Positive Tuberculin Skin Test Research Articles

Differential positive TSPOT assay responses to ESAT-6 and CFP-10 in health care workers

BackgroundThe TSPOT.TB (TSPOT) diagnostic test for latent tuberculosis infection is based on a cell-mediated response to the Mycobacteria tuberculosis antigens, ESAT-6 and/or CFP-10, producing an “interferon-gamma footprint”. We investigated the within-sample and within-subject variability of positive TSPOT assays due to the individual assay antigens' reactivity. MethodsPositive TSPOT assay frequencies due to ESAT-6 or CFP-10 among health care workers (HCWs) at 6-month intervals for 18 months were compared. Differences in result interpretation (positive or negative) for ESAT-6 and CFP10 and potential prognostic factors were investigated. ResultsThere were 576 positive results in 8805 TSPOT assays representing 2418 participants. A significant difference was detected in positive TSPOT results due to a positive response to either ESAT-6, CFP-10 or both antigens at baseline through 12 M (p < 0.001), but not for the 18 M follow-up. Gender, ethnicity, occupation, previous positive tuberculin skin test (TST) and study site were significantly associated with specific antigen positivity. ConclusionsAmong our HCW samples with positive TSPOT assays, CFP-10 induced a larger proportion of positive TSPOT results than ESAT-6. Potential causes for this finding include: BCG vaccinated subpopulations, certain jobs, history of positive TST, U.S. birth, and study site. A high proportion of single-positive specimens may reflect false-positives results.

The tuberculin skin test still matters for the screening of latent Tuberculosis infections among Inflammatory Bowel Disease patients

Background and aimsThere is a high risk of Tuberculosis among patients medicated with anti-tumour necrosis factor α (anti-TNFα) that can be mitigated by treating latent Tuberculosis infections (LTI). This study aimed to evaluate the performance of Tuberculin Skin test (TST) and Quantiferon-TB Gold in Tube (QFT-GIT) in a population of patients suffering from Inflammatory Bowel Diseases. MethodsThe cohort analyzed in this study consisted of 250 patients, of whom 15% were therapy-naïve and 85% were medicated: 70% under immunosuppressive therapy and 30% on anti-TNFα. A LTBI was diagnosed following a positive result in either of the tests and their performance and concordance were evaluated. ResultsFifty-eight and 24 patients had a positive TST and QFT-GIT, respectively. In 72 (29%) patients LTBI was diagnosed, of whom 8 (21%) were therapy-naïve. TST had an overall higher sensitivity (81% vs. 35%) and a higher Negative Predictive Value (93% vs. 80%) when compared to QFT-GIT test; this superiority was consistently maintained irrespective of the presence and kind of backbone immunosuppressive therapies. The concordance between both tests was weak. ConclusionsOur results underscore the need to maintain the TST on LTBI diagnosis in patients about to start or switch anti-TNFα therapy in an intermediate Tuberculosis incidence context.

Prevalence and incidence rates of latent tuberculous infection in a large prison in Iran.

Prisons can act as reservoirs of tuberculous infection. Previous studies have shown that the prevalence of latent tuberculous infection (LTBI) is high in prisons. To investigate the prevalence and incidence rates of LTBI and contributing factors in a prison population in Iran. In March 2013, inmates at the Hamadan Central Prison were invited to participate in a voluntary two-stage screening programme using the tuberculin skin test (TST). In the first stage, the standard TST was administered and read, and was repeated in negative cases to identify cases with delayed TST reactivity and boosted reaction. In the second stage, inmates with a true-negative TST underwent repeat screening 6 months later to identify incident LTBI. Information about risk factors was obtained using structured interviews. Among 1208 screened inmates, TST positivity was recorded in 756 cases (prevalence 62.6%). HIV-positive inmates and cigarette smokers were also more likely to have LTBI. In 380 inmates returning for a follow-up visit, the 6-month incidence rate was 7.6%. Two cases of pulmonary tuberculosis were identified during the period of study. LTBI prevalence and incidence rates among Iranian prisoners are high. Comprehensive plans are needed to for effective TB control among prisoners.

Risk of tuberculosis after lung transplantation: the value of pretransplant chest computed tomography and the impact of mTOR inhibitors and azathioprine use.

