Ocular Immunology and Inflammation

ISSN: 0927-3948 (Print) 1744-5078 (Online) Journal homepage: http://www.tandfonline.com/loi/ioii20

The Collaborative Ocular Tuberculosis Study

(COTS)-1: A Multinational Description of the
Spectrum of Choroidal Involvement in 245 Patients
with Tubercular Uveitis

Rupesh Agrawal, Dinesh Visva Gunasekeran, Aniruddha Agarwal, Ester

Carreño, Kanika Aggarwal, Bhaskar Gupta, Dhananjay Raje, Somasheila
I. Murthy, Mark Westcott, Soon Phaik Chee, Peter McCluskey, Ho Su Ling,
Stephen Teoh, Luca Cimino, Jyotirmay Biswas, Shishir Narain, Manisha
Agarwal, Padmamalini Mahendradas, Moncef Khairallah, Nicholas Jones,
Ilknur Tugal-Tutkun, Kalpana Babu, Soumayava Basu, Richard Lee, Hassan
Al-Dhibi, Bahram Bodaghi, Alessandro Invernizzi, Debra A. Goldstein, Carl P.
Herbort, Talin Barisani-Asenbauer, Julio J. González-López, Sofia Androudi,
Reema Bansal, Bruttendu Moharana, Sarakshi Mahajan, Simona Esposti,
Anastasia Tasiopoulou, Sengal Nadarajah, Mamta Agarwal, Sharanya
Abraham, Ruchi Vala, Joanne Lord, Ramandeep Singh, Aman Sharma,
Kusum Sharma, Manfred Zierhut, Onn Min Kon, John Kempen, Emmett
T. Cunningham, Andres Rousselot, Quan Dong Nguyen, Carlos Pavesio &
Vishali Gupta

To cite this article: Rupesh Agrawal, Dinesh Visva Gunasekeran, Aniruddha Agarwal, Ester
Carreño, Kanika Aggarwal, Bhaskar Gupta, Dhananjay Raje, Somasheila I. Murthy, Mark Westcott,
Soon Phaik Chee, Peter McCluskey, Ho Su Ling, Stephen Teoh, Luca Cimino, Jyotirmay Biswas,
Shishir Narain, Manisha Agarwal, Padmamalini Mahendradas, Moncef Khairallah, Nicholas Jones,
Ilknur Tugal-Tutkun, Kalpana Babu, Soumayava Basu, Richard Lee, Hassan Al-Dhibi, Bahram
Bodaghi, Alessandro Invernizzi, Debra A. Goldstein, Carl P. Herbort, Talin Barisani-Asenbauer,
Julio J. González-López, Sofia Androudi, Reema Bansal, Bruttendu Moharana, Sarakshi Mahajan,
Simona Esposti, Anastasia Tasiopoulou, Sengal Nadarajah, Mamta Agarwal, Sharanya Abraham,
Ruchi Vala, Joanne Lord, Ramandeep Singh, Aman Sharma, Kusum Sharma, Manfred Zierhut,
Onn Min Kon, John Kempen, Emmett T. Cunningham, Andres Rousselot, Quan Dong Nguyen,
Carlos Pavesio & Vishali Gupta (2018): The Collaborative Ocular Tuberculosis Study (COTS)-1: A
Multinational Description of the Spectrum of Choroidal Involvement in 245 Patients with Tubercular
Uveitis, Ocular Immunology and Inflammation, DOI: 10.1080/09273948.2018.1489061

To link to this article: https://doi.org/10.1080/09273948.2018.1489061

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Ocular Immunology & Inflammation, 2018; 00(00): 1–11
© Taylor & Francis Group, LLC
ISSN: 0927-3948 print / 1744-5078 online
DOI: 10.1080/09273948.2018.1489061

