Varicella

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Varicella is an acute infectious disease caused by varicellazoster virus (VZV). Primary varicella infection (chickenpox) 

was not reliably distinguished from smallpox until the end of 

the 19th century. In 1875, Rudolf Steiner demonstrated that 

chickenpox was caused by an infectious agent by inoculating 

volunteers with the vesicular fluid from a patient with acute 

varicella. In 1954, Thomas Weller used cell culture to isolate 

VZV from vesicular fluid of patients with varicella or zoster. A 

live, attenuated varicella vaccine was developed in Japan in 

the 1970s. The vaccine virus was developed from virus isolated 

by Michiaki Takahashi from vesicular fluid from an otherwise 

healthy child with varicella disease. Varicella vaccine was 

licensed for general use in Japan and Korea in 1988, and in the 

United States in 1995 for persons age 12 months or older. In 

2005, a combination measles, mumps, rubella, and varicella 

(MMRV) vaccine was licensed in the United States for persons 

age 12 months through 12 years. 

Varicella-Zoster Virus

VZV is a DNA virus and is a member of the herpesvirus 

group. Like other herpesviruses, VZV persists in the body as a 

latent infection after the primary (first) infection; VZV persists 

in sensory nerve ganglia. Primary infection with VZV results 

in varicella. Latent infection can reactivate resulting in 

herpes zoster (shingles). The virus has a short survival time in 

the environment. 

Pathogenesis

VZV enters the host through the respiratory tract and 

conjunctiva. It replicates at the site of entry in the nasopharynx 

and in regional lymph nodes. A primary viremia occurs 4 to 6 

days after infection and disseminates the virus to other organs, 

such as the liver, spleen, and sensory ganglia. Further replication 

occurs in the viscera, followed by a secondary viremia, with viral 

infection of the skin. Virus can be cultured from mononuclear 

cells of an infected person from 5 days before to 1 to 2 days 

after the appearance of the rash. 

Clinical Features

The incubation period is 14 to 16 days after exposure, with 

a range of 10 to 21 days. The incubation period may be 

prolonged (e.g., up to 28 days or more) in those who have 

received postexposure prophylaxis with varicella specific 

immune globulin. 

Adriana Lopez, MHS; Theresa Harrington, MD, MPH&TM; and Mona Marin, MD

Varicella

● Acute infectious disease caused 

by varicella-zoster virus (VZV)

● Distinguished from smallpox at 

the end of the 19th century

● Live, attenuated varicella 

vaccine developed in 1970s

● Varicella and MMRV vaccines 

licensed for use in the U.S. in 

1995 and 2005, respectively

Varicella-Zoster Virus (VZV)

● Herpesvirus (DNA)

● Primary infection results in 

varicella (chickenpox)

● Reactivation of latent infection 

results in herpes zoster 

(shingles)

● Short survival in environment 

Varicella Pathogenesis

● Enters through respiratory tract 

and conjunctiva

● Replication in nasopharynx and 

regional lymph nodes

● Primary viremia 4 to 6 days 

after infection

● Multiple organs infected during 

viremia

● Secondary viremia with viral 

skin infection after replication

Varicella Clinical Features

● Incubation period 14 to 16 days 

(range, 10 to 21 days)

● Prolonged incubation period 

if received postexposure 

prophylaxis with varicella 

specific immune globulin
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Varicella

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Primary Infection (Varicella) 

A mild prodrome may precede the onset of a rash. Adults may 

have 1 to 2 days of fever and malaise prior to rash onset, but in 

children the rash is often the first sign of disease. 

In individuals who have not received varicella vaccine, the 

rash is generalized and pruritic and progresses rapidly (within 

24 hours) from macules to papules to vesicular lesions before 

crusting. The rash usually appears first on the scalp, face 

or trunk, and then spreads to the extremities; the highest 

concentration of lesions is on the trunk. Lesions also can occur 

on mucous membranes of the oropharynx, respiratory tract, 

vagina, conjunctiva, and the cornea. Lesions are usually 1 to 

4 mm in diameter. The vesicles are superficial and delicate 

and contain clear fluid on an erythematous base. Vesicles 

may rupture or become purulent before they dry and crust. 

Successive crops appear over several days, with lesions present 

in all stages of development at the same time. For example, 

macular lesions may be observed in the same area of skin as 

mature vesicles. Healthy children usually have 250 to 500 lesions 

in 2 to 4 successive crops. 

The clinical course in healthy children is generally mild, fever (up 

to 102°F) and other systemic symptoms (e.g., malaise, headache) 

usually resolve within 2 to 4 days after onset of the rash. Adults 

may have more severe disease and have a higher incidence of 

complications. Immunocompromised children may develop 

a severe progressive form of varicella characterized by high 

fever, extensive vesicular eruption, and high complication rates. 

Persons infected with human immunodeficiency virus (HIV) are 

also at risk for severe, prolonged illness. 

Recovery from primary varicella infection usually results in 

lifetime immunity. In otherwise healthy persons, a second 

occurrence of varicella is uncommon; it is more common in 

immunocompromised persons. As with other viral diseases, 

re-exposure to natural (wild) varicella may lead to reinfection 

that boosts antibody titers without causing clinical illness or 

detectable viremia. 

Breakthrough varicella is defined as varicella due to infection 

with wild-type VZV occurring more than 42 days after varicella 

vaccination; breakthrough infection can occur after 1 or 

2 doses of vaccine. With decreasing incidence of varicella 

overall and increasing varicella vaccination coverage, more 

than half of varicella cases reported during the mature 

phase of the vaccination program are breakthrough varicella 

cases. Breakthrough varicella is less severe than varicella 

in unvaccinated persons, with the median number of skin 

lesions commonly less than 50; vesicular lesions are less 

common and the lesions are commonly papules that do 

not progress to vesicles. Varicella in vaccinated persons is 

Primary Infection (Varicella)

● Rash often first sign of disease 

in children; adults may have 1 

to 2 days of fever and malaise 

before rash

● In unvaccinated individuals, 

generalized and pruritic rash 

progresses rapidly

● Clinical course in healthy 

children is mild; adults may 

have more severe disease

● Recovery usually results in 

lifetime immunity
Varicella

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22

typically shorter in duration and has a lower incidence of 

fever than in unvaccinated persons. However, about 25% 

to 30% of breakthrough varicella cases in vaccinees who 

received one dose have clinical features more similar to those 

in unvaccinated children, and complications with visceral 

dissemination, hospitalizations, or death, although uncommon, 

have been reported. 

