Telemedicine Screening for Cytomegalovirus RetinitisUsing Digital Fundus Photography

Jinesh M. Shah, FRCSEd (UK),1 Seo W. Leo, FRCSEd (UK),2,3

James C. Pan, FRCSEd (UK),3,4 Vernon K. Yong, FRCSEd (UK),3

Elizabeth P. Wong, BSc (Hons),3 Tock H. Lim, FRCSEd (UK),3

and Stephen C. Teoh, FRCSEd (UK)3

1Yong Loo Lin School of Medicine, National Universityof Singapore, Singapore.

2Dr Leo Adult & Paediatric Eye Specialist, Singapore.3National Healthcare Group Eye Institute, Departmentof Ophthalmology, Tan Tock Seng Hospital, Singapore.

4Nobel Eye & Vision Centre, Singapore.

AbstractBackground: Screening for cytomegalovirus retinitis (CMVR) is

important in patients with acquired immune deficiency syndrome

and low CD4 + counts. However, many human immunodeficiency

virus (HIV) patients lack access to specialist ophthalmological

care. Telemedicine screening is a cost-effective method for

screening these patients. We aimed to report the use of composite

nine-field digital fundus photography (DFP) images for CMVR

screening. We report its sensitivity and specificity in detecting

CMVR and the level of agreement with gold-standard binocular

indirect ophthalmoscopy. Materials and Methods: An audit was

performed on our national CMVR screening program that screened

all HIV patients referred to the Ophthalmology Department at Tan

Tock Seng Hospital, Singapore. All patients underwent retinal

screening with DFP. Images were categorized as CMVR-positive,

CMVR-negative, suspicious, or unreadable by blinded retinal spe-

cialists. Patients subsequently underwent dilated gold-standard

indirect ophthalmoscopy by a different retinal specialist. Diagnoses

were categorized as CMVR-positive, CMVR-negative, or unread-

able. Sensitivity and specificity of retinal findings on DFP and

kappa values for level of agreement between the two screening

methods were calculated. Results: Three hundred seventy screen-

ings on 188 patients were performed. Twenty-three eyes diagnosed

with CMVR on indirect ophthalmoscopy were also identified on

DFP (100% sensitivity). A 99.9% specificity was achieved. The

fundus photograph of one eye without CMVR was read as CMVR-

positive because of an artifact, accounting for a false-positive.

Kappa values ranged from 0.739 to 0.987. Conclusions: DFP is a

sensitive and specific method of screening HIV patients for CMVR

and has a high level of agreement with indirect ophthalmoscopy.

Key words: ophthalmology, telemedicine, telehealth

Introduction

Cytomegalovirus retinitis (CMVR) is the most common

ocular infection affecting acquired immune deficiency

syndrome (AIDS) patients and is an important cause of

blindness among these patients.1,2 It is found in up to a

third of AIDS patients in Southeast Asia.1 The incidence of CMVR is

higher in patients with CD4+ counts <100 cells/lL.3 In the absence of

immune recovery from highly active antiretroviral therapy (HAART),

it is associated with a 60% increase in mortality.4 With modern-day

HAART, CMVR incidence has declined 60–75%,5 and patients with

initial opportunistic infections are also recovering and surviving

longer.5 However, in patients who have commenced HAART, undi-

agnosed and untreated CMVR has an increased risk of developing

immune reconstitution uveitis, a significant cause of visual mor-

bidity among this group.6 Thus underlying CMVR needs to be iden-

tified in both HAART-naive and -treated patients to prevent visual

complications and irreversible visual loss.

Currently, the majority of 34 million HIV cases worldwide occur in

low- to middle-income countries.7 Many human immunodeficiency

virus (HIV) patients still progress to AIDS with decreased CD4 +

counts because of a lack of diagnostic facilities, financial constraints,

and late diagnosis, in both developed and especially developing

countries.4 This increases their risk of complications from opportu-

nistic infections such as CMVR. Therefore, there are large numbers of

patients susceptible to CMVR requiring regular screening. In this

modern day, with increased accessibility to HAART, there are in-

creasing public programs worldwide for early HIV detection and

treatment to prevent AIDS. However, similar screening programs for

CMVR are uncommon.8 Many developing countries lack adequate

facilities and healthcare personnel trained in retinal disease to di-

agnose CMVR. As such, the vast majority of patients requiring reg-

ular CMVR screening will simply not receive it as specialist care is

both limited and inaccessible.

