varicella• a case-controlled study of the varicella vaccine in children showed that the vaccine...

Quality Ratings: The preponderance of data supporting guidance statements are derived from:

level 1 studies, which meet all of the evidence criteria for that study type;

level 2 studies, which meet at least one of the evidence criteria for that study type; or

level 3 studies, which meet none of the evidence criteria for that study type or are derived from expert opinion, commentary, or consensus.

Study types and criteria are defined at http://smartmedicine.acponline.org/criteria.html

Disclaimer: The information included herein should never be used as a substitute for clinical judgement and does not represent an official position of the American College of Physicians. Because all PIER modules are updated regularly, printed web pages or PDFs may rapidly become obsolete.

Therefore, PIER users should compare the module updated date on the offical web site with any printout to ensure that the information is the most

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CME Statement: The American College of Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide

continuing education for physicians. The American College of Physicians designates this enduring material for a maximum of 1 AMA PRA Category 1

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their habits of critical inquiry and balanced judgement, and to contribute to better patient care. Disclosures: Joseph Truglio, MD, current author of this

module, has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations. Deborah Korenstein, MD, FACP, Co-Editor, PIER, has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or

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Varicella View online at http://pier.acponline.org/physicians/diseases/d275/d275.html

Module Updated: 2013-02-05

CME Expiration: 2016-02-05

Author

Joseph Truglio, MD

Table of Contents

1. Prevention .........................................................................................................................2

2. Screening ..........................................................................................................................6

3. Diagnosis ..........................................................................................................................7

4. Consultation ......................................................................................................................10

5. Hospitalization ...................................................................................................................12

6. Therapy ............................................................................................................................13

7. Patient Education ...............................................................................................................16

8. Follow-up ..........................................................................................................................17

References ............................................................................................................................18

Glossary................................................................................................................................21

Tables ...................................................................................................................................23

Figures .................................................................................................................................26

http://pier.acponline.org/physicians/diseases/d275/d275.html

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1. Prevention Top

Offer varicella vaccine to all susceptible individuals.

1.1 Vaccinate all children under age 13 years and all individuals aged 13 years or older who do not have evidence of immunity.

Recommendations

• Immunize all children under age 13 years with two doses of varicella-containing vaccine:

Administer the first dose at age 12 months to 15 months

Administer the second dose at age 4 years to 6 years or earlier if the interval between the first and second

dose is more than 3 months

For the first dose of varicella vaccine at age 12 months to 47 months, use the individual varicella vaccine unless the parent or caregiver express a preference for the combined live attenuated MMRV vaccine

• Administer a second dose catch-up varicella vaccine to children, adolescents, and adults who

previously received only one dose:

Note that the minimum recommended interval between the first and second dose is 3 months for children aged 12 years or younger, and 4 weeks for persons aged 13 years or older

For the second dose at age 15 months to 12 years or for the first dose at age 48 months or older, use combined live attenuated MMRV vaccine

• Assess all healthy adults for varicella immunity (see information on soliciting a reported history),

and give those without evidence of immunity two doses of single-antigen varicella vaccine 4 weeks

to 8 weeks apart.

• Target the following specific susceptible groups for vaccination:

Persons who have close contact with other individuals who are at high risk for serious varicella

complications, including health care workers and family contacts of immunocompromised persons

Persons in environments in which VZV transmission is likely, including teachers of young children, daycare employees, and residents and staff in institutional settings

Persons in other environments in which varicella transmission can occur, including college students, inmates, and military personnel

Nonpregnant women of childbearing age

International travelers

• Note that the use of varicella vaccine is not approved in pregnant women; upon completion of

pregnancy, give women without evidence of varicella immunity the first dose of vaccine before

discharge from the hospital, and a second dose 4 to 8 weeks later.

• Be aware that varicella vaccine is contraindicated in individuals with altered cellular immunity

caused by disease or drug therapy; however, consider vaccination for HIV-infected children aged 1

year to 8 years with CD4+ T-lymphocyte percentages of 15% or higher, and HIV-infected

individuals aged over 8 years with CD4+ T-lymphocyte counts ≥200 cells/µL, giving eligible

individuals two doses of single-antigen vaccine 3 months apart.

Evidence

• A case-controlled study of the varicella vaccine in children showed that the vaccine had 85% (CI,

78% to 90%) efficacy for preventing chickenpox and 97% efficacy against severe and moderately

severe disease (1).

• A 2008 structured review of varicella vaccination in the U.S. found that vaccination had 80% to

85% efficacy for the prevention of clinical disease and over 95% efficacy for the prevention of

severe disease. The review also found that the U.S. vaccination program resulted in substantial

reductions in hospitalizations for varicella (by over 75%) and varicella deaths (by over 74%) (2).

• A review of active surveillance data collected from 350,000 subjects from 1995 to 2004 found that

the annual rate of breakthrough cases significantly increased with time from vaccination, from 1.6

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cases per 1000 person-years within 1 year of vaccination to 58.2 cases per 1000 person-years

after 9 years. Children who had been vaccinated more than 5 years before infection were more

likely to have severe cases (3).

