Download Hypertensive anterior uveitis

Staff Lecture 2015.4.15
Uveitic Glaucoma
Hypertensive anterior uveitis
성빈센트병원 안과
최진아
Glaucoma associated with
Ocular inflammation
• Clinical course
– Acute
– Subacute
– Chronic
• Etiology
- Infectious
- Non-infectious
• Location
–
–
–
–
Anterior 45.8 %
Intermediate 15.3 %
posterior 14.5 %
Panuveitis (anterior and posterior) 24.5%
Non-infectious
uveitic condition
Infectious uveitic
condition
• Bacterial and fungal disease
• AIDS
• Acute retinal necrosis and
progressive outer retinal
necrosis
• Other viral disease
– HSV keratitis and keratouveitis
– H.zoster ophthalmicus
•
•
•
•
Ocular toxoplasmosis
Ocular histoplasmosis
Toxocara canis
Post-surgical endophthalmitis
• Anterior uveitis
– Idiopathic
– HLA-B27 associated
– HLA-B27 associated with
systemic disease
•
•
•
•
•
•
•
•
•
•
•
Scleritis
Intermediate uveitis
Sarcoidosis
Sympathetic ophthalmia
Vogt-Koyaagi-Harada disease
Birdshot Retinochoroidopathy
Behcet’s disease
Retinal vasculitis
Serpiginous Choroidopathy
White-dot syndrome
Marsquarade syndrome
Anterior uveitis
• The most common form of uveitis
• Associated complications such as glaucoma may
result in severe visual loss
• Major indicator
– Presence of cells and flare in the anterior chamber
• Category
– Irititis (inflammation of the iris)
– Iridocyclitis (inflammation of the iris and ciliary body)
• The form of ocular inflammation producing the
elevation of intraocular pressure is iridocyclitis.
Aqueous production
• Inflammation of the ciliary body
– Reduced aqueous production
Aqueous Outflow
•
Acute mechanism
•
– Open angle
• Inflammatory cells and fibrin
• Prostaglandin
• Swelling or dysfunction of the
trabecular lamellae or endothelium
• Precipitates on the trabecular meshwork
• Use of corticosteroid
– Closed angle
• Acute pupillary block glaucoma
• Uveal effusion with forward rotation of
the ciliary body
• Displacement of the lens-iris diaphragm
due to exudative retinal detachment
Chronic mechanism
– Scarring and
obliteration of
outflow channel
– Overgrowth of
fibrovascular
membrane
– Synechial closure of
the angle
– Posterior synechiae
and iris bombe
Syndromes of Anterior Uveitis Uveitis, Mosby
Disease
Age
Sex
Ocular
Redness
HLAB27
Steroid
response
Systemic finding
Idiopathic
Any
Either
Yes
No
Yes
None
HLA-B27, ocular
only
15-40
M>F
Yes
Yes
Yes
None
Ankylosing
spondylitis
15-40
M>F
Yes
Yes
Yes
Spondylitis, sacroiliitis
Reiter’s syndrome 15-40
M>F
Yes
Yes
Yes
Arthritis, urethritis,
mucocutaneous lesion
Juvenile
rheumatoid
arthritis
3-16
F>M
No
No
Yes
Pauciarticular arthritis
Fuchs’
iridocyclitis
Any
Either
No
No
Yes / No
None
PosnerSchlossman
syndrome
Adult
Either
No
No
Yes
None
Schwartz
syndrome
Adult
Either
No
No
1. Onset of IOP elevation
2. Correlation between inflammation
Noand IOP elevation
None
Ocular ischemia
>50
Either
Yes
No
No
Carotid insufficiency
Kawasaki disease
1-18
Either
Yes
No
Yes
Skin rash..
Glaucomatocyclitic crisis
: Posner-Schlossmann
syndrome
• Uniocular, young to middle
aged adult
• Recurrent attack of mild
uveitis with marked
elevation of IOP ranged of
40-60 mmHg
• Between attack : IOP and
facility of aqueous outflow
usually normal
Fuchs Heterochromic
Cyclitis
• Mild uveitis, heterochromia,
cataract, occasional
glaucoma
• Uveitis runs a single, very
protracted course
• IOP elevation occur as a
late, serious complication
Case I HAU
A 27 year-old female with ocular discomfort (OS)
History of Posner-Schlossman syndrome for several years
IOP: 36 mm Hg
• On low magnification slit lamp examination, the cornea showed some fine
keratic precipitates.
