The effectiveness and cost-effectiveness of screening for latent tuberculosis among migrants in the EU/EEA A systematic review

LTBI among migrants will be critical to achieve TB elimination. Methods: We conducted a systematic review to determine effectiveness (performance of diagnostic tests, efficacy of treatment, uptake and completion of screening and treatment) and a second systematic review on cost-effectiveness of LTBI screening programmes for migrants living in the EU/ EEA. Results: We identified seven systematic reviews and 16 individual studies that addressed our aims.


Introduction
Tuberculosis (TB) control programmes in the European Union/European Economic area (EU/EEA) have successfully managed to reduce TB rates by 50% over the past 20 years [1][2][3][4].Although EU/EEA countries are committed to the ambitious World Health Organisation (WHO) goal of TB elimination, the rate of TB decline of 4.3% per year over the past decade (2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016) in the region is insufficient to achieve this goal [1][2][3][4][5].It is projected that a mean decline of 18% per year will be necessary to meet the WHO goal and that TB control strategies must be scaled up, including addressing the burden of latent TB infection (LTBI) [3,5,6].The foreign-born population makes up an increasing and considerable number and proportion of all TB cases in EU/EEA countries with a low TB incidence (< 10 cases/100,000 population) [7].The majority of these cases are due to reactivation of LTBI acquired in the patients' countries of origin.Although foreign-born people make up 11.4% of the population in the EU/EEA, they represented more than one quarter of reported TB cases in 2015 [4,8,9].This burden is even greater in EU/ EEA countries with low TB incidence where often more than half of all reported TB cases occur in migrants [4].This is because a considerable proportion of migrants were born in high TB burden countries where 26-46% of the population are latently infected with TB [4,[10][11][12][13].The WHO has only conditionally recommended LTBI screening among migrants living in low TB burden countries (< 100 cases/100,000 population) owing to reservations about implementation and the low quality of evidence of the effectiveness and cost-effectiveness of LTBI programmes in these settings [6].Screening the potentially large pool of latently infected migrants and treating those found to be positive poses an enormous challenge in the EU/EEA, especially since less than half of these countries have such programmes [11,14,15].The aim of this study was to conduct a systematic review on the effectiveness and cost-effectiveness of screening for latent TB among migrants to the EU/EEA to inform migrant screening guidelines.

Overall approach and key questions
This review supports a project of the European Centre for Disease Prevention and Control (ECDC) to develop guidance on screening for six infectious diseases (chronic hepatitis C, hepatitis B, HIV, TB (active and latent), and intestinal parasites) in newly arrived migrants to the EU/EEA.The project followed the new Grading of Recommendations Assessment, Development and Evaluation (GRADE)-ADOLOPMENT approach to conduct systematic reviews on screening migrant populations for these six infectious diseases [16].The review protocol and the methods of ADOLOPMENT guideline development have been published [16,17].All reviews followed a Cochrane methodological approach and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methods for reporting systematic reviews [18].For this review, we developed research questions (PICO), an analytic framework to illustrate the screening evidence pathway, and identified and prioritised clinicallyimportant outcomes [19].These evidence-based review methods were first described by the United States (US) Preventative Task Force [19,20].We sought to answer two research questions: (i) what is the effectiveness of screening migrants arriving or living in the EU/EEA for LTBI and (ii) what is the resource use, costs and cost-effectiveness of screening migrants for LTBI?To address these questions, we developed an analytic framework (Figure 1) and the following key questions along the LTBI screening evidence pathway: (i) what are the test properties of LTBI screening tests: tuberculin skin test (TST), interferon gamma release assay (IGRA) or sequential TST/IGRA, (ii) what are the efficacy and harms of LTBI therapies, (iii) what is the uptake of screening and treatment and completion of treatment, and (iv) what is the cost-effectiveness of LTBI screening and treatment for migrants [17].

