Purpose
To evaluate clinical features and long-term visual outcome of cytomegalovirus (CMV) retinitis in patients without human immunodeficiency virus (HIV) infection, and to determine factors that predict visual outcome.
Design
Retrospective cohort study.
Methods
Consecutive patients with CMV retinitis without HIV infection were reviewed. Main outcome measures included clinical features, proportion of eyes with 6-month and final visual acuity (VA) <20/70 and <20/400, and odds ratios of factors associated with poor visual outcome.
Results
A total of 20 eyes from 13 patients were included with a median follow-up time of 17 months. All had at least 6 months of follow-up except 1 patient who died from sepsis at 1 month. At presentation, 50% of eyes had VA <20/70 and 25% had VA <20/400. Zone 1 involvement occurred in 55% and vitreous haze ≥grade 2+ occurred in 25%. Recurrence occurred in 33.3% at a mean time of 6.4 ± 3.3 weeks after discontinuation of anti-CMV therapy. The retinal detachment rate was 21.7% per eye-year and mortality rate was 11.7% per person-year. At final visit, 60% had VA <20/70 and 35% had VA <20/400. Macular involvement was significantly associated with poor final VA <20/400 (odds ratio = 25.00, P = .016).
Conclusions
CMV retinitis without HIV infection was often aggressive at presentation. Significant intraocular inflammation was not uncommon. The long-term visual outcome was poor, especially in those with macular involvement.
Cytomegalovirus (CMV) retinitis is an opportunistic infection that usually occurs in immunocompromised patients with human immunodeficiency virus (HIV) infection. HIV-related CMV retinitis typically occurs when the CD4+ T cell count is less than 50 cells/μL, with a lifetime risk of 25%–40%. The presentation has been well described in the literature, with a typical pattern of confluent retinal opacification and intralesional hemorrhage along major vascular arcades (fulminant form) or punctate granular opacification without much hemorrhage (indolent form). Intraocular inflammation is typically absent or minimal. It is the leading cause of irreversible visual loss after HIV infection in developing countries.
Non-HIV-related CMV retinitis is much less common. It has been reported in patients given intensive immunosuppressive therapy for hematologic malignancies, autoimmune diseases and organ transplantation, and after local steroid administration. Unlike the typical presentation in patients with HIV infection, the presentation of CMV retinitis in non-HIV-infected patients has been reported to be variable. Vascular involvement and intraocular inflammation have also been reported to be very common. Some patients presented atypically with a mixed clinical picture of panretinal occlusive vasculopathy with intraocular inflammation and peripheral, slowly progressive granular retinitis. The difference in presentation could be related to different severity of immunosuppression and different degree of cell-mediated immunity.
Although the clinical features of CMV retinitis related to HIV infection have been well described in the literature, studies evaluating the characteristics in patients without HIV infection were limited. Only 3 large series have been published—1 including 30 eyes in 18 patients, 1 including 22 eyes in 18 patients, and the other including 23 eyes in 15 patients. Data on long-term visual outcome were limited, and prognostic factors associated with visual outcome had not been studied. Therefore, this study was performed to evaluate the clinical features and long-term visual outcome of CMV retinitis in non-HIV patients, and to determine factors that predicted visual outcome.
Methods
Patients
The medical records of consecutive patients newly diagnosed with CMV retinitis and treated at the Eye Clinic of the University of Hong Kong between January 1, 2009 and December 31, 2014 were reviewed. The diagnosis of CMV retinitis was based on (1) presence of active retinitis and (2) presence of CMV in intraocular fluid or blood confirmed by DNA polymerase chain reaction (PCR) analysis and/or CMV pp65 antigenemia assays. Patients with HIV infection were excluded from the study. The study was approved by the institutional review board at the University of Hong Kong, and conducted according to the Declaration of Helsinki.
Ophthalmologic Examination and Data Collection
A complete ophthalmologic examination was performed at all visits, which included visual acuity (VA) test, tonometry, slit-lamp biomicroscopy, and dilated fundus examination by indirect ophthalmoscopy. All VA tests were performed with Snellen chart with patients’ own refractive correction and pinhole, and the value converted to logMAR for statistical analysis. A value of 2.6 logMAR units was assigned for VA of count fingers, 2.7 logMAR units for hand movement, 2.8 logMAR units for light perception (LP), and 2.9 logMAR units for no light perception. Fundus photographs were used to evaluate the location of disease, extent of lesion, number of lesions, severity of vitreous haze, and presence of retinal vasculitis.
