QuantiFERON-TB Gold In-Tube Assay Research Articles

Vitamin D supplements for fracture prevention in schoolchildren in Mongolia: analysis of secondary outcomes from a multicentre, double-blind, randomised, placebo-controlled trial

Vitamin D supplementation has been shown to increase total hip areal bone mineral density in healthy children and adolescents. We aimed to investigate whether supplementing schoolchildren living in Mongolia with weekly vitamin D3 for 3 years affected fracture risk. We did a multicentre, double-blind, randomised, placebo-controlled trial across 18 public schools in Ulaanbaatar, Mongolia. Schoolchildren were eligible if they were aged 6-13 years at screening, had a negative QuantiFERON-TB Gold In-tube assay (QFT) result, were not hypersensitive to vitamin D or immunocompromised, did not use vitamin D supplements, did not have clinical signs of rickets, and had no intention of leaving Ulaanbaatar within 3 years. Participants were randomly assigned (1:1) to receive either vitamin D (oral dose of 14 000 international units [IU] vitamin D3, once per week) or placebo for 3 years using permuted block randomisation stratified by school of attendance. Participants, care providers, and all trial staff were masked to group assignment during the intervention. Prespecified secondary outcomes were incidence of fractures and adverse events, ascertained using questionnaires. The fracture and safety analyses included participants who completed at least one follow-up fracture questionnaire. We estimated adjusted risk ratios (RRs) and 95% CIs using generalised linear models with binomial distribution and a log link function with adjustment for school of attendance. The trial is registered with ClinicalTrials.gov, NCT02276755, and the intervention ended in May, 2019. Between Sept 2, 2015, and March 20, 2017, 11 475 children were invited to participate in the study and 8851 were recruited and randomly assigned to receive either vitamin D (n=4418) or placebo (n=4433). 8348 participants were included in the fracture and safety analyses (4176 [94·5%] in the vitamin D group and 4172 [94·1%] in the placebo group). Of these, 4125 (49·4%) were female, 4223 (50·6%) were male, and 7701 (92·2%) were of Khalkh ancestry. Median age was 9·2 years (IQR 8·0-10·7) and 7975 (95·5%) participants had baseline serum 25-hydroxyvitamin D concentrations less than 50 nmol/L. During a median follow-up of 3·0 years (IQR 2·9-3·1), 268 (6·4%) participants in the vitamin D group and 253 (6·1%) in the placebo group reported one or more fractures (adjusted RR 1·10, 95% CI 0·93-1·29; p=0·27). Incidence of adverse events did not differ between study groups. Oral vitamin D supplementation at a dose of 14 000 IU/week for 3 years was safe, but did not influence fracture risk in schoolchildren living in Mongolia who had a high baseline prevalence of vitamin D deficiency. US National Institutes of Health.

The association between diabetes status and latent-TB IGRA levels from a cross-sectional study in eastern China.

There is a debate regarding the sensitivity of the QuantiFERON-TB Gold In-Tube (QFT) among people with diabetes, and prior studies have shown heterogeneous results. We evaluated whether the QFT TB antigen was modified among persons with differing diabetes status and other related risk factors. A cross-sectional study of 5,302 people was conducted to screen latent tuberculosis infection (LTBI) in eastern China. The QFT assay was performed as an indicator of LTBI. Fasting plasma glucose (FPG) was collected from each participant; the definition of diabetes followed the guidelines from the American Diabetes Association. Participants were classified into normoglycemia, prediabetes, undiagnosed diabetes, and previously diagnosed diabetes to evaluate the relationship between the QFT TB antigen and distinct diabetes status. TB antigen values from the QFT were statistically different among participants with differing diabetes status (P = 0.008). Persons with undiagnosed diabetes had a higher TB antigen value (0.96 ± 0.20) than persons with normoglycemia (0.50 ± 0.02, P < 0.05). However, the TB antigen values demonstrated no significant difference among the four different diabetic groups when stratified by the standard cutoff for the QFT (P = 0.492 for the positive group and P = 0.368 for the negative group). In a linear regression model, we found that FPG, age, and smoking were positively associated with the QFT TB antigen value (P = 0.017, P < 0.001, and P < 0.001). Diabetes status had little influence on the level of QFT TB antigen response among IGRA-positive persons. However, FPG, old age, and smoking were important risk factors for increasing levels of QFT TB antigen.

