Dr. Aniruddha Agarwal, A15367, Dr. Kanika Aggarwal, Dr. Vishali Gupta
Title: The Collaborative Ocular Tuberculosis Study (COTS)-1: Polymerase Chain Reaction in the diagnosis and management of Tubercular Uveitis: Real world scenario: Report 3
Authors:
Aniruddha AGARWAL1, Rupesh AGRAWAL2,3,4,5, Dinesh Visva GUNASEKERAN2,3,4, Dhananjay RAJE6, Bhaskar GUPTA7, Kanika AGGARWAL1, Somasheila L MURTHY8, Mark WESTCOTT3, CHEE Soon Phaik5,9, Peter MCCLUSKEY10, HO Su Ling2, Stephen TEOH2, Luca CIMINO11, Jyotirmay BISWAS12, Shishir NARAIN13, Manisha AGARWAL14, Padmamalini MAHENDRADAS15, Moncef KHAIRALLAH16, Nicholas JONES17, Ilknur TUGAL-TUTKUN18, Kalpana BABU19, Soumayava BASU20, Ester CARREÑO21, Richard LEE21, Hassan el DHIBI22, Bahram BODAGHI23, Alessandro INVERNIZZI24, Debra A. GOLDSTEIN25, Carl P HERBORT26, Talin BARISANI27, Julio J GONZÁLEZ-LÓPEZ28, Sofia ANDROUDI29, Reema BANSAL1, Bruttendu MOHARANA1, Sarakshi MAHAJAN1, Simona ESPOSTI3, Anastasia TASIOPOULOU3, Sengal NADARAJAH3, Mamta AGARWAL12, Sharanaya ABRAHAM12, Ruchi VALA15, Ramandeep SINGH1, Aman SHARMA30, Kusum SHARMA31, Manfred ZIERHUT32, Onn Min KON33, Emmett Cunningham34, Quan Dong NGUYEN35, Carlos PAVESIO3, Vishali GUPTA1.
Affiliations
- Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh
- National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore
- Moorfields Eye Hospital, NHS Foundation Trust, London, United Kingdom
- School of Medicine, National University of Singapore, Singapore
- Singapore Eye Research Institute, Singapore
- CSTAT, Royal Statistician Society, London
- Royal Berkshire Hospital, NHS Foundation Trust, Reading, United Kingdom
- Tej Kohli Cornea Institute, LV Prasad Eye Institute, Kallam Anji Reddy Campus, Hyderabad, India
- Singapore National Eye Centre, Singapore
- Department of Clinical Ophthalmology & Eye Health, Central Clinical School, Save Sight Institute, The University of Sydney, Sydney, Australia
- Ocular Immunology Unit, Department of Ophthalmology, Arcispedale-IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
- Sankara Nethralaya, Chennai, India
- Shroff Eye Centre, New Delhi, India
- Dr Shroff’s Charity Eye Hospital Daryaganj, New Delhi, India
- Narayana Nethralaya, Bangalore, India
- Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Tunisia
- University of Manchester, United Kingdom
- Istanbul University, Istanbul Faculty of Medicine, Department of Ophthalmology, Turkey
- Prabha Eye Clinic & Research centre, Vittala International Institute of Ophthalmology, Bangalore, India
- LV Prasad Eye Institute, Bhubaneswar, India
- Bristol Eye Hospital, United Kingdom
- King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia
- DHU SightRestore, University of Pierre and Marie Curie, Paris, France
- Eye Clinic, Department of Biomedical and Clinical Science “L. Sacco”, Luigi Sacco Hospital, University of Milan, Italy
- Northwestern University, Feinberg School of Medicine, Department of Ophthalmology. Chicago, Illinois, USA
- Centre for Ophthalmic Specialised Care & University of Lausanne, Lausanne, Switzerland
- Laura Bassi Centre of Expertise Ocuvac, Center for Pathophysiology, Immunology and Infectiology, Medical University of Vienna.
