Beyond the Clinic: The Activation of Diverse Cellular and Humoral Factors Shapes the Immunological Status of Patients with Active Tuberculosis.

Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis (TB), has killed nearly one billion people in the last two centuries. Nowadays, TB remains a major global health problem, ranking among the thirteen leading causes of death worldwide. Human TB infection spans different levels of stages: incipient, subclinical, latent and active TB, all of them with varying symptoms, microbiological characteristics, immune responses and pathologies profiles. After infection, Mtb interacts with diverse cells of both innate and adaptive immune compartments, playing a crucial role in the modulation and development of the pathology. Underlying TB clinical manifestations, individual immunological profiles can be identified in patients with active TB according to the strength of their immune responses to Mtb infection, defining diverse endotypes. Those different endotypes are regulated by a complex interaction of the patient's cellular metabolism, genetic background, epigenetics, and gene transcriptional regulation. Here, we review immunological categorizations of TB patients based on the activation of different cellular populations (both myeloid and lymphocytic subsets) and humoral mediators (such as cytokines and lipid mediators). The analysis of the participating factors that operate during active Mtb infection shaping the immunological status or immune endotypes of TB patients could contribute to the development of Host Directed Therapy.

Flow cytometric detection of IFN-γ production and Caspase-3 activation in CD4+ T lymphocytes to discriminate between healthy and Mycobacterium bovis naturally infected water buffaloes.

Tuberculosis has a negative economic impact on buffalo farming, and it poses a potential threat to human health. Interferon-gamma (IFN-γ) plays a central role in protection against mycobacterial diseases, illustrating the importance of T-cell mediated immune responses in tuberculosis infection. Recently, the expression of Caspase-3, a critical executor of apoptosis, in M. tuberculosis-specific IFN-γ+CD4+ T cells was used as a new marker to distinguish active from latent tuberculosis infection in humans. The aims of this work were to develop a whole blood flow cytometric assay to detect the production of IFN-γ and the activation of Caspase-3 by CD4+ T lymphocytes from water buffalo and to evaluate whether these parameters can discriminate between healthy and M. bovis naturally infected buffaloes. A total of 35 Italian Mediterranean buffaloes were grouped in two groups: uninfected and M. bovis infected (based on the results of antemortem diagnostic tests: single intradermal tuberculin (SIT) and ELISA IFN-γ tests). Whole blood was incubated for 6 h with tubercular antigens: PPD-B, PPD-A, ESAT-6/CFP-10 and a new mix of precocious secreted antigens (PA). Our results showed a significant increase in the percentage of IFN-γ+CD4+ T cells in infected compared to the uninfected animals after each stimulus. Improved sensitivity of the assay was obtained by including the stimulation with the new mix of PA. Interestingly, we observed a concomitant decrease in percentage of Caspase-3+CD4+ T cells in M. bovis infected animals compared to the control healthy ones, regardless of the stimulus used. Overall, these results showed that M. bovis infection activates CD4+ T lymphocytes to produce IFN-γ and at the same time causes a concomitant decrease of Caspase-3 activation in CD4+ T cells. This study for the first time in water buffalo describes the development of a whole blood flow cytometric assay for the detection of IFN-γ producing CD4+ T cells and proposes the expression of active Caspase-3 as an additional bovine TB biomarker. Although further studies are needed to better understand the mechanisms of Caspase-3-mediated cell death during tuberculosis, our data can help to better understand the cellular immune response to M. bovis infection in buffalo species.

They do not have symptoms - why do they need to take medicines? Challenges in tuberculosis preventive treatment among children in Cambodia: a qualitative study.