• A randomized, controlled trial in children aged 4 years to 6 years who were previously vaccinated

with MMR and varicella vaccine showed that antibody responses following MMRV were similar to

responses following second doses with the component vaccines (4).

• A separate randomized, controlled trial in children aged 12 months to 23 months found a 1-year

antibody persistence rate of over 95% after a single dose of MMRV (5).

• In 2010, the Advisory Committee on Immunization Practices advised that providers considering

using the MMRV vaccine for the first dose at age 12 months to 47 months discuss the risks and

benefits with the parents or caregivers of the child. This decision was based on postlicensure data

finding that in children aged 12 months to 24 months, the combined MMRV vaccine resulted in one

additional febrile seizure per 2300 to 2600 doses, compared with the MMR vaccine and varicella

vaccine as separate injections in the same visit. The Committee identified personal or family history

of seizure as a precaution for MMRV use (6).

• A 2004 study of U.S. national hospital charges found that annual rates of hospitalization for

varicella decreased from >0.5 hospitalizations per 10,000 from 1993 to 1995 to 0.13 per 10,000

by 2001 hospital charges for varicella decreased from $161.1 million in 1993 to $66.3 million in

2001 (7).

• A 2005 U.S. population-based study evaluated trends over time in varicella health care use and

found that rates of ambulatory visits for varicella declined by 59% from the prevaccination period

to 2002, and total medical expenditures for varicella hospitalizations and ambulatory visits

decreased by 74% (8).

• A 2005 review of U.S. death records evaluated the impact of the varicella vaccination program. The

study found 145 deaths per year related to varicella between 1990 and 1994, and 66 deaths per

year associated with varicella between 1999 and 2001 (9).

• The recommendation to vaccinate children, adolescents, and adults against varicella is included in

the Advisory Committee on Immunization Practices of the CDC and in other sources (10; 11).

• The CDC Advisory Panel on Immunization Practices recommends that all health care workers have

evidence of immunity to varicella and that those without immunity receive two doses of varicella

vaccine 4 weeks to 8 weeks apart.

• A 1997 cost-effectiveness analysis evaluated the cost-effectiveness of varicella vaccination in

health care workers. In the baseline model, vaccination resulted in cost savings, but the cost-

effectiveness hinged on the rate of vaccine-induced rash and the presence of a policy to restrict

work in recipients with rash (12).

• A pilot trial found that varicella vaccination was well tolerated in children with asymptomatic or

mildly symptomatic HIV infection. A follow-up study found similar results in HIV-infected children

with moderate symptoms (CDC clinical category B) and/or moderate immune suppression (CDC

immunologic category 2) as well as in children with previously advanced infection who had become

asymptomatic and improved to immunologic category 1 (13).

Rationale

• Because adolescents and adults who develop varicella are at higher risk for more severe disease

and complications (especially pneumonitis), these groups derive significant benefit from

vaccination.

• Vaccination provides virtually complete protection against severe manifestations of varicella.

‘Breakthrough’ varicella that occurs in an immunized person after exposure to VZV is almost always

mild.

1.2 Administer varicella vaccine to susceptible individuals after VZV exposure to prevent or modify the disease.

Recommendations

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5903a1.htm

http://pediatrics.aappublications.org/content/105/1/136.long

http://www.cdc.gov/vaccines/vpd-vac/varicella/hcp-vacc.htm

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• Administer varicella vaccine to a susceptible individual who has had close contact with VZV within 3

to 4 days of exposure.

• Use standard doses of vaccine for prevention in those who never had varicella (see information on

vaccines).

• Recognize that up to one-half of patients who receive postexposure immunization may develop

mild signs and symptoms of chickenpox.

• Do not give varicella vaccine to pregnant women or individuals with other contraindications to

vaccination.

Evidence

• A 2008 Cochrane review evaluated the effectiveness of postexposure varicella vaccination and

included three studies with 110 children who had household contact with varicella. Most vaccination

was given within 3 days of exposure. Overall, 18% of vaccinated children developed varicella

compared with 78% of unvaccinated children, and vaccinated children with varicella had mild

disease (14).

Rationale

• Symptoms of varicella usually develop approximately 15 days after exposure. Administration of

varicella vaccine within the first few days after exposure to wild-type VZV produces a protective (or

partially protective) immune response.

Comments

• In an outbreak setting, the Advisory Committee on Immunization Practices recommends that

persons who do not have adequate evidence of immunity should receive their first or second dose

of varicella vaccine as appropriate, provided the appropriate interval has elapsed (3 months for

individuals aged 12 months to 12 years and 4 weeks or more for individuals aged 13 years or

older).

• Postexposure vaccination is likely to be more effective and less expensive than preemptive therapy

with acyclovir (15).

1.3 Administer a product containing varicella antibodies to seronegative pregnant women and other susceptible patients at high risk for severe disease

who have been exposed to VZV.

