CLINICAL INVESTIGATION

Infectious causes of posterior uveitis and panuveitis in Thailand

Natedao Kongyai • Kessara Pathanapitoon •

Wasna Sirirungsi • Paradee Kunavisarut •

Jolanda D. F. de Groot-Mijnes • Aniki Rothova

Received: 2 November 2011 / Accepted: 26 March 2012 / Published online: 28 April 2012

� Japanese Ophthalmological Society 2012

Abstract

Purpose To determine the infectious causes of posterior

uveitis (PU) and panuveitis (panU) in Thailand.

Methods We investigated the infectious causes of uveitis

involving the posterior segment of the eye by using real-time

polymerase chain reaction (PCR) for cytomegalovirus (CMV),

herpes simplex virus (HSV-1, HSV-2), varicella zoster virus

and Toxoplasma gondii (T. gondii) DNA in intraocular sam-

ples of 80 human immunodeficiency virus (HIV)-negative

patients. Additionally, in 61 patients, we performed Gold-

mann–Witmer coefficient (GWC) analysis for T. gondii.

Results Twenty-four (30 %) patients with PU and/or

panU had a positive PCR result. Overall, CMV was the

most frequently identified organism. While CMV was the

most common cause of uveitis in the patients on immu-

nosuppressive medications for nonocular disorders, HSV

was the most common cause of posterior and panuveitis in

the patients not receiving such medication. In 38 PU

patients, CMV was the most common detected pathogen.

In 42 panU patients, CMV and HSV-2 were the most fre-

quently identified pathogens. Out of 61 paired samples

analyzed for T. gondii by GWC analysis, only 1 revealed a

positive result. There was no difference in PCR results

between aqueous humor and vitreous samples.

Conclusions CMV was the most frequently identified

infectious organism in posterior and panuveitis of HIV-1-

negative Thai patients. Aqueous humor and vitreous sam-

ples showed similar diagnostic values in PCR analysis.

Keywords Posterior uveitis � Panuveitis � Polymerase

chain reaction � Intraocular fluids � Thailand

Introduction

The etiological spectrum of infectious uveitis differs

throughout the world because of various factors, including

geographic and demographic influences [1–3]. In Western

countries, the most frequent anatomical type of uveitis is

anterior uveitis (AU), whereas in Africa, Asia and South

America, the involvement of the posterior eye segment is

more common [1–3]. Uveitis located in the posterior eye

segment is usually severe and frequently associated with

infections, while the majority of anterior uveitis cases are

temporary, frequently mild and of non-infectious origins.

Early detection of infection is important because specific

antibiotic treatment can be employed for patients with

infections, whereas non-infectious uveitis is usually treated

with immunosuppressive drugs.

Herpes viruses and Toxoplasma gondii (T. gondii) rep-

resent the most common causes of infectious posterior

N. Kongyai � W. Sirirungsi

Department of Medical Technology, Faculty of Associated

Medical Sciences, Chiang Mai University, Chiang Mai, Thailand

K. Pathanapitoon (&) � P. Kunavisarut

Department of Ophthalmology, Faculty of Medicine,

Chiang Mai University, 110 Intawaroros Road,

Chiang Mai 50200, Thailand

e-mail: kpathana@mail.med.cmu.ac.th

J. D. F. de Groot-Mijnes

Department of Virology, University Medical Center Utrecht,

Utrecht, The Netherlands

J. D. F. de Groot-Mijnes � A. Rothova

Department of Ophthalmology, University Medical Center

Utrecht, Utrecht, The Netherlands

A. Rothova

Department of Ophthalmology, Erasmus Medical Center,

Rotterdam, The Netherlands

123

Jpn J Ophthalmol (2012) 56:390–395

DOI 10.1007/s10384-012-0144-5

uveitis (PU) in Western countries, but a different spectrum

of infections might be encountered in other geographical

areas [1–3]. Although T. gondii and herpetic infections

were recognized as the major causes of infectious posterior

and panuveitis (PU) in Asian populations, in those studies,

the specific diagnoses were based mainly on clinical

grounds, sometimes in combination with laboratory blood

analysis and imaging studies of the chest [2–4].

