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Varicella-Zoster Virus
Varicella-zoster virus (VZV) causes primary, latent, and reactivation infections. The primary infection is manifested as varicella (chickenpox) and results in establishment of a lifelong latent infection of sensory ganglionic neurons. Reactivation of the latent infection causes herpes zoster (shingles). Although often a mild illness of childhood, varicella can cause substantial morbidity and mortality in otherwise healthy children. Morbidity and mortality are higher in immunocompetent infants, adolescents, and adults as well as in immunocompromised persons. Varicella predisposes to severe group A streptococcus and staphylococcus aureus infections. A clinically modified disease can occur among vaccinated persons (breakthrough varicella), usually with milder presentation. Varicella and herpes zoster can be treated with antiviral drugs. Primary clinical disease can be prevented by immunization with live-attenuated varicella vaccine. Two herpes zoster vaccines are available for persons 50 yr of age and older to boost their immunity to VZV and prevent herpes zoster and its major complication, painful postherpetic neuralgia. One is a recombinant subunit (non-live) adjuvanted vaccine, and the other is a live vaccine that contains the same VZV strain used in the varicella vaccine but with a higher potency.
Etiology
VZV is a neurotropic human herpesvirus with similarities to herpes simplex virus. VZV enveloped viruses contain double-stranded DNA genomes that encode 71 proteins, including proteins that are targets of cellular and humoral immunity.
Epidemiology
Before the introduction of varicella vaccine in 1995, varicella was an almost universal communicable infection of childhood in the United States. Most children were infected by 10 yr of age, with fewer than 5% of adults remaining susceptible. This pattern of infection at younger ages remains characteristic in all countries in temperate climates. In contrast, in tropical areas, children acquire varicella at older ages and a higher proportion of young adults remain susceptible, leading to a higher proportion of cases occurring among adults. In the United States, prior to introduction of varicella vaccination, annual varicella epidemics occurred in winter and spring, and there were about 4 million cases of varicella, 11,000-15,000 hospitalizations, and 100-150 deaths every year. Varicella is a more serious disease in young infants, adults, and immunocompromised persons, in whom there are higher rates of complications and deaths than in healthy children. Within households, transmission of VZV to susceptible individuals occurs at a rate of 65–86%; more casual contact, such as occurs in a school classroom, is associated with lower attack rates among susceptible children. Persons with varicella may be contagious 24-48 hr before the rash is evident and until vesicles are crusted, usually 3-7 days after onset of rash, consistent with evidence that VZV is spread by aerosolization of virus in cutaneous lesions; spread from oropharyngeal secretions may occur but to a much lesser extent. Susceptible persons may also acquire varicella after close, direct contact with adults or children who have herpes zoster, again via aerosolization of virus in skin lesions.
Since implementation of the varicella vaccination program in 1996, there have been substantial declines in varicella morbidity and mortality in the United States. By 2006, prior to implementation of the 2-dose program, 1-dose vaccination coverage had reached 90% and varicella incidence had declined 90–91% since 1995 in sites where active surveillance was being conducted; varicella-related hospitalizations had declined 84% from prevaccine years. Varicella-related deaths decreased by 88% from 1990-1994 to 2005-2007; in persons younger than 20 yr of age there was a 97% decline in deaths. Declines in morbidity and mortality were seen in all age groups, including infants younger than 12 mo of age who were not eligible for vaccination, indicating protection from exposure by indirect vaccination effects. Although the age-specific incidence has declined in all age groups, the median age at infection has increased, and cases occur predominantly in children in upper elementary school rather than in the preschool years. This change in varicella epidemiology highlights the importance of offering vaccine to every susceptible child, adolescent, and adult. The continued occurrence of breakthrough infections and of outbreaks in settings with high 1-dose varicella vaccine coverage, together with the evidence that 1 dose is only approximately 85% effective against all varicella, prompted adoption in 2006 of a routine 2-dose childhood varicella vaccination program with catch-up vaccination of all individuals without evidence of immunity. Between 2006 and 2014, varicella incidence declined further by approximately 85% and fewer outbreaks were reported; varicella-related hospitalizations too declined 38% during the 2-dose period (through 2012). Overall, from prevaccine years varicella incidence declined by 97% and hospitalizations by 93% through 2014 and 2012, respectively.