We aimed to report the use of composite montage images derived

from nine-field digital fundus photography (DFP) for CMVR

screening. We report its sensitivity and specificity in detecting CMVR

and establish the level of agreement with indirect fundus ophthal-

moscopy, the gold standard for diagnosis of retinal pathologies.

Materials and MethodsWe conducted an audit of our CMVR screening program for HIV

patients referred to the Department of Ophthalmology at the Center

for Communicable Diseases, the national center for HIV manage-

ment, at Tan Tock Seng Hospital, Singapore. All patients with any of

the following criteria were recruited for screening: (a) any visual

DOI: 10.1089/tmj.2012.0233 ª M A R Y A N N L I E B E R T , I N C . � VOL. 19 NO. 8 � AUG UST 2013 TELEMEDICINE and e-HEALTH 627

symptoms and/or history of (b) CD4 + count <50 cells/lL, (c) AIDS

defining illness, and (d) opportunistic infections. An AIDS-defining

illness referred to the list of diseases published by the U.S. Centers for

Disease Control and Prevention, which may be used to define AIDS.9

An opportunistic infection was defined as an infection caused by a

microorganism that did not ordinarily cause disease but was capable

of doing so under impaired host immunity.10 The audit was con-

ducted over a 12-month period. Basic epidemiological data were

recorded on a standardized form that included demographic char-

acteristics (age, gender, ethnicity) and reason(s) for referral.

After pupil dilation with tropicamide (1%) eyedrops, patients un-

derwent DFP by a qualified technician using a Zeiss (Oberkochen,

Germany) FF450 fundus camera with a Kodak (Rochester, NY)

DCS620 digital-back. Nine standardized fields of 50� each were

captured and stored in raw .tiff format. Automated panoramic re-

construction of the nine images into one composite montage image

of the retinal fundus was performed. The composite image was read

by a retinal specialist blinded to the patient’s history. Features sug-

gestive of CMVR, as well as other features such as vitreous haze and

HIV retinopathy, were noted. CMVR was diagnosed based on the

characteristic clinical appearance of lesions, typically consisting of

an area of retinal opacification (necrosis or edema) surrounded by

granular infiltrates and a silvery-white border marking the edge of

the active borders, with variable amounts of retinal hemorrhage and

inflammatory vascular sheathing.11 Each fundus photograph was

then classified as ‘‘active CMVR positive,’’ ‘‘active CMVR negative,’’

‘‘CMVR suspicious,’’ or ‘‘unreadable/poor view.’’ Patients previously

diagnosed with CMVR with inactive current residual lesions were not

considered to have active CMVR.

Diagnosis was confirmed with dilated indirect ophthalmoscopy by

another trained ophthalmologist after each patient was asked for

visual symptoms. Indirect ophthalmoscopy is the gold standard for

diagnosis of any retinal pathology, including CMVR. A detailed

retinal drawing was made for each eye, with the location of disease

categorized into three zones: Zone 1 encompassed an area one disc

diameter from the edge of the optic nerve or two disc diameters from

the center of the fovea, Zone 2 extended from the edge of Zone 1

approximately to the equator as marked by a circle identified by the

vortex vein ampullae, and Zone 3 extended anteriorly from the edge

of Zone 2 to the ora serrata.4 Each fundus was again classified as

‘‘active CMVR positive,’’ ‘‘active CMVR negative,’’ or unreadable/

poor view. CMVR-positive patients, defined as having CMVR in at

least one eye, would exit the audit and be treated appropriately

according to protocol.11 Patients who were CMVR-negative and had

‘‘unreadable/poor’’ fundi would continue to return for screening of

both eyes at 3-month intervals, for resolution of media opacity and

screening of the fellow eye.

