The immune response in tubercular uveitis and its implications for treatment: From anti-tubercular treatment to host-directed therapies.

Tubercular uveitis (TB-uveitis) remains a conundrum in the uveitis field, which is mainly related to the diverse clinical phenotypes of TB-uveitis. Moreover, it remains difficult to differentiate whether Mycobacterium tuberculosis (Mtb) is present in the ocular tissues, elicits a heightened immune response without Mtb invasion in ocular tissues, or even induces an anti-retinal autoimmune response. Gaps in the immuno-pathological knowledge of TB-uveitis likely delay timely diagnosis and appropriate management. In the last decade, the immunopathophysiology of TB-uveitis and its clinical management, including experts' consensus to treat or not to treat certain conditions with anti-tubercular treatment (ATT), have been extensively investigated. In the meantime, research on TB treatment, in general, is shifting more toward host-directed therapies (HDT). Given the complexities of the host-Mtb interaction, enhancement of the host immune response is expected to boost the effectiveness of ATT and help overcome the rising burden of drug-resistant Mtb strains in the population. This review will summarize the current knowledge on the immunopathophysiology of TB-uveitis and recent advances in treatment modalities and outcomes of TB-uveitis, capturing results gathered from high- and low-burden TB countries with ATT as the mainstay of treatment. Moreover, we outline the recent progress of HDT development in the pulmonary TB field and discuss the possibility of its applicability to TB-uveitis. The concept of HDT might help direct future development of efficacious therapy for TB-uveitis, although more in-depth research on the immunoregulation of this disease is still necessary.

Tuberculous Scleritis and Multidrug Resistance.

PURPOSE: To present a case of necrotizing sclerokeratitis in a patient with multidrug-resistant tuberculosis and study the challenges in diagnosis and management of anterior tuberculous scleritis. METHODS: Retrospective observational case report and review of anterior tuberculous scleritis. RESULTS: A 28-year-old woman, previously diagnosed as presumed tubercular panuveitis, presented with necrotizing sclerokeratitis and progressed to develop panophthalmitis. Laboratory investigations revealed multidrug-resistant Mycobacterium tuberculosis as the etiological agent. We reviewed cases of anterior tuberculous scleritis published in the literature, with regards to clinical features, microbiological investigations, treatment, and outcomes. Treatment includes standard antitubercular therapy, with or without systemic corticosteroids. Poor response to treatment is seen either due to delayed diagnosis or drug resistance, and the significance of the same is highlighted in our case. CONCLUSION: Diagnosis of tuberculous scleritis is a challenge. Therapeutic failure must alert the clinician for drug resistance which is diagnosed early, can prevent the devastating outcomes.

Ocular tuberculosis in a calf.

BACKGROUND: Bovine tuberculosis is a chronic inflammatory disease that causes granuloma formation mainly in retropharyngeal, tracheobronchial, mediastinal lymph nodes and lungs of bovines. The presence of these lesions in other tissues such as the eyeball is very rare and difficult to diagnose. This study describes macroscopic and microscopic pathological findings in a calf with ocular and meningeal tuberculosis. CASE PRESENTATION: March 2019, an eight-month-old Holstein Friesian calf was identified in a dairy farm located in central Mexico with a clinical cough, anorexia, incoordination, corneal opacity and vision loss. At necropsy, pneumonia, lymphadenitis, meningitis, and granulomatous iridocyclitis were observed. The histopathological examination revealed granulomatous lesions in lung tissue, lymph nodes, meninges and eyes with the presence of acid-fast bacilli associated with Mycobacterium spp. CONCLUSION: To the best of our knowledge, this is the first report that describes macroscopic and microscopic pathological findings of ocular tuberculosis in cattle. This report highlights the importance of considering bovine tuberculosis in the differential diagnosis of corneal opacity and loss of vision in cattle.

PRESUMED TUBERCULOUS MULTIFOCAL RETINITIS IN PATIENTS UNDER TREATMENT WITH BIOLOGIC AGENTS.