• On high magnification slit lamp examination, fine hammered silverappearance of entire corneal endothelium was seen.
Choi JA, La TY, International Journal of Ophthalmology, 2014
Case I HAU
Case 2 HAU
A 53-year-old male with suddenly decreased VA(OD)
BCVA: 0.15, IOP: 55mmHg
Preoperative images:
The slit lamp exam shows
(A) Fine round or stellate keratic precipitates and fine filaments on the
endothelium between the keratic precipitates
(B) Patchy loss of the iris pigment epithelium.
Lee JA and Choi JA, KJO, in Press
Case 2 HAU
After the Ahmed valve implantation
(A) The valve tip was well positioned at superotemporal side (POD 1d)
(B) The slit lamp shows depigmented atrophic iris and posterior
synechiae(POD 8m)
(C) Before PPKP
Case 2 HAU
Remarkable changes of corneal endothelial cell density:
(A) Before Ahmed valve implantation
(B) POD 7 months after Ahmed valve implantation
(C) POD 13 months after Ahmed valve implantation
(D) Before cataract surgery
Hypertensive Anterior Uveitis
- associated with virus
I.
Clinical
Characteristics
: CMV
Corneal
endothelium
II. Etiology
: T-cell senescence
vs. lymphopenia
1. Clinical characteristics of HAU
Emerging viral anterior uveitis
• A cause of what previously had been considered to be
idiopathic ocular inflammations
• Acute, recurrent and chronic anterior uveitis associated
with IOP elevation
• Three members of the lifelong Herpesviridae family
– herpes simplex virus (HSV)
– varicella zoster virus (VZV)
– most recently, cytomegalovirus (CMV)
1. Clinical characteristics of HAU
I. HSV-associated anterior uveitis
• Recurrent conjunctivitis, keratitis, and uveitis
• 28% had IOP elevation and 10% had glaucomatous
damage in patients with HSV keratouveitis.
• Disciform or stromal form keratitis
– More associated with IOP elevation and keratitic precipitate
1. Clinical characteristics of HAU
II. VZV-associated anterior uveitis
• Characteristic cutaneous vesicular eruption along the
trigemimal distribution
• Often occurs with herpes zoster ophthalmicus
• Keratitis and uveitis
• Commonly leads to glaucoma
• Sectorial iris atrophy
• Mutton fat keratic precipitates
1. Clinical characteristics of HAU
III. CMV-associated anterior uveitis
• the pathogen most recently implicated in anterior uveitis
• acute, recurrent or chronic disease.
• present as acute relapsing hypertensive anterior uveitis
–
–
–
–
Posner-Schlossman syndrome (PSS)
Fuchs’ heterochromic iridocyclitis (FHI)
Corneal endotheliitis
Sector iris atrophy with iritis
• Often fail to respond to corticosteroid
1. Clinical characteristics of CMV-HAU
Typical feature of CMV anterior uveitis
Acute form
Chronic form
• Episodic hypertensive anterior
uveitis
• resembling the PosnerSchlossmann syndrome, with
attacks of mild iritis, elevated IOP
and diffuse corneal epithelial
edema, and a few fine KPs.
• Although the IOP is normal in
between attacks and the angles
are open, about 23% of these
eyes may develop glaucomatous
damage as a result of the
repeated attacks.
• a chronic variety of CMVassociated anterior uveitis
• manifests in a manner similar to
Fuchs heterochromic iridocyclitis
• (FHI) with asymptomatic, mild
inflammation, and diffuse stellate
KPs.
• There may be diffuse iris atrophy.
• Posterior synechiae are typically
• absent.
• The IOP is often elevated and
glaucomatous optic atrophy is seen
in 36%.
Corneal endotheliitis
• white, medium sized, nodular deposits were also
noted on the endothelium
• a surrounding translucent halo
• range from a small localized area to diffuse
bullous keratopathy
• In eyes with focal edema, a sharp demarcation
line may be present
• The KPs are usually seen in the inferior half of
the cornea and may be diffuse, linear, or
organized in a ring pattern or appear as a coinlike lesion.
