Martin G. Myers Jane F. Seward Philip S. LaRussa

Transcription

1 Martin G. Myers Jane F. Seward Philip S. LaRussa 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 causes increased morbidity and mortality in adolescents, adults, and immunocompromised persons, and predisposes to severe group A streptococcus and Staphylococcus aureus infections. Chickenpox and herpes zoster, if needed, can be treated with antiviral drugs. Initial infection can be prevented by immunization with live-attenuated VZV vaccine and there will soon be another VZV vaccine for older individuals intended to boost their immunity to VZV in order to reduce the rates of herpes zoster and its major complication, painful postherpetic neuralgia. ETIOLOGY. VZV is a neurotropic human herpesvirus with similarities to herpes simplex virus, which is also α- herpesvirus. These viruses are enveloped with double-stranded DNA genomes that encode more than 70 proteins, including proteins that are targets of cellular and humoral immunity. EPIDEMIOLOGY. Prior to the introduction of vaccine in 1995, varicella was an almost universal communicable infection of childhood in the United States. Most children were infected by 15 yr of age, with fewer than 5% of adults remaining susceptible. Annual varicella epidemics occurred in winter and spring, accounting for about 4 million cases, 11,000 15,000 hospitalizations, and deaths every year. Varicella is a more serious disease with higher rates of complications and deaths among infants, adults, and immunocompromised persons. 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 from 24 to 48 hr before the rash appears and until vesicles are crusted, usually 3 7 days after onset of rash. Susceptible children may also acquire varicella after close, direct contact with adults or children who have herpes zoster. Since implementation of the varicella vaccination program, there have been substantial declines in varicella morbidity and mortality. By 2000, varicella cases had declined 71% to 84% in sites where active surveillance was being conducted; further declines have occurred through By 2001, national varicella hospitalizations had declined 75% compared with hospitalizations from 1993 to 1995, and deaths had decreased by 74% or more among all persons 50 yr of age. Morbidity and mortality declined the most among children 1 4 yr of age (>92% decline in deaths) followed by children 5 9 yr of age (89% decline in deaths). However, declines were seen in all age groups, including infants <12 mo of age who are being protected from exposure by indirect vaccination effects. The change in varicella epidemiology with cases

2 now occurring predominantly in children in upper elementary school rather than in the preschool years highlights the importance of offering vaccine to every susceptible child, adolescent, and adult. The continued occurrence of breakthrough infections, though most commonly mild, has stimulated discussions regarding the possible need for a 2nd dose of vaccine for children. Herpes zoster, because it is due to the reactivation of latent VZV, is uncommon in childhood and shows no seasonal variation in incidence. The lifetime risk for herpes zoster for individuals with a history of varicella is 10 15%, with 75% of cases occurring after 45 yr of age. Herpes zoster is very rare in healthy children <10 yr of age except for infants who were infected in utero or in the 1st year of life; herpes zoster in children tends to be milder than disease in adults and is less frequently associated with postherpetic neuralgia. However, 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. An investigational live-attenuated VZV vaccine given to older adults reduces both the frequency of herpes zoster and its most frequent complication, postherpetic neuralgia. PATHOGENESIS. VZV is transmitted in respiratory 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 day incubation period, virus replicates in the local lymphoid tissue followed by a brief subclinical viremia that spreads the virus to the reticuloendothelial system. Widespread cutaneous lesions occur during a 2nd 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 upper respiratory mucosal sites during the late incubation period, permitting spread to susceptible contacts 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 result in 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 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 prior to the universal childhood vaccination program. It has variable severity but is usually self-limited. It may be associated with severe complications, including bacterial superinfection, pneumonia, encephalitis, bleeding disorders, congenital

3 infection, and life-threatening perinatal infection. Herpes zoster, uncommon in children, causes localized cutaneous symptoms, but may disseminate in immunocompromised patients. Varicella. The illness usually begins 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 hr before the rash appears. Temperature elevation is usually moderate, usually from 100 to 102 F but may be as high as 106 F; fever and other systemic symptoms persist during the 1st 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 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 ). The distribution of the rash is predominantly central or centripetal, in contrast to smallpox, where the rash 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 is 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 period of 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.