Gut microbiota composition can reflect immune responses of latent tuberculosis infection in patients with poorly controlled diabetes

BackgroundDiabetes mellitus (DM) is a major risk factor for tuberculosis (TB). Evidence has linked the DM-related dysbiosis of gut microbiota to modifiable host immunity to Mycobacterium tuberculosis infection. However, the crosslinks between gut microbiota composition and immunological effects on the development of latent TB infection (LTBI) in DM patients remain uncertain.MethodsWe prospectively obtained stool, blood samples, and medical records from 130 patients with poorly-controlled DM (pDM), defined as ever having an HbA1c > 9.0% within previous 1 year. Among them, 43 had LTBI, as determined by QuantiFERON-TB Gold in-Tube assay. The differences in the taxonomic diversity of gut microbiota between LTBI and non-LTBI groups were investigated using 16S ribosomal RNA sequencing, and a predictive algorithm was established using a random forest model. Serum cytokine levels were measured to determine their correlations with gut microbiota.ResultsCompared with non-LTBI group, the microbiota in LTBI group displayed a similar alpha-diversity but different beta-diversity, featuring decrease of Prevotella_9, Streptococcus, and Actinomyces and increase of Bacteroides, Alistipes, and Blautia at the genus level. The accuracy was 0.872 for the LTBI prediction model using the aforementioned 6 microbiome-based biomarkers. Compared with the non-LTBI group, the LTBI group had a significantly lower serum levels of IL-17F (p = 0.025) and TNF-α (p = 0.038), which were correlated with the abundance of the aforementioned 6 taxa.ConclusionsThe study results suggest that gut microbiome composition maybe associated with host immunity relevant to TB status, and gut microbial signature might be helpful for the diagnosis of LTBI.

QuantiFERON-TB Gold Plus and QuantiFERON-TB Gold In-tube assays for detecting latent tuberculosis infection in Thai healthcare workers.

Detecting latent tuberculosis infection (LTBI) is important, especially in high-risk populations including healthcare workers (HCWs). QuantiFERON-TB Gold Plus (QFT-Plus) is a new version of the interferon-gamma release assays (IGRAs) to replace the QuantiFERON-TB Gold In-tube (QFT-GIT). However, data on the use of QFT-Plus for LTBI detection in high TB-burden countries are limited. This study was conducted in a TB-endemic setting in Thailand. HCWs were enrolled in the study and underwent both tests during the annual health screening. The testing results were compared and the concordance was determined. Of 102 HCWs, 11 (10.78%) were positive according to both tests, and 15 (14.71%) were positive according to QFT-Plus. The overall agreement between assays was 96.08%, with Cohen's kappa coefficient (k) at 0.82. All four discordant results occurred with QFT-GIT negative and QFT-Plus positive. The comparison between QFT-GIT and QFT-Plus based on each antigen tube (TB1 or TB2) exhibited similar concordance with 99.02% and 95.10% agreement, respectively. The intra-comparison between TB1 and TB2 of QFT-Plus also showed good concordance at 96.08%. Among this group of HCWs, the LTBI prevalence of any positive results in both tests was low. Overall, the study showed good agreement between QFT-Plus and QFT-GIT (k = 0.82) with a minimal difference, suggesting similar assay performance to that mainly carried out in TB-low incidence countries. The results support the use of QFT-Plus for detecting LTBI in a format similar to QFT-GIT.

The exhaustion of lymphocytes is the main factor that decreases the sensitivity of QFT-GIT detection in silicosis

BackgroundTuberculosis infection is a major complication of silicosis, but there is no study on whether silicosis can affect the sensitivity of QuantiFERON-TB Gold In-Tube (QFT-GIT) assays. This study will analyze the relationship between silicosis and QFT-GIT, determine the main factor of the QFT-GIT sensitivity decrease in silicosis and explore the methods to increase the sensitivity.MethodsSilicosis patients with positive tubercle bacillus cultures were collected. The QFT-GIT, flow cytometry and blocking antibodies were used.ResultsThe sensitivity of QFT-GIT in silicosis patients (58.46%) was significantly decreased and the expression of PD-1 on T cells and CD56+NK cells in pulmonary tuberculosis combined with silicosis were higher than normal tuberculosis patients and silicosis only patients. Further analysis found that the ratio of PD-1+CD4+T and IFN-γwere negatively correlated and blockaded the PD-1 pathway with antibodies can restore the sensitivity of QFT-GIT in silicosis.ConclusionsThis is the first study to analyze the relationship between immune exhaustion and QFT-GIT in silicosis and found that the sensitivity of QFT-GIT was decreased by the expression of PD-1 on lymphocytes. Antibody blocking experiments increased the expression of IFN-γ and provided a new method to improve the sensitivity of QFT in silicosis. The study also found that silicosis can increase PD-1 expression. As PD-1 functions in infectious diseases, it will promote immune exhaustion in silicosis and lead to tuberculosis from latent to active infection. The study provided theoretical evidence for the diagnosis and immunotherapy of silicosis complications, and it has great value in clinical diagnostics and treatment.

