Immune profiles of MCP-1 with M tb antigens and recombinant cytokines stimulation in tuberculosis.

Tuberculosis is caused by Mycobacterium tuberculosis (M tb), which is recognized by macrophages and produces inflammatory cytokines, and chemokines at the site of infection. The present study was proposed to understand the interaction of M tb antigens, cytokines, and chemokines. We have evaluated the chemokine MCP-1 levels and its expression in PBMCs stimulated with M tb antigens Ag85A, ESAT6 and recombinant cytokines rhTNF-α, rhIFN-γ, rhTGF-ß, and rhIL-10 in active pulmonary TB (APTB) patients, household contacts (HHC) at 0 months, 6 months and healthy controls (HC). We have observed low levels of MCP-1 with Ag85A, ESAT6, and rhTNF-α stimulations in APTB 0M compared to HHC and HC (p < 0.0067, p < 0.0001, p < 0.01, p < 0.005, p < 0.0065, p < 0.0001) and significantly increased after treatment with rhTNF-α. The MCP-1 levels with rhIFN-γ were high in APTB, HHC at 0 M and significant between APTB 0 M vs. 6 M, HHC vs. HC, and HHC 0M vs. 6M (p < 0.0352, p < 0.0252, p < 0.00062). The rhTGF-ß, rhIL-10 induced high MCP-1 levels in APTB, HHC compared to HC (p < 0.0414, p < 0.0312, p < 0.004, p < 0.0001) and significantly decreased after treatment with rhIL-10 (p < 0.0001). The MCP-1 expression was low with all the stimulations in APTB 0M when compared to HC and after treatment. Whereas, HHC shown low MCP-1 expression with rhTNF-α, rhIFN-γ and Ag85A and high with rhTGF-ß, rhIL-10 and ESAT6. In conclusion, the study determined the differential expression and production of MCP-1 with M tb antigens and recombinant cytokines. Further, cohort studies are required to study these interaction to identify the high risk individuals, which might help for TB control.

Evaluation of an artificial intelligence (AI) system to detect tuberculosis on chest X-ray at a pilot active screening project in Guangdong, China in 2019.

BACKGROUND: Although computer-aided detection (CAD) software employed with Artificial Intelligence (AI) system has been developed aiming to assist tuberculosis (TB) triage, screening, and diagnosis, its clinical performance for tuberculosis screening remains unknown. OBJECTIVE: To evaluate performance of an CAD software for detecting TB on chest X-ray images at a pilot active TB screening project. METHODS: A CAD software scheme employed with AI was used to screen chest X-ray images of participants and produce probability scores of cases being positive for TB. CAD-generated TB detection scores were compared with on-site and senior radiologists via several performance evaluation indices including area under the ROC curves (AUC), specificity, sensitive, and positive predict value. Pycharm CE and SPSS statistics software packages were used for data analysis. RESULTS: Among 2,543 participants, eight TB patients were identified from this screening pilot program. The AI-based CAD system outperformed the onsite (AUC = 0.740) and senior radiologists (AUC = 0.805) either using thresholds of 30% (AUC = 0.978) and 50% (AUC = 0.859) when taking the final diagnosis as the ground truth. CONCLUSIONS: The AI-based CAD software successfully detects all TB patients as identified from this study at a threshold of 30%. It demonstrates feasibility and easy accessibility to carry out large scale TB screening using this CAD software equipped in medical vans with chest X-ray imaging machine.

One Step Forward: Successful End-of-Treatment Outcomes of Patients With Drug-Resistant Tuberculosis Who Received Concomitant Bedaquiline and Delamanid in Mumbai, India.

