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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.
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Prevalence estimates of tuberculosis infection in adults in Denmark: a retrospective nationwide register-based cross-sectional study, 2010 to 2018
BackgroundTuberculosis (TB) elimination requires identifying and treating persons with TB infection (TBI).
AimWe estimate the prevalence of positive interferon gamma release assay (IGRA) tests (including TB) and TBI (excluding TB) in Denmark based on TBI screening data from patients with inflammatory bowel disease (IBD) or inflammatory rheumatic disease (IRD).
MethodsUsing nationwide Danish registries, we included all patients with IBD or IRD with an IGRA test performed between 2010 and 2018. We estimated the prevalence of TBI and positive IGRA with 95% confidence intervals (CI) in adolescents and adults aged 15–64 years after sample weighting adjusting for distortions in the sample from the background population of Denmark for sex, age group and TB incidence rates (IR) in country of birth.
ResultsIn 13,574 patients with IBD or IRD, 12,892 IGRA tests (95.0%) were negative, 461 (3.4%) were positive and 221 (1.6%) were indeterminate, resulting in a weighted TBI prevalence of 3.2% (95% CI: 2.9–3.5) and weighted positive IGRA prevalence of 3.8% (95% CI: 3.5–4.2) among adults aged 15–64 years in the background population of Denmark. Unweighted TBI prevalence increased with age and birthplace in countries with a TB IR higher than 10/100,000 population.
ConclusionEstimated TBI prevalence is low in Denmark. We estimate that 200,000 persons have TBI and thus are at risk of developing TB. Screening for TBI and preventive treatment, especially in persons born in high TB incidence countries or immunosuppressed, are crucial to reduce the risk of and eliminate TB.
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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.
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Inventory study on completeness of tuberculosis case notifications in Poland in 2018
BackgroundEvaluating tuberculosis (TB) notification completeness is important for monitoring TB surveillance systems, while estimating the TB disease burden is crucial for control strategies.
AimWe conducted an inventory study to assess TB reporting completeness in Poland in 2018.
MethodsUsing a double-pronged inventory approach, we compared notifications of culture-positive TB cases in the National TB Register to records of diagnostic laboratories. We calculated under-reporting both with observed and capture–recapture (CRC)-estimated case numbers. We further compared the notifications by region (i.e. voivodship), sex, and age to aggregated data from hospitalised TB patients, which provided an independent estimate of reporting completeness.
ResultsIn 2018, 4,075 culture-positive TB cases were notified in Poland, with 3,789 linked to laboratory records. Laboratories reported further 534 TB patients, of whom 456 were linked to notifications from 2017 or 2019. Thus, 78 (534 – 456) cases were missing in the National TB Register, yielding an observed TB under-reporting of 1.9% (78/(4,075 + 78) × 100). CRC-modelled total number of cases in 2018 was 4,176, corresponding to 2.4% ((4,176 – 4,075)/4,176 × 100) under-reporting. Based on aggregated hospitalisation data from 13 of 16 total voivodeships, under-reporting was 5.1% (3,482/(3,670 – 3,482) × 100), similar in both sexes but varying between voivodeships and age groups.
ConclusionsOur results suggest that the surveillance system captures ≥ 90% of estimated TB cases in Poland; thus, the notification rate is a good proxy for the diagnosed TB incidence in Poland. Reporting delays causing discrepancies between data sources could be improved by the planned change from a paper-based to a digital reporting system.
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Tuberculosis incidence in foreign-born people residing in European countries in 2020
Anca Vasiliu , Niklas Köhler , Ekkehardt Altpeter , Tinna Rán Ægisdóttir , Marina Amerali , Wouter Arrazola de Oñate , Ágnes Bakos , Stefania D’Amato , Daniela Maria Cirillo , Reinout van Crevel , Edita Davidaviciene , Irène Demuth , Jose Domínguez , Raquel Duarte , Gunar Günther , Jean-Paul Guthmann , Sophia Hatzianastasiou , Louise Hedevang Holm , Zaida Herrador , Urška Hribar , Conny Huberty , Elmira Ibraim , Sarah Jackson , Mogens Jensenius , Kamilla Sigridur Josefsdottir , Anders Koch , Maria Korzeniewska-Kosela , Liga Kuksa , Heinke Kunst , Christian Lienhardt , Beatrice Mahler , Mateja Janković Makek , Inge Muylle , Johan Normark , Analita Pace-Asciak , Goranka Petrović , Despo Pieridou , Giulia Russo , Olena Rzhepishevska , Helmut J.F. Salzer , Marta Sá Marques , Daniela Schmid , Ivan Solovic , Mariya Sukholytka , Petra Svetina , Mariya Tyufekchieva , Tuula Vasankari , Piret Viiklepp , Kersti Villand , Jiri Wallenfels , Stefan Wesolowski , Anna-Maria Mandalakas , Leonardo Martinez , Dominik Zenner , Christoph Lange and on behalf of the TBnetBackgroundEuropean-specific policies for tuberculosis (TB) elimination require identification of key populations that benefit from TB screening.