BACKGROUND: Latent tuberculosis (TB) infection has been known as a seedbed for TB disease later in life. The interruption from latent TB infection to TB disease can be done through TB preventive treatment (TPT). In Cambodia, only 40.0% of children under five years old who were the household contacts to bacteriologically confirmed TB cases were initiated with TPT in 2021. Scientific studies of context-specific operational challenges in TPT provision and uptake among children are scarce, particularly in high TB-burden countries. This study identified challenges in TPT provision and uptake among children in Cambodia from the perspective of healthcare providers and caregivers. METHODS: Between October and December 2020, we conducted in-depth interviews with four operational district TB supervisors, four clinicians and four nurses in charge of TB in referral hospitals, four nurses in charge of TB in health centers, and 28 caregivers with children currently or previously on TB treatment or TPT, and those who refused TPT for their eligible children. Data were audio recorded along with field notetaking. After verbatim transcription, data analyses were performed using a thematic approach. RESULTS: The mean age of healthcare providers and caregivers were 40.19 years (SD 12.0) and 47.9 years (SD 14.6), respectively. Most healthcare providers (93.8%) were male, and 75.0% of caregivers were female. More than one-fourth of caregivers were grandparents, and 25.0% had no formal education. Identified key barriers to TPT implementation among children included TPT side effects, poor adherence to TPT, poor understanding of TPT among caregivers, TPT risk perception among caregivers, TPT's child-unfriendly formula, TPT supply-chain issues, caregivers' concern about the effectiveness of TPT, being non-parental caregivers, and poor community engagement. CONCLUSION: Findings from this study suggest that the national TB program should provide more TPT training to healthcare providers and strengthen supply chain mechanisms to ensure adequate TPT drug supplies. Improving community awareness of TPT among caregivers should also be intensified. These context-specific interventions will play a crucial role in expanding the TPT program to interrupt the development from latent TB infection to active and ultimately lead to ending TB in the country.

Preventive effects of Mycobacterium tuberculosis DNA vaccines on the mouse model with latent tuberculosis infection.

Background: About a quarter of the world's population with latent tuberculosis infection (LTBI) are the main source of active tuberculosis. Bacillus Calmette Guerin (BCG) cannot effectively control LTBI individuals from developing diseases. Latency-related antigens can induce T lymphocytes of LTBI individuals to produce higher IFN-γ levels than tuberculosis patients and normal subjects. Herein, we firstly compared the effects of M. tuberculosis (MTB) ag85ab and 7 latent DNA vaccines on clearing latent MTB and preventing its activation in the mouse LTBI model. Methods: A mouse LTBI model was established, and then immunized respectively with PBS, pVAX1 vector, Vaccae vaccine, ag85ab DNA and 7 kinds of latent DNAs (including rv1733c, rv2660c, rv1813c, rv2029c, rv2628, rv2659c and rv3407) for three times. The mice with LTBI were injected with hydroprednisone to activate the latent MTB. Then, the mice were sacrificed for the bacterial count, histopathological examination, and immunological evaluation. Results: Using chemotherapy made the MTB latent in the infected mice, and then using hormone treatment reactivated the latent MTB, indicating that the mouse LTBI model was successfully established. After the mouse LTBI model was immunized with the vaccines, the lung colony-forming units (CFUs) and lesion degree of mice in all vaccines group were significantly decreased than those in the PBS group and vector group (P<0.0001, P<0.05). These vaccines could induce antigen-specific cellular immune responses. The number of IFN-γ effector T cells spots secreted by spleen lymphocytes in the ag85ab DNA group was significantly increased than those in the control groups (P<0.05). In the splenocyte culture supernatant, IFN-γ and IL-2 levels in the ag85ab, rv2029c, and rv2659c DNA groups significantly increased (P<0.05), and IL-17A levels in ag85ab and rv2659c DNA groups also significantly increased (P<0.05). Compared with the PBS and vector groups, the proportion of CD4+CD25+FOXP3+ regulatory T cells in spleen lymphocytes of ag85ab, rv2660c, rv2029c, and rv3407 DNA groups were significantly reduced (P<0.05). Conclusions: MTB ag85ab and 7 kinds of latent DNA vaccines showed immune preventive efficacies on a mouse model of LTBI, especially the rv2659c, and rv1733c DNA. Our findings will provide candidates for the development of new multi-stage vaccines against TB.

