Cross-border outbreak of extensively drug-resistant tuberculosis linked to a university in Romania.

Extensively drug-resistant (XDR) tuberculosis (TB) poses a threat to public health due to its complicated, expensive and often unsuccessful treatment. A cluster of three XDR TB cases was detected among foreign medical students of a Romanian university. The contact investigations included tuberculin skin testing or interferon gamma release assay, chest X-ray, sputum smear microscopy, culture, drug susceptibility testing, genotyping and whole-genome sequencing (WGS), and were addressed to students, personnel of the university, family members or other close contacts of the cases. These investigations increased the total number of cases to seven. All confirmed cases shared a very similar WGS profile. Two more cases were epidemiologically linked, but no laboratory confirmation exists. Despite all the efforts done, the source of the outbreak was not identified, but the transmission was controlled. The investigation was conducted by a team including epidemiologists and microbiologists from five countries (Finland, Israel, Romania, Sweden and the UK) and from the European Centre for Disease Prevention and Control. Our report shows how countries can collaborate to control the spread of XDR TB by exchanging information about cases and their contacts to enable identification of additional cases and transmission and to perform the source investigation.

Tuberculosis notification rate decreases faster in residents of native origin than in residents of foreign origin in the EU/EEA, 2010 to 2015.

To estimate trends in tuberculosis (TB) notification rates by geographical origin, we retrieved surveillance data from 2010 to 2015 for 29 European Union and European Economic Area countries. The TB notification rate decreased at an annual rate of 5.3%. The decrease in notification rate was higher in native residents (7.0%) than in those of foreign origin (3.7%). Targeted screening and facilitated access to care and treatment could help prevent and control TB in migrants.

Strengthening TB infection control in specialized health facilities in Romania--using a participatory approach.

INTRODUCTION: In 2012, the tuberculosis (TB) notification rate among Romanian TB facility doctors and nurses was 7.2 times higher than in the general population. This indicates that transmission is ongoing inside TB facilities and that TB infection control measures are insufficient. To help prevent nosocomial TB transmission a project was implemented that aimed at providing nationwide tailor-made technical assistance in TB infection control (TB-IC) in TB treatment facilities, including the development of TB infection control plans. The objective of the present article is to describe the implementation of the project and to discuss successes and challenges. STUDY DESIGN: The project was an implementation study using two methods of evaluation: (1) a cross sectional questionnaire study; and (2) collection of information, during the training, on challenges related to infection control and to the project implementation. METHODS: The project team developed a TB facility infection control (TB-IC) plan template, together with the Romanian experts. The template was discussed and agreed upon with the experts at a meeting and thereafter distributed by email to all TB facilities. Afterwards, a training of trainers (TOT) seminar was organized which included the provision of information about different training methods, as well as information about TB-IC. The TOT was followed by training for key TB-IC providers. Information about use of the TB-IC template was gathered through a self-administered questionnaire sent to all participants of the expert meeting and the training (42 people). Additionally, non-systematized discussions were held on broader challenges in TB-IC implementation during the training. RESULTS: Within the project 42 key TB-IC service providers were trained in TB-IC, including 9 who were trained at a TOT seminar. The trainees were specialists working at the national level, such as country TB coordinators, or at the TB facility level: TB doctors, epidemiologists, laboratory specialists and maintenance engineers. Out of 42 key TB-IC service providers who were trained, only eighteen responded to the questionnaire (no reminders were sent). Out of these, 14 had used the TB-IC plan template after the project team disseminated it to them by email. The remaining four TB-IC service providers indicated that they were planning to use the template to develop or update their facility TB-IC plans. Related to the use of TB-IC plan template, the following broader challenges in TB-IC were identified: a lack of authority of the individuals responsible for TB-IC to implement the TB-IC measures, lack of training among facility epidemiologists on TB, underdeveloped system for reporting TB in healthcare workers, difficulties with triage of the TB suspects, and poor facility infrastructure hampering implementation of TB-IC measures. DISCUSSION: Implementing TB-IC plans in Romanian health care facilities proved to be challenging, mainly due to the fact that the national infection control plan for TB was not yet adopted at the time of project implementation, and therefore there was neither a regulatory framework to support TB facility-IC planning nor any related budget allocations for the implementation of the facilities' TB-IC plans. Nonetheless, most respondents who answered the questionnaire (18 of 42 responded) indicated that they had started using the TB-IC plan template, which represents a full package of infection control measures that, when implemented effectively and in its entirety, may be expected to reduce nosocomial transmission. The study's limitations are: very low survey response rate, thus there is a likelihood of responder bias.

