Tuberculosis in people of Ukrainian origin in the European Union and the European Economic Area, 2019 to 2022.

Approximately five million Ukrainians were displaced to the EU/EEA following the Russian invasion of Ukraine. While tuberculosis (TB) notification rates per 100,000 Ukrainians in the EU/EEA remained stable, the number of notified TB cases in Ukrainians increased almost fourfold (mean 2019-2021: 201; 2022: 780). In 2022, 71% cases were notified in three countries, and almost 20% of drug-resistant TB cases were of Ukrainian origin. Targeted healthcare services for Ukrainians are vital for early diagnosis and treatment, and preventing transmission.

Characteristic SNPs defining the major multidrug-resistant Mycobacterium tuberculosis clusters identified by EuSeqMyTB to support routine surveillance, EU/EEA, 2017 to 2019.

BackgroundThe EUSeqMyTB project, conducted in 2020, used whole genome sequencing (WGS) for surveillance of drug-resistant Mycobacterium tuberculosis in the European Union/European Economic Area (EU/EEA) and identified 56 internationally clustered multidrug-resistant (MDR) tuberculosis (TB) clones.AimWe aimed to define and establish a rapid and computationally simple screening method to identify probable members of the main cross-border MDR-TB clusters in WGS data to facilitate their identification and track their future spread.MethodsWe screened 34 of the larger cross-border clusters identified in the EuSeqMyTB pilot study (2017-19) for characteristic single nucleotide polymorphism (SNP) signatures that could identify and define members of each cluster. We also linked this analysis with published clusters identified in previous studies and identified more distant genetic relationships between some of the current clusters.ResultsA panel of 30 characteristic SNPs is presented that can be used as an initial (routine) screen for members of each cluster. For four of the clusters, no unique defining SNP could be identified; three of these are closely related (within approximately 20 SNPs) to one or more other clusters and likely represent a single established MDR-TB clade composed of multiple recent subclusters derived from the previously described ECDC0002 cluster.ConclusionThe identified SNP signatures can be integrated into routine pipelines and contribute to the more effective monitoring, rapid and widespread screening for TB. This SNP panel will also support accurate communication between laboratories about previously identified internationally transmitted MDR-TB genotypes.

Monitoring the progress achieved towards ending tuberculosis in the European Union/European Economic Area, 2018 to 2021.

We report progress in the European Union/European Economic Area (EU/EEA) towards the Sustainable Development Goal target for tuberculosis (TB) and for the associated global/regional targets. The TB notification rate and the number of TB deaths declined since 2015 but, if current trends continue, the EU/EEA will not reach the 2030 targets. Performance on treatment initiation targets declined sharply during 2020-2021, while the percentage of TB cases with successful treatment outcomes remains low, at 47.9% of the multidrug-resistant TB cases.

Influenza returns with a season dominated by clade 3C.2a1b.2a.2 A(H3N2) viruses, WHO European Region, 2021/22.

In the WHO European Region, COVID-19 non-pharmaceutical interventions continued slowing influenza circulation in the 2021/22 season, with reduced characterisation data. A(H3) predominated and, in some countries, co-circulated with A(H1)pdm09 and B/Victoria viruses. No B/Yamagata virus detections were confirmed. Substantial proportions of characterised circulating virus subtypes or lineages differed antigenically from their respective northern hemisphere vaccine components. Appropriate levels of influenza virus characterisations should be maintained until the season end and in future seasons, when surveillance is adapted to integrate SARS-CoV-2.

Limited Capability for Testing Mycobacterium tuberculosis for Susceptibility to New Drugs.

We surveyed availability of phenotypic drug susceptibility testing for drug-resistant Mycobacterium tuberculosis in Europe. Of 27 laboratories, 17 tested for linezolid, 11 for clofazimine, 9 for bedaquiline, and 6 for delamanid during 2019. Our findings indicate that testing capacity for newer and repurposed tuberculosis drugs exists, but its availability is limited.

Use of a whole genome sequencing-based approach for Mycobacterium tuberculosis surveillance in Europe in 2017-2019: an ECDC pilot study.

