Varicella-Zoster Virus

Practice Essentials
Varicella-zoster virus (VZV) causes chickenpox and herpes zoster (shingles). Chickenpox follows
initial exposure to the virus and is typically a relatively mild, self-limited childhood illness with a
characteristic exanthem, but can become disseminated in immunocompromised children.
Reactivation of the dormant virus results in the characteristic painful dermatomal rash of herpes
zoster, which is often followed by pain in the distribution of the rash (postherpetic neuralgia).
Essential update: New CDC guidelines for varicella-zoster virus immune globulin use
In July 2013, the CDC issued updated recommendations for the use of varicella-zoster immune
globulin (VariZIG) to reduce the severity of VZV infection, extending the window for postexposure
prophylaxis for those at high risk for severe varicella.
[1, 2]
The FDA's original approval of VariZIG
recommended use within 4 days, but subsequent studies have shown that the treatment is effective
for up to 10 days after exposure.
Other recommendations include the use of VariZIG in the following patients:
Immunocompromised patients without evidence of immunity
Newborn infants whose mothers have varicella symptoms between 5 days before and 2 days after
delivery
Hospitalized premature infants born at 28 weeks of gestation or later whose mothers do not have
evidence of immunity to varicella
Hospitalized premature infants born at less than 28 weeks of gestation or who weigh less than 1000
g at birth, regardless of their mothers' evidence of immunity to varicella
Pregnant women without evidence of immunity

Signs and symptoms
Pain and paresthesia are typically the first symptoms of VZV infection. Until the characteristic
vesicular rash erupts, diagnosis may be difficult. A prodromal period during which symptoms may vary
is common. Pain occurs in 41% of patients, itching in 27%, and paresthesias in 12%.
During the acute illness, patients may experience the following:
Pain (90%)
Helplessness and depression (20%)
Flulike symptoms (12%)
Herpes zoster (shingles)
The most common presentation is the shingles vesicular rash, which most commonly affects a
thoracic dermatome
After a prodromal illness of pain and paresthesias, erythematous macules and papules develop and
progress to vesicles within 24 hours
The vesicles eventually crust and resolve
Pain and sensory loss are the usual symptoms
Motor weakness also occurs and is frequently missed on examination
Cases of actual monoplegia due to VZV brachial plexus neuritis have been reported
Zoster multiplex
Shingles may appear in multiple dermatomes, both contiguous and noncontiguous, on either side of
the body
Immunocompromised individuals are more susceptible
Terminology depends on the number of involved dermatomes and on whether the condition is
unilateral or bilateral (eg, zoster duplex unilateralis refers to the involvement of 2 unilateral
dermatomes)
Cases of zoster simultaneously occurring in 7 noncontiguous dermatomes have been reported
Zoster sine herpete
VZV infection may reactivate without causing cutaneous vesicles. These patients have severe
dermatomal pain, possible motor weakness and possible hypesthesia, but no visible rash or vesicles.
VZV infection may present as acute peripheral facial palsy in 8-25% of patients who have no
cutaneous vesicles. This is more common in immunosuppressed patients who use acyclovir (or other
agents) as zoster prophylaxis.
[3]

