Kathleen H. Harriman, Gilberto F. Chavez

Infectious Agent

• Varicella-zoster virus (VZV) is a member of the herpesvirus family.
• Humans are the only reservoir of the virus, and disease occurs only in humans.

Mode of Transmission

VZV is transmitted from person to person by direct contact, inhalation of aerosols from vesicular fluid of skin lesions of acute varicella or zoster, or infected respiratory tract secretions that might also be aerosolized.

• The virus enters the host through the upper respiratory tract or the conjunctiva.
• In utero infection can also occur as a result of transplacental passage of virus during maternal varicella infection.
• The period of contagiousness is estimated to begin 1–2 days before the onset of rash and to end when all lesions are crusted, typically 4–7 days after onset of rash in immunocompetent persons, but this period may be longer in immunocompromised persons.

Occurrence

• Varicella occurs worldwide. In temperate climates, varicella tends to be a childhood disease, with peak incidence during late winter and early spring. In tropical climates, infection tends to occur at older ages, resulting in higher susceptibility among adults than in temperate climates.
• Before introduction of varicella vaccine in the United States in 1995, varicella was endemic, and virtually all persons were infected by adulthood. Since implementation of the varicella vaccination program, the epidemiology and clinical characteristics of varicella have changed, with substantial declines in morbidity and mortality. The incidence of varicella has steadily declined in all age groups, with the greatest decline among children 1–4 years of age.

Risk for Travelers

• Varicella vaccine is routinely used for vaccination of healthy children in only some countries, including the United States, Uruguay, Qatar, Australia, Canada, Costa Rica, Germany, and South Korea.
• The risk for varicella infection is higher for people traveling to most other parts of the world than it is in the United States. However, VZV is still widely circulating in the United States. Additionally, exposure to herpes zoster (shingles), while less common than varicella, poses a risk for varicella infection in susceptible travelers.
• Travelers at highest risk for severe varicella disease are immunocompromised persons or pregnant women without a history of varicella disease or vaccination.

Clinical Presentation

• Varicella is generally a mild disease in children. It usually lasts 4–7 days and is characterized by a short (1- to 2-day) or absent prodromal period (low-grade fever, malaise) and by a pruritic rash consisting of crops of macules, papules, and vesicles (on average 250–500 lesions), which appear in three or more successive waves and resolve by crusting.
• Serious complications are the exception but can occur, mainly in infants, adolescents, adults, and immunocompromised persons. They include secondary bacterial infections of skin lesions, pneumonia, cerebellar ataxia, and encephalitis.
• The average incubation period for varicella is 14–16 days (range 10–21 days).
• A modified varicella, known as breakthrough disease, can occur in some vaccinated persons, because the vaccine is 70%–90% effective in preventing disease. Breakthrough varicella is most commonly (~70%–80% of cases) mild, with <50 skin lesions, less fever, and shorter duration of rash. The rash may be atypical in appearance with fewer vesicles and predominance of maculopapular lesions. Nevertheless, breakthrough varicella is infectious (although less than varicella in unvaccinated persons). Persons with breakthrough varicella should be isolated for as long as lesions persist.

Diagnosis

• Skin lesions are the preferred specimen for laboratory confirmation of varicella disease.
  • Vesicular fluid or a scab can be used to identify VZV by using polymerase chain reaction (PCR). Rapid diagnostic tests (PCR, direct fluorescent antibody) are the methods of choice.
  • VZV can also be isolated from scrapings of a vesicle base during the first 3–4 days of the eruption.
  • Collecting skin lesion specimens from breakthrough cases can be challenging because the rash is often maculopapular with few or no vesicles. If lesions are not present, scraping of the lesion is recommended.
• Serologic tests for confirmation of disease:
  • A significant rise in serum varicella IgG antibody from acute- and convalescent-phase samples by any standard serologic assay can confirm a diagnosis retrospectively, but may not be reliable in immunocompromised people.
  • Commercially available tests are not sufficiently sensitive to reliably demonstrate vaccine-induced immunity.

Postexposure Prophylaxis

Vaccine

• Varicella vaccine is recommended for postexposure administration for healthy unvaccinated persons without other evidence of immunity.
• Administration of varicella vaccine to exposed susceptible persons ≥12 months of age, as soon as possible within 72 hours and possibly up to 120 hours after exposure, may prevent or modify disease and is recommended if there are no contraindications to use. In several studies, protective efficacy was reported as ≥90% when children were vaccinated within 3 days of exposure.