AimWe aimed to identify groups of foreign-born individuals residing in European countries that benefit most from targeted TB prevention screening.
MethodsThe Tuberculosis Network European Trials group collected, by cross-sectional survey, numbers of foreign-born TB patients residing in European Union (EU) countries, Iceland, Norway, Switzerland and the United Kingdom (UK) in 2020 from the 10 highest ranked countries of origin in terms of TB cases in each country of residence. Tuberculosis incidence rates (IRs) in countries of residence were compared with countries of origin.
ResultsData on 9,116 foreign-born TB patients in 30 countries of residence were collected. Main countries of origin were Eritrea, India, Pakistan, Morocco, Romania and Somalia. Tuberculosis IRs were highest in patients of Eritrean and Somali origin in Greece and Malta (both > 1,000/100,000) and lowest among Ukrainian patients in Poland (3.6/100,000). They were mainly lower in countries of residence than countries of origin. However, IRs among Eritreans and Somalis in Greece and Malta were five times higher than in Eritrea and Somalia. Similarly, IRs among Eritreans in Germany, the Netherlands and the UK were four times higher than in Eritrea.
ConclusionsCountry of origin TB IR is an insufficient indicator when targeting foreign-born populations for active case finding or TB prevention policies in the countries covered here. Elimination strategies should be informed by regularly collected country-specific data to address rapidly changing epidemiology and associated risks.
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Tuberculosis in times of war and crisis: Epidemiological trends and characteristics of patients born in Ukraine, Germany, 2022
More LessThe Russian invasion of Ukraine in 2022 caused a large migration to other European countries, including Germany. This movement impacted the TB epidemiology, as Ukraine has a higher prevalence of TB and multidrug-resistant TB rates compared to Germany. Our descriptive analysis of TB surveillance data reveals important information to improve TB care in people displaced from Ukraine. We observed an expected increase in the number of TB patients born in Ukraine, which is, however, so far below WHO/Europe estimates.
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Developing evidence-informed indicators to monitor HIV pre-exposure prophylaxis programmes across EU/EEA countries: a multi-stakeholder consensus
Several countries in the European Union (EU) and European Economic Area (EEA) established and/or scaled up HIV pre-exposure prophylaxis (PrEP) programmes between 2016 and 2023. Data on PrEP programmes’ performance and effectiveness in reaching those most in need will be needed to assess regional progress in the roll-out of PrEP. However, there is a lack of commonly defined indicators for routine monitoring to allow for minimum comparability. We propose a harmonised PrEP monitoring approach for the EU/EEA, based on a systematic and evidence-informed consensus-building process involving a broad and multidisciplinary expert panel. We present a set of indicators, structured along relevant steps of an adapted PrEP care continuum, and offer a prioritisation based on the degree of consensus among the expert panel. We distinguish between ‘core’ indicators deemed essential for any PrEP programme in the EU/EEA, vs ‘supplementary’ and ‘optional’ indicators that provide meaningful data, yet where experts evaluated their feasibility for data collection and reporting as very context-dependent. By combining a standardised approach with strategic opportunities for adaptation and complementary research, this monitoring framework will contribute to assess the impact of PrEP on the HIV epidemic in Europe.