We investigated the infectious causes of uveitis

involving the posterior segment of the eye by analyzing the

intraocular fluids using real-time polymerase chain reaction

(PCR). In addition, we assessed the diagnostic values of

aqueous humor and vitreous humor samples.

Materials and methods

Eighty intraocular fluid samples from 80 consecutive

patients with PU (n = 38) and panU (n = 42) of unknown

origin and negative results in the uveitis screening protocol

(see below) were collected at the Department of Ophthal-

mology, Chiang Mai University Hospital from 2005 to

2010. Uveitis classification was performed according to the

anatomic localization recommended by the SUN working

group [5]. All patients tested negative for human immu-

nodeficiency virus type 1 (HIV-1). We attempted to collect

the samples in a systematic manner without inclusion bias.

Aqueous sampling was carried out as a second diagnostic

step in patients with negative initial screening, which

included chest X-rays and various laboratory tests,

including erythrocyte sedimentation rates, complete blood

counts and serology for Treponema pallidum. When

appropriate, the tuberculin skin test and serology for

T. gondii were also administered. Intraocular fluid samples

and paired plasma were collected from the patients

approximately within 1 or 2 weeks after the presentation.

Vitreous collection was principally performed as a third

diagnostic step, with the exception of those patients with

retinal detachment or extremely severe vitritis where

therapeutically pars plana vitrectomy (PPV) was required

and vitreous samples could be collected during surgery

without previous aqueous humor acquisition.

Ten out of the 80 patients received immunosuppressive

medications for systemic diseases or organ transplants.

This study was performed with the approval of the local

medical ethics committee and complied with the tenets of

the Declaration of Helsinki.

Intraocular fluid specimens included 54 aqueous humor

and 26 vitreous humor samples. All samples were stored at

-70 �C until laboratory analyses. The laboratory investi-

gations were performed at the Division of Clinical

Microbiology, Department of Medical Technology, Faculty

of Associated Medical Sciences, Chiang Mai University,

Chiang Mai, Thailand. All 80 intraocular fluid samples

were analyzed for cytomegalovirus (CMV), herpes simplex

virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), vari-

cellar zoster virus (VZV) and T. gondii DNA by real-time

PCR.

Real-time PCR analysis was performed as follows.

Nucleic acid was extracted from 25 ll of intraocular fluid

using the QIAamp� DNA Blood Mini Kit (QIAGEN, Inc.,

Germantown, MD, USA). Before extraction, 2,500–5,000

copies/ml of phocid herpes virus type 1 (PhHV-1) were

added to each sample to monitor the quality of extraction

and the amplification procedures [6]. Each focal pathogenic

DNA was separately analyzed by real-time PCR with a

repeated cycling program as previously described [7, 8].

Briefly, 10 ll of the extracted nucleic acid was added to

15 ll of the real-time PCR mixture (DyNAmoTM Probe

qPCR kit, New England Biolabs Inc., Keilaranta, Espoo,

Finland), which contained specific primers and probes.

Then, real-time PCR was performed in a Chromo4TM-Real-

time PCR Detector Machine (DNA Engine�, Bio-Rad,

Hercules, CA, USA) [8].

In addition, in 61 out of the 80 patients, paired plasma

and intraocular samples were tested for active intraocular

production of a specific antibody against T. gondii

by Goldmann–Witmer coefficient (GWC) analysis. The

amount of specific immunoglobulin G (IgG) against

T. gondii in plasma and intraocular fluid was determined by

Sirion� ELISA classic Toxoplasma gondii IgG kits (Serion

Immunodiagnostica GmbH, Wurzburg, Germany). The

assay was performed according to the manufacturer’s

instructions. Total IgG concentrations were measured by an

in-house ELISA using commercially available reagents.

For the total IgG concentration determination, seven serial

two-fold dilutions of a nephelometer N Protein standard SL

(Dade Behring, Siemens Healthcare Diagnostics, Products

GmbH, Marburg, Germany) were included. A GWC value

equal to or greater than 3 was considered positive and

indicative of active intraocular antibody production [7].

