Special Issue "Tuberculosis: Clinical Applications in the Diagnosis and Treatment"

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Pulmonology".

Deadline for manuscript submissions: closed (30 November 2019).

Special Issue Editors

Dr. Daniela Maria Cirillo
E-Mail Website
Guest Editor
IRCCS San Raffaele Scientific Institute
Interests: Mycobacterium tuberculosis pathogenesis; Tuberculosis transmission; Nontuberculous mycobacteria; diagnosis and treatment of tuberculosis; multidrug resistant tuberculosis ; whole genome sequencing in diagnostic
Dr. Enrico Tortoli
E-Mail Website
Guest Editor
IRCCS San Raffaele Scientific Institute
Interests: Mycobacterium tuberculosis; Nontuberculous mycobacteria; mycobacterial microbiology; Mycobacterium phylogenesis

Special Issue Information

Dear Colleagues,

Tuberculosis (TB) continues to be a major cause of human suffering more than a century after its causative agent was discovered and more than six decades since effective treatments were developed. It infects a third of humanity and is a leading infectious cause of death worldwide, rivaling the impact of HIV/AIDS.


In this special issue, we focus on strengths and limitations of newer tests that are available for the diagnosis of latent and active tuberculosis and rapid detection of drug resistance, specifically, tests that measure release of IFN-γ in response to stimulation by Mycobacterium tuberculosis antigens, nucleic acid amplification for identification of M. tuberculosis complex, and rapid tests for detecting drug resistance.


On behalf of the Journal of Clinical Medicine you are cordially invited to contribute with an article to the special issue "Tuberculosis: Clinical Applications in the Diagnosis and Treatment". Research, Review, Mini Review, Case reports, Case Series, Clinical Cases will be considered for publication.

Dr. Daniela Maria Cirillo
Dr. Enrico Tortoli
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • TB diagnostics
  • Molecular diagnosis of TB
  • Conventional diagnosis of TB
  • Whole Genome Sequencing
  • Treatment of susceptible and resistant TB
  • Susceptibility testing of M. tuberculosis
  • Tuberculosis Transmission
  • Tuberculosis pathogenesis

Published Papers (14 papers)

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Research

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Open AccessArticle
Whole Genome Sequencing Results Associated with Minimum Inhibitory Concentrations of 14 Anti-Tuberculosis Drugs among Rifampicin-Resistant Isolates of Mycobacterium Tuberculosis from Iran
J. Clin. Med. 2020, 9(2), 465; https://doi.org/10.3390/jcm9020465 - 07 Feb 2020
Cited by 4 | Viewed by 1166
Abstract
Accurate and timely detection of drug resistance can minimize the risk of further resistance development and lead to effective treatment. The aim of this study was to determine the resistance to first/second-line anti-tuberculosis drugs in rifampicin/multidrug-resistant Mycobacterium tuberculosis (RR/MDR-MTB) isolates. Molecular epidemiology of [...] Read more.
