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.
Cytomegalovirus (CMV) retinitis is an opportunistic infection affecting severely immunocompromised persons, most commonly those with HIV infection or iatrogenic immunosuppression. The incidence of CMV retinitis has decreased dramatically in industrialized countries because of widespread use of highly active antiretroviral therapy. However, CMV retinitis remains prevalent in some parts of the world. In particular, CMV retinitis has been observed in as many as one third of patients with AIDS in areas of Southeast Asia.
The clinical characteristics of CMV retinitis have been well described in industrialized countries, both before and after the introduction of widespread highly active antiretroviral therapy. Retinal infection with CMV usually becomes clinically evident at CD4 counts of less than 50 cells/μL. CMV retinitis at higher CD4 counts is uncommon, although active disease can be seen in early immune reconstitution. Active retinal infection is characterized by progressive white areas of retinal necrosis and edema, with small white satellite lesions at the leading edge of the active retinitis. Lesions often have been classified into an indolent/granular form or a fulminant/edematous form, although the severity of opacity may be a more useful clinical description of disease. Numerous studies have reported the clinical features of CMV retinitis, although these usually have described populations of predominantly white and Latino men from industrialized countries. The clinical appearance of CMV retinitis has not been well characterized in geographic regions where the HIV epidemic is now most prevalent, including Southeast Asia. Clinical characteristics may be different in Southeast Asia because of differences in health care access and antiretroviral use, as well as cultural norms that may cause patients to delay seeking medical attention unless they have severe illness. In addition, there is emerging evidence that host genetic factors may contribute to expression of CMV disease in patients with AIDS; these genetic factors may differ in Asian patients. In this report, we describe the clinical characteristics of patients and eyes with newly diagnosed, untreated CMV retinitis at an ocular infectious disease clinic in northern Thailand.
Methods
Study Design
We conducted a prospective study at the Ocular Infectious Diseases Clinic at the Maharaj Nakorn Chiang Mai Hospital, a university-based tertiary medical center. From August 7, 2008, through April 9, 2009, all patients making an initial visit to the clinic who were not treated previously for CMV retinitis were interviewed and examined according to a prespecified protocol using a standardized data form. We documented the characteristics of all patients at presentation, regardless of whether they were being treated with antiretroviral drugs. Patients provided demographic and clinical information, including HIV status and date of diagnosis, antiretroviral use and duration of treatment, and most recent and nadir CD4 count. No attempt was made to confirm these self-reported answers. Visual symptoms and visual acuity were assessed by ophthalmic technicians and ophthalmology residents. An ophthalmologist with at least 4 years of experience examining patients with CMV retinitis (So.A., Sa.A., or C.J.) performed indirect ophthalmoscopy to determine the presence of CMV retinitis, vitreous haze, and retinal detachment. If CMV retinitis was present, the examiner also documented the size of the lesion to the nearest 5% (using indentational indirect ophthalmoscopy if necessary), the zones affected, and whether the lesion appeared to be active. A detailed retinal drawing was performed for each examined eye. All patients subsequently underwent fundus photography with a Topcon TRC-NW 6S camera (Topcon, Tokyo, Japan), resulting in 9 individual 45-degree photographs to cover all quadrants of the retina and 1 composite photograph with an 85-degree angle of coverage. Photographs were examined retrospectively by 1 author (J.D.K.) for several features that were not recorded by the examining ophthalmologist, including: retinitis appearance (fulminant/edematous versus indolent/granular), intralesional hemorrhages, frosted branch angiitis, and retinitis involving the optic nerve, vascular arcades, or fovea. Photographs also were reviewed by 1 author (G.N.H.) for retinitis border opacity.
Definitions
Low vision was defined as best-corrected visual acuity worse than 6/18 (20/60), but better than or equal to 3/60 (20/400). Blindness was defined as best-corrected visual acuity worse than 3/60 (20/400). Unilateral low vision was defined as low vision in one eye and visual acuity of 20/60 or better in the other. Unilateral blindness was defined as blindness in one eye and visual acuity of 20/400 or better in the other. CMV retinitis zones were defined according to accepted criteria. Zone 1 included the area within 3000 μm of the anatomic macula or within 1500 μm of the margin of the optic disc; zone 2 was defined as the area that extends anteriorly from zone 1 to the clinical equator of the eye; and zone 3 was defined as the remaining retina that extends to the ora serrata. CMV retinitis lesion size was defined as the percentage of retinal area affected by disease and was categorized as 10% or less, 11% to 25%, 26% to 50%, and more than 50%. CMV retinitis was classified as active or inactive based on the impression of the examining ophthalmologist. Vitreous haze was graded during the clinical examination according to the Standardization of Uveitis Nomenclature Working Group criteria (4+ if the optic nerve head was obscured, 3+ if the optic nerve head was present but with blurry borders, 2+ if the retinal vessels could be visualized better, and 1+ if the optic nerve head and retinal vessels were defined even better). Retinal detachment was defined as the presence of any type of retinal detachment detected by indirect ophthalmoscopy. Multifocal disease was defined as the presence of more than 1 focus of retinitis, as judged from the ophthalmologist’s detailed retinal drawing.