Whole genome sequencing (WGS) can be used for molecular typing and characterisation of Mycobacterium tuberculosis complex (MTBC) strains. We evaluated the systematic use of a WGS-based approach for MTBC surveillance involving all European Union/European Economic Area (EU/EEA) countries and highlight the challenges and lessons learnt to be considered for the future development of a WGS-based surveillance system.WGS and epidemiological data of patients with rifampicin-resistant (RR) and multidrug-resistant (MDR) tuberculosis (TB) were collected from EU/EEA countries between January 2017 and December 2019. WGS-based genetic relatedness analysis was performed using a standardised approach including both core genome multilocus sequence typing (cgMLST) and single nucleotide polymorphism (SNP)-based calculation of distances on all WGS data that fulfilled minimum quality criteria to ensure data comparability.A total of 2218 RR/MDR-MTBC isolates were collected from 25 countries. Among these, 56 cross-border clusters with increased likelihood of recent transmission (≤5 SNPs distance) comprising 316 RR/MDR-MTBC isolates were identified. The cross-border clusters included between two and 30 resistant isolates from two to six countries, demonstrating different RR/MDR-TB transmission patterns in Western and Eastern EU countries.This pilot study shows that a WGS-based surveillance system is not only feasible but can efficiently elucidate the dynamics of in-country and cross-border RR/MDR-TB transmission across EU/EEA countries. Lessons learnt from this study highlight that the establishment of an EU/EEA centralised WGS-based surveillance system for TB will require strengthening of national integrated systems performing prospective WGS surveillance and the development of clear procedures to facilitate international collaboration for the investigation of cross-border clusters.

Epidemic and pandemic viral infections: impact on tuberculosis and the lung: A consensus by the World Association for Infectious Diseases and Immunological Disorders (WAidid), Global Tuberculosis Network (GTN), and members of the European Society of Clinical Microbiology and Infectious Diseases Study Group for Mycobacterial Infections (ESGMYC).

Major epidemics, including some that qualify as pandemics, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), HIV, influenza A (H1N1)pdm/09 and most recently COVID-19, affect the lung. Tuberculosis (TB) remains the top infectious disease killer, but apart from syndemic TB/HIV little is known regarding the interaction of viral epidemics and pandemics with TB. The aim of this consensus-based document is to describe the effects of viral infections resulting in epidemics and pandemics that affect the lung (MERS, SARS, HIV, influenza A (H1N1)pdm/09 and COVID-19) and their interactions with TB. A search of the scientific literature was performed. A writing committee of international experts including the European Centre for Disease Prevention and Control Public Health Emergency (ECDC PHE) team, the World Association for Infectious Diseases and Immunological Disorders (WAidid), the Global Tuberculosis Network (GTN), and members of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Mycobacterial Infections (ESGMYC) was established. Consensus was achieved after multiple rounds of revisions between the writing committee and a larger expert group. A Delphi process involving the core group of authors (excluding the ECDC PHE team) identified the areas requiring review/consensus, followed by a second round to refine the definitive consensus elements. The epidemiology and immunology of these viral infections and their interactions with TB are discussed with implications for diagnosis, treatment and prevention of airborne infections (infection control, viral containment and workplace safety). This consensus document represents a rapid and comprehensive summary on what is known on the topic.

European Union training programme for tuberculosis laboratory experts: design, contribution and future direction.

BACKGROUND: Tuberculosis (TB) control programmes rely heavily on laboratories to support both clinical care and public health. Qualified personnel with adequate technical and managerial skills comprise an integral component of any quality assured laboratory. Training a new generation of TB laboratory specialists was identified as a critical priority in the European Union /European Economic Area (EU/EEA). A tailored training programme for TB reference laboratory professionals was developed and implemented within the European Reference Laboratory Network for Tuberculosis to increase the pool of technical experts available to step into leadership roles in the TB laboratory community. Three cohorts of selected laboratory specialists participated in a series of trainings from 2009 to 2016. METHODS: We conducted an evaluation of the training programme using a structured questionnaire administered via the EUSurvey website, with the aim of documenting the benefits and contribution as well as suggesting improvements and future direction of the programme. All graduated participants and all current ERLTB-Net members were invited to participate in the online survey and descriptive quantitative analysis was performed. RESULTS: The evaluation found significant benefits for both the participants and the participants' institutions, with improvements being reported in laboratory practices and management including implementation of new diagnostic techniques and career progression for participants. The training programme differed from other international and European initiatives in a number of important ways; the curriculum is unique in the scope and range of topics covered; the programme targets senior level professionals and future directors; cohorts were limited to 8-10 participants; and the programme involved a number of workshops (5-7) taking place over a two-year period. Relationships and collaborations established between individuals and institutions were valued as an important success of the initiative. Suggestions on how the impact of the programme could be enhanced included equipping participants to perform laboratory assessments in low-resource settings outside the EU, thus bolstering global TB control. CONCLUSION: Based on the findings presented the training programme has proved to be successful in developing leadership, expertise, partnerships and networks to support TB laboratories and has contributed significant benefits to strengthening European National Reference laboratories in the fight against TB.

