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.

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.

Time-and-motion tool for the assessment of working time in tuberculosis laboratories: a multicentre study.

SETTING: Implementation of novel diagnostic assays in tuberculosis (TB) laboratory diagnosis requires effective management of time and resources. OBJECTIVE: To further develop and assess at multiple centres a time-and-motion (T&M) tool as an objective means for recording the actual time spent on running laboratory assays. DESIGN: Multicentre prospective study conducted in six European Union (EU) reference TB laboratories. RESULTS: A total of 1060 specimens were tested using four laboratory assays. The number of specimens per batch varied from one to 60; a total of 64 recordings were performed. Theoretical hands-on times per specimen (TTPS) in h:min:s for Xpert® MTB/RIF, mycobacterial interspersed repetitive unit-variable number of tandem repeats genotyping, Ziehl-Neelsen staining and manual fluorescence microscopy were respectively 00:33:02 ± 00:12:32, 00:13:34 ± 00:03:11, 00:09:54 ± 00:00:53 and 00:06:23 ± 00:01:36. Variations between laboratories were predominantly linked to the time spent on reporting and administrative procedures. Processing specimens in batches could help save time in highly automated assays (e.g., line-probe) (TTPS 00:14:00 vs. 00:09:45 for batches comprising 7 and 31 specimens, respectively). CONCLUSIONS: The T&M tool can be considered a universal and objective methodology contributing to workload assessment in TB diagnostic laboratories. Comparison of workload between laboratories could help laboratory managers justify their resource and personnel needs for the implementation of novel, time-saving, cost-effective technologies, as well as identify areas for improvement.

Tuberculosis in migrants in low-incidence countries: epidemiology and intervention entry points.

As tuberculosis (TB) rates continue to decline in native populations in most low TB incidence countries, the proportion of TB patients born outside their country of residence ('foreign-born') increases. Some low-incidence countries have experienced a substantial increase in TB rates related to recent increases in the number of asylum seekers and other migrants from TB-endemic countries. However, average TB rates among the foreign-born in low-incidence countries declined moderately in 2009-2015. TB in foreign-born individuals is commonly the result of reactivation of latent infection with Mycobacterium tuberculosis acquired outside the host country. Transmission is generally low in low-incidence countries, and transmission from migrants to the native population is often modest. Variations in levels and trends in TB notifications among the foreign-born are likely explained by differences and fluctuations in the number and profile of migrants, as well as by variations in TB control, health and social policies in the host countries. To optimise TB care and prevention in migrants from endemic to low-incidence countries, we propose a framework for identifying possible TB care and prevention interventions before, during and after migration. Universal access to high-quality care along the entire migration pathway is critical. Screening for active TB and latent tuberculous infection should be tailored to the TB epidemiology, adapted to the needs of specific migrant groups and linked to treatment. Ultimately, the long-term TB elimination goal can be reached only if global health and socio-economic inequalities are dramatically reduced. Low-incidence countries, most of which are among the wealthiest nations, need to contribute through international assistance.

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.

Measuring socio-economic data in tuberculosis prevalence surveys.

Addressing social determinants in the field of tuberculosis (TB) has received great attention in the past years, mainly due to the fact that worldwide TB incidence has not declined as much as expected, despite highly curative control strategies. One of the objectives of the World Health Organization Global Task Force on TB Impact Measurement is to assess the prevalence of TB disease in 22 high-burden countries by active screening of a random sample of the general population. These surveys provide a unique opportunity to assess socio-economic determinants in relation to prevalent TB and its risk factors. This article describes methods of measuring the socio-economic position in the context of a TB prevalence survey. An indirect measurement using an assets score is the most feasible way of doing this. Several examples are given from recently conducted prevalence surveys of the use of an assets score, its construction, and the analyses of the obtained data.

Why do tuberculosis patients default in Tashkent City, Uzbekistan? A qualitative study.

