US Pharm. 2014;39(5):39-43.
virus is responsible for causing a primary varicella infection
(chickenpox) and a secondary herpes zoster infection (shingles).
Although varicella typically manifests as a mild disease in otherwise
healthy children, it can also manifest as a moderate-to-severe disease,
most notably in immunocompromised and adult hosts. Acyclovir is the
antiviral agent of choice for the management of varicella infections.
However, in acyclovir-resistant varicella infections, foscarnet is the
recommended antiviral agent for use. Routine vaccination with Varivax
has been very effective in reducing chickenpox incidence in the United
States; it confers immunity and also reduces clinical manifestation of
Varicella-zoster virus (VZV) is a double-stranded DNA
virus that belongs to the Alpha-herpesvirinae subfamily of the
Herpesviridae family of eight herpes viruses. It is responsible for an
infection that manifests as separate illnesses in two phases of the
human life cycle: 1) a primary infection, varicella (chickenpox),
typically in childhood; and 2) a secondary herpes zoster (HZ) infection
(shingles) through reactivation of the latent virus in the central
nervous system (CNS), typically in the elderly. This article aims to
review the epidemiology, clinical manifestations, complications,
management, and prevention of childhood chickenpox, including recent
advances in therapeutic management of varicella and CDC recommendations.
Varicella is a highly contagious infection that occurs
only in humans, with a secondary attack rate of up to 90% in susceptible
(seronegative) household contacts.1-3 Prior to the
development of the varicella vaccine in 1995, chickenpox was reported to
be endemic in the United States, with approximately 4 million cases,
resulting in about 11,000 hospitalizations and 100 deaths per year.1,4,5 In temperate climates, it exhibits an annual epidemic trend, peaking in late winter to spring.1,2
Varicella is primarily a disease of childhood with approximately 90% of
the cases, 67% of varicella hospitalizations, and about 50% of related
deaths reported in children.2-4,6 Historically, children
between the ages of 1 and 4 years accounted for 39% of cases, while
children aged 5 to 9 years and adults ≥20 years accounted for 38% and
7%, respectively (National Health Interview Survey data, 1990-1994).5
Transmission and Pathophysiology
Varicella is primarily transmitted human-to-human via the
nasopharynx or conjunctiva, through mucosal inoculation with droplets
and aerosols from VZV- or HZ- infected persons. The infectious period
occurs within 1 to 2 days before the onset of rash (through
nasopharyngeal secretions) or within 5 to 7 days after appearance of
rash (through skin lesions). This period of contagiousness can be
extended in immunocompromised persons.1-2,7,8 The virus has an average incubation period of 14 to 16 days (range: 10-21 days).1-3,7
After inoculation, there is a primary viremia phase where
the virus disseminates and multiplies in the viscera and
reticuloendothelial tissues. A secondary viremia phase occurs at about
14 days post infection where there is a viral spread to the
nasopharyngeal surface and the skin, leading to the appearance of
typical maculopapular vesicular rashes.2,3,7 These vesicular
rashes are highly concentrated with the virus and are very contagious
until crusted. The virus can also infiltrate the CNS and become dormant
in the dorsal root and cranial nerve ganglia, to be reactivated at a
later period in the human life cycle as HZ infection.7 While
there is a favorable outcome with the primary infection, children with
underlying HIV infection showed a higher incidence of the secondary
zoster infection in early stages of life.7,8
Clinical Manifestations and Laboratory Findings
Varicella is characterized by a generalized itchy,
blister-like rash, usually associated with fever, headache, malaise,
myalgia, and loss of appetite.1-3,7 The rash first
appears as macules, then progresses through the papular and vesicular
stages, before crusting over within a short period of time (within 24-48
hours). The lesions typically start on the face and scalp and then
progress to the trunk and extremities, appearing throughout the body at
different stages of development.3,7
Varicella infection can lead to secondary complications
from either viruses or bacteria. The most common complication is
secondary bacterial infections, especially infections caused by group A
beta-hemolytic streptococci or staphylococci. These infections can
manifest as impetigo, cellulitis, erysipelas, and skin lesions from
staphylococcal exfoliative toxin.3,7 Extracutaneous secondary
complications include pneumonia, osteomyelitis, myocarditis, sepsis,
necrotizing fasciitis, and CNS involvement, which is the most common in
CNS involvements range from mild complications like
cerebellar ataxia to serious complications such as Reye syndrome, an
acute illness characterized by rapidly progressive encephalopathy and
fatty degra-dation of the liver. The syndrome presents as severe
vomiting and confusion, encephalitis, meningitis, and vasculitis, which
can lead to stroke.9 Varicella infection is usually more
severe in immunocompromised patients with an increased risk of
dissemination and infection to other organs.3,8,10
Laboratory testing is not necessary for most cases of
varicella infection, but it is routinely used for suspected disseminated
infection. It may also be utilized in atypical cases. VZV antibodies
can be detected via direct fluorescence (DF). The virus from skin
lesions, or cerebrospinal fluid in cases of CNS involvement, can be
detected via polymerase chain reaction (PCR).2,7,10
Serologic testing for VZV antibodies is not recommended
for the diagnosis of VZV but can be useful in determining if an
individual is at risk.2 A positive immunoglobulin G (IgG) and
IgM suggest a primary VZV infection. A positive IgG, which can persist
for years, and a negative IgM imply vaccination or a primary infection,
conferring a protective immunity against reinfection.2 A
negative IgG and negative IgM indicate the absence of prior exposure to
VZV and nonimmunity. A negative reading does not rule out a VZV
infection. IgM commercial assays are prone to both false-positive and
false-negative results; IgG commercial assays are prone to
false-negative results (10%-20%).2 Retesting should be done in 2 to 3 weeks if a negative reading is obtained.