Herpes zoster is caused by the reactivation of latent VZV. It is not common in childhood and shows no seasonal variation in incidence. Zoster is not caused by exposure to a patient with varicella; in fact, exposures to varicella boost the cell-mediated immune response to VZV in individuals with prior infection, decreasing the likelihood of reactivation of latent virus. The lifetime risk for herpes zoster for individuals with a history of varicella is at least 30%, with 75% of cases occurring after 45 yr of age. Herpes zoster is unusual in healthy children younger than 10 yr of age, with the exception of those infected with VZV in utero or in the 1st yr of life, who have an increased risk for development of zoster in the 1st few yr of life. Herpes zoster in otherwise healthy children tends to be milder than herpes zoster in adults, is less frequently associated with acute pain, and is generally not associated with postherpetic neuralgia. In children receiving immunosuppressive therapy for malignancy or other diseases and in those who have HIV infection, herpes zoster occurs more frequently, occasionally multiple times, and may be severe. The attenuated VZV in the varicella vaccine can establish latent infection and reactivate as herpes zoster. However, the risk for development of subsequent herpes zoster is lower after vaccination than after natural VZV infection among both healthy and immunocompromised children. Although the Oka vaccine type VZV is attenuated, the severity of zoster caused by the Oka strain seems to be similar to that caused by the natural or wild type VZV; some reports indicated milder clinical features among vaccine recipients but without being statistically significant. Vaccinated children who do develop zoster may have disease resulting from either vaccine or wild-type VZV, due to breakthrough varicella or subclinical infection of some vaccinees with wild-type VZV occurring at some point after immunization.
Pathogenesis
Primary infection (varicella) results from inoculation of the virus onto the mucosa of the upper respiratory tract and tonsillar lymphoid tissue. During the early part of the 10-21 day incubation period, virus replicates in the local lymphoid tissue and spreads to T lymphocytes, causing a viremia that delivers the virus to skin where innate immunity controls VZV replication for some days. After innate immunity is overcome in skin, widespread cutaneous lesions develop as the incubation period ends. Adaptive host immune responses, especially cellular immunity, limit viral replication and lead to recovery from infection. In the immunocompromised child, the failure of adaptive immunity, especially cellular immune responses, results in continued viral replication that may lead to prolonged and/or disseminated infection with resultant complications of infection in the lungs, liver, brain, and other organs.
Latent infection develops during the incubation period or the disease itself. VZV is transported in a retrograde manner through sensory axons to the dorsal root ganglia throughout the spinal cord and to cranial nerve ganglia. Latency may also develop from viremia, infecting spinal and cranial nerve ganglia as well autonomic ganglia which do not project to the skin, including the enteric nervous system of the intestine. Latency of VZV occurs only in ganglionic neurons. Subsequent reactivation of latent VZV causes herpes zoster, usually manifested by a vesicular rash that is unilateral and dermatomal in distribution. Reactivation of VZV may also occur without a rash; examples are unilateral dermatomal pain without rash ( zoster sine herpete ), aseptic meningitis, and gastrointestinal illness (enteric zoster). During herpes zoster, necrotic changes may be produced in the neurons and surrounding satellite cells in associated ganglia. The skin lesions of varicella and herpes zoster have identical histopathology, and infectious VZV is present in both. Varicella elicits humoral and cell-mediated immunity that is highly protective against symptomatic reinfection. Suppression of cell-mediated immunity to VZV correlates with an increased risk for VZV reactivation as herpes zoster.
