Drivers determining tuberculosis disease screening yield in four European screening programmes: a comparative analysis.

BACKGROUND: The World Health Organization End TB Strategy emphasises screening for early diagnosis of tuberculosis (TB) in high-risk groups, including migrants. We analysed key drivers of TB yield differences in four large migrant TB screening programmes to inform TB control planning and feasibility of a European approach. METHODS: We pooled individual TB screening episode data from Italy, the Netherlands, Sweden and the UK, and analysed predictors and interactions for TB case yield using multivariable logistic regression models. RESULTS: Between 2005 and 2018 in 2 302 260 screening episodes among 2 107 016 migrants to four countries, the programmes identified 1658 TB cases (yield 72.0 (95% CI 68.6-75.6) per 100 000). In logistic regression analysis, we found associations between TB screening yield and age (≥55 years: OR 2.91 (95% CI 2.24-3.78)), being an asylum seeker (OR 3.19 (95% CI 1.03-9.83)) or on a settlement visa (OR 1.78 (95% CI 1.57-2.01)), close TB contact (OR 12.25 (95% CI 11.73-12.79)) and higher TB incidence in the country of origin. We demonstrated interactions between migrant typology and age, as well as country of origin. For asylum seekers, the elevated TB risk remained similar above country of origin incidence thresholds of 100 per 100 000. CONCLUSIONS: Key determinants of TB yield included close contact, increasing age, incidence in country of origin and specific migrant groups, including asylum seekers and refugees. For most migrants such as UK students and workers, TB yield significantly increased with levels of incidence in the country of origin. The high, country of origin-independent TB risk in asylum seekers above a 100 per 100 000 threshold could reflect higher transmission and re-activation risk of migration routes, with implications for selecting populations for TB screening.

Recurrent tuberculosis in the Netherlands - a 24-year follow-up study, 1993 to 2016.

BackgroundNot 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.

Strengthening Tuberculosis Services for Children and Adolescents in Low Endemic Settings.

In low tuberculosis-burden countries, children and adolescents with the highest incidence of tuberculosis (TB) infection or disease are usually those who have immigrated from high-burden countries. It is, therefore, essential that low-burden countries provide healthcare services to immigrant and refugee families, to assure that their children can receive proper testing, evaluation, and treatment for TB. Active case-finding through contact tracing is a critical element of TB prevention in children and in finding TB disease at an early, easily treated stage. Passive case-finding by evaluating an ill child is often delayed, as other, more common infections and conditions are suspected initially. While high-quality laboratory services to detect Mycobacterium tuberculosis are generally available, they are often underutilized in the diagnosis of childhood TB, further delaying diagnosis in some cases. Performing research on TB disease is difficult because of the low number of cases that are spread over many locales, but critical research on the evaluation and treatment of TB infection has been an important legacy of low-burden countries. The continued education of medical providers and the involvement of educational, professional, and non-governmental organizations is a key element of maintaining awareness of the presence of TB. This article provides the perspective from North America and Western Europe but is relevant to many low-endemic settings. TB in children and adolescents will persist in low-burden countries as long as it persists throughout the rest of the world, and these wealthy countries must increase their financial commitment to end TB everywhere.

Tuberculosis contact investigation following the stone-in-the-pond principle in the Netherlands - Did adjusted guidelines improve efficiency?

BackgroundIn 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.

Discovery and validation of a personalized risk predictor for incident tuberculosis in low transmission settings.