Accurate and timely detection of drug resistance can minimize the risk of further resistance development and lead to effective treatment. The aim of this study was to determine the resistance to first/second-line anti-tuberculosis drugs in rifampicin/multidrug-resistant Mycobacterium tuberculosis (RR/MDR-MTB) isolates. Molecular epidemiology of strains was determined using whole genome sequencing (WGS)-based genotyping. A total of 35 RR/MDR-MTB isolates were subjected to drug susceptibility testing against first/second-line drugs using 7H9 Middlebrook in broth microdilution method. Illumina technology was used for paired-end WGS applying a Maxwell 16 Cell DNA Purification kit and the NextSeq platform. Data analysis and single nucleotide polymorphism calling were performed using MTBseq pipeline. The genome-based resistance to each drug among the resistant phenotypes was as follows: rifampicin (97.1%), isoniazid (96.6%), ethambutol (100%), levofloxacin (83.3%), moxifloxacin (83.3%), amikacin (100%), kanamycin (100%), capreomycin (100%), prothionamide (100%), D-cycloserine (11.1%), clofazimine (20%), bedaquiline (0.0%), and delamanid (44.4%). There was no linezolid-resistant phenotype, and a bedaquiline-resistant strain was wild type for related genes. The Beijing, Euro-American, and Delhi-CAS were the most populated lineage/sublineages. Drug resistance-associated mutations were mostly linked to minimum inhibitory concentration results. However, the role of well-known drug-resistant genes for D-cycloserine, clofazimine, bedaquiline, and delamanid was found to be more controversial. Full article
(This article belongs to the Special Issue Tuberculosis: Clinical Applications in the Diagnosis and Treatment)
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Open AccessArticle
Accuracy of the QIAxcel Automated System for MIRU-VNTR Genotyping of Mycobacterium tuberculosis in Two Limited Resource Settings
J. Clin. Med. 2020, 9(2), 389; https://doi.org/10.3390/jcm9020389 - 01 Feb 2020
Viewed by 808
Abstract
Mycobacterial interspersed repetitive units variable number tandem repeat (MIRU-VNTR) typing of Mycobacterium tuberculosis complex (MTBC) isolates, based on 24 loci, is still widely used as the standard for routine molecular surveillance of tuberculosis (TB). QIAxcel system is proposed as an affordable tool that [...] Read more.
Mycobacterial interspersed repetitive units variable number tandem repeat (MIRU-VNTR) typing of Mycobacterium tuberculosis complex (MTBC) isolates, based on 24 loci, is still widely used as the standard for routine molecular surveillance of tuberculosis (TB). QIAxcel system is proposed as an affordable tool that could replace conventional gel electrophoresis and provide high concordance with the reference methods regarding MIRU-VNTR typing of MTBC. We aimed to evaluate the QIAxcel accuracy for allele calling of MIRU-VNTR loci in two regional reference laboratories. A total of 173 DNA were used for the study. Results obtained with QIAxcel were compared to the reference results obtained with an ABI 3730 DNA analyzer. In Albania, the overall agreement with the reference method was 97.92%. A complete agreement result was obtained for 17 loci. In Tunisia, the overall agreement with the reference method was 98.95%. A complete agreement result was obtained for 17 loci. Overall agreement in both centers was 98.43%. In our opinion, use of QIAxcel technology has the potential to be reliable, given an optimized algorithm. Inaccuracies in sizing of long fragments should be solved, especially regarding locus 4052. Full article
(This article belongs to the Special Issue Tuberculosis: Clinical Applications in the Diagnosis and Treatment)
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Open AccessArticle
Fenofibrate Facilitates Post-Active Tuberculosis Infection in Macrophages and is Associated with Higher Mortality in Patients under Long-Term Treatment
J. Clin. Med. 2020, 9(2), 337; https://doi.org/10.3390/jcm9020337 - 25 Jan 2020
Viewed by 772
Abstract
Background: Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that infects and persists in macrophages. This study aimed to investigate the effects of long-term fenofibrate treatment in patients with tuberculosis (TB), and the intracellular viability of Mtb in human macrophages. Methods: Epidemiological [...] Read more.
