Varicella-Zoster Virus Infections

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Chapter 245 Varicella-Zoster Virus Infections

Varicella-zoster virus (VZV) causes primary, latent, and recurrent infections. The primary infection is manifested as varicella (chickenpox) and results in establishment of a lifelong latent infection of sensory ganglion neurons. Reactivation of the latent infection causes herpes zoster (shingles). Although often a mild illness of childhood, chickenpox can cause substantial morbidity and mortality in otherwise healthy children; it increases morbidity and mortality in immunocompetent infants, adolescents, adults, as well as in immunocompromised persons; it predisposes to severe group A streptococcus and Staphylococcus aureus infections. Varicella and herpes zoster can be treated with antiviral drugs. Primary clinical disease can be prevented by immunization with live-attenuated VZV vaccine (varicella vaccine). Herpes zoster vaccine (zoster vaccine), which contains the same VZV strain used in the varicella vaccine but with a higher potency, is recommended for persons ≥60 yr of age to boost their immunity to VZV in order to reduce the rates of herpes zoster and its major complication, painful postherpetic neuralgia.


Before the introduction of varicella vaccine in 1995, varicella was an almost universal communicable infection of childhood in the USA. Most children were infected by 15 yr of age, with fewer than 5% of adults remaining susceptible. This pattern of infection at younger ages is characteristic in all countries in temperate climates. In tropical areas, varicella occurs among older persons, with many cases occurring among adults. In the USA, annual varicella epidemics occurred in winter and spring, accounting for about 4 million cases, 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. Patients with varicella are contagious 24-48 hr before the rash is evident and until vesicles are crusted, usually 3-7 days after onset of rash. Susceptible persons may also acquire varicella after close, direct contact with adults or children who have herpes zoster.

Since implementation of the 1-dose varicella vaccination program in 1995, there have been substantial declines in varicella morbidity and mortality in the USA. By 2005, vaccination coverage had increased to 90% and varicella cases had declined 90-91% from those in 1995 in sites where active surveillance was being conducted. By 2002, varicella-related hospitalizations had declined 88% from 1994 and 1995. Deaths had decreased by 87% overall from 1990-1994 to 2003-2005; in persons age <20 yr there was a 96% decline in deaths. Declines in morbidity and mortality were seen in all age groups, including infants <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 now are occurring 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, though most commonly mild, and of outbreaks in settings with high 1-dose varicella vaccine coverage prompted adoption in 2006 of a routine 2-dose childhood varicella vaccination program for all individuals without evidence of immunity, regardless of age.

Herpes zoster is due to the reactivation of latent VZV. It is uncommon in childhood and shows no seasonal variation in incidence. Zoster is not caused by exposure to a patient with varicella; 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 10-20%, with 75% of cases occurring after 45 yr of age. Herpes zoster is very rare in healthy children <10 yr of age, with the exception of infants who were infected in utero or in the 1st year of life, who have an increased risk for development of zoster in the first years of life. Herpes zoster in children tends to be milder than disease in adults and is less frequently associated with postherpetic neuralgia. Herpes zoster occurs more frequently, occasionally multiple times, and may be severe in children receiving immunosuppressive therapy for malignancy or other diseases and in those who have HIV infection. The zoster vaccine, recommended for adults 60 yr of age and older, reduces both the frequency of herpes zoster and its most frequent complication, postherpetic neuralgia.

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 vaccine than after natural VZV infection among immunocompromised children. Post-licensure data also suggest the same trend in healthy vaccinees.


VZV is transmitted in oropharyngeal secretions and in the fluid of skin lesions either by airborne spread or through direct contact. 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- to 21-day incubation period, virus replicates in the local lymphoid tissue, and then a brief subclinical viremia spreads the virus to the reticuloendothelial system. Widespread cutaneous lesions occur during a second viremic phase that lasts 3-7 days. Peripheral blood mononuclear cells carry infectious virus, generating new crops of vesicles during this period of viremia. VZV is also transported back to the mucosa of the upper respiratory tract and oropharynx during the late incubation period, permitting spread to susceptible contacts 1-2 days before the appearance of rash. Host immune responses limit viral replication and facilitate recovery from infection. In the immunocompromised child, the failure of immune responses, especially cell-mediated immune responses, results in continued viral replication that may lead to disseminated infection with resultant complications in the lungs, liver, brain, and other organs. Virus is transported in a retrograde manner through sensory axons to the dorsal root ganglia throughout the spinal cord, where the virus establishes latent infection in the neurons and satellite cells associated with these axons. Subsequent reactivation of latent virus causes herpes zoster, a vesicular rash that usually is dermatomal in distribution. During herpes zoster, necrotic changes may be produced in the 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 USA before the universal childhood vaccination program. It has variable severity but is usually self limited. It may be associated with severe complications, including staphylococcal and streptococcal superinfection, pneumonia, encephalitis, bleeding disorders, congenital infection, and life-threatening perinatal infection. Herpes zoster, uncommon in children, causes localized cutaneous symptoms but may disseminate in immunocompromised patients.


