Training clinicians treating HIV to diagnose cytomegalovirus retinitis.

PROBLEM: Acquired immunodeficiency syndrome (AIDS)-related cytomegalovirus (CMV) retinitis continues to be a neglected source of blindness in resource-poor settings. The main issue is lack of capacity to diagnose CMV retinitis in the clinical setting where patients receive care and all other opportunistic infections are diagnosed. APPROACH: We developed and implemented a four-day workshop to train clinicians working in human immunodeficiency virus (HIV) clinics how to perform binocular indirect ophthalmoscopy and diagnose CMV retinitis. Workshops comprised both classroom didactic instruction and direct clinical eye examinations in patients with advanced AIDS. Between 2007 and 2013, 14 workshops were conducted in China, Myanmar and the Russian Federation. LOCAL SETTING: Workshops were held with local clinicians at HIV clinics supported by nongovernmental organizations, public-sector municipal hospitals and provincial infectious disease referral hospitals. Each setting had limited or no access to locally- trained ophthalmologists, and an HIV-infected population with advanced disease. RELEVANT CHANGES: Clinicians learnt how to do binocular indirect ophthalmoscopy and to diagnose CMV retinitis. One year after the workshop, 32/38 trainees in Myanmar did systematic eye examination for early diagnosis of CMV retinitis as standard care for at-risk patients. In China and the Russian Federation, the success rates were lower, with 10/15 and 3/5 trainees, respectively, providing follow-up data. LESSONS LEARNT: Skills necessary for screening and diagnosis of CMV retinitis can be taught in a four-day task-oriented training workshop. Successful implementation depends on institutional support, ongoing training and technical support. The next challenge is to scale up this approach in other countries.

Burden of HIV-related cytomegalovirus retinitis in resource-limited settings: a systematic review.

BACKGROUND: Cytomegalovirus (CMV) is a late-stage opportunistic infection in people living with human immunodeficiency virus (HIV)/AIDS. Lack of ophthalmological diagnostic skills, lack of convenient CMV treatment, and increasing access to antiretroviral therapy have all contributed to an assumption that CMV retinitis is no longer a concern in low- and middle-income settings. METHODS: We conducted a systematic review and meta-analysis of published and unpublished studies reporting prevalence of CMV retinitis in low- and middle-income countries. Eligible studies assessed the occurrence of CMV retinitis by funduscopic examination within a cohort of at least 10 HIV-positive adult patients. RESULTS: We identified 65 studies from 24 countries, mainly in Asia (39 studies, 12 931 patients) and Africa (18 studies, 4325 patients). By region, the highest prevalence was observed in Asia with a pooled prevalence of 14.0% (11.8%-16.2%). Almost a third (31.6%, 95% confidence interval [CI], 27.6%-35.8%) had vision loss in 1 or both eyes. Few studies reported immune status, but where reported CD4 count at diagnosis of CMV retinitis was <50 cells/µL in 73.4% of cases. There was no clear pattern of prevalence over time, which was similar for the period 1993-2002 (11.8%; 95% CI, 8%-15.7%) and 2009-2013 (17.6%; 95% CI, 12.6%-22.7%). CONCLUSIONS: Prevalence of CMV retinitis in resource low- and middle-income countries, notably Asian countries, remains high, and routine retinal screening of late presenting HIV-positive patients should be considered. HIV programs must ensure capacity to manage the needs of patients who present late for care.

CMV retinitis in China and SE Asia: the way forward.

