Reducing the burden of TB among migrants to low TB incidence countries.

BACKGROUND: International migrants to low TB incidence countries are disproportionately affected by TB compared to the native population: migrants are at increased risk for TB transmission and TB disease due to a variety of personal, environmental and socio-economic determinants experienced during the four phases of migration (pre-departure, transit, arrival and early settlement, return travel).OBJECTIVE: To provide an up-to-date overview of the determinants that drive the TB burden among migrants, as well as effective and feasible interventions to address this for each migration phase.METHODS: We conducted a literature review by searching PubMed and the grey literature for articles and reports on determinants and interventions addressing migrant health and TB.RESULTS: Lowering the risk of TB transmission and TB disease among migrants would be most effective by improving the socio-economic position of migrants pre-, during and after migration, ensuring universal health coverage, and providing tailored and migrant-sensitive care and prevention activities.CONCLUSION: In addition to migrant-sensitive health services and cross-border collaboration between low TB incidence countries, there is a need for international financial and technical support for endemic countries.

Country differences and determinants of yield in programmatic migrant TB screening in four European countries.

INTRODUCTION The WHO End TB Strategy emphasises early diagnosis and screening of TB in high-risk groups, including migrants. We analysed TB yield data from four large migrant TB screening programmes to inform TB policy.METHODS We pooled routinely collected individual TB screening episode data from Italy, the Netherlands, Sweden and the United Kingdom under the European Union Commission E-DETECT.TB grant, described characteristics of the screened population, and analysed TB case yield.RESULTS We collected data on 2,302,260 screening episodes among 2,107,016 migrants, mostly young adults aged 18-44 years (77.8%) from Asia (78%) and Africa (18%). There were 1,658 TB cases detected through screening, with substantial yield variation (per 100,000): 201.1 for Sweden (95% confidence intervals CI 111.4-362.7), 68.9 (95% CI 65.4-72.7) for the United Kingdom, 83.2 (95% CI 73.3-94.4) for the Netherlands and 653.6 (95% CI 445.4-958.2) in Italy. Most TB cases were notified among migrants from Asia (n = 1,206, 75/100,000) or Africa (n = 370, 76.4/100,000), and among asylum seekers (n = 174, 131.5/100,000), migrants to the Netherlands (n = 101, 61.9/100,000) and settlement visa migrants to the United Kingdom (n = 590, 120.3/100,000).CONCLUSIONS We found considerable variations in yield across programmes, types of migrants and country of origin. These variations may be partly explained by differences in migration patterns and programmatic characteristics.

Clinical standards for the diagnosis, treatment and prevention of TB infection.

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) decreases the risk of developing TB disease and its associated morbidity and mortality. The aim of these clinical standards is to guide the assessment, management of TB infection (TBI) and implementation of TPT.METHODS: A panel of global experts in the field of TB care was identified; 41 participated in a Delphi process. A 5-point Likert scale was used to score the initial standards. After rounds of revision, the document was approved with 100% agreement.RESULTS: Eight clinical standards were defined: Standard 1, all individuals belonging to at-risk groups for TB should undergo testing for TBI; Standard 2, all individual candidates for TPT (including caregivers of children) should undergo a counselling/health education session; Standard 3, testing for TBI: timing and test of choice should be optimised; Standard 4, TB disease should be excluded prior to initiation of TPT; Standard 5, all candidates for TPT should undergo a set of baseline examinations; Standard 6, all individuals initiating TPT should receive one of the recommended regimens; Standard 7, all individuals who have started TPT should be monitored; Standard 8, a TBI screening and testing register should be kept to inform the cascade of care.CONCLUSION: This is the first consensus-based set of Clinical Standards for TBI. This document guides clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage TBI.

[Preventing TB among immigrants; aiming for an integrated approach to infectious diseases]. / Preventie van tbc bij migranten.

Tuberculosis (TB) still occurs frequently in the Netherlands among immigrants from countries where the disease is highly endemic, despite the mandatory TB screening upon settling in the Netherlands. The TB-ENDPoint study shows that immigrants from populations at risk for TB are prepared to be screened for latent TB infection (LTBI) and to complete preventative treatment. Cost-effectiveness analysis will have to determine whether and in which target groups screening can replace the present X-ray screening for TB. A targeted approach, in which LTBI screening is combined with screening for other infectious diseases such as hepatitis B and C and HIV, could favourably influence cost-effectiveness. Further research into implementation, involving all stakeholders, would be useful to optimize combined screening.

Tuberculin skin test reaction depends on type of purified protein derivative: implications for cut-off values.

