Herpes simplex virus 1 (HSV-1) and HSV-2 establish latency in different neuronal subtypes (A5+ and KH10+) in murine trigeminal ganglia, results which correlate with restricted productive infection in these neurons in vitro. HSV-2 latency-associated transcript (LAT) contains a cis-acting regulatory element near the transcription start site that promotes productive infection in A5+ neurons and a second element in exon 1 that inhibits productive infection in KH10+ neurons. HSV-1 contains no such regulatory sequences, demonstrating different mechanisms for regulating productive HSV infection in neurons.

To describe a case series of patients with unilateral, posterior interstitial keratitis presumed to be caused by herpes simplex virus.Retrospective case series.Five patients were found to have unilateral, posterior interstitial keratitis. Three of the involved eyes had decreased corneal sensation, and 2 eyes had corneal stromal neovascularization. All patients were treated with topical steroids and an oral antiviral, and among those with long-term follow-up, clinical improvement required treatment over an extended duration. A review of the literature revealed 1 reported case with a similar clinical appearance, although that case was attributed to Lyme disease.The clinical presentation of unilateral, posterior interstitial keratitis may be a rare manifestation of herpes simplex virus keratitis.

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In order to understand factors that may influence latency-associated transcription and latency-associated transcript (LAT) phenotypes, we studied the expression of the herpes simplex virus 2 (HSV-2) LAT-associated microRNAs (miRNAs). We mapped the transcription initiation sites of all three primary miRNA transcripts and identified the ICP4-binding sequences at the transcription initiation sites of both HSV-2 LAT (pri-miRNA for miR-I and miR-II, which target ICP34.5, and miR-III, which targets ICP0) and L/ST (a pri-miRNA for miR-I and miR-II) but not at that of the primary miR-H6 (for which the target is unknown). We confirmed activity of the putative HSV-2 L/ST promoter and found that ICP4 trans-activates the L/ST promoter when the ICP4-binding site at its transcription initiation site is mutated, suggesting that ICP4 may play a dual role in regulating transcription of L/ST and, consequently, of miR-I and miR-II. LAT exon 1 (containing LAT enhancer sequences), together with the LAT promoter region, comprises a bidirectional promoter required for the expression of both LAT-encoded miRNAs and miR-H6 in latently infected mouse ganglia. The ability of ICP4 to suppress ICP34.5-targeting miRNAs and to activate lytic viral genes suggests that ICP4 could play a key role in the switch between latency and reactivation.

Importance

The HSV-2 LAT and viral miRNAs expressed in the LAT region are the most abundant viral transcripts during HSV latency. The balance between the expression of LAT and LAT-associated miRNAs and the expression of lytic viral transcripts from the opposite strand appears to influence whether individual HSV-infected neurons will be latently or productively infected. The outcome of neuronal infection may thus depend on regulation of gene expression of the corresponding primary miRNAs. In the present study, we characterize promoter sequences responsible for miRNA expression, including identification of the primary miRNA 5' ends and evaluation of ICP4 response. These findings provide further insight into the virus' strategy to tightly control expression of lytic cycle genes (especially the neurovirulence factor, ICP34.5) and suggest a mechanism (via ICP4) for the transition from latency to reactivated productive infection.

Purpose

The objective of this study was to determine current practices and opinions among cornea specialists for treating and preventing recurrences of herpes zoster ophthalmicus (HZO).

Methods

In November 2010, a survey of 15 questions was distributed to The Cornea Society listserv. Questions identified respondents' treatment practices for recurrent HZO and opinions regarding prolonged antiviral prophylaxis and zoster vaccine.

Results

Of 100 respondents, the majority were cornea specialists (83 of 98, 85%). Eighty-seven percent (84 of 97) reported treating recurrent or chronic cases of HZO in the last year. The most common choice of treatment in the posed recurrent HZO clinical scenario was a combination of oral antiviral and topical corticosteroid (63 of 100, 63%), although significant variability existed in the duration of oral antiviral administration. Fifty-four respondents (56%) believed that prolonged acyclovir prophylaxis could reduce recurrent signs of HZO; 28% (27 of 98) believed that recurrences of HZO could be reduced after the period of acyclovir administration. For patients with a history of HZO, most respondents reported not recommending the adult zoster vaccine (63 of 98, 64%), but 46% (43 of 94) believed that the vaccine could reduce recurrent signs or did not know.

