Screening for tuberculosis infection and effectiveness of preventive treatment among people with HIV in low-incidence settings.

OBJECTIVE: To determine the yield of screening for latent tuberculosis infection (LTBI) among people with HIV (PWH) in low tuberculosis (TB) incidence countries (<10 TB cases per 100 000 persons). DESIGN: A systematic review and meta-analysis were performed to assess prevalence and predictive factors of LTBI, rate of TB progression, effect of TB preventive treatment (TPT), and numbers needed to screen (NNS). METHODS: PubMed and Cochrane Library were searched for studies reporting primary data, excluding studies on active or paediatric TB. We extracted LTBI cases, odds ratios, and TB incidences; pooled estimates using a random-effects model; and used the Newcastle-Ottawa scale for bias. RESULTS: In 51 studies with 65 930 PWH, 12% [95% confidence interval (CI) 10-14] had a positive LTBI test, which was strongly associated with origin from a TB-endemic country [odds ratio (OR) 4.7] and exposure to TB (OR 2.9). Without TPT (10 629 PWH), TB incidence was 28/1000 person-years (PY; 95% CI 12-45) for LTBI-test positive versus 4/1000 PY (95% CI 0-7) for LTBI-test-negative individuals. Among 625 PWH (1644 PY) receiving TPT, 15 developed TB (6/1000 PY). An estimated 20 LTBI-positive individuals would need TPT to prevent one case of TB, and numbers NNS to detect LTBI or prevent active TB varied according to a-priori risk of LTBI. CONCLUSION: The relatively high prevalence of LTBI among PWH and the strong correlation with origin from a TB-endemic country support risk-stratified LTBI screening strategies for PWH in low-incidence countries and treating those who test positive.

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.

Tuberculosis Surveillance in Romania Among Vulnerable Risk Groups Between 2015 and 2017.

Purpose: 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.

Barriers and enablers to implementing tuberculosis control strategies in EU and European Economic Area countries: a systematic review.

Meeting the 2035 WHO targets of reducing tuberculosis incidence by 90% from 2015 levels requires the implementation of country-specific tuberculosis control strategies. This systematic review aims to identify factors that facilitate or impede the implementation of such strategies in EU and European Economic Area (EEA) settings. Focusing on providers of care, health system constraints, and social and political factors, this Review complements available evidence on the accessibility of tuberculosis services to recipients of care. Databases were searched for EU and EEA articles published between Jan 1, 1997, and Nov 6, 2020, that presented empirical data on tuberculosis policies, strategies, guidelines, or interventions. 2061 articles were screened and 65 were included. The most common barrier to tuberculosis control strategies described the divergence of health-care practices from guidelines, often related to inadequate knowledge or perceived usefulness of the guidelines by clinicians. The most commonly identified enabler to tuberculosis control strategies was the documented positive attitudes of health-care workers towards tuberculosis programmes. Divergence between clinical practice and guidelines was described in most EU and EEA settings, indicating the need for a focused review of guideline adherence. Strengths of this study involve its broad inclusion criteria and wide range of tuberculosis control strategies analysed.

Use of targeted mobile X-ray screening and computer-aided detection software to identify tuberculosis among high-risk groups in Romania: descriptive results of the E-DETECT TB active case-finding project.

OBJECTIVE: To 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. DESIGN: Descriptive study. SETTINGS: Prisons 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. PARTICIPANTS: 5510 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. INTERVENTIONS: Radiological 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 MEASURES: Ten 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. RESULTS: The 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. CONCLUSIONS: Given 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.

Collaborative tuberculosis/HIV activities in the European Region.

INTRODUCTION: An estimated 12% of tuberculosis (TB) patients are co-infected with HIV in the World Health Organization European Region (the Region). Reducing morbidity and mortality from HIV-associated TB requires strong collaboration between TB and HIV services at all levels with integrated people-centred models of care. METHODS: We collected information on the current models of integration of TB and HIV services in the Region via a comprehensive survey among the TB and HIV National Focal Points, and identified challenges and opportunities. RESULTS: 47 out of 55 (85%) countries responded. HIV testing in all TB patients and screening for active TB in all people living with HIV (PLHIV) was recommended in 40 (85%) and 34 (72%) countries, respectively. 30 (64%) countries recommended latent TB infection (LTBI) screening in all PLHIV, while 13 (28%) had a selective approach and four (9%) did not recommend LTBI screening. In most countries, testing for HIV and screening for active TB and LTBI was done by the specialist treating the patient, i.e. TB patients were tested for HIV by a TB specialist in 42 (89%) countries and PLHIV were screened for active TB by an HIV specialist in 34 (72%) countries. CONCLUSIONS: TB and HIV care are well integrated in policies of especially high TB and high HIV burden countries; however, implementation needs to be improved. Continuous monitoring of TB and HIV services integration enables assessing the quality of TB/HIV care and to identify where further improvements are needed.