Use of Varicella Zoster Immune Globulin (VZIG)

• In certain circumstances, postexposure prophylaxis with VZIG is recommended.
• The decision to administer VZIG to a person exposed to varicella should be based on 1) whether the person is susceptible, 2) whether the exposure is likely to result in infection, and 3) whether the person is at greater risk for complications than the general population.
• Persons at greater risk for severe complications who are not candidates for varicella vaccination who may benefit from postexposure prophylaxis with VZIG include:
  • susceptible immunocompromised persons (including people being treated with chronic corticosteroids ≥2 mg/kg of body weight or a total of 20 mg/day of prednisone or equivalent)
  • susceptible pregnant women
  • newborns whose mothers had onset of varicella within 5 days before and 2 days after delivery
  • preterm infants at ≥28 weeks gestation whose mothers are susceptible to varicella
  • preterm infants at <28 weeks gestation or ≤1,000 g birth weight, regardless of maternal history or serostatus.
• VZIG provides maximum benefit when administered as soon as possible after exposure, but may be effective if administered as late as 96 hours after exposure.
• The product currently in use in the United States, VariZIG, is available under an Investigational New Drug protocol and can be obtained from the sole authorized U.S. distributor, FFF enterprises (Temecula, California) (24-hour telephone, 800-843-7477 or www.fffenterprises.com).
• If administration of VariZIG does not appear possible within 96 hours of exposure, administration of immune globulin intravenous (IGIV) should be considered as an alternative (IGIV should also be administered within 96 hours of exposure).

Treatment

• Oral acyclovir is not recommended for routine use in healthy children with varicella but should be considered for otherwise healthy people at increased risk for moderate to severe disease, e.g., persons aged >12 years; people with chronic cutaneous or pulmonary disorders; receiving long-term salicylate therapy; and receiving short, intermittent or aerosolized courses of corticosteroids.
• Intravenous antiviral therapy, when administered within 24 hours of onset of rash is recommended for immunocompromised persons, including patients being treated with chronic corticosteroids.

Preventive Measures for Travelers

Although vaccination against varicella is not a requirement for entry into any country (including the United States), persons traveling or living abroad should ensure that they are immune.

Vaccine

• Varicella vaccine contains live, attenuated VZV. It is available as a monovalent formulation and in combination formulation, as measles–mumps–rubella–varicella (MMRV) vaccine, which is licensed in the United States for children 1–12 years only.
• Two doses of varicella-containing vaccine are now recommended for all susceptible persons older than one year without contraindications. The first dose should be administered at 12–15 months of age and the second dose at 4–6 years of age. A second catch-up dose of varicella vaccination is recommended for children, adolescents and adults who previously have received one dose. The minimum interval for children younger than 13 years is 3 months. The ACIP now recommends that all others at least 13 years of age without evidence of immunity be vaccinated with two doses of varicella vaccine at an interval of 4–8 weeks. In case of uncertainty, prior varicella disease is not a contraindication to varicella vaccination.
• Evidence of immunity to varicella includes any of the following:
  • Documentation of age-appropriate vaccination:
    • Preschool-age children aged ≥12 months: 1 dose
    • School-age children, adolescents, and adults: 2 doses
  • Laboratory evidence of immunity or laboratory confirmation of disease
  • Birth in the United States before 1980 (not a criterion for health-care personnel, pregnant women, and immunocompromised persons)
  • A health-care provider diagnosis of varicella or a health-care provider verification of a history of varicella disease
  • A health-care provider diagnosis of herpes zoster or a health-care provider verification of a history of herpes zoster disease

Adverse Reactions

• The most common adverse reactions following varicella vaccine are injection site complaints (pain, soreness, redness, and swelling) that are self-limited. Fever was reported in uncontrolled trials in 15% of children and 10% of adolescents and adults. A macular or vaccine rash usually consisting of a few lesions at the injection site was reported in 3% and 1% of persons receiving the first and second dose, respectively. A generalized rash with a small number of lesions may rarely occur, within 3 weeks of vaccination.
• Varicella vaccine is a live-virus vaccine that induces latent infection similar to that caused by wild VZV. Consequently, zoster caused by vaccine virus has been reported. This appears to occur at a lower rate than following natural infection but longer term follow-up is needed.