PURPOSE: To report unique retinal fundus lesions and treatment outcomes of intraocular tuberculosis in patients under anti-tumor necrosis factor treatment. METHODS: Retrospective review of two patients with laboratorial evidence of tuberculosis who had bilateral ocular signs and symptoms not attributable to other diseases. Multimodal imaging was analyzed at the time of presentation and after the treatment initiation. The study patients underwent standard treatment for tuberculosis. RESULTS: Clinical and laboratory findings were consistent with the diagnosis of presumed tuberculosis. Color fundus photograph revealed the presence of multifocal yellowish retinal spots in the study eyes. On fluorescein angiography, the retinal lesions seen on color fundus photograph showed early hypofluorescence with progressive staining of its edges. Occlusive vasculitis with peripheral nonperfusion was also observed in both cases. Spectral domain optical coherence tomography demonstrated increased reflectivity and thickness on the topography of retinitis lesions. After specific antibiotic treatment for tuberculosis, there was complete disappearance of the retinal lesions in all study eyes. CONCLUSION: We report two unique cases of bilateral presumed intraocular tuberculosis presenting as multifocal retinitis in patients under biologic agent treatment. Anti-tumor necrosis factor agents may be related to unusual fundus manifestations of tuberculosis.

TREATMENT OF REFRACTORY TUBERCULAR SERPIGINOUS-LIKE CHOROIDITIS WITH INTRAVITREAL METHOTREXATE.

PURPOSE: To describe a case of tubercular serpiginous-like choroiditis that progressed, despite antitubercular medication, corticosteroids, and immunomodulatory treatment, which ultimately quieted after two intravitreal methotrexate injections. METHODS: Case report. RESULTS: A 35-year-old woman reported a shadow in the left eye for 2 weeks. She presented with tubercular serpiginous-like choroiditis in the right eye 2 years prior. At that time, she was started on antituberculosis therapy but was noncompliant and lost to follow-up. On re-presentation, there was a new active left-eye serpiginous lesion, with repeat positive QuantiFERON gold testing. Four antituberculosis drugs were started, followed by corticosteroids and azathioprine, with continued progression despite aggressive treatment. She was finally given 2 intravitreal methotrexate injections (400 µg/0.1 cc) 1 month apart, with final arrest of lesion extension. The uveitis remained quiet for over 24 months, and the patient was able to discontinue all systemic therapy. CONCLUSION: Intravitreal methotrexate injections halted progression of treatment-refractory tubercular serpiginous-like choroiditis.

Collaborative Ocular Tuberculosis Study Consensus Guidelines on the Management of Tubercular Uveitis-Report 1: Guidelines for Initiating Antitubercular Therapy in Tubercular Choroiditis.

TOPIC: An international, expert-led consensus initiative organized by the Collaborative Ocular Tuberculosis Study (COTS), along with the International Ocular Inflammation Society and the International Uveitis Study Group, systematically developed evidence- and experience-based recommendations for the treatment of tubercular choroiditis. CLINICAL RELEVANCE: The diagnosis and management of tubercular uveitis (TBU) pose a significant challenge. Current guidelines and literature are insufficient to guide physicians regarding the initiation of antitubercular therapy (ATT) in patients with TBU. METHODS: An international expert steering subcommittee of the COTS group identified clinical questions and conducted a systematic review of the published literature on the use of ATT for tubercular choroiditis. Using an interactive online questionnaire, guided by background knowledge from published literature, 81 global experts (including ophthalmologists, pulmonologists, and infectious disease physicians) generated preliminary consensus statements for initiating ATT in tubercular choroiditis, using Oxford levels of medical evidence. In total, 162 statements were identified regarding when to initiate ATT in patients with tubercular serpiginous-like choroiditis, tuberculoma, and tubercular focal or multifocal choroiditis. The COTS group members met in November 2018 to refine these statements by a 2-step modified Delphi process. RESULTS: Seventy consensus statements addressed the initiation of ATT in the 3 subtypes of tubercular choroiditis, and in addition, 10 consensus statements were developed regarding the use of adjunctive therapy in tubercular choroiditis. Experts agreed on initiating ATT in tubercular choroiditis in the presence of positive results for any 1 of the positive immunologic tests along with radiologic features suggestive of tuberculosis. For tubercular serpiginous-like choroiditis and tuberculoma, positive results from even 1 positive immunologic test were considered sufficient to recommend ATT, even if there were no radiologic features suggestive of tuberculosis. DISCUSSION: Consensus guidelines were developed to guide the initiation of ATT in patients with tubercular choroiditis, based on the published literature, expert opinion, and practical experience, to bridge the gap between clinical need and available medical evidence.

