Secondary Logo

Journal Logo

Review Article

Recent Advances in Diagnosis and Treatment of Infectious Uveitis Prevalent in Asia-Pacific Region

Patel, Anamika MS; Kelgaonkar, Anup MS; Kaza, Hrishikesh DNB; Tyagi, Mudit MS; Murthy, Somasheila MS; Pathengay, Avinash FRCS; Basu, Soumyava MS

Author Information
Asia-Pacific Journal of Ophthalmology: January-February 2021 - Volume 10 - Issue 1 - p 99-108
doi: 10.1097/APO.0000000000000367
  • Open

Abstract

Uveitis across the world is characterized by wide-ranging variations in etiology, prevalence, clinical presentations, and treatment outcomes. These variations are influenced by geographical location, racial and genetic factors, prevalence of infections, socio-economic conditions, and availability of resources for diagnosis and treatment.1 The Asia-Pacific region covers a large area that supports a large and diverse population.2 Majority of the countries have seen rapid economic progress in recent years. This has led to a unique situation in the Asia-Pacific countries, where diseases characteristic to developing countries are prevalent on the one hand, and resources to diagnose and treat these diseases are increasingly available on the other. Thus, the Asia-Pacific countries have been able to provide unique perspectives on a wide variety of diseases.

In the case of uveitis, one of the foremost areas of research in Asia-Pacific countries has been infectious uveitis. Infections are known to account for at least 50% of all cases of uveitis of known etiology in developing countries.3 Even in uveitis of unknown etiology, a significant proportion is thought to be related directly or indirectly to infections.4 The nature of these infections can range from common causes such as tuberculosis (TB), toxoplasmosis, and herpesviruses, to rare ones such as chikungunya, dengue, and trematode-induced uveitis. Indeed, some of the infections, such as leprosy or leptospirosis, are almost unique to the Asia-Pacific.5

Considering the wide variety of microorganisms that can potentially cause intraocular infection, the majority of the ongoing research in infectious uveitis is directed at the etiological diagnosis of these infections. This is a challenging task because multiple infections may have identical clinical presentations, and a single infection may have multiple clinical presentations. Additionally, many infections are not identifiable in aqueous or vitreous samples obtained from patients. In this paper, we will review the major contributions in the diagnosis and treatment of different types of infectious uveitis from countries of the Asia-Pacific. Each section will identify the major challenges in a specific form of infectious uveitis and list significant recent contributions (2015–till date) to the field, primarily from the Asia-Pacific, but also from other regions, wherever relevant. This review is not exhaustive and mainly intends to highlight the direction of research in the field.

OCULAR TOXOPLASMOSIS

Toxoplasma gondii is possibly the most common cause of infectious uveitis worldwide.6 Despite its wide prevalence, our understanding of the disease has evolved very little because the parasite was first identified in human retinal tissue nearly 70 years ago.7 The pathomechanisms of human ocular toxoplasmosis (OT) are very poorly understood.8 Most drugs used for antitoxoplasma treatment are from the early antibiotic era.9 Prevention and treatment of recurrent toxoplasmosis is yet not clear.10 Finally, definitive diagnosis of OT, either by polymerase chain reaction (PCR) or detection of antibodies in ocular fluids, is yet to find widespread application in most uveitis clinics. These tests are particularly valuable in atypical presentations of OT that cannot be distinguished clinically from other forms of infectious and non-infectious uveitis.

Clinical Studies

These have focussed on comparing recurrent with primary infections, newer imaging modalities, laboratory diagnosis, and prevention of recurrent infection. A large study (n = 190) combining patients from Brazil, India, and Singapore found geographical variations in presentation between different regions.11 They did not observe any difference in age between patients presenting with recurrent (remote infection) and primary OT (recent infection). Bilateral and macular infections were also lower compared with earlier studies. In Australia, OT patients were found to have fewer recurrences and better visual outcomes than reported elsewhere.12 The patients were mostly treated with oral clindamycin and prednisolone. As in other forms of uveitis, multimodal imaging has been used to characterize inflammation in the neurosensory retina, and secondary changes in the choroid, retinal vasculature, vitreous, and optic disc.13 It also helps in identifying local complications such as choroidal neovascularization, epiretinal membrane, and vascular occlusions. One interesting application of multimodal imaging has been in the characterization of atypical OT lesions, such as punctate outer retinal toxoplasmosis (Fig. 1). In laboratory investigations, serum IgM for T. gondii was found to be a specific biomarker for primary OT, without retinochoroidal scars at presentation.14 Testing of ocular fluids for PCR-based diagnosis of OT or the Goldman-Witmer coefficient continues limited to select clinics.15,16 Local treatment with intravitreal clindamycin had been reported earlier and has been favorably compared with classical oral therapy in a randomized control trial (RCT).17 More recently, treatment with intravitreal trimethoprim/sulfamethoxazole (1.28 mg/0.08 mL) and dexamethasone has also been reported, with no retinal toxicity.18 Finally, in a placebo-controlled RCT from Brazil, prophylaxis with trimethoprim-sulfamethoxazole (160/800 mg) every 2 days for 311 days was found to prevent recurrences during a 3-year follow-up.19

FIGURE 1
FIGURE 1:
Punctate outer retinal toxoplasmosis (PORT) lesions with choroidal neovascular membrane. (A, B) Fundus fluorescence angiograms of fresh PORT lesions show early hypofluorescence (A) and late phase hyperfluorescence (B). (C, D) Indocyanine green angiogram showing early phase hypofluorescent lesions (C) that in subsequent frames become either less hypofluorescent or isofluorescent (D).

Basic Research

There have been interesting developments in understanding the pathomechanisms of OT.8 Most are in vitro studies using T. gondii tachyzoites and human retinal cell lines, although monkey models of OT have been reported. T. gondii can cross the retinal vascular endothelium by 3 mechanisms: leukocyte taxis, transmigration, and by infection of endothelial cells.20 Retinal Müller glial cells seem to be the preferred initial host cells, although other cell types can be infected. Infection of retinal pigment epithelium (RPE) produces growth factors such as vascular endothelial growth factor (VEGF) and thrombospondin-1 that induce proliferation of adjacent uninfected cells.21 This leads to the hyperpigmentation seen in OT, and renders the uninfected cells more susceptible to infection. Blockade of growth factors reversed the proliferation phenotype of uninfected cells. Finally, variations in both host and parasite genotypes may influence the clinical manifestation of OT.22 Further understanding of pathomechanisms will help in preventing and in developing new drug targets for OT.

