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.

Janko van Beek, Marjo Haanperä, Pieter W. Smit, Silja Mentula, Hanna Soini

Culture-based assays are currently the gold standard for drug susceptibility testing (DST) for Mycobacterium tuberculosis. They provide good sensitivity and specificity, but are time-consuming. The objective of this study was to evaluate whether whole genome sequencing (WGS), combined with software tools for data analysis, can replace routine culture based assays for drug susceptibility testing of M. tuberculosis.

F. Mhimbira, H. Hiza, E. Mbuba, J. Hella, L. Kamwela, M. Sasamalo, M. Ticlla, K. Said, G. Mhalu, M. Chiryamkubi, C. Schindler, K. Reither, S. Gagneux, L. Fenner

To describe the prevalence of respiratory pathogens in tuberculosis (TB) patients and in their household contact controls, and to determine the clinical significance of respiratory pathogens in TB patients.

P. Helbling, S. Kröger, W. Haas, S. Brusin, D.M. Cirillo, R. Groenheit, J.-P. Guthmann, H. Soini, D. Hendrickx, M.J. van der Werf

An analysis of a cluster of 29 migrants with multidrug-resistant (MDR) tuberculosis (TB) strains with an identical whole genome sequencing pattern (difference of maximally one single nucleotide polymorphism) identified in seven European countries in 2016–2017 has been published in Lancet Infectious Diseases [1]. The investigation of this cluster led to the conclusion that cases are most likely linked to a larger Mycobacterium tuberculosis clone circulating in northern Somalia/Djibouti, and that transmission likely occurred prior to arrival in Europe [1,2].

W. Liu, J. Chen, Y. Shen, J. Jin, J. Wu, F. Sun, Y. Wu, L. Xie, Y. Zhang, W. Zhang

Pyrazinamide (PZA) is a crucial first-line tuberculosis (TB) drug recommended for both drug-susceptible and multidrug-resistant Mycobacterium tuberculosis. This study aimed to evaluate the performance of the sequencing method of pncA, rpsA and panD mutations in detecting PZA resistance in multidrug-resistant (MDR) TB isolates.

J.F. Gallo, J.M.W. Pinhata, V. Simonsen, V.M.N. Galesi, L. Ferrazoli, R.S. Oliveira

To describe the prevalence, associated factors, treatment outcomes and transmission of extensively drug-resistant (XDR) tuberculosis (TB) in the state of São Paulo, Brazil, for 2011 to 2013.

G. Satta, M. Lipman, G.P. Smith, C. Arnold, O.M. Kon, T.D. McHugh

Nearly two decades after completion of the genome sequence of Mycobacterium tuberculosis (MTB), and with the advent of next generation sequencing technologies (NGS), whole-genome sequencing (WGS) has been applied to a wide range of clinical scenarios. Starting in 2017, England is the first country in the world to pioneer its use on a national scale for the diagnosis of tuberculosis, detection of drug resistance, and typing of MTB.

M.K. Pedersen, T. Lillebaek, A.B. Andersen, H. Soini, M. Haanperä, R. Groenheit, J. Jonsson, E. Svensson

To compare the epidemiology of tuberculosis (TB) in Denmark, Sweden and Finland, by focusing on the native population in order to identify epidemiologic differences and thus indirectly possible differences in TB control.

A. Javaid, I. Ullah, H. Masud, A. Basit, W. Ahmad, Z.A. Butt, M. Qasim

: We aimed to determine the characteristics, treatment outcomes and risk factors for poor treatment outcomes among multidrug-resistant (MDR) tuberculosis (TB) patients in Khyber Pakhtunkhwa province, Pakistan.

L. Zhang, Q. Meng, S. Chen, M. Zhang, B. Chen, B. Wu, G. Yan, X. Wang, Z. Jia

To examine treatment outcomes and factors associated with poor outcome of multidrug-resistant (MDR) tuberculosis (TB) in China.