Central nervous system deficits
More common in immunocompromised individuals, but do occur in the general population
CNS involvement may become apparent 3 weeks after the onset of the initial rash
The manifestations are usually bilateral
The physical findings may progress
The underlying pathology typically progresses for 3 or more weeks
Progression for 6 months in immunocompromised individuals has been reported
Recurrence is rare but has been reported
Zoster encephalitis is also rare but is reported in otherwise healthy individuals
Ramsay-Hunt syndrome
This syndrome occurs when the geniculate ganglion is involved. The clinical presentation includes the
following:
A peripheral facial palsy
Pain in the ear and face
Vesicles in the external ear canal (not always present)
Additional auditory and vestibular symptoms in some cases
Keratitis (herpes ophthalmicus)
Caused by reactivation of VZV infection in the ophthalmic division of the trigeminal nerve.
The presentation may include conjunctivitis or corneal ulcers
Complications include blindness
Vesicles do not have to be present
Rarely, the virus migrates along the intracranial branches of the trigeminal nerve, causing
thrombotic cerebrovasculopathy with severe headache and hemiplegia
See Clinical Presentation for more detail.
Diagnosis
When the presentation includes the typical dermatomal rash, additional studies are not required.
Studies to consider in specific situations include the following:
If the diagnosis is in doubt, a Tzanck smear or culture of vesicular fluid can be performed
In cases of zoster sine herpete, DNA analysis via PCR can be used
In cases of acyclovir-resistant VZV, detections of mutations in thymidine kinase can be determined
by PCR and sequence analysis
MRI may be useful if myelitis or encephalitis is suspected
Lumbar puncture may be helpful if signs suggest myelitis or encephalitis
See Workup for more detail.
Management
Treatment options are based on the following:
Patient age
Patient immune state
Duration of symptoms
Presentation
Antiviral medications decrease the duration of symptoms and the likelihood of postherpetic neuralgia,
especially when initiated within 2 days of the onset of rash. Oral acyclovir may be prescribed in
otherwise healthy patients who have typical cases. Compared with oral acyclovir, other medications
(eg, valacyclovir, penciclovir, famciclovir) may decrease the duration of the patient's pain.
Varicella zoster immune globulin (VariZIG) is indicated for administration to high-risk individuals within
10 days (ideally within 4 days) of chickenpox (VZV) exposure.
[4]
High- risk groups include the
following:
Immunocompromised children and adults
Newborns of mothers with varicella shortly before or after delivery
Premature infants
Infants less than younger than 1 year of age
Adults without evidence of immunity
Pregnant women
See Treatment and Medication for more detail.
Image library
Typical zoster in the vicinity of right popliteal fossa in a vertebral nerve L4 distribution.
Background
Varicella-zoster virus (VZV) is the cause of chickenpox and herpes zoster (also called shingles).
Chickenpox follows initial exposure to the virus and is typically a relatively mild, self-limited childhood
illness with a characteristic exanthem.
Approximately 1 per 4000 children develops VZV encephalitis, an acute neurologic disorder with
potentially severe complications. In addition, immunocompromised children (eg, those receiving
chemotherapy for leukemia or those with advancedHIV infection) can develop disseminated VZV
infection, a potentially fatal complication.
After primary infection, VZV remains dormant in sensory nerve roots for life. Upon reactivation, the
virus migrates down the sensory nerve to the skin, causing the characteristic painful dermatomal rash.
After resolution, many individuals continue to experience pain in the distribution of the rash
(postherpetic neuralgia). In addition, reactivation of VZV infection can cause a spectrum of atypical
presentations, ranging from self-limited radicular pain without rash to spinal cord disease with
weakness.
Pathophysiology
The host immunologic mechanisms suppress replication of the virus. Reactivation can occur if host
immune mechanisms are compromised. This may be caused by medications, illness, malnutrition, or
by the natural decline in immune function with aging. Upon reactivation, the virus migrates along
sensory nerves and produces sensory loss, pain, and other neurologic complications. If motor nerve
roots are also involved, weakness can develop in addition to sensory changes. Leptomeningeal
involvement is rare but may develop when the ophthalmic branch of the trigeminal nerve is involved.
Frequency
United States
The rate of occurrence is about 5 persons per 1000 population. Immunosuppression increases this
risk. The risk of postherpetic neuralgia increases with age. Approximately 50% of patients older than
60 years may have temporary or prolonged pain syndrome.
The frequency of VZV infection may decrease as the immunized children become adults.
International
VZV infection occurs with the same frequency in the United States and internationally.
Mortality/Morbidity
Severe pain and insomnia are most bothersome to patients. About 95% of patients with zoster
experience severe pain during the illness.
Other presentations of zoster, including ocular (keratitis) and spinal cord (myelitis) presentations, may
result in additional morbidity.
Bacterial superinfection (impetiginization) of vesicular skin lesions can occur.
Race
The vesicular eruption of VZV infection may be more difficult to diagnose in patients with darker skin.
Sex
VZV infection occurs with equal frequency in males and females.
Age
After primary infection, zoster can occur at any age. However, the risk of zoster increases with age.
The risk of postherpetic neuralgia also increases with advancing age.
History
Pain and paresthesia are typically the first symptoms. Until the characteristic vesicular rash erupts,
diagnosis may be difficult.
A prodromal period during which symptoms may vary is common. Pain occurs in 41% of patients,
itching in 27%, and paresthesias in 12%.
During the acute illness, 90% of patients experience pain, 20% describe helplessness and
depression, and 12% experience flulike symptoms.
Physical
Herpes zoster (shingles)
The most common presentation is the shingles vesicular rash, which most commonly affects a
thoracic dermatome.
After a prodromal illness of pain and paresthesias, erythematous macules and papules develop and
progress to vesicles within 24 hours. The vesicles eventually crust and resolve.
Pain and sensory loss are the usual symptoms, but motor weakness also occurs and is frequently
missed on examination. Motor weakness results when the viral activity extends beyond the sensory
root to involve the motor root. Cases of actual monoplegia due to varicella-zoster virus (VZV)
brachial plexus neuritis have been reported.