The risk of tuberculosis (TB) is variable among individuals with latent Mycobacterium tuberculosis infection (LTBI), but validated estimates of personalized risk are lacking. In pooled data from 18 systematically identified cohort studies from 20 countries, including 80,468 individuals tested for LTBI, 5-year cumulative incident TB risk among people with untreated LTBI was 15.6% (95% confidence interval (CI), 8.0-29.2%) among child contacts, 4.8% (95% CI, 3.0-7.7%) among adult contacts, 5.0% (95% CI, 1.6-14.5%) among migrants and 4.8% (95% CI, 1.5-14.3%) among immunocompromised groups. We confirmed highly variable estimates within risk groups, necessitating an individualized approach to risk stratification. Therefore, we developed a personalized risk predictor for incident TB (PERISKOPE-TB) that combines a quantitative measure of T cell sensitization and clinical covariates. Internal-external cross-validation of the model demonstrated a random effects meta-analysis C-statistic of 0.88 (95% CI, 0.82-0.93) for incident TB. In decision curve analysis, the model demonstrated clinical utility for targeting preventative treatment, compared to treating all, or no, people with LTBI. We challenge the current crude approach to TB risk estimation among people with LTBI in favor of our evidence-based and patient-centered method, in settings aiming for pre-elimination worldwide.

Towards elimination of childhood and adolescent tuberculosis in the Netherlands: an epidemiological time-series analysis of national surveillance data.

BACKGROUND: Tuberculosis (TB) in children and adolescents is a sentinel event for ongoing transmission. In the Netherlands, epidemiological characteristics of childhood and adolescent TB have not been fully evaluated. Therefore, we aimed to assess TB epidemiology within this population to provide guidance for TB elimination. METHODS: A retrospective time-series analysis using national surveillance data from 1993-2018 was performed in children (aged <15 years) and adolescents (aged 15-19 years) with TB. Poisson regression models offset with log-population size were used to estimate notification rates and rate ratios. Trends in notification rates were estimated using average annual percentage changes (AAPC) based on the segmented linear regression analysis. RESULTS: Among 3899 children and adolescents with TB notified during 1993-2018, 2418 (62%) were foreign-born (725 (41.3%) out of 1755 children and 1693 (78.9%) out of 2144 adolescents). The overall notification rate in children was 2.3 per 100 000 person-years, declining steadily during the study period (AAPC -10.9%, 95% CI -12.6--9.1). In adolescents, the overall notification rate was 8.4 per 100 000 person-years, strongly increasing during 1993-2001 and 2012-2018. Compared to Dutch-born children and adolescents, substantially higher notification rates were observed among African-born children and adolescents (116.8 and 316.6 per 100 000 person-years, respectively). Additionally, an increasing trend was observed in African-born adolescents (AAPC 18.5%, 95% CI 11.9-25.5). Among the foreign-born population, those from countries in the horn of Africa contributed most to the TB caseload. CONCLUSION: TB notification rate among children was low and constantly declining across different demographic groups. However, heterogeneities were shown in adolescents, with an increasing trend in the foreign-born, particularly those from Africa.

Strategies to reach and motivate migrant communities at high risk for TB to participate in a latent tuberculosis infection screening program: a community-engaged, mixed methods study among Eritreans.

BACKGROUND: In the Netherlands, migrant populations with a high tuberculosis (TB) incidence are an important target group for TB prevention. However, there is a lack of insight in effective community-engaged strategies to reach and motivate these migrants to participate in latent TB infection (LTBI) screening and treatment programs. METHODS: In cocreation with Eritrean key figures and TB staff, we designed and executed six strategies to reach and motivate Eritrean communities to participate in LTBI programs, in five regions in the Netherlands. We registered participation in LTBI education and screening, and LTBI treatment uptake and completion. We used semi-structured group and individual interviews with Eritrean participants, key figures, and TB staff to identify facilitators and barriers. RESULTS: Uptake of LTBI education (13-75%) and consequent screening (10-124%) varied between strategies. LTBI screening uptake > 100% resulted from educated participants motivating others to participate in screening. Two strategies, using face-to-face promotion and targeting smaller groups, were the most successful. The program resulted in high LTBI treatment initiation and completion (both 97%). Reported program barriers included: competing priorities in the target group, perceived good health, poor risk perception, and scepticism towards the program purpose. TB staff perceived the program as useful but demanding in terms of human resources. CONCLUSIONS: Eritrean migrant communities can be successfully reached and motivated for LTBI screening and treatment programs, when sufficient (human) resources are in place and community members, well-connected to and trusted by the community, are engaged in the design and execution of the program.

