Active Mycobacterium Tuberculosis Infection Research Articles

RNA Profiling Analysis of the Serum Exosomes Derived from Patients with Active and Latent Mycobacterium tuberculosis Infection.

Tuberculosis (TB) has exceeded HIV as the most lethal infectious disease globally for two consecutive years. Moreover, one third of the world’s population is estimated to have latent tuberculosis infection (LTBI). This is mainly because of difficulties associated with diagnosis and treatment for both TB and LTBI patients. Exosomes provide a promising research tool for TB diagnosis and treatment because they are released from various cells containing valuable biochemical information related to disease. In this study, we performed RNA-sequencing analysis on exosomes derived from clinical specimens of healthy controls (HC), active tuberculosis (ATB), and LTBI patients. Our results revealed the distinct gene expression profiles of the exosomes from LTBI and ATB patients. (1) We identified many distinct up-regulated and down-regulated differentially expressed genes (DEGs) in LTBI and ATB samples, and further screened the top-20 DEGs which might provide a potential panel for differentiation of HC, LTBI, and ATB. (2) We classified all the DEGs into six expression patterns, screened the top-20 genes in each pattern, and mainly focused on those highly expressed in LTBI and ATB. (3) Some Mycobacterium tuberculosis (Mtb) RNAs were only enriched in the exosomes of LTBI samples. (4) Pathway and function analysis further indicated down-regulated signaling pathways/immune response and up-regulated apoptosis/necrosis. Our findings indicate the selective packaging of RNA cargoes into exosomes under different stages of Mtb infection, while facilitating the development of potential targets for the diagnosis, prevention and treatment of tuberculosis.

Coincident Type 2 diabetes mellitus modulates the systemic and antigen – specific induction of Type 1, Type 17, and other cytokines in both active and latent tuberculosis

Abstract Type 2 diabetes mellitus (DM) is known to be a major risk factor for the development of active tuberculosis, although its influence on active and latent Mycobacterium tuberculosis infection and disease remains poorly characterized. To identify the influence of coincident DM on cytokine levels in active pulmonary tuberculosis and latent tuberculosis, we examined circulating levels of a panel of cytokines in the plasma of individuals with PTB-DM or PTB alone and LTB-DM or LTB alone. PTB-DM is characterized by elevated circulating levels of type 1 (IFNγ, TNFα, and IL-2), type 2 (IL-5), type 17 (IL-17A) but decreased circulating levels of IL-10 family of cytokines (IL-19, IL-20, IL-22 and IL-24). This was associated with increased systemic levels of other pro-inflammatory cytokines (IL-1β, IL-6, and IL-18) and an anti-inflammatory cytokine (IL-10) but not type 1 IFNs. In contrast, LTB-DM is characterized by diminished circulating levels of type 1 (IFNγ, IL-2, and TNFα), type 17 (IL-17F), IL-10 family (IL-10, IL-19, IL-20 and IL-24) and other pro-inflammatory (IL-1β and IL-18) cytokines. Moreover, PTB-DM showed increased levels of pro-inflammatory cytokines upon tuberculosis antigen stimulation whereas LTB-DM showed diminished pro-inflammatory cytokines upon tuberculosis antigen stimulation. Our data reveal that PTB-DM is characterized by heightened cytokine responsiveness, indicating that chronic inflammation underlying DM potentially contributes to increased immune pathology. On the other hand, LTB-DM is characterized by diminished production of cytokines, implicated in the control of M. tuberculosis, allowing for a potential immunological mechanism that could account for the increased risk of active tuberculosis.

