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.

Circulation of pertussis and poor protection against diphtheria among middle-aged adults in 18 European countries.

Reported incidence of pertussis in the European Union (EU) and the European Economic Area (EEA) varies and may not reflect the real situation, while vaccine-induced protection against diphtheria and tetanus seems sufficient. We aimed to determine the seroprevalence of DTP antibodies in EU/EEA countries within the age groups of 40-49 and 50-59 years. Eighteen countries collected around 500 samples between 2015 and 2018 (N = 10,302) which were analysed for IgG-DTP specific antibodies. The proportion of sera with pertussis toxin antibody levels ≥100 IU/mL, indicative of recent exposure to pertussis was comparable for 13/18 countries, ranging between 2.7-5.8%. For diphtheria the proportion of sera lacking the protective level (<0.1 IU/mL) varied between 22.8-82.0%. For tetanus the protection was sufficient. Here, we report that the seroprevalence of pertussis in these age groups indicates circulation of B. pertussis across EU/EEA while the lack of vaccine-induced seroprotection against diphtheria is of concern and deserves further attention.

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.

Whole-Genome Sequencing as Tool for Investigating International Tuberculosis Outbreaks: A Systematic Review.

Background: Whole-genome sequencing (WGS) can support the investigation of tuberculosis (TB) outbreaks. The technique has been applied to estimate the timing and directionality of transmission and to exclude cases from an investigation. This review assesses how WGS was applied in international outbreak investigations and discusses the advantages and challenges of the application of WGS. Methods: Databases were searched for reports on international TB outbreak investigations. Information was extracted on: Why was WGS applied?; How was WGS applied?; Organizational issues; WGS methodology; What was learned/what were the implications of the WGS investigation?; and challenges and lessons learned. Results: Three studies reporting on international outbreak investigations were identified. Retrospective WGS sequencing was performed in all studies and prospective typing in two to study TB transmission. In one study, WGS data were produced centrally (i.e., in one laboratory) and analysis was done centrally. In two studies, WGS data production was done in a decentralized manner, and analysis was centralized in one laboratory. Three groups of professionals were involved in the international outbreak investigation: public health authorities, laboratory experts, and clinicians. The reported WGS methodology applied differed between the studies in some aspects, e.g., sequencing platform; quality measures, percentage of the reference genome covered, and the mean genomic coverage; analysis, use of a reference genome or de novo assembly; and software used for alignment and analysis. In all three studies, in-house scripts were used for variance calling, and the single nucleotide polymorphism (SNP) approach was used for analysis. All outbreak investigation reports stated that WGS refuted suspected transmission events and provided supporting evidence for epidemiological data. Several challenges were reported of which most were not related to WGS. The only challenge related to WGS was the timeframe of getting WGS data if WGS is not routinely performed. Conclusions: WGS was considered a useful addition in international TB outbreak investigations. Further standardization of the WGS methodology and good structures for international collaboration and coordination are needed to take full advantage of this new technology. Whether the use of WGS results in earlier detection of cases and thus limits transmission still needs to be determined.

Improvement in serological diagnosis of pertussis by external quality assessment.

PURPOSE: Serological analysis is an essential tool for the diagnosis of pertussis or whooping cough, disease surveillance and the evaluation of vaccine effectiveness against Bordetella pertussis. Accurate measurement of anti-pertussis toxin (anti-PT) IgG antibody levels in sera is essential. These measurements are usually performed using immunological methods such as ELISA and multiplex immunoassays. However, there are a large number of different assay systems available, and therefore standardization and harmonization between the methods are needed to obtain comparable data. METHODOLOGY: In collaboration with ECDC, the EUPert-LabNet network has organized three External Quality Assessment (EQA) schemes (2010, 2012 and 2016), which initially identified the diverse range of techniques and reagents being used throughout Europe. This manuscript discusses the findings of each of the EQA rounds and their impact on the participating laboratories. RESULTS: The studies have shown an increasing number of laboratories (from 65% to 92%) using only the recommended coating antigen, purified PT, in immunoassays, as this allows exact quantification of serum anti-PT IgG and since PT is only produced by Bordetella pertussis this prevents cross-reactivity with other species. There has also been an increase in the numbers of laboratories (from 59% to 92%), including a WHO reference serum in their assays, which allows anti-PT IgG concentrations to be measured in International Units, thus enabling the comparison of results from different methods and laboratories. In addition, manufacturers have also considered these recommendations when they produce commercial ELISA kits. CONCLUSION: The three EQA rounds have resulted in greater harmonization in methods among different laboratories, showing a significant improvement of the ELISA methods used for serodiagnosis of pertussis.

