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.

Michael D. Stutz, Marc Pellegrini

Mycobacterium tuberculosis interferes with the ability of its host cell to undergo apoptosis. Arnett et al. report that the pathogen promotes macrophage survival by engaging the nuclear receptor PPARγ to induce the antiapoptotic protein MCL-1, yielding insights into the pathogenesis of tuberculosis and potentially unlocking new avenues for therapeutic intervention.

Abstract Background Tuberculosis, bacterial community-acquired pneumonia (CAP), and Pneumocystis jirovecii pneumonia (PJP) are the three commonest causes of hospitalisation in HIV-infected adults. Prompt diagnosis and treatment initiation are important to reduce morbidity and mortality, but are hampered by limited diagnostic resources in resource poor settings. C-reactive protein (CRP) and procalcitonin have shown diagnostic utility for respiratory tract infections, however few studies have focussed on their ability to distinguish between tuberculosis, CAP, and PJP in HIV-infected inpatients. Methods We evaluated the diagnostic accuracy of CRP and procalcitonin, compared with composite reference standards, to discriminate between the three target infections in adult HIV-infected inpatients in two district level hospitals in Cape Town, South Africa. Participants were admitted with current cough and danger signs in accordance with the WHO algorithm for tuberculosis in seriously ill HIV-infected patients. Study clinicians were blinded to CRP and procalcitonin results. Results Two hundred forty-eight participants met study case definitions: 133 with tuberculosis, 61 with CAP, 16 with PJP, and 38 with mixed infection. In the 210 particpants with single infections the differences in median CRP and procalcitonin concentrations between the three infections were statistically significant, but distributions overlapped considerably. CRP and procalcitonin concentrations were highest in the CAP group and lowest in the PJP group. CRP and procalcitonin cut-offs with sensitivities of ≥90% were found for all three target infection pairs, but corresponding specificities were low. Highest receiver operating characteristic areas under the curve for CRP and procalcitonin were for PJP versus tuberculosis and PJP versus CAP (0.68 and 0.71, and 0.74 and 0.69 respectively). Conclusions CRP and procalcitonin showed limited value in discriminating between the three target infections due to widely overlapping distributions, but diagnostic accuracy was higher for discriminating PJP from CAP or tuberculosis. Our findings show limitations for CRP and procalcitonin, particularly for discriminiation of tuberculosis form CAP, however they may have greater diagnostic utility as part of a panel of biomarkers or in clinical prediction rules.

Francesco Bisognin, Giulia Lombardi, Donatella Lombardo, Maria Carla Re, Paola Dal Monte

by Francesco Bisognin, Giulia Lombardi, Donatella Lombardo, Maria Carla Re, Paola Dal Monte Background The new Xpert MTB/RIF Ultra assay (Ultra, Cepheid, Sunnyvale, USA) is a cartridge-based automated diagnostic test that can simultaneously identify Mycobacterium tuberculosis complex (MTB) and resistance to Rifampicin (RIF). With respect to the previous version Xpert MTB/RIF assay (Xpert), IS6110/IS1081 repetitive elements probes have been added allowing the detection of lower MTB load, defined by the new semi-quantitative category “trace” with indeterminate RIF resistance. The aim of this study was to evaluate performance of the new version Ultra on Xpert-negative, but TB culture-positive clinical samples. Methods The de-identified frozen samples (-20 °C) collected over a 4-year period (February 2014-October 2017), which had previously resulted smear-negative, Xpert-negative but MTB culture-positive, were analyzed with Ultra. The de-frosted samples were loaded into the cartridge using the same process as the previous version, according to manufacturer’s instruction. Results During the study period 382 MTB culture-positive samples were archived: 314 resulted Xpert-positive and 68 Xpert-negative. Thirty-one of the 68 Xpert-negative samples resulted positive with Ultra, with an overall improvement in MTB detection of 45.6%. Out of 36 Xpert-negative respiratory samples, 18 resulted Ultra-positive with the following semi-quantitative loads: “low”(n = 1), “very low”(n = 11), “trace”(n = 6), with an improvement in MTB detection of 50%. The best performance was achieved on bronchoalveolar lavage specimens (53.8%). Out of 32 Xpert-negative non-respiratory samples, 13 resulted Ultra-positive with the following semi-quantitative loads: “very low”(n = 7), “trace”(n = 6), with an improvement in MTB detection of 40.6%. The best performance was achieved on biopsies (55.6%) and lymph nodes (50%). The new category “trace” detected 12 out of the 31 Ultra-positive MTB samples; in the remaining 19 samples RIF susceptibility was determined with 100% concordance with the phenotypic susceptibility test. The mean time to positivity of samples found negative by Ultra was significantly longer in comparison to positive samples in liquid culture. Conclusions Our results are consistent with the few studies published so far and confirm the better performance of Ultra compared to the previous version in both respiratory and non-respiratory smear-negative samples, with an overall improvement of 45.6%.