Molecular surveillance of multi- and extensively drug-resistant tuberculosis transmission in the European Union from 2003 to 2011.

The European Centre for Disease Prevention and Control (ECDC) initiated a project on the molecular surveillance of multi- and extensively drug-resistant tuberculosis (MDR-/XDR-TB) transmission in the European Union (EU) in the period from 2009 to 2011. In total, 2,092 variable number of tandem repeat (VNTR) patterns of MDR-/XDR-TB Mycobacterium tuberculosis isolates were collected, originating from 24 different countries in the period 2003 to 2011. Of the collected VNTR patterns, 45% (n=941) could be assigned to one of the 79 European multiple-country molecular fingerprint clusters and 50% of those (n=470) belonged to one extremely large cluster caused by Beijing strains of one genotype. We conclude that international transmission of MDR-/XDR-TB plays an important role in the EU, especially in the eastern part, and is significantly related to the spread of one strain or clone of the Beijing genotype. Implementation of international cluster investigation in EU countries should reveal underlying factors of transmission, and show how TB control can be improved regarding case finding, contact tracing, infection control and treatment in order to prevent further spread of MDR-/XDR-TB in the EU.

Drug resistance among tuberculosis cases in the European Union and European Economic Area, 2007 to 2012.

The European Union and European Economic Area (EU/EEA) tuberculosis (TB) surveillance system collects detailed information on resistance to TB drugs. Using this information, we provide an overview of the current TB drug resistance situation and trends in the EU/EEA by performing a descriptive analysis, including analysis of treatment outcomes, of the TB cases reported between January 2007 and December 2012. The percentages of TB cases with different drug resistance patterns have been stable with about 90% of the new laboratory-confirmed cases pan-susceptible, 6% monodrug-resistant, 2% polydrug-resistant, 2% multidrug drug-resistant (MDR) TB - excluding extensively drugresistant (XDR) TB -, and 0.2% XDR-TB. In previously treated laboratory-confirmed TB cases, the percentage with MDR-TB excluding XDR-TB declined until 2010 to 16% and remained stable thereafter. During the study period, the percentages of cases with monodrug- and polydrug-resistant TB remained constant at about 8% and 2% whereas the percentage of XDR-TB cases increased slightly to 2.6%. Treatment outcome results for all cases have been stable with overall 77.9% of the pan-susceptible cases, 69.6% of the monoresistant cases, 68.2% of the polyresistant cases, 32.2% of the MDR-TB cases (excluding XDR-TB), and 19.1% of the XDR-TB cases treated successfully. The treatment success rate target for new pulmonary culture-positive MDR-TB cases of 70% has not been reached. In addition, drug resistance surveillance can be improved by more complete reporting of drug susceptibility results and treatment outcome.

Extrapulmonary tuberculosis in the European Union and European Economic Area, 2002 to 2011.

Tuberculosis (TB) is decreasing in the European Union/European Economic Area (EU/EEA), but remains a significant public health problem. Although pulmonary TB accounts for the majority of the cases and is the main transmissible form of the disease, extrapulmonary TB also contributes to the burden of disease and does not receive specific attention in international control strategies. We performed a descriptive analysis to assess the burden and trends of extrapulmonary TB in EU/EEA countries. During 2002­11, 167,652 cases of extrapulmonary TB were reported by the 30 Member States. Extrapulmonary TB accounted for 19.3% of all notified cases, ranging from 5.8% to 44.4% among the Member States. Overall, TB notification rates decreased in 2002­11 due to a decrease in pulmonary TB. Notification rates of extrapulmonary TB remained stable at 3.4 per 100,000 in 2002 and 3.2 per 100,000 in 2011. Thus the proportion of extrapulmonary TB increased from 16.4% in 2002 to 22.4% in 2011. Of all extrapulmonary TB cases reported during 2002­11, 37.9% were foreign-born or citizens of another country, 33.7% were culture-confirmed, and the overall treatment success was 81.4%. A significant percentage of notified TB cases are extrapulmonary, and in contrast to pulmonary TB, extrapulmonary TB rates are not decreasing.