Clinical Manifestations
Varicella is an acute febrile rash illness that was common in children in the United States before the universal childhood vaccination program. It has variable severity but is usually self-limited. It may be associated with severe complications, including bacterial superinfection, especially with staphylococci and group A streptococci, pneumonia, encephalitis, bleeding disorders, congenital infection, and life-threatening perinatal infection. Herpes zoster is not common in children and typically causes localized cutaneous symptoms, but may disseminate in immunocompromised patients.
Varicella in Unvaccinated Individuals
The illness usually begins 14-16 days after exposure, although the incubation period can range from 10 to 21 days. Subclinical varicella is rare; almost all exposed, susceptible persons experience a rash, albeit so mild in some cases that it may go unnoticed. Prodromal symptoms may be present, particularly in older children and adults. Fever, malaise, anorexia, headache, and occasionally mild abdominal pain may occur 24-48 hr before the rash appears. Temperature elevation is usually 37.8-38.9°C (100-102°F) but may be as high as 41.1°C (106°F); fever and other systemic symptoms usually resolve within 2-4 days after the onset of the rash.
Varicella lesions often appear first on the scalp, face, or trunk. The initial exanthem consists of intensely pruritic erythematous macules that evolve through the papular stage to form clear, fluid-filled vesicles. Clouding and umbilication of the lesions begin in 24-48 hr. While the initial lesions are crusting, new crops form on the trunk and then the extremities; the simultaneous presence of lesions in various stages of evolution is characteristic of varicella ( Fig. 280.1 ). The distribution of the rash is predominantly central or centripetal, with the greatest concentration on the trunk and proximally on the extremities. Ulcerative lesions involving the mucosa of the oropharynx and vagina are also common; many children have vesicular lesions on the eyelids and conjunctivae, but corneal involvement and serious ocular disease are rare. The average number of varicella lesions is about 300, but healthy children may have fewer than 10 to more than 1,500 lesions. In cases resulting from secondary household spread and in older children, more lesions usually occur, and new crops of lesions may continue to develop for more than 7 days. The exanthem may be much more extensive in children with skin disorders, such as eczema or recent sunburn. Hypopigmentation or hyperpigmentation of lesion sites persists for days to weeks in some children, but severe scarring is unusual unless the lesions were secondarily infected.
The differential diagnosis of varicella includes vesicular rashes caused by other infectious agents, such as herpes simplex virus, enterovirus, monkey pox, rickettsial pox, and S. aureus; drug reactions; disseminated herpes zoster; contact dermatitis; and insect bites (especially for breakthrough varicella). Severe varicella was the most common illness confused with smallpox before the eradication of smallpox.
Varicelliform Rashes in Vaccinated Individuals
Varicelliform rashes that occur after vaccination could be a result of wild-type VZV, vaccine strain VZV, or other etiologies (e.g., insect bites, coxsackievirus). During days 0-42 after vaccination, the likelihood of rash from wild-type or vaccine strain VZV varies depending on the stage of a country's vaccination program. In the early stages of a vaccine program, rash within 1-2 wk is still most commonly caused by wild-type VZV, reflecting exposure to varicella before vaccination could provide protection. Rash occurring 14-42 days after vaccination is a result of either wild-type or vaccine strains, reflecting exposure and infection before protection from vaccination or an adverse event of vaccination (vaccine-associated rash), respectively. As wild-type varicella continues to decline as a consequence of the vaccination program, wild-type VZV circulation will also decline and rashes in the interval 0-42 days after vaccination will be less commonly caused by wild-type VZV. Spread of vaccine type VZV from a vaccinee with skin lesions has occurred, but is rare. The resulting illness in contacts is either asymptomatic or extremely mild with only a few vesicular lesions. Clinical reversion of the vaccine virus to virulence has not been described.