ORIGINAL ARTICLE

The Collaborative Ocular Tuberculosis Study

(COTS)-1: A Multinational Description of the
Spectrum of Choroidal Involvement in 245 Patients
with Tubercular Uveitis
Rupesh Agrawal*1,2,3, Dinesh Visva Gunasekeran*1,3,4, Aniruddha Agarwal 5, Ester Carreño6,
Kanika Aggarwal5, Bhaskar Gupta7, Dhananjay Raje8, Somasheila I. Murthy9, Mark Westcott1,
Soon Phaik Chee2,10, Peter McCluskey11, Ho Su Ling3, Stephen Teoh3, Luca Cimino 12, Jyotirmay
Biswas13, Shishir Narain14, Manisha Agarwal15, Padmamalini Mahendradas16, Moncef
Khairallah17, Nicholas Jones18, Ilknur Tugal-Tutkun19, Kalpana Babu20, Soumayava Basu21,
Richard Lee6, Hassan Al-Dhibi22, Bahram Bodaghi23, Alessandro Invernizzi 24, Debra A.
Goldstein25, Carl P. Herbort26, Talin Barisani-Asenbauer27, Julio J. González-López28, Sofia
Androudi29, Reema Bansal5, Bruttendu Moharana5, Sarakshi Mahajan5, Simona Esposti1,
Anastasia Tasiopoulou1, Sengal Nadarajah1, Mamta Agarwal13, Sharanya Abraham13, Ruchi
Vala16, Joanne Lord30, Ramandeep Singh5, Aman Sharma31, Kusum Sharma32, Manfred Zierhut33,
Onn Min Kon34, John Kempen35,36, Emmett T. Cunningham37,38,39, Andres Rousselot40, Quan
Dong Nguyen39, Carlos Pavesio1, and Vishali Gupta5

1
Department of Medical retina and uveitis, Moorfields Eye Hospital, NHS Foundation Trust, London, UK,
2
Department of Ophthalmology, Singapore Eye Research Institute, Singapore, 3National Healthcare Group Eye
Institute, Tan Tock Seng Hospital, Singapore, 4School of Medicine, National University of Singapore,
Singapore, 5Advanced Eye Centre, Department of Ophthalmology, Postgraduate Institute of Medical Education
and Research (PGIMER), Chandigarh, India, 6Department of Ophthalmology, Bristol Eye Hospital, Bristol,
UK, 7Department of Ophthalmology, Royal Berkshire Hospital, NHS Foundation Trust, Reading, UK, 8MDS
Bioanalytics, India, 9Dept of Statistics, Tej Kohli Cornea Institute, LV Prasad Eye Institute, Nagpur, India,
10
Department of Ophthalmology, Singapore National Eye Centre, Singapore, 11Department of Clinical
Ophthalmology & Eye Health, Central Clinical School, Save Sight Institute, The University of Sydney,
Sydney, Australia, 12Ocular Immunology Unit, Department of Ophthalmology, Arcispedale-IRCCS
Arcispedale Santa Maria Nuova, Reggio Emilia, Italy, 13Department of Ophthalmology, Sankara Nethralaya,
Chennai, India, 14Department of Ophthalmology, Shroff Eye Centre, New Delhi, India, 15Department of
Ophthalmology, Dr Shroff’s Charity Eye Hospital Daryaganj, New Delhi, India, 16Department of
Ophthalmology, Narayana Nethralaya, Bangalore, India, 17Department of Ophthalmology, Fattouma
Bourguiba University Hospital, University of Monastir, Monastir, Tunisia, 18Department of Ophthalmology,
University of Manchester, Manchester, UK, 19Department of Ophthalmology, Istanbul Faculty of Medicine,
Istanbul University, Istanbul, Turkey, 20Department of Ophthalmology, Prabha Eye Clinic & Research centre,
Vittala International Institute of Ophthalmology, Bangalore, India, 21Department of Ophthalmology, LV
Prasad Eye Institute, Bhubaneswar, India, 22Department of Ophthalmology, King Khaled Eye Specialist
Hospital, Riyadh, Kingdom of Saudi Arabia, 23Department of Ophthalmology, DHU SightRestore, University
of Pierre and Marie Curie, Paris, France, 24Eye Clinic, Department of Biomedical and Clinical Science “L.
Sacco”, Luigi Sacco Hospital, University of Milan, Milan, Italy, 25Department of Ophthalmology,
Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA, 26Centre for Ophthalmic

Received 30 January 2018; revised 6 June 2018; accepted 11 June 2018

Correspondence: Vishali Gupta, MD, Professor of Ophthalmology, Advanced Eye Centre, Post graduate Institute of Medical Education and
Research, Chandigarh, India. E-mail: vishalisara@yahoo.co.in
*Joint first authors
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/ioii.

