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1 23
Graefe's Archive for Clinical and
Experimental Ophthalmology
Incorporating German Journal of
Ophthalmology
ISSN 0721-832X
Volume 251
Number 6
Graefes Arch Clin Exp Ophthalmol
(2013) 251:1607-1612
DOI 10.1007/s00417-013-2287-6
Searching for viral antibodies and genome
in intraocular fluids of patients with Fuchs
uveitis and non-infectious uveitis
Luca Cimino, Raffaella Aldigeri, Maria
Parmeggiani, Lucia Belloni, Carlo
Alberto Zotti, Luigi Fontana, Alessandro
Invernizzi, et al.
1 23
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INFLAMMATORY DISORDERS
Searching for viral antibodies and genome in intraocular
fluids of patients with Fuchs uveitis and non-infectious uveitis
Luca Cimino &Raffaella Aldigeri &Maria Parmeggiani &
Lucia Belloni &Carlo Alberto Zotti &Luigi Fontana &
Alessandro Invernizzi &Carlo Salvarani &
Luca Cappuccini
Received: 31 July 2012 /Revised: 11 January 2013 /Accepted: 12 February 2013 / Published online: 3 March 2013
#Springer-Verlag Berlin Heidelberg 2013
Abstract
Background To characterise the polyspecific intraocular an-
tibody synthesis in aqueous humor of patients with Fuchs
uveitis and other types of non-infectious uveitis.
Methods Aqueous and serum samples collected from 24
patients with Fuchs uveitis, 21 patients with non-infectious
uveitis, and 27 healthy subjects undergoing elective cataract
surgery (control group) were analysed. In addition, vitreous
samples, collected from seven uveitis patients (five Fuchs
and two panuveitis) during retinal surgery, were examined.
Specific immunoglobulin G antibodies against cytomegalo-
virus (CMV), rubella virus, herpes simplex virus (HSV),
and varicella zoster virus (VZV) were investigated, and
Goldmann–Witmer coefficients (GWCs) were calculated.
Real-time PCR was performed to detect viral genome for
HSV, VZV, and CMV, while nested PCR was conducted to
detect rubella RNA.
Results None of the control samples tested positive for any of
the viral antibodies investigated. Intraocular antibody produc-
tion was found in eight samples of patients affected by Fuchs
uveitis (6/8 positive for rubella virus and 2/8 positive for
herpes virus). Among patients with non-infectious uveitis,
three tested positive for intraocular antibody production (one
RV, one HSV and one for VZV). PCR was positive for RV in
two patients with Fuchs uveitis, in three patients with non-
infectious uveitis (one for RV and two for HSV), and in three
control subjects (one for CMV and one for HSV).
Conclusions Our series confirmed the presence of specific
viral antibodies, especially against rubella virus, in the sub-
group of patients affected by Fuchs uveitis, suggesting that
this virus may be responsible for this chronic inflammatory
condition. Rubella virus is probably the main causative
agent of Fuchs uveitis, but other viruses may also be in-
volved in the pathogenesis of this disease.
Keywords Fuchs uveitis .Aqueous humor .Intraocular
antibody .Rubella virus .Goldmann–Witmer coefficient .
PCR
Introduction
Anterior uveitis is the most common form of intraocular
inflammation, accounting for 50–60 % of all cases of uveitis
[1]. In our previous paper, Fuchs uveitis, a mostly unilateral
granulomatous uveitis that involves the anterior segment and
the vitreous body, represented the most frequent diagnosis.
Since no certain etiopathologic agent has ever been iden-
tified and no diagnostic test has been developed, the diag-
nosis of Fuchs is based on clinical findings. This condition
has some specific clinical characteristics, the main ones
being sparsely distributed stellate granulomatous keratic
L. Cimino (*):C. A. Zotti :L. Fontana :L. Cappuccini
Eye Unit, Arcispedale Santa Maria Nuova - IRCCS,
Viale Risorgimento 80,
42123 Reggio Emilia, Italy
e-mail: l.cimino64@gmail.com
R. Aldigeri
Department of Clinical and Experimental Medicine,
University of Parma, Parma, Italy
M. Parmeggiani :L. Belloni
Clinical Immunology, Allergy and Advanced Biotechnologies
Unit, Arcispedale Santa Maria Nuova - IRCCS, Reggio Emilia,
Italy
A. Invernizzi
Eye Clinic, Department of Clinical Science, Luigi Sacco Hospital,
Milan, Italy
C. Salvarani
Rheumatology Unit, Arcispedale Santa Maria Nuova - IRCCS,
Reggio Emilia, Italy
Graefes Arch Clin Exp Ophthalmol (2013) 251:1607–1612
DOI 10.1007/s00417-013-2287-6
Author's personal copy
precipitates, iris stromal atrophic changes, vitritis, absence
of synechiae, and cystoid macular oedema [2]; when these
signs are all present, the diagnosis of Fuchs is not difficult.
