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Year : 2022  |  Volume : 2  |  Issue : 3  |  Page : 703-704

Commentary: Tubercular granuloma: Insights into the pathogenesis and emerging therapies

Vitreoretina and Uvea Services, Indira Gandhi Eye Hospital and Research Centre, Gurugram, Haryana, India

Date of Web Publication16-Jul-2022

Correspondence Address:
Dr. Vikram V Koundanya
Indira Gandhi Eye Hospital and Research Centre, Sector – 62, Gurugram, Haryana - 122 102
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijo.IJO_654_22

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How to cite this article:
Koundanya VV. Commentary: Tubercular granuloma: Insights into the pathogenesis and emerging therapies. Indian J Ophthalmol Case Rep 2022;2:703-4

How to cite this URL:
Koundanya VV. Commentary: Tubercular granuloma: Insights into the pathogenesis and emerging therapies. Indian J Ophthalmol Case Rep [serial online] 2022 [cited 2022 Oct 6];2:703-4. Available from: https://www.ijoreports.in/text.asp?2022/2/3/703/351209

Choroidal tubercular granulomas are quite common in tuberculosis (TB) endemic and densely populated countries such as ours. They pose a tough challenge to the treating physician as they are vision-threatening and often quite aggressive in their clinical course. They are also more common in patients with multi-drug resistant TB and hence are often refractory to standard care of management. The above case highlights this fact, and such cases demand out-of-the-box thinking. Many authors have reported successful management of such refractory cases with novel therapies. To explore newer therapies, we must dive into the basic pathogenesis of the disease to find potential therapeutic targets. In this short commentary, I have tried to summarize the inner workings of a granuloma, various novel therapies, and possible therapeutic targets for the future.

Granuloma formation: Host protective or detrimental?

TB results from a complex interaction between the host and Mycobacterium tuberculosis (Mtb). The main feature of this complex immune interaction is the formation of an organized aggregate of immune cells called a granuloma. In theory, such a concentrated immune response should sequester and eradicate the bacterium; however, the large number of TB cases worldwide suggests that granuloma formation often fails to eradicate Mtb, and some bacilli can actually survive in a dormant state inside these granulomas. Data generated in the last decade suggest that the early events of granuloma formation are very well orchestrated by Mtb for its benefit, and it slowly adapts to life within the granuloma by developing an array of strategies to evade host immune mechanisms.[1] Animal studies have shown that Mtb exploits granuloma formation for their proliferation and dissemination within the host.[2] A better understanding of the inner workings of the granuloma and recognition of granuloma as an important site of bacterial proliferation can potentially lead to the development of new therapeutic strategies.

Basic pathogenesis of granuloma formation and role of anti-tubercular drugs

A macrophage infected with Mtb secretes various chemokines and recruits new macrophages by inducing rapid chemotaxis. The infected cell, after its death due to apoptosis, is then phagocytosed by the recruited macrophages. The bacteria then multiply within the newly recruited cells, and once these infected cells also die; they are again phagocytosed by additionally recruited macrophages. In this process, some of the infected cells manage to egress and disseminate from the granuloma and infect new cells.[2] Anti-tubercular therapy (ATT) decreases this multiplication and hence the dissemination of Mtb.

This could explain the dramatic response to intravitreal moxifloxacin in the above case report.[3] The intravitreal route offers the advantage of a higher concentration of the drug locally and if such positive evidence accumulates over time, it could bring a drastic change in the management of tubercular choroiditis.

Role of anti-vascular endothelial growth factor (VEGF)

Mtb have developed techniques to survive the hypoxic state in granulomas by inducing complex transcriptional networks, which promote angiogenesis and improve oxygenation within the hypoxic granuloma.[4] Suppression of granuloma-associated angiogenesis by the administration of VEGF-A inhibitors, such as ranibizumab or bevacizumab, reduces bacterial burdens and acts synergistically with first-line drugs to kill the bacteria. Many authors have reported excellent responses to anti-VEGF in choroidal granulomas.[5] In clinical experience, I have found that large granulomas with exudative retinal detachment respond very well to anti-VEGF. It is best to combine them with intravitreal anti-tubercular drugs, such as moxifloxacin, as they act synergistically.

Immunomodulatory drugs and host-directed therapies (HDT)

Intravitreal methotrexate has also shown good clinical response in a few refractory tubercular choroiditis cases.[6] Methotrexate exhibits its anti-inflammatory effects by multiple mechanisms, one of them being increasing adenosine release, which decreases leukocyte chemotaxis and accumulation, which is crucial for granuloma formation.

A novel strategy, in the fight against TB, that is, showing good promise is the development of host-directed therapies (HDTs) that can be used as adjunct therapy with the standard treatment regimens. HDTs are aimed at augmenting the host's defense mechanisms and decreasing tissue damage, leading to improved clinical outcomes and reducing the duration of treatment. Many such drugs, which inhibit the inflammatory pathways implicated in granuloma formation, are being studied currently. Of these, a tumor necrosis factor (TNF)-α blocker—etanercept, a lipo-oxygenase blocker–zileuton, and a cholesterol biosynthesis blocker—simvastatin have shown promising results.[7]

  References Top

Ramakrishnan L. Revisiting the role of the granuloma in tuberculosis. Nat Rev Immunol 2012;12:352-66.  Back to cited text no. 1
Davis JM, Ramakrishnan L. The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell 2009;136:37–49.  Back to cited text no. 2
Babu K, Shah D, Murthy KR. Refractory bilateral choroiditis due to presumed ocular tuberculosis responding to intravitreal moxifloxacin. Indian J Ophthalmol Case Rep 2022;3:700-3.  Back to cited text no. 3
Oehlers SH, Cronan MR, Scott NR, Thomas MI, Okuda KS, Walton EM, etal. Interception of host angiogenic signalling limits mycobacterial growth. Nature 2015;517:612–5.  Back to cited text no. 4
Jain S, Agarwal A, Gupta V. Resolution of large choroidal tuberculoma following monotherapy with intravitreal ranibizumab. Ocul Immunol Inflamm 2020;28:494-7.  Back to cited text no. 5
Tsui E, Fern CM, Goldberg NR. Treatment of refractory tubercular serpiginous-like choroiditis with intravitreal methotrexate. Retin Cases Brief Rep 2021;15:169-73.  Back to cited text no. 6
Ndlovu H, Marakalala MJ. Granulomas and inflammation: Host-directed therapies for tuberculosis. Front Immunol 2016;7:434.  Back to cited text no. 7


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