OBJECTIVES:To achieve global TB control, more sensitive and user-friendly diagnostic tools for tuberculosis infection (TBI) are necessary, as it is a potential transmission reservoir. VIDASⓇ TB-IGRA (bioMérieux) is a fully automated assay recently developed. We report here the results of a global, multicenter, cross-sectional, prospective study to evaluate the diagnostic accuracy of the assay. METHODS:Patients with TB disease (n=200) or participants at varying levels of TB exposure risk (n=1460; mixed TB-exposure risk population) were tested with both the VIDASⓇ TB-IGRA and the QuantiFERONⓇ-TB Gold Plus (QFTⓇ-Plus, QIAGEN). RESULTS:In culture-confirmed TB cases, VIDASⓇ TB-IGRA had a sensitivity significantly higher than QFTⓇ-Plus (97.5% vs 80.7%, P<0.0001). Specificity evaluated in blood donors from a low-prevalence country (n=125) was high for both VIDASⓇ TB-IGRA and QFTⓇ-Plus (97.6% [93.1-99.5] vs 95.2% [89.8-98.2]; P=0.083), respectively. In the whole mixed TB-exposure risk population, negative (NPA) and positive percent agreement (PPA) were 90.1% (1097/1217) and 92.1% (223/242), respectively. However, regression analyses revealed that VIDASⓇ TB-IGRA correlated better with the TB-exposure risk gradient than QFTⓇ‑Plus. CONCLUSIONS:Compared with QFTⓇ-Plus, VIDASⓇ TB-IGRA was significantly more sensitive without a reduction in specificity, and it correlated better with an exposure gradient, suggesting that it is a valuable tool for TBI diagnosis.

Stage IIIA N2 NSCLC presents a significant clinical challenge, with suboptimal survival rates despite therapeutic advancements, highlighting the need for more effective treatments.

Formalin-fixed paraffin-embedded (FFPE) material is the mainstay for molecular profiling in non-small lung cancer (NSCLC). However, this pathway is suboptimal for both DNA/RNA quality and turnaround time (TAT), so hampering clinical decision-making. To overcome this, fresh endobronchial ultrasound-guided biopsy (EBUS) material was assessed as an alternative formalin-free DNA/ RNA pathway as part of a multidisciplinary quality improvement activity.

Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause significant disease in both immunocompromised and immunocompetent individuals. The incidence of NTM pulmonary disease (NTM-PD) is rising globally. Diagnostic challenges persist and treatment efficacy is variable. This article provides an overview of NTM-PD for clinicians. We discuss how common it is, who is at risk, how it is diagnosed and the multidisciplinary approach to its clinical management.

Background: Detection and treatment of individuals with presumed latent tuberculosis (TB) infection (i.e., excluding active disease; LTBI) is imperative to achieve global TB control, as they represent a potential transmission reservoir. However, more sensitive and user–friendly diagnostic tools are needed. Methods: We evaluated the accuracy for TB infection detection of the new VIDAS® TB–IGRA (bioMérieux), a fully automated, single tube (thus eliminating the need for batch testing) overnight incubation assay, compared to the QuantiFERON®–TB Gold Plus (QFT–Plus, QIAGEN), in a global multi–centre cross–sectional study ([NCT04048018][1]) that included patients with TB disease (n=200) or participants at varying levels of TB exposure (n=1460; mixed exposure–risk–population). Results: VIDAS® TB–IGRA identified TB disease with greater sensitivity than QFT–Plus (97.5% vs. 80.7%, P<0.01%), and yielding significantly fewer false–negatives (2.5% vs. 17.5%; P<0.01%) and indeterminate results (1.0% vs. 9.5%; P=0.02%). In the mixed exposure–risk–population, negative (NPA) and positive percent agreement (PPA) were 90.1% (1097/1217) and 92.1% (223/242), respectively. PPA increased with TB–exposure risk (up to 95.7% for high–risk participants), whereas NPA decreased (starting from 96.9% for low–risk participants). Regression analyses revealed that VIDAS® TB–IGRA had a better fit with the risk–exposure gradient than the QFT‑Plus. Specificity in extremely low TB–exposure risk participants (n = 125) was high for both VIDAS® TB–IGRA and QFT–Plus (97.6% vs. 95.2%; P=8.33%). Conclusions: VIDAS® TB–IGRA displayed greater sensitivity than QFT–Plus, had a lower indeterminate rate, correlated better with an exposure gradient, and was highly specific, suggesting that it is a potentially valuable tool for the diagnosis of LTBI. ### Competing Interest Statement All authors had financial support from bioMérieux for performing this study. ### Clinical Trial NCT04048018 ### Funding Statement This study was funded by bioMérieux ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The following gave ethical approval for this work: - The French National Ethics committee (CPP, ref. 2019-A00998-49) - The UK Health Research Authority (Wales Research Ethics Committee 7, REC refs: 19/WA/0284 and 19/WA/0285) - The INMI "L. Spallanzani" (Rome, Italy) Ethics Committee (approval n°35/2019) - The "Comité de Ética en Investigación del Hospital General de Mexicali" (Mexico, ref. 02-01-HGMXL/FMED-UABC-2019-08-29-254) - In South Africa: - Pharma ethics refs. 190822774 and 190822777 - University of Cape Town Human Research Ethics Committee ref. 840/2019 - In USA: - Western Institutional Review Board (WIRB, tracking numbers: 20191965; 20192037; 20192039) - The Rutgers University Institutional Review Board (Refs: Pro2019001840 and Pro2019001936) - The Stanford University Institutional Review Board (eProtocol number: 53485) - The University of Illinois at Chicago Institutional Review Board (research protocol number: 2019-1145) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04048018&atom=%2Fmedrxiv%2Fearly%2F2024%2F07%2F05%2F2024.07.03.24309158.atom