Efficacy and Risk Factors of Interferon-Gamma Release Assays among HIV-Positive Individuals.

Latent tuberculosis is prevalent in HIV-infected people and has an impact on the progression of AIDS. The aim of this study is to match a more accurate IGRA method for the better detection of latent tuberculosis infection in HIV patients. All 2394 patients enrolled were tested using three IGRA methods. The positive rate consistency of pairwise comparison and risk factors were analyzed. Receiver operator characteristic (ROC) curve analysis was applied to evaluate the diagnostic value of T-SPOTTB. The positive rates of the three methods were statistically different (p < 0.001). The CD4+ T cell number statistically impacted the QuantiFERON and Wan Tai tests after the analysis with univariate logistic regression, while no statistical difference was observed in T-SPOT.TB. Additionally, there was a better sensitivity and specificity of T-SPOT.TB if the positive cut-off value of ESAT-6 and CFP-10 was 4.5 and 5.5, respectively. This study provides an insight into the IGRA methods and demonstrated that the positive response detected via QuantiFERON declined with decreased CD4+ T cells in the HIV-infected population; T-SPOT.TB functions independently of the CD4+ T cell level and Wan Tai was affected in some cases. This will be useful in the diagnosis of LTBI in the HIV-infected population, which will be a key step toward TB elimination in China.

Influence of genetic variability in toll-like receptors (TLR 2, TLR 4, and TLR 9) on human immunodeficiency virus-1 disease progression.

Background: It has been demonstrated that toll-like receptors (TLR2), TLR4, and TLR9 which were initially known for recognizing bacterial products are involved in the detection of viral components. It was planned to undertake a prospective longitudinal study among ethnically homogeneous antiretroviral treatment and antitubercular treatment naïve human immunodeficiency virus (HIV)-positive patients representing the north Indian population. The aim of the study was to investigate the influence of TLR2, TLR4, and TLR9 polymorphism in HIV disease progression. Methods: The present study was designed to investigate genetic polymorphism in TLRs (TLR2, TLR4, and TLR9) among HIV-infected patients with and without TB coinfection. The study population consisted of two groups: (i) HIV-positive patients without TB infection and disease (n = 223, HIV-positive patients); (ii) HIV-positive patients with latent tuberculosis infection (LTBI) (n = 150, HIV-positive LTBI patients). These participants were of either gender between 18 and 60 years of age and treatment naïve for both TB and HIV. HIV-positive and HIV-positive LTBI patients were longitudinally followed up for t2 years to study HIV disease progression. Results: On comparing TLR2 and TLR4 allelic and genotypic frequencies between 306 HIV-positive patients (no TB/AIDS) and 47 HIV-positive patients progressed to active TB/AIDS, no significant difference was observed between the two groups. The frequency of "A" allele in TLR9 was found to be significantly increased in 47 HIV-positive patients who progressed to active TB/AIDS (61.7%) as compared to 42.16% in 306 HIV-positive patients (no TB/AIDS), (P < 0.001). Furthermore, a significantly increased frequency of "AA" genotype in TLR9 was observed in 47 HIV-positive patients progressed to active TB/AIDS (55.32%) as compared to 20.26% in HIV-positive patients (no TB/AIDS). Conclusion: Findings of the present study revealed that genetic variability in TLR9 may influence HIV disease progression. The AA genotype in TLR9 may be associated with progression to TB/AIDS for 2 years in HIV-positive patients.

Nutritional status and patterns of anemia in sudanese adult patients with active pulmonary tuberculosis: A cross-sectional study.