However, as most patients present with only a few of these
typical features, many authors over the years have tried to
define some diagnostic criteria in order to support clinicians
in the less obvious cases. These criteria, however, remain
controversial.
Fuchs uveitis has been associated with intraocular presence
of rubella virus (RV) antibodies and genome [3–11]. Recently,
other viruses like herpes simplex virus (HSV), varicella zoster
virus (VZV), and cytomegalovirus (CMV) have been proven
to be important causes of anterior uveitis [8,12]. The various
types of viral anterior uveitis have similar features, and should
be suspected in eyes with diffuse fine stellate keratic precip-
itates, iris atrophy, or ocular hypertension.
This study used two different diagnostic approaches to
detect the presence of viruses in the aqueous and vitreous
samples of patients [9,13,14], the Goldmann–Witmer co-
efficient (GWC) [3,13,14], and the real-time polymerase
chain reaction (PCR). Our aim was to investigate the role of
viral agents in the pathogenesis of Fuchs uveitis by compar-
ing Fuchs uveitis patients with patients affected by other
forms of non-infectious uveitis, and with controls having no
form of intraocular inflammation, and to determine the
contribution of GWC and of real-time PCR to the diagnosis
of anterior uveitis in a clinical setting.
Methods
Patients
The diagnosis of Fuchs uveitis was based on the presence of
the following clinical features: unilateral uveitis involving
the anterior segment and the vitreous body, absence of acute
symptoms (pain, photophobia), characteristic sparsely dis-
tributed Fuchs stellate keratic precipitates (SKP), diffuse iris
stromal atrophy with or without heterochromia, vitritis, ab-
sence of synechiae, and the absence of cystoid macular
edema [2]. Between March 2009 and March 2011, aqueous
humour (AH) and serum samples were simultaneously col-
lected from 24 consecutive patients affected by Fuchs uve-
itis (study group) and from 21 consecutive patients with
other forms of non-infectious uveitis (control uveitis group)
examined at the Immunology Eye Unit of the Azienda
Ospedaliera IRCCS, Arcispedale S.M. Nuova in Reggio
Emilia, Italy, who underwent cataract surgery. Vitreous
samples were also collected in seven of these patients (five
Fuchs and two panuveitis) during retinal surgery. AH sam-
ples from 27 consecutive patients with no history of intra-
ocular inflammation who underwent elective cataract
surgery were used as controls (control cataract group).
The study was performed according to the tenets of the
Declaration of Helsinki. All patients were informed of the
investigation, and their written consent was obtained before
the study.
The non-infectious uveitis group included 21 patients
affected by HLA B27+ (n=1), Behçet’s disease (n=2),
idiopathic uveitis (n=11), juvenile idiopathic arthritis (n=
4), sarcoidosis (n=2), and VKH (n= 1).
The ocular fluid samples and sera were stored in sterile
tubes at −20 °C until processing. The required volume of
intraocular fluid sample was 30 μl for each virus. Nucleic
acid was collected in a total volume of 50 μl. For amplifi-
cation, 20 μl were used. For protein quantification in intra-
ocular fluid and serum, albumin and total immunoglobulin
G concentration were analyzed with immunochemical neph-
elometry (Siemens, Germany). To match the requested vol-
ume for routine analysis, aqueous humor samples required
pre-dilution with 0.9 % NaCl (1:5–1:10 depending on total
protein concentration).
Antigen specific IgG antibodies against CMV, RV, HSV,
and VZV (IgG
spec
) were measured using a commercially avail-
able one-point quantification ELISA assay (Enzygnost, Sie-
mens, Germany) according to the manufacturer’s instructions.
Albumin and IgG in aqueous humor and serum were analyzed
with immunochemical nephelometry (Siemens, Germany).
