PENCEGAHAN VARISELA

Varicella vaccine.
Several studies conducted in Europe, Japan, and the United States from the early
1970s through the early 1990s demonstrated that live attenuated (Oka strain)
VVZ vaccines were immunogenic and efficacious in protecting susceptible children
against varicella. Although breakthrough cases of varicella were observed
following subsequent exposure to wild-type VVZ, they were relatively mild.
Similar results were obtained in adults when two doses were given 4-8 weeks
apart. Vaccinated children and adults developed breakthrough varicella caused by
wild-type VVZ at a rate of 1%-3% per year compared to an attack rate of 8%-13%
per year in unvaccinated children. On the basis of these data, the FDA licensed
the Oka/Merck varicella vaccine in the United States in 1995. In 2005, the FDA
approved a combined measles, mumps, rubella, and varicella vaccine (MMRV) for
routine immunization of children 12 months to 12 years of age.
Because of the frequency of breakthrough varicella caused by wild-type VVZ, the
Advisory Committee on Immunization Practices (ACIP) now recommends two 0.5
mL doses of varicella vaccine for healthy children aged 12 months, adolescents,
and adults without evidence of immunity. For children aged 12 months to 12
years, the recommended minimum interval between the two doses is 3 months,
although the second dose may be administered as soon as 28 days after the first.
For persons aged > 13 years, the recommended minimum interval 4 weeks.
Single-antigen varicella vaccine is approved for use among healthy children aged
12 months to 12 years. Because of the increased severity of varicella in adults,
susceptible adults should be identified and vaccinated. High priority should be
given to vaccinating adults who may be at increased risk for exposure or
transmission and who do not have evidence of immunity, including (1)healthy
care providers, (2)household contacts of immunocompromised persons,
(3)persons who live or work in environments in which transmission of VVZ is likely
(e.g., teachers, day care employees, residents, and staff in institutional settings),
(4)persons who live or work in environments in which transmission has been
reported (e.g., college students, inmates and staff members of correctional
institutions, and military personnel), (5)nonpregnant women of childbearing age,
(6)adolescents and adults living in households with children, and (7)international
travelers. Second dose catch-up varicella vaccination is recommended for
children, adolescents, and adults who previously received only one dose.
The immunity to varicella induced by varicella vaccine is not as solid as that
induced by wild-type VVZ infection, and the duration of vaccine-induced
immunity is not yet known. However, a high percentage of children followed long-
term have remained seropositive. Recent experience in clinical practice indicates
that vaccine efficacy in children is modestly lower than that reported in clinical
trials, and outbreaks of breakthrough varicella in school and day care centers do
occur. In a prospective, population-based study, vaccine effectiveness for
prevention of all disease was 78.9% (95% Cl, 69.7-85.3%); for prevention of
moderate disease was 92% (50-500 lesions) and for prevention of severe disease
and physician visits was 100%. A CDC analysis of 10 years of surveillance data for
varicella (1995-2004) showed that the annual rate of breakthrough varicella
significantly increased with the time since vaccination, from 1.6 cases per 1,000
person-years (95%, 1.2-2.0) within 1 year after vaccination to 9.0 per 1,000
person-years (95% Cl, 6.9-11.7) at 5 years and 58.2 per 1,000 person-years (95%
Cl, 36.0-94.0) at 9 years. Although most breakthough varicella in children are
characterized by mild disease, more recent reports indicate that 25%-30% of
breakthough cases are not mild and are clinically similar to varicella in
unvaccinated children. Interestingly, cases of breakthough varicella in household
settings were half as contagious as cases of varicella in unvaccinated persons,
although the minority of breakthough cases with 50 lesions or more were as
contagious as cases in unvaccinated persons. In adults, approximately 20% of
vaccinees lose detectable antibodies to VVZ over time, but continue to be
partially protected. Of the 48 million doses of varicella vaccine distributed
between 1995 and 2005, there were 25,306 adverse events reported
(52.7/100,000 doses distributed) to the FDAs Vaccine Adverse Event Reporting
System and the Centers for Disease Control and Prevention (CDC) 95% of which
were nonserious events, mainly minor rashes and injection site reactions. Serious
adverse events were rare (2.6/100,000 doses distributed) and, in the majority, a
causal relationship between the serious adverse event and varicella vaccine could
not be established.
Herpes zoster has been reported in vaccinees, but it occurs at a significantly lower
frequency than herpes zoster in persons of similar age following varicella caused
by wild-type VVZ. Cases of laboratory confirmed herpes zoster in vaccinees from
several studies included some cases caused by reactivation of the vaccine virus
and others caused by reactivation of wild-type virus acquired prior to vaccination
as a consequence of unrecognized varicella.
POSTEXPOSURE PROPHYLAXIS AND INFECTION CONTROL
Patients with varicella and herpes zoster may transmit VVZ to susceptible
individuals. Preventive measures include the varicella vaccine, investigational
high-titer zoster immune globulin (VariZIG), and postexposure chemoprophylaxis
with acyclovir.
Active immunization with the live attenuated varicella vaccine is effective in
preventing illness or modifying varicella severity in children if used within 3 days
after exposure. Whereas protection afforded by zoster immune globulin is
transient, varicella vaccine induces long-lasting (active) immunity to VVZ and
protection against subsequent exposures. Therefore, the ACIP recommends
varicella vaccine for postexposure prophylaxis is unvaccinated persons without
evidence of immunity.
Passive immunization with VZIG was an effective preventive strategy, but the
production of VZIG has been discontinued in the United States. An investigational
new drug application (IND). The investigational VariZIG is a purified human
immune globulin prepared from plasma containing high levels of antibody to VVZ
(immunoglobulin class G [IgG]). This product can be requested for patients who
have been exposed to varicella and who are at increased risk for severe disease
and complications.
Chemoprophylaxis with acyclovir also has been studied in susceptible children
following household exposure to varicella. Children who received postexposure
treatment with acyclovir experienced fewer and less severe cases of varicella than
children in the control group. However, appropriate timing is critical, and
immunity to varicella may not be achieved, especially with early postexposure
treatment. In addition, there is concern that resistant strains of VVZ may be
selected by promiscuous application of this approach. Hence, postexposure
antiviral chemotherapy is not recommended for routine use in children.
Infection control practices for VVZ increase in importance with the age and
compromised immune status of the exposed, susceptible individual. There is no
need to prevent exposure os susceptible normal children to VVZ, but careful
isolation procedures should be enforced to prevent infection of susceptible
immunocompromised patients, newborn infants, and dults, particularly women of
childbrearing age. Exposure of susceptible immunocompromised patients to VVZ
warrants reduction in the dosage of glucocorticoids and other
immunosuppressive drugs, and administration of investigational VariZIG. Hospital
and longterm care facility personnel without a clear history of varicella of herpes
zoster should be tested for antibody to VVZ, and susceptible personnel vaccinated
against varicella. Appropriate leave from work should be instituted following VVZ
exposure of any susceptible personnel who are not vaccinated. In hospital,
airborne and contact precautions are recommended until all lesions are crusted
for patients with varicella, immunocompromised patients with localized herpes
zoster, and any patient with disseminated herpes zoster. Contact precautions are
recommended for immunocompetent patients with localized herpes zoster.

