Latent Tuberculosis Infection Cases Research Articles

Immune Subtyping in Latent Tuberculosis.

Latent tuberculosis infection (LTBI) poses a major roadblock in the global effort to eradicate tuberculosis (TB). A deep understanding of the host responses involved in establishment and maintenance of TB latency is required to propel the development of sensitive methods to detect and treat LTBI. Given that LTBI individuals are typically asymptomatic, it is challenging to differentiate latently infected from uninfected individuals. A major contributor to this problem is that no clear pattern of host response is linked with LTBI, as molecular correlates of latent infection have been hard to identify. In this study, we have analyzed the global perturbations in host response in LTBI individuals as compared to uninfected individuals and particularly the heterogeneity in such response, across LTBI cohorts. For this, we constructed individualized genome-wide host response networks informed by blood transcriptomes for 136 LTBI cases and have used a sensitive network mining algorithm to identify top-ranked host response subnetworks in each case. Our analysis indicates that despite the high heterogeneity in the gene expression profiles among LTBI samples, clear patterns of perturbation are found in the immune response pathways, leading to grouping LTBI samples into 4 different immune-subtypes. Our results suggest that different subnetworks of molecular perturbations are associated with latent tuberculosis.

An outbreak of pulmonary tuberculosis and a follow-up investigation of latent tuberculosis in a high school in an eastern city in China, 2016-2019.

In October 2016, a senior high school student was diagnosed with sputum-smear positive [SS(+)] pulmonary tuberculosis (TB). We conducted an investigation of an outbreak in the school, including among students and teachers diagnosed with latent TB, who we followed until July 2019. We defined latent TB infection (LTBI) as a tuberculin skin test (TST) induration of 15mm or larger; probable TB as a chest radiograph indicative of TB plus productive cough/hemoptysis for at least 2 weeks, or TST induration of 15mm or larger; and confirmed TB as two or more positive sputum smears or one positive sputum smear plus a chest radiograph indicative of TB or culture positive with M. tuberculosis. We conducted mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) typing based on 24 loci in the isolates. Between October 2016 and July 2019, we identified 52 cases, including nine probable, six confirmed, and 37 LTBI cases. The index case-student had attended school continuously despite having TB symptoms for almost three months before being diagnosed with TB. We obtained three isolates from classmates of the index case in 2016; all had identical MIRU-VNTR alleles with the index case. The LTBI rate was lower among students (7.41%, 30/405) than among teachers (26.92%, 7/26) (rate ratio [RR] = 0.28, 95% confidential interval [CI]: 0.13-0.57). Among the 17 students who had latent TB and refused prophylaxis in October 2016, 23.53% (4/17) became probable/confirmed cases by July 2019. None of the six teachers who also refused prophylaxis became probable or confirmed cases. Of the 176 students who were TST(-) in October 2016, 1.70% (3/176) became probable/confirmed cases, and among the 20 teachers who were TST(-), 1 became a probable case. Delayed diagnosis of TB in the index patient may have contributed to the start of this outbreak; lack of post-exposure chemoprophylaxis facilitated spread of the outbreak. Post-exposure prophylaxis is strongly recommended for all TST-positive students; TST-negative students exposed to an SS(+) case should be followed up regularly so that prophylaxis can be started if LTBI is detected.

A Tuberculose pulmonar, em lactente jovem, diagnosticada pela avaliação de contato - Relato de caso

The purpose of this report is to emphasize the importance of tuberculosis (TB) contacts evaluation in order to detect cases of latent tuberculosis infection (LTBI) and active TB. This case reports a two-month-old infant diagnosed with pulmonary TB with a bacilliferous mother whose diagnosis of TB occurred in the second week of puerperium. The correct evaluation of the child allowed the early diagnosis and treatment of pulmonary TB, avoiding its evolution to severe forms of the disease (miliary TB and meningoencephalitis) and its sequelae or deadly outcome.

A multidrug-resistant tuberculosis outbreak in a language school: Tokyo, Japan, 2019-2020.