Recommendations

• In addition to seronegative pregnant women, consider passive immunization after exposure in:

Susceptible immunocompromised patients

Neonates whose mothers have signs and symptoms of varicella from 5 days before to 2 days after delivery

Premature infants born at >28 weeks gestation who are exposed during the neonatal period and whose mothers do not have evidence of immunity

Premature infants born at <28 weeks gestation or who weigh ≤1000 g at birth and were exposed during

the neonatal period, regardless of maternal history

• Give VariZIG, 125 U per 10 kg (maximum, 625 U, minimum dose 125 U), as a deep intramuscular

injection within 96 hours of the exposure.

• VariZIG is an investigational purified human immunoglobulin product and should be requested

under an investigational new drug application.

• If administration of VariZIG within 96 hours of exposure is not possible, consider administration of

IVIG, 400 mg/kg, which may contain varying amounts of VZV-specific IgG.

Evidence

• The guidelines of the CDC Advisory Committee on Immunization Practices recommend that

susceptible pregnant and immunocompromised individuals who are exposed to VZV should receive

passive immunization (11).

http://www.cdc.gov/mmwr/preview/mmwrhtml/00042990.htm

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• A 1994 observational study of pregnant women with varicella included 1373 women. Rates of

congenital varicella in their babies varied based on gestational age at exposure, but there were no

cases among the babies of the 97 women who had received postexposure prophylaxis before

developing clinical varicella (16).

• The value of VZIG in the prevention of varicella has been documented in immunocompetent

children (17) but has not been evaluated prospectively in adult populations.

Rationale

• Because of incomplete information about the safety of the live-virus varicella vaccine during

pregnancy, postexposure vaccination is not recommended for this population. However, because of

the increased risk for complications caused by varicella during pregnancy, passive immunization is

recommended.

Comments

• The true VZV serologic status of a pregnant woman with a negative history of varicella is often not

known. The clinician may be faced with a decision to initiate passive immunoprophylaxis empirically

or wait for serologic studies. The ideal time to determine the VZV serologic status is before

pregnancy when vaccination can be offered to those who are confirmed to be seronegative.

• Theoretically, prophylactic or preemptive therapy with acyclovir for a pregnant woman exposed to

VZV should be effective but is unproven. Acyclovir is not FDA-approved for use during pregnancy

(11).

• VZIG is no longer available in the U.S. VariZIG is a similar product FDA-approved for postexposure

prophylaxis of susceptible high-risk patients who are ineligible for varicella vaccine for up to 10

days postexposure, although its efficacy is greatest within the first few days.

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6112a4.htm

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2. Screening Top

Assess all healthy adults and adolescents to determine whether they have evidence of immunity to varicella.

2.1 Ask patients about a history of varicella or herpes zoster disease and perform serologic testing or vaccinate patients without a clear history of

disease.

Recommendations

• Recognize that individuals with a provider-verified history of varicella or herpes zoster and those

born in the U.S. before 1980 (with the exception of health care providers, pregnant women, and

immunocompromised persons) do not require serologic testing.

• Vaccinate persons who lack documentation of adequate vaccination; serologic testing is not useful

for individuals who report vaccination, because vaccine-induced immunity is not always detected

with the available commercial tests.

• Vaccinate all persons without evidence of immunity to VZV (see section on Prevention).

• Note that the administration of varicella vaccine to an individual who is already immune does not

result in adverse effects.

Evidence

• Before the vaccination era, serologic surveys showed that >90% of the U.S. population had been

infected by VZV by age 20 years. The incidence of varicella in adults (aged >20 years) was 175

cases per 100,000 person-years (18).

• A 2004 study found that Mexican-born U.S. residents had a higher varicella susceptibility rate

(20%) than individuals born in the U.S. (3%) (19).

• Most laboratories use an ELISA or latex agglutination test to detect VZV IgG, which is a reliable

marker for previous varicella. These assays are less sensitive for detecting VZV IgG after

vaccination (20).

• A strategy of serologically screening health care workers with no history of VZV infection and

vaccination of the individuals who are not immune has been judged to be cost effective (21).

Rationale

• Some U.S. adults have not had chickenpox or received the VZV vaccine and are at risk for

significant morbidity if they develop varicella.

• Many adults with no history of varicella are seropositive, indicating previous unrecognized varicella.

• Adults with no history of varicella who do not develop disease after intimate exposure (e.g., a child

with chickenpox in the same household) are almost certainly immune.

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3. Diagnosis Top

Recognize that typical cases of varicella can be diagnosed reliably on the basis of history and physical exam.

3.1 Suspect varicella in an adolescent or adult with constitutional symptoms, a diffuse vesicular rash in various stages of development, and no previous

history of chickenpox.

Recommendations

• Suspect varicella in an adolescent or adult who presents with the following:

No previous history of varicella

A history of exposure to varicella or herpes zoster approximately 2 weeks before the onset of illness (but exposure is not often recognized)

Fever and constitutional symptoms

A distinctive diffuse rash with vesicles, papules, and scales in various stages of development

• Ask adults with varicella about respiratory symptoms, because pneumonitis is relatively common.

• Look for superinfection of skin lesions, cerebellar ataxia, and evidence of pneumonitis on lung

exam.