Background: Malnutrition increases the risk of developing tuberculosis (TB) and causes reactivation of latent pulmonary TB. On the other hand, TB is a recognized cause of malnutrition. Evaluation of the nutritional status and anemia of tuberculous patients with active disease is an important step toward TB management.The objectives of the study were to determine the nutritional status and patterns of anemia in adult patients with active pulmonary TB. Methods: A.cross-sectional hospital-based study was performed on newly diagnosed patients with sputum-positive pulmonary TB. The nutritional status, total percentage of body fat (BF%), anemia, and general health of each patient were assessed with measurements of the body mass index (BMI), skin fold thickness, complete blood counts, and biochemical tests. Results: Patients' ages ranged from 16- to 74-year old, with the majority between 20- and 40-year old. Male: female ratio was 2:1. The majority of males and females (91.2% and 84.5%, respectively) had low BF%. Underweight (BMI < 18.5) was 62%, whereas overweight (BMI ≥25.0) was 4%. BMI showed a significant decline with chronicity of the illness (P < 0.001). Eighty participants showed anemia, 90% microcytic hypochromic, and 10% normocytic normochromic. Serum albumin was low in 21%, with no relation to renal disease and insignificant association with proteinuria. Conclusion: Patients with active pulmonary TB are likely to have microcytic hypochromic anemia, low BF%, and low BMI, especially with a long duration of the disease.

Mycobacterium tuberculosis-specific cytokine responses according to HIV status among household contacts of people with TB.

Following exposure to Mycobacterium tuberculosis (Mtb), a coordinated host response comprising both pro- and anti-inflammatory cytokines is critical for pathogen control. Although tuberculosis (TB) remains the leading cause of death among people with human immunodeficiency virus (HIV), the impact of HIV infection on Mtb-specific immune responses remains unclear. In this cross-sectional study of TB-exposed household contacts with and without HIV, we collected remaining supernatant from interferon-gamma release assay (IGRA) testing (QuantiFERON-TB Gold Plus [QFT-Plus]) and measured Mtb-specific pro-inflammatory, anti-inflammatory, and regulatory cytokine responses with a multiplex assay of 11 analytes. While people with HIV had lower responses to mitogen stimulation for some cytokines (granulocyte-macrophage colony-stimulating factor [GM-CSF], interleukin [IL]-2, IL-10, IL-17A, IL-22), there was no difference in cytokine levels for people with and without HIV following stimulation with Mtb-specific antigens. Future studies are necessary to explore whether changes in Mtb-specific cytokine responses over time are associated with distinct clinical outcomes following exposure to TB.

Progress on diagnosis and treatment of latent tuberculosis infection.

One fourth of the global population has been infected with Mycobacterium tuberculosis, and about 5%-10% of the infected individuals with latent tuberculosis infection (LTBI) will convert to active tuberculosis (ATB). Correct diagnosis and treatment of LTBI are important in ending the tuberculosis epidemic. Current methods for diagnosing LTBI, such as tuberculin skin test (TST) and interferon-γ release assay (IGRA), have limitations. Some novel biomarkers, such as transcriptome derived host genes in peripheral blood cells, will help to distinguish LTBI from ATB. More emphasis should be placed on surveillance in high-risk groups, including patients with HIV infection, those using biological agents, organ transplant recipients and those in close contact with ATB patients. For those with LTBI, treatment should be based on the risk of progression to ATB and the potential benefit. Prophylactic LTBI regimens include isoniazid monotherapy for 6 or 9 months, rifampicin monotherapy for 4 months, weekly rifapentine plus isoniazid for 3 months (3HP regimen) and daily rifampicin plus isoniazid for 3 months (3HR regimen). The success of the one month rifapentine plus isoniazid daily regimen (1HP regimen) suggests the feasibility of an ultra-short treatment strategy although its efficacy needs further assessment. Prophylactic treatment of LTBI in close contact with MDR-TB patients is another challenge, and the regimens include new anti-tuberculosis drugs such as bedaquiline, delamanid, fluoroquinolone and their combinations, which should be carefully evaluated. This article summarizes the current status of diagnosis and treatment of LTBI and its future development direction.

Time to diagnosis and treatment of pulmonary tuberculosis in indigenous peoples: a systematic review.