1
2 R. Agrawal et al.

Specialised Care & University of Lausanne, Laussane, Switzerland, 27Laura Bassi Centre of Expertise Ocuvac,
Center for Pathophysiology, Immunology and Infectiology, Medical University of Vienna, Vienna, Austria,
28
Department of Ophthalmology, Ramón y Cajal University Hospital,Madrid, Spain, 29Department of
Ophthalmology, University of Thessaly, Thessaly, Greece, 30Southampton Health Technology Assessments
Centre (SHTAC), Southampton, United Kingdom, 31Department of Rheumatology, Postgraduate Institute of
Medical Education and Research (PGIMER), Chandigarh, India, 32Department of Microbiology, Postgraduate
Institute of Medical Education and Research (PGIMER), Chandigarh, India, 33Centre of Ophthalmology,
University of Tuebingen, Tuebingen, Germany, 34Chest and Allergy Clinic, St Mary’s Hospital, Imperial
College Healthcare NHS Trust, London, 35Department of Ophthalmology, Massachusetts Eye and Ear, Boston,
USA, 36The Discovery Eye Center, MyungSung Christian Medical Center and MyungSung Medical School,
Addis Ababa, Ethiopia, 37The Department of Ophthalmology, California Pacific Medical Center, San Francisco,
California, USA, 38The Department of Ophthalmology, Byers Eye Institute, Stanford University School of
Medicine, Stanford, California, USA, 39The Francis I. Proctor Foundation, UCSF School of Medicine, San
Francisco, California, USA, and 40Department of Ophthalmology, Universidad del Salvador of Buenos Aires,
Buenos Aires, Argentina

ABSTRACT
Purpose: To contribute a global description of the spectrum of choroidal involvement in tubercular uveitis (TBU).
Methods: Retrospective cohort study of TBU patients with choroidal involvement from 25 centers between
January 2004 and December 2014. Medical records of patients with a minimum follow-up of 1 year were
reviewed.
Results: 245 patients were included. The phenotypic variations included serpiginous-like choroiditis (SLC) (46%),
tuberculoma (13.5%), multifocal choroiditis (MFC) (9.4%), ampiginous choroiditis (9%), among others. 219
patients were treated with anti-tubercular therapy (ATT) (n = 219/245, 89.38%), 229 patients with steroids
(n = 229/245, 93.47%) and 28 patients with immunosuppressive agents (n = 28/245, 11.42%). Treatment failure
was noted in 38 patients (n = 38/245, 15.5%). Patients with SLC and ampiginous choroiditis appeared to have
superior outcomes on survival analysis (p = 0.06).
Conclusion: This study provides a comprehensive description of choroidal involvement in TBU. Patients with SLC
and ampiginous choroiditis may have better clinical outcomes.
Keywords: Anti-tubercular therapy, choroiditis, ocular, tuberculosis, uveitis