Mycobacterium Tuberculosis Modulates Fibroblast Growth Factor and Vascular Endothelial Growth Factor in Ocular Tuberculosis.

Purpose: To evaluate the role of angiogenic growth factors in the pathogenesis of intraocular tuberculosis.Methods: Retinal Pigment Epithelium (RPE) cells were infected with varying dilution of Mycobacterium tuberculosis (MTB), ranging from several thousand to a few MTB bacilli to replicate paucibacillary conditions. Angiogenesis growth factors were evaluated using multiplex fluorescent bead based flow cytometry in the culture supernatant of RPE cells infected with MTB, vitreous fluids and tear samples of uveitis patients visiting retina clinic.Results: Vascular endothelial growth factor (VEGF) levels were elevated and fibroblast growth factors (FGFs) were down regulated in RPE-infected MTB cells. Similar pattern of VEGF and FGF was observed in the vitreous of IOTB patients. However, no changes were observed in tear samples.Conclusions: MTB exploits the angiogenesis growth factors for pathogenesis by decreasing FGF with concomitant surge of VEGF in MTB infected RPE as well in the vitreous of IOTB patients.

Clinical and Multimodal Imaging Findings in Disseminated Mycobacterium Chimaera.

PURPOSE: To characterize the ophthalmic clinical and multimodal imaging findings of disseminated Mycobacterium chimaera infection after cardiothoracic surgery. DESIGN: Observational case series. PARTICIPANTS: Four patients (8 eyes) with disseminated M. chimaera infection. METHODS: Patients were evaluated with biomicroscopy, OCT and OCT angiography, fundus autofluorescence, and fluorescein and indocyanine green angiography. MAIN OUTCOME MEASURES: Clinical and multimodal imaging findings of patients with disseminated M. chimaera infection. RESULTS: All 4 patients were white men with a mean age of 65.5 years (range, 60-75 years) who had aortic valve or root infection, or both, with M. chimaera diagnosed by culture, gene sequencing, or both. All 4 patients demonstrated bilateral choroidal lesions on funduscopy and evidence of osteomyelitis by imaging, culture analysis, or both at the time of ocular diagnosis. Indocyanine green and OCT angiography revealed numerous additional subclinical choroidal lesions and were used to track disease response to therapy. Fluorescein angiography and fundus autofluorescence were useful in determining lesion age and activity. All patients were treated with 3- or 4-drug antimycobacterial therapy. Three underwent revision of cardiothoracic surgery with removal of infected graft. One patient went on to demonstrate progressive ocular disease that was noted before each of his surgical revisions. Two patients showed improvement in ocular and systemic disease, however one of them developed a choroidal neovascular membrane. The final patient was a single encounter whose clinical and imaging findings showed longstanding inactive disease. CONCLUSIONS: Ophthalmologists should be aware of the systemic and ocular findings of this rare life-threatening disease. Multimodal imaging is useful in corroborating a diagnosis of ocular M. chimaera and particularly in evaluating patient response to therapy, because choroidal activity seems to mimic systemic activity. Treating physicians should be aware of the co-occurrence of choroiditis and osteomyelitis. Choroidal neovascular membrane can also be a late complication of this disease.

Cytopathology and Polymerase Chain Reaction of Vitreous Fluid in Tubercular Intermediate Uveitis.

Purpose: Cytopathology of vitreous is most commonly done to diagnose vitreoretinal lymphoma in eyes with nonspecific inflammation. Vitreous cytopathology features of tuberculous intermediate uveitis have not been described in literature.Case report: We report a case of a healthy 35-year-old female who showed granulomatous inflammatory changes on vitreous cytopathology with polymerase chain reaction confirming a diagnosis of intraocular tuberculosis.Conclusion: This case highlights the role of cytopathology in determining the etiology and pathogenesis behind the elusive diagnosis of intermediate uveitis. Polymerase chain reaction can further help in confirming the diagnosis and allowing commencement of appropriate therapy.

