The varicella-zoster virus (VZV) causes two distinct diseases, varicella (chickenpox) as the primary infection, and later, when VZV reactivates, herpes zoster (shingles). Varicella is an acute illness characterized by fever and generalized, pruritic, vesicular rash typically consisting of 250 to 500 lesions in varying stages of development and resolution. The rash is maculopapular for a few hours, vesicular for 3 to 4 days, then crusts, leaving granular scabs. The vesicles are unilocular and collapse on puncture, in contrast to the multilocular, non-collapsing vesicles of smallpox. Lesions commonly occur in successive crops, with several stages of maturity present at the same time; they tend to have central distribution, and are more abundant on covered than on exposed parts of the body. Lesions may appear on the scalp, high in the axilla, on mucous membranes of the mouth and upper respiratory tract, and on the conjunctivae; they tend to occur in areas of irritation, such as sunburn or diaper rash. They may be so few as to escape observation.
Mild, atypical and inapparent infections occur, especially among vaccinated individuals (breakthrough varicella). Breakthrough varicella is defined as varicella developing more than 42 days after vaccination; most breakthrough disease is mild, without fever, and with skin rash of <50 lesions that are atypical, with papules that do not progress to vesicles, and which may be so few in numbers as to escape observation.
Occasionally, especially in adults and in persons with cellular immune deficiencies such as malignancies and HIV/AIDS, fever and constitutional manifestations may be severe. Although varicella is usually a benign childhood disease, and is rarely rated as an important public health problem, varicella zoster virus may induce pneumonia or encephalitis, sometimes with persistent sequelae or death. Secondary bacterial infections of the vesicles may leave disfiguring scars, or result in necrotizing fasciitis or septicemia.
The case-fatality rate is lower for children (1:100 000 infected in the 5–9 age group) than for adults (1:5 000). Serious complications include pneumonia (viral and bacterial), secondary bacterial infections, hemorrhagic complications and encephalitis. Children with acute leukemia, including those in remission after chemotherapy, are at increased risk of disseminated disease, which is fatal in 5%–10% of cases. Neonates who develop varicella between ages 5 and 10 days are at increased risk of developing severe generalized varicella. Among neonates whose mothers develop the disease 5 days prior to or within 2 days after delivery and who do not receive VZIG (see below) or antiviral therapy, the case-fatality rate can reach 30%. Infection early in pregnancy, at 0–12 weeks, may be associated with fetal death or congenital varicella syndrome in 1% of cases, and at 13–20 weeks gestation with a 2% risk. Cases consistent with congenital varicella syndrome have been reported post 20 weeks gestation. Clinical varicella was a frequent antecedent of Reye syndrome, before the association of Reye syndrome with aspirin use for viral infections was identified.
Herpes zoster (shingles), which occurs in about 10–20% of the population, is a local manifestation of reactivation of latent varicella infection in the dorsal root ganglia. Vesicles with an erythematous base are restricted to skin areas supplied by sensory nerves of a single or associated group of dorsal root ganglia. Rash is typically unilateral, and most commonly affects thoracic, cervical, and ophthalmic dermatomes. Small numbers of lesions may appear outside the primary dermatome. Lesions are histologically identical to those of varicella, deeper seated, and more closely aggregated. The rash lasts about 7–10 days, and heals within 2–4 weeks. Complications develop in about 30% of herpes zoster cases; the most common is chronic severe pain or post-herpetic neuralgia (PHN). Although the definition of PHN has been inconsistent, PHN is defined as pain that persists after the rash heals, ranging from any duration to 30–90 days after rash resolution; it can, however, last for months, or even years. Herpes zoster may result in permanent neurological damage such as cranial nerve palsy and contralateral hemiplegia, or visual impairment following herpes zoster ophthalmia. The incidence of both herpes zoster and post-herpetic neuralgia increase with age; persons with malignant neoplasm and those infected with HIV also have a high risk of herpes zoster, with higher rates among children. Herpes zoster is more common following hematopoietic stem cell and solid organ transplants, especially in the first year. In the immunosuppressed and those with malignancies, but sometimes in otherwise healthy individuals with fewer lesions, extensive chickenpox-like lesions may appear outside the dermatome. Intrauterine infection is associated with herpes zoster in children. Occasionally, a varicelliform eruption follows shortly after herpes zoster, and rarely there is a secondary eruption of zoster after chickenpox.