- Ramón y Cajal University Hospital, IRYCIS, Universidad de Alcala, Spain
- University of Thessaly, Greece
- Department of Rheumatology, PGIMER, Chandigarh
- Department of Microbiology, PGIMER, Chandigarh
- Centre of Ophthalmology, University of Tuebingen, Germany
- Chest and Allergy Clinic, St Mary’s Hospital, Imperial College Healthcare NHS Trust, United Kingdom
- Francis I. Proctor Foundation for Research in Ophthalmology, University of California, San Francisco, USA
- Byres Eye Institute, Stanford University, Palo Alto, California, United States of America
Corresponding author:
Vishali Gupta, MD
Professor of Ophthalmology,
Advanced Eye Centre,
Post graduate Institute of Medical Education and Research (PGIMER),
Chandigarh, India.
Email: vishalisara@yahoo.co.in
Contact number: +919417565506
Key words:
Tuberculosis;
Polymerase Chain Reaction;
Choroiditis;
Choroidal tuberculoma;
Anti-tubercular therapy
Financial support: The research was partially funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology.
Disclosures: There is no conflict of interest for any author.
ABSTRACT
Purpose: To analyze the role of polymerase chain reaction (PCR) of ocular fluids in management of tubercular (TB) anterior, intermediate, posterior and panuveitis.
Methods: In Collaborative Ocular Tuberculosis Study (COTS)-1 (25 centers, n=962), patients with TB-related uveitis were included. 59 patients undergoing PCR of intraocular fluids (18 females; 53 Asian Indians) were included.
Results: 59 (6.13%) of COTS-1 underwent PCR analysis. PCR was positive for Mycobacterium TB in 33 patients (23 males; all Asian Indians). 26 patients were PCR negative (18 males). 8 patients with negative PCR had systemic TB. Anti-TB therapy was given in 18 negative and 31 PCR cases. At 1-year follow-up, 5 patients with positive PCR (15.15%) and 3 with negative PCR (11.54%) had persistence/worsening of inflammation.
Conclusions: Data from COTS-1 suggests that PCR is not commonly done for diagnosing intraocular TB and positive/negative results may not influence management or treatment outcomes in the real world scenario.
INTRODUCTION
Tuberculosis (TB) is a major cause of morbidity and mortality in many countries, and a significant public health problem worldwide. The World Health Organization (WHO) estimates that there are currently about 8.8 million new cases of TB and 1.6 million deaths from TB every year.1 The ocular manifestations of tuberculosis are protean and easily masquerade as other ocular inflammatory diseases. Tubercular uveitis (TBU) is associated with significant visual morbidity.2 Currently, the diagnosis of TBU is a conundrum, with a conglomerate of clinical signs not pathognomonic for TB, radiologic findings and immunologic tests.3 The tuberculin skin test (TST) and interferon-γ-release assay (IGRA), although widely used in the diagnostic process, cannot differentiate between active disease and latent infection. Strong clinical suspicion of TBU in the presence of negative immunological diagnosis creates a dilemma for the management of these patients.
Various attempts have been made to aid the clinician in diagnosing TBU, including clinical, imaging, and histopathological characterization.3-7 Recently proposed guidelines for the diagnosis of TBU encompass exclusion of other known etiologies of uveitis, suggestive clinical history and signs, supportive investigations such as positive Mantoux test, chest radiograph (CXR) findings, IGRA, and response to anti-tubercular therapy (ATT).8 However, since the detection of unequivocal evidence of TB infection for ocular disease is often challenging, there is a diagnostic uncertainty for TBU highlighted in the literature. Polymerase chain reaction (PCR), a type of nucleic acid amplification technique (NAAT), has been employed in the diagnosis of TBU in several reports published in the literature.6,7,9-14 The technique of PCR amplifies small quantities of DNA of small genomic sequences from tissues and fluids. In the context of TBU, PCR has been shown to be of great benefit in the diagnosis of this paucibacillary condition.15,16 Rapid analysis with PCR for diagnosing TBU is possible using novel techniques such as conventional and real-time PCR.7,17
The exact role of NAATs such as PCR in the diagnosis of TBU in the diagnosis and management of TBU has not been evaluated in a multicenter approach. As per the latest classification proposed for TBU, positive PCR has been considered to be confirmatory. Thus, in the index study, data from the Collaborative Ocular Tuberculosis Study (COTS)-1 was analysed to see how frequently and reliably experts were using PCR as a diagnostic criterion in deciding about treatment initiation based on PCR positivity. In addition, influence of the PCR results on the outcomes have been discussed.