Descriptive analysis was performed with continuous variables

summarized either as means with standard deviations or as medians

with ranges. The independent-samples t test, Fisher’s exact test, and

the Mann–Whitney test were used for comparison between the

CMVR-positive and non-CMVR patients’ ages, gender, and CD4 +

count, respectively. Using indirect ophthalmoscopy as the gold

standard, sensitivity, specificity, and kappa statistics for DFP were

calculated. Data analysis was performed using IBM SPSS Statistics

(version 19; IBM Corp., New York, NY).

ResultsSCREENING PROFILE

During the 12-month period, 370 screenings (740 eyes) were per-

formed on 188 HIV patients. All patients referred for screening were

included. Ninety-six patients underwent one screening, and 48.9% of

patients received more than one screening: 28 patients underwent two

screenings, 41 patients completed three screenings, 20 patients un-

derwent four screenings, and 3 patients completed five screenings.

DEMOGRAPHIC PROFILE OF PATIENTS (TABLE 1)The mean age of the 188 patients was 43.9 – 11.0 years. There were

164 males (87.2%). There were 166 Chinese patients (88.3%), 6 Indian

patients (3.2%), 4 Malay patients (2.1%) and 12 patients (6.4%)

classified as white and/or Eurasian. The median CD4 + count was 30

cells/lL (range, 1–827 cells/lL). The mean age of the 17 CMVR pa-

tients was 43.9 – 6.0 years, compared with the 171 non-CMVR pa-

tients with a mean age of 43.9 – 11.4 years ( p = 0.981). Fifteen of the

17 CMVR patients (88.2%) were males ( p > 0.999), compared with the

171 non-CMVR patients (of whom 87.1% were males). Sixteen

(94.1%) CMVR patients were Chinese, and 1 (5.56%) was Indian. The

median CD4 + count of the CMVR patients was 15 cells/lL (range, 2–

104 cells/lL) compared with 33 cells/lL (range, 1–827 cells/lL) in the

HIV patients with no CMVR ( p = 0.035).

Table 1. Patient Demographics

WITHOUTCMVR

WITHCMVR P VALUE

Number of patients [n (%)] 171 (90.96) 17 (9.04)

Gender [n (%)] > 0.999a

Male 149 (87.13) 15 (88.24)

Female 22 (12.87) 2 (11.76)

Ethnicity [n (%)]

Chinese 150 (87.72) 16 (94.12) 0.563a

Malay 4 (2.34) 0 (0.00)

Indian 5 (2.92) 1 (5.88)

Other 12 (7.02) 0 (0.00)

Age (years) [mean (standard deviation)] 43.9 (11.4) 43.9 (6.0) 0.981b

CD4 + count (cells/lL) [median (range)] 33 (1–827) 15 (2–104) 0.035c,d

aBy Fisher’s exact test.bBy independent-samples t test.cBy Mann–Whitney test.dSignificant difference.

CMVR, cytomegalovirus retinitis.

SHAH ET AL.

628 TELEMEDICINE and e-HEALTH AUGUST 2013

SCREENING OUTCOME (TABLE 2)Twenty-four eyes (3.2%) from 18 patients (9.6%) were read as

‘‘positive’’ for active CMVR on DFP, whereas 675 eyes were reported

as ‘‘negative’’ for active CMVR. Twenty-five eyes (3.4%) were re-

ported ‘‘suspicious’’ for CMVR. The photographs of 16 eyes from 8

patients were ‘‘unreadable’’: 6 eyes had dense cataracts, 1 was

phthisical, and 1 had vitreous hemorrhage secondary to proliferative

diabetic retinopathy. After indirect ophthalmoscopy, 23 eyes (3.1%)

from 17 patients (9.0%) were confirmed to have active CMVR, with 6

patients having bilateral disease on presentation; 701 eyes were

‘‘CMVR-negative,’’ whereas the same 16 eyes had ‘‘unreadable’’ fundi.

SENSITIVITY AND SPECIFICITY (TABLE 2)The sensitivity of DFP screening was 100% as all 23 eyes with

active CMVR were identified. There was 1 case of false-positive

reading on DFP as the fundus photograph of one eye with no CMVR

was read as positive because of a lens reflective artifact in the pe-

ripheral region. As such, the specificity of our DFP screening was

99.9%.