Background: Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that infects and persists in macrophages. This study aimed to investigate the effects of long-term fenofibrate treatment in patients with tuberculosis (TB), and the intracellular viability of Mtb in human macrophages. Methods: Epidemiological data from the National Health Insurance Research Database of Taiwan were used to present outcomes of TB patients treated with fenofibrate. In the laboratory, we assessed Mtb infection in macrophages treated with or without fenofibrate. Mtb growth, lipid accumulation in macrophages, and expression of transcriptional genes were examined. Results: During 11 years of follow-up, TB patients treated with fenofibrate presented a higher risk of mortality. Longer duration of fenofibrate use was associated with a significantly higher risk of mortality. Treatment with fenofibrate significantly increased the number of bacilli in human macrophages in vitro. Fenofibrate did not reduce, but induced an increasing trend in the intracellular lipid content of macrophages. In addition, dormant genes of Mtb, icl1, tgs1, and devR, were markedly upregulated in response to fenofibrate treatment. Our results suggest that fenofibrate may facilitate intracellular Mtb persistence. Conclusions: Our data shows that long-term treatment with fenofibrate in TB patients is associated with a higher mortality. The underlying mechanisms may partly be explained by the upregulation of Mtb genes involved in lipid metabolism, enhanced intracellular growth of Mtb, and the ability of Mtb to sustain a nutrient-rich reservoir in human macrophages, observed during treatment with fenofibrate. Full article
(This article belongs to the Special Issue Tuberculosis: Clinical Applications in the Diagnosis and Treatment)
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Open AccessArticle
Latent Tuberculosis Infection Treatment Completion while Shifting Prescription from Isoniazid-Only to Rifampicin-Containing Regimens: A Two-Decade Experience in Milan, Italy
J. Clin. Med. 2020, 9(1), 101; https://doi.org/10.3390/jcm9010101 - 31 Dec 2019
Cited by 6 | Viewed by 1396
Abstract
To tackle the tuberculosis (TB) epidemic, in 2014 the World Health Organization launched the End TB Strategy, which includes action to prevent latent TB infection (LTBI) reactivation. Available preventive treatments (PT) are based on either isoniazid (INH) alone or rifampicin (RIF)-containing regimens. This [...] Read more.
To tackle the tuberculosis (TB) epidemic, in 2014 the World Health Organization launched the End TB Strategy, which includes action to prevent latent TB infection (LTBI) reactivation. Available preventive treatments (PT) are based on either isoniazid (INH) alone or rifampicin (RIF)-containing regimens. This study aims to assess and compare PT completion rates, the occurrence of adverse events, and the time of dropout among those receiving INH-alone or RIF-containing regimens at Villa Marelli Institute, Milan, Italy, covering the period from 1992 to 2018. A total of 19,670 subjects, belonging to various risk groups—mainly young (median age of 29 years), foreign-born (73.3%), and males (58.8%)—with presumed LTBI were prescribed PT (79.3% INH-alone and 20.7% RIF-containing regimens). The treatment completion rate was 79.4% on average, with higher rates among those receiving RIF-containing regimens (85.6%) compared to those that were prescribed INH-alone (77.8%) (p < 0.0001). Notably, some of the high-risk groups for progression of LTBI were more likely to complete PT from RIF-containing regimens. These groups included recent TB contact (89.9%, p < 0.0001), healthcare workers (93.5%, p < 0.0001), and homeless people (76.6%, p < 0.0001). Irrespectively of the chosen PT regimen, most of the dropouts occurred between the start of the treatment and the first follow-up visit (14.3%, 15.2% for those on INH-alone vs. 11.1% for those on RIF-containing regimens). Further shortening of the PT regimen is therefore an aim to ensure adherence, even though it might need further efforts to enhance the patient’s attitude towards starting and carrying out PT. Full article
(This article belongs to the Special Issue Tuberculosis: Clinical Applications in the Diagnosis and Treatment)
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Open AccessArticle
Treatment with Tumor Necrosis Factor-α Inhibitors, History of Allergy, and Hypercalcemia Are Risk Factors of Immune Reconstitution Inflammatory Syndrome in HIV-Negative Pulmonary Tuberculosis Patients
J. Clin. Med. 2020, 9(1), 96; https://doi.org/10.3390/jcm9010096 - 30 Dec 2019
Cited by 1 | Viewed by 899
Abstract
Immune reconstitution inflammatory syndrome (IRIS) is an immune reaction that occurs along with the recovery of the patient’s immunity. Tuberculosis-related IRIS (TB-IRIS) upon tumor necrosis factor (TNF)-α inhibitor treatment has been reported in non-human immunodeficiency virus (HIV) patients. However, the importance of biological [...] Read more.