Tuberculosis (TB) remains a major global threat and diagnosis of active TB ((ATB) both extra-pulmonary (EPTB), pulmonary (PTB)) and latent TB (LTBI) infection remains challenging, particularly in high-burden countries which still rely heavily on conventional methods. Although molecular diagnostic methods are available, e.g., Cepheid GeneXpert, they are not universally available in all high TB burden countries. There is intense focus on immune biomarkers for use in TB diagnosis, which could provide alternative low-cost, rapid diagnostic solutions. In our previous gene expression studies, we identified peripheral blood leukocyte (PBL) mRNA biomarkers in a non-human primate TB aerosol-challenge model. Here, we describe a study to further validate select mRNA biomarkers from this prior study in new cohorts of patients and controls, as a prerequisite for further development. Whole blood mRNA was purified from ATB patients recruited in the UK and India, LTBI and two groups of controls from the UK (i) a low TB incidence region (CNTRLA) and (ii) individuals variably-domiciled in the UK and Asia ((CNTRLB), the latter TB high incidence regions). Seventy-two mRNA biomarker gene targets were analyzed by qPCR using the Roche Lightcycler 480 qPCR platform and data analyzed using GeneSpring™ 14.9 bioinformatics software. Differential expression of fifty-three biomarkers was confirmed between MTB infected, LTBI groups and controls, seventeen of which were significant using analysis of variance (ANOVA): CALCOCO2, CD52, GBP1, GBP2, GBP5, HLA-B, IFIT3, IFITM3, IRF1, LOC400759 (GBP1P1), NCF1C, PF4V1, SAMD9L, S100A11, TAF10, TAPBP, and TRIM25. These were analyzed using receiver operating characteristic (ROC) curve analysis. Single biomarkers and biomarker combinations were further assessed using simple arithmetic algorithms. Minimal combination biomarker panels were delineated for primary diagnosis of ATB (both PTB and EPTB), LTBI and identifying LTBI individuals at high risk of progression which showed good performance characteristics. These were assessed for suitability for progression against the standards for new TB diagnostic tests delineated in the published World Health Organization (WHO) technology product profiles (TPPs).

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in adults is an essential tool for investigating mediastinal and hilar lymphadenopathy. It is now integral to the diagnostic and staging algorithm for lung cancer [1], as well as the diagnosis of other malignancies, lymphoma and non-malignant granulomatous conditions, such as sarcoidosis and tuberculosis. The comparable diagnostic yield, along with decreased complications, has reduced the requirement for previously standard surgical biopsy sampling [2, 3]. This first European case series demonstrates that EBUS-TBNA, well established in the diagnosis of mediastinal and hilar adenopathy in adults, is a safe and useful diagnostic alternative to invasive surgical biopsy in the paediatric population http://bit.ly/389Uvq4

