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Ioana Munteanu,1 Nicoleta Cioran,1,2 Rob van Hest,3,4 Ibrahim Abubakar,5 Alistair Story,6,7 Domnica Chiotan,1 Gerard de Vries,8,9 Beatrice Mahler1,10 1Department of Pneumology, Marius Nasta Institute of Pneumology, Bucharest, Romania; 2 3rd Department – Complementary Sciences, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania; 3Department of Tuberculosis Control, Regional Public Health Service Groningen, Groningen, The Netherlands; 4Department of Lung Diseases and Tuberculosis, University Medical Centre Groningen (UMCG), Groningen, The Netherlands; 5Institute for Global Health, University College London, London, UK; 6Institute of Health Informatics, University College London, London, UK; 7Find and Treat, University College Hospitals NHS Foundation Trust, London, UK; 8KNCV Tuberculosis Foundation, The Hague, The Netherlands; 9Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands; 10 4th Department – Cardio-Thoracic Pathology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, RomaniaCorrespondence: Nicoleta Cioran, Department of Pneumology, Marius Nasta Institute of Pneumology, Soseaua Viilor nr.90, Sector 5, Bucharest, Romania, Tel +40 745 419 994, Fax +40 213 373 801, Email nicoleta.cioran@umfcd.roPurpose: Romania has the highest tuberculosis (TB) burden in the European Union/European Economic Area (EU/EEA) comprising almost a quarter (23.4%) of the reported patients in 2017, and a TB notification rate six times higher than the EU/EEA average. Although the overall TB notification rate in Romania declined from 154/100.000 individuals to 66/100.000 individuals in the general population between 2002 and 2017, TB notification rates remain high in certain vulnerable populations groups such as prisoners, the homeless population and among drug users.Patients and Methods: We conducted a descriptive study regarding TB monitoring data in Romania, including the aforementioned TB risk groups.Results: Analysis regarding notified TB cases among these risk groups indicates that TB rates are 7 to 18 times higher than in the general population. One of the most alarming aspects regards the exceedingly high proportion of HIV-seropositivity among drug users and the high mortality rates among the homeless population and among drug users with TB.Conclusion: This data underlines the importance of early identification among social risk groups using outreach active case-finding (ACF) activities, possibly combining TB screening with screening for other common, possibly life-threatening, co-morbidities for which an effective treatment is available. ACF could have a decisive role in TB control and eradication in Romania, when aimed at these high-risk groups.Keywords: Romania, tuberculosis, notification rate, risk groups

ObjectiveTo implement and assess the mobile X-ray unit (MXU) equipped with digital radiography, computer-aided detection (CAD) software and molecular point of care tests to improve early tuberculosis (TB) diagnosis in vulnerable populations in a TB outreach screening programme in Romania.DesignDescriptive study.SettingsPrisons in Bucharest and other cities in the southern part of Romania, homeless shelters and services for problem drug users in Bucharest, and Roma populations in Bucharest and Craiova.Participants5510 individuals attended the MXU service; 5003 persons were radiologically screened, 61% prisoners, 15% prison staff, 11% Roma population, 10% homeless persons and/or problem drug users and 3% other.InterventionsRadiological digital chest X-ray (CXR) screening of people at risk for TB, followed by CAD and human reading of the CXRs, and further TB diagnostics when the pulmonologist classified the CXR as suggestive for TB.Primary and secondary outcome measuresTen bacteriologically confirmed TB cases were identified translating into an overall yield of 200 per 100 000 persons screened (95% CIs of 109 to 368 per 100 000). Prevalence rates among homeless persons and/or problem drug users (826/100 000; 95% CI 326 to 2105/100 000) and the Roma population (345/100 000; 95% CI 95 to 1251/100 000) were particularly high.ResultsThe human reader classified 6.4% (n=317) of the CXRs as suspect for TB (of which 32 were highly suggestive for TB); 16.3% of all CXRs had a CAD4TB version 6 score >50. All 10 diagnosed TB patients had a CAD4TB score >50; 9 had a CAD4TB score >60.ConclusionsGiven the high TB prevalence rates found among homeless persons and problem drug users and in the Roma population, targeted active case finding has the potential to deliver a major contribution to TB control in Romania.

Background Progress 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. Aim We 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. Methods We 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. Results Observed 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. Conclusion Inventory 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.

