Tuberculosis (TB) is an infectious disease that poses a serious threat to human health. About a quarter of the world's population were infected with Mycobacterium tuberculosis in 2020, and the majority of them were latently infected. Approximately 5%-10% of the population with latent tuberculosis infection may progress to active TB disease. Identifying latent TB infection from active TB by biomarkers and screening people with latent TB infection at high risk of progression for preventive treatment by biomarkers that can reliably predict the progression is one of the most effective strategies to control TB. This article reviews the progress of research on transcriptional and immunological biomarkers for identifying TB infection and predicting the progression from latent infection to active TB, with the aim of providing new ideas for tuberculosis control.
Humans ; Latent Tuberculosis/diagnosis* ; Tuberculosis/diagnosis* ; Mycobacterium tuberculosis/genetics* ; Biomarkers

BACKGROUND: Differential diagnosis of active tuberculosis (ATB) and latent tuberculosis infection (LTBI) has been a challenge for clinicians in high TB burden countries. The purpose of this study was to improve the accuracy of differential diagnosis of ATB and LTBI by using fluorescent immunospot (FluoroSpot) assay to detect specific Th1 cell immune responses. The novel mycobacterium tuberculosis (MTB) latency-associated antigens Rv1733c and synthetic long peptides derived from Rv1733c (Rv1733c SLP) were used based on virulence factors early secreting antigen target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10). METHODS: Fifty-seven ATB cases, including 20 pathogen-confirmed ATB and 37 clinically diagnosed ATB, and 36 LTBI cases, were enrolled between January and December 2017. FluoroSpot assay was used to detect the interferon γ (IFN-γ) and interleukin 2 (IL-2) secreted by the specific T cells after being stimulated with MTB virulence factors ESAT-6 and CFP-10, MTB latency-associated antigens Rv1733c and Rv1733c SLP. The receiver operating characteristic (ROC) curve was used to define the best cutoff value of latency-associated antigens in the use of differentiating ATB and LTBI. The sensitivity, specificity, predictive value, and likelihood ratio of ESAT-6 and CFP-10-FluoroSpot combined with latency-associated antigen in the differential diagnosis of ATB and LTBI were also calculated. RESULTS: Following the stimulation with Rv1733c and Rv1733c SLP, the frequency of single IL-2-secreting T cells stimulated by Rv1733c SLP had the largest area under the ROC curve, which was 0.766. With a cutoff value of 1 (spot-forming cells [SFCs]/2.5 × 105 peripheral blood mononuclear cells) for frequency, the sensitivity and specificity of distinguishing ATB from LTBI were 72.2% and 73.7%, respectively. ESAT-6 and CFP-10-FluoroSpot detected the frequency and proportion of single IFN-γ-secreting T cells; the sensitivity and specificity of distinguishing ATB from LTBI were 82.5% and 66.7%, respectively. Combined with the frequency of single IL-2-secreting T cells stimulated by Rv1733c SLP on the basis of ESAT-6 and CFP-10-FluoroSpot, the sensitivity and specificity increased to 84.2% and 83.3%, respectively. CONCLUSION Rv1733c SLP, combined with ESAT-6 and CFP-10, might be used as a candidate antigen for T cell-based tuberculosis diagnostic tests to differentiate ATB from LTBI.
Antigens, Bacterial ; Diagnosis, Differential ; Humans ; Latent Tuberculosis/diagnosis* ; Leukocytes, Mononuclear ; Mycobacterium tuberculosis ; Tuberculosis/diagnosis*