It is necessary to determine the incidence and risk factors for tuberculosis (TB), as well as strategies to assess and treat latent tuberculosis infection (LTBI) in lung transplant recipients. A retrospective cohort study of 398 lung transplant recipients was performed. Episodes of TB were studied and the incidence rate was calculated. Logistic regression analysis was used to analyze specific variables as potential risk factors for TB. Median follow-up was 558days (range 1-6636). Six cases (1.5%) of TB were documented in 398 transplant patients. The incidence density of TB was 406.3 cases/10(5) patient-years (95% confidence interval [CI] 164.7-845), which is higher than in the general population (13.10 cases/10(5) person-years). All cases occurred in the period 1993-2006, when the tuberculin skin test (TST) and treatment of LTBI in positive TST patients were not part of the protocol. Pretransplant computed tomography (CT) showed residual lesions in 50% of patients who developed TB, although the TST was negative and the chest radiograph was inconclusive. Multivariate analysis identified the presence of residual lesions in the pretransplant chest CT (odds ratio [OR] 11.5, 95% CI 1.9-69.1, P=0.008), use of azathioprine (OR 10.6, 95% CI 1.1-99.1, P=0.038), and use of everolimus (OR 6.7, 95% CI 1.1-39.8, P=0.036) as independent risk factors for TB. Residual lesions in the pretransplant chest CTs and the use of azathioprine and mTOR inhibitors are associated with the risk of TB.

Evaluation of immunologic response of salivary sIg-A in pediatric tuberculosis patients to antigen Ag38-rec of Mycobacterium tuberculosis Indonesian strain

Objective: We studied the immune response of salivary secretory immunoglobulin A (sIg-A) from a pediatric tuberculosis (TB) group (scoring ≥6) and non-TB group (scoring &lt;6) against recombinant Ag38 (Ag38-rec) fromMycobacterium tuberculosis Indonesian strain.Materials and Methods: Seventy-eight children were divided into three groups; those with TB (n=26), those with suspected TB (n=26), and healthy children (n=26), their saliva was collected, and salivary sIg-A was challenged with purified Ag38-rec using the dot blot method. A change of color from white to dark blue indicated a positive reaction.Results: The immune response of sIg-A of children with TB and those with suspected TB to Ag38-rec was not significantly different. In the TB group, Ag38-rec showed a higher sensitivity than protein purified derivative (PPD) (70.8% vs. 62.5%), but a lower specificity (26.9% vs. 34.62%). However, within both groups (scoring ≥6) as well as non-TB group (scoring &lt;6) Ag38-rec was able to identify children with a positive TST (tuberculin skin test) better than PPD.Conclusion: The antigen Ag38-rec could not distinguish between children with TB (scores ≥6 and &lt;6). However, it demonstrated the potential of Ag38-rec for use in screening for TB infection among children with suspect TB (scores &lt;6).

Comparative Evaluation of Allergodiagnostic of Tuberculosis in Children

The comparative analysis of results of the tuberculin skin test (TST) and of the skin test with the recombinant tuberculosis allergen (Diaskintest - DST) in 7978 children with active tuberculosis revealed for the first time in 2013 - 2014 was carried out. The negative DST result and positive TST result are observed at 551 (6.91%) of patients. 92 patients (1.15%) had negative both tests, and at 98 people (1.23%) DST has yielded positive result, PM - negative. Other patients had positive both tests. In general, by means of DST tuberculosis initially hasn't been revealed at 643 (8.06%) patients, and by means of TST - at 190 (2.38%) patients. The difference is statistically reliable (t = 9.16; P < 0.05). Dynamics of tests results at patients with active tuberculosis was studied. The result of DST remained negative for a year in18.7% of patients, in 26,7% of patients with initially negative DST the result became positive in 3 months, in 2.7% - a year after the first testing. Tuberculosis of various forms and localizations, including TB+, was diagnosed for children with initially negative results of DST and positive TST.

Quantitative IFN-γ and IL-2 Response Associated with Latent Tuberculosis Test Discordance in HIV-infected Pregnant Women.

