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Image A: TB infection inside the eye, called as serpiginous-like choroiditis
B: Fluorescent-tagged immune cells and TB bacteria forming a granuloma inside the eye of a zebrafish embryo. The red fluorescent cells are the immune cells called macrophages, that have engulfed the yellow-fluorescent TB bacteria.
- L V Prasad Eye Institute raises awareness on Ocular (eye) TB and talks about the latest research
India
healthysoch
New Delhi, March 21, 2023:
TB bacteria can spread from the lungs to any part of the body, including the eyes. With the rise in TB cases worldwide, Ocular (eye) TB cases are also on the rise. Ocular TB must be treated with a full course of anti-TB medications after evaluation by an expert Ophthalmologis. In a year, LVPEI manages over 1000 cases of Ocular TB across its network centres. Ocular TB can be difficult to diagnose through the standard TB test, and much depends on an ophthalmologist estimating its probability accurately.
To standardize the diagnosis and treatment of ocular TB, the Indian Government is taking dedicated measures, such as the Indian Extrapulmonary TB (INDEX-TB) guidelines, also endorsed by WHO. Ocular tuberculosis has become one of the most intensively researched topics in ophthalmology. The novel Zebrafish model was used to study the presence of TB bacteria in the eye.
LVPEI is the only institute in the country to have a dedicated zebrafish research lab to study the causes and diagnosis of Ocular TB.
“Is there tuberculosis (TB) in the eye? How do you get TB in the eye? This question is often asked not only by the public, but also by physicians who treat patients with TB. This is surprising as the TB bacteria was first discovered in the eye in 1884”, says Dr Soumyava Basu, Network Head, Uveitis Services, L V Prasad Eye Institute. This discovery was two years after Dr Robert Koch announced the identification of the bacterium that causes TB, Mycobacterium tuberculosis, in 1882 on 24 March. 24 March is now being recognized as World TB Day by the World Health Organization (WHO).
“The bacteria causing TB can spread from the lungs to any part of the body, including the eyes. Every year, more than 2.5 million new cases of tuberculosis are diagnosed in India. With the rising TB cases, we are also seeing a rise in Ocular (eye) TB. It is one of the most common causes of inflammation (Uveitis) in the eye,” adds Dr Basu. Annually, L V Prasad Eye Institute sees over 1000 ocular TB patients across its network centres. The symptoms may range from pain and redness in the eye to blurred vision, or a combination of both. Ocular TB must be treated with a full course of anti-TB medications after evaluation by an expert Ophthalmologist. These medications resolve the inflammation in the eye and prevent recurrence.
Diagnosis of Ocular TB
The TB bacteria is rarely found in eye fluids, making it difficult to diagnose or treat. Most patients with ocular TB don’t have any signs of TB in the lungs or elsewhere in the body. TB in the eye cannot be detected by the standard tests used for diagnosing TB in other parts of the body. Thus, much of it depends on accurately estimating the probability of having ocular TB by an ophthalmologist. Most patients with ocular TB (though not all), at least in TB endemic countries, have very characteristic clinical findings that can be picked up by an ophthalmologist who after doing a blood or skin test to rule out the probability of any other infection can confirm the presence of TB in the eye. Although this approach is not flawless, studies across the globe have shown that anti-TB treatments work well for patients diagnosed with ocular TB in this way. Untreated, or if treated inappropriately, patients can develop moderate to severe visual impairment, that may be difficult to reverse.
Research in Ocular TB
One of the key research questions in ocular TB is how do these bacteria really get into the eye? The answer to this question was first attempted by researchers in the United States in the early 1900s, when they injected TB bacteria into the blood of rabbits and found that bacteria could enter the eye, and cause disease similar to what is seen in humans. This was the time, when there was no treatment for TB, and public hygiene was also poor in the Western world. Therefore, a large number of people in those countries contracted TB infection, and many of them also developed ocular TB. However, the first drugs for TB came out in the 1940s, and public hygiene also improved. Therefore, Western researchers lost interest in TB, and ocular TB research went into a slumber, with the question remaining unanswered for nearly 100 years.
In 2009, Prof Narsing Rao at the University of Southern California in Los Angeles, decided to look at TB in guinea pig eyes. At that time, researchers at Johns Hopkins University (Baltimore, Maryland) were studying the mechanisms of TB in guinea pigs. The guinea pig model was unique, as these animals were infected through their lungs with aerosol containing TB bacteria. This mimicked the ‘natural’ route of TB infection in humans. The eyeballs of these guinea pigs were transported from the east coast of the United States (Baltimore) to the west (Los Angeles), where Prof Rao’s team studied them for signs of eye infection. They found that guinea pigs that were treated early with anti-TB drugs did not develop eye infection, whereas the untreated ones showed signs of eye infection nearly two months after they were first infected. Thus, the story of how TB bacteria got into the eye in people, began to unfold. It appeared that the bacteria that infected the lungs entered the bloodstream, before the body’s immune system could control them, and landed in the eye.
However, one question still remained unanswered. The eye is a highly protected organ (called “immune-privileged”), which prevents microbes or immune cells from easily entering the eye. Then, how do the TB bacteria enter the eye? For further understanding, Dr Soumyava Basu sought help from Prof Lalita Ramakrishnan at the University of Cambridge.
Prof Ramakrishnan had developed a model of TB infection in the zebrafish embryo that provided unique insights into the mechanisms of TB. The zebrafish (small, striped fish about two inches in size) originally found in the Gangetic waters, are now being used in many fields of research. The embryos of these fish are truly fascinating. Their eyes become anatomically similar to the adult eye (with all the layers of the retina) within three days of fertilization. Researchers are also able to keep the embryo transparent through chemical treatment and add fluorescent tags to their immune cells. Now, if you add a fluorescent tag of a different colour to the TB bacteria, you can watch live under the microscope, how these bacteria interact with the different cells of the body. Dr Basu persuaded Prof Ramakrishnan to check the eyes of the zebrafish embryos that she was infecting in her lab. They found that nearly 60% of the infected embryos not only had infection in the eye, but some of them were also developing aggregates of immune cells called granulomas in the retina, to control the eye infection.
To study further on how the TB bacteria entered the eye, the Zebrafish lab was established at L V Prasad Eye Institute in 2016 at its Bhubaneswar campus.LVPEI is the only institute in the country to have this dedicated facility. “Our experiments in the Zebrafish Lab proved that the TB bacteria were able to cross the barriers of the eye, either on their own, or by hitchhiking on the immune cells (called the Trojan Horse mechanism after the Greek mythological story). There was enough evidence to believe that these bacteria could beat the barriers of the eye and cause potentially blinding diseases such as ocular TB, choroiditis or retinal vasculitis”, explains Dr Basu. More recently, Dr Basu’s research has been focussed on understanding ways to differentiate true ocular TB patients (who need anti-TB therapy), from those with other forms of uveitis, but positive TB tests (not requiring anti-TB therapy).
“Ocular TB has become one of the most intensely researched topics in ophthalmology across the world. Ophthalmologists from across the world are also collaborating and learning from each other about this disease. The government has made attempts such as the Indian Extrapulmonary TB (INDEX-TB) guidelines, also endorsed by the WHO, to standardize the diagnosis and treatment of ocular TB. The future surely carries hope for patients with this condition, to have their vision restored, and lead a healthy life”, concludes Dr Basu.
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