Contraindications

Allergy

• Persons with severe allergy (hives, swelling of the mouth or throat, difficulty breathing, hypotension, and shock) to gelatin or neomycin or who have had a severe allergic reaction to a prior dose of vaccine should not be vaccinated.
• Single-antigen varicella vaccine does not contain egg protein or preservative. For the combination MMRV vaccine, live measles and live mumps vaccine are produced in chick embryo culture. However, the risk for serious allergic reactions after administration of measles- or mumps-containing vaccines in persons who are allergic to eggs is low.

Altered Immunity

Persons with immunosuppression of cellular immune function resulting from leukemia, lymphomas of any type, generalized malignancy, immunodeficiency disease, or immunosuppressive therapy should not be vaccinated. Treatment with low-dose prednisone (e.g., <2 mg/kg of body weight/day or <20 mg/day) or aerosolized steroid preparations is not a contraindication to varicella vaccination. Persons whose immunosuppressive therapy with steroids has been stopped for 1 month (3 months for chemotherapy) may be vaccinated. In addition, persons with impaired humoral immunity may now be vaccinated. Because children infected with HIV are at greater risk for morbidity from varicella and herpes zoster than are healthy children, the ACIP recommends that varicella vaccine should be considered for HIV-infected children at least 12 months of age with CD4+ T-lymphocyte percentages ≥15% and without evidence of varicella immunity. Eligible children should receive two doses of single-antigen varicella vaccine, with a minimum 3-month interval between doses. Vaccination (two doses, administered 3 months apart) may be considered for HIV-infected older children, adolescents and adults with CD4+ T-lymphocyte count ≥200 cells/mL, after weighing the risks and benefits.

Pregnancy

Women known to be pregnant or attempting to become pregnant should not receive varicella vaccine. Pregnancy should be avoided for 1 month following varicella vaccination. Breastfeeding is not a contraindication to the varicella vaccination.

Precautions

Illness

Vaccination of persons who have acute severe illness, including untreated, active tuberculosis, should be postponed until recovery.

Recent Administration of Blood, Plasma, or Immune Globulin

The effect of the administration of immune globulin (IG) on the response to varicella virus vaccine is unknown. Because of the potential inhibition of the antibody response by passively transferred antibodies, varicella vaccines should not be administered for 3–11 months, depending on the dosage, after administration of blood (except washed red cells), plasma, or IG.

Use of Salicylates

No adverse events following varicella vaccination related to the use of salicylates (e.g., aspirin) have been reported to date. However, the manufacturer recommends that vaccine recipients avoid the use of salicylates for 6 weeks after receiving varicella vaccine because of the association between aspirin use and Reye syndrome following varicella.

References

1. CDC. Prevention of varicella. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morbid Mortal Wkly Rep. 2007;56(RR-4):1–40.
2. Gershon AA, Takahasi M, Seward J. Varicella vaccine. In: Plotkin SA, Orenstein WA, editors. Vaccines. 4th ed. Philadelphia: W.B. Saunders; 2004:783–823.
3. Seward JF, Watson BM, Peterson CL, et al. Varicella disease after introduction of varicella vaccine in the United States, 1995–2000. JAMA. 2002;287(5):606–11.
4. CDC. Decline in annual incidence of varicella-selected states, 1990–2001. MMWR Morbid Mortal Wkly Rep. 2003;52(37):884–5.
5. Guris D, Jumaan AO, Mascola L, et al. Changing varicella epidemiology in active surveillance sites—United States, 1995–2005. J Infect Dis. 2008;197(Suppl 2):S71–5.
6. WHO. Immunization summary: The 2007 edition. [cited 2008 April 14]. Available from: http://www.unicef.org/publications/files/Immunization_Summary_2007.pdf (PDF)
7. CDC. A new product (VariZIG) for postexposure prophylaxis of varicella available under an Investigational New  Drug application expanded access protocol. MMWR Morbid Mortal Wkly Rep. 2006;55:1–2.
8. 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(2):132–7.
9. Seward JF. Update on varicella. Pediatr Infect Dis J. 2001;20(6):19–21.
10. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-05):1–30.