Search strategy and selection criteria
Following the GRADE-ADOLOPMENT process, we identified an evidence review that assessed the effectiveness of latent TB infection (LTBI) screening among migrants, published in 2011 by the Canadian Collaboration on Immigrant and Refugee Health (CCIRH), and used this as a starting point for our literature search (anchoring review) [16,21].The CCIRH review included systematic reviews on the effectiveness of LTBI screening in migrants up to 2008 but did not review cost-effectiveness.We therefore conducted two separate searches to address our research questions.The first search updated the CCIRH evidence review and identified systematic reviews and guidelines on the effectiveness and cost-effectiveness of TB screening programmes in migrant populations from 2005 to 2016.The second search identified individual studies on the resource use, costs and cost-effectiveness of TB screening programmes for migrants over a longer time, 2000 to 2016, given these topics were not covered in the CCIRH evidence review.For the first search, MEDLINE via Ovid, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL),    TST in BCG-vaccinated: specificity: 59% .

Study selection and quality assessment
We identified and included systematic reviews and evidence-based guidelines that directly addressed each key question along the LTBI screening evidence chain (Figure 1) and prioritised those focusing on newly arrived (< 5 years in the host country) migrants.Migrant populations included non-forced economic migrants, refugees and asylum seekers, and illegal migrants who may have been forced to flee conflict, natural disaster, or economic peril [17].We only included studies published in full and in English or French.If more than one version of a systematic review was identified, the most recent was considered.Studies were excluded if there were not relevant to the key questions, if they were not a systematic review or guideline, if the study methodology was unclear, and if they focussed only on non-generalisable subgroups (such as healthcare workers or HIV-positive people) or addressed only active TB screening.Two authors screened the titles and abstracts, assessed selected full-text articles for eligibility and extracted data from included articles.Disagreements were resolved by consensus or by a third author.The methodological quality of systematic reviews was assessed using the AMSTAR tool (A Measurement Tool To Assess Systematic Reviews) and the quality of individual studies was assessed with the Newcastle-Ottawa scale [22,23].The GRADE criteria were applied to assess the quality and certainty of the evidence of the individual studies included in the systematic reviews [24].

Data extraction and synthesis
The following information was extracted from each study; study design, objectives, analyses, quality of the individual studies included in the systematic review, population examined, number of included studies, total number of participants included, intervention, outcome and results.We created GRADE evidence profiles and summary of findings tables for each outcome where appropriate.
For each of the cost-effectiveness studies we extracted the following data: economic methods used (e.g.microcosting study, within-trial cost-utility analysis, Markov model), description of the case base population, the intervention and the comparator, absolute size and relative difference in resource use, and cost-effectiveness results (e.g.incremental net benefits (INB) or incremental cost-effectiveness ratio (ICER)) [25].The certainty of economic evidence in each study was assessed using the relevant items from the 1997 Drummond checklist [26].All currencies were converted to 2015 Euros using the Cochrane web-based currency conversion tool: https://eppi.ioe.ac.uk/costconversion/default.aspx.

Search results
In the first search on the effectiveness and cost-effectiveness of TB screening programmes in migrants, we retrieved 3,375 studies and identified 22 [28].

Table 1c
Characteristics of included studies for the effectiveness of latent tuberculosis screening, 2005-2016

Table 2a
Characteristics of included studies for the resource use, costs and cost-effectiveness of latent tuberculosis screening, 2000-2016        The Drummond Criteria include [26]: (i) Was a well-defined question posed in answerable form?(ii) Was a comprehensive description of the competing alternatives given (i.e. can you tell who did what to whom, where, and how often)?(iii) Was the effectiveness of the programme or services established?(iv) Were all the important and relevant costs and consequences for each alternative identified?(v) Were costs and consequences measured accurately in appropriate physical units (e.g.hours of nursing time, number of physician visits, lost working days, gained life years)?(vi) Were the cost and consequences valued credibly?(vii) Were costs and consequences adjusted for differential timing?(viii) Was an incremental analysis of costs and consequences of alternatives performed?(ix) Was allowance made for uncertainty in the estimates of costs and consequences?(x) Did the presentation and discussion of study results include all issues of concern to users? ).