Background: Tuberculous pleural infection is the most common form of extrapulmonary TB infection. Pleural fluid glucose has been used to aid diagnosis of bacterial pleural infections including TB however the data for its utility in pleural TB is limited. Aim: To identify the utility of pleural fluid glucose as a biomarker in the diagnosis of TB pleural infections. Methods: We conducted a retrospective case series collection of 106 patients diagnosed with pleural Tuberculosis at a tertiary pleural service from 2010 to 2019. All patients received treatment for TB as per UK national guidelines adjusted to culture sensitivities. Results: 106 patients were initially included, with 12 excluded due to insufficient data. A total of 64/94 patients had pleural fluid sent for glucose measurement. All but 2 patients had a pleural fluid glucose less than 7mmol/L. 39/64 (61%) patients had a pleural fluid glucose ranging 4.1-6.0mmol/L and 20/64 (31%) patients had a pleural fluid glucose of <4.0mmol/L. Patients who were either pleural fluid AFB culture or pleural biopsy culture positive had on average a lower pleural fluid glucose level. The average fluid glucose for all patients was 4.55mmol/L, this was lower at 3.63mmol/L if fluid culture was positive, 3.82mmol/L if biopsy culture was positive and 3.27mmol/L if fluid and biopsy cultures were positive. Conclusion: Pleural fluid glucose appears to be low in patients who are pleural fluid or biopsy culture positive, however it is not significantly lower when compared to all patients with TB pleural infection. Therefore unlike in other bacterial pleural infections, we suggest that pleural fluid glucose may not be a useful marker in aiding the diagnosis of pleural TB infection.

Background: Tuberculous pleural infection is the most common form of extrapulmonary TB, pleural fluid adenosine deaminase (pfADA) has been used to provide supportive evidence for a diagnosis of TB. Alternatively, reports suggest pleural histology has a sensitivity of 69-97% and can, therefore, be used as a biomarker for the diagnosis of pleural TB. Aim: To identify the utility of pleural biopsy histology and pfADA in the diagnosis of pleural TB. Methods: We conducted a retrospective case series collection of 106 patients diagnosed with pleural Tuberculosis at a tertiary pleural service from 2010 to 2019. All patients received treatment for TB as per UK national guidelines and adjusted for culture sensitivities. Results: 106 patients were identified, of which 12 were excluded due to insufficient data. 77 patients had a pleural biopsy performed, 50 had pfADA sent; 42 patients had pleural biopsy histology tested and a pfADA measurement. In 100% (42/42) the measured pfADA was ≥30 IU/l; of which 90% (38/42) had granulomatous inflammation on the histopathology biopsy specimen. Of these 40 patients had pfADA >45 IU/l. Of patients with pfADA > 45 IU/l, 65% (26/40) had necrotising granuloma, 25% (10/40) had non-necrotising granuloma, and 10% (4/40) did not have granulomas. Those that did not have granulomas were treated on pleural fluid culture and ADA with positive clinical history. Conclusion: Pleural biopsy histology demonstrating granulomatous inflammation in combination with pfADA >45 IU/l is a useful biomarker for diagnosing pleural TB.

We report the first case of TB associated with triplet therapy (chemotherapy and immunotherapy concurrently) for lung cancer, developing just 44 days after treatment initiation. We feel that several important learning points arise from the discussion that are likely to be very relevant to the broad readership of Thorax , and have important clinical and scientific implications. In the three discussion paragraphs, we highlight that: 1) Triplet therapy is now standard first-line treatment for inoperable lung cancer. 2) TB reactivation is increasingly recognised as an adverse effect of immune checkpoint inhibition, but sending diagnostic samples is critical to avoid a missed diagnosis. 3) These insights from novel cancer immunotherapies are challenging the traditional views of the host-pathogen interaction in TB, with wide implications for future control strategies. We propose that the cases reported in the literature are likely to be the tip of the iceberg as most people with lung cancer managed with antiprogrammed death-1 agents who develop new lung lesions will be treated with standard antibiotics and then palliated when they do not respond.

Ocular tuberculosis (OTB) is a complex and heterogeneous condition that is poorly characterised and understood.There are a variety of ophthalmic phenotypes that are recognised as 'typical' in the global literature:1. Peripheral occlusive retinal vasculitis, or Eales disease 2. Serpiginous-like (or ampiginous) chorioretinitis 3. Choroidal granuloma

Abstract This chapter describes a case of Mycobacterium malmoense in a male ex-smoker with chronic obstructive pulmonary disease. The approaches to a diagnosis of pulmonary non-tuberculous mycobacterial disease are discussed, including key laboratory features and associated radiological changes. The factors influencing the decision to treat and treatment regimen selected are reviewed, along with evidence from landmark trials regarding drug combinations and the role of surgery in managing non-tuberculous mycobacterial disease. This case was complicated by a secondary diagnosis of invasive aspergillosis, and the challenges of treating non-tuberculous mycobacteria and Aspergillus concurrently are highlighted. Non-tuberculous mycobacterial infection in HIV-positive patients can behave differently to non-tuberculous mycobacterial disease in immunocompetent individuals. Restoring immunocompetence is key to the success of non-tuberculous mycobacterial treatment in these individuals, but beware Mycobacterium avium complex-related immune restoration inflammatory syndrome.