AGREEMENT BETWEEN BOTH DEVICESThe overall agreement between DFP and indirect ophthalmos-

copy was 0.739 (95% confidence interval, 0.643, 0.834). If the

CMVR-suspicious cases on DFP were excluded, the kappa value

increased to 0.987 (95% confidence interval, 0.961, 1.000). All 16

eyes that were unreadable on DFP were also unreadable on indirect

ophthalmoscopy.

DiscussionTelemedicine diagnosis with fundus photography is particularly

suited for diagnosis of retinal diseases such as CMVR as diagnosis is

clinical, based on typical fundus appearances. Telemedicine has al-

ready been shown to be effective in screening for diabetic retinop-

athy and retinopathy of prematurity.12,13 With increased Internet

connectivity and telecommunication worldwide, telemedicine is able

to reach out to patients even in remote locations. Furthermore,

telemedicine is cost-effective for both doctor and patient, as man-

power and traveling costs of screening visits are reduced. These are

important, as many HIV patients are financially challenged and lack

accessibility to specialist care. As such, examining at-risk HIV pa-

tients for CMVR in underserved areas remotely via telemedicine with

DFP is a novel solution of reaching out to patients who would oth-

erwise not have access to specialist ophthalmological care. This study

investigated telemedicine’s validity against traditional gold-standard

methods for CMVR screening before institution of possible screening

programs.

Successful implementation of such a screening program in rural

areas depends on feasibility of application. Retinal cameras are very

common, and technicians are easily trained to perform retinal fundus

photography with nine-field views obtained by having the patient

look in different directions.

Cost-effectiveness is also important for telemedicine to be widely

used in developing countries. One of the main factors is manpower

cost associated with the evaluating reviewers. In assessing the fea-

sibility of telemedicine screening, we used expert graders (consultant

retinal specialists) to avoid any limitation due to observer expertise.

With feasibility now demonstrated from our study, we propose that

the evaluation of photographs can be performed by trained retinal

graders whom we feel will be able to perform reading of fundus

photographs as it requires identification of defined visual charac-

teristics; this identification can be trained. The high rate of CMVR

identification was promising given that, unlike the clinical reviewers,

the photo reviewers did not receive any patient information. This

suggests that even when remotely screening for CMVR, photo re-

viewers need not have detailed clinical information and that fundus

photographs alone are adequate for CMVR diagnosis. Without the

apparent need to evaluate patient information, the graders do not

require specialist medical knowledge, and thus the sourcing and

training of non-expert technician graders for evaluating fundus

photographs are simplified.

Telemedicine allows mobility of trained technicians, decreasing

specialist care manpower requirements. The screening process can be

further streamlined with the help of defined enrollment criteria for

the screening program to identify and screen only those patients most

at risk. This then allows ophthalmologists

to focus their time and energies on patients

with significant pathology.

The general quality of our photographs

was good as evidenced by the fact that the

same 16 eyes were unreadable on both DFP

and indirect ophthalmoscopy. Thus clinical

examination did not aid in clarifying any of

the unreadable photos. We also found that a

single composite nine-field image per pa-

tient was adequate to determine CMVR

presence, without needing to additionally

evaluate each of the nine-field images

separately. Evaluation of a single compos-

ite image, which can achieve up to a 95–

105� field of view, saves time and possibly

Table 2. Distribution of Screening Outcomes of 740 Eyes After IndirectOphthalmoscopy and Digital Fundus Photography

DIGITAL FUNDUS PHOTOGRAPHINDIRECTOPHTHALMOSCOPY NO YES SUSPICIOUS UNREADABLE TOTAL

No 675 1 25 0 701

Yes 0 23 0 0 23

Unreadable 0 0 0 16 16

Total 675 24 25 16 740

Sensitivity was defined as (number of true-positives/[number of true-positives + number of false-negatives]) =23/23 = 100%. Specificity was defined as (number of true-negatives/[number of true-negatives + number of false-

positives]) = 675/676 = 99.9%.

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reduces reviewer fatigue from reading multiple images for 1 patient.

We propose that a single high-resolution composite image without

under- or overlap may be adequate for CMVR screening.