Table 2i
Characteristics of included studies for the resource use, costs and cost-effectiveness of latent tuberculosis screening, 2000-2016 latent TB screening in migrant populations (Figure 2).After removal of duplicates, 2,884 studies were screened by title and abstract.A total of 127 studies were selected for full text assessment.We did not identify any single study on the effectiveness of LTBI screening in migrants or the general population.We therefore included seven systematic reviews that addressed the LTBI screening chain of evidence; the test properties of LTBI screening tests (n = 3) [20,27,28], the efficacy and harms of LTBI therapies (n = 2) [29,30], and the LTBI care cascade including uptake of screening and treatment initiation and completion (n = 2) [31,32].In the economic search 2,869 articles were identified.After duplicate removal 2,740 articles were screened by title and abstract (Figure 3).A total of 37 studies underwent full text assessment and 16 individual studies were included [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48].

Performance of diagnostic tests for latent tuberculosis infection
Three systematic reviews assessed the properties of the diagnostic tests used in LTBI screening (Table 1).The systematic reviews by Pai et al. and Kahwati et al. evaluated the performance of TST and IGRA in populations not vaccinated with bacillus Calmette-Guérin (BCG) and found that the TST, at a 10 mm cut-off, and IGRA had similar and good sensitivity (79%) and high specificity (> 97%) to detect LTBI [20,27].In addition, Pai et al. showed that the TST was limited by lower specificity (59%) in BCG-vaccinated populations [27].
The third systematic review by Kik et al. estimated the ability of TST or IGRA to predict the risk of developing active TB among those with LTBI [28].We included and present the data from eight of the 29 studies in the Kik review as they were the only ones that performed both TST and IGRA in the same study subjects and compared the results to those with a negative test [28].

Efficacy and harms of therapy for latent tuberculosis infection
Two systematic reviews examined the efficacy and associated harms of latent TB therapies to prevent the development of active TB [29,30]

Latent tuberculosis infection care cascade: screening uptake and completion of therapy
Two systematic reviews reported on the LTBI care cascade including the uptake of screening and treatment as well as initiation and completion of therapy [31,32].

Resource use, cost and cost-effectiveness of screening for latent tuberculosis infection
The cost-effectiveness analysis of studies summarised in our review focused primarily on comparisons between LTBI screening strategies (e.g.TST, IGRA or sequential TST/IGRA), comparisons with other screening techniques such as chest radiography (CXR) for active TB, a combination of CXR/TST, or no screening, among different risk groups (Table 2).The strategies compared were heterogeneous across most studies.Eleven of the 16 included studies addressed an LTBI screening strategy and included a migrant group; however, only three studies were specifically about migrants in EU/EEA countries [35,40,48].The costeffectiveness of screening strategies was dependant on test characteristics, which tests were being compared, the cost of tests and whether or not the population was BCG-vaccinated.
Four studies reported that screening with a singlestep IGRA was less costly or more cost-effective relative to TST screening in migrants to prevent incident TB [33,35,36,48].In one study in the US by  [35,48].
Other studies investigated the optimal LTBI testing strategy in different high-risk populations such as contacts of active cases or migrants from TB-endemic countries [38,39,41].Sequential TST/IGRA testing was preferred over single TST or IGRA, especially in those who had a high likelihood of a true positive TST (LTBI prevalence > 5%) and were BCG-vaccinated after infancy [39,41].Oxlade et al. found that sequential TST-IGRA screening was cost-effective compared with singlestep IGRA screening.That study suggested that it was most cost-effective to use an IGRA to screen TSTpositive cases, and that IGRA screening was favoured only among those who had received BCG vaccination after infancy [41].In a French study by Deuffic-Burban, sequential TST-IGRA screening was a more cost-effective strategy for BCG-vaccinated close contacts of active TB patients than IGRA alone [39].For TST-IGRA compared with no testing, the ICER was EUR 560 (EUR 581, as per 2015) per year of life gained (YLG), and for IGRA compared with TST-IGRA, the ICER was EUR 730 (EUR 757) per YLG in the scenario when LTBI prevalence was more than 5%.This was robust across a wide range of LTBI prevalence.In the study by Pooran et al., sequential TST-IGRA testing was more cost-effective compared with no screening or single-step TST, with an incremental cost per active case prevented of GBP 37,699 (EUR 48,020) to GBP 37,206 (EUR 47,392) among contacts of active TB [38].