The samples of intraocular fluid (1:15–1:60 dilution
depending on total protein concentration) and serum
(1:3,000 dilution) were analysed paired in the same analyt-
ical run. The antibody index (AI) (modified Goldmann–
Witmer Index) was calculated for each virus as previously
described [3]; briefly, the measured optical density was
evaluated as arb.unit by reference to a standard curve. After
multiplication with the dilution factor, we calculated the
specific antibody quotient, QIgG
spec
=IgG
spec
(aqueous hu-
mor)/IgG
spec
(serum) and total antibody quotient QIgG
tot
=
IgG
tot
(aqueous humor)/IgG
tot
(serum) using the aqueous hu-
mor and serum antibody concentrations. The hyperbolic
discrimination line (Q
Lim
) between the blood-derived and
the eye-derived IgG fraction was calculated as QLim ¼
0:93 QAlb2þ6106
0:51:7
hi
103,whereQ
Alb
is
the albumin quotient (Q
Alb
=Alb(aqueous humor)/Alb(serum)).
When QIgG
tot
<Q
lim
, AI was calculated as QIgG
spec
/QIgG
tot
,
when QIgG
tot
>Q
lim
the corrected AI was calculated with AI=
QIgG
spec
/Q
Lim
.
In the event of a multiple positive AI, the highest titer
was considered to indicate the causative pathogen.
The intraocular fluid was examined for the presence of
herpes simplex virus (HSV) types 1 and 2, varicella zoster
virus (VZV), cytomegalovirus (CMV), and rubella virus.
Viral nucleic acids were isolated from intraocular fluid
samples using NucliSens easyMAG system (Biomerieux,
France). The required volume of intraocular fluid sample
1608 Graefes Arch Clin Exp Ophthalmol (2013) 251:1607–1612
Author's personal copy
was 30 μl for each virus. Nucleic acid was collected in a total
volume of 50 μl. For amplification, 20 μl were used. Real-
time PCR analysis was performed for HSV 1 and 2, VZV, and
CMV using commercial kits according to manufacturer’spro-
tocols (Elite MGB Real Time, Nanogen Advanced Diagnos-
tics, Italy). Nested PCR was conducted to detect rubella virus
RNA, according to the manufacturer’s instructions (Rubella
oligomix Alert kit, Nanogen Advanced Diagnostics).
All samples were analysed for intraocular antibody produc-
tion, and PCR was restricted to a subgroup of samples (n=54
aqueous and n=7 vitreous) due to the limited volume of fluid
collected.
Statistical analysis
Data were analysed using SPSS software (version 20.0;
SPSS inc., Chicago, IL, USA). Continuous variables were
tested for normal distribution, and non-parametric tests such
as Kruskal–Wallis and Mann–Whitney were used to com-
pare AI values among groups. The chi-square test was used
for categorical variables. A P-value of less than 0.05 was
considered significant.
Results
We tested the serological parameters against RV, HSV,
CMV, and VZV in all 72 patients for a total of 81 samples
(74 aqueous and seven vitreous).
The characteristics of study population are summarized
in Table 1. The mean age of patients was statistically differ-
ent (P=0.006), uveitis patients being younger than controls.
There was a predominance of males in the study group
(Fuchs) compared with the other groups (P= 0.043).
In the control cataract group, the antibody index (AI) was
negative and equal to 0 for all agents (Table 1). Since the
distribution of AI was not normal, despite the log-
transformation, we used the non-parametric Kruskal–Wallis
test and Mann–Whitney tests to assess the differences
among groups. Analysis of AI between the study group
and the control uveitis group (Mann–Whitney test) was
statistically significant for CMV (p=0.018), rubella (p=
0.016) and VZV (P=0.001) but not for HSV (p= 0.292). In
fact, mean AI for rubella virus was higher among Fuchs
patients than in control uveitis patients, while the mean AI
for VZV was higher in the control uveitis group (Table 1).
The AI tested positive in ten out of 45 patients (22 %).
Positive AI was present in 25 % of samples (7/24) from the
study group and 14 % of samples (3/21) from the control
uveitis group (chi-square test P=0.07) (Table 2).
In the study group, five samples tested positive for rubel-
la; among these, there was additional reactivity against HSV
in one case and against CMV in another case. In both cases,
the AI for rubella tested high (30.47 vs 3.81 and 650 vs 5
respectively). One patient in the control uveitis group also
showed reactivity against RV (AI= 4.3) and HSV (AI=13.1).
Two out of five vitreous samples tested positive for RV
antibodies. One of these patients (AI=30.47) also tested
positive for HSV both in the aqueous and vitreous samples
(11.8 and 3.81 respectively).
None of the vitreous samples in the control uveitis group
tested positive.
PCR analysis was positive in three cataract control sam-
ples (16 %), four samples from the study group (19 %), and
three samples from the control uveitis group (14 %) (Table 3).
Two samples from the study group were positive for
rubella and two for CMV. In the control uveitis group, one
sample was positive for rubella and two for HSV, and in the
control cataract group, one sample was positive for CMV
and two for HSV. None of the samples positive for antibody
production tested positive for the presence of viral genes.