Complications

Acute varicella is generally mild and self-limited, but it may be 

associated with complications. Secondary bacterial infections 

of skin lesions with Staphylococcus or Streptococcus (primarily 

invasive group A) are the most common cause of hospitalization 

and outpatient medical visits and can lead to death. Pneumonia 

following varicella is usually viral but may be bacterial. Primary 

viral pneumonia is uncommon among immunocompetent 

children but is the most common complication in adults. 

Secondary bacterial pneumonia is more common in children 

younger than age 1 year. Central nervous system manifestations 

of varicella range from aseptic meningitis to encephalitis. 

Encephalitis is an infrequent complication of varicella (1 per 

50,000 cases of varicella in unvaccinated children) and may 

lead to seizures and coma. Diffuse cerebral involvement is 

more common in adults than in children. Involvement of 

the cerebellum, with resulting cerebellar ataxia, is the most 

common central nervous system manifestation (1 per 4,000 

cases of varicella in unvaccinated children) and generally has a 

good outcome. Reye syndrome may follow varicella, although 

this outcome has become very rare with the recommendation 

to not use aspirin or other salicylates to reduce fever in children 

with varicella. Rare complications of varicella include aseptic 

meningitis, transverse myelitis, Guillain-Barré syndrome, 

thrombocytopenia, hemorrhagic varicella, purpura fulminans, 

glomerulonephritis, myocarditis, arthritis, orchitis, uveitis, iritis, 

and hepatitis. 

The risk of complications from varicella varies with age. 

Complications are infrequent among healthy children. 

They occur much more frequently in persons older than 

age 15 years and infants younger than age 1 year. In the 

prevaccine era, approximately 10,500 persons with varicella 

required hospitalization each year. Hospitalization rates were 

approximately 1 to 2 per 1,000 cases among healthy children 

and 14 per 1,000 cases among adults. The fatality rate for 

varicella was approximately 1 per 100,000 cases among children 

age 1 through 14 years, 6 per 100,000 cases among persons 

age 15 through 19 years, and 21 per 100,000 cases among 

adults. Most deaths occur in immunocompetent children and 

adults. Since 1995, when the varicella vaccination program was 

implemented, hospitalizations and deaths from varicella have 

declined in the United States 93% and 94%, respectively.

Varicella Complications

● Bacterial infection of skin 

lesions

● Pneumonia

● Central nervous system 

manifestations

● Reye syndrome (rare)
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Varicella

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Immunocompromised persons have a high risk of disseminated 

disease (up to 36% in one report). These persons may have 

multiple organ system involvement, and the disease may 

become fulminant and hemorrhagic. The most frequent 

complications in immunocompromised persons are pneumonia 

and encephalitis. Children with HIV infection are at increased 

risk for morbidity from varicella and herpes zoster. Severe and 

even fatal varicella has been reported in otherwise healthy 

children on high-dose corticosteroids (e.g., 2 milligrams per 

kilogram per day or more of prednisone or equivalent) for 

treatment of asthma and other illnesses.

The onset of maternal varicella from 5 days before to 2 days 

after delivery may result in overwhelming infection of the 

neonate, with a fatality ratio as high as 30% if antivirals are not 

given. This severe disease is the result of fetal exposure to VZV 

without the benefit of passive maternal antibody. The usual 

interval from onset of rash in a mother to onset in her neonate 

is 9 to 15 days but it can be as short as 2 days. Infants born to 

mothers with onset of maternal varicella more than 5 days prior 

to delivery usually have a benign course, attributed to passive 

transfer of maternal antibody across the placenta.

Congenital VZV Infection

Primary maternal varicella infection in the first 20 weeks of 

gestation is occasionally associated with abnormalities in the 

newborn, including hypoplasia of an extremity, skin scarring, 

localized muscular atrophy, encephalitis, cortical atrophy, 

chorioretinitis, microcephaly, and low birth weight. This 

constellation of abnormalities, collectively known as congenital 

varicella syndrome, was first recognized in 1947. The risk of 

congenital abnormalities from primary maternal varicella 

infection is very low (less than 2%). Children infected with VZV 

in utero may develop herpes zoster early in life without having 

had extrauterine varicella. Isolated case-reports of congenital 

varicella syndrome have been reported in women infected after 

20 weeks of gestation with the latest occurring at 28 weeks of 

gestation. Rare reports of congenital birth defects following 

maternal zoster exist, but whether they represent congenital 

varicella syndrome is unclear. 

Laboratory Testing

Laboratory testing, whenever possible, or epidemiological 

linkage to a typical case or laboratory-confirmed case, 

should be sought to confirm or rule out varicella. Rapid VZV 

identification techniques are indicated for a case with severe or 

unusual disease to initiate specific antiviral therapy. Laboratory 

techniques in use allow differentiation of wild-type and vaccine 

strains of VZV.

Polymerase chain reaction (PCR) is the method of choice for 

laboratory diagnosis of varicella. Real-time PCR methods are 

Congenital VZV Infection

● Results from maternal infection 

in the first 20 weeks of 

gestation

● Associated with newborn 

limb hypoplasia, skin scarring, 

localized muscular atrophy, 

encephalitis, cortical atrophy, 

chorioretinitis, microcephaly, 

and low birth weight
Varicella

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22

widely available and are the most sensitive and specific of the 

available tests. Results are available within several hours. If 

real-time PCR is unavailable, the direct fluorescent antibody 

(DFA) method can be used, although it is less sensitive 

than PCR and requires more meticulous specimen collection 

and handling. 

Skin lesions are the preferred sample for laboratory confirmation 

of varicella. Specimens are best collected by unroofing a vesicle, 

preferably a fresh fluid-filled vesicle, and then rubbing the base 

of a skin lesion with a polyester swab. Crusts from lesions are 

also excellent specimens for PCR. Because viral proteins persist 

after cessation of viral replication, PCR and DFA may be positive 

when viral cultures are negative.