• Obtain lab confirmation only if the diagnosis is uncertain.

• See figure Crops of Vesicles and Pustules on the Back of a 27-Year-Old Female Nurse.

• See figure Close-up of Vesicles and Pustules on the Arm of an 18-Year-Old Man with Chickenpox.

• See figure Vescicle of Early Chickenpox.

Evidence

• Consensus.

• Among adults with varicella, 15% to 20% have radiographic evidence of pneumonitis; 5% to 10%

have respiratory symptoms (22; 23; 24).

Rationale

• The appearance of varicella is distinctive, and a clinical diagnosis is usually accurate and reliable.

Comments

• Immunocompromised patients with acyclovir-resistant virus can have hyperkeratotic, verrucous

lesions.

• Constitutional symptoms may precede the rash by 24 to 48 hours.

• As the use of varicella vaccine becomes more widespread, physicians may have less experience

with clinical diagnosis of varicella, which may place increased reliance on laboratory diagnostic

methods.

• The rash of varicella is characterized by rapid evolution of lesions over 8 to 12 hours and by

successive crops of new lesions. Lesions first appear on the head, then move to the trunk, and

finally to the extremities.

• Cerebellar ataxia is the most common neurological abnormality associated with varicella, occurring

in approximately 1 of every 4000 cases; less common CNS complications of varicella include

encephalitis, transverse myelitis, and aseptic meningitis (25).

3.2 Obtain lab confirmation of varicella only when the clinical diagnosis is uncertain using direct immunofluorescent staining of material from skin

lesions.

Recommendations

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• Obtain lab confirmation of varicella if the clinical presentation is atypical or if the patient is

immunocompromised.

• Order direct immunofluorescent staining of smears of cellular material from skin lesions as the

simplest and most rapid method for diagnosis.

• Consider serologic confirmation by detecting VZV IgM acutely or by demonstrating a four-fold rise

in VZV IgG between acute and convalescent sera that is obtained approximately 4 weeks apart.

• See table Laboratory and Other Studies for Varicella.

Evidence

• Routinely available methods include viral culture, DFA assay, and demonstration of seroconversion

(26; 27).

• The most widely available serologic assays for the detection of VZV antibody are ELISA and latex

agglutination. Latex agglutination may be slightly more sensitive than ELISA for the detection of

antibody after natural infection or vaccination. ELISA tests range in sensitivity from 86% to 97%

and range in specificity from 82% to 99% for detecting antibody after natural varicella infection

(11).

• Studies that have compared the methods for VZV diagnosis have confirmed that direct antigen

detection using immunofluorescent techniques is the most reliable rapid diagnostic test.

Immunofluorescent staining of skin scrapings using VZV- and HSV-specific monoclonal antibodies

can provide a rapid and specific diagnosis (28; 29).

• Culture for VZV is highly specific but is slow, insensitive, and expensive (26; 27).

• PCR allows for testing of cerebrospinal fluid, blood, and serum and has been found to be more

sensitive and more rapid than conventional culture techniques (30; 31; 32).

Rationale

• Sometimes the diagnosis of varicella is uncertain. A common diagnostic dilemma is deciding

whether cutaneous vesicles are caused by HSV or VZV.

3.3 Recognize that varicella may be atypical or confused with other disorders

that manifest with fever and rash.

Recommendations

• Consider alternative diagnoses in patients with suspected varicella, especially in adolescents or

adults with a previous history of chickenpox or who have received the varicella vaccine.

• Recognize that second varicella infections can occur.

• Recognize that vaccinated individuals may develop mild manifestations of varicella after exposure

to wild-type VZV, or they may develop a mild, varicella-like rash within 2 weeks of vaccination due

to infection with vaccine virus.

• See table Differential Diagnosis of Varicella.

Evidence

• A study of patients with acute varicella found that 10.8% reported a history of varicella which was

believed to be erroneous (36).

• A 2008 structured review of varicella vaccination in the U.S. found that vaccination had 80% to

85% efficacy for the prevention of clinical disease and over 95% efficacy for the prevention of

severe disease. The review also found that the U.S. vaccination program resulted in substantial

reductions in hospitalizations for varicella (by over 75%) and varicella deaths (by over 74%) (2).

• Secondary cases of varicella in immunocompetent persons have been reported (37).

Rationale

• Accurate and expeditious clinical diagnosis is essential to optimal management.

Comments

• In the past, smallpox and generalized vaccinia infection were the most important differential

diagnoses. A febrile prodrome poorly distinguishes smallpox from varicella.

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4. Consultation Top

Consider consultation with an appropriate specialist when the clinical diagnosis is uncertain and/or the patient is seriously ill. Consider consultation with an appropriate specialist for patients with suspected visceral involvement; otherwise, management of uncomplicated varicella is straightforward.

4.1 Seek consultation with an infectious diseases specialist, dermatologist, and/or other specialist to help clarify the differential diagnosis.

Recommendations

• Ask an infectious diseases specialist to review the differential diagnosis and advise appropriate

diagnostic testing.

