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Grand Rounds

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shingles. schingles (medieval Latin) cingulum (Latin) ... Diagnosed as shingles and treated with acyclovir 800 mg 5x/d. Prednisone dose increased to 15/d ... – PowerPoint PPT presentation

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Title: Grand Rounds


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

2
Andys previous grand rounds
85
75
70
60?
Time (min)
Sweets Stem cells Eosinophils
Today (projected)
3
Andys previous grand rounds
  • Total time for three grand rounds 230 min.
  • Average per grand rounds 77 min. (902 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
herpes zoster
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
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

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, RR30, 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. Fathers 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 18, consistent
    with previous VZV infection or immunization
  • Convalescent serum taken 5 wks later had a titer
    of 18192

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 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 Reyes 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
    DAngelo (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) v491, p465 p39/446 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, p161 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
51
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. 589-20.
  • Prediliction for recurrence in same dermatome
    (4/9)

52
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

53
  • 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 Ref Hope-Simon
RE, Proc R Soc London (1965) 58, 9-20.
54
  • 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
55
  • 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 Ref Ragozzino et
al., Medicine-Baltimore (1982) 61, 310-6.
56
  • 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 Ref Oberg and
Svedmyr, Scand J Infect Dis (1969) 1, 47-49.
57
  • 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 Ref Weber and
Pekllecchia, JAMA (1965) 192, 572-7.
58
The Phantom Menace airborne VZV in the setting
of herpes zoster
59
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

60
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 fil
ter 3 ND ND -- -- -- -- -- -- 4 yes yes -- -- yes
-- yes -- 5 -- yes -- -- yes -- -- -- 6 yes yes y
es 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 NDnot done Acyclovir IV
given days 3 to 7 all vesicles encrusted
completely by day 11
61
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

62
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
75
Air filters
PBMCs
PCR positivity
50
25
0
0
2
4
6
8
10
12
Days of illness
63
A New Hope - brivudin
64
  • For strains of VZV found to be resistant
  • to acyclovir, the most appropriate
  • therapy is
  • foscarnet
  • valaciclovir
  • famciclovir
  • vidarabine
  • idoxuridine

Source McCrary, Severson and Tyring, JAAD
(1999) 41, 1-14 CME examination
65
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

66
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

67
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- RR1.13 (1.01-1.27),
    p0.014

68
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 el
evated GGT 1 4
69
  • For strains of VZV found to be resistant
  • to acyclovir, the most appropriate
  • therapy is
  • foscarnet
  • valaciclovir
  • famciclovir
  • vidarabine
  • idoxuridine

Source McCrary, Severson and Tyring, JAAD
(1999) 41, 1-14 CME examination
70
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

71
Foscarnet
  • Not orally available given IV
  • Renal toxicity
  • Seizures, anemia, neuropathy, penile ulcers

72
The Clone Wars - pityriasis lichenoides as yet
another manifestation of VZV?
73
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

74
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

75
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