Engaging with civil society to improve access to LTBI screening for new migrants in England: a qualitative study.

The latent tuberculous infection (LTBI) programme in England, UK, offers testing and treatment to new migrants from high tuberculosis incidence countries. However, the rates of LTBI testing, treatment acceptance and completion are suboptimal and appropriate access should be improved. To gain insight from the community, community-based organisations (CBOs) and public sector stakeholders on interventions that facilitate collaboration to improve health care outreach and delivery. Three stakeholder meetings and five focus group discussions were held using thematic analysis to identify themes arising from participants' perspectives. Four overarching themes emerged from the discussions. These were related to capacity of service providers, collaboration between stakeholders, migrant cultures and trust between migrants and service providers, and highlighted the complementary skill sets that different sectors bring to the collaboration, as well as the barriers that need to be surmounted. Stigma could be reduced by making LTBI testing routine. Community members could act as champions of health promotion to raise awareness on LTBI testing, and provide a bridge between communities and primary care services. Public service providers, community members and CBOs are willing to collaborate to support primary care delivery of testing for LTBI and other communicable and non-communicable diseases. Policy and commissioning support are needed to facilitate this collaboration. .

Discordance in latent tuberculosis (TB) test results in patients with end-stage renal disease.

OBJECTIVES: This natural experiment was designed to assess the impact of exposure to an active case of tuberculosis (TB) on a group of immunosuppressed individuals, with end-stage renal disease over an extended follow-up. STUDY DESIGN: Close contacts of people with sputum smear-positive Mycobacterium tuberculosis are at high risk of infection, particularly immunosuppressed individuals. An infectious TB healthcare worker worked in a renal dialysis unit for a month before diagnosis, with 104 renal dialysis patients, was exposed for ≥8 h. METHODS: Patients were informed and invited for screening 8-10 weeks postexposure. They either underwent standard two-step assessment with tuberculin skin test (TST) and QuantiFERON®-TB Gold (Cellestis GmbH; QFN) interferon-gamma release assay (IGRA) or after consent, enrolled in a study where these two tests were performed simultaneously with T-SPOT®-TB (Oxford Immunotec Ltd; TSPOT). Patients within the study were followed up for 2 years from exposure, with QFN and TSPOT repeated at months 3 and 6 from the first testing. RESULTS: Of 104 exposed individuals, 75 enrolled in the study. There was a high degree of discordance among QFN, TSPOT and TST. This was seen at both the first time point and also over time in subjects who were retested. No patients had active TB at the baseline testing. None received treatment for latent TB infection. Over the following 2 years, no one developed TB disease. CONCLUSION: This study suggests that there is a low risk of progression to active TB in low-incidence countries even in high-risk groups. This plus the degree of the test result discordance emphasises the complexities of managing TB in such settings as it is unclear which of these tests, if any, provides the best diagnostic accuracy.

Novel interferon-gamma assays for diagnosing tuberculosis in young children in India.

SETTING: The tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) are used as supportive evidence to diagnose active tuberculosis (TB). Novel IGRAs could improve diagnosis, but data are lacking in young children. DESIGN: Children (age 5 years) with suspected TB were prospectively screened at a tertiary hospital in Pune, India; the children underwent TST, and standard (early secretory antigenic target 6 and culture filtrate protein 10) and enhanced (five additional novel antigens) enzyme-linked immunospot (ELISpot) assays. RESULTS: Of 313 children (median age 30 months) enrolled, 92% had received bacille Calmette-Guérin vaccination, 53% were malnourished and 9% were coinfected with the human immunodeficiency virus (HIV); 48 (15%) had TB, 128 (41%) did not, and TB could not be ruled out in 137 (44%). The sensitivity of enhanced (45%) and standard (42%) ELISpot assays for diagnosing TB was better than that of TST (20%) (P  0.03); however, enhanced ELISpot was not more sensitive than the standard ELISpot assay (P = 0.50). The specificity of enhanced ELISpot, standard ELISpot and TST was respectively 82% (95%CI 74-89), 88% (95%CI 81-94) and 98% (95%CI 93-100). Rv3879c and Rv3615c, previously reported to be promising antigens, failed to improve the diagnostic performance of the ELISpot assay. CONCLUSION: The TST and the standard and novel ELISpot assays performed poorly in diagnosing active TB among young children in India.

