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A. Properties of Virus

  1. Double stranded DNA alpha-herpesvirus (125kb genome, 70 genes)
  2. Two disease entities: chicken pox (primary infection), shingles (reactivation)
  3. Virus persists in various tissues in latent form
    1. Most commonly, virus persists with specific viral proteins expressed in neurons
    2. Both central (CNS) and peripheral nervous (PNS) system neurons can be latently infected
    3. Most commonly, sensory neurons or the dorsal root ganglion contain latent virus
    4. Thoracic sensory neurons and cranial nerves (CN) are most common
    5. Of the CN, CN V (ophthalmic branch) and CN VII are most commonly affected
    6. Reactivation of latent infection is called zoster (see below)
    7. Reactivation of latent virus occurs in elderly, immunosuppressed, and high stress
  4. Transmission
    1. Patients most contagious 1-2 before to shortly after onset of chicken pox
    2. Virus can be transmitted until lesions are crusted, or up to 7 days of herpes zoster
  5. Vaccination is only known method to prevent lifelong (latent) infection

B. Disease Entities

  1. Chicken Pox
    1. Chicken pox is a systemic infection
    2. VZV lives dormant in dorsal root ganglion cells
    3. Typically affects children age
    4. Multiple maculo-papular lesions which become vesicles and then crust
  2. Herpes Zoster (Shingles) [2,3]
    1. Symptomatic reactivation of VZV in a specific dermatome is called Shingles
    2. Most commonly occurs in persons >60 years and in immunocompromised persons
    3. Over 500,000 cases in USA annually (1.5-3.0 cases per 1000 person-years)
    4. 10-25% will develop post-herpetic neuralgia
    5. Shingles is characterized by a highly painful cutaneous rash
    6. Skin lesions are maculopapular / pustular eruptions in (usually) dermatomal location
    7. Severe lancinating pain occurs at site
    8. Lesions crust over in 10-14 days with most therapy, but pain usually takes longer
    9. Untreated post-herpetic pain ("neuralgia") may last up to 120 days on average
    10. Incidence of post-herpetic neuralgia increases with increasing age (30% by age 50)
    11. Intractable post-herpetic neuralgia (>120 days) is not uncommon
    12. Elevated cerebrospinal fluid (CSF) interleukin 8 (IL-8) concentrations associated with ~2.7X increased risk of post-herpetic neuralgia [36]
    13. Zoster without herpetic rash ("zoster sine herpete") has been reported
    14. Rate of zoster in HIV+ persons is ~30 per 1000 person-years
  3. Ramsay-Hunt Syndrome
    1. Reactivation of virus in the geniculate ganglion is linked to Ramsay-Hunt Syndrome
    2. This syndrome includes facial palsy, anterior taste loss, tinnitus, hearing loss, vertigo
    3. VZV DNA is found in ~90% of patients with RHS
  4. Complications of VZV Infection
    1. Post-herpetic neuralgia (see below)
    2. Other CNS complications (see below)
    3. Superinfection, most commonly with Streptococcus pyogenes (Group A), may present with toxic shock syndrome, positive blood cultures
    4. Death - mainly in adults with over-exuberant immunologic reactions
  5. VZV vaccination reduces death due to varicella by >50% in USA since implenetation [6]

C. Diagnosis

  1. Appearance of lesions
  2. Pruritus
  3. Tzanck preparation of leading edge tissue
  4. IL8 levels in CSF may be useful to predict post-herpetic neuralgia risk [36]
  5. Transmission by direct contact with lesions
  6. May interact with others if lesions are completely covered