SETTING: Due to purified protein derivative (PPD) RT23 stock-outs in 2014, PPD-Tubersol and PPD-Bulbio have been used for latent tuberculosis infection (LTBI) testing in the Netherlands.OBJECTIVE: To determine whether PPD-RT23, PPD-Tubersol and PPD-Bulbio were associated with differential indurations and confirmation using interferon-gamma release assays (IGRAs).DESIGN: LTBI surveillance data from 2013 to 2016 were extracted. Regression analyses were used to determine whether IGRA confirmation of TST-positive indurations depended on PPD, controlling for sex, age, incidence in country of origin, and bacille Calmette-Guérin (BCG) status.RESULTS: A total of 20 956 individuals were tested with PPD-RT23: 10 382 with PPD-Tubersol and 18 562 with PPD-Bulbio. Overall, 21% with PPD-Bulbio had an induration of ≥5 mm compared to 12% of those tested with PPD-RT23 and PPD-Tubersol. Compared to PPD-RT23, PPD-Bulbio indurations ≥5 mm were significantly less often IGRA-confirmed among contacts (aOR 1.3, 95% CI 1.1-1.6) and BCG-vaccinated immigrants (PPD-RT23, aOR 2.4, 95% CI 1.4-4.1). Increasing the PPD-Bulbio cut-off from ≥5 to ≥10 mm would save respectively 26%, 42%, and 35% of IGRAs among contacts, health care workers (HCWs) and BCG-vaccinated immigrants, with small absolute numbers of positive IGRAs missed (range 0-55 annually).CONCLUSION: PPD-Bulbio shows larger TST indurations than other PPDs, but is less often IGRA-confirmed. Increasing the TST cut-off from 5 to 10 mm prior to testing with an IGRA in HCWs and immigrants is recommended.

Active case finding and treatment adherence in risk groups in the tuberculosis pre-elimination era.

Vulnerable populations, including homeless persons, high-risk drug and alcohol users, prison inmates and other marginalised populations, contribute a disproportionate burden of tuberculosis (TB) cases in low-incidence settings. Drivers of this disease burden include an increased risk of both TB transmission in congregate settings, and progression from infection to active disease. Late diagnosis and poor treatment completion further propagate the epidemic and fuel the acquisition of drug resistance. These groups are therefore a major priority for TB control programmes in low-incidence settings. Targeted strategies include active case finding (ACF) initiatives and interventions to improve treatment completion, both of which should be tailored to local populations. ACF usually deploys mobile X-ray unit screening, which allows sensitive, high-throughput screening with immediate availability of results. Such initiatives have been found to be effective and cost-effective, and associated with reductions in proxy measures of transmission in hard-to-reach groups. The addition of point-of-care molecular diagnostics and automated X-ray readers may further streamline the screening pathway. There is little evidence to support interventions to improve adherence among these risk groups. Such approaches include enhanced case management and directly observed treatment, while video-observed therapy (currently under evaluation) appears to be a promising tool for the future. Integrating outreach services to include both case detection and case-management interventions that share a resource infrastructure may allow cost-effectiveness to be maximised. Integrating screening and treatment for other diseases that are prevalent among targeted risk groups into TB outreach interventions may further improve cost-effectiveness. This article reviews the existing literature, and highlights priorities for further research.

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

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

Extent and origin of resistance to antituberculosis drugs in the Netherlands, 1993 to 2011.

The elimination of tuberculosis (TB) is threatened by an apparent increase in the level of resistance in Mycobacterium tuberculosis. In the Netherlands, where the majority of TB patients are migrants, resistance may also be increasing. We conducted a retrospective study, using 18,294 M. tuberculosis isolates from TB cases notified between 1993 and 2011. We investigated the trends in antituberculosis drug resistance, focusing on the country of birth of the patients and whether resistance had developed during treatment or was the result of transmission of resistant M. tuberculosis strains. For both scenarios, we determined whether this had happened in or outside the Netherlands. Antituberculosis drug resistance was found in 13% of all cases analysed and showed an increasing trend among patients who had been born in the Netherlands (p<0.001) and a decreasing trend among foreign-born (p=0.02) over the study period. Since 2005, the proportion of M. tuberculosis resistant strains among all strains tested has increased in both groups (p=0.03 and p=0.01, respectively). Overall, we found a significantly increasing trend when excluding streptomycin resistance (p<0.001). The trend was most markedly increased for isoniazid resistance (p = 0.01). Although resistance was mainly due to transmission of resistant strains, mostly outside the Netherlands or before 1993 (when DNA fingerprinting was not systematically performed), in some cases (n=45), resistance was acquired in the Netherlands. We conclude that antituberculosis drug resistance is increasing in the Netherlands, mostly related to migration from high TB-incidence countries, but also to domestic acquisition.