Basant Joshi, Trisasi Lestari, Stephen Michael Graham, Sushil Chandra Baral, Sharat Chandra Verma, Gokarna Ghimire, Bandana Bhatta, Shyam Prakash Dumre, Adi Utarini

by Basant Joshi, Trisasi Lestari, Stephen Michael Graham, Sushil Chandra Baral, Sharat Chandra Verma, Gokarna Ghimire, Bandana Bhatta, Shyam Prakash Dumre, Adi Utarini Background Tuberculosis (TB) is a major public health problem in low and middle-income countries. Early detection and enrolment of TB cases is a challenge for National TB Programs. Objective To understand the performance and feasibility for scale-up of Xpert MTB/RIF assay for the TB diagnosis in Nepal. Design Implementation research employed mixed-method sequential explanatory design. The results of Xpert MTB/RIF assay were analysed in 26 TB diagnostic centres where Xpert machines had been installed before 2015. In-depth interviews and focus group discussions were conducted with stakeholders, purposively selected to represent experiences in centres that were functioning well, poorly or not functioning. Results During a one-year period in 2015/16, 23,075 Xpert MTB/RIF assays were performed in 21 diagnostic centres with 22,288 people also tested by sputum microscopy. Among these, 77% had concordant (positive or negative) results, demonstrating fair agreement (Kappa score, 0.3) between test results. Test failure and positivity rates in diagnostic centres ranged from 2.6% to 13.4% and 6.5% to 49%, respectively. The number of cartridges per positive result varied from 2.3 to 10.2. Xpert assay was positive in 3314 (15% of all cases) sputum smear microscopy negative cases. Of 4280 bacteriologically confirmed cases by Xpert assay, 355 (8%) were rifampicin resistant. Xpert machines were no longer functioning regularly throughout the year in 5 diagnostic centres. The main barriers for effective implementation of Xpert in Nepal were the lack of: timely supply of cartridges; replacement of damaged modules; maintenance of Xpert machines; and stock verification for timely procurement of cartridges. Inadequate laboratory infrastructure for maintaining functional Xpert equipment further challenges implementation and scale-up. Conclusion The implementation of Xpert MTB/RIF assay has increased case-finding of TB and MDR-TB in Nepal. However, there is a need to improve laboratory performance and strengthen laboratory infrastructure for optimal utilisation and scale-up of Xpert.

Yousang Ko, Ho Young Lee, Yong Bum Park, Su Jin Hong, Jeong Hwan Shin, Seok Jin Choi, Changhwan Kim, So Young Park, Jin Young Jeong