OCULAR TUBERCULOSIS

The Asia-Pacific has been the crucible for nearly all major recent developments in ocular tuberculosis (OTB). It should be expected as this region accounts for nearly 60% of the global TB burden and majority of the high TB-endemic countries.23 The past 2 decades, in particular, have seen tremendous activity in the field. The most significant advances during this period have been in the identification of new clinical signs of OTB,24–27 application of multimodal imaging in characterization of OTB lesions,28,29 more sensitive molecular diagnostic techniques,30–33 and demonstration of the therapeutic effect of anti-TB therapy (ATT) in clinically diagnosed OTB.34–36 Alongside, there have been new insights into the histopathology of OTB,37–39 especially involvement of the RPE,40–42 and attempts at understanding pathomechanisms of OTB through animal models and human samples.43–45 Despite these achievements, there remain major lacunae in our understanding of OTB. These include lack of objective methods for accurate clinical diagnosis, absence of standardization of molecular diagnostic techniques, and unpredictability of therapeutic response to ATT. In this section, we will describe the most recent developments in clinical and basic research in OTB.

Clinical Studies

Much of the recent clinical research on OTB has been conducted by consortia of multiple centers, spreading across many countries. All of these study groups have major contributions from the Asia-Pacific. Most prominent among these is the Collaborative Ocular Tuberculosis Study (COTS).46,47 Although the details of each of the COTS reports are beyond the scope of this review, in general, the COTS data have described the distribution of OTB across the globe, its systemic associations, the clinical presentations of individual phenotypes such as choroiditis, retinal vasculitis, and anterior uveitis (AU), and their response to therapy.48–50 The group has also standardized nomenclature for different forms of OTB51 and defined “cure” as the absence of recurrent inflammation for 24 months after completion of ATT.52 Most recently, the group published consensus guidelines for initiating ATT in different forms of OTB in TB-endemic and nonendemic countries.53,54 Together these reports are remarkable in their overall coverage of the disease and in providing us a global perspective of OTB. However, they are also weighed down by the inherent weaknesses of retrospective data (especially multicentric) and consensus-based studies between diverse groups.

Among other multicentric studies, the Global Ocular Inflammation Workshops recently reported prognostic factors for OTB in the Asia-Pacific.55 These included duration of disease, previous corticosteroid therapy, coexistent HIV, disease-specific imaging features, multidrug-resistant TB, and duration of ATT. There have also been significant single-center studies from the Asia-Pacific. The association of serpiginous-like choroiditis (SLC) with TB has been widely studied in the past 2 decades.24–26 New clinical signs have also been identified in other forms of OTB. For example, the presence of subvascular lesions, focal vascular tortuosities, and occlusive vasculitis were found to be predictive of TB retinal vasculitis in high-endemic countries (Fig. 2).27 Ocular imaging has been a major supplement in the diagnosis and follow-up of OTB, especially SLC. Fundus autofluorescence, optical coherence tomography (OCT), and OCT angiography have all been used for the identification of disease pattern and response to treatment in SLC.56,57 There have also been several advances in molecular diagnosis of OTB. These include application of novel gene targets and new PCR techniques such as multitarget PCR, real-time quantitative PCR, and normalized quantitative PCR.30,31,33,58 Alternative molecular diagnostic techniques such as loop-mediated isothermal amplification have also been tested for ocular fluids.32 Although these modifications have increased the positivity rates in ocular fluid samples, they have not yet managed to popularize molecular diagnosis in clinical practice.

FIGURE 2
FIGURE 2:
Tubercular retinal vasculitis: color fundus photograph of left eye showing dense perivascular infiltrates with active retinitis lesion (∗), overlying a blood vessel.

In treatment, several studies have now confirmed the beneficial effect of ATT in the management of OTB.34–36 These can either manifest as a resolution of inflammation or as non-recurrence for at least 2 years after completion of ATT. In addition, multiple local therapies have been identified for the ancillary treatment of OTB. These include sustained-release dexamethasone implant in SLC,59 anti-VEGF therapy for choroidal tuberculoma,60 and therapeutic pars plana vitrectomy for resolution of inflammation.61

Basic Research

There have been several new advances in understanding the pathomechanisms of OTB, in conjunction with the clinical studies.62,63 It started in the past decade with the development of the guinea pig model, which demonstrated the dissemination of Mycobacterium tuberculosis (Mtb) from lungs to the eye, to cause granulomatous inflammation.43 The other major development was the localization of Mtb in the RPE in human tissues,40 and in vitro studies to identify unique functional characteristics of RPE in phagocytosis and harboring of Mtb.41,42 More recently, live microscopy in a zebrafish model has been used to demonstrate the localization of mycobacteria at the blood-retinal barriers and interaction with macrophages to form early granuloma in the eye.44 A possible role of autoimmunity in OTB has been investigated by isolation of T cells from vitreous samples of OTB and flow cytometric analysis of their functional responsiveness to Mtb and retinal autoantigens.45 It was found that intraocular T cells are responsive to both Mtb and retinal autoantigens, with the autoreactive T cells being more proinflammatory and resistant to activation-induced cell death. Future research will identify specific pathomechanisms in different forms of OTB that will aid in targeted diagnosis and treatment of these conditions. Finally, type-1 interferon gene signatures from serum have been used to stratify QuantiFERON-positive patients with unknown uveitis, into those with high versus low likelihood of having active TB uveitis.64 Such biomarker studies will be critical for diagnostic and therapeutic decision making in future.

VIRAL UVEITIS

A wide range of viral infections—common and emerging—has been linked to ocular inflammation. The present section mainly deals with the common herpesvirus infections, whereas the emerging infections have been covered in the “miscellaneous” section. Herpesviruses, viz. herpes simplex virus serotypes 1 and 2, varicella-zoster virus (VZV), and cytomegalovirus (CMV), have been linked to anterior and posterior segment inflammation. The common challenge for both viral anterior and posterior uveitis is the ubiquity of human herpesvirus infections (seropositivity rates ranging from 60% to 100%) and the latency-reactivation cycle that drives the clinical course of the disease.65 Beyond this, there seems to be a reasonable separation between the clinical settings of anterior and posterior uveitis.