4 The differential diagnosis of varicella includes vesicular rashes caused by other infectious agents, such as herpes simplex virus, enterovirus, monkey pox, rickettsial pox, or S. aureus; drug reactions; contact dermatitis; and insect bites. Severe varicella was the most common illness confused with smallpox before the eradication of smallpox. Because of concerns about smallpox as a potential bioterrorism threat, both smallpox and smallpox vaccine rashes must be considered again in the differential diagnosis of severe chickenpox. Varicella in Vaccinated Individuals ( Breakthrough Varicella ). Vaccine is >95% effective in preventing severe varicella and is most commonly about 80% (range %) effective at preventing all disease after exposure to wild-type VZV. This means that following close exposure to VZV, as may occur in a household or an outbreak setting in a school or daycare center, 1 of every 5 vaccinated children may develop breakthrough varicella. Exposure to VZV may also result in asymptomatic infection in the previously immunized child. In contrast, 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 wk of vaccination was most commonly wildtype VZV, while rash occurring 2 6 weeks after vaccination was due to either the wild or vaccine strains. As varicella disease continues to decline, rashes in the interval 0 42 days postvaccination will be less commonly caused by wild-type VZV. The rash in breakthrough disease is frequently atypical, predominantly maculopapular, vesicles are seen less commonly, and the illness is most commonly mild with <50 lesions and little or no fever. Breakthrough cases are less contagious than wild-type infections within household settings. Typical breakthrough cases (<50 lesions) are about ⅓ 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. Progressive Varicella. Progressive varicella, with visceral organ involvement, coagulopathy, severe hemorrhage, and continued vesicular lesion development, is a dreaded 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 this. 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

5 after the diagnosis of varicella pneumonia. Children who acquire varicella after organ transplantation are also at risk for progressive VZV infection. Children on 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 asthmatics 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 HIV infection. Immunization of HIV-infected children who have a CD4 count greater than 15% as well as children with leukemia and solid organ tumors who are stable on maintenance chemotherapy has reduced this problem. Since the advent of the universal immunization program, immunocompromised children are less likely to be exposed to varicella. Neonatal Chickenpox. Newborns have particularly high mortality in the circumstances of a susceptible mother contracting varicella around the time of delivery. Infants whose mothers develop varicella in the period from 5 days prior to delivery to 2 days afterward are at high risk for severe varicella. The infant acquires the infection transplacentally as a result of maternal viremia, which may occur up to 48 hr prior to the maternal rash. Depending on when virus crosses the placenta, the infant's rash may occur toward the end of the 1st week to the early part of the 2nd week of life. 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 develops varicella more than 5 days prior to delivery, she still may pass virus to the soon-to-be-born child, but infection is attenuated due to transmission of maternal antibody across the placenta. This moderating effect of maternal antibody occurs if delivery occurs after 30 wk of gestation, when maternal immunoglobulin G (IgG) is able to cross the placenta. The recommendations for human varicellazoster immune globulin (VariZIG) reflect the differing risks to the exposed infant. Newborns whose mothers develop varicella 5 days before to 2 days after delivery should receive 1 vial. Although neonatal varicella may occur in about half of these infants despite administration of VariZIG, it is usually mild. Every premature infant born at <28 wk of gestation to a mother with active chickenpox at delivery (even if the maternal rash has been present for >1 wk) should receive VariZIG. Because perinatally acquired varicella may be life threatening, the infant should be treated with acyclovir (10 mg/kg every 8 hr IV) when lesions develop. Neonatal chickenpox 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. Infants with community-acquired chickenpox who develop severe varicella, especially those who develop a complication such as pneumonia, hepatitis, or encephalitis, should also receive treatment with intravenous acyclovir (10 mg/kg every 8 hr IV). Congenital Varicella Syndrome. When pregnant women contract chickenpox early in pregnancy, experts estimate that as many as 25% of the fetuses may become infected. Fortunately, clinically apparent disease in the infant is uncommon: up to 2% of fetuses whose mothers had varicella in the 1st 20 wk of pregnancy may demonstrate a VZV embryopathy. The period of greatest risk to the fetus correlates with the gestational period when there is major development and innervation of the limb buds and maturation of the eyes. Fetuses infected at 6 12 wk of

