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.
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.
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
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.
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.
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.
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
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.
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.
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
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
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
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.
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
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 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
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
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.
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