TREATMENT
The nucleoside analogues acyclovir, famciclovir, valacyclovir, and brivudin and the

pyrophosphate analog foscarnet show efficacy in treating VZV infections. Acyclovir is a

guanosine analog that is selectively phosphorylated by VZV thymidine kinase (it is a poor

substrate for cellular thymidine kinase) and thus is concentrated in infected cells. Cellular

enzymes then convert acyclovir monophosphate to acyclovir triphosphate, which interferes with

viral DNA synthesis by inhibiting viral DNA polymerase. VZV is approximately tenfold less

sensitive to acyclovir than HSV.

Two prodrugs, valacyclovir and famciclovir, are better and more reliably absorbed than acyclovir

after oral administration. Thus, they produce much higher blood levels of antiviral activity and

permit less frequent dosing than acyclovir. Valacyclovir is a valine ester of acyclovir that is

converted enzymatically to acyclovir after absorption. Famciclovir is a prodrug of penciclovir, a

nucleoside analogue similar to acyclovir in mechanism of action and antiviral activity against

VZV and HSV. Famciclovir is converted enzymatically to penciclovir after absorption.

Brivudin is a uracil analogue with very high activity against VZV. Although effective in the

treatment of herpes zoster, and licensed for such use outside the United States, it is not licensed

in the United States, in part because of a potentially lethal interaction with 5-flurouracil.