Immune reconstitution inflammatory syndrome (IRIS) is an immune reaction that occurs along with the recovery of the patient’s immunity. Tuberculosis-related IRIS (TB-IRIS) upon tumor necrosis factor (TNF)-α inhibitor treatment has been reported in non-human immunodeficiency virus (HIV) patients. However, the importance of biological treatment, as a risk factor of IRIS, has not yet been established. In this study, we examined TB-IRIS in non-HIV patients to explore the role of TNF-α inhibitor treatment. Out of 188 patients with pulmonary TB, seven patients had IRIS. We examined univariate logistic and multivariate analysis to elucidate risk factors of TB-IRIS. Univariate analysis indicated that usage of immunosuppressive drugs, TNF-α inhibitors, and history of food or drug allergy were significantly related with TB-IRIS. On initial treatment, the values of serological markers such as serum albumin and serum calcium were significantly related with TB-IRIS. There was a higher mortality rate in patients with TB-IRIS. Furthermore, multivariate analysis revealed that usage of TNF-α inhibitors, history of allergy, and serum hypercalcemia were related to TB-IRIS. Usage of TNF-α inhibitors, history of allergy, and serum hypercalcemia may be independent predictors of TB-IRIS in non-HIV patients. Since higher mortality has been reported for TB-IRIS, we should pay attention to TB patients with these risk factors. Full article
(This article belongs to the Special Issue Tuberculosis: Clinical Applications in the Diagnosis and Treatment)
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Open AccessArticle
PrimeStore MTM and OMNIgene Sputum for the Preservation of Sputum for Xpert MTB/RIF Testing in Nigeria
J. Clin. Med. 2019, 8(12), 2146; https://doi.org/10.3390/jcm8122146 - 04 Dec 2019
Cited by 3 | Viewed by 916
Abstract
Background: Xpert MTB/RIF (GX) for tuberculosis (TB) diagnosis is often located in reference laboratories, and sputum needs to be transported using a cold chain. Transport media to preserve sputum are available, but performance data under programmatic conditions are limited. Methods: Sputum samples were [...] Read more.
Background: Xpert MTB/RIF (GX) for tuberculosis (TB) diagnosis is often located in reference laboratories, and sputum needs to be transported using a cold chain. Transport media to preserve sputum are available, but performance data under programmatic conditions are limited. Methods: Sputum samples were collected from patients with presumptive TB in Nigeria. One sputum was transported in a cold chain, tested immediately with GX and cultured. One sputum was swabbed and stored in PrimeStore-Molecular-Transport-Medium (Primestore), and the remainder was stored in OMNIGene-sputum (Omnigene), kept for seven days and tested with GX. Results: Of 248 patients, 63 were fresh-sputum culture-positive and 56 GX-positive (sensitivity 88.9%, 95% CI: 78.4–95.4%). Four of 185 culture-negative patients were GX-positive (specificity 97.8%, 94.6–99.4%). Omnigene GX and Primestore GX were positive in 56/62 (90.3%, 80.1–96.4%) and 49/62 (79.0%, 66.8–88.3%) culture-positive, respectively, and 1/185 (99.5%, 97.0–100.0%) and 3/185 (98.4%, 95.3–99.7%) were culture-negative patients. 14 Human Immunodeficiency Virus (HIV)-infected and 44 HIV-uninfected patients were culture-positive. Omnigene and Primestore detected 12/14 (85.7%, 57.2–98.2%) and 5/14 (35.7%, 12.8–64.9%) HIV-infected and 41/44 (93.2%, 81.3–98.6%) HIV-uninfected culture-positive patients. Interpretation: Omnigene stored and fresh sputum samples had similar GX results. The GX results of Primestore-stored samples were similar to those found in the fresh sputum of non-HIV infected patients, but GX-positivity was lower in HIV-infected patients. This was likely due to the lower amount of bacilli collected by the swab and transferred to PrimeStore. Full article
(This article belongs to the Special Issue Tuberculosis: Clinical Applications in the Diagnosis and Treatment)
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Open AccessArticle
Clinical Characteristics and Outcomes of Surgically Resected Solitary Pulmonary Nodules Due to Nontuberculous Mycobacterial Infections
J. Clin. Med. 2019, 8(11), 1898; https://doi.org/10.3390/jcm8111898 - 07 Nov 2019
Cited by 2 | Viewed by 700
Abstract
Background: Limited data are available regarding the detailed characteristics and outcomes of surgically resected nontuberculous mycobacterial (NTM) granulomas. Methods: We evaluated the characteristics of 49 NTM granulomas presenting as solitary pulmonary nodules (SPNs) between January 2007 and December 2016. Results: Twenty-five patients (51%) [...] Read more.