D. Therapy [1,4]

  1. Efficacy of oral anti-virals only documented when started within 72 hours of rash
    1. Antiviral therapy reduces acute pain
    2. Also reduces the incidence and duration of post-herpetic neuralgia [7]
  2. Approved Anti-Viral Therapy for Chicken Pox and/or Shingles
    1. Acyclovir
    2. Famciclovir
    3. Valacyclovir
  3. Varicella Zoster (Chicken Pox)
    1. Normal Host: acyclovir 20mg/kg (up to 800mg/dose) qid x 5 days (or 5x/day x 7 days)
    2. Randomized controlled trial showed efficacy if used within 24 hours in normal hosts
    3. Immunocompromised host: 10mg/kg iv q8 x 10-14 days
  4. Herpes Zoster (Shingles) [2]
    1. Famciclovir (Famvir®): 500mg po tid x 7 days OR
    2. Valacyclovir (Valtrex®): 1000mg po tid x 7 days OR
    3. Acyclovir 800mg 5x d x 7-10 days
    4. Immunocompromised: acyclovir 10mg/kg iv q8 x 10-14 days
    5. Doses need to be reduced for renal dysfunction
    6. Vaccination with live-attenuated VZV vaccine reduced zoster by ~50% in age >60 years [14]
  5. Famciclovir (Famvir®)
    1. 500-750mg po tid x 7 days is as effective as acyclovir
    2. Accelerates lesion healing and reduced duration of viral shedding
    3. Reduces average time of post-herpetic neuralgia by ~50% (to ~60 days)
    4. High oral bioavailability (~77%) and converted to penciclovir by viral thymidine kinase
  6. Valacyclovir (Valtrex®) [10]
    1. Good oral absorption and conversion by hydrolysis to acyclovir in liver
    2. Overall, 3-5X more bioavailablility than acyclovir
    3. Dose is 1000mg po tid for 7 days for herpes zoster
    4. Tolerated well except in immunosuppressed patients who rarely developed a microangiopathic hemolytic anemia
    5. Price is ~35% less for 7 day course of therapy than acyclovir or famciclovir
  7. Acyclovir Dosing
    1. 800mg PO 5X per day for 7-10 days reduces acute pain in zoster infection
    2. Also reduces incidence of post-herpetic neuralgia in some studies
    3. Treatment for 21 days ± prednisolone (40mg/d) had no effect on post-herpetic neuralgia
    4. Low oral bioavailability makes frequent dosing required
    5. Converted to chain terminator by viral thymidine kinase
    6. Viral DNA polymerase selectively uses acyclovir triphosphate
    7. Higher iv doses (10mg/kg iv q8 hours) must be used for disseminated disease
  8. Foscarnet for acyclovir resistant strains
  9. Glucocorticoids [2]
    1. Reduces rates of post-herpetic neuralgia if used early in course
    2. Moderate but clear improvement in healing and alleviation of acute zoster pain [2]
    3. Dose is generally 1mg/kg x 7 days, 0.5mg/kg x 7 days, then 15mg/day x 7 days
    4. Intrathecal methylprednisolone (IT MPS) 60mg weekly with lidocaine (up to 4 doses) is effective for intractable postherpetic neuralgia [13]
    5. IT MPS reduced pain area, spinal fluid interleukin 8 levels, and diclofenac (NSAID) use [13]
  10. Special Hosts
    1. Acyclovir also reduces length of symptoms and shedding in children (20mg/kg PO qid 5d)
    2. Any eye involvement should receive intravenous therapy and usually be hospitalized
    3. Immunocompromised hosts should be given high dose therapy to prevent systemic spread
    4. Many immunocompromised hosts (organ transplant, HIV) require lifelong prophylaxis
  11. Prophylaxis [12]
    1. Healthy non-immune adults and children exposed to VZV should receive prophylaxis
    2. Prophylaxis with live attenuated vaccine (below) or varicella immune globulin
    3. Varicella immune globulin should be used in any person with vaccine contraindications
    4. Varicella immune globulin (VariZIG®) 125 Units/10kg body weight IM x 1
    5. If varicella immune globulin is not available, than pooled human intavenous immune globulin (IVIG) at 400mg/kg x 1 dose should be used
    6. Prophylaxis with either vaccine or immune globulin >96 hours after exposure is of questionable value
  12. Capsaicin (Zostrix®): topical pain control in shingles

E. Primary VZV Vaccine (Varivax®) [1,14,15]

  1. Safe and effective over long term
    1. No increased incidence of shingles (herpes zoster) in vaccinated patients
    2. Very few serious adverse events reported, most with unclear relationship to vaccine
  2. Indications
    1. Young people who have not had natural chicken pox by age ~12 months
    2. Immunocompetent persons >12 months of age without any history of VZV infection
    3. For persons >12 years of age, 2 doses of vaccine given 4-8 weeks apart recommended
    4. Two doses of vaccine are required to prevent waning immunity over time [18]
  3. Efficacy
    1. Larger studies have show 100% protection at one year, 96% at two years post-vaccine
    2. Vaccination reduced transmission by >80% after intense exposure of children
    3. Vaccination reduces symptoms and disease duration in all persons exposed to VZV
    4. Vaccine is 87-97% effective for preventing moderate and severe infection [23]
    5. Vaccine reduced cases of hospitalization for VZV >70% in areas with ~80% vaccination levels [8]
    6. Vaccine efficacy wanes after ~1 year, but breakthrough cases remain mild [11]
    7. Reduced mortality by >50% in USA since implementation [6]
    8. Vaccine associated with reduction of hospitalizations by 88%, ambulatory visits by 59% [5]
    9. After 5 years following single vaccination, increased risk of breakthrough VZV [18]