BACKGROUND: The Médecins Sans Frontières Clinic in Mumbai, India, has been providing concomitant bedaquiline (BDQ) and delamanid (DLM) in treatment regimen for patients with drug-resistant tuberculosis (DR-TB) and limited therapeutic options, referred from other healthcare institutions, since 2016. The study documents the end-of-treatment outcomes, culture-conversion rates, and serious adverse events (SAEs) during treatment. METHODS: This was a retrospective cohort study based on routinely collected program data. In clinic, treatment regimens are designed based on culture drug sensitivity test patterns and previous drug exposures, and are provided for 20-22 months. BDQ and DLM are extended beyond 24 weeks as off-label use. Patients who initiated DR-TB treatment including BDQ and DLM (concomitantly for at least 4 weeks) during February 2016-February 2018 were included. RESULTS: Of the 70 patients included, the median age was 25 (interquartile range [IQR], 22-32) years and 56% were females. All except 1 were fluoroquinolone resistant. The median duration of exposure to BDQ and DLM was 77 (IQR, 43-96) weeks. Thirty-nine episodes of SAEs were reported among 30 (43%) patients, including 5 instances of QTc prolongation, assessed as possibly related to BDQ and/or DLM. The majority (69%) had culture conversion before 24 weeks of treatment. In 61 (87%), use of BDQ and DLM was extended beyond 24 weeks. Successful end-of-treatment outcomes were reported in 49 (70%) patients. CONCLUSIONS: The successful treatment outcomes of this cohort show that regimens including concomitant BDQ and DLM for longer than 24 weeks are effective and can be safely administered on an ambulatory basis. National TB programs globally should scale up access to life-saving DR-TB regimens with new drugs.

Prevalence of active tuberculosis and associated factors among people with chronic psychotic disorders at St. Amanuel Mental Specialized Hospital and Gergesenon Mental Rehabilitation center, Addis Ababa, Ethiopia.

BACKGROUND: Tuberculosis (TB) is an airborne chronic infectious disease mainly caused by Mycobacterium tuberculosis complex bacteria. Currently, about 1.7 billion (26%) of the world's population are considered to be infected with M. tuberculosis. The risk of acquiring tuberculosis is higher on some segments of societies including people with severe mental illness. As a result, World health organization (WHO) strongly recommends screening for tuberculosis in such risk groups and setting. METHODS: A cross-sectional study was conducted to assess the prevalence of active tuberculosis and associated factors among patients with chronic psychotic disorders admitted at St. Amanuel Mental Specialized Hospital and Gergesenon Mental rehabilitation center from February to June, 2020. All admitted patients were screened for any sign of TB as recommended by WHO. Presumptive TB cases were identified. Sputum samples were collected and tested by Xpert MTB/RIF assay. Data analysis was performed using SPSS version 25.0 statistical software and Chi square analysis was used to test the statistical association. RESULTS: From a total 3600 pschotic patients screened for TB, 250 (6.94%) presumptive tuberculosis cases were detected. From these, 27 (10.8%) were positive by Xpert MTB/RIF assay. Most of the patients were males (68.4%). The mean ± SD age of the participant was 36.5 ± 9.7 years. The overall prevalence of tuberculosis was found to be 750 per 100,000 population. The number of patients per room (p = 0.039) was associated with Xpert MTB/RIF positive active tuberculosis. CONCLUSION: The prevalence of active tuberculosis among chronic psychotic patients was high. Number of admitted patients per room was identified as risk factors for Xpert MTB/RIF positive active tuberculosis. Therefore, to control TB transmission in chronic mental health treatment facilities, efforts should be directed to periodic screening for early case detection and improving the number of patients per room.

Bacille Calmette Guérin (BCG) and new TB vaccines: Specific, cross-mycobacterial and off-target effects.

The Bacille Calmette Guérin (BCG) vaccine was developed over a century ago and has become one of the most used vaccines without undergoing a modern vaccine development life cycle. Despite this, the vaccine has protected many millions from severe and disseminated forms of tuberculosis (TB). In addition, BCG has cross-mycobacterial effects against non-tuberculous mycobacteria and off-target (also called non-specific or heterologous) effects against other infections and diseases. More recently, BCG's effects on innate immunity suggest it might improve the immune response against viral respiratory infections including SARS-CoV-2. New TB vaccines, developed over the last 30 years, show promise, particularly in prevention of progression to disease from TB infection in young adults. The role of BCG in the context of new TB vaccines remains uncertain as most participants included in trials have been previously BCG immunised. BCG replacement vaccines are in efficacy trials and these may also have off-target effects.

Detailed characterization of human Mycobacterium tuberculosis specific HLA-E restricted CD8+ T cells.

