scholarly journals Quantitative Analysis of Gamma Interferon Release Assay Response in Children with Latent and Active Tuberculosis

2017 ◽  
Vol 56 (2) ◽  
Author(s):  
Giulia Lombardi ◽  
Roberta Petrucci ◽  
Ilaria Corsini ◽  
Maria Letizia Bacchi Reggiani ◽  
Francesca Visciotti ◽  
...  
Keyword(s):  
Immune Response ◽  
Pediatric Population ◽  
Active Tuberculosis ◽  
University Hospital ◽  
Content Type ◽  
Release Assay ◽  
Latent Tb ◽  
Specific Antigens ◽  
Ifn Γ ◽  
Latent Tb Infection

ABSTRACT The use of interferon gamma (IFN-γ) release assays (IGRAs) for the diagnosis of tuberculosis (TB) infection in children is still under debate because of concerns about the immature immune response in children. The aim of this study was to investigate quantitative values of the QuantiFERON-TB Gold In-Tube (QFT-IT) test, a commercially available IGRA, in a large cohort of children screened for TB infection. A retrospective analysis was conducted on samples from 517 children aged 0 to 14 years old at the Pediatric Unit of S. Orsola-Malpighi University Hospital of Bologna (Italy); quantitative responses to QFT-IT stimuli were analyzed according to diagnosis and age. Elevated IFN-γ values in the QFT-IT nil (background) tube were statistically associated with diagnosis of active TB. Quantitative IFN-γ response to Mycobacterium tuberculosis-specific antigens (TB Ag) was not significantly different in children with active TB compared to those with latent TB infection (LTBI), even though the median values were higher in the first group. When children were grouped by age, those less than 5 years old produced significantly higher levels of IFN-γ in response to TB Ag if they had active TB (median 10 IU/ml) than those with LTBI (median 1.96 IU/ml). IFN-γ response to mitogen increased with age. The overall rate of indeterminate results was low (3.9%), and no indeterminate QFT-IT values were observed in active or latent TB patients. In conclusion, quantitative QFT-IT values could provide further information to clinicians to manage TB in children, and these observations could be transferred to the new version of the test, QuantiFERON-TB Gold Plus, which to date lacks data from the pediatric population.

scholarly journals Characterization of Host and Microbial Determinants in Individuals with Latent Tuberculosis Infection Using a Human Granuloma Model

mBio ◽  
2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Evelyn Guirado ◽  
Uchenna Mbawuike ◽  
Tracy L. Keiser ◽  
Jesus Arcos ◽  
Abul K. Azad ◽  
...  
Keyword(s):  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
Immune Status ◽  
Host Immune Response ◽  
Granuloma Formation ◽  
Content Type ◽  
Transcriptional Signature ◽  
Latent Tb ◽  
Latent Tb Infection

ABSTRACTGranulomas sit at the center of tuberculosis (TB) immunopathogenesis. Progress in biomarkers and treatment specific to the human granuloma environment is hindered by the lack of a relevant and tractable infection model that better accounts for the complexity of the host immune response as well as pathogen counterresponses that subvert host immunity in granulomas. Here we developed and characterized anin vitrogranuloma model derived from human peripheral blood mononuclear cells (PBMCs) and autologous serum. Importantly, we interrogated this model for its ability to discriminate between host and bacterial determinants in individuals with and without latent TB infection (LTBI). By the use of this model, we provide the first evidence that granuloma formation, bacterial survival, lymphocyte proliferation, pro- and anti-inflammatory cytokines, and lipid body accumulation are significantly altered in LTBI individuals. Moreover, we show a specific transcriptional signature ofMycobacterium tuberculosisassociated with survival within human granuloma structures depending on the host immune status. Our report provides fundamentally new information on how the human host immune status and bacterial transcriptional signature may dictate early granuloma formation and outcome and provides evidence for the validity of the granuloma model and its potential applications.IMPORTANCEIn 2012, approximately 1.3 million people died from tuberculosis (TB), the highest rate for any single bacterial pathogen. The long-term control of TB requires a better understanding ofMycobacterium tuberculosispathogenesis in appropriate research models. Granulomas represent the characteristic host tissue response to TB, controlling the bacilli while concentrating the immune response to a limited area. However, complete eradication of bacteria does not occur, sinceM. tuberculosishas its own strategies to adapt and persist. Thus, theM. tuberculosis-containing granuloma represents a unique environment for dictating both the host immune response and the bacterial response. Here we developed and characterized anin vitrogranuloma model derived from blood cells of individuals with latent TB infection that more accurately defines the human immune response and metabolic profiles ofM. tuberculosiswithin this uniquely regulated immune environment. This model may also prove beneficial for understanding other granulomatous diseases.