Discussion
There were no single studies that directly addressed the effectiveness of latent TB screening programmes on the health outcomes of migrants.Therefore, we evaluated the LTBI screening chain of evidence.The majority of TB cases in low TB incidence countries in the EU/ EEA occur in migrants born in countries with higher TB incidence and occur primarily due to reactivation of latent infection.The tools to detect and treat LTBI, however, have many limitations.IGRA and TST have high sensitivity to detect LTBI but they both predicted the development of active TB poorly [20,27,28].All latent TB therapies were equivalent but their effectiveness in preventing the development of active TB was only low to moderate [29,30].RIF regimens may be preferable because they have considerably lower hepatotoxicity and higher treatment completion rates than INH [30].The LTBI care cascade is weak as only a minority of patients (both general population and migrants) eligible for LTBI screening actually complete LTBI treatment [31].Limited economic analyses of LTBI screening among migrants suggest that targeted screening for young migrants from high TB incidence countries (> 150/100,000) is the most cost-effective strategy [35].
The WHO End TB Strategy, with a goal to eliminate TB by 2050, highlights the need to decrease the substantial reservoir of individuals with latent TB infection at risk of progression to active TB [49,50].A substantial proportion of migrants were born in high TB burden countries and many have latent TB infection (26-46%) [4,13].A major challenge is identifying those at highest risk for progression to active disease so that targeted programmes can be developed that will promote the health of migrants and have the highest public health impact.
Ca 5-15% of individuals with latent infection will develop active TB during their lifetime [51,52].The groups at highest risk of progression to active TB disease are those with immunosuppressive conditions (i.e.HIV infection, immunosuppressive therapies with anti-tumour necrosis factor treatment, organ transplantation or dialysis) and those infected recently [6].The risk of disease progression is greatest close to the time of infection, with almost half of disease progression cases occurring within the first 2-3 years after exposure [53].Migrants arriving from endemic areas have the highest rates of active TB soon after arrival in host countries, which is probably due to recent exposure in their countries of origin.Fifty per cent of cases, however, occur 5 or more years after arrival and the risk remains elevated throughout their lifetime [54][55][56][57].
Being an asylum seeker or refugee, TB exposure during crowded conditions or perilous journeys to host countries, or recent travel back to TB-endemic countries of origin may also increase the risk of active TB in the migrant population [58][59][60].The complex epidemiology of TB among migrants needs to be taken into consideration when developing LTBI programmes for this population to ensure the highest individual and public health benefit.The lack of robust populationbased data is, however, a major obstacle in developing targeted LTBI programmes for migrants.Estimates on the individual, combined and attributable population contribution of each of these risk factors to developing TB among migrants will be required.There are also few studies on cost-effectiveness to inform latent TB programmes concerning migrants.Only two studies conducted in the UK specifically addressed which migrant groups should be targeted for LTBI screening and treatment [35,48].These results however, may not be generalisable to all EU/EEA countries as willingness to pay thresholds, per capita health care expenditures, and health priorities vary between countries.
In addition to these data gaps, the tools to diagnose and treat latent TB have limitations.The LTBI care cascade is weak, lowering the effectiveness and impact of screening programmes.Both TST and IGRA poorly predict the small proportion (< 15%) of those infected with TB who will progress to active disease.As a consequence, a large number of people need to be screened and treated to prevent one case of active TB [6].Operational issues related to TST and IGRA may decrease screening uptake: The TST requires a second visit 48-72 h after the first visit to read the skin test induration (test result) and IGRA testing is generally costlier than TST and may not be as widely available in EU/EEA countries [61].Patients with latent TB are asymptomatic and thus long treatment regimens ranging from 3 to 9 months lead to poor treatment completion [32].The latent TB care cascade involves several steps including identifying patients in need of screening, offering screening and treatment by providers, and uptake and completion of screening and treatment by patients.This process requires the understanding and engagement of patients and providers.The low proportion of those eligible for screening who complete LTBI treatment is a result of losses at every point of the care cascade because of barriers at patient, provider and structural level [31].
Migrants encounter several barriers in accessing healthcare and consequently, treatment initiation (23-97%) and completion rates (7-86%) are variable [21,32,62,63].In addition, practitioners may lack adequate knowledge of which migrants should be screened and treated [21,64].Addressing barriers at both the patient and provider level will therefore be required to strengthen the LTBI care cascade and to ensure individual and public health benefits of LTBI programmes.With the adoption of the WHO End TB Strategy there is recognition of the importance of scaling up preventive therapy.Less than half of EU/EEA countries, however, have LTBI programmes for migrants and there are numerous challenges to developing and implementing new programmes [11,14,15].These include the heterogeneity of populations and migrant subgroups affected by TB in individual EU/EAA countries as well as economic and operational considerations.LTBI screening programmes will therefore need to be tailored to the local TB epidemiology in host countries, the TB risk in migrant sub-groups, and implementation based on the health priorities and economic and healthcare capacity in each setting [2,3].