For statistical analysis, we used Fisher’s exact test and

Pearson’s Chi-square test to compare the diagnostic values

of the aqueous humor and vitreous humor analysis. P val-

ues below 0.05 were considered significant. All statistical

calculations were performed using STATATM 10.1 soft-

ware (Statacorp, College Station, TX, USA).

Results

The average age of the patients was 42 years (range

6–67 years), and the male-to-female ratio was 1:1.2.

The results of the PhHV-1 internal control real-time

PCR implied successful nucleic acid extraction and no

inhibition of the amplification reactions in all the samples.

Infectious causes of posterior uveitis 391

123

Positive PCR results for any of the investigated agents

were found in 24/80 (30 %) patients. CMV was the most

frequently detected pathogen (12/80; 15 % of all and

12/24; 50 % of those with a positive PCR). HSV-1, HSV-2,

VZV and T. gondii were found in similar low percentages

(3–10 %, Table 1).

The infectious causes of PU and panU were similar;

however, HSV-2 and VZV were detected solely in panU

(Table 1). CMV was the most common cause of PU

(21 %), followed by HSV-1 and T. gondii. In panU, CMV

and HSV-2 were most commonly detected (both 10 %). All

10 patients receiving immunosuppressive medications were

positive for CMV in PCR, while only 2/70 patients who did

not received immunosuppressive agents had a positive PCR

result for CMV (P \ 0.001). In patients without immuno-

suppressive medications, HSV was the most common

cause of uveitis located in the posterior eye segment (7 out

of 70, 10 %).

In addition to PCR, GWC analysis for T. gondii revealed

a positive result in 1/61 patients (1.6 %, Table 2). This

patient was a 55-year-old woman with unilateral panuveitis

and focal retinitis, a negative result for PCR and positive

GWC result (5.28).

A comparison between aqueous humor and vitreous

humor PCR results is given in Table 3. Aqueous humor

samples exhibited positive PCR results in 19/54 (35 %)

and vitreous humor samples in 5/26 (19 %) (P = 0.145;

Pearson Chi-square analysis; Table 3). VZV (n = 2) and

T. gondii (n = 3) were detected solely in the aqueous

humor samples. When PU and panU were compared, no

differences were observed in either the aqueous humor or

the vitreous humor.

Clinical features of patients are given in Table 4. Ten

out of 12 (83 %) CMV-positive patients were considered

partially immunosuppressed because of immunosuppres-

sive drugs (in contrast to 0/12 patients positive for the other

investigated infection agents, P \ 0.001, and to 3/56

patients of undetermined etiology, P \ 0.001, Fisher’s

exact test). Clinical features of HSV-1 infection included

focal retinitis, vitritis and tractional retinal detachment.

Three out of 4 patients with HSV-2 infection were younger

than 30 years, and all had clinical characteristics of acute

retinal necrosis (extensive necrotic peripheral retinitis with

hemorrhages).

Four patients were diagnosed with ocular toxoplasmo-

sis: three with real-time PCR and one additional patient

with GWC, but none of these had positive results in both

examinations. Three patients had focal retinitis and one

had retinal vasculitis without any focal retinal lesions

detectable.

Our study included 10 patients with focal retinitis of

unknown origin who were negative in real-time PCR (10/

10) and GWC (8/8) for T. gondii. Toxoplasma serology

was negative in 2 out of 7 tested.

Acute retinal necrosis (ARN) was diagnosed clinically

in 9 patients, of whom 4 were associated with positive PCR

results for CMV, 3 for HSV-2 and 1 for VZV.

Discussion

In our study, CMV was identified as the most common

infectious entity in HIV-negative patients with PU and

panU (12/80; 15 %). High percentages of CMV infections

in our posterior and/or panuveitis patients differ from a

previous study in which the main culprit was Toxoplasma

gondii [9]. Reports on CMV-associated posterior or pan-

uveitis in HIV-negative patients are limited and usually

described in post-transplant patients with severe immuno-

suppression [10–13]. In our series, the use of immuno-

suppressive drugs played a definite role in the development

of CMV-associated PU and panU as these medications

were being used in 83 % of our CMV-positive patients.

