Diagnosis Of Latent Tuberculosis Research Articles

Immunologic-based Diagnosis of Latent Tuberculosis Among Children Younger Than 5 Years of Age Exposed and Unexposed to Tuberculosis in Tanzania.

Childhood tuberculosis (TB) is acquired after exposure to an infectious TB case, often within the household. We prospectively screened children 6-59 months of age, exposed and unexposed to an infectious TB case within the same household, for latent tuberculosis infection (LTBI), in Dar es Salaam, Tanzania. We collected medical data and clinical specimens (to evaluate for helminths, TB and HIV coinfections) and performed physical examinations at enrollment and at 3-month and 6-month follow-up surveys. LTBI was assessed using QuantiFERON-TB Gold (QFT) at enrollment and at 3 months. In total, 301 children had complete data records (186 with TB exposure and 115 without known TB exposure). The median age of children was 26 months (range: 6-58); 52% were females, and 4 were HIV positive. Eight children (3%) developed TB during the 6-month follow-up. We found equal proportions of children with LTBI among those with and without exposure: 20% (38/186) versus 20% (23/115) QFT-positive, and 2% (4/186) versus 4% (5/115) indeterminate QFT. QFT conversion rate was 7% (22 children) and reversion 8% (25 children). Of the TB-exposed children, 72% initiated isoniazid preventive therapy, but 61% of parents/caregivers of children with unknown TB exposure and positive QFT refused isoniazid preventive therapy. In this high burden TB setting, TB exposure from sources other than the household was equally important as household exposure. Nearly one third of eligible children did not receive isoniazid preventive therapy. Evaluation for LTBI in children remains an important strategy for controlling TB but should not be limited to children with documented TB exposure.

Newer Diagnostic Tests and their Application in Pediatric TB.

The diagnosis of childhood tuberculosis is a challenge due to the pauci-bacillary nature of infection and the difficulty in obtaining appropriate sample. In the past 2-3 decades, many new tests were introduced for the diagnosis of tuberculosis (TB) and some of them have been evaluated for their application in pediatric tuberculosis as well. There is an attempt to improve smear microscopy by introducing light-emitting diode (LED) fluorescence microscopy and there are also some automated digital microscopy platforms under evaluation. Introduction of automated liquid culture platform along with rapid molecular based identification methods have considerably reduced the time delay in mycobacterial culture. Recent addition of many nucleic acid amplification platforms like Amplicor PCR, Genprobe, Xpert MTB/Rif, line probe assays, loop mediated isothermal amplification etc are also been found to be useful. Latest techniques like microarray and gene sequencing are also being used in clinical laboratories with variable results. Indirect methods of TB diagnosis like T cell based assays including tuberculin skin test and interferon-gamma release assays have their role primarily in the diagnosis of latent TB. Biomarkers are the latest addition in the battery of TB diagnostic tests facilitating diagnosis using easily accessible samples like urine, blood and breath of patients. Many biomarkers are still under evaluation and some of them are found to have a potential role as promising diagnostic tests of future.

Validation and Clinical Application of Interferon-Gamma Release Assay for Diagnosis of Latent Tuberculosis Infection in Children.

Background:India has the highest tuberculosis (TB) burden, accounting for one-fifth of the global incidence and two-third of the cases in Southeast Asia with an estimated 1.9 million new cases every year. Identifying and treating latent TB infection (LTBI) can reduce the risk of development of active disease by up to 90%, thereby decreasing a major burden to the prevalence of the disease, and thus reducing potential sources in future.Aim:Early diagnosis of LTBI by tuberculin skin test (TST) and a newer interferon-gamma release assay (IGRA).Materials and Methods:Seventy-seven clinically asymptomatic household contacts (≤18 years) of confirmed pulmonary TB patients were enrolled to compare the performance of TST and IGRA to diagnose LTBI. At baseline, all participants underwent testing for IGRA and TST.Results:TST showed positivity of 22%, while IGRA demonstrated positivity of 40% in the diagnosis of latent TB. Kappa value at 95% confidence interval was 0.4753, indicates a moderate agreement between the two tests. This indicates that IGRA is a better predictor of latent TB. Maximum positive percentage was in the age group of 16–18 years in both the tests followed by 1–5 years.Aim:Early diagnosis of LTBI by tuberculin skin test (TST) and a newer interferon-gamma release assay (IGRA).