METHODS
COTS-1 is a retrospective cohort study of patients diagnosed with TBU from January 2004 to December 2014 from 25 centers worldwide. In this study, demographics, clinical features, laboratory investigations, imaging evaluation, systemic examination, management, and treatment outcomes were obtained for 962 patients. This study was conducted with ethical approval obtained by each participating centre from their local institutional ethics committee. The list of all the participating centers along with the principal investigators for each site is provided in Appendix 1.
Study Subjects
For the purpose of the study, the diagnostic criteria for TBU was previously established. These criteria were based on the presence of suggestive clinical features as listed in Appendix 2. In The inclusion criteria for the COTS-1 study were:
- Satisfied study diagnostic criteria for TBU
- Availability of patient medical records with details of ophthalmic examination at baseline and follow-up reviews
- Ancillary and laboratory investigations done to exclude relevant differential diagnoses.
- Completed a minimum follow-up of one year
In the present report, subset of patients from the COTS-1 undergoing PCR analysis of ocular fluids (from anterior chamber paracentesis/vitreous paracentesis or diagnostic vitrectomy) were analysed. PCR was performed by the treating uveitis specialist on discretionary basis, in cases of diagnostic dilemma, or along with diagnostic vitrectomy. PCRs were performed at all the study sites in a standardized and stringent manner in designated laboratories. Commonly identified sequences include IS6110, MPB64, and protein b. PCR was performed on aqueous, vitreous fluid, or both. Results of the PCR were noted for all the patients undergoing the test.
In the COTS-1 study, patients with TBU were treated with ATT along with corticosteroids and/or immunosuppression as directed by attending physicians in collaboration with respiratory or infectious disease physicians. This treatment protocol was as per the individual institutional protocols. The route of drug delivery for steroids and use of steroid-sparing immunosuppressive agents was guided by clinical phenotype, severity of TBU, patients’ co-morbidities, and treatment response on a case-by-case basis as directed by the attending speciality-trained ophthalmologist. Treatment failure was determined using defined criteria based on treatment regimen received. Treatment failure was defined as patients with any of the following;
- Persistence or recurrence of inflammation within 6 months of completing ATT
- Inability to taper oral corticosteroids to <10mg/day or topical steroid drops to <2 drops/day
- Recalcitrant inflammation necessitating steroid-sparing immunosuppressive therapy
Data collection
In the COTS-1 study, data of all the patients was collected using a novel data entry platform. The platform was conceived to address the heterogeneous nature of this disease and incorporate several variables associated with the condition. Variables for which data was not entered were treated as missing values with pairwise deletion for statistical analysis. Given the observational retrospective nature of the data as well as lack of a gold standard diagnostic test, multiple imputation was not attempted. For the index study, data of patients undergoing PCR analysis of ocular fluids (aqueous, vitreous, or both) irrespective of the positivity was included for the analysis.
Statistical analysis
For the purpose of data analysis, GraphPad Prism® (GraphPad Software Inc., La Jolla, CA) version 6.0 was used. Missing data was addressed by pairwise deletion. Frequencies were described for individual variables. Quantitative variables were described as mean along with their standard deviations (SD). Categorical variables were compared between the groups using Chi-square test.
RESULTS
In the COTS-1 Study, 962 patients with TBU were retrospectively enrolled from 25 centers all over the world. Of the 962 patients, only 59 patients (6.13%) underwent analysis of PCR. The patients who underwent PCR had a mean age of 36.33 ± 14 years (range: 11 – 74 years). There were 41 males (69.49%) in the cohort. The ethnicity was predominantly Asian (53 patients; 89.83%). The geographical origin was also predominantly Asian (49 patients; 83.05%). The demographic characteristics are described in Table 1.
PCR analysis of ocular fluids was performed at a few centers from amongst the participating study centers, with 45 study subjects (76.27%) from India. The details of the centers performing PCR analysis is provided in Table 2. Diagnostic vitrectomy was performed in 3 patients.