Clinical Studies

Viral AU is typically found in immunocompetent individuals and is characterized most consistently by unilateral hypertensive uveitis with variable morphology of keratic precipitates (KPs) and iris atrophy.66 Broadly, there are three clinical phenotypes of viral AU, which are as follows: granulomatous AU with or without corneal involvement, Posner-Schlossman syndrome (PSS)–like uveitis, and Fuchs uveitis syndrome (FUS).67,68 The latter two phenotypes have been bestowed with unique perspectives from the Asia-Pacific. CMV has emerged as the major cause of PSS in Asian countries, ranging from 52% positivity in Singapore,69 to 26.4% in Thailand,70 but only 8.3% in India.71 The clinical features supporting acute CMV infection are very high intraocular pressure (>40 mm Hg), male gender, corneal endothelitis, coin-shaped lesions, linear arrangement of KPs, and diffuse iris atrophy.72 Chronic CMV AU (in Asian countries), however, presents as FUS with mild ciliary congestion and anterior chamber (AC) inflammation, and diffuse stellate KPs.67 Progressive corneal endothelial cell loss could be seen (Fig. 3). As in other viral AU, the diagnosis of CMV AU is based on aqueous humor analysis for both PCR and Goldman-Witmer coefficient, preferably, during intraocular pressure spikes. Both oral valganciclovir and topical ganciclovir 0.15% gel have been used to treat and prevent recurrences of CMV AU, and RCTs are currently ongoing to compare the efficacy of each route.73

FIGURE 3
FIGURE 3:
Cytomegalovirus anterior uveitis (chronic) in a 34-year-old man. A, Discrete white medium-sized keratic precipitates localized to the central cornea. B, Specular microscopy images with reduced endothelial cell count and abnormal cell morphology in the right eye.

Viral posterior uveitis also presents three distinct phenotypes—acute retinal necrosis (ARN), progressive outer retinal necrosis, and CMV retinitis.65 Although ARN is found in both immunocompetent and immunosuppressed individuals, progressive outer retinal necrosis and CMV retinitis are typically found in the immunosuppressed though the latter has also been reported in apparently immunocompetent individuals. The most common causes of ARN are herpes simplex virus (1 and 2) and VZV, although rare cases have also been reported with Epstein-Barr virus, CMV, and toxoplasma infections. It was first reported from Japan in 197174 and has traditionally been a disease of immunocompetent patients. More recently, immune dysfunction has been observed in up to 50% of patients with ARN.75 This includes local immunosuppression due to injection of periocular or intravitreal corticosteroids. In diagnostics, OCT has emerged useful in distinguishing viral retinitis from toxoplasma retinochoroiditis. The absence of inflammatory deposits on the inner retinal surface and posterior hyaloid and preservation of choroidal architecture are characteristics of viral retinitis.76 Although there has been no significant recent development in the management of viral retinitis, an emerging area of concern is the increasing incidence in patients using biologic therapy.65 These include tumor necrosis factor inhibitors (etanercept, infliximab, adalimumab), B-cell inhibitor (rituximab), anti–T-cell biologics (antithymocyte globulin and alemtuzumab), and leucocyte receptor inhibitor (natalizumab). All the above biologic agents are associated with CMV retinitis, except natalizumab, which has been linked to VZV retinitis.77

Basic Research

The study of immunopathogenesis of herpetic uveitis has been limited by the absence of animal models because VZV cannot replicate in nonhuman cells. Hence, immunological studies are based on aqueous samples collected during fulminant infection and provide only snapshots of the inflammatory process during the most active phase of the disease.78 These studies do not provide any insights into the factors affecting the initiation and resolution of the disease. Unlike herpetic uveitis, intraocular CMV infections have been studied in mouse models using murine CMV.79,80 In immunocompetent mice, murine CMV infections presented as AU, whereas retinitis developed only after induction of immunosuppression. The latter suggests that immunosuppression allows murine CMV retinal infection through the ciliary body and choroid, which is not possible in immunocompetent mice. In latent or chronic infection, viral deoxyribonucleic acid was detectable in the anterior uvea (iris stroma), even months after infection, suggesting a potential reservoir of latent CMV infection.81 Aqueous cytokine studies in human CMV AU did not reveal any significant difference between CMV PCR positive and negative samples.82

OCULAR SYPHILIS

Syphilis, caused by Treponema pallidum, is known to cause 10 to 12 million new infections each year.83 Several countries from the Asia-Pacific have reported a surge in syphilis cases in recent years. Syphilis notifications tripled in Australia between 2006 and 2016 (from 4.3 to 13.4 per 100,000 population).84 In China, it has become the third leading infectious disease.85 Although uveitis is common in late tertiary syphilis, it is being increasingly recognized in the early (primary and secondary) stages of syphilis.86 Ocular syphilis may precede the diagnosis of systemic disease in up to half of all cases.87 Other than placoid chorioretinitis and punctate inner retinitis, nearly all manifestations of ocular syphilis are nonspecific.88–91 The most significant challenge for clinicians lies in distinguishing these nonspecific manifestations from other etiologies, majority of which would have a higher prevalence than syphilis. The other unanswered questions are the relationship between ocular and neurosyphilis, the role of lumbar puncture in ocular syphilis, the ideal antibiotic treatment, the role of corticosteroids (if any), and the distinction between relapse (recrudescence) and reinfection in patients with recurrent disease.

As in other forms of posterior uveitis, ocular imaging has provided crucial insights into the disease process.92 For example, spectral domain OCT in placoid chorioretinitis has revealed outer retinal abnormalities such as disruption of the inner segment/outer segment band, nodular thickening of the RPE, and full-thickness involvement of miliary lesions (Fig. 4).93 The relationship between ocular and neurosyphilis has been described in a Japanese study of 20 HIV-infected patients with ocular syphilis who were investigated with lumbar puncture.94 In this study, 53% of patients had cerebrospinal fluid abnormalities. It has been suggested that HIV-positive patients with ocular syphilis are more likely to have neurosyphilis,95 and serial cerebrospinal fluid examinations (every 6 months) in patients with abnormal cerebrospinal fluid initially can help in determining the need for additional therapy. Unfortunately, nearly all published data on ocular syphilis comprises case reports and small case series, which preclude meaningful conclusions from these studies.

FIGURE 4
FIGURE 4:
Pattern recognition in ocular syphilis. A, Fundus photograph of the right eye showing the characteristic outer retinal placoid chorioretinitis lesion (yellow arrow). B, Optical coherence tomography (OCT) line scan through the lesion shows areas of irregularity or loss of ellipsoid zone (yellow arrow), neurosensory detachment with hyperreflective dots and areas of thinned and thickened retinal pigment epithelium. C, Fundus photograph showing miliary retinal lesions in syphilis. D, OCT vertical line scan through the miliary lesions reveals hyperreflectivity through the full thickness of the retina (yellow arrows).

MISCELLANEOUS INFECTIONS

This section includes several emerging infectious uveitis, most of which are endemic in one or other region of the Asia-Pacific. All of these infections are associated with some forms of febrile illness before the onset of ocular symptoms, and are therefore also included under an umbrella term, “post-fever retinitis.”96 Majority of these infections are viral, typically arboviral, although they may also be bacterial. The most significant bacterial infection is rickettsiosis, caused by intracellular gram-negative bacteria of family Rickettsiaceae.97 It is the second most common nonmalarial febrile illness in southeast Asia, after dengue. Rickettsia conorii (Indian tick typhus, Mediterranean spotted fever) has been reported to cause multifocal posterior pole retinitis, retinal vasculitis, and disc and macular edema.98 OCT angiography imaging of these lesions reveals capillary nonperfusion in the superficial and deep capillary plexus, and pruning of vessels temporal to the disc.99 It is unclear yet if such capillary occlusion is the primary mechanism or a secondary effect of the retinal inflammation.