• Ask a dermatologist to review the differential diagnosis and to consider obtaining a skin biopsy for

cultures and histopathology.

• Consider asking a clinical microbiologist to assist with collecting samples for specialized virologic

testing.

• Note that a pediatrician who is experienced with diagnosing and managing varicella may be a

valuable resource.

Evidence

• Consensus.

Rationale

• Establishing a diagnosis of varicella in a seriously ill adolescent or adult is an essential prerequisite

for the initiation of appropriate antiviral therapy.

4.2 Obtain expert consultation to assist with the management of patients with varicella pneumonitis, encephalitis, or severe cutaneous bacterial

infection.

Recommendations

• Consult an infectious disease specialist for help in using intravenous acyclovir, if necessary.

• Consult a pulmonary medicine or critical care specialist to assist with the ventilatory management

in patients with varicella pneumonitis and significant hypoxemia.

• Consult a neurologist for assistance with the management of varicella with CNS involvement.

Evidence

• Consensus.

Rationale

• Complications of varicella in adults, while uncommon, can result in substantial morbidity and

mortality.

4.3 Obtain expert consultation to assist with the management of pregnant

women with varicella.

Recommendations

• Consult an obstetrician or fetal-maternal medicine specialist to assist with the management of

pregnant women with varicella.

Evidence

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• Women who contract varicella while pregnant (especially in the second or third trimester) have an

estimated 10% risk for developing severe VZV pneumonitis (52).

• Although acyclovir is not FDA-approved for use during pregnancy, no fetal toxicity attributable to

acyclovir has been documented and the risk-benefit ratio clearly supports use of acyclovir in the

setting of maternal varicella pneumonia (55; 56).

• A rare but well-defined congenital fetal varicella syndrome may result when a pregnant woman

acquires varicella during the first or second trimester of pregnancy (62; 63). This embryopathy is

characterized by limb hypoplasia, ocular and neurological abnormalities, and distinctive cicatricial

skin scarring in a dermatomal pattern (64). Fortunately, fetal varicella syndrome is uncommon,

arising in only 2% of the cases of maternal varicella that occur during the first 20 weeks of

gestation (65).

• If maternal varicella appears during a window of approximately 5 days before to 2 days after

delivery, the neonate is at high risk (24% to 48%) for developing perinatal varicella (66; 67).

Perinatally acquired varicella is characterized by serious visceral organ involvement, including lung,

liver, and CNS disease, and a mortality rate of 30% (68; 69). The period of greatest risk is when

the infant is delivered after the onset of maternal viremia but before maternal antibody develops.

Infants delivered during the high-risk window should receive passive immunization with a product

containing VZV-specific antibodies (70). Intravenous acyclovir therapy should be instituted

immediately if the neonate shows any signs of varicella.

Rationale

• Primary VZV infection during pregnancy has the potential to cause serious complications for both

mother and child.

Comments

• Aggressive antiviral therapy is recommended for a pregnant woman with varicella who has any

evidence of pulmonary involvement, including cough, shortness of breath, or an abnormal chest

radiograph. Data from clinical trials are lacking, but several case series have reported clinical

improvement with acyclovir therapy given to pregnant women with varicella pneumonitis (71).

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5. Hospitalization Top

Adults and adolescents with serious complications of varicella benefit from hospitalization.

5.1 Consider hospitalizing patients with serious complications of varicella.

Recommendations

• Hospitalize patients with VZV pneumonitis (cough, dyspnea, abnormal chest radiograph) for

therapy with intravenous acyclovir, supplemental oxygen, and close monitoring to assess the need

for ventilatory support.

• Hospitalize patients with evidence of neurologic involvement (e.g., encephalitis, transverse

myelitis) for intravenous acyclovir therapy and supportive care.

• Hospitalize patients with serious bacterial superinfections of the skin (e.g., streptococcal cellulitis)

for intravenous antibiotics.

• Avoid hospitalization of patients with uncomplicated varicella to reduce the risk for nosocomial

transmission of VZV.

• See figure Varicella Pneumonia.

Evidence

• In the prevaccine era in the U.S., approximately 4 million cases of varicella were reported annually,

with 4000 to 9000 hospitalizations and 100 deaths. Although <5% of varicella cases occurred in

patients aged >20 years, 55% of varicella-related deaths occurred in this age group (38). From

1990 to 1994, adults in the U.S. had a 25-fold greater risk for dying from varicella than children

aged 1 year to 4 years, and most of these adults were previously healthy (39).

• A case-control study of 347 pregnant women with VZV infection evaluated risk factors for varicella

pneumonia. Women with VZV pneumonia were more likely to smoke (OR, 5.1; CI, 1.6 to 16.7) and

to have 100 skin lesions or more (OR, 1.59; CI, 1.9 to 130.2) (40).

• From January 2003 to June 2004, eight deaths related to varicella were reported to the CDC; six

persons were unvaccinated, and the vaccination status of two persons was not known. Three-

fourths of the fatal cases were in persons under age 20 years (41).