Conclusions

Many cornea specialists are managing recurrent or chronic cases of HZO, but there is variability in the use of topical corticosteroids and antivirals. Additionally, no consensus exists on the efficacy of prolonged antiviral therapy or the adult zoster vaccine to reduce chronic or recurrent disease. These results demonstrate the need for further systematic study of treatment and prophylaxis for recurrent and chronic HZO.

Purpose

The World Health Organization (WHO) recommends that Southeast Asian countries have ≥ 1 ophthalmologist per 100,000 persons, equally distributed in urban and rural areas. However, regional patterns of eye care have been poorly characterized. This study investigates the distribution of ophthalmologists in Thailand and provides regional estimates of access to ophthalmologists.

Methods

We geocoded the work address of ophthalmologists listed in the 2008 directory of the Royal College of Ophthalmologists of Thailand. We determined the number of ophthalmologists per 100,000 persons at the national, provincial, and district levels using data from the 2000 Thai Population Census, and assessed demographic factors associated with meeting the WHO recommendation of ≥ 1 ophthalmologist per 100,000 persons.

Results

In 2008, Thailand had 1.52 ophthalmologists per 100,000 persons; however, only 20 of 76 provinces (26%) and 134 of 926 districts (14%) met the WHO recommendation of ≥ 1 ophthalmologist per 100,000 persons. District factors associated with not meeting the WHO recommendation included a high proportion of children, a high proportion of elderly, and a high proportion of rural residents.

Conclusion

Thailand meets the WHO's goal for access to ophthalmologic care, but the distribution of ophthalmologists is uneven, with less access to ophthalmologic care in rural areas.

The emergence of clinical metagenomics as an unbiased, hypothesis-free approach to diagnostic testing is set to fundamentally alter the way infectious diseases are detected. Long envisioned as the solution to the limitations of culture-based conventional microbiology, next generation sequencing methods will soon mature, and our attention will inevitably turn to how they can be applied to areas of medicine which need it most urgently. In ophthalmology, the demand for this technology is particularly pressing for the care of infectious corneal ulcers, where current diagnostic tests may fail to identify a causative organism in over half of cases. However, the optimism found in the budding discourse surrounding clinical metagenomics belies the reality that clinicians and scientists will soon be inundated by oppressive volumes of sequencing data, much of which will be foreign and unfamiliar. Therefore, our success in translating clinical metagenomics is likely to hinge on how we make sense of these data, and understanding its implications for the interpretation and implementation of sequencing into routine clinical care. In this consortium-led review, we provide an outline of these data-related issues and how they may be used to inform technical workflows, with the hope that we may edge closer to realizing the potential of clinical metagenomics for this important unmet need.

Aim

To determine if poor access to healthcare is associated with increased cytomegalovirus (CMV) retinitis risk among patients with HIV with CD4 counts of <100 cells/μL screened in a resource-limited setting.

Methods

This is a prospective cross-sectional study. Patients with known HIV and a CD4 count of <100 cells/μL attending an HIV clinic in Chiang Mai, Thailand, completed a standardised questionnaire and underwent dilated fundus examination. Participants without CMV retinitis were invited for repeated examinations every 3 months until their CD4 count exceeded 100 cells/μL. The relationship between various potential risk factors and CMV retinitis was assessed with logistic regression.

Results

103 study participants were enrolled. At enrolment, the mean age was 37.5 (95% CI 35.7 to 39.2) years, 61.2% (95% CI 51.6% to 70.7%) were male and the mean CD4 count was 29.5 (95% CI 25.9 to 33.1) cells/μL. 21 eyes from 16 (15.5%) participants were diagnosed with CMV retinitis. In multivariate analyses, CMV retinitis was significantly associated with lower CD4 count (OR 1.42 per 10-cell decrement, 95%CI 1.05 to 1.93), longer travel time to clinic (OR 3.85 for those with >30-min travel time, 95% CI 1.08 to 13.8) and lower income (OR 1.22 per US$50 less income, 95% CI 1.02 to 1.47).