Typical zoster in the vicinity of right popliteal fossa in a vertebral nerve L4 distribution.

Human herpesvirus (HHV) type 3. Intraoral herpes zoster closely resembles recurrent HHV-1 infection, but the lesions
generally follow a dermatome and stop sharply at the midline, as shown here. However, the rules for common sites of
occurrence of HHV-1 and HHV-3 often do not apply to patients who are immunocompromised. Courtesy of Sheldon
Mintz, DDS.
Zoster multiplex
Shingles may appear in multiple dermatomes, both contiguous and noncontiguous, on either side of
the body.
They are more common in individuals who are immunocompromised.
Terminology depends on the number of involved dermatomes and on whether the condition is
unilateral or bilateral. For example, zoster duplex unilateralis refers to the involvement of 2 unilateral
dermatomes. Cases of zoster simultaneously occurring in 7 noncontiguous dermatomes have been
reported.
Zoster sine herpete
VZV infection may reactivate without causing cutaneous vesicles. These patients have severe
dermatomal pain, possible motor weakness and possible hypesthesia, but no visible rash or
vesicles.
Studies show that VZV infection may present as acute peripheral facial palsy in 8-25% of patients
who have no cutaneous vesicles. This is more common in immunosuppressed patients who use
acyclovir (or other agents) as zoster prophylaxis.
[3]

Myelitis
VZV infection may also cause central nervous system deficits.
Although deficits are more common in immunocompromised individuals, such presentations do
occur in the general population.
In one report, the condition began as a typical shingles rash, but spinal cord involvement became
apparent 3 weeks after the onset of the initial rash.
The manifestations are usually bilateral. The physical findings may progress.
The underlying pathology typically progresses for 3 or more weeks. Progression for 6 months in
immunocompromised individuals has been reported.
With intravenous acyclovir treatment, most cases fully resolve. Recurrence is rare but has been
reported.
Zoster encephalitis is also rare but is reported in otherwise healthy individuals. Due to the
effectiveness of 2-dose vaccinations, fewer cases of VZV encephalitis occur,
[5]
yet most cases in
vaccinated individuals are due to wild type from the vaccine strain.
[6]