AIDS-related CMV retinitis is a common clinical problem in patients with advanced HIV/AIDS in China and Southeast Asia. The disease is causing blindness, and current clinical management, commonly characterized by delayed diagnosis and inadequate treatment, results in poor clinical outcomes: 21%-36% of eyes with CMV retinitis are already blind at the time the diagnosis is first established by an ophthalmologist. CMV retinitis also identifies a group of patients at extraordinary risk of mortality, and the direct or indirect contribution of extra-ocular CMV disease to AIDS-related morbidity and mortality is currently unmeasured and clinically often overlooked. The obvious way to improve clinical management of CMV retinitis is to screen all patients with CD4 counts < 100 cells/µL with indirect ophthalmoscopy at the time they first present for care, and to provide systemic treatment with oral valganciclovir when active CMV retinitis is detected. Treatment of opportunistic infections is an integral part of HIV management, and, with appropriate training and support, CMV retinitis screening and treatment can be managed by the HIV clinicians, like all other opportunistic infections. Access to ophthalmologist has been problematic for HIV patients in China, and although non-ophthalmologists can perform screening, sophisticated ophthalmological skills are required for the management of retinal detachment and immune recovery uveitis, the major complications of CMV retinitis. CMV retinitis has been clinically ignored, in part, because of the perceived complexity and expense of treatment, and this obstacle can be removed by making valganciclovir affordable and widely available. Valganciclovir is an essential drug for developing successful programs for management of CMV retinitis in China and throughout SE Asia.

Contralateral Eye Involvement and Retinal Detachment in Patients with Cytomegalovirus Retinitis Treated with Intravitreous Ganciclovir.

Purpose: To determine the incidence of contralateral eye involvement and retinal detachment in HIV-infected patients with cytomegalovirus retinitis treated with repeated intravitreous ganciclovir.Methods: In a prospective cohort study in Northern Thailand, HIV-infected patients with cytomegalovirus retinitis were treated with antiretroviral therapy and intravitreous ganciclovir injections and followed for 3 months for contralateral cytomegalovirus retinitis and retinal detachment.Results: Of 49 participants with unilateral cytomegalovirus retinitis at enrollment, 7 developed contralateral eye involvement (4.8/100 person-months, 95% CI 1.9-9.8). Of 105 eyes without a retinal detachment at enrollment, 6 developed a retinal detachment (2.0/100 eye-months, 95% CI 0.7-4.3). Baseline clinical factors were not associated with the development of either outcome.Conclusion: Eyes treated with intravitreous ganciclovir experienced retinal detachment at a rate similar to other populations treated with systemic antivirals. The risk of contralateral eye involvement was relatively high during the first 3 months after initial diagnosis despite the institution of antiretroviral therapy.

Bilateral Placoid Choroiditis in an HIV-Positive Patient With Cryptococcus neoformans Meningitis and Disseminated Cryptococcal Disease.

Purpose: We report a presumptive case of bilateral placoid choroiditis secondary to disseminated Cryptococcus neoformans infection and review the literature on choroidal involvement of C neoformans. Methods: A case report is presented. Results: A 35-year-old HIV-positive man presented with disseminated cryptococcal infection. Cryptococcal meningitis was confirmed by lumbar puncture, and skin involvement was confirmed by microscopy of scrapings from a papular, umbilicated, ulcerated lesion. Ophthalmologic examination revealed intact visual acuity, clear vitreous, and multiple yellowish, placoid-appearing choroidal lesions in the posterior pole bilaterally. Conclusions: Multifocal choroiditis caused by C neoformans is an uncommon manifestation of disseminated infection, and placoid yellowish choroidal lesions are an unusual variant. These findings must be differentiated from choroidal tuberculosis and other infections. Multifocal choroiditis typically occurs in AIDS patients and may precede the presentation of meningitis. In such patients, choroidal lesions warrant investigation for systemic, life-threatening opportunistic infections.

Routine Immediate Eye Examination at the Point of Care for Diagnosis of AIDS-Related Cytomegalovirus Retinitis Among Patients With a CD4 Count <100 in Myanmar.

A retrospective review of diagnosis of cytomegalovirus retinitis (CMVR) before and after introduction of routine immediate eye examination among AIDS patients in Myanmar with an absolute CD4 T-cell count <100 cells/µL demonstrated an increased detection of CMVR from 1.1% (14/1233) to 10.7% (65/608), an improvement of ~10-fold. Diagnosis of CMVR was achieved a mean of 2 days after clinic enrollment.

