Diagnosis and Management of Varicella Zoster Virus Infections

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Diagnosis and Management of Varicella Zoster
Virus Infections

• Hank Balfour
• Professor of Laboratory Medicine
  PathologyProfessor of Pediatrics
• University of Minnesota International Center
• for Antiviral Research and Epidemiology (I CARE)
• Minneapolis, USA

The mission of I CARE is research and training
in Clinical Trials, Virology, and Pharmacology
pertaining to chronic viral infections. For
more information please visit our website
http//www.lamp.med.umn.edu/actu/
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Introduction

• Varicella zoster virus is a member of the
  herpesvirus family
• Varicella zoster virus causes varicella,
  chickenpox and shingles
• Varicella zoster virus primary infection and
  reactivation can cause disease
• Varicella zoster virus can cause substantial
  morbidity
• Varicella zoster primary infection and
  reactivation can cause considerable pain
• Varicella zoster infections can be treated, and
  swift initiation of the appropriate treatment is
  most effective

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Herpesvirus phylogenetic tree (Major capsid
protein gene)
HHV-8
HVS
EHV-2
?
?
EBV
HSV-1
HSV-2
EHV-1
Non-human herpesviruses EHV Equine
herpesvirus HVS Herpesvirus saimiri PRV
Pseudorabies virus
?
PRV
VZV
HHV-7
Moore PS, Gao SJ, Dominguez G, Cesarman E, Lungu
O, Knowles DM et al. Primary characterization of
a herpesvirus agent associated with Kaposis
sarcomae. J Virol 199670549558.
HHV-6
CMV
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Laboratory diagnosis of VZV infection

• Immune status
• Antibody detection by ELISA
• Acute infection
• Viral culture or antigen detection using lesion
  swabs or vesicular aspirates
• PCR of body fluids (especially CSF)

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VZV cytopathic effect in diploid fibroblasts
A streak of both pyknotic and enlarged infected
cells is seen against a background of normal
spindle-shaped cells
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Epidemiology of VZV infections

• Primary infection (varicella or chickenpox)
• Temperate climates
• occurs during childhood
• 95 acquisition by age 14
• The tropics more often an adult disease

Climate affects the age VZV is acquired Garnett
GP, Cox MJ, Bundy DA, Didier JM, St Catharine J.
The age of infection with varicella-zoster virus
in St Lucia, West Indies. Epidemiol Infect
1993110362372.
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Epidemiology of VZV infections

• Likelihood of reactivation infection (herpes
  zoster or shingles)
• Immunocompetent
• risk increases with age
• Immunosuppressed
• greater risk regardless of age

Risk of shingles increases with age Ragozzino MW,
Melton LJ 3rd, Kurtland LT, Chu CP, Perry HO.
Population-based study of herpes zoster and its
sequelae. Medicine 198261310316.
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Chickenpox correlation of clinical and viral
events

• Modal incubation period from infection to rash
  14 days (range 1221 days)
• Prodrome fever, malaise, headache abdominal pain
  may precede rash by 12 days especially in
  adolescents and adults

From Balfour HH Jr, Heussner RC. Herpes Diseases
and Your Health. Minneapolis, USA University of
Minnesota Press, 1984.
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Typical chickenpox skin lesions in an
immunocompetent boy
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Chickenpox palatal lesion in an immunocompetent
child
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Chickenpox lip lesions in an immunocompetent boy
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Chickenpox time to events in normal hosts
--------------Median days to---------------
Event Children Adolescents Adults Loss
of fever 2 2 3.5 No new
lesions 2 3 5 Max lesion number 2 4 3 L
oss of pruritus 2.5 7 7 50
healing 8 7 8
All data are from randomized, placebo-controlled
double-blind trials Medians from placebo
recipients Medians from those who received
aciclovir 4872 hours after onset of rash
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Immediate or delayed aciclovir therapy for
chickenpox
177 patients treated within 24 h (Group A), 48 h
(B1) or 72 h (B2) of rash
24 h
72 h
48 h
Median days to 50 healing
A B1
B2 Study group
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Complications of chickenpox
Complication Method of Diagnosis
Bacterial cellulitis Culture and Gram
stain Pneumonia Clinical findings and chest
X-ray Central nervous system Cerebellar
ataxia Clinical ataxia, nuchal rigidity,
nystagmus Encephalitis PCR of CSF for
VZV
____ Listed in order of frequency in
immunocompetent hosts Fasciitis also reported in
small number of patients Rare CNS complications
include Guillain-Barré and Reyes syndromes
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Most common serious complication chickenpox
pneumonia
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Chickenpox in pregnant women and neonates

• Chickenpox during pregnancy may result in
• Maternal pneumonia
• Congenital malformations especially if mother
  infected in first 20 weeks gestation
• Neonatal chickenpox if mother develops chickenpox
  1 week of delivery
• Neonates at risk of severe illness if develop
  chickenpox before 28 days old

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Chickenpox in the immunocompromised host
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Prevention of chickenpox

• Pre-exposure prophylaxis chickenpox vaccine
  (Varivaxr)
• Clinical category Dosage Comments
• Healthy children 1 dose Give after 15 months if
• 112 years old (0.5 ml SC) possible
• Healthy susceptible 2 doses, May be
  cost-effective to
• person 48 weeks screen patients for
  antibodies
• 13 years old apart and only immunize
  seronegatives, because 80 of
  persons in this age group are seropositive