Evaluation of serum inflammatory biomarkers as predictors of treatment outcome in pulmonary tuberculosis.

OBJECTIVE: To evaluate C-reactive protein (CRP), globulin and white blood cell (WBC) count as predictors of treatment outcome in pulmonary tuberculosis (PTB). METHODS: An observational study of patients with active PTB was conducted at a tertiary centre. All patients had serum CRP, globulin and WBC measured at baseline and at 2 months following commencement of treatment. The outcome of interest was requirement for extension of treatment beyond 6 months. RESULTS: There were 226 patients included in the study. Serum globulin 45 g/l was the only baseline biomarker evaluated that independently predicted requirement for treatment extension (OR 3.42, 95%CI 1.597.32, P 0.001). An elevated globulin level that failed to normalise at 2 months was also associated with increased requirement for treatment extension (63.9% vs. 5.1%, P 0.001), and had a low negative likelihood ratio (0.07) for exclusion of requirement for treatment extension. On multivariable analysis, an elevated globulin that failed to normalise at 2 months was independently associated with requirement for treatment extension (OR 6.13, 95%CI 2.2316.80, P 0.001). CONCLUSIONS: Serum globulin independently predicts requirement for treatment extension in PTB and outperforms CRP and WBC as a predictive biomarker. Normalisation of globulin at 2 months following treatment commencement is associated with low risk of requirement for treatment extension.

Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis.

OBJECTIVES: To determine whether BCG vaccination protects against Mycobacterium tuberculosis infection as assessed by interferon γ release assays (IGRA) in children. DESIGN: Systematic review and meta-analysis. Searches of electronic databases 1950 to November 2013, checking of reference lists, hand searching of journals, and contact with experts. SETTING: Community congregate settings and households. INCLUSION CRITERIA: Vaccinated and unvaccinated children aged under 16 with known recent exposure to patients with pulmonary tuberculosis. Children were screened for infection with M tuberculosis with interferon γ release assays. DATA EXTRACTION: Study results relating to diagnostic accuracy were extracted and risk estimates were combined with random effects meta-analysis. RESULTS: The primary analysis included 14 studies and 3855 participants. The estimated overall risk ratio was 0.81 (95% confidence interval 0.71 to 0.92), indicating a protective efficacy of 19% against infection among vaccinated children after exposure compared with unvaccinated children. The observed protection was similar when estimated with the two types of interferon γ release assays (ELISpot or QuantiFERON). Restriction of the analysis to the six studies (n=1745) with information on progression to active tuberculosis at the time of screening showed protection against infection of 27% (risk ratio 0.73, 0.61 to 0.87) compared with 71% (0.29, 0.15 to 0.58) against active tuberculosis. Among those infected, protection against progression to disease was 58% (0.42, 0.23 to 0.77). CONCLUSIONS: BCG protects against M tuberculosis infection as well as progression from infection to disease.Trial registration PROSPERO registration No CRD42011001698 (www.crd.york.ac.uk/prospero/).

Harnessing local and systemic immunity for vaccines against tuberculosis.