Influence of Vitamin D Supplementation on Growth, Body Composition, and Pubertal Development Among School-aged Children in an Area With a High Prevalence of Vitamin D Deficiency

Vitamin D deficiency (defined as 25-hydroxyvitamin D [25(OH)D] <20 ng/mL) is prevalent among children living in temperate climates and has been reported to associate independently with stunting, obesity, and early activation of the hypothalamic-pituitary-gonadal axis. Phase 3 randomized clinical trials to investigate the influence of long-term vitamin D replacement on growth, body composition, and pubertal development of school-aged children with vitamin D deficiency are lacking. To determine whether weekly oral vitamin D supplementation influences linear growth, body composition, or pubertal development in school-aged children living in a setting where vitamin D deficiency is highly prevalent. This secondary analysis of a double-blind, placebo-controlled randomized clinical trial was conducted from June 2016 to June 2019 at 18 grade schools in Ulaanbaatar, Mongolia. School-aged children (6 to 13 years at baseline) attending participating schools were included. Exclusion criteria included a positive QuantiFERON-TB Gold in-tube assay result, conditions or medications associated with altered vitamin D metabolism, use of vitamin D supplements, signs of rickets, or intention to move from Ulaanbaatar within 4 years. Of 11 475 children invited to participate in the study, 9814 underwent QFT testing, and 8851 with negative results were included in the study. All but 1 participant in the placebo group completed follow-up and were included in the present analysis. Data were analyzed from November 2021 to February 2022. Weekly oral doses of vitamin D3, 14 000 IU, (n = 4418), or placebo (n = 4433) for 3 years. Mean z scores for height for age, body mass index for age, and waist-to-height ratio; mean percentage body fat, fat mass, and fat-free mass; and mean Tanner scores for pubertal development. Of 8851 participants, 4366 (49.3%) were female, and 8165 (92.2%) were of Khalkh ethnicity; the mean (SD) age was 9.4 (1.6) years. A total of 8453 participants (95.5%) were vitamin D deficient at baseline, and mean end-of-study 25(OH)D concentrations among participants randomized to vitamin D vs placebo were 31.0 vs 10.7 ng/mL (mean difference, 20.3; 95% CI; 19.9-20.6). However, vitamin D supplementation did not influence mean height for age, body mass index for age, waist-to-height ratio, percentage body fat, fat mass, fat-free mass, or Tanner scores, either overall or within subgroups defined by baseline 25(OH)D concentration less than 10 ng/mL vs 10 ng/mL or greater, estimated calcium intake less than 500 mg/d vs 500 mg/d or greater, or male vs female sex. In school-aged children in this study with low baseline vitamin D status, oral vitamin D3 supplementation at a dose of 14 000 IU per week for 3 years was effective in elevating 25(OH)D concentrations but did not influence growth, body composition, or pubertal development. ClinicalTrials.gov Identifier: NCT02276755.

Host, technical, and environmental factors affecting QuantiFERON-TB Gold In-Tube performance in children below 5 years of age

Interferon-gamma release assays performance can be impaired by host-related, technical and environmental factors, but data in young children are limited. We performed a cross-sectional study of children < 5 years-of-age at risk of tuberculosis (TB), using QuantiFERON-TB Gold In-Tube (QFT-GIT) assays. The impact of the following was evaluated: (i) host-related [age; hematological parameters; erythrocyte sedimentation rate (ESR); C-reactive protein (CRP); and tobacco smoke exposure (TSE) based on serum cotinine concentrations], (ii) technical (pre-analytical delay) and (iii) environmental factors (annual season; monthly temperatures). Of 204 children, 35 (17.2%) were diagnosed with latent TB infection or TB disease. QFT-GIT results were indeterminate in 14 (6.9%) patients. In multivariate analysis, younger age and higher ESR were associated with lower positive control responses (beta: 0.247, p = 0.002 and − 0.204, p = 0.007, respectively), and increasing age was associated with lower rates of indeterminate QFT-GIT results [OR (95% CI) 0.948 (0.903–0.996) per month, p = 0.035]. In children with positive QFT-GIT results, average monthly temperatures correlated with antigen responses (r = 0.453, p = 0.020); also, antigen responses were lower in winter than in other seasons (p = 0.027). Serum cotinine concentrations determined in a subgroup of patients (n = 41) indicated TSE in 36 (88%), positive control responses being lower in children with TSE (p = 0.034). In children < 5 years-of-age, young age, elevated ESR, temperature, annual season and TSE can affect the performance of QFT-GIT assays.