Quantification of circulating Mycobacterium tuberculosis antigen peptides allows rapid diagnosis of active disease and treatment monitoring

Tuberculosis (TB) is a major global health threat, resulting in an urgent unmet need for a rapid, non-sputum-based quantitative test to detect active Mycobacterium tuberculosis (Mtb) infections in clinically diverse populations and quickly assess Mtb treatment responses for emerging drug-resistant strains. We have identified Mtb-specific peptide fragments and developed a method to rapidly quantify their serum concentrations, using antibody-labeled and energy-focusing porous discoidal silicon nanoparticles (nanodisks) and high-throughput mass spectrometry (MS) to enhance sensitivity and specificity. NanoDisk-MS diagnosed active Mtb cases with high sensitivity and specificity in a case-control study with cohorts reflecting the complexity of clinical practice. Similar robust sensitivities were obtained for cases of culture-positive pulmonary TB (PTB; 91.3%) and extrapulmonary TB (EPTB; 92.3%), and the sensitivities obtained for culture-negative PTB (82.4%) and EPTB (75.0%) in HIV-positive patients significantly outperformed those reported for other available assays. NanoDisk-MS also exhibited high specificity (87.1-100%) in both healthy and high-risk groups. Absolute quantification of serum Mtb antigen concentration was informative in assessing responses to antimycobacterial treatment. Thus, a NanoDisk-MS assay approach could significantly improve the diagnosis and management of active TB cases, and perhaps other infectious diseases as well.

Multisystem Langerhans Cell Histiocytosis with Fatal Outcome in Adult Patient: A Case Report

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by abnormal proliferation of cells with a Langerhans cell phenotype, which comprises a wide range of clinical presentations. The reported patient is a 55-year old female with multy-sistem LCH and pulmonary tuberculosis. During diagnostic processing, infiltrates of Langerhans cells (S-100+, CD1a+) in the epidermis, intestinal mucosa and bone marrow, were discovered. Transbronchial needle biopsy of the lung revealed non-specific clusters of macrophages (CD68+, CD1a-). Although CD1a was negative, positive CD68, thoracic MSCT and clinical findings indicated pulmonary LCH. Corticosteroid treatment led to significant clinical improvement. Seven months after treatment with corticosteroids the patient developed a spontaneous left-sided pneumothorax. Thoracic HR (high resolution)-MSCT was highly suggestive for active Mycobacterium tuberculosis (MT) infection together with the positive QUANTIFERON-TB test and typical symptoms. One week after starting standard triple antituberculotic therapy the patient developed hypovolemic shock. Despite all medical efforts, the patient died on the thirteenth day of intensive treatment for multiple organ failure.

Determination of Urinary Neopterin/Creatinine Ratio to Distinguish Active Tuberculosis from Latent Mycobacterium tuberculosis Infection.

Background. Biomarkers to distinguish latent from active Mycobacterium (M.) tuberculosis infection in clinical practice are lacking. The urinary neopterin/creatinine ratio can quantify the systemic interferon-gamma effect in patients with M. tuberculosis infection. Methods. In a prospective observational study, urinary neopterin levels were measured by enzyme linked immunosorbent assay in patients with active tuberculosis, in people with latent M. tuberculosis infection, and in healthy controls and the urinary neopterin/creatinine ratio was calculated. Results. We included a total of 44 patients with M. tuberculosis infection and nine controls. 12 patients had active tuberculosis (8 of them culture-confirmed). The median age was 15 years (range 4.5 to 49). Median urinary neopterin/creatinine ratio in patients with active tuberculosis was 374.1 micromol/mol (129.0 to 1072.3), in patients with latent M. tuberculosis infection it was 142.1 (28.0 to 384.1), and in controls it was 146.0 (40.3 to 200.0), with significantly higher levels in patients with active tuberculosis (p < 0.01). The receiver operating characteristics curve had an area under the curve of 0.84 (95% CI 0.70 to 0.97) (p < 0.01). Conclusions. Urinary neopterin/creatinine ratios are significantly higher in patients with active tuberculosis compared to patients with latent infection and may be a significant predictor of active tuberculosis in patients with M. tuberculosis infection.