Latent tuberculosis screening and treatment among asylum seekers: a mixed-methods study.

INTRODUCTION: Evidence on conditions for implementation of latent tuberculosis infection (LTBI) screening and treatment among asylum seekers is needed to inform tuberculosis (TB) control policies. We used mixed-methods to evaluate the implementation of an LTBI screening and treatment programme among asylum seekers in the Netherlands. METHODS: We offered voluntary LTBI screening to asylum seekers aged ≥12 years living in asylum seeker centres from countries with a TB incidence >200 per 10 000 population. We calculated LTBI screening and treatment cascade coverage, and assessed associated factors with Poisson regression using robust variance estimators. We interviewed TB care staff (seven group interviews) and Eritrean clients (21 group and 21 individual interviews) to identify programme enhancers and barriers. RESULTS: We screened 719 (63% of 1136) clients for LTBI. LTBI was diagnosed among 178 (25%) clients; 149 (84%) initiated LTBI treatment, of whom 129 (87%) completed treatment. In-person TB and LTBI education, the use of professional interpreters, and collaboration with partner organisations were enhancers for LTBI screening uptake. Demand-driven LTBI treatment support by TB nurses enhanced treatment completion. Factors complicating LTBI screening and treatment were having to travel to public health services, language barriers and moving from asylum seeker centres to the community during treatment. CONCLUSION: LTBI screening and treatment of asylum seekers is feasible and effective when high quality of care is provided, including culture-sensitive TB education throughout the care cascade. Additionally, collaboration with partner organisations, such as agencies responsible for reception and support of asylum seekers, should be in place.

Implementation of latent tuberculosis infection screening and treatment among newly arriving immigrants in the Netherlands: A mixed methods pilot evaluation.

INTRODUCTION: To reach pre-elimination levels of tuberculosis (TB) incidence in the Netherlands, prevention of TB among immigrants through diagnosis and treatment of latent TB infection (LTBI) is needed. We studied the feasibility of a LTBI screening and treatment program among newly arriving immigrants for national implementation. METHODS: We used mixed methods to evaluate the implementation of LTBI screening and treatment in five Public Health Services (PHS) among immigrants from countries with a TB incidence >50/100,000 population. We used Poisson regression models with robust variance estimators to assess factors associated with LTBI diagnosis and LTBI treatment initiation and reported reasons for not initiating or completing LTBI treatment. We interviewed five PHS teams using a semi-structured method to identify enhancing and impeding factors for LTBI screening and treatment. RESULTS: We screened 566 immigrants; 94 (17%) were diagnosed with LTBI, of whom 49 (52%) initiated and 34 (69%) completed LTBI treatment. LTBI diagnosis was associated with male gender, higher age group, higher TB incidence in the country of origin and lower level of education. Treatment initiation was associated with PHS (ranging from 29% to 86%), lower age group, longer intended duration of stay in the Netherlands, and lower level of education. According to TB physicians, clients and their consulted physicians in the home country lacked awareness about benefits of LTBI treatment. Furthermore, TB physicians questioned the individual and public health benefit of clients who return to their country of origin within the foreseeable future. CONCLUSIONS: Doubt of physicians in both host country and country of origin about individual and public health benefits of LTBI screening and treatment of immigrants hampered treatment initiation: the high initiation proportion in one PHS shows that if TB physicians are committed, the LTBI treatment uptake can be higher.

Building a European database to gather multi-country evidence on active and latent TB screening for migrants.

