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Grand Rounds

Grand Rounds. Andy Chien, MD, PhD University of Washington Division of Dermatology. Andy’s previous grand rounds. 85. 75. 70. 60?. Time (min). Sweet’s Stem cells Eosinophils Today (projected). Andy’s previous grand rounds.

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Grand Rounds

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  1. Grand Rounds Andy Chien, MD, PhD University of Washington Division of Dermatology

  2. Andy’s previous grand rounds 85 75 70 60? Time (min) Sweet’s Stem cells Eosinophils Today (projected)

  3. Andy’s previous grand rounds • Total time for three grand rounds: 230 min. • Average per grand rounds: 77 min. (9:02 am) • Total time over so far: 50 min.

  4. varicella diminutive of variola (medieval Latin): “pustule” variare (Latin): “to vary or change” varius (Latin): “various, mottled”

  5. chickenpox ? ? gican (Old English): “to itch” chiche-pois (French): “chick-pea” pokkes (Middle English) pocc (Old English) beu (hypothetical Indo-European root): “to swell”

  6. herpeszoster herpes (Greek): “creeping” zoster (Greek): “belt, girdle” shingles schingles (medieval Latin) cingulum (Latin): “belt, girdle”

  7. Varicella zoster virus • Herpes family double-stranded DNA virus (smallest genome of herpesviruses) • Produces two clinically distinct syndromes • Acquired by inhalation or contact, with primary infection of conjunctiva or upper airway mucosa

  8. Primary varicella • Days 2-4: initial viral replication in regional lymph nodes • Days 4-6: primary viremia • Subsequent second round of viral replication in liver, spleen, other organs • Secondary viremia seeds capillaries and then epidermis by day 14-16

  9. Herpes zoster • VZV spreads from skin/mucosa into sensory nerve endings • Virus travels to dorsal root ganglion and becomes latent • Reactivation occurs with decreased cell-mediated immunity • Initial replication occurs in affected DRG after reactivation

  10. Herpes zoster • Ganglionitis ensues, with inflammation and neuronal necrosis • Pain ensues with travel of the virus down the sensory nerve

  11. Great moments in varicella history • 1767 - Heberden distinguishes chickenpox and herpes zoster • 1875 - Steiner innoculates volunteers with fluid from varicella blister, demonstrating infectious transmission • 1888 - von Bokay notices that chickenpox developed in susceptible children following exposure to a patient with herpes zoster (pub. 1892)

  12. Great moments in varicella history • 1932 - Bruusgarrd (and earlier Kundratiz in 1922) innoculate children with zoster vesicle fluid; the children get chickenpox • 1942 - Garland hypothesizes that zoster was the result of reactivation of VZV acquired earlier in life • 1953 - Weller isolates VZV from primary varicella and zoster (confirmed in 1984 using restriction endonucleases by Straus et al.)

  13. Great moments in varicella history • 1970s - Takahashi and colleagues in Japan develop attenuated “Oka” strain of VZV for vaccination (genetic basis of attenuation remains unknown today) • 1986 - Davison and Scott publish the complete DNA sequence of VZV

  14. Great moments in varicella history • 1987 - Lowe et al. design first genetically-engineered strain of VZV • 1995 - VZV vaccine becomes available in the United States

  15. 14-21 day incubation Mild to no preceding illness Lesions most numerous on trunk Palms and soles spared Lesions at varying stages of development Scabs form 4-7 days after rash appears Vesicles do collapse on puncture 7-17 day incubation Fevers, severe systemic symptoms precede rash by 2-3 days Lesions most numerous on face, arms, legs Palms and soles involved Lesions at same stage of development Scabs form 10-14 days after rash appears Vesicles do not collapse on puncture Chickenpox versus smallpox

  16. Scar Wars • 11 yo Guatemalan female, previously healthy • Since four days prior to admission, noted to have fever and itchy crusted blisters on forehead, trunk • Two brothers (7 and 13 yo) noted to have similar rash three weeks prior; several children at school also had chickenpox in past two-three weeks

  17. Scar Wars • Came to ER due to confusion and increased work of breathing overnight • At the ER, pt became obtunded, RR=30, SaO2= 70%, hypotensive • Patient intubated, started on abx and ACV (10 mg/kg q8)

  18. Scar Wars • PMH: none • Allergies: NKDA • Meds: none • FH: younger brother died in Guatemala at age 2 of “chickenpox”. Mom with no known history of increased morbidity with chickenpox, but some of her 9 siblings had long course. Father’s history unknown. • SH: came to US at age 5, lives with parents and two brothers

  19. Scar Wars • Afebrile, intubated, sedated • “The face is edematous. She has raised vesicular lesions in varying stages spaced densely throughout her face, neck, trunk and upper extremities. They become less dense as they extend down her abdomen and lower extremities. She has a few very light lesions (which are not raised) on her feet.”