Clinical features and demographic data including age, sex, associated systemic diseases, concurrent medications, and comorbidities were recorded. The presence of CMV in intraocular fluid sample and blood was reviewed. The duration of intravitreal and systemic anti-CMV treatment was evaluated. Recurrence of retinitis, retinal detachment, and mortality in the follow-up period were documented.
Definitions
Two levels of VA were analyzed: <20/70 (6/18) to 20/400 (6/120) (moderate to severe impairment) and <20/400 (blindness). Location of retinitis, extent of retinitis, and types of retinitis were defined based on previous studies. Location of disease was divided into 3 zones: zone 1 consisted of the area within 3000 μm of the center of the macula (macular involvement) or within 1500 μm of the margin of the optic disc (disc involvement), zone 2 consisted of the area anterior to zone 1 to the equator, and zone 3 consisted of the area anterior to zone 2 to the ora serrata. Extent of lesion was determined based on the amount of retinal area involved by retinitis as a percentage of total retinal area. It was categorized into 4 groups: ≤10% in Group 1, 11%–25% in Group 2, 26%–50% in Group 3, and >50% in Group 4. Severity of vitreous haze was classified according to the Standardization of Uveitis Nomenclature (SUN) Working Group and previous studies : graded 1+ when the optic nerve head and retinal vessels were mildly blurred, 2+ when there was more significant blurring, 3+ when the optic nerve head was still visible but with blurred borders and retinal vessels could not be visualized, and 4+ when the optic nerve head was obscured. Retinal vasculitis was identified by vascular sheathing of retinal vessels with fuzzy border. Recurrence of retinitis was defined as occurrence of new lesion of any size after the initial retinitis had been treated and had become inactive. Increase in uveitis alone without new retinitis lesion was not considered as recurrence because the uveitis could be due to immune recovery. Only patients who had a considerable length of follow-up of at least 6 months were included in the analysis of recurrence rate.
Outcome and Statistical Analysis
Primary outcome measures included proportion of eyes with VA <20/70 and VA <20/400 at 6 months and at final visit. Secondary outcome measures included recurrence rate, retinal detachment rate, and mortality rate. SPSS was used for statistical analysis (IBM SPSS V.19; IBM Corp, Armonk, New York, USA). All demographic data were expressed as mean ± standard deviation. Factors that might predict final VA were evaluated in univariate logistic regression analyses. If there was more than 1 factor associated with P value <.05 in univariate level, the factors would be entered into a multivariate logistic regression model. A P value of <.05 was considered as statistically significant. All tests were 2-sided.
Results
Patients
A total of 14 patients were diagnosed as having CMV retinitis in the study period. One patient was excluded because of presence of HIV infection, leaving a total of 20 eyes from 13 patients meeting the inclusion and exclusion criteria ( Tables 1 and 2 , and Figure 1 ). Six patients had unilateral involvement and 7 had bilateral involvement. The mean age of patients at presentation was 49.6 ± 21.3 years (range, 15–75 years) and 8 of them were male (61.5%). The underlying diseases were predominantly hematologic malignancies (11 patients, 84.6%), followed by autoimmune disease (1 patient, 7.7%) and organ transplantation (1 patient, 7.7%). The median follow-up time was 17 months. All had at least 6 months of follow-up except 1 patient who died of sepsis at 1 month after presentation. Mean follow-up was 18.95 months (range, 1–70 months). Hematologic characteristics of 5 out of 13 subjects (3 unilateral retinitis, 2 bilateral retinitis) have been reported previously ( Table 1 ).
| Patient No. | Eye | Age | Sex | Predisposing Disease | Remarks | Length of FU (mo) | Outcome |
|---|---|---|---|---|---|---|---|
| 1 | Unilateral | 18 | F | Lymphoplasmacytic lymphoma | BMT 3 months before presentation | 26 | Living |
| 2 | Bilateral | 52 | F | ALL | On cyclosporine A | 18 | Living |
| 3 | Bilateral | 15 | M | AML | BMT 4 months before presentation | 6 | Living |
| 4 | Bilateral | 17 | F | ALL | Last chemotherapy (HD-MTX) 9 months before presentation | 6 | Living |
| 5 a | Bilateral | 72 | M | Follicular lymphoma | Last chemotherapy (RFND) 6 months before presentation | 17 | Living |
| 6 a | Unilateral | 75 | M | Follicular lymphoma | Intravenous rituximab 2 months before presentation | 10 | Died |
| 7 | Unilateral | 63 | F | Rheumatoid arthritis | On cyclophosphamide | 70 | Living |
| 8 a | Unilateral | 67 | M | CLL | Last chemotherapy (RFND) 1 month before presentation | 23 | Living |
| 9 | Bilateral | 66 | M | MALT lymphoma | Last chemotherapy (R-2CDA) 2 months before presentation | 1 | Died |
| 10 a | Bilateral | 48 | F | Follicular lymphoma | Last chemotherapy (R-GEMOX) 1 month before presentation | 7 | Died |
| 11 a | Unilateral | 38 | M | CLL | Last chemotherapy (RFND) 2 months before presentation | 66 | Living |
| 12 | Bilateral | 60 | M | AML | Last chemotherapy (CLARA) 2 months before presentation | 6 | Died |
| 13 | Unilateral | 54 | M | Kidney transplant | On tacrolimus and prednisolone | 62 | Living |
a Hematologic characteristics of Patients 5, 6, 8, 10, and 11 have been reported previously.