BACKGROUND AND AIM: Screening for active and latent TB among migrants in low TB incidence countries may constitute an important contribution to TB elimination. E-DETECT TB, a European multi-county collaboration, aims to address the present lack of evidence on effectiveness of migrant TB screening by collating data in an international database and perform cross-country pooled and comparative analyses of screening coverage, results and linkage to care. METHOD: A database was established using migrant TB screening data from participating countries' national screening programs, national screening pilots and local research projects. All partner countries contributed to a common agreed protocol with standardized variables, pooling available numerator and denominator screening data from participating countries and sites. RESULTS: All collaborating members drafted and agreed upon a data sharing accord as well as a protocol that clearly defined responsibilities and data governance principles. The database has been created and data transfer is ongoing. CONCLUSION: By persistence and focus the project has overcome considerable administrative, practical and legal challenges. This international collaboration provides greater power of analysis of harmonized data and thereby a unique opportunity to contribute migrant TB screening evidence. E-DETECT TB has started to invite other countries to contribute data to the database.

Comparison of different treatments for isoniazid-resistant tuberculosis: an individual patient data meta-analysis.

BACKGROUND: Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ. METHODS: Studies with regimens and outcomes known for individual patients with INH-R tuberculosis were eligible, irrespective of the number of patients if randomised trials, or with at least 20 participants if a cohort study. Studies were identified from two relevant systematic reviews, an updated search of one of the systematic reviews (for papers published between April 1, 2015, and Feb 10, 2016), and personal communications. Individual patient data were obtained from authors of eligible studies. The individual patient data meta-analysis was performed with propensity score matched logistic regression to estimate adjusted odds ratios (aOR) and risk differences of treatment success (cure or treatment completion), death during treatment, and acquired rifampicin resistance. Outcomes were measured across different treatment regimens to assess the effects of: different durations of REZ (≤6 months vs >6 months); addition of a fluoroquinolone to REZ (fluoroquinolone plus 6 months or more of REZ vs 6 months or more of REZ); and addition of streptomycin to REZ (streptomycin plus 6 months of rifampicin and ethambutol and 1-3 months of pyrazinamide vs 6 months or more of REZ). The overall quality of the evidence was assessed using GRADE methodology. FINDINGS: Individual patient data were requested for 57 cohort studies and 17 randomised trials including 8089 patients with INH-R tuberculosis. We received 33 datasets with 6424 patients, of which 3923 patients in 23 studies received regimens related to the study objectives. Compared with a daily regimen of 6 months of (H)REZ (REZ with or without isoniazid), extending the duration to 8-9 months had similar outcomes; as such, 6 months or more of (H)REZ was used for subsequent comparisons. Addition of a fluoroquinolone to 6 months or more of (H)REZ was associated with significantly greater treatment success (aOR 2·8, 95% CI 1·1-7·3), but no significant effect on mortality (aOR 0·7, 0·4-1·1) or acquired rifampicin resistance (aOR 0·1, 0·0-1·2). Compared with 6 months or more of (H)REZ, the standardised retreatment regimen (2 months of streptomycin, 3 months of pyrazinamide, and 8 months of isoniazid, rifampicin, and ethambutol) was associated with significantly worse treatment success (aOR 0·4, 0·2-0·7). The quality of the evidence was very low for all outcomes and treatment regimens assessed, owing to the observational nature of most of the data, the diverse settings, and the imprecision of estimates. INTERPRETATION: In patients with INH-R tuberculosis, compared with treatment with at least 6 months of daily REZ, addition of a fluoroquinolone was associated with better treatment success, whereas addition of streptomycin was associated with less treatment success; however, the quality of the evidence was very low. These results support the conduct of randomised trials to identify the optimum regimen for this important and common form of drug-resistant tuberculosis. FUNDING: World Health Organization and Canadian Institutes of Health Research.

Policy and practice of programmatic management of latent tuberculosis infection in The Netherlands.