Of the 59 patients undergoing PCR analysis, positive results were obtained in 33 patients (55.93%) (23 males; all Asian Indians). Among the 33 patients with positive TB PCR, there was anterior uveitis in 1 patient (3.03%), intermediate uveitis in 1 patient (3.03%), posterior uveitis in 20 patients (60.06%), and panuveitis in 11 patients (33.33%). The phenotypic variants of choroiditis among 20 patients with posterior uveitis included serpiginous-like choroiditis in 10 patients, choroidal tubercles in 4 patients, multifocal choroiditis in 5 patients, and ampiginous choroiditis in 1 patient. Macular edema was present in 4 patients (3 with panuveitis and 1 patient with choroidal tubercles). Presence of other clinical signs such as anterior chamber cells, flare, vitritis and snow ball exudates is further detailed in Table 3. 26 patients had negative PCR (8 females; 21 were Asians including 1 Chinese and 1 Malay, and 2 patients were Caucasian). The distribution of uveitis among TB PCR negative cases were: anterior uveitis (2 patients), intermediate uveitis (1 patient), posterior uveitis (13 patients) and panuveitis (10 patients). Further details of the patients with TB PCR negativity is also provided in Table 3.
Corroborative systemic investigations among patients with positive PCR were also analysed. Among 33 patients with positive PCR, tuberculin skin test was performed in 30 patients, and the results were positive in 22 patients (66.66%). QuantiFERON TB Gold was performed in 10/33 patients and was positive in 4 patients (40%). One patient was positive for TB-T spot test. Six patients (18.18%) were diagnosed with systemic (pulmonary/ extrapulmonary TB). Computed tomography (CT) scans showed “suggestive lesions” (paratracheal/mediastinal nodes, parenchymal lesions) in 5 patients (15.15%). Among patients with negative PCR (n=26), 14 patients underwent tuberculin skin test which was positive in 10 patients (71.42%). Of the 6 patients undergoing QuantiFERON TB Gold testing, positive results were observed in 3 patients (50%). 8/26 (30.77%) patients were diagnosed with pulmonary/ extrapulmonary TB (including 1 patient with miliary TB and 1 patient with TB meningitis). The details of systemic TB among the two groups is provided in Table 4.
Treatment with ATT was given in 31/33 patients with PCR positive TBU (93.94%) compared to 18 patients with PCR negative results (78.26%). Second-line ATT with injection streptomycin was given in 2 patients with positive PCR and 2 patients with negative PCR (for extrapulmonary severe TB). Two patients among the PCR positive group who did not receive ATT were both Asian Indian males diagnosed with posterior uveitis, had positive tuberculin skin tests, no evidence of systemic TB, and responded with healing of choroiditis lesions to oral steroids alone. All the patients with TB PCR positive results received oral steroids and 2 patients received additional immunosuppression (oral azathioprine).
The criteria for treatment failure were predefined in the COTS-1 study as mentioned in the methodology. Among patients with TB PCR positive results, at 1-year follow-up, 5 patients (15.15%) showed treatment failure (with persistent or worsening of inflammation compared to baseline). Of these, 2 patients were diagnosed with posterior and 3 with panuveitis. Four out of 5 patients were treated with ATT. Among patients with negative PCR, 3 patients (11.54%) showed treatment failure at the end of 12 months (2 patients with posterior and 1 with panuveitis). Among these 3 patients, 2 patients received ATT. Two patients also received long-term immunosuppression with azathioprine and methotrexate (one each, respectively) in addition to corticosteroids.
DISCUSSION
In the recent literature, there have been a number of published reports including case reports that describe the utility of PCR analysis of ocular fluids in the rapid detection of TBU especially in cases where the diagnosis is challenging and inconclusive using conventional clinical, imaging, and other ancillary testing.6,7,9-14 Using PCR techniques, detection of TB genes such as IS6110, MPB64, and protein b enables diagnosis of ocular TB without the need for detection of acid fast bacilli, which are rarely observed due to the paucibacillary nature of the disease. Modifications of conventional PCR are being performed to enhance the diagnostic capabilities of this technique. Quantitative or real-time PCR is a modification of conventional PCR that utilizes fluorescent probes enabling faster detection and quantification of pathogen load in the specimen.13 Sometimes, techniques such as nested PCR, which is less complex compared to the real-time PCR may be employed to save the cost and reduce the technical difficulties.10 Since the reported diagnostic sensitivity of single target (such as IS6110 or MPB64) was suboptimal (less than 40% for IS6110 and 66.6% for MPB64),15 multi-targeted approach wherein several genes are simultaneously amplified has also been evaluated. Using multi-targeted PCR, the sensitivity of TB PCR has increased to 77.7%.6
A study of the literature demonstrates that while the technique of PCR is being increasingly employed in the diagnostic armamentarium of TBU, various centers follow different protocols and techniques for detection of TB genome in ocular samples. Once the PCR report confirms positivity, it is thought that the uveitis is a manifestation of infective/immune response due to the presence of the bacilli.17,18 PCR positive results then maybe used by clinicians to initiate therapy with ATT with a goal to prevent recurrences.18 However, in reality, PCR has several shortcomings including the lack of standardization that has led to the use of in-house developed PCR by some centres, low sensitivity as well as delay in getting the results of PCR.