Collaborative Ocular Tuberculosis Study Consensus Guidelines on the Management of Tubercular Uveitis-Report 2: Guidelines for Initiating Antitubercular Therapy in Anterior Uveitis, Intermediate Uveitis, Panuveitis, and Retinal Vasculitis.

TOPIC: The Collaborative Ocular Tuberculosis Study (COTS), supported by the International Ocular Inflammation Society, International Uveitis Study Group, and Foster Ocular Immunological Society, set up an international, expert-led consensus project to develop evidence- and experience-based guidelines for the management of tubercular uveitis (TBU). CLINICAL RELEVANCE: The absence of international agreement on the use of antitubercular therapy (ATT) in patients with TBU contributes to a significant heterogeneity in the approach to the management of this condition. METHODS: Consensus statements for the initiation of ATT in TBU were generated using a 2-step modified Delphi technique. In Delphi step 1, a smart web-based survey based on background evidence from published literature was prepared to collect the opinion of 81 international experts on the use of ATT in different clinical scenarios. The survey included 324 questions related to tubercular anterior uveitis (TAU), tubercular intermediate uveitis (TIU), tubercular panuveitis (TPU), and tubercular retinal vasculitis (TRV) administered by the experts, after which the COTS group met in November 2019 for a systematic and critical discussion of the statements in accordance with the second round of the modified Delphi process. RESULTS: Forty-four consensus statements on the initiation of ATT in TAU, TIU, TPU, and TRV were obtained, based on ocular phenotypes suggestive of TBU and corroborative evidence of tuberculosis, provided by several combinations of immunologic and radiologic test results. Experts agreed on initiating ATT in recurrent TAU, TIU, TPU, and active TRV depending on the TB endemicity. In the presence of positive results for any 1 of the immunologic tests along with radiologic features suggestive of past evidence of tuberculosis infection. In patients with a first episode of TAU, consensus to initiate ATT was reached only if both immunologic and radiologic test results were positive. DISCUSSION: The COTS consensus guidelines were generated based on the evidence from published literature, specialists' opinions, and logic construction to address the initiation of ATT in TBU. The guidelines also should inform public policy by adding specific types of TBU to the list of conditions that should be treated as tuberculosis.

Insights into the molecular pathogenesis of ocular tuberculosis.

Unclear pathogenic mechanisms underlying the ocular tuberculosis (OTB) has resulted in perplexity related to the diagnosis and management of the disease. Developments in experimental research and innovations in molecular diagnostics have recently provided a new understanding of disease pathogenesis and natural history. The current review focuses on the new insights into OTB pathogenesis, derived from in vivo and in vitro studies on Mycobacterium tuberculosis dissemination and localization into the eye, in combination with histopathological studies on chorioretinal tissue and vascular network. Advances in the knowledge of OTB have influenced disease management in the clinical setting and lead to reconsideration of the role of existing treatments and suggesting potential new therapeutic approaches.

Pathogenesis of ocular tuberculosis: New observations and future directions.

Ocular tuberculosis (OTB) encompasses all forms of intra- and extra-ocular inflammation associated with Mycobacterium tuberculosis (Mtb) infection. However, the organism is rarely found in ocular fluid samples of diseased eyes, rendering the pathomechanisms of the disease unclear. This confounds clinical decision-making in diagnosis and treatment of OTB. Here, we critically review existing human and animal data related to ocular inflammation and TB pathogenesis to unravel likely pathomechanisms of OTB. Broadly there appear to be two fundamental mechanisms that may underlie the development of TB-associated ocular inflammation: a. inflammatory response to live/replicating Mtb in the eye, and b. immune mediated ocular inflammation induced by non-viable Mtb or its components in the eye. This distinction is significant as in direct Mtb-driven mechanisms, diagnosis and treatment would be aimed at detection of Mtb-infection and its elimination; while indirect mechanisms would primarily require anti-inflammatory therapy with adjunctive anti-TB therapy. Further, we discuss how that most clinical phenotypes of OTB likely represent a combination of both mechanisms, with one being predominant than the other.

Ocular tuberculosis epidemiology, clinic features and diagnosis: A brief review.