F. Secondary (Herpes Zoster) Vaccine (Zostavax®) [14,40,41]

  1. Live attenuated vaccine with ~14 times as much VZV as Varivax®
  2. Approved for prevention of herpes zoster (shingles) in persons at least 60 years old
  3. In persons >60 years old, reduced shingles by 50% and post-herpetic neuralgia ~67% [14]
  4. Adverse effects very mild, mainly injection site reactions
  5. Dose: initial sc injection 0.65mL followed in 4-8 weeks by second dose [16]
  6. Single dose recommended in all persons >60 years regardless of previous disease [41]

G. Post-Herpetic Neuralgia (PNH) [2,7]

  1. Occurs in ~20% after shingles or trigeminal neuralgia [17]
    1. Incidence increases with increasing age, may be ~30% in persons >50 yrs old
    2. Over time, symptoms decline: 7% of patients with pain at 3 months, 3% at 1 year
  2. Pain in lancinating and throbbing, and lasts an average of 120 days after skin resolution
  3. Etiology
    1. VZV persists in dormant state in sensory nerves
    2. Waning of cellular immunity to virus permits eruption from nerve to skin infection
    3. Nerve endings in skin are highly irritated or destroyed
    4. Dorsal root ganglion shows inflammation, necrosis and neuronal loss
    5. Scarring may occur with altered sensory function
    6. Altered central nervous system processing has also been shown
    7. Therefore, pain is due to a combination of CNS and peripheral nerve abnormalities
    8. Should be distinguished from trigeminal neuralgia, which is not due to herpes viruses [9]
  4. Treatments [21]
    1. Topical application of capsaicin (Zostrix®) can relieve pain by substance P depletion
    2. Lidocaine cream or patch (Lidoderm®) or bupivicaine local injection often helpful
    3. Tricyclic antidepressants: Amitriptyline (Elavil®) 12.5-25mg po qhs (up to100mg bid)
    4. Desipramine or nortriptyline are better tolerated than amitriptyline in older patients
    5. Gabapentin or Pregabalin (see below)
    6. Carbamazepine (Tegretol®) 400mg/d po may be effective for treatment of pain [19]
    7. Moderate to severe pain: tramadol (Ultram®) or oxycodone
    8. Opiates are generally not recommended chronically (use if others have failed)
    9. Nerve blocks may be effective for short term pain relief
    10. Epidural steroids with local anesthetics do not prevent postherpetic neuralgia [39]
  5. Gabapentin (Neurontin®) [21]
    1. Various effects on brain neurotransmitters, particularly g-AminoButyric Acid (GABA)
    2. Dose: 900-3600 mg qd divided (2-3 times)
    3. Generally well tolerated with very good efficacy in reducing post-herpetic pain
    4. Side effects: diziness, somnolence, ataxia
  6. Pregabalin (Lyrica®) [37]
  7. Duloxetine (Cymbalta®) [38]
    1. Mixed serotonin-norepinephrine reuptake inhibitor (SNRI)
    2. Approved for depression and diabetic neuropathic pain
    3. May have efficacy in PNH
    4. Dose is 60mg po qd for diabetic neuropathic pain
    5. Nausea, dizziness, somnolence, constipation, asthenia are side effects
  8. Prevention
    1. Incidence reduced ~25% with anti-viral therapy when started within 3 days
    2. Famciclovir or valacyclovir as usually used but overall effect is moderate [7,17]
    3. Combination of amitriptyline (25mg qd) + acyclovir early in disease course may reduce incidence of post-herpetic neuralgia >70% versus acyclovir alone [20]
    4. Prednisone 40-60mg po qd, 2-3 week taper, may reduce pain if begun within 3 days [2]
    5. Glucocorticoids reduce early pain but was no different than placebo at 6 months
    6. In persons >60 years old, live-attenuated vaccine reduced zoster ~50% and post-herpetic neuralgia ~67% [14]

H. Central Nervous System Complications [3]

  1. Mainly occurs in immunocompromised patients
  2. Myelitis, usually transverse, may occur
    1. Rash is not required for diagnosis
    2. Cerebrospinal fluid (CSF) findings are not definitive
    3. Physical findings of paresis, sensory level neuropathy, and loss of sphincter tone
    4. Magnetic resonance imaging T2 weighting shows hyperdensities at level
    5. Aggressive treatment with antivirals is usually given
  3. Encephalitis [35]
    1. Infrequent complication of VZV infection
    2. Now known to be a vasculopathy that affects large or small blood vessels
    3. Unifocal large-vessel arteritis (granulomatous arteritis) usually affects elderly immunocompetent persons
    4. Multifocal vasculopathy usually found in immunodeficient patients
    5. Detection of VZV antibody in CSF may be useful for diagnosis
  4. Meningitis and ventriculitis have been found infrequently in immunocompromised

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