by Yousang Ko, Ho Young Lee, Yong Bum Park, Su Jin Hong, Jeong Hwan Shin, Seok Jin Choi, Changhwan Kim, So Young Park, Jin Young Jeong Background Little is known about the correlation between microbiological yield and radiographic activity, on chest computed tomography (CT), in suspected pulmonary tuberculosis (PTB) cases, despite CT being widely used, clinically. Methods We used multicenter retrospective data, obtained from medical records, focusing on the diagnostic performance for definite PTB. We categorized patients into four groups, by radiographic activity: definitely active, probably active, indeterminate activity, and probably inactive. Results Of the 650 patients included, 316 had culture-confirmed PTB; 190 (29.2%), 323 (49.7%), 70 (10.8%), and 67 (10.3%) were classified into the definitely active, probably active, indeterminate activity, and probably inactive groups, respectively. The corresponding observed culture rates for CT radiographic activity were 61.6%, 60.7%, 4.3% and 0%, respectively. When not only culture rates but TB-PCR and histological results were taken into consideration as definite PTB, it showed 66.6%, 67.2%, 14.3%, and 0% of each CT radiographic activity, respectively. Regarding the diagnostic performance for definite PTB, radiographic activity displayed high sensitivity (97.1%, 95% confidence interval (CI), 94.6–98.5) and negative predictive values (92.7%, 95% CI, 86.6–96.2), considered definitely and probably active PTB. Apart from PTB, other etiologies, according to radiographic activity, were predominantly respiratory infections such as bacterial pneumonia and non-tuberculous mycobacterial infection. Conclusions Radiographic activity showed good diagnostic performance, and can be used easily in clinical practice. However, clinicians should consider other possibilities, because radiologic images do not confirm microbiological PTB.

Martha Priedeman Skiles, Siân L. Curtis, Gustavo Angeles, Stephanie Mullen, Tatyana Senik

by Martha Priedeman Skiles, Siân L. Curtis, Gustavo Angeles, Stephanie Mullen, Tatyana Senik Ukraine is among the top 20 highest drug-resistant tuberculosis burden countries in the world. Driving the high drug-resistant tuberculosis rates is an unchecked treatment default rate. This evaluation measures the effect of social support provided to tuberculosis patients at risk of defaulting on treatment during outpatient treatment. Five tuberculosis patient cohorts, served in three oblasts from 2011 and 2012, were constructed from medical records to compare risk factors for default, receipt of social services, and treatment outcome. Regression analyses were used to identify risk factors predictive of treatment default and to estimate the impact of the social support program on treatment default, controlling for risk, disease status, and demographics. In 2012, tuberculosis patients receiving social support in Ukraine reduced their probability of defaulting on continuation treatment by 10 percentage points compared to high-risk patients who did not receive social support in 2012 or 2011. Treatment success rates for the high-risk patients receiving social support were comparable to the low-risk cohorts and significantly improved over the high-risk comparison cohorts. Further research is recommended to quantify the costs and benefits for scaling-up social support services, evaluate social support program fidelity, identify which populations respond best to select services, and what barriers might still exist to achieve better adherence. With that information, tailoring programs to most effectively reach and serve clients in a patient-centered approach may reap substantial rewards for Ukraine.

Sumona Datta, Luis E. Gonzales-Huerta and Carlton A. Evans

Andrew R. DiNardo, Alexander W. Kay, Gugu Maphalala, Nadine M. Harris, Celia Fung, Godwin Mtetwa, Pilar Ustero, Sindisiwe Dlamini, Ngan Ha, Edward A. Graviss, Rojelio Mejia and Anna M. Mandalakas

Abstract. A quantifiable, stool-based, Mycobacterium tuberculosis (Mtb) test has potential complementary value to respiratory specimens. Limit of detection (LOD) was determined by spiking control stool. Clinical test performance was evaluated in a cohort with pulmonary tuberculosis (TB) (N = 166) and asymptomatic household TB child contacts (N = 105). Stool-quantitative polymerase chain reaction (qPCR) results were compared with sputum acid-fast bacilli (AFB) microscopy, GeneXpert MTB/RIF (Xpert MTB/RIF), and cultures. In Mtb stool-spiking studies, the LOD was 96 colony-forming units/50 mg of stool (95% confidence interval [CI]: 84.8–105.6). Among specimens collected within 72 hours of antituberculosis treatment (ATT) initiation, stool qPCR detected 22 of 23 (95%) of culture-positive cases. Among clinically diagnosed cases that were Xpert MTB/RIF and culture negative, stool qPCR detected an additional 8% (3/37). Among asymptomatic, recently TB-exposed participants, stool PCR detected Mtb in two of 105 (1.9%) patients. Two months after ATT, the Mtb quantitative burden in femtogram per microliters decreased (Wilcoxon signed-rank P < 0.001) and persistent positive stool PCR was associated with treatment failure or drug resistance (relative risk 2.8, CI: 1.2–6.5; P = 0.012). Stool-based qPCR is a promising complementary technique to sputum-based diagnosis. It detects and quantifies low levels of stool Mtb DNA, thereby supporting adjunct diagnosis and treatment monitoring in pulmonary TB.