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A One Health approach revealed the long-term role of Mycobacterium caprae as the hidden cause of human tuberculosis in a region of Spain, 2003 to 2022
Miguel Martínez-Lirola , Marta Herranz , Sergio Buenestado Serrano , Cristina Rodríguez-Grande , Eva Dominguez Inarra , Jose Antonio Garrido-Cárdenas , Ana María Correa Ruiz , María Pilar Bermúdez , Manuel Causse del Río , Verónica González Galán , Julia Liró Armenteros , Jose María Viudez Martínez , Silvia Vallejo-Godoy , Ana Belén Esteban García , María Teresa Cabezas Fernández , Patricia Muñoz , Laura Pérez Lago and Darío García de ViedmaIntroductionMycobacterium caprae is a member of the Mycobacterium tuberculosis complex (MTBC) not routinely identified to species level. It lacks specific clinical features of presentation and may therefore not be identified as the causative agent of tuberculosis. Use of whole genome sequencing (WGS) in the investigation of a family microepidemic of tuberculosis in Almería, Spain, unexpectedly identified the involvement of M. caprae.
AimWe aimed to evaluate the presence of additional unidentified M. caprae cases and to determine the magnitude of this occurrence.
MethodsFirst-line characterisation of the MTBC isolates was done by MIRU-VNTR, followed by WGS. Human and animal M. caprae isolates were integrated in the analysis.
ResultsA comprehensive One Health strategy allowed us to (i) detect other 11 M. caprae infections in humans in a period of 18 years, (ii) systematically analyse M. caprae infections on an epidemiologically related goat farm and (iii) geographically expand the study by including 16 M. caprae isolates from other provinces. Integrative genomic analysis of 41 human and animal M. caprae isolates showed a high diversity of strains. The animal isolates’ diversity was compatible with long-term infection, and close genomic relationships existed between isolates from goats on the farm and recent cases of M. caprae infection in humans.
DiscussionZoonotic circulation of M. caprae strains had gone unnoticed for 18 years. Systematic characterisation of MTBC at species level and/or extended investigation of the possible sources of exposure in all tuberculosis cases would minimise the risk of overlooking similar zoonotic events.
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Active tuberculosis screening among the displaced population fleeing Ukraine, France, February to October 2022
More LessPersons fleeing Ukraine since February 2022 have potentially higher risk of tuberculosis (TB) vs all European Union countries. Interest of active TB screening among this population is debated and not widely adopted. In this screening intervention by a network of TB centres in France, the number needed to screen (NNS) was 862 to find one case. This experience shows that this strategy may be relevant for TB control in situations of massive displacement, similar to that following the Russian invasion.
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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.
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Integrated use of laboratory services for multiple infectious diseases in the WHO European Region during the COVID-19 pandemic and beyond
Daniel Simões , Soudeh Ehsani , Maja Stanojevic , Natalia Shubladze , Gulmira Kalmambetova , Roger Paredes , Daniela Maria Cirillo , Ana Avellon , Irina Felker , Florian P Maurer , Askar Yedilbayev , Francis Drobniewski , Lara Vojnov , Anne S Johansen , Nicole Seguy , Masoud Dara and on behalf of the European Laboratory Initiative on TB, HIV and viral hepatitis core group membersTechnical advances in diagnostic techniques have permitted the possibility of multi-disease-based approaches for diagnosis and treatment monitoring of several infectious diseases, including tuberculosis (TB), human immunodeficiency virus (HIV), viral hepatitis and sexually transmitted infections (STI). However, in many countries, diagnosis and monitoring, as well as disease response programs, still operate as vertical systems, potentially causing delay in diagnosis and burden to patients and preventing the optimal use of available resources. With countries facing both human and financial resource constraints, during the COVID-19 pandemic even more than before, it is important that available resources are used as efficiently as possible, potential synergies are leveraged to maximise benefit for patients, continued provision of essential health services is ensured. For the infectious diseases, TB, HIV, hepatitis C (HCV) and STI, sharing devices and integrated services starting with rapid, quality-assured, and complete diagnostic services is beneficial for the continued development of adequate, efficient and effective treatment strategies. Here we explore the current and future potential (as well as some concerns), importance, implications and necessary implementation steps for the use of platforms for multi-disease testing for TB, HIV, HCV, STI and potentially other infectious diseases, including emerging pathogens, using the example of the COVID-19 pandemic.
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Country-specific approaches to latent tuberculosis screening targeting migrants in EU/EEA* countries: A survey of national experts, September 2019 to February 2020
BackgroundMigrants in low tuberculosis (TB) incidence countries in the European Union (EU)/European Economic Area (EEA) are an at-risk group for latent tuberculosis infection (LTBI) and are increasingly included in LTBI screening programmes.