Background: Limited data are available regarding the detailed characteristics and outcomes of surgically resected nontuberculous mycobacterial (NTM) granulomas. Methods: We evaluated the characteristics of 49 NTM granulomas presenting as solitary pulmonary nodules (SPNs) between January 2007 and December 2016. Results: Twenty-five patients (51%) were male and 27 (55%) were never-smokers. Seven (14%) patients had a history of tuberculosis. More than half (51%) of patients were asymptomatic. On chest computed tomography, the median SPN diameter was 18 mm, and approximately half of all SPNs (49%) were located in the upper lobes on chest computed tomography. NTM strain were preoperatively isolated from sputum (46%, 12/26), bronchial wash fluid (54%, 14/26), and needle biopsy specimens (12%, 3/26). Mycobacterium avium (71%, 22/31) was the organism most commonly isolated, followed by Mycobacterium intracellulare (16%, 5/31). Postoperative pneumothorax and atelectasis developed in four (8%) patients and one (2%) patient, respectively. Five patients received postoperative antibiotic therapy. Over a median follow-up period of 18.0 months, one patient with residual lesions after surgery started macrolide-based therapy due to aggravated symptoms. Conclusions: Most NTM granulomas can be treated completely by surgical resection without antibiotic therapy, and microbiological examination of surgical specimens is important for optimal management. Full article
(This article belongs to the Special Issue Tuberculosis: Clinical Applications in the Diagnosis and Treatment)
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Open AccessArticle
Mitochondrial DNA Variants in Patients with Liver Injury Due to Anti-Tuberculosis Drugs
J. Clin. Med. 2019, 8(8), 1207; https://doi.org/10.3390/jcm8081207 - 13 Aug 2019
Cited by 3 | Viewed by 1091
Abstract
Background: Hepatotoxicity is the most severe adverse effect of anti-tuberculosis therapy. Isoniazid’s metabolite hydrazine is a mitochondrial complex II inhibitor. We hypothesized that mitochondrial DNA variants are risk factors for drug-induced liver injury (DILI) due to isoniazid, rifampicin or pyrazinamide. Methods: We obtained [...] Read more.
Background: Hepatotoxicity is the most severe adverse effect of anti-tuberculosis therapy. Isoniazid’s metabolite hydrazine is a mitochondrial complex II inhibitor. We hypothesized that mitochondrial DNA variants are risk factors for drug-induced liver injury (DILI) due to isoniazid, rifampicin or pyrazinamide. Methods: We obtained peripheral blood from tuberculosis (TB) patients before anti-TB therapy. A total of 38 patients developed DILI due to anti-TB drugs. We selected 38 patients with TB but without DILI as controls. Next-generation sequencing detected point mutations in the mitochondrial DNA genome. DILI was defined as ALT ≥5 times the upper limit of normal (ULN), or ALT ≥3 times the ULN with total bilirubin ≥2 times the ULN. Results: In 38 patients with DILI, the causative drug was isoniazid in eight, rifampicin in 14 and pyrazinamide in 16. Patients with isoniazid-induced liver injury had more variants in complex I’s NADH subunit 5 and 1 genes, more nonsynonymous mutations in NADH subunit 5, and a higher ratio of nonsynonymous to total substitutions. Patients with rifampicin- or pyrazinamide-induced liver injury had no association with mitochondrial DNA variants. Conclusions: Variants in complex I’s subunit 1 and 5 genes might affect respiratory chain function and predispose isoniazid-induced liver injury when exposed to hydrazine, a metabolite of isoniazid and a complex II inhibitor. Full article
(This article belongs to the Special Issue Tuberculosis: Clinical Applications in the Diagnosis and Treatment)
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Open AccessArticle
Application of Laser Scanning Confocal Microscopy for the Visualization of M. tuberculosis in Lung Tissue Samples with Weak Ziehl–Neelsen Staining
J. Clin. Med. 2019, 8(8), 1185; https://doi.org/10.3390/jcm8081185 - 07 Aug 2019
Cited by 2 | Viewed by 1480
Abstract
One of the key requirements for the diagnosis of pulmonary tuberculosis is the identification of M. tuberculosis in tissue. In this paper, we present the advantages of specific fluorescent antibody labelling, combined with laser scanning confocal microscopy (LSCM), for the detection of M. [...] Read more.