HLA-E presented antigens are interesting targets for vaccination given HLA-Es' essentially monomorphic nature. We have shown previously that Mycobacterium tuberculosis (Mtb) peptides are presented by HLA-E to CD8+ effector T cells, but the precise phenotype and functional capacity of these cells remains poorly characterized. We have developed and utilized in this study a new protocol combining HLA-E tetramer with intracellular staining for cytokines, transcription factors and cytotoxic molecules to characterize these cells in depth. We confirm in this study the significantly increased ex vivo frequency of Mtb-peptide/HLA-E-TM+ CD8+ T cells in the circulation of patients with active tuberculosis (TB). HLA-E restricted CD8+ T cells from TB patients produced more IL-13 than cells from controls or subjects with latent tuberculosis infection (LTBI). Compared to total CD8+ T cells, HLA-E restricted cells produced more IFNγ, IL-4, IL-10, and granulysin but less granzyme-A. Moreover, compared to "classical" Mtb specific HLA-A2 restricted CD8+ T cells, HLA-E restricted CD8+ T cells produced less TNFα and perforin, but more IL-4. In conclusion, HLA-E restricted- Mtb specific cells can produce Th2 cytokines directly.

Clinical diagnosis of sensory neuropathy in HIV patients treated with tenofovir: A 6-month follow-up study.

BACKGROUND: Sensory neuropathy (SN) is a common and often painful neurological condition associated with HIV-infection and its treatment. However, data on the incidence of SN in neuropathy-free individuals initiating combination antiretroviral therapies (cART) that do not contain the neurotoxic agent stavudine are lacking. AIMS: We investigated the 6-month incidence of SN in ART naïve individuals initiating tenofovir (TDF)-based cART, and the clinical factors associated with the development of SN. METHODS: 120 neuropathy-free and ART naïve individuals initiating cART at a single center in Johannesburg, South Africa were enrolled. Participants were screened for SN using clinical signs and symptoms at study enrolment and approximately every 2-months for a period of ~6-months. Diagnostic criteria for symptomatic SN was defined by the presence of at least one symptom (pain/burning, numbness, paraesthesias) and at least two clinical signs (reduced vibration sense, absent ankle reflexes or pin-prick hypoaesthesia). Diagnostic criteria for asymptomatic SN required at least two clinical signs only (as above). RESULTS: A total of 88% of the cohort completed three visits within the 6-month period. The 6-month cumulative incidence of neuropathy was 140 cases per 1000 patients (95% CI: 80-210) at an incidence rate of 0.37 (95% CI: 0.2-0.5) per person year. Height and active tuberculosis (TB) disease were independently associated with the risk of developing SN (P < .05). INTERPRETATION: We found that within the first 6 months of starting cART, incident SN persists in the post-stavudine era, with 11 (9%) of individuals developing asymptomatic SN, and 9 (8%) developing symptomatic SN.

Investigation of household contacts of pulmonary tuberculosis patients increases case detection in Mwanza City, Tanzania.

BACKGROUND: Tuberculosis (TB) contact tracing is a key strategy for containing TB and provides addition to the passive case finding approach. However, this practice has not been implemented in Tanzania, where there is unacceptably high treatment gap of 62.1% between cases estimated and cases detected. Therefore calls for more aggressive case finding for TB to close this gap. We aimed to determine the magnitude and predictors of bacteriologically-confirmed pulmonary TB among household contacts of bacteriologically-confirmed pulmonary TB index cases in the city of Mwanza, Tanzania. METHODS: This study was carried out from August to December 2016 in Mwanza city at the TB outpatient clinics of Tertiary Hospital of the Bugando Medical Centre, Sekou-Toure Regional Hospital, and Nyamagana District Hospital. Bacteriologically-confirmed TB index cases diagnosed between May and July 2016 were identified from the laboratory registers book. Contacts were traced by home visits by study TB nurses, and data were collected using a standardized TB screening questionnaire. To detect the bacterioriologically-confirmed pulmonary TB, two sputum samples per household contact were collected under supervision for all household contacts following standard operating procedures. Samples were transported to the Bugando Medical Centre TB laboratory for investigation for TB using fluorescent smear microscopy, GeneXpert MTB/RIF and Löwenstein-Jensen (LJ) culture. Logistic regression was used to determine predictors of bacteriologically-confirmed pulmonary TB among household contacts. RESULTS: During the study period, 456 household contacts from 93 TB index cases were identified. Among these 456 household contacts, 13 (2.9%) were GeneXpert MTB/RIF positive, 18 (3.9%) were MTB-culture positive and four (0.9%) were AFB-smear positive. Overall, 29 (6.4%) of contacts had bacteriologically-confirmed pulmonary TB. Predictors of bacteriologically-confirmed pulmonary TB among household contacts were7being married (Odds ratio [OR], 3.3; 95% confidence interval [CI], 1.4-8.0; p = 0.012) and consuming less than three meals a day (OR, 3.7; 95% CI, 1.6-8.7; p = 0.009). CONCLUSIONS: Our data suggest that in Mwanza, Tanzania, seven in 100 contacts living in the same house with a TB patient develop bacteriologically-confirmed pulmonary TB. These results therefore underscore the need to implement routine TB contact tracing to control tuberculosis in high TB burden countries such as Tanzania.

