Tuberkulose

Abstract Background Tuberculosis is a disease that may affect any organ of the body. Multifocal tuberculosis involving multiple systems with associated symptoms are rare, which makes the diagnosis challenging. Distinguishing multifocal tuberculosis from lesions metastatic from system malignancy is difficult. Single detection method is difficult to make a diagnosis. A combination of multiple methods is essential. Case presentation A 17-year-old male presented with a 20 days weakness of lower limbs, which aggravated for 6 days. The PET/CT showed increased metabolism of ileocecal intestinal and terminal ileum wall, multiple enlarged lymph node (LNs), multiple osteolytic bone lesions, and soft tissue intensity belong T7 and T8 vertebrae. To confirm the diagnosis of the disease, a biopsy of the mediastinum lymph nodes was carried out. Polymerase chain reaction (PCR) test of the specimen was positive for the Mycobacterium tuberculosis, the T-SPOT and Xpert MTB/RIF test were also positive, which suggested the presence of Mycobacterium tuberculosis. The final diagnosis was multifocal tuberculosis, the patients received the resection of the mass in the spine. Anti-tuberculosis drugs were given. The myodynamia and muscle tension of the patients recovered following the therapy. Conclusions Our results indicated that Multifocal tuberculosis should also be taken into consideration when lesions metastatic from system malignancy were suspected from images results even without the clinical symptoms of tuberculosis, and combination of multiple diagnosis methods were essential for the diagnosis of multifocal disease.…

Effective use of antibiotics is critical to control the global tuberculosis pandemic. High-dose isoniazid (INH) can be effective in the presence of low-level resistance.

Abstract Background Health-care workers (HCWs) are an epidemiological group with increased exposure to tuberculosis (TB), especially at health-care facilities (HCFs) with poor TB infection control in high-TB-burden settings. China is a high-TB-burden country, and the comprehensive measures for stopping TB transmission at some HCFs were not implemented well owing to limited resources and other factors. The purpose of this study was to review risk of occupational exposure to TB among HCWs and its change trend, and identify epidemiological characteristics of pulmonary tuberculosis (PTB) among HCWs in Henan, central part of China. Methods A retrospective cohort study was conducted from 2010 to 2017. All HCWs and teachers in Henan were enrolled to the study as exposed group and non-exposed control group, respectively. Relative risk (RR), attributable risk (AR) and AR percent (AR%) were used to measure the association between the occupational exposure and PTB, and estimated with Poisson regression. Results The study results showed a total of 1663 cases of PTB were reported among the HCWs in Henan, accounting for 3.2‰ of all PTB cases reported in the whole population, and annual incidence rate of PTB among HCWs declined by 34% from 2010 to 2017. Over the eight years, the incidence rate of PTB among HCWs was 43.7 cases per 100,000 person-years (PYs), significantly higher than that among teachers (18.8 cases/100,000 PYs), and RR, AR and AR% were estimated to 2.3, 24.9 cases per 100,000 PYs and 57%, respectively. Among HCWs, males were more likely to suffer from PTB than females (adjusted RR: 1.3; 95%CI: 1.2–1.4), and HCWs aged under 25 years had the highest relative risk over all age groups with adjusted RR equaling to 8.3 (95%CI: 6.9-9.9) calculated with those aged 45–54 years as the reference. Conclusions Although overall incidence rate of PTB among HCWs showed decreasing temporal trends over the period of 2010–2017, attributable risk of occupational exposure to TB among HCWs did not decrease in Henan, and TB infection at HCFs for males, young or senior HCWs, especially for young HCWs is of much concern.…

AbstractIn Indonesia, BCG protection against M. tuberculosis infection decreased with increasing exposure to the pathogen. We aimed to validate these findings in Africa. Poisson regression was used to estimate BCG protection, stratified by exposure using an exposure score, against ELISPOT conversion at 3 months in 220 Gambian case contacts. While the interaction between BCG and exposure was not significant (p=0.13), BCG protection was strongest in the lowest exposure tertile (RR, 0.35 [95% CI,0.15-0.82]; P=0.02), and the RRs for the middle and highest tertile were 0.50 (0.30-0.83; P=0.008) and 0.71 (0.45-1.13; P=0.1) respectively. These results are consistent with those from Indonesia.