Japan has successfully reduced the burden of tuberculosis (TB) in the past seven decades; however, there are still some issues in eliminating TB. Its presence in immigrants, particularly multidrug-resistant (MDR) TB, is one of them. In mid-September 2019, a teenage Chinese male student in a morning class of a Japanese language school in Tokyo, Japan, was diagnosed with sputum smear-positive pulmonary MDR-TB. The outbreak cases were analyzed in a cohort study. We investigated 138 students and 18 teachers, of whom 81 (51.9%) were male, 115 (73.7%) were aged from 20 to 29 years, and 124 (76.9%) were from China. Four other students in the same classroom and another in a different classroom from the index patient in the morning classes were also diagnosed with MDR-TB disease by the end of November 2020. In addition, 31 cases of latent TB infection (LTBI) were detected among the students and teachers. Students in the same classroom had the highest risk of TB infection (78.9%, 95% confidence interval [CI]: 54.4%-93.9%) with a relative risk of 8.6 (95% CI: 3.9-19.0), followed by students in the other classrooms of the morning classes (25.9%, 95% CI: 15.0%-39.7%) with a relative risk of 2.8 (95% CI: 1.2-6.8), compared with the afternoon class students (9.2%, 95% CI: 3.5-19.0) who had minimal contact with the index patient. National TB programs should adopt prophylaxis regimens for MDR-TB LTBI cases and provide prophylaxis to them, particularly if related to an outbreak. The Japanese government should screen immigrants for TB, particularly those from TB-endemic areas.

Utility of the Interferon-Gamma Release Assay for Latent Tuberculosis Infection Screening among Indian Health-Care Workers.

Background:The utility of interferon-gamma release assays (IGRAs) for latent tuberculosis infection (LTBI) screening among health-care workers (HCWs) in low- and middle-income countries (LMICs) remains unclear.Methods:This was a prospective cohort study among HCW trainees undergoing annual LTBI screening via tuberculin skin test (TST) and QuantiFERON® TB Gold Test-in-tube (QFT-GIT) in Pune, India. TST induration ≥ 10 mm and QFT-GIT ≥ 0.35 IU/ml were considered positive. Test concordance was evaluated at entry among the entire cohort and at 1 year among baseline TST-negative participants with follow-up testing. Overall test agreement was evaluated at both timepoints using the kappa statistic: fair (k < 0.40), good (0.41 ≥ k ≤0.60), or strong (k > 0.60).Results:Of 200 participants, prevalent LTBI was detected in 42 (21%) via TST and 45 (23%) via QFT-GIT; QFT-GIT was positive in 27/42 (64%) TST-positive and 18/158 (11%) TST-negative trainees. Annual TST conversion was 28% (40/142) and included 11 trainees with baseline TST-/IGRA+; QFT-GIT was positive in 17/40 (43%) TST-positive and 5/102 (5%) TST-negative trainees. Overall test concordance was 84% (k = 0.52; 95% confidence interval [CI]: 0.38–0.66) and 80% (k = 0.44; 95% CI: 0.29–0.59) at baseline and 12 months, respectively.Conclusions:We observed good overall agreement between TST and QFT-GIT, and QFT-GIT detected additional LTBI cases among TST-negative trainees with possible early detection of LTBI conversion. Overall, our results support the use of IGRA for annual LTBI screening among HCWs in a high burden LMIC setting.

Analysis of 605 tuberculosis outbreaks in Japan, 1993-2015: time, place and transmission site.

Since 1993, reports on tuberculosis (TB) outbreaks have been collected in Japan; however, there has never been an overall analysis of these TB outbreaks. We aim to provide one here. The TB outbreak data were obtained from the Ministry of Health, Labour and Welfare and are described in terms of time, place and transmission site. The average number of TB cases and latent tuberculosis infection (LTBI) were compared by the transmission site. Some 605 TB outbreaks with 3491 TB cases were reported in 1993-2015 with an increasing trend (r = 0.45), during which time 728 777 TB cases were reported nationwide. On an average, TB outbreaks occurred more often in April to May (5.5 outbreaks per 2 months) than in December to January (3.4). The most common transmission sites were workplaces (n = 255), followed by health facilities (n = 144), schools (n = 60) and welfare facilities (n = 48). Psychiatric hospitals and nursing homes had the highest average number of TB cases per outbreak (8.5 each), whereas schools and prisons had the highest numbers of LTBI cases (29.1 and 38.9, respectively). Countries, particularly those that have resources to investigate TB outbreaks, should collect and analyse findings of TB outbreaks, as it informs surveillance systems and eventually strengthens general health systems.

Schistosoma mansoni Infection Is Associated With a Higher Probability of Tuberculosis Disease in HIV-Infected Adults in Kenya.