PCR testing that discriminates between vaccine and wild-type 

VZV is available free of charge through the specialized reference 

laboratories at CDC and the American Public Health Laboratory 

Association Vaccine Preventable Diseases Reference Centers. 

For diagnosis of acute varicella infection, serologic confirmation 

includes a significant rise in varicella immune globulin class G 

(IgG) by any standard serologic assay. Testing using commercial 

kits for IgM antibody is not recommended since available 

methods lack sensitivity and specificity; false-positive IgM 

results are common in the presence of high IgG levels. 

A variety of serologic tests for varicella antibody are 

available commercially to assess disease-induced immunity. 

Commercial enzyme-linked immunosorbent assays 

(ELISAs) are recommended for the purpose of screening. 

There is evidence to suggest that the latex agglutination 

method, another method to test for serologic IgG, may give 

false-positive results that could mistakenly categorize a 

susceptible person as immune. 

Antibody resulting from vaccination is generally of lower titer 

than antibody resulting from varicella disease and commercially 

available serologic IgG tests are not sufficiently sensitive to 

detect low levels of antibody following vaccination. Therefore, 

routine testing for varicella immunity following vaccination is 

not recommended. 

Epidemiology

Occurrence

Varicella occurs worldwide. In countries in temperate climates, 

it is primarily a childhood disease, with most children infected 

by age 10 years. In tropical areas, children acquire varicella at 

older ages and therefore a higher proportion of young adults 

remain susceptible, resulting in a higher proportion of cases 

occurring among adults. The reason(s) for this difference in age 

distribution are not known with certainty. 

Varicella Epidemiology

● Reservoir

■ Human

● Transmission

■ Person-to-person 

■ Direct contact with vesicular 

fluid or inhalation of aerosols

● Temporal pattern

■ Peak in winter and early 

spring

● Communicability 

■ 1 to 2 days before onset of 

rash until all lesions have 

formed crusts
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Reservoir

VZV, the virus that causes both varicella (chickenpox) and zoster 

(shingles), is an exclusively human pathogen. No animal or 

insect source or vector is known to exist. 

Transmission

VZV transmission occurs person-to-person by direct contact 

with vesicular fluid or by inhalation of aerosols from vesicular 

fluid of skin lesions of acute varicella or zoster. Transmission may 

also occur from infected respiratory tract secretions of patients 

with varicella that might also be aerosolized. Skin lesions are 

considered the major source of transmissible VZV. Transmission 

of VZV would cause varicella, not zoster, in a VZV-naïve person. 

Temporal Pattern

In temperate areas, varicella has a distinct seasonal fluctuation, 

with the highest incidence occurring in winter and early spring. 

High rates of vaccination coverage in the United States have 

eliminated discernible seasonality of varicella. Less seasonality is 

also reported in tropical areas. 

Communicability

The period of communicability extends from 1 to 2 days before 

the onset of rash until all lesions have formed crusts. The virus 

has not been isolated from crusted lesions. Vaccinated persons 

who contract varicella may develop lesions that do not crust 

(macules and papules only). Isolation guidance for these 

persons is to restrict contact with others until no new lesions 

appear within a 24-hour period. 

Varicella is highly contagious. Secondary attack rates among 

susceptible household contacts of persons with varicella are 

between 61% and 100%. Zoster is much less infectious as 

varicella, i.e., about 1/5 as infectious as varicella. 

Secular Trends in the United States

In the prevaccine era, varicella was endemic in the United 

States, and virtually all persons acquired varicella by adulthood. 

As a result, the number of cases occurring annually was 

estimated to approximate the birth cohort, or about 4 million 

per year. The majority of cases (approximately 90%) occurred 

among children younger than age 15 years. In the 1990s, the 

highest age-specific incidence of varicella was among children 

age 1 to 4 years, who accounted for 39% of all cases. This age 

distribution was probably a result of earlier exposure to VZV in 

preschool and child care settings. Adults age 20 years or older 

accounted for only 7% of cases. 

Varicella Secular Trends 

in the United States 

● Virtually all persons acquired 

varicella by adulthood before 

vaccine

● Since vaccine, varicella 

incidence has declined an 

average of 97%

■ Decline has occurred in 

all age groups
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The incidence of varicella, as well as varicella-related 

hospitalizations, has decreased significantly since 

implementation of the national varicella vaccination program 

in 1995. Overall, varicella incidence declined an average of 97% 

from prevaccine years (from 1993–1995 to 2013–2014) based 

on data from four states that have been continuously reporting 

varicella to the National Notifiable Diseases Surveillance System 

(NNDSS) since before the varicella vaccination program. Cases 

declined in all age groups, including infants who are not eligible 

for vaccination and adults whose rates of vaccination are low, 

indicating community protection benefits of the vaccination 

program. The second dose of varicella vaccine was added to 

the national program in 2007. During the 2-dose era, data 

from 40 states that reported varicella cases to NNDSS have 

shown an 85% decline in varicella incidence from 2005–2006 to 

2013–2014, with the greatest declines among children age 5 to 

14 years (85% to 89%). 

One-dose varicella vaccine coverage among children age 19 

through 35 months has been 90% to 91% since 2007; varicella 

vaccination coverage of at least 2 doses among adolescents 

age 13 through 17 years without a history of varicella has been 

greater than 85% since 2016.

Varicella Vaccines

Two live, attenuated VZV-containing vaccines for the prevention 

of varicella are licensed for use in the United States. VAR 

(Varivax) vaccine is single-antigen varicella vaccine and MMRV 

(ProQuad) vaccine is a combination measles, mumps, rubella, 

and varicella vaccine.

Characteristics

VAR vaccine is derived from the Oka strain of VZV. The virus 

was attenuated by sequential passage in human embryonic 

lung cell culture, embryonic guinea pig fibroblasts, and 

in WI-38 human diploid cells. The Oka/Merck vaccine has 

undergone further passage through MRC-5 human diploid cell 

cultures for a total of 31 passages. The vaccine is reconstituted 

with sterile water and contains gelatin. VAR vaccine is 

administered by the subcutaneous route. Each dose of VAR 

vaccine contains neomycin as an antibiotic. It contains no 

adjuvant or preservative. 