Stephanie Gati, Rhoda Chetty, Douglas Wilson and Jacqueline M. Achkar

Abstract. Human immunodeficiency virus (HIV) infection is a major risk factor for the development of active tuberculosis (TB), one of the deadliest infectious diseases globally. The high mortality associated with the disease can be reduced by early diagnosis and prompt antituberculous treatment initiation. Facilities in TB-endemic regions are increasing the use of nucleic acid amplification (e.g., GeneXpert), which provides rapid results but may have suboptimal sensitivity in HIV-associated TB. Our objective was to evaluate the current practices for TB diagnosis at Edendale Hospital, a large regional hospital in KwaZulu-Natal, South Africa—a TB-endemic region with high HIV prevalence. In this cross-sectional study, all adult inpatients newly started on TB treatment at Edendale were identified over a 6-week period. Demographics, clinical information, diagnostic test results, and outcomes were documented. Pulmonary TB (PTB), extrapulmonary TB (EXTB), and PTB + EXTB were defined as disease evidence in the lungs, other organs, or both, respectively. Ninety-four cases were identified, of which 83% were HIV-associated. Only 30% of all TB patients were microbiologically confirmed, consisting of 7/16 (44%) HIV-uninfected and 21/78 (27%) HIV-infected TB patients. Smear microscopy and mycobacterial culture were seldom ordered. Ultrasound was performed in about one-third of suspected EXTB cases and was valuable in identifying abdominal TB. In this clinical setting with a high incidence of HIV-associated TB, TB diagnosis was more commonly based on clinical assessment and imaging results than on mycobacterial gold standard test confirmation.

Betânia M. F. Nogueira, Valéria C. Rolla, Kevan M. Akrami, Susan M. Kiene

by Betânia M. F. Nogueira, Valéria C. Rolla, Kevan M. Akrami, Susan M. Kiene…

Abstract Background Diabetes is associated with increased risk of tuberculosis (TB) treatment failure, death, and relapse compared to patients without diabetes. Current TB regimens are available as fixed dose combination (FDC) and separate tablets (ST), in which using the former is purported to make it easier to adhere and complete treatment. So far there are no studies assessing the performance of FDC compared to ST in diabetic patients with pulmonary TB. Methodology A retrospective cohort study was conducted, and included eight hospitals in Qatar in which patients diagnosed with pulmonary TB received rifampin, isoniazid, pyrazinamide, and ethambutol (as FDC or ST) given as directly observed therapy. Sputum smears for acid fast bacilli were tested weekly. We included patients admitted between December 2012 and December 2015, ≥18 years old, diagnosed with TB with pretreatment positive sputum smears, and having diabetes. Patients with Mycobacterium tuberculosis that was resistant to any first-line drug were excluded. Blood glucose was monitored closely and controlled to

Kandler, J. L., Mercante, A. D., Dalton, T. L., Ezewudo, M. N., Cowan, L. S., Burns, S. P., Metchock, B., on behalf of Global PETTS Investigators, Cegielski, P., Posey, J. E.