Tuberculosis (TB) is a major systemic infection that has tuberculosis.10 It was first described in 2003 and because
seen strides of progress through concerted interna- of its phenotypic resemblance to serpiginous choroiditis,
tional research efforts.1 Ocular involvement in TB or it was named as serpiginous-like choroiditis (SLC).10 TB
tuberculous uveitis (TBU) is associated with significant SLC typically presents as multifocal, choroiditis lesions
morbidity,2 and has been weakly associated with in- with a serpiginoid spread, noncontiguous to optic disc,
hospital mortality in disseminated TB.3 Choroidal present all over the fundus, with moderate vitritis in a
involvement in TBU is difficult to manage due to its young healthy male.4,11 This phenotype has been
multiple phenotypes and uncertainties in the interpre- reported in apparently healthy individuals with latent
tation of investigations.4 The choroidal tubercles are TB infection. Following this first report, several reports of
the most commonly reported manifestations of TBU this phenotype and its association with TB were reported
that are generally seen in patients with miliary TB and from both endemic and non-endemic regions in the
indicate the hematogenous spread of the disease.4 world.12–16 A number of series on TB SLC have been
Choroidal tubercles appear as round, small, multiple, published from countries endemic to TB such as India,
well-defined lesions. Large choroidal tuberculomas whereas limited reports have been published from the
may represent the multi-bacillary disease and may Western world. Paucity of literature on TB SLC from the
mimic intraocular tumours.4–8 The latter is attributed Western developed countries suggests potential regional
to geographical variation as well as altered results variations in phenotypic expression of choroidal invol-
following treatment with corticosteroids and other vement in TBU. In addition, since unequivocal evidence
immunosuppressive agents, which patients often of the infection is often challenging to detect, there is a
receive for their inflammatory eye disease before etiol- diagnostic uncertainty for choroidal involvement in TBU
ogy of TB is suspected and investigated.9 highlighted in the literature. Various attempts have been
A relatively new phenotype of choroidal involvement made to aid the clinician in diagnosis, especially SLC
of TB, representing the paucibacillary disease has pre- phenotype due to its protean manifestations.17–21
sumed hypersensitivity response to Mycobacterium

Ocular Immunology & Inflammation

 COTS-1: TB-associated Choroiditis 3

Though there are several single-center studies 1. Persistence or recurrence of inflammation within
describing the different phenotypic expressions of 6 months of completing ATT
choroidal involvement in TBU, there is no multicenter 2. Inability to taper oral corticosteroids to <10 mg/day
international study studying the phenotypic variation or topical steroid drops to <2 drops/day
and treatment practices in different populations. The 3. Recalcitrant inflammation necessitating steroid-
present study describes the largest cohort of 245 sparing immunosuppressive therapy
patients with choroidal involvement of TBU and regio-
nal variation in phenotypic expression and presents
the spectrum of choroidal involvement in TB.
Data collection

A novel data entry platform was conceived to address the

METHODS heterogeneous nature of this disease. The follow-up vari-
able of treatment failure was assessed for at standardized
COTS-1 is a retrospective cohort study of patients diag- 6-month time intervals from initial diagnosis – 6 months,
nosed with TBU from January 2004–December 2014 in 25 12 months, 18 months, and 24 months. Variables for
multinational centers.22 Demographics, ocular pheno- which data was not entered were treated as missing
types, investigations, management, and treatment out- values with pairwise deletion for statistical analysis.
comes were collated from medical records. This study Given the observational retrospective nature of the data
was conducted with ethical approval obtained by each as well as lack of a gold standard diagnostic test, multiple
participating center from their local institutional ethics imputations were not attempted.
committee. Participating centers are listed in Appendix 1.
The diagnostic criteria for TBU were established based
on the presence of suggestive clinical features in Appendix Statistical analysis
2. The inclusion criteria for the COTS-1 study were:
Frequencies were obtained for different study vari-
ables. Nonparametric survival analysis was performed
1. Satisfied study diagnostic criteria for TBU.
using Kaplan–Meier plots for various phenotypes of
2. Availability of patient medical records with
choroidal involvement in TBU. The statistical signifi-
details of ophthalmic examination at baseline
cance of the difference in the survival rates across
and follow-up reviews
phenotypes was determined using log-rank test,
3. Ancillary and laboratory investigations done to
based on the predefined criteria for treatment failure.
exclude relevant differential diagnoses.
The analysis was performed using SPSS and signifi-
4. Completed a minimum follow-up of 1 year.
cance tested at 5%.