Factors Associated with False Negative Interferon-γ Release Assay Results in Patients with Tuberculosis: A Systematic Review with Meta-Analysis

Background: Although interferon-γ release assay (IGRA) is widely used for diagnosis of latent tuberculosis (TB) infection, which factors are related to false negative results are uncertain. The aim of this systematic review was to describe the risk factors associated with false negative IGRA results. Methods: Two authors independently identified studies designed to evaluate risk factors for false negative IGRA results from PubMed, the Cochrane Register of Control Trial database, and EMBASE assessed on October 22, 2018. Meta-analyses were conducted with random-effect models and heterogeneity was calculated with the I2 method. Findings: Of 1,377 titles and abstracts screened, 47 full texts were selected for review, and we finally included 17 studies in this systematic review. The most commonly studied risk factor (14 studies) was advanced age followed by low peripheral lymphocyte counts (7 studies), and these factors were associated with false negative results even under different TB prevalence (pooled odds ratio, 2.06; 95%CI, 1.68-2.52 in advanced age, and 7.93; 95%CI, 1.74-36.09 in low peripheral lymphocyte counts, respectively). However, detailed procedure of these assays were not clearly stated in many studies and the cut-off value of these factors were varied. Interpretation: Advanced age and low peripheral lymphocyte counts may be common risk factors for false negative IGRA results, suggesting people with these factors need careful followed-up even if they have negative IGRA results. Standardization of the assay procedure and assessment of risk factors with common definition and the same cut-off value are needed. Funding Statement: The authors state: There was no funding source for this study. Declaration of Interests: The authors declare declare no competing interests.

Evaluating results of an interferon-γ release assay in patients with autoimmune disease who are taking hydroxychloroquine

Evaluating results of an interferon-γ release assay in patients with autoimmune disease who are taking hydroxychloroquine

Assessment of an ultra-sensitive IFNγ immunoassay prototype for latent tuberculosis diagnosis.

Worldwide there are about 1.7 billion individuals with latent tuberculosis infection (LTBI) and only 5% to 15% will develop active tuberculosis (TB). It is recommended to treat only those most at risk of developing active TB to avoid problems of drug resistance. LTBI diagnosis involves reviewing the individual's medical history, physical examination, and biological tests. Interferon gamma release assays (IGRA) can yield "undeterminate" or "uncertain" results, which makes clinical management decisions difficult. We assessed an ultra-sensitive immunoassay prototype based on single molecule array (SiMoA) technology to evaluate its overall performance, and in particular, its performance for indeterminate and uncertain positive or negative samples, as classified by the results from the current ELISA technique used for IFNγ quantification. We analyzed samples from hospitalized or consulting patients and healthcare workers from three hospitals in Paris, previously classified as negative (n = 30), positive (n = 35), uncertain negative (n = 25), uncertain positive (n = 31), or indeterminate (n = 30). We observed that with the SiMoA assay 83.3% of the indeterminate samples became interpretable and could be classified as negative, whereas 74% of uncertain positive samples were classified as positive. Most uncertain negative samples (72%) were reclassified as uncertain positive (68%) or positive (4%). The results suggest that the ultra-sensitive SiMoA IFNγ assay could represent a useful tool for the identification of true positive and negative samples among those giving indeterminate or uncertain results with the TB IGRA assay currently used.

Index of Stimulation and TNFα Measurements Used for laboratory Diagnosis of Latent Tuberculosis as a New Principle

Index of Stimulation and TNFα Measurements Used for laboratory Diagnosis of Latent Tuberculosis as a New Principle

Generation of a T cell receptor (TCR)-like single domain antibody (sDAb) against a Mycobacterium Tuberculosis (Mtb) heat shock protein (HSP) 16kDa antigen presented by Human Leukocyte Antigen (HLA)-A*02