The spread of tuberculosis is directly related to the processes of globalization and migration. Tuberculosis has also been the main cause of fatality associated with antimicrobial resistance and also the main cause of death in people who have HIV infection. Additionally, tuberculosis smites the lungs in 80% of patients, and in the remaining 20% of patients the tuberculosis may smites other organs, such as the vision/eye. Ocular tuberculosis is a specific infectious disease of bacterial etiology with a chronic and persistent course, the prognosis of which is extremely doubtful. Even effective chemotherapy can be accompanied by a decrease in visual acuity, and clinical recovery is not always persistent. Ocular tuberculosis often leads to permanent disability and, as a result, the quality of life of patients decreases. A statistical reporting of this disease does not always reflect the true picture, since ocular tuberculosis sometimes develops against the background of an existing specific lesion in the lung tissue. Currently, ocular tuberculosis remains substantially a conjectural clinical diagnosis. This review paper presents an analytical review of the literature on the epidemiology, clinical features, and diagnosis methods of ocular tuberculosis. The results of recent studies that focused on the modern clinical manifestations of this pathology, its diagnosis, and complex therapy are systematized. The development of new rational regimens and pathogenetic treatment methods are also highlighted in this review.

Mycobacterium tuberculosis does not show evidence of molecular DNA in human cadaveric ocular tissues in an endemic setting.

BACKGROUND: Mycobacterium tuberculosis (MTB) in latent infection has been demonstrated in pulmonary/extra-pulmonary locations (lung, spleen, liver, kidney, adipose tissue) in autopsy studies, but its presence in ocular tissues in the latent state is not known. METHODS: We conducted molecular and histopathological study of 100 cadaver eyes (50 humans) who died from causes other than tuberculosis (TB) (and were potential candidates for corneal transplantation) to detect MTB in ocular tissues in an endemic setting. After removal of the corneal button, an 8 to 10 mm block of tissue (choroid, retina and part of the vitreous) was excised from the remaining globe for DNA isolation. Gel-based IS6110 and devR3 polymerase chain reaction (PCR) assays were done, followed by real-time PCR using beta actin gene as an internal control. Sixteen randomly selected DNA samples were double checked using a commercial kit for MTB and non-tuberculous mycobacteria (NTM) DNA. The remaining larger part of the globe was subjected to histopathology. RESULTS: The mean age was 65.14 ± 18 years. All 100 samples were negative for both IS6110 and devR, and all 16 samples were negative with NTM MTB commercial kit. All samples were negative with Ziehl-Neelsen stain for acid fast bacilli and none showed any inflammation or granulomatous pathology. CONCLUSIONS: MTB could not be detected in human ocular tissues in latent state in India, a TB-endemic country. This may suggest the inability of MTB to seed ocular tissues in the latent state, unlike other organs which serve as reservoirs for the bacilli in the absence of manifest disease.

Resolution of Large Choroidal Tuberculoma following Monotherapy with Intravitreal Ranibizumab.

Background: Ocular tuberculosis can have protean manifestations. Anti-tubercular therapy (ATT) and oral steroids are employed in the management of this condition. There is evidence in the literature which has highlighted the use of intravitreal anti-vascular endothelial growth factor drugs as an adjunct to systemic therapy.Report of the Case: A 44-year-old male presented with a decrease of vision in the right eye was diagnosed choroidal tuberculoma with massive exudation and subretinal fluid. The patient was treated with intravitreal ranibizumab injection. The lesion regressed completely within 6 weeks without any additional systemic corticosteroids and ATT without any recurrence over 6 months during follow-up.Conclusions: Ranibizumab monotherapy may lead in complete regression of vascularized tubercular choroidal granulomas without the need of adjunctive ATT and corticosteroids. After intravitreal injection of ranibizumab, the lesion may be observed for regression over several weeks.

Interstitial Keratitis with Corneal Perforation as the Presenting Sign of Systemic Tuberculosis.