One of the key requirements for the diagnosis of pulmonary tuberculosis is the identification of M. tuberculosis in tissue. In this paper, we present the advantages of specific fluorescent antibody labelling, combined with laser scanning confocal microscopy (LSCM), for the detection of M. tuberculosis in histological specimens of lung tissues. We demonstrate that the application of LSCM allows: (i) The automatic acquisition of images of the whole slice and, hence, the determination of regions for subsequent analysis; (ii) the acquisition of images of thick (20–40 μm) slices at high resolution; (iii) single bacteria identification; and (iv) 3D reconstruction, in order to obtain additional information about the distribution, size, and morphology of solitary M. tuberculosis; as well as their aggregates and colonies, in various regions of tuberculosis inflammation. LSCM allows for the discrimination of the non-specific fluorescence of bacteria-like particles and their aggregates presented in histological lung samples, from the specific fluorescence of labelled M. tuberculosis, using spectrum emission analysis. The applied method was effective in the identification of M. tuberculosis in lung histological samples with weak Ziehl–Neelsen staining. Altogether, combining immunofluorescent labelling with the application of LSCM visualization significantly increases the effectiveness of M. tuberculosis detection. Full article
(This article belongs to the Special Issue Tuberculosis: Clinical Applications in the Diagnosis and Treatment)
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Open AccessArticle
Clinical Characteristics and Treatment Outcomes of Definitive versus Standard Anti-Tuberculosis Therapy in Patients with Tuberculous Lymphadenitis
J. Clin. Med. 2019, 8(6), 813; https://doi.org/10.3390/jcm8060813 - 07 Jun 2019
Cited by 2 | Viewed by 1134
Abstract
Although it is necessary to culture Mycobacterium tuberculosis from tuberculous lymphadenitis (TBL) patients for definitive therapy, based on the drug-sensitivity test (DST), substantial cases remain culture-negative. Limited data are available regarding the treatment outcomes after standard anti-tuberculosis therapy in culture-negative TBL. The aim [...] Read more.
Although it is necessary to culture Mycobacterium tuberculosis from tuberculous lymphadenitis (TBL) patients for definitive therapy, based on the drug-sensitivity test (DST), substantial cases remain culture-negative. Limited data are available regarding the treatment outcomes after standard anti-tuberculosis therapy in culture-negative TBL. The aim of this study was to compare the recurrence rates between definitive anti-tuberculosis therapy, based on DST and standard anti-tuberculosis therapy in culture-negative TBL. A multicenter retrospective cohort study was performed from 2011 to 2015 in South Korea. The study population was divided into two groups according to treatment type. A total of 234 patients with TBL were analyzed, who were treated with definitive (84 patients) and standard anti-tuberculosis (150 patients) therapy, respectively. During a 28.0 (24.0–43.0) month follow-up period, nine cases (3.8%) had recurrence of TB after treatment completion. The recurrence rate was not significantly different between the two groups (2/84, 2.4% in definitive anti-tuberculosis therapy group versus 7/150, 4.7% in standard anti-tuberculosis therapy group, p = 0.526). The recurrence in all nine cases was diagnosed as clinical recurrence rather than microbiological recurrence. Therefore, culture-negative TBL can be treated with standard anti-TB medication, although DST is not available but clinically stable after initiation of treatment. Full article
(This article belongs to the Special Issue Tuberculosis: Clinical Applications in the Diagnosis and Treatment)
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Open AccessArticle
Isoniazid Concentration and NAT2 Genotype Predict Risk of Systemic Drug Reactions during 3HP for LTBI
J. Clin. Med. 2019, 8(6), 812; https://doi.org/10.3390/jcm8060812 - 06 Jun 2019
Cited by 4 | Viewed by 1099
Abstract
Weekly rifapentine and isoniazid therapy (known as 3HP) for latent tuberculosis infection (LTBI) is increasingly used, but systemic drug reactions (SDR) remain a major concern. Methods: We prospectively recruited two LTBI cohorts who received the 3HP regimen. In the single-nucleotide polymorphism (SNP) cohort, [...] Read more.
