Grand Rounds

Andy Chien, MD, PhD

University of Washington
Division of Dermatology
 Andy’s previous grand rounds
90
80 85
70 75
60
70
Time 50 60?
(min) 40
30
20
10
0
Sweet’s Stem cells Eosinophils Today
(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): chiche-pois (French):

“to itch” “chick-pea”

pokkes (Middle English)

pocc (Old English)

beu (hypothetical Indo-European root): “to swell”

 herpes zoster

herpes (Greek): zoster (Greek):

“creeping” “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)
 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
• 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
 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,
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 terms
of 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 lesions

b) hypoplastic limbs
c) hypertelorism
d) cortical atrophy
e) low birth weight

Source: McCrary, 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 [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 terms
of 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
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 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.
 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: McCrary, 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 5x/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: McCrary, 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: McCrary, 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: McCrary, 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: McCrary, Severson and Tyring, JAAD (1999) 41, 1-14 CME examination
The risk of dissemination in immuno-
compromised patients with herpes
zoster 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 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 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 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: McCrary, 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: McCrary, 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: McCrary, 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 immuno-
compromised patients with herpes
zoster 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 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 1.2-5.5m 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 -- yes
8 ND ND -- yes yes yes yes yes
14 ND ND yes -- yes yes -- yes
21 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
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.

100
Skin
Throat
PCR positivity

75
Air filters
PBMCs
50

25

0
0 2 4 6 8 10 12
Days of illness
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: McCrary, 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 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 13
Headache 6 7
Abd pain 5 4
Dizziness 4 1
Vomiting 3 7
elevated GGT 1 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: McCrary, 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 (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