Tuberkulose

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.

Kendall E, Malhotra S, Cook-Scalise S, et al.

AbstractBackgroundMany candidate regimens for universal treatment of tuberculosis combine novel and existing, widely-used drugs. Appropriate implementation requires evidence-based, context-specific drug-susceptibility testing (DST) strategies.MethodsWe created a Markov state-transition model of 100,000 adults with TB receiving a novel, fluoroquinolone (FQ)-containing regimen. We estimated clinical outcomes and resource utilization with no FQ-DST, universal use of FQ-DST, or FQ-DST only in patients with rifampin-resistant TB (‘targeted FQ-DST’). We considered scenarios of stronger (South Africa) and weaker (Southeast Asia) correlation of fluoroquinolone resistance with rifampin resistance.ResultsRelative to no FQ-DST, targeted FQ-DST increased cure of FQ-resistant TB by 7.5% (interquartile range 6.7-9.2%) in South Africa and 1.7% (0.7 -2.5%) in Southeast Asia. However, rare FQ resistance among the more-prevalent rifampin-susceptible TB accounted for 50% of FQ-resistant TB in South Africa and 83% in Southeast Asia. As a result, universal FQ-DST further increased cure of FQ-resistant TB by 3.4% (2.3-5.4%) in South Africa and 5.8% (5.1-6.3%) in Southeast Asia. With targeted FQ-DST, one additional patient was cured per 50 (42-70) tests in South Africa and 44 (37-51) in Southeast Asia. When expanding from targeted to universal FQ-DST, one additional cure required 3500 (2300-5500) tests in South Africa and 410 (370-450) in Southeast Asia. The impact of FQ-DST was sensitive to overall treatment effectiveness, regimen robustness to loss of fluoroquinolone activity, and prevalence of both moxifloxacin and pyrazinamide resistance.ConclusionsFQ-DST improved patient outcomes and was particularly important for high-risk patient groups and less-robust regimens. A universal strategy was favored in generalized epidemics of fluoroquinolone resistance.

Abstract Background Ligands of the receptor for advanced glycation end products (RAGE) are key signalling molecules in the innate immune system but their role in tuberculosis-diabetes comorbidity (TB-DM) has not been investigated. Methods We examined the systemic levels of soluble RAGE (sRAGE), advanced glycation end products (AGE), S100A12 and high mobility group box 1 (HMGB1) in participants with either TB-DM, TB, DM or healthy controls (HC). Results Systemic levels of AGE, sRAGE and S100A12 were significantly elevated in TB-DM and DM in comparison to TB and HC. During follow up, AGE, sRAGE and S100A12 remained significantly elevated in TB-DM compared to TB at 2nd month and 6th month of anti-TB treatment (ATT). RAGE ligands were increased in TB-DM individuals with bilateral and cavitary disease. sRAGE and S100A12 correlated with glycated hemoglobin levels. Within the TB-DM group, those with known diabetes (KDM) revealed significantly increased levels of AGE and sRAGE compared to newly diagnosed DM (NDM). KDM participants on metformin treatment exhibited significantly diminished levels of AGE and sRAGE in comparison to those on non-metformin regimens. Conclusions Our data demonstrate that RAGE ligand levels reflect disease severity and extent in TB-DM, distinguish KDM from NDM and are modulated by metformin therapy.…

Jonathan Izudi, Imelda K Tamwesigire, Francis Bajunirwe

Yan Lin, Yunlong Bai, Tiejuan Zhang, Wanli Kang, Demei Kang, Qiang Miao, Yunlong Wang, Hongshan Shao, Xiangwen Li, Grania Brigden, Riitta A. Dlodlo, Anthony D. Harries

Tropical Medicine &International Health, Volume 0, Issue ja, -Not available-.

Tornheim J, Madugundu A, Paradkar M, et al.