• In Alberta, Canada, from 2000 to 2002, the incidence of varicella-associated group A streptococcal

disease was 0.73 cases per 100,000 children. Most cases presented with bacteremia; arthritis and

osteomyelitis also occurred. However, there were no cases of necrotizing fasciitis (42).

Rationale

• Adults who develop complications of varicella require hospitalization for intravenous acyclovir

therapy and supportive care to limit morbidity and mortality.

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6. Therapy Top

Use antiviral drugs to reduce the duration of illness and other medications to alleviate symptoms in adolescents and adults with uncomplicated varicella.

6.1 Prescribe oral acyclovir to shorten the duration of constitutional

symptoms and the formation of new lesions.

Recommendations

• Begin treatment within the first 24 hours of the onset of rash, when possible.

• Administer acyclovir, 800 mg, po qid for 5 days, to immunocompetent adults and adolescents with

uncomplicated varicella.

• See table Drug Treatment for Varicella.

Evidence

• A 1992 randomized, controlled trial compared acyclovir with placebo in adults with varicella.

Patients receiving acyclovir had a shorter duration of new lesion formation (2.7 compared with 3.3

days), a 46% reduction in the maximum number of lesions, faster healing (5.6 compared with 7.4

days), and shorter duration of fever (0.5 days) (43).

• A 2005 Cochrane review of acyclovir to treat varicella in healthy children and adolescents included

three randomized, controlled trials which were of moderate quality. Acyclovir resulted in fewer days

with fever (−1.1 days [CI, −1.3 to −0.9]) and a reduction in the maximum number of lesions (−76

lesions [CI, −145 to −8]) but no other significant differences (44).

• A study of children, adolescents, and adults with varicella who were treated at various times after

onset of rash showed that the maximum benefit of acyclovir occurred in those treated within 24

hours of onset compared with those treated after 48 hours, but some benefit was apparent in

persons treated between 24 hours and 48 hours (45).

• Although antiviral therapy is considered optional for healthy children with varicella, the higher

potential for morbidity clearly favors treatment in adults (46).

Rationale

• Any decrease in the duration of acute illness is beneficial given that immunocompetent adolescents

and adults with varicella can be seriously ill (with high fever, hundreds of cutaneous lesions, and

incapacitating constitutional symptoms) and that they are likely to miss >7 days of school or work.

Comments

• Valacyclovir and famciclovir are effective against VZV, but have not been studied for chickenpox.

• It is not clear whether acyclovir therapy reduces the risk for complications such as pneumonitis or

encephalitis.

• For immunocompromised patients, use acyclovir, 10 to 15 mg/kg, iv every 8 hours for 7 to 10 days

(47).

6.2 Treat patients who have varicella complicated by visceral dissemination with iv acyclovir.

Recommendations

• Administer acyclovir, 10 to 12.5 mg/kg iv every 8 hours (for patients with normal renal function),

in adolescents or adults hospitalized with varicella pneumonitis or CNS involvement.


Evidence

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• No controlled clinical trials of acyclovir for complications of varicella have been done.

Recommendations about acyclovir therapy for VZV pneumonitis are based on data from anecdotal

reports (46; 48; 49; 50; 51).

• Several case series have reported clinical improvement with acyclovir therapy given to pregnant

women with varicella pneumonitis (52; 53).

• Although acyclovir is not FDA-approved for use during pregnancy, no fetal toxicity attributable to

acyclovir has been documented and the risk-benefit ratio clearly supports the use of acyclovir in

this setting (54; 55).

• The Acyclovir in Pregnancy Registry monitored over 1200 pregnancies with exposure to acyclovir,

and found no significant differences in rates or types of birth defects in these pregnancies

compared with the general population (56).

Rationale

• Acyclovir inhibits viral replication and can limit tissue injury caused by VZV.

Comments

• Some severely immunocompromised patients receiving acyclovir for chronic varicella may develop

acyclovir-resistant virus, in which case foscarnet, 40 mg/kg iv every 8 hours, should be

administered.

• No prospective studies of acyclovir therapy for VZV encephalitis are available.

• Combination therapy of acyclovir plus corticosteroids has been proposed for use in varicella

pneumonitis and encephalitis, but no data from controlled trials are available to support this

approach (57).

6.3 Treat for constitutional symptoms with oral antihistamines and

acetaminophen.

Recommendations

• Prescribe oral antihistamines (e.g., hydroxyzine hydrochloride, 25 mg, po tid) for more severe

pruritus.

• Use acetaminophen for relief of fever, headache, and myalgias.

• Avoid salicylates and NSAIDs.


Evidence

• A clear association between aspirin use and the development of Reye's syndrome has been

described in children with varicella (58).

• An increased incidence of necrotizing fasciitis has been attributed to NSAIDs (e.g., ibuprofen) use

by children with varicella (59; 60).

Rationale

• In children with varicella, salicylates and NSAIDs have been associated with development of Reye's

syndrome and necrotizing fasciitis, respectively.

6.4 Use topical agents and other strategies to relieve pruritus in patients with

varicella.