Pregnant women with latent tuberculosis infection (LTBI) are at high risk for development of TB, especially if infected with HIV. To assess the performance of LTBI tests in pregnant and postpartum women infected with HIV, investigate the immunology behind discordance in pregnancy, and explore the implications for the development of postpartum TB. We screened pregnant women in their second/third trimester and at delivery for LTBI using the tuberculin skin test (TST) and IFN-γ release assay (IGRA) (QuantiFERON Gold). A subset of antepartum women had longitudinal testing, with repeat testing at delivery and postpartum and additional cytokines measured from the IGRA supernatant. The kappa statistic and Wilcoxon rank sum test were used to determine agreement and comparison of cytokine concentrations, respectively. Of 252 enrolled, 71 (28%) women had a positive IGRA but only 27 (10%) had a positive TST (P < 0.005). There was 75% agreement (kappa, 0.25). When stratified by pregnancy versus delivery, 20% had IGRA(+)/TST(-) discordance at each time point. A positive IGRA was associated with known TB contact (odds ratio, 3.6; confidence interval, 1.2-11.1; P = 0.02). Compared with IGRA(+)/TST(+), women with IGRA(+)/TST(-) discordance had significantly less IFN-γ (1.85 vs. 3.48 IU/ml; P = 0.02) and IL-2 (46.17 vs. 84.03 pg/ml; P = 0.01). Five developed postpartum TB, of which three had IGRA(+)/TST(-) discordance during pregnancy. Choice of LTBI test in pregnant women infected with HIV affects results. Pregnant women with IGRA(+)/TST(-) discordance had less IFN-γ and IL-2 than those with concordant-positive results and may represent an especially high-risk subset for the development of active TB postpartum.

PTH-069 Active Tuberculosis in Patients with Inflammatory Bowel Disease After Treatment with Anti-TNF Therapy

Introduction Anti-tumour necrosis factor agents (anti–TNF) are major advances in the management of inflammatory bowel disease (IBD) however they are associated with a 5 fold increased risk of Mycobacterium tuberculosis (TB) infection. All patients should be screened for latent TB infection (LTBI) prior to anti-TNF therapy. Here, we review active TB cases after anti-TNF therapy to identify lessons to be learned. Methods All patients with IBD treated with anti-TNF between March 2007-November 2015 were identified from pharmacy database. Those who developed active TB were identified from the London TB register. Clinical and electronic notes were reviewed. LTBI screening is with history, Chest X-Ray (CXR) and tuberculin skin test (TST) before July 2013 or Quantiferon Gold Assay (QFT-G) after July 2013. Results Of 596 patients treated with anti-TNF, 6 had active TB. 5 had Crohn’s and 1 had Ulcerative Colitis. 3 were male, none had HIV. Age range was 24–49 years. 5 were Caucasian, 1 was UK born but of Pakistani origin. 3 were on Adalimumab (ADA) at time of TB diagnosis and 2 on Infliximab (IFX), 3 were on at least 1 other immunosuppressive. 1 was not on anti-TNFs at TB diagnosis but received IFX 3 months earlier. Time from initiation of anti-TNF to TB diagnosis ranged from 3–41 months (median:13, IQR = 32). 3 had culture confirmed TB, 1 was MTB complex PCR positive but culture negative and 2 had presumed TB. All isolated cultures were fully sensitive. 2 had miliary TB, 2 abdominal TB, 1 pleuro-pulmonary TB and 1 both pulmonary and pericardial TB. Treatment duration was 6–12 months, 5 patients completed treatment and 1 remains on treatment. 3 had prior vaccination for TB, 1 did not and the vaccination status of 2 was unknown. 4 patients had negative TSTs pre-anti-TNF (3 while immunosuppressed), 1 had an indeterminate QFT-G test (while immunosuppressed) and 1 had neither. All patients had normal CXR prior to anti-TNF. No patients received LTBI treatment. Conclusion All cases were considered low epidemiological risk for LTBI . None had a positive TST or QFT-G, however the risk of false negatives is high in immunosuppression. As some patients screened may receive prolonged and recurrent courses of anti-TNF, we recommend discussion around when patients should be rescreened. It is unclear if these cases represent de novo infection or reactivation of latent disease but re-screening may have identified them at the latent stage. As it is not possible to prevent all cases of active TB, there must be continued focus on prompt diagnosis and treatment, alongside comprehensive screening by working with local TB services. Disclosure of Interest None Declared

Interferon Gamma Release Assay versus Tuberculin Skin Testing among Healthcare Workers of Highly Diverse Origin in a Moderate Tuberculosis Burden Country.