6 gestation appear to have maximal interruption with limb development; fetuses infected at wk may have eye and brain involvement. In addition, viral damage to the sympathetic fibers in the cervical and lumbosacral cord may lead to divergent effects such as Horner syndrome and dysfunction of the urethral or anal sphincters. Most of the stigmata can be attributed to virus-induced injury to the nervous system, although there is no obvious explanation why certain regions of the body are preferentially infected during fetal VZV infection. The stigmata involve mainly the skin, extremities, eyes, and brain ( Table ). The characteristic cutaneous lesion has been called a cicatrix, a zigzag scarring, in a dermatomal distribution, often associated with atrophy of the affected limb. The characteristic cicatricial scarring may represent the cutaneous residua of VZV infection of the sensory nerves, analogous to herpes zoster. The virus may select tissues that are in a rapid developmental stage, such as the limb buds. This may result in 1 or more shortened and malformed extremities ( Fig ). The remainder of the torso may be entirely normal in appearance. Alternatively, there may be neither skin nor limb abnormalities, but the infant may show cataracts or even extensive aplasia of the entire brain. Occasionally, calcifications are evident within a microcephalic head ( Fig ). Histologic examination of the brain demonstrates necrotizing cerebral lesions involving the leptomeninges, cortex, and adjacent white matter.

7 TABLE Stigmata of Varicella-Zoster Virus Fetopathy DAMAGE TO SENSORY NERVES Cicatricial skin lesions Hypopigmentation DAMAGE TO OPTIC STALK AND LENS VESICLE Microphthalmia Cataracts Chorioretinitis Optic atrophy DAMAGE TO BRAIN/ENCEPHALITIS Microcephaly Hydrocephaly Calcifications Aplasia of brain DAMAGE TO CERVICAL OR LUMBOSACRAL CORD Hypoplasia of an extremity Motor and sensory deficits Absent deep tendon reflexes Anisocoria Horner syndrome Anal/urinary sphincter dysfunction

8 Figure Newborn with congenital varicella syndrome. The infant had severe malformations of both lower extremities and cicatricial scarring over his left abdomen.

9 Figure MRI of a newborn with encephalitis secondary to congenital varicella syndrome. The intrauterine infection occurred about 3 mo antepartum, at which time there was extensive necrosis of the cerebral hemispheres. The image of the newborn head was taken with the patient supine; therefore, there is a fluid-fluid interface in the dependent occiput (A). The hydrocephalus (C) and calcifications in the basal ganglia (D) are visible; a cranial artifact (B) is seen secondary to a scalp vein needle.

10 Many infants with severe manifestations of congenital varicella syndrome (atrophy and scarring of a limb) have significant neurologic deficiencies, whereas those with only isolated stigmata, amenable to treatment, develop normally throughout childhood. Infants with neonatal chickenpox who receive prompt antiviral therapy have an excellent prognosis. The diagnosis of VZV fetopathy is based mainly on the history of gestational chickenpox combined with the stigmata seen in the fetus. Virus cannot be cultured from the affected newborn, but viral DNA may be detected in tissue samples by polymerase chain reaction (PCR). Some infants have VZV-specific IgM antibody detectable in the cord blood sample, although the IgM titer drops quickly postpartum and can be nonspecifically positive. Chorionic villus sampling and fetal blood collection for the detection of viral DNA, virus, or antibody have been used in an attempt to diagnose fetal infection and embryopathy. The usefulness of these tests for patient management and counseling has not been defined. Because these tests may not distinguish between infection and disease, their utility may primarily be that of reassurance when the test is negative. A persistently positive VZV IgG antibody titer after mo of age is a reliable indicator of prenatal infection in the asymptomatic child, as is the development of zoster in the 1st year of life without evidence of postnatal infection. Although varicella immune globulin has often been administered to the susceptible mother exposed to chickenpox, it is uncertain as to whether this modifies infection in the fetus. Similarly, acyclovir treatment may be given to the mother with severe varicella. A prospective registry of acyclovir use in the 1st trimester demonstrated that the occurrence of birth defects approximates that found in the general population. The size of the registry, however, is too small (n = 756) to conclude that acyclovir is safe for pregnant women and their fetuses. Acyclovir should only be considered when the benefit to the mother outweighs the potential risk to the fetus. The efficacy of acyclovir treatment of pregnant women in preventing or modifying the severity of congenital varicella is not known. Finally, since the damage caused by fetal VZV infection does not progress in the postpartum period, antiviral treatment of infants with congenital VZV syndrome is not indicated. Herpes Zoster. Herpes zoster manifests as vesicular lesions clustered within 1 or less commonly 2 adjacent dermatomes ( Fig ). In the elderly, herpes zoster typically begins with burning pain, with clusters of skin lesions in a dermatomal pattern. Almost half of the elderly with herpes zoster develop complications; the most frequent complication is postherpetic neuralgia, a painful condition that affects the nerves despite resolution of the shingles skin lesions. Unlike herpes zoster in adults, in children it is infrequently associated with localized

