Chapter 22: 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 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.

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.

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.

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, 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 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.

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.

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.

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.

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.

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.

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.

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.

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.

Evidence of immunity to varicella includes any of the following:

• Documentation of age-appropriate vaccination:
  • 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.

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 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.

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 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.

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.

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.