Dual latent tuberculosis screening with tuberculin skin tests and QuantiFERON-TB assays before TNF-α inhibitor initiation in children in Spain

Tumor-necrosis-factor-α inhibitors (anti-TNF-α) are associated with an increased risk of tuberculosis (TB) disease, primarily due to reactivation of latent TB infection (LTBI). We assessed the performance of parallel LTBI screening with tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube assays (QFT-GIT) before anti-TNF-α treatment in children with immune-mediated inflammatory disorders in a low TB-burden setting. We conducted a multicenter cohort study involving 17 pediatric tertiary centers in Spain. LTBI was defined as the presence of a positive TST and/or QFT-GIT result without clinical or radiological signs of TB disease. A total of 270 patients (median age:11.0 years) were included, mainly with rheumatological (55.9%) or inflammatory bowel disease (34.8%). Twelve patients (4.4%) were diagnosed with TB infection at screening (LTBI, n = 11; TB disease, n = 1). Concordance between TST and QFT-GIT results was moderate (TST+/QFT-GIT+, n = 4; TST−/QFT-GIT+, n = 3; TST+/QFT-GIT-, n = 5; kappa coefficient: 0.48, 95% CI: 0.36–0.60). Indeterminate QFT-GIT results occurred in 10 patients (3.7%) and were associated with young age and elevated C-reactive protein concentrations. Eleven of 12 patients with TB infection uneventfully completed standard LTBI or TB treatment. During a median follow-up period of 6.4 years, only 2 patients developed TB disease (incidence density: 130 (95% CI: 20–440) per 100,000 person-years), both probable de novo infections.Conclusion: A substantial number of patients were diagnosed with LTBI during screening. The dual strategy identified more cases than either of the tests alone, and test agreement was only moderate. Our data show that in children in a low TB prevalence setting, a dual screening strategy with TST and IGRA before anti-TNF-α treatment is effective.What is Known:• The optimal screening strategy for latent tuberculosis in children with immune-mediated inflammatory disorders remains uncertain.• Children receiving anti-TNF-α drugs are at increased risk of developing severe tuberculosis disease.What is New:• A dual screening strategy, using TST and an IGRA assay, identified more children with latent tuberculosis than either of the tests alone.• Identification and treatment of latent tuberculosis before initiation of anti-TNF-α therapy averted incident tuberculosis cases.

Analysis of the diagnostic efficacy of the QuantiFERON-TB Gold In-Tube assay for preoperative differential diagnosis of spinal tuberculosis.

BackgroundDifferential diagnosis of spinal tuberculosis is important for the clinical management of patients, especially in populations with spinal bone destruction. There are few effective tools for preoperative differential diagnosis in these populations. The QuantiFERON-TB Gold In-Tube (QFT-GIT) test has good sensitivity and specificity for the diagnosis of tuberculosis, but its efficacy in preoperative diagnosis of spinal tuberculosis has rarely been investigated.MethodA total of 123 consecutive patients with suspected spinal tuberculosis hospitalized from March 20, 2020, to April 10, 2022, were included, and the QFT-GIT test was performed on each patient. We retrospectively collected clinical data from these patients. A receiver operating characteristic (ROC) curve was plotted with the TB Ag-Nil values. The cutoff point was calculated from the ROC curve of 61 patients in the study cohort, and the diagnostic validity of the cutoff point was verified in a new cohort of 62 patients. The correlations between TB Ag-Nil values and other clinical characteristics of the patients were analyzed.ResultsOf the 123 patients included in the study, 51 had confirmed tuberculosis, and 72 had non-tuberculosis disease (AUC=0.866, 95% CI: 0.798-0.933, P<0.0001). In patients with spinal tuberculosis, the QFT-GIT test sensitivity was 92.16% (95% CI: 80.25%-97.46%), and the specificity was 67.14% (95% CI: 54.77%-77.62%). The accuracy of diagnostic tests in the validation cohort increased from 77.42% to 80.65% when a new cutoff point was selected (1.58 IU/mL) from the ROC curve of the study cohort. The TB Ag-Nil values in tuberculosis patients were correlated with the duration of the patients’ disease (r=0.4148, P=0.0025).ConclusionThe QFT-GIT test is an important test for preoperative differential diagnosis of spinal tuberculosis with high sensitivity but low specificity. The diagnostic efficacy of the QFT-GIT test can be significantly improved via application of a new threshold (1.58 IU/mL), and the intensity of the QFT-GIT test findings in spinal tuberculosis may be related to the duration of a patient’s disease.

