# 1: Collaborative Ocular Tuberculosis Study (COTS): What does it represent?

The conundrum faced by uveitis specialists is the challenge of establishing a clear and irrefutable connection between uveitis and tuberculosis (TB), due to the absence of direct evidence. Despite the use of various corroborative tests, such as PPD skin test, QuantiFERON TB Gold test or T-spot TB, chest x-ray, or chest CT scan (CECT chest), the accuracy of these diagnostic methods remains limited and varies across regions. The lack of widespread availability and standardization of molecular diagnostic tests only exacerbates the difficulty for ophthalmologists in convincing infectious disease specialists to initiate Anti-Tuberculosis Treatment (ATT).

The Collaborative Ocular Tuberculosis Study (COTS) was formed by a global community of uveitis experts with the goal of determining the global profile of ocular TB, documenting regional variations, and addressing the uncertainties in the diagnosis and management of TB. COTS 1, a retrospective multinational cohort study, was the largest data set on ocular TB and combined data from 25 leading international eye care centers, guided by renowned uveitis specialists from around the world, including a total of 945 patients diagnosed with ocular TB. The COTS Consensus was then developed to establish a consensus among these experts and to establish standardised nomenclature and create guidelines for the diagnosis and management of ocular TB.

# 2: Ocular tuberculosis is a disease of young and middle aged Asians

The COTS 1 data revealed a noteworthy trend in the average age of presentation for ocular TB, with a peak in the fourth decade of life and a slight male predominance. The study also highlighted a significant correlation between the disease and Asian ethnicity, as well as geographical origin, with a higher incidence of ocular TB in individuals of Asian descent. This discovery suggests that even individuals who have migrated from high-endemic to low-endemic countries will continue to have a higher risk of developing ocular TB as a cause of uveitis, making it crucial for treating experts to take this into consideration. The presence of a genetic predisposition for this disease among individuals of Asian origin underscores the importance of heightened vigilance in the screening and management of ocular TB.

# 3: Ocular TB occurs as isolated disease without any association with Systemic TB

The COTS-1 data highlights the fact that over 90% of patients diagnosed with ocular TB do not present with any systemic evidence of TB, indicating that ocular TB is an extrapulmonary form of the disease that occurs in isolation. The absence of systemic TB should not be used as a criterion against the diagnosis of ocular TB.

Choroidal TB as the dominant presentation: The study found that posterior uveitis was the most common anatomic location for ocular TB, followed by pan uveitis, intermediate uveitis, and anterior uveitis. In contrast to the popular belief that ocular TB is a chronic condition, the data showed that nearly half of the patients had an acute onset of the disease. Choroidal TB was the most commonly observed form of presentation, seen in 65% of patients, with serpiginous-like choroiditis being the most common phenotype for which ATT was prescribed. Retinal vasculitis was the second most common phenotype of ocular TB, and the occlusive variety of retinal vasculitis was associated with TB in endemic countries. Conversely, the TB retinal vasculitis reported from non-endemic countries was non-occlusive in nature.

#4: Choroidal TB is the commonest presentation

The most common location for ocular TB was found to be the posterior uvea, followed by pan uveitis, intermediate uveitis, and anterior uveitis. Despite the common belief that ocular TB is a chronic condition, our data showed that nearly half of the patients had an acute onset. The most common form of presentation was choroidal TB, seen in 65% of patients, with serpiginous-like choroiditis being the most common phenotype requiring treatment with ATT. The second most common phenotype for ocular TB was retinal vasculitis, with the occlusive variety being associated with TB etiology in endemic countries, while the non-occlusive variety was reported from non-endemic countries.

# 5: Immunological Tests of Tuberculosis are relevant

The diagnosis of ocular TB is often supported through various immunological tests, with the Mantoux test being the most common one, especially in endemic countries. This test was reported to have a positive result in 87% of suspected ocular TB patients. The next most frequently used test was the QuantiFERON TB gold, which had a positive result in 89% of patients, followed by the T-spot TB with a positivity rate of 92%. Although the use of these tests may vary, data from the COTS indicated that a combination of these tests can be highly effective in detecting ocular TB patients, with 80-90% of patients with uveitis and suspected TB showing positive results for at least latent TB. The availability of these tests may vary depending on the country, but utilizing a combination of them can help in the diagnosis of ocular TB.

#6: CT Scan preferred to Chest X ray in ocular TB

It's crucial for ophthalmologists to be aware that radiology is not performed to identify active pulmonary TB, as only a small percentage of patients with ocular TB will exhibit evidence of systemic TB. The purpose of radiology is to detect previous exposure to Mycobacterium tuberculosis. Ghons focus, seen as calcified hilar nodes, is the key evidence to look for. Chest X-rays are commonly used for screening in developing countries, however, the data from the COTS-1 indicates that chest CT scans are far more effective in detecting healed or old pulmonary TB, with a detection rate of 69% compared to only 27% with chest X-rays.