A considerable proportion of the world’s population is latently infected with Mycobacterium tuberculosis (MTB) complex (LTBI) but in low-incidence counties as the Netherlands (4.6 TB cases/100.000 /year) LTBI prevalence is predominantly found among the elder population and foreign-born residents. In resource-rich countries implementation of immunosuppressive therapies with “biologicals”, show a rapid rise with increased risk of LTBI progressing to, often serious forms of, active TB. Worldwide it is advised to screen all candidates for of immunosuppressive therapies for TB with a chest X-ray and LTBI with at least one test [interferon gamma release assays (IGRAs) and/or tuberculin skin tests (TSTs)]. Screening requires an acceptable balance between over-diagnosis and under-diagnosis, also because the tests are not perfect and can be false-negative and false-positive in populations almost without exposure. We developed a guideline advising a stratified pre-immunosuppression screening policy, using a questionnaire classifying candidates in three screening strategies, based upon their age, country of birth, documented TB contacts and tests in the past and other risk factors, such as profession and travel history. A very low risk group can start with immune therapy immediately and a very high risk group should receive preventive treatment for LTBI, both without the need for further testing. A medium risk group should be tested by TST and IGRA and receive preventive treatment if at least one test is positive. Since the questionnaire is not yet validated monitoring of this approach on a national level is needed to evaluate the performance of this stratified screening strategy, based upon risk analysis.

Efficiency and yield of an active TB case-finding programme during and after an outbreak can guide scaling downhttp://ow.ly/ZT1Me

In low tuberculosis (TB) incidence countries foreign-born patients constitute a high percentage of the TB burden, up to 90% in Scandinavian countries [1] and 73% in the Netherlands in 2014 [2]. Several European Union (EU) countries have developed screening strategies to identify TB in migrants at an early stage and prevent transmission, but there is no uniform EU policy [3–5]. In the Netherlands, TB screening of migrants has been stipulated in the Alien's Act since 1966. At that time, screening was mainly carried out for migrant workers from Southern European countries, Morocco and Turkey. Since the 1990s, TB screening has increasingly included immigrants and asylum seekers from other countries in the world. For the screening of asylum seekers a mobile radiography screening programme has been in place since 1992 with national coverage [6]. The annual overall yield of TB screening has been well above 200 cases per 100 000 persons screened until a few years ago [6, 7]. It declined to 85 cases per 100 000 persons screened in 2014, due to the high number of asylum seekers from countries with traditionally low TB incidence rates such as Iran, Iraq and, predominantly, Syria [2]. Screening asylum seekers from areas with a TB incidence of

Europe is facing a refugee crisis in which hundreds of thousands of displaced persons, often originating from tuberculosis (TB) high-endemic countries, risked their lives for a safer and better future in the European Union (EU) [1]. Among these asylum seekers a considerable proportion were accompanied or unaccompanied minors [2, 3]. Screening practices for TB and latent TB infection (LTBI) among refugees are highly variable in the EU [4, 5]. Details of practices, including mandatory radiographic screening for intrathoracic TB among children of all ages, and aggregate yield of TB entry screening among asylum seekers in the Netherlands from 2012 to September 2015 have been described [1, 6]. Entry screening for LTBI was not routine. We present the results of radiographic TB screening among >34 000 asylum seeker children in the Netherlands 2013–2017 (age groups suggested by the authors) and discuss options for policy changes. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Wolters has nothing to disclose. Conflict of interest: Dr. Akkerman has nothing to disclose. Conflict of interest: Dr. Aartsma has nothing to disclose. Conflict of interest: Dr. de Lange has nothing to disclose. Conflict of interest: Dr. Scholvinck has nothing to disclose. Conflict of interest: Dr. van der Werf has nothing to disclose. Conflict of interest: Dr. Van Hest has nothing to disclose.

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

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 100TB 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. Keywords: Elimination, Latent tuberculosis infection, Prevention, Screening, Tuberculosis, Municipal Public Health Service

There is need to collect, analyse and compare TB screening data from migrants in EU countries more systematically http://ow.ly/x2eQ303k2CK

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.Descriptive study.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.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).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.