Challenges in diagnosing extrapulmonary tuberculosis in the European Union, 2011.

In the European Union (EU) 72,334 tuberculosis (TB) cases were notified in 2011, of which 16,116 (22%) had extrapulmonary tuberculosis (EPTB). The percentage of TB cases with EPTB ranged from 4% to 48% in the reporting countries. This difference might be explained by differences in risk factors for EPTB or challenges in diagnosis. To assess the practices in diagnosis of EPTB we asked European Union/European Economic Area (EU/EEA) countries to participate in a report describing the diagnostic procedures and challenges in diagnosing EPTB. Eleven EU Member States participated and reports showed that in the majority EPTB is diagnosed by a pulmonologist, sometimes in collaboration with the doctor who is specialised in the organ where the symptoms presented. In most countries a medical history and examination is followed by invasive procedures, puncture or biopsy, to collect material for confirmation of the disease (by culture/histology/cytology). Some countries also use the tuberculin skin test or an interferon-gamma-release-assay. A wide variety of radiological tests may be used. Countries that reported challenges in the diagnosis of EPTB reported that EPTB is often not considered because it is a rare disease and most medical professionals will not have experience in diagnosing EPTB. The fact that EPTB can present with a variety of symptoms that may mimic symptoms of other pathologies does pose a further challenge in diagnosis. In addition, obtaining an appropriate sample for confirmation of EPTB was frequently mentioned as a challenge. In summary, diagnosis of EPTB poses challenges due to the diversity of symptoms with which EPTB may present, the low level of suspicion of clinicians, and due to the difficulty in obtaining an adequate sample for confirmation.

Experiences from 4 Years of Organization of an External Quality Assessment for Mycobacterium tuberculosis Whole-Genome Sequencing in the European Union/European Economic Area.

Here, we report the development and key features of the first external quality assessment (EQA) scheme for Mycobacterium tuberculosis whole-genome sequencing (WGS). The results of four rounds (2017 to 2020) of implementation within the European tuberculosis reference laboratories network (ERLTB-Net-2) are presented and discussed. EQA panels comprising 10 genomic DNAs were distributed to ERLTB-Net 2 laboratories volunteering to participate in this exercise. Since 2018, five FASTQ files were added to better assess the dry WGS processes, and in 2020, three of the five files were replaced by synthetic files (providing additional flexibility for the mutations included in the panels). Ten National tuberculosis reference laboratories participated in all four EQA rounds, and seven participated in at least one. High-confidence resistance mutations were correctly identified by all laboratories, but challenges remained with respect to the identification of mixed loci and interpretation of rare mutations. M. tuberculosis genotyping and clustering analysis was >90% accurate for pure samples with the main challenges being related to the analysis of mixed genotypes and DNA FASTQ files. The development and implementation of this WGS EQA scheme has contributed to the continuous improvement in performance of participating laboratories in M. tuberculosis WGS and data analysis. This scheme can serve as a model of comprehensive quality assessment for M. tuberculosis WGS that can be replicated in different settings worldwide. IMPORTANCE The wider availability of whole-genome sequencing (WGS) coupled to new developments in bioinformatic tools and databases to interpret Mycobacterium tuberculosis complex WGS data has accelerated the adoption of this method for the routine prediction of antimycobacterial drug resistance and genotyping, thus necessitating the establishment of a comprehensive external quality control system. Here, we report 4 years of development and results from such a panel.

Prevalence of inappropriate tuberculosis treatment regimens: a systematic review.