The diagnostic label of choroidal involvement of TBU

was conferred to patients who satisfied these criteria for RESULTS
TBU and had any form of choroidal involvement on initial
presentation. Phenotype classification was directed by the 245 patients with choroidal involvement of TBU were
attending uveitis-trained ophthalmologist. There was included in this study. Patients had a mean age of
non-informative right censoring as patients are followed- 39.52 ± 15.3 (range 9–90 years), predominantly males
up for 2 years regardless of treatment response. Reasons (n = 131/245, 53.5%), of Asian ethnicity (n = 159/245,
for incomplete follow-up in some patients include patient 64.9%), and geographical origin (n = 141/245, 57.6%).
transfer to other centers, death, and loss to follow-up. Demographics and clinical features are further described
Treatment regimen with anti-tubercular therapy in Table 1.
(ATT) and/or immunosuppression was directed by Of the 245 patients with choroidal involvement of
attending physicians in collaboration with respiratory TBU, the phenotypic variants reported were serpigi-
or infectious disease physicians as per individual insti- nous-like choroiditis (SLC, n = 113/245, 46.1%)
tutional protocols. The route of drug delivery for ster- (Figure 1C), choroidal tuberculomas (CTC, n = 33/
oids and use of steroid-sparing immunosuppressive 245, 13.5%) (Figure 1E), and multifocal choroiditis
agents was guided by clinical phenotype, severity of (MFC, n = 23/245, 9.4%) (Figure 1D). Rare phenotypic
TBU, patients’ co-morbidities, and treatment response variants of choroiditis observed in our study included
on a case-by-case basis as directed by the attending ampiginous choroiditis (APC, n = 22/245, 9.0%)
specialty-trained ophthalmologist. (Figure 1B), Acute posterior multifocal placoid pig-
Treatment failure for individual patients on follow- ment epitheliopathy (APMPPE, n = 8/245, 3.3%)
up was determined using defined criteria based on (Figure 1A) and other types of choroiditis did not fit
treatment regimen received. Treatment failure was into any of the descriptions above (n = 46/245, 18.8%).
defined as patients with any of the following; Prevalence of specific clinical signs is detailed in

© 2018 Taylor & Francis Group, LLC

4 R. Agrawal et al.

TABLE 1. Demographic characteristics of patients with choroi- tomography (CT) scans of the thorax (n = 39/60,
dal involvement of tuberculosis (n = 245). 65.0%), 168 Mantoux tests (n = 168/206, 81.6%), 16
Tb-T Spot tests (n = 16/17, 94.1%), 90 QuantiFERON
Summary
Variable statistics Gold-in-tube (QFT) tests (n = 90/101, 89.1%), and 17
patients with TB polymerase chain reactions (n = 17/
Age in years (Mean, SD, Range) 39.52, 15.32, 27, 63.0%). 219 patients were treated with ATT
9–90 (n = 219/245, 89.38%), 229 patients with steroid ther-
Gender [N (%)] Female 114 (46.5%)
Male 131 (53.5%)
apy (n = 229/245, 93.46%), and 28 patients with ster-
Race [N (%)] African/Black 10 (4.1%) oid-sparing immunosuppressive agents (n = 28/245,
Asian 159 (64.9%) 11.42%).
European/White 53 (21.6%) Treatment failure was noted in 38 patients
Hispanic 1 (0.4%) (n = 38/245, 15.5%) based on the predefined criteria.
Middle-Eastern 22 (9%)
Region [N (%)] Asia/East 141 (57.6%)
The rates of treatment failure among patients that
Australia 5 (2%) received ATT (n = 34/219, 15.5%) and those that did
Middle-East 37 (15.1%) not receive ATT (n = 4/26, 15.4%) were similar in
West (Europe, America, Africa) 62 (25.3%) frequency (p = 0.99). Treatment failure is further
broken down by phenotype and depicted in
Table 4 for the 245 patients with clear descriptions
Table 2. A breakdown in the prevalence of specific for the type of choroidal involvement.
phenotypes by geographical region is detailed in Regional variations in the use of ATT and outcomes
Table 3. In the West, TB SLC was only observed in are described further in Table 5. In this cohort of
approximately one quarter of patients diagnosed with patients with choroidal involvement of TBU, survival
choroidal involvement of TB, whereas it was observed analysis based on the time to treatment failure was
in more than 40% of patients in the other regions conducted. Among patients that received ATT, those
(Figure 2). with APC and SLC appeared to have better outcomes
Positive corroborative investigations include 44 as shown in Figure 3. However, this was not statisti-
chest x-rays (n = 44/196, 22.4%), 39 computed cally significant (X2 = 10.61, p = 0.06).