BACKGROUND: Tuberculosis (TB) control in Tashkent City, Uzbekistan, is organised in accordance with the DOTS strategy. Intensive phase treatment is provided in hospital, while the continuation phase is given on an ambulatory basis. In 2005, the defaulter rate was 21%. An earlier quantitative study explored when patients default and identified some of the risk factors associated with default, but did not answer the question: 'Why do patients default?' OBJECTIVE: To investigate reasons for defaulting and to identify possible solutions. METHODS: We conducted a qualitative follow-up study consisting of 32 in-depth interviews with defaulters, patients who had completed treatment and health care providers. RESULTS: Communication between patients and health care staff is poor. Patients lack proper information on TB and its treatment. There is a widespread belief that TB is not curable. Hospitalisation is problematic due to poor general conditions in TB hospitals, costs incurred by patients during hospitalisation and because TB patients need to earn a living or take care of their families. CONCLUSION: Poor communication between health care staff and TB patients is a key issue underlying several of the causes of default identified, and needs to be addressed. Reducing the period of hospitalisation may also improve adherence to TB treatment.

Drug prescribing practices for tuberculosis in Uzbekistan.

SETTING: Uzbekistan has had 100% DOTS coverage since 2005; however, the treatment success rate has remained at around 80% for the last 4 years. Surveys from the capital city of Tashkent and from western Uzbekistan have shown high levels of primary multidrug resistance. OBJECTIVE: To assess treatment regimens prescribed for new cases of tuberculosis (TB), including the prescription of additional non-TB drugs, and the cost implications for the patient. DESIGN: We randomly sampled 30 clusters of seven new TB patients. Enrolled patients were interviewed and their medical records were reviewed. RESULTS: In general, the treatment regimens prescribed were correct; doses were high rather than low. Second-line anti-tuberculosis drugs were rarely prescribed. In addition to anti-tuberculosis drugs, patients were prescribed on average seven to eight non-TB drugs. The rationale for prescribing the non-TB drugs was, however, questionable. Patients incurred substantial costs for these drugs, some of which were not without risk. CONCLUSION: Prescriptions of anti-tuberculosis drugs for new TB patients are adequate; however, the practice of prescribing additional non-TB drugs needs to be reconsidered.

Reforming tuberculosis control in Ukraine: results of pilot projects and implications for the national scale-up of DOTS.

The period of economic transition has had severe consequences for health and health systems in Ukraine. The tuberculosis (TB) situation illustrates this. The strategy recommended by the World Health Organization (WHO) for TB, directly observed treatment short-course (DOTS), has the potential to provide real improvements in TB services, forming the basis of the response to the growing epidemic. In 2002, Ukraine, financially supported by USAID and the European Community (EC), began to introduce DOTS through pilot projects in Mariupol and Kyiv City. The aim of this study is to assess the feasibility, effectiveness, health service cost, patient cost, and the cost-effectiveness of these pilots, in order to inform the national scale-up of DOTS. The study finds that DOTS is feasible and has the potential to be both effective and cost-effective in Ukraine. Following this study, Ukraine adopted DOTS as a national TB control strategy in 2005. However, the pilots also found that there are several evidence-related concerns and perverse economic incentives to both providers and patients that will need to be addressed if national scale-up is to be successful. These include concerns related to the treatment of MDR-TB, economic benefits to some patients to remain hospitalized, and payments to providers and health facilities that support current practices. These will need to be addressed if Ukraine is to develop an effective response to its emerging TB epidemic.

Tuberculosis prevalence surveys: rationale and cost.