AbstractBackgroundGene expression profiling is emerging as a tool for tuberculosis diagnosis and treatment response monitoring, but limited data specific to Indian children and incident tuberculosis infection (TBI) exist.Methods16 pediatric Indian tuberculosis cases were age- and sex-matched to 32 tuberculosis-exposed controls (13 developed incident TBI without subsequent active tuberculosis). Longitudinal samples were collected for RNAseq. Differential expression analysis generated gene lists that identify tuberculosis diagnosis and tuberculosis treatment response. Data were compared with published gene lists. Population-specific risk score thresholds were calculated.Results71 genes identified tuberculosis diagnosis and 25 treatment response. Within-group expression was partially explained by age, sex, and incident TBI. Transient changes in gene expression were identified after both infection and treatment. Application of 27 published gene lists to our data found variable performance for tuberculosis diagnosis (sensitivity 0.38–1.00, specificity 0.48–0.93) and treatment response (sensitivity 0.70–0.80, specificity 0.40–0.80). Our gene lists found similarly variable performance when applied to published datasets for diagnosis (sensitivity 0.56–0.85, specificity 0.50–0.85) and treatment response (sensitivity 0.49– 0.86, specificity 0.50–0.84).ConclusionsGene expression profiles among Indian children with confirmed tuberculosis were distinct from adult-derived gene lists, highlighting the importance of including distinct populations in differential gene expression models.

Noguera-Julian A, , Calzada-HernÁndez J, et al.

AbstractBackgroundIn adults, anti-tumor-necrosis-factor (TNF)-α therapy is associated with progression of latent tuberculosis infection (LTBI) to tuberculosis (TB) disease. The existing paediatric data are very limited.MethodsRetrospective multi-centre study within the Paediatric Tuberculosis Network European Trials Group, capturing patients

Johana Monteserin, Laura Pérez-Lago, Noemí Yokobori, Roxana Paul, Sandra Rodríguez Maus, Norberto Simboli, Vegard Eldholm, Beatriz López, Darío García de Viedma and Viviana Ritacco

Abstract. Two Mycobacterium tuberculosis strains—M (sublineage 4.1) and Ra (sublineage 4.3)—have long prevailed in Argentina among patients with multidrug-resistant tuberculosis (MDR-TB). Recently, budget constraints have hampered the surveillance of MDR-TB transmission. Based on whole-genome sequence analysis, we used M- and Ra-specific single nucleotide polymorphisms to tailor two multiplex allele-specific polymerase chain reactions (PCRs), which we applied to 252 stored isolates (95% of all newly diagnosed MDR-TB cases countrywide, 2015–2017). Compared with the latest data available (2007–2009), the M strain has receded (80/324 to 20/252, P < 0.0001), particularly among cross-border migrants (12/58 to 0/53, P = 0.0003) and HIV-infected people (30/97 to 7/74, P = 0.0007), but it still accounts for 4/12 new cases of extensively drug-resistant TB. Differently, the Ra strain remained stable in frequency (39/324 to 33/252) and contributed marginally to the extensive drug-resistance load (1/12). Our novel strategy disclosed recent trends of the two major MDR-TB strains, providing meaningful data to allocate control interventions more efficiently.…

Kennedy, J. M., Georges, A., Bassenden, A. V., Vidal, S. M., Berghuis, A. M., Taniuchi, I., Majewski, J., Lathrop, M., Behr, M. A., Langlais, D., Gros, P.

We have used a genome-wide screen in N-ethyl-N-nitrosourea (ENU) mutagenized mice to identify genes in which recessive loss of function mutations protect against pathological neuroinflammation. We identified an R367Q mutation in the ZBTB7B (ThPOK) protein which homozygosity causes protection against experimental cerebral malaria (ECM) caused by infection with Plasmodium berghei ANKA (PbA). Zbtb7bR367Q homozygous mice show a defect in the lymphoid compartment expressed as severe reduction in the number of single positive CD4 T cells in the thymus and in the periphery, reduced brain infiltration of pro-inflammatory leukocytes in PbA infected mice and reduced production of pro-inflammatory cytokines by primary T cells ex vivo and in vivo. Dampening of proinflammatory immune responses in Zbtb7bR367Q mice is concomitant to increased susceptibility to infection with avirulent (Mycobatcerium bovis, BCG) and virulent (M. tuberculosis, H37Rv) mycobacteria. The R367Q mutation maps to the first DNA-binding zinc finger domain of ThPOK, and causes a loss of base contact by R367 in the major groove of DNA which is predicted to impair DNA binding. Global immunoprecipitation of ThPOK-containing chromatin complexes coupled to DNA sequencing (ChIP-seq) identified transcriptional networks and candidate genes likely to play a key role in CD4+/CD8+ T cell development and in the expression of lineage specific functions of these cells. This study highlights ThPOK as a global regulator of immune function in which alterations may affect normal responses to infectious and inflammatory stimuli.…