The discovery of heat shock protein 16 kDa antigen protein has deepen the understanding of latent tuberculosis since it was found to be primarily expressed by Mycobacterium tuberculosis during latent phase leading to the rapid optimization and development in terms of diagnosis and therapeutics. Recently, T cell receptor-like antibody has been explored extensively targeting various diseases due to its dual functionality (T cell receptor and antibody). In this study, a TCR-like domain antibody (A2/Ab) with the binding capacity to Mtb heat shock protein (HSP) 16 kDa antigen presented by major histocompatible complex (MHC) HLA-A*02 was successfully generated via biopanning against human domain antibody library. The generated antibody (A2/Ab) exhibited strong functionality and binding capacity against the target assuring the findings of this study to be beneficial for the development of latent tuberculosis diagnosis and immunotherapeutics in future.

Management practices of tuberculosis in children among pediatric practitioners in Mangalore, South India

IntroductionIn spite of having BCG vaccination and tuberculosis control program for the last 50 years, prevalence of tuberculosis continues to be high in India. Inadequate diagnostic methods, suboptimal treatment and monitoring, and the lack of vigilant reporting system are some of the contributing factors for the failure of TB control. ObjectivesTo know the current practices among local pediatricians regarding management of TB. Materials and methodsField based cross sectional study. All the registered pediatricians who were practicing in Mangalore, (list – local IAP branch) were included in the study. A structured Questionnaire on signs and symptoms of TB, diagnosis, strategies adopted in treatment, MDR tuberculosis and reporting of cases to RNTCP was asked. Management practice standards according to the Updated National Guidelines for Pediatric Tuberculosis in India, 2012, RNTCP guidelines in consensus with IAP, latest at the time of the study. Results50 pediatricians participated in the study with 62% having an attachment to the teaching institution. More than 50% identified all the symptoms of TB. 64% were sending chest X-ray, Mantoux test and gastric lavage/induced sputum examination for AFB to diagnose TB. 22% were not stressing for AFB examination. Still 16% told serological tests as one of the diagnostic modality. 52% were not aware about the diagnosis of latent TB. In 16% of their cases ATT was on a trial basis. Only 52% of the clinicians are adhering to updated national (RNTCP) guidelines. 30% felt still there are drawbacks in the current RNTCP guidelines. 72% knew the correct definition of MDR tuberculosis. But only 36% of them knew the diagnostic method (gene expert/CB NAAT) of confirming the MDR TB. ConclusionManagement practices are found to be still suboptimum. Better engagement of the private sector is urgently required to improve TB management practices and to prevent diagnostic delay and drug resistance.

Co-Expression of hbha and mtb32C Genes from Mycobacterium tuberculosis H37Rv in a Prokaryotic System

Background: Heparin-binding hemagglutinin (HBHA) protein is a surface adhesin that mediates the attachment of Mycobacterium tuberculosis to host cells by its own unique, carboxyl-terminal region. The methylated HBHA has a specific motif with a lysine-, alanine-, and proline-rich domain. More recently, it has been shown that HBHA protein has potential activity in stimulating immune responses, and is a promising new candidate for diagnostic applications besides a protective antigen against tuberculosis. Objectives: The aim of this study was to isolate a mycobacterial latency gene (hbha), and subsequently produce its protein as a new antigen for the Interferon-Gamma Release Assay test (IGRAs). Methods: In the present work, hbha and mtb32C genes were isolated from the Mycobacterium tuberculosis H37Rv genome using the polymerase chain reaction (PCR) method. The PCR products and pet21+ vector were digested with specific restriction enzymes and then submitted to the ligation procedure. Escherichia coli BL21-CodonPlus (DE3) competent cells were transformed with the recombinant mtb32C-hbha -pet21+ vector. Expression of recombinant protein (Mtb32C-HBHA) was confirmed with Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis (SDS-PAGE) and western blot methods. Results: Detection of a 500-bp gene and sequencing of recombinant pet-mtb32C-hbha vector, all confirmed the accuracy of the cloning procedure. A 36-KDa band of Mtb32C-HBHA protein was also detected by western blotting. Conclusions: In this study, expression of Mtb32C-HBHA protein was successfully done, in the prokaryotic system. Further studies are needed to evaluate the efficacy of recombinant Mtb32C-HBHA protein in diagnosis of latent tuberculosis.