For 3 years, Europe has faced an increasing refugee crisis in which hundreds of thousands of displaced persons are risking their lives to seek a safer and better future in the European Union (EU). Many of these migrants originate from highly tuberculosis (TB)-endemic countries. Furthermore, their travel conditions are often poor, allowing potential transmission of infectious diseases, including TB. The Netherlands have observed an increased influx of asylum seekers since 2012 too, with fluctuating numbers every month, and a sharp increase in the summer of 2015, putting constraints on the process of registration, identification, application and accommodation, including mandatory radiographic screening for intrathoracic TB. We describe the impact of such migration on the Public Health TB Clinic of Groningen (responsible for nearly all TB entry screening for asylum seekers in the Netherlands), and our flexible and efficient practice model for daily radiographic TB screening. We report the yield of this intervention over the last 4 years, and reflect on issues concerning entry screening. The Dutch practice model for radiographic TB screening of asylum seekers has proved feasible

IntroductionThe current refugee crisis emphasizes the need for information on infectious diseases and resistant microorganisms in asylum seekers with possible consequences for public health and infection control.MethodsWe collected data from asylum seekers admitted to our university hospital or who presented at the Emergency Department (n = 273). We collected general and demographic characteristics including country of origin, the reason of presentation, and the screening results of multi-drug resistant organisms.Results67% of the patients were male with a median age of the study group of 24 years (IQR 15-33); 48% of the patients had an infectious disease-predominantly malaria with P. vivax or tuberculosis. Patients also reported with diseases which are less common-e. g. leishmaniasis, or even conditions rarely diagnosed in Europe-e. g. louse borne relapsing fever. A carriage rate of 31% for multi-drug resistant microorganisms (MDRO) was observed, with ESBL-expressing E. coli (n = 20) being the most common MDRO. No carriage of Carbapenemase Producing Enterobacteriaceae was found.ConclusionThe current refugee crisis in Europe challenges hospitals to quickly identify and respond to communicable diseases and the carriage of MDRO. A rapid response is necessary to optimize the treatment of infectious diseases amongst asylum seekers to maximize infection control.

Statins are members of a class of pharmaceutical widely used to reduce high levels of serum cholesterol. In addition, statins have so-called "pleiotropic effects," which include inflammation reduction, immunomodulation, and antimicrobial effects. An increasing number of studies are emerging which detail the attenuation of bacterial growth and in vitro and in vivo virulence by statin treatment. In this review, we describe the current information available concerning the effects of statins on bacterial infections and provide insight regarding the potential use of these compounds as antimicrobial therapeutic agents.

Rationale: In 2002, a mobile radiographic screening program was started in Rotterdam to respond to high rates of tuberculosis (TB) among illicit drug users and homeless persons. Objectives: We studied trends and characteristics of TB among these risk groups and assessed the impact of the screening program on transmission, using molecular typing. Methods: Description of trends, and of demographic and disease-related characteristics of tuberculosis cases among these risk groups between 1993 and 2005. TB was considered to result from recent transmission if the mycobacterial DNA fingerprints of cases were identical to those of other cases in the risk groups in the previous 2 years. Measurements and Main Results: During the study period, 206 individuals with TB among illicit drug users and homeless persons were notified, representing 11.4% of the total case load of 1,811 in Rotterdam. The annual number of tuberculosis cases declined from 24 at the start of the screening program to 11 cases in 2005. The screening program identified 28 cases (a prevalence rate of 327 per 100,000 radiographs), of which 12 were smear positive. In 1997-2002, more than 80% of the illicit drug users or homeless persons with TB were infected with one of the Mycobacterium tuberculosis strains prevalent among these risk groups. After nearly 4 years of systematic radiographic screening this proportion declined to 45% in 2005. Conclusions: DNA fingerprinting can be a useful tool to evaluate the impact of a TB screening program. We advocate that screening of illicit drug users and homeless persons should be continued to prevent a resurgence of TB.

Background: In early 2001 there were indications that tuberculosis (TB) was increasingly becoming a problem among drug addicts and homeless persons in Rotterdam, after a periodical screening was discontinued in 1997. A contact investigation around a homeless drug addicted man in Rotterdam with infectious pulmonary TB is described. Contact investigation: A total of 507 drug addicts, homeless persons, and staff of facilities for these risk groups were examined with tuberculin skin testing (TST) and chest radiography. DNA fingerprinting of mycobacteriological cultures through Restricted Fragment Length Polymorphism methodology and molecular epidemiology investigation through cluster analysis were performed. Outcome: TST showed an infection prevalence of 29%, especially among staff of services for drug addicts and homeless persons. Six persons with active intrathoracic TB were identified. Cluster analysis demonstrated no relation with the initial case but showed intense transmission of TB among drug addicts and homeless persons in Rotterdam by multiple sources. As a consequence of the findings, a proposal to the Council of the City of Rotterdam resulted in the re-introduction of a comprehensive TB screening programme among these risk groups with mobile digital X-ray units (MXUs). Conclusion: This contact investigation gradually obtained the characteristics of a screening of drug addicts and homeless persons. Novel technologies, such as MXUs, facilitate appropriate and efficient outreach approaches to TB control among difficult-to-reach groups. This method and knowledge of individual fingerprints and clusters of TB patients are indispensable for underpinning proposals for change of local TB control strategies and convincing local authorities of the rationale.