MMRV vaccine contains measles, mumps, and rubella virus 

of equal titer and identical to those in the MMR vaccine. The 

titer of Oka Varicella-Zoster virus is higher in MMRV vaccine 

than in VAR, a minimum of 9,772 plaque-forming units (PFU) 

versus 1,350 PFU, respectively. The vaccine is reconstituted 

with sterile water and contains gelatin. MMRV vaccine is 

administered by the subcutaneous route. Each dose of 

MMRV vaccine contains neomycin as an antibiotic. It contains 

no adjuvant or preservative. 

Varicella Vaccines

● VAR (Varivax)

● MMRV (ProQuad)

Varicella Vaccine Characteristics

● Live, attenuated vaccines

● VAR contains neomycin 

and gelatin

● MMRV contains neomycin 

and gelatin

● Administered by 

subcutaneous injection
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Vaccination Schedule and Use

VAR or MMRV can be used to implement the vaccination 

recommendations for prevention of varicella. VAR vaccine 

(Varivax) is licensed for use in persons age 12 months or older. 

MMRV (ProQuad) is licensed for use in children age 12 months 

through 12 years. 

VAR (Varivax)

VAR vaccine is licensed for use in persons age 12 months 

or older. It is administered as a 2-dose series. Dose 1 is 

recommended for children age 12 through 15 months. Dose 

2 is recommended at age 4 through 6 years at the same visit 

as the second dose of MMR vaccine, but may be given as early 

as 3 months after dose 1 (the minimum interval for children 

younger than age 13 years). However, if dose 2 is administered 

at least 4 weeks after dose 1, it does not need to be repeated. 

For persons age 13 years or older, the minimum interval 

between doses is 4 weeks. Testing for varicella immunity 

following 2 doses of vaccine is not necessary because 99% 

of persons are seropositive after the second dose. Moreover, 

available commercial assays are not sensitive enough to detect 

antibody following vaccination in all instances. VAR vaccine has 

been shown to be safe and effective in healthy children when 

administered at the same time as MMR vaccine at separate sites 

and with separate syringes. If varicella and MMR vaccines are 

not administered at the same visit, they should be separated 

by at least 4 weeks. Varicella vaccine may be administered 

simultaneously with all other childhood vaccines. 

Children with a clinician-diagnosed or verified history of typical 

varicella can be assumed to be immune to varicella. Serologic 

testing of children prior to vaccination is not warranted 

because the majority of children between age 12 months and 

12 years without a clinical history of varicella are not immune. 

Prior history of varicella is not a contraindication to varicella 

vaccination, so when in doubt as to history, varicella vaccine 

should be administered. Because serologic evidence of VZV 

infection has been documented in 96%-97% of U.S.-born adults 

age 20-29 years and in 97%-99% of adults age 30 years or older 

tested during 1998–1999, individuals who were born in the 

United States before 1980 are considered to have evidence of 

immunity except for health-care personnel (risk of spreading 

VZV to high-risk patients), pregnant women (risk of transmission 

to fetus which might result in congenital varicella syndrome), 

and immunocompromised persons (risk of severe disease). 

Varicella vaccine should be administered to all adolescents and 

adults age 13 years or older who do not have evidence of varicella 

immunity. Persons age 13 years or older should receive two doses 

of VAR vaccine separated by at least 4 weeks. If there is a lapse of 

more than 4 weeks after the first dose, the second dose may be 

administered at any time without repeating the first dose. 

Varicella Vaccination Schedule

● 2-dose series at age 12 through 

15 months and age 4 through 

6 years

● Minimum age for dose 

1 is 12 months

● Minimum interval for dose 1 

to 2 is:

■ 3 months for children age 

12 months–12 years 

(although a 4-week interval 

is valid)

■ 4 weeks for persons age 

13 years and older (VAR only)

● Discuss risks and benefits of 

MMRV versus separate VAR

■ Separate MMR and VAR 

vaccines preferred for dose 1 

in ages 12 through 47 months

■ MMRV preferred for dose 2 

and dose 1 at age 48 months 

or older
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All health care personnel should be immune to varicella. 

In health care settings, serologic screening of personnel 

who are uncertain of their varicella history, or who claim 

not to have had the disease, is likely to be cost-effective. 

Testing for immunity following vaccination is not necessary. 

Seroconversion does not always result in full protection 

against disease, although no data regarding correlates of 

protection are available for adults. Vaccinated healthcare 

personnel exposed to VZV should be monitored daily from 

day 8 to 21 after exposure through the employee health or 

infection control program to screen for fever, skin lesions, 

and systemic symptoms. In addition, health care personnel 

should be instructed to immediately report fever, headache, 

or other constitutional symptoms and any skin lesions that 

may be atypical. The person should be placed on sick leave 

immediately if symptoms occur. The risk of transmission of 

vaccine virus from a vaccinated person to a susceptible contact 

is very low, and the benefits of vaccinating susceptible health 

care personnel clearly outweigh this potential risk. 

MMRV (ProQuad)

MMRV vaccine is licensed for use in children age 12 months 

through 12 years. MMRV vaccine may be used for both dose 

1 and dose 2 of measles, mumps, and rubella vaccination and 

varicella vaccination in children younger than age 13 years. 

The minimum interval between doses of MMRV is 3 months. 

However, if dose 2 is administered at least 4 weeks following 

dose 1, it does not need to be repeated. 

For the first dose of measles, mumps, rubella, and varicella 

vaccines at age 12 through 47 months, either separate MMR 

and varicella (VAR) vaccines, or MMRV vaccine, may be used. 

However, the risk of febrile seizures is about twice as high for 

children receiving MMRV vaccine versus separate MMR and 

VAR vaccines. Providers who are considering administering 

MMRV should discuss the benefits and risks of both vaccination 

options with the parents. Unless the parent or caregiver 

expresses a preference for MMRV, separate MMR vaccine and 

VAR vaccine should be administered for the first dose in this 

age group. For the second dose of measles, mumps, rubella, 

and varicella vaccines at any age and for the first dose at age 48 

months or older, the use of MMRV generally is preferred over 

separate injections of its equivalent component vaccines (i.e., 

MMR vaccine and VAR vaccine). 

