Brief Report: Retinal Microvasculature and Immune Restoration Among South Eastern Asian Patients With HIV/AIDS Over a 9-Month Antiretroviral Therapy.

BACKGROUND: Longitudinal evidence on retinal microvasculature and subsequent systemic inflammatory alteration is lacking. We investigated the association between retinal microvasculature and immune response among patients with HIV/AIDS over a 9-month antiretroviral therapy. METHODS: We conducted a prospective cohort study on patients with HIV/AIDS at Singapore Communicable Disease Centre since June 2011. We recruited all eligible patients and then reviewed them every 3 months over a 9-month follow-up, including performing blood tests (CD4+/CD8+ T-cell counts and HIV viral load), blood pressure, anthropometry measurements, and retinal photography at each visit. We assessed retinal vascular indexes using a semiautomated computer-based program. Finally, we applied a linear mixed model to analyze associations between baseline retinal vascular indexes and 9-month changes of CD4+/CD8+ T-cell counts and HIV viral load throughout study observation, after adjusting for major confounders. RESULTS: We found that narrower arteriolar caliber (per 10 µm decrease), wider venular caliber (per 10 µm increase), and larger arteriolar branching angle (per 10° increase) in the retina assessed at baseline were significantly associated with 9-month reductions in CD4+ T-cell count by 52.97 cells/µL (P = 0.006), 33.55 cells/µL (P = 0.01), and 39.09 cells/µL (P = 0.008), accordingly. CONCLUSION: Patients with HIV/AIDS with a suboptimal retinal microvascular morphology tended to fail immune restoration undertaking a 9-month antiretroviral therapy.

UNUSUAL CAUSE OF BRANCH RETINAL ARTERY OCCLUSION: POLYCYTHEMIA IN A TRANSGENDER MAN FROM UNREGULATED TESTOSTERONE USE.

PURPOSE: We report a transgender patient with branch retinal artery occlusion who had secondary polycythemia from unregulated testosterone injections and review the literature on the mechanisms of supraphysiologic and standard doses of testosterone causing a hypercoagulable state. METHODS: Case report. RESULTS: A 45-year-old Chinese transgender man with no medical history presented with a 1-week history of a scotoma in his left eye vision. Ophthalmologic examination revealed retinal pallor and edema along the superotemporal arteriole in the left eye. Optical coherence tomography showed increased thickness of the inner retinal layers of the superotemporal retina. Fluorescein angiography demonstrated an arm-retina time of 1 minute and 43 seconds, with no vascular sheathing and capillary fallout. A diagnosis of left superotemporal branch retinal artery occlusion was made. Initial blood tests revealed a hemoglobin level of 19.3 g/dL (11.8-14.6 g/dL), hematocrit of 62% (34.3-43.0%), and erythrocytes of 6.56 × 1012/L (3.7-4.8 × 1012/L). He revealed later that he had been on weekly testosterone injections (testosterone enanthate 250-mg depot injection) since 2011. He was also exposed to a moderately high altitude, when his symptoms occurred, raising the possibility of worsening hypercoagulability resulting in his thrombotic event. CONCLUSION: To the best of our knowledge, this is the first documented case of a trans man who developed branch retinal artery occlusion after self-administering supraphysiological doses of testosterone. In a young patient with no history of cardiovascular risk factors who develops retinal arterial occlusion, other causes such as hypercoagulable syndromes must be excluded. This case warns of the dangers of unregulated testosterone use, especially at supraphysiologic doses, and the risks of thrombotic events from secondary polycythemia.

Clinical Features and CD4+ T Cells Count in AIDS Patients with CMV Retinitis: Correlation with Mortality.

PURPOSE: To explore the all-cause mortality in patients with acquired immune deficiency syndrome (AIDS) and Cytomegalovirus (CMV) retinitis. METHODS: A retrospective cohort study of patients with CMV retinitis (CMVR) presented to a tertiary referral center in Singapore from January 1, 2004, through December 31, 2015. RESULTS: A total of 144 patients were studied (87 survived, 11 lost to follow up, 46 died). Patients with bilateral CMVR and six-month follow up CD4 + T cell count < 50 cells/mm3 have shorter time to mortality, compared to patients with CD4 + T cell count > 50 cells/mm3 (p < .001) and unilateral disease (p = .043). Baseline CD4 + T cell count, size and zone of initial primary retinitis lesions, recurrences of retinitis, and timing of combined antiretroviral therapy (cART) are not significantly associated with mortality. CONCLUSION: Bilateral ocular involvement and lack of immune recovery in patients with AIDS and CMVR are associated with shorter survival time.

Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) - Report 2: Pattern of Uveitis Investigations in Singapore.

Purpose: To analyze the pattern of laboratory investigations of uveitis at a tertiary referral eye care center in Singapore.Methods: Retrospective analysis of 2040 uveitis cases from the Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) database over a 12-year period (2004 - 2015).Results: Patients with retinal vasculitis (RV) had the most tests utilized per patient (6.79), followed by intermediate uveitis (IU) (5.25), panuveitis (Pan) (5.12), posterior uveitis (PU) (4.17), anterior uveitis (AU) (2.75), and keratouveitis (KU) (1.10). The most frequently utilized test for infective etiology were the VDRL (41.3%), Syphilis IgG (29.5%), and T-SPOT.TB (24.6%). For autoimmune tests, ANA was most utilized (18.2%), followed by anti-dsDNA (14.8%), and HLA-B27 (12.4%).Conclusion: There was high utilization of autoimmune tests such as ANA, anti-dsDNA, RF, and ANCA, despite its limited yield. Rationalization of investigations in patients with ocular inflammation via a stepladder approach may help optimize the use of limited resources.

Ocular Autoimmune Systemic Inflammatory Infectious Study - Report 3: Posterior and Panuveitis.

PURPOSE: To report the pattern of posterior and panuveitis at a tertiary referral center in Singapore. METHODS: Subgroup retrospective analysis of 334 new posterior and panuveitis cases, from the Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) database. Descriptive analysis was performed and visual outcome and complications were reported. RESULTS: The etiology for posterior uveitis and panuveitis was infectious in 162 patients (48.5%), non-infectious in 144 patients (43.1%), and idiopathic in 28 patients (8.4%). More patients with bilateral disease had a non-infectious etiology (n = 82, 50.9%) (p = 0.012). The most common complication was epiretinal membrane (n = 20, 12.3%) for the infectious group and cystoid macular edema (n = 12, 8.3%) for the non-infectious group. CONCLUSIONS: The proportion of etiologies in our cohort varies from other studies. Understanding the variations and demographic associations allows the diagnosis and management of posterior and panuveitis to be further improved.

Treatment outcome in patients with presumed tubercular uveitis at a tertiary referral eye care centre in Singapore.

AIM: To report the clinical features and outcome of patients with presumed tubercular uveitis (TBU). METHODS: Retrospective analysis of patients with presumed TBU at a tertiary referral eye care centre in Singapore between 2007 and 2012 was done. Main outcome measures were failure of complete resolution of uveitis or recurrence of inflammation. RESULTS: Fifty three patients with mean age of 44.18 ± 15.26 years with 54.72% being males were included. 19 (35.85%) had bilateral involvement, with panuveitis and anterior uveitis being the most common presentations. 36 (67.92%) patients received antitubercular therapy (ATT), and 28 received concurrent systemic steroids. 15 (28.30%) eyes of 11 (30.55%) patients in the ATT group and 4 (21.05%) eyes of 3 (17.64%) patients in the non-ATT group had treatment failure (p value = 0.51). CONCLUSION: The use of ATT, with or without concurrent corticosteroid, may not have a statistically significant impact in improving treatment success in patients with presumed TBU.

Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) - Report 1: Epidemiology and Classification.