BACKGROUND: Time to diagnosis and treatment is a major factor in determining the likelihood of tuberculosis (TB) transmission and is an important area of intervention to reduce the reservoir of TB infection and prevent disease and mortality. Although Indigenous peoples experience an elevated incidence of TB, prior systematic reviews have not focused on this group. We summarize and report findings related to time to diagnosis and treatment of pulmonary TB (PTB) among Indigenous peoples, globally. METHODS: A Systematic review was performed using Ovid and PubMed databases. Articles or abstracts estimating time to diagnosis, or treatment of PTB among Indigenous peoples were included with no restriction on sample size with publication dates restricted up to 2019. Studies that focused on outbreaks, solely extrapulmonary TB alone in non-Indigenous populations were excluded. Literature was assessed using the Hawker checklist. Registration Protocol (PROSPERO): CRD42018102463. RESULTS: Twenty-four studies were selected after initial assessment of 2021 records. These included Indigenous groups from five of six geographical regions outlined by the World Health Organization (all except the European Region). The range of time to treatment (24-240 days), and patient delay (20 days-2.5 years) were highly variable across studies and, in at least 60% of the studies, longer in Indigenous compared to non-Indigenous peoples. Risk factors associated with longer patient delays included poor awareness of TB, type of health provider first seen, and self-treatment. CONCLUSION: Time to diagnosis and treatment estimates for Indigenous peoples are generally within previously reported ranges from other systematic reviews focusing on the general population. However among literature examined in this systematic review that stratified by Indigenous and non-Indigenous peoples, patient delay and time to treatment were longer compared to non-Indigenous populations in over half of the studies. Studies included were sparse and highlight an overall gap in literature important to interrupting transmission and preventing new TB cases among Indigenous peoples. Although, risk factors unique to Indigenous populations were not identified, further investigation is needed as social determinants of health among studies conducted in medium and high incidence countries may be shared across both population groups. Trial registration N/a.

[Progress in research of prophylactic therapy in contacts of rifampicin-resistant tuberculosis patients].

Tuberculosis (TB) prophylactic therapy for latent infection, which can reduce the risk for the development of active TB, is an important measure in TB control. China recommends prophylactic therapy for latent tuberculosis infection (LTBI) in some key populations to reduce the risk for TB. Contacts of patients with multi-drug and rifampicin-resistant TB (MDR/RR-TB) are at high risk for the infection with drug-resistant pathogen, however, no unified prophylactic therapy regimen has been recommended for LTBI due to exposure to MDR/RR-TB patients. This paper summarizes the current MDR/RR-TB prophylactic therapy regimen and its protection effect based on the results of the retrieval of literature, guidelines, expert consensus and technical specifications to provide reference for the prevention and control of LTBI.

Abdominal Lymphadenopathies: Lymphoma, Brucellosis or Tuberculosis? Multidisciplinary Approach-Case Report and Review of the Literature.

Abdominal pain represents a frequent symptom for referral to emergency departments and/or internal medicine outpatient setting. Similarly, fever, fatigue and weight loss are non-specific manifestations of disease. The present case describes the diagnostic process in a patient with abdominal pain and a palpable abdominal mass. Abdominal ultrasonography confirmed the presence of a mass in the mesogastrium. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) scans oriented toward calcific lymphadenopathies with increased metabolism in the positron emission tomography-computed tomography (PET-CT) scan. Laboratory examinations were inconclusive, although serology for Brucella and the Quantiferon test were positive. After multidisciplinary discussion, the patient underwent surgical excision of the abdominal mass. Histological examination excluded malignancies and oriented toward brucellosis in a patient with latent tuberculosis. The patient was treated with rifampin 600 mg qd and doxycycline 100 mg bid for 6 weeks with resolution of the symptoms. In addition, rifampin was continued for a total of 6 months in order to treat latent tuberculosis. This case underlines the need for a multidisciplinary approach in the diagnostic approach to abdominal lymphadenopathies.