Clinical relevance of false-negative interferon-gamma release assays in patients with tuberculous pleurisy in an intermediate tuberculosis burden country

BackgroundThere have been few studies to verify factors associated with a false-negative interferon-gamma release assay (IGRA) in patients with tuberculous pleurisy. We investigated the clinical relevance of false-negative results of the blood QuantiFERON-TB Gold In-Tube (QFT-GIT) assay and its risk factors in patients diagnosed with pleural tuberculosis (TB).MethodsMedical records of 650 pleural TB patients in a tertiary hospital between January 2009 and December 2020 were reviewed retrospectively. Patients who underwent the blood QFT-GIT assay and pleural fluid analysis before starting anti-TB medication were included.ResultsOf 199 patients with pleural TB who were performed QFT-GIT assay, 36 (18.1%) were false-negative results. These patients tended to be older than those with a positive result (P=0.060). The QFT-GIT-false-negative group of had significantly more comorbidities such as end-stage renal disease (ESRD), haematological cancer or pneumoconiosis than the QFT-GIT-positive group. Hypoproteinaemia and pH >6 in pleural fluid were associated with a false-negative QFT-GIT. Of the 199 patients, 163 (81.9%) were cured or completed anti-TB treatment; 13 patients (6.5%) died. The QFT-GIT-negative patients had significantly worse outcomes including mortality [unfavourable outcome: 33.3% (12/36 patients) in QFT-GIT-negative groups vs. 14.7% (24/163 patients) in QFT-GIT-positive groups, P<0.017; overall mortality: 16.7% (6/36 patients) vs. 4.3% (7/163 patients), respectively, P<0.015].ConclusionsIn pleural TB, a false-negative QFT-GIT result was 18.1% in a country of intermediate TB incidence. This discordant result in GFT-GIT was associated with ESRD, pneumoconiosis, hypoproteinaemia and a poor outcome. Clinicians should keep in mind the possibility of false-negativity in the blood IGRA test, especially in specific situations and its impact on TB outcome in managing patients with pleural TB.

Morphologic Spectrum of Lymphadenopathy in Adult-onset Immunodeficiency (Anti-interferon-γ Autoantibodies).

Adult-onset immunodeficiency syndrome (AOIS) caused by anti-interferon-γ autoantibodies is an emerging disease. Affected patients present typically with systemic lymphadenopathy, fatigue, and fever. We studied 36 biopsy specimens, 31 lymph nodes, and 5 extranodal sites, of AOIS confirmed by serum autoantibody or QuantiFERON-TB Gold In-Tube assay. We describe the morphologic features and the results of ancillary studies, including special stains, immunohistochemistry, and molecular testing. The overall median age of these patients was 60.5 years (range, 41 to 83 y) with a male-to-female ratio of 20:16. All biopsy specimens showed nontuberculous mycobacterial infection, and most cases showed the following histologic features: capsular thickening with intranodal sclerosing fibrosis, irregularly distributed ill-formed granulomas or histiocytic aggregates with neutrophilic infiltration, interfollicular expansion by a polymorphic infiltrate with some Hodgkin-like cells that commonly effaces most of the nodal architecture and proliferation of high endothelial venules. In situ hybridization analysis for Epstein-Barr virus-encoded RNA showed scattered (<1%) to relatively more common (4% to 5%) positive cells in 29 of 30 (97%) tested specimens, reflecting immune dysregulation due to an interferon-γ defect. In the 31 lymph node specimens, 23 (74%) cases showed increased immunoglobulin G4-positive plasma cells (4 to 145/HPF; mean, 49.7/HPF) with focal areas of sclerosis reminiscent of immunoglobulin G4-related lymphadenopathy, 4 (13%) cases resembled, in part, nodular sclerosis Hodgkin lymphoma, and 9 (29%) cases mimicked T-cell lymphoma. Among 33 patients with available clinical follow-up, 20 (61%) showed persistent or refractory disease despite antimycobacterial therapy, and 1 patient died of the disease. We conclude that the presence of ill-defined granulomas, clusters of neutrophils adjacent to the histiocytic aggregates, and some Epstein-Barr virus-positive cells are features highly suggestive of AOIS. A high index of clinical suspicion and awareness of the morphologic features and differential diagnosis of AOIS are helpful for establishing the diagnosis.

Low-dose steroids are associated with indeterminate QuantiFERON-TB Gold In-Tube assay results in immunocompetent children

Immunocompromised status can result in indeterminate QuantiFERON-TB Gold In-Tube (QFT-GIT) results, but the association of indeterminate results with immunocompetent status in children is unknown. Therefore, we aimed to identify factors associated with indeterminate QFT-GIT results for immunocompetent children. We conducted a retrospective chart review of children (aged ≤ 18 years) who underwent QFT-GIT between September 2006 and July 2017 at the Severance Hospital, Seoul, South Korea. Of the 2037 QFT-GIT assays included in the present study, 7.7% yielded indeterminate QFT-GIT results. Multivariable logistic regression analysis identified younger age (OR 0.88; 95% CI 0.836–0.927; P < 0.001), elevated white blood cell (WBC) count (OR 1.066; 95% CI 1.020–1.115; P = 0.005), decreased albumin levels (OR 0.505; 95% CI 0.316–0.807; P = 0.004), and low-dose steroid therapy (< 1 mg/kg per day of prednisone or equivalent for < 2 weeks) (OR 76.146; 95% CI 8.940–648.569; P < 0.001) as significant factors influencing indeterminate results. Younger age, high WBC count, low albumin levels, and low-dose steroid therapy were associated with indeterminate QFT-GIT results. Low-dose steroid therapy had the highest OR for the indeterminate results compared to other significant risk factors. Our study suggests that screening for steroid doses is important prior to performing interferon-gamma release assays for immunocompetent children.