Among the arboviral infections, the most relevant ones for the Asia-Pacific are chikungunya, dengue, and West Nile fever. Although chikungunya was first reported in Asia in 2005, it has been rampant since then, with major outbreaks reported from the Indian subcontinent nearly every year.100 The ocular manifestations of chikungunya infection were also described from India.101 They are varied and include nearly ocular tissue ranging from conjunctivitis and AU (most common) to retinitis, choroiditis, and optic neuritis. Confocal microscopy shows dendritic KPs. In dengue fever, ocular manifestations are seen in about 8% of patients, and are characterized by retinitis, macular edema, retinal hemorrhages, periphlebitis, and yellow subretinal spots at the fovea (Fig. 5).96,102 Acute macular neuroretinopathy, with superficial and deep capillary plexus ischemia on OCT angiography, has also been described in dengue fever.103 A possible role of immune complex-mediated occlusive vasculopathy has been suggested by a transient decrease in serum C4 levels in dengue maculopathy patients.102 Finally, West Nile virus causes discrete, white, retinitis lesions, with or without capillary nonperfusion, the latter leading to poor visual prognosis.104 Molecular diagnosis with reverse transcriptase–PCR or reverse transcriptase loop-mediated isothermal amplification assays of serum/plasma samples has been reported from South India.105

FIGURE 5
FIGURE 5:
Dengue retinitis: multiple retinitis lesions in the left eye of a 40-year-old male patient with history of fever and skin rashes, positive dengue IgM, and a platelet count of <22,000 (figure courtesy: Dr Padmamalini Mahendradas, Narayana Netralaya, Bengaluru, India).

The treatment of these conditions is limited by the lack of knowledge about the presence of viable virus in ocular tissues during active inflammation. Local and systemic corticosteroids and anti-VEGF agents have been used for controlling inflammation. Several exciting studies have been initiated to understand how such viruses reach, replicate, and persist in the eye.106 One focus has been the potential role of the RPE in the long-term persistence of these viruses. For example, human RPE cells (ARPE-1) infected with Ebola virus showed a robust type-1 interferon transcriptional response that could contribute to the persistence of the live virus within the eye.107

INFECTIOUS UVEITIS PECULIAR TO ASIA-PACIFIC COUNTRIES

The most unique among these entities is seasonal hyperacute panuveitis. This condition is restricted almost entirely to Nepal and is characterized by 2-year cycles, typically starting at end of the monsoon.108 It is unilateral, of rapid onset, and presents with hypopyon uveitis with dense fibrin in pupillary area (white pupil in red eye).109 The condition has long been linked to exposure to moths, although it could not be replicated in animal models. Another fascinating entity is the trematode-induced granulomatous AU. It was first reported in young boys from South India who had a history of swimming in a village pond.110 Molecular studies have now identified the trematode as Procerovum varium.111 Another zoonotic disease causing uveitis is leptospirosis. Major outbreaks of leptospirosis have been reported from several Asian countries. The uveitis is typically anterior, nongranulomatous (with hypopyon in 12% cases), and is often temporally separated from the systemic infection.112 The gold standard for diagnosis is the microagglutination test. Systemic antibiotics during the septicemic phase do not offer any protection against uveitis, which is typically managed with local or systemic corticosteroid therapy. Finally, we include leprosy that has the highest rate of ocular complications among all systemic bacterial infections.113 It is still prevalent in pockets of Asia and Africa. The ocular manifestations are typically seen in lepromatous leprosy patients with either ongoing or completed multidrug therapy. These include chronic granulomatous iridocyclitis, diffuse iris atrophy, iris pearls, miotic pupils, and complicated cataract, apart from adnexal and ocular surface manifestations. A recent histopathological study has highlighted the predilection for anterior segment inflammation in these eyes.114

INFECTIOUS SCLERITIS

Infectious scleritis comprises approximately 5% to 18% of all scleritis.115 The prevalence of infectious etiology seems to correlate with the geographical location and livelihood patterns of the population.116 The initial presentation of some of the infectious scleritis is often similar to autoimmune scleritis, and differentiation between the two remains a major challenge.117 Microbiological diagnosis is often elusive as the organisms lie deep within the scleral layers and repeated biopsy is sometimes required for its identification. Fungal scleritis is notorious for eluding microbiological diagnosis (Fig. 6)118 and delayed diagnosis in these cases is associated with poor outcomes. In the absence of a microbiological diagnosis, many patients are treated with corticosteroids alone, further complicating the management. Even after identification of the infection, treatment remains challenging due to poor drug penetration, lack of microbicidal activity, or drug resistance.116

FIGURE 6
FIGURE 6:
Fungal scleritis: a 65-year-old woman with 4-month history of redness and pain after injury with wood, presented with (A) a scleral nodule with surrounding scleral thinning. Dematiaceous fungi were detected after 2 scleral biopsies. (B) Initial worsening noted after antifungal therapy. (C) Final outcome after 3 months with continued oral and topical antifungal therapy.

Among recent advances in this field, the differentiating features of infectious scleritis are now better understood. These include nodular or necrotizing nodular lesion(s), purulent exudates, conjunctival ulceration and slough, visible pus points or scleral abscesses, and presence of hypopyon or KPs.116,117 Histopathological evaluation of scleral biopsy is critical to identify deep-seated infection. Herpes zoster scleritis shows zones of granulomatous inflammation around central necrosis,119 whereas tubercular scleritis shows caseating granulomas and multinucleated giant cells with or without acid-fast bacilli.120 Special stains such as periodic acid–Schiff for fungi and acid-fast stain for atypical mycobacteria and Nocardia may be required.121 Molecular diagnosis with PCR is being increasingly applied for rare infections.120,122 Finally, noninvasive techniques such as anterior segment OCT and ultrasound biomicroscopy have been used to grade the severity of inflammation and monitor response to therapy.123,124

CONCLUSIONS

Our understanding of infectious uveitis has evolved significantly in the past 5 years with major contributions from the Asia-Pacific. The diagnosis, management, and pathomechanisms of common infectious uveitides are now better understood, whereas several new infections have been recognized as causes of intraocular infection. Multicentric studies, newer imaging modalities, and better availability of laboratory investigations should facilitate further development of the field.