| Patient No. | Eye | Presenting VA | Final VA | Aqueous Humor CMV a | Blood CMV b | Systemic Anti-CMV Therapy | Intravitreal Anti-CMV Therapy | Outcome (Time of Recurrence After Stopping Anti-CMV Therapy) | Complications | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Types of Therapy | Duration in Weeks | Types of Therapy | Duration in Weeks | No. of Injections | ||||||||
| 1 | Left | HM | 20/1200 | − | − | FOS → VGCV | 10.6 | GCV | 6.0 | 9 | Recurrence (5.0 weeks) | Nil |
| 2 | Right | 20/200 | 20/200 | + | − | GCV → VGCV | 8.0 | GCV | 14.0 | 17 | Remission | Nil |
| Left | 20/400 | 20/200 | + | GCV | 16.3 | 19 | Remission | Nil | ||||
| 3 | Right | 20/100 | 20/40 | + | + | GCV → VGCV | 16.7 | GCV | 3.3 | 5 | Remission | Nil |
| Left | 20/30 | 20/30 | − | GCV | 10.3 | 12 | Remission | Nil | ||||
| 4 | Right | LP | HM | + | + | FOS | 0.7 | GCV | 0.1 | 1 | Remission | RRD |
| Left | 20/600 | HM | + | GCV | 0.1 | 1 | Remission | RRD | ||||
| 5 | Right | 20/1200 | HM | + | + | VGCV | 19.3 | GCV, FOS | 10.0 | 13 | Remission | Nil |
| Left | 20/30 | 20/40 | + | GCV | 4.9 | 9 | Remission | Nil | ||||
| 6 | Left | CF | HM | Not done | − | FOS → VGCV | 16.9 | GCV | 5.6 | 6 | Recurrence (8.7 weeks) | AACG, RRD |
| 7 | Left | 20/30 | 20/300 | Not done | + | VGCV | 17.0 | GCV | 4.3 | 4 | Recurrence (8.6 weeks) | Nil |
| 8 | Right | 20/30 | 20/200 | + | + | GCV → VGCV | 15.6 | GCV | 23.7 | 33 | Remission | Nil |
| 9 | Right | 20/100 | CF | + | + | GCV | 3.1 | GCV | 2.6 | 6 | Remission | Nil |
| Left | 20/400 | 20/200 | + | GCV | 2.6 | 6 | Remission | Nil | ||||
| 10 | Right | 20/70 | 20/20 | + | + | GCV → VGCV | 17.6 | GCV | 5.4 | 9 | Recurrence (2.7 weeks) | Nil |
| Left | 20/30 | 20/25 | + | GCV | 5.4 | 9 | Recurrence (2.7 weeks) | Nil | ||||
| 11 | Right | 20/20 | 20/200 | + | + | FOS → VGCV | 0.6 | GCV | 1.6 | 3 | Recurrence (10.4 weeks) | RRD |
| 12 | Right | 20/50 | 20/30 | + | − | VGCV | 14.6 | GCV | 6.0 | 8 | Remission | Nil |
| Left | 20/40 | 20/40 | + | GCV | 6.0 | 8 | Remission | Nil | ||||
| 13 | Right | 20/50 | 20/30 | + | + | GCV → VGCV | 13.6 | GCV | 2.1 | 4 | Remission | RRD |
a Polymerase chain reaction analysis for CMV DNA in aqueous humor.
b Polymerase chain reaction analysis for CMV DNA in blood and/or CMV pp65 antigenemia assay.