FIGURE 1. (A) The panel shows images of a 35-year-old female with acute posterior multifocal placoid pigment epitheliopathy like
appearance of tubercular uveitis (TBU). She had positive Mantoux test and chest computerized tomography revealed evidence of
granulomatous disease. (B) This figure represents clinical phenotype of TBU resembling ampiginous choroiditis in a 25-year-old young
male with positive immunological tests for TB and evidence of extrapulmonary TB. (C) The panel shows a 36-year-old Asian Indian
female with typical phenotype of TB serpiginous-like choroiditis. Fundus photography shows presence of yellowish choroiditis lesions
in the posterior pole and peripapillary region with fuzzy edges and active margins suggestive of active disease. Her Mantoux test was
strongly positive (18 × 21 mm) and her chest computerized tomography (contrast-enhanced) showed presence of subcentimetric lymph
nodes in the precarinal and mediastinal areas. (D) This panel shows multifocal variety of TBU in a young Asian Indian male (32-year-
old) with positive QuantiFERON TB Gold® test and past history of pulmonary TB. (E) Fundus photograph of a 21-year-old Asian
Indian girl shows presence of a large TB choroidal granuloma in the inferonasal quadrant. She was diagnosed with pulmonary TB and
plural effusion as well. Her vitreous biopsy was positive for TB by polymerase chain reaction assay.

Ocular Immunology & Inflammation

 COTS-1: TB-associated Choroiditis 5

TABLE 2. Clinical signs of patients with choroidal involvement of tuberculosis (n = 245).

Variable Value N (%)

Type of Choroidal involvement Serpiginous-like choroiditis (SLC) 113 (46.1%)

of TB Choroidal tuberculoma (CTC) 33 (13.5%)
Multifocal choroiditis (MFC) 23 (9.4%)
Ampiginous choroiditis (APC) 22 (9.0%)
Acute Placoid Multifocal Posterior Pigment Epitheliopathy 8 (3.3%)
(APMPPE)
Choroiditis that is none of the above (CNA) 46 (18.8%)
Vitreous Haze Absent 187 (76.3%)
Present 58 (23.7%)
Snow balls Absent 230 (93.9%)
Present 15 (6.1%)
Snow banking Absent 242 (98.8%)
Present 3 (1.2%)
Disc Hyperaemia/Oedema Absent 182 (74.3%)
Present 63 (25.7%)
Macular Oedema Absent 198 (80.8%)
Present 47 (19.2%)

