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Herpesviridae

Herpesviridae. T. Mazzulli, MD, FRCPC Department of Microbiology Mount Sinai Hospital. Varicella Zoster Virus (VZV). highly contagious; >90% of cases occur in children <9 years of age infectious 2 days before until full crusting winter, spring; incubation period 10 - 21 days

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Herpesviridae

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  1. Herpesviridae T. Mazzulli, MD, FRCPC Department of Microbiology Mount Sinai Hospital

  2. Varicella Zoster Virus (VZV) • highly contagious; >90% of cases occur in children <9 years of age • infectious 2 days before until full crusting • winter, spring; incubation period 10 - 21 days • airborne; direct contact with lesions • subclinical infections are - uncommon • immunity is lifelong but latent in nerve root ganglia  - reactivation (shingles / zoster)

  3. Varicella Zoster Virus Transmission:

  4. Varicella Zoster Virus 3 Clinical Syndromes: • A) Chickenpox - fever, irritability, vesicles spread over 4 - 7 days • majority uncomplicated - more severe in adults, pregnant women • disseminated in immunocompromised patients

  5. VZV: Latency VZV establishes latency in the dorsal root ganglion Posterior column spinal cord VZV moves along the sensory nerveto the dorsal root ganglion Chickenpox rash Skin Dorsal root ganglion 1. Straus SE, Oxman MN. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 5th ed. Vol 2. McGraw-Hill; 1999:2427-50 2. Silverstein S, Straus SE. In: Arvin AM, Gershon AA, eds. Varicella-Zoster Virus: Virology and Clinical Management. Cambridge, UK: Cambridge University Press; 2000:123-141

  6. Complications from Varicella • Case fatality rates (per 100,000 cases): • Adults: 30 deaths • Infants: 7 deaths • Children (1 to 19 yrs): 1 – 1.5 deaths • 37/53 (70%) chickenpox deaths from 1987 to 1996 occurred in those >15 yrs of age in Canada • Immunocompromised Children: • Dissemination in 30% • Mortality in 7 to 10% CCDR Feb 2004:30

  7. Varicella (Chickenpox) • Pre-Vaccine: • 4 million cases/yr in USA – 11,000 hospitalizations • Complications (175,000/yr): • 2o bacterial skin and soft tissue infections including invasive Group A Strep (40 to 60 fold increase), necrotizing fasciitis, toxic shock-like syndrome • Otitis media, bacteremia, pneumonitis, osteomyelitis, septic arthritis, endocarditis • Encephalitis, cerebellar ataxia, hepatitis • Congenital Varicella (2%) CCDR, Feb 4, 2004:30; Galil et al. Pediatr Infect Dis J. 2002:21; Plotkin, Pediatr 1996:97(2)

  8. Vaccine Preventable Deaths in Children and Adolescents from 1990 - 1994 239 185 No. of deaths in patients <20 yrs of age MMWR 1998;47(18)

  9. Varicella Zoster Virus • B) Zoster (Shingles)- dermatomal distribution; • reactivation of latent virus • zoster infectious to others - they get chickenpox, not zoster • scarring; post-herpetic neuralgia

  10. Shingles: Risk Factors • Advancing age1,2 • Level of VZV-specific, cell-mediated immunity (CMI) naturally wanes with increasing age2 • Severity of shingles increases with age1 • Immunosuppression1 • HIV – AIDS1 • Organ Transplants1 • Malignances1 • Immunosuppressive therapies1 1. Gnann J et al. NEJM 2002; 347:340-46 2. Arvin A et al. NEJM 2005; 352:226-67

  11. Incidence of Herpes Zoster by Age The incidence of herpes zoster increases significantly with age, with 67% of cases occurring in persons over 50 years of age. Johnson R. et al. JID 2007 11(Suppl 2) S43-48

  12. Alberta Incidence Rates of HZ: 1986 - 2002 Alberta Public Varicella Vaccine Program Initiated Zoster rate is increasing, and this increase is accelerating. Russell ML Epidemiology Infect. 2007: 1-6