How many patients with rheumatic diseases and TNF inhibitors treatment have latent tuberculosis?

ObjectivesSpanish clinical guidelines recommend screening patients for tuberculosis (TB) before TNF inhibitors (TNFi) treatment. Our objective was to estimate the prevalence of TST seroconversion as an estimation of the prevalence of latent TB in patients with rheumatic diseases and TNFi treatment that have already been screened for tuberculosis. MethodsTST, booster and chest x-ray were performed to patients with rheumatic diseases, TNFi treatment, negative tuberculin skin tests before treatment and that were attending the rheumatology Department of three different hospitals in Barcelona. According to the Spanish Society Rheumatology guidelines, these patients had not received TB prophylaxis treatment. ResultsOne hundred and forty patients were included in the study. The tuberculin skin test was positive in 4.28% (n=6) of the patients. 50% of the patients were undergoing TNFi ≤ 2 years, being two of the patients only one year on the TNFi when a positive TST was detected. This shows that a conversion of the TST can occur even few months or years after the TNFi is started. ConclusionsThe present study observed that 4.28% of patients with rheumatic diseases on TNFi who did not have performed a pre-treatment TB prophylaxis, had a conversion of the TST. Moreover, the conversion of the TST had been within the first two years of treatment in half of the patients of our cohort. In spite of these results, false TST positives in the diagnosis of latent TB cannot be excluded as an explanation for our results.

A triple-helix molecular switch-based electrochemical aptasensor for interferon-gamma using a gold electrode and Methylene Blue as a redox probe

Detection and quantitation of interferon-gamma (IFN-γ) in blood is of vital importance for diagnosis of latent tuberculosis. The authors describe an electrochemical aptasensor for IFN-γ that is based on a triple-helix molecular switch (THMS). The combination of a THMS with amperometry makes the sensor selective, sensitive and fast (50 min). In the presence of IFN-γ, the structure of the THMS is disassembled and the electrochemical probes, Methylene Blue (MB), can only bind to the signal transduction probe (STP) on the surface of the gold electrode, this leading to a weak peak current. However, in the absence of IFN-γ, the structure of THMS is preserved and MB can interact with the THMS to result in strong current (typically measured at −0.24 V vs. silver reference electrode). Under optimized conditions, the assay has a 3 pg·mL−1 detection limit and a linear range that extends from 10 to 1500 pg·mL−1. Employed to the determination of IFN-γ in spiked serum samples, it gave recoveries that ranged from 91.3% to 102.8%.

An amplified fluorescent aptasensor based on single-stranded DNA binding protein, copper and silica nanoparticles for sensitive detection of interferon-gamma

It is great significance to identify interferon-gamma (IFN-γ), as a biological marker for diagnosis of latent tuberculosis, in serum samples. In this paper, a novel fluorescent aptasensor was fabricated and applied for sensitive and specific detection of IFN-γ. This biosensor was based on hairpin structure of oligonucleotide, single-stranded DNA-binding protein (SSB), copper nanoparticles (CuNPs) and silica nanoparticles coated with streptavidin (SNPs-Streptavidin). The presences of double-stranded DNA (dsDNA) region and poly thymine (T) in the hairpin structure of the oligonucleotide, SSB and SNPs-streptavidin caused IFN-γ determination with high selectivity and sensitivity. Upon addition of IFN-γ, the hairpin structure of the oligonucleotide was disassembled and therefore, poly T strand interacted with SSB and a weak fluorescence signal was obtained. Without introduction of IFN-γ, the hairpin structure of oligonucleotide was preserved and fluorescent CuNPs were formed on the stem region of hairpin structure of oligonucleotide, resulting in strong fluorescence intensity. Under optimal conditions, concentration as low as 1 pg/mL IFN-γ could be detected, with a linear range between 10 pg/mL and 4 ng/mL. The presented method was further performed for detection of IFN-γ in the spiked human serum samples and the recoveries were 92.52%–98.32%, showing the great potential of the proposed analytical method in biomedical analysis.