HSV was the most common cause of both the posterior and

panuveitis in those patients not receiving immunosup-

pressive medications.

The small number of ocular toxoplasmosis cases (5 %) in

our series is distinct from the West, where ocular

Table 1 Detection of infectious agents by real-time PCR in intra-

ocular fluids of posterior uveitis and panuveitis patients

Infectious

agents

Positive results of real-time PCR (%)

Posterior uveitis

(N = 38)

Panuveitis

(N = 42)

Total

(N = 80)

CMV 8 (21 %) 4 (10 %) 12 (15 %)

HSV-1 2 (5 %) 1 (2 %) 3 (4 %)

HSV-2 0 (0 %) 4 (10 %) 4 (5 %)

VZV 0 (0 %) 2 (5 %) 2 (3 %)

T. gondii 2 (5 %) 1 (2 %) 3 (4 %)

Total 12 (31 %) 12 (29 %) 24 (30 %)

PCR, polymerase chain reaction; CMV, cytomegalovirus; HSV-1,

herpes simplex virus type 1; HSV-2, herpes simplex virus type 2;

VZV, varicella zoster virus; T. gondii, Toxoplasma gondii

Table 2 Detection of Toxoplasma gondii by Goldmann–Witmer

coefficient in intraocular fluids of posterior uveitis and panuveitis

patients

Infectious

agents

Positive results of Goldmann–Witmer coefficient (%)

Posterior

uveitis

(N = 31)

Panuveitis

(N = 30)

Total (posterior and

panuveitis) (N = 61)

Toxoplasmagondii

0 (0 %) 1 (3.3 %) 1 (1.6 %)

392 N. Kongyai et al.

123

toxoplasmosis represents a major cause of posterior segment

inflammations [14, 15]. Absence of ocular toxoplasmosis

was noted in China as well [16]. Causes for these regional

differences are unknown; various factors such as diet,

hygiene, infection of the environment by cysts and differ-

ences in pathogenicity of the regional strains might all be

involved. In addition, the age in which seroconversion and

parasitemia takes place might also play a role. Seropreva-

lence for T. gondii in Thailand was 17 % [17], comparable

to China (14.8 %) [18] and India (24 %) [19], but lower than

in Indonesia (58–70 %) [20, 21] and higher than in Vietnam

(4.2 %) [22]. When compared to the West, seroprevalence

for T. gondii in Thailand was lower than in the Netherlands

(41 %) and France (75 %), but similar to the US

(14–22.5 %) where T. gondii infections represent the most

common cause of intraocular infections in PU [1, 23]. Fur-

ther research is required to clarify these discrepancies.

Herpetic infectious uveitis is reported in many previous

studies. The prevalence of herpetic uveitis among PU and

panU patients varies between 0.6 and 4 % [4, 24–27].

Herpetic infections in the posterior eye segment are pre-

dominantly associated with clinical features of ARN

[28, 29]. In our study, the prevalence of positive PCR

results for HSV and VZV was lower than in Europe [7]. All

4 patients with ARN were positive for either HSV or VZV;

however, similar to previous reports, these viruses were

also identified in the patients with non-ARN panuveitis and

with vasculitis [30, 31].

So far, there is no agreement on which specimens

(aqueous humor or vitreous humor) should be examined for

the detection of infectious agents in posterior segment

uveitis. Until now, a systematic comparison of the diag-

nostic values of the aqueous humor and vitreous humor

samples in posterior uveitis has not been available. In the US,

analysis of the vitreous humor is recommended in patients

with atypical or severe uveitis because it renders a sufficient

volume of specimens for multiple examinations [32, 33].