Health care workers (HCW’s) are always at an increased risk of contracting tuberculosis (TB) infection. In Saudi Arabia, Interferon Gamma Release Assay (IGRA) has not been evaluated as a screening tool for latent TB infection (LTBI) among HCW’s considering their high demographic diversity. During February 2012 to January 2015 a cross sectional study has been conducted in a tertiary care center with maximum demographically diverse staff population in the capital city-Riyadh. After a short interview and consenting, all the candidates were subjected to tuberculin skin test (TST) and QuantiFERON TB gold In-tube test (QFT). A logistic regression analysis was carried out for establishing the associations between putative risk factors and the diagnostic tests. The candidates were classified according to geographical origin and a detailed analysis was conducted on the impact of their origin towards the results of TST and QFT. Of the 1595 candidates enrolled, 90.6% were BCG vaccinated, female (67.9%) and mainly nurses (53.2%). Candidates with high risk of suspected or confirmed TB patient exposure were 56.1% and 76.5% of them had <10 year’s work experience. TST positivity was observed in 503 (31.5%) candidates, while QFT was positive among 399 (25%). Majority of the candidates were non-Saudi (83%) and predominantly (52.4%) from Western Pacific region. Concordant results were obtained in 14.2% of positive cases and 57.7% negative cases. The disagreements between the two tests were relatively high (kappa co-efficient-0.312±0.026, p value- <0.00001) as TST positive/QFT negative discordance was 54.8% while TST negative/QFT positive discordance was 15.7%. Age of the candidates, BCG vaccination, and South East Asian origin were associated with TST positivity while Occupational TB exposure and geographical origin of the candidates were associated with QFT positivity. A regular follow up on recently TST converted candidates showed no progression to active TB. The putative factors associated with the discordance were origin of the candidate (p value <0.001), profession (p value-0.001), BCG vaccination (p value-0.001) and occupational TB exposure level (P value-0.001). The study demonstrated high level prevalence of LTBI among the demographically diverse study candidates. The agreement between QFT and TST was poor, thus QFT alone cannot be recommended in our setting for a routine LTBI screening. Origin of the candidates has strong association with the results of TST and QFT. The discordant results particularly TST negative and QFT positive needs more detailed analysis.

Latent Tuberculosis in Pregnancy: A Systematic Review.

BackgroundIn countries with low tuberculosis (TB) incidence, immigrants from higher incidence countries represent the major pool of individuals with latent TB infection (LTBI). The antenatal period represents an opportunity for immigrant women to access the medical system, and hence for potential screening and treatment of LTBI. However, such screening and treatment during pregnancy remains controversial.ObjectivesIn order to further understand the prevalence, natural history, screening and management of LTBI in pregnancy, we conducted a systematic literature review addressing the screening and treatment of LTBI, in pregnant women without known HIV infection.MethodsA systematic review of 4 databases (Embase, Embase Classic, Medline, Cochrane Library) covering articles published from January 1st 1980 to April 30th 2014. Articles in English, French or Spanish with relevant information on prevalence, natural history, screening tools, screening strategies and treatment of LTBI during pregnancy were eligible for inclusion. Articles were excluded if (1) Full text was not available (2) they were case series or case studies (3) they focused exclusively on prevalence, diagnosis and treatment of active TB (4) the study population was exclusively HIV-infected.ResultsOf 4,193 titles initially identified, 208 abstracts were eligible for review. Of these, 30 articles qualified for full text review and 22 were retained: 3 cohort studies, 2 case-control studies, and 17 cross-sectional studies. In the USA, the estimated prevalence of LTBI ranged from 14 to 48% in women tested, and tuberculin skin test (TST) positivity was associated with ethnicity. One study suggested that incidence of active TB was significantly increased during the 180 days postpartum (Incidence rate ratio, 1.95 (95% CI 1.24–3.07). There was a high level of adherence with both skin testing (between 90–100%) and chest radiography (93–100%.). In three studies from low incidence settings, concordance between TST and an interferon-gamma release assay was 77, 88 and 91% with kappa values ranging from 0.26 to 0.45. In low incidence settings, an IGRA may be more specific and less sensitive than TST, and results do not appear to be altered by pregnancy. The proportion of women who attended follow-up visits after positive tuberculin tests varied from 14 to 69%, while 5 to 42% of those who attended follow-up visits completed a minimum of 6 months of isoniazid treatment. One study raised the possibility of an association of pregnancy/post-partum state with INH hepatitis (risk ratio 2,5, 95% CI 0.8–8.2) and fatal hepatotoxicity (rate ratio 4.0, 95% CI 0.2–258). One study deemed INH safe during breastfeeding based on peak concentrations in plasma and breast milk after INH administration.ConclusionPregnancy is an opportunity to screen for LTBI. Interferon-gamma release assays are likely comparable to tuberculin skin tests and may be used during pregnancy. Efforts should be made to improve adherence with follow-up and treatment post-partum. Further data are needed with respect to safety and feasibility of antepartum INH therapy, and with respect to alternative treatment regimens.