Weekly rifapentine and isoniazid therapy (known as 3HP) for latent tuberculosis infection (LTBI) is increasingly used, but systemic drug reactions (SDR) remain a major concern. Methods: We prospectively recruited two LTBI cohorts who received the 3HP regimen. In the single-nucleotide polymorphism (SNP) cohort, we collected clinical information of SDRs and examined the NAT2, CYP2E1, and AADAC SNPs. In the pharmacokinetic (PK) cohort, we measured plasma drug and metabolite levels at 6 and 24 h after 3HP administration. The generalised estimating equation model was used to identify the factors associated with SDRs. Candidate SNPs predicting SDRs were validated in the PK cohort. A total of 177 participants were recruited into the SNP cohort and 129 into the PK cohort, with 14 (8%) and 13 (10%) in these two cohorts developing SDRs, respectively. In the SNP cohort, NAT2 rs1041983 (TT vs. CC+CT, odds ratio [OR] [95% CI]: 7.00 [2.03–24.1]) and CYP2E1 rs2070673 (AA vs. TT+TA, OR [95% CI]: 3.50 [1.02–12.0]) were associated with SDR development. In the PK cohort, isoniazid level 24 h after 3HP administration (OR [95% CI]: 1.61 [1.15–2.25]) was associated with SDRs. Additionally, the association between the NAT2 SNP and SDRs was validated in the PK cohort (rs1041983 TT vs. CC+CT, OR [95% CI]: 4.43 [1.30–15.1]). Conclusions: Isoniazid played a role in the development of 3HP-related SDRs. This could provide insight for further design of a more optimal regimen for latent TB infection. Full article
(This article belongs to the Special Issue Tuberculosis: Clinical Applications in the Diagnosis and Treatment)
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Open AccessArticle
The Clinical Significance of Programmed Death-1, Regulatory T Cells and Myeloid Derived Suppressor Cells in Patients with Nontuberculous Mycobacteria-Lung Disease
J. Clin. Med. 2019, 8(5), 736; https://doi.org/10.3390/jcm8050736 - 23 May 2019
Cited by 8 | Viewed by 1263
Abstract
Background: Increasing expression of programmed death-1 (PD-1) in patients with nontuberculous mycobacteria lung disease (NTM-LD) has been reported, but its role in clinical characteristics and outcomes remains unclear. Methods: We enrolled 96 participants, including 46 with Mycobacterium avium complex (MAC)-LD, 23 with M. [...] Read more.