Inflammatory response following initial improvement with anti-tuberculosis (TB) treatment has been termed a paradoxical reaction (PR). HIV co-infection is a recognised risk, yet little is known about other predictors of PR, although some biochemical markers have appeared predictive. We report our findings in an ethnically diverse population of HIV-infected and uninfected adults.

BACKGROUND CONTEXT: National guidelines for treatment of spinal TB (sTB) recommend a 6-month quadruple chemotherapy regimen. Spinal magnetic resonance imaging (MRI) is increasingly used to monitor disease progression as optimal treatment duration remains uncertain.

Mycobacterium tuberculosis is estimated to have infected one third of the world's population and continues to be a significant cause of mortality and morbidity [1]. There is a need for new and improved diagnostics or treatment-monitoring tools and blood-based mRNA diagnostics are a potential solution [2]. Gene expression microarray analysis of human blood has been widely used to profile the host transcriptional response in active tuberculosis (TB) to identify potential biomarkers and better understand the host immune response [2]. So far, there has been a relative lack of concordance in the actual genes being identified from the published studies [2, 3], although there has been agreement in some of the pathways identified. Interferon (IFN) signalling has been identified as a dominant signature in many of the individual studies [2, 4]; however, when significant gene lists were combined from eight publicly available TB datasets, TREM1 (triggering receptor expressed on myeloid cells 1) signalling became the most significant pathway [5]. Modular and meta-profiling identify a common transcriptional response of patients with TB versus healthy controls

The C - reactive protein (CRP) response is often measured in patients with active tuberculosis (TB) yet little is known about its relationship to clinical features in TB, or whether responses differ between ethnic groups or with different Mycobacterium tuberculosis (M.tb) strain types. We report the relationship between baseline serum CRP prior to treatment and disease characteristics in a metropolitan population with TB resident in a low TB incidence region.

Background Mycobacterium tuberculosis infection is a leading cause of infectious death worldwide. Gene-expression microarray studies profiling the blood transcriptional response of tuberculosis (TB) patients have been undertaken in order to better understand the host immune response as well as to identify potential biomarkers of disease. To date most of these studies have focused on pulmonary TB patients with gene-expression profiles of extra-pulmonary TB patients yet to be compared to those of patients with pulmonary TB or sarcoidosis. Methods A novel cohort of patients with extra-pulmonary TB and sarcoidosis was recruited and the transcriptional response of these patients compared to those with pulmonary TB using a variety of transcriptomic approaches including testing a previously defined 380 gene meta-signature of active TB. Results The 380 meta-signature broadly differentiated active TB from healthy controls in this new dataset consisting of pulmonary and extra-pulmonary TB. The top 15 genes from this meta-signature had a lower sensitivity for differentiating extra-pulmonary TB from healthy controls as compared to pulmonary TB. We found the blood transcriptional responses in pulmonary and extra-pulmonary TB to be heterogeneous and to reflect the extent of symptoms of disease. Conclusions The transcriptional signature in extra-pulmonary TB demonstrated heterogeneity of gene expression reflective of symptom status, while the signature of pulmonary TB was distinct, based on a higher proportion of symptomatic individuals. These findings are of importance for the rational design and implementation of mRNA based TB diagnostics.

A 24-year-old man was referred to the haematologists for investigation of unexplained anaemia on the background of a 6-month history of exertional breathlessness, mild cough and night sweats. Investigations revealed iron-deficiency anaemia (haemoglobin 94 g/L), thrombocytosis and markedly elevated inflammatory markers (C-reactive protein (CRP) 235 mg/L). A CT scan of his chest identified a large expansile filling defect within the left main pulmonary artery, almost entirely occluding the left-sided pulmonary circulation, which had high-grade 18F-fluorodeoxyglucose (FDG) uptake on a subsequent positron emission tomography (PET) CT (figure 1). Figure 1 CT pulmonary angiogram and positron emission tomography CT merged image showing high-grade 18F-fluorodeoxyglucose (FDG) uptake in a 35 mm lesion within the left main pulmonary artery. The lesion …