Grand Rounds Andy Chien MD Ph D University

Grand Rounds Andy Chien, MD, Ph. D University of Washington Division of Dermatology

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

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.

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

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

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

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

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

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

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

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)

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. )

Great moments in varicella history • 1970 s - 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

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

Chickenpox versus smallpox • 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

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

Scar Wars • Came to ER due to confusion and increased work of breathing overnight • At the ER, pt became obtunded, RR=30, Sa. O 2= 70%, hypotensive • Patient intubated, started on abx and ACV (10 mg/kg q 8)

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

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. ”

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 p. H= 7. 18, HCO 3= 17 • Studies – CXR showed diffuse bilateral pulmonary infiltrates

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

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

The efficacy of the VZV vaccine (in terms of seroconversion) is estimated to be more than: a) 50% b) 60% c) 70% d) 80% e) 90% Source: Mc. Crary, Severson and Tyring, JAAD (1999) 41, 1 -14 CME examination

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

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 [Mc. Crary, Severson and Tyring (1999) JAAD 41, 1 -14] • Annual international incidence estimated at 80 -90 million [Mehta PN (2004) e. Medicine online]

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. ]

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

Complications and mortality in varicella • CNS is most common extracutaneous site; symptoms include Reye’s syndrome, acute cerebellar ataxia, encephalitis, myelitis [Mc. Kendall 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]

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. ]

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, S 91 -8. ]

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) e. Medicine online] • HIV and other defects of cell-mediated immunity

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

Treatment and prevention • Vaccination • VZIG as post-exposure prophylaxis in individuals at high risk – 125 U/10 kg (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

The efficacy of the VZV vaccine (in terms of seroconversion) is estimated to be more than: a) 50% b) 60% c) 70% d) 80% e) 90% Source: Mc. Crary, 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.

Randomized control trials of VZV vaccination Weibel et al. 956 pts (NEJM 1984) v=491, p=465 1 dose of vaccine v= 0/468 p=39/446 100% PE at 9 mos NNT= 11. 8 Kuter et al. v= 163, p= 161 (Vaccine 1991) f/u of Weibel et al. v= 23/468 95% PE at 7 yrs Varis & Vesikari (J Inf Dis 1996) v= 7% p= 25% 72 -88% PE at mean of 29 mos. (low dose vs. high dose) NNT= 5. 5 493 pts v= 332, p=161 Summarized by Skull and Wang (2001) Arch Dis Child 85, 83 -90.

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

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

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)

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

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

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 5 x/d – Prednisone dose increased to 15/d – Rash resolved completely according to the patient

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

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

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

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

The incidence of shingles in a person with a history of varicella is: a) 10% b) 20% c) 30% d) 40% e) 50% Source: Mc. Crary, Severson and Tyring, JAAD (1999) 41, 1 -14 CME examination

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

Ophthalmic zoster is complicated by ocular disease in what percentage of patients: a) 1% b) 10 -20% c) 20 -70% d) 30 -50% e) More than 90% Source: Mc. Crary, Severson and Tyring, JAAD (1999) 41, 1 -14 CME examination

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

The risk of dissemination in immunocompromised patients with herpes zoster can be estimated at: a) 10% b) 20% c) 40% d) 60% e) 80% Source: Mc. Crary, Severson and Tyring, JAAD (1999) 41, 1 -14 CME examination

Recurrent herpes zoster • 1900 – Head & Campbell report “recurrent zoster” in 3 out of 400 patients with zoster [Head and Campbell (1900) Brain 23, 353. ] • 1964 – Hope-Simpson reports 8 of 192 patients with “second attacks” of zoster, one of 192 with “third attack” of zoster [Hope. Simpson (1965) Proc R Soc Med. 58: 9 -20. ] – Prediliction for recurrence in same dermatome (4/9)

Recurrent herpes zoster • 1957 – Leurer reports 70 yo F with “recurrent zoster” [Leurer J (1957) BJD 69, 282 -3. ] • Two pediatric cases – 5 y. o. female with no underlying illness, 3 attacks within one year on right thoracic ribs [Bansal R (2001) Int J Dermatol 40, 542] – 5 y. o. male with h/o ITP, first S 2 -3, then C 6 15 months later [Nikkels AF et al. (2004) Ped Derm 21, 18 -23. ] • An unproven entity? [Heskel and Hanifin (1984) JAAD 10, 486 -90]

The incidence of shingles in a person with a history of varicella is: a) 10% b) 20% c) 30% d) 40% e) 50% Source: Mc. Crary, Severson and Tyring, JAAD (1999) 41, 1 -14 CME examination Ref: Hope-Simon RE, Proc R Soc London (1965) 58, 9 -20.

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

Ophthalmic zoster is complicated by ocular disease in what percentage of patients: a) 1% b) 10 -20% c) 20 -70% d) 30 -50% e) More than 90% Source: Mc. Crary, Severson and Tyring, JAAD (1999) 41, 1 -14 CME examination Ref: Ragozzino et al. , Medicine-Baltimore (1982) 61, 310 -6.

A few vesicles can be found remote from the primarily affected dermatome in what percentage of immunocompetent pts: a) 5 -10% b) 10 -20% c) 20 -40% d) 40 -60% e) 60 -70% Source: Mc. Crary, Severson and Tyring, JAAD (1999) 41, 1 -14 CME examination Ref: Oberg and Svedmyr, Scand J Infect Dis (1969) 1, 47 -49.