scholarly journals The immune response to tuberculosis infection in the setting ofHelicobacter pyloriand helminth infections

2012 ◽  
Vol 141 (6) ◽  
pp. 1232-1243 ◽  
Author(s):  
S. PERRY ◽  
A. H. CHANG ◽  
L. SANCHEZ ◽  
S. YANG ◽  
T. D. HAGGERTY ◽  
...  
Keyword(s):  
Helminth Infection ◽  
Healthy Adult ◽  
Interferon Γ ◽  
Cytokine Responses ◽  
Helminth Infections ◽  
Release Assay ◽  
Latent Tb ◽  
Ifn Γ ◽  
H Pylori ◽  
Latent Tb Infection

SUMMARYWe screened 176 healthy, adult (aged 18–55 years) US refugees from tuberculosis (TB)-endemic countries to evaluate whether cytokine responses to latent TB infection (LTBI) are modified in the setting of concurrentH. pyloriand helminth infection. As measured by the Quantiferon-TB GOLD interferon-γ release assay, a total 38 (22%) subjects had LTBI, of which 28 (74%) also wereH. pyloriseropositive and/or helminth infected. Relative to ten subjects with LTBI only, 16 subjects with concurrentH. pyloriinfection had significantly elevated levels of IFN-γ, and nine subjects with bothH. pyloriand helminth infection had significantly elevated levels of IFN-γ, IL-2, IL-13, and IL-5.H. pyloriis associated with enhanced IFN-γ responses to TB, even in the setting of concurrent helminth infection. Efficacy of TB vaccines may vary with the co-existence of these three infections in the developing world.

Surveillance of Employees of Swiss Federal Asylum Centres for Latent Tuberculosis Infection

Respiration ◽  
2021 ◽  
pp. 369-373
Author(s):  
Jean-Pierre Zellweger ◽  
Ariane Zellweger-Landry ◽  
Jean-Marie Egger ◽  
Annette Koller-Doser ◽  
Axel Jeremias Schmidt
Keyword(s):  
Asylum Seekers ◽  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
Active Tuberculosis ◽  
Interferon Gamma Release Assay ◽  
Work Related ◽  
Release Assay ◽  
Latent Tb ◽  
Latent Tb Infection

Background: Asylum seekers in Switzerland have to register in federal asylum centres (FACs) before formal permission to enter the country. Some of them may have active tuberculosis (TB), exposing fellow refugees and employees. Objectives: The aim of this study was to assess the risk of TB infection among employees of Swiss FACs. Methods: Between 2010 and 2018, a free interferon-gamma release assay (IGRA) was offered to all employees of 8 FACs, at employment and at yearly intervals. We defined latent TB infection as IGRA conversion from negative to positive. IGRA-positive employees were referred to a medical centre for further clinical follow-up. Results: 1,427 tests were performed among 737 employees (54.6% male). 403 (55%) persons were tested only once; 330 (44.5%) were tested several times; for 4 (0.5%) persons, the number of IGRA tests is unknown. Twenty employees (2.7%) had a positive IGRA at baseline, 2 (0.6%) converted from negative to positive during follow-up, resulting in an incidence of 22/10,000 person-years. We observed no case of active TB among employees. Conclusions: The prevalence of latent TB among employees to Swiss FACs and the risk of acquiring TB infection through work-related exposure are low. Yearly IGRA controls in the absence of documented TB exposure seem unnecessary.

scholarly journals Identification of Immunological Biomarkers Which May Differentiate Latent Tuberculosis from Exposure to Environmental Nontuberculous Mycobacteria in Children

