations or reporting biomarkers for extrapulmonary TB were excluded. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies—2 (QUADAS-2) framework. No meta-analysis was done because the published childhood TB biomarkers studies were mostly early stage studies and highly heterogeneous.ResultsThe 29 studies included in this systematic review comprise 20 case-control studies, six cohort studies and three cross-sectional studies. These studies reported diverse and heterogeneous forms of biomarkers requiring different types of clinical specimen and laboratory assays. Majority of the studies (27/29 [93%]) either did not meet the criteria in at least one of the four domains of the QUADAS-2 reporting framework or the assessment was unclear. However, the diagnostic performance of biomarkers reported in 22 studies met one or both of the WHO-recommended minimal targets of 66% sensitivity and 98% specificity for a new diagnostic test for TB disease in children, and/or 90% sensitivity and 70% specificity for a triage test.ConclusionWe found that majority of the biomarkers for diagnosis of TB in children are promising but will need further refining and optimization to improve their performances. As new data are emerging, stronger emphasis should be placed on improving the design, quality and general reporting of future studies investigating TB biomarkers in children.

Tuberculosis Prevention: an Under Prioritized yet Critical Intervention to Reduce Child Tuberculosis Morbidity and Mortality

Identification of vulnerable household tuberculosis (TB) contacts, particularly children under 5 years of age, has been recommended for over 10 years by the World Health Organization (WHO), but uptake has been poor in TB high-burden settings where this intervention is most needed. In part due to this failure of TB contact management, the burden of TB disease in children under 5 years of age is grossly underestimated leading to increased morbidity and mortality. In light of these unfortunate realities, it is critical to identify children exposed to TB and provide preventive treatment before they progress to active TB disease. This review highlights the role of TB prevention for children under 5 years of age and suggests strategies for improved TB prevention in high-burden settings. There have been examples of both programmatic and non-programmatic interventions that have successfully improved TB contact management and preventive therapy implementation. Here, we discuss some of these interventions and use the WHO health system building blocks to provide recommendations for improving TB prevention through isoniazid preventive therapy. Further, we describe the significant contributions of the BCG vaccine to TB prevention in young children and the need to ensure continuous supply of this critical vaccination. Without such devotion to TB prevention, we are unlikely to meet the global END TB targets, and children under 5 years of age will continue to experience preventable morbidity and mortality secondary to TB disease.