PURPOSE: This study aimed to evaluate ichroma™ IGRA-TB, a novel point-of-care platform for assaying IFN-γ release, and to compare it with QuantiFERON-TB Gold In-Tube (QFT-GIT) for identifying Mycobacterium tuberculosis (M. tb) infection. MATERIALS AND METHODS: We recruited 60 healthy subjects, and blood samples were obtained in QFT-GIT blood collection tubes. The blood collection tubes were incubated at 37℃, and culture supernatant was harvested after 18–24 hours. IFN-γ responses were assessed by the ichroma™ IGRA-TB cartridge and the QFT-GIT IFN-γ enzyme-linked immunosorbent assay. Three active TB patients were recruited as a positive control for M. tb infection. RESULTS: The area under the receiver operating characteristic curve of the ichroma™ IGRA-TB test for differentiating between infected and non-infected individuals was 0.9706 (p < 0.001). Inconsistent positivity between the two tests was found in three participants who showed weak positive IFN-γ responses ( < 1.0 IU/mL) with QFT-GIT. However, the two tests had excellent agreement (95.2%, κ=0.91, p < 0.001), and a very strong positive correlation was observed between the IFN-γ values of both tests (r=0.91, p < 0.001). CONCLUSION: The diagnostic accuracy demonstrated in this study indicates that the ichroma™ IGRA-TB test could be used as a rapid diagnostic method for detecting latent TB infection. It may be particularly beneficial in resource-limited places that require cost-effective laboratory diagnostics.
Diagnosis ; Enzyme-Linked Immunosorbent Assay ; Feasibility Studies ; Healthy Volunteers ; Humans ; Korea ; Latent Tuberculosis ; Methods ; Mycobacterium tuberculosis ; Point-of-Care Systems ; ROC Curve ; Tuberculosis

In order to eliminate tuberculosis worldwide by 2050, effective management of latent tuberculosis infection is essential, and policy-makers have begun to recognize the importance of scaling up preventive therapy. The current guideline recommends targeted latent tuberculosis infection testing that identifies high-risk groups based on risk stratification for progression from latent infection to active disease. Both the tuberculin skin test and interferon-gamma releasing assay have a similar diagnostic efficacy for predicting progression to active tuberculosis. The Korean guideline recommends 9-month isoniazid monotherapy as the standard treatment; however, more evidence supports that short course rifampicin-based regimen is both more effective and tolerable than isoniazid monotherapy.
Diagnosis ; Interferon-gamma ; Interferon-gamma Release Tests ; Isoniazid ; Latent Tuberculosis ; Skin Tests ; Tuberculin ; Tuberculosis

BACKGROUND: This study aimed to compare the indicators (the rates of diagnosis, need for treatment, treatment initiation, and treatment completion) of management of latent tuberculosis infection (LTBI) in contacts and to identify the impact of active tuberculosis (TB) index case characteristics on the exposed population in congregated settings, such as schools, workplaces, and medical institutes. METHODS: The data of 8,648 clusters in the TB epidemiological investigation database between 2013 and 2016 were extracted and analyzed to evaluate the indicators and perform multilevel logistic regression (MLR) analyses to identify the factors affecting each indicator. RESULTS: The rates of total LTBI diagnosis, need for treatment, treatment initiation, and treatment completion were 15.2%, 10.2%, 69.4%, and 76.6%, respectively. After adjusting for other factors on MLR, the probability of diagnosis and need for treatment of latent TB in contacts was higher in most types of facilities than in schools. Conversely, treatment completion rates in these facilities were lower. Notably, the correctional institutions showed the highest odds ratio (OR) relative to school for LTBI diagnosis (OR, 6.37) and need for treatment (OR, 4.49) and the lowest OR for treatment completion (OR, 0.10). CONCLUSION: This study provided evidence for the implementation of latent TB control policies in congregated settings.
Academies and Institutes ; Diagnosis ; Humans ; Korea ; Latent Tuberculosis ; Logistic Models ; Odds Ratio ; Tuberculosis