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. Prodromal symptoms may be present, particularly in older children and adults. Fever, malaise, anorexia, headache, and occasionally mild abdominal pain may occur 24-48 hours before the rash appears. Temperature elevation is usually moderate, usually 100-102°F, but may be as high as 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. 245-1). The distribution of the rash is predominantly central or centripetal, in contrast to that in smallpox, which is more prominent on the face and distal extremities. Ulcerative lesions involving the mucosa of 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 a longer time. 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. Severe varicella was the most common illness confused with smallpox before the eradication of smallpox.

Varicella in Vaccinated Individuals (“Breakthrough Varicella”)

One dose of varicella vaccine is >97% effective in preventing severe varicella and is 85% (median; 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 receiving 1-dose vaccination children may experience breakthrough varicella. Exposure to VZV may also result in asymptomatic infection in the previously immunized child. Breakthrough disease is varicella that occurs in a person vaccinated >42 days before rash onset and is caused by wild-type VZV. In the early stages of the varicella vaccination program, rash occurring within the 1st 2 weeks after vaccination was most commonly wild-type VZV, reflecting exposure to varicella before vaccination could provide protection. Rash occurring 14-42 days after vaccination was due to either wild or vaccine strains, reflecting breakthrough varicella or vaccine-associated rash, respectively. As varicella disease continues to decline, rashes in the interval 0-42 days after vaccination will be less commonly caused by wild-type VZV. The rash in breakthrough disease is frequently atypical and predominantly maculopapular, vesicles are seen less commonly, and 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 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) are about a third as contagious as unvaccinated cases, whereas breakthrough cases with ≥50 lesions are as contagious as wild-type cases. Therefore, 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, child-care, and school settings.

Fewer studies have evaluated the performance of the 2-dose varicella vaccine regimen. One clinical trial estimated the 2-dose vaccine effectiveness for preventing all disease at 98%. Breakthrough cases have been reported among 2-dose vaccinees, although recipients of 2 doses of varicella vaccine are less likely to have breakthrough disease than those receiving one dose.

Progressive Varicella

Progressive varicella, with visceral organ involvement, coagulopathy, severe hemorrhage, and continued vesicular lesion development, is a severe complication of primary VZV infection. Severe abdominal pain, which may reflect involvement of mesenteric lymph nodes or the liver, or the appearance of hemorrhagic vesicles in otherwise healthy adolescents and adults, immunocompromised children, pregnant women, and newborns, may herald severe disease. Although rare in healthy children, the risk for progressive varicella is highest in children with congenital cellular immune deficiency disorders and those with malignancy, particularly if chemotherapy was given during the incubation period and the absolute lymphocyte count is <500 cells/mm3. The mortality rate for children who acquired varicella while undergoing treatment for malignancy and who were not treated with antiviral therapy approaches 7%; varicella-related deaths usually occur within 3 days after the diagnosis of varicella pneumonia. Children who acquire varicella after organ transplantation are also at risk for progressive VZV infection. Children undergoing long-term, low-dose systemic corticosteroid therapy are not considered to be at higher risk for severe varicella, but progressive varicella does occur in patients receiving high-dose corticosteroids and has been reported in patients receiving inhaled corticosteroids as well as in asthmatic persons receiving multiple short courses of systemic corticosteroid therapy. Unusual clinical findings of varicella, including lesions that develop a unique hyperkeratotic appearance and continued new lesion formation for weeks or months, have been described in children with untreated, late stage HIV infection. Immunization of HIV-infected children who have a CD4+ T-lymphocyte value ≥15% as well as children with leukemia and solid organ tumors who are in remission and whose chemotherapy can be interrupted for 2 wk around the time of immunization or has been terminated has reduced this problem. Since the advent of the universal immunization program, many children who would become immunocompromised later in life because of disease or treatment are protected before the immunosuppression occurs; also, due to reductions in varicella incidence, immunocompromised children are less likely to be exposed to varicella.

Neonatal Varicella

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