Screening of Serum Biomarkers for Distinguishing between Latent and Active Tuberculosis Using Proteome Microarray.

OBJECTIVE: To identify potential serum biomarkers for distinguishing between latent tuberculosis infection (LTBI) and active tuberculosis (TB). METHODS: A proteome microarray containing 4,262 antigens was used for screening serum biomarkers of 40 serum samples from patients with LTBI and active TB at the systems level. The interaction network and functional classification of differentially expressed antigens were analyzed using STRING 10.0 and the TB database, respectively. Enzyme-linked immunosorbent assays (ELISA) were used to validate candidate antigens further using 279 samples. The diagnostic performances of candidate antigens were evaluated by receiver operating characteristic curve (ROC) analysis. Both antigen combination and logistic regression analysis were used to improve diagnostic ability. RESULTS: Microarray results showed that levels of 152 Mycobacterium tuberculosis (Mtb)-antigen- specific IgG were significantly higher in active TB patients than in LTBI patients (P < 0.05), and these differentially expressed antigens showed stronger associations with each other and were involved in various biological processes. Eleven candidate antigens were further validated using ELISA and showed consistent results in microarray analysis. ROC analysis showed that antigens Rv2031c, Rv1408, and Rv2421c had higher areas under the curve (AUCs) of 0.8520, 0.8152, and 0.7970, respectively. In addition, both antigen combination and logistic regression analysis improved the diagnostic ability. CONCLUSION: Several antigens have the potential to serve as serum biomarkers for discrimination between LTBI and active TB.

Effectiveness of isoniazid preventative therapy in reducing incidence of active tuberculosis among people living with HIV/AIDS in public health facilities of Addis Ababa, Ethiopia: a historical cohort study.

BACKGROUND: Human Immunodeficiency Virus (HIV) pandemic has exacerbated tuberculosis disease especially in Sub-Saharan African countries. The World Health Organization (WHO) and Joint United Nations Program on HIV/AIDS (UNAIDS) have recommended Isoniazid Preventive Therapy (IPT) for HIV infected patients to reduce the burden of tuberculosis (TB). Ethiopia has been implementing IPT since 2007. However, effectiveness of IPT in averting occurrence of active tuberculosis among HIV infected patients has not been assessed. METHODS: Retrospective cohort study was employed using secondary data from public health institutions of Addis Ababa. Descriptive statistics and Generalized Linear Model based on Poisson regression was used for data analysis. RESULTS: From 2524 HIV infected patients who were followed for 4106 Person-Years, a total of 277 incident Tuberculosis (TB) cases occurred. TB Incidence Rate was 0.21/100 Person-Year, 0.86/100 Person-Year & 7.18/100 Person-Year among IPT completed, in-completed and non-exposed patients, respectively. The adjusted Incidence Rate Ratio (aIRR) among IPT completed vs. non-exposed patients was 0.037 (95% CI, 0.016-0.072). Gender, residence area, employment status, baseline WHO stage of the disease (AIDS) and level of CD4 counts were identified as risk factors for TB incidence. The aIRR among patients who took Highly Active Anti- Retroviral Therapy (HAART) with IPT compared to those who took HAART alone was 0.063 (95% CI 0.035-0.104). IPT significantly reduced occurrence of active TB for 3 years. CONCLUSIONS: IPT significantly reduced tuberculosis incidence by 96.3% compared to IPT non-exposed patients. Moreover concomitant use of HAART with IPT has shown a significant reduction in tuberculosis incidence by 93.7% than the use of HAART alone. Since IPT significantly protected occurrence of active TB for 3 years, its implementation should be further strengthened in the country.