REFERENCES

1. de Smet MD, Taylor SR, Bodaghi B, et al. Understanding uveitis: the impact of research on visual outcomes. Prog Retin Eye Res 2011; 30:452–470.
2. United Nations ESCAP [Internet]. 2020 [cited December 17, 2020]. Available from: https://www.unescap.org/sites/default/files/SPPS-Factsheet-Population-Trends-v3.pdf. Accessed September 21, 2020.
3. London NJ, Rathinam SR, Cunningham ET Jr. The epidemiology of uveitis in developing countries. Int Ophthalmol Clin 2010; 50:1–17.
4. Forrester JV, Kuffova L, Dick AD. Autoimmunity, autoinflammation, and infection in uveitis. Am J Ophthalmol 2018; 189:77–85.
5. Rathinam SR, Cunningham ET Jr. Infectious causes of uveitis in the developing world. Int Ophthalmol Clin 2000; 40:137–152.
6. Kijlstra A, Petersen E. Epidemiology, pathophysiology, and the future of ocular toxoplasmosis. Ocul Immunol Inflamm 2014; 22:138–147.
7. Wilder HC. Toxoplasma chorioretinitis in adults: a preliminary study of forty-one cases diagnosed by microscopic examination [letter]. Arch Ophthalmol 1952; 47:425.
8. Smith JR, Ashander LM, Arruda SL, et al. Pathogenesis of ocular toxoplasmosis. Prog Retin Eye Res 2020; 100882doi:10.1016/j.preteyeres.2020.100882.
9. Casoy J, Nascimento H, Silva LMP, et al. Effectiveness of treatments for ocular toxoplasmosis. Ocul Immunol Inflamm 2020; 28:249–255.
10. Pradhan E, Bhandari S, Gilbert RE, Stanford M. Antibiotics versus no treatment for toxoplasma retinochoroiditis. Cochrane Database Syst Rev 2016; 2016:CD002218.
11. Huang PK, Jianping C, Vasconcelos-Santos DV, et al. Ocular toxoplasmosis in tropical areas: analysis and outcome of 190 patients from a multicenter collaborative study. Ocul Immunol Inflamm 2018; 26:1289–1296.
12. Yates WB, Chiong F, Zagora S, Post JJ, Wakefield D, McCluskey P. Ocular toxoplasmosis in a tertiary referral center in Sydney, Australia—clinical features, treatment, and prognosis. Asia Pac J Ophthalmol 2019; 8:280–284.
13. Brandão-de-Resende C, Balasundaram MB, Narain S, Mahendradas P, Vasconcelos-Santos DV. Multimodal imaging in ocular toxoplasmosis. Ocul Immunol Inflamm 2020; 28:1196–1204.
14. Park SW, Kim SH, Kwon HJ, Lee SM, Byon IS, Lee JE. Diagnostic value of positive findings of Toxoplasma gondii–specific immunoglobulin M serum antibody in uveitis patients to confirm ocular toxoplasmosis. Ocul Immunol Inflamm 2019; 27:583–590.
15. Rahimi Esboei B, Kazemi B, Zarei M, et al. Evaluation of RE and B1 genes as targets for detection of Toxoplasma gondii by nested PCR in blood samples of patients with ocular toxoplasmosis. Acta Parasitol 2019; 64:384–389.
16. Farhadi A, Haniloo A, Fazaeli A, Moradian S, Farhadi M. PCR-based diagnosis of toxoplasma parasite in ocular infections having clinical indications of toxoplasmosis. Iran J Parasitol 2017; 12:56–62.
17. Soheilian M, Ramezani A, Azimzadeh A, et al. Randomized trial of intravitreal clindamycin and dexamethasone versus pyrimethamine, sulfadiazine, and prednisolone in treatment of ocular toxoplasmosis. Ophthalmology 2011; 118:134–141.
18. Choudhury H, Jindal A, Pathengay A, Bawdekar A, Albini T, Flynn HW Jr. The role of intravitreal trimethoprim/sulfamethoxazole in the treatment of toxoplasma retinochoroiditis. Ophthalmic Surg Lasers Imaging Retina 2015; 46:137–140.
19. Fernandes Felix JP, Cavalcanti Lira RP, Cosimo AB, Cardeal da Costa RL, Nascimento MA, Leite Arieta CE. Trimethoprim-sulfamethoxazole versus placebo in reducing the risk of toxoplasmic retinochoroiditis recurrences: a three-year follow-up. Am J Ophthalmol 2016; 170:176–182.
20. Furtado JM, Bharadwaj AS, Ashander LM, Olivas A, Smith JR. Migration of Toxoplasma gondii–infected dendritic cells across human retinal vascular endothelium. Invest Ophthalmol Vis Sci 2012; 53:6856–6862.
21. Lie S, Vieira BR, Arruda S, et al. Molecular basis of the retinal pigment epithelial changes that characterize the ocular lesion in toxoplasmosis. Microorganisms 2019; 7:405.
22. Lie S, Rochet E, Segerdell E, Ma Y, et al. Immunological molecular responses of human retinal pigment epithelial cells to infection with Toxoplasma gondii. Front Immunol 2019; 10:708.
23. Wu J, Dalal K. Tuberculosis in Asia and the Pacific: the role of socio-economic status and health system development. Int J Prev Med 2012; 3:8–16.
24. Gupta V, Gupta A, Arora S, Bambery P, Dogra MR, Agarwal A. Presumed tubercular serpiginous-like choroiditis: clinical presentations and management. Ophthalmology 2003; 110:1744–1749.
25. Gupta A, Bansal R, Gupta V, Sharma A, Bambery P. Ocular signs predictive of tubercular uveitis. Am J Ophthalmol 2010; 149:562–570.
26. Vasconcelos-Santos DV, Rao PK, Davies JB, Sohn EH, Rao NA. Clinical features of tuberculous serpiginous-like choroiditis in contrast to classic serpiginous choroiditis. Arch Ophthalmol 2010; 128:853–858.
27. Kaza H, Tyagi M, Pathengay A, Basu S. Clinical predictors of tubercular retinal vasculitis in a high-endemic country [published online ahead of print May 5, 2020]. Retina 2020; doi:10.1097/IAE.0000000000002829.
28. Agarwal A, Mahajan S, Khairallah M, Mahendradas P, Gupta A, Gupta V. Multimodal imaging in ocular tuberculosis. Ocul Immunol Inflamm 2017; 25:134–145.
29. Bansal R, Basu S, Gupta A, Rao N, Invernizzi A, Kramer M. Imaging in tuberculosis-associated uveitis. Indian J Ophthalmol 2017; 65:264–270.
30. Sharma K, Gupta V, Bansal R, Sharma A, Sharma M, Gupta A. Novel multitargeted polymerase chain reaction for diagnosis of presumed tubercular uveitis. J Ophthalmic Inflamm Infect 2013; 3:25.
31. Balne PK, Modi RR, Choudhury N, et al. Factors influencing polymerase chain reaction outcomes in patients with clinically suspected ocular tuberculosis. J Ophthalmic Inflamm Infect 2014; 4:10.