The lung is the portal of entry for Mycobacterium tuberculosis (Mtb) and animal experimental evidence indicates that local immune defense mechanisms are crucial for protective immunity. Immunization via the lower respiratory tract efficiently induces a dividing, activated, antigen-dependent, lung-resident, memory T-cell population, which is partly recoverable by bronchoalveolar lavage. These cells can inhibit the growth of Mtb in the lungs immediately after infection. Delivery of appropriate signals to the lung innate immune system is critical for induction of effective local immunity. In contrast after parenteral immunization, antigen-specific cells may be found in lung tissue but few are recoverable by lavage and inhibition of mycobacterial growth is delayed. Harnessing both local and systemic immunity can provide highly effective protection in animal models and the evidence suggests that taken in aggregate, multiple animal models may predict the success of novel vaccine strategies in humans.

Tuberculosis screening of migrants to low-burden nations: insights from evaluation of UK practice.

Tuberculosis (TB) primarily occurs in the foreign-born in European countries, such as the UK, where increasing notifications and the high proportion of foreign-born cases has refocused attention on immigrant (new entrant) screening. We investigated how UK primary care organisations (PCOs) screen new entrants and whether this differs according to TB burden in the PCOs (incidence < 20 or ≥ 20 cases per 100,000 per annum). An anonymous, 20-point questionnaire was sent to all 192 UK PCOs asking which new entrants are screened, who is screened for active TB/latent TB infection (LTBI) and the methods used. Descriptive analyses were undertaken. Categorical responses were compared using the Chi-squared test. 177 (92.2%) out of 192 PCOs responded; all undertook screening action in response to abnormal chest radiographs, but only 107 (60.4%) screened new entrants for LTBI. Few new entrants had active TB diagnosed (median 0.0%, interquartile range (IQR) 0.0-0.5%) but more were identified with LTBI (median 7.85%, IQR 4.30-13.50%). High-burden PCOs were significantly less likely to screen new entrants for LTBI (OR 0.26, 95% CI 0.12-0.54; p<0.0001). Among PCOs screening for LTBI, there was substantial deviation from national guidance in selection of new entrant subgroups and screening method. Considerable heterogeneity and deviation from national guidance exist throughout the UK new entrant screening process, with high-burden regions undertaking the least screening. Forming an accurate picture of current front-line practice will help to inform future development of European new entrant screening policy.

The clinical significance of radiologically detected silent pulmonary nodules in early breast cancer.

BACKGROUND: Increasing numbers of patients with early cancer undergo routine staging using computerized tomography (CT). Those in whom indeterminate pulmonary nodules are visualized without the presence of other metastatic lesions represent a clinical dilemma regarding their management as early breast cancer or metastatic disease. PATIENTS AND METHODS: Medical records of breast cancer patients who underwent thoracic CT scans between the years 2002 and 2008 were analyzed. Those with obvious metastatic disease were excluded. Patients were identified via the radiology database by searching for the terms: 'suspicious lung metastases' and 'indeterminate nodules'. RESULTS: Out of 1578 new patients assessed from 2002 to 2008, we carried out 802 staging CT scans. Thirty-four cases (4.2%) with indeterminate pulmonary nodules were identified. We categorized cases by size and number of nodules. At a median follow-up of 18 months, there were no changes in lesion size in 86% of patients with a solitary nodule <1 cm and 89% with multiple subcentimeter nodules. In contrast, in 100% of cases with pulmonary nodules >1 cm, the nodules had progressed at follow-up (chi(2), P = 0.004). CONCLUSIONS: Breast cancer cases with subcentimeter indeterminate pulmonary lesions and no evidence of metastases elsewhere are unlikely to represent metastatic disease. Treatment with curative intent or entry into clinical trials should not be excluded.

Recent advances in diagnostic technology: applications in autoimmune and infectious diseases.

Biomarkers are used ubiquitously as indicators of biological health. The development of genomic and proteomic multiplex technologies have enormously amplified biomarker discovery and application to diagnostic and therapeutic decisions in clinical practice. New technologies are now available that simultaneously identify a wide spectrum of biomarkers and save time and costs. Multiplexed assays can be coupled to other disease specific indicators (i.e., cytokines, single nucleotide polymorphisms) in order to get more powerful information. However, there is an urgent need for validation/standardization of the new assays before they are adopted into clinical diagnostics. It is worthy to note a new assay, T cell interferon gamma release (TIGRAs), which has recently been introduced in the diagnosis of latent tuberculosis infection. It seems to perform better than tuberculin skin test in patients with inflammatory rheumatic diseases. In this review, we focus on advantages and limits of novel approaches to the detection of autoantibody profiles in autoimmune diseases or pathogen signatures in microbiology.