• In Singapore, CMV was found to be the infective
agent in 22.8% of eyes with hypertensive
anterior uveitis and in all the cases of corneal
endotheliitis.
Ophthalmology 2007;114:798–803
Am J Ophthalmol 2012;153:445–453
1. Clinical characteristics of CMV-HAU
Association of viral load with IOP elevation
Jpn J Ophthalmol 2013:57:497–502
Graefes Arch Clin Exp Ophthalmol
2014:252:117–124
1. Clinical characteristics of CMV-HAU
Association of viral load with corneal endothelial
cell loss
•
Correlation between
cytomegalovirus (CMV) viral
load and corneal endothelial
cell damage (r=0.664; p=0.036)
Br J Ophthalmol 2010;94:336e340
Jpn J Ophthalmol 2013:57:497–502
1. Clinical characteristics of CMV-HAU
• Mean patient age : 66.9±10.9 yrs
• 85 males (80.2%), 21 females
(19.8%)
• Patients were commonly
diagnosed with anterior uveitis
and ocular hypertension prior to
confirmation of CMV endotheliitis.
• Coin-shaped lesions were
observed in 70.6%, and linear
keratic precipitates in 8.3% of the
patients, respectively.
Br J Ophthalmol. 2015;99(1):54-8.
1. Clinical characteristics of CMV-HAU
Treatment of CMV anterior uveitis (1)
• Ganciclovir
– first phosphorylated by the viral kinase UL97,
– further phosphorylated by cellular kinases to Ganciclovir
triphosphate
– inhibits the viral DNA polymerase UL54
– Systemic form
– Intravitreal
– Topical form (gel)
– Side effect : neutropenia, thrombocytopenia, anemia, renal
dysfunction, confusion, nausea, and thrombophlebitis
1. Clinical characteristics of CMV-HAU
Treatment of CMV anterior uveitis (2)
• Valganciclovir
– a valine ester of Ganciclovir, which has much better oral
bioavailability than Ganciclovir
• Foscarnet
– Side effect : nephrotoxicity, electrolyte imbalance, nausea,
vomiting, penile ulceration, headache, seizure, thrombophlebitis
• Cidofovir
– Seldom used
1. Clinical characteristics of CMV-HAU
Treatment of CMV anterior uveitis (3)
• All virostatic and no virucidal
• In majority of the cases, the inflammation resolves with
therapy.
• Inflammation frequently recurs after the anti-CMV
treatment is stopped.
• The optimal modality as well as duration of therapy has
yet to be determined for non-HIV patients with anterior
segment disease.
1. Clinical characteristics of CMV-HAU
Br J Ophthalmol. 2015;99(1):54-8.
Br J Ophthalmol 2010;94:1648e1652
Graefes Arch Clin Exp
Ophthalmol 2014; 252:117–124
1. Clinical characteristics of CMV-HAU
Prognosis of CMV anterior uveitis
• 36.4% of patients required surgical treatment in addition
to oral valganciclovir administration to stabilize the IOP
in CMV-related Posner- Schlossman syndrome.
Graefes Arch Clin Exp Ophthalmol
2014;252(1):117–124.
Patients with CMV-positive
eyes with a disease duration
over 5 years were likely to
require glaucoma surgery
(P =0.024, log-rank test).
Am J Ophthalmol 2014;158:1024–1031
1. Clinical characteristics of CMV-HAU
Cytomegalovirus as a cause of
acute endothelial cell loss in
immunocompetent patients with
hypertensive anterior uveitis
1.Clinical
Clinicalcharacteristics
characteristicsofofHA
CMV-HAU
Method
• Seoul St. Mary’s Hospital from March 2009 to June 2014
• Clinical comparative study design
• Inclusion criteria
– (1) mild anterior uveitis with keratic precipitates (KPs)
– (2) increased intraocular pressure (IOP).
• Exclusion criteria
– (1) presence of inflammation in vitreous or retina; and (2) presence
of corneal changes for a known cause; for example, those with
corneal dystrophies.