Resistance to the first-line anti-tuberculosis (TB) drug, isoniazid (INH), is widespread, and the mechanism of resistance is unknown in approximately 15% of INH-resistant (INH-R) strains. To improve molecular detection of INH-R TB, we used whole genome sequencing (WGS) to analyze 52 phenotypically INH-R Mycobacterium tuberculosis complex (MTBC) clinical isolates that lacked the common katG S315T or inhA promoter mutations. Approximately 94% (49/52) of strains had mutations at known INH-associated loci that were likely to confer INH resistance. All such mutations would be detectable by sequencing more DNA adjacent to existing target regions. Use of WGS minimized the chances of missing infrequent INH resistance mutations outside commonly targeted hotspots. We used recombineering to generate 12 observed clinical katG mutations in the pansusceptible H37Rv reference strain and determined their impact on INH resistance. Our functional genetic experiments have confirmed the role of seven suspected INH resistance mutations and discovered five novel INH resistance mutations. All recombineered katG mutations conferred resistance to INH at a minimum inhibitory concentration of ≥0.25 μg/mL and should be added to the list of INH resistance determinants targeted by molecular diagnostic assays. We conclude that WGS is a useful tool for detecting uncommon INH resistance mutations that would otherwise be missed by current targeted molecular testing methods, and suggest that its use (or use of expanded conventional or NGS-based targeted sequencing) may provide earlier diagnosis of INH-R TB.

Shin S, Modongo C, Baik Y, et al.

AbstractBackgroundHeteroresistant Mycobacterium tuberculosis (Mtb) infections (concomitant infection with drug-resistant and drug-susceptible Mtb) may explain the higher risk of poor tuberculosis (TB) treatment outcomes observed among patients with mixed-strain Mtb infections. We investigated the clinical effect of mixed infections while controlling for pre-treatment heteroresistance among a population-based sample of TB patients starting first-line TB therapy in Botswana.MethodsWe performed 24-locus MIRU-VNTR and targeted deep sequencing on baseline primary cultured isolates to detect mixed infections and heteroresistance, respectively. Drug sensitive, micro-heteroresistant, macro-heteroresistant, and fixed-resistant infections were defined as

Shintaro Hayashi , Daniel Chandramohan

Abstract Objective To assess the risk of active TB in people with DM and the factors associated with this risk. Methods Systematic review and meta‐analysis. We searched the literature for studies that reported the effect of DM on TB controlled for the effect of age. Studies that had not established the diagnosis of DM prior to detecting active TB were excluded. Study quality was assessed by Newcastle‐Ottawa scale and we conducted a meta‐analysis using random‐effects models. Results 14 studies (8 cohort and 6 case‐control studies) that involved 22,616,623 participants met the selection criteria and were included in the analysis. There was substantial variation between studies in the estimates of the effect of DM on TB. However, the pooled estimates from 7 high‐quality studies showed that diabetic people have a 1.5‐fold increased risk of developing active TB versus those without DM (95%CI 1.28‐1.76), with relatively small heterogeneity (I2 44%). The increased risk of TB was observed predominantly among DM populations with poor glycaemic control. Conclusion There is evidence suggesting an increased risk of developing TB among people with DM, and that improving glycaemic control in DM patients would reduce the risk of developing TB. An integrated approach is needed to control the dual burden of DM and TB. This article is protected by copyright. All rights reserved.

Victor S. Santos, Delia Goletti, Konstantina Kontogianni, Emily R. Adams, Barbara Molina-Moya, Jose Dominguez, Valeriu Crudu, Paulo R.S. Martins-Filho, Morten Ruhwald, Lovett Lawson, John S. Bimba, Alberto L. Garcia-Bastero, Linda Petrone, Basir S. Kabeer, Klaus Reither, Luis E. Cuevas

We examined the data reported in studies for diagnostic purposes and discuss whether their intended use could be extended to triage, as rule in or rule out tests to select individuals who should undergo further confirmatory tests.

Ignacio Monedero-Recuero

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 3, Page 302-304, August 1, 2018.

Gunar Günther

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 3, Page 379-386, August 1, 2018.