  20. Scar Wars • Labs • FA of vesicle swab positive for VZV • Blood cultures 2/2 bottles with Group A Strep • AST= 1066, ALT= 538 • WBC= 3.1, Hct= 34%, Plts= 5 • Lactic acid= 3.3 • Initial ABG pH= 7.18, HCO3= 17 • Studies • CXR showed diffuse bilateral pulmonary infiltrates

  21. Scar Wars • Improved slowly over 6 weeks • left lung pneumothorax occurs; chest tubes placed • Bone marrow biopsy showed severe panhypoplasia • 13 yo brother hospitalized for two weeks due to varicella complications; 7 yo brother with 3 wk course

  22. Scar Wars • Initial VZV titer on admission >1:8, consistent with previous VZV infection or immunization • Convalescent serum taken 5 wks later had a titer of 1:8192

  23. The efficacy of the VZV vaccine (in terms • of seroconversion) is estimated to be • more than: • 50% • 60% • 70% • 80% • 90% Source: McCrary, Severson and Tyring, JAAD (1999) 41, 1-14 CME examination

  24. Each of the following is seen with • maternal VZV infection in the first • trimester except: • cicatricial skin lesions • hypoplastic limbs • hypertelorism • cortical atrophy • low birth weight Source: McCrary, Severson and Tyring, JAAD (1999) 41, 1-14 CME examination

  25. Epidemiology of primary varicella • 90% of cases occur at <10 years of age; maximum incidence ages 1-6 • 8.2% military recruits (17-19 yo) seronegative [Strueiving et al. (1993) Am J Public Health 83, 1717-20] • Approximately 4500 hospitalizations annually in the US [McCrary, Severson and Tyring (1999) JAAD 41, 1-14] • Annual international incidence estimated at 80-90 million [Mehta PN (2004) eMedicine online]

  26. Epidemiology of primary varicella • Older children more likely to have prodromal symptoms[Whitney RJ (1990) Antiviral agents and viral diseases of man. Raven Press, NY] • Higher risk of herpes zoster in healthy children infected with VZV during infancy [Kakourou T et al.(1998) JAAD 39, 207-10; Baba K et al. (1986) J Pediatr 372-7.] • Highly contagious, with >90% household transmission rate [Ross AH (1962) NEJM 267, 369-76.] • 10-35% transmission rate with secondary contacts like school [Ross AH (1962) NEJM 267, 369-76.]

  27. Complications and mortality in varicella • In healthy children aged 1-14, mortality rate estimated at 2/100,000 [Mehta PN (2004) eMedicine online] • Bacterial superinfection is most common complication; Staph exotoxin can result in bullous varicella [Melish ME (J Pediatr (1973) 83, 1019-21]

  28. Complications and mortality in varicella • CNS is most common extracutaneous site; symptoms include Reye’s syndrome, acute cerebellar ataxia, encephalitis, myelitis [McKendall and Kiawans (1978) Handbook of clinical neurology. Elsevier Press] • Rare complications: myocarditis, appendicitis, glomerulonephritis, hepatitis, pancreatitis, vasculitis, arthritis, keratitis, iritis, optic neuritis [Whitney RJ (1990) Antiviral agents and viral diseases of man. Raven Press, NY]

  29. Varicella encephalitis • Estimated incidence of 1-2 episodes per 10,000 cases[Choo PW et al. (1995) J Infect Dis 172, 706-12.] • Seizures in 29-52% of cases [Gibbs FA et al. (1964) Arch Neurol 10, 15-25; Grifith, Salam and Adams (1970) Acta Neurol Scand 46, 279-300.] • Role of VZV replication in pathogenesis still unclear • Estimated mortality of 5-10%, but most cases have complete or near-complete recovery [Preblud and D’Angelo (1979) J Infect Dis 140, 257-60.]

  30. Varicella pneumonia • Frequent complication of adult varicella infection; occurs in 1/400 cases[Krugman, Goodrich and Ward (1957) NEJM 257, 843-8] • 10% mortality in immunocompetent patients [Weber and Pellecchia (1965) JAMA 192, 572-7.] • 30% mortality in immunocompromised patients [Weber and Pellecchia (1965) JAMA 192, 572-7.] • 2.7-16.3% of healthy adults with varicella will have radiologic evidence of pneumonitis; a third of these will have respiratory symptoms [Gnann JW (2002) J Infect Dis 186, S91-8.]

  31. Risk factors for severe varicella • First month of life, particularly if mom is seronegative • Delivery before 28 weeks • High dose steroids (1-2 mg/kg/d) immediately preceding viral incubation [Dowell and Bresee (1993) Pediatrics 92, 223-8.] • Malignancy; visceral dissemination seen in almost 30% of patients with leukemia and immunosuppression [Mehta PN (2004) eMedicine online] • HIV and other defects of cell-mediated immunity

  32. Risk factors for severe varicella • Pregnancy; higher risk of both severe varicella and varicella pneumonia [Mehta PN (2004) eMedicine online] • Acquisition of varicella in late adolescence or adulthood • ? Familial susceptibility to severe varicella

  33. Treatment and prevention • Vaccination • VZIG as post-exposure prophylaxis in individuals at high risk • 125U/10kg (max 625 U), given IM, NEVER IV • Mothers with varicella 5 days before to 2 days after delivery • Immunocompromised individuals with no reliable history • 3 weeks duration of protection • Exclude kids from school until sixth day of rash

  34. The efficacy of the VZV vaccine (in terms • of seroconversion) is estimated to be • more than: • 50% • 60% • 70% • 80% • 90% Source: McCrary, Severson and Tyring, JAAD (1999) 41, 1-14 CME examination Ref: White CJ et al., Pediatrics (1991) 87, 604-10. VARIVAX trial of healthy children.