11 pain, hyperesthesia, pruritus, and low-grade fever. In children, the rash is mild, with new lesions appearing for a few days; symptoms of acute neuritis are minimal; and complete resolution usually occurs within 1 2 wk. In contrast to adults, postherpetic neuralgia is very unusual in children. Approximately 4% of patients suffer a 2nd episode of herpes zoster; 3 or more episodes are rare. Transverse myelitis with transient paralysis is a rare complication of herpes zoster. An increased risk for herpes zoster early in childhood has been described in children who acquire varicella in the 1st year of life as well as in those whose mothers have a varicella infection in the 3rd trimester of pregnancy ( Fig ). Figure Herpes zoster involving the lumbar dermatome. (From Mandell GL, Bennett JE, Dolin R [editors]: Principles and Practice of Infectious Diseases, 6th ed, Vol 2. Philadelphia, Elsevier, 2005, p 1783.)

12 Figure Clusters of grouped vesicles on the erythematous bases over the sacrum and popliteal fossa, corresponding to the left S1 dermatome, in a 7 mo old boy who had varicella at age 3 wk after being exposed to his infected sister. (From Kurlan JG, Connelly BL, Lucky AW: Herpes zoster in the first year of life following postnatal exposure to varicella-zoster virus. Arch Dermatol 2004;140: ) Immunocompromised children may have more severe herpes zoster, which is similar to that in adults, including postherpetic neuralgia. Immunocompromised patients may also experience disseminated cutaneous disease that mimics varicella, as well as visceral dissemination with pneumonia, hepatitis, encephalitis, and disseminated intravascular coagulopathy. Severely immuno compromised children, particularly those with HIV infection, may have unusual, chronic or relapsing cutaneous disease, retinitis, or central nervous system (CNS) disease without rash. A lower risk for herpes zoster in vaccinated children with leukemia compared with those who have had varicella disease suggests that varicella vaccine virus reactivates less commonly than wild-type VZV. The risk for herpes zoster in

13 healthy vaccinated children may be lower than in children who had wild-type varicella disease, although many more years of follow-up will be needed to determine that this is the case. DIAGNOSIS. Laboratory evaluation has not been considered necessary for the diagnosis or management of healthy children with varicella or herpes zoster. However, as disease declines to low levels, laboratory confirmation of all varicella cases may be necessary. The atypical nature of breakthrough varicella, with a higher proportion of rashes being papular rather than vesicular, will pose diagnostic challenges. In addition, severe cases of varicella may need virologic confirmation to distinguish from pox virus infections. Leukopenia is typical during the 1st 72 hr; it is followed by a relative and absolute lymphocytosis. Results of liver function tests are also usually (75%) mildly elevated. Patients with neurologic complications of varicella or uncomplicated herpes zoster have a mild lymphocytic pleocytosis and a slight to moderate increase in protein in the cerebrospinal fluid; the glucose concentration is usually normal. Unusual or very severe varicella in otherwise immunocompetent individuals must be distinguished from smallpox, which may occur following deliberate release of smallpox virus (see Chapter 711 ). A suspected case of smallpox should be reported immediately to the local and state health departments. A protocol for evaluating patients with acute vesicular-pustular rash illness for the possibility of smallpox is available on the CDC website at Rapid laboratory diagnosis of VZV is often important in high-risk patients and is sometimes important for infection control. Confirmation of varicella (or herpes simplex virus) can be accomplished by most referral hospital laboratories and all state health laboratories. VZV can be identified quickly by direct fluorescence assay of cells from cutaneous lesions, and by PCR amplification testing. Although multinucleated giant cells can be detected with nonspecific stains (Tzanck smear), they have poor sensitivity and do not differentiate VZV from herpes simplex virus infections. Infectious virus may be recovered using tissue culture methods; shell vial assays have decreased the time needed for culture from 7 10 days to 3 4 days. VZV IgG antibodies can be detected by several methods and a 4-fold rise in IgG antibodies is also confirmatory of acute infection. VZV IgG antibody tests can also be valuable to determine the immune status of individuals whose clinical history of varicella is unknown or equivocal. Testing for VZV IgM antibodies is not useful for clinical diagnosis because commercially available methods are unreliable and the kinetics of the IgM response are not well defined. Reliable VZV-specific IgM assays are available in certain reference laboratories, and a capture-igm assay is available at the national VZV laboratory at Centers for Disease Control. TREATMENT. Antiviral treatment modifies the course of both varicella and herpes zoster. Antiviral drug resistance is rare but has occurred in children with HIV infection who have been treated with acyclovir for extended periods of time; foscarnet is the only drug available for the treatment of acyclovir-resistant VZV infections. Varicella.

