Varicella

Grand Rounds

Andy Chien, MD, PhD

University of Washington

Division of Dermatology

Andy’s previous grand rounds

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Sweet’s Stem cells Eosinophils Today (projected)

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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”

varius (Latin): “various, mottled”

variare (Latin): “to vary or change”

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 cell-mediated 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)


• 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.)


• 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


• 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, SaO2= 70%, hypotensive

• Patient intubated, started on abx and ACV (10 mg/kg q8)

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 pH= 7.18, HCO3= 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 termsof seroconversion) is estimated to be more than:

a) 50%b) 60%c) 70%d) 80%e) 90%

Source: McCrary, 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 lesionsb) hypoplastic limbsc) hypertelorismd) cortical atrophye) low birth weight


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]

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) eMedicine 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 [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]

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, S91-8.]

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) eMedicine 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) eMedicine 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– 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

The efficacy of the VZV vaccine (in termsof seroconversion) is estimated to be more than:

a) 50%b) 60%c) 70%d) 80%e) 90%

Source: McCrary, Severson and Tyring, JAAD (1999) 41, 1-14 CME examinationRef: 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 v= 0/468 100% PE at 9 mos(NEJM 1984) v=491, p=465 p=39/446 NNT= 11.81 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.

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 lesionsb) hypoplastic limbsc) hypertelorismd) cortical atrophye) low birth weight


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


• 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


• 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


• 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


• 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


• 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%


The percentage of patients with herpes zoster who experience pain in the involved dermatome prior to developmentof a rash is:

a) 50%b) 60%c) 70%d) 80%e) 90%


Ophthalmic zoster is complicated byocular disease in what percentage ofpatients:

a) 1%b) 10-20%c) 20-70%d) 30-50%e) More than 90%


A few vesicles can be found remote fromthe primarily affected dermatome in whatpercentage of immunocompetent pts:

a) 5-10%b) 10-20%c) 20-40%d) 40-60%e) 60-70%


The risk of dissemination in immuno-compromised patients with herpeszoster can be estimated at:

a) 10%b) 20%c) 40%d) 60%e) 80%


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 S2-3, then C6 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: McCrary, Severson and Tyring, JAAD (1999) 41, 1-14 CME examinationRef: 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 developmentof a rash is:

a) 50%b) 60%c) 70%d) 80%e) 90%


Ophthalmic zoster is complicated byocular disease in what percentage ofpatients:

a) 1%b) 10-20%c) 20-70%d) 30-50%e) More than 90%

Source: McCrary, Severson and Tyring, JAAD (1999) 41, 1-14 CME examinationRef: Ragozzino et al., Medicine-Baltimore (1982) 61, 310-6.

A few vesicles can be found remote fromthe primarily affected dermatome in whatpercentage of immunocompetent pts:

a) 5-10%b) 10-20%c) 20-40%d) 40-60%e) 60-70%

Source: McCrary, Severson and Tyring, JAAD (1999) 41, 1-14 CME examinationRef: Oberg and Svedmyr, Scand J Infect Dis (1969) 1, 47-49.

The risk of dissemination in immuno-compromised patients with herpeszoster can be estimated at:

a) 10%b) 20%c) 40%d) 60%e) 80%

Source: McCrary, Severson and Tyring, JAAD (1999) 41, 1-14 CME examinationRef: 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 1.2-5.5m 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 ND ND -- -- -- -- -- --4 yes yes -- -- yes -- yes --5 -- yes -- -- yes -- -- --6 yes yes yes yes -- -- -- --7 yes yes -- -- yes yes -- yes8 ND ND -- yes yes yes yes yes14 ND ND yes -- yes yes -- yes21 ND ND yes -- yes -- -- --37 -- -- -- -- -- -- -- 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

Days of illness

PC

R p

osi

tivi

ty

0 2 4 6 8 10 120

25

50

75

100Skin

ThroatAir filters

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.

A New Hope - brivudin

For strains of VZV found to be resistantto acyclovir, the most appropriatetherapy is:

a) foscarnetb) valaciclovirc) famciclovird) vidarabinee) idoxuridine


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 uM; more potent in culture

than acyclovir (MIC 0.93 uM) or penciclovir (3.6 uM) 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 5x/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 5x/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 treatment- Brivudin (614 pts) Acyclovir (613 pts)related event

Nausea 16 13Headache 6 7Abd pain 5 4Dizziness 4 1Vomiting 3 7elevated GGT 1 4

For strains of VZV found to be resistantto acyclovir, the most appropriatetherapy is:

a) foscarnetb) valaciclovirc) famciclovird) vidarabinee) idoxuridine


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 (7d-30mo)

• 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

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Varicella