  13. Shingles: Canadian Epidemiology • Estimated ~30% lifetime risk of one VZV reactivation1; ~50% if live to 80 years of age • Estimated 129,882 cases of Shingles per year1 • ~90% of cases occur in immunocompetent people; >2/3 in patients >50 years of age4 • ~15% of shingles episodes will result in PHN • 19,865 episodes/year2 • 31% in adults over 65 y.o.2 • Brisson M. et al. Epidemiol. Infect. 2001; 127:305-14 • Brisson M. CIC 2004 • Jung et al, Neurology 2004; 62:1545-51 • Straus SE, Oxman MN In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 5th ed. Vol 2. New York, NY: McGraw-Hill;1999:2427-50

  14. Shingles: Clinical Disease • Vesicular rash: • Healthy: unilateral (does not cross the midline) involving a single dermatome; heals within 4 weeks • Immunocompromised: may disseminate • Lesions usually crust over and heal by 4 weeks • Acute pain: • Pain & paraesthesia usually precede rash • 40% of pts experience pain >4 days before rash • May be sharp/stabbing/shooting/burning/throbbing • Occurs in >90% of pts >60 yrs Oxman MN. In: Arvin AM, Gershon AA. Eds. Varicella-Zoster Virus, Virology and Clinical Management. Cambridge Press 2000

  15. VZV: Reactivation Posterior column spinal cord Dorsal root ganglion Site of VZV replication Arvin AM. Varicella-zoster virus. In: Knipe DM, Howley PM, eds. Fields Virology. 4th ed. Vol 2. New York, NY: Lippincott Williams & Wilkins; 2001:2731-67 Straus SE, Oxman MN. Varicella and herpes zoster. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 5th ed. Vol 2. New York, NY: McGraw-Hill; 1999:2427-50

  16. Shingles: Dermatomal Distribution Region Frequency Thoracic 55% Cranial 25% Lumbar 14% Cervical 12% Sacral 3% Generalized 1% Dworkin RH et al. In: Watson CPN, Gerson AA, eds. Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition. Vol 11. Amsterdam, The Netherlands: Elsevier Science B.V. 2001; 39-64

  17. Neurologic Ophthalmic Cutaneous Dissemination Shingles: Complications

  18. Shingles: Neurologic Complications • Post-herpetic neuralgia (PHN) (10 – 20%): • Pain along cutaneous nerves persisting >30 days after lesions have healed • Most common complication; Allodynia; May lead to depression1 • 30 to 50% in adults over 65 y.o.; lasts >6 mos in 30-50%3 • Motor neuropathies (1- 5%): • Cranial: Ramsey Hunt syndrome2 (shingles around the ear with loss of taste in the anterior 2/3 of tongue & ipsilateral facial palsy) • Peripheral: diaphragmatic paralysis & lower motor paresis2 • Other: Meningitis, Encephalitis (0.1 – 0.2%) 1. Gilden, D. Herpes 2004; 11(suppl):89A-94A; 2. Gilden DH In: Arvin AM, Gershon AA, eds. Varicella-Zoster Virus,Virology and Clinical Management. Cambridge Press 2000; 299-316; 3. Brisson M. CIC 2004

  19. Prevalence of PHN and Duration of Pain Associated With PHN Increase With Age 100 >1 yr 6 - 12 mo 80 1 - 6 mo <1 mo 60 Percent of patients reporting pain 40 20 0 0-19 20-29 30-39 40-49 50-59 60-69 ≥79 Age (years) Kost R et al. N Engl J Med. 1996;355:32-42.

  20. Shingles: Ophthalmic Complications Herpes Zoster Ophthalmicus: • 10% of shingles cases affect the Ophthalmic Branch of the Trigeminal Nerve (forehead and upper face) • 93% suffer acute pain, which persists at 6 months in 1/3 of cases(70% of cases > 80 years old)2 • All layers of the eye may be affected: conjunctivitis (mainly), iritis, keratitis, uveitis, optic neuritis, glaucoma, corneal scarring1 1. Opstelten, W. BMJ 2005; 331:147-151 2. Pavan-Langston Ophthalmic zoster in herpes zoster and postherpetic neuralgia, 2nd revised and enlarged edition 2001: 119-129

  21. Shingles: Cutaneous Complications • Bacterial superinfection • 2% of cases • Most commonly due to Staphylococcus aureus andGroup A Streptococcus • Can lead to cellulitis and scarring Lycka BAS et al. Dermatologic aspects of herpes zoster in herpes zoster and postherpetic neuralgia, 2nd revision and enlarged edition 2001; 97-106