Completeness of tuberculosis (TB) notification: inventory studies and capture-recapture analyses, six European Union countries, 2014 to 2016.

BackgroundProgress towards the World Health Organization's End TB Strategy is monitored by assessing tuberculosis (TB) incidence, often derived from TB notification, assuming complete case detection and reporting. This assumption is unlikely to hold in many settings, including European Union (EU) countries.AimWe aimed to assess observed and estimated completeness of TB notification through inventory studies and capture-recapture (CRC) methodology in six EU countries: Croatia, Denmark, Finland, the Netherlands, Portugal Slovenia.MethodsWe performed record linkage, case ascertainment and CRC analyses of data collected retrospectively from at least three national TB-related registers in each country between 2014 and 2016.ResultsObserved completeness of TB notification by inventory studies was 73.9% in Croatia, 98.7% in Denmark, 83.6% in Finland, 81.6% in the Netherlands, 85.8% in Portugal and 100% in Slovenia. Subsequent CRC analysis estimated completeness of TB notification to be 98.4% in Denmark, 76.5% in Finland and 77.0% in Portugal. In Croatia, CRC analyses produced implausible results while in the Netherlands and Slovenia, it was methodologically considered not meaningful.ConclusionInventory studies and CRC methodology suggest a TB notification completeness between 73.9% and 100% in the six EU countries. Mandatory reporting by clinicians and laboratories, and cross-checking of registers, strongly contributes to accurate notification rates, but hospital episode registers likely contain a considerable proportion of false-positive TB records and are thus less useful. Further strengthening routine surveillance to count TB cases, i.e. incidence, accurately by employing record-linkage of high-quality TB registers should make CRC studies obsolete in EU countries.

Will we reach the Sustainable Development Goals target for tuberculosis in the European Union/European Economic Area by 2030?

We assessed progress towards the Sustainable Development Goals target for tuberculosis in the European Union/European Economic Area using the latest tuberculosis (TB) surveillance and Eurostat data. Both the TB notification rate and the number of TB deaths were decreasing before 2015 and the TB notification rate further declined between 2015 and 2017. With the current average decline in notification rate and number of TB deaths however, the EU/EEA will not reach the targets by 2030.

Isoniazid (INH) mono-resistance and tuberculosis (TB) treatment success: analysis of European surveillance data, 2002 to 2014.

INTRODUCTION: Isoniazid (INH) is an essential drug for tuberculosis (TB) treatment. Resistance to INH may increase the likelihood of negative treatment outcome. AIM: We aimed to determine the impact of INH mono-resistance on TB treatment outcome in the European Union/European Economic Area and to identify risk factors for unsuccessful outcome in cases with INH mono-resistant TB. METHODS: In this observational study, we retrospectively analysed TB cases that were diagnosed in 2002-14 and included in the European Surveillance System (TESSy). Multilevel logistic regression models were applied to identify risk factors and correct for clustering of cases within countries. RESULTS: A total of 187,370 susceptible and 7,578 INH mono-resistant TB cases from 24 countries were included in the outcome analysis. Treatment was successful in 74.0% of INH mono-resistant and 77.4% of susceptible TB cases. In the final model, treatment success was lower among INH mono-resistant cases (Odds ratio (OR): 0.7; 95% confidence interval (CI): 0.6-0.9; adjusted absolute difference in treatment success: 5.3%). Among INH mono-resistant TB cases, unsuccessful treatment outcome was associated with age above median (OR: 1.3; 95% CI: 1.2-1.5), male sex (OR: 1.3; 95% CI: 1.1-1.4), positive smear microscopy (OR: 1.3; 95% CI: 1.1-1.4), positive HIV status (OR: 3.3; 95% CI: 1.6-6.5) and a prior TB history (OR: 1.8; 95% CI: 1.5-2.2). CONCLUSIONS: This study provides evidence for an association between INH mono-resistance and a lower likelihood of TB treatment success. Increased attention should be paid to timely detection and management of INH mono-resistant TB.