# 7: PCR is not popular method of diagnosing Ocular TB

The findings from the real-world data indicated that PCR for Mycobacterium tuberculosis in intraocular fluids was not a widely performed test, with only 6% of patients undergoing the test. This may be due to the fact that PCR for Mycobacterium TB is not standardized and many institutions use their own in-house primers. The data indicated that most of the patients who underwent intraocular fluid analysis by PCR tests were of Indian origin. Furthermore, the experts' decisions to treat with ATT were not solely based on the PCR results, as more than 50% of patients who had negative PCR results were still treated with ATT. These findings emphasize the need for standardization and wider use of PCR testing in the diagnosis of ocular TB.

# 8: ATT reduces the risk of recurrences

The results of the real-world data analysis emphasize the importance of administering ATT in patients diagnosed with ocular TB. Posterior uveitis was the most commonly affected anatomical location, with half of the patients experiencing an acute onset of the disease. Mantoux test, QuantiFERON TB gold, and T-spot TB were the most frequently used immunological tests for ocular TB, with positivity rates ranging from 80-90% in patients suspected of having ocular TB. Chest CT scan was found to be more effective in detecting old or healed pulmonary TB compared to chest X-rays. Although PCR for Mycobacterium TB was not widely performed in intraocular fluid analysis, the data suggested that over 50% of patients with negative PCR results were still treated with ATT. The treatment failure rate was 12.7% following the initiation of ATT, with a higher rate seen in western populations, immigrant populations, and patients with panuveitis, significant vitreous haze, and prior exposure to immunosuppressive therapy. Overall, the data highlights the importance of early initiation of ATT in reducing treatment failure and improving visual outcomes.

#9: Highlights of COTS Consensus:

The aim of the COTS Consensus was to establish a set of guidelines for starting ATT in patients diagnosed with ocular TB. The guidelines were created through a two-stage Delphi process, in which experts were presented with various case scenarios based on the patient's country of origin, presentation phenotype, first episode or recurrent disease, and the results of various immunological and radiologic tests. The following highlights summarize the outcomes of this consensus.

• Strong Consensus to treat Serpiginous like choroiditis in the following Scenarios:
  • Both immunological (Mantoux and TB Gold) and one radiologic (chest x-ray or CECT chest) positive
  • Both immunological (Mantoux and TB Gold) tests positive and radiologic (chest x-ray or CECT chest) test either negative or not done.
  • One immunological (Mantoux and TB Gold) and one radiologic (chest x-ray or CECT chest) positive
• Strong Consensus to treat TB granulomas if both immunological (Mantoux and TB Gold) and one radiologic (chest x-ray or CECT chest) positive.
• Strong Consensus to treat Active Retinal Vasculitis if both immunological (Mantoux and TB Gold) and one radiologic (chest x-ray or CECT chest) positive or one immunological (Mantoux and TB Gold) and one radiologic (chest x-ray or CECT chest) positive. The experts agreed that inactive retinal vasculitis that one may encounter following vitrectomy for so called Eales disease or incidentally should not be treated.
• Strong Consensus to treat Panuveitis if both immunological (Mantoux and TB Gold) and one radiologic (chest x-ray or CECT chest) positive or one immunological (Mantoux and TB Gold) and one radiologic (chest x-ray or CECT chest) positive.
• Strong Consensus to treat Anterior Uveitis if it is recurrent and both immunological (Mantoux and TB Gold) and one radiologic (chest x-ray or CECT chest) positive.
• Since many of the phenotypes including Serpiginous like choroiditis and TB vasculitis are immune mediated reactions to TB, experts agreed on the concomitant use of corticosteroids to prevent paradoxical worsening and to minimize the ocular damage due to inflammation.

Please note that these recommendations apply only if the expert feels that the patient has phenotype that is suggestive of TB and has ruled out all other possible etiologies. COTS Consensus does not recommend blind administration of ATT to all Uveitis patients who have positive tests.

#10: COTS Calculator in day-to-day Practice:

The Collaborative Ocular Tuberculosis Study (COTS) Calculator, a web-based tool designed to assist doctors in deciding whether to initiate antitubercular therapy (ATT) in patients with ocular TB. The calculator was developed based on consensus guidelines obtained from a previous study called COTS Consensus. The study used a two-step Delphi method involving 81 experts who evaluated 486 clinical scenarios. The median scores and ranges of the experts' responses were used to develop the COTS Calculator. The tool generates a median score from 1 to 5 based on the conditions present in the patient, with a score of 5 indicating the expert consensus to initiate ATT. The calculator is a low-cost and evidence-based tool to help guide ATT initiation and holds promise for improving the standard of care for ocular TB patients, but further validation studies are needed to determine its clinical utility and reliability.