14 The only antiviral drug available in liquid formulation that is licensed for pediatric use is acyclovir. Given the safety profile of acyclovir and its demonstrated efficacy in the treatment of varicella, treatment of all children, adolescents, and adults with varicella is acceptable. However, acyclovir therapy is not recommended routinely by the American Academy of Pediatrics for treatment of uncomplicated varicella in the otherwise healthy child because of the marginal benefit, the cost of the drug, and the low risk for complications of varicella. Oral therapy with acyclovir (20 mg/kg/dose, maximum 800 mg/dose) given as 4 doses/day for 5 days should be used to treat uncomplicated varicella in nonpregnant individuals >13 yr of age and children >12 mo of age with chronic cutaneous or pulmonary disorders; receiving short-term, intermittent, or aerosolized corticosteroids; receiving long-term salicylate therapy; and possibly 2nd cases in household contacts. To be most effective, treatment should be initiated as early as possible, preferably within 24 hr of the onset of the exanthem. There is dubious clinical benefit if initiation of treatment is delayed more than 72 hr after onset of the exanthem. Acyclovir therapy does not interfere with the induction of VZV immunity. Intravenous therapy is indicated for severe disease and for varicella in immunocompromised patients (even after 72 hr duration of rash). Acyclovir has been used to treat varicella in pregnant women; its safety for the fetus has not been established. Some experts recommend the use of famciclovir or valacyclovir in older children who can swallow tablets. While these drugs do not have specific Food and Drug Administration approved indications for treatment of varicella, they are highly active against VZV by the same mechanism as acyclovir and are better absorbed by the oral route than is acyclovir. Any patient who has signs of disseminated VZV, including pneumonia, severe hepatitis, thrombocytopenia, or encephalitis, should receive immediate treatment. Intravenous acyclovir (500 mg/m2 every 8 hr IV) therapy initiated within 72 hr of development of initial symptoms decreases the likelihood of progressive varicella and visceral dissemination in high-risk patients. Treatment is continued for 7 days or until no new lesions have appeared for 48 hr. Delaying antiviral treatment in high-risk individuals until it is obvious that prolonged new lesion formation is occurring is not advisable because visceral dissemination occurs during the same time period. Herpes Zoster. Antiviral drugs are effective for treatment of herpes zoster. In healthy adults, acyclovir (800 mg 5 times a day PO for 5 days), famciclovir (500 mg tid PO for 7 days), and valacyclovir (1,000 mg tid PO for 7 days) reduce the duration of the illness and the risk for developing postherpetic neuralgia; concomitant corticosteroid usage improves the quality of life in the elderly. In otherwise healthy children, herpes zoster is a less severe disease, and postherpetic neuralgia is rare. Therefore, treatment of uncomplicated herpes zoster in the child with an antiviral agent may not always be necessary, although some experts would treat with oral acyclovir (20 mg/kg/dose, maximum 800 mg/dose) to shorten the duration of the illness. Use of corticosteroids for herpes zoster in otherwise healthy children is not recommended. In contrast, herpes zoster in immunocompromised children can be severe and disseminated disease may be life threatening. Patients at high risk for disseminated disease should receive acyclovir (500 mg/m2 or 10 mg/kg every 8 hr IV). Oral acyclovir, famciclovir, or valacyclovir are options for immunocompromised patients with uncomplicated herpes zoster and who are considered at low risk for visceral dissemination.