Active cytomegalovirus retinitis after the start of antiretroviral therapy.

Patients with AIDS-related cytomegalovirus (CMV) retinitis receiving combined antiretroviral therapy (cART), but not specific anti-CMV therapy, consistently showed active retinitis for several months. Delayed diagnosis and treatment of CMV retinitis may have severe consequences. Patients first entering care with advanced HIV infection and vulnerability to reactivation of latent CMV infection should be screened immediately for CMV retinitis by dilated indirect ophthalmoscopy and treated with specific anti-CMV therapy without delay, in addition to cART.

Visual acuity outcomes in cytomegalovirus retinitis: early versus late diagnosis.

AIMS: To determine if early dilated fundus examination for cytomegalovirus (CMV) retinitis leads to better visual outcomes in areas with limited HIV care, where patients may have long-standing retinitis before they are diagnosed with HIV. METHODS: Twenty-four eyes of 17 patients with CMV retinitis who were seen at an urban HIV clinic in Chiang Mai, Thailand, were included in this retrospective cohort study. Participants were divided into two groups based on the amount of time from the first documented CD4 count below 100 cells/mm3 to the first eye examination for CMV retinitis. Average visual acuity in each group was calculated at the time CMV retinitis was first detected, and then at 3, 6 and 12 months after diagnosis. RESULTS: The group of patients who received an eye examination within approximately 4 months of the initial low CD4 count measurement had better baseline visual acuity (median 20/30,IQR 20/20 to 20/60) compared with patients who presented later (median 20/80, 20/60 to hand motion); p=0.03). Visual acuity did not change significantly during the 12-month study period in either the early group (p=0.69) or late group (p=0.17). CONCLUSION: In this study, patients who were examined sooner after a low CD4 count had better vision than patients who were examined later. Routine early screening of patients with CD4 counts under below 100 cells/mm3 may detect earlier disease and prevent vision loss.

Fundus findings in a series of patients with extrapulmonary tuberculosis in Thailand.

AIM: The aim of this study was to determine the frequency of fundus abnormalities among patients who are undergoing or have recently completed treatment for extrapulmonary tuberculosis (eTB). METHODS: This is a prospective cross-sectional study conducted in a TB clinic of a tertiary hospital in northern Thailand. All patients who had eTB between January 2014 and August 2015 were invited by telephone to return to the clinic for fundus photography. Three uveitis specialists reviewed all photographs to identify posterior segment lesions that were consistent with ocular TB. RESULTS: A total of 265 patients were diagnosed with eTB during the specified period, of which 118 (44.5%) were reached by telephone and 60 (50.8%) participated in the study. A total of 7 eyes from six patients (10.0% of participants, 95% CI 2.2% to 17.8%) had lesions consistent with ocular TB. The group with possible ocular TB lesions was on average 16.8 years older than those without ocular lesions (p=0.01), but the two groups were otherwise not significantly different. CONCLUSION: Ocular lesions consistent with TB were not rare in a group of patients who were undergoing or had recently completed treatment for eTB. Fundus examination may provide diagnostic information that could influence a clinician's beliefs when diagnosing eTB. Given the low costs and immediate results of eye examination, this diagnostic test should be considered in patients suspected for eTB, especially when other tests are negative.

Risk factors for CMV retinitis among individuals with HIV and low CD4 count in northern Thailand: importance of access to healthcare.

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.

Eye examination for early diagnosis of disseminated tuberculosis in patients with AIDS.

Choroidal tuberculosis is present in 5-20% of patients with disseminated tuberculosis, and point-of-care dilated binocular indirect ophthalmoscopy eye examination can provide immediate diagnosis. In geographical areas of high tuberculosis prevalence and in susceptible patients (CD4 counts less than 200 cells per µL) detection of choroidal granulomas should be accepted as evidence of disseminated tuberculosis. With training and proper support, eye screening can be done by HIV/AIDS clinicians, allowing early tuberculosis treatment. In regions with a high burden of tuberculosis, we recommend that eye screening be a standard part of the initial assessment of susceptible patients, including at a minimum all patients with HIV/AIDS with CD4 less than 100 cells per µL with or without eye symptoms, and with or without suspicion of disseminated tuberculosis.