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Prevention of chickenpox

• Post-exposure prophylaxis VZ immune globulin
  (VZIG) must be given within 96 h of exposure
• Clinical category Dosage Comments
• Premature newborns 1 vial (1.25 ml) IM
  Gestational age lt28 wk all hospital
  exposures gestational age gt28 wk
  hospital exposure if
  mother seronegative
• Term newborn s 1 vial IM If exposed in
  hospital when lt28 days old
• Pregnant women 5 vials IM
• Infants with maternal 1 vial IM If mother
  develops
• chickenpox chickenpox 7 days of
• delivery
• Immunocompromised 1 vial/10 kg
• patients body weight IM  

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Prevention of chickenpox

• Post-exposure prophylaxis aciclovir (Zovirax)
• Clinical category Dosage Comments
• Susceptible 20 mg/kg Best results when
• household members (max 800 mg) initiated
  79
• 4 x daily for 7 days days
  post-exposure
• Pregnant women 800 mg orally Option when
• Immunocompromised 5 x daily for exposure
  not
• patients 710 days recognized until
• 5th day

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Antiviral therapy for chickenpox
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Antiviral therapy for chickenpox

• Clinical category Pregnant women
  Neonatal chickenpox
• Treatment of choice   Oral aciclovir i.v.
  aciclovir
• 800 mg 4 x daily 10 mg/kg every 8 h
• for 5 days for 7 days if
• evidence of visceral
• chickenpox
• Alternative treatment i.v. aciclovir None
• 10 mg/kg every 8 h for
  7 days
• Comments Aciclovir not
• approved for use
• in pregnancy
• (Pregnancy
• Category B)
•  

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Antiviral therapy for chickenpox

• Clinical Category Immunocompromised patients
• Treatment of choice i.v. acyclovir 10 mg/kg
• every 8 h for 10 days
• Alternative treatment Switch to oral aciclovir
  800 mg
• 5 x daily to complete 10-day course
• Comments Switch from i.v. to oral aciclovir
  should not be made until patient is
  afebrile, has ceased forming new
  lesions, and has no evidence of
  visceral chickenpox

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Herpes zoster time to events
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Herpes zoster day 2
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Herpes zoster day 3
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Herpes zoster day 6
Many lesions drying and crusting but fresh crop
of vesicles (lower right red arrow)
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Herpes zoster day 8
Same patient 2 days later most lesions
flattening and crusting, including crop of
lesions fresh on day 6
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Trigeminal herpes zoster day 2
These patients should be treated with antivirals
and referred to an ophthalmologist for
management of herpes zoster ophthalmicus
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Effect of immune status on progression of herpes
zoster
Day 8
Day 8
Immunocompetent adult
14-year-old with Hodgkins disease
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Zoster shortly after haematopoietic stem cell
transplantation
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Treatment for herpes zoster
Antiviral therapy considered for patients with
mild pain presenting within 72 h of rash onset
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Barriers to appropriate management of herpes
zoster

• Lack of clear initial symptoms due to variable
  nature of prodromal pain
• Delay in getting an appointment once rash appears
  and patients fear of illness
• Time between consultation and dispensing drugs
• Lack of physician awareness of patients
  suffering
• Perception that treatments are too expensive or
  toxic

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Complications of herpes zoster

• Major complication in otherwise healthy adults
• is post-herpetic neuralgia (PHN)
• Risk factors for PHN are
• Advancing age
• Presence of a prodrome
• Acute pain severity
• In immunocompromised patients, complications are
  cutaneous and visceral (lungs, liver, CNS, bone
  marrow) dissemination and PHN

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Why is herpes zoster painful?
Pathways of pain perception
Axons and peripheral nerves are damaged by VZV
reactivation and the subsequent inflammatory
response. This coupled with altered signal
processing in the CNS causes hyperactive pain
responses to non-noxious stimuli
Kost RG, Straus SE. Postherpetic
neuralgiapathogenesis, treatment, and
prevention. N Engl J Med 19963353242.
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Antiviral therapy for zoster-associated pain

• Major rationale to use antiviral drugs for herpes
  zoster is to prevent/reduce duration/intensity of
  pain
• Antiviral therapy during acute illness shortens
  mean duration of associated pain by 12 weeks.
  Valaciclovir and famciclovir are equally
  effective and superior to aciclovir
• Treatment during acute illness especially
  important as symptomatic treatment of established
  post-herpetic neuralgia is difficult and
  high-dose aciclovir ineffective

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Management of post-herpetic neuralgia
Best approaches

• Education on QoL matters, use of cold packs,
  appropriate clothing
• Analgesic therapy - Paracetamol - Oral opioids
  (levorphanol) - Lidocaine patch
• Tricyclic antidepressants - Amitriptyline or
  nortriptyline
• Anticonvulsants - Gabapentin

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Diagnosis and management of VZV infections
Summary

• VZV infections cause substantial morbidity in all
  age groups
• VZV infections are preventable and treatable
• Research priorities include
• Understanding why epidemiology of chickenpox
  differs in tropical versus temperate climates
• Assessing effect of viral load on severity
• Better understanding of VZV latency