Large Genomic Deletions (6 to 63 kbp, LGDs) were observed in isoniazid-resistant Mycobacterium tuberculosis (Mtb) mutants derived from four Mtb strains. These LGDs had no growth defect in vitro, but could be defective for intracellular growth, and showed varying sensitivities towards oxidative stress despite lacking katG. The LGDs region comprises 74 genes, mostly of unknown function, that may be important for Mtb intracellular growth and Mtb protection against oxidative stress.…

Ethionamide (ETA), an isonicotinic acid derivative, is part of multidrug-resistant tuberculosis (MDR-TB) regimen. The current guidelines deprioritized ETA due to potential less effectiveness compared to other agents. Our aim was to develop a population pharmacokinetic (PK) model and simulate ETA dosing regimens to assess target attainment. This study included subjects from four different sites, including both healthy volunteers and patients with MDR-TB. The TB centers included were two in the US and one in Bangladesh. Patients who received ETA and had at least one drug concentration reported were included. The population PK model was developed, 1,000-2,250 mg total daily regimens were simulated, and target attainment using published minimum inhibitory concentrations (MICs) and 1.0-log kill and resistance suppression targets were assessed using Pmetrics R package. We included 1,167 ethionamide concentrations from 94 subjects. The final population model was a one-compartment model with first-order elimination and absorption with a lag-time. The mean (SD) final population parameter estimates were: absorption rate constant 1.02 hr-1 (1.11), elimination rate constant 0.69 hr-1 (0.46), volume of distribution 104.16 L (59.87), and lag-time 0.43 hr (0.32). Total daily dose of 1,500 mg or more was needed to achieve ≥90% 1.0-log kill target attainment at MIC 1 mg/L, and 2,250 mg/day achieved 80% resistance suppression target attainment at MIC 0.5 mg/L. In conclusion, we developed a population PK model and assessed target attainment for different ETA regimens. Patients may not be able to tolerate the doses needed to achieve the predefined targets supporting current recommendations for ETA deprioritization.…

M. Jaspard et al.

Tropical Medicine & International Health, EarlyView.

Tropical Medicine & International Health, EarlyView.

Tropical Medicine & International Health, Accepted Article.

Tropical Medicine & International Health, EarlyView.

Tropical Medicine & International Health, EarlyView.

Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) is the apparent clinical or radiological deterioration seen in pre-existing lesions or emergence of new lesions of Tuberculosis (TB) after Anti-Retroviral Therapy (ART) initiation among HIV-TB coinfected patients, despite temporary improvement with anti-TB treatment (ATT) and effective virological suppression (Gopalan et al., 2014, Lawn et al., 2005, Lawn et al., 2007). The dynamics of this phenomenon that frequents concomitant therapy especially in the scenario of advanced HIV and early ART initiation, is explained by the cytokine storm that gets unleashed with ART (Bourgarit et al., 2006, Tadokera et al., 2011).

