Randomised controlled trial to evaluate the effectiveness of using the RD-1-based C-Tb skin test as a replacement for blood-based interferon-γ release assay for detection of, and initiation of preventive treatment for, tuberculosis infection: RID-TB:Dx study protocol

IntroductionThe predictive utility for incident tuberculosis (TB) of the purified protein derivative tuberculin skin test and region of difference 1 (RD1)-based interferon-gamma release assays (IGRA) is comparable; and either is recommended to test for latent TB infection (LTBI). Despite associated high costs of IGRA, sites participating in LTBI screening in many high-income settings pragmatically favour IGRA due to its higher specificity and simpler logistics. A new RD1-based skin test, C-Tb, could offer an acceptable and as accurate, cheaper alternative to IGRA. Evaluating the impact of C-Tb on process and patient-related outcomes would provide important information to help guide its use in LTBI testing strategies.Methods and analysisThis is a pragmatic multicentre, open-label, non-inferiority, randomised controlled trial. The trial will assess the initiation of LTBI treatment following a positive result of the randomised test as the primary outcome. Participants will be randomised to receive the C-Tb test (intervention) or IGRA (usual care, control) for initiation of treatment. We will enrol 1530 participants in England aged≥16 years who are eligible for LTBI testing and treatment according to UK guidance. In the C-Tb arm, skin induration will be assessed 2–3 days after intradermal injection and measured in millimetres of induration. Results of IGRA will be obtained in line with standard practice. Behavioural studies will explore people’s experiences, perspectives and preferences of LTBI testing and treatment. Economic analysis will estimate cost-effectiveness of changes to the diagnostic algorithm for LTBI. The protocol was developed with Patient and Public Involvement (PPI), which will continue throughout the trial.Ethics and disseminationEthics approval has been obtained from The NHS Health Research Authority (269485). We will share results of the trial in peer-reviewed journals and conferences.Trial registration numberEudraCT 2019-002592-34; ISRCTN17936038.

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

Background In low tuberculosis (TB) incidence countries, contact investigation (CI) requires not missing contacts with TB infection or disease without unnecessarily evaluating non-infected contacts. Aim We assessed whether updated guidelines for the stone-in-the-pond principle and their promotion improved CI practices. Methods This retrospective study used surveillance data to compare CI outcomes before (2011–2013) and after (2014–2016) the guideline update and promotion. Using negative binomial regression and logistic regression models, we compared the number of contacts invited for CI per index patient, the number of CI scaled-up according to the stone-in-the-pond principle, the TB and latent TB infection (LTBI) testing coverage, and yield. Results Pre and post update, 1,703 and 1,489 index patients were reported, 27,187 and 21,056 contacts were eligible for CI, 86% and 89% were tested for TB, and 0.70% and 0.73% were identified with active TB, respectively. Post update, the number of casual contacts invited per index patient decreased statistically significantly (RR = 0.88; 95% CI: 0.79–0.98), TB testing coverage increased (OR = 1.4; 95% CI: 1.2–1.7), and TB yield increased (OR = 2.0; 95% CI: 1.0–3.9). The total LTBI yield increased from 8.8% to 9.8%, with statistically significant increases for casual (OR = 1.2; 95% CI: 1.0–1.5) and community contacts (OR = 2.0; 95% CI: 1.6–3.2). The proportion of CIs appropriately scaled-up to community contacts increased statistically significantly (RR = 1.8; 95% CI: 1.3–2.6). Conclusion This study shows that promoting evidence-based CI guidelines strengthen the efficiency of CIs without jeopardising effectiveness. These findings support CI is an effective TB elimination intervention.

“If I’ve got latent TB, I would like to get rid of it”: Derivation of the CARD (Constraints, Actions, Risks, and Desires) Framework informed by South African healthcare worker perspectives on latent tuberculosis treatment

Background Healthcare workers (HWs) have at least twice the risk of tuberculosis (TB) compared to the general population. There is growing emphasis on latent TB infection (LTBI) in high-risk populations. Yet we know little about HWs’ perspectives of LTBI testing and treatment to inform implementation in high-incidence settings. We developed a qualitative networked approach to analyze HWs’ perspectives on LTBI testing and treatment. Methods We conducted 22 in-depth interviews with nurse and physician stakeholders, who had been recruited as part of a larger study evaluating TB transmission risk in HWs at Tygerberg Hospital, Cape Town, South Africa. We performed open coding to identify emergent themes and selective coding to identify relevant text citations. We used thematic analysis to inductively derive the CARD (Constraints, Actions, Risks, Desires) framework. Results All HWs desired to avoid developing TB but few felt this was actionable. Despite LTBI knowledge gaps, safety and cost concerns, most HWs reported hypothetical willingness to take LTBI treatment. The CARD framework showed that desire and action related to LTBI testing and treatment was clearly framed by the interactions between constraints, administrative action, and risk. The surprise HWs described on receiving a negative LTBI (Quantiferon-Plus) result suggests LTBI testing may recalibrate HWs’ perceptions regarding the futility of actions to reduce their TB risk. Conclusions LTBI testing and treatment are acceptable to HWs and could counteract the perceived inevitability of occupational TB infection that currently may limit risk reduction action. This should be coupled with administrative leadership and infrastructural support. The CARD analytic framework is a helpful tool for implementation scientists to understand current practices within complex health systems. Application of CARD could facilitate the development of contextually-relevant interventions to address important public health problems such as occupational TB.