Potential use of in vitro tests in the diagnosis of tuberculosis (literature review)

SummaryThe search for methods to improve early diagnosis of tuberculosis has been particularly active in the last two decades. Diagnostics of latent tuberculosis infection will increase the efficacy of anti-tuberculosis measures. Tu-berculosis in HIV patients, which is increasingly common in the incident population, has specific clinical, immuno-logical, and pathomorphological characteristics posing challenges to diagnosis confirmation. HIV-infected indi-viduals have a 30-fold risk of tuberculosis compared with the general population. Diagnostic challenges are par-ticularly high at the stage of severe immunodeficiency. In the last two decades, IGRAs, which have a higher specifi-city versus tuberculin skin tests, have been increasingly used. We present a literature review of studies comparing the diagnostic efficacy of T-SPOT.TB and QuantiFERON-TB Gold in-Tube assays in patients with suspected active tuberculosis. According to literature data, QuantiFERON assay more frequently yields false negative results in HIV patients with markedly decreased CD4+ cell counts. T-SPOT.TB sensitivity is essentially independent of age, whereby the sensitivity of QuantiFERON-TB reduces after the age of 30 years. T-SPOT.TB assay was not found to be affected by drug therapy. Based on this literature review, we assume that the use of T-SPOT.TB assay is most ap-propriate in the following cases: in patients taking drugs that inhibit gamma interferon production (glucocorti-coids); in patients taking drugs that reduce leukocyte lev-els (NSAIDs: aspirin, paracetamol, Ketorol; also cytostatic agents etc.); in children under 5 years and in elderly sub-jects. T-SPOT.TB appears to be a promising test within the assessment of HIV-infected patients.

Usefulness of the IgA and IgG Responses to Macrophage Migration Inhibitory Factor for the Diagnosis of Tuberculosis.

Serological tests offer the potential in order to improve the diagnosis of tuberculosis (TB). Macrophage migration inhibitory factor (MIF) plays a protective role in infection control in TB; however, to date, no studies on antibody responses to MIF have been reported. We measured immunoglobulin (Ig)A and IgG responses to MIF in individuals with either active tuberculosis (ATB; n = 65), latent tuberculosis (LTBI; n = 53), or in non-infected individuals (NI; n = 62). The QuantiFERON-TB Gold In-Tube (QFT-GIT) assay was used in order to screen for LTBI. The level of IgA against MIF was significantly lower in LTBI and ATB patients than in NI individuals, was significantly related to LTBI and ATB diagnosis, and it could discriminate between LTBI and ATB. In contrast, the level of IgG against MIF was significantly lower in LTBI patients than in NI individuals and was significantly related to LTBI diagnosis. Anti-MIF IgG levels were significantly lower in AFB-negative TB, minimal TB, and new ATB patients, than in the NI group. IgA and IgG levels against MIF both showed significant negative correlations with IFN-γ levels, as assessed using the QFT-GIT test. Although none of the antibodies could achieve high diagnostic predictive power individually, our results suggest the possibility of using IgA antibody responses to MIF in the diagnosis of LTBI and ATB.

Effect of pregnancy and HIV infection on detection of latent TB infection by Tuberculin Skin Test and QuantiFERON-TB Gold In-Tube assay among women living in a high TB and HIV burden setting

ObjectiveTo investigate the effect of pregnancy and Human immunodeficiency virus (HIV) infection on detection performances of tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube (QFTGIT) for the diagnosis of latent tuberculosis infection (LTBI) among women living in high TB and HIV endemic setting. MethodA cross-sectional study was conducted among women with and without pregnancy and HIV infection. Three-hundred twenty women were enrolled in this study and were diagnosed using TST and QFTGIT for the detection of LTBI. ResultsOverall prevalence of LTBI among the enrolled women was 55.6%, 46.3% and 51.1% as determined by TST, QFTGIT and concordant TST/QFTGIT results, respectively. Our study revealed that pregnancy or HIV infection reduced the rate of detection of LTBI by TST and QFTGIT tests, with the utmost effect observed in HIV-positive pregnant women. Additionally, we observed that the concordance between TST and QFTGIT among women increased with the presence of pregnancy and/or HIV infection. A history of contact with TB patients was significantly associated with positivity of TST and QFTGIT. ConclusionThis study demonstrated that both pregnancy and HIV infection profoundly affected the detection performance of TST and QFTGIT, which may be associated with immunosuppression of anti-mycobacterial immunity in women with pregnancy and/or HIV infection.