Conclusions

CD4 count, low income and longer travel time to clinic were significant risk factors for CMV retinitis among patients with HIV in a resource-limited setting. These results suggest that reducing blindness from CMV retinitis should focus on increasing accessibility of screening examinations to poor and hard-to-reach patients.

Purpose

To determine risk factors predictive of retinal detachment in patients with cytomegalovirus (CMV) retinitis in a setting with limited access to ophthalmic care.

Design

Case-control study.

Methods

Sixty-four patients with CMV retinitis and retinal detachment were identified from the Ocular Infectious Diseases and Retina Clinics at Chiang Mai University. Three control patients with CMV retinitis but no retinal detachment were selected for each case, matched by calendar date. The medical records of each patient were reviewed, with patient-level and eye-level features recorded for the clinic visit used to match cases and controls, and also for the initial clinic visit at which CMV retinitis was diagnosed. Risk factors for retinal detachment were assessed separately for each of these time points using multivariate conditional logistic regression models that included 1 eye from each patient.

Results

Patients with a retinal detachment were more likely than controls to have low visual acuity (odds ratio [OR], 1.24 per line of worse vision on the logMAR scale; 95% confidence interval [CI], 1.16-1.33) and bilateral disease (OR, 2.12; 95% CI, 0.92-4.90). Features present at the time of the initial diagnosis of CMV retinitis that predicted subsequent retinal detachment included bilateral disease (OR, 2.68; 95% CI, 1.18-6.08) and lesion size (OR, 2.64 per 10% increase in lesion size; 95% CI, 1.41-4.94).

Conclusion

Bilateral CMV retinitis and larger lesion sizes, each of which is a marker of advanced disease, were associated with subsequent retinal detachment. Earlier detection and treatment may reduce the likelihood that patients with CMV retinitis develop a retinal detachment.

Importance

Cytomegalovirus (CMV) retinitis continues to be a leading cause of blindness in many developing countries. Telemedicine holds the potential to increase the number of people screened for CMV retinitis, but it is unclear whether nonophthalmologists could be responsible for interpreting fundus photographs captured in a telemedicine program.

Objective

To determine the accuracy of nonophthalmologist photographic graders in diagnosing CMV retinitis from digital fundus photographs.

Design, setting, and participants

Fifteen nonexpert graders each evaluated 182 mosaic retinal images taken from the eyes of patients with AIDS who were evaluated at the Ocular Infectious Diseases Clinic at Chiang Mai University in Chiang Mai, Thailand.

Main outcomes and measures

Graders diagnosed each image as CMV retinitis present, CMV retinitis absent, or unknown. The results from each grader were compared with those of an indirect ophthalmoscopic examination from an experienced on-site ophthalmologist as well as with the consensus grade given by a panel of CMV retinitis experts.

Results

Relative to the on-site ophthalmologist, the sensitivity of remote CMV retinitis diagnosis by nonexpert graders ranged from 64.0% to 95.5% (mean, 84.1%; 95% CI, 78.6%-89.6%)), and the specificity ranged from 65.6% to 92.5% (mean, 82.3%; 95% CI, 76.6%-88.0%)). Agreement between nonexpert and expert graders was high: the mean sensitivity and specificity values of nonexpert diagnosis using expert consensus as the reference standard were 93.2% (95% CI, 90.6%-95.8%) and 88.4% (95% CI, 85.4%-91.1%), respectively. Mean intrarater reliability also was high (mean Cohen κ, 0.83; 95% CI, 0.78-0.87).

Conclusions and relevance

The sensitivity and specificity of remote diagnosis of CMV retinitis by nonexpert graders was variable, although several nonexperts achieved a level of accuracy comparable to that of CMV retinitis experts. More intensive training and periodic evaluations would be required if nonexperts are to be used in clinical practice.