High Incidence of Active Tuberculosis in Asylum Seekers from Eritrea and Somalia in the First 5 Years after Arrival in the Netherlands.

Three quarters of tuberculosis (TB) patients in the Netherlands are foreign-born; 26% are from Eritrea or Somalia. We analyzed TB incidence rates in asylum seekers from Eritrea and Somalia in the first 5 years after arrival in the Netherlands (2013-2017) and performed survival analysis with Cox proportional hazards regression to analyze the effect of age and sex on the risk for TB. TB incidence remained high 5 years after arrival in asylum seekers from Eritrea (309 cases/100,000 person-years) and Somalia (81 cases/100,000 person-years). Age >18 years was associated with a higher risk for TB in asylum seekers from Eritrea (3.4 times higher) and Somalia (3.7 times higher), and male sex was associated with a 1.6 times higher risk for TB in asylum seekers from Eritrea. Screening and treating asylum seekers from high-incidence areas for latent TB infection upon arrival would further reduce TB incidence in the Netherlands.

Effectiveness of interventions for reducing TB incidence in countries with low TB incidence: a systematic review of reviews.

AIMS: What is the evidence base for the effectiveness of interventions to reduce tuberculosis (TB) incidence in countries which have low TB incidence? METHODS: We conducted a systematic review of interventions for TB control and prevention relevant to low TB incidence settings (<10 cases per 100 000 population). Our analysis was stratified according to "direct" or "indirect" effects on TB incidence. Review quality was assessed using AMSTAR2 criteria. We summarised the strength of review level evidence for interventions as "sufficient", "tentative", "insufficient" or "no" using a framework based on the consistency of evidence within and between reviews. RESULTS: We found sufficient review level evidence for direct effects on TB incidence/case prevention of vaccination and treatment of latent TB infection. We also found sufficient evidence of beneficial indirect effects attributable to drug susceptibility testing and adverse indirect effects (measured as sub-optimal treatment outcomes) in relation to use of standardised first-line drug regimens for isoniazid-resistant TB and intermittent dosing regimens. We found insufficient review level evidence for direct or indirect effects of interventions in other areas, including screening, adherence, multidrug-resistant TB, and healthcare-associated infection. DISCUSSION: Our review has shown a need for stronger evidence to support expert opinion and country experience when formulating TB control policy.

Research Needs on Respiratory Health in Migrant and Refugee Populations. An Official American Thoracic Society and European Respiratory Society Workshop Report.

Migrants represent a diverse population comprising workers, students, undocumented individuals, and refugees. Worldwide, approximately 1 billion people were considered migrants in 2016. Notably, about 65 million of these migrants were forcibly displaced from their homes, and 20 million were considered refugees. While the geopolitical consequences of such migration continue to be considered, less is known about the impact of these events on the respiratory health of migrants and refugees. In recognition of this knowledge gap, the American Thoracic Society and the European Respiratory Society brought together investigators with diverse and relevant expertise to participate in a workshop and develop a consensus on research needs on the respiratory health of migrants and refugees. The workshop focused on environmental and occupational hazards, chronic noninfectious diseases, and respiratory infectious diseases, which were presented by experts in three distinct sessions, each culminating with panel discussions. A writing committee collected summaries prepared by speakers and other participants, and the information was collated into a single document. Recommendations were formulated, and differences were resolved by discussion and consensus. The group identified important areas of research need, while emphasizing that reducing the burden of pulmonary, critical care, and sleep disorders in migrants and refugees will require a concerted effort by all stakeholders. Using best research practices, considering how research impacts policies affecting migrant and refugee populations, and developing new approaches to engage and fund trainees, clinical investigators, and public health practitioners to conduct high-quality research on respiratory health of migrants and refugees is essential.

Patient support for tuberculosis patients in low-incidence countries: A systematic review.