1. Clinical characteristics of CMV-HAU
• Aqueous sampling
– Using a 30-gauge needle, 100 µL aqueous humor was aspirated
under aseptic conditions and subjected to a polymerase chain
reaction (PCR) assay for CMV and HSV DNA.
• PCR
– DNA was extracted from the aqueous humor samples using a
QIAamp DNA minikit (Qiagen, Valencia, CA, USA).
– Quantitative CMV-DNA PCR testing was performed using an
AccuPower CMV Quantitative PCR Kit (Bioneer, Daejun,
Republic of Korea).
– For HSV PCR, the HSV 1/2 PCR Kit (Bio-Core, Seoul, Republic
of Korea) was used.
1. Clinical characteristics of HAU
Clinical parameters of 42 patients with
hypertensive anterior uveitis
Gender (M:F)
29:13
Age (range), years
57.6 (25–88)
Spherical equivalent, D
-2.6 (-11.25–0.00)
Glaucoma operation,%
22 (52.4%)
Corneal endothelial cell count, cells/mm2
1,908 (625–3067)
Unilaterality
39 (92.9%)
KPs at baseline examination
28 (67.8%)
Anterior chamber reaction with 1+ or less
37 (88.1%)
Severe peripheral anterior synechiae
0 (0.0%)
Typical feature of P-S syndrome
14 (33.3%)
Comparisons
ofClinical
Clinical
and
Immunologic
Characteristics
in
Comparisons of
and
Immunologic
Characteristics
in
Subjects
with
without
CMV-PCR
(+) in Aqueous
Subjects with
or or
without
CMV-PCR
(+) in Aqueous
Humor Humor
Characteristics
CMV-positive Subjects
CMV-negative subjects
P value
n=6
n = 16
Male, n(%)
6 (100%)
13 (86.7%)
0.500
Age, years
47.5 ± 14.8
67.6 ± 11.8
0.006
Initial BCVA
0.65 ± 0.29
0.58 ± 0.29
0.569
Final BCVA
0.47 ± 0.46
0.52 ± 0.30
0.733
Spherical equivalent, D
-3.6 ± 4.2
0.0 ± 1.6
0.031
Axial length, mm
25.7 ± 1.5
24.4 ± 0.7
0.053
Average RNFL thickness, µm
66.2 ± 16.7
77.8 ± 19.1
0.132
Corneal endothelial cell count, mm2
1245 ± 560
1981 ± 387
0.009
Unilaterality, n(%)
83.3
80.0
0.684
KPs at baseline examination, n(%)
83.3
73.3
0.550
4 (66.7%)
5 (33.3%)
0.331
100.0
92.9
0.714
Demographic characteristics
Ocular characteristics
Presence of PAS, n(%)
Anterior chamber reaction with < 1+, n(%)
Characteristics
CMV-positive
CMV-negative
subjects
subjects
5 (83.3%)
5 (33.3%)
0.055
Baseline IOP, mmHg
28.83 ± 8.25
22.73 ± 7.86
0.132
Maximum IOP, mmHg
37.17 ± 8.03
39.53 ± 13.02
0.622
2.67 ± 0.81
2.67 ± 0.81
0.970
Chronic , n(%)
4 (66.7%)
13 (86.7%)
0.544
Recurrent, n(%)
2 (33.3%)
2 (13.3%)
4 (66.7%)
10 (66.7%)
0.701
Ahmed valve, n(%)
3 (75.0%)
2 (20.0%)
0.095
Trabeculectomy or ExPRESS glaucoma filtration
1 (25.0%)
8 (80.0%)
HSV PCR positivity, n(%)
0 (0.0%)
1 (6.2%)
0.727
CMV RQ PCR, copies/mL
46048.8 ± 91334.5
Negative
n/a
Lens status, phakic,, n(%)
Number of antiglaucoma medication, n
P value
Course of uveitis
Glaucoma operation, n(%)
device, n(%)
1. Clinical characteristics of HAU
Association
between
presence
in aqueous
Association between
thethe
presence
CMV CMV
DNA inDNA
aqueous
and
corneal
endothelial
cell count
patients
with anterior
and
corneal
endothelial
cell in
count
in patients
with anterior
hypertensive uveitishypertensive uveitis
Model 1
Model 2
Model 3
Adjusted for age, gender,
Adjusted for age and
Unadjusted
lens status, and history of
gender
glaucoma surgery
CMV positivity
P value
B (CI)
B (CI)
B (CI)
672.4
734.4
1034.2
(77.0–1267.9)
(116.4–1352.4)
(631.3–1437.1)
0.029
0.023
< 0.001
1. Clinical characteristics of HAU
In CMV-associated uveitis, extensive corneal
endothelial cell damage may occur.