Tuberculosis Infection in Early Childhood and the Association with HIV-exposure in HIV-uninfected Children in Rural Uganda.

In high tuberculosis (TB) burden countries, a significant proportion of the latent TB reservoir is established by the age 5 years. There are critical knowledge gaps in our understanding of the age-specific prevalence of TB infection and the influence of HIV exposure on TB infection in the first 5 years of life among HIV-uninfected children in sub-Saharan Africa. We measured TB infection with the Quantiferon Gold-in-Tube (QFT) and tuberculin skin tests (TST) in 447 children ≤60 months and their 284 HIV-infected and IV-uninfected mothers in rural Uganda. The overall prevalence of TB infection in children ≤60 months by TST was 24% (95% confidence intervals [CI]: 19.9-27.9). The prevalence of TST positivity was highest among children in their first year of life (36%; 95% CI: 26.0-45.9) and declined with age to 19% at 36-60 months of age, χ test for trend P = 0.014. In contrast, 4% (95% CI: 1.9-5.87%) of children had a positive QFT, and there was no trend detected with age, P = 0.576. QFT positivity was detected as early as 5 months. HIV-exposed uninfected children had significantly higher odds of TB infection by QFT (odds ratio [OR]: 21.2; P = 0.008; 95% CI: 2.2-204.7) or positive TST or QFT (OR, 2.4; P = 0.020; 95% CI: 1.2-5.1) compared with HIV-unexposed uninfected children, adjusting for age, BCG vaccination and a positive maternal TST or QFT. An appreciable prevalence of TB infection was detected in early childhood. HIV-exposed uninfected children have a higher risk for TB infection compared with children born to HIV-uninfected mothers.

Epidemiologically characterized high and low transmission isolates of Mycobacterium tuberculosis induce distinct infection outcomes in mice

Abstract In a study of household contacts of infectious TB cases (HHC) conducted by us in Brazil, “index” cases were categorized into High (HT) and Low (LT) transmission groups based on the proportion of household contacts with a positive tuberculin skin test. In this study we wanted to determine whether Mycobacterium tuberculosis (Mtb) isolates with different transmission phenotypes diverged in their interaction with the host immune system. Initial in vitro analysis of 15 isolates from each group revealed significantly higher levels of TNF produced by macrophages infected with HT isolates. Two each of the HT and LT isolates were further characterized in vivo in the C3HeB/FeJ mice which develop lesions characteristic of human TB. Through the course of these infections, both the LT isolates exhibited a significantly higher bacterial burden and enhanced cellular recruitment to the lungs. Mice infected with the LT isolates exhibited early pulmonary inflammation that rapidly progressed to widespread consolidation of the granulomatous lesions. In contrast, mice infected with the two HT isolates formed organized cellular aggregates that contained abundant lymphocytes and foamy macrophages. Interestingly, pathological progression of the cellular aggregates into caseous fibrotic lesions, with abundant extracellular bacilli, was observed with one of the HT isolates. Furthermore, elevated levels of the pro-inflammatory cytokines IL-1β, IL-6 and IL-17 were found in the lungs of mice infected with the LT isolates. These results suggest that distinct interactions between microbe and host immunity might lead to differential trajectory in intracellular growth pattern and lung pathology that underlie differences in transmission potential.