Identification of HLA-A*11:01-restricted Mycobacterium tuberculosis CD8(+) T cell epitopes.

New vaccines are needed to combat Mycobacterium tuberculosis (MTB) infections. The currently employed Bacillus Calmette-Guérin vaccine is becoming ineffective, due in part to the emergence of multidrug-resistant tuberculosis (MDR-TB) strains and the reduced immune capacity in cases of HIV coinfection. CD8(+) T cells play an important role in the protective immunity against MTB infections, and the identification of immunogenic CD8(+) T cell epitopes specific for MTB is essential for the design of peptide-based vaccines. To identify CD8(+) T cell epitopes of MTB proteins, we screened a set of 94 MTB antigens for HLA class I A*11:01-binding motifs. HLA-A*11:01 is one of the most prevalent HLA molecules in Southeast Asians, and definition of T cell epitopes it can restrict would provide significant coverage for the Asian population. Peptides that bound with high affinity to purified HLA molecules were subsequently evaluated in functional assays to detect interferon-γ release and CD8(+) T cell proliferation in active pulmonary TB patients. We identified six novel epitopes, each derived from a unique MTB antigen, which were recognized by CD8(+) T cells from active pulmonary TB patients. In addition, a significant level of epitope-specific T cells could be detected ex vivo in peripheral blood mononuclear cells from active TB patients by an HLA-A*11:01 dextramer carrying the peptide Rv3130c194-204 (from the MTB triacylglycerol synthase Tgs1), which was the most frequently recognized epitope in our peptide library. In conclusion, this study identified six dominant CD8(+) T cell epitopes that may be considered potential targets for subunit vaccines or diagnostic strategies against TB.

Improving T-cell assays for diagnosis of latent TB infection: Confirmation of the potential role of testing Interleukin-2 release in Iranian patients.

BACKGROUND: Since gamma interferon release assays (IGRAs) cannot differentiate between active tuberculosis and latent tuberculosis infection (LTBI), development of rapid and specific diagnosis tools are essential for discriminating between active tuberculosis (TB) from LTBI. Both IGRAs are based on Mycobacterium tuberculosis-specific antigens, namely, early secretory antigenic target 6 (ESAT-6) and 10kDa culture filtrate (CFP-10). The aim of this study was to evaluate the potential value of IL-2 secretion by whole blood cells after stimulation with rESAT-6 and rCFP-10 for discriminating between active and latent tuberculosis. METHODS: Interleukin-2 and IFN-γ were measured after blood stimulation of 90 cases (30 with active TB, 30 with LTBI and 30 healthy controls) with recombinant ESAT-6 and CFP-10. Receiver operating characteristic (ROC) curve analysis was conducted to determine the best IL-2 and IFN-γ result thresholds in discriminating between cases with active or latent TB, and the corresponding sensitivity and specificity were recorded. RESULTS: The IFN-γ release assay demonstrated a good sensitivity and specificity (sensitivity 83-84% and specificity 92%) for diagnosis of tuberculosis. The discrimination performance of IL-2 assay (assessed by the area under ROC curve) between LTBI and patients with active TB were 0.75 and 0.8 following stimulation with rESAT-6 and rCFP-10, respectively. Maximum discrimination was reached at a cut-off of 11.6pg/mL for IL-2 after stimulation with recombinant rESAT-6 with 72% sensitivity and 79% specificity and 10.7pg/mL for IL-2 following stimulation with rCFP-10 with 75% sensitivity and 79% specificity, respectively. CONCLUSION: This study demonstrates that rESAT-6 and rCFP-10 can provide a sensitive and specific diagnosis of TB. In addition, it was shown that IL-2 may be serving as a marker for discriminating LTBI and active TB.

Long-term follow-up of contacts of drug-resistant tuberculosis cases in high-burden areas of Mumbai, India.