PURPOSE: To report the epidemiology and classification of ocular inflammation at a tertiary eye care center in Singapore. METHODS: Retrospective cohort study of the clinical records of consecutive new cases from the Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) database from 2004-2015. RESULTS: A total of 2200 patients were studied from the OASIS database. The most common anatomic diagnosis was anterior uveitis (55.9%), posterior uveitis (17.5%), panuveitis (9.6%), and intermediate uveitis (4.7%). In addition, scleritis (6.1%), keratouveitis (2.8%), retinal vasculitis (2.2%), and episcleritis (1.2%) were observed. Etiology was established in 65.1%, with 35.2% of patients associated with non-infectious etiologies. The most common etiologies found were presumed tuberculosis (7.2%), followed by cytomegalovirus infection (6.9%), herpetic infection (6.3%), HLA-B27-associated anterior uveitis (4.2%), and ankylosing spondylitis (3.8%). CONCLUSIONS: The pattern of ocular inflammation in Singapore has similarities with both Western and Asian populations. Anterior uveitis was the most common, with non-infectious etiologies being slightly more common than infectious etiologies.

Ocular Toxoplasmosis in Tropical Areas: Analysis and Outcome of 190 Patients from a Multicenter Collaborative Study.

PURPOSE: To describe clinical findings and outcomes for ocular toxoplasmosis in an international multicenter collaborative study. METHODS: Retrospective analysis of 190 patients diagnosed with ocular toxoplasmosis from three study sites (Brazil, India, and Singapore). RESULTS: There were 93 (48.9%) females with a mean age of 32.8 years. The most common symptoms were isolated blurring of vision (36.8%), followed by blurring of vision with floaters (21.1%). Treatment regimens varied largely from monotherapy to multiple combination therapies. Final visual acuity of ≥20/40 was achieved in 106 (74.2%) patients. In a median follow-up period of 31 weeks (range 12-749 weeks), 83/190 (43.7%) patients suffered a relapse. CONCLUSIONS: There appears to be geographical variation in the presentation of ocular toxoplasmosis. Compared to previous studies, we did not observe the '"dual peak" phenomenon of chronic and active disease based on age at presentation, and there was less bilateral and macular involvement (but more peripheral involvement).

Dataset of longitudinal analysis of tear cytokine levels, CD4, CD8 counts and HIV viral load in dry eye patients with HIV infection.

The data presented in this article shows the longitudinal analysis of tear fluid cytokine profiles, blood CD4 and CD8 counts and HIV viral load in 34 dry eye patients with HIV infection during the HAART therapy. Clinical samples were collected from HIV patients with dry eye disease at the time of presentation to the clinic (visit 1), three months (visit 2) and 6 months (visit 3) after the presentation. At each time point tear samples were evaluated for 41 cytokines using Luminex bead based multiplex assay and blood samples were tested for HIV viral load and CD4 and CD8 counts.

Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS)-report 4: analysis and outcome of scleritis in an East Asian population.

BACKGROUND: The purpose of this study is to evaluate the spectrum of scleritis from database of Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) at a tertiary eye referral eye institute in Singapore. Clinical records of 120 patients with scleritis from a database of 2200 patients from Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) were reviewed. RESULTS: 56.6% were females, with a mean age of 48.6 ± 15.9 years. 75 (62.5%) had diffuse anterior scleritis, 25 (20.8%) had nodular anterior scleritis, 7 (5.8%) had necrotizing anterior scleritis and 13 (10.8%) had posterior scleritis. Ocular complications were observed in 53.3% of patients, including anterior uveitis (42.5%), raised intraocular pressure (12.5%), and corneal involvement (11.7%). Autoimmune causes were associated with 31 (25.8%) of patients, and 10 (8.3%) patients had an associated infective etiology, much higher than Caucasian studies. 53.3% of patients were treated with oral corticosteroids while 26.7% required immunosuppressives. CONCLUSIONS: Infective etiology needs to be considered in patients of scleritis from Asian origin. In our study and in OASIS database, scleritis was associated with systemic autoimmune disease and ocular complications.

Dataset of tear film cytokine levels in dry eye disease (DED) patients with and without HIV infection.

The tear film cytokine profiling data in this article was obtained from a prospective case-control study with a sample size of 34 dry eye disease (DED) patients with HIV infection and 32 DED patients without HIV infection, see "A distinct cytokines profile in tear film of dry eye disease (DED) patients with HIV infection" (R. Agrawal, P.K. Balne, A. Veerappan, V.B. Au, B. Lee, E. Loo, A. Ghosh, L. Tong, S.C. Teoh, J. Connolly, P. Tan, 2016) [1]. Tear samples were collected from all the subjects using Schirmer׳s strips and cytokine profiling was done using the Luminex bead based multiplex assay with a panel of 41 analytes. The cytokine level differences in each group of subjects were analyzed using logistic regression models.