METHODS OF SPECIFIC DIAGNOSIS OF TUBERCULOSIS: A MODERN VIEW ON THE PROBLEM

This review presents modern views on the problems of immunodiagnosis of tuberculosis. We have examined the advisability of the use of immunological methods for diagnosis of active tuberculosis and detection of latent tuberculous infection. It is shown that nowadays the use of serological diagnostic methods is not recommended because of contradictory information about their accuracy and limited diagnostic significance. Advantages and disadvantages of current methods of assessment of cell-mediated immune response that are used as screening tests for diagnosis of latent tuberculosis have been analyzed. We point to advisability of combination of different methods that are available nowadays with the use of skin tests as the first step of diagnosis, and improvement of techniques of antigens injections that are used for them.

Comparison of the Quantiferon tb gold assay and tuberculin skin test to detect tuberculosis infection among tuberculosis patient contact

Introduction: Tuberculosis is a communicable disease and therefore TB patient contacts are at higher risk of developing TB infection. So screening and diagnosis of latent TB is done by QFT Gold assay and Tuberculin skin test (TST). Methodology: A total of 100 TB patient contacts were taken for study, blood was drawn and processed by using the QFT G assay followed by immediate administration of TST solution in subjects forearm. Data were analyzed and results were compared. Results: QFT G assay detect LTBI with sensitivity of 88.88% and specificity of 90%. TST Sensitivity 68%, Specificity 16%. Conclusions: QFT G Assay have higher detection rate among TB contact patient. Keywords: QFT G quantiferon TB Gold, LTBI- Latent tuberculosis infection, TST – Tuberculin skin test

Interferon Gamma Release Assay in response to PE35/PPE68 proteins: a promising diagnostic method for diagnosis of latent tuberculosis.

Tuberculosis control relies on the identification and preventive treatment of people who are latently infected with Mycobacterium tuberculosis (Mtb). PE/PPE proteins have been reported to elicit CD4 and/or CD8 responses either in the form of whole recombinant proteins or as individual peptides. Very few of the PE and PPE proteins have been previously tested for responses in patients with TB and healthy donors. This is the first study to evaluate the Interferon Gamma Release Assay (IGRA) after stimulation with PE35 and PPE68. The antigen-specific levels of IFN-γ following stimulation with QuantiFERON-TB gold in-tube (QFT-G-IT) antigens, and PE35 and PPE68 recombinant proteins were evaluated in 79 children and 102 adults, respectively. Using QFT-G-IT kit, latent tuberculosis infection (LTBI) was detected in 26 children (33%) and 41 adults (40%); IGRA following stimulation with PE35 and PPE68 recombinant proteins, was positive, respectively, in 36 (46%) and 32 (40.5%) children, respectively. In addition, 53 adults (52%) had positive results following stimulation with these two proteins. The sensitivity and specificity of IGRA following stimulation with recombinant PE35 in children were 76% and 80%, and following stimulation with recombinant PPE68 in this group, it was 73% and 75%, respectively. Meanwhile, there is no gold standard test for LTBI. Our designed tests using PE35 and PPE68 PE/PPE proteins, two PE/PPE proteins not present in BCG vaccins, which elicit CD4 and/or CD8 responses, might be helpful for rapid diagnosis of TB and improve the detection of LTBI. However, further validation studies to determine the advantage of IGRAs using these proteins, alone or combined, are highly recommended.

