herpes zoster- origins herpes zoster “shingles” a one sided and widespread skin disease...

Download herpes zoster- origins Herpes Zoster “Shingles” A one sided and widespread skin disease Ganglionic latency (like HSV-1? No….) Immune Resolution Adult-Child

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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 Neurons Support cells
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  • Risk Factors for zoster Risk 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 -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 zoster VZV 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 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.
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  • 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
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  • To Brain: Conscious Perception of Pain Why does shingles cause pain? Spinothalamic Tract A fibers C 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 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 dont work -PHN is multifactorial syndrome Topical Acyclovir Oral 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 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)
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  • EKC 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 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 Diseases 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 valacyclovirHSV-1 and VZV Ganciclovir and valganciclovir CMV retinitis Foscarnet (phosphonformate)CMV (GCV r ) HSV,VZV Cidofovir CMV (GCVr ) HAARTHIV/AIDs
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  • Acyclovir, gancyclovir and derivatives
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  • l 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 Acyclovir Liver The new oral versions - valtrex l ACV is degraded in stomach and not good orally l Val forms are Ester derivatives- higher oro-bioavailability e.g. 63-72% stomach absorption vs 15% for ACV l drug is de-esterified by liver to give serum ACV l Allows high oral dosing (esp those needed for VZV) liver
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  • ACV - 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) 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
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  • l GCV Mechanism of action l similar to ACV- requires initial phosphorylation l 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) 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 GCV r CMV in transplants rarely used on HSV and VZV ARN cases Rarely used on systemic HSV and VZV OH P P OH O OH O OH P CH O OH O PFA P-P