Analysis and Outcomes of Cataract Surgery in Patients with Acquired Immunodeficiency Syndrome.

PURPOSE: To investigate the surgical outcomes, complications and postoperative progression in HIV patients undergoing cataract surgery in a teaching hospital. METHODS: A retrospective cohort study of patients with HIV/AIDS who had cataract surgery from January 2000 until December 2011 at a tertiary referral multidisciplinary hospital in Singapore. RESULTS: We identified 44 eyes from 29 patients. Preoperatively, 41.3% had no ophthalmic manifestations of HIV/AIDS, while 16 eyes had quiescent cytomegalovirus retinitis (CMVR). Postoperatively, 1 eye developed new CMVR, while 1 eye had reactivation of previous CMVR. Of eyes with new or previous CMVR, 1 eye developed rhegmatogenous retinal detachment (RD) postoperatively. Only 3 eyes had prolonged postoperative inflammation. There were no cases of endophthalmitis or cystoid macular edema. Postoperative improvement of at least two Snellen lines was achieved in 86.6% of eyes. CONCLUSIONS: Cataract surgery in HIV patients is generally safe, regardless of CD4 count, but their general and ocular health should be optimized preoperatively.

Immune recovery uveitis in HIV patients with cytomegalovirus retinitis in the era of HAART therapy-a 5-year study from Singapore.

BACKGROUND: The aim of this study is to analyse the clinical features of HIV patients with cytomegalovirus retinitis (CMVR) developing immune recovery uveitis (IRU) while on highly active antiretroviral therapy (HAART) and to identify the risk factors, visual outcomes and complications of IRU. RESULTS: Majority (n = 26, 86.7 %) of patients were male, with 76.7 % (n = 23) of patients having bilateral disease. Twenty-seven eyes (50.9 %) had both anterior uveitis and vitritis. The median CD4 at IRU was 210 cells/µL (IQR 140-279), with 86.7 % having CD4 >100 cells/µL. The median duration from initiation of HAART to IRU was significantly different between those <50 years old (median 763 days, IQR 174-1872 days) and those ≥50 years old (median 161 days, IQR 84.5-278 days). Fourteen eyes (26.4 %) had loss of one or more Snellen lines visual acuity at 6 months while the rest maintained or improved vision. Complications developed in 21 eyes, with cataract (66.7 %), glaucoma and ocular hypertension (33.3 %) being the most common. The risk of complications was associated with the absolute difference in CD4 counts at IRU and at HAART commencement (p = 0.041). Age was also negatively associated with the duration from HAART to IRU (p = 0.005, Spearman's rho coefficient = -0.503). CONCLUSIONS: It is common to have both anterior uveitis and vitritis in IRU. There was a positive association between the increase in CD4 from HIV to IRU diagnoses and the risk of developing complications. Younger patients appeared to develop IRU later than older patients after HAART, suggesting that long-term follow-ups are essential for these patients.

Optical Coherence Tomography Angiography Findings in Dengue-Related Maculopathy: A Case Report.

The ophthalmic manifestations of dengue fever include a visually impairing maculopathy, where patients are left with a central or paracentral relative scotoma. The authors present a case of a 26-year-old female patient returning from Thailand with unilateral reduction in visual acuity and a central scotoma associated with dengue fever. The authors report the use of the optical coherence tomography angiography (OCTA) as a noninvasive imaging platform to demonstrate its value in showing the persistent changes corresponding to the functional central scotoma in dengue-related maculopathy, which often cannot be visualized clinically or by standard OCT and fundus fluorescein angiography. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1057-1060.].

A distinct cytokines profile in tear film of dry eye disease (DED) patients with HIV infection.