Rapid diagnosis of Mycobacterium tuberculosis meningitis by enumeration of cerebrospinal fluid antigen-specific T-cells.

SETTING: Hospital in-patients with suspected tuberculous meningitis (TBM), predominantly in India. OBJECTIVE: To determine whether interferon-gamma (IFN-gamma) secreting Mycobacterium tuberculosis antigen-specific T-cells are present in the cerebrospinal fluid (CSF) of patients with TBM and to evaluate the feasibility of CSF enzyme-linked immunospot (ELISpot) for the diagnosis of active TBM. DESIGN: Prospective blinded hospital-based study. RESULTS: The overnight ELISpot assay detected M. tuberculosis antigen-specific IFN-gamma secreting T-cells in CSF from nine of 10 prospectively recruited patients with TBM, and zero of seven control patients with meningitis of other aetiology. This corresponds to a diagnostic sensitivity of 90% (95%CI 56-100) and specificity of 100% (95%CI 59-100). CONCLUSION: This pilot study demonstrates proof-of-principle for a new T-cell-based diagnostic test for TBM which is rapid, sensitive and specific.

Rapid diagnosis of CNS tuberculosis by a T-cell interferon-gamma release assay on cerebrospinal fluid mononuclear cells.

Central nervous system tuberculosis remains a clinical diagnostic challenge. The ex vivo Mycobacterium tuberculosis-specific enzyme-linked immunospot assay (ELISPOT) is a novel assay for the rapid detection of M. tuberculosis-specific T-lymphocytes in the peripheral blood. However, when performed on peripheral blood, this assay cannot distinguish between active tuberculosis or latent tuberculosis infection. On the assumption that M. tuberculosis-specific T-lymphocytes migrate to sites of infection, we were able to demonstrate high levels of M. tuberculosis-specific cells by ELISPOT in the cerebrospinal fluid of a patient with tuberculous meningitis and intracerebral tuberculoma four weeks before cerebrospinal fluid culture became positive for M. tuberculosis by culture.

Safety and cost savings of an improved three-day rule for stool culture in hospitalised children and adults.

Stools sent for culture from patients after three days of hospitalisation have a low yield (<1%) for bacterial enteric pathogens (BEP), excluding Clostridium difficile, and are expensive to process. A 'three-day rule' for rejection of specimens has previously been validated in adults. We evaluated a three-day rule for paediatric stool samples by retrospective review of all stool culture results from 1995 to 2002. Excluding C. difficile, yield for BEP in samples sent within three days following admission was 97/3751 (2.59%) compared with 3/1511 (0.2%) in samples sent more than three days after admission. The criteria for culture would have been met if the rule had been applied for these three samples. We prospectively evaluated potential savings if the rule were applied for both children and adults over a two-month period in 2000. Savings were greater for adults than for children. Of 490 stools from children, 38 (7.8%) samples did not meet the criteria for culture and of 206 stools from adult patients, 64 (31%) did not meet the criteria for culture. We implemented the rule between 1 March 2003 and 31 March 2006. A total of 14 439 stool samples were received from inpatients requesting culture for BEP, excluding C. difficile. Of these, 5744 (39.8%) were rejected because the criteria for culture were not met. This was estimated as an annual saving of 11,848 pounds to the Trust laboratory. If extrapolated to all NHS Trusts, the potential savings could be in the order of 1.18 million pounds annually.

A systematic review of rapid diagnostic tests for the detection of tuberculosis infection.