Modeling the Impact of Recommendations for Primary Care–Based Screening for Latent Tuberculosis Infection in California

Objective Targeted testing and treatment of persons with latent tuberculosis infection (LTBI) is a critical component of the US tuberculosis (TB) elimination strategy. In January 2016, the California Department of Public Health issued a tool and user guide for TB risk assessment (California tool) and guidance for LTBI testing, and in September 2016, the US Preventive Services Task Force (USPSTF) issued recommendations for LTBI testing in primary care settings. We estimated the epidemiologic effect of adherence to both recommendations in California. Methods We used an individual-based Markov micro-simulation model to estimate the number of cases of TB disease expected through 2026 with baseline LTBI strategies compared with implementation of the USPSTF or California tool guidance. We estimated the risk of LTBI by age and country of origin, the probability of being in a targeted population, and the probability of presenting for primary care based on available data. We assumed 100% adherence to testing guidance but imperfect adherence to treatment. Results Implementation of USPSTF and California tool guidance would result in nearly identical numbers of tests administered and cases of TB disease prevented. Perfect adherence to either recommendation would result in approximately 7000 cases of TB disease averted (40% reduction compared with baseline) by 2026. Almost all of this decline would be driven by a reduction in the number of cases among non–US-born persons. Conclusions By focusing on the non–US-born population, adherence to LTBI testing strategies recommended by the USPSTF and the California tool could substantially reduce the burden of TB disease in California in the next decade.

A Targeted Screening Program for Latent Tuberculosis Infection Among Hematopoietic Cell Transplant Recipients

Background US hematopoietic cell transplantation (HCT) recipients have a low prevalence of latent tuberculosis infection (LTBI), but if latently infected they are at risk for progression to active tuberculosis. At our center, all HCT recipients underwent LTBI testing pretransplant by tuberculin skin testing (TST) until 2013 when we implemented a targeted screening program. Our objective was to assess the utility of our screening program that incorporated a pretransplant LTBI questionnaire to target TST and QuantiFERON TB Gold (QFT) testing. Methods We performed a retrospective cohort study of HCT recipients undergoing first transplant from 2014 to 2016. Patients with positive, indeterminate, and a subset with negative QFT results underwent electronic medical record (EMR) review to assess TST results and risk factors for LTBI. Results Among 1290 eligible recipients, 457 (35%) had at least 1 risk factor for LTBI on the pretransplant questionnaire; nonwhites were more likely to undergo LTBI testing (P < .0001). Overall, 16 of 1290 (1.2%) had at least 1 positive LTBI test. Of those screened by QFT, 14 of 457 (3%) were positive and 52 (11%) were indeterminate. Among those undergoing EMR review, 123 of 267 (46%) had TST records; 4 of 123 (3%) positive by both TST and QFT, and 2 (2%) by TST alone. Two or more risk factors were reported among the majority of LTBI-positive patients (15 of 16 [94%]). All patients with at least 1 positive test for LTBI (n = 16) were evaluated, and 11 of 16 (69%) were recommended to receive treatment. Conclusions Incorporating a pretransplant LTBI questionnaire allowed for an approximate 65% reduction in LTBI testing when compared with universal testing among this low prevalence population.

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.

Evaluating latent tuberculosis testing and treatment programme for new migrants in South East England