Helminth infections can modulate immunity to Mycobacterium tuberculosis (Mtb). However, the effect of helminths, including Schistosoma mansoni (SM), on Mtb infection outcomes is less clear. Furthermore, HIV is a known risk factor for tuberculosis (TB) disease and has been implicated in SM pathogenesis. Therefore, it is important to evaluate whether HIV modifies the association between SM and Mtb infection. HIV-infected and HIV-uninfected adults were enrolled in Kisumu County, Kenya, between 2014 and 2017 and categorized into 3 groups based on Mtb infection status: Mtb-uninfected healthy controls, latent TB infection (LTBI), and active TB disease. Participants were subsequently evaluated for infection with SM. We used targeted minimum loss estimation and super learning to estimate a covariate-adjusted association between SM and Mtb infection outcomes, defined as the probability of being Mtb-uninfected healthy controls, LTBI, or TB. HIV status was evaluated as an effect modifier of this association. SM was not associated with differences in baseline demographic or clinical features of participants in this study, nor with additional parasitic infections. Covariate-adjusted analyses indicated that infection with SM was associated with a 4% higher estimated proportion of active TB cases in HIV-uninfected individuals and a 14% higher estimated proportion of active TB cases in HIV-infected individuals. There were no differences in estimated proportions of LTBI cases. We provide evidence that SM infection is associated with a higher probability of active TB disease, particularly in HIV-infected individuals.

Implementing contact tracing for tuberculosis in Kyrgyz Republic and risk factors for positivity using QuantiFERON-TB Gold plus

BackgroundEffective active case finding (ACF) activities are essential for early identification of new cases of active tuberculosis (TB) and latent TB infection (LTBI). Accurate diagnostics as well as the ability to identify contacts at high risk of infection are essential for ACF, and have not been systematically reported from Central Asia. The objective was to implement a pilot ACF program to determine the prevalence and risk factors for LTBI and active TB among contacts of individuals with TB in Kyrgyz Republic using Quantiferon-TB Gold plus (QuantiFERON).MethodsAn enhanced ACF project in the Kyrgyz Republic was implemented in which close and household (home) contacts of TB patients from the Issyk-Kul Oblast TB Center were visited at home. QuantiFERON and the tuberculin skin test (TST) alongside clinical and bacteriological examination were used to identify LTBI and active TB cases among contacts. The association for QuantiFERON positivity and risk factors were analysed and compared to TST results.ResultsImplementation of ACF with QuantiFERON involved close collaboration with the national sanitary and epidemiological services (SES) and laboratories in the Kyrgyz Republic. From 67 index cases, 296 contacts were enrolled of whom 253 had QuantiFERON or TST results; of those 103 contacts had LTBI (positive TST or IGRA), and four (1.4%) active TB cases were detected. Index case smear microscopy (OR 1.76) and high household density (OR 1.97) were significant risk factors for QuantiFERON positivity for all contacts. When stratified by age, association with smear positivity disappeared for children below 15 years. TST was not associated with any risk factor.ConclusionsThis is the first time that ACF activities have been reported for Central Asia, and provide insight for implementation of effective ACF in the region. These ACF activities using QuantiFERON led to increase in the detection of LTBI and active cases, prior to patients seeking treatment. Household density should be taken into consideration as an important risk factor for the stratification of future ACF activities.

The study of tuberculosis outbreak in a high school—Shanghai, China, 2017–2018

To investigate the attack rate of active tuberculosis (TB) cases and detection rate of latent tuberculosis infection (LTBI) cases, and to identify possible factors contributed to the outbreak in a high school. We analyzed the investigation data of 35 teachers and 108 students, including active TB cases and their close contacts. The symptoms inquiry, tuberculin skin test (TST), and chest X-ray/CT scan were conducted in the close contact screening. We did variable-number-of-tandem-repeat genotyping and whole-genome sequencing of isolates. The time interval between the onset of symptoms and diagnosis was 36 days. The total attack rate of active TB was 7.69% (11/143), with a class attack rate of 27.78% (10/36) among students. The genetic differences between any two available isolates were less than 5 SNPs. Approximately 15.38% (22/143) of persons were LTBI cases, and the total detection rates of LTBI for students and teachers were 7.40% (8/108) and 40% (14/35), respectively. Being in the same class as the index case resulted in a significantly higher risk of being diagnosed with active TB (P = 0.0001, RR = 18.51, 95%CI (2.44,140.42)) and either LTBI and MTB infection (RR = 14.40, RR = 16.46, respectively) compared with that of students in a non-index class. The case-finding delay should be reduced to prevent the spread in classes and schools. Effective surveillance and regulated screening for student contacts should be strengthened in schools to detect infections early.