Immunogenicity and Vaccine Efficacy

VAR (Varivax)

After one dose of VAR vaccine, 97% of children age 12 months 

through 12 years develop detectable antibody titers. More than 

90% of vaccine responders maintain antibody for at least 6 

years. In Japanese studies, 97% of children had antibody 7 to 10 

years after vaccination. 

Varicella Vaccine Efficacy

● Effectiveness:

■ 82% for dose 1

■ 92% for dose 2
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Varicella

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Among healthy adolescents and adults age 13 years or older, 

an average of 78% develop antibody after dose 1, and 99% 

develop antibody after a second dose given 4 to 8 weeks later. 

Antibody persisted for at least 1 year in 97% of recipients after 

the second dose. 

Immunity appears to be long-lasting, and is probably 

permanent in the majority of vaccine recipients. Breakthrough 

infection is significantly milder than infection among 

unvaccinated persons, with fewer lesions (generally fewer than 

50), many of which are maculopapular rather than vesicular. 

Most persons with breakthrough infection do not have fever. 

Although findings of some studies have suggested otherwise, 

most investigations have not identified time since vaccination 

as a risk factor for breakthrough varicella. Some investigations 

have identified asthma, use of steroids, and vaccination at 

younger than age 15 months as risk factors for breakthrough 

varicella, but other investigations did not. 

Interference from live viral vaccine could reduce vaccine 

effectiveness. A study of 115,000 children in two health 

maintenance organizations during 1995 to 1999 found 

that children who received varicella vaccine less than 30 

days after MMR vaccination had a 2.5-fold increased risk of 

breakthrough varicella compared with those who received 

varicella vaccine before, simultaneously with, or more than 

30 days after MMR vaccine. 

Studies have shown that a second dose of varicella vaccine 

boosts immunity and reduces the risk of breakthrough disease 

in children. A meta-analysis of postlicensure estimates found 

the effectiveness of 1 dose of varicella vaccine to be 82% 

against any clinical varicella and 98% against severe disease. 

Two doses of vaccine demonstrated 92% effectiveness against 

any clinical varicella. 

MMRV (ProQuad)

MMRV vaccine was licensed on the basis of non-inferiority 

of immunogenicity of the antigenic components rather than 

the clinical efficacy. Clinical studies involving healthy children 

age 12 through 23 months indicated that those who received 

a single dose of MMRV vaccine developed similar levels of 

antibody to measles, mumps, rubella, and varicella as children 

who received MMR vaccine and VAR vaccine concomitantly at 

separate injection sites. 

Varicella Immunity

Evidence of immunity to varicella includes any of the following: 

• Documentation of age-appropriate vaccination: 

Varicella Immunity

● Documentation of 

age-appropriate vaccination

● Laboratory evidence of 

immunity

● Laboratory confirmation of 

disease

● Birth in the U.S. before 1980

■ Exception: Health care 

personnel, pregnant women, 

and immunocompromised 

persons

● Health care provider diagnosis 

or verification of varicella 

disease

● History of herpes zoster 

based on health care provider 

diagnosis or verification of 

disease history
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■ Preschool-aged children (age 12 months or older): 

1 dose 

■ School-aged children, adolescents, and adults: 2 doses

• Laboratory evidence of immunity: commercial assays can 

be used to assess disease-induced immunity, but they lack 

adequate sensitivity to reliably detect vaccine-induced 

immunity (i.e., they may yield false-negative results). 

• Laboratory confirmation of disease

• Birth in the United States before 1980 (except for health 

care personnel, pregnant women, and immunocompromised persons for whom birth in the United States 

before 1980 should not in itself be considered evidence of 

immunity). Persons born outside the United States should 

meet one of the other criteria for varicella immunity.

• A health care provider diagnosis or verification of varicella 

disease: verification of history or diagnosis of typical 

disease can be done by any healthcare provider (e.g., 

school or occupational clinic nurse, nurse practitioner, 

physician assistant, physician). For persons reporting a 

history of or presenting with atypical and/or mild cases, 

assessment by a physician or designee is recommended, 

and one of the following should be sought: a) an epidemiologic link to a typical varicella case, or b) evidence 

of laboratory confirmation if laboratory testing was 

performed at the time of acute disease. When such documentation is lacking, a person should not be considered 

as having a valid history of disease, because other diseases 

may mimic mild or atypical varicella. 

• History of herpes zoster based on health care provider 

diagnosis or verification of disease history. 

Postexposure Prophylaxis

VAR Vaccine

Data from the United States and Japan in a variety of settings 

indicate that varicella vaccine is 70% to 100% effective in 

preventing illness or modifying the severity of illness if used 

within 3 days, and possibly up to 5 days, after exposure. 

ACIP recommends the vaccine for postexposure prophylaxis 

within 3 through 5 days after exposure for persons age 

12 months or older who do not have evidence of varicella 

immunity and who do not have contraindications to 

vaccination. If exposure to varicella does not cause infection, 

postexposure vaccination should induce protection against 

subsequent exposure. If the exposure results in infection, 

there is no evidence that administration of varicella vaccine 

during the incubation period or prodromal stage of illness 

Varicella Vaccine 

Postexposure Prophylaxis

● Varicella vaccine is 

recommended for use in 

persons age 12 months or older 

without evidence of varicella 

immunity within 3 through 5 

days after exposure to varicella

■ 70%-100% effective if given 

within 3 days of exposure 

(possibly up to 5 days)
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increases the risk for vaccine-associated adverse reactions. 

Although postexposure use of varicella vaccine has potential 

applications in hospital settings, preexposure vaccination 

of all health care personnel without evidence of varicella 

immunity is the recommended and preferred method for 

preventing varicella in health care settings. 

Varicella outbreaks in some settings (e.g., childcare facilities 

and schools) can persist up to 6 months. Varicella vaccine has 

been used successfully to control these outbreaks. During a 

varicella outbreak, persons who have received one dose of 

varicella vaccine should receive a second dose, provided the 

appropriate vaccination interval has elapsed since the first 

dose (3 months for persons age 12 months through 12 years 

and at least 4 weeks for persons age 13 years or older). 