  35. Randomized control trials of VZV vaccination Weibel et al. 956 pts v= 0/468 100% PE at 9 mos (NEJM 1984) v=491, p=465 p=39/446 NNT= 11.8 1 dose of vaccine Kuter et al. v= 163, p= 161 v= 23/468 95% PE at 7 yrs (Vaccine 1991) f/u of Weibel et al. Varis & Vesikari 493 pts v= 7% 72-88% PE at mean of 29 mos. (J Inf Dis 1996) v= 332, p=161 p= 25% (low dose vs. high dose) NNT= 5.5 Summarized by Skull and Wang (2001) Arch Dis Child 85, 83-90.

  36. Indications for vaccination • Age 12 mos.-13 y.o. • one dose, can be given with MMR • Age 13 y.o.-”young adulthood” • two doses at 4-8 wk intervals • consider serologic testing first

  37. Contraindications for vaccination • Congenital immunodeficiency, blood dyscrasia • Hematologic malignancies • can give to ALL in remission [Gershon AA et al. (1984) JAMA 252(3):355-62] • Symptomatic HIV • Pregnancy • Intercurrent illness

  38. Contraindications for vaccination • Corticosteroids of 2 mg/kg/d or higher for 1 month or longer • exposure to varicella or herpes zoster within 21 days • neomycin allergy • blood products (including IVIG) within 5 months • salicylates within 6 wks (relative)

  39. Each of the following is seen with • maternal VZV infection in the first • trimester except: • cicatricial skin lesions • hypoplastic limbs • hypertelorism • cortical atrophy • low birth weight Source: McCrary, Severson and Tyring, JAAD (1999) 41, 1-14 CME examination

  40. The Zoster Strikes Back? • 66 yo F with longstanding history of photosensitivity and history of actinic reticuloid and CTCL/erythroderma presentation • Long-standing prednisone usage dating back 4 years prior to clinic visit • Currently on 30/29 mg/d alternating dose, with improvement in photosensitivity

  41. The Zoster Strikes Back? • 5 months prior, pt was on prednisone at 10/d and noted a painful blistering rash on the left buttock and left inner leg • Diagnosed as shingles and treated with acyclovir 800 mg 5x/d • Prednisone dose increased to 15/d • Rash resolved completely according to the patient

  42. The Zoster Strikes Back? • 2 months ago, pt hospitalized with left arm cellulitis for 4 days • Discharged on prednisone 40/d with taper • Hospitalized again 5 weeks ago for complications of pseudomembranous colitis • Prednisone increased from 18/d to 30/d, then increased again to 60/d with taper • Rash that appeared similar to previous “shingles” episode reappeared, persisted until this clinic visit

  43. The Zoster Strikes Back? • ROS unremarkable; no constitutional or prodromal symptoms • Main symptom was itching on leg • FBS of 80-90 in am • ALL: codeine, sulfa • Meds: prednisone (30/29), atenolol, Zaroxolyn, levoxyl, Mg/K supplements, Premarin, Prevacid, Starlix

  44. The Zoster Strikes Back? • P = 64, BP = 142/78 • On exam, the left inner lower leg had single and grouped 1-2 mm vesicles on an erythematous base • Punctate scars were present on left inner lower leg; the patient said these scars were from the previous eruption 5 months ago

  45. The Zoster Strikes Back? • FA and viral culture of vesicle on left leg was POSITIVE for VZV

  46. The incidence of shingles in a person • with a history of varicella is: • 10% • 20% • 30% • 40% • 50% Source: McCrary, Severson and Tyring, JAAD (1999) 41, 1-14 CME examination

  47. The percentage of patients with herpes • zoster who experience pain in the • involved dermatome prior to development • of a rash is: • 50% • 60% • 70% • 80% • 90% Source: McCrary, Severson and Tyring, JAAD (1999) 41, 1-14 CME examination

  48. Ophthalmic zoster is complicated by • ocular disease in what percentage of • patients: • 1% • 10-20% • 20-70% • 30-50% • More than 90% Source: McCrary, Severson and Tyring, JAAD (1999) 41, 1-14 CME examination

  49. A few vesicles can be found remote from • the primarily affected dermatome in what • percentage of immunocompetent pts: • 5-10% • 10-20% • 20-40% • 40-60% • 60-70% Source: McCrary, Severson and Tyring, JAAD (1999) 41, 1-14 CME examination

  50. The risk of dissemination in immuno- • compromised patients with herpes • zoster can be estimated at: • 10% • 20% • 40% • 60% • 80% Source: McCrary, Severson and Tyring, JAAD (1999) 41, 1-14 CME examination

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