Childhood multidrug-resistant tuberculosis in the European Union and European Economic Area: an analysis of tuberculosis surveillance data from 2007 to 2015.

BackgroundConfirming tuberculosis (TB) in children and obtaining information on drug susceptibility is essential to ensure adequate treatment. We assessed whether there are gaps in diagnosis and treatment of multidrug-resistant (MDR) TB in children in the European Union and European Economic Area (EU/EEA), quantified the burden of MDR TB in children and characterised cases. Methods: We analysed surveillance data from 2007 to 2015 for paediatric cases younger than 15 years. Results: In that period, 26 EU/EEA countries reported 18,826 paediatric TB cases of whom 4,129 (21.9%) were laboratory-confirmed. Drug susceptibility testing results were available for 3,378 (17.9%), representing 81.8% of the confirmed cases. The majority (n = 2,967; 87.8%) had drug-sensitive TB, 249 (7.4%) mono-resistant TB, 64 (1.9%) poly-resistant TB, 90 (2.7%) MDR TB and eight (0.2%) had extensively drug-resistant (XDR) TB. MDR TB was more frequently reported among paediatric cases with foreign background (adjusted odds ratio (aOR) = 1.73; 95% confidence interval (95% CI): 1.12-2.67) or previous TB treatment (aOR: 6.42; 95% CI: 3.24-12.75). Successful treatment outcome was reported for 58 of 74 paediatric MDR TB cases with outcome reported from 2007 to 2013; only the group of 5-9 years-olds was significantly associated with unsuccessful treatment outcome (crude odds ratio (cOR) = 11.45; 95% CI: 1.24-106.04). Conclusions: The burden of MDR TB in children in the EU/EEA appears low, but may be underestimated owing to challenges in laboratory confirmation. Diagnostic improvements are needed for early detection and adequate treatment of MDR TB. Children previously treated for TB or of foreign origin may warrant higher attention.

Migration-related tuberculosis: epidemiology and characteristics of tuberculosis cases originating outside the European Union and European Economic Area, 2007 to 2013.

Migrants arriving from high tuberculosis (TB)-incidence countries may pose a significant challenge to TB control programmes in the host country. TB surveillance data for 2007-2013 submitted to the European Surveillance System were analysed. Notified TB cases were stratified by origin and reporting country. The contribution of migrant TB cases to the TB epidemiology in EU/EEA countries was analysed. Migrant TB cases accounted for 17.4% (n = 92,039) of all TB cases reported in the EU/EEA in 2007-2013, continuously increasing from 13.6% in 2007 to 21.8% in 2013. Of 91,925 migrant cases with known country of origin, 29.3% were from the Eastern Mediterranean, 23.0% from south-east Asia, 21.4% from Africa, 13.4% from the World Health Organization European Region (excluding EU/EEA), and 12.9% from other regions. Of 46,499 migrant cases with known drug-susceptibility test results, 2.9% had multidrug-resistant TB, mainly (51.7%) originating from the European Region. The increasing contribution of TB in migrants from outside the EU/EEA to the TB burden in the EU/EEA is mainly due to a decrease in native TB cases. Especially in countries with a high proportion of TB cases in non-EU/EEA migrants, targeted prevention and control initiatives may be needed to progress towards TB elimination.

The effect of migration within the European Union/European Economic Area on the distribution of tuberculosis, 2007 to 2013.

Immigration from tuberculosis (TB) high-incidence countries is known to contribute notably to the TB burden in low-incidence countries. However, the effect of migration enabled by the free movement of persons within the European Union (EU)/European Economic Area (EEA) on TB notification has not been analysed. We analysed TB surveillance data from 29 EU/EEA countries submitted for the years 2007-2013 to The European Surveillance System. We used place of birth and nationality as proxy indicators for native, other EU/EEA and non-EU/EEA origin of the TB cases and analysed the characteristics of the subgroups by origin. From 2007-2013, a total of 527,467 TB cases were reported, of which 129,781 (24.6%) were of foreign origin including 12,566 (2.4%) originating from EU/EEA countries other than the reporting country. The countries reporting most TB cases originating from other EU/EEA countries were Germany and Italy, and the largest proportion of TB cases in individuals came from Poland (n=1,562) and Romania (n=6,285). At EU/EEA level only a small proportion of foreign TB cases originated from other EU/EEA countries, however, the uneven distribution of this presumed importation may pose a challenge to TB programmes in some countries.