BACKGROUND: Drug-resistant tuberculosis (DRTB) is a significant public health threat particularly in high burden areas like Mumbai, India. Contacts of DRTB cases are highly vulnerable to infection and development of active disease. In this study we assess long-term outcomes of contacts of DRTB cases, focusing on active TB development and the potential role of IGRA, vitamin D status and supplementation. METHODS: A cohort of 262 DRTB contacts identified from a prior case-control study conducted in Mumbai were enlisted for the study. Interviews were conducted, and data were analysed using descriptive statistics and logistic regression. RESULTS: Of the 262 contacts, 34.73% had LTBI. Three contacts (1.36%) developed active TB, with a crude incidence rate of 4.64 per 1000 people. Vitamin D deficiency was prevalent in 75.3% of contacts, and all three TB cases were vitamin D deficient. Vitamin D supplementation showed a non-significant trend in reducing TB risk (OR = 0.56, p = 0.492). IGRA status did not significantly predict TB development. CONCLUSION: This study provides valuable insights into the long-term outcomes of contacts of DRTB cases. While baseline IGRA did not prove to predict development of active TB, association between vitamin D deficiency and TB development highlights the need for larger studies and development of more effective screening tools. The study contributes valuable information to TB control strategies in high-burden areas.

The Yield of Active Tuberculosis Disease and Latent Tuberculosis Infection in Tuberculosis Household Contacts Investigated Using Chest X-ray in Yogyakarta Province, Indonesia.

In Indonesia, the implementation of tuberculosis (TB) contact investigation is limited, with low detection rates. We report the yield of and risk factors for TB disease and infection for household contacts (HHCs) investigated using chest X-ray (CXR) screening. We identified HHCs aged five years and above of bacteriologically confirmed index cases from 2018 to 2022 in Yogyakarta City and Kulon Progo. All HHCs were offered screening for TB symptoms; TB infection testing with either tuberculin skin testing or interferon gamma release assay; and referral for CXR. Sputum from those with symptoms or CXR suggestive of TB was tested with Xpert MTB/RIF. Risk factors for active TB disease and latent TB infection (LTBI) were identified by logistic regression models. We screened 2857 HHCs for TB between June 2020 and December 2022, with 68 (2.4%) diagnosed with active TB. Of 2621 HHCs eligible for LTBI investigation, 1083 (45.7%) were diagnosed with LTBI. The factors associated with active TB were age, being underweight, diabetes mellitus, urban living, and sleeping in the same house as an index case. Factors associated with LTBI were increasing age and male gender. Conclusions: Screening for HHC including CXR and TST/IGRA yielded a moderate prevalence of TB disease and infection.

Identification of differentially recognized T cell epitopes in the spectrum of Mtb infection.

Tuberculosis caused by Mycobacterium tuberculosis is one of the leading causes of death from a single infectious agent. Identifying dominant epitopes and comparing their reactivity in different tuberculosis (TB) infection states can help design diagnostics and vaccines. We performed a proteome-wide screen of 20,610 Mtb derived peptides in 21 Active TB (ATB) patients 3-4 months post-diagnosis of pulmonary TB (mid-treatment) using an IFNγ and IL-17 Fluorospot assay. Responses were mediated exclusively by IFNγ and identified a total of 137 unique epitopes, with each patient recognizing, on average, 8 individual epitopes and 22 epitopes (16%) recognized by 2 or more participants. Responses were predominantly directed against antigens part of the cell wall and cell processes category. Testing 517 peptides spanning TB vaccine candidates and ESAT-6 and CFP10 antigens also revealed differential recognition between ATB participants mid-treatment and healthy IGRA+ participants of several vaccine antigens. An ATB-specific peptide pool consisting of epitopes exclusively recognized by participants mid-treatment, allowed distinguishing participants with active pulmonary TB from healthy interferon-gamma release assay (IGRA)+/- participants from diverse geographical locations. Analysis of longitudinal samples indicated decreased reactivity during treatment for pulmonary TB. Together, these results show that a proteome-wide screen of T cell reactivity identifies epitopes and antigens that are differentially recognized depending on the Mtb infection stage. These have potential use in developing diagnostics and vaccine candidates and measuring correlates of protection.