Strategies for the management of varicella infection are aimed at symptom management and prevention of secondary complications.3,7
Treatment options include supportive measures, antiviral therapy,
varicella-zoster immune globulin (human) (VZIG or VariZIG), and
management of secondary complications. Due to varicella’s high
contagiousness, all persons admitted as inpatients with VZV or HZ
infection should be placed on airborne plus contact precaution to reduce
risk of transmission.7,10 All close contacts of infected
persons without evidence of immunity should receive immunization or
VariZIG, preferably within 72 hours, but up to 5 days, post exposure.10
Symptomatic Measures: As a self-limiting
disease, varicella infection in otherwise healthy children can often be
treated solely with symptomatic management and prevention of secondary
complications. Good hygiene (e.g., daily baths, preferably with
antibacterial soap) and thorough skin care are important for the
prevention of secondary bacterial infections.1 The child’s
fingernails should also be cut short in an effort to prevent secondary
bacterial skin infections. Further measures of supportive therapy
include OTC medications such as acetaminophen for fever, topical agents
that include calamine, daily lukewarm soaks with colloidal oatmeal, and
oral or topical antihistamines; the latter three will provide management
and a soothing relief of the pruritus.1-3 Aspirin should be
avoided in varicella-infected children due to its association with Reye
syndrome; acetaminophen should be the antipyretic of choice in children,
with appropriate dosing (TABLE 1).1,7
Antiviral Therapy: In otherwise healthy
children <12 years of age, varicella is often of benign manifestation
and self-limiting; routine antiviral therapy may not provide much
clinical benefit and is therefore not routinely recommended in this
population. But it may help prevent secondary complications in at-risk
populations including immunocompromised children and children on
immunosuppressive therapy.1-3,7,10-13 Vidarabine and
interferon-alfa were the initial antiviral agents studied in at-risk
populations with varicella infections, but were later replaced by
acyclovir, a safer and more effective therapy.2
Acyclovir, an antiviral agent used in the management of
varicella, is available in both oral and IV formulations. It is an
acyclic analogue of guanosine that must be phosphorylated by viral
thymidine kinase and subsequently by host cell enzymes into its active
triphosphate form for its antiviral activity through inhibition of viral
DNA polymerase (FIGURE 1). Acyclovir is the antiviral agent of
choice in the treatment of varicella and should be initiated within 24
hours of the onset of rash.1-3,7 It has been proven to
shorten both the duration and severity of chickenpox by decreasing viral
shedding and the formation of new lesions, as well as by accelerating
lesion healing in both healthy and immunologically compromised children.1-3,7
Alternative antiviral agents for varicella include
valacyclovir, the L-valine ester of acyclovir that is converted to
acyclovir after oral administration, and famciclovir. Both agents are
clinically used for varicella infections; however, lack of sufficient
clinical efficacy trials prevents the use of these drugs as first-line
agents for this indication. Additionally, famciclovir is not
FDA-approved for varicella.2 Valacyclovir has approximately
55% bioavailability and therefore requires less frequent dosing in
contrast to oral acyclovir, which has a low oral bioavailability; only
about 10 to 20% of the oral acyclovir dose becomes bioavailable.