Knowledge, attitudes, practices and education among students in a faculty of health

Objective To determine tuberculosis (TB) knowledge, attitudes, practices, education and Tuberculin Skin Test (TST) positivity among Colombian health professions students in their last year of study. Methods A cross-sectional study was conducted using a self-reported questionnaire about TB knowledge, attitudes, practices and education with 193 students of medicine, nursing, dentistry, physical therapy, speech and language therapy, occupational therapy, clinical laboratory studies and emergency care. A TST was performed on 153 of the students. Results Although most of survey respondents perceived the TB education they received to be "sufficient", the results regarding their knowledge of TB do not support such perceptions: 35.2% of participants did not identify TB risk factors, 33.7 % of participants identified Colombian TB incidence, and only 1.6 % identified appropriate initial treatment for TB. In regards to practices, 50 % of respondents admitted that they would take care of a patient without a high efficiency mask. The TST was positive in 35 % of participants. Conclusions Our results show that there are opportunities to improve TB education in this health faculty, there is also a need to improve safety practices in the facilities where students work in order to reduce their risk of conversion.

Diagnosing active and latent tuberculosis among Iranian HIV-infected patients.

To screen for Tuberculosis (TB) in human immunodeficiency virus (HIV) people in an effort to improve early TB diagnosis and reduce TB transmission. A prospective study was conducted on adult HIV people from 2008 to 2011. Three samples of sputum, cell blood count, tuberculin skin test (TST) and chest X-ray were obtained from all patients. The characteristics of HIV patients with TB and HIV patients without TB were compared to each other. Of the 154 HIV patients included, 58 (38%) had tuberculosis with a mean CD4 cell count of 68 cells/mm3 . Active TB was found in 56 (47%) patients with a history of intravenous drug use. Cough (OR = 3.1, 95% CI 1.2-7.79), positive TST (OR = 8.15, 95% CI 3.28-20.25) and an abnormal chest X-ray (OR = 5.1, 95% CI 1.84-14.2) were the predicting factors for detecting active TB among HIV patients. The sensitivity and specificity of a combination of any symptoms with chest X-ray, smear, TST or all of these were 96.5% and 86.5%, respectively. CD4 cell count <100 (OR = 2.67; 95% CI 1.23-5.78) and smoking (OR = 13.4; 95% CI 3.04-59.4) remained independently associated with TB in a multivariate analysis. There was a high prevalence of TB within the HIV population. Screening for TB among these patients can be carried out at every clinic or health facility using a combination of symptoms, TST, chest X-ray and smear sample.

Positive Tuberculin Skin Test Among Health Care Workers: Prevalence and Risk Factors in Teaching Hospitals of a Highly Endemic Region for Tuberculosis, Zahedan, Iran

Background: Tuberculosis (TB) is not only considered as a community acquired disease, but also as an occupational infection. Health care workers (HCWs) in several countries show an increasing pattern for TB. Objectives: The current study aimed to determine the prevalence of positive tuberculin skin test (TST) among HCWs in a highly endemic area for TB in Iran, namely Zahedan, the capital of Sistan and Baluchestan province, located in Southeast of Iran, near the border of Afghanistan. Patients and Methods: In a cross sectional study in 2009, 328 HCWs from all five teaching hospitals in Zahedan were recruited. Inclusion criteria were lack of history of TB in family, receiving BCG vaccination within the first six month after the birth without later booster dose. Age, gender, job, working experience, history of exposure to a known patient with TB and TB vaccine scar were registered. The outcome was positive results during two TSTs (induration > 10 mm). A logistic regression was implemented to determine the predictors of positive TST result. Results: TST was positive in 198 (60.4%) health care workers out of 328. Likelihood of positive TST among HCWs increased in nurses (OR = 4.617, 95% CI = 1.181-18.054, P = 0.028), increasing working experience (OR = 1.178, 95% CI = 1.131 - 1.226, P 0.05). Conclusions: The prevalence of positive TST in HCWs in teaching hospitals in Zahedan is so high. Tuberculosis prevention programs should be implemented for HCWs and personnel of hospitals in Zahedan.