Tuberculosis in migrants: epidemiology, resistance and outcome in Milan, Italy.

BACKGROUND: Human migration and the ever-changing geopolitical scenarios are redefining the epidemiology and the management of tuberculosis (TB), especially in low-TB burden countries welcoming high rates of people from high-TB burden countries. METHODS: We conducted an observational retrospective mono-centric study in a Northern-Italy TB reference centre from 1 January 1990 to 31 December 2019, focusing on the differences in epidemiology, resistance patterns and treatment outcomes between Italians and migrants with active TB. Data were collected from medical records. RESULTS: A total of 10555 patients were included, 4614 Italians and 5941 migrants. Among migrants, higher rates of rifampin-resistant (RR) or multidrug-resistant (MDR) TB were reported, as well as higher rates of loss to follow-up. Among Italians, higher mortality rates and a higher number of extrapulmonary TB cases were found. CONCLUSION: Our study describes one of the largest cohorts of patients with active TB in Italy, highlighting the need for tailored approaches in native and migrant populations.

Integrating TB screening into house-to-house polio vaccination campaigns.

SETTING: In July 2019, the Anambra State (south-east Nigeria) TB Control Programme implemented the integration of TB case-finding with the polio vaccination campaign with the support of the WHO. OBJECTIVE: To improve TB case-finding from communities leveraging already existing polio structures. DESIGN: Vaccination teams were trained to ask for symptoms of TB in each household and to document details of people presumed to have TB. Community TB workers subsequently tracked those identified for subsequent sample collection. We report the numbers detected, and the proportion of wards that reported people with TB. Regression analyses were used to estimate the relationship between ward characteristics and reporting. Odds ratios (ORs) with associated 95% confidence intervals (CIs) are also reported. RESULTS: Of 281 people with presumptive TB, 32 were diagnosed with TB; 21% (70/330) of wards identified at least one presumptive, while 5% (18/330) of the people were identified with TB. Peri-urban slums were most likely to identify presumptives (adjusted OR [aOR] 11.52, 95% CI 1.62-81.79), while Riverine areas were most likely to identify a person with TB (aOR 3.59, 95% CI 1.16-11.01). CONCLUSION: Integrating community TB case-finding into house-to-house vaccination campaigns can boost case detection. This approach proved effective in areas perennially underserved by routine healthcare services.

CONTEXTE: En juillet 2019, le programme de lutte contre la TB de l'État d'Anambra (sud-est du Nigeria) a mis en œuvre l'intégration de la recherche de cas de TB à la campagne de vaccination contre la polio avec le soutien de l'OMS. OBJECTIF: Améliorer la recherche de cas de TB auprès des communautés en s'appuyant sur les structures déjà existantes de la polio. METHODES: Les équipes de vaccination ont été formées à rechercher les symptômes de la TB dans chaque foyer et à consigner les coordonnées des personnes présumées tuberculeuses. Les agents communautaires de lutte contre la TB ont ensuite suivi les personnes identifiées pour la collecte ultérieure d'échantillons. Nous rapportons le nombre de personnes détectées et la proportion de quartiers qui ont signalé des personnes atteintes de TB. Des analyses de régression ont été utilisées pour estimer la relation entre les caractéristiques des municipalités et la déclaration. Les odds ratio (OR) et les intervalles de confiance (IC) à 95 % associés sont également rapportés. RÉSULTATS: Sur 281 personnes présumées tuberculeuses, 32 ont été diagnostiquées tuberculeuses ; 21 % (70/330) des quartiers ont identifié au moins une personne présumée tuberculeuse, tandis que 5% (18/330) des personnes ont été identifiées tuberculeuses. Les bidonvilles périurbains étaient les plus susceptibles d'identifier des présomptifs (OR ajusté [aOR] 11,52 ; IC 95 % 1,62­81,79), tandis que les zones riveraines étaient les plus susceptibles d'identifier une personne tuberculeuse (aOR 3,59 ; IC 95 % 1,16­11,01). CONCLUSION: L'intégration de la recherche communautaire de cas de TB dans les campagnes de vaccination de porte à porte peut améliorer la détection des cas. Cette approche s'est avérée efficace dans des zones toujours mal desservies par les services de santé de routine.