15 COMPLICATIONS. The complications of VZV infection occur with varicella, or with reactivation of infection, more commonly in immunocompromised patients. In the otherwise healthy child, mild varicella hepatitis is relatively common but rarely clinically symptomatic. Mild thrombocytopenia occurs in 1 2% of children with varicella and may be associated with transient petechiae. Purpura, hemorrhagic vesicles, hematuria, and gastrointestinal bleeding are rare complications that may have serious consequences. Cerebellar ataxia occurs in 1 in every 4,000 cases. Other complications of varicella, some of them rare, include encephalitis, pneumonia, nephritis, nephrotic syndrome, hemolytic-uremic syndrome, arthritis, myocarditis, pericarditis, pancreatitis, and orchitis. Bacterial Infections. Secondary bacterial infections of the skin, usually caused by group A streptococci and S. aureus, may occur in up to 5% of children with varicella. These range from superficial impetigo to cellulitis, lymphadenitis, and subcutaneous abscesses. An early manifestation of secondary bacterial infection is erythema of the base of a new vesicle. Recrudescence of fever 3 4 days after the initial exanthem may also herald a secondary bacterial infection. Varicella is a well-described risk factor for serious invasive infections caused by group A streptococcus, which can have a fatal outcome. The more invasive infections, such as varicella gangrenosa, bacterial sepsis, pneumonia, arthritis, osteomyelitis, cellulitis, and necrotizing fasciitis, account for much of the morbidity and mortality of varicella in otherwise healthy children. Bacterial toxin-mediated diseases (toxic shock syndrome) also may complicate varicella. A substantial decline in varicella-related invasive bacterial infections has been associated with the use of the varicella vaccine. Encephalitis and Cerebellar Ataxia. Encephalitis (1/50,000 cases of varicella) and acute cerebellar ataxia (¼,000 cases of varicella) are welldescribed neurologic complications of varicella; morbidity from CNS complications is highest among patients younger than 5 yr or older than 20 yr. Nuchal rigidity, altered consciousness, and seizures characterize meningoencephalitis. Patients with cerebellar ataxia have a gradual onset of gait disturbance, nystagmus, and slurred speech. Neurologic symptoms usually begin 2 6 days after the onset of the rash but may occur during the incubation period or after resolution of the rash. Clinical recovery is typically rapid, occurring within hr, and is usually complete. Although severe hemorrhagic encephalitis, analogous to that caused by herpes simplex virus, is very rare in children with varicella, the consequences are similar to herpes encephalitis. Reye syndrome of encephalopathy and hepatic dysfunction associated with varicella has become rare since salicylates are no longer routinely used as antipyretics (see Chapter 358 ). Pneumonia. Varicella pneumonia is a severe complication that accounts for most of the increased morbidity and mortality in adults and other high-risk populations, but pneumonia may also complicate varicella in young children. Respiratory symptoms, which may include cough, dyspnea, cyanosis, pleuritic chest pain, and hemoptysis, usually begin within 1 6 days after the onset of the rash. Smoking has been described as a risk factor for severe pneumonia complicating varicella. The frequency of varicella pneumonia may be greater in the parturient and may lead to premature termination of pregnancy.