2013 ◽  
Vol 21 (2) ◽  
pp. 133-142 ◽  
Author(s):  
Yun-Gyoung Hur ◽  
Amelia C. Crampin ◽  
Christina Chisambo ◽  
James Kanyika ◽  
Rein Houben ◽  
...  
Keyword(s):  
Nontuberculous Mycobacteria ◽  
Latent Tuberculosis ◽  
Control Group ◽  
Content Type ◽  
Interleukin 5 ◽  
Bcg Vaccination ◽  
Early Secretory Antigenic Target ◽  
Latent Tb ◽  
Ifn Γ ◽  
Latent Tb Infection

ABSTRACTA positive gamma interferon (IFN-γ) response toMycobacterium tuberculosisearly secretory antigenic target-6 (ESAT-6)/culture filtrate protein-10 (CFP-10) has been taken to indicate latent tuberculosis (TB) infection, but it may also be due to exposure to environmental nontuberculous mycobacteria in which ESAT-6 homologues are present. We assessed the immune responses toM. tuberculosisESAT-6 and cross-reactive responses to ESAT-6 homologues ofMycobacterium aviumandMycobacterium kansasii. Archived culture supernatant samples from children at 3 years post-BCG vaccination were tested for cytokine/chemokine responses toM. tuberculosisantigens. Furthermore, the IFN-γ responses toM. tuberculosisantigens were followed up for 40 children at 8 years post-BCG vaccination, and 15 TB patients were recruited as a control group for theM. tuberculosisESAT-6 response in Malawi. IFN-γ enzyme-linked immunosorbent assays (ELISAs) on supernatants from diluted whole-blood assays, IFN-γ enzyme-linked immunosorbent spot (ELISpot) assays, QuantiFERON TB Gold-In Tube tests, and multiplex bead assays were performed. More than 45% of the responders toM. tuberculosisESAT-6 showed IFN-γ responses toM. aviumandM. kansasiiESAT-6. In response toM. tuberculosisESAT-6/CFP-10, interleukin 5 (IL-5), IL-9, IL-13, and IL-17 differentiated the stronger IFN-γ responders toM. tuberculosisESAT-6 from those who preferentially responded toM. kansasiiandM. aviumESAT-6. A cytokine/chemokine signature of IL-5, IL-9, IL-13, and IL-17 was identified as a putative immunological biosignature to differentiate latent TB infection from exposure toM. aviumandM. kansasiiin Malawian children, indicating that this signature might be particularly informative in areas where both TB and exposure to environmental nontuberculous mycobacteria are endemic.

A Summary of the Third Global Interferon-γ Release Assay Symposium

2013 ◽  
Vol 34 (6) ◽  
pp. 619-624 ◽  
Author(s):  
Antonino Catanzaro ◽  
Charles Daley
Keyword(s):  
Immune Response ◽  
Tuberculin Skin Test ◽  
Skin Test ◽  
Interferon Γ ◽  
Enzyme Linked Immunosorbent Assay ◽  
In Vitro Tests ◽  
The Third ◽  
Specific Antigens ◽  
Ifn Γ

Studies over the past several decades have dramatically increased our understanding of the immune response to Mycobacterium tuberculosis infection, and advances in proteomics and genomics have led to a new class of immune-diagnostic tests, termed interferon-γ (IFN-γ) release assays (IGRAs), which appear to obviate many of the problems encountered with the tuberculin skin test (TST). Worldwide, 2 IGRAs are currently commercially available. QuantiFERON-TB Gold In-Tube (Cellestis) is a third-generation product that uses an enzyme-linked immunosorbent assay to measure IFN-γ generated in whole blood stimulated with M. tuberculosis–specific antigens. T-Spot-TB (Oxford Immunotec) employs enzyme-linked immunosorbent spot technology to enumerate the number of purified lymphocytes that respond to M. tuberculosis–specific antigens by producing IFN-γ. These in vitro tests measure the host immune response to M. tuberculosis–specific antigens, which virtually eliminates false-positive cross reactions caused by bacillus Calmette-Guérin vaccination and/or exposure to environmental nontuberculous mycobacteria that plague the interpretation and accuracy of the tuberculin skin test (TST). The high specificity of IGRAs, together with sensitivity commensurate with or better than that of the TST, promises an accurate diagnosis and the ability to focus tuberculosis-control activities on those who are actually infected with M. tuberculosis. The Third Global Symposium was held over a 3-day period and was presented by the University of California, San Diego, Continuing Medical Education department; slides and sound recordings of each presentation are available at http://cme.ucsd.edu/igras/syllabus.html. A moderated discussion is also available at http://cme.ucsd.edu/igrasvideo. This document provides a summary of the key findings of the meeting, specifically focusing on the use of IGRAs in screening healthcare worker populations.