Xinting Yang, Nanying Che, Hongfei Duan, Zichen Liu, Kun Li, Hua Li, Chao Guo, Qingtao Liang, Yang Yang, Yuxuan Wang, Jing Song, Weili Du, Zhang Chen, Yahong Wang, Yun Zhang, HaiBo Wang, Xiaoyou Chen

Tuberculous pleurisy (TP) diagnosis remains difficult, with the sensitivity of Xpert MTB/RIF (Xpert) and mycobacterial culture (culture) only about 30% to 50%. We aimed to assess the diagnostic performance of a cell-free Mycobacterium tuberculosis DNA test (cf-TB) in pleural effusion for TP.

Walsh K, Koenig S.

mortalityHIV-associated tuberculosishospitalizationTB-LAM testing…

Gupta-Wright A, Fielding K, Wilson D, et al.

AbstractBackgroundTB is the major killer of people living with HIV globally, with suboptimal diagnostics and management contributing to high case-fatality rates.MethodsA prospective cohort of confirmed (Xpert MTB/RIF and/or Determine TB-LAM Ag positive) TB patients identified through screening HIV-positive inpatients with sputum and urine diagnostics in Malawi and South Africa (STAMP trial). Urine was tested prospectively (intervention) or retrospectively (standard of care arm). We defined baseline clinical phenotypes using hierarchical cluster analysis, and also used Cox regression analysis to identify associations with early mortality (≤56 days).ResultsOf 322 patients with TB confirmed between October 2015 and September 2018, 78.0% had ≥1 positive urine test. Antiretroviral therapy (ART) coverage was 80.2% among those not newly diagnosed, but with median CD4 count 75 cells/µL and high HIV viral loads. Early mortality was 30.7% (99/322), despite near-universal prompt TB treatment. Older age, male sex, ART before admission, poor nutritional status, lower haemoglobin, and positive urine tests (TB-LAM and/or Xpert MTB/RIF) were associated with increased mortality in multivariate analyses. Cluster analysis (on baseline variables) defined 4 patient subgroups with early mortality ranging from 9.8% to 52.5%. Although unadjusted mortality was 9.3% lower in South Africa than Malawi, in adjusted models mortality was similar in both countries (HR 0.9, p=0.729).ConclusionsMortality following prompt inpatient diagnosis of HIV-associated TB remained unacceptably high, even in South Africa. Intensified management strategies are urgently needed, for which prognostic indicators could potentially guide both development and subsequent use.

Abstract Background Monocytes are the predominant innate immune cells at the early stage of Mycobacterium tuberculosis (M. tb) infection as the host defense against intracellular pathogens. Understanding the profile of different monocyte subpopulations and the dynamics of monocyte-related biomarkers may be useful for the diagnosis and prognosis of tuberculosis. Methods We enrolled 129 individuals comprising patients with pulmonary tuberculosis (PTB) (n = 39), tuberculous pleurisy (TBP) (n = 28), malignant pleural effusion (MPE) (n = 21), latent tuberculosis infection (LTBI) (n = 20), and healthy controls (HC) (n = 21). Surface expression of CD14, CD16, and CD163 on monocytes was detected using flow cytometry. In addition, soluble CD163 (sCD163) was determined by enzyme linked immunosorbent assay. Results Higher frequency of CD14+CD16+ (15.7% vs 7.8%, P 

Flynn A, Aiona K, Haas M, et al.

AbstractBackgroundEfforts to expand treatment of latent tuberculosis infection (LTBI) raise concerns for missed subclinical active tuberculosis (TB) and acquired drug-resistance.MethodsWe conducted a retrospective cohort review of patients who began LTBI therapy between January 1, 2006 and December 31, 2017 at the Denver Metro TB Clinic, Colorado, USA. Electronic databases and chart review were used for data collection. Subsequent active TB diagnoses in this cohort were determined using the state of Colorado TB database through June 30, 2018.Results8472 patients started LTBI treatment during the study period with 46% prescribed nine months of isoniazid and 43% four months of rifampin. 24 (0.28%) developed active TB, 10 during and 14 after LTBI therapy. Culture confirmation was obtained for 13 (54%) and none had acquired drug-resistance. Patients diagnosed during (n=10) versus after treatment (n=14) were less likely to be culture-confirmed (30% versus 71%) and less likely to have pulmonary disease (20% vs 57%).ConclusionsSubclinical TB missed by symptom screening and chest radiography was rare in our mostly HIV-negative cohort. Culture negative, extrapulmonary disease was more common with TB diagnosed during than after LTBI treatment. We found no evidence for acquired drug resistance in LTBI patients subsequently diagnosed with active TB.