Unraveling methylation changes of host macrophages in Mycobacterium tuberculosis infection

To characterize at high resolution DNA methylation changes of cytokines which occur in the genome of macrophages in association with Mycobacterium tuberculosis (MTB) infection We studied the methylation profiles of THP-1 derived macrophage cells infected with clinical MTB strains [Beijing/W & non-Beijing/W lineage, sensitive (INH(S), RIF(S)) & resistant (INH(R), RIF(R)) strains] and of host macrophages from MTB infected cohorts (active & latent patients) with the human methylation CpG islands microarrays. Methylated modification on the promoter sequences of cytokines and their receptors were found to be associated with MTB infection in a strain- and host-dependent manner. Our epigenetic analyses revealed that infection with Beijing/W MTB strains enhanced IL6R, IL4R and IL17R hyper-methylations in infected macrophages. Validation of IL6R methylated sequence confirmed that MTB infection induced DNA methylation of CpG67 region in the IL6R promoter. In addition, studies on the human macrophage methylation profiles from the patient cohorts indicated that the methylation rate of IL17 family members and related genes were significantly altered in patients with active MTB infections. Our study offered novel insights into the epigenetic changes in the interaction of host macrophages in MTB infections and warrant further explorations into these changes in modulating the immune response in active and latent MTB infections.

Two potential sites of protein‐protein interaction within the Mycobacterium tuberculosis DNA gyrase complex

Recent World Health Organization studies have shown that one‐third of the global population are carriers of latent or active Mycobacterium tuberculosis (TB) infection. With the emergence of antibiotic resistant TB, it is crucial to understand the current drug targets in the treatment of this disease. One of these targets is DNA gyrase, the target of fluoroquinolones and a protein vital to cell function and replication. The goal of this project is to characterize binding interactions between the GyrA and GyrB subunits of M. tuberculosis DNA gyrase. Molecular modeling of the DNA gyrase complex was performed by superimposition of solved GyrA and GyrB M. tuberculosis structures (PDB ID's 3IFZ, 3M4I) over a solved structure of the highly homologous S. pneumoniae Topoisomerase IV protein/DNA complex (PDB ID 3K9F). Structural overlay was performed by the Magic Fit tool in SwissPdb Viewer. The resulting model was used to identify potential sites of charge‐charge interaction between the GyrA and GyrB subunits. Molecular cloning, site‐directed mutagenesis, functional, and structural assays have been utilized to investigate the two identified potential sites of interaction. Initial results from supercoiling assays suggest that the GyrB K658 residue is important for function, as well as a possible interaction occurring between the GyrA R26 residue and the GyrB residues D684 and E685. Gel shift and pull down assays investigating the strength of interaction between wild type and mutant subunits are ongoing.

Early dynamics of T helper cell cytokines and T regulatory cells in response to treatment of active Mycobacterium tuberculosis infection.

Biomarkers that can identify tuberculosis (TB) disease and serve as markers for efficient therapy are requested. We have studied T cell cytokine production [interferon (IFN)-γ, interleukin (IL)-2, tumour necrosis factor (TNF)-α] and degranulation (CD107a) as well as subsets of CD4+ T regulatory cells (Tregs) after in-vitro Mycobacterium tuberculosis (Mtb) antigen stimulation [early secretory antigenic target (ESAT)-6, culture filtrate protein (CFP)-10, antigen 85 (Ag85)] in 32 patients with active tuberculosis (TB) disease throughout 24 weeks of effective TB treatment. A significant decline in the fraction of Mtb-specific total IFN-γ and single IFN-γ-producing T cells was already observed after 2 weeks of treatment, whereas the pool of single IL-2+ cells increased over time for both CD4+ and CD8+ T cells. The Treg subsets CD25highCD127low, CD25highCD147++ and CD25highCD127lowCD161+ expanded significantly after Mtb antigen stimulation in vitro at all time-points, whereas the CD25highCD127lowCD39+ Tregs remained unchanged. The fraction of CD25highCD127low Tregs increased after 8 weeks of treatment. Thus, we revealed an opposing shift of Tregs and intracellular cytokine production during treatment. This may indicate that functional signatures of the CD4+ and CD8+ T cells can serve as immunological correlates of early curative host responses. Whether such signatures can be used as biomarkers in monitoring and follow-up of TB treatment needs to be explored further.

