herpes zoster- origins Herpes Zoster “Shingles” A one sided and widespread skin disease...
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![Page 1: herpes zoster- origins Herpes Zoster “Shingles” A one sided and widespread skin disease Ganglionic latency (like HSV-1? No….) Immune Resolution Adult-Child.](https://reader036.fdocuments.in/reader036/viewer/2022062421/56649e385503460f94b29bc0/html5/thumbnails/1.jpg)
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herpes zoster-origins
Herpes Zoster“Shingles”
A one sided and widespread skin
disease
Ganglionic latency
(like HSV-1?No….)
Immune Resolution
Adult-Child contact
Replication in Tonsilar epith
T cell mediated Viremia to skin
Latent for decades…Then reactivation
Chickenpox
NeuronsSupport cells
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Risk Factors for zosterRisk Factors for zoster Age
- most zoster occurs in those over 50
Cellular immune status – AIDS– Radiation Therapy– Cancer (esp. lymphoma)– Immunosuppresion from medical therapies
BMT & Transplants (30-55% in a year!)
Evidence suggests CD4 >> CD8 are critical to control of VZV latency
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Herpes Zoster -signsHerpes Zoster -signs Pain
– Before, during and after
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
Fever & Depression. Tic (“tic deleroux”)
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Ocular Problems of zosterOcular Problems of zosterVZV can potentially infect every
ocular tissue !!
Punctate epithelial keratitis (PEK) Dendritic keratitis
– w/o terminal bulbi Stromal inflammation
– Harder to treat than HSV-1! Neurotrophic keratitis
– Total loss of sensation– ulceration
Rarer Findings Uveitis, retinitis, Acute retinal necrosis.
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Neurotrophic KeratopathyNeurotrophic KeratopathyThe diabetic foot ulcer of the eyeThe 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.
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Chronic Pain after zoster –Post Chronic Pain after zoster –Post Herpetic NeuralgiaHerpetic 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
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To Brain:Conscious Perception
of Pain
Why does shingles cause pain?
Why does shingles cause pain?
SpinothalamicTract
A fibersC fibers
Spinal cord
Dorsal root ganglion
SENSORY NERVES
Latent VZV Reactivated VZV replicates in DRG…..
Ouch!!!Yeow
!!
-damages DRG, Induces Inflammation …
Brain Signals To supress Nociception- interneurons
Duh…
-damages interneuron that blocks pain-changes and C fiber physiology……
Chronic Pain!
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Zoster TreatmentZoster Treatment
1. Treat the eye and active virus in skin
2. 3-5 + fold higher HSV-1 ACV dose needed for effect on VZV
3. Treat the post-herpetic pain
-Tricyclic antidepressants (gabapentin)-Amitryptilline -Corticosteroids
_Many PHN treatments don’t work -PHN is multifactorial syndrome
Topical AcyclovirOral Valacylcovir
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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)
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Adenoviral Adenoviral InfectionsInfections
• 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)
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EKCEKC transferred by hands, instruments, solutions. Adenovirus can survive >35 days on a
surface Epidemics arise from optometrists and
ophthalmologists offices.
Patients remain infectious for 14 days after onset of symptoms
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Clinical SymptomsClinical Symptoms
Foreign Body Sensation Tearing Photophobia Sore Throat Breathing Problems Conjuntivitis NO ANTIVIRAL YET
Subeptielial inflitrates(immune mediated)may last long time -require steroids
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Other Viruses causing Other Viruses causing Diseases of the EyeDiseases of the Eye
CMV (Fuchs? with HIV/AIDS Epstein Barr virus
– Both common herpesviruses affecting most people
Entero/coxsacivirus HIV (and everything resulting from it) Newcastle disease virus Vaccinia Mollocsum papilloma
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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
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Acyclovir, gancyclovir and Acyclovir, gancyclovir and derivativesderivatives
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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
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Valacyclovir“Valtrex”
AcyclovirLiver
The ‘new’ oral versions - “valtrex”
ACV 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)
liver
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ACV - ResistanceACV - Resistance Readily arises in culture
– Defect /loss of TK in culture– DNA polymerase mutation altering affinity for ACV-
ppp
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…..
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Ganciclovir (Cytovene)Ganciclovir (Cytovene)
Used for hCMV only– – CMV retinitis – organ transplants
Now oral version -Val-GCV– Ester Protects in stomach
Poor retinal/brain barriers crossing
Use Ocular implants
NN
NNH
O
O
NH2
OH
OH
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GCV Mechanism of action
similar to ACV- requires initial phosphorylation
DNA 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)Foscarnet (phosphonoformate)
Mechanism of action:– All polymerases need P-P as a cofactor– PFA is analog of P-P– 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
OH P P OH
OOH
OHO
OH P CH
O
OH
OH
O
PFA
P-P