Anastasia Koch, Helen Cox

Among the 10 million annual deaths predicted to be due to antimicrobial resistance by 2050, a quarter could be attributable to drug-resistant tuberculosis.1 In The Lancet Infectious Diseases, Andrei Dadu and colleagues report that despite declining tuberculosis incidence in eastern Europe and central Asia, rifampicin-resistant/multidrug-resistant (herein drug-resistant) tuberculosis is increasing or remaining stable. Only two of the 17 countries assessed showed declining drug-resistant tuberculosis notifications in the most recent years (since the last joinpoint or from the first year of available data if no joinpoint was identified),2 clearly highlighting the continued threat that drug-resistant tuberculosis represents.

Andrei Dadu, Arax Hovhannesyan, Sevim Ahmedov, Marieke J van der Werf, Masoud Dara

Our findings suggest that countries in the WHO European Region are more successful in controlling drug-susceptible tuberculosis than drug-resistant forms, and as a result, the proportion of drug-resistant strains among newly notified patients with tuberculosis is increasing in many settings. Two countries showed that it is possible to decrease incidence of both drug-susceptible and drug-resistant tuberculosis. If no additional efforts are made in prevention and care of patients with drug-resistant tuberculosis, further decline of the tuberculosis burden will be halted.

Lindsay McKenna, Jennifer Furin

Around 10 million people become sick with tuberculosis, and more than 1·2 million people die from the disease each year.1 WHO has proposed some ambitious targets in their End TB Strategy,2 and global leaders committed to reaching these targets within the next decade. As these deadlines approach, the rhetoric has increased but has produced seemingly little progress, creating an air of desperation among all cadres engaged in the fight against tuberculosis.

C Andrew Basham, Kamila Romanowski, James C Johnston

WHO developed the End TB Strategy1 as a blueprint and call to action for governments worldwide to work towards tuberculosis elimination. The strategy's goal to reduce mortality from tuberculosis by 95% from 2015 to 2035 has major implications for health policy and planning. Globally, millions of people survive after tuberculosis treatment each year. From 2000 to 2018, WHO estimates that 58 million deaths were averted by interventions for tuberculosis among HIV-negative people and interventions for both tuberculosis and HIV among HIV-positive people.

Dinesh C Sharma

India accounted for 25% of the global burden of tuberculosis with an estimated 2·8 million new cases in 2018. The Government has set an ambitious target of tuberculosis elimination by 2025, much ahead of the Sustainable Development Goals framework set for 2030. Besides rolling out the National Strategic Plan to achieve the target, several new steps have been initiated, such as notification of new cases by private health providers to the Government, active case finding, drug resistance surveys, and nutritional support for patients with tuberculosis.

Ammara Mushtaq

On Aug 14, 2019, the US Food and Drug Administration (FDA) approved the drug pretomanid to be used in combination with bedaquiline and linezolid to treat drug-resistant tuberculosis. Developed by the non-profit organisation, TB Alliance, pretomanid has been shown to increase treatment success in multidrug-resistant and extensively drug-resistant tuberculosis.

Conor D Tweed, Rodney Dawson, Divan A Burger, Almari Conradie, Angela M Crook, Carl M Mendel, Francesca Conradie, Andreas H Diacon, Nyanda E Ntinginya, Daniel E Everitt, Frederick Haraka, Mengchun Li, Christo H van Niekerk, Alphonse Okwera, Mohammed S Rassool, Klaus Reither, Modulakgotla A Sebe, Suzanne Staples, Ebrahim Variava, Melvin Spigelman

B200PaZ is a promising regimen to treat patients with drug-susceptible tuberculosis. The bactericidal activity of both these regimens suggests that they have the potential to shorten treatment, and the simplified dosing schedule of B200PaZ could improve treatment adherence in the field. However, these findings must be investigated further in a phase 3 trial assessing treatment outcomes.