The risk of dissemination in immunocompromised patients with herpes zoster can be estimated at: a) 10% b) 20% c) 40% d) 60% e) 80% Source: Mc. Crary, Severson and Tyring, JAAD (1999) 41, 1 -14 CME examination Ref: Weber and Pekllecchia, JAMA (1965) 192, 572 -7.

The Phantom Menace – airborne VZV in the setting of herpes zoster

“Detection of VZV DNA in air samples from hospital rooms” Sawyer MH et al. (1994) J Infect Dis 169, 91 -4. • PCR assay of air filter samples from patients with varicella and herpes zoster • VZV DNA found in 64/78 (82%) of room samples with varicella patients • VZV DNA found in 9/13 (70%) of room samples with herpes zoster patients • VZV detected 1. 2 -5. 5 m from patient beds for 1 -6 days

“Rapid contamination of the environment with VZV DNA from a patient with herpes zoster” Yoshikawa T et al. (2001) J Med Virol 63, 64 -66. Days Serum PBMCs hands throat chair door table filter 3 4 5 6 7 8 14 21 37 ND yes -yes ND ND ND -- ND yes yes ND ND ND -- ---yes yes -- ---yes ---- -yes yes yes -- ----yes yes --- -yes ----yes yes -yes ND=not done *Acyclovir IV given days 3 to 7 **all vesicles encrusted completely by day 11

Detection of VZV DNA in throat swabs of patients with herpes zoster and on air purifer filters”. Suzuki K et al. (2002) J Med Virol 66, 567 -70. • 12 pts (9 adults, 3 kids) with herpes zoster determined by clinical exam and FA positivity for VZV • air filter placed 1 -2 m away from and 1 m above pt beds • PCR detection attempted from skin, throat, air purifier filters and PBMCs

Detection of VZV DNA in throat swabs of patients with herpes zoster and on air purifer filters”. Suzuki K et al. (2002) J Med Virol 66, 567 -70. PCR positivity 100 Skin Throat Air filters 75 PBMCs 50 25 0 0 2 4 6 8 Days of illness 10 12

A New Hope - brivudin

For strains of VZV found to be resistant to acyclovir, the most appropriate therapy is: a) foscarnet b) valaciclovir c) famciclovir d) vidarabine e) idoxuridine Source: Mc. Crary, Severson and Tyring, JAAD (1999) 41, 1 -14 CME examination

Brivudin • [(E)-e-(2 -bromovinyl)-2’-deoxyuridine] • nucleoside analog, highly selective for HSV and VZV (competitive polymerase inhibitor like sorivudine) • Requires thymidine kinase • MIC of 0. 0033 u. M; more potent in culture than acyclovir (MIC 0. 93 u. M) or penciclovir (3. 6 u. M) against VZV

Brivudin • dosed once daily 125 mg • licensed for treatment of herpes zoster in Austria, Belgium, Germany, Greece, Italy, Luxemborg, Portugal, Spain • Similar results in two large multi-center phase III double-blind RCTs – Brivudin 125 qd vs acyclovir 800 5 x/d – Brivudin 125 qd vs famvir 250 tid

“Oral brivudin in comparison with acyclovir for improved therapy of herpes zoster in immunocompetent patients: results of a randomized, double-blind multicentered study” Sawko WW and the Brivudin Herpes Zoster Study Group (2003) Antiviral Res 59, 49 -56. • 1227 immunocompetent pts with clinical zoster (1188 completed trial; 21 + 18 withdrawn) • brivudin 125 mg qd x 7 days VS. acyclovir 800 mg 5 x/d x 7 days • equivalent “time to full crust” and “time to loss of crust” • brivudin better than acyclovir in “time to formation of last vesicle”- RR=1. 13 (1. 01 -1. 27), p=0. 014

“Oral brivudin in comparison with acyclovir for improved therapy of herpes zoster in immunocompetent patients: results of a randomized, double-blind multicentered study” Sawko WW and the Brivudin Herpes Zoster Study Group (2003) Antiviral Res 59, 49 -56. Potential treatmentrelated event Nausea Headache Abd pain Dizziness Vomiting elevated GGT Brivudin (614 pts) 16 6 5 4 3 1 Acyclovir (613 pts) 13 7 4 1 7 4

For strains of VZV found to be resistant to acyclovir, the most appropriate therapy is: a) foscarnet b) valaciclovir c) famciclovir d) vidarabine e) idoxuridine Source: Mc. Crary, Severson and Tyring, JAAD (1999) 41, 1 -14 CME examination

Foscarnet • a. k. a. “trisodium phosphonoformic acid” • exhibits in vitro activity against all herpes viruses • Noncompetitive inhibitor of viral DNA polymerase • not dependent on phosphorylation by thymidine kinase • thymidine kinase-negative strains seen increasingly in HIV population

Foscarnet • Not orally available; given IV • Renal toxicity • Seizures, anemia, neuropathy, penile ulcers

The Clone Wars pityriasis lichenoides as yet another manifestation of VZV?

“Is VZV involved in the etiopathogeny of pityriasis lichenoides” Boralevi F et al. (2003) JID • 13 pts with clinical and histological PL (9 PLC, 4 PLEVA) and 22 normal controls • mean delay in dx for PL group = 6 mo (7 d 30 mo) • PCR performed blind on skin biopsies • all PL patients given option for trial of acyclovir for two weeks

“Is VZV involved in the etiopathogeny of pityriasis lichenoides? ” Boralevi F et al. (2003) JID • PCR+ for VZV DNA in 8/13 PL patients (6 PLC, 2 PLEVA) • no positive PCR from 22 controls • 10/12 patients with improvement on ACV; 2 resolved, 6 with >50% improvement by dermatologist assessment