Distinct substrate selectivity of a metabolic hydrolase from Mycobacterium tuberculosis.

The transition between dormant and active Mycobacterium tuberculosis infection requires reorganization of its lipid metabolism and activation of a battery of serine hydrolase enzymes. Among these serine hydrolases, Rv0045c is a mycobacterial-specific serine hydrolase with limited sequence homology outside mycobacteria but structural homology to divergent bacterial hydrolase families. Herein, we determined the global substrate specificity of Rv0045c against a library of fluorogenic hydrolase substrates, constructed a combined experimental and computational model for its binding pocket, and performed comprehensive substitutional analysis to develop a structural map of its binding pocket. Rv0045c showed strong substrate selectivity toward short, straight chain alkyl esters with the highest activity toward four atom chains. This strong substrate preference was maintained through the combined action of residues in a flexible loop connecting the cap and α/β hydrolase domains and in residues close to the catalytic triad. Two residues bracketing the substrate-binding pocket (Gly90 and His187) were essential to maintaining the narrow substrate selectivity of Rv0045c toward various acyl ester substituents, as independent conversion of these residues significantly increased its catalytic activity and broadened its substrate specificity. Focused saturation mutagenesis of position 187 implicated this residue, as the differentiation point between the substrate specificity of Rv0045c and the structurally homologous ybfF hydrolase family. Insertion of the analogous tyrosine residue from ybfF hydrolases into Rv0045c increased the catalytic activity of Rv0045 by over 20-fold toward diverse ester substrates. The unique binding pocket structure and selectivity of Rv0045c provide molecular indications of its biological role and evidence for expanded substrate diversity in serine hydrolases from M. tuberculosis.

Comparison of the clinical courses and chemotherapy outcomes in metastatic colorectal cancer patients with and without active Mycobacterium tuberculosis or Mycobacterium kansasii infection: a retrospective study.

BackgroundAlthough active Mycobacterium tuberculosis (MTB) or Mycobacterium Kansasii (MK) infection could be present in patients with metastatic colorectal cancer (m-CRC), no study is available on the clinical courses and chemotherapy outcomes of these patients. The present study therefore aimed to retrospectively examine whether m-CRC patients with and without active MTB or MK infection could receive cancer chemotherapy similarly.MethodsThis study enrolled 30 m-CRC patients who received first-line chemotherapy between January 31, 2006 and January 31, 2013 at our institution, The clinical courses and tumor response of those with and without active MTB or MK infection were examined and compared.ResultsOf 30 m-CRC patients, 6 had active MTB infection, 1 with active MK and the other 23 had neither MTB nor MK. No significant demographic differences were observed between patients with MTB or MK and those without. Chemotherapy response rates of all patients, those with MTB or MK, and those without were 40.0%, 28.6% and 43.5%, respectively. Among patients with MTB or MK, 1 treated with bevacizumab experienced grade-3 hemoptysis while others did not report any severe toxicity. Median survival time of all studied patients, those with MTB or MK, and those without was 26.3, 36.7 and 22.6 months, respectively. No significant difference in overall survival was observed between patients with MTB or MK and those without. Multivariate analysis revealed that performance status and liver metastasis were significant prognostic factors of overall survival (P = 0.004 and 0.030, respectively), whereas other factors, including MTB or MK infection, were not. In our study, all 7 patients with MTB or MK did not experience infection relapse during or after cancer chemotherapy.ConclusionsOur results indicate that m-CRC patients with MTB or MK should be able to safely and effectively continue cancer chemotherapy to subsequently achieve comparable survival duration to those without the infection if they receive proper MTB or MK treatment.

Comparison of Culture and PCR Methods for Diagnosis of Mycobacterium tuberculosis in Different Clinical Specimens.