scholarly journals Bovine Immune Response to Vaccination and Infection with Leptospira borgpetersenii Serovar Hardjo

mSphere ◽  
2021 ◽  
Vol 6 (2) ◽  
Author(s):  
Jennifer H. Wilson-Welder ◽  
David P. Alt ◽  
Jarlath E. Nally ◽  
Steven C. Olsen
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Lymph Nodes ◽  
Γδ T Cells ◽  
Regional Lymph Nodes ◽  
Content Type ◽  
Oil Emulsion ◽  
Leptospira Borgpetersenii ◽  
Ifn Γ ◽  
Experimental Challenge

ABSTRACT This study examined the humoral and cellular response of cattle vaccinated with two commercial leptospiral vaccines, Leptavoid and Spirovac, and a novel bacterin vaccine using Seppic Montanide oil emulsion adjuvant. Vaccination was followed by experimental challenge. All vaccinated cattle were protected from colonization of the kidney and shedding of Leptospira in urine, as detected by culture and immunofluorescence assay. Agglutinating antibody titers were detected in vaccinated cattle at 4 weeks following vaccination, with small anamnestic response detected following experimental challenge. Only animals vaccinated with the oil emulsion-adjuvanted bacterin produced significant IgG2 titers following vaccination, and nonvaccinated animals produced serum IgA titers after experimental challenge. CD4+ and γδ T cells from vaccinated cattle proliferated when cultured with antigen ex vivo. Cellular responses included a marked proliferation of γδ T cells immediately following experimental challenge in vaccinated cattle and release of gamma interferon (IFN-γ), interleukin 17a (IL-17a), and IL-12p40 from stimulated cells. Proliferative and cytokine responses were found not just in peripheral mononuclear cells but also in lymphocytes isolated from renal lymph nodes at 10 weeks following experimental challenge. Overall, effects of leptospirosis vaccination and infection were subtle, resulting in only modest activation of CD4+ and γδ T cells. The use of Seppic Montanide oil emulsion adjuvants may shorten the initiation of response to vaccination, which could be useful during outbreaks or in areas where leptospirosis is endemic. IMPORTANCE Leptospirosis is an underdiagnosed, underreported zoonotic disease of which domestic livestock can be carriers. As a reservoir host for Leptospira borgpetersenii serovar Hardjo, cattle may present with reproductive issues, including abortion, birth of weak or infected calves, or failure to breed. Despite years of study and the availability of commercial vaccines, detailed analysis of the bovine immune response to vaccination and Leptospira challenge is lacking. This study evaluated immunologic responses to two efficacious commercial vaccines and a novel bacterin vaccine using an adjuvant chosen for enhanced cellular immune responses. Antigen-specific responsive CD4 and γδ T cells were detected following vaccination and were associated with release of inflammatory cytokines IFN-γ and IL-17a after stimulation. CD4 and γδ cells increased in the first week after infection and, combined with serum antibody, may play a role in clearance of bacteria from the blood and resident tissues. Additionally, these antigen-reactive T cells were found in the regional lymph nodes following infection, indicating that memory responses may not be circulating but are still present in regional lymph nodes. The information gained in this study expands knowledge of bovine immune response to leptospirosis vaccines and infection. The use of oil emulsion adjuvants may enhance early immune responses to leptospiral bacterins, which could be useful in outbreaks or situations where leptospirosis is endemic.

scholarly journals Gamma Interferon Is Required for Chlamydia Clearance but Is Dispensable for T Cell Homing to the Genital Tract

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Jennifer D. Helble ◽  
Rodrigo J. Gonzalez ◽  
Ulrich H. von Andrian ◽  
Michael N. Starnbach
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Chlamydia Trachomatis ◽  
Genital Tract ◽  
Gamma Interferon ◽  
Cell Homing ◽  
Content Type ◽  
T Cell Homing ◽  
Ifn Γ