Tuberculosis and Leprosy Co-Infection: A Perspective on Diagnosis and Treatment

BackgroundThe Marshall Islands are known to be endemic for both leprosy and tuberculosis (TB). Active TB needs to be ruled out in all cases of leprosy, as treatment will lead to rifampin monotherapy of undiagnosed TB co-infection. The use of protein based interferon gamma release assays (IGRAS) to test for latent TB in leprosy endemic areas is confounded by the crossreactivity of T-cell response to the antigenic homologs of these proteins in Mycobacterium leparae.MethodsThe Purified Protein Derivative (PPD) skin test may have some utility in the diagnosis of latent TB in the setting of paucibacillary leprosy, however “giant reactions” to PPD testing have been documented in monoinfection with multibacillary leprosy.ResultsA 32-year-old Marshallese woman presented to the surgical department with symptoms concerning for osteomyelitis of the third distal phalanx, multiple burn wounds on both hands, and hypoaesthetic- hypopigmented skin lesions. She was referred to the National Hansen’s institute where a limited disarticulation of the distal phalanx and a slit skin biopsy was performed. Fite stain was negative, but PCR was positive for Mycobacterium leprae. The patient also had a strongly positive IGRA test for TB, and a positive PPD skin test. A chest x-ray showed a subtle infiltrate in the right middle lobe, three induced sputa were AFB negative by smear - however 1/3 was culture positive for drug-susceptible TB. The patient then underwent standard drug therapy for TB with the addition of dapsone for the treatment of Hanson’s. Repeat sputum cultures were negative at one month, and the patient had improvement in her skin hypopigmentation within four months of therapy.ConclusionThe immunological milieu of the host appears to paradoxically influence susceptibility to mycobacterial coinfection, with no consensus regarding whether prior exposure to one offers protection or predisposition to the other. The clinical implications of failure to identify active TB in a case of leprosy can not be understated, and positive IGRA or PPD testing in leprosy should not be considered falsely positive without further investigation. If treatment for paucibacillary leprosy is to be considered before ruling out active TB then minocycline may temporarily replace Rifampin.Disclosures All authors: No reported disclosures.

QuantiFERON conversion following tuberculin administration is common in HIV infectionand relates to baseline response.

BackgroundHIV-1 infection impairs tuberculosis (TB) specific immune responses affecting the diagnosis of latent TB. We aimed to (1) determine the proportion of HIV-1-infected adults with a negative QuantiFERON®-TB Gold in-tube (QFT-GIT) and Tuberculin skin testing (TST) that convert to QFT-GIT positive following TST, and (2) evaluate the relationship between conversion and baseline QFT-GIT results.MethodsHIV-1 infected adults being screened for a TB vaccine study in South Africa underwent QFT-GIT followed by TST. As per protocol, QFT-GIT was repeated if randomization was delayed allowing for evaluation of TST boosting in a proportion of participants.ResultsOf the 22 HIV-1 infected, TST and QFT-GIT negative adults (median CD4 477/mm3 IQR 439–621) who had QFT-GIT repeated after median 62 days (IQR 49–70), 40.9 % (95 % CI 18.6–63.2 %) converted. Converters had a significantly greater increase in the background subtracted TB antigen response (TBAg-Nil – all units IU/mL) following TST, 0.82 (IQR 0.39–1.28) vs 0.03 (IQR −0.05–0.06), p = 0.0001. Those who converted also had a significantly higher baseline TBAg-Nil 0.21(IQR 0.17–0.26) vs 0.02(IQR 0.01–0.07), p = 0.002. Converters did not differ with regard to CD4 count or ART status. ROC analysis showed a baseline cut off of 0.15 correctly classified 86.4 % of converters with 88.9 % sensitivity.ConclusionsOur findings support the possibility that there are 2 distinct groups in an HIV-1 infected population with negative QFT-GIT and TST; a true negative group and a group showing evidence of a weak Mtb specific immune response that boosts significantly following TST resulting in conversion of the test result that may represent false negatives. Further evaluation of whether a lower cut off may improve sensitivity of QFT-GIT in this population is warranted.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-016-1875-6) contains supplementary material, which is available to authorized users.

How many patients with rheumatic diseases and TNF inhibitors treatment have latent tuberculosis?

ObjectivesSpanish clinical guidelines recommend screening patients for tuberculosis (TB) before TNF inhibitors (TNFi) treatment. Our objective was to estimate the prevalence of TST seroconversion as an estimation of the prevalence of latent TB in patients with rheumatic diseases and TNFi treatment that have already been screened for tuberculosis. MethodsTST, booster and chest x-ray were performed to patients with rheumatic diseases, TNFi treatment, negative tuberculin skin tests before treatment and that were attending the rheumatology Department of three different hospitals in Barcelona. According to the Spanish Society Rheumatology guidelines, these patients had not received TB prophylaxis treatment. ResultsOne hundred and forty patients were included in the study. The tuberculin skin test was positive in 4.28% (n=6) of the patients. 50% of the patients were undergoing TNFi ≤ 2 years, being two of the patients only one year on the TNFi when a positive TST was detected. This shows that a conversion of the TST can occur even few months or years after the TNFi is started. ConclusionsThe present study observed that 4.28% of patients with rheumatic diseases on TNFi who did not have performed a pre-treatment TB prophylaxis, had a conversion of the TST. Moreover, the conversion of the TST had been within the first two years of treatment in half of the patients of our cohort. In spite of these results, false TST positives in the diagnosis of latent TB cannot be excluded as an explanation for our results.