The appearance of retinitis was classified according to prior studies. Briefly, indolent/granular lesions consisted of granular opacification with visible choroidal detail or opacification only at the border of the lesion with trace or no hemorrhage and no vascular sheathing. Fulminant/edematous lesions consisted of dense confluent areas of retinal opacification and the absence of a clear central atrophic area. Border opacity was graded based on standard photographs as mild (1+) if the border was exclusively faint and did not obscure the underlying choroid or was composed of satellites only; as moderate (2+) in the presence of isolated segments of more dense retinal whitening that partially obscured the underlying choroid; as marked (3+) in the presence of confluent whitening of most of the border that partially obscured the underlying choroid; and as severe (4+) if the opacity was so dense that no choroidal details could be observed. Intralesional hemorrhages were based on criteria used in prior studies, with the term minimum denoting a few scattered punctate spots of blood, moderate denoting many spots of blood or occasional blotchy areas of blood not obscuring the underlying structures, and marked denoting dense, confluent, solid red blood that obscured the view of underlying structures. Frosted branch angiitis was defined as present if multiple retinal vessels displayed characteristic vascular sheathing in an area remote from a focus of retinitis. Retinitis location was categorized as involving the optic nerve, arcades, or fovea if retinitis affected any part of these structures.
Statistical Analysis
Descriptive statistics were performed for demographic and clinical characteristics of patients with CMV retinitis. We calculated proportions for categorical variables and medians with interquartile ranges (IQRs) for continuous variables. The Wilcoxon rank-sum test was used to test differences in CD4 counts in different populations of patients. We also calculated the proportion of eyes with the clinical signs described above. Results are displayed for the subgroup with visual acuity worse than 20/60 (low vision or worse) and for the subgroup with visual acuity of 20/60 or better (normal vision), as well as for the total population. The Fisher exact test was used to assess for associations between low vision and each of the clinical findings, using a level of significance of α = 0.05. Backward stepwise logistic regression was performed using the presence of low vision or worse as the outcome variable and all clinical signs as explanatory variables, accounting for nonindependence of fellow eyes. We performed univariate logistic regression analyses using various signs of clinical severity (categorized as present or absent) as the outcome variable and lesion size (used as a proxy for duration of retinitis) as a continuous explanatory variable.
We estimated the date of onset of CMV retinitis infection for each patient, based on the lesion size in the percentage of retina affected. For these calculations, we estimated the total retinal surface area to be 1128 mm 2 , assuming a spherical eyeball with an inner scleral radius of 11 mm and an ora serrata 29 degrees anterior to the equator. We assumed a single circular lesion, with a central focus of CMV retinitis and a rate of progression of 61 μm per day. We acknowledge that this technique of determining the date of retinitis onset is imprecise. Therefore, in a sensitivity analysis, we repeated the analysis assuming a faster rate of progression (120 μm per day), multifocal disease (2 completely separate circular lesions with central foci of CMV retinitis), and a smaller eye (inner scleral radius of 10 mm, resulting in a total retinal surface area of 933 mm 2 ). Note that these are conservative assumptions for progression rate, which could underestimate the duration of CMV retinitis infection. The Wilcoxon sign-rank test was used to assess whether the estimated duration of disease was different from the duration of antiretroviral therapy. All statistical analyses were performed with Stata software version 10 (Stata Corp, College Station, Texas, USA).
Results
Patient Characteristics
During the 8 months of the study, 123 patients were examined for the first time at the Ocular Infectious Diseases Clinic, all of whom were infected with HIV. Of the 123 patients, 52 patients with newly diagnosed CMV retinitis and 37 patients without CMV retinitis were examined prospectively. Because of logistical constraints, 34 patients without CMV retinitis were not examined using the prospective data form and are not discussed in this report.