  22. Shingles Complications: Dissemination • Cutaneous dissemination • Definition: 20 lesions outside the principally affected dermatome • Occurs in 2% of shingles cases • Visceral dissemination • Pneumonia, hepatitis, encephalitis • Often associated with cutaneous dissemination • Occurs in 15-30% of immunocompromised hosts • Potentially fatal Lycka BAS et al. Dermatologic aspects of herpes zoster in herpes zoster and postherpetic neuralgia, 2nd revision and enlarged edition 2001; 97-106

  23. Varicella Zoster Virus • Varicella in pregnancy and newborn • Congenital: • uncommon; 2% of fetuses borne to mothers with chickenpox in 1st 20 wks • limb hypoplasia, CNS retardation, muscular atrophy • Perinatal: • Risk if mother develops chickenpox 5 days before or up to 48 hours postpartum • High risk of disseminated disease with multi-organ involvement • Mortality as high as 30%

  24. Congenital Varicella

  25. Varicella Zoster Virus • Diagnosis: • clinical diagnosis • serology for immune status • direct detection - EM, immunofluorescence • isolation - vesicular fluid

  26. Varicella: Diagnosis Laboratory Diagnosis: Mounsey AL. Amer Fam Physician 2005;72(6)

  27. Herpes Zoster: Approach to Treatment • Antivirals: • Acyclovir • Famciclovir • Valacyclovir • Supportive Care • General: • Topical (eg. Calamine lotion), Analgesics, Antidepressants, ? steroids Volpi A et al. Am J Clin Dermatal. 2005; 6: 317-25

  28. Varicella Zoster Virus • Treatment: • Chickenpox/zoster – ACV can be used in normal and immunocompromised host • Normal host with chickenpox: • shortens duration by 1 day, number of lesions by 25% and decreases constitutional symptoms by 1/3 • Started within 24 hours • Normal host with zoster: • Reduces acute neuritis and accelerates cutaneous healing

  29. Shingles: Antiviral Treatment • Valacyclovir: 1000 mg po tid x 7 d • PHN in pts >50 yrs; median duration of pain = 38 d vs 51 d with acyclovir (p = 0.001) • Famciclovir: 500 mg po q8h x 7 d • PHN in pts >50 yrs; median duration of PHN = 63 d vs 163 d with placebo (p = 0.004) • Acyclovir: 800 mg po 5x/d x 7 d • Median time to pain resolution 41 d vs 101 d in those >50 yrs; 2-fold acceleration of pain resolution and decrease PHN at 3 & 6 months compared to placebo J Microbiol Immunol Inf 2004;37:75; Antimicrob Agents Chemother 1995;39:1546; Clin Infect Dis 1996;22:341

  30. Antiviral Therapy for Herpes ZosterRandomized, Controlled Clinical Trial of Valacyclovir and Famciclovir Therapy in Immunocompetent Patients 50 Years of Older • Treatment Groups – Randomized to valacyclovir (1g TID) or famciclovir (500mg TID) for 7 days. • Mean Age 68  Follow-up – 24 weeks • Main Outcome Measures: Assess resolution of zoster-associated pain and PHN, rash healing, and treatment safety. Tyring SK et al. Antiviral therapy for herpes zoster. Arch Fam Med 2000;9:863-9.

  31. Shingles: Antiviral Therapy Patients who derive the most benefit from treatment include: • Adult patients ≥50 years of age1 • Patients with severe acute shingles2 • Patients with shingles ophthalmicus2 • Immunocompromised patients2 • Strauss SE, Oxman MN. In: Freedberg IM, Eisen AZ, Wolff K et al, eds. Fitzpatrick’s Dermatology in General Medicine. 5th ed. Vol 2. New York, NY: McGraw-Hill; 1999:2427-50 • Gnann JW, Whitley RJ. N Engl J Med. 2002;347:340-46

  32. Varicella Zoster Virus • Treatment: • Antiviral therapy for zoster should be started within 72 hours; After 72 hrs - use in elderly, patients with severe acute pain, & immunocompromised • Use of corticorsteroids in treatment of zoster remains controversial • Aspirin is contraindicated in persons with varicella because of the risk of Reye’s syndrome • Valacyclovir and Famciclovir licenced for zoster

  33. Varicella Zoster Virus Prevention: • Varicella zoster immune globulin (VZIG); prolongs incubation period to 28 days; given within 96 hr of exposure