DISCUSSION vitritis/choroidal tubercles, and recommend testing

for TB etiology in such presentations even in regions
The current study provides the first ever description of without endemic TB.8,12,14,24 The current investiga-
geographical variations in the phenotypic expression tion provides a comprehensive overview of the vari-
and treatment outcomes of choroidal involvement of ety of clinical signs and phenotypes of choroidal
TBU. While SLC was clearly the most prevalent phe- involvement in TB. All patients presenting with
notype in the Asia Pacific region, it was less prevalent these features should be investigated for TB as a
in the West. Furthermore, APC is a phenotype of chor- possible etiology of choroiditis, given that patients
oiditis that is infrequently reported in association with with TBU often present without any symptoms of
TBU,23 but was found to encompass roughly 10% of systemic TB6,26,27 and that TBU can be associated
patients with choroidal involvement of TB across all with serious morbidity4 especially in patients not
regions in this investigation. Finally, the possibility of appropriately treated with ATT.28
variation in the responsiveness of the different pheno- Based on the clinical and laboratory criteria pro-
types to ATT is highlighted, and may relate to some vided in the study, it can be observed that patients
phenotypes of TBU that have been postulated to with phenotypes such as APMPPE have been diag-
involve immunological response to prior or latent TB nosed with ocular TB by international uveitis experts.
as opposed to active ocular infection.24,25 Using a dia- It may be possible that cases of ocular TB may be
grammatic representation, we have also illustrated the overestimated due to various reasons such as endemi-
spectrum of choroidal involvement in TBU with pro- city of TB, lack of gold standard in the diagnosis,
posed postulation about contributory role of mycobac- variable imaging findings on chest radiography/CT
terium activity and immune system activity (Figure 4) scanning, and heterogenous practices by pulmonolo-
in pathogenesis of choroidal involvement in TB. The gists and internists. Therefore, it is important to recog-
illustration suggests that there may be varied clinical nize the clinical phenotype of choroidal involvement
phenotypes based on the interaction and activity of as this may help in predicting the rates of therapeutic
mycobacterium bacilli and immune system. success/failure with ATT.
Prior case series have described choroidal involve- It is imperative to note that there are no published
ment of TBU as a multifocal SLC with significant randomized controlled trials defining the

TABLE 3. Regional variation in phenotypes of patients with choroidal involvement of tuberculosis.

Choroidal involvement

CTC MFC APC APMPPE CAN

Region SLC (n = 113) (n = 33) (n = 23) (n = 22) (n = 8) (n = 46)

Asia/East 79 (69.9%) 18 (54.5%) 11 (47.8%) 12 (54.5%) 3 (37.5%) 18 (39.1%)

Australia 3 (02.7%) 1 (03.0%) 1 (04.3%) 0 0 0
Middle-East 15 (13.3%) 1 (03.0%) 6 (26.1%) 4 (18.2%) 1 (12.5%) 10 (21.7)
West (Europe, America, Africa) 16 (14.2%) 13 (39.4%) 5 (21.7%) 6 (27.3%) 4 (50.0%) 18 (39.1)

© 2018 Taylor & Francis Group, LLC

6 R. Agrawal et al.

FIGURE 2. Visual representation of geographical variation in the reported proportions of phenotypic variants in patients with
choroidal involvement of tuberculosis.

TABLE 4. Treatment failures according to choroidal involvement and ATT.

Choroidal involvement [No. of failures/No. of patient with or without ATT]

ATT given SLC CTC MFC APC APMPPE CAN

Yes 10/104 (9.6%) 6/30 (20%) 3/18 (16.7%) 1/21 (4.8%) 2/7 (28.6%) 12/39 (30.8%)
No 1/9 (11.1%) 2/3 (66.7%) 1/5 (20%) 0/1 (0%) 0/1 (0%) 0/7 (0%)

TABLE 5. Regional variations in the use of anti-tubercular therapy (ATT) and outcomes in patients with choroidal involvement of
tuberculosis.

Region wise frequency of treatment failure [No. of failures/Valid n (%)]

Asia West
Variable (n = 141) Australia (n = 5) Middle-east (n = 37) (n = 62)

ATT used No 1/18 (5.6%) 0/2 (0%) 0 3/6 (50.0%)

Yes 11/123 (8.9%) 0/3 (0%) 6/37 (16.2%) 17/56 (30.4%)
Treatment regimens received No ATT or steroid 0/2 (0%) 0/2 (0%) 0 2/3 (66.7%)
Steroid only 1/16 (6.25%) 0 0 1/3 (33.3%)
ATT only 1/4 (25.0%) 0/1 (0%) 0/5 (0%) 1/4 (25.0%)
ATT and steroid 10/119 (8.4%) 0/2 (0%) 6/37 (16.2%) 16/52 (30.7%)

Ocular Immunology & Inflammation

 COTS-1: TB-associated Choroiditis 7

FIGURE 3. Survival analysis in patients with choroidal involvement of tuberculosis based on use of anti-tubercular therapy (ATT).