Rhegmatogenous Retinal Detachment in Patients with Acute Syphilitic Panuveitis.

PURPOSE: To describe the clinical characteristics and surgical management of rhegmatogenous retinal detachment (RD) in patients with acute syphilitic panuveitis. METHODS: Retrospective case series and comprehensive literature review. RESULTS: Including present and previously reported cases, we identified 11 eyes in 8 patients with acute syphilitic panuveitis that developed a rhegmatogenous RD. Seven of 11 eyes (63.6%) were repaired with a combined scleral buckling, vitrectomy, and endolaser photocoagulation surgery; 1 eye (9.1%) was repaired with scleral buckling only; and 2 eyes (18.2%) with vitrectomy only. Cryotherapy was used to treat a giant retinal tear in 1 eye (9.1%). Four eyes (36.4%) redetached and 3 underwent a second vitrectomy surgery. CONCLUSIONS: Although uncommon, rhegmatogenous RD can occur in patients with moderate to severe acute syphilitic panuveitis. We believe scleral buckling, vitrectomy, endolaser photocoagulation, and silicone oil tamponade give the best chance for successful retinal reattachment.

Retinal detachment associated with AIDS-related cytomegalovirus retinitis: risk factors in a resource-limited setting.

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.

Telemedicine screening for cytomegalovirus retinitis at the point of care for human immunodeficiency virus infection.

IMPORTANCE: Cytomegalovirus (CMV) retinitis is a leading cause of blindness in many developing countries, likely the result of inadequate screening. Telemedicine screening for CMV retinitis instituted at the point of care for human immunodeficiency virus (HIV) infection may allow for earlier detection. OBJECTIVES: To determine the diagnostic accuracy of retinal photography in detecting CMV retinitis at the point of HIV care and to characterize the clinical manifestations of CMV retinitis detected through the screening program. DESIGN, SETTING, AND PARTICIPANTS: We enrolled 103 participants from a population of 258 patients with HIV and a CD4 level of less than 100/µL treated at an HIV clinic in Thailand from June 2010 through June 2012. We captured mosaic fundus photographs through a dilated pupil using a digital fundus camera. An experienced on-site ophthalmologist masked to the results of the fundus images subsequently examined each eye with indirect ophthalmoscopy and recorded the clinical findings on a standardized form. Three remote graders evaluated each image for CMV retinitis. INTERVENTION: Fundus photography and indirect ophthalmoscopy. MAIN OUTCOMES AND MEASURES: Sensitivity and specificity of telemedicine relative to indirect ophthalmoscopy for diagnosis of CMV retinitis and clinical features of CMV retinitis lesions. RESULTS: Sixteen patients (15.5%) were diagnosed as having CMV retinitis, of whom 5 (31%) had bilateral disease. Of the 21 eyes (10.2%) with CMV retinitis, 7 (33%) had visual symptoms. Retinitis lesions occupied less than 10% of the total retinal surface area in 13 of 21 eyes (62%) and did not involve the posterior pole (ie, zone 1) in 15 of 21 eyes (71%). Mean logMAR visual acuity in affected eyes was 0.41 (95% CI, 0.11-0.71; Snellen equivalent, 20/50 [95% CI, 20/25-20/100]). The mean sensitivity for the 3 remote graders in detecting CMV retinitis on fundus photography was 30.2% (95% CI, 10.5%-52.4%), and mean specificity was 99.1% (95% CI, 97.8%-100.0%). The CMV retinitis lesions missed by the remote graders (false-negative findings) were more likely to be small (P = .001) and located in the peripheral retina (P = .04). CONCLUSIONS AND RELEVANCE: Patients undergoing screening at a clinic for HIV treatment had less extensive retinitis than patients in recent reports from an ophthalmology clinic. Retinal photography with the camera used in this study was not highly sensitive in detecting CMV retinitis but may identify disease with an immediate threat to vision. Improved accuracy will require a camera that can more easily image the peripheral retina.