Treatment with antiviral agents is optional in otherwise
healthy children ≤12 years of age, but the American Academy of
Pediatrics (AAP) recommends antiviral therapy in adolescents (children
>12 years of age); children >12 months who are on long-term
salicylate therapy; children with chronic pulmonary or skin problems;
and children receiving aerosolized corticosteroids. IV acyclovir is
recommended to prevent or treat disseminated varicella in
immunocompromised children, including those receiving oral
corticosteroids ≥2 mg/kg/day (or prednisolone 20 mg/day equivalent) for
≥2 weeks; in HIV-infected persons; and in those receiving
immunosuppressive therapy. IV therapy unfortunately requires
hospitalization, posing a risk of nosocomial infections. Alternatively,
high-dose oral acyclovir or valacyclovir may be used for mildly
TABLE 2 summarizes the recommended agents and dosing for management of varicella infection in children and adolescents.7
Acyclovir resistance has only been reported in rare cases, often in
immunocompromised patients. It is more often reported in HIV-infected
persons, in whom acyclovir may be used long term, thereby creating a
selection for thymidine kinase–negative or mutant virus.7,13,14
In this case, the virus fails to produce thymidine kinase, or produces a
genetically altered form of the enzyme, which is necessary for the
initial phosphorylation of the drug.14 Acyclovir-resistance can be clinically defined when patients fail to respond to acyclovir therapy.2
Thus, children with acyclovir-resistant varicella infection should be
treated with foscarnet, a pyrophosphate analogue that, unlike acyclovir,
does not require further phosphorylation for activity.15 It
has direct action on viral DNA polymerase and acts by selectively
inhibiting pyrophosphate–binding sites on viral DNA polymerase.15 Moreover, foscarnet is only available via IV route.
Prevention and Prophylaxis
Varicella Vaccine: Varivax (Merck
& Co., Inc.), a single-agent vaccine containing a live, attenuated
(Oka strain) virus, is recommended to prevent varicella infection in
healthy persons >12 months of age who do not have any
contraindication to the vaccine (TABLE 3).16,17
Routine varicella vaccination occurs between ages 12 and 18 months, with
the second dose administered between ages 4 and 6 years.16
ProQuad (Merck & Co., Inc.), a measles/mumps/rubella/varicella
(MMRV) combination vaccine, is licensed for use in persons aged 12
months to 12 years with a similar dosing schedule.18
Nonimmunized adolescents should receive two doses of
varicella vaccine, with a minimum interval of 4 weeks between doses. The
vaccine is safe and well tolerated in healthy children and adolescents.
Common adverse effects of Varivax include reactions at the
injection-site (i.e., pain, redness, swelling, rash), fever, and
Since its license, Varivax has been highly effective in reducing incidence of varicella.6,17,19
According to a 14-year prospective study of varicella incidence and
long-term effectiveness of the varicella vaccine by Kaiser Permanente
Vaccine Study Center, incidence of varicella decreased by about 10-fold
from the prevaccine era.19 Effectiveness of Varivax is reported as 85% to 90%.17,20,21
Varivax can also be utilized for postexposure prophylaxis to prevent or
reduce the severity of the illness; efficacy is maximized if
administered within 72 hours of exposure.10,16-20,22
Varicella-Zoster Immune Globulin: VariZIG, a purified human IgG, provides passive immunity to persons at high risk of severe chickenpox (TABLE 4); it can also prevent or ameliorate clinical varicella if administered within 10 days of exposure.23
Factors to consider before utilizing VariZIG include: 1) lack of
evidence of immunity, 2) exposure likely to result in infection, and 3)
greater risk for complications than in the general population.23
VariZIG should be administered ideally within 96 hours (up
to 10 days) after exposure. VariZIG should not be given concurrently
with Varivax. Considering that the passive transfer of immunoglobulin
could interfere with the efficacy of live attenuated vaccines such as
MMRV, vaccination should be deferred until ≥5 months after VariZIG
administration.23 Patients should be monitored for 28 days
after VariZIG exposure for signs and symptoms of varicella infection,
and antiviral therapy should promptly be initiated if these occur.
Common adverse effects of VariZIG include reactions at the injection
site and headaches. The recommended dose of VariZIG is 125 IU/10 kg of
body weight (≤625 IU). For patients weighing ≤2.0 kg, administer 62.5
IU, and 125 IU for patients weighing 2.1 to 10.0 kg.23
Antiviral Postexposure Prophylaxis: Where
VariZIG is not indicated, high-dose oral acyclovir 20 mg/kg/dose (≤800
mg) 4 times daily for 7 days or Varivax may be used as postexposure
prophylaxis; efficacy is maximized if treatment is initiated within 24
hours of symptoms.7
Varicella infection (chickenpox) is a common illness of
childhood. In otherwise healthy children ≥12 years old, the illness is
often mild and can be managed with supportive therapy. If required,
antiviral therapy can be initiated within 24 hours of the onset of rash.
The most effective way to prevent a varicella outbreak is through
universal immunization with varicella vaccine. This strategy not only
prevents a severe or complicated form of the disease in healthy
children, but it also serves to protect at-risk children including those
who are immunologically compromised and cannot receive live vaccines.
Furthermore, post exposure can be managed with varicella-zoster
immunoglobulin preparation, an antiviral agent, or the vaccine.
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2. Arvin AM. Antiviral therapy for varicella and herpes zoster. Semin Pediatr Infect Dis. 2002;13:12-21.
3. Heininger U, Seward JF. Varicella. Lancet. 2006;368:1365-1376.
4. Wharton M. The epidemiology of varicella-zoster virus infections. Infect Dis Clin N Am. 1996;10:571-581.
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6. Nguyen HQ, Jumaan AO, Seward JF. Decline in mortality
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