Factors Associated with Latent Tuberculosis Infection among the Hospital Employees in a Tertiary Hospital of Northeastern Thailand.

Latent tuberculosis infection (LTBI) can develop into tuberculosis (TB). The WHO requires the discovery and management of LTBI among high-risk groups. Health care workers (HCWs) constitute a high-risk group. Factors associated with LTBI among HCWs in Thailand need further study. The current study aimed to explore the factors related to LTBI among Thai HCWs. A hospital-based, matched case-control study was conducted. All cases and controls were HCWs at a tertiary hospital in northeastern Thailand. Between 2017 and 2019, a total of 85 cases of interferon-γ release assays (IGRAs)-proven LTBI, and 170 control subjects were selected from a hospital (two controls per case). The two recruited controls were individually matched with LTBI cases by sex and age (±5 years). Secondary data were obtained from the occupational health and safety office. Case HCWs had a higher proportion of significant factors than control HCWs (i.e., working closely with pulmonary TB—94.1% vs. 88.8%, and working in the area of aerosol-generating procedures (AGPs) 81.2% vs. 69.4%). The bivariate conditional logistic regression showed that the occurrence of LTBI in HCWs was statistically significant (p-value < 0.05), particularly with respect to: workplaces of AGPs (crude OR = 1.90, 95% CI: 1.01–3.58, p = 0.041); among HCWs performing AGPs (crude OR = 2.04, 95% CI: 1.20, 3.48, p = 0.007); and, absent Bacille Calmette-Guérin (BCG) scar (crude OR = 2.59, 95% CI: 1.50–4.47, p = 0.001). Based on the multivariable conditional logistics analysis, HCWs who performed AGPs while contacting TB cases had a statistically significant association with LTBI (adjusted OR = 1.82, 95% CI: 1.04–3.20, p = 0.035). HCWs who reported the absence of a BCG scar had a statistically significant association with LTBI (adjusted OR = 2.49, 95% CI: 1.65–5.36, p = 0.001), whereas other factors including close contact with TB (adjusted OR = 2.44, 95% CI: 0.74, 8.09, p = 0.123) were not significantly associated with LTBI. In conclusion, HCWs who performed AGPs and were absent a BCG scar had a significant association with LTBI, while other factors played a less critical role.

Tuberculosis Infection Screening in 5468 Italian Healthcare Students: Investigation of a Borderline Zone Value for the QFT-Test.

Healthcare workers are at an increased risk of contracting Mycobacterium tuberculosis infection. Tuberculin skin test (TST) and interferon gamma release assay (IGRA) represent the available tests most used for the diagnosis of latent tuberculosis infection (LTBI). Different borderline zones have been proposed for defining conversions and reversions to improve the interpretation of the IGRA test results as part of serial testing. From 2012 to 2017, 5468 health students of an Italian University Hospital were screened for tuberculosis infection through the execution of the TST and, in case of positivity, of the QuantiFERON-TB® Gold In-Tube assay (QFT–GIT). The QFT–GIT is considered “borderline” with values from 0.35 to 0.99 IU/mL. Among the students who performed the QFT–GIT assay, 27 subjects presented a range of values defined as borderline. The QFT–GIT was repeated after 90 days on 19 subjects with borderline values and showed a negativization of the values in 14 students and a positive conversion in three cases, while for two students, a borderline value was also found for the second test, with a 74% regression of the borderline cases. The introduction of QuantiFERON borderline values is a useful assessment tool to bring out LTBI case candidates for chemoprophylaxis.

Prevalence of Latent Tuberculosis in the Multiple Sclerosis Clinic and Effect of Multiple Sclerosis Treatment on Tuberculosis Testing.