BACKGROUND: In-hospital detection of newly diagnosed active pulmonary tuberculosis (TB) is important for prevention of potential outbreaks. Here, we report our experience of the aggressive contact investigation strategy in a university hospital in the Republic of Korea after healthcare workers (HCWs), patients, and visitors experience an in-hospital exposure to active pulmonary TB. METHODS: A contact investigation after the unexpected detection of newly diagnosed active pulmonary TB (index patients) was performed in a university hospital from August 2016 to April 2017. Initial and 3-month-post-exposure chest radiographs were advised for all patients, visitors, and HCWs in close contact with the index patients. An additional tuberculous skin test or interferon gamma releasing assay was performed at the time of exposure and 3 months post-exposure in HCWs in close contact with the index patients. RESULTS: Twenty-four index patients were unexpectedly diagnosed with active pulmonary TB after admission to the hospital with unassociated diseases. The median time from admission to TB diagnosis was 5 days (range, 1–22 days). In total, 1,057 people were investigated because of contact with the index patients, 528 of which had close contact (206 events in 157 HCWs, 322 patients or visitors). Three months post exposure, 9 (9.2%) among 98 TB-naïve close contact HCWs developed latent tuberculosis infections (LTBIs). Among the 65 close contact patients or visitors, there was no radiological or clinical evidence of active pulmonary TB. CONCLUSION: An aggressive contact investigation after an unexpected in-hospital diagnosis of active pulmonary TB revealed a high incidence of LTBI among TB-naïve HCWs who had contact with the index patients.
Delivery of Health Care ; Diagnosis ; Disease Outbreaks ; Humans ; Incidence ; Infection Control ; Interferons ; Latent Tuberculosis ; Mycobacterium ; Radiography, Thoracic ; Republic of Korea ; Skin Tests ; Tuberculosis, Pulmonary

PURPOSE: The purpose of this study was to provide basic data on the infection prevention management program, which is one of the infectious disease control program by identifying the prevalence and risk factors of latent tuberculosis infection (LTBI) in healthcare workers.METHODS: We surveyed a total of 3,046 LTBI test results, including those of 2,269 existing staff and 777 new employees. An interferon-gamma release assay (IGRA) for the diagnosis of LTBI was performed using QuantiFERON®-TB Gold In-Tube (QFT-IT). The risk factors of LTBI were analyzed using logistic regression analysis.RESULTS: The overall prevalence of LTBI was 16.0% (487/3,046). The prevalence of LTBI in the existing staff was 17.9% (406/2,269) and the prevalence of LTBI in new employees was 10.4% (81/777). Multivariate logistic regression analysis revealed that the risk factors of latent tuberculosis infection among the existing staff were gender, age and work period wheres, the risk factor amongst the new employees depended on their age.CONCLUSION: The LTBI was not related to the type of occupation and work unit. Therefore, while establishing an infection control program for the prevention of tuberculosis infection at medical institurions, institutional heads and infection control experts should encompass a policy for all the employees.
Communicable Diseases ; Delivery of Health Care ; Diagnosis ; Head ; Infection Control ; Interferon-gamma Release Tests ; Latent Tuberculosis ; Logistic Models ; Occupations ; Prevalence ; Risk Factors ; Tuberculosis

BACKGROUND: It remains uncertain if interferon-γ release assays (IGRAs) are superior to the tuberculin skin test (TST) for the diagnosis of active tuberculosis (TB) or latent tuberculosis infection (LTBI) in immunosuppressed populations including people with human immunodeficiency virus (HIV) infection. The purpose of this study was to systematically review the performance of IGRAs and the TST in people with HIV with active TB or LTBI in low and high prevalence TB countries. METHODS: We searched the MEDLINE database from 1966 through to January 2017 for studies that compared results of the TST with either the commercial QuantiFERON-TB Gold in Tube (QFTGT) assay or previous assay versions, the T-SPOT.TB assay or in-house IGRAs. Data were summarized by TB prevalence. Tests for concordance and differences in proportions were undertaken as appropriate. The variation in study methodology was appraised. RESULTS: Thirty-two studies including 4,856 HIV subjects met the search criteria. Fourteen studies compared the tests in subjects with LTBI in low TB prevalence settings. The QFTGT had a similar rate of reactivity to the TST, although the first-generation version of that assay was reactive more commonly. IGRAs were more frequently positive than the TST in HIV infected subjects with active TB. There was considerable study methodology and population heterogeneity, and generally low concordance between tests. Both the TST and IGRAs were affected by CD4 T-cell immunodeficiency. CONCLUSION: Our review of comparative data does not provide robust evidence to support the assertion that the IGRAs are superior to the TST when used in HIV infected subjects to diagnose either active TB or LTBI.
Diagnosis ; HIV Infections ; HIV ; Humans ; Interferon-gamma Release Tests ; Latent Tuberculosis ; Population Characteristics ; Prevalence ; Skin Tests ; Skin ; T-Lymphocytes ; Tuberculin Test ; Tuberculin ; Tuberculosis