Ramsay-Hunt syndrome
This syndrome occurs when the geniculate ganglion is involved.
The clinical presentation includes a peripheral facial palsy, pain in the ear and face, and vesicles in
the external ear canal.
Additional auditory and vestibular symptoms may be present. The vesicles are not present in all
cases.
Keratitis (herpes ophthalmicus)
This is caused by reactivation of VZV infection in the ophthalmic division of the trigeminal nerve.
The presentation may include conjunctivitis or corneal ulcers. Complications include blindness.
The vesicles do not have to be present.
Rarely, in cases of herpes ophthalmicus, the virus migrates along the intracranial branches of the
trigeminal nerve, causing thrombotic cerebrovasculopathy with severe headache and hemiplegia.
Causes
Immunosuppression increases the risk of both typical shingles and atypical presentations, such as
myelitis, encephalitis, disseminated disease, and visceral involvement.
Laboratory Studies
When the presentation includes the typical dermatomal rash, additional studies are not required.
If the diagnosis is in doubt, a Tzanck smear can be performed and has a sensitivity of about 60%. To
obtain a Tzanck smear, remove the crust from a vesicle and scrape the underlying moist skin with a
No. 15 surgical blade. Smear the cells from the vesicle base onto a slide, fix for 1 minute with
absolute alcohol, and stain with Wright stain (other staining methods can also be used).
The diagnosis can also be confirmed with a culture of vesicular fluid that is positive for varicella-zoster
virus (VZV).
In cases of zoster sine herpete, DNA analysis via polymerase chain reaction (PCR) can be used for
early diagnosis if laboratory turnaround time is reasonably short. If not, the decision of whether to start
empiric acyclovir must be based on clinical grounds alone.
In cases of acyclovir-resistant VZV, detections of mutations in thymidine kinase can be determined by
PCR and sequence analysis. Acyclovir-resistance may occur in stem cell transplant recipients.
[7]

Imaging Studies
MRI may be useful if myelitis or encephalitis is suspected.
Procedures
Lumbar puncture may be helpful if signs suggest myelitis or encephalitis. The cerebrospinal fluid
(CSF) shows increased levels of protein and pleocytosis because the inflammatory response involves
the leptomeninges. CSF PCR can be used to detect VZV DNA.
Although seldom necessary, biopsy results provide a definitive diagnosis.
Histologic Findings
The varicella zoster virus is a DNA virus with a genome that encodes 70 proteins.
The Tzanck preparation shows characteristic findings of giant cells with 2-15 nuclei. Recently infected
epithelial cells contain a single enlarged nucleus with a thick nuclear membrane.
After reactivation, meningeal biopsy samples show a local inflammatory response, consisting of
plasma cells and lymphocytes, that encompasses the leptomeninges.
Evidence has shown that motor neuron involvement is demyelinating rather than axonal.
Medical Care
Treatment options are based on the patient's age, immune state, duration of symptoms, and
presentation.
Several studies indicate that antiviral medications decrease the duration of symptoms and the
likelihood of postherpetic neuralgia, especially when initiated within 2 days of the onset of rash. In
typical cases that involve individuals who are otherwise healthy, oral acyclovir may be prescribed. An
important study by Kubeyinje (1997) suggested that the use of acyclovir in healthy young adults with
zoster is not clearly justified, especially in situations of limited economic resources.
[8]

Acyclovir has 2 limitationsbioavailability and the existence of some resistant strains of varicella-
zoster virus (VZV).
Other medications, including valacyclovir, penciclovir, and famciclovir, are also available. They may
have an increasing role in the treatment of typical zoster. Studies suggest that, when compared with
oral acyclovir, the new medications may decrease the duration of the patient's pain.
Varicella zoster immune globulin (VariZIG) is indicated for administration to high-risk individuals within
10 days (ideally within 4 days) of chickenpox (varicella zoster virus) exposure.
[4]

High risk groups include:
Immunocompromised children and adults
Newborns of mothers with varicella shortly before or after delivery
Premature infants
Infants less than one year of age
Adults without evidence of immunity
Pregnant women
Dworkin et al (2009) conducted a randomized, placebo-controlled trial of oral oxycodone and oral
gabapentin as potential treatments for acute pain in patients with herpes zoster. They found that
controlled-release oxycodone was superior to placebo in the early period of pain (1-14 d). Gabapentin
was not shown to yield a significantly greater relief of pain than placebo, although it conferred modest
pain relief during the first week.
[9]

Surgical Care
Surgical care may be required for complications of zoster, such as necrotizing fasciitis.
Consultations
Consultation with a neurologist is indicated in cases of myelitis or encephalitis.
Consultation with an infectious disease specialist may be helpful if bacterial superinfection or viral
resistance to acyclovir is evident.
Consultation with an ophthalmologist is indicated upon optic involvement.
Consultation with a dermatologist may be helpful when the rash is atypical.