Inventory study of non-tuberculous mycobacteria in the European Union.

BACKGROUND: Since non-tuberculous mycobacteria (NTM) disease is not notifiable in most European Union (EU) and European Economic Area (EEA) countries, the epidemiological situation of the >150 NTM species is largely unknown. We aimed to collect data on the frequency of NTM detection and NTM species types in EU/EEA countries. METHODS: Officially nominated national tuberculosis reference laboratories of all EU/EEA countries were asked to provide information on: laboratory routines for detection and identification of NTM, including drug sensitivity testing (DST) methods; data on the number and type of NTM species identified; coverage and completeness of the provided data on NTM; type and number of human specimens tested for NTM; and number of specimens tested for Mycobacterium tuberculosis complex and NTM. This information was summarized and the main results are described. RESULTS: In total, 99 different NTM species were identified with M. avium, M. gordonae, M. xenopi , M. intracellulare, and M. fortuitum identified most frequently. Seven percent of the NTM species could not be identified. NTM was cultured from between 0.4-2.0% of the specimens (data from four countries). The laboratories use culturing methods optimised for M. tuberculosis complex. Identification is mainly carried out by a commercial line probe assay supplemented with sequencing. Most laboratories carried out DST for rapid growers and only at the explicit clinical request for slow growers. CONCLUSION: It is likely that the prevalence of NTM is underestimated because diagnostic procedures are not optimized specifically for NTM and isolates may not be referred to the national reference laboratory for identification. Due to the diagnostic challenges and the need to establish the clinical relevance of NTM, we recommend that countries should concentrate detection and identification in only few laboratories.

Tuberculosis treatment outcome monitoring in European Union countries: systematic review.

Treatment success measured by treatment outcome monitoring (TOM) is a key programmatic output of tuberculosis (TB) control programmes. We performed a systematic literature review on national-level TOM in the 30 European Union (EU)/European Economic Areas (EEA) countries to summarise methods used to collect and report data on TOM. Online reference bibliographic databases PubMed/MEDLINE and EMBASE were searched to identify relevant indexed and non-indexed literature published between January 2000 and August 2010. The search strategy resulted in 615 potentially relevant indexed citations, of which 27 full-text national studies (79 data sets) were included for final analysis. The selected studies were performed in 10 EU/EEA countries and gave a fragmented impression of TOM in the EU/EEA. Publication year, study period, sample size, databases, definitions, variables, patient and outcome categories, and population subgroups varied widely, portraying a very heterogeneous picture. This review confirmed previous reports of considerable heterogeneity in publications of TOM results across EU/EEA countries. PubMed/MEDLINE and EMBASE indexed studies are not a suitable instrument to measure representative TOM results for the 30 EU/EEA countries. Uniform and complete reporting to the centralised European Surveillance System will produce the most timely and reliable results of TB treatment outcomes in the EU/EEA.

First worldwide proficiency study on variable-number tandem-repeat typing of Mycobacterium tuberculosis complex strains.

Although variable-number tandem-repeat (VNTR) typing has gained recognition as the new standard for the DNA fingerprinting of Mycobacterium tuberculosis complex (MTBC) isolates, external quality control programs have not yet been developed. Therefore, we organized the first multicenter proficiency study on 24-locus VNTR typing. Sets of 30 DNAs of MTBC strains, including 10 duplicate DNA samples, were distributed among 37 participating laboratories in 30 different countries worldwide. Twenty-four laboratories used an in-house-adapted method with fragment sizing by gel electrophoresis or an automated DNA analyzer, nine laboratories used a commercially available kit, and four laboratories used other methods. The intra- and interlaboratory reproducibilities of VNTR typing varied from 0% to 100%, with averages of 72% and 60%, respectively. Twenty of the 37 laboratories failed to amplify particular VNTR loci; if these missing results were ignored, the number of laboratories with 100% interlaboratory reproducibility increased from 1 to 5. The average interlaboratory reproducibility of VNTR typing using a commercial kit was better (88%) than that of in-house-adapted methods using a DNA analyzer (70%) or gel electrophoresis (50%). Eleven laboratories using in-house-adapted manual typing or automated typing scored inter- and intralaboratory reproducibilities of 80% or higher, which suggests that these approaches can be used in a reliable way. In conclusion, this first multicenter study has documented the worldwide quality of VNTR typing of MTBC strains and highlights the importance of international quality control to improve genotyping in the future.