Patients with a compromised immune system are at risk for converting from latent tuberculosis infection (LTBI) to active tuberculosis (TB) infection. Multiple sclerosis (MS) therapies may put individuals with LTBI at higher risk of TB. Patients at the Beth Israel Deaconess Medical Center MS Clinic were screened for TB as part of routine testing with the QuantiFERON-TB Gold In-Tube (QFT-GIT) assay (Cellestis Ltd) from 2013 to 2017. Patients were tested either before or during immunomodulatory therapy. Four of 222 patients (1.8%; 95% CI, 0.1%-3.6%) had positive QFT-GIT results; three patients had risk factors for TB, having emigrated from TB-endemic countries or worked in the health care industry. Twenty-eight of 222 patients (12.6%) had an indeterminate assay result, and 75.0% of these occurred in patients taking dimethyl fumarate. Fingolimod, natalizumab, or anti-CD20 treatments showed 0% to 7.7% indeterminate results. The prevalence of LTBI was 1.8% in the Beth Israel Deaconess Medical Center MS Clinic. Not all LTBI cases were associated with known risk factors for TB. Screening for LTBI before starting immunosuppressive agents for MS could help prevent activation of TB. Dimethyl fumarate use is associated with indeterminate QFT-GIT results, possibly due to functional effects on lymphocytes and levels of cytokines, such as interferon gamma. In contrast, fingolimod use was rarely associated with indeterminate QFT-GIT results despite a high rate of lymphopenia in virtually all patients.

Global trends and gaps in research related to latent tuberculosis infection

BackgroundThere is a global commitment to eliminating tuberculosis (TB). It is critical to detect and treat cases of latent TB infection (LTBI), the reservoir of new TB cases. Our study assesses trends in publication of LTBI-related research.MethodsWe used the keywords (“latent tuberculosis” OR “LTBI” OR “latent TB”) to search the Web of Science for LTBI-related articles published 1995–2018, then classified the results into three research areas: laboratory sciences, clinical research, and public health. We calculated the proportions of LTBI-related articles in each area to three areas combined, the average rates of LTBI-related to all scientific and TB-related articles, and the average annual percent changes (AAPC) in rates for all countries and for the top 13 countries individually and combined publishing LTBI research.ResultsThe proportion of LTBI-related articles increased over time in all research areas, with the highest AAPC in laboratory (38.2%/yr), followed by public health (22.9%/yr) and clinical (15.1%/yr). South Africa (rate ratio [RR] = 8.28, 95% CI 5.68 to 12.08) and India (RR = 2.53, 95% CI 1.74 to 3.69) had higher RRs of overall TB-related articles to all articles, but did not outperform the average of the top 13 countries in the RRs of LTBI-related articles to TB-related articles. Italy (RR = 1.95, 95% CI 1.45 to 2.63), Canada (RR = 1.73, 95% CI 1.28 to 2.34), and Spain (RR = 1.53, 95% CI 1.13 to 2.07) had higher RRs of LTBI-related articles to TB-related articles.ConclusionsHigh TB burden countries (TB incidence > 100 per 100,000 population) published more overall TB-related research, whereas low TB burden countries showed greater focus on LTBI. Given the potential benefits, high TB burden countries should consider increasing their emphasis on LTBI-related research.

Ethical issues in expanding latent TB management in high burden countries.

Global efforts are being made to eliminate tuberculosis (TB) as a public health problem by 2030. These efforts are being thwarted by the challenge of effective management to minimise the progression of latent TB infection (LTBI) to TB, thereby interrupting the chain of transmission. Approximately 5%-10% LTBI cases eventually develop TB in their lifetime with the risk being higher in children, people living with HIV/AIDS (PLHIV), undernourished people, and patients with diabetes, chronic kidney disease, silicosis, and other comorbid conditions. Apart from operational barriers, complex ethical issues govern decision-making processes in either retaining current LTBI management practices or advocating implementation of the latest World Health Organization guidelines, which suggest extending treatment to vulnerable groups who have a higher risk of progression to TB. Newer LTBI treatment regimens have a diminished risk of toxicity that allays threats to patient safety. Public health justification for treating LTBI can also override patient autonomy, but the lack of a patient-centred approach is associated with poor adherence and treatment outcomes. Cost-effectiveness studies need to evaluate the gains and losses accruing from funding treatment of LTBI versus similar costs in nutritional interventions for managing undernutrition. Similarly, the impact of diverting resources available for management of the existing active TB control programmes to expanding LTBI treatment also needs to be assessed. In conclusion, a comprehensive LTBI treatment strategy built on the basis of high-quality evidence is the best way forward for resolving the ethical considerations at the heart of LTBI management in the developing world. Keywords: Tuberculosis; India; Latent TB; Medical ethics.