Telemedicine diagnosis of cytomegalovirus retinitis by nonophthalmologists.

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.

Clinical features of newly diagnosed cytomegalovirus retinitis in northern Thailand.

PURPOSE: To characterize the clinical manifestations of cytomegalovirus (CMV) retinitis in northern Thailand. DESIGN: Prospective, observational, cross-sectional study. METHODS: We recorded characteristics of 52 consecutive patients newly diagnosed with CMV retinitis at a tertiary university-based medical center in northern Thailand. Indirect ophthalmoscopy by experienced ophthalmologists was supplemented with fundus photography to determine the proportion of eyes with various clinical features of CMV retinitis. RESULTS: Of the 52 patients with CMV retinitis, 55.8% were female. All were HIV-positive. The vast majority (90.4%) had started antiretroviral therapy. CMV retinitis was bilateral in 46.2% of patients. Bilateral visual acuity worse than 20/60 was observed in 23.1% of patients. Of 76 eyes with CMV retinitis, 61.8% had zone I disease and 21.6% had lesions involving the fovea. Lesions larger than 25% of the retinal area were observed in 57.5% of affected eyes. CMV retinitis lesions commonly had marked or severe border opacity (47.4% of eyes). Vitreous haze often was present (46.1% of eyes). Visual impairment was more common in eyes with larger retinitis lesions. Retinitis lesion size, used as a proxy for duration of disease, was associated with fulminant appearance (odds ratio, 1.24; 95% confidence interval, 1.01 to 1.51) and marked or severe border opacity (odds ratio, 1.36; 95% confidence interval, 1.11 to 1.67). Based on lesion size, retinitis preceded antiretroviral treatment in each patient. CONCLUSIONS: Patients seeking treatment at a tertiary medical center in northern Thailand had advanced CMV retinitis, possibly because of delayed diagnosis. Earlier screening and treatment of CMV retinitis may limit progression of disease and may prevent visual impairment in this population.

CMV retinitis screening and treatment in a resource-poor setting: three-year experience from a primary care HIV/AIDS programme in Myanmar.

BACKGROUND: Cytomegalovirus retinitis is a neglected disease in resource-poor settings, in part because of the perceived complexity of care and because ophthalmologists are rarely accessible. In this paper, we describe a pilot programme of CMV retinitis management by non-ophthalmologists. The programme consists of systematic screening of all high-risk patients (CD4 <100 cells/mm3) by AIDS clinicians using indirect ophthalmoscopy, and treatment of all patients with active retinitis by intravitreal injection of ganciclovir. Prior to this programme, CMV retinitis was not routinely examined for, or treated, in Myanmar. METHODS: This is a retrospective descriptive study. Between November 2006 and July 2009, 17 primary care AIDS clinicians were trained in indirect ophthalmoscopy and diagnosis of CMV retinitis; eight were also trained in intravitreal injection. Evaluation of training by a variety of methods documented high clinical competence. Systematic screening of all high-risk patients (CD4 <100 cells/mm3) was carried out at five separate AIDS clinics throughout Myanmar. RESULTS: A total of 891 new patients (1782 eyes) were screened in the primary area (Yangon); the majority of patients were male (64.3%), median age was 32 years, and median CD4 cell count was 38 cells/mm3. CMV retinitis was diagnosed in 24% (211/891) of these patients. Bilateral disease was present in 36% of patients. Patients with active retinitis were treated with weekly intravitreal injection of ganciclovir, with patients typically receiving five to seven injections per eye. A total of 1296 injections were administered. CONCLUSIONS: A strategy of management of CMV retinitis at the primary care level is feasible in resource-poor settings. With appropriate training and support, CMV retinitis can be diagnosed and treated by AIDS clinicians (non-ophthalmologists), just like other major opportunistic infections.