A 72-year-old woman presented with recurrent painful erythematous nodules and ulcers on both legs. Latent tuberculosis was proven by a positive interferon-gamma release assay, and a histopathology examination revealed septolobular panniculitis with vasculitis. The initial diagnosis was erythema induratum associated with tuberculosis, but the leg ulcers became worse despite anti-tuberculosis medication and wound dressing. Computed tomography angiography showed occlusion of the superficial femoral and popliteal arteries bilaterally, supporting that the vascular event contributes to the ulcers according to the vascular territories. Under the diagnosis of peripheral arterial occlusive disease, she was treated with percutaneous transluminal angioplasty and antiplatelet medication. The skin ulcers were resolved. Elderly patients with erythema induratum have a risk of coincidental peripheral arterial occlusive disease, therefore dermatologists should be aware of the possibility of underlying vascular disease, so even minor trauma like skin biopsy can evoke serious condition shown in this patient. Here, we report a case of drastically aggravated erythema induratum due to co-existing peripheral arterial occlusive disease, which resolved with vascular intervention after not responding to antituberculosis medication.
Aged ; Angiography ; Angioplasty ; Arterial Occlusive Diseases* ; Bandages ; Biopsy ; Diagnosis ; Erythema Induratum* ; Erythema* ; Female ; Humans ; Interferon-gamma Release Tests ; Latent Tuberculosis ; Leg ; Leg Ulcer ; Panniculitis ; Popliteal Artery ; Skin ; Skin Ulcer ; Tuberculosis ; Ulcer ; Vascular Diseases ; Vasculitis ; Wounds and Injuries

OBJECTIVETo identify potential serum biomarkers for distinguishing between latent tuberculosis infection (LTBI) and active tuberculosis (TB).

METHODSA proteome microarray containing 4,262 antigens was used for screening serum biomarkers of 40 serum samples from patients with LTBI and active TB at the systems level. The interaction network and functional classification of differentially expressed antigens were analyzed using STRING 10.0 and the TB database, respectively. Enzyme-linked immunosorbent assays (ELISA) were used to validate candidate antigens further using 279 samples. The diagnostic performances of candidate antigens were evaluated by receiver operating characteristic curve (ROC) analysis. Both antigen combination and logistic regression analysis were used to improve diagnostic ability.

RESULTSMicroarray results showed that levels of 152 Mycobacterium tuberculosis (Mtb)-antigen- specific IgG were significantly higher in active TB patients than in LTBI patients (P < 0.05), and these differentially expressed antigens showed stronger associations with each other and were involved in various biological processes. Eleven candidate antigens were further validated using ELISA and showed consistent results in microarray analysis. ROC analysis showed that antigens Rv2031c, Rv1408, and Rv2421c had higher areas under the curve (AUCs) of 0.8520, 0.8152, and 0.7970, respectively. In addition, both antigen combination and logistic regression analysis improved the diagnostic ability.

CONCLUSIONSeveral antigens have the potential to serve as serum biomarkers for discrimination between LTBI and active TB.

Adolescent ; Adult ; Aged ; Antibodies, Bacterial ; Antibody Specificity ; Antigens, Bacterial ; Biomarkers ; blood ; Female ; Humans ; Latent Tuberculosis ; blood ; diagnosis ; Logistic Models ; Male ; Middle Aged ; Mycobacterium tuberculosis ; Protein Array Analysis ; methods ; Proteome ; genetics ; Proteomics ; methods ; ROC Curve ; Young Adult