Background. Severe liver injury has been attributed to preventive treatment of latent tuberculosis infection with a 2-month course of rifampin-pyrazinamide. Methods. A retrospective cohort study in The Netherlands compared the hepatotoxicity of preventive treatment with rifampin-pyrazinamide with that of preventive treatment with isoniazid, and also with that of treatment for active tuberculosis containing at least isoniazid, rifampin, and pyrazinamide. Results. Preventive treatment with rifampin-pyrazinamide caused severe hepatotoxicity more often than did preventive treatment with isoniazid (odds ratio [OR], 2.61; 95% confidence interval [CI], 1.26-5.39; P = .012), especially in patients

In developed countries most patients with tuberculosis are not infectious, can readily access health services, and complete treatment successfully with minimal supervision from a health worker. As a result they make only limited demands on services and pose little public health risk. By contrast, many socially excluded patients are at risk of delayed presentation, poor adherence, and loss to follow-up. A recent persistent outbreak in London including over 220 drug resistant cases and disproportionately affecting homeless people, prisoners, and problem drug users clearly illustrates the urgent need to strengthen tuberculosis control among socially excluded groups.1 Mycobacterium tuberculosis can infect anyone but predominantly affects the poor. Globally, 98% of deaths from tuberculosis are in the poorest countries.2 In rich countries tuberculosis mainly occurs in people born abroad and in socially excluded groups. In London, which accounted for over 40% of all reported cases in the UK in 2004, rates of tuberculosis have more than doubled since 19873 and are highest among homeless people, problem drug users, people living with HIV, prisoners, and new immigrants, particularly those from countries experiencing chronic civil conflict.4 These risk groups are prevalent in major cities across the developed world. Tuberculosis control is founded on early case detection and complete treatment to minimise transmission and prevent the emergence of drug resistance. But patients from these groups are unlikely to present promptly and take treatment lasting a minimum of six months, and the assumption that they will do so is no longer a basis for effective tuberculosis control. Recent guidelines from the National Institute for Health and Clinical Excellence (NICE) provide a comprehensive review of the evidence supporting clinical diagnosis and management of tuberculosis and measures for its prevention and control.5 They discuss tuberculosis control and future research priorities in some socially excluded groups, specifically homeless people and prisoners. The guidelines do not mention other groups with high rates, such as drug and alcohol misusers.6 A recent summary from the Netherlands discusses case detection and control among drug users and homeless people.7 Among these groups conventional contact investigation is often not feasible, a low proportion of infected individuals are eligible for preventive treatment, and only a minority may complete the treatment. NICE recommends that active case finding should be carried out among street homeless people (including those using homeless shelters) by chest x ray screening on an opportunistic or symptomatic basis; the guidelines suggest simple incentives for attending, such as hot drinks and snacks. People with a history of homelessness and drug and alcohol problems are over-represented in the prison population, and prisons can aggravate transmission of tuberculosis. So the guidelines recommend entry screening for prisoners through a health questionnaire, followed by a chest x ray for those with signs and symptoms of active disease, but this approach will miss asymptomatic cases. Active case finding among prisoners contributes to tuberculosis control in the community, and chest radiography has been shown to be more cost effective than symptom screening or tuberculin testing and identifies substantially more cases than other screening methods.8 Mobile chest radiography targeted at high risk groups in communities where many of them live or meet, such as homeless shelters or services for drug users, is used in the Netherlands and France and is being evaluated in London.9 Recommendations to confirm diagnosis and promote treatment continuity include hospital admission for homeless people and those with a clear socio-economic need, allocation of a named key worker for all patients, and risk assessment to identify patients unlikely to adhere to treatment. Adherence is known to be complicated by the lack of secure accommodation, destitution, and addiction.10 NICE recommends directly observed therapy (DOT) for homeless people and those who are likely to be poorly adherent, recognising that DOT alone is unlikely to lead to improved outcomes unless provided in conjunction with a package of supportive care tailored to patients' needs.11 The guidelines emphasise the importance of stable accommodation, financial support to cover transport and prescription costs, and treatment arrangements that are practicable for the patient. Many observational studies point to the effectiveness of directly observed therapy, but the evidence from randomised controlled trials is conflicting.12 If the major determinants of a disease are social, so must be the remedies.13 Tuberculosis cannot be controlled unless the disease is tackled effectively among socially excluded groups. This demands coordinated action beyond established control strategies that will require significant and sustained investment.