Hypertensive Anterior Uveitis
- associated with virus
I.
Clinical
Characteristics
: CMV
Corneal
endothelium
II. Etiology
: T-cell senescence
vs. lymphopenia
2. Etiology of CMV-HAU
Latency of CMV
• HCMV establishes lifelong latency after the primary
infection.
– a reversibly quiescent state in which viral genomes are maintained,
but viral gene expression is highly restricted and no virus is
produced
• Seropositivity
– In industrialized countries, such as Australia and the United States,
seroprevalence of CMV is about 60%
– In less developed regions it is about 90%.
• the primary sites of HCMV latency
– CD34+ myeloid progenitor cells
• non-permissive
• specific human cellular DNA-binding proteins in the nucleus bind to
the CMV immediate-early (IE) promoter and inhibit transcription,
thereby blocking the production of infectious particles.
2. Etiology of CMV-HAU
CMV Reactivation from
Latency
• As the latently infected myeloid progenitor
cells divide and differentiate into monocytes,
the virus is carried out of the bone marrow in
circulating monocytes and subsequently in
tissue macrophages and dendritic cells
throughout the body.
• When latently infected macrophages and dendritic cells
subsequently become highly activated, the conditions inside the
nucleus change.
• The human cellular DNA binding proteins that previously bound
to the CMV immediate-early promoter disappear, permitting the
virus to reactivate from latency.
2. Etiology of CMV-HAU
The host immune response against CMV
• B cell response
– In response to
primary CMV
infection, anti-CMV
antibody is produced
initially as IgM
followed by IgG,
which persists lifelong.
• T cell response
– The most important immune
responses against CMV are
CD4+ T cells and CD8+T cells.
– patients who have severely
impaired T-cell responses can
develop serious CMV disease
despite having anti-CMV
antibody
• eg, solid organ transplantation,
allogeneic bone marrow
transplantation
• in advanced HIV infection,
immunosuppressive treatment
2. Etiology of CMV-HAU
Viral Escape from host immune system
• In infected cells, the virus can
produce over 250 proteins, but
only about 50–60 are believed to
be essential for viral replication.
– Thus, the vast majority of these
viral proteins enable the virus to coexist with its host.
• to facilitate viral production
• to avoid detection and elimination of
the virus by the immune system.
• CMV immune evasion genes
– interfere with the MHC Class I
antigen presentation pathway
2. Etiology of CMV-HAU
Questions
WHY DOES CMV REACTIVATE IN ANTERIOR
CHAMBER OF “IMMUNOCOMPETENT”?
ARE THEY REALLY
“IMMUNOCOMPETENT”?
2. Etiology of CMV-HAU
Question 1
WHY DOES CMV REACTIVATE IN
ANTERIOR CHAMBER OF
“IMMUNOCOMPETENT”?
2. Etiology of CMV-HAU
I. Chronic inflammation
CMV reactivation in inflamed tissue
• HCMV may be reactivated when these cells are recruited
to sites of inflammation.
-In vitro, latent virus in macrophages
can be reactivated by allogeneic
stimulation of peripheral blood
mononuclear cells or by differentiation
into dendritic cells.
-Inflammatory cytokines such as
tumor necrosis factor (TNF) ,
interferon (IFN) and granuocytemonocyte colony-stimulating factor
seem to be important in this process.
Chronic inflammation as a trigger for CMV reactivation in
anterior chamber?