Foscarnet is an analogue of inorganic pyrophosphate that inhibits the replication of all known

herpesviruses in vitro. It exerts its antiviral activity by selective inhibition at the pyrophosphate-

binding site of virus specific DNA polymerase and reverse transcriptases at concentratitons that

do not affect cellular DNA polymerases. Foscarnet does not require phosphorylation by

thymidine kinase to be activated and is therefore active against acyclovir-resistant VZV mutants

that have reduced or altered thymidine kinase activity.

Topical antiviral therapy lacks efficacy in patients with varicella and herpes zoster and is not

recommended. Systemic therapy, either oral or parenteral is required. Because of their superior

pharmacokinetics, the lower sensitivity of VZV compared to HSV and the existence o barriers to

the entry of antiviral agents into tissues that are sites of VZV replication, famciclovir or

valacyclovir are preferred to acyclovir for oral therapy of VZV infections. Acyclovir resistant

VZV has been documented in varicella and herpes zoster in patients with advanced AIDS.

Because of the mechanism of acyclovir resistance (mutations in the viral thymidine kinase gene)

these acyclovir resistant mutants are cross resisntant to ganciclovir, valacyclovir, famciclovir,

and penciclovir. They usually respond to foscarnet, 40 mg IV every 8 hours; however, the

infections commonly recur after treatment has ended.

Treatment of Varicella

TOPICAL. In normal children, varicella is generally benign and selflimited. Cool compresses or

calamine lotion locally, oral antihistamines, and tepid baths with baking soda or collosdal
oatmeal (3 cups per tub of water) may relieve itching. Creams and lotions containing

glucocorticoids and occlusive ointments should not be used. Antipyretics may be needed, but

salicylates must be avoided because of their association with Reye syndrome. Minor bacterial

infections are treated with warm soaks. Bacterial cellulitis requires systemic antimicrobial

therapy that is effective against Staphylococcus aureus and group A -hemolytic streptococcus.

ANTIVIRAL

Normal Children. A large randomized, controlled trial of acyclovir treatment of healthy children

2 to 12 years of age found that early treatment (within 24 hours of the appearance of rash) with

oral acyclovir (20 mg/kg four times a day for 5 days) modestly reduced the maximum number of

lesions, the time to cessation of new lesion formation, and the duration of the rash, fever, and

constitutional symptoms when compared with placebo. Treatment initiated more than 24 hours

after rash onset was not effective. Because varicella is a relatively benign infection in children

and the clinical benefits of treatment are modest, is does not require routine acyclovir treatment.

However, many have favored its use when cost is not a concem, when it can be begun in time to

benefit the patient (within 24 hours of rash onset), and when there is a perceived need to speed

resolution of the infection so that parents can comfortably return to work. Because secondary

cases among susceptible children in the household are generally more severe than the index

cases, and because early initiation of treatment is more readily accomplished in secondary cases,

treatment with acyclovir seems reasonable for such secondary cases.

Normal Adolescent and Adults. A randomized, controlled trial of acyclovir treatment of healthy

adolescents 13 to 18 years of age found that early treatment with oral acyclovir (800 mg five

times a days for 5 days) reduced the maximum number of lesions and time to cessation of new
lesion formation compared with placebo. A randomized, placebo-controlled trial of oral

acyclovir in healthy young adults with varicella showed that early treatment (within 24 hours of

rash onset) with oral acyclovir (800 mg five times a day for 7 days) significantly reduced the

time to crusting of lesions, the extent of disease, and duration of symptoms and fever. Thus,

routine treatment of varicella in adults seems reasonable. Although bot tested, it is likely that

famsiclovir 500 mg orally every 8 hours, or valasiclovir 1000 mg orally every 8 hours, would be

convenient and appropriate substitutes for acyclovir in normal adolescents and adults. Many

physicians do not prescribe pral acyclovir in uncomplicated varicella during pregnancy because

the risk to the fetus of treatment is unknown. Other physicians recommend oral acyclovir for

infections in the third trimester when organogenesis is complete, when there may be a

heightened risk of varicella pneumonia, and when infection can be spread to the newborn.

Intravenous acyclovir is often considered for pregnant women with varicella who have extensive

cutaneous and/or systemic disease.

Complications of Varicella in Normal Persons. Uncontrolled trials in immunocompetent adults

with varicella pneumonia suggest that early treatment (within 36 hours of hospitalization) with

intravenous acyclovir (10 mg/kg every 8 hours) may reduce fever and tachypnea and improve

oxygenation. Other serious complications of varicella in the immunocompetent host, such as

encephalitis, meningoencephalitis, myelitis, and ocular complication, should be treated with

intravenous acyclovir.