Added value of interferon-gamma release assays in screening for tuberculous infection in the Netherlands.

BACKGROUND: Interferon-gamma release assays (IGRAs) are reported to be more specific for the diagnosis of latent tuberculous infection (LTBI) than the tuberculin skin test (TST). The two-step procedure, TST followed by an IGRA, is reported to be cost-effective in high-income countries, but it requires more financial resources. OBJECTIVE: To assess the added value of IGRA compared to TST alone in the Netherlands. METHODS: Test results and background data on persons tested with an IGRA were recorded by the Public Municipal Health Services in a web-based database. The number of persons diagnosed with LTBI using different screening algorithms was calculated. RESULTS: In those tested with an IGRA, at least 60% of persons who would have been diagnosed with LTBI based on TST alone had a negative IGRA. Among those with a TST reaction below the cut-off for the diagnosis of LTBI, 13% had a positive IGRA. For 41% of persons tested with an IGRA after TST, the IGRA influenced whether or not an LTBI diagnosis would be made. CONCLUSION: With the IGRA as reference standard, a high proportion of persons in low-prevalence settings are treated unnecessarily for LTBI if tested with TST alone, while a small proportion eligible for preventive treatment are missed. Incremental costs of the two-step strategy seem to be balanced by the improved targeting of preventive treatment.

Tuberculosis seasonality in the Netherlands differs between natives and non-natives: a role for vitamin D deficiency?

SETTING: The seasonality of tuberculosis (TB) incidence suggests that the risk of infection or development of disease has a seasonal component. OBJECTIVE: To investigate factors associated with seasonal patterns of TB disease in the Netherlands by splitting notifications according to origin (natives vs. non-natives) and disease site (pulmonary TB [PTB] vs. extra-pulmonary TB [EPTB]). We focus on the presence of a seasonal peak, as much debate has centred on factors enhancing transmission vs. disease development. DESIGN: Monthly notifications were derived from culture sample dates of all cases between 1993 and 2008. We fitted seasonal autoregressive integrated moving average (SARIMA) models to the time series. Seasonal decomposition revealed seasonal trends. To assess the seasonality of the peak, we repeated the analysis omitting December (trough) notifications. RESULTS: TB notifications show a seasonal pattern, with a peak in spring and a trough in winter, which is present in both PTB and EPTB and in both natives and non-natives. However, when excluding December notifications, seasonality only holds in non-native EPTB and non-native TB notifications. CONCLUSION: A seasonal peak in TB notifications (March-June) is apparent in non-natives, but is absent in natives. This peak is driven by the seasonality of EPTB notifications, which are highest in June-July. The contribution of winter crowding is discussed. Vitamin D deficiency, enhancing disease development at the end of winter-early spring, seems the most likely factor explaining the yearly peak in EPTB.

Coverage and yield of tuberculosis contact investigations in the Netherlands.

SETTING: An increasing proportion of tuberculosis (TB) patients in low-incidence countries are immigrants. It is unclear whether contact investigations among immigrant patients are adequate. OBJECTIVE: To determine whether ethnicity of pulmonary TB patients was associated with coverage and yield of contact investigations in the Netherlands. DESIGN: Contact investigation results were extracted from records of patients reported in the nationwide surveillance register in 2006 and 2007. Prevalence odds ratios (PORs) with 95% confidence intervals (CIs) were calculated to determine the association between patient ethnicity and coverage of contact investigations and the yield of individuals with Mycobacterium tuberculosis infection or TB. RESULTS: Of the 1040 pulmonary TB patients reported, 642 (62%) were eligible for analysis. Compared to close contacts of Dutch patients, close contacts of immigrant patients were significantly less likely to be examined for TB (89% vs. 93%, POR 0.6, 95%CI 0.5-0.7) and infection (50% vs. 75%, POR 0.3, 95%CI 0.3-0.4), whereas the yield was significantly higher for disease (1.5% vs. 0.4%, POR 3.4, 95%CI 1.8-6.4) and infection (13% vs. 10%, POR 1.2, 95%CI 1.0-1.5). CONCLUSION: The effectiveness of contact investigations in the Netherlands can be optimised by expanding the investigation of contacts of immigrant patients.