2. Etiology of CMV-HAU
II. Ocular immune privilege
• Direct venous drainage of
aqueous humor
– Lack of lymphatic drainage
• Anterior –chamber associated
immune deviation
– eye-derived CD1+ APCs
– Induction of the antigen-specific
regulatory T cells mediate
ACAID emerge from the cell
clusters
• CD4+ Treg cell (afferent)
• CD8+ Treg cells (efferent)
2. Etiology of CMV-HAU
• Intraocular immunosuppressive microenvironment
TGF beta
T cell : inhibit proliferation and effector
functions
upregulate the Treg
B cells: inhibit proliferation, IgA
production
Macrophage: inhibit proliferation and
prevent the production of reactive
oxygen and nitrogen.
Acts as an chemoattractant
Fibroblast : increased collagen
synthesis
2. Etiology of CMV-HAU
III. Chronic topical steroid use
• Immunosuppression by steroid
– mainly achieved by the derangement of primarily T
lymphocyte and monocyte/macrophage functions
• inhibits the function of NF-κB (IκB gene)
• NF-kB
– a key activator of proinflammatory cytokines
– an important transcription factor involved in T cell activation
• diminish the transcription of IL-1 and TNF-α by APCs
• prevent the upregulation of MHC expression
• Phospholipase A2, and consequently the entire arachidonic
acid cascade, is also inhibited.
• They decrease the leukocyte response to various
chemokines and chemotactins; by inhibiting vasodilators
such as histamine and prostacyclin
2. Etiology of CMV-HAU
III. Chronic topical steroid use
Steroid inhibits the
function of NF-κB
(IκB gene)
Sabiston Textbook of surgery
Cytomegalovirus endotheliitis
after fluocinolone acetonide
(Retisert) implant in a patient
with Behçet uveitis
• A 40-year-old man received a
Retisert implant in the left eye for
recurrent Behcet uveitis.
• PCR for aqueous humor detected
3.9 × 104 copies/mL of CMV DNA.
Ocul Immunol Inflamm 2011;19(4):282-3
Cytomegalovirus Retinitis After
Intravitreous Triamcinolone
Injection in a Patient with
Central Retinal Vein Occlusion
A 77‐year‐old woman with macular
edema due to central retinal vein
occlusion (CRVO) developed
peripheral retinitis 4 months after
IVTA.
Korean J Ophthalmol. 2008;22(2):143-4
Chronic ocular
inflammation
Chronic steroid
Ocular immune
use
privilege
Persistent viral activation
even in immunocompetent?
2. Etiology of CMV-HAU
Question 2
ARE THEY REALLY
“IMMUNOCOMPETENT”?
2. Etiology of CMV-HAU
Immunosenescence
(Immune aging)
• The gradual
deterioration of the
immune system brought
on by natural age
advancement.
• increased frequency of
morbidity and mortality
among the elderly.
• T-cell functional
dysregulation as a
biomarker for
immunosenescence
Immune Risk Phenotype
2. Etiology of CMV-HAU
• Multiple latent persistent
viral infections, including
HSV, varicella-zoster virus,
EBV, and, above all, CMV.
• Human CMV appears to be
the most immunodominant
antigen encountered by the
immune system throughout
the life of most individuals.
• The response against
HCMV mediated by CD8+ T
cells in healthy elderly
persons may constitute as
much as 50% of the entire
CD8+ repertoire.
2. Etiology of CMV-HAU
• Memory inflation of the antiviral T cell population
– repeated interactions between CMV and Ag-specific T
cells, which can occupy up to 50% of the human T cell
pool in late life
– Due to CMV’s exquisite immune evasion and
reactivation properties.
• Gradual accumulation of late-differentiated, antigenspecific, oligoclonal T cells, particularly within the CD8+
T-cell compartment
– critically shortened telomeres
– loss of CD28 and/or gain of CD57 expression
– defined as CD8+CD28- or CD8+CD57+ T lymphocytes
2. Etiology of CMV-HAU
Immunity & Ageing 2012, 9:23
Age and CMV infection are major driving forces contributing to
the deterioration of innate and adaptive immunity
2. Etiology of CMV-HAU
Immunologic status of patients
with hypertensive anterior uveitis
2. Etiology of CMV-HAU
Method
• 2014.3~ 2015.2 St. Vincent’s Hospital
• Prospective study design
• Hypertensive Anterior Uveitis
– Inclusion criteria
• (1) anterior uveitis with keratic precipitates (KPs)
• (2) increased intraocular pressure (IOP).