The index study provides a unique and comprehensive multi-center approach on the utility of PCR in the diagnosis and management of TBU, along with the outcomes of the patients as compared to those who were deemed negative on PCR testing. An important observation from this study is that PCR is employed for diagnosing TB in a small subset of patients by the treating uveitis specialists. Of the 962 patients with TBU in the COTS-1 study, only 59 patients underwent PCR analysis of ocular samples (less than 6.2%). This study also shows that very few centers world-over perform PCR on patients with TBU as elucidated in Table 2. Based on this analysis, it can be stated that only few clinicians utilize PCR-based diagnosis for TBU and that too for a reserved subset of patients.
The striking feature of the study is that several patients (8/26; 30.77%) who tested negative using PCR of ocular samples were diagnosed with systemic TB, including miliary TB in 1 patient and TB meningitis in 1 patient. Thus, sensitivity of the test seems to be a significant limiting factor in the management of TBU. Even amongst the patients who tested positive for TB using PCR in our cohort, 2 patients did not receive ATT whereas more than half patients who were negative on PCR were prescribed ATT by the treating uveitis specialist. This finding highlights the current limitations of PCR-based diagnosis in the management of TBU.
The most significant limiting factor in the utility of PCR for diagnosis of ocular TB is the immense heterogeneity of the test. Most centers in the world performing PCR on ocular fluids use in-house primers which results in great variability in the results. Thus, there is no standardization of the primers used to detect the TB genome. In addition, one may expect variable results on testing different samples such as aqueous, vitreous, ocular pathology samples, and samples obtained from diagnostic vitrectomy (diluted versus undiluted). In such a scenario, it may be challenging to utilize TB PCR positivity as a gold standard for the diagnosis of ocular TB.
In a recently published classification of ocular TB published by Gupta et al,3 PCR positive for TB genes has been designated as confirmed ocular TB. However, various limitations of this technique are being increasingly recognized. Lack of standardization is a major limitation. In addition, limited use and lack of data from the Western population and patients of different ethnicities (other than Asian Indians) are other limitations of this technique. Treatment failures among patients with PCR-positive TBU in our cohort also needs further investigations. While possible reasons could be drug resistance, treatment failure may be related to certain phenotypes or due to other mechanisms including immunological pathways that have led to the persistence of the inflammation.19
A highlight of the index manuscript is that while 55.93% patients tested positive for TB using PCR, the treating uveitis specialists seemed to largely rely on the constellation of their clinical findings commensurate with TB uveitis, imaging findings, and presence of other systemic immunological features (such as tuberculin skin test/QuantiFERON) and systemic TB to base their decision on whether to initiate ATT or not. This implies that the technique of PCR in the diagnosis of TBU is still in its infancy and needs significant advancement to gain wider acceptability and reliability. Further research in this area is warranted using international collaborative efforts to develop standardized techniques from ocular samples, be it aqueous, vitreous or tissue biopsies.
Limitations of this study include its retrospective methodology resulting in missing data, lack of uniform follow-up, investigations, and unstandardized use of ophthalmic imaging. There were differences in the time period when PCR analysis was done, for instance, during acute presentation or during the course of disease follow-up. Data analysis revealed that there were only a handful of patients undergoing PCR analysis from the West, which could lead to incomplete evaluation of this technique. Furthermore, there were small numbers of patients belonging to each phenotypic manifestation, such as serpiginous choroiditis, choroidal tuberculomas, and other such entities. The retrospective data collected also represents patients visiting the various study centers in 2014; since then there has been an improvement in the techniques of PCR. However, the limitations of PCR such as lack of standardization, use of in-house PCRs and suboptimal sensitivity still persist today. Thus, future collaborations are much needed to expand the number of patients undergoing PCR analysis in a prospective manner to enable robust analyses of the outcomes in relation to the PCR results.