32. Balne PK, Barik MR, Sharma S, Basu S. Development of a loop-mediated isothermal amplification assay targeting the mpb64 gene for diagnosis of intraocular tuberculosis. J Clin Microbiol 2013; 51:3839–3840.
33. Sudheer B, Lalitha P, Kumar AL, Rathinam S. Polymerase chain reaction and its correlation with clinical features and treatment response in tubercular uveitis. Ocul Immunol Inflamm 2018; 26:845–852.
34. Bansal R, Gupta A, Gupta V, Dogra MR, Bambery P, Arora SK. Role of antitubercular therapy in uveitis with latent/manifest tuberculosis. Am J Ophthalmol 2008; 146:772–779.
35. Kee AR, Gonzalez-Lopez JJ, Al-Hity A, et al. Antitubercular therapy for intraocular tuberculosis: a systematic review and meta-analysis. Surv Ophthalmol 2016; 61:628–653.
36. Agrawal R, Gupta B, Gonzalez-Lopez JJ, et al. The role of antitubercular therapy in patients with presumed ocular tuberculosis. Ocul Immunol Inflamm 2015; 23:40–46.
37. Wroblewski KJ, Hidayat AA, Neafie RC, Rao NA, Zapor M. Ocular tuberculosis: a clinicopathologic and molecular study. Ophthalmology 2011; 118:772–777.
38. Basu S, Mittal R, Balne PK, Sharma S. Intraretinal tuberculosis. Ophthalmology 2012; 119:2192–2193.
39. Kawali A, Emerson GG, Naik NK, Sharma K, Mahendradas P, Rao NA. Clinicopathologic features of tuberculous serpiginous-like choroiditis. JAMA Ophthalmol 2018; 136:219–221.
40. Rao NA, Saraswathy S, Smith RE. Tuberculous uveitis: distribution of Mycobacterium tuberculosis in the retinal pigment epithelium. Arch Ophthalmol 2006; 124:1777–1779.
41. Nazari H, Karakousis PC, Rao NA. Replication of Mycobacterium tuberculosis in retinal pigment epithelium. JAMA Ophthalmol 2014; 132:724–729.
42. La Distia Nora R, Walburg KV, van Hagen PM, et al. Retinal pigment epithelial cells control early Mycobacterium tuberculosis infection via interferon signaling. Invest Ophthalmol Vis Sci 2018; 59:1384–1395.
43. Rao NA, Albini TA, Kumaradas M, Pinn ML, Fraig MM, Karakousis PC. Experimental ocular tuberculosis in guinea pigs. Arch Ophthalmol 2009; 127:1162–1166.
44. Takaki K, Ramakrishnan L, Basu S. A zebrafish model for ocular tuberculosis. PLoS One 2018; 13:e0194982.
45. Tagirasa R, Parmar S, Barik MR, Devadas S, Basu S. Autoreactive T cells in immunopathogenesis of TB-associated uveitis. Invest Ophthalmol Vis Sci 2017; 58:5682–5691.
46. Agrawal R, Gunasekeran DV, et al. Collaborative Ocular Tuberculosis Study (COTS)–1 Study Group. Clinical features and outcomes of patients with tubercular uveitis treated with antitubercular therapy in the Collaborative Ocular Tuberculosis Study (COTS)–1. JAMA Ophthalmol 2017; 135:1318–1327.
47. Testi I, Agrawal R, Mahajan S, et al. Tubercular uveitis: nuggets from Collaborative Ocular Tuberculosis Study (COTS)–1. Ocul Immunol Inflamm 2019; 1–9. doi:10.1080/09273948.2019.1646774.
48. Agrawal R, Gunasekeran DV, et al. The Collaborative Ocular Tuberculosis Study (COTS)–1: a multinational description of the spectrum of choroidal involvement in 245 patients with tubercular uveitis. Ocul Immunol Inflamm 2018; 1–11. doi:10.1080/09273948.2018.1489061.
49. Gunasekeran DV, Agrawal R, et al. COTS-1 Study Group. The Collaborative Ocular Tuberculosis Study (COTS)–1: a multinational review of 251 patients with tubercular retinal vasculitis. Retina 2019; 39:1623–1630.
50. Agrawal R, Betzler B, Testi I, et al. The Collaborative Ocular Tuberculosis Study (COTS)–1: a multinational review of 165 patients with tubercular anterior uveitis. Ocul Immunol Inflamm 2020; 1–10. doi:10.1080/09273948.2020.1761400.
51. Agrawal R, Agarwal A, Jabs DA, et al. Standardization of nomenclature for ocular tuberculosis—results of Collaborative Ocular Tuberculosis Study (COTS) workshop. Ocul Immunol Inflamm 2019; 1–11. doi:10.1080/09273948.2019.1653933.
52. Agarwal A, Agrawal R, Raje D, et al. Twenty-four month outcomes in the Collaborative Ocular Tuberculosis Study (COTS)–1: defining the “cure” in ocular tuberculosis. Ocul Immunol Inflamm 2020; 1–9. doi:10.1080/09273948.2020.1761401.
53. Agrawal R, Testi I, Mahajan S, et al. Collaborative Ocular Tuberculosis Study consensus guidelines on the management of tubercular uveitis—report 1: guidelines for initiating antitubercular therapy in tubercular choroiditis. Ophthalmology 2020; doi:10.1016/j.ophtha.2020.01.008.
54. Agrawal R, Testi I, Bodaghi B, et al. 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. Ophthalmology 2020; doi:10.1016/j.ophtha.2020.06.052.
55. Basu S, La Distia Nora R, Rao NA, Jiang X, Fuady A. International Ocular TB Study Group. Prognostic factors for TB-associated uveitis in the Asia-Pacific region: results of a modified Delphi survey. Eye 2020; 34:1693–1701.
56. Mandadi SKR, Agarwal A, Aggarwal K, et al. Novel findings on optical coherence tomography angiography in patients with tubercular serpiginous-like choroiditis. Retina 2017; 37:1647–1659.
57. Agarwal A, Aggarwal K, Mandadi SKR, et al. Longitudinal follow-up of tubercular serpiginous-like choroiditis using optical coherence tomography angiography [published online ahead of print August 18, 2020]. Retina 2020; doi:10.1097/IAE.0000000000002915.
58. Barik MR, Rath S, Modi R, Rana R, Reddy MM, Basu S. Normalized quantitative polymerase chain reaction for diagnosis of tuberculosis-associated uveitis. Tuberculosis 2018; 110:30–35.
59. Jain L, Panda KG, Basu S. Clinical outcomes of adjunctive sustained-release intravitreal dexamethasone implants in tuberculosis-associated multifocal serpigenoid choroiditis. Ocul Immunol Inflamm 2018; 26:877–883.
