Mycobacterium Tuberculosis-Associated Uveitis: Infection and Autoimmunity

The pathophysiology of Mycobacterium tuberculosis (_Mtb_)-associated uveitis is not entirely understood, and in consequence, the diagnosis and the treatment of _Mtb_-associated uveitis are challenging. The studies included in this thesis aim to increase our knowledge of this debilitating ocular disorder and aim to develop specific biomarkers for its diagnosis. The studies performed in this thesis further indicate that _Mtb_ infection plays a crucial role in a significant proportion of patients "with uveitis of undetermined cause" but positive QFT reaction. Two specific clinical manifestations were recognized in patients with uveitis of undetermined cause and positive QFT in the Netherlands, a country not endemic to _Mtb_. QFT positive patients with uveitis might benefit from ATT, despite the absence of systemic signs of active TB. In Indonesia, infectious uveitis was the most common type of uveitis and uveitis in the setting of systemic TB was one of its major causes. Further, _Mtb_ infected RPE cells dominantly showed interferon signaling canonical pathway and network. In the peripheral blood, type 1 IFN gene signature score stratified _Mtb­_-associated uveitis in three types. These findings might form the basis for a prospective trial with ATT and/or corticosteroids. Lastly, we found no evidence that antibodies against retinal antigens are involved in the pathogenesis in _Mtb_-associated uveitis, and we assume that -if autoimmune processes are involved- a cellular response is more likely

Antiviral treatment for acute retinal necrosis:A systematic review and meta-analysis

Acute retinal necrosis is a progressive intraocular inflammatory syndrome characterized by diffuse necrotizing retinitis that can lead to a poor visual outcome, mainly from retinal detachment. The antiviral treatment approach for acute retinal necrosis varies as there are no established guidelines. We summarize the outcomes of acute retinal necrosis with available antiviral treatments. Electronic searches were conducted in PubMed/MEDLINE, EMBASE, Scopus, and Google Scholar for interventional and observational studies. Meta-analysis was performed to evaluate the pooled proportion of the predefined selected outcomes. This study was registered in PROSPERO (CRD42022320987). Thirty-four studies with a total of 963 participants and 1,090 eyes were included in the final analysis. The estimated varicella-zoster virus and herpes simplex virus polymerase chain reaction-positive cases were 63% (95% CI: 55–71%) and 35% (95% CI: 28–42%), respectively. The 3 main antiviral treatment approaches identified were oral antivirals alone, intravenous antivirals alone, and a combination of systemic (oral or intravenous) and intravitreal antivirals. The overall pooled estimated proportions of visual acuity improvement, recurrence, and retinal detachment were 37% (95% CI: 27–47%), 14% (95% CI: 8–21%), and 43% (95% CI: 38–50%), respectively. Patients treated with systemic and intravitreal antivirals showed a trend towards better visual outcomes than those treated with systemic antivirals (oral or intravenous) alone, even though this analysis was not statistically significant (test for subgroup differences P = 0.83).</p

Type 1 interferon-inducible gene expression in QuantiFERON Gold TB-positive uveitis: A tool to stratify a high versus low risk of active tuberculosis?

QuantiFERON-Gold TB (QFT)-positive patients with undetermined cause of uveitis are problematic in terms of whether to diagnose and treat them for tuberculosis (TB). Here, we investigated whether peripheral blood expression of type 1 interferon (IFN)-inducible genes may be of use to stratify QFT-positive patients with uveitis into groups of high versus low risk of having active TB-associated uveitis. We recruited all new uveitis patients in Cipto Mangunkusumo Hospital, Jakarta, Indonesia for one year. We included 12 patients with uveitis and clinically diagnosed active pulmonary TB, 58 QFT-positive patients with uveitis of unknown cause, 10 newly diagnosed sputum-positive active pulmonary TB patients without uveitis and 23 QFT-negative healthy controls. Expression of 35 type 1 IFN-inducible genes was measured in peripheral blood cells from active pulmonary TB patients without uveitis and healthy controls. Differentially expressed genes were identified and used for further clustering analyses of the uveitis groups. A type-1 IFN gene signature score was calculated and the optimal cut-off value for this score to differentiate active pulmonary TB from healthy controls was determined and applied to QFT-positive patients with uveitis of unknown cause. Ten type 1 IFN-inducible genes were differentially expressed between active pulmonary TB and healthy controls. Expression of these 10 genes in QFT-positive patients with uveitis of unknown cause revealed three groups: 1); patients resembling active pulmonary TB, 2); patients resembling healthy controls, and 3); patients displaying an in-between gene expression pattern. A type 1 IFN gene signature score ≥5.61 displayed high sensitivity (100%) and specificity (91%) for identification of active TB. Application of this score to QFT-positive patients with uveitis of unknown cause yielded two groups with expected different likelihood (high vs. low) of having active-TB uveitis, and therefore may be useful in clinical management decisions

Comparative Assessment of Short-Term Tendon-Scleral Postoperative Inflammation and α-Smooth Muscle Actin Expression following Oral and Topical Diclofenac Administration for Strabismus Surgery in Rabbits