Thus, in summary, the technique of PCR analysis in the diagnosis of TBU has a number of pitfalls. Significant improvements in the diagnostic capabilities of PCR by means of further research, or development of newer diagnostic techniques are needed in the management of TBU. International collaborative efforts and further bench-side research is required to address these concerns.
Acknowledgements and Declarations:
The research was partially funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. This sponsor supported some of the research man-hours that were contributed by all our part-time collaborators from the Moorfields Eye Hospital that are salaried as Ophthalmology clinicians by the hospital. Debra A. Goldstein is supported by an unrestricted grant from Research to Prevent Blindness (RPB). Vishali Gupta is supported by grant from Department of Biotechnology, India. Julio J GONZÁLEZ-LÓPEZ2 is supported by study grants from Abbvie, Allergan, and Angelini.
Funders played no part in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; nor the decision to submit the manuscript for publication.
Rupesh AGRAWAL, Dinesh Visva GUNASEKERAN, Robert GRANT, and Dhananjay RAJE had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
All authors do not have any conflicts of interests to declare.
Tables
| Table 1: Demographic characteristics of subjects undergoing polymerase chain reaction analysis from the COTS-1 | |||
| TB PCR +
(n = 33) |
TB PCR –
(n = 26) |
||
| Age | Mean ± SD (years) | 38.84 ± 15.64 | 32.43 ± 12.68 |
| Gender | Male (n, %) | 23 (69.69) | 18 (69.23) |
| Female (n, %) | 10 (30.30) | 8 (30.77) | |
| Race | Asian (n, %) | 29 (87.87) | 24 (92.31) |
| Caucasian (n, %) | 3 (9.09) | 0 | |
| Middle-Eastern (n, %) | 1 (3.03) | 2 (7.69) | |
| Bilaterality | n (%) | 16 (48.48) | 14 (53.85) |
| TB: tuberculosis; PCR: polymerase chain reaction; SD: standard deviation | |||
| Table 3: Clinical features of patients undergoing polymerase chain reaction analysis of ocular samples in the COTS-1 | |||
| TB PCR +
(n = 33) |
TB PCR –
(n = 26) |
||
| Anatomical Site of Uveitis | Anterior | 1 (3.03) | 2 (7.69) |
| Intermediate | 1 (3.03) | 1 (3.84) | |
| Posterior | 20 (60.06) | 13 (50) | |
| Panuveitis | 11 (33.33) | 10 (38.46) | |
| Anterior Chamber Inflammation | 10 (30.30) | 8 (30.77) | |
| Vitreous Haze | 7 (21.21) | 3 (11.54) | |
| Vitreous Cells | 6 (18.18) | 4 (15.38) | |
| Snow Balls | 3 (9.09) | 2 (7.69) | |
| Disc Edema | 7 (21.21) | 2 (7.69) | |
| Macular Edema | 4 (12.12) | 2 (7.69) | |
| Retinal Vasculitis | 9 (27.27) | 2 (7.69) | |
| Choroiditis | Serpiginous-like | 10 (30.30) | 5 (19.23) |
| Multifocal | 5 (15.15) | 3 (11.54) | |
| Tubercles | 4 (12.12) | 3 (11.54) | |
| Others | 1 (3.03) | 2 (7.69) | |
| Table 4: Details regarding systemic tubercular infection among patients evaluated for ocular tuberculosis using polymerase chain reaction in the COTS-1 | |||
| TB PCR +
(n = 33) |
TB PCR –
(n = 26) |
||
| Immunological Tests*
[n (%)] |
Tuberculin Skin Test | 22/30 (66.66) | 10/14 (71.42) |
| IGRA | 4/10 (40) | 3/6 (50) | |
| Tb-T Spot | 1 | – | |
| CT-Scan Chest* [n (%)] | 5/33 (15.15) | 4/26 (15.38) | |
| Pulmonary TB [n (%)] | 3 (9.09) | 3 (11.54) | |
| Extrapulmonary TB [n (%)] | 3 (9.09) | 5 (19.23) | |
| CT-Scan: computerized tomography (chest); IGRA: Interferon gamma release assay; TB: tuberculosis; PCR: polymerase chain reaction
* Since different set of investigations were performed in every patient, the total number of patients differs for each test. The percentages are calculated accordingly. |
|||
Appendix 1
| Participating centres | ||
| Site No. | Site Name | Investigators |
| 001 | National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore | Ho Su Ling |
| 002 | Moorfields Eye Hospital, London, United Kingdom | Carlos Pavesio
Mark Westcott |
| 003 | Advanced Eye Centre, PGIMER Chandigarh, India | Vishali Gupta |