A tuberculosis outbreak in a psychiatric hospital: Kanagawa, Japan, 2012.

In January 2012, an inpatient in a ward of a psychiatric hospital with nearly 300 beds in Kanagawa, Japan, was diagnosed with sputum smear-positive pulmonary tuberculosis (TB). Here we characterise the TB outbreak cases and identify the population at risk. TB was diagnosed when a person tested bacteriologically positive for TB or was determined to have TB by a physician. A latent TB infection (LTBI) case was defined as a person tested positive by interferon-gamma release assay (IGRA). A total of 125 contacts were screened via IGRA and chest X-ray. In all, 15 TB and 15 LTBI cases were found by the end of October 2012, and thereafter no additional TB case was found. Of the 15 TB cases, eight were culture-positive and all the isolates had identical variable number tandem repeat patterns. Twenty-four of the 56 (42.9%, 95% confidence interval (CI) 29.7-56.8) inpatients in the ward had either TB or LTBI with a relative risk of 8.6 (95% CI 1.2-59.3), compared to the staff members who did not work full-time in the ward (one of 20 (5.0%, 95% CI 0.0-24.9)). We recommend that psychiatric hospitals conduct periodic screening of staff members and inpatients for TB to prevent nosocomial TB outbreaks.

Differed IL-1 Beta Response between Active TB and LTBI Cases by Ex Vivo Stimulation of Human Monocyte-Derived Macrophage with TB-Specific Antigen.

Background The difference of macrophage-specific interleukin-1 beta (IL-1b) response between latent tuberculosis infection (LTBI) and active tuberculosis (TB) remains less studied. Method We performed this prospective study and recruited active TB patients, contacts with LTBI, and uninfected contacts. The gene and protein expression of human monocyte-derived macrophage (hMDM) after ex vivo stimulation by early secretory antigenic target-6KD (ESAT-6) and tuberculin purified protein derivatives (PPD) was studied by real-time PCR and flow cytometry. The effect of caspase-1 inhibitor was also studied. Result The IL-1b gene expression after 6 hr ESAT-6 1 μg/ml stimulation was different among active TB patients (n = 12), LTBI cases (n = 12), and uninfected contacts (n = 23) (log fold change: 0.98 ± 1.26 vs. 2.20 ± 0.96 vs. 2.20 ± 0.96, P = 0.013). The IL-1b gene expression at 24 hours was higher than that at 6 hours in LTBI cases (n = 4) and uninfected contacts (n = 6). After 24 hr ESAT-6 1 μg/ml stimulation, the percentage of IL-1b-expressed hMDM was borderline lower in the active TB patients (n = 9) than in the LTBI cases (n = 10) (14.0 ± 11.2% vs. 31.6 ± 22.5%, P = 0.065). Compared with ESAT-6 1 μg/ml stimulation but without the addition of caspase-1 inhibitor (CasI) (55.6 ± 16.3%), the percentage of IL-1b-positive hMDMs decreased after addition of CasI (50 μg/ml CasI: 49.8 ± 18.2%, P = 0.078; 100 μg/ml CasI: 46.6 ± 20.8%, P = 0.030; 150 μg/ml CasI: 33.7 ± 15.5%, P = 0.016). Conclusions This study revealed that macrophage-specific IL-1b response differed among different stages of Mycobacterium tuberculosis infection. The role of IL-1b and inflammasome in the process of LTBI progressing to active TB warrants further investigation.

A Model Based on the Combination of IFN-γ, IP-10, Ferritin and 25-Hydroxyvitamin D for Discriminating Latent From Active Tuberculosis in Children.

In recent years, pediatric research on tuberculosis (TB) has focused on addressing new biomarkers with the potential to be used as immunological non-sputum-based methods for the diagnosis of TB in children. The aim of this study was to characterize a set of cytokines and a series of individual factors (ferritin, 25-hydroxyvitamin D [25(OH)D], parasite infections, and nutritional status) to assess different patterns for discriminating between active TB and latent TB infection (LTBI) in children. The levels of 13 cytokines in QuantiFERON-TB Gold In-Tube (QFT-GIT) supernatants were analyzed in 166 children: 74 with active TB, 37 with LTBI, and 55 uninfected controls. All cytokines were quantified using Luminex or ELISA. Ferritin and 25(OH)D were also evaluated using CLIA, and Toxocara canis Ig-G antibodies were detected with a commercial ELISA kit. The combination of IP-10, IFN-γ, ferritin, and 25(OH)D achieved the best diagnostic performance to discriminate between active TB and LTBI cases in children in relation to the area under receiver operating characteristic (ROC) curve 0.955 (confidence interval 95%: 0.91–1.00), achieving optimal sensitivity and specificity for the development of a new test (93.2 and 90.0%, respectively). Children with TB showed higher ferritin levels and an inverse correlation between 25(OH)D and IFN-γ levels. The model proposed includes a combination of biomarkers for discriminating between active TB and LTBI in children to improve the accuracy of TB diagnosis in children. This combination of biomarkers might have potential for identifying the onset of primary TB in children.