Latent tuberculosis infection (LTBI) screening and preventive treatment is one of the components of the World Health Organization (WHO) End TB strategy, and particularly relevant for low tuberculosis (TB) incidence countries, i.e. less than 100 TB cases per million population. The Netherlands is such a low-incidence country with traditionally a strong emphasis on programmatic management of LTBI, e.g. examining contacts of infectious TB patients by the public health services. Increasingly, curative services are involved in LTBI management of clinical risk groups. The country recently adopted a five-year strategic national plan recommending LTBI screening of high-risk migrants populations. A monitoring and evaluation system is already in place to measure programme performance and guide policy. Research on LTBI screening of migrants is on-going and results should inform future decisions in scaling-up this intervention. Several challenges remain for programmatic LTBI management, such as securing financial resources and the right professional cadre for implementation; availability of screening tests and drugs; collecting additional data for monitoring and evaluation, in line with the WHO indicators for LTBI programmatic management; developing cultural-sensitive and client-centred education for migrants; reducing patient costs for LTBI screening and preventive treatment; and assessing cost-effectiveness and impact on TB epidemiology.

Risk of developing tuberculosis disease among persons diagnosed with latent tuberculosis infection in the Netherlands.

Diagnosis and preventive treatment of latent tuberculosis infection (LTBI) among high-risk groups is recommended to achieve tuberculosis (TB) elimination in low-incidence countries.We studied TB incidence rates among those notified with LTBI in the Netherlands from 2005 to 2013 and analysed associated risk factors. We stratified analyses by target group for screening, and by initiation and completion of preventive treatment.The incidence for those completing, stopping and not receiving preventive treatment was 187, 436 and 355 per 100 000 person-years for contacts of TB patients, respectively, and 63, 96 and 110 per 100 000 person-years for other target groups. The rate ratio for TB development among contacts compared to other target groups was 3.1 (95% CI 2.0-4.9). In both groups, incidence was highest in the first year after diagnosis. Independent factors associated with progression to TB among contacts were age <5 years and stopping preventive treatment within 28 days compared to those not receiving preventive treatment. Among other target groups, being foreign born was the only risk factor associated with the risk of developing TB.We conclude that the epidemiological impact of preventive treatment is highest in contacts of TB patients and limited in other target groups for LTBI management in the Netherlands.

[Tuberculosis among asylum-seekers in the Netherlands: a descriptive study among the two largest groups of asylum-seekers]. / Tuberculose bij asielzoekers in Nederland: descriptief onderzoek onder de 2 grootste groepen asielzoekers.

OBJECTIVE: To investigate the prevalence and incidence of tuberculosis (TB) among the two largest groups of asylum-seekers in the Netherlands, i.e. Syrians and Eritreans/Ethiopians. DESIGN: Descriptive study. METHOD: We collected data from the screening of Syrian and Eritrean/Ethiopian asylum-seekers for the period January 2013 - September 2015 and linked these to notifications in the Netherlands Tuberculosis Register. RESULTS: Asylum-seekers from Syria and Eritrea/Ethiopia represented 65% and 72% of all asylum applications in 2014 and in the first nine months of 2015 respectively. Fourteen Syrian asylum-seekers applying during the study period were diagnosed with tuberculosis. The prevalence was 22 cases per 100,000 persons screened upon arrival (95% CI: 10-44), while the incidence within the first year after arrival was 19 per 100,000 persons (95% CI: 3-62). Tuberculosis was diagnosed in 133 Eritrean/Ethiopian asylum-seekers applying during the study period. The prevalence was 283 cases per 100,000 persons screened upon arrival (95% CI: 198-393) and the incidence in the first year after arrival was 1394 per 100,000 persons (95% CI: 1095-1751). CONCLUSION: In the last two years, most asylum-seekers have originated from Syria and among them tuberculosis is relatively uncommon. However, among Eritrean/Ethiopian asylum-seekers, prevalence and incidence in the first year in the Netherlands are high. This suggests that many of them have been recently infected, in their country of origin or during the journey. Other interventions are required, such as screening for latent infection, to prevent tuberculosis among high-risk asylum-seekers and further reduce the incidence of this disease in the Netherlands.