Study limitations
Our study was limited by the fact that we did not retrieve any studies that directly estimated the effectiveness of LTBI screening programmes among migrants or the general population.There are limited data on the costeffectiveness of LTBI screening in these populations.
The search was limited by the fact that it was conducted only up until May 2016 and that we only included studies published in English or French.A recent narrative review of the effectiveness and cost-effectiveness, however, found similar literature and findings as our study [65].Our findings are further limited by the low or very low quality of most of the original studies that were included in the systematic reviews.

Evidence gaps and future directions
Better evidence is urgently needed on the individual, combined and attributable population contribution of risk factors leading to progression from LTBI to active TB in migrants.Intervention studies that determine how to improve the identification of target populations and retain them in care along with cost-effectiveness studies that use this intervention and the epidemiological data will be needed to develop programmes with the highest impact.Ultimately, better diagnostic tests that accurately predict those individuals who will develop active TB as well as shorter, well-tolerated and more effective treatment to promote adherence, will be needed to achieve TB elimination.

Conclusions
The latent TB burden among migrants needs to be addressed in order to promote the health of this population and to achieve TB elimination in the EU/EEA.At present, broad implementation of LTBI screening and treatment programmes is hindered by the large pool of migrants with LTBI (a small proportion of whom will develop active TB), diagnostic tests that poorly predict which individuals will develop active TB, long LTBI treatment regimens, as well as several patient, provider and institutional barriers that lead to poor uptake of screening and treatment completion.Despite these limitations, migrant-focused latent TB screening programmes may be effective and cost-effective if they are highly targeted and well implemented.
developing the methods.DZ, MP, MvW and AM provided substantial content on the research question and design.CG, IM, BA and MW wrote the manuscript.CNAC, MW, BS, TM and CH reviewed and selected the literature, and extracted and synthesised the data.RM, AT and NR conducted the review and synthesised the data for cost-effectiveness analysis.All authors read and approved the manuscript.

Figure 1
Figure 1Analytic framework for latent tuberculosis screening in migrants

Figure 2
Figure 2 PRISMA flow diagram, literature search for the effectiveness and cost-effectiveness of latent tuberculosis screening, 1 January 2005-12 May 2016

Figure 3
Figure 3 PRISMA flow diagram, literature search for the resource use, costs and cost-effectiveness of latent tuberculosis, 1 January 2000-31 May 2016

Table 1a
Characteristics of included studies for the effectiveness of latent tuberculosis screening, 2005-2016