16 PROGNOSIS. Primary varicella has a mortality rate of 2 3 per 100,000 cases with the lowest case fatality rates among children 1 9 yr of age (-1 death per 100,000 cases). Compared with these age groups, infants have a 4 times greater risk of dying and adults have a 25 times greater high risk of dying. Approximately 100 deaths occurred in the USA annually before the introduction of the VZV vaccine; the most common complications among people who died from varicella were pneumonia, CNS complications, secondary infections, and hemorrhagic conditions. The mortality rate of untreated primary infection in immunocompromised children is 7 14% and may approach 50% in untreated adults with pneumonia. Neuritis with herpes zoster should be managed with appropriate analgesics. Postherpetic neuralgia can be a severe problem in adults and may persist for months, requiring care by a specialist in pain management. PREVENTION. VZV transmission is difficult to prevent because the infection is contagious for hr before the rash appears. Infection control practices, including caring for infected patients in isolation rooms with filtered air systems, are essential. All health care workers should have documented VZV immunization or immunity. Susceptible health care workers who have had a close exposure to VZV should not care for high-risk patients during the incubation period. Vaccine. Varicella is a vaccine-preventable disease. Live virus varicella vaccine is available as a monovalent vaccine and is also available in combination with measles, mumps, and rubella (MMRV) vaccines. Administration of varicella vaccine within 4 wk of MMR vaccine has been associated with a higher risk for breakthrough disease; therefore, it is recommended that the vaccines either be administered simultaneously at different sites or be given at least 4 wk apart. Simultaneous administration of the vaccines may also be accomplished by immunizing with the MMRV vaccine. Varicella vaccine is recommended for routine administration to children at mo and at 4 6 yr of age. Catch-up vaccination with the second dose is recommended for children and adolescents who received only 1 dose. Vaccination with 2 doses, separated by at least 4 wk, is also recommended for children, adolescents, and adults without evidence of immunity. Breakthrough disease may be more common in children vaccinated with a single dose younger than 15 mo. Varicella vaccine is contraindicated in children with cell-mediated immune deficiencies, although the vaccine may be administered to children with acute lymphoblastic leukemia who are in remission and who meet enrollment criteria under a research protocol, and the vaccine may also be considered for HIV-infected children with a CD4 count greater than 15%. Both these groups should receive 2 doses of vaccine, 3 months apart. Specific guidelines for immunizing these children should be reviewed before vaccination. Children with isolated humoral immune deficiencies may receive VZV vaccine. Vaccine virus establishes latent infection; however, the risk for developing subsequent herpes zoster is lower after vaccine than after natural VZV infection among immunocompromised children. Postlicensure data also suggest the same trend in healthy vaccinees.

17 A new VZV vaccine formulation was licensed in 2006 for use as a single immunization of individuals >60 yr of age for prevention of herpes zoster reactivation and to decrease the frequency of postherpetic neuralgia. It is not indicated for the treatment of zoster or postherpetic neuralgia. Postexposure Prophylaxis. Vaccine given to normal children within 3 5 days after exposure (as soon as possible is preferred) is effective in preventing or modifying varicella, especially in a household setting where exposure is very likely to result in infection. Varicella vaccine is now recommended for postexposure use, for outbreak control. Oral acyclovir administered late in the incubation period may modify subsequent varicella in the normal child; however, its use in this manner is not recommended until it can be further evaluated. High-titer anti-vzv immune globulin as postexposure prophylaxis is recommended for immunocompromised children, pregnant women, and newborns exposed to maternal varicella. Human varicella-zoster immune globulin (VariZIG) is distributed by FFF Enterprises, California, ( ) to be administered intramuscularly within 96 hr of exposure. The recommended dose is 1 vial (125 units) for each 10 kg increment (maximum 625 units) given intramuscularly as soon as possible but within 96 hr after exposure. Although licensed pooled intravenous immune globulin (IVIG) preparations contain antivaricella antibodies, the titer varies from lot to lot. The recommended dose of IVIG for postexposure prophylaxis is 400 mg/kg administered once within 96 hr of exposure. Immunocompromised patients who have received high-dose IVIG ( mg/kg) for other indications within 2 3 wk before VZV exposure can be expected to have serum antibodies to VZV. Newborns whose mothers develop varicella 5 days before to 2 days after delivery should receive 1 vial of VariZIG. VariZIG is also indicated for pregnant women, premature infants <28 wk of gestation (<1,000 g) who were exposed to varicella, and premature infants >28 wk of gestation who are exposed to varicella and whose mother has no evidence of varicella immunity. If possible, adults should be tested for VZV IgG antibodies before VariZIG administration because many adults with no clinical history of varicella are immune. Anti-VZV antibody prophylaxis may ameliorate disease but does not eliminate the possibility of progressive disease, nor does it assure that varicella is not transmitted to close susceptible contacts; patients should be monitored and treated with acyclovir if necessary once lesions develop. Close contact between a susceptible high-risk patient and a patient with herpes zoster is also an indication for VariZIG prophylaxis. Passive antibody administration or treatment does not reduce the risk for herpes zoster or alter the clinical course of varicella or herpes zoster when given after the onset of symptoms.