Abstract Background Interferon-γ release assays (IGRA) with Resuscitation promoting factor (Rpf) proteins enhanced tuberculosis (TB) screening and diagnosis in adults but have not been evaluated in children. Children often develop paucibacillary TB and their immune response differs from that of adults, which together affect TB disease diagnostics and immunodiagnostics. We assessed the ability of Rpf to identify infection among household TB-exposed children in The Gambia and investigated their ability to discriminate Mycobacterium tuberculosis complex (MTBC) infection from active TB disease in children. Methods Detailed clinical investigations were done on 93 household TB-exposed Gambian children and a tuberculin skin test (TST) was administered to asymptomatic children. Venous blood was collected for overnight stimulation with ESAT-6/CFP-10-fusion protein (EC), purified protein derivative and RpfA, B, C, D and E. Interferon gamma (IFN-γ) production was measured by ELISA in supernatants and corrected for the background level. Infection status was defined by IGRA with EC and TB disease by mycobacterial confirmation and/or clinical diagnosis. We compared IFN-γ levels between infected and uninfected children and between infected and TB diseased children using a binomial logistic regression model while correcting for age and sex. A Receiver Operating Characteristics analysis was done to find the best cut-off for IFN-γ level and calculate sensitivity and specificity. Results Interferon gamma production was significantly higher in infected (IGRA+, n = 45) than in uninfected (IGRA-, n = 20) children after stimulation with RpfA, B, C, and D (P = 0.03; 0.007; 0.03 and 0.003, respectively). Using RpfB and D-specific IFN-γ cut-offs (33.9 pg/mL and 67.0 pg/mL), infection was classified with a sensitivity-specificity combination of 73–92% and 77–72% respectively, which was similar to and better than 65–75% for TST. Moreover, IFN-γ production was higher in infected than in TB diseased children (n = 28, 5 bacteriologically confirmed, 23 clinically diagnosed), following RpfB and D stimulation (P = 0.02 and 0.03, respectively). Conclusion RpfB and RpfD show promising results for childhood MTBC infection screening, and both performed similar to and better than the TST in our study population. Additionally, both antigens appear to discriminate between infection and disease in children and thus warrant further investigation as screening and diagnostic antigens for childhood TB.…

Clinical symptoms of active tuberculosis (TB) can range from a simple cough to more severe reactions, such as irreversible lung damage and, eventually, death, depending on disease progression. In addition to its clinical presentation, TB has been associated with several other disease-induced systemic complications, such as hyponatremia and glucose intolerance. Here, we provide an overview of the known, although ill-described, underlying biochemical mechanisms responsible for the clinical and systemic presentations associated with this disease and discuss novel hypotheses recently generated by various omics technologies. This summative update can assist clinicians to improve the tentative diagnosis of TB based on a patient’s clinical presentation and aid in the development of improved treatment protocols specifically aimed at restoring the disease-induced imbalance for overall homeostasis while simultaneously eradicating the pathogen. Furthermore, future applications of this knowledge could be applied to personalized diagnostic and therapeutic options, bettering the treatment outcome and quality of life of TB patients.…

Abstract Background Extra pulmonary manifestation of tuberculosis (TB) accounts for approximately one-half of TB cases in HIV-infected individuals with pleural TB as the second most common location. Even though mycobacteria are cleared, mycobacterial antigens may persist in infected tissues, causing sustained inflammation and chronicity of the disease. The aim of this study was to explore various mycobacterial antigens in pleural effusions, the impact of HIV infection and CD4+ T-cell depletion on the presence of antigens, and the diagnostic potential of antigens for improved and rapid diagnosis of pleural TB. Methods Pleural fluid specimens were collected from patients presenting with clinically suspected pleural TB, and processed routinely for culture, cytology, and adenosine deaminase activity analysis. HIV status and CD4+ T-cell counts were recorded. Pleural fluid mononuclear cells (PFMC) were isolated, and cell smears were stained with acid-fast staining and immunocytochemistry for various mycobacterial antigens. Real-time and nested-PCR were performed. Patients were categorized as pleural TB or non-TB cases using a composite reference standard. Performance of the mycobacterial antigens as diagnostic test was assessed. Results A total of 41 patients were enrolled, of which 32 were classified as pleural TB and 9 as non-TB. Thirteen patients had culture confirmed pleural TB, 26 (81%) were HIV-TB co-infected, and 64% had

Abstract Background Globally, tuberculosis (TB) remains the leading cause of death from a single infectious disease. TB treatment outcome is an important indicator for the effectiveness of a national TB control program. This study aimed to assess treatment outcomes of TB patients and its determinants in Batkhela, Khyber Pakhtunkhwa, Pakistan. Methods A retrospective cohort study was designed using all TB patients who were enrolled at District Head Quarter (DHQ) Hospital Batkhela, Pakistan, from January 2011 to December 2014. A binary logistic regression models were used to identify factors associated with successful TB treatment outcomes defined as the sum of cure and completed treatment. Results A total of 515 TB patients were registered, of which 237 (46%) were males and 278 (53.98%) females. Of all patients, 234 (45.44%) were cured and 210 (40.77%) completed treatment. The overall treatment success rate was 444 (86.21%). Age 0–20 years (adjusted odds ratio, AOR = 3.47; 95% confidence interval, CI) = 1.54–7.81; P = 0.003), smear-positive pulmonary TB (AOR) = 3.58; 95% CI = 1.89–6.78; P = 