Table 2b
Characteristics of included studies for the resource use, costs and cost-effectiveness of latent tuberculosis screening, 2000-2016 BCG: Bacillus Calmette-Guérin; CAD: Canadian dollar; CEA: cost effective analysis; CXR: chest radiography; ELISpot: Enzyme-Linked ImmunoSpot; GBP: British pound; EUR: Euro; HIV: human immunodeficiency virus; ICER: incremental cost-effectiveness ratio; IGRA: Interferon Gamma Release Assay; INB: incremental net benefit; INH: isoniazid; LTBI: latent tuberculosis infection; NHS: National Health Service; NICE: The National Institute for Health and Care Excellence; PSA: probabilistic sensitivity analysis; PZA: pyrazinamide; QALY: quality-adjusted life years; Gold In-Tube; QFT: QuantiFERON; QFT-GIT: QuantiFERON-TB, Gold In-Tube; RIF: rifampicin; RMP: rifampicin; SC; South Carolina; TB: tuberculosis; TST: tuberculin skin test; T-SPOT.TB: ELISPOT assay for tuberculosis; UK: United Kingdom; US: United States; USD: US dollar; YLG: years of life gained.The Drummond Criteria include [26]: (i) Was a well-defined question posed in answerable form?(ii) Was a comprehensive description of the competing alternatives given (i.e. can you tell who did what to whom, where, and how often)?(iii) Was the effectiveness of the programme or services established?(iv) Were all the important and relevant costs and consequences for each alternative identified?(v) Were costs and consequences measured accurately in appropriate physical units (e.g.hours of nursing time, number of physician visits, lost working days, gained life years)?(vi) Were the cost and consequences valued credibly?(vii) Were costs and consequences adjusted for differential timing?(viii) Was an incremental analysis of costs and consequences of alternatives performed?(ix) Was allowance made for uncertainty in the estimates of costs and consequences?(x) Did the presentation and discussion of study results include all issues of concern to users?All currencies were converted to 2015 Euros using the Cochrane web-based currency conversion tool: https://eppi.ioe.ac.uk/costconversion/default.aspx.Resource use was expressed in cost per person and classified as low (savings or ≤ USD 1,000/person or EUR 808), moderate (USD 1,000-100,000/person or EUR 808-80,845) or high (USD ≥ 100,000/person or EUR > 80,845).

Table 2c
Characteristics of included studies for the resource use, costs and cost-effectiveness of latent tuberculosis screening, 2000-2016 Was a comprehensive description of the competing alternatives given (i.e. can you tell who did what to whom, where, and how often)?(iii)Was the effectiveness of the programme or services established?(iv)Were all the important and relevant costs and consequences for each alternative identified?(v)Were costs and consequences measured accurately in appropriate physical units (e.g.hours of nursing time, number of physician visits, lost working days, gained life years)?(vi)Were the cost and consequences valued credibly?(vii)Were costs and consequences adjusted for differential timing?(viii)Was an incremental analysis of costs and consequences of alternatives performed?(ix)Was allowance made for uncertainty in the estimates of costs and consequences?(x)Did the presentation and discussion of study results include all issues of concern to users?All currencies were converted to 2015 Euros using the Cochrane web-based currency conversion tool: https://eppi.ioe.ac.uk/costconversion/default.aspx.Resource use was expressed in cost per person and classified as low (savings or ≤ USD 1,000/person or EUR 808), moderate (USD 1,000-100,000/person or EUR 808-80,845) or high (USD ≥ 100,000/person or EUR > 80,845).