60. Babu K, Murthy PR, Murthy KR. Intravitreal bevacizumab as an adjunct in a patient with presumed vascularized choroidal tubercular granuloma. Eye 2010; 24:397–399.
61. Kaza H, Modi R, Rana R, et al. Effect of adjunctive pars plana vitrectomy on focal posterior segment inflammation: a case-control study in tuberculosis-associated uveitis. Ophthalmol Retina 2018; 2:1163–1169.
62. Basu S, Elkington P, Rao NA. Pathogenesis of ocular tuberculosis: new observations and future directions. Tuberculosis. 2020;124:101961.
63. Basu S, Rao N, Elkington P. Animal models of ocular tuberculosis: implications for diagnosis and treatment. Ocul Immunol Inflamm 2020; 1–7. doi:10.1080/09273948.2020.1746358.
64. La Distia Nora R, Sitompul R, Bakker M, et al. Type 1 interferon-inducible gene expression in QuantiFERON Gold TB-positive uveitis: a tool to stratify a high versus low risk of active tuberculosis? PLoS One 2018; 13:e0206073.
65. Wu XN, Lightman S, Tomkins-Netzer O. Viral retinitis: diagnosis and management in the era of biologic immunosuppression: a review. Clin Exp Ophthalmol 2019; 47:381–395.
66. De Groot-Mijnes JDF, Chan ASY, Chee SP, Verjans GMGM. Immunopathology of virus-induced anterior uveitis. Ocul Immunol Inflamm 2018; 26:338–346.
67. Chan NS, Chee SP. Demystifying viral anterior uveitis: a review. Clin Exp Ophthalmol 2019; 47:320–333.
68. Groen-Hakan F, Babu K, Tugal-Tutkun I, et al. Challenges of diagnosing viral anterior uveitis. Ocul Immunol Inflamm 2017; 25:710–720.
69. Chee SP, Jap A. Presumed Fuchs heterochromic iridocyclitis and Posner-Schlossman syndrome: comparison of cytomegalovirus-positive and negative eyes. Am J Ophthalmol 2008; 146:883–889.
70. Kongyai N, Sirirungsi W, Pathanapitoon K, et al. Viral causes of unexplained anterior uveitis in Thailand. Eye 2012; 26:529–534.
71. Babu K, Kini R, Philips M, Subbakrishna DK. Clinical profile of isolated viral anterior uveitis in a South Indian patient population. Ocul Immunol Inflamm 2014; 22:356–359.
72. Chee SP, Bacsal K, Jap A, Se-Thoe SY, Cheng CL, Tan BH. Clinical features of cytomegalovirus anterior uveitis in immunocompetent patients. Am J Ophthalmol 2008; 145:834–840.
73. Takhar JS, Joye AS, Somkijrungroj T, et al. A double-masked randomized 4-week, placebo-controlled study in the US, Thailand, and Taiwan to compare the efficacy of oral valganciclovir and topical 2% ganciclovir in the treatment of cytomegalovirus anterior uveitis: study protocol. BMJ Open 2019; 9:e033175.
74. Urayama A. Unilateral acute uveitis with retinal periarteritis and detachment. Jpn J Clin Ophthalmol 1971; 25:607–619.
75. Butler NJ, Moradi A, Salek SS, et al. Acute retinal necrosis: presenting characteristics and clinical outcomes in a cohort of polymerase chain reaction–positive patients. Am J Ophthalmol 2017; 179:179–189.
76. Invernizzi A, Agarwal AK, Ravera V, et al. Comparing optical coherence tomography findings in different aetiologies of infectious necrotizing retinitis. Br J Ophthalmol 2018; 102:433–437.
77. Sood AB, Kumar G, Robinson J. Bilateral acute retinal necrosis in a patient with multiple sclerosis on natalizumab. J Ophthalmic Inflamm Infect 2016; 6:26.
78. Takase H, Kubono R, Terada Y, et al. Comparison of the ocular characteristics of anterior uveitis caused by herpes simplex virus, varicella-zoster virus, and cytomegalovirus. Jpn J Ophthalmol 2014; 58:473–482.
79. Hayashi K, Kurihara I, Uchida Y. Studies of ocular murine cytomegalovirus infection. Invest Ophthalmol Vis Sci 1985; 26:486–493.
80. Bale JF Jr, O’Neil ME, Folberg R. Murine cytomegalovirus ocular infection in immunocompetent and cyclophosphamide-treated mice. Potentiation of ocular infection by cyclophosphamide. Invest Ophthalmol Vis Sci 1991; 32:1749–1756.
81. Chan AS, Mehta JS, Al Jajeh I, Iqbal J, Anshu A, Tan DT. Histological features of cytomegalovirus-related corneal graft infections, its associated features and clinical significance. Br J Ophthalmol 2016; 100:601–606.
82. Li J, Ang M, Cheung CM, et al. Aqueous cytokine changes associated with Posner-Schlossman syndrome with and without human cytomegalovirus. PLoS One 2012; 7:e44453.
83. Centers for Disease Control and Prevention. Sexually transmitted disease surveillance 2018. National profile—overview. Available from: https://www.cdc.gov/std/stats18. Accessed September 21, 2020.
84. Australian National Notifiable Diseases Surveillance. Number of notifications of syphilis <2 years. Available from: http://www9.health.gov.au/cda/source/rpt_2.cfm.
85. Chen XS, Yin YP, Wang QQ, Wang BX. Historical perspective of syphilis in the past 60 years in China: eliminated, forgotten, on the return. Chin Med J 2013; 126:2774–2779.
86. Marra CM. Update on neurosyphilis. Curr Infect Dis Rep 2009; 11:127–134.
87. Tsuboi M, Nishijima T, Yashiro S, et al. Time to development of ocular syphilis after syphilis infection. J Infect Chemother 2018; 24:75–77.
88. Tuddenham S, Ghanem KG. Ocular syphilis: opportunities to address important unanswered questions. Sex Transm Infect 2016; 92:563–565.
89. Moradi A, Salek S, Daniel E, et al. Clinical features and incidence rates of ocular complications in patients with ocular syphilis. Am J Ophthalmol 2015; 159:334–343.
90. Amaratunge BC, Camuglia JE, Hall AJ. Syphilitic uveitis: a review of clinical manifestations and treatment outcomes of syphilitic uveitis in human immunodeficiency virus-positive and negative patients. Clin Exp Ophthalmol 2010; 38:68–74.
91. Tyagi M, Kaza H, Pathengay A, et al. Clinical manifestations and outcomes of ocular syphilis in Asian Indian population: Analysis of cases presenting to a tertiary referral center. Indian J Ophthalmol 2020; 68:1881–1886.