Background Tuberculosis (TB) cases in England often originate from high burden TB countries due to ’reactivation’ of the latent TB infection (LTBI), an asymptomatic and non-infectious phase lasting years. 5,137 TB cases were notified in England in 2017, and 71% of these patients were born outside the UK. This mixed-method study evaluated the implementation of the four LTBI testing and treatment programme for new migrants in South East (SE) England. Methods A retrospective database (May 2016-Feb 2018) review was undertaken to identify LTBI cases using multiple data sources; LTBI testing laboratories, LTBI programmes, and the national TB team at Public Health England. In addition, a survey questionnaire was emailed to 51 stakeholders (45% response rate) and five in-depth interviews were conducted with LTBI programme leads/TB nurses to explore the challenges of the programme. Quantitative data were analysed using descriptive summary statistics and qualitative interviews were analysed using thematic content analysis. Results Of the 5931 eligible patients, 40 % (n = 2391) accepted the LTBI test and 13.4% (n = 321) tested positive. 93.1% (n = 299) of the positive patients were referred for treatment and 63.8% (n = 191) of these accepted the treatment. The programme also picked up 18 active TB cases, an unexpected incidental finding. Results from the survey and the interviews identified laboratory arrangements, workforce, and data collection/management as the greatest challenges for the LTBI programme. Patient focused care, cultural understanding, success in testing/treating migrants, and raising awareness amongst professionals/communities were highlighted as achievements of the programme. Conclusions This study found that LTBI programmes in SE England are in line with national expectations and other LTBI programmes in England. The study recognises the achievements and good practice of the LTBI teams in SE England and identifies key barriers to improve the service for the future. Key messages Data collection and management is the biggest challenges of the LTBI programmes in SE England. The LTBI programmes in SE England are in line with national expectations.

1882. Tuberculosis in the Department of Veterans Affairs: Missed Opportunities for Prevention

Background US and global elimination of tuberculosis (TB) is an important goal. Despite decreased incidence, CDC predicts elimination of TB in the US will not occur in the 21st century without improved detection and treatment of latent TB infection (LTBI). We describe the current burden of active TB infection and LTBI testing and treatment among patients within the Department of Veterans Affairs (VA). Methods Using the 2009 CDC case definition for laboratory-confirmed TB, we queried VA data sources from January 2010 to December 2018 for Mycobacterium tuberculosis detected via culture or nucleic acid amplification test (NAAT) from specimens from all body sites. For all TB patients, we extracted demographic, ICD-9 and ICD-10 risk factor, and LTBI testing and treatment data. Results Between 2010 and 2018, the average annual incidence of TB was 1.7 cases per 100,000 unique users of VA care (ranging from a high of 2.8 in 2010 to low of 0.8 in 2018). For 899 identified cases, demographic factors associated with highest TB rates were age between 45 and 64, Asian race, and residence in District of Columbia (Table 1). The most frequently occurring risk factors were substance abuse, diabetes, and homelessness. Of 90 patients with susceptibility documentation, 14 (15%) had resistance to 1 or more anti-TB drug (1 with multi-drug-resistant TB). Fifteen patients (1.7%) died within 7 days of their TB diagnosis; in all but 2 cases, TB was the primary cause of death (Table 2). Figure 1 depicts screening and treatment for LTBI among patients with TB. Only 228/899 (25.4%) TB patients had LTBI screening ≥ 3 months prior to diagnosis. Of the 347 TB patients never screened for LTBI, 264 (76%) had ≥ 1 documented TB risk factor. Among 228 patients screened for LTBI >3 months prior to active disease, 69 (30%) screened positive; however, only 24 (35%) had LTBI treatment initiated. Conclusion Although rates of TB infection are decreasing, VHA providers would benefit from education on recognizing patients with risk factors which place them at high risk for TB who should be screened for LTBI. CDC recommends preventive treatment of patients who screen positive for LTBI, and provider collaboration with local public health departments to provide directly observed therapy in cases where adherence may be in question. Disclosures All Authors: No reported Disclosures.

Estimates of Testing for Latent Tuberculosis Infection and Cost, United States, 2013

Objectives: Tracking trends in the testing of latent tuberculosis infection (LTBI) can help measure tuberculosis elimination efforts in the United States. The objectives of this study were to estimate (1) the annual number of persons tested for LTBI and the number of LTBI tests conducted, by type of test and by public, private, and military sectors, and (2) the cost of LTBI testing in the United States. Methods: We searched the biomedical literature for published data on private-sector and military LTBI testing in 2013, and we used back-calculation to estimate public-sector LTBI testing. To estimate costs, we applied Medicare-allowable reimbursements in 2013 by test type. Results: We estimated an average (low-high) 13.3 million (11.3-15.4 million) persons tested for LTBI and 15.3 million (12.9-17.7 million) LTBI tests, of which 13.2 million (11.1-15.3 million) were tuberculin skin tests and 2.1 million (1.8-2.4 million) were interferon-γ release assays (IGRAs). Eighty percent of persons tested were in the public sector, 18% were in the private sector, and 2% were in the military. Costs of LTBI tests and of chest radiography totaled $314 million (range, $256 million to $403 million). Conclusions: To achieve tuberculosis elimination, millions more persons will need to be tested in all sectors. By targeting testing to only those at high risk of tuberculosis and by using more specific IGRA tests, the incidence of tuberculosis in the United States can be reduced and resources can be more efficiently used.