However, both vitreous tapping and vitrectomy are invasive

Table 3 Comparison of aqueous humor and vitreous humor analysis by real-time PCR in posterior and panuveitis patients

Infectious

agent

Intraocular fluid samples (N = 80) P value; Pearson’s

Chi-square test (aqueous

humor versus vitreous humor)Aqueous humor

(N = 54)

Vitreous humor

(N = 26)

CMV 9 (17 %) 3 (12 %) 0.547

HSV-1 2 (4 %) 1 (4 %) 0.975

HSV-2 3 (6 %) 1 (4 %) 0.742

VZV 2 (4 %) 0 0.320

T. gondii 3 (6 %) 0 0.221

Total 19 (35 %) 5 (19 %) 0.145

PCR, polymerase chain reaction; CMV, cytomegalovirus; HSV-1, herpes simplex virus type 1; HSV-2, herpes simplex virus type 2; VZV,

varicella zoster virus; T. gondii, Toxoplasma gondii

Table 4 Clinical manifestations of patients with posterior uveitis and panuveitis, and results of real-time PCR analysis

Positive PCR result N (80) Male-to-

female

ratio

Average

age

(years)

Focal

retinitis

ARN

features

Choroiditis Retinal

vasculitis

Retinal detachment Optic

neuritis

CMV 12 6:6 46 3 4 0 3 Tractional, n = 1 0

HSV-1 3 2:1 43 1 0 0 0 Tractional, n = 1 0

HSV-2 4 2:2 29 1 3 0 0 Rhegmatogenous, n = 1 1

VZV 2 0:2 49 1 1 0 0 0 0

T. gondii 3 3:0 44 3 0 0 1 0 0

Total patients with

positive PCR

results

24 13:11 43 9 8 0 4 Tractional, n = 2

rhegmatogenous, n = 1

1

PCR-negative

intraocular fluid

analysis

56 24:32 40 10 1 4 9 Tractional, n = 4 exudative,

n = 5 rhegmatogenous,

n = 1

7

PCR, polymerase chain reaction; CMV, cytomegalovirus; HSV-1, herpes simplex virus type 1; HSV-2, herpes simplex virus type 2; VZV,

varicella zoster virus; T. gondii, Toxoplasma gondii; ARN, acute retinal necrosis

Infectious causes of posterior uveitis 393

123

procedures with potential adverse effects, limited accessi-

bility and high costs [32, 33], whereas aqueous humor sam-

pling can be performed conveniently even in an outpatient

setting and is reported to be safe in the hands of an experi-

enced ophthalmologist [34]. Tests performed with aqueous

humor samples showed high diagnostic values, even in

patients with uveitis located in the posterior segment [9, 35,

36]. Our findings on positive results from aqueous humor

samples are in accordance with previous reports on the

diagnostic value of aqueous humor analysis in posterior

uveitis [9, 35, 36]. In our study the aqueous humor and the

vitreous humor samples had similar diagnostic values.

It is reported that the diagnostic efficacy of aqueous humor

analysis can be improved with the concurrent use of GWC

and PCR [7, 37]. Errera et al. recently reported the sensitivity

and specificity of real-time PCR and GWC in intraocular

samples of posterior uveitis patients’ collected at different

time points during the clinical course. GWC showed higher

diagnostic values for T. gondii detection, especially when the

test was carried out late in the disease course [37]. However,

in our study, GWC for T. gondii was found positive in one

patient only. The higher prevalence of positive PCR in ocular

toxoplasmosis in our series could be explained in part by a

severe inflammation encountered in our patients.

There are several limitations to our study, including the

fact that, like in other series from tertiary centers, sampling

of material for intraocular analysis was performed with a

strong selection bias. Obviously, less severe cases with

clinically easily recognized uveitis entities would not be

sampled. Our results are based on only five tested patho-

gens, which implies that other infections were not con-

sidered. The sensitivity of real-time PCR, the immune

status of the patient and the timing of specimen collection

during the course of disease might also have affected the

results since specific antibodies and genomes of pathogens

are present in the plasma and intraocular fluid at different

times during infection.

Despite these limitations, our findings provide an insight

into the causative agents of infectious posterior uveitis and

panuveitis in HIV-1-negative Thai patients and further

reveal that an analysis of the aqueous is highly informative

for inflammations of the posterior eye segment.

Conclusions

CMV infection represents the most frequently identified

infectious organism in posterior and panuveitis in HIV-

negative patients in Thailand. PCR examinations of the

aqueous humor and vitreous humor samples exhibited

similar diagnostic values.

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