Table 2d
Characteristics of included studies for the resource use, costs and cost-effectiveness of latent tuberculosis screening, 2000-2016 : Bacillus Calmette-Guérin; CAD: Canadian dollar; CEA: cost effective analysis; CXR: chest radiography; ELISpot: Enzyme-Linked ImmunoSpot; GBP: British pound; EUR: Euro; HIV: human immunodeficiency virus; ICER: incremental cost-effectiveness ratio; IGRA: Interferon Gamma Release Assay; INB: incremental net benefit; INH: isoniazid; LTBI: latent tuberculosis infection; NHS: National Health Service; NICE: The National Institute for Health and Care Was a comprehensive description of the competing alternatives given (i.e. can you tell who did what to whom, where, and how often)?(iii)Was the effectiveness of the programme or services established?(iv)Were all the important and relevant costs and consequences for each alternative identified?(v)Were costs and consequences measured accurately in appropriate physical units (e.g.hours of nursing time, number of physician visits, lost working days, gained life years)?(vi)Were the cost and consequences valued credibly?(vii)Were costs and consequences adjusted for differential timing?(viii)Was an incremental analysis of costs and consequences of alternatives performed?(ix)Was allowance made for uncertainty in the estimates of costs and consequences?(x)Did the presentation and discussion of study results include all issues of concern to users?All currencies were converted to 2015 Euros using the Cochrane web-based currency conversion tool: https://eppi.ioe.ac.uk/costconversion/default.aspx.Resource use was expressed in cost per person and classified as low (savings or ≤ USD 1,000/person or EUR 808), moderate (USD 1,000-100,000/person or EUR 808-80,845) or high (USD ≥ 100,000/person or EUR > 80,845).

Table 2e
Characteristics of included studies for the resource use, costs and cost-effectiveness of latent tuberculosis screening, 2000-2016 BCG: Bacillus Calmette-Guérin; CAD: Canadian dollar; CEA: cost effective analysis; CXR: chest radiography; ELISpot: Enzyme-Linked ImmunoSpot; GBP: British pound; EUR: Euro; HIV: human immunodeficiency virus; ICER: incremental cost-effectiveness ratio; IGRA: Interferon Gamma Release Assay; INB: incremental net benefit; INH: isoniazid; LTBI: latent tuberculosis infection; NHS: National Health Service; NICE: The National Institute for Health and Care Excellence; PSA: probabilistic sensitivity analysis; PZA: pyrazinamide; QALY: quality-adjusted life years; Gold In-Tube; QFT: QuantiFERON; QFT-GIT: QuantiFERON-TB, Gold In-Tube; RIF: rifampicin; RMP: rifampicin; SC; South Carolina; TB: tuberculosis; TST: tuberculin skin test; T-SPOT.TB: ELISPOT assay for tuberculosis; UK: United Kingdom; US: United States; USD: US dollar; YLG: years of life gained.The Drummond Criteria include [26]: (i) Was a well-defined question posed in answerable form?(ii) Was a comprehensive description of the competing alternatives given (i.e. can you tell who did what to whom, where, and how often)?(iii) Was the effectiveness of the programme or services established?(iv) Were all the important and relevant costs and consequences for each alternative identified?(v) Were costs and consequences measured accurately in appropriate physical units (e.g.hours of nursing time, number of physician visits, lost working days, gained life years)?(vi) Were the cost and consequences valued credibly?(vii) Were costs and consequences adjusted for differential timing?(viii) Was an incremental analysis of costs and consequences of alternatives performed?(ix) Was allowance made for uncertainty in the estimates of costs and consequences?(x) Did the presentation and discussion of study results include all issues of concern to users?All currencies were converted to 2015 Euros using the Cochrane web-based currency conversion tool: https://eppi.ioe.ac.uk/costconversion/default.aspx.Resource use was expressed in cost per person and classified as low (savings or ≤ USD 1,000/person or EUR 808), moderate (USD 1,000-100,000/person or EUR 808-80,845) or high (USD ≥ 100,000/person or EUR > 80,845).