92. Pichi F, Neri P. Multimodal imaging patterns of posterior syphilitic uveitis: a review of the literature, laboratory evaluation, and treatment. Int Ophthalmol 2020; 40:1319–1329.
93. Pathengay A, Kaza H, Tyagi M, Patel A, Pappuru RR, Agrawal H. Miliary retinal lesions in ocular syphilis: imaging characteristics and outcomes. Ocul Immunol Inflamm 2019; 1–5. doi:10.1080/09273948.2019.1659830.
94. Tsuboi M, Nishijima T, Yashiro S, et al. Prognosis of ocular syphilis in patients infected with HIV in the antiretroviral therapy era. Sex Transm Infect 2016; 92:605–610.
95. Lee SY, Cheng V, Rodger D, Rao N. Clinical and laboratory characteristics of ocular syphilis: a new face in the era of HIV coinfection. J Ophthalmic Inflamm Infect 2015; 5:56.
96. Mahendradas P, Kawali A, Luthra S, et al. Post-fever retinitis—newer concepts. Indian J Ophthalmol 2020; 68:1775–1786.
97. Kawali A, Mahendradas P, Srinivasan P, et al. Rickettsial retinitis—an Indian perspective. J Ophthalmic Inflamm Infect 2015; 5:37.
98. Balasundaram MB, Manjunath M, Baliga G, Kapadi F. Ocular manifestations of Rickettsia conorii in South India. Indian J Ophthalmol 2018; 66:1840–1844.
99. Shanmugam M, Konana VK, Ramanjulu R, Divyansh Mishra KC, Sagar P, Kumar D. Optical coherence tomography angiography features of retinitis post–rickettsial fever. Indian J Ophthalmol 2019; 67:297–300.
100. Weaver SC, Lecuit M. Chikungunya virus and the global spread of a mosquito-borne disease. N Engl J Med 2015; 372:1231–1239.
101. Mahendradas P, Ranganna SK, Shetty R, et al. Ocular manifestations associated with chikungunya. Ophthalmology 2008; 115:287–291.
102. Su DH, Bacsal K, Chee SP, et al. Dengue Maculopathy Study Group. Prevalence of dengue maculopathy in patients hospitalized for dengue fever. Ophthalmology 2007; 114:1743–1747.
103. Li M, Zhang X, Ji Y, Ye B, Wen F. Acute macular neuroretinopathy in dengue fever: short-term prospectively followed-up case series. JAMA Ophthalmol 2015; 133:1329–1333.
104. Khairallah M, Ben Yahia S, Ladjimi A, et al. Chorioretinal involvement in patients with West Nile virus infection. Ophthalmology 2004; 111:2065–2070.
105. Sivakumar RR, Prajna L, Arya LK, et al. Molecular diagnosis and ocular imaging of West Nile virus retinitis and neuroretinitis. Ophthalmology 2013; 120:1820–1826.
106. Hartley C, Bavinger JC, Kuthyar S, Shantha JG, Yeh S. Pathogenesis of uveitis in Ebola virus disease survivors: evolving understanding from outbreaks to animal models. Microorganisms 2020; 8:594.
107. Smith JR, Todd S, Ashander LM, et al. Retinal pigment epithelial cells are a potential reservoir for Ebola virus in the human eye. Transl Vis Sci Technol 2017; 6:12.
108. Upadhyay MP, Rai NC, Ogg JE, Shrestha BR. Seasonal hyperacute panuveitis of unknown etiology. Ann Ophthalmol 1984; 16:38–44.
109. Upadhyay M, Kharel Sitaula R, Shrestha B, et al. Seasonal hyperacute panuveitis in Nepal: a review over 40 years of surveillance. Ocul Immunol Inflamm 2019; 27:709–717.
110. Rathinam SR, Usha KR, Rao NA. Presumed trematode-induced granulomatous anterior uveitis: a newly recognized cause of intraocular inflammation in children from South India. Am J Ophthalmol 2002; 133:773–779.
111. Rathinam SR, Arya LK, Usha KR, Prajna L, Tandon V. Novel etiological agent: molecular evidence for trematode-induced anterior uveitis in children. Arch Ophthalmol 2012; 130:1481–1484.
112. Rathinam SR. Ocular leptospirosis. Curr Opin Ophthalmol 2002; 13:381–386.
113. Ffytche TJ. The continuing challenge of ocular leprosy. Br J Ophthalmol 1991; 75:123–124.
114. Wroblewski KJ, Hidayat A, Neafie R, Meyers W. The AFIP history of ocular leprosy. Saudi J Ophthalmol 2019; 33:255–259.
115. Lane J, Nyugen E, Morrison J, et al. Clinical features of scleritis across the Asia-Pacific region. Ocul Immunol Inflamm 2019; 27:920–926.
116. Murthy SI, Sabhapandit S, Balamurugan S, et al. Scleritis: differentiating infectious from noninfectious entities. Indian J Ophthalmol 2020; 68:1818–1828.
117. Murthy SI, Sati A, Sangwan V. Infectious scleritis mimicking severe ocular inflammation: atypical initial presentation. BMJ Case Rep 2013; 2013:bcr2013008686.
118. Reddy JC, Murthy SI, Reddy AK, Garg P. Risk factors and clinical outcomes of bacterial and fungal scleritis at a tertiary eye care hospital. Middle East Afr J Ophthalmol 2015; 22:203–211.
119. Bhat PV, Jakobiec FA, Kurbanyan K, Zhao T, Foster CS. Chronic herpes simplex scleritis: characterization of 9 cases of an underrecognized clinical entity. Am J Ophthalmol 2009; 148:779–789.
120. Kesen MR, Edward DP, Rao NA, Sugar J, Tessler HH, Goldstein DA. Atypical infectious nodular scleritis. Arch Ophthalmol 2009; 127:1079–1080.
121. Sahu SK, Sharma S, Das S. Nocardia scleritis—clinical presentation and management: a report of 3 cases and review of literature. J Ophthalmic Inflamm Infect 2012; 2:7–11.
122. Loureiro M, Rothwell R, Fonseca S. Nodular scleritis associated with herpes zoster virus: an infectious and immune-mediated process. Case Rep Ophthalmol Med 2016; 2016:8519394.
123. Shoughy SS, Jaroudi MO, Kozak I, Tabbara KF. Optical coherence tomography in the diagnosis of scleritis and episcleritis. Am J Ophthalmol 2015; 159:1045–1049.
124. Hau SC, Devarajan K, Ang M. Anterior segment optical coherence tomography angiography and optical coherence tomography in the evaluation of episcleritis and scleritis. Ocul Immunol Inflamm 2019; 1–8. doi 10.1080/09273948.2019.1682617.
Keywords:

Asia-Pacific; diagnosis; infectious uveitis; pathogenesis; recent advances; treatment

Copyright © 2021 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.