Recommendations

• Manage mild pruritus with topical dressings (e.g., cold calamine lotion with diphenhydramine) and

tepid baths that contain baking soda or colloidal starch.

• Advise patients to trim fingernails closely to avoid skin excoriations.

• Recommend a daily bath with an antibacterial soap to reduce the risk for cutaneous bacterial

superinfection.

Evidence

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• Consensus.

Rationale

• The chief complaints of adults with varicella are usually pruritus and fever. The simple measures

described above provide symptomatic relief. Controlling pruritus also may reduce the risk for skin

excoriations and secondary cellulitis.

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7. Patient Education Top

Advise patients about possible complications and transmission of infection even though varicella is generally a self-limited illness.

7.1 Educate ambulatory patients with varicella about the potential complications and the transmission risks of VZV.

Recommendations

• Instruct patients to report the following:

Cough or shortness of breath

Headache, neck stiffness, seizure, or focal weakness

Expanding areas of skin erythema or tenderness

• Instruct patients to avoid any contact with other people who have not had varicella, especially

young infants, pregnant women, and immunocompromised individuals.

• Make patients aware that they are contagious and can transmit varicella to other susceptible

individuals for approximately 2 days before and 4 to 5 days after the appearance of the rash.

• Advise patients that they may return to school or work when all cutaneous lesions have crusted.

Evidence

• Varicella is highly infectious, and attack rates of 61% to 87% have been observed among

susceptible household contacts (61).

Rationale

• Patients who develop symptoms that suggest pneumonitis, encephalitis, or cellulitis should return

for follow-up evaluation immediately. Informing ambulatory patients when they are contagious

prevents the unnecessary spread of infection.

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8. Follow-up Top

Consider scheduled follow-up only in atypical cases or in patients with disease complications, because varicella is most often a self-limited illness.

8.1 Provide close follow-up for patients with varicella who develop

complications or in whom the diagnosis is unconfirmed.

Recommendations

• Follow up with patients who have an atypical or clinically unconfirmed case of varicella to collect

convalescent sera for serologic confirmation of the infection.

• Administer varicella vaccine to patients in whom serologic testing shows no evidence of VZV

infection.

• Carefully follow patients who develop complications of varicella until the condition has resolved or

stabilized.

• When possible, attempt to keep patients with active varicella out of the office or clinic to avoid the

risk for nosocomial transmission.

Evidence

• Consensus.

Rationale

• Most patients with varicella, whether or not they receive antiviral therapy, resolve their illness

without complications; routine follow-up of these patients is not necessary. The drugs used to treat

varicella are well tolerated and do not require follow-up evaluations to monitor for adverse effects.

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References Top

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Glossary Top

AIDS acquired immunodeficiency syndrome

CBC complete blood count

CDC Centers for Disease Control and Prevention

CNS central nervous system

CrCl

creatinine clearance

DFA

direct fluorescent antibody

DNA deoxyribonucleic acid

ELISA enzyme-linked immunosorbent assay

HIV

human immunodeficiency virus

HSV herpes simplex virus

IgG immunoglobulin G

IgM immunoglobulin M

iv intravenous

IVIG intravenous immunoglobulin

MMR measles, mumps, rubella

MMRV

measles, mumps, rubella, varicella

NSAID nonsteroidal anti-inflammatory drug

PCR polymerase chain reaction test

po

oral

qid four times daily

tid three times daily

VZIG varicella-zoster immunoglobulin

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VZV

varicella-zoster virus

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Tables Top

Laboratory and Other Studies for Varicella

Test Notes

Viral culture Sensitivity 30-70%; specificity 100%. Recovery of VZV is highly dependent on the stage of the lesions,

the quality of the specimen collected, and the time elapsed between specimen collection and tissue

culture inoculation. Fluid from fresh vesicles should be aspirated into a tuberculin syringe containing viral transport media and then delivered immediately to the virology laboratory. If delay is

unavoidable, refrigerate the specimen on wet ice; do not freeze. Growth of VZV in tissue culture may

take 3-14 days (33; 34)

Antigen detection DFA detection is more sensitive than viral culture (28). Using a modified Tzanck technique, cells are

scraped from the base of the lesion with a scalpel or needle, smeared on a glass slide, and stained

using fluorescein-conjugated monoclonal antibodies to detect viral glycoproteins. DFA can distinguish

between HSV and VZV

Serology Most laboratories use ELISA or latex agglutination. Serum antibodies appear several days after the

onset of varicella and peak at 2-3 weeks; a four-fold rise in serum IgG between acute and convalescent

sera is diagnostic (35). Demonstration of VZV-specific IgM indicates acute infection, but often lacks

sensitivity and specificity

PCR Useful for detecting VZV DNA in cerebrospinal fluid, serum, or blood, but is not widely available; PCR

has been found to be more sensitive than culture isolation (30)

DFA = direct fluorescent antibody; DNA = deoxyribonucleic acid; ELISA = enzyme-linked immunosorbent assay; HSV = herpes simplex virus; IgG = immunoglobulin G; IgM = immunoglobulin M; PCR =

polymerase chain reaction test; VZV = varicella-zoster virus.