Table 2f
Characteristics of included studies for the resource use, costs and cost-effectiveness of latent tuberculosis screening, 2000-2016 Bacillus Calmette-Guérin; CAD: Canadian dollar; CEA: cost effective analysis; CXR: chest radiography; ELISpot: Enzyme-Linked ImmunoSpot; GBP: British pound; EUR: Euro; HIV: human immunodeficiency virus; ICER: incremental Was a comprehensive description of the competing alternatives given (i.e. can you tell who did what to whom, where, and how often)?(iii)Was the effectiveness of the programme or services established?(iv)Were all the important and relevant costs and consequences for each alternative identified?(v)Were costs and consequences measured accurately in appropriate physical units (e.g.hours of nursing time, number of physician visits, lost working days, gained life years)?(vi)Were the cost and consequences valued credibly?(vii)Were costs and consequences adjusted for differential timing?(viii)Was an incremental analysis of costs and consequences of alternatives performed?(ix)Was allowance made for uncertainty in the estimates of costs and consequences?(x)Did the presentation and discussion of study results include all issues of concern to users?All currencies were converted to 2015 Euros using the Cochrane web-based currency conversion tool: https://eppi.ioe.ac.uk/costconversion/default.aspx.Resource use was expressed in cost per person and classified as low (savings or ≤ USD 1,000/person or EUR 808), moderate (USD 1,000-100,000/person or EUR 808-80,845) or high (USD ≥ 100,000/person or EUR > 80,845).

Table 2g
Characteristics of included studies for the resource use, costs and cost-effectiveness of latent tuberculosis screening, 2000-2016 Was a comprehensive description of the competing alternatives given (i.e. can you tell who did what to whom, where, and how often)?(iii)Was the effectiveness of the programme or services established?(iv)Were all the important and relevant costs and consequences for each alternative identified?(v)Were costs and consequences measured accurately in appropriate physical units (e.g.hours of nursing time, number of physician visits, lost working days, gained life years)?(vi)Were the cost and consequences valued credibly?(vii)Were costs and consequences adjusted for differential timing?(viii)Was an incremental analysis of costs and consequences of alternatives performed?(ix)Was allowance made for uncertainty in the estimates of costs and consequences?(x)Did the presentation and discussion of study results include all issues of concern to users?All currencies were converted to 2015 Euros using the Cochrane web-based currency conversion tool: https://eppi.ioe.ac.uk/costconversion/default.aspx.Resource use was expressed in cost per person and classified as low (savings or ≤ USD 1,000/person or EUR 808), moderate (USD 1,000-100,000/person or EUR 808-80,845) or high (USD ≥ 100,000/person or EUR > 80,845).
[26]ish pound; EUR: Euro; HIV: human immunodeficiency virus; ICER: incremental cost-effectiveness ratio; IGRA: Interferon Gamma Release Assay; INB: incremental net benefit; INH: isoniazid; LTBI: latent tuberculosis infection; NHS: National Health Service; NICE: The National Institute for Health and Care Excellence; PSA: probabilistic sensitivity analysis; PZA: pyrazinamide; QALY: quality-adjusted life years; Gold In-Tube; QFT: QuantiFERON; QFT-GIT: QuantiFERON-TB, Gold In-Tube; RIF: rifampicin; RMP: rifampicin; SC; South Carolina; TB: tuberculosis; TST: tuberculin skin test; T-SPOT.TB: ELISPOT assay for tuberculosis; UK: United Kingdom; US: United States; USD: US dollar; YLG: years of life gained.The Drummond Criteria include[26]: (i) Was a well-defined question posed in answerable form?(ii)Was a comprehensive description of the competing alternatives given (i.e. can you tell who did what to whom, where, and how often)?(iii)Was the effectiveness of the programme or services established?(iv)Were all the important and relevant costs and consequences for each alternative identified?(v)Were costs and consequences measured accurately in appropriate physical units (e.g.hours of nursing time, number of physician visits, lost working days, gained life years)?(vi)Were the cost and consequences valued credibly?(vii)Were costs and consequences adjusted for differential timing?(viii)Was an incremental analysis of costs and consequences of alternatives performed?(ix)Was allowance made for uncertainty in the estimates of costs and consequences?(x)Did the presentation and discussion of study results include all issues of concern to users?All currencies were converted to 2015 Euros using the Cochrane web-based currency conversion tool: https://eppi.ioe.ac.uk/costconversion/default.aspx.Resource use was expressed in cost per person and classified as low (savings or ≤ USD 1,000/person or EUR 808), moderate (USD 1,000-100,000/person or EUR 808-80,845) or high (USD ≥ 100,000/person or EUR > 80,845).