Current status and future landscape of diagnosing tuberculosis infection.

Interferon-γ release assays (IGRAs), such as QuantiFERON-TB Gold (QFT) or T-SPOT.TB, are frequently used as tools for the diagnosis of tuberculosis (TB) infection in the 21st century. QFT-Plus recently emerged as the fourth generation of QFT assays and has replaced QFT In-Tube. However, IGRAs have several problems regarding the identification of active, latent, and cured TB infection, and the time-consuming diagnosis of TB infection because of the overnight incubation of clinical specimens or complexity of measuring the level of interferon (IFN)-γ. To easily diagnose TB infection and quickly compare it with conventional IGRAs, many in vitro tests are developed based on assays other than enzyme-linked immunosorbent assay or enzyme-linked immunospot, such as the fluorescent lateral flow assay that requires less manual operation and a shorter time. Simplified versions of IGRAs are emerging, including QIAreach QuantiFERON-TB. On the other hand, to distinguish active TB from latent or cured TB infection, new immunodiagnostic biomarkers beyond IFN-γ are evaluated using QFT supernatants. While IFN-γ or IFN-γ-related chemokine such as IFN-γ induced protein 10 is a potential biomarker in patients with active TB, interleukin-2 or latency-associated antigen such as heparin-binding hemagglutinin may be useful to distinguish active TB from latent or cured TB infection. There are no potential biomarkers to fully distinguish the time-phase of TB infection at present. It is necessary to discover new immunodiagnostic biomarkers to facilitate decisions on treatment selection for active or latent TB infection.

Performance of T-Track® TB, a Novel Dual Marker RT-qPCR-Based Whole-Blood Test for Improved Detection of Active Tuberculosis.

Tuberculosis (TB) is one of the leading causes of death by an infectious disease. It remains a major health burden worldwide, in part due to misdiagnosis. Therefore, improved diagnostic tests allowing the faster and more reliable diagnosis of patients with active TB are urgently needed. This prospective study examined the performance of the new molecular whole-blood test T-Track® TB, which relies on the combined evaluation of IFNG and CXCL10 mRNA levels, and compared it to that of the QuantiFERON®-TB Gold Plus (QFT-Plus) enzyme-linked immunosorbent assay (ELISA). Diagnostic accuracy and agreement analyses were conducted on the whole blood of 181 active TB patients and 163 non-TB controls. T-Track® TB presented sensitivity of 94.9% and specificity of 93.8% for the detection of active TB vs. non-TB controls. In comparison, the QFT-Plus ELISA showed sensitivity of 84.3%. The sensitivity of T-Track® TB was significantly higher (p < 0.001) than that of QFT-Plus. The overall agreement of T-Track® TB with QFT-Plus to diagnose active TB was 87.9%. Out of 21 samples with discordant results, 19 were correctly classified by T-Track® TB while misclassified by QFT-Plus (T-Track® TB-positive/QFT-Plus-negative), and two samples were misclassified by T-Track® TB while correctly classified by QFT-Plus (T-Track® TB-negative/QFT-Plus-positive). Our results demonstrate the excellent performance of the T-Track® TB molecular assay and its suitability to accurately detect TB infection and discriminate active TB patients from non-infected controls.

Diagnostic biomarkers for active tuberculosis: progress and challenges.

Tuberculosis (TB) is a leading cause of morbidity and mortality from a single infectious agent, despite being preventable and curable. Early and accurate diagnosis of active TB is critical to both enhance patient care, improve patient outcomes, and break Mycobacterium tuberculosis (Mtb) transmission cycles. In 2020 an estimated 9.9 million people fell ill from Mtb, but only a little over half (5.8 million) received an active TB diagnosis and treatment. The World Health Organization has proposed target product profiles for biomarker- or biosignature-based diagnostics using point-of-care tests from easily accessible specimens such as urine or blood. Here we review and summarize progress made in the development of pathogen- and host-based biomarkers for active TB diagnosis. We describe several unique patient populations that have posed challenges to development of a universal diagnostic TB biomarker, such as people living with HIV, extrapulmonary TB, and children. We also review additional limitations to widespread validation and utilization of published biomarkers. We conclude with proposed solutions to enhance TB diagnostic biomarker validation and uptake.