PURPOSE: To investigate the tear cytokine profile in HIV patients with dry eye disease (DED) and study the association between the severity of ocular inflammatory complications and tear cytokines levels. We postulate that HIV-mediated inflammation may be the underlying pathogenic mechanism for HIV-associated DED. METHODS: The current prospective case-control study compared tear film cytokine profiles in DED patients with HIV infection (n=34) and age/gender-matched DED patients without HIV infection [controls (n=32)]. Participants were recruited from tertiary referral eye care centre and communicable disease clinics, Singapore. Ocular surface health was documented using tear film, Schirmer's test, corneal staining, and conjunctival injection measurements. Tear samples were collected using Schirmer's strips and analysed for the levels of 41 cytokines using Luminex bead assay. Logistic regression models were performed to determine correlation and significance. RESULTS: Among the 41 cytokines analysed, statistically significant differences were observed in the mean values of epithelial growth factor (EGF), growth related oncogene (GRO) and interferon gamma-induced protein 10 (IP-10). EGF and IP-10 levels were higher and GRO levels were lower in the tears of DED patients with HIV infection compared to DED patients without HIV infection. No significant association was found between varying levels of ocular surface parameters and cytokine concentrations in HIV patients with DED (p>0.05). CONCLUSIONS: EGF and IP-10 were significantly elevated and GRO levels were lower in the tear profile of HIV patients with DED compared to immunocompetent patients with DED. This study suggests a novel cytokine driven paradigm for ocular inflammatory complications of HIV infection. Additional studies in large organised cohorts can validate the results.

Dataset of aqueous humor cytokine profile in HIV patients with Cytomegalovirus (CMV) retinitis.

The data shows the aqueous humor cytokine profiling results acquired in a small cohort of 17 HIV patients clinically diagnosed with Cytomegalovirus retinitis using the FlexMAP 3D (Luminex®) platform using the Milliplex Human Cytokine® kit. Aqueous humor samples were collected from these patients at different time points (pre-treatment and at 4-weekly intervals through the 12-week course of intravitreal ganciclovir treatment) and 41 cytokine levels were analyzed at each time point. CMV DNA viral load was assessed in 8 patients at different time points throughout the course of ganciclovir treatment. The data described herein is related to the research article entitled "Aqueous humor immune factors and cytomegalovirus (CMV) levels in CMV retinitis through treatment - The CRIGSS study" (Iyer et al., 2016) [1]. Cytokine levels against the different time points which indicate the response to the given treatment and against the CMV viral load were analyzed.

Aqueous humor immune factors and cytomegalovirus (CMV) levels in CMV retinitis through treatment - The CRIGSS study.

PURPOSE: This study aims to perform comprehensive longitudinal immune factor analysis of aqueous humor in relation to the aqueous CMV viral load and systemic CD4 counts during treatment of patients with co-infection of HIV and CMVR. METHODS: Aqueous humor samples were collected from 17 HIV-positive patients with CMVR scheduled to undergo weekly intravitreal ganciclovir therapy as part of the prospective CMV Retinitis Intravitreal Ganciclovir Singapore Study (CRIGSS) over the course of 1year. Full data across all the 4 time points was obtained and analyzed for CMV DNA viral load, 41 cytokine and chemokine factors using real-time PCR with the FlexMAP 3D (Luminex®) platform and assessed using the Milliplex Human Cytokine® kit. RESULTS: The following immune factors (Spearman correlation coefficient r value in parenthesis, p<0.05) showed strong correlation with CMV DNA load in the aqueous - MCP-1 (0.80, IFN-g (0.83), IP-10 (0.82), IL-8 (0.81), fractalkine (0.73), RANTES (0.68) - while the following showed moderate correlation - PDGF-AA (0.58), Flt-3L (0.59) and G-CSF (0.53). Only PDGF-AA revealed a statistically significant negative correlation with serum CD4 levels (r=-0.74). CONCLUSION: Immune factors that correlate with intraocular CMV DNA load are identified. They are indicative of a Th1 and monocyte-macrophage mediated response, and exhibit a decreasing trend longitudinally through the course of treatment. These factors may be an important new consideration in individualizing the treatment of patients with CMVR.

Efficacy and safety of topical ganciclovir in the management of cytomegalovirus (CMV)-related anterior uveitis.