Background:Tuberculosis remains a global epidemic, especially in developing countries, including Iran. Rapid diagnosis of active Mycobacterium tuberculosis infection plays a critical role in controlling the spread of tuberculosis. Conventional methods may take up to several weeks or longer to produce results. In addition to multiplicity of steps involved in conventional detection, including isolation, identification and drug susceptibility testing, the slow growth rate of M. tuberculosis is also responsible for this lengthy time.Objectives:The aim of this study was to compare the polymerase chain reaction (PCR) and culture methods for the detection of M. tuberculosis in different clinical specimens.Materials and Methods:This study was performed on different samples (urine, gastric aspirate, bronchoalveolar lavage, pleural fluid, cerebrospinal fluid, ascetic fluid and joint fluid specimens) of tuberculosis suspected patients. M. tuberculosis DNA was extracted directly from different samples using two different protocols. Next, PCR was performed using three sets of specific primers to detect members of Mycobacterium genus, M. tuberculosis complex and non-tuberculosis Mycobacteria. The results were then compared with that of the culture method, which is considered as the gold standard method.Results:The concordance rate between the three sets of primers was calculated and IS6110/buffer PCR method showed good agreement with the LJ culture method (κ = 0.627, P < 0.0001). The sensitivity of IS6110/buffer PCR was 58.33%, with specificity of 77.78%; the positive and negative predictive values were 100% and 78.26%, respectively. Buffer method for DNA extraction was proved to give a higher accuracy to PCR in comparison with the boiling method.Conclusions:PCR method is a valuable, cost-effective and alternative tool for quick diagnosis of active tuberculosis in different clinical specimens.

Evaluation of specific humoral immune response and cross reactivity against Mycobacterium tuberculosis antigens induced in mice immunized with liposomes composed of total lipids extracted from Mycobacterium smegmatis

The development of a new tuberculosis (TB) vaccine has become one of the main objectives of the scientific community. Protein antigens have been widely explored as subunit TB vaccines, however lipid antigens could be equally important to be used or included in such a vaccine. The aim of this study was to demonstrate the potential of a liposome formulation composed of an extract of lipids from Mycobacterium smegmatis (Ms) as a TB vaccine candidate. We evaluated the immunogenicity of this formulation as well as the cross reactive response against antigens from Mycobacterium tuberculosis (MTb) in BALB/c mice. We determined the anti-liposome IgG response in sera from TB patients and from healthy subjects who displayed a positive (PPD+) or negative (PPD-) tuberculin skin test. A significant increase in anti-liposome IgG (p<0.05) was detected in animals immunized with Bacille Calmette-Guérin (BCG) compared with all groups, and in the group immunized with liposomes from Ms (LMs) compared to animals immunized with either LMs adjuvanted with aluminium (LMs-A) or the negative control group (phosphate buffered saline, PBS) respectively. With respect to the cross reactive response against a cocktail of cell wall antigens (CWA) from MTb, significantly higher IgG levels were observed in animals immunized with BCG and LMs compared to negative controls and either, aluminium-adjuvanted liposomes (LMs-A) or montanide (LMs-M) (p<0.05). Furthermore, the anti-liposome IgG response was significantly superior in sera from pulmonary TB patients compared to PPD+ and PPD- healthy subjects (p<0.001) suggesting the expression of these antigens in vivo during active MTb infection. The results obtained provide some evidence for the potential use of liposomes containing total lipid extracts of Ms as a TB vaccine candidate.

