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Tuberculosis is an airborne disease caused by Mycobacterium tuberculosis (Mtb) and can manifest both pulmonary and extrapulmonary disease, including ocular tuberculosis (OTB). Accurate diagnosis and swift optimal treatment initiation for OTB is faced by many challenges combined with the lack of standardized treatment regimens this results in uncertain OTB outcomes. The purpose of this study is to summarize existing diagnostic approaches and recently discovered biomarkers that may contribute to establishing OTB diagnosis, choice of anti-tubercular therapy (ATT) regimen, and treatment monitoring. The keywords ocular tuberculosis, tuberculosis, Mycobacterium , biomarkers, molecular diagnosis, multi-omics, proteomics, genomics, transcriptomics, metabolomics, T-lymphocytes profiling were searched on PubMed and MEDLINE databases. Articles and books published with at least one of the keywords were included and screened for relevance. There was no time limit for study inclusion. More emphasis was placed on recent publications that contributed new information about the pathogenesis, diagnosis, or treatment of OTB. We excluded abstracts and articles that were not written in the English language. References cited within the identified articles were used to further supplement the search. We found 10 studies evaluating the sensitivity and specificity of interferon-gamma release assay (IGRA), and 6 studies evaluating that of tuberculin skin test (TST) in OTB patients. IGRA (Sp = 71-100%, Se = 36-100%) achieves overall better sensitivity and specificity than TST (Sp = 51.1-85.7%; Se = 70.9-98.5%). For nuclear acid amplification tests (NAAT), we found 7 studies on uniplex polymerase chain reaction (PCR) with different Mtb targets, 7 studies on DNA-based multiplex PCR, 1 study on mRNA-based multiplex PCR, 4 studies on loop-mediated isothermal amplification (LAMP) assay with different Mtb targets, 3 studies on GeneXpert assay, 1 study on GeneXpert Ultra assay and 1 study for MTBDRplus assay for OTB. Specificity is overall improved but sensitivity is highly variable for NAATs (excluding uniplex PCR, Sp = 50-100%; Se = 10.5-98%) as compared to IGRA. We also found 3 transcriptomic studies, 6 proteomic studies, 2 studies on stimulation assays, 1 study on intraocular protein analysis and 1 study on T-lymphocyte profiling in OTB patients. All except 1 study evaluated novel, previously undiscovered biomarkers. Only 1 study has been externally validated by a large independent cohort. Future theranostic marker discovery by a multi-omics approach is essential to deepen pathophysiological understanding of OTB. Combined these might result in swift, optimal and personalized treatment regimens to modulate the heterogeneous mechanisms of OTB. Eventually, these studies could improve the current cumbersome diagnosis and management of OTB., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Polymerase chain reaction (PCR) is currently considered the method of choice for diagnosing ocular tuberculosis. However, the sensitivity and specificity of PCR using ocular samples remain uncertain. Our meta-analysis aimed to review the diagnostic accuracy of PCR testing in confirming ocular tuberculosis, with responses to antitubercular therapy (ATT) as reference indices., Methods: A systematic literature search of the PubMed, EBSCOHost, Scopus, and Google Scholar databases was performed using the standardized PRISMA guideline. Observational studies reporting both PCR MTb positivity and ATT response were included. Meta-analysis was performed to estimate the pooled positivity rate, sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratios (DOR), and summary receiver operating curves (SROC)., Results: The pooled positivity rate for PCR MTb was 0.55 (95% CI 0.44-0.67). The overall sensitivity and specificity were 88% (95% CI 83-92) and 71% (95% CI 60-80), respectively. The pooled DOR was 12.15 (95% CI 5.55-26.62). The area under the SROC was 0.83., Conclusions: The diagnostic accuracy of PCR Mtb is not sufficient for use as a benchmark for ocular TB diagnosis routinely based on ATT response. A negative result may help avoid prescribing unnecessary ATT in dilemmatic cases., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Bacille Calmette-Guerin (BCG) vaccination remains a routine immunization in primary care in tuberculosis (TB)-endemic areas, though several studies found that its efficacy was inconclusive. Natural resistance-asociated machrophage protein 1 (NRAMP1) polymorphism has been shown to result in higher susceptibility to TB. Information on genetic susceptibility in populations will be useful in planning the application of the BCG vaccine. The present study explored BCG efficacy in a rural Timor population with specific NRAMP1 polymorphism in a TB-endemic region of eastern Indonesia., Methodology: A case-control study with 64 newly diagnosed pulmonary TB patients and 65 healthy controls was performed. BCG scars were examined by a physician. NRAMP1 polymorphism was evaluated using molecular methods., Results: Half of the subjects (65; 50.4%) had a clear presenting BCG scar on the upper arm, suggesting a successful BCG vaccination. Among the subjects, D543N NRAMP1 polymorphism, history of contact with TB patients, and not having a clear BCG scar on the upper arm tended to be significantly association with active TB. The significant differences were more profound when subjects were divided based on presenting BCG scar. Subjects without clear BCG scars had significant association with developing TB disease (p = 0.014). In multivariate analysis, history of previous contact with TB patients and unclear presenting BCG scar were associated with active TB (OR 9.2; 2.0-43.8 95% CI, OR 4.8; 2.1-11.0 95% CI, respectively)., Conclusions: BCG vaccination in our population was effective for TB protection, especially in highly endemic areas of TB, regardless genetic susceptibility.