Varicella-Zoster Immune Globulin

A Varicella-Zoster Immune Globulin (VZIG [VariZIG]) is 

licensed for use in the United States for postexposure 

prophylaxis for persons who do not have evidence of 

varicella immunity and who have contraindications for 

varicella vaccine. VariZIG is a purified human immune 

globulin preparation made from plasma containing high 

levels of anti-varicella antibodies (IgG) that is lyophilized. 

When properly reconstituted, VariZIG is approximately a 5% 

solution of IgG that can be administered intramuscularly.

Patient groups recommended by ACIP to receive VariZIG 

for postexposure prophylaxis include the following: 

• Immunocompromised patients without evidence of 

immunity to varicella

• Neonates whose mothers have signs and symptoms of 

varicella around the time of delivery (i.e., 5 days before 

to 2 days after)

• Hospitalized preterm infants born at 28 weeks gestation or 

later whose mothers do not have evidence of immunity

• Hospitalized preterm infants born earlier than 28 weeks’ 

gestation or who weigh 1,000 grams or less at birth, 

regardless of maternal history of varicella disease 

or vaccination 

• Pregnant women without evidence of immunity 

to varicella
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22

Contraindications and Precautions 

to Vaccination

As with other vaccines, a history of a severe allergic reaction

(anaphylaxis) to a vaccine component or following a prior

dose is a contraindication to further doses. Moderate or severe

acute illness (with or without fever) in a patient is considered a

precaution to vaccination, although persons with minor illness

may be vaccinated.

Contraindications and precautions are similar for both

varicella-containing vaccines. VAR vaccine and MMRV vaccine

both contain minute amounts of neomycin and gelatin but do

not contain egg protein. Persons with alpha-gal allergy may

wish to consult their physician before receiving a vaccine that

contains gelatin.

Persons who are immunosuppressed due to leukemia,

lymphoma, generalized malignancy, immune deficiency disease,

or immunosuppressive therapy should not be vaccinated with a

varicella-containing vaccine. However, treatment with low-dose

(e.g., less than 2 milligrams per kilogram of body weight per

day), alternate-day, topical, replacement, or aerosolized steroid

preparations is not a contraindication to vaccination.

The interval until immune reconstruction varies with the

intensity and type of immunosuppressive therapy, radiation

therapy, underlying disease, and other factors, complicating

the ability to make a definitive recommendation for an

interval after cessation of immunosuppressive therapy when

live-virus vaccines can be administered safely and effectively.

Current recommendations are for patients to be vaccinated

with varicella vaccine when in remission and at least three

months after cancer chemotherapy, with evidence of

restored immunocompetence. Varicella vaccine (as a 2-dose

regimen if there is sufficient time) should be administered

to immunocompetent patients without evidence of varicella

immunity, if it can be administered at least 4 weeks before

initiating immunosuppressive therapy.

Other immunosuppressive medications include human immune

mediators such as interleukins and colony-stimulating factors,

immune modulators, and medicines such as tumor necrosis

factor-alpha inhibitors and anti-B cell antibodies. Live vaccines

should be withheld 3 months following such therapies, and

withheld at least 6 months following therapy with anti-B cell

antibodies. Some experts recommend longer than 6 months

following anti-B cell antibodies.

A family history of congenital or hereditary immunodeficiency

in first-degree relatives (i.e., parents and siblings), unless the

immune competence of the potential vaccine recipient has

been substantiated clinically or verified by a laboratory, is a 

contraindication for MMR, MMRV, or VAR vaccine.

Varicella Vaccine Contraindications

● Contraindication

■ Severe allergic reaction

to vaccine component or

following a prior dose

■ Immunosuppression due

to leukemia, lymphoma,

generalized malignancy,

immune deficiency disease, or

immunosuppressive therapy

■ Family history of congenital or

heredity immunodeficiency in

first-degree relatives

■ HIV infection*

■ Hematopoietic stem cell

transplant (wait 24 months)

■ Pregnancy

*Contraindicated for MMRV; contraindicated 

for VAR depending on CD4 count

Varicella Vaccine Precautions

● Precaution

■ Moderate or severe

acute illness

■ Alpha-gal allergy (consult

with physician)

■ Receipt of antibodycontaining blood products

(wait 3 to 11 months

to vaccinate)

■ Need for tuberculosis testing*

■ Receipt of specific antiviral

drugs 24 hours before

vaccination

■ Simultaneous use of aspirin or

aspirin-containing products

■ Personal or family history of

seizures of any etiology*

*MMRV only
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 22

Persons with severe cellular immunodeficiency resulting from 

infection with HIV, including persons diagnosed with acquired 

immunodeficiency syndrome (AIDS) should not receive 

varicella vaccine. HIV-infected children with CD4+ T-lymphocyte 

percentage of 15% or higher, and older children and adults with 

a CD4+ count of 200 per microliter or higher may be considered 

for vaccination. These persons may receive MMR vaccine and 

VAR vaccine, but should not receive MMRV vaccine. 

The effect of the administration of antibody-containing blood 

products (e.g., immune globulin, whole blood or packed 

red blood cells, or intravenous immune globulin) on the 

response to varicella vaccine virus is unknown. Because of the 

potential inhibition of the response to vaccination by passively 

transferred antibodies, neither VAR vaccine nor MMRV vaccine 

(nor MMR vaccine) should be administered for 3 to 11 months 

after receipt of antibody-containing blood products. The 

interval between the antibody-containing blood product and 

receipt of VAR, MMR, or MMRV vaccine is determined by the 

type of product administered. Antibody-containing products 

should not be given for 2 weeks following vaccination unless 

the benefits exceed those of the vaccine. In such cases, vaccine 

recipients should either be revaccinated later at the appropriate 

intervals (ranging 3 to 11 months), or tested for immunity and 

revaccinated if seronegative.

Varicella-containing vaccines may be administered a minimum 

of 24 months after hematopoietic stem cell transplant to 

patients who do not have graft versus host disease, are 

considered immunocompetent, and whose last dose of 

intravenous immunoglobulin (IVIG) was 8 to 11 months 

previously. Nonimmune family members, close contacts, and 

health care personnel associated with the patient should be 

vaccinated before that time.