Laboratory tests—such as visualization of virus by electron micrograph (EM); virus isolation in cell cultures; demonstration of viral antigen in smears using direct fluorescent antibody (DFA) of viral DNA by PCR, or of a rise in serum antibodies—are not routinely required for diagnosis, but are useful in complicated cases and in epidemiological studies. In the vaccine era, viral strain identification may be needed (e.g. to document whether herpes zoster in a vaccine recipient is due to vaccine or wild virus). Several antibody assays are now commercially available, but they are not sensitive enough to be used for post-immunization testing of immunity. Multinucleated giant cells may be detected in Giemsa-stained (Tzanck smear) scrapings from the base of a lesion; these are not found in vaccinia lesions, but do occur in herpes simplex lesions. They are not specific for varicella infections, and the availability of rapid direct fluorescent antibody testing has limited their value for clinical testing.
Human (alpha) herpesvirus 3 (varicella-zoster virus, VZV), a member of the Herpesvirus group.
Worldwide. Infection with human (alpha) herpesvirus 3 is nearly universal. In temperate climates, at least 90% of the population has had chickenpox by age 15, and at least 95% by young adulthood. In temperate zones, chickenpox occurs most frequently in winter and early spring. The epidemiology of varicella in tropical countries differs from temperate climates, with a higher proportion of cases occurring among adults. Herpes zoster occurrence has been described most commonly in developed countries where Zoster occurs more commonly in older people 50 years of age.
Mode of transmission
Person-to-person by direct contact, droplet or airborne spread of vesicle fluid, or secretions of the respiratory tract of chickenpox cases, or of vesicle fluid of patients with herpes zoster; indirectly through articles freshly soiled by discharges from vesicles and mucous membranes of infected people. In contrast to vaccinia and variola, scabs from varicella lesions are not infective. Varicella in unvaccinated persons is one of the most readily communicable of diseases, especially in the early stages of the eruption; secondary attack rates in susceptible household contacts range from 61% to 100%. Herpes zoster has a lower rate of transmission: data from a household study showed that 20% of those who are varicella seronegative develop varicella when they are in contact with persons who have herpes zoster.
10–21 days; commonly 14–16 days; may be prolonged as long as 28 days after passive immunization against varicella (see 9A2), and may be shortened in the immunodeficient.
Period of communicability
As long as 5 days, but usually 1–2 days before onset of rash, and continuing until all lesions are crusted (usually about 5 days). Contagiousness may be prolonged in patients with altered immunity. The secondary attack rate among susceptible siblings is 60%–100%. Patients with herpes zoster may be infectious for a week after the appearance of vesiculopustular lesions. Susceptible individuals should be considered infectious for 10–21 days following exposure.
Susceptibility to varicella is universal among those not previously infected or vaccinated; ordinarily a more severe disease of adults than of children. Infection usually confers long immunity; second attacks are rare in immunocompetent persons but have been documented; subclinical reinfection is common. Viral infection remains latent; disease may recur years later as herpes zoster. Herpes zoster occurs in about 15% of older adults, and rarely in children.
Neonates whose mothers are not immune and patients with leukemia may suffer severe, prolonged or fatal chickenpox. Adults with cancer—especially of lymphoid tissue, with or without steroid therapy—immunodeficient patients and those on immunosuppressive therapy may have an increased frequency of severe herpes zoster, both localized and disseminated.