Molecular and genomic typing for tuberculosis surveillance: A survey study in 26 European countries.

BACKGROUND: Molecular typing and whole genome sequencing (WGS) information is used for (inter-) national outbreak investigations. To assist the implementation of these techniques for tuberculosis (TB) surveillance and outbreak investigations at European level there is a need for inter-country collaboration and standardization. This demands more information on molecular typing practices and capabilities of individual countries. We aimed to review the use of molecular/genomic typing for TB surveillance in European Union and European Economic Area countries in 2016; assess its public health value; and collect experiences on typing data use for cross-border cluster investigations. METHOD: A web-based questionnaire was provided to all TB National Focal Points. The questionnaire consisted of three parts: i) Use and integration of molecular and genomic typing data into TB surveillance; ii) Cross-border cluster investigation and international collaboration, and iii) Perception and evaluation of public health benefits of molecular and genomic typing for TB surveillance. RESULTS: Of 26 responding countries, 20 used molecular typing for TB surveillance, including nine applying WGS. The level of integration into the national surveillance was heterogeneous. Among six countries not using typing for TB surveillance, more than half planned its implementation soon. Overall, most countries perceived an added public health value of molecular typing for TB control. Concerning international cluster investigations, countries had little experience and did not have standard protocols to exchange typing data. CONCLUSION: Our study shows a wide use of molecular and genomic typing data for TB surveillance in EU/EEA countries and reveals that transition to WGS-based typing is ongoing or is considered in most countries. However, our results also show a high heterogeneity in the use and integration of typing data for TB surveillance. Standardization of typing data use for TB surveillance is needed and formal procedures should be developed to facilitate international collaboration.

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.

Determinants of site of tuberculosis disease: An analysis of European surveillance data from 2003 to 2014.

BACKGROUND: We explored host-related factors associated with the site of tuberculosis (TB) disease using variables routinely collected by the 31 EU/EEA countries for national surveillance. METHODS: Logistic regression models were fitted to case-based surveillance data reported to the European Centre for Disease Prevention and Control for TB cases notified from 2003 to 2014. Missing data on HIV infection and on susceptibility to isoniazid and rifampicin for many patients precluded the inclusion of these variables in the analysis. Records from Finland, Lithuania, Spain and the United Kingdom were excluded for lack of exact details of disease localisation; other records without one or more variable (e.g. previous treatment history, geographical origin) or who had mixed pulmonary and extrapulmonary disease or more than one form of extrapulmonary disease were also removed (total exclusion = 38% of 913,637 notifications). RESULTS: 564,916 TB cases reported by 27 EU/EEA countries had exclusive pulmonary (PTB; 83%) or extrapulmonary (EPTB; 17%) disease. EPTB was associated with age <15 years (aOR: 5.50), female sex (aOR: 1.60), no previous TB treatment (aOR: 3.10), and geographic origin (aOR range: 0.52-3.74). Origin from the Indian subcontinent or Africa was most strongly associated with lymphatic, osteo-articular and peritoneal/digestive localization (aOR>3.7), and age <15 years with lymphatic (aOR: 17.96) and central nervous system disease (aOR: 11.41). CONCLUSIONS: Awareness of host-related determinants of site of TB is useful for diagnosis. The predilection for EPTB among patients originating from countries outside Europe may reflect strain preferences for disease localization, geographic/ethnic differences in disease manifestation and other factors, like HIV.

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.