Comparison of IGRA and TST in the diagnosis of latent tuberculosis among women of reproductive age in South India.

BACKGROUND: Latent tuberculosis infection (LTBI) is a mycobacterial infection defined on the basis of cellular immune response to mycobacterial antigens. The tuberculin skin test (TST) and the Interferon-Gamma Release Assay (IGRA) are the two tests currently used to establish the diagnosis of LTB. Literature suggests that a study regarding tuberculosis (TB) infection among women of reproductive age group is limited. METHODS: Female household contact, married, aged 18-49 years underwent written consent form and are screened for LTBI using the TST and IGRA. Participants are injected with TST [5 tuberculin unit (TU), purified protein derivative (PPD)] and IGRA [QuantiFERON®-TB Gold Plus kit (QFT-Plus)]. All the household contacts were followed-up for one year for incident TB cases. Statistical analysis was done using STATA version 14 (StataCorp., Texas, USA). Cohen's kappa test was used to determine the agreement between two tests. RESULTS: The prevalence of LTBI was found to be 69% (either TST or IGRA positive). Positivity rate of IGRA was higher when compared to that of TST. Out of 139 participants, 68 (49%) tested positive for TST, 80 (57.6%) tested positive for IGRA and 52 (37.4%) tested positive for both. Discordant results were observed in about two fifth of the study population and there was poor agreement between the two tests. CONCLUSION: Longitudinal studies are required to detect incident TB cases to evaluate the usefulness of these tests. The study was found that IGRA is more consistent to diagnosis of latent tuberculosis infection than the TST. Such studies can also be performed in varied settings among different populations which would help us to improve the diagnosis of LTBI and consequently help in TB control.

New insights on tuberculosis transmission dynamics and drug susceptibility profiles among the prison population in Southern Brazil based on whole-genome sequencing.

BACKGROUND: The rate of tuberculosis (TB) infection among the prison population (PP) in Brazil is 28 times higher than that in the general population, and prison environment favors the spread of TB. OBJECTIVE: To describe TB transmission dynamics and drug resistance profiles in PP using whole-genome sequencing (WGS). METHODS: This was a retrospective study of Mycobacterium tuberculosis cultivated from people incarcerated in 55 prisons between 2016 and 2019; only one isolate per prisoner was included. Information about movement from one prison to another was tracked. Clinical information was collected, and WGS was performed on isolates obtained at the time of TB diagnosis. RESULTS: Among 134 prisoners included in the study, we detected 16 clusters with a total of 58 (43%) cases of M. tuberculosis. Clusters ranged from two to seven isolates with five or fewer single nucleotide polymorphism (SNP) differences, suggesting a recent transmission. Six (4.4%) isolates were resistant to at least one anti-TB drug. Two of these clustered together and showed resistance to rifampicin, isoniazid, and fluoroquinolones, with 100% concordance between WGS and phenotypic drug-susceptibility testing. Prisoners with clustered isolates had a high amount of movement between prisons (two to eight moves) during the study period. CONCLUSIONS: WGS demonstrated the recent transmission of TB within prisons in Brazil. The high movement among prisoners seems to be related to the transmission of the same M. tuberculosis strain within the prison system. Screening for TB before and after the movement of prisoners using rapid molecular tests could play a role in reducing transmission.

Protocol for pragmatic randomized clinical trial to evaluate the completion of treatment of latent Mycobacterium tuberculosis infection with Isoniazid in the 300 mg formulation.