This article is the first of the educational series 'Assessing tuberculosis (TB) prevalence through population-based surveys'. The series will give overall guidance in conducting cross-sectional surveys of pulmonary TB (PTB) disease. TB prevalence surveys are most valuable in areas where notification data obtained through routine surveillance are of unproven accuracy or incomplete, and in areas with an estimated prevalence of bacteriologically confirmed TB of more than 100 per 100,000 population. To embark on a TB prevalence survey requires commitment from the national TB programme, compliance in the study population, plus availability of trained staff and financial resources. The primary objective of TB prevalence surveys is to determine the prevalence of PTB in the general population aged >or=15 years. Limitations of TB prevalence surveys are their inability to assess regional or geographic differences in prevalence of TB, estimate the burden of childhood TB or estimate the prevalence of extra-pulmonary TB. The cost of a prevalence survey is typically US$ 4-15 per person surveyed, and up to US$ 25 per person with radiographic screening. A survey of 50,000 people, of limited precision, would typically cost US$ 200,000-1,250,000.

Prevalence of tuberculous infection and incidence of tuberculosis: a re-assessment of the Styblo rule.

OBJECTIVE: To evaluate the validity of the fixed mathematical relationship between the annual risk of tuberculous infection (ARTI), the prevalence of smear-positive tuberculosis (TB) and the incidence of smear-positive TB specified as the Styblo rule, which TB control programmes use to estimate the incidence of TB disease at a population level and the case detection rate. METHODS: Population-based tuberculin surveys and surveys on prevalence of smear-positive TB since 1975 were identified through a literature search. For these surveys, the ratio between the number of tuberculous infections (based on ARTI estimates) and the number of smear-positive TB cases was calculated and compared to the ratio of 8 to 12 tuberculous infections per prevalent smear- positive TB case as part of the Styblo rule. FINDINGS: Three countries had national population-based data on both ARTI and prevalence of smear-positive TB for more than one point in time. In China the ratio ranged from 3.4 to 5.8, in the Philippines from 2.6 to 4.4, and in the Republic of Korea, from 3.2 to 4.7. All ratios were markedly lower than the ratio that is part of the Styblo rule. CONCLUSION: According to recent country data, there are typically fewer than 8 to 12 tuberculous infections per prevalent smear-positive TB case, and it remains unclear whether this ratio varies significantly among countries. The decrease in the ratio compared to the Styblo rule probably relates to improvements in the prompt treatment of TB disease (by national TB programmes). A change in the number of tuberculous infections per prevalent smear-positive TB case in population-based surveys makes the assumed fixed mathematical relationship between ARTI and incidence of smear-positive TB no longer valid.

Evaluation of case management in the integrated schistosomiasis-control programme in Mali.

Currently, schistosomiasis control in Mali is mainly based on treatment with praziquantel (PZQ). The policy is to ensure (1). the treatment, every 3 years, of school-age children in all areas where the prevalence of haematuria (an indicator of Schistosoma haematobium infection) in this age-group is >30%, and (2). the sound management of all patients presenting with haematuria or (bloody) diarrhoea (an indicator of S. mansoni infection) at health centres. In the present study, the application of case management was evaluated by visiting 60 healthcare facilities in four geographical areas and interviewing the health-workers at these facilities. The presence of S. haematobium and S. mansoni was reported in the coverage areas of 83% and 37%, respectively, of the healthcare facilities investigated. Health-worker knowledge of the main symptoms of schistosome infection was good and patients exhibiting symptoms attributable to schistosome infection were very likely to receive adequate treatment, particularly (at a frequency of about 80%) when they presented with haematuria. At health-centre level, patients were often directly treated with PZQ, whereas health-workers in district hospitals and private clinics requested a diagnostic test prior to any treatment. PZQ was available in most healthcare facilities but not in the private clinics. The mean cost of treatment of a patient with S. haematobium infection (euro; 2.30) was very similar to the corresponding cost for S. mansoni infection (euro; 2.37). The cost of the PZQ represented approximately 50% of the total costs borne by the patients when presenting at health centres. Patients with the symptoms of S. haematobium infection in Mali can expect adequate diagnosis and treatment in agreement with the recommendations of the World Health Organization. Patients presenting with symptoms related to S. mansoni infection are, however, less likely to be correctly diagnosed. The relatively high costs of treatment and the infrequency with which cases of schistosomiasis seek healthcare necessitate policy decisions, to ensure an affordable and more attractive, clinical system of case management.