Accurate diagnosis of latent tuberculosis in children, people who are immunocompromised or at risk from immunosuppression and recent arrivals from countries with a high incidence of tuberculosis: systematic review and economic evaluation.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB) [(Zopf 1883) Lehmann and Neumann 1896], is a major cause of morbidity and mortality. Nearly one-third of the world's population is infected with MTB; TB has an annual incidence of 9 million new cases and each year causes 2 million deaths worldwide. To investigate the clinical effectiveness and cost-effectiveness of screening tests [interferon-gamma release assays (IGRAs) and tuberculin skin tests (TSTs)] in latent tuberculosis infection (LTBI) diagnosis to support National Institute for Health and Care Excellence (NICE) guideline development for three population groups: children, immunocompromised people and those who have recently arrived in the UK from high-incidence countries. All of these groups are at higher risk of progression from LTBI to active TB. Electronic databases including MEDLINE, EMBASE, The Cochrane Library and Current Controlled Trials were searched from December 2009 up to December 2014. English-language studies evaluating the comparative effectiveness of commercially available tests used for identifying LTBI in children, immunocompromised people and recent arrivals to the UK were eligible. Interventions were IGRAs [QuantiFERON(®)-TB Gold (QFT-G), QuantiFERON(®)-TB Gold-In-Tube (QFT-GIT) (Cellestis/Qiagen, Carnegie, VA, Australia) and T-SPOT.TB (Oxford Immunotec, Abingdon, UK)]. The comparator was TST 5 mm or 10 mm alone or with an IGRA. Two independent reviewers screened all identified records and undertook a quality assessment and data synthesis. A de novo model, structured in two stages, was developed to compare the cost-effectiveness of diagnostic strategies. In total, 6687 records were screened, of which 53 unique studies were included (a further 37 studies were identified from a previous NICE guideline). The majority of the included studies compared the strength of association for the QFT-GIT/G IGRA with the TST (5 mm or 10 mm) in relation to the incidence of active TB or previous TB exposure. Ten studies reported evidence on decision-analytic models to determine the cost-effectiveness of IGRAs compared with the TST for LTBI diagnosis. In children, TST (≥ 5 mm) negative followed by QFT-GIT was the most cost-effective strategy, with an incremental cost-effectiveness ratio (ICER) of £18,900 per quality-adjusted life-year (QALY) gained. In immunocompromised people, QFT-GIT negative followed by the TST (≥ 5 mm) was the most cost-effective strategy, with an ICER of approximately £18,700 per QALY gained. In those recently arrived from high TB incidence countries, the TST (≥ 5 mm) alone was less costly and more effective than TST (≥ 5 mm) positive followed by QFT-GIT or T-SPOT.TB or QFT-GIT alone. The limitations and scarcity of the evidence, variation in the exposure-based definitions of LTBI and heterogeneity in IGRA performance relative to TST limit the applicability of the review findings. Given the current evidence, TST (≥ 5 mm) negative followed by QFT-GIT for children, QFT-GIT negative followed by TST (≥ 5 mm) for the immunocompromised population and TST (≥ 5 mm) for recent arrivals were the most cost-effective strategies for diagnosing LTBI that progresses to active TB. These results should be interpreted with caution given the limitations identified. The evidence available is limited and more high-quality research in this area is needed including studies on the inconsistent performance of tests in high-compared with low-incidence TB settings; the prospective assessment of progression to active TB for those at high risk; the relative benefits of two-compared with one-step testing with different tests; and improved classification of people at high and low risk for LTBI. This study is registered as PROSPERO CRD42014009033. The National Institute for Health Research Health Technology Assessment programme.