Soo Jung Kim, Shinhee Ye, Eunhee Ha, Eun Mi Chun

by Soo Jung Kim, Shinhee Ye, Eunhee Ha, Eun Mi Chun Introduction Overweight or obesity might be protective factors of tuberculosis (TB), but the evidence is inconclusive. The objective of study was to evaluate association between BMI and incident TB. Methods The National Health Insurance database was used. Eligible participants were individuals aged 20–89 years without history of TB before 2007, and who underwent national health examinations between January 2002 and December 2006. The latest record of BMI was used as the exposure and categorized as follows: 30 kg/m2 did not show protective effect of TB in female under 50 years. Additionally, BMI >30 kg/m2 did not decrease incident TB in diabetics. Conclusion Our study suggests that high BMI might be associated with decreased risk of TB. However, very high BMI did not reduce the risk of TB in young females or diabetics participants with in Korean population.

Wei Wu, Meifang Yang, Min Xu, Cheng Ding, Yongtao Li, Kaijin Xu, Jifang Shen, Lanjuan Li

by Wei Wu, Meifang Yang, Min Xu, Cheng Ding, Yongtao Li, Kaijin Xu, Jifang Shen, Lanjuan Li TB infection in patients after kidney transplantation remains a concern in a successful long-term outcome. This retrospective, descriptive study was performed on tuberculosis infection after kidney transplantation in the Department of Infectious Disease of the First Affiliated Hospital of Zhejiang University, a tertiary care hospital in China, from January 2011 to April 2017, with the aim to explain the clinical features of active tuberculosis after kidney transplantation and explore the correlated factors for diagnostic delay and mortality. It included 48 cases. All these cases were followed up for at least 12 months after anti-tuberculosis therapy, except the ones who died during this period. The median time of transplantation to active tuberculosis of these 48 patients was about 5.4 years. The time from a first hospital visit to the diagnosis (diagnostic delay) of 12 (25%) cases was more than 30 days. The correlated factors for the diagnostic delay more than 30 days were a fever for more than 2 weeks and antibiotic use for more than 2 weeks. Nine (18.8%) cases died during the anti-tuberculosis therapy or following-up period due to TB relapse. The risk factors for mortality were severe complications, such as encephaledema, severe pneumonia, intestinal perforation, liver function failure, and the following multiple-organ failure. In conclusion, the possibility of tuberculosis infection should be carefully assessed and sometimes diagnostic anti-tuberculosis therapy may be required for patients who had a fever for more than 2 weeks or used antibiotics for more than 2 weeks after kidney transplantation. Severe complications and the following multiple-organ failure might increase the mortality among these patients.

Vijayashree Yellappa , Tullia Battaglioli , Sanath Kumar Gurum , Devadasan Narayanan , Patrick Van der Stuyft

Abstract Objectives To assess a multicomponent intervention to improve private practitioners (PPs) involvement in referral of presumptive pulmonary TB (PTB) cases to the Revised National TB Control Programme (RNTCP) for sputum examination. Methods Randomised controlled trial. We randomly allocated all 189 eligible PPs in Tumkur city, South India, to intervention or control arm. The intervention, implemented between December 2014 and January 2016, included two sets of activities, one targeted at health system strengthening (building RNTCP staff capacity to collaborate with PPs, provision of feedback on referrals through SMS) and one targeted at intervention PPs (training in RNTCP, provision of referral pads and education materials and monthly visits to PPs by RNTCP staff). Crude and adjusted referral and PTB case‐finding rate ratios were calculated with negative binomial regression. Results PPs referred 836 individuals (548 from intervention and 169 from control arm PPs) of whom 176 were diagnosed with bacteriologically confirmed PTB. The proportion (95% confidence interval) of referring PPs [0.59 (0.49, 0.68) vs. 0.42 (0.32, 0.52) in the intervention and control arm, respectively], mean referral rate per PP‐year [(5.7 (3.8, 8.7) vs. 1.8 (1.2, 2.8)] and smear‐positive PTB case‐finding rate per PP‐year [(1.5 (0.9, 2.2) vs. 0.6 (0.3, 0.9)] were significantly higher in the intervention than the control arm. Stratifying by qualification, a statistically significant difference in the above indicators remained only among GPs and internists. Overall, surgeons, paediatricians and gynaecologists referred few patients. PP referrals contributed to 20% of the sputum smear positive PTB cases detected by RNTCP in Tumkur city (14% were from intervention arm PPs). Conclusions We demonstrated the effectiveness of a health system‐oriented intervention to improve PP’s referrals of presumptive PTB cases to RNTCP.