INTRODUCTION: It is essential to strengthen the treatment of latent tuberculosis infection (LTBI) to break the chain of transmission. The drug used worldwide for the treatment of LTBI is Isoniazid. A clinical trial conducted in Brazil has demonstrated the bioequivalence of Isoniazid in the 300 mg formulation with 3 tablets in the 100 mg formulation. Further studies are needed to evaluate the completion of treatment with Isoniazid 300 mg single tablet. OBJECTIVE: Describing a protocol for a clinical trial to evaluate the completion of treatment of LTBI with the drug Isoniazid in 300 mg tablet formulation compared to the use of Isoniazid in 100 mg tablet formulation. METHODS: This is a pragmatic, multicenter, randomized, open-label clinical trial registered on the Rebec RBR-2wsdt6 platform. Individuals 18 years of age or older with an indication for treatment of LTBI will be included, with only 1 individual per family nucleus. Individuals whose index case of active TB is categorized as retreatment, multidrug-resistant and extremely resistant, individuals transferred from the original center two or more weeks after the onset of treatment, and persons deprived of liberty will be excluded. The study intervention will be the treatment of LTBI with 1 tablet of Isoniazid 300 mg. The control group will receive the treatment of LTBI with 3 tablets of Isoniazid 100 mg. Follow-up will be performed at month 1, month 2 and at the end of treatment. The primary outcome will be completion of treatment. CONCLUSION: It is expected that with the treatment with the 300 mg formulation, more patients will complete the treatment based on the complexity index of pharmacotherapy. Our study intends to substantiate theoretical and operational strategies that respond to the demand for incorporation of a new formulation of the drug for the treatment of LTBI in the Unified Health System network.

Optimising diagnosis and treatment of tuberculosis infection in community and primary care settings in two urban provinces of Viet Nam: a cohort study.

OBJECTIVES: To end tuberculosis (TB), the vast reservoir of 1.7-2.3 billion TB infections (TBIs) must be addressed, but achieving global TB preventive therapy (TPT) targets seems unlikely. This study assessed the feasibility of using interferon-γ release assays (IGRAs) at lower healthcare levels and the comparative performance of 3-month and 9-month daily TPT regimens (3HR/9H). DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: This cohort study was implemented in two provinces of Viet Nam from May 2019 to September 2020. Participants included household contacts (HHCs), vulnerable community members and healthcare workers (HCWs) recruited at community-based TB screening events or HHC investigations at primary care centres, who were followed up throughout TPT. PRIMARY AND SECONDARY OUTCOMES: We constructed TBI care cascades describing indeterminate and positivity rates to assess feasibility, and initiation and completion rates to assess performance. We fitted mixed-effects logistic and stratified Cox models to identify factors associated with IGRA positivity and loss to follow-up (LTFU). RESULTS: Among 5837 participants, the indeterminate rate was 0.8%, and 30.7% were IGRA positive. TPT initiation and completion rates were 63.3% (3HR=61.2% vs 9H=63.6%; p=0.147) and 80.6% (3HR=85.7% vs 9H=80.0%; p=0.522), respectively. Being male (adjusted OR=1.51; 95% CI: 1.28 to 1.78; p<0.001), aged 45-59 years (1.30; 1.05 to 1.60; p=0.018) and exhibiting TB-related abnormalities on X-ray (2.23; 1.38 to 3.61; p=0.001) were associated with positive IGRA results. Risk of IGRA positivity was lower in periurban districts (0.55; 0.36 to 0.85; p=0.007), aged <15 years (0.18; 0.13 to 0.26; p<0.001), aged 15-29 years (0.56; 0.42 to 0.75; p<0.001) and HCWs (0.34; 0.24 to 0.48; p<0.001). The 3HR regimen (adjusted HR=3.83; 1.49 to 9.84; p=0.005) and HCWs (1.38; 1.25 to 1.53; p<0.001) showed higher hazards of LTFU. CONCLUSION: Providing IGRAs at lower healthcare levels is feasible and along with shorter regimens may expand access and uptake towards meeting TPT targets, but scale-up may require complementary advocacy and education for beneficiaries and providers.

Risk of tuberculosis transmission by children in Hamburg, Germany.