| 004 | LV Prasad Eye Institute, Hyderabad, India | Somasheila Murthy |
| 005 | Singapore National Eye Centre, Singapore | Chee Soon Phaik |
| 006 | Department of Clinical Ophthalmology & Eye Health, Central Clinical School, Save Sight Institute, The University of Sydney, Sydney, Australia. | Peter McCluskey |
| 007 | Ocular Immunology Unit, Department of Ophthalmology, Arcispedale-IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia, Italy | Luca Cimino |
| 008 | Sankara Nethrayala, Chennai, India | J. Biswas |
| 009 | Shroff Eye Centre, New Delhi, India | Shishir Narain |
| 010 | Dr Shroff’s Charity Eye Hospital Daryaganj, New Delhi, India | Manisha Agarwal |
| 011 | Narayana Nethralaya, Bangalore, India | Padmamalini Mahendradas |
| 012 | Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Tunisia | Moncef Khairallah |
| 013 | University of Manchester, United Kingdom | Nicholas Jones |
| 014 | Istanbul University, Istanbul Faculty of Medicine, Department of Ophthalmology, Turkey | Ilknur Tugal-Tutkun |
| 015 | Prabha Eye Clinic & Research centre, Vittala International Institute of Ophthalmology, Bangalore, India | Kalpana Babu Murthy |
| 016 | LV Prasad Eye Institute, Bhubaneswar, India | Soumyava Basu |
| 017 | Bristol Eye Hospital, United Kingdom | Richard Lee, Ester |
| 018 | King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia (KSA) | Hassan el Dhibi |
| 019 | University of Pierre and Marie Curie, Paris, France | Baharam Bodaghi |
| 020 | Luigi Sacco Hospital, University of Milan, Italy | Alessandro Invernizzi |
| 021 | Northwestern University, Feinberg School of Medicine, Department of Ophthalmology. Chicago, Illinois, United States of America | Debra A. Goldstein |
| 022 | Centre for Ophthalmic Specialised Care & University of Laussane, Laussane, Switzerland | Carl P Herbort Jr |
| 023 | Medical University of Vienna | Talin Barisani |
| 024 | Ramón y Cajal University Hospital, IRYCIS, Universidad de Alcala, Spain | Julio J González-López |
| 025 | University of Thessaly, Greece | Sofia Androudi |
| Appendix 2: Criteria for diagnosis of intraocular tuberculosis for inclusion into COTS* |
| *Patients have to satisfy 1 and 2, along with either 3 or 4 for inclusion into COTS.
1) Clinical signs suggestive of ocular tuberculosis including; a. Anterior uveitis (granulomatous or non-granulomatous), Iris nodules, Ciliary body granuloma b. Intermedia uveitis (granulomatous or non-granulomatous with exudates in the pars plana or peripheral uvea, or with snow balls) c. Posterior and Panuveitis, Choroidal tubercle, Choroidal granuloma, Subretinal abscess, Serpiginous-like choroiditis d. Retinitis, Retinal vasculitis, Neuroretinitis, Optic neuritis, Endogenous ophthalmitis, Panophthalmitis, Scleritis 2) Exclusion of other uveitic entities where relevant based on clinical manifestations of disease and regional epidemiology 3) Investigations documenting the mycobacteria or its genome a. Demonstration of Acid-Fast Bacilli (AFB) by microscopy or culture of M. tuberculosis from ocular fluid b. Positive polymerase chain reaction from ocular fluid for IS 6110 or other conserved sequences in mycobacterial genome c. Evidence of confirmed active extra-pulmonary tuberculosis (by microscopic examination or culture of a tissue sample from the affected tissue) 4) Corroborative investigations a. Positive Mantoux reaction (must be accompanied by information regarding antigen and amount of tuberculin injected, along with institutional practices in interpreting the test) b. Interferon Gamma Release Assay (IGRA) such as Quantiferon TB Gold (must be accompanied by information regarding institutional practices in interpreting the test) c. Evidence of healed or active tuberculosis on chest radiography (must be accompanied by information regarding practices by institution radiologists regarding clinical features that are considered evidence in this regard)
|
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