– Exclusion criteria
• (1) presence of inflammation in vitreous or retina
• (2) presence of corneal changes for a known cause; for example, those
with corneal dystrophies.
• Controls
– Cataract patients
– No sign of uveitis
– No episode of increased IOP
• Leukocyte subset frequency determination
– PBMC (peripheral blood mononuclear cells)
• Obtained by density gradient centrifugation
– FACS
•
•
•
•
•
CD57 FITC (IM0466U)
CD28 PE (IM2071U)
CD4 PE – CY 5.5 (9522-16)
CD8 PE – CY 7 (9536-17)
All reagents from Beckman Coulter, Inc.
• Serum cytokine level determination
– Cytokines were measured using a Luminex system (Luminex
Corp).
– IFN-γ, IL-2, IL-6
– TGF-β1,2,3
2. Etiology of CMV-HAU
Comparison of Clinical Parameters between patients
with hypertensive anterior uveitis and controls
HAU
Control
15
12
61.2 ± 11.6
63.4 ± 7.2
0.590
6 (46.1%)
4 (36.4%)
0.697
CMV IgG titer, AU/mL
208.2 ± 55.8
168.4 ± 73.8
0.303
HSV IgG titer, AU/mL
6.6 ± 2.3
8.0 ± 0.0
0.119
2098.1 ± 650.2
2796.9 ± 333.2
0.001
n
Age, yrs
Gender, % of female
Corneal endothelial cell
count, cells/mm2
P value
HAU
Controls
2. Etiology of CMV-HAU
Acute hematologic effects of
interferon alpha, interferon gamma,
tumor necrosis factor alpha and
Interleukin 2 Ann Hematol (1991) 62:25-31
2. Etiology of CMV-HAU
Peripheral Blood Lymphopenia
due to lymphocyte homing
• A recent infection
• viral, bacterial,
and fungal agents (m/c)
• Idiopathic CD4+
lymphocytopenia
• Corticosteroid use
• Malnutrition
• Systemic lupus erythematosus
• Severe stress
• Intense or prolonged physical
exercise
• Rheumatoid arthritis
• Sarcoidosis
• Malignancies leukemia or
advanced Hodgkin's disease
• Iatrogenic conditions
• Chemotherapy
• Large doses of radiation
• Characterized by a transient
reduction of peripheral blood
lymphocyte counts, a phenomenon
called “lymphopenia”
• Induced by the redistribution of
circulating lymphocytes from the
blood to other lymphoid
compartments (homing), resulting
in the inability to access target
organs.
2. Etiology of CMV-HAU
Peripheral Blood Lymphopenia
due to lymphocyte homing
• Pre-transplant Lymphopenia
(absolute lymphopenia < 500
cells/mm3) Is a Novel Prognostic
Factor in CMV and non-CMV
Invasive Infections After Liver
Transplantation.
Liver transplantation
2014;20(12):1497
• Lymphopenia, presence of
symptoms and other infections
and older age are significant risk
factors for a poor outcome for
CMV infection in rheumatic
disease.
Rheumatology 2008;47:1373
2. Etiology of CMV-HAU
Aging vs. CMV effect
on immune function
• Aging
– decreased immune cell function
– lower antibody responses to influenza
vaccination
• CMV effect in young adults
– young CMV-infected adults
– an overall up-regulation of immune
function
– Enhanced antibody responses to
influenza vaccination
– Increased CD8+ T cell sensitivity
– Elevated levels of circulating IFN-γ
compared to uninfected individuals
Sci Transl Med. 2015 Apr 1;7(281):281ra43.
Summary in CMV-associated
hypertensive anterior uveitis
– CMV was a significant etiological factor in
hypertensive anterior uveitis patients in Korea.
– In CMV-associated uveitis, extensive corneal
endothelial cell damage may occur.
• Special caution is needed for patients with CMV-positive
hypertensive anterior uveitis, given its adverse effects on the
corneal endothelium.
– Patients with hypertensive anterior uveitis do not
appears to accompany typical immune aging.
• The mechanism of hypertensive anterior uveitis seems to be
related with systemic immune activation and resultant relative
lymphopenia, rather than T-cell senescence.
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