Background: Increasing expression of programmed death-1 (PD-1) in patients with nontuberculous mycobacteria lung disease (NTM-LD) has been reported, but its role in clinical characteristics and outcomes remains unclear. Methods: We enrolled 96 participants, including 46 with Mycobacterium avium complex (MAC)-LD, 23 with M. abscessus (MAB)-LD, and 27 controls. We measured expressions of PD-1, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and regulatory T (Treg) cells on CD4+ lymphocytes and myeloid-derived suppressor cells (MDSCs) and analyzed their association with clinical features and radiographic outcomes. Results: The percentage of PD-1 on CD4+(PD-1+CD4+) lymphocytes and MDSCs were higher in the MAC-LD group than the controls. There were no intergroup differences regarding CTLA-4+CD4+ lymphocytes. Higher PD-1+CD4+ lymphocytes were found in M. intracellulare- and M. avium-LD than in other MAC-LD. Positive sputum acid-fast stains and fibrocavitary radiographic lesions were correlated with elevated PD-1+CD4+ lymphocytes and Treg cells. The percentage of PD-1+CD4+ lymphocytes at the initial and 2 months of follow-up significantly predicted subsequent radiographic progression. Conclusion: As markers of immune tolerance, PD-1+CD4+ lymphocytes and MDSCs were higher in MAC-LD patients. The levels of PD-1+CD4+ and Treg cells were correlated with high mycobacteria bacilli burden in NTM-LD. Monitoring the expressions of PD-1+CD4+ lymphocytes may predict radiographic progression. Full article
(This article belongs to the Special Issue Tuberculosis: Clinical Applications in the Diagnosis and Treatment)
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Review

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Open AccessReview
Point-Of-Care Urine LAM Tests for Tuberculosis Diagnosis: A Status Update
J. Clin. Med. 2020, 9(1), 111; https://doi.org/10.3390/jcm9010111 - 31 Dec 2019
Cited by 14 | Viewed by 2331
Abstract
Most diagnostic tests for tuberculosis (TB) rely on sputum samples, which are difficult to obtain and have low sensitivity in immunocompromised patients, patients with disseminated TB, and children, delaying treatment initiation. The World Health Organization (WHO) calls for the development of a rapid, [...] Read more.
Most diagnostic tests for tuberculosis (TB) rely on sputum samples, which are difficult to obtain and have low sensitivity in immunocompromised patients, patients with disseminated TB, and children, delaying treatment initiation. The World Health Organization (WHO) calls for the development of a rapid, biomarker-based, non-sputum test capable of detecting all forms of TB at the point-of-care to enable immediate treatment initiation. Lipoarabinomannan (LAM) is the only WHO-endorsed TB biomarker that can be detected in urine, an easily collected sample. This status update discusses the characteristics of LAM as a biomarker, describes the performance of first-generation urine LAM tests and reasons for slow uptake, and presents considerations for developing the next generation of more sensitive and impactful tests. Next-generation urine LAM tests have the potential to reach adult and pediatric patients regardless of HIV status or site of infection and facilitate global TB control. Implementation and scale-up of existing LAM tests and development of next-generation assays should be prioritized. Full article
(This article belongs to the Special Issue Tuberculosis: Clinical Applications in the Diagnosis and Treatment)
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Open AccessReview
Short-Course Regimen for Multidrug-Resistant Tuberculosis: A Decade of Evidence
J. Clin. Med. 2020, 9(1), 55; https://doi.org/10.3390/jcm9010055 - 25 Dec 2019
Cited by 10 | Viewed by 1136
Abstract
About ten years ago, the first results of the so-called “Bangladesh regimen”, a short regimen lasting nine months instead of 20 months, revolutionized multidrug-resistant tuberculosis (MDR-TB) treatment. Similar short regimens were studied in different settings, relying for their efficacy on a later generation [...] Read more.
About ten years ago, the first results of the so-called “Bangladesh regimen”, a short regimen lasting nine months instead of 20 months, revolutionized multidrug-resistant tuberculosis (MDR-TB) treatment. Similar short regimens were studied in different settings, relying for their efficacy on a later generation fluoroquinolone, either gatifloxacin, moxifloxacin, or levofloxacin. We review the published material on short MDR-TB regimens, describe their different compositions, their results in national tuberculosis programs in middle- and low-income countries, the risk of acquiring resistance to fluoroquinolone, and the occurrence of adverse events. With over 80% success, the regimen performs much better than longer regimens (usually around 50%). Monitoring of adverse events allows adapting its composition to prevent severe adverse events such as deafness. We discuss the current applicability and usefulness of the short injectable-containing regimen given the 2019 recommendation of the World Health Organization (WHO) for a new long all-oral regimen. We conclude that the most effective fluoroquinolone is gatifloxacin, currently not listed as an essential medicine by WHO. It is a priority to restore its status as an essential medicine. Full article
(This article belongs to the Special Issue Tuberculosis: Clinical Applications in the Diagnosis and Treatment)
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