Purpose: Wound healing and fibrosis modulation are considered pivotal for the long-term outcome of strabismus surgery. Nonsteroidal anti-inflammatory drugs, including diclofenac sodium, are inflammation suppressive drugs that may modulate wound healing, including postoperative inflammation. This study aimed to compare the effect of oral and 0.1% topical diclofenac sodium on short-term inflammation and α-smooth muscle actin (α-SMA) expression at the tendon-scleral attachment site following strabismus surgery in an experimental rabbit model. Methods: Superior rectus recession was performed in 12 eyes of six New Zealand rabbits. Rabbits were divided into three groups: oral diclofenac 2 × 5 mg/kg for three days (group A), 0.1% diclofenac sodium eye drops 3 times/day for three days (group B), and controls (group C). On postoperative day 14, enucleation was performed. Macroscopic adhesion score, microscopic adhesion score, percentage of postoperative inflammation area (Masson’s trichrome staining), and α-SMA (immunohistochemistry staining) were assessed. Data analysis was performed using a semi-quantitative and quantitative assessment with ImageJ. All groups were compared with reciprocal staining intensity (RSI) values to measure α-SMA expression. Results: All groups showed no difference in macroscopic (p = 0.13) and microscopic adhesion scores (p = 0.28). The percentage of postoperative inflammation area in group B (12.44% (8.63–18.29)) was significantly lower than group A (26.76% (21.38–37.56) p = 0.03) and group C (27.80% (16.42–36.28), p = 0.04). Comparative RSI analysis found that group B had a significantly lower α-SMA expression than group C (174.08 ± 21.78 vs 212.58 ± 12.06, p = 0.04). Conclusion: The results suggest that compared to oral, the administration of topical diclofenac showed a more significant reduction of short-term postoperative inflammation and α-SMA expression at the tendon-scleral attachment site following strabismus surgery

The diagnostic value of polymerase chain reaction for ocular tuberculosis diagnosis in relation to antitubercular therapy response: a meta-analysis

Background: Polymerase chain reaction (PCR) is currently considered the method of choice for diagnosing ocular tuberculosis. However, the sensitivity and specificity of PCR using ocular samples remain uncertain. Our meta-analysis aimed to review the diagnostic accuracy of PCR testing in confirming ocular tuberculosis, with responses to antitubercular therapy (ATT) as reference indices.  Methods: A systematic literature search of the PubMed, EBSCOHost, Scopus, and Google Scholar databases was performed using the standardized PRISMA guideline. Observational studies reporting both PCR MTb positivity and ATT response were included. Meta-analysis was performed to estimate the pooled positivity rate, sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratios (DOR), and summary receiver operating curves (SROC).  Results: The pooled positivity rate for PCR MTb was 0.55 (95% CI 0.44–0.67). The overall sensitivity and specificity were 88% (95% CI 83–92) and 71% (95% CI 60–80), respectively. The pooled DOR was 12.15 (95% CI 5.55–26.62). The area under the SROC was 0.83.  Conclusions: The diagnostic accuracy of PCR Mtb is not sufficient for use as a benchmark for ocular TB diagnosis routinely based on ATT response. A negative result may help avoid prescribing unnecessary ATT in dilemmatic cases

The diagnostic value of polymerase chain reaction for ocular tuberculosis diagnosis in relation to antitubercular therapy response

Background: Polymerase chain reaction (PCR) is currently considered the method of choice for diagnosing ocular tuberculosis. However, the sensitivity and specificity of PCR using ocular samples remain uncertain. Our meta-analysis aimed to review the diagnostic accuracy of PCR testing in confirming ocular tuberculosis, with responses to antitubercular therapy (ATT) as reference indices.  Methods: A systematic literature search of the PubMed, EBSCOHost, Scopus, and Google Scholar databases was performed using the standardized PRISMA guideline. Observational studies reporting both PCR MTb positivity and ATT response were included. Meta-analysis was performed to estimate the pooled positivity rate, sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds rati

Anti-tubercular therapy in the treatment of tubercular uveitis: A systematic review and meta-analysis

We quantitatively evaluated the efficacy of antitubercular therapy (ATT) in tubercular uveitis (TBU) patients. Main outcome measures include inflammation recurrence, inflammation reduction, complete resolution of inflammation, improved visual acuity (VA), ability to taper corticosteroids to < 10 mg/day without inflammatory progression, and use of adjunctive immunosuppressants while on ATT. This review is prospectively registered in PROSPERO (CRD42020206845). Forty-nine studies reporting data for 4,017 TBU patients were included. In comparative studies, the odds ratio (OR) of inflammatory recurrence was 0.33 (95%CI:0.19-0.60) for TBU patients treated with ATT±corticosteroid versus no ATT. For TBU patients treated with ATT±corticosteroid, the pooled absolute incidences of inflammatory recurrence, inflammatory reduction, complete resolution of inflammation, and visual acuity improvement were 13% (n=310/2,216; 95%CI:9-18), 81% (n=217/276; 95%CI: 62-95), 83% (n=1,167/1,812; 95%CI: 77-89), and 65% (n=347/542; 95%CI:51-78), respectively. Corticosteroids were tapered to <10 mg/day without inflammatory progression in 91% (n=326/395; 95%CI:78-99) of patients, 9% (n=121/1,376; 95%CI:6-13) of whom were administered concomitant immunosuppressive agents alongside ATT. We conclude that treatment of TBU with ATT±corticosteroid is associated with a high level of control or improvement of inflammation. More prospective studies with detailed reporting of ATT regimens, patient subgroups, and outcomes are required to better evaluate ATT effectiveness