The median age of the 52 patients with CMV retinitis was 37.5 years (range, 14 to 57 years); approximately half were female ( Table 1 ). HIV was diagnosed a median of 1.8 years before examination. CMV retinitis was a relatively infrequent initial presentation for HIV; only 5 (10%) patients were diagnosed with CMV retinitis within 3 months of being diagnosed with HIV. The vast majority (47/52; 90.4%) of patients diagnosed with CMV retinitis were receiving antiretroviral therapy at the time of diagnosis. Of patients receiving antiretroviral therapy with available data, 41 of 45 (91%) had been started on antiretroviral therapy between 1 and 2 months prior, and the remaining 4 (9%) had started treatment less than 1 month prior. Of the 5 patients not receiving antiretroviral therapy, 2 had been recently diagnosed, 2 had been lost to follow-up by their internist, and in 1, antiretroviral resistance developed. Of 38 patients who remembered their most recent CD4 count, 24 (63.2%) reported a CD4 count of less than 50 cells/μL (range, 1 to 434 cells/μL). Of note, 9 patients (23.7%) reported a recent CD4 count of 100 cells/μL or more. Only 20 patients recalled a CD4 nadir; of those, 17 (85.0%) reported their lowest CD4 count to be less than 50 cells/μL. Almost half (24/52; 46.2%) of patients had bilateral CMV retinitis on their initial presentation. There was a high prevalence of visual impairment in this population; visual acuity of worse than 20/60 was observed in both eyes of 12 patients (23.1%) and 1 eye of 29 patients (55.8%). Blindness, defined as visual acuity worse than 20/400, was not uncommon. Four patients were bilaterally blind, and 19 patients were unilaterally blind.
| Characteristic | No. a | Proportion, %, or Median (IQR) |
|---|---|---|
| Median age, y (IQR) | 52 | 37.5 (32.5 to 44) |
| Female | 52 | 55.8% |
| HIV+ | 52 | 100% |
| Diagnosed ≤ 3 mos ago | 52 | 9.6% |
| Diagnosed ≤ 6 mos ago | 52 | 38.5% |
| Years since HIV diagnosis, median (IQR) | 52 | 1.8 (0.3 to 7.4) |
| Currently receiving antiretroviral therapy | 52 | 90.4% |
| Started antiretroviral < 1 mo ago | 45 | 8.9% |
| Started antiretroviral < 2 mos ago | 45 | 100% |
| Median duration of therapy, wks (IQR) | 45 | 5.4 (4.7 to 6.3) |
| Most recent CD4 count b | ||
| Median (IQR), per μL | 38 | 32.5 (7 to 98) |
| < 50 cells/μL | 38 | 63.2% |
| Nadir CD4 count b | ||
| Median (IQR), per μL | 20 | 25 (6 to 37.5) |
| < 50 cells/μL | 20 | 85.0% |
| CMV retinitis | ||
| Bilateral | 52 | 46.2% |
| Unilateral c | 52 | 53.8% |
| Right eye | 28 | 46.4% |
| Left eye | 28 | 53.6% |
| Low vision d | ||
| Bilateral | 52 | 5.8% |
| Unilateral | 52 | 28.8% |
| Blindness e | ||
| Bilateral | 52 | 7.7% |
| Unilateral, with contralateral low vision | 52 | 9.6% |
| Unilateral | 52 | 26.9% |
a Number of patients with complete data.
b CD4 count values are by patient report.
c In 4 patients classified as having unilateral CMV, the presence of CMV retinitis in the contralateral eye could not be determined.
d Defined as best-corrected visual acuity worse than 20/60 but 20/400 or better.
e Defined as best-corrected visual acuity worse than 20/400.
Ocular Findings on Examination
Of 76 eyes diagnosed with CMV retinitis, the median visual acuity was 20/80 (IQR, 20/30 to 20/1200), with 43 eyes (56.6%) classified as low vision or worse and 23 eyes (30.3%) classified as blind ( Table 2 ). Visual symptoms were present in the vast majority of patients and usually consisted of blurriness, floaters, or a scotoma. CMV retinitis commonly was located in multiple zones of the retina, although 12 (15.8%) of 76 eyes had retinitis localized solely to zone 3. A wide distribution of CMV retinitis lesion size was observed; the median percentage of the retina affected was 30% (IQR, 5% to 90%), and 42 (56.8%) of 74 eyes with available data had lesions affecting more than 25% of the retina. Active inflammatory retinitis was seen in 62 (87.3%) of 71 eyes with available data. The 6 patients with quiescent disease all were taking antiretroviral drugs and had a higher recent CD4 count (median, 155 cells/μL; IQR, 125 to 401 cells/μL in 5 patients with data) compared with patients with active lesions (median, 26 cells/μL; IQR, 7 to 50 cells/μL in 33 patients with data; P = .004, Wilcoxon rank-sum test). Multifocal retinitis was noted in 18 (23.7%) of 76 eyes, and retinal detachment was noted in 5 (6.6%) of 76 eyes.