Risk of travelling to the country of origin for tuberculosis among immigrants living in a low-incidence country.

SETTING: Two thirds of tuberculosis (TB) patients in the Netherlands are foreign-born. OBJECTIVE: To determine if travelling to the country of origin is a risk factor for TB among two different immigrant groups that have lived in the Netherlands for at least 2 years. DESIGN: In this unmatched case-control study, the frequency and duration of travel to the country of origin in the preceding 12 months were compared between adult Moroccan and Turkish TB patients and community controls. RESULTS: Moroccan patients had travelled more often (26/32 = 81%) in the preceding year than Moroccan controls (472/816 = 58%). The travel-associated odds ratio (OR) for TB among Moroccans was 3.2 (95%CI 1.3-7.7), and increased to 17.2 (95%CI 3.7-79) when the cumulative duration of travel exceeded 3 months. The corresponding population fraction of Moroccan TB cases attributable to recent travel was 56% (95%CI 19-71). Among Turkish immigrants TB was not associated with travel (OR 0.9, 95%CI 0.3-2.4). CONCLUSION: Travel to the country of origin was a risk factor for TB among Moroccans, but not among Turkish people living in the Netherlands. The difference in travel-associated OR between these two immigrant groups is probably related to differences in TB incidence in these countries.

Tuberculosis contact investigation in low prevalence countries: a European consensus.

Contact investigation to identify individuals with tuberculosis and latent infection with Mycobacterium tuberculosis is an important component of tuberculosis control in low tuberculosis incidence countries. This document provides evidence-based and best-practice policy recommendations for contact tracing among high- and medium-priority contacts in a variety of settings. It provides a basis for national guidelines on contact investigation and tuberculosis outbreak management, and should support countries and tuberculosis control managers in evaluating and revising national policies. A review of existing guidelines, a literature search, several meetings and consultation with experts were used to formulate and grade recommendations for action during contact investigation. Available tests to identify individuals with latent infection with M. tuberculosis are designed to identify immune response against mycobacterial antigens and have variable predictive value for the likelihood to develop active tuberculosis in different populations. Contact investigation should therefore be limited to situations with a clear likelihood of transmission or to those with a higher probability of developing active tuberculosis, for instance, young children and immunocompromised persons. A risk assessment-based approach is recommended, where the need to screen contacts is prioritised on the basis of the infectiousness of the index case, intensity of exposure and susceptibility of contacts.

The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement.

Anti-tumour necrosis factor (TNF) monoclonal antibodies or soluble TNF receptors have become an invaluable treatment against chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. Individuals who are treated with TNF antagonists are at an increased risk of reactivating latent infections, especially tuberculosis (TB). Following TNF antagonist therapy, the relative risk for TB is increased up to 25 times, depending on the clinical setting and the TNF antagonist used. Interferon-γ release assays or, as an alternative in individuals without a history of bacille Calmette-Guérin vaccination, tuberculin skin testing is recommended to screen all adult candidates for TNF antagonist treatment for the presence of latent infection with Mycobacterium tuberculosis. Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test and an interferon-γ release assay, as there are insufficient data in children to recommend one test over the other. Consequently, targeted preventive chemotherapy is highly recommended for all individuals with persistent M. tuberculosis-specific immune responses undergoing TNF antagonist therapy as it significantly reduces the risk of progression to TB. This TBNET consensus statement summarises current knowledge and expert opinions and provides evidence-based recommendations to reduce the TB risk among candidates for TNF antagonist therapy.

Predictive value for progression to tuberculosis by IGRA and TST in immigrant contacts.

The authors determined the positive predictive value (PPV) for progression to tuberculosis (TB) of two interferon-gamma release assays (IGRAs), QuantiFERON-TB Gold In-tube (QFT-GIT) and T-SPOT.TB, and the tuberculin skin test (TST) in immigrants contacts. Immigrant close contacts of sputum smear-positive TB patients were included when aged > or =16 yrs and their TST result was > or =5 mm 0 or 3 months after diagnosis of the index patient. Contacts were followed for the next 2 yrs for development of TB disease. Of 339 immigrant contacts with TST > or =5 mm, 324 and 299 had valid results of QFT-GIT and T-SPOT.TB, respectively. Nine contacts developed active TB. One patient had not been tested with TST, while another patient had not been tested with QFT-GIT and T-SPOT.TB. The PPV for progression to TB during this period was 9/288 = 3.1% (95% CI 1.3-5.0%) for TST > or =10 mm, 7/184 = 3.8% (95% CI 1.7-5.9%) for TST > or =15 mm, 5/178 = 2.8% (95% CI 1.0-4.6%) for QFT-GIT and 6/181 = 3.3% (95% CI 1.3-5.3%) for T-SPOT.TB. Sensitivity was 100%, 88%, 63% and 75%, respectively. The predictive values of QFT-GIT, T-SPOT.TB and TST for progression to TB disease among immigrant close contacts were comparable.