Breakthrough varicella is disease that occurs in a person vaccinated more than 42 days before rash onset and is caused by wild-type virus . One dose of varicella vaccine is 98% effective in preventing moderate and severe varicella and is 82% (95% confidence interval [CI]: 79–85%; range: 44–100%) effective in preventing all disease after exposure to wild-type VZV. This means that after close exposure to VZV, as may occur in a household or an outbreak setting in a school or daycare center, about 1 of every 5 children who received 1 dose of vaccine may experience breakthrough varicella. Exposure to VZV may also result in asymptomatic infection in the previously immunized child. The rash in breakthrough disease is frequently atypical and predominantly maculopapular, and vesicles are seen less commonly. The illness is most commonly mild with <50 lesions, shorter duration of rash, fewer complications, and little or no fever. However, approximately 25–30% of breakthrough cases in vaccines who received 1 dose are not mild, with clinical features more similar to those of wild-type infection. Breakthrough cases are overall less contagious than wild-type infections within household settings, but contagiousness varies proportionally with the number of lesions; typical breakthrough cases (<50 lesions) is about one-third as contagious as disease in unvaccinated cases, whereas breakthrough cases with ≥50 lesions are as contagious as wild-type cases. Consequently, children with breakthrough disease should be considered potentially infectious and excluded from school until lesions have crusted or, if there are no vesicles present, until no new lesions are occurring. Transmission has been documented to occur from breakthrough cases in household, childcare, and school settings.
Two doses of varicella vaccine provide better protection than a 1-dose schedule. One clinical trial estimated the 2-dose vaccine effectiveness for preventing all disease at 98%; the estimate is 92% (95% CI: 88–95%; range: 84–98%) in conditions of everyday clinical practice. Institution of 2 doses routinely in the United States substantially reduced the school outbreaks that were occurring among children who had received only 1 dose. Breakthrough cases have been reported among 2-dose vaccines; however, recipients of 2 doses of varicella vaccine are less likely to have breakthrough disease than those who received 1 dose. Additionally, data suggest that breakthrough varicella may be further attenuated among 2-dose vaccine recipients.
Neonatal Varicella
Mortality is particularly high in neonates born to susceptible mothers who contract varicella around the time of delivery. Infants whose mothers demonstrate varicella in the period from 5 days prior to delivery to 2 days afterward are at high risk for severe varicella. These infants acquire the infection transplacentally as a result of maternal viremia, which may occur up to 48 hr prior to onset of maternal rash. The infant's rash usually occurs toward the end of the 1st wk to the early part of the 2nd wk of life (although it may be as soon as 2 days). Because the mother has not yet developed a significant antibody response, the infant receives a large dose of virus without the moderating effect of maternal anti-VZV antibody. If the mother demonstrates varicella more than 5 days prior to delivery, she still may pass virus to the soon-to-be-born child, but infection is attenuated because of transmission of maternal VZV-specific antibody across the placenta. This moderating effect of maternal antibody is present if delivery occurs after about 30 wk of gestation, when maternal immunoglobulin (Ig) G is able to cross the placenta in significant amounts. The recommendations for use of human varicella-zoster immunoglobulin (VZIG) differ based on when the infant is exposed to varicella. Newborns whose mothers develop varicella during the period of 5 days before to 2 days after delivery should receive VZIG as soon as possible after birth. Although neonatal varicella may occur in about half of these infants despite administration of VZIG, it is milder than in the absence of VZIG administration. All premature infants born < 28 wk of gestation to a mother with active varicella at delivery (even if the maternal rash has been present for >1 wk) should receive VZIG. If VZIG is not available, intravenous immunoglobulin (IVIG) may provide some protection, although varicella-specific antibody titers may vary from lot to lot. Because perinatally acquired varicella may be life threatening, the infant should usually be treated with acyclovir (10 mg/kg every 8 hr IV) when lesions develop. Neonatal varicella can also follow a postpartum exposure of an infant delivered to a mother who was susceptible to VZV, although the frequency of complications declines rapidly in the weeks after birth. Recommendations for VZIG administration for these infants are presented in the postexposure prophylaxis section. Neonates with community-acquired varicella who experience severe varicella, especially those who have a complication such as pneumonia, hepatitis, or encephalitis, should also receive treatment with intravenous acyclovir (10 mg/kg every 8 hr). Infants with neonatal varicella who receive prompt antiviral therapy have an excellent prognosis.
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