OBJECTIVES: To evaluate the effectiveness of available rapid diagnostic tests to identify tuberculosis (TB) infection. DATA SOURCES: Electronic databases were searched from 1975 to August 2003 for tests for active TB and to March 2004 for tests for latent tuberculosis infection (LTBI). REVIEW METHODS: Studies were selected and evaluated that (1) tested for LTBI, (2) compared tuberculin skin test (TST) and interferon-gamma assays based on ESAT-6 and CFP-10 antigens and (3) provided information on TB exposure or bacille Calmette-Guerin (BCG) vaccination or HIV status. For each test comparison, the sensitivity, specificity and 95% confidence intervals (CIs) were calculated. Sources of heterogeneity were investigated by adding covariates to the standard regression model. The authors examined whether interferon-gamma assays were more strongly associated with high versus low TB exposure than TST. Odds ratios (ORs) were calculated for the association between test results and exposures from each study along with their 95% CIs. Within each study, the OR value for one test was divided by that for another to produce a ratio of OR (ROR). RESULTS: A total of 212 studies were included, providing 368 data sets. A further 19 studies assessing fully automated liquid culture were included. Overall, nucleic acid amplification test (NAAT) accuracy was far superior when applied to respiratory samples as opposed to other body fluids. The better quality in-house studies, were, for pulmonary TB, much better at ruling out TB than the commercial tests (higher sensitivity), but were less good at ruling it in (lower specificity), but it is not possible to recommend any one over another owing to a lack of direct test comparisons. The specificity of NAAT tests was high when applied to body fluids, for example for TB meningitis and pleural TB, but sensitivity was poor, indicating that these tests cannot be used reliably to rule out TB. High specificity estimates suggest that NAAT tests should be the first-line test for ruling in TB meningitis, but that they need to be combined with the result of other tests in order to rule out disease. Evidence for NAAT tests in other forms of TB and for phage-based tests is significantly less prolific than for those above and further research is needed to establish accuracy. There is no evidence to support the use of adenosine deaminase (ADA) tests for diagnosis of pulmonary TB; however, there is considerable evidence to support their use for diagnosis of pleural TB and to a slightly lesser extent for TB meningitis. Anti-TB antibody test performance was universally poor, regardless of type of TB. Fully automated liquid culture methods were superior to culture on solid media, in terms of their speed and their precision. In total, 13 studies were included. Assays based on RD1 specific antigens, ESAT-6 or CFP-10, correlate better with intensity of exposure, and therefore are more likely than TST/purified protein derivative (PPD)-based assays to detect LTBI accurately. An additional advantage is that they are more likely to be independent of BCG vaccination status and HIV status. CONCLUSIONS: The NAAT tests provide a reliable way of increasing the specificity of diagnosis (ruling in disease) but sensitivity is too poor to rule out disease, especially in smear-negative (paucibacillary) disease where clinical diagnosis is equivocal and where the clinical need is greatest. For extra-pulmonary TB, clinical judgement has both poor sensitivity and specificity. For pleural TB and TB meningitis, adenosine deaminase tests have high sensitivity but limited specificity. NAATs have high specificity and could be used alongside ADA (or interferon-gamma) to increase sensitivity for ruling out disease and NAAT for high specificity to rule it in. All studies from low-prevalence countries strongly suggest that the RD1 antigen-based assays are more accurate than TST- and PPD-based assays for diagnosis of LTBI. If their superior diagnostic capability is found to hold up in routine clinical practice, they could confer several advantages on TB control programmes. Further research for active TB needs to establish diagnostic accuracy in a wide spectrum of patients, against an appropriate reference test, and avoiding the major sources of bias. For LTBI, research needs to address different epidemiological and clinical settings, to evaluate the performance of the main existing commercial assays in head-to-head comparison in both developed and developing countries, and to assess the role of adding more TB-specific antigens to try to improve diagnostic sensitivity.