Progress towards tuberculosis elimination: secular trend, immigration and transmission.

This study aimed to determine to what extent tuberculosis trends in the Netherlands depend on secular trend, immigration and recent transmission. Data on patients in the Netherlands Tuberculosis Register in the period 1993-2007 were matched with restriction fragment length polymorphism (RFLP) patterns of Mycobacterium tuberculosis isolates. Index patients were defined as patients with pulmonary tuberculosis whose isolates had RFLP patterns not observed in another patient in the previous 2 yrs. Among 8,330 patients with pulmonary tuberculosis the isolates of 56% of native and 50% of foreign-born patients were clustered. Of these, 5,185 were included in detailed analysis: 1,376 native index patients, 2,822 foreign-born index patients and 987 secondary cases within 2 yrs of diagnosis of the index case. The incidence of native and foreign-born index patients declined by 6% and 2% per year, respectively. The number of secondary cases per index case was 0.24. The decline of native cases contributed most to the overall decline of tuberculosis rates and was largely explained by a declining prevalence of latent infection. Tuberculosis among immigrants was associated with immigration figures. Progress towards elimination of tuberculosis would benefit from intensifying diagnosis and treatment of latent infection among immigrants and global tuberculosis control.

[Estimation of the incidence of tuberculosis in The Netherlands in 2030]. / Projectie van het aantal tuberculosepatiënten in Nederland in 2030.

OBJECTIVE: To estimate the number of cases of tuberculosis (TB) in 2030 for the purpose of planning future TB control. DESIGN: Statistical modelling in 5-year intervals until 2030. METHOD: The number of Dutch TB cases infected by a Dutch source was estimated using a survival model. The number ofnon-Dutch patients was estimated by calculating the proportion of culture-positive TB patients among first-generation immigrants in 2005 and applying this proportion to the projected size of the non-Dutch population. It was assumed that each non-Dutch TB patient infected by a non-Dutch source would cause one infection in the population in The Netherlands. RESULTS: The estimated number of TB cases is expected to decrease to 877 in 2010. Only a limited decrease in the number of TB patients is expected after 2010 as the number of non-Dutch TB cases increases due to increased immigration. This increase negates the expected decrease in Dutch TB patients infected by a Dutch source. In 2030, non-Dutch TB cases will account for 85% of all TB cases. The proportion of non-Dutch TB cases is greater in the 4 largest cities, i.e. Amsterdam, Rotterdam, The Hague and Utrecht (89%) than in the rest of The Netherlands (76%). CONCLUSION: The decrease in TB incidence observed over the past several years may cease by 2010 due to an increase in non-Dutch TB patients as a result of increased immigration. However, the confidence intervals associated with these estimates were large. Future TB control efforts must be organised in a flexible way so that they can be adapted to changing epidemiological situations.

Coverage and yield of entry and follow-up screening for tuberculosis among new immigrants.

The aim of the present study was to determine the effectiveness of entry screening for tuberculosis and biannual follow-up screening among new immigrants in The Netherlands. To achieve this, the present authors analysed screening, prevalence and incidence data of 68,122 immigrants, who were followed for 29 months. Patients diagnosed within 5 months and 6-29 months after entry screening were considered to be detected at entry and during the follow-up period, respectively. Coverage of the second to fifth screening rounds was 59, 46, 36 and 34%, respectively. Yield of entry screening was 119 per 100,000 individuals, and prevalence at entry was 131 per 100,000. Average yield of follow-up screening was highest among immigrants with abnormalities on chest radiography (CXR) at entry (902 per 100,000 individuals). When excluding these, yield of follow-up screening was 9, 37 and 97 per 100,000 screenings for immigrants from countries with tuberculosis incidences of <100, 100-200 and >200 per 100,000, respectively. The incidence during follow-up in individuals with a normal CXR was 11, 58 and 145 per 100,000 person-yrs follow-up in these groups. The proportion of cases detected through screening declined per screening round from 91 to 31%. Yield of entry screening was high. Overall coverage and yield of follow-up screening was low. Follow-up screening of immigrants with a normal chest radiograph from countries with an incidence of <200 per 100,000 individuals was therefore discontinued.