Interferon‐gamma release assays can effectively screen migrants for the tuberculosis infection, but urgent, active cases need clinical recognition

Increasing numbers of migrants to Sweden are screened for tuberculosis (TB), and a rational approach to screening is required. We evaluated positive tuberculin skin tests (TSTs) and interferon-gamma release assays (IGRAs) on paediatric migrants in relation to the TB incidence in the corresponding foreign-born populations in Stockholm. This study examined the characteristics of migrants under the age of 18 who were referred to a paediatric TB clinic at Karolinska University Hospital from 2008 to 2014 by primary care centres in Stockholm County. We saw 943 TST-positive children with a median age of 14 years at the TB clinic and performed IGRAs on 557. IGRA positivity ranged from 64% in migrants from Somalia to 20% in those from the former Soviet Union and eastern Europe, with an estimated population level prevalence of 18.8% and 4.2%, respectively. These were significantly correlated to TB incidence in foreign-born Stockholm children. We diagnosed active TB in 20 screened migrants, and advanced, symptomatic TB was diagnosed in 10 recently arrived migrants without screening. IGRAs showed higher specificity than TST in identifying tuberculosis. TB screening should focus on migrants from high-incidence countries, but this may be inadequate to detect advanced TB cases.

A prospective cohort study of latent tuberculosis in adult close contacts of active pulmonary tuberculosis patients in Korea.

Background/Aims:The objective of this prospective study was to evaluate the diagnosis and treatment of latent tuberculosis infection (LTBI) in adult close contacts of active pulmonary tuberculosis (TB) patients in Korea.Methods:Adult close contacts of active pulmonary TB patients were recruited at a regional tertiary hospital in Korea. The participants were tested for LTBI using the tuberculin skin test (TST) and/or QuantiFERON-TB Gold (QFT-G) test. LTBI patients, who consented to treatment, were randomly assigned to receive isoniazid for 9 months (9INH) or rifampin for 4 months (4RIF).Results:We examined 189 adult close contacts (> 18 years) of 107 active pulmonary TB patients. The TST and QFT-G were positive (≥ 10 mm) in 75/183 (39.7%) and 45/118 (38.1%) tested participants, respectively. Among 88 TST or QFT-G positive LTBI participants, 45 participants were randomly assigned to receive 4RIF (n = 21) or 9INH (n = 24), respectively. The average treatment duration for the 4RIF and 9INH groups was 3.3 ± 1.3 and 6.1 ± 2.7 months, respectively. Treatment was completed in 25 participants (4RIF, n = 16; 9INH, n = 9). LTBI participants who accepted treatment were more likely to be women and have more cavitary lesions on the chest radiographs of index cases and positive TST and QFT-G results compared to those who refused treatment.Conclusions:About 40% of adult close contacts of active pulmonary TB patients had LTBI; about 50% of these LTBI participants agreed to treatment.

In Vivo Molecular Dissection of the Effects of HIV-1 in Active Tuberculosis.

Increased risk of tuberculosis (TB) associated with HIV-1 infection is primarily attributed to deficient T helper (Th)1 immune responses, but most people with active TB have robust Th1 responses, indicating that these are not sufficient to protect against disease. Recent findings suggest that favourable outcomes following Mycobacterium tuberculosis infection arise from finely balanced inflammatory and regulatory pathways, achieving pathogen control without immunopathology. We hypothesised that HIV-1 and antiretroviral therapy (ART) exert widespread changes to cell mediated immunity, which may compromise the optimal host protective response to TB and provide novel insights into the correlates of immune protection and pathogenesis. We sought to define these effects in patients with active TB by transcriptional profiling of tuberculin skin tests (TST) to make comprehensive molecular level assessments of in vivo human immune responses at the site of a standardised mycobacterial challenge. We showed that the TST transcriptome accurately reflects the molecular pathology at the site of human pulmonary TB, and used this approach to investigate immune dysregulation in HIV-1/TB co-infected patients with distinct clinical phenotypes associated with TST reactivity or anergy and unmasking TB immune reconstitution inflammatory syndrome (IRIS) after initiation of ART. HIV-1 infected patients with positive TSTs exhibited preserved Th1 responses but deficient immunoregulatory IL10-inducible responses. Those with clinically negative TSTs revealed profound anergy of innate as well as adaptive immune responses, except for preservation of type 1 interferon activity, implicated in impaired anti-mycobacterial immunity. Patients with unmasking TB IRIS showed recovery of Th1 immunity to normal levels, but exaggerated Th2-associated responses specifically. These mechanisms of immune dysregulation were localised to the tissue microenvironment and not evident in peripheral blood. TST molecular profiling categorised different mechanisms of immunological dysfunction in HIV-1 infection beyond the effects on CD4 T cells, each associated with increased risk of TB disease and amenable to host-directed therapies.