AimTo investigate current approaches and implement LTBI screening in recently arrived migrants in the EU/EEA and Switzerland.
MethodsAt least one TB expert working at a national level from the EU/EEA and one TB expert from Switzerland completed an electronic questionnaire. We used descriptive analyses to calculate percentages, and framework analysis to synthesise free-text responses.
ResultsExperts from 32 countries were invited to participate (30 countries responded): 15 experts reported an LTBI screening programme targeting migrants in their country; five reported plans to implement one in the near future; and 10 reported having no programme. LTBI screening was predominantly for asylum seekers (n = 12) and refugees (n = 11). Twelve countries use ‘country of origin’ as the main eligibility criteria. The countries took similar approaches to diagnosis and treatment but different approaches to follow-up. Six experts reported that drop-out rates in migrants were higher compared with non-migrant groups. Most of the experts (n = 22) called for a renewed focus on expanding efforts to screen for LTBI in migrants arriving in low-incidence countries.
ConclusionWe found a range of approaches to LTBI screening of migrants in the EU/EEA and Switzerland. Findings suggest a renewed focus is needed to expand and strengthen efforts to meaningfully include migrants in these programmes, in order to meet regional and global elimination targets for TB.
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Pregnancy and post-partum tuberculosis; a nationwide register-based case–control study, Denmark, 1990 to 2018
BackgroundPregnancy increases the risk of tuberculosis (TB), however, data on TB epidemiology in pregnant women are limited.
AimTo guide possible interventions, we analysed risk factors for TB in pregnant and post-partum women.
MethodsWe conducted a nationwide retrospective register-based case–control study from January 1990 to December 2018 in Denmark. Cases were women diagnosed with TB during their pregnancy or in the post-partum period. We selected two control groups: pregnant or post-partum women without TB, and non-pregnant women with TB. Differences were assessed by chi-squared or Fisher’s exact test. Risk factors for TB were identified through logistic regression and estimated by odds ratio (OR).
ResultsWe identified 392 cases, including 286 pregnant and 106 post-partum women. Most were migrants (n = 366; 93%) with a shorter median time spent in Denmark (2.74 years; interquartile range (IQR): 1.52–4.64) than non-pregnant TB controls (3.98 years; IQR: 1.43–8.51). Cases less likely had a Charlson comorbidity index ≥ 2compared with non-pregnant TB controls (p < 0.0001), and had no increased risk of severe disease (p = 0.847). Migrants from other World Health Organization regions than Europe, especially Africa (OR: 187; 95%CI: 125–281) had persistently higher odds of TB.
ConclusionsIn Denmark, the risk of TB in pregnant and post-partum women is increased in migrant women who have stayed in the country a median time of approximately 3 years. We recommend increased focus on TB risk during pregnancy and suggest evaluating targeted TB screening of selected at-risk pregnant women to promote early case finding and prevent TB among mothers and their newborn children.
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Recurrent tuberculosis in the Netherlands – a 24-year follow-up study, 1993 to 2016
More LessBackgroundNot all treated tuberculosis (TB) patients achieve long-term recovery and reactivation rates reflect effectiveness of TB treatment.
AimWe aimed to estimate rates and risk factors of TB reactivation and reinfection in patients treated in the Netherlands, after completed or interrupted treatment.
MethodsRetrospective cohort study of TB patients with available DNA fingerprint data, registered in the Netherlands Tuberculosis register (NTR) between 1993 and 2016. Reactivation was defined as an identical, and reinfection as a non-identical Mycobacterium tuberculosis strain in sequential episodes.
ResultsReactivation rate was 55/100,000 person-years (py) for patients who completed, and 318/100,000 py for patients who interrupted treatment. The risk of reactivation was highest in the first 5 years after treatment in both groups. The incidence rate of reactivation was 228/100,000 py in the first 2 years and 57/100,000 py 2–5 years after completed treatment. The overall rate of reinfection was 16/100,000 py. Among those who completed treatment, patients with male sex, mono or poly rifampicin-resistant TB and a previous TB episode had significantly higher risk of reactivation. Extrapulmonary TB was associated with a lower risk. Among patients who interrupted treatment, directly observed treatment (DOT) and being an undocumented migrant or people experiencing homelessness were associated with a higher risk of reactivation.