Abstract Background At present, there are few studies on polymorphism of Mycobacterium tuberculosis (Mtb) gene and how it affects the TB epidemic. This study aimed to document the differences of polymorphisms between tuberculosis hot and cold spot areas of Guangxi Zhuang Autonomous Region, China. Methods The cold and hot spot areas, each with 3 counties, had been pre-identified by TB incidence for 5 years from the surveillance database. Whole genome sequencing analysis was performed on all sputum Mtb isolates from the detected cases during January and June 2018. Single nucleotide polymorphism (SNP) of each isolate compared to the H37Rv strain were called and used for lineage and sub-lineage identification. Pairwise SNP differences between every pair of isolates were computed. Analyses of Molecular Variance (AMOVA) across counties of the same hot or cold spot area and between the two areas were performed. Results As a whole, 59.8% (57.7% sub-lineage 2.2 and 2.1% sub-lineage 2.1) and 39.8% (17.8% sub-lineage 4.4, 6.5% sub-lineage 4.2 and 15.5% sub-lineage 4.5) of the Mtb strains were Lineage 2 and Lineage 4 respectively. The percentages of sub-lineage 2.2 (Beijing family strains) are significantly higher in hot spots. Through the MDS dimension reduction, the genomic population structure in the three hot spot counties is significantly different from those three cold spot counties (T-test p = 0.05). The median of SNPs distances among Mtb isolates in cold spots was greater than that in hot spots (897 vs 746, Rank-sum test p 

Immigration from areas of high incidence is thought to have fueled the resurgence of tuberculosis (TB) in areas of low incidence. To reduce the risk of disease in low-incidence areas, the main countermeasure has been the screening of immigrants on arrival. This measure is based on the assumption of a prompt decline in the incidence of TB in immigrants during their first few years of residence in a country with low overall incidence. We have documented that this assumption is not true for 619 Somali immigrants reported in Denmark as having TB. The annual incidence of TB declined only gradually during the first 7 years of residence, from an initial 2,000 per 100,000 to 700 per 100,000. The decline was described by an exponential function with a half-time of 5.7 (95% confidence interval 4.0 to 9.7) years. This finding seriously challenges the adequacy of the customary practice of screening solely on arrival.

As countries approach the elimination phase of tuberculosis, specific problems and challenges emerge, due to the steadily declining incidence in the native population, the gradually increasing importance of the importation of latent tuberculosis infection and tuberculosis from other countries and the emergence of groups at particularly high risk of tuberculosis. Therefore, a Working Group of the World Health Organization (WHO), the International Union Against Tuberculosis and Lung Disease (IUATLD) and the Royal Netherlands Tuberculosis Association (KNCV) have developed a new framework for low incidence countries based on concepts and definitions consistent with those of previous recommendations from WHO/IUATLD Working Groups. In low-incidence countries, a broader spectrum of interventions is available and feasible, including: 1) a general approach to tuberculosis which ensures rapid detection and treatment of all the cases and prevention of unnecessary deaths; 2) an overall control strategy aimed at reducing the incidence of tuberculosis infection (risk-group management and prevention of transmission of infection in institutional settings) and 3) a tuberculosis elimination strategy aimed at reducing the prevalence of tuberculosis infection (outbreak management and provision of preventive therapy for specified groups and individuals). Government and private sector commitment towards elimination, effective case detection among symptomatic individuals together with active case finding in special groups, standard treatment of disease and infection, access to tuberculosis diagnostic and treatment services, prevention (e.g. through screening and bacille Calmette-Guéria immunization in specified groups), surveillance and treatment outcome monitoring are prerequisites to implementing the policy package recommended in this new framework document.

Infliximab is a humanized antibody against tumor necrosis factor alpha (TNF-alpha) that is used in the treatment of Crohn's disease and rheumatoid arthritis. Approximately 147,000 patients throughout the world have received infliximab. Excess TNF-alpha in association with tuberculosis may cause weight loss and night sweats, yet in animal models it has a protective role in the host response to tuberculosis. There is no direct evidence of a protective role of TNF-alpha in patients with tuberculosis.