A personal or family (i.e., sibling or parent) history of seizures 

of any etiology is a precaution for MMRV vaccine. Children with 

a personal or family history of seizures of any etiology should 

ideally be vaccinated with separate MMR and VAR vaccines 

because the risks for using MMRV vaccine in this group of 

children generally outweigh the benefits.

Receipt of specific antiviral drugs (acyclovir, famciclovir, or 

valacyclovir) 24 hours before vaccination is a precaution for VAR 

or MMRV vaccination. These antiviral drugs should be avoided 

for 14 days after vaccination if possible. 

Although there is no evidence that either varicella or 

varicella vaccine exacerbates tuberculosis, vaccination is not 

recommended for persons known to have untreated active 

tuberculosis. Tuberculosis testing is not a prerequisite for 

varicella vaccination. 
Varicella

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22

Simultaneous use of aspirin or aspirin-containing products 

is a precaution for VAR or MMRV vaccine. The manufacturer 

recommends that vaccine recipients avoid the use of 

salicylates for 6 weeks after receiving VAR or MMRV vaccine 

because of the association between aspirin use and Reye 

syndrome following varicella. 

The need for tuberculin skin testing or interferon-gamma 

release assay (IGRA) testing is a precaution for MMRV vaccine.

Prior history of varicella is not a contraindication to varicella 

vaccination, so when in doubt as to history, varicella vaccine 

should be administered.

Women known to be pregnant or attempting to become 

pregnant should not receive a varicella-containing vaccine.

Vaccination in Pregnancy

Wild-type varicella poses a low risk to the fetus. Because the 

virulence of the attenuated virus used in the vaccine is less 

than that of the wild-type virus, the risk to the fetus, if any, 

should be even lower from vaccine virus. Because the effects 

of the varicella virus on the fetus are unknown, pregnant 

women should not be vaccinated. Nonpregnant women 

who are vaccinated should avoid becoming pregnant for 1 

month after each injection. For persons without evidence 

of immunity, having a pregnant household member is not a 

contraindication for vaccination.

Routine pregnancy testing of women of childbearing age 

before administering a live-virus vaccine is not recommended. 

If a pregnant woman is inadvertently vaccinated or becomes 

pregnant within 4 weeks after varicella vaccination, she should 

be counseled about the theoretical basis of concern for the 

fetus; however, varicella vaccination during pregnancy should 

not be considered a reason to terminate pregnancy.

To monitor the pregnancy outcomes of women inadvertently 

vaccinated with VZV-containing vaccines immediately before 

or during pregnancy, Merck and CDC established the Merck/

CDC Pregnancy Registry for VZV-Containing Vaccines. From 

inception of the registry in 1995 through March 2012, no cases 

of congenital varicella syndrome and no increased prevalence 

of other birth defects have been detected among women 

vaccinated within 3 months before or during pregnancy. 

Although a small risk for congenital varicella syndrome 

cannot be ruled out, the low number of exposures being 

registered each year in addition to the rarity of the outcome, 

were too low to improve on the estimate of the risk within 

a reasonable timeframe. Therefore, new patient enrollment 

was discontinued as of October 16, 2013. Merck continues to 

monitor pregnancy outcomes after inadvertent exposures to 

VZV-containing vaccines during pregnancy or within 3 months 
344

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 22

before conception. CDC and the Food and Drug Administration 

continue to monitor adverse events after vaccination with 

VZV-containing vaccines through the Vaccine Adverse Event 

Reporting System (VAERS). New cases of exposure immediately 

before or during pregnancy or other adverse events after 

vaccination with VAR vaccine or MMRV vaccine should be 

reported to Merck (telephone, 1-877-888-4231) and to VAERS 

(https://vaers.hhs.gov/index.html). 

Postpartum vaccination of women without evidence of 

immunity need not be delayed because of breastfeeding. 

Single-antigen varicella vaccine should be administered to 

nursing mothers without evidence of immunity. 

Vaccine Safety 

The most common adverse reactions following varicella vaccine 

are local reactions, such as pain, soreness, erythema, and 

swelling. Based on information from the manufacturer’s clinical 

trials of varicella vaccine, local reactions are reported by 19% of 

children and by 24% of adolescents and adults (33% following 

the second dose). These local adverse reactions are generally 

mild and self-limited. A varicella-like rash at injection site is 

reported by 3% of children and by 1% of adolescents and adults 

following the second dose. In both circumstances, a median 

of two lesions have been present. These lesions generally 

occur within 2 weeks and may be maculopapular rather than 

vesicular. A generalized varicella-like rash is reported by 4% to 

6% of recipients of varicella vaccine (1% after the second dose 

in adolescents and adults), with an average of five lesions. Most 

of these generalized rashes occur within 3 weeks and may be 

mainly maculopapular. 

Systemic reactions are not common. Fever within 42 days 

of vaccination is reported by 15% of children and 10% of 

adolescents and adults. The majority of these episodes of 

fever have been attributed to concurrent illness rather than 

to the vaccine. 

Varicella vaccine is a live virus vaccine and may result in a 

latent infection, similar to that caused by wild varicella virus. 

Consequently, zoster caused by the vaccine virus has been 

reported. Not all these cases have been confirmed as having 

been caused by vaccine virus. The risk of zoster following 

vaccination was assessed among children and is much lower 

(~79% lower) than that following infection with wild-type virus. 

The majority of cases of zoster following vaccine have been 

mild and have not been associated with complications such as 

postherpetic neuralgia; however, in children cases of herpes 

zoster with meningitis have been reported. 