Depression and recovery of IL-17A secretion in mitogen responses in patients with active tuberculosis-a prospective observational study

T-helper cell 17 (Th17) is a distinct subset of CD4+ T lymphocytes that is important in the pathogenesis of Mycobacterium tuberculosis infection. This study aims to investigate the characteristics of interleukin (IL)-17A and Th17-related cytokines after stimulation with phytohemagglutinin in patients with active tuberculosis (TB). This prospective cohort study enrolled patients with culture-confirmed active TB. QuantiFERON-TB Gold In-Tube (QFT-GIT) assay was performed upon TB diagnosis and at 2 months after TB treatment. Their non-TB-specific secretion of IL-17A and Th17-related cytokines were measured in supernatants of mitogen tubes in QFT-GIT and compared to those of active TB contacts with or without latent TB infection. We analyzed the association between IL-17A secretions and TB presentation and treatment outcomes. A total of 108 patients with TB and 64 non-TB cases were enrolled. The secretion of IL-17A, IL-21, IL-23, and IL-6 were lower in active TB patients upon TB diagnosis. In active TB patients, lower IL-17A secretions were associated with higher grades of sputum smear. In the multivariate analysis, lower IL-17A secretions served as an independent factor associated with 2-month culture non-conversion (odds ratio 23.04, 95% confidence interval [CI] 1.69-84.78) and on-treatment mortality (hazard ratio 28.54, 95% CI 1.30-99.25). The levels of IL-23, and IL-6 significantly increased after 2 months of anti-TB treatment. The non-TB-specific IL-17A secretions were lower in active TB patients upon TB diagnosis and associated with higher disease severity and worse treatment outcomes. Trend of recovery of the depressed Th17-related cytokines was noted after effective anti-TB treatment.

Vitamin D Supplements for Prevention of Tuberculosis Infection and Disease

BackgroundVitamin D metabolites support innate immune responses to Mycobacterium tuberculosis. Data from phase 3, randomized, controlled trials of vitamin D supplementation to prevent tuberculosis infection are lacking.MethodsWe randomly assigned children who had negative results for M. tuberculosis infection according to the QuantiFERON-TB Gold In-Tube assay (QFT) to receive a weekly oral dose of either 14,000 IU of vitamin D3 or placebo for 3 years. The primary outcome was a positive QFT result at the 3-year follow-up, expressed as a proportion of children. Secondary outcomes included the serum 25-hydroxyvitamin D (25[OH]D) level at the end of the trial and the incidence of tuberculosis disease, acute respiratory infection, and adverse events.ResultsA total of 8851 children underwent randomization: 4418 were assigned to the vitamin D group, and 4433 to the placebo group; 95.6% of children had a baseline serum 25(OH)D level of less than 20 ng per milliliter. Among children with a valid QFT result at the end of the trial, the percentage with a positive result was 3.6% (147 of 4074 children) in the vitamin D group and 3.3% (134 of 4043) in the placebo group (adjusted risk ratio, 1.10; 95% confidence interval [CI], 0.87 to 1.38; P=0.42). The mean 25(OH)D level at the end of the trial was 31.0 ng per milliliter in the vitamin D group and 10.7 ng per milliliter in the placebo group (mean between-group difference, 20.3 ng per milliliter; 95% CI, 19.9 to 20.6). Tuberculosis disease was diagnosed in 21 children in the vitamin D group and in 25 children in the placebo group (adjusted risk ratio, 0.87; 95% CI, 0.49 to 1.55). A total of 29 children in the vitamin D group and 34 in the placebo group were hospitalized for treatment of acute respiratory infection (adjusted risk ratio, 0.86; 95% CI, 0.52 to 1.40). The incidence of adverse events did not differ significantly between the two groups.ConclusionsVitamin D supplementation did not result in a lower risk of tuberculosis infection, tuberculosis disease, or acute respiratory infection than placebo among vitamin D–deficient schoolchildren in Mongolia. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT02276755.)

Evolution of Interferon-Gamma Release Assay Results and Submillisievert Chest CT Findings among Close Contacts of Active Pulmonary Tuberculosis Patients.