  34. Varicella Zoster Virus Prevention: • Vaccines: • Varicella (chickenpox) vaccine • Zoster (shingles) vaccine

  35. Varicella Zoster Virus Prevention: • Varicella Vaccines: • live attenuated virus • >95% antibody response; 85% protection • at least 10 years of protection

  36. Varicella Vaccination • 2 formulations available in Canada since 2002: • Varivax III and Varilrix • Live attenuated vaccines (Oka strain) • Minimum potency ranges from 1350 to 1995 pfu • Subcutaneous • Can be given with MMR, DTaP, IPV, Hib, pneumococcal conjugate-7, meningococcal C-conjugate, Hepatits B, and Influenza vaccines using separate syringes at separate sites • 2 doses being recommended

  37. Varicella Vaccination: Immunogenicity

  38. Varicella Vaccines: Efficacy • Clinical breakthrough: • 70 – 90% vaccine efficacy for varicella of any severity and 93 – 100% for moderate to severe disease • Majority occur in day care and schools • Herpes Zoster: • Varivax – 14 cases/100,000 person-years (compared to 68/100,000 after natural infection) • Varilrix – 7.7 cases per 10,000 child-months of observation • Mortality: • 56% decrease compared to pre-vaccine era CCDR Feb 2004:30; Davis M. Expert Rev Vaccines 2006:5(2)

  39. Varicella Vaccine: Indications • Healthy children >12 mos (1 dose) • Publicly funded for 1yr old OR 5 yr old susceptible children (OR high risk persons) • Healthy individuals >13 yrs (2 doses at least 28 days apart) • If unknown or negative history of varicella, may check serology as 80% are immune despite negative history • Post-vaccination serologic testing is NOT recommended • Women should avoid pregnancy for 1 month after vaccination CCDR Feb 2004:30

  40. Varicella Vaccine: Indications • Susceptible, immunocompromised individuals (up to 2 doses): • Contraindicated in T-cell immunodeficiency; OK for those with humoral, neutrophil, complement deficiencies and asplenia • Varilrix may be used in children with acute lymphocytic leukemia (ALL) in remission • May be used in those taking <2 mg prednisone/kg daily to a maximum of 20 mg/day for <2 wks and in children >12 mos with asymptomatic HIV CCDR Feb 2004:30

  41. Zoster (Shingles) Vaccine

  42. Zoster vaccination Aging & Zoster Risk Varicella Exposure Silent reactivation? VZV T-cells Zoster Threshold Herpes Zoster Varicella Age Arvin A. Aging, Immunity, and the varicella-zoster virus. N Engl J Med 2005;352(22):2266-7. Arvin A, NEJM 352:2266, 2005

  43. Zoster (Shingles) Vaccine • Vaccine type: • Live attenuated OKA/MERCK VZV vaccine (Zoster Vaccine) • Administration: • Subcutaneaous injection of 0.5 ml • Vaccine potency: • Range from 18,700 to 60,000 PFU • Median potency: 24,600 PFU • Minimal potency of the Zoster Vaccine at least 14 times greater than the Varicella live attenuated Oka/ Merck VZV vaccine.

  44. Shingles Vaccine Prevention Study • Double-blind, placebo-controlled, multi-centered trial, 22 sites • Study timeline: Nov-1998 to Apr-2004 • 38,546 subjects ≥ 60 years of age - Age-stratified (60 to 69 years, ≥70 years) • 90% had one of more underlying medical conditions • Randomized 1:1 to receive VZV vaccine or placebo • Median 3.12 years of surveillance for HZ Oxman MN. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. New Eng J Med 2005;352(22):2271-84.

  45. Shingles Vaccine Prevention Study • Confirmed cases: 315 in vaccine group vs 642 in placebo group • PCR positive for VZV DNA (wild-type) in 93.3% and 93.5% respectively [NO vaccine strain DNA detected in any patient with suspected HZ] • Vaccine effectiveness: • Herpes Zoster: 51% • Post-herpetic neuralgia: 61.1% • Burden of illness: 66.5% Oxman MN. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. New Eng J Med 2005;352(22):2271-84.

  46. Number Needed to Vaccinate (NNV):Comparison to other Adult Vaccines *Incidence rate per 1,000; tAnnual incidence rate in >65 yrs of age Kelly H et al. Vaccine 2004:22(17-18)

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