Olson, Alex; Ragan, Elizabeth J.; Nakiyingi, Lydia; Lin, Nina; Jacobson, Karen R.; Ellner, Jerrold J.; Manabe, Yukari C.; Sagar, Manish

Background: Mycobacterium tuberculosis (TB) infection induces systemic inflammation that could impact HIV-1 persistence. Setting: HIV-1 seropositive individuals either with or without pulmonary TB disease were recruited in Kampala, Uganda Methods: Plasma cytokines, HIV-1 DNA, and cell-associated (ca)-RNA were compared among those co-infected with TB (cases) to those without TB (controls). TB co-infected cases and controls were compared at presentation (n = 15 and n = 16 respectively) and at around 6 months after HIV-1 treatment initiation among those that had achieved virologic suppression (n = 6 and n = 8 respectively). At follow-up, the TB co-infected cases had also finished TB treatment. Results: Prior to treatment, the TB co-infected cases as compared to the controls had higher levels of soluble(s)-CD163 (p = 0.0002) and interleukin (IL)-6 (p = 0.006) but lower levels of macrophage chemoattractant protein (MCP)-1 (p = 0.04). After treatment, the TB co-infected cases as compared to controls still had higher plasma s-CD163 levels (p = 0007). Controls as compared to the co-infected cases had higher ca-RNA per DNA template both at baseline (p = 0.03) and at follow-up (p = 0.07). Levels of ca-RNA per DNA copy at follow up showed a negative correlation with baseline plasma sCD163 (p = 0.008) and IL-6 (p = 0.05) levels. Conclusions: TB disease is associated with inflammation and decreased HIV-1 RNA expression relative to the number of infected cells, both pre and post viral suppression. Infections present prior to anti-retroviral initiation impacts HIV-1 latency. Corresponding author: Manish Sagar MD, Address: Manish Sagar, Boston University, 650 Albany Street, Room 647, Boston, MA 02118, Phone: (617) 414-5239, Fax: (617) 414-5280, Email: msagar@bu.edu, The authors report no conflicts of interest related to this work. This work was supported by National Institutes of Health grants AI122209, 1U54TR00102, and D43TW009771; Boston University Clinical and Translational Science Institute 1UL1TR001430. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Jagielski, T., Bakuła, Z., Brzostek, A., Minias, A., Stachowiak, R., Kalita, J., Napiorkowska, A., Augustynowicz-Kopec, E., Zaczek, A., Vasiliauskiene, E., Bielecki, J., Dziadek, J.

Resistance of Mycobacterium tuberculosis to rifampicin, mediated by mutations in the rpoB gene, coding for the beta-subunit of RNA polymerase, poses a serious threat to the efficacy of clinical management and thus control programs of TB. The contribution of many individual rpoB mutations to the development and level of RMP resistance remains elusive. In this study, the incidence of mutations throughout the rpoB gene among 115 Mycobacterium tuberculosis clinical isolates, both resistant and susceptible to RMP was determined. Of the newly-discovered rpoB mutations, the role of three substitutions in the causation of RMP resistance was empirically tested. The results from in vitro mutagenesis experiments were combined with the assessment of the prevalence of rpoB mutations, and their reciprocal co-occurrences, across global M. tuberculosis populations.Twenty-two different types of mutations in the rpoB gene were identified and distributed among 59 (90.8%) RMP-resistant strains. The minimum inhibitory concentrations (MICs) of RMP were within the range of 40-800 mg/L, with MIC50 and MIC90 values of 400 and 800 mg/L, respectively. None of the mutations (Gln429His, Met434Ile, Arg827Cys) inspected for their role in the development of RMP resistance produced a RMP-resistant phenotype in isogenic M. tuberculosis H37Rb strain-derived mutants. These mutations are supposed to compensate for fitness impairment incurred by other mutations directly associated with drug resistance.

Ankur Gupta-Wright, Elizabeth L Corbett, Joep J van Oosterhout, Douglas Wilson, Daniel Grint, Melanie Alufandika-Moyo, Jurgens A Peters, Lingstone Chiume, Clare Flach, Stephen D Lawn, Katherine Fielding

Urine-based tuberculosis screening did not reduce overall mortality in all HIV-positive inpatients, but might benefit some high-risk subgroups. Implementation could contribute towards global targets to reduce tuberculosis mortality.