In Table 4, we report the different distribution of clinical
features in patients with Fuchs uveitis that tested positive
and negative for rubella (AI or PCR). The most frequent
ophthalmologic findings were the presence of small keratic
precipitates (96 %), followed by vitreitis (83 %) and
heterochromia (75 %). There was no significant difference
in the distribution of ocular signs between the two groups.
The mean age of rubella positive and negative patients did
not differ significantly.
Table 1 General features of pa-
tients and mean values ± SD of
intraocular antibody index (AI)
against the different viruses
*Mann–Whitney test, p<0.05
†chi-square test, p<0.05
Control
cataract
group
Study group Control uveitis group P-value
Number of subjects 27 24 21
Mean age ± SD
(years)
59 ± 22 44 ± 14 40 ± 24 0.006
*
Male/female 13/14 16/8 6/15 0.038
†
Mean AI for CMV 0.00 0.54 ± 1.17 (range 0–5.1) 0.85 ± 0.78 (range 0–2.4) 0.018
*
Mean AI for rubella 0.00 25.47 ± 122.56 (range 0–650) 1.66 ± 2.64 (range 0–13.7) 0.016
*
Mean AI for VZV 0.00 0.33 ± 0.60 (range 0–1.9) 2.17 ± 6.45 (range 0–33.6) 0.001
*
Mean AI for HSV 0.00 3.83 ± 15.59 (range 0–82.5) 1.21 ± 2.52 (range 0–13.1) 0.292
Graefes Arch Clin Exp Ophthalmol (2013) 251:1607–1612 1609
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Discussion
Our results indicate that AI is more likely than PCR to be
positive in detecting the presence of viral infection [3,4,
10]. In our series, the sensitivity of AI was 25 % and the
sensitivity of PCR was 19 % [3,4,10]. Intraocular antibody
production against rubella virus was present in five out of 24
patients (21 %) with Fuchs uveitis, suggesting that rubella
could be associated with the disease. Our results differ
somehow from those previously reported [3,4,14], where
the association between rubella intraocular production and
Fuchs uveitis was present in more than 90 % of patients.
Nevertheless, we found that five out of seven patients
(75 %) with a positive AI were positive for rubella, suggesting
that this virus could be the most important viral agent involved
in the pathogenesis of Fuchs. The presence of multiple posi-
tive tests in four uveitis patients, three among Fuchs patients
and one among control uveitis patients, suggests co-infection
by different pathogens. This is a common finding previously
reported in different papers [13,14].
In fact, with high seropositivity for herpes viruses in the
Italian adult population, multiple positiveAI is not completely
unexpected, but is characteristic of a subset of co-infected
patients with multiple ocular involvement.
As in the literature, in the case of multiple positive AI
results we considered the highest titer as the causative agent
[13]. This choice is based on the theory that among the
different diseases for which the patient results positive, the
infection causing the clinical picture will generate the highest
immune reaction. In this theory, remaining positive AI can be
explained as the trace of inactive previous infection involving
the eye. The rubella RNA was found in two out of 18 (11 %)
Fuchs patients negative for AI, in one case appearing in the
vitreous sample, and in the second case in the aqueous sample.
This may suggest that during different phases of inflamma-
tion, viral RNA or antibody production may be found in the
vitreous or in the aqueous, and that both AI and PCR could be
useful in confirming the diagnosis of Fuchs uveitis.
Selective inflammatory involvement of different ocular
districts could be another explanation for unexpected findings.
In our opinion, for unknown reasons inflammation may
be restricted to anterior chamber structures in certain pa-
tients, whereas the anterior vitreous could be the main target
in the remaining patients. This different localisation of the
inflammatory process might also explain the Fuchs uveitis
clinical spectrum, justifying the condition with anterior
signs only, as well as patients with intense vitreitis.
However, such compartmental distribution of the inflam-
mation could not be demonstrated, so that further studies are
required to confirm the hypotheses of the authors.