Invasive fungal infection in Chinese patients with systemic lupus erythematosus

Invasive fungal infection (IFI) can be a lethal complication in systemic lupus erythematosus (SLE). The aim of this study was to determine the characteristics of hospitalized SLE patients with IFI, and identify the risk factors compared to SLE with other major infections or those with active disease alone. Data from 18 SLE in-patients with IFI at Shanghai Renji Hospital between January 2007 and January 2011 were collected by chart review. SLE patients with either active Mycobacterium tuberculosis (n = 19) or other bacterial infections (n = 17), or active SLE (n = 54) in the same period acted as controls. SLE in-patients with IFI (n = 11) from January 2002 to December 2006 was considered as a historical control group. The most frequent pathogens of SLE-IFI was Cryptococcus neoformans (n = 9, 50.0 %), followed by Aspergillus and Candida (both n = 3, 16.7 %). The infection sites included lung (n = 8, 44.4 %), central nervous system (n = 8, 44.4 %), and disseminated IFI (n = 2, 11.1 %). Three patients (16.7 %) died from IFI. Compared with other major infections, IFI patients were younger, with shorter SLE disease duration, lower C-reactive protein response, higher corticosteroids, and antibiotics exposure. Compared with active SLE, IFI patients had elevated alanine transaminase level, higher corticosteroids and antibiotics exposure. In multivariate analysis, the only significant risk factors for IFI were maximum prednisolone exposure ≥45 mg/day prior to infection or flare within 3 months (OR = 10.284, 95 %CI (2.877, 36.836)). Compared with the historical SLE-IFI patients, the short-term survival improved over time (63.6 % versus 83.3 %). SLE-IFI is a unique entity that characterized by certain aforementioned parameters compared with other major infections or disease flare in SLE. Familiar with the disease pattern along with appropriate antifungal treatment may lead to a better outcome in SLE-IFI patients.

Dysfunction of Natural Killer T Cells in Patients with Active Mycobacterium tuberculosis Infection

Natural killer T (NKT) cells are known to play a protective role in the immune responses of mice against a variety of infectious pathogens. However, little is known about the detailed information of NKT cells in patients with Mycobacterium tuberculosis infection. The aims of this study were to examine NKT cell levels and functions in patients with active M. tuberculosis infection, to investigate relationships between NKT cell levels and clinical parameters, and to determine the mechanism responsible for the poor response to α-galactosylceramide (α-GalCer). NKT cell levels were significantly lower in the peripheral blood of pulmonary tuberculosis and extrapulmonary tuberculosis patients, and the proliferative responses of NKT cells to α-GalCer were also lower in patients, whereas NKT cell levels and responses were comparable in latent tuberculosis infection subjects and healthy controls. Furthermore, this NKT cell deficiency was found to be correlated with serum C-reactive protein levels. In addition, the poor response to α-GalCer in M. tuberculosis-infected patients was found to be due to increased NKT cell apoptosis, reduced CD1d expression, and a defect in NKT cells. Notably, M. tuberculosis infection was associated with an elevated expression of the inhibitory programmed death-1 (PD-1) receptor on NKT cells, and blockade of PD-1 signaling enhanced the response to α-GalCer. This study shows that NKT cell levels and functions are reduced in M. tuberculosis-infected patients and these deficiencies were found to reflect the presence of active tuberculosis.

Interferon-gamma release assay for diagnosing Mycobacterium tuberculosis infections in patients with systemic lupus erythematosus

Our aim was to analyze the performance of an interferon-gamma release assay, QuantiFERON-TB Gold (QFT-2G), for diagnosing Mycobacterium tuberculosis (MTB) infection in patients with systemic lupus erythematosus (SLE). We performed the QFT-2G and tuberculin skin test (TST) in 71 SLE patients. The QFT-2G results of 279 patients with other connective tissue diseases (CTD) and 35 healthy controls were analyzed. Of the 71 SLE patients, two (2.8%) were positive and 46 (64.8%) were negative by QFT-2G. All SLE patients had no evidence of active MTB infection, apart from one. QFT-2G produced a significantly higher number of indeterminate results in patients with SLE (23/71, 32.4%) compared with those with other CTD (5.7%) or healthy controls (0%) (p < 0.0001 and p < 0.0001). Decreased lymphocyte counts and high SLEDAI scores in SLE patients were shown to be risk factors for indeterminate results by multivariate analysis (p = 0.02 and p = 0.04). Among all patients with CTD, SLE itself and lymphocytopenia were found to be independent risks for indeterminate results (p = 0.00000625 and p = 0.000107). In conclusion, QFT-2G may have more potential to assist in the diagnosis of active and latent MTB infection than TST in SLE patients. However, because of the high frequency of indeterminate results, caution must be used when interpreting the results of QFT-2G among SLE patients, especially those who have parallel or subsequent flares.