In our study, we showed that DFP was an effective method of

screening for CMVR with 100% sensitivity and 99.9% specificity

compared with indirect ophthalmoscopy. There was also substantial

agreement between both methods (kappa value of 0.739).14 This is in

agreement with a study by Ausayakhun et al.8 in Northern Thailand

showing that telemedicine can be an accurate and reliable way of

screening for CMVR. It is noteworthy that the level of agreement

between DFP and indirect fundus ophthalmoscopy rose from 0.739 to

0.987 when ‘‘CMVR-suspicious’’ patients were excluded. Indirect

ophthalmoscopy is the gold standard for CMVR diagnosis, and thus

no case was classified as ‘‘suspicious’’ on indirect ophthalmoscopy.

In our study, all cases found to be suspicious by DFP were diag-

nosed as ‘‘CMVR-negative’’ after indirect ophthalmoscopy. There

was almost perfect agreement between the two methods for

‘‘CMVR positive/negative’’ and ‘‘unreadable’’ fundi,14 and the dif-

ferences in kappa values were due to the ‘‘suspicious’’ lesions caused

by artifacts and illumination limitations on DFP. Therefore, we

conclude that DFP has a high level of agreement with indirect

ophthalmoscopy.

The reliability of our study was increased with a large study

population. Furthermore, 34.0% had been followed up for at least 6

months, and almost half (48.9%) underwent two or more screen-

ings. Patients at risk of CMVR with risk factors such as low CD4 +

counts or history of AIDS-defining illness or opportunistic infec-

tion may develop CMVR over time, and thus multiple screening

visits allowed numerous opportunities to capture CMVR, if any.

However, we acknowledge our study had some limitations. One

possible limitation was observer bias as the ophthalmologist who

took the history also conducted the ophthalmic examination for the

same patient, and thus the diagnosis of CMVR may have been

influenced by the knowledge of a patient’s CD4 + count, presence of

symptoms, and AIDS-defining illnesses. However, we believe that

this mirrors the clinical setting more closely. Second, because the

clinical reviewers were trained ophthalmologists, the influence of a

clinical history on clinical examination should be minimal. Third, it

is theoretically possible that DFP may miss small lesions within

Zone 3. However, only 2% of newly diagnosed CMVR patients have

lesions confined to Zone 3 at diagnosis.15 CMVR progresses at an

average rate of 24 lm/day in patients who were not on anti-cyto-

megalovirus treatment or HAART.16 Even if small lesions in Zone 3

were present and undetected on DFP, we believe that our screening

time interval of 3 months was sufficient to detect the lesions prior to

development of significant visual loss secondary to macula or optic

disc involvement, the major cause of CMVR-related visual loss.4

Nonetheless, the advent of ultra-wide-field imaging such as with

the Optomap� imaging system (Optos PLC, Dunfermline, Scotland,

United Kingdom) may increase the peripheral view. Mudvari et al.17

reported that the Optomap captured 48% greater retinal area and

40% greater CMVR area compared with standard nine-field pho-

tography when imaging for CMVR.

We have demonstrated that, compared with indirect ophthal-

moscopy by trained ophthalmologists, composite nine-field digital

fundus photography is a useful, sensitive, and specific screening

tool for CMVR detection in HIV patients and that there is a high

level of agreement between both techniques. Based on our results,

only patients who were positive or suspicious for disease, or those

with unreadable photographs, will need to be recalled for clinical

review and treatment, saving much time for most patients and re-

ducing clinic workload for ophthalmologists. It is hoped that this

will be adopted by many communities worldwide, especially in

rural areas or places where specialty care to detect and treat early

CMVR is limited, hence reducing the incidence of permanent visual

loss from CMVR.

AcknowledgmentsThe origin of this work/study was the National Healthcare Group

Eye Institute, Department of Ophthalmology, Tan Tock Seng Hospi-

tal, Singapore.

Disclosure StatementNo competing financial interests exist.

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Address correspondence to:

Stephen C. Teoh, FRCSEd (UK)

National Healthcare Group Eye Institute

Department of Ophthalmology

Tan Tock Seng Hospital

11 Jalan Tan Tock Seng, 308433

Singapore

E-mail: stephen_teoh@ttsh.com.sg

Received: September 15, 2012

Revised: November 7, 2012

Accepted: November 8, 2012

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