Continuous isoniazid for the treatment of latent tuberculosis infection in people living with HIV.

This systematic review was carried out to determine the effectiveness of continuous isoniazid (given for at least 36 months) for the treatment of latent tuberculosis infection (LTBI) in people living with HIV (PLHIV). Six databases and HIV and tuberculosis (TB) conference abstract books were searched for randomized controlled trials that compared the effectiveness of continuous isoniazid with 6 months of isoniazid. Outcomes of interest were TB incidence, mortality, adverse events and risk of drug resistance. Data were pooled using fixed-effects meta-analysis. Three studies were included, from Botswana, South Africa and India. The risk of active TB was 38% lower among patients receiving continuous isoniazid compared with isoniazid regimen for 6 months [relative risk (RR) 0.62, 95% confidence interval (CI): 0.42-0.89; I = 0%], and 49% lower for those with a positive tuberculin skin test (TST) (RR 0.51, 95% CI: 0.30-0.86; I = 7%). Similarly, individuals with positive TST had a 50% lower chance of death (RR 0.50, 95% CI: 0.27-0.91; I = 3%). Two studies found no evidence of an increase in adverse events in the continuous isoniazid group, whereas a third study, that used a different definition for adverse events, found strong evidence of increase. There was no evidence of increased drug resistance when continuous isoniazid was given. For PLHIV in settings with high TB and HIV prevalence and transmission, continuous isoniazid for at least 36 months is beneficial and probably outweighs the risk of increased adverse events compared with an isoniazid regimen for 6 months.

Oral administration of heat-inactivated Mycobacterium bovis reduces the response of farmed red deer to avian and bovine tuberculin

Orally delivered mycobacterial antigens may not sensitize the immunized animals causing a positive tuberculin skin test response. As the first step to address this critical issue, we characterized the response of farmed red deer (Cervus elaphus) to orally delivered heat-inactivated Mycobacterium bovis. Thirty-two adult red deer hinds from a farm known to be free of tuberculosis (TB) were randomly assigned to two different treatment groups, immunized (n=24) and control (n=8). Immunized hinds were dosed orally with 2ml of PBS containing 6×106 heat-inactivated M. bovis. The mean skin test response of immunized deer to both avian purified protein derivative (aPPD) and bovine PPD (bPPD) was consistently lower in immunized than in control hinds. One year after immunization, immunized hinds had a significant reduction in the skin test response to aPPD and in the ELISA antibody levels against both aPPD and bPPD (24–36% reduction; P<0.05). By contrast, no significant change was observed in the skin test response to phytohaemagglutinin, or in the ELISA antibody levels against the M. bovis specific antigen MPB70. The mRNA levels for C3, IFN-γ and IL-1β and serum protein levels for IFN-γ and IL-1β did not vary between immunized and control deer. However, serum C3 protein levels were significantly higher (P=0.001) in immunized than in control deer six months after immunization. These results confirm that oral heat-inactivated M. bovis does not sensitize farmed red deer and therefore does not cause false-positive responses in the tuberculin skin test. The absence of sensitization in orally immunized deer opens the possibility of testing the vaccine in deer and possibly other ruminants without the risk of causing false-positive reactions in TB-tests. This study also provided the first evidence that orally-delivered inactivated mycobacterial antigens elicit some kind of immune response in a ruminant.