BACKGROUND: Patient support during tuberculosis treatment is expected to be more often available and more customized in low tuberculosis incidence, high-resource settings than in lower-resource settings. The aim of this systematic review is to provide an overview of tuberculosis patient support interventions implemented in low-incidence countries and an evaluation of their effects on treatment-related outcomes as well as their acceptability by patients and providers. METHODS: PubMed, Social Science Citation Index and Cumulative Index to Nursing and Allied Health and Literature were searched for the period 01.2006-05.2016 on publications describing tuberculosis patient support interventions in low-incidence countries (<20 patients per 100,000 population). RESULTS: Through our search strategy, 1875 unique publications were identified. Forty publications were included: 17 evaluated patient support quantitatively, 9 qualitatively and 14 only described the patient support. Nineteen publications assessed treatment supervision options only, 21 assessed (combinations of) treatment supervision, socio-economic, psycho-emotional, health-educational and other support. Of eight studies quantitatively evaluating the effects of support with a control group, four showed positive effects: two out of three that used combinations of patient support and two out of five that compared treatment supervision options. Heterogeneity of interventions precluded pooling of results. Qualitative and descriptive studies showed that patients appreciated individualized support including treatment supervision, psycho-emotional and socio-economic support; and digital health interventions. CONCLUSION: Our review shows that a variety of patient support interventions is implemented in low-incidence countries. Although only a few interventions were evaluated quantitatively, we identified potential best practices. The scarcity of evidence on effectiveness, however, indicates the need for further research to evaluate potential best practices.

Tuberculosis in the European Union and European Economic Area: a survey of national tuberculosis programmes.

How many European Union (EU) and European Economic Area (EEA) countries have national tuberculosis (TB) control plans/strategies, and what are the priority actions/populations and barriers to implementation?In order to answer this question, a survey of EU/EEA national TB programme leads was undertaken.The response rate was 100% (31 countries). 55% of countries reported having a national TB strategy, all of which were in implementation; five countries were preparing a strategy. 74% had a defined organisational TB control structure with central coordination and 19% had a costed programme budget; few organisational structures included patient/civil society representation. The most frequently mentioned priority TB control actions were: reaching vulnerable population groups (80%), screening for active TB in high-risk groups (63%), implementing electronic registries (60%), contact tracing and outbreak investigation (60%), and tackling multidrug-resistant TB (60%). Undocumented migrants were the most commonly (46%) identified priority population. Perceived obstacles to implementation included barriers related to care recipients (lack of TB knowledge, treatment seeking/adherence), care providers (including need for specialist training of nurses and doctors) and health system constraints (funding, communication between healthcare and social care systems).This survey has provided an insight into TB control programmes across the EU/EEA that will inform the development of a TB strategy toolkit for member states.

Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis.

BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Correction: Epidemiological links between tuberculosis cases identified twice as efficiently by whole genome sequencing than conventional molecular typing: A population-based study.

[This corrects the article DOI: 10.1371/journal.pone.0195413.].

Epidemiological links between tuberculosis cases identified twice as efficiently by whole genome sequencing than conventional molecular typing: A population-based study.

BACKGROUND: Patients with Mycobacterium tuberculosis isolates sharing identical DNA fingerprint patterns can be epidemiologically linked. However, municipal health services in the Netherlands are able to confirm an epidemiological link in only around 23% of the patients with isolates clustered by the conventional variable number of tandem repeat (VNTR) genotyping. This research aims to investigate whether whole genome sequencing (WGS) is a more reliable predictor of epidemiological links between tuberculosis patients than VNTR genotyping. METHODS: VNTR genotyping and WGS were performed in parallel on all Mycobacterium tuberculosis complex isolates received at the Netherlands National Institute for Public Health and the Environment in 2016. Isolates were clustered by VNTR when they shared identical 24-loci VNTR patterns; isolates were assigned to a WGS cluster when the pair-wise genetic distance was ≤ 12 single nucleotide polymorphisms (SNPs). Cluster investigation was performed by municipal health services on all isolates clustered by VNTR in 2016. The proportion of epidemiological links identified among patients clustered by either method was calculated. RESULTS: In total, 535 isolates were genotyped, of which 25% (134/535) were clustered by VNTR and 14% (76/535) by WGS; the concordance between both typing methods was 86%. The proportion of epidemiological links among WGS clustered cases (57%) was twice as common than among VNTR clustered cases (31%). CONCLUSION: When WGS was applied, the number of clustered isolates was halved, while all epidemiologically linked cases remained clustered. WGS is therefore a more reliable tool to predict epidemiological links between tuberculosis cases than VNTR genotyping and will allow more efficient transmission tracing, as epidemiological investigations based on false clustering can be avoided.