FIGURE 4. The diagrammatic representation of spectrum of choroidal involvement in tubercular uveitis and possible contributory role
of mycobacterium and immune system activity.

© 2018 Taylor & Francis Group, LLC

8 R. Agrawal et al.

management of ocular TB. Furthermore, there are no Research Centre at Moorfields Eye Hospital NHS
consensus guidelines amongst the uveitis experts Foundation Trust and UCL Institute of
world over regarding the treatment of ocular TB Ophthalmology. This sponsor supported some of the
including duration of ATT, ATT regime, and also research man-hours that were contributed by all our
regarding the concurrent use of oral corticosteroids, part-time collaborators from the Moorfields Eye
or immunomodulatory therapy (either systemic Hospital that are salaried as Ophthalmology clinicians
or local). This represents a limitation of the present by the hospital. Debra A. Goldstein is supported by an
study that evaluates the outcomes of choroidal unrestricted grant from Research to Prevent Blindness
involvement in ocular TB. The COTS study aims to (RPB). Vishali Gupta is supported by grant from
highlight such differences in the world wide practice Department of Biotechnology (DBT), India. Julio J
patterns. Gonalez-Lopez is supported by study grants from
Limitations of this study relate to its retrospective AbbVie, Allergan, and Angelini.
methodology including missing data, lack of informa-
tion on immigration status/immunocompromised
state, and unstandardized use of investigations such ORCID
as chest x-ray and CT scans of the chest for imaging.
Furthermore, there were small numbers of patients in Aniruddha Agarwal http://orcid.org/0000-0003-
some categories including patients with descriptions of 4985-9855
choroiditis phenotype from Australia and patients that Luca Cimino http://orcid.org/0000-0001-7956-9950
did not receive ATT. This would have contributed to Alessandro Invernizzi http://orcid.org/0000-0003-
the lack of statistical significance on survival analysis, 3400-1987
which did not yield statistically significant differences
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DECLARATION OF INTEREST nous-like choroiditis in northern India. Natl Med J India.
2016;29:247.
The authors report no conflicts of interest. The authors 10. Gupta V, Gupta A, Arora S, Bambery P, Dogra MR,
alone are responsible for the content and writing of the Agarwal A. Presumed tubercular serpiginouslike choroidi-
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The research was partially funded by the National for tuberculosis in a non-endemic area. Br J Ophthalmol.
Institute for Health Research (NIHR) Biomedical 2013;97:644–647.

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10 R. Agrawal et al.

APPENDIX 1

Participating centers

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 Peter McCluskey
University of Sydney, Sydney, Australia.
007 Ocular Immunology Unit, Department of Ophthalmology, Arcispedale-IRCCS Arcispedale Santa Maria Luca Cimino
Nuova, Reggio Emilia, Italy
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, Moncef Khairallah
University of Monastir, Tunisia
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
Carreño
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, Debra A. Goldstein
United States of America
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, Spain Julio J González-
López
025 University of Thessaloniki, Greece Sofia Androudi

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 COTS-1: TB-associated Choroiditis 11

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. Any of the following clinical signs suggestive of ocular tuberculosis including:

a. Anterior uveitis (granulomatous or non-granulomatous) with or without iris nodules or Ciliary body granuloma or

b. Intermediate uveitis (granulomatous or non-granulomatous with exudates in the pars plana or peripheral uvea with snow balls) or

c. Posterior or Panuveitis - Choroidal tubercle or Choroidal granuloma or Subretinal abscess or Serpiginous-like choroiditis or retinitis or
retinal vasculitis or Neuroretinitis or Optic neuritis or Endogenous ophthalmitis or Panophthalmitis or 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 pulmonary or extrapulmonary 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)

© 2018 Taylor & Francis Group, LLC