A potential threat to the success of new tuberculosis (TB) drugs is the development of resistance. Using drugs in appropriate regimens, such as those recommended in the World Health Organization (WHO) treatment guidelines, prevents the development of resistance. We performed a systematic review to assess the prevalence of inappropriate prescription of TB drugs for the treatment of TB. MEDLINE, EMBASE and other databases were searched for relevant articles in January 2011. Observational studies published from 2000 that included TB patients receiving treatment were selected. A treatment regimen was considered inappropriate if the regimen was not a WHO recommended regimen. 37 studies were included. Inappropriate treatment regimens were prescribed in 67% of studies. The percentage of patients receiving inappropriate regimens varied between 0.4% and 100%. In 19 studies the quality of treatment regimen reporting was low. Despite the fact that assessment of inappropriate treatment was hampered by low quality of reporting, our data indicate a reasonable amount of inappropriate prescription of TB treatment regimens. Thus, there is a risk that new drugs will be used in inappropriate treatment regimens, even with WHO guidelines in place, introducing the risk of resistance development. This article highlights the need to improve implementation of the WHO treatment of TB guidelines.

Prevalence of smear-positive tuberculosis in persons aged ≥ 15 years in Bangladesh: results from a national survey, 2007-2009.

The aim of this study was to determine the nationwide prevalence of smear-positive tuberculosis (TB) in Bangladesh. A multi-stage cluster survey of a random sample of persons aged ≥ 15 years was included in 40 clusters (20 urban, 20 rural). Two sputum samples were collected from study participants and tested initially by fluorescence microscopy and confirmed by the Ziehl-Neelsen method. The crude and adjusted prevalence rates and 95% confidence intervals (CIs) were calculated using standard methods. A total of 33 new smear-positive TB cases were detected among 52 098 individuals who participated in the study. The average participation rate was over 80%. The overall crude prevalence of new smear-positive TB in persons aged ≥ 15 years was estimated as 63.3/100 000 (95% CI 43.6-88.9) and the adjusted prevalence was 79.4/100 000 (95% CI 47.1-133.8). TB prevalence was higher in males (n = 24) and in rural areas (n = 20). The prevalence was highest in the 55-64 years age group (201/100 000) and lowest in 15-24 years age group (43.0/100 000). The prevalence was higher in persons with no education (138.6/100 000, 95% CI 78.4-245.0). The overall prevalence of smear-positive TB was significantly lower than the prevalence estimate of the previous nationwide survey in Bangladesh in 1987-1988 (870/100 000).

Uptake of the lateral flow urine LAM test in Europe and Central Asia.

INTRODUCTION: Since 2015 (updated in 2019), the WHO has recommended to include the commercial lateral flow urine lipoarabinomannan TB test (LF-LAM), AlereLAM, in the diagnostic toolkit for severely ill people living with HIV.METHODS: To assess the current use and barriers to the implementation of the test, we conducted an electronic survey among national focal points and managers of TB and HIV programmes in the 53 Member States of the WHO European Region and a European network of clinicians working in TB and HIV medicine.RESULTS: In all, 45 individual responses (37 countries) were received from programme managers and focal points and 17 responses (14 countries) from clinicians. Only eight countries reported adopting LF-LAM policies, with only four currently using the AlereLAM (Armenia, Belarus, Ukraine and Uzbekistan). The most commonly reported barriers to implementing the test were the small number of eligible patients (with HIV-TB co-infections), the test not being included in the TB or HIV programme´s mandate and lack of budget allocation.CONCLUSION: Consistent with findings from high TB burden countries in Africa and Asia, the survey demonstrated that uptake of AlereLAM is almost non-existent. Addressing the identified barriers and the intrinsic limitations of the test could help to increase the use of the test.

TB management in the European Union/European Economic Area: a multi-centre survey.

BACKGROUND: Essential TB care in the European Union/European Economic Area (EU/EEA) comprises 21 standards for the diagnosis, treatment and prevention of TB that constitute the European Union Standards for Tuberculosis Care (ESTC).METHODS: In 2017, we conducted an audit on TB management and infection control measures against the ESTC standards. TB reference centres in five EU/EEA countries were purposely selected to represent the heterogeneous European TB burden and examine geographic variability.RESULTS: Data from 122 patients, diagnosed between 2012 and 2015 with multidrug-resistant TB (n = 49), extensively drug-resistant TB (XDR-TB) (n = 11), pre-XDR-TB (n = 29) and drug-susceptible TB (n = 33), showed that TB diagnosis and treatment practices were in general in agreement with the ESTC.CONCLUSION: Overall, TB management and infection control practices were in agreement with the ESTC in the selected EU/EEA reference centres. Areas for improvement include strengthening of integrated care services and further implementation of patient-centred approaches.