Background: Ocular surface and corneal involvement in tuberculosis is seldom seen. We report a patient of pulmonary and presumed ocular tuberculosis with immune keratitis along with corneal perforation as the presenting signs.Methods: A middle-aged male presented with stromal keratitis, deep corneal vascularization, and two corneal perforations. Necrotic Mantoux test and cavitary lesion on computerized tomography of the chest clinched the diagnosis of tuberculosis-related interstitial keratitis.Results: Tubercular interstitial keratitis was successfully managed with antitubercular therapy, oral and topical steroids while cyanoacrylate glue was used to seal the corneal perforations.Conclusions: Although corneal involvement is uncommon in ocular tuberculosis, in patients with interstitial keratitis who respond poorly to conventional therapy, a possibility of systemic tuberculosis should be considered in endemic countries.

Prevalence of Positive QuantiFERON-TB Gold In-Tube Test in Uveitis and its Clinical Implications in a Country Nonendemic for Tuberculosis.

PURPOSE: To report on the prevalence and clinical implications of positive QuantiFERON-Gold (QFT-G) test results in the diagnostic evaluation of a large cohort of consecutive patients with uveitis in the Netherlands. DESIGN: Retrospective cross-sectional study. METHODS: This study included 710 consecutive patients who all underwent evaluation for uveitis including QFT-G testing. The ocular features, comorbidity, and abnormalities in diagnostic imaging and laboratory tests were registered for QFT-G-positive patients with uveitis. RESULTS: Of all patients, 13% (92/710) were positive for QFT-G. Previously treated tuberculosis (TB) was documented in 2 patients. Of all 92 QFT-G-positive patients, culture-proven active TB was observed in 1 case. The proportion of patients with uveitis of unknown etiology was higher in QFT-G-positive than in the QFT-G-negative patients (54/92, 59% vs 238/618, 39%; P = .0004). The uveitis features of QFT-G-positive patients were mainly nonspecific. Of all QFT-G-positive patients with uveitis, 17 patients had chest imaging changes suggesting either TB or sarcoidosis. Twenty-nine QFT-G-positive patients with otherwise unexplained uveitis completed antituberculous therapy (29/710; 4% of all included patients) with beneficial effect in most cases. CONCLUSION: The QFT-G tested positive in 13% of patients with uveitis in the Netherlands, whereas only sporadic patients had a documented previous or active TB infection. The proportion of patients with unexplained uveitis was higher in QFT-G-positive patients. Though the association between uveitis and a positive QFT-G test might be coincidental, the majority of treated QFT-G-positive patients with otherwise unexplained severe uveitis cause had a beneficial response to antituberculous therapy.

Comparison of wide-field swept source optical coherence tomography angiography and fundus autofluorescence in tubercular serpiginous-like choroiditis.

Purpose: To evaluate the potential clinical utility of wide-field swept source optical coherence tomography angiography (SS-OCTA) using a prototype device compared to a wide-field fundus autofluorescence (FAF) for analysis of the disease activity in eyes with tubercular serpiginous-like choroiditis (TBSLC). Methods: Using a prototype SS-OCTA device (PLEX Elite, Carl Zeiss Meditec, Dublin, CA), 17 eyes of 12 consecutive patients with TBSLC were imaged and multiple 12 mm × 12 mm OCTA scans were captured, which were montaged to create wide-field montage OCTA images scans. A wide- FAF (Eidon, CenterVue, Padova, Italy) was performed in the same sitting. Two masked graders independently analyzed OCTA and FAF images for the presence of choroidal lesions, recorded the number of lesions identifiable, and provided a subjective grading for the activity of individual lesion, which were then compared. Results: The total number of lesions identified on FAF were 282 (posterior pole lesions, n = 129 and peripheral lesions n = 153) and on wide-field SS-OCTA were 230 (posterior pole lesions, n = 108 and peripheral lesions n = 122). Active choroidal lesions were comparable on the two machines (n = 28 on FAF and n = 28 on SS-OCTA, respectively); whereas numerous healed lesions were identified on FAF (n = 219) as compared to SS-OCTA (n = 170). There was good correlation among the devices for healed lesions (Pearson correlation, r = 0.82) and active lesions (r = 0.88). Conclusion: There was good correlation between FAF and wide-field SS-OCTA for detection of disease activity in TBSLC; however, FAF depicted greater number of healed lesions compared to wide-field SS-OCTA.