ConclusionsBoth patients who completed or interrupted TB treatment should be considered as risk groups for reactivation for at least 2–5 years after treatment. They patients should be monitored and guidelines should be in place to enhance early detection of recurrent TB.
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Tuberculosis contact investigation following the stone-in-the-pond principle in the Netherlands – Did adjusted guidelines improve efficiency?
More LessBackgroundIn low tuberculosis (TB) incidence countries, contact investigation (CI) requires not missing contacts with TB infection or disease without unnecessarily evaluating non-infected contacts.
AimWe assessed whether updated guidelines for the stone-in-the-pond principle and their promotion improved CI practices.
MethodsThis retrospective study used surveillance data to compare CI outcomes before (2011–2013) and after (2014–2016) the guideline update and promotion. Using negative binomial regression and logistic regression models, we compared the number of contacts invited for CI per index patient, the number of CI scaled-up according to the stone-in-the-pond principle, the TB and latent TB infection (LTBI) testing coverage, and yield.
ResultsPre and post update, 1,703 and 1,489 index patients were reported, 27,187 and 21,056 contacts were eligible for CI, 86% and 89% were tested for TB, and 0.70% and 0.73% were identified with active TB, respectively. Post update, the number of casual contacts invited per index patient decreased statistically significantly (RR = 0.88; 95% CI: 0.79–0.98), TB testing coverage increased (OR = 1.4; 95% CI: 1.2–1.7), and TB yield increased (OR = 2.0; 95% CI: 1.0–3.9). The total LTBI yield increased from 8.8% to 9.8%, with statistically significant increases for casual (OR = 1.2; 95% CI: 1.0–1.5) and community contacts (OR = 2.0; 95% CI: 1.6–3.2). The proportion of CIs appropriately scaled-up to community contacts increased statistically significantly (RR = 1.8; 95% CI: 1.3–2.6).
ConclusionThis study shows that promoting evidence-based CI guidelines strengthen the efficiency of CIs without jeopardising effectiveness. These findings support CI is an effective TB elimination intervention.
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Early COVID-19 pandemic’s toll on tuberculosis services, WHO European Region, January to June 2020
BackgroundEssential health services, including for tuberculosis (TB), are being affected by public health and social measures (PHSM) introduced to control COVID-19. In many settings, TB resources, facilities and equipment are being redirected towards COVID-19 response.
AimWe sought to assess the COVID-19 pandemic’s impact on TB services in the World Health Organization (WHO) European Region.
MethodsThe fifty-three European Region Member States were asked to report qualitative and quantitative data in quarter one and two (Q1 and Q2) 2020. TB notifications were triangulated with the severity score on domestic movement restrictions to assess how they may have influenced TB detection.
ResultsTwenty-nine countries reported monthly TB notifications for the first half of 2019 and 2020. TB notifications decreased by 35.5% during Q2 2020 compared with Q2 2019, which is six-fold more than the average annual decrease of 5.1% documented during 2015–2019. The number of patients enrolled in rifampicin-resistant/multidrug-resistant TB treatment also decreased dramatically in Q2 2020, by 33.5%. The highest movement restriction severity score was observed between April and May 2020, which coincided with the highest observed decrease in TB notifications.
ConclusionA decrease in TB detection and enrolment to treatment may cause increases in TB burden and threatens the Region’s ability to reach the TB targets of the 2030 Sustainable Development Goals, still this might be mitigated with rapid restoration of TB services and the implementation of targeted interventions during periods with severe PHSM in place, such as those introduced in response to the COVID-19 pandemic.
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Impact of the COVID-19 pandemic on tuberculosis national reference laboratory services in the WHO European Region, March to November 2020
We assessed the impact of COVID-19 on diagnostic services for tuberculosis (TB) by national reference laboratories in the WHO European Region. Of 35 laboratories, 30 reported declines in TB sample numbers, amounting up to > 50% of the pre-COVID-19 volumes. Sixteen reported reagent or consumable shortages. Nineteen reallocated ressources to SARS-CoV-2 testing, resulting in an overall increase in workload, largely without a concomitant increase in personnel (n = 14). This poses a risk to meeting the 2025 milestones of the End TB Strategy.
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