| Characteristic | All Eyes (%) | Low Vision or Worse a | Normal Vision b | P Value c | ||
|---|---|---|---|---|---|---|
| No. | % | No. | % | |||
| Visual acuity | ||||||
| Low vision | 26.3 | 20/43 | 46.5 | 0/33 | 0 | |
| Blindness | 30.3 | 23/43 | 53.5 | 0/33 | 0 | |
| Visual symptoms | ||||||
| Any symptoms | 90.8 | 43/43 | 100 | 26/33 | 78.8 | .002 |
| Blurriness | 84.2 | 42/43 | 97.7 | 22/33 | 66.7 | .06 |
| Floaters | 17.1 | 8/43 | 18.6 | 5/33 | 15.2 | 1.00 |
| Flashes | 7.9 | 3/43 | 7.0 | 3/33 | 9.1 | .67 |
| Scotoma | 10.5 | 5/43 | 11.6 | 3/33 | 9.1 | .65 |
| Retinitis location | ||||||
| Involving optic disc | 23.0 | 13/41 | 31.7 | 4/33 | 12.1 | .06 |
| Involving arcades | 56.8 | 32/41 | 78.0 | 10/33 | 30.3 | < .001 |
| Involving fovea | 21.6 | 16/41 | 39.0 | 0/33 | 0 | < .001 |
| Most posterior zone | .04 | |||||
| Zone 1 | 61.8 | 31/43 | 72.1 | 16/33 | 48.5 | |
| Zone 2 | 22.4 | 9/43 | 20.9 | 8/33 | 24.2 | |
| Zone 3 | 15.8 | 3/43 | 7.0 | 9/33 | 27.3 | |
| Lesion size (%) | .003 | |||||
| ≤ 10 | 28.4 | 5/41 | 12.2 | 16/33 | 48.5 | |
| 11 to 25 | 14.9 | 6/41 | 14.6 | 5/33 | 15.2 | |
| 26 to 50 | 29.7 | 14/41 | 34.1 | 8/33 | 24.2 | |
| > 50 | 27.0 | 16/41 | 39.0 | 4/33 | 12.1 | |
| Retinitis appearance | .37 | |||||
| Granular | 11.8 | 7/43 | 16.3 | 2/33 | 6.1 | |
| Fulminant | 60.5 | 26/43 | 60.5 | 20/33 | 60.6 | |
| Indeterminant | 27.6 | 10/43 | 23.3 | 11/33 | 33.3 | |
| Border opacity | .06 | |||||
| 1+ | 5.3 | 0/43 | 0 | 4/33 | 12.1 | |
| 2+ | 9.2 | 3/43 | 7.0 | 4/33 | 12.1 | |
| 3+ | 25.0 | 12/43 | 27.9 | 7/33 | 21.2 | |
| 4+ | 22.4 | 13/43 | 30.2 | 4/33 | 12.1 | |
| Unknown | 38.2 | 15/43 | 34.9 | 14/33 | 42.4 | |
| Intralesional hemorrhage | .10 | |||||
| None | 36.5 | 10/41 | 24.4 | 17/33 | 51.5 | |
| Minimum | 18.9 | 9/41 | 22.0 | 5/33 | 15.2 | |
| Moderate | 20.3 | 9/41 | 22.0 | 6/33 | 18.2 | |
| Marked | 24.3 | 13/41 | 31.7 | 5/33 | 15.2 | |
| Vitreous haze | .04 | |||||
| None | 53.9 | 18/43 | 41.9 | 23/33 | 69.7 | |
| Grade 1+ | 28.9 | 14/43 | 32.6 | 8/33 | 24.2 | |
| Grade 2+ | 13.2 | 9/43 | 20.9 | 1/33 | 3.0 | |
| Grade 3+ | 3.9 | 2/43 | 4.7 | 1/33 | 3.0 | |
| Other characteristics | ||||||
| Active CMVR | 87.3 | 34/39 | 87.2 | 28/32 | 87.5 | 1.00 |
| Frosted branch angiitis | 13.5 | 6/41 | 14.6 | 4/33 | 12.1 | 1.00 |
| Multifocal retinitis | 23.7 | 9/43 | 20.9 | 9/33 | 27.3 | .59 |
| Retinal detachment | 6.6 | 5/43 | 11.6 | 0/33 | 0 | .07 |
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