ABSTRACT While there is no effective vaccine against Chlamydia trachomatis infection, previous work has demonstrated the importance of C. trachomatis-specific CD4+ T cells (NR1 T cells) in pathogen clearance. Specifically, NR1 T cells have been shown to be protective in mice, and this protection depends on the host’s ability to sense the cytokine gamma interferon (IFN-γ). However, it is unclear what role NR1 production or sensing of IFN-γ plays in T cell homing to the genital tract or T cell-mediated protection against C. trachomatis. Using two-photon microscopy and flow cytometry, we found that naive wild-type (WT), IFN-γ−/−, and IFN-γR−/− NR1 T cells specifically home to sections in the genital tract that contain C. trachomatis. We also determined that protection against infection requires production of IFN-γ from either NR1 T cells or endogenous cells, further highlighting the importance of IFN-γ in clearing C. trachomatis infection. IMPORTANCE Chlamydia trachomatis is an important mucosal pathogen that is the leading cause of sexually transmitted bacterial infections in the United States. Despite this, there is no vaccine currently available. In order to develop such a vaccine, it is necessary to understand the components of the immune response that can lead to protection against this pathogen. It is well known that antigen-specific CD4+ T cells are critical for Chlamydia clearance, but the contexts in which they are protective or not protective are unknown. Here, we aimed to characterize the importance of gamma interferon production and sensing by T cells and the effects on the immune response to C. trachomatis. Our work here helps to define the contexts in which antigen-specific T cells can be protective, which is critical to our ability to design an effective and protective vaccine against C. trachomatis.

scholarly journals PO 8383 THE ROLE OF PLASMA B CELLS IN MYCOBACTERIUM TUBERCULOSIS INFECTION AND DISEASE

2019 ◽  
Vol 4 (Suppl 3) ◽  
pp. A31.2-A31
Author(s):  
Awa Gindeh ◽  
Simon Donkor ◽  
Olumuyiwa Owolabi
Keyword(s):  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
B Cells ◽  
B Cell ◽  
Bacterial Infections ◽  
Relative Proportion ◽  
Post Treatment ◽  
Latent Tb ◽  
Latent Tb Infection

BackgroundTuberculosis (TB) is still a major global health problem with about one-quarter of the global population infected with the causative pathogen, Mycobacterium tuberculosis (Mtb). The role of T-cells in the adaptive immune response against Mtb has been extensively studied with little information on the role of B-cells. B-cells produce antibodies and differentiate into plasma and memory B-cells. Plasmablasts are a subset of plasma cells only present in the peripheral circulation following an ongoing infection or vaccination. Immunoglobulin G’(IgG) especially IgG2 mounts more efficient immune response against bacterial infections, mainly attributed to the high affinity of IgG2 binding to the Fcγ receptor. Therefore, we hypothesised that Mtb-specific IgG +plasmablasts may be a useful biomarker of TB infection status.MethodsEx-vivo B-cell enzyme-linked immunospot (ELISPOT) was used to identify plasmablasts responses to Mtb-specific antigens ESAT-6/CFP-10 (EC), together with non-specific Mtb purified protein derivative (PPD) and a positive (total IgG) and negative (media only) control from adults with active TB pre- and post-treatment (n=20) or with latent TB infection (LTBI; n=20) in The Gambia.ResultsFrequencies of Mtb-specific plasmablasts were significantly higher in active TB cases pre-treatment compared to post-treatment (p<0.0001) and LTBI with no difference seen following PPD stimulation. Interestingly, total IgG +cells were lower in the cases at recruitment but increased following treatment indicating the relative proportion of Mtb-specific responses were also significantly different (p=0.034) prior to therapy.ConclusionThese data show that B-cell responses are differentially modulated during active and latent TB infection, suggesting that plasmablasts may be a useful biomarker for TB infection in TB-endemic settings.

scholarly journals How Well Does TSTin3D Predict Risk of Active Tuberculosis in the Canadian Immigrant Population? An External Validation Study