Russell R. Kempker, Nestani Tukvadze, Lisa Sthreshley, Lisa Sharling, Dawn L. Comeau, Matthew J. Magee, Carlos del Rio, Zaza Avaliani and Henry M. Blumberg

Abstract. In 2004, there existed limited tuberculosis (TB) research capacity in the country of Georgia. In response, a collaborative research training program (RTP) supported by a National Institutes of Health Fogarty International Center Global Infectious Diseases grant was formed between a U.S. academic institution and the National Center for Tuberculosis and Lung Disease (NCTLD) and other institutions in Georgia. We sought to assess outcomes of this RTP. The TB RTP combined didactic and mentored research training for Georgian trainees. Long-term trainees were supported for a 2-year period and with posttrainee career development mentoring. Metrics used to measure program performance included publications, grants received, and career advancement. From 2004 to 2015, 20 trainees participated in the program with 15 (75%) authoring a total of 65 publications in PubMed-listed journals. The median number of publications per trainee was six (interquartile range 2–14). A total of 16 (80%) trainees remain working in the area of TB; nine were promoted to leadership positions and three to lead research units at Georgian institutions. Ten (50%) trainees were the principal investigator (PI) of a peer-reviewed external grant after Fogarty-supported training, and 40% served as research mentors. Annual TB-related research funding at the NCTLD increased from $5,000 in 2005 to ∼$1.5 million in 2017. A Georgian Fogarty trainee was either PI, site PI, or coinvestigator on > 90% of all research funding. We believe that the NIH Fogarty-funded TB research training grant has made critical contributions to increasing the TB-related research infrastructure and capacity in Georgia, particularly at the NCTLD.

Beate Kampmann

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 8, Page 1058-1064, April 15, 2018.

Nicolas A Menzies, Emory Wolf, David Connors, Meghan Bellerose, Alyssa N Sbarra, Ted Cohen, Andrew N Hill, Reza Yaesoubi, Kara Galer, Peter J White, Ibrahim Abubakar, Joshua A Salomon

Mathematical modelling is commonly used to evaluate infectious disease control policy and is influential in shaping policy and budgets. Mathematical models necessarily make assumptions about disease natural history and, if these assumptions are not valid, the results of these studies can be biased. We did a systematic review of published tuberculosis transmission models to assess the validity of assumptions about progression to active disease after initial infection (PROSPERO ID CRD42016030009).

M. J. Oxtoby and E. M. Dufort…

Abstract Background Mycobacterium tuberculosis drug resistance is a major challenge to the use of standardized regimens for tuberculosis (TB) therapy, especially among previously treated patients. We aimed to investigate the frequency and pattern of drug resistance among previously treated patients with smear-positive pulmonary tuberculosis at the Korle-Bu Teaching Hospital Chest Clinic, Accra. Methods This was a cross-sectional survey of mycobacterial isolates from previously treated patients referred to the Chest Clinic Laboratory between October 2010 and October 2013. The Bactec MGIT 960 system for mycobactrerial culture and drug sensitivity testing (DST) was used for sputum culture of AFB smear-positive patients with relapse, treatment failure, failure of smear conversion, or default. Descriptive statistics were used to summarize patient characteristics, and frequency and patterns of drug resistance. Results A total of 112 isolates were studied out of 155 from previously treated patients. Twenty contaminated (12.9%) and 23 non-viable isolates (14.8%) were excluded. Of the 112 studied isolates, 53 (47.3%) were pan-sensitive to all first-line drugs tested Any resistance (mono and poly resistance) to isoniazid was found in 44 isolates (39.3%) and any resistance to streptomycin in 43 (38.4%). Thirty-one (27.7%) were MDR-TB. Eleven (35.5%) out of 31 MDR-TB isolates were pre-XDR. MDR-TB isolates were more likely than non-MDR isolates to have streptomycin and ethambutol resistance. Conclusions The main findings of this study were the high prevalence of MDR-TB and streptomycin resistance among previously treated TB patients, as well as a high prevalence of pre-XDR-TB among the MDR-TB patients, which suggest that first-line and second-line DST is essential to aid the design of effective regimens for these groups of patients in Ghana.