Screening Young Children for Latent Tuberculosis in England: Lessons Learned from the Field

Objective Tuberculosis (TB) can affect young children, resulting in serious disease at a young age or reactivation later in life. Identifying cases of latent TB infection (LTBI) in children exposed to active cases is important to prevent morbidity and mortality. There is currently limited guidance on appropriate testing methods in situations involving mass screening of children in low TB incidence settings such as England. This study describes case reports of two separate occasions in which nursery-age children in England underwent LTBI screening and explores the decisions involved in choosing the most appropriate test and screening process. Methods A literature search, review of health protection case and incident management notes, and interviews with key stakeholders were conducted. Results Two different tests—tuberculin skin testing and interferon gamma release assay—were used in each respective screening situation and the decision between the two was taken based on cohort, organizational, and index case risk factors. Screening took place in dedicated secondary care clinics. No cases of LTBI were identified from either screening incident. Conclusion Our study highlights the lack of definitive guidance for mass LTBI screening of young children and presents the approaches to decision making that can be adopted by others. Further research is required to test the approach suggested in this article and to ensure that evidence-based national guidance provides a consistent and effective approach to such incidents.

Mycobacterium tuberculosis-specific cytokine biomarkers for the diagnosis of childhood TB in a TB-endemic setting

The tuberculin skin test and interferon-gamma release assays have limitations in diagnosing tuberculosis (TB), particularly in children. This study investigated the performance of candidate M. tuberculosis-specific cytokine biomarkers for TB in children in a TB-endemic setting. A total of 237 children with a household contact with smear-positive pulmonary TB were recruited. Importantly, a group of children with illnesses other than TB (sick controls) was included to assess specificity.Median IFN-ɣ, IL-1ra, IL-2, IL-13, IP-10, MIP-1β and TNF-α responses were significantly higher in children with active TB and latent TB infection (LTBI) than in both healthy and sick control children. Three of these cytokines – IL-2, IL-13 and IP-10 – showed better performance characteristics than IFN-ɣ, with IL-2 achieving positive and negative predictive values of 97.7% and 90.7%, respectively. Furthermore, IL-1ra and TNF-α responses differed significantly between active TB and LTBI cases, suggesting that they may be stage-specific biomarkers.Our data indicate that incorporating these biomarkers into future blood-based TB assays could result in substantial performance gains.

The Infectivity of Pulmonary Tuberculosis in Korean Army Units: Evidence from Outbreak Investigations.

BackgroundTuberculosis (TB) causes substantial health burden to the Korean military. This study aims to assess the impact of infectious TB cases on close and casual contacts in the Korean Army settings based on contact investigation data.MethodsSix Army units with infectious TB cases from September 2012 to May 2013 were enrolled in the study. We analyzed the clinical data from close and casual contacts screened using the tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube to identify latent tuberculosis infection (LTBI) cases. For the control group, 286 military conscripts with no reported TB exposure were tested by TST only.ResultsOf the 667 contacts of index cases, LTBI cases identified were as follows: 21.8% of close contacts of smear-positive cases (71/326), 8.5% of casual contacts of smear-positive cases (26/305), and 2.8% of close contacts of smear-negative cases (1/36). In the control group, 16.8% showed positivity in TST. In a multivariate analysis, having stayed in the same room or next room with TB patients was identified as a risk factor of LTBI.ConclusionUsing the data from TB contact investigations in the Korean Army units, we found an overall LTBI rate of 14.7% among the contacts screened. This study demonstrates that contacts living in the same building, especially the same room or next room, with TB patients are at a high risk of acquiring LTBI, serving as additional evidence for defining close and casual contacts of a TB patient with regard to Army barrack settings.