Immunocompromised Patients. Controlled trials in immunocompromised patients with varicella

demonstrated that treatment with intravenous acyclovir decreased the incidence of life-

threatening visceral complications when treatment was initiated within 72 hours of rash onset.

Immune compromise, however, is a continuum ranging from minimal to severe. Intravenous

acyclovir has been the standard of care for varicella in patients with substantial

immunodeficiency. Although oral therapy with famcyclovir or valacyclovir might suffice for

patients with mild degrees of immune impairment, there are no controlled clinical trials to guide

the decision.

COMPLICATIONS

In the normal child, varicella is rarely complicated. The most common complications is the

secondary bacterial infection of skin lesions, usually by staphylococci or streptococci, which

mary produce impetigo, furuncles, cellulitis,erycipelais, and, rarely, gangrene. These local

infections often lead to scarring and, rarely, to septicemia with metastatic infection of other

organs. Bullous lesions may develop when vesicles are superinfected by staphylococci that

produce exloliative toxins. Invasive group A streptococcal infections are particularly virulent. In

the absence of varicella, vaccination, up to one-third of invasive group A streptococcal

infections are associated with varicella, they usually occur within 2 weeks of the onset of the

varicella rash. Widespread varicella vaccination appears to have markedly reduced the

percentage of invasive group A streptococcal hospitalizations associated with varicella in the

United States.

Secondary bacterial pneumonia, otitis media, and suppurative meningitis are rate complications

and typically respond to appropriate antibiotic therapy. However, bacterial superinfection is

common and potentially life-threatening in leukopenic patients. Other complications reflect a

basic defect in the capacity of the host to limit VZV replication and dissemination.

In adults, fever and constitutional symptoms are more prominent and prolonged, the rash of

varicella is more profuse, and complications are more frequent. High rates of complications have
been reported in adults not born in the United States. Primary varicella pneumonia is the major

complication of adult varicella. Some patients are virtually asymptomatic, but others develop

severe respiratory embarrassment, with cough, dyspnea, tachypnea, high fever, pleuritic chest

pain, cyanosis, and hemoptysis 1 to 6 days after onset of the rash. The severity of the symptoms

usually exceeds the physical findings, but the roentgenogram typically reveals diffuse,

peribronchial nodular densities throughout both lung fields with a tendency to concentrate in the

penhilar regions and at the bases. The mortality in adults with frank varicella pneumonia has

been estimated to be between 10 percent and 30 percent, but it is less than 10 percent if

immunocompromised patients are excluded.

Varicella during pregnancy is a threat to both mother and fetus. Disseminated infection and

varicella pneumonia may results in maternal death, but reither the incidence nor the severity of

varicella pneumonia appear to be significantly increased by pregnancy. The fetus may die as a

consequence of premature labot or maternal death caused by severe varicella pneumonia, but

varicella during pregnancy does not, otherwise, substantially increase fetal mortality.

Nevertheless, even in uncomplicated varicella, maternal viremia can result in intrauterine

(congenital) VZV infection, and a characteristic constellation of congenital abnormalities.

Perinatal varicella is more serious than varicella in infants infected even a few weeks later.

The morbidity and mortality of varicella are markedly increased in immunocompromised

patients. In these patients, continued virus raplication and dissemination results in a prolonged

high-level viremia, a more extensive rash, a longer period of new vesicle formation, and

clinically significant visceral dissemination. Immunosuppressed and glucocorticoidcreated

patients may develop pneumonia, hepatitis, encephalitis, and hemorrhagie complications of

varicella, which range in severity from mild febrile purpura to severe and often fatal purpura

fulminans and malignant varicella.

Although elevated aminotransferase levels are common, clinical hepatitis is rare except, as a

complication of progressive varicella. Others care complications of varicella include myocarditis,

glomerulonephritis, orchitis, pancreatitis, gastritis and ulcerative lesions of the bowel, arthritis,

Henoch-Schdrilen vasculitis, optic neuritis, keratitis, and iritis. The pathogenesis of many of

these complications has not been delineated, but direct parenchymal and endovascular VZV

infection, or vasculitis induced by VZV antigen-antibody complexes, appear to be responsible in

most cases.