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Theranostics 2023; 13(7):2088-2113. doi:10.7150/thno.81488 This issue Cite

Review

Diagnosis and biomarkers for ocular tuberculosis: From the present into the future

Zhang Ludi¹, Ashita Ashish Sule², Ramar Perumal Samy³, Ikhwanuliman Putera^4,5,6,7, Benjamin Schrijver⁵, Paul Edward Hutchinson⁸, Jayantha Gunaratne⁹, Indu Verma¹⁰, Amit Singhal^1,11,12, Rina La Distia Nora^4,5,13, P. Martin van Hagen^5,6, Willem A Dik⁵, Vishali Gupta¹⁴, Rupesh Agrawal^{1,3,15,16,17,18,19✉}

1. Lee Kong Chian School of Medicine, Nanyang Technological University of Singapore, Singapore.
2. Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
3. National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore, Singapore.
4. Department of Ophthalmology, Faculty of Medicine Universitas Indonesia - CiptoMangunkusmoKirana Eye Hospital, Jakarta, Indonesia.
5. Laboratory Medical Immunology, Department of Immunology, ErasmusMC, UniversityMedical Centre, Rotterdam, the Netherlands.
6. Department of Internal Medicine, Division of Clinical Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
7. Department of Ophthalmology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
8. Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
9. Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
10. Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
11. A*SATR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
12. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
13. University of Indonesia Hospital (RSUI), Depok, West Java, Indonesia.
14. Advanced Eye Centre, Post-Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
15. Duke NUS Medical School, Singapore, Singapore.
16. Singapore Eye Research Institute, Singapore, Singapore.
17. National Institute for Health Research Biomedical Research Centre, Moorfields Eye Hospital, London, UK.
18. School of Pharmacy, Nantong University, Nantong, P. R. China.
19. Department of Mechanical Engineering, University College London, London, United Kingdom.

✉ Corresponding author: A/Prof (Dr) Rupesh Agrawal, Senior Consultant, National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore 308433, Email: Rupesh_agrawalcom.sg.

Abstract

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.

Keywords: Ocular tuberculosis, molecular diagnostic techniques, biomarkers, multi-omic, precision medicine

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