2020 ◽  
Author(s):  
Joseph H Puyat ◽  
Hennady P Shulha ◽  
Robert Balshaw ◽  
Jonathon R Campbell ◽  
Stephanie Law ◽  
...  
Keyword(s):  
External Validation ◽  
Predictive Performance ◽  
Vital Statistics ◽  
Active Tuberculosis ◽  
Skin Tests ◽  
Interferon Gamma Release Assay ◽  
Positive Skin ◽  
Release Assay ◽  
Latent Tb Infection ◽  
Time Frames

Abstract Background The online Tuberculin Skin Test/Interferon Gamma Release Assay (TST/IGRA) Interpreter V3.0 (TSTin3D), a tool for estimating the risk of active tuberculosis (TB) in individuals with latent TB infection (LTBI), has been in use for more than a decade, but its predictive performance has never been evaluated. Methods People with a positive TST or IGRA result from 1985 to 2015 were identified using a health data linkage that involved migrants to British Columbia, Canada. Comorbid conditions at the time of LTBI testing were identified from physician claims, hospitalizations, vital statistics, outpatient prescriptions, and kidney and HIV databases. The risk of developing active TB within 2 and 5 years was estimated using TSTin3D. The discrimination and calibration of these estimates were evaluated. Results A total of 37 163 individuals met study inclusion criteria; 10.4% were tested by IGRA. Generally, the TSTin3D algorithm assigned higher risks to demographic and clinical groups known to have higher active TB risks. Concordance estimates ranged from 0.66 to 0.68 in 2- and 5-year time frames. Comparing predicted to observed counts suggests that TSTin3D overestimates active TB risks and that overestimation increases over time (with relative bias of 3% and 12% in 2- and 5-year periods, respectively). Calibration plots also suggest that overestimation increases toward the upper end of the risk spectrum. Conclusions TSTin3D can discriminate adequately between people who developed and did not develop active TB in this linked database of migrants with predominately positive skin tests. Further work is needed to improve TSTin3D’s calibration.

scholarly journals SP110 Polymorphisms Are Genetic Markers for Vulnerability to Latent and Active Tuberculosis Infection in Taiwan

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
So-Yi Chang ◽  
Mei-Ling Chen ◽  
Meng-Rui Lee ◽  
Yun-Chieh Liang ◽  
Tzu-Pin Lu ◽  
...  
Keyword(s):  
Genetic Susceptibility ◽  
Nuclear Protein ◽  
Case Control Study ◽  
Latent Infection ◽  
Active Tuberculosis ◽  
Taiwanese Population ◽  
Latent Tb ◽  
Latent Tb Infection ◽  
Necrosis Factor ◽  
Control Study

One-fourth of the human population is estimated to have been exposed to Mycobacterium tuberculosis (Mtb) and carries the infection in its latent form. This latent infection presents a lifelong risk of developing active tuberculosis (TB) disease, and persons with latent TB infection (LTBI) are significant contributors to the pool of active TB cases. Genetic polymorphisms among hosts have been shown to contribute to the outcome of Mtb infection. The SP110 gene, which encodes an interferon-induced nuclear protein, has been shown to control host innate immunity to Mtb infection. In this study, we provide experimental data demonstrating the ability of the gene to control genetic susceptibility to latent and active TB infection. Genetic variants of the SP110 gene were investigated in the Taiwanese population (including 301 pulmonary TB patients, 68 LTBI individuals, and 278 healthy household contacts of the TB patients), and their association with susceptibility to latent and active TB infection was examined by performing an association analysis in a case-control study. We identified several SNPs (rs7580900, rs7580912, rs9061, rs11556887, and rs2241525) in the SP110 gene that are associated with susceptibility to LTBI and/or TB disease. Our studies further showed that the same SNPs may have opposite effects on the control of susceptibility to LTBI versus TB. In addition, our analyses demonstrated that the SP110 rs9061 SNP was associated with tumor necrosis factor-α (TNFα) levels in plasma in LTBI subjects. The results suggest that the polymorphisms within SP110 have a role in controlling genetic susceptibility to latent and active TB infection in humans. To the best of our knowledge, this is the first report showing that the SP110 variants are associated with susceptibility to LTBI. Our study also demonstrated that the identified SP110 SNPs displayed the potential to predict the risk of LTBI and subsequent TB progression in Taiwan.

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