Methods of control
- Preventive measures:
- Live attenuated varicella virus vaccines are licensed throughout the world. A quadrivalent vaccine (MMRV) has been licensed for use in healthy children aged 12 months to 12 years. In industrialized countries, a first dose is recommended for routine immunization of children aged 12 to 18 months and a second dose is routinely recommended at 4–6 years of age for children up to 12 years who have not had varicella. The second dose may be given at early as 3 months after the first. One dose of the vaccine has a cumulative preventive efficacy estimated at 70%–90% in children followed for up to 10 years. A second dose catch-up vaccination is recommended for persons who previously received only one dose. If an immunized person does get “break-through varicella,” it is usually a mild case with fewer lesions (up to 50, frequently not vesicular), mild or no fever, and of shorter duration. If administered within 3 days of exposure, varicella vaccine is likely to prevent or at least modify disease in a case contact. The protection against herpes zoster induced by varicella vaccine, administered either in childhood or in adult populations, is not yet sufficiently documented in the general population; however, postlicensure data, mostly among immunocompromised children, indicate that children immunized with varicella vaccine seem to have a lower risk and milder herpes zoster than children who had natural varicella infection. Large scale vaccination of children and older adults may have an important impact on the incidence of herpes zoster and post herpetic neuralgia.
For persons ≥13 years of age, two doses of varicella vaccine 4–8 weeks apart are also recommended for susceptible persons without evidence of immunity. The criteria for evidence of VZV immunity were revised in 2006. People born after 1980 with a history of a typical disease are considered immune and exempt from varicella vaccination, if their history is verified by a health care provider; however, for those with a history of atypical disease, a physician or a designee assessment is recommended in addition to evidence of a typical or a lab-confirmed varicella case.
Vaccination is offered without confirmation of seronegativity. Priority groups for adult immunization include close contacts of persons at high risk for serious complications; persons who live or work in environments where transmission of varicella is likely (e.g. teachers of young children, day care employees, residents and staff in institutional settings) or can occur (e.g. college students, inmates and staff members of correctional institutions and military personnel); non-pregnant women of childbearing age; adolescents and adults in households with children; and international travelers.
In immunocompromised persons, including persons with advanced HIV infection, varicella vaccination is currently contraindicated. However, varicella vaccine should be considered for HIV-infected children with CD4+ T-lymphocyte counts ≥200 cells/μL (≥15%). Varicella vaccine may also be considered for HIV-infected adolescents and adults with CD4+ counts ≥200 cells/μL. Other contraindications for varicella vaccination include a history of anaphylactic reactions to any component of the vaccine (including neomycin), pregnancy (theoretical risk to the fetus—pregnancy should be avoided for 4 weeks following vaccination), ongoing severe illness, and advanced immune disorders.
Except for patients with acute lymphatic leukemia in stable remission, ongoing treatment with systemic steroids (adults 20 mg/day, children 1 mg/kg/day) is considered a contraindication for varicella vaccination. However, persons who have discontinued corticosteroid therapy for at least a month can be vaccinated. Varicella vaccine may be administered to people on inhaled, nasal, and topical steroids. A history of congenital immune disorders in close family members is a relative contraindication. Routine childhood immunization against varicella may be considered in countries where the disease is a public health and socioeconomic problem, where immunization is affordable, and where sustained high vaccine coverage (85%–90%) can be achieved. Persons over 13 years of age require 2 doses of vaccine 4–8 weeks apart.
A mild varicella-like rash at the site of vaccine injection or at distant sites has been observed in 2%–4% of children and about 5% of adults. Rare occasions of mild herpes zoster following vaccination show that the currently used vaccine strains may induce latency, with the subsequent risk of reactivation, although the rate seems to be lower than after natural disease. Duration of immunity after one dose is unknown, but antibodies have persisted for at least 10 years; persistence of antibody has occurred in the presence of circulating wild virus. At time of writing in early 2008, one study has found that incidence and severity of breakthrough varicella increased with time since vaccination, while another study did not find a loss of vaccine effectiveness over time.