Presenting Clinical Features
At presentation, the mean VA was 0.94 ± 0.91 logMAR units (range, 0.00–2.80) (Snellen equivalent ∼20/200, range LP to 20/20). Fifty percent had VA <20/70 and 25% had VA <20/400. Anterior segment signs included anterior chamber cells (75%), keratic precipitates (15%), posterior synechiae (10%), and raised intraocular pressure of more than 21 mm Hg (5%) ( Table 3 ). The majority had zone 1 involvement (11 eyes, 55%), an extent of 11%–25% retinal area involvement (10 eyes, 50%), presence of vitreous haze (11 eyes, 55%), and retinal vasculitis (14 eyes, 70%) ( Table 3 ). Significant vitreous haze of ≥grade 2+ occurred in 5 eyes (25%).
| Clinical Features | No. of Eyes (N = 20) | % |
|---|---|---|
| Anterior segment signs | ||
| Anterior chamber cells | 15 | 75.0 |
| Keratic precipitates | 3 | 15.0 |
| Posterior synechiae | 2 | 10.0 |
| Raised IOP >21 mm Hg | 1 | 5.0 |
| Most posterior zone | ||
| Zone 1 | 11 | 55.0 |
| Zone 2 | 9 | 45.0 |
| Zone 3 | 0 | 0.0 |
| Extent of lesion | ||
| ≤10% | 2 | 10.0 |
| 11%–25% | 10 | 50.0 |
| 26%–50% | 3 | 15.0 |
| >50% | 5 | 25.0 |
| Vitreous haze | ||
| 0 | 9 | 45.0 |
| 1+ | 6 | 30.0 |
| 2+ | 3 | 15.0 |
| 3+ | 2 | 10.0 |
| 4+ | 0 | 0.0 |
| Other features | ||
| Disc involvement | 10 | 50.0 |
| Macular involvement | 9 | 45.0 |
| Retinal vasculitis | 14 | 70.0 |
Investigation Results
Aqueous humor tapping was performed in 18 eyes for CMV DNA PCR analysis, and 16 eyes revealed positive results (88.9%). All 13 patients underwent blood tests, either CMV pp65 antigenemia assays or CMV DNA PCR analysis, and 9 patients showed positive results (69.2%) ( Table 2 ).
Treatment
All patients received combined systemic and intravitreal anti-CMV therapy ( Table 2 ). Systemic therapies included intravenous ganciclovir, intravenous foscarnet, and oral valganciclovir. The mean duration of systemic therapy was 11.9 ± 6.7 weeks (range, 0.6–19.3 weeks). Except for 1 patient (Patient 4), who received only 1 intravitreal injection of ganciclovir to both eyes, all patients received regular intravitreal injections of anti-CMV agents (ganciclovir and/or foscarnet) to the affected eyes at a frequency of once to twice every week. The mean duration of intravitreal injections was 6.5 ± 5.9 weeks (range, 0.1–23.7 weeks) and the mean number of intravitreal injections was 9.1 ± 7.3 (range, 1–33). No intravitreal ganciclovir implant was given. No progression of retinitis was observed after treatment.
Recurrence of Retinitis
After excluding 1 patient (2 eyes) who died at 1 month after presentation, recurrence of CMV retinitis occurred in 6 out of 18 eyes (33.3%) ( Table 2 ). Recurrence occurred at a mean time of 6.4 ± 3.3 weeks (range, 2.7–10.4 weeks) after discontinuation of initial anti-CMV therapy and at a mean time of 19.9 ± 5.4 weeks (range, 12.0–25.6 weeks) after diagnosis. Duration of systemic therapy, duration of intravitreal therapy, number of intravitreal anti-CMV injections, severity of vitreous haze, and extent of retinitis lesion were not associated with risk of recurrence by logistic regression analyses ( P = .228, P = .738, P = .294, P = .425, P = .998, respectively). All recurrences resolved with a second course of intravitreal and systemic anti-CMV therapy. Two eyes (Patients 1 and 11) had second recurrence after stopping treatment, and were treated successfully with a third course of intravitreal and systemic anti-CMV therapy. No eyes had more than 2 episodes of recurrences.
Retinal Detachment
Five eyes (25%) from 4 patients developed retinal detachment. The retinal detachment rate was 21.7% per eye-year. One patient had bilateral retinal detachment at presentation (Patient 4, Figure 2 ) and underwent operation with pars plana vitrectomy, laser photocoagulation, and silicone oil injection. She had bilateral removal of silicone oil at 6 months and the retina remained attached all along during the follow-up period.