Dominant TNF-α+ Mycobacterium tuberculosis–specific CD4+ T cell responses discriminate between latent infection and active disease

Rapid diagnosis of active Mycobacterium tuberculosis (Mtb) infection remains a clinical and laboratory challenge. We have analyzed the cytokine profile (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2)) of Mtb-specific T cells by polychromatic flow cytometry. We studied Mtb-specific CD4+ T cell responses in subjects with latent Mtb infection and active tuberculosis disease. The results showed substantial increase in the proportion of single-positive TNF-α Mtb-specific CD4+ T cells in subjects with active disease, and this parameter was the strongest predictor of diagnosis of active disease versus latent infection. We validated the use of this parameter in a cohort of 101 subjects with tuberculosis diagnosis unknown to the investigator. The sensitivity and specificity of the flow cytometry-based assay were 67% and 92%, respectively, the positive predictive value was 80% and the negative predictive value was 92.4%. Therefore, the proportion of single-positive TNF-α Mtb-specific CD4+ T cells is a new tool for the rapid diagnosis of active tuberculosis disease.

Mycobacterium tuberculosis infection in transplant recipients: early diagnosis and treatment of resistant tuberculosis

To provide a better understanding and summarize recent advances in the diagnosis and treatment of Mycobacterium tuberculosis (MTB) infection in solid organ transplant (SOT) candidates and recipients. Despite advances in SOT medicine, MTB causes substantial morbidity and mortality in SOT recipients, with reported prevalence rates of 0.4-6%. The primary source of posttransplant MTB is reactivation of pretransplant latent MTB infection. The short-term mortality rate in SOT recipients with drug-susceptible active MTB is 30%. In immunocompromised persons with extensively drug-resistant MTB, the mortality rate approaches 100%. Clinical presentation is often atypical with more than half of SOT recipients presenting with extrapulmonary or disseminated disease. Pretransplant latent MTB infection screening and treatment is the cornerstone for preventing reactivation and dissemination of active MTB posttransplant. Treatment of active MTB in SOT recipients is problematic, given significant drug toxicity and interaction with immunosuppressive agents. A high degree of suspicion for latent and active MTB infection in SOT candidates and recipients is warranted to establish a timely diagnosis and initiate life-saving appropriate therapy.

Tuberculosis in liver transplant recipients: A systematic review and meta-analysis of individual patient data

Mycobacterium tuberculosis (MTB) causes substantial morbidity and mortality in liver transplant recipients. We examined the efficacy of isoniazid latent Mycobacterium tuberculosis infection (LTBI) treatment in liver transplant recipients and reviewed systematically all cases of active MTB infection in this population. We found 7 studies that evaluated LTBI treatment and 139 cases of active MTB infection in liver transplant recipients. Isoniazid LTBI treatment was associated with reduced MTB reactivation in transplant patients with latent MTB risk factors (0.0% versus 8.2%, P = 0.02), and isoniazid-related hepatotoxicity occurred in 6% of treated patients, with no reported deaths. The prevalence of active MTB infection in transplant recipients was 1.3%. Nearly half of all recipients with active MTB infection had an identifiable pretransplant MTB risk factor. Among recipients who developed active MTB infection, extrapulmonary involvement was common (67%), including multiorgan disease (27%). The short-term mortality rate was 31%. Surviving patients were more likely to have received 3 or more drugs for MTB induction therapy (P = 0.003) and to have been diagnosed within 1 month of symptom onset (P = 0.01) and were less likely to have multiorgan disease (P = 0.01) or to have experienced episodes of acute transplant rejection (P = 0.02). Compared with the general population, liver transplant recipients have an 18-fold increase in the prevalence of active MTB infection and a 4-fold increase in the case-fatality rate. For high-risk transplant candidates, isoniazid appears safe and is probably effective at reducing MTB reactivation. All liver transplant candidates should receive a tuberculin skin test, and isoniazid LTBI treatment should be given to patients with a positive skin test result or MTB pretransplant risk factors, barring a specific contraindication. Liver Transpl 15:894-906, 2009. (c) 2009 AASLD.