Anthony S. Fauci and Robert W. Eisinger

Abstract. Controlling and ultimately ending tuberculosis (TB) as a public health scourge will require a multifaceted and comprehensive approach involving the intensification of public health efforts, including scaling-up the delivery of current diagnostic, preventive, and therapeutic tools. However, a critically important element in the effort to end TB is an accelerated biomedical research effort to address the many unanswered questions about the disease process itself and to develop improved and innovative countermeasures. An intensive effort toward these research goals will facilitate the achievement of the aspirational goal of ending TB.

Nandy, A., Mondal, A. K., Pandey, R., Arumugam, P., Dawa, S., Jaisinghani, N., Rao, V., Dash, D., Gandotra, S.

Mycobacterium tuberculosis (Mtb), a successful human pathogen, utilizes multiple carbon sources from the host, but adapts to a fatty acid rich environment in vivo. We sought to delineate the physiologic response of Mtb to a lipid rich environment by using differentiated adipocytes as a model system. RNA sequencing based global transcriptome profiling of bacilli was performed from infected adipocytes and preadipocytes. Genes involved in de novo fatty acid synthesis were downregulated while those predicted to be involved in triglyceride biosynthesis were upregulated in bacilli isolated from adipocytes indicating reliance on host derived fatty acids. Transcription factor network analysis indicated suppression of IdeR regulated genes, suggestive of decreased iron uptake by Mtb in the adipocyte model. This suppression of iron uptake was incident with elevated ferritin and iron levels in adipocytes compared to preadipocytes. Consistent with the role of iron in mediating oxidative stress, we observed upregulation of genes involved in mitigating oxidative stress in Mtb isolated from adipocytes. We provide evidence that oleic acid, a major host derived fatty acid, helps in reducing the bacterial cytoplasm, thereby providing a safe haven for a Mtb mutant that is sensitive to iron mediated oxidative stress. Via an independent mechanism, host ferritin is also able to rescue growth of this mutant. Our work highlights the inherent synergy between macronutrients and micronutrients of the host environment that converge to provide resilience to the pathogen. This complex synergy afforded by the adipocyte model of infection will aid identification of genes required by Mtb in a caseous host environment.

Moideen, K., Kumar, N. P., Nair, D., Banurekha, V. V., Bethunaickan, R., Babu, S.

Granulocytes are activated during tuberculosis (TB) infection and act as immune effector cells and granulocyte responses are implicated in TB pathogenesis. Plasma levels of neutrophil and eosinophil granular proteins provide an indirect measure of degranulation. In this study, we wanted to examine the levels of neutrophil and eosinophil granular proteins in individuals with pulmonary tuberculosis (PTB) and to compare them with the levels in latent TB (LTB) individuals. Hence, we measured the plasma levels of myeloperoxidase (MPO), neutrophil elastase, and proteinase-3; major basic protein (MBP), eosinophil derived neurotoxin (EDN), eosinophil cationic protein (ECP) and eosinophil peroxidase (EPX) in these individuals. Finally, we also measured the levels of all of these parameters in PTB individuals following anti-tuberculosis (ATT) treatment. Our data reveal that PTB individuals are characterized by significantly higher plasma levels of MPO, elastase, human proteinase 3 as well as MBP and EDN in comparison to LTB individuals. Our data also reveal that ATT resulted in reversal of all of these changes, indicating an association with TB disease. Finally, our data show that the systemic levels of MPO and proteinase-3 can significantly discriminate PTB from LTB individuals. Thus, our data suggest that neutrophil and eosinophil granular proteins could play a potential role in the innate immune response and therefore, the pathogenesis of pulmonary TB.