Tuberculosis surveillance in adolescents: what to learn from European Union/European Economic Area data?

OBJECTIVE: To describe tuberculosis (TB) characteristics in the adolescent 10-19 years age group that is often underrepresented in surveillance and studies despite the high global TB burden estimated for this group.SETTING AND DESIGN: We use the case-based data reported to the European Surveillance System (TESSy) from European Union (EU)/European Economic Area (EEA) countries between 2007 and 2016 to describe notification rates, TB characteristics and treatment outcomes among adolescent TB cases. We also compare TB characteristics in young adolescents (10-14 years) and older adolescents (15-19 years).RESULTS: For the period 2007 to 2016, 705 826 TB cases were reported to TESSy by 29 EU/EEA countries, 38 054 (5.4%) of which were adolescents. The overall EU/EEA notification rate among adolescents was 6.9 per 100 000 population, 3.5 among young adolescents and 10.1 among older adolescents. The two adolescent groups had differences regarding sex distribution, site of disease, sputum smear microscopy positivity, laboratory confirmation and treatment outcome.CONCLUSION: Younger and older adolescents should be analysed as separate groups when studying and reporting TB, particularly to inform better targeting of TB prevention and care interventions in the future, in order to improve outcomes.

Journeys to tuberculosis treatment: a qualitative study of patients, families and communities in Jogjakarta, Indonesia.

BACKGROUND: Many tuberculosis (TB) patients in Indonesia are diagnosed late. We seek to document patient journeys toward TB diagnosis and treatment and factors that influence health care seeking behavior. METHODS: TB patients in Jogjakarta municipality (urban) and Kulon Progo district (rural) were recruited from health care facilities participating in the DOTS strategy and health care facilities not participating in the DOTS strategy, using purposive sampling methods. Data were collected through in-depth interviews with TB patients and members of their family and through Focus Group Discussions (FGD) with community members. RESULTS: In total, 67 TB patients and 22 family members were interviewed and 6 FGDs were performed. According to their care seeking behavior patients were categorized into National TB program's (NTP) dream cases (18%), 'slow-but-sure patients' (34%), 'shopaholics' (45%), and the NTP's nightmare case (3%). Care seeking behavior patterns did not seem to be influenced by gender, place of residence and educational level. Factors that influenced care seeking behavior include income and advice from household members or friends. Family members based their recommendation on previous experience and affordability. FGD results suggest that the majority of people in the urban area preferred the hospital or chest clinic for diagnosis and treatment of TB whereas in the rural area private practitioners were preferred. Knowledge about TB treatment being free of charge was better in the urban area. Many community members from the rural area doubted whether TB treatment would be available free of charge. CONCLUSION: Most TB patients took over a month to reach a DOTS facility after symptoms appeared and had consulted a number of providers. Their income and advice from household members and friends were factors that influenced their care seeking behavior most.

Role and value of whole genome sequencing in studying tuberculosis transmission.

BACKGROUND: Tuberculosis (TB) remains a serious public health threat worldwide. Theoretically ultimate resolution of whole genome sequencing (WGS) for Mycobacterium tuberculosis complex (MTBC) strain classification makes this technology very attractive for epidemiological investigations. OBJECTIVES: To summarize the evidence available in peer-reviewed publications on the role and place of WGS in detection of TB transmission. SOURCES: A total of 69 peer-reviewed publications identified in Pubmed database. CONTENT: Evidence from >30 publications suggests that a cut-off value of fewer than six single nucleotide polymorphisms between strains efficiently excludes cases that are not the result of recent transmission and could be used for the identification of drug-sensitive isolates involved in direct human-to-human TB transmission. Sensitivity of WGS to identify epidemiologically linked isolates is high, reaching 100% in eight studies with specificity (17%-95%) highly dependent on the settings. Drug resistance and specific phylogenetic lineages may be associated with accelerated mutation rates affecting genetic distances. WGS can be potentially used to distinguish between true relapses and re-infections but in high-incidence low-diversity settings this would require consideration of epidemiological links and minority alleles. Data from four studies looking into within-host diversity highlight a need for developing criteria for acceptance or rejection of WGS relatedness results depending on the proportion of minority alleles. IMPLICATIONS: WGS will potentially allow for more targeted public health actions preventing unnecessary investigations of false clusters. Consensus on standardization of raw data quality control processing criteria, analytical pipelines and reporting language is yet to be reached.