Mycobacterium tuberculosis infection in immunocompromised hosts: A diagnostic challenge

The number of cases of tuberculosis (TB) in the United States declined by 45% between 1993 and 2006. This decline occurred disproportionately among United States–born persons (66%) compared to foreign-born individuals, among whom the number of cases actually increased by 5%. In solid-organ transplant recipients, the incidence of Mycobacterium tuberculosis (MTB) infection worldwide ranges between 0.35% and 15%, depending on the level of endemicity. This rate can be 36to 74-fold greater than that in the general population. The majority of MTB cases after transplantation represent reactivation of latent tuberculosis infection (LTBI), although acquisition of primary TB infection posttransplant and transmission of MTB via the transplanted organ are infrequent possibilities. Active TB in the posttransplantation setting can pose a number of challenges: atypical presentation leading to a delay in diagnosis, therapy associated with drug interactions and toxicities, graft rejection, and formidable morbidity and mortality. This is of particular concern in both patients with end-stage liver disease awaiting liver transplantation and liver transplant recipients, given the hepatotoxicity of several anti-TB medications and their associated drug interactions with immunosuppressants. In this issue of Liver Transplantation, Holty et al. present a systematic review and meta-analysis of TB in liver transplant recipients. They included cases of active MTB infection following liver transplantation as well as transplant candidates or recipients who received 6 months of therapy for LTBI prior to transplantation. The prevalence of active TB in liver transplant recipients was 1.3%. Extrapulmonary infection was seen in 67%, multiorgan involvement was seen in 27%, and 31% died. Tuberculin skin test (TST) results were as follows: a) Among 38 cases of posttransplant active TB with known pretransplant TST status, 37% were TST-positive, 53% were negative, and 11% were anergic; among 17 of these patients who had a posttransplant TST, only 35% were positive. b) In 3 studies with 2972 patients who underwent liver transplantation, 31% of the patients had a pretransplant TST, and 13% of these were positive. None of the TST-positive patients who received isoniazid therapy for at least 6 months developed active TB, whereas 7 TST-positive patients developed active disease without such therapy (mean follow-up, 54 months). Short-term mortality in patients with active posttransplant TB was 31%, with 65% of deaths directly attributed to MTB infection. Because reactivation of LTBI represents the majority of posttransplant cases of active TB, it is prudent to screen and identify such patients before transplantation for consideration of appropriate therapy for LTBI. Until recently, TST was the only test available for LTBI diagnosis. As noted previously, TST was notoriously insensitive: 64% of patients with posttransplant active TB were either TST-negative or anergic prior to transplantation, and 65% of patients had a negative posttransplant TST in the setting of active TB. TST has

Tuberculous constrictive pericarditis with concurrent active pulmonary tuberculous infection: a case report

IntroductionIn some particular endemic area, it is not uncommon to see patients with tuberculosis pericarditis. However, it takes a period of time from tuberculous pericarditis to constrictive pericarditis. There is still no report of tuberculous constrictive pericarditis concurrent with active pulmonary TB infection in a patient without previous pulmonary TB infection history. Therefore, we reported a TB constrictive pericarditis with rare disease progress.Case presentationWe report the case of a 63-year-old Taiwanese man with tuberculous constrictive pericarditis concurrent with active pulmonary tuberculous infection presenting with progressive extremities edema, puffy face, abdominal distension and dyspnea on exertion found to be caused by right heart failure. The patient was cured by pericardial stripping and anti-tuberculosis chemotherapy. We reviewed other cases of tuberculous constrictive pericarditis from the literature and described the peculiarities of this case.ConclusionsRapid diagnosis and treatment of constrictive pericarditis are crucial to reduce mortality. In some endemic areas, Mycobacterium tuberculosis infection should be taken into consideration during diagnostic evaluations for constrictive pericarditis. Surgical intervention is still the treatment of choice when the patient has the symptoms or signs of pericardial constriction and right heart failure. Our case is a constant reminder that active Mycobacterium tuberculosis infection does present itself with uncommon presentations.