- Protect high-risk individuals who cannot be immunized—e.g. non-immune neonates and the immunodeficient—from exposure, by immunizing household or other close contacts.
- Varicella-zoster immune globulin (VZIG or VariZIG), prepared from the plasma of normal blood donors with high VZV antibody titer, effectively modifies or prevents disease if given within 96 hours after exposure (see 9B5).
A herpes zoster vaccine for older adults has been approved and recommended for use in the USA for healthy persons aged 60 years or older.
- Control of patient, contacts and the immediate environment:
- Report to local health authority: In many countries, not a reportable disease; varicella-related deaths became nationally notifiable in the USA on January 1, 1999 and cases became nationally notifiable on January 2005; Class 3 (see Reporting).
- Isolation: Exclude children from school, medical offices, emergency rooms or public places until vesicles become dry and crusted, usually after 5 days in non-immunized children and 1–4 days with breakthrough varicella in immunized children; exclude infected adults from workplace and avoid contact with susceptibles. In hospital, observe strict isolation, because of the risk of varicella in susceptible immunocompromised patients.
- Concurrent disinfection: Articles soiled by discharges from the nose and throat.
- Quarantine: Usually none. However, in places where susceptible children with known recent exposure must remain for medical reasons, the risk of spread to steroid-treated or immunodeficient patients may justify quarantine of known contacts for at least 10–21 days after exposure (up to 28 days if VZIG was given).
- Protection of contacts: Varicella vaccine is effective in preventing illness or modifying severity if used within 3 days, and possibly up to 5 days, of exposure; it is recommended for susceptible persons following exposure to varicella.
VZIG within 96 hours of exposure may prevent or modify disease in susceptible close contacts of cases. It is available in several countries for high-risk persons exposed to chickenpox, and indicated for newborns of mothers who develop chickenpox within 5 days prior to or 2 days after delivery. There is no assurance that administering VZIG to a pregnant woman will prevent congenital malformations in the fetus, but it may modify varicella severity in the pregnant woman.
Antiviral drugs such as acyclovir appear useful in preventing or modifying varicella in exposed individuals if given within a week of exposure. Most studies have been carried out in immunocompromised children, with few data available for healthy children. A dose of 80 mg/kg/day in 4 divided doses has been used, but no regimen is as yet generally recommended for this purpose.
- Investigation of contacts and source of infection: The source of infection may be a case of varicella or herpes zoster. All contacts, especially if ineligible for post-exposure immunization, should be evaluated promptly for administration of VZIG. Infectious patients should be isolated until all lesions are crusted; exposed susceptibles eligible for immunization should receive vaccine immediately to control or prevent an outbreak.
- Specific treatment: Antiviral therapy is moderately effective in treating varicella and herpes zoster infections: acyclovir, valacyclovir or famcyclovir are considered the agents of choice for treatment of varicella. These drugs, as well as brivudin, have been shown to help shorten the duration of the infection and possibly post-herpetic neuralgia in herpes zoster; they may shorten the duration of symptoms and reduce acute and chronic pain, especially if administered within 48–72 hours of rash onset. In case of resistance, foscarnet is considered the second line drug. For the treatment of post-herpetic neuralgia, amptryptilin, gabapentin, pregabalin or carbamazepine are recommended.
- Epidemic measures: Outbreaks of varicella are common in schools and other institutional settings; they may be protracted, disruptive and associated with complications. Infectious cases should be isolated, and susceptible contacts immunized promptly (or referred to their health care provider for immunization). Persons ineligible for immunization, such as susceptible pregnant females and those at high risk for severe disease (as above), should be evaluated immediately for administration of VZIG.
- Disaster implications: Outbreaks of chickenpox may occur among children crowded together in emergency housing situations.
- International measures: See C.
[CCDM19: A. Jumaan, D. Lavanchy]
[CCDM18: D. Lavanchy]
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