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of topical ganciclovir 0.15 % gel in the management of patients with cytomegalovirus (CMV) anterior uveitis. RESULTS: This was a retrospective cohort study of the disease course of 31 patients (33 eyes) with aqueous polymerase chain reaction (PCR) positive for CMV. Data from a total of 160 episodes of anterior uveitis flare for 20 years, dating from December 1992 to December 2012, was collected. All patients were treated with concomitant topical anti-inflammatory medication. The disease course of each eye was analysed before and after the use of topical ganciclovir 0.15 %. The mean age at initial presentation of anterior uveitis was 57.5 ± 12.6 years. Twenty-eight (90.3 %) patients were Chinese. Patients on topical ganciclovir gel had a statistically significant fewer episodes of uveitis flare per person year (median -0.88 episodes/person years, p = 0.029). The time-to-quiescence was not significantly affected by topical ganciclovir use (median -1.25 days, p = 0.610). In the survival analysis using the Cox regression model, the use of topical ganciclovir was associated with a lower risk of recurrence, but this was not statistically significant (hazard ratio = 0.857, 95 % CI 0.543-1.36, p = 0.511). The overall median time-to-recurrence was 290 days (95 % CI 113 to 274 days) and 164 days (125 to 404 days) (p = 0.492), with and without topical ganciclovir, respectively. CONCLUSIONS: Topical ganciclovir may be beneficial in reducing the frequency of recurrence in patients with CMV anterior uveitis, but it was not statistically associated with prolonging the time-to-recurrence. The time-to-quiescence was also not significantly affected by topical ganciclovir. Prospective studies with a larger number of patients would be required to verify our findings.

A prospective case-control study to investigate retinal microvascular changes in acute dengue infection.

Dengue infection can affect the microcirculation by direct viral infection or activation of inflammation. We aimed to determine whether measured retinal vascular parameters were associated with acute dengue infection. Patients with acute dengue were recruited from Communicable Diseases Center, Singapore and age-gender-ethnicity matched healthy controls were selected from a population-based study. Retinal photographs were taken on recruitment and convalescence. A spectrum of quantitative retinal microvascular parameters (retinal vascular caliber, fractal dimension, tortuosity and branching angle) was measured using a semi-automated computer-based program. (Singapore I Vessel Assessment, version 3.0). We included 62 dengue patients and 127 controls. Dengue cases were more likely to have wider retinal arteriolar and venular calibers (158.3 µm vs 144.3 µm, p < 0.001; 227.7 µm vs 212.8 µm, p < 0.001; respectively), higher arteriolar and venular fractal dimensions (1.271 vs 1.249, p = 0.002; 1.268 vs. 1.230, p < 0.001, respectively), higher arteriolar and venular tortuosity (0.730 vs 0.546 [x10(4)], p < 0.001; 0.849 vs 0.658 [x10(4)], p < 0.001; respectively), compared to controls. Resolution of acute dengue coincided with decrease in retinal vascular calibers and venular fractal dimension. Dengue patients have altered microvascular network in the retina; these changes may reflect pathophysiological processes in the immune system.

Trends in Patterns of Posterior Uveitis and Panuveitis in a Tertiary Institution in Singapore.

PURPOSE: The study aims to analyze the trends of posterior uveitis and panuveitis patients seen by a tertiary eye center in Singapore between 2004 and 2012. METHODS: We conducted a retrospective analysis of 363 consecutive new cases of posterior uveitis and panuveitis. The cases were segregated into idiopathic, infectious, or noninfectious. RESULTS: We found statistically significant differences between etiologies and ethnicity (p = 0.014). We noticed a statistically significant downward trend (Spearman's rho (ρ) = -0.812, p = 0.008) for dengue uveitis, and an upward trend for the idiopathic category (Spearman's rho (ρ) = 0.753, p = 0.019). CONCLUSIONS: We observed differences between etiologies and ethnicity, pointing toward potential susceptibility variations. There was an upward trend of idiopathic causes, possibly due to better control of systemic and infectious etiologies. The dengue uveitis incidence correlates well with our national statistics. The downward trend of dengue uveitis could be due to the introduction of Singapore's dengue surveillance in 2005, emphasizing the importance of controlling the disease.