Does immigration from a high-prevalence area contribute to an increased risk of tuberculosis in a low-incidence country? The tuberculosis incidence in Somalia is among the highest ever registered. Due to civil war and starvation, nearly half of all Somalis have been forced from their homes, causing significant migration to low-incidence countries. In Denmark, two-thirds of all tuberculosis patients are immigrants, half from Somalia. To determine the magnitude of Mycobacterium tuberculosis transmission between Somalis and Danes, we analyzed DNA fingerprint patterns of isolates collected in Denmark from 1992 to 1999, comprising >97% of all culture-positive patients (n = 3,320). Of these, 763 were Somalian immigrants, 55.2% of whom shared identical DNA fingerprint patterns; 74.9% of these were most likely infected before their arrival in Denmark, 23.3% were most likely infected in Denmark by other Somalis, and 1.8% were most likely infected by Danes. In the same period, only 0.9% of all Danish tuberculosis patients were most likely infected by Somalis. The Somalian immigrants in Denmark could be distributed into 35 different clusters with possible active transmission, of which 18 were retrieved among Somalis in the Netherlands. This indicated the existence of some internationally predominant Somalian strains causing clustering less likely to represent recent transmission. In conclusion, M. tuberculosis transmission among Somalis in Denmark is limited, and transmission between Somalis and Danes is nearly nonexistent. The higher transmission rates between nationalities found in the Netherlands do not apply to the situation in Denmark and not necessarily elsewhere, since many different factors may influence the magnitude of active transmission.

The whole-genome fingerprinting technique, fluorescent amplified-fragment length polymorphism (FAFLP) analysis, was applied to Mycobacterium tuberculosis. Sixty-five clinical isolates were analyzed to determine the value of FAFLP as a stand-alone genotyping technique and to compare it with the well-established IS6110 typing system. The genome sequence of M. tuberculosis strain H37Rv (S. T. Cole et al., Nature 393:537-544, 1998) was used to model computer-generated informative primer combination(s), and the precision and reproducibility of FAFLP were evaluated by comparing the results of in vitro and computer-generated experiments. Multiplex FAFLP was used to increase resolving power in a predictable and systematic fashion. FAFLP analysis was broadly congruent with IS6110 typing for those strains with multiple IS6110 copies. It was also able to resolve an epidemiologically unlinked group of strains with only one copy of IS6110; up to 10% of clinical isolates may fall into this category. For certain epidemiological investigations, it was concluded that a combination of FAFLP and IS6110 typing would give higher resolution than would either alone. FAFLP data were digital, precise, reproducible, and suitable for rapid electronic dissemination, manipulation, interlaboratory comparison, and storage in national or international epidemiological databases. Because FAFLP samples and analyzes base substitution across the genome as a whole, FAFLP could generate new information about the microevolution of the M. tuberculosis complex.

To estimate the risk and prevalence of Mycobacterium tuberculosis (MTB) infection and tuberculosis (TB) incidence, prevalence, and mortality, including disease attributable to human immunodeficiency virus (HIV), for 212 countries in 1997.

The present study is based on notified cases of tuberculosis (TB) in the National tbc. register 1972-1996. A decline in Tb incidence was seen from 1972 and until the mid-1980's. Subsequently the trend has reversed due to an increasing number of TB cases in foreigners. In 1996, 60% of all cases of TB in Denmark were found in foreigners reflecting the rising number of refugees and their families arriving in Denmark from highly endemic areas, mainly Somalia. Among native Danes the TB incidence fell from 14 per 100,000 in 1972 to 4 per 100,000 in the 1980's and stabilized at this very low level. The unchanged incidence in Danes covers a falling incidence in the older and a rising incidence in the younger and middle-aged adult population, mainly in the capital. Approximately half of the cases occur in high-risk groups. The TB-epidemic is close to elimination in the indigenous Danish population, but the disease is maintained at a low level probably due to increased patient and doctor delay and resulting microepidemics primarily in high-risk populations.