Sarcoidosis and tuberculosis (TB) are two granulomatous diseases that often share overlapping clinical features, including uveitis. We measured 368 inflammation-related proteins in serum in both diseases, with and without uveitis from two distinct geographically separated cohorts: sarcoidosis from the Netherlands and TB from Indonesia. A total of 192 and 102 differentially expressed proteins were found in sarcoidosis and active pulmonary TB compared to their geographical healthy controls, respectively. While substantial overlap exists in the immune-related pathways involved in both diseases, activation of B cell activating factor (BAFF) signaling and proliferation-inducing ligand (APRIL) mediated signaling pathways was specifically associated with sarcoidosis. We identified a B-lymphocyte activation signature consisting of BAFF, TNFRSF13B/TACI, TRAF2, IKBKG, MAPK9, NFATC1, and DAPP1 that was associated with sarcoidosis, regardless of the presence of uveitis. In summary, a difference in B-lymphocyte activation is a key discriminative immunological feature between sarcoidosis/ocular sarcoidosis (OS) and TB/ocular TB (OTB). Sarcoidosis patients exhibit higher level of serum B cell activation signature compared to tuberculosis, regardless of uveitis manifestation. [ABSTRACT FROM AUTHOR]

BACKGROUND Tuberculosis (TB) is a common cause of intraocular inflammation in Indonesia. As no accurate biomarker can confirm the diagnosis, ophthalmologists often rely on systemic findings, such as tuberculin skin test, interferon-gamma release assay (IGRA), and chest X-ray (CXR) for TB suspicion. This study aimed to evaluate IGRA and CXR in classifying intraocular TB among patients with a clinically undifferentiated cause of uveitis. METHODS This cross-sectional study included 116 patients (a total of 163 affected eyes) with a clinically undifferentiated cause of uveitis. IGRA and CXR were performed as part of the workup. Data on visual acuity, anterior chamber inflammation grade, and anatomical classification of uveitis were recorded. As there were no confirmed ocular tuberculosis (OTB) in our cases, eyes were classified into probable OTB, possible OTB, and unclassified. RESULTS Overall, 93 patients (80.2%) with a clinically undifferentiated cause of uveitis had positive IGRA, whereas 10 (8.6%) had CXR results suggestive of TB. More than one- third of the patients were blind (visual acuity <3/60), and panuveitis was the commonest anatomical classification. A trend was identified in patients with panuveitis, who often showed ≥2+ cell anterior chamber inflammation (p for trend = 0.023), according to OTB criteria (probable OTB = 3/4, 75.0%; possible OTB = 44/67, 65.7%; unclassified = 2/9, 22.2%). Furthermore, the clinically undifferentiated uveitis cases were eligible to be stratified into probable (8.6%) and possible (75.0%) OTB categories after IGRA and CXR examinations. CONCLUSIONS The combination of IGRA and CXR is valuable for classifying and diagnosing TB-related uveitis. A multidisciplinary approach is essential when the cause of uveitis is unknown. [ABSTRACT FROM AUTHOR]

Tubercular uveitis (TB-uveitis) remains a conundrum in the uveitis field, which is mainly related to the diverse clinical phenotypes of TB-uveitis. Moreover, it remains difficult to differentiate whether Mycobacterium tuberculosis (Mtb) is present in the ocular tissues, elicits a heightened immune response without Mtb invasion in ocular tissues, or even induces an anti-retinal autoimmune response. Gaps in the immuno-pathological knowledge of TB-uveitis likely delay timely diagnosis and appropriate management. In the last decade, the immunopathophysiology of TB-uveitis and its clinical management, including experts' consensus to treat or not to treat certain conditions with anti-tubercular treatment (ATT), have been extensively investigated. In the meantime, research on TB treatment, in general, is shifting more toward host-directed therapies (HDT). Given the complexities of the host- Mtb interaction, enhancement of the host immune response is expected to boost the effectiveness of ATT and help overcome the rising burden of drug-resistant Mtb strains in the population. This review will summarize the current knowledge on the immunopathophysiology of TB-uveitis and recent advances in treatment modalities and outcomes of TB-uveitis, capturing results gathered from high- and low-burden TB countries with ATT as the mainstay of treatment. Moreover, we outline the recent progress of HDT development in the pulmonary TB field and discuss the possibility of its applicability to TB-uveitis. The concept of HDT might help direct future development of efficacious therapy for TB-uveitis, although more in-depth research on the immunoregulation of this disease is still necessary. [ABSTRACT FROM AUTHOR]