In MMRV vaccine prelicensure studies conducted among 

children age 12 to 23 months, fever (reported as abnormal or 

Varicella Vaccine Safety

VAR

● Rash at injection site

■ 1–3%

● Generalized rash

■ 4–6%

● Fever

■ 10–15%

MMRV

● Fever of 102oF or higher

■ 21.5%

● Febrile seizures

■ 1 additional per 2,300 

to 2,600 children age 12 

through 23 months
Varicella

345

22

elevated greater than or equal to 102°F oral equivalent) was 

observed 5 to 12 days after vaccination in 21.5% of MMRV 

vaccine recipients compared with 14.9% of MMR vaccine and 

VAR vaccine recipients. Measles-like rash was observed in 3.0% 

of MMRV vaccine recipients compared with 2.1% of those 

receiving MMR vaccine and VAR vaccine. Two postlicensure 

studies indicated that one additional febrile seizure per 2,300 

to 2,600 children age 12 through 23 months occurred 5 to 

12 days after the first dose of MMRV vaccine, compared with 

children who had received the first dose of MMR vaccine and 

VAR vaccine administered as separate injections at the same 

visit. Data from postlicensure studies do not suggest that this 

increased risk exists for children age 4 to 6 years receiving the 

second dose of MMRV vaccine.

Transmission of Varicella Vaccine Virus

Accumulated evidence supports that healthy, vaccinated 

persons have minimal risk for transmitting the varicella 

vaccine virus to contacts; through 2018 only 13 cases from 11 

immunocompetent vaccine recipients have been documented, 

most commonly among household contacts. Transmission of 

vaccine virus was reported only from vaccine recipients who 

developed a varicella-like or herpes zoster rash after vaccination. 

Secondary cases of varicella caused by the vaccine virus have 

been typically mild. In studies of household contacts, several 

instances of asymptomatic seroconversion have been observed. 

If a vaccinated person develops a rash, it is recommended 

that close contact with persons who do not have evidence of 

varicella immunity and who are at high risk of complications 

of varicella, such as immunocompromised persons, be avoided 

until the rash has resolved. As a safeguard, medical facilities 

should consider precautions for personnel in whom rash 

occurs after vaccination. Health care personnel in whom a 

vaccine-related rash occurs should avoid contact with persons 

without evidence of immunity who are at high risk of serious 

complications until all lesions resolve or no new lesions appear 

within a 24-hour period. 

Vaccine Storage and Handling

For storage and handling specifics, please refer to the 

manufacturer. For complete information on best practices and 

recommendations, please refer to CDC’s Vaccine Storage and 

Handling Toolkit, www.cdc.gov/vaccines/hcp/admin/storage/

toolkit/storage-handling-toolkit.pdf.
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Surveillance and Reporting of Varicella 

Varicella was removed from the list of nationally notifiable 

conditions in 1981, but some states continued to report 

cases to CDC. Varicella was added back to the list of 

nationally notifiable conditions in 2003. As of 2019, 40 states 

have been conducting case-based varicella surveillance. 

For information on guidance for state and local health 

department staff who are involved in surveillance activities 

for vaccine-preventable diseases, please consult the Manual 

for the Surveillance of Vaccine-Preventable Diseases, 

www.cdc.gov/vaccines/pubs/surv-manual/chapters.html

Acknowledgements

The editors would like to acknowledge Valerie Morelli, 

Ginger Redmon, Cindy Weinbaum, and Skip Wolfe for their 

contributions to this chapter. 

NOTES
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Selected References

Bialek S, Perella D, Zhang J, et al. Impact of a routine two-dose 

varicella vaccination program on varicella epidemiology. 

Pediatrics 2013;132(5):e1134-40.

CDC. FDA Approval of an Extended Period for Administering 

VariZIG for Postexposure Prophylaxis of Varicella. MMWR

2012;61(12):212. 

CDC. Immunization of health-care personnel. Recommendations 

of the Advisory Committee on Immunization Practices (ACIP). 

MMWR 2011;60(RR-7):1–45.

CDC. Prevention of varicella: recommendations of the 

Advisory Committee on Immunization Practices (ACIP). MMWR

2007;56(No. RR-4):1–40. 

CDC. Updated Recommendations for Use of VariZIG-United 

States, 2013. MMWR 2013;62(28):574–6. 

CDC. Use of combination measles, mumps, rubella, and varicella 

vaccine: recommendations of the Advisory Committee on 

Immunization Practices (ACIP). MMWR 2010;59(No. RR-3):1–12.

Galil K, Brown C, Lin F, et al. Hospitalizations for varicella 

in the United States, 1988 to 1999. Pediatr Infect Dis J 2002 

Oct;21(10):931–5.

Leung J, Broder K, Marin M. Severe varicella in persons 

vaccinated with varicella vaccine (breakthrough varicella): a 

systematic review. Expert Rev Vaccines 2017;16(4):391–400. 

Leung J, Marin M. Update on trends in varicella mortality during 

the varicella vaccine era, United States 1990-2016. Human 

vaccines & Immunotherapeutics 2018;14:10, 2460–63. 

Lopez A, Zhang J, Marin M. Epidemiology of varicella during 

the 2-dose varicella vaccination program – United States, 

2005-2014. MMWR 2016;65:902–5. 

Leung J and Harpaz R. Impact of the Maturing Varicella 

Vaccination Program on Varicella and Related Outcomes in 

the United States: 1994-2012. J Pediatric Infect Dis Soc 2016 

Dec;5(4):395–402. doi: 10.1093/jpids/piv044. 

Kuter B, Matthews H, Shinefield H, et al. Ten year follow-up of 

healthy children who received one or two injections of varicella 

vaccine. Pediatr Infect Dis J 2004;23:132–7. 

Marin M, Marti M, Kambhampati A, et al. Varicella vaccine 

effectiveness worldwide: a systematic review and meta-analysis. 

Pediatrics 2016;137:1–10. 

NOTES
348

Varicella

 22

Marin M, Zhang J, Seward J. Near elimination of varicella deaths 

in the United States following implementation of the childhood 

vaccination. Pediatrics 2011;128:214–20.

Marin M, Leung J, Gershon A. Transmission of vaccine 

strain varicella-zoster virus: a systematic review. Pediatrics 

2019;144(3):e20191305 

Seward J, Watson B, Peterson C, et al. Varicella disease 

after introduction of varicella vaccine in the United States, 

1995–2000. JAMA 2002;287:606–11. 

Seward J, Zhang J, Maupin T, et al. Contagiousness of 

varicella in vaccinated cases: a household contact study. 

JAMA 2004;292:704–8.

NOTES