In our series, we considered intraocular antibody produc-
tion to be positive when AI exceeded 3.0, as suggested in a
Table 2 Frequency of AI positivity (AI ≥3.0) against viruses in the
different groups, including aqueous and vitreous samples
Control cataract
group
Study
group
Control uveitis
group
P-value
N=27 N=28 N=26
AI negative 27 (100 %) 21(75 %) 23 (88 %) 0.072
AI positive 0 7 (25 %) 3 (12 %)
CMV 0 0 0
Rubella 0 5 1
VZV 0 0 1
HSV 0 2 1
*Chi-square test,p<0.05
Tab l e 3 Specific PCR positivity against viruses in the different
groups, including aqueous and vitreous samples
Control
cataract
group
Study
group
Control
uveitis
group
P-value
(chi-square
test)
N=19 N=21 N=21
PCR negative 16 (84 %) 17 (81 %) 18 (86 %) 0.43
PCR positive 3 (16 %) 4 (19 %) 3 (14 %)
CMV 1 2 0
Rubella 0 2 1
VZV 0 0 0
HSV 2 0 2
Table 4 Ophthalmologic findings in study group patients positive and
negative for rubella
AI or PCR rubella
positive (n=7)
AI or PCR rubella
negative (n=17)
Mean age 37 ± 14 46 ± 14
M:F ratio 4:3 12:5
Cataract 3 (43 %) 6 (35 %)
Vitreitis 6 (86 %) 14 (82 %)
SKP 7 (100 %) 16 (94 %)
Heterochromia 6 (86 %) 12 (70 %)
Glaucoma 1 (14 %) 4 (23 %)
Iris atrophy 4 (57 %) 12 (70 %)
Table 5 History of rubella immunization among groups
Rubella vaccination
Yes No Not known
Control cataract group 3 (11 %) 23 (85 %) 1 (4 %)
Study group 3 (12 %) 17 (71 %) 4 (17 %)
Control uveitis group 6 (28 %) 13 (62 %) 2 (10 %)
1610 Graefes Arch Clin Exp Ophthalmol (2013) 251:1607–1612
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previous paper [4]. This choice was based on evidence that
the serum antibody positivity of many viral diseases for
which we tested is common in the general population. It
was decided that an increase in cut-off from 1.5 to 3.0 would
improve test specificity, and avoid false positive results from
patients with previous pathogen contact but no related ocu-
lar involvement.
We wish to stress that AI showed great variability even in
patients positive for intraocular production of rubella anti-
bodies, making it difficult to correlate these values to the
ophthalmologic findings. In fact, distribution of the cardinal
clinical signs of Fuchs did not differ between patients
resulting positive or negative for rubella, suggesting we
cannot correlate severity of disease with viral infection.
As reported in Table 5, the history of rubella immuniza-
tion was similar among the three groups (P=0.33), with a
high prevalence of negative immunization against rubella.
The vaccination was introduced in Italy in 1972 for pre-
pubescent females and then replaced by the combined mea-
sles–mumps–rubella (MMR) vaccine in the early 1990s.
However, coverage in children remains suboptimal, with
wide regional variations. [15]
Several etiopathogenic mechanisms have been proposed
for Fuchs uveitis, and we agree with the hypothesis that the
disease might be a phenotypical final common pathway of
different pathogenic mechanisms, rather than the result of a
single pathogenic process [17].
In conclusion, our results confirm a role for rubella virus
in the pathogenesis of Fuchs uveitis, but they also strongly
suggest the plausible existence of one or more additional
agents that could be responsible of this condition.
GWC specificity for rubella in Fuchs uveitis compared to
non-infectious uveitis was very high (95 %), while sensitiv-
ity was only 29 % (likelihood ratio of a positive result = 5.8).
Given a pre-test probability of 17 % for Fuchs uveitis, the
post-test probability of a positive result (GWC) is only
54 %, suggesting this test is not useful for confirming
diagnosis, which remains essentially based on clinical
findings.
Fuchs uveitis rarely leads to the typical long-term conse-
quences of chronic uveitis, and there is no known anti-
inflammatory treatment for changing the course of the dis-
ease [17]; anti-inflammatories should therefore be reserved
for sight-threatening complications, like glaucoma.
One possible limit of this study, compared with previous
reports, was the low number of samples. However, our re-
sults partially agree with the previously assessed role of
rubella in the pathogenesis of Fuchs uveitis [3,4,6,7,10,
14,16], and demonstrate that intraocular fluid analysis is a
valuable tool for better understanding the pathogenesis of
this inflammatory eye disease.
A recent paper attempted to assess the role of viral
infection in unexplained anterior uveitis in an
immunocompetent Thai population. The most frequent
agent identified was CMV (10/30), while five out of 21
(21 %) samples tested positive for rubella, three of which
presenting the clinical features of Fuchs uveitis [18]. This
result confirms that in some cases the clinical features of
Fuchs uveitis could be associated with rubella but also with
other viral infection, for example CMV, and that we need
further analysis with more patients in order to provide more
insight into the relationship between AI and/or PCR posi-
tivity and Fuchs uveitis patients.
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