Transcript viral eye infections and treatment

herpes zosterorigins
Immune
Resolution
Replication in
Tonsilar epith
T cell mediated
Viremia to skin
Adult-Child
contact
Chickenpox
Herpes Zoster
“Shingles”
A one sided and
widespread skin
disease
Neurons
Support cells
Ganglionic
latency
(like HSV-1?
No….)
Latent for decades…
Then
reactivation
Risk Factors for zoster

Age
- most zoster occurs in those over 50
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Cellular immune status
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AIDS
Radiation Therapy
Cancer (esp. lymphoma)
Immunosuppresion from medical therapies
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BMT & Transplants (30-55% in a year!)
Evidence suggests CD4 >> CD8 are critical to
control of VZV latency
Herpes Zoster -signs
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Pain
– Before, during and after
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Vesicular skin lesions
Lesions do not cross the midline
of the face -come from ganglia
 Many lesions over wide area-viral replication in the ganglia
-many neurons deliver virus to skin
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Fever & Depression.
 Tic (“tic deleroux”)
Ocular Problems of zoster
VZV can potentially infect
every ocular tissue !!
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Punctate epithelial keratitis
(PEK)
Dendritic keratitis
– w/o terminal bulbi
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Stromal inflammation
– Harder to treat than HSV-1!
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Neurotrophic keratitis
– Total loss of sensation
– ulceration
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Rarer Findings
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Uveitis, retinitis,
Acute retinal necrosis.
Neurotrophic Keratopathy
The diabetic foot ulcer of the eye
•
~ 8% of HZO patients develop total loss of corneal sensation
~ 3% of HZO patients develop neurotrophic ulceration
Iatrogenic
insults are the main reason that neurotrophic corneas
get into trouble.
Chronic Pain after zoster –Post
Herpetic Neuralgia
“Constant deep burning
or aching”
“Intermittent sharp,stabbing”
Allodynia
-pain invoked by light or innocuous stimulation, (e.g.
clothing, wind gust) -may last long after removal
-is the most distressing component of PHN
-is the most common
-is the most debilitating
Why does shingles cause pain?
Yeow!
Ouch!!!
!
Dorsal root ganglion
Duh…
To Brain:
Conscious Perception
of Pain
Ad fibers
C fibers
Brain Signals
To supress
Nociception
- interneurons
SENSORY
NERVES
Spinothalamic
Tract
Latent VZV
Reactivated VZV replicates
in DRG…..
-damages DRG, Induces Inflammation … Spinal cord
-damages interneuron that blocks pain
-changes ad and C fiber physiology……
Chronic Pain!
Zoster Treatment
1.
Treat the eye and active virus in skin
Topical Acyclovir
Oral Valacylcovir
2.
3.
3-5 + fold higher HSV-1 ACV dose
needed for effect on VZV
Treat the post-herpetic pain
-Tricyclic antidepressants (gabapentin)
-Amitryptilline -Corticosteroids
_Many PHN treatments don’t work
-PHN is multifactorial syndrome
Vaccination to prevent zoster
– 10 fold higher virus than varicella vaccine
– VZV immune people get it!
– Recommended to those over 60
– only human herpesvirus vaccine
– Protection Results:- not everyone……
– 51% drop in zoster
– 68% fall in burden
of illness ( includes PHN)
Adenoviral
Infections
• non-enveloped virus,
• 34Kbp DS-DNA, many viral proteins
• At least 51 identified Serotypes
• Two major ocular diseases
• Epidemic Keratoconjunctivitis (8 and 19)
• Pharyngoconjunctival fever (3,4, & 7)
EKC

transferred by hands, instruments, solutions.
 Adenovirus can survive >35 days on a
surface
 Epidemics arise from optometrists and
ophthalmologists offices.
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Patients remain infectious
for 14 days after onset
of symptoms
Clinical Symptoms
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Foreign Body Sensation
Tearing
Photophobia
Sore Throat
Breathing Problems
Conjuntivitis
NO ANTIVIRAL YET
Subeptielial inflitrates
(immune mediated)
may last long time
-require steroids
Other Viruses causing
Diseases of the Eye

CMV (Fuchs? with HIV/AIDS
 Epstein Barr virus
– Both common herpesviruses affecting most people
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Entero/coxsacivirus
HIV (and everything resulting from it)
Newcastle disease virus
Vaccinia Mollocsum
papilloma
Important Ophthalmic antivirals
Triflourothymidine
HSV-1>> VZV
Acyclovir and valacyclovir
HSV-1 and VZV
Ganciclovir and valganciclovir
CMV retinitis
Foscarnet (phosphonformate)
CMV (GCVr) HSV,VZV
Cidofovir
CMV (GCVr)
HAART
HIV/AIDs
Acyclovir, gancyclovir and
derivatives
ACV
Mechanism of Action
–HSV VZV Thymidine (nucleoside) Kinase activates it
–ACV TP binds Viral DNA polymerase >>>>> cell pol
–Incorporated into DNA - acts as DNA chain terminator
The ‘new’ oral versions - “valtrex”
liver
Valacyclovir
“Valtrex”
ACV
Liver
Acyclovir
is degraded in stomach and not good orally
“Val”
forms are Ester derivatives- higher oro-bioavailability
–e.g. 63-72% stomach absorption vs 15% for ACV
drug
is de-esterified by liver to give serum ACV
Allows
high oral dosing (esp those needed for VZV)
ACV - Resistance
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Readily arises in culture
– Defect /loss of TK in culture
– DNA polymerase mutation altering affinity for ACV-
ppp
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Rarely occurs in vivo
– TK needed for reactivation and pathogensis of
HSV,VZV
– Occurs in AIDS due to long term treatments
– Seems HSV VZV must make a ‘little” TK…..
Ganciclovir (Cytovene)
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O
Used for hCMV only–
– CMV retinitis
– organ transplants
H2N
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Now oral version -Val-GCV
HO
– Ester Protects in stomach
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Poor retinal/brain barriers
crossing
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Use Ocular implants
N
HN
HO
N
N
O
GCV
Mechanism of action
similar
DNA
to ACV- requires initial phosphorylation
chain terminator
–CMV has no TK gene!!!
–CMV uses the UL97 viral protein kinase
to phosphorylate GCV!!
–Unlike ACV, GCV-PPP Inhibits both host and
viral polymerase-toxic!
GCV Resistance
Arises frequently (longer treatments)
•10% In Retinitis and organ transplants
•Change in polymerase, viral protein kinase or both
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Foscarnet (phosphonoformate)
O
Mechanism of action:
–
–
–
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All polymerases need P-P as a cofactor
PFA is analog of P-P
OH
binds to DNA polymerase -blocks P-P binding
Resistance? - altered DNA polymerase
Efficacy/toxicity
– active on ACV GCV resistant viruses
 HSV VZV and CMV
– Toxic - bone, kidney, neuronal deposits
Uses:
– CMV retinitis and GCVr CMV in transplants
– rarely used on HSV and VZV ARN cases
– Rarely used on systemic HSV and VZV
P
OH
P OH
P-P
OH O
O
OH
OH P
OH
PFA
CH
O