BACKGROUND: Data from a prospective molecular-epidemiologic study (1997-2021) in Hamburg, Germany, were evaluated to assess the transmission risk of Mycobacterium tuberculosis complex (Mtbc) by children <15 years in a low-incidence setting. METHODS: Isolates of Mtbc were genotyped whole genome sequencing, applying a core genome multilocus sequence typing scheme. Close contacts of culture-confirmed children were examined for latent Mtbc infections (LTBI) with particular focus on IGRA testing. RESULTS: Out of 3154 culture-confirmed tuberculosis (TB) cases, 79 (2.5%) were children <15 years. Of those, 52 (58%) had pulmonary TB. Genotyping revealed that 35 of the 52 children (67%) were epidemiologically confirmed secondary cluster members; all of their source cases were adults. Six immigrant children presented without a presumed source case; their TB diagnoses came on average 48 weeks (interquartile range [IQR] 71) after their arrival in Germany. Three German-born children were determined to have been infected by adult relatives while visiting their parents' home country. Of the 317 children's close contacts tested with QuantiFERON-TB Gold-In Tube for LTBI, only 21 (6.6%) were positive. Absent a history of prior exposure or immigration from a high-incidence country, none of the contacts of younger (<10 years) TB-afflicted children was latently infected, whereas 2 older children infected 12 of their contacts, children and adults. During a mean observational period of 551 weeks (IQR 735) on average, no secondary TB cases appeared. CONCLUSIONS: Children with pulmonary TB disease, especially those aged below 10 years, rarely transmit Mtbc to their close contacts in a low-incidence setting.

STAT3 regulation of Mtb-specific T cell function in active pulmonary tuberculosis patients.

BACKGROUND: Tuberculosis (TB) remains one of the most serious infectious diseases in the world. Our aim was to investigate the regulatory role of STAT3 and pSTAT3 in the regulation of T cell immunophenotype and cell function. METHODS: Twenty-five active pulmonary tuberculosis (APTB) patients, 18 latent tuberculosis infection (LTBI) patients, and 20 healthy controls (HCs) enrolled in this study. T cell phenotype and expression of STAT3 and pSTAT3 were detected by flow cytometry. RESULTS: Compared with HCs, the expression of pSTAT3 in CD4+ T and CD8+ T cells in peripheral blood of APTB patients was increased, and the expression was higher in pleural effusion. Multifunctional T cells that simultaneously secrete IFN-γ, TNF-α and IL-17A have higher pSTAT3 expression levels. Mtb-specific T cells from APTB patients had a higher cell frequency of the STAT3+ pSTAT3+ phenotype and a reduced cell frequency of the STAT3+ pSTAT3- phenotype compared with LTBI patients. Mtb-specific T cells with STAT3+ pSTAT3+ phenotype had higher expression of PD-1 and PD-L1, while cells with STAT3+ pSTAT3- phenotype had higher expression of Bcl-2. CONCLUSIONS: STAT3 and pSTAT3 in T cells of APTB patients feature in the process of anti-apoptosis and cytokine secretion. At the same time, the higher pSTAT3 may be related to the degree of cell functional exhaustion. The pSTAT3 level of T cells is related to the infection status and may indicate the clinical activity of the disease, which provides a new idea for the clinical identification and treatment of active pulmonary tuberculosis.

Latent tuberculosis and computational biology: A less-talked affair.

Tuberculosis (TB) is a pervasive and devastating air-borne disease caused by the organisms belonging to the Mycobacterium tuberculosis (Mtb) complex. Currently, it is the global leader in infectious disease-related death in adults. The proclivity of TB to enter the latent state has become a significant impediment to the global effort to eradicate TB. Despite decades of research, latent tuberculosis (LTB) mechanisms remain poorly understood, making it difficult to develop efficient treatment methods. In this review, we seek to shed light on the current understanding of the mechanism of LTB, with an accentuation on the insights gained through computational biology. We have outlined various well-established computational biology components, such as omics, network-based techniques, mathematical modelling, artificial intelligence, and molecular docking, to disclose the crucial facets of LTB. Additionally, we highlighted important tools and software that may be used to conduct a variety of systems biology assessments. Finally, we conclude the article by addressing the possible future directions in this field, which might help a better understanding of LTB progression.