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Differential Diagnosis of Varicella

Disease Characteristics

Varicella Successive crops of new lesions evolving into small vesicles with a small area of surrounding erythema

Mild cases can occur in vaccinated individuals. Often preceded or accompanied by constitutional

symptoms in adults

Impetigo Pustular and crusted lesions, usually on the extremities and face; usually afebrile

Caused by group A streptococci; uncommon in adults

Insect bites Biting and stinging insects (e.g., fire ants) can cause multiple vesicular or pustular lesions with fever

Competent adults should relate a history of insect exposure

Disseminated HSV Generalized cutaneous vesicles that may be difficult to distinguish from varicella

Only occurs in immunocompromised individuals

Rickettsialpox (R. akari) A painless papule with eschar forms at the mite bite site; a generalized papulovesicular rash appears 3-

7 days later

Uncommon disease; patient may report exposure to mice

Enterovirus infection (e.g., hand, foot, and mouth disease) Febrile illness with vesicular eruption that involves the mouth, hands, and feet; unlike varicella, the

vesicular rash rarely becomes widespread

Caused by coxsackievirus A16 and other enteroviruses; occurs most often in children aged <10 years

Allergic reactions (e.g., drug reaction) Highly variable syndromes of fever and rash (e.g., Stevens-Johnson syndrome, toxic epidermal

necrolysis)

Skin changes are often large bullae rather than small discreet vesicles

Sweet's syndrome Pustular neutrophilic dermatitis accompanied by fever, arthritis, and leukocytosis

Associated with underlying malignancy in 25% of cases

Smallpox Deep-seated, firm, well-circumscribed vesicles or pustules all in the same stage of development in any

one part of the body. Lesions occur after a prodrome of 1-4 days with high fever and have a centrifugal

distribution (more on face and distal extremities)

Caused by smallpox virus

HSV = herpes simplex virus.

http://pier.acponline.org/physicians/diseases/d054/d054.html

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Drug Treatment for Varicella

Drug or Drug Class Dosing Side Effects Precautions Clinical Use

Acyclovir (Zovirax) 800 mg PO qid for 5 days. If immuno-

compromised: 10-15 mg/kg IV q8hr for

7-10 days. Pneumonitis or CNS

involvement: 10-12.5 mg/kg IV q8hr

Crystalluria and nephrotoxicity more

likely with large parenteral doses.

Neurotoxicity, especially with high

doses. Injection site reactions, GI side

effects, headache. TTP and HUS in

immuno-compromised patients

May need to adjust dose if CrCl<50.

Avoid nephrotoxic drugs. Maintain

hydration. Caution with elderly

Acute treatment

Valacyclovir (Valtrex) 1 g PO tid GI side effects, headache,

nephrotoxicity, CNS side effects, rash.

TTP and HUS in immuno-compromised patients

Adjust dose if CrCl<50. Avoid

nephrotoxic drugs. Maintain hydration.

Caution with elderly

Famciclovir (Famvir) 500 mg PO q8hr GI side effects, headache, CNS side

effects, rash, neutropenia,

hepatotoxicity

Adjust dose if CrCl<60. Caution with

elderly

Foscarnet IV (Foscavir) 40 mg/kg IV q8-12hr Headache, nausea, vomiting, diarrhea,

myelosuppression, mineral and

electrolyte imbalances, cardiac

arrhythmias, fever, rash

Nephrotoxicity, seizures. Decrease

dose if CrCl<1.4 mL/min/kg. Avoid

nephrotoxic drugs

For acyclovir resistance

= first-line agent; = black box warning; bid = twice daily; CKD = chronic kidney disease; CNS = central nervous system; CrCl = creatinine clearance; GI = gastrointestinal; HUS = hemolytic-uremic

syndrome; IM = intramuscular; IV = intravenous; PO = oral; q8hr = every 8 hours; qd = once daily; qid = four times daily; SC = subcutaneous; tid = three times daily; TTP = thrombotic thrombocytopenic

purpura.

PIER provides key prescribing information for practitioners but is not intended to be a source of comprehensive drug information.

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Figures Top

Crops of Vesicles and Pustules on the Back of a 27-Year-Old Female Nurse

The rash of varicella is characterized by rapid evolution of lesions over 8 to 12 hours and by successive crops of new lesions. Lesions may first appear on the head, then move to the trunk, and finally to the extremities. On any part of the body lesions can be identified in different stages of development (macules, papules, vesicles, pustules).

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Close-up of Vesicles and Pustules on the Arm of an 18-Year-Old Man with Chickenpox

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Varicella Pneumonia

Chest radiograph that demonstrates diffuse bilateral infiltrates in a 30-year-old pregnant woman with chickenpox.

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Vesicle of Early Chickenpox

Early varicella lesions present as a thin-walled, clear vesicle (dew drop) which develops on top of the area of redness. This "dew drop on a rose petal" lesion is characteristic for early chickenpox.

varicella• a case-controlled study of the varicella vaccine in children showed that the vaccine...

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