How to identify tuberculosis cases in a prevalence survey.

The identification of pulmonary tuberculosis (TB) cases in a prevalence survey is a challenge, as diagnostic methods are labour-intensive and large numbers of individuals need to be screened because the prevalence rate is low (almost never greater than 1,200 per 100,000 population). Three testing methods are used: questionnaires, chest radiography (CXR) and bacteriological tests, including sputum smear microscopy and culture. These methods can be applied in four strategies to identify cases. The most sensitive strategy is to apply all methods to each eligible individual. The next most sensitive option is to apply the questionnaire, CXR and sputum smear microscopy to each eligible individual and obtain sputum for culture from those individuals with symptoms, abnormalities on the CXR or a positive smear. If laboratory capacity is limited, screening using symptom enquiry and CXR can be used to select those individuals at highest risk of TB. These individuals are then requested to submit sputum for smear microscopy and culture. If neither CXR nor culture is available, sputum samples may be collected from all eligible individuals and examined by an enhanced microscopy method such as fluorescence microscopy. Case definitions are ideally based on the combined results of symptom enquiry, CXR and bacteriology.

Is there an increased risk of TB relapse in patients treated with fixed-dose combination drugs in Indonesia?

SETTING: South Sulawesi Province, Republic of Indonesia. OBJECTIVE: To compare relapse rates among tuberculosis (TB) patients treated with fixed-dose combination drugs (FDCs) and patients treated with the same regimen using loose drugs. METHODOLOGY: Between 1999 and 2001, new smear-positive TB patients were randomly allocated to treatment with four-drug FDCs or loose drugs to study differences in treatment outcomes. Although it was not in the original study design, in 2004-2005 we performed a follow-up study by home visit of cured patients. We conducted an interview and tried to collect a sputum sample from each patient. If the patient was absent or had died, a proxy interview was conducted. The sputum samples were examined by microscopy and culture. RESULTS: The overall relapse rate was 7.0% in patients who were able to produce a sputum sample. Relapse appeared to be more frequent in the FDC group compared to the loose drug group (10.1% vs. 2.7%, P = 0.074). CONCLUSION: This is the first documented long-term follow-up study of patients treated with four-drug FDCs. There is an indication that treatment of new sputum smear-positive TB patients with FDCs provides an increased risk of relapse compared to treatment with loose drugs. The long-term results of treatment with FDCs should be carefully evaluated in other settings.

First national tuberculin survey in Nepal.

SETTING: The size of the tuberculosis (TB) problem in Nepal is unknown, as no national tuberculin or TB prevalence survey has yet been performed. OBJECTIVE: To assess the prevalence of TB infection and the annual risk of TB infection (ARTI) in primary schoolchildren in the three ecological zones (mountains, hills and terai) and Kathmandu valley. DESIGN: A representative sample of primary schoolchildren were tuberculin skin tested using the Mantoux method. The data were analysed using cut-off levels to define infection and by the mirror method. RESULTS: Of 19577 children registered, 17260 (88.2%) were available for analysis. Seventy-eight per cent had a visible bacille Calmette-Guérin scar. The best estimate of the prevalence of TB infection was 7.0% (95%CI 4.2-9.7), with an ARTI of 0.86% (95%CI 0.49-1.23) using the mirror method, with a mode at 16 mm. Although the ARTI was higher in Kathmandu and the mountains compared to the hills and terai, the difference between the areas was not significant. CONCLUSION: The ARTI in Nepal is lower than previous estimates, indicating a decrease in transmission or overestimation of previous estimates. To obtain information about the trend of the ARTI in Nepal, the survey needs to be repeated in 5 to 7 years.