BackgroundLatent tuberculosis (TB) infection among TB contacts is diagnosed using plain chest radiography and interferon-gamma release assays (IGRAs). However, plain chest radiographs often miss active TB, and the results of IGRA could fluctuate over time. The purpose of this study was to elucidate changes in the results of the serial IGRAs and in the findings of the serial submillisievert chest computed tomography (CT) scans among the close contacts of active pulmonary TB patients.MethodsPatients age 20 or older with active pulmonary TB and their close contacts were invited to participate in this study. Two types of IGRA (QuantiFERON-TB Gold In-Tube assay [QFT-GIT] and the T-SPOT.TB test [T-SPOT]) and submillisievert chest CT scanning were performed at baseline and at 3 and 12 months after enrollment.ResultsIn total, 19 close contacts participated in this study. One was diagnosed with active pulmonary TB and was excluded from further analysis. At baseline, four of 18 contacts (22.2%) showed positive results for QFT-GIT and T-SPOT; there were no discordant results. During the follow-up, transient and permanent positive or negative conversions and discordant results between the two types of IGRAs were observed in some patients. Among the 17 contacts who underwent submillisievert chest CT scanning, calcified nodules were identified in seven (41.2%), noncalcified nodules in 14 (82.4%), and bronchiectasis in four (23.5%). Some nodules disappeared over time.ConclusionThe results of the QFT-GIT and T-SPOT assays and the CT images may change during 1 year of observation of close contacts of the active TB patients.

Latent Tuberculosis Infection Increases in Kidney Transplantation Recipients Compared With Transplantation Candidates: A Neglected Perspective in Tuberculosis Control.

BackgroundThe prevalence and incidence of latent tuberculosis infection (LTBI) in patients with kidney transplantation remain unclear.MethodsIn this prospective study, we enrolled kidney transplantation candidates (KTCs) and recipients (KTRs) from 2014 to 2018. We defined LTBI as a positive result of QuantiFERON-TB Gold In-tube (QFT). We analyzed the predictors for LTBI acquisition and followed up on QFT assay test for 2 years among those initially without LTBI.ResultsOf 425 patients enrolled, 305 (71.8%) patients belonged to the KTC group and 120 (28.2%) to the KTR group. The initial QFT showed positive results in 32 (10.5%) and 24 (20.0%) patients in the KTC and KTR groups, respectively (P = .009). The QFT response value in patients with LTBI was higher in the KTR group than in the KTC group (1.85 vs 1.06 IU/mL, P = .046). Multivariate logistic regression showed that old age, absence of bacillus Calmette–Guérin (BCG) scar, presence of donor-specific antibody, and KTR group were independent factors for positive LTBI. For participants with initial negative QFT, positive QFT conversion within a 2-year follow-up was higher after kidney transplantation (20%) than in KTCs (5.5%) (P = .034).ConclusionsThis study is the first cohort to follow up LTBI status in patients with kidney transplantation and shows its higher prevalence and incidence in KTRs. It indicates that surveillance of LTBI after renal transplantation is important. In addition to status of kidney transplantation, old age, no BCG vaccination, and positive donor-specific antibody are also positive predictors for LTBI.

Diagnostic Potential of IgG and IgA Responses to Mycobacterium tuberculosis Antigens for Discrimination among Active Tuberculosis, Latent Tuberculosis Infection, and Non-Infected Individuals

Tuberculosis remains a major public health problem. Conventional tests are inadequate to distinguish between active tuberculosis (ATB) and latent tuberculosis infection (LTBI). We measured antibody responses to Mycobacterium tuberculosis antigens (Mycobacterium tuberculosis chorismate mutase (TBCM), antigen 85B (Ag85B), early secreted antigen-6 (ESAT-6), and culture filtrate protein-10 (CFP-10) in ATB, LTBI, and non-infected (NI) individuals. Serum immunoglobulin G (IgG) and immunoglobulin A (IgA) levels were measured and the QuantiFERON-TB Gold In-Tube assay was used to diagnose LTBI. IgG levels against TBCM were significantly higher in LTBI than NI subjects. IgG and IgA levels against Ag85B and IgG levels against CFP-10 were significantly higher in ATB, followed by LTBI, and then NI. When the ATB group was subdivided, IgG levels against Ag85B and CFP-10 were significantly higher in each subgroup compared with those in LTBI and NI groups. Positive correlation trends between interferon-gamma and IgG levels against Ag85B, TBCM, and CFP-10 and IgA levels against Ag85B in LTBI and NI subjects were observed. Age- and sex-adjusted models showed that IgG against TBCM and CFP-10 was independently related to LTBI diagnosis, and IgG against Ag85B was independently related to the diagnosis of ATB and could distinguish between LTBI and ATB. Overall, IgG antibody responses to TBCM, Ag85B, and CFP-10 can discriminate among ATB, LTBI, and NI groups.