Varicella

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.

Figure 245-1 A, Varicella lesions in unvaccinated persons display the characteristic “cropping” distribution, or manifest themselves in clusters; the simultaneous presence of lesions in various stages of evolution is characteristic. B, Breakthrough varicella lesions are predominantly maculopapular, and vesicles are less common; the illness is most commonly mild with <50 lesions.

(A, Courtesy of the Centers for Disease Control and Prevention [CDC]; B, Courtesy of the CDC and Dr. John Noble, Jr.)

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

Mortality is particularly high in neonates born to susceptible mothers who contracted 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. The infant acquires 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 week to the early part of the 2nd week 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 >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 30 wk of gestation, when maternal immunoglobulin G (IgG) is able to cross the placenta. The recommendations for human varicella zoster immune globulin (VariZIG) reflect the differing risks to the exposed infant. Newborns whose mothers demonstrate varicella 5 days before to 2 days after delivery should receive 1 vial of VariZIG as soon as possible. Although neonatal varicella may occur in about half of these infants despite administration of VariZIG, it is usually mild. All premature infants born <28 wk gestation to a mother with active varicella at delivery (even if the maternal rash has been present for >1 wk) should receive VariZIG. If VariZIG is not available, intravenous immune globulin (IGIV) 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 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. Infants 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 IV acyclovir (10 mg/kg every 8 hr IV). Infants with neonatal varicella who receive prompt antiviral therapy have an excellent prognosis.

Congenital Varicella Syndrome

In utero transmission of VZV can occur; however, because most adults in temperate climates are immune, varicella complicating pregnancy is unusual. When pregnant women do contract varicella 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: the congenital varicella syndrome occurs in approximately 0.4% of infants born to women who have varicella during pregnancy before 13 wk of gestation and approximately 2% of infants born to women with varicella between 13 and 20 wk of gestation. Before availability of varicella vaccine in the USA, 44 cases of congenital varicella syndrome were estimated to occur each year. The congenital varicella syndrome is characterized by cicatricial skin scarring in a zoster-like distribution, limb hypoplasia, and neurologic (e.g., microcephaly, cortical atrophy, seizures, and mental retardation), eye (e.g., chorioretinitis, microphthalmia, and cataracts), renal (e.g., hydroureter and hydronephrosis) and autonomic nervous system abnormalities (neurogenic bladder, swallowing dysfunction, and aspiration pneumonia). 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 characteristic cutaneous lesion has been called a cicatrix, a zigzag scarring, in a dermatomal distribution, often associated with atrophy of the affected limb (Fig. 245-2). Many infants with severe manifestations of congenital varicella syndrome (atrophy and scarring of a limb) have significant neurologic deficiencies.

Figure 245-2 Newborn with congenital varicella syndrome. The infant had severe malformations of both lower extremities and cicatricial scarring over his left abdomen.

There are rare case reports of fetal abnormalities following the development of herpes zoster in the mother; whether or not these cases truly represent the congenital varicella syndrome is unclear. If it does occur, the congenital syndrome acquired as a result of maternal herpes zoster is exceedingly rare.

The diagnosis of VZV fetopathy is based mainly on the history of gestational varicella combined with the presence of characteristic abnormalities in the newborn infant. Virus cannot be cultured from the affected newborn, but viral DNA may be detected in tissue samples by polymerase chain reaction (PCR). VZV-specific IgM antibody is detectable in the cord blood sample in some infants, 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 result is negative. A persistently positive VZV IgG antibody titer at 12-18 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.

Varicella immune globulin has often been administered to the susceptible mother exposed to varicella, but whether this step modifies infection in the fetus is uncertain. 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. Acyclovir is a class B drug for pregnancy and should be considered only when the benefit to the mother outweighs the potential risk to the fetus. The efficacy of acyclovir treatment of the pregnant woman in preventing or modifying the severity of congenital varicella is not known, but its use should be considered to protect the mother from severe disease. Finally, because 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. 245-3). In the elderly, herpes zoster typically begins with burning pain followed by clusters of skin lesions in a dermatomal pattern. Almost half of the elderly with herpes zoster experience 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, zoster in children is infrequently associated with localized 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. Unlike in 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 infection with VZV in utero or in the 1st year of life (Fig. 245-4).

Figure 245-3 Herpes zoster involving the lumbar dermatome.

(From Mandell GL, Bennett JE, Dolin R, editors: Principles and practice of infectious diseases, ed 6, vol 2, Philadelphia, 2005, Elsevier, p 1783.)

Figure 245-4 Many groups of blisters occurring over the arm in a child with herpes zoster.

(From Weston WL, Lane AT, Morelli JG: Color textbook of pediatric dermatology, ed 3, Philadelphia, 2002, Mosby, Fig. 8-28.)

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 immunocompromised children, particularly those with advanced HIV infection, may have unusual, chronic or relapsing cutaneous disease, retinitis, or central nervous system (CNS) disease without rash. The finding of a lower risk for herpes zoster among vaccinated children with leukemia than in those who have had varicella disease suggests that varicella vaccine virus reactivates less commonly than wild-type VZV. The risk for herpes zoster in 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.

Varicella

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 can 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, individuals receiving short-term, intermittent, or aerosolized corticosteroid therapy, individuals receiving long-term salicylate therapy, and possibly secondary cases among 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 less clinical benefit if treatment is initiated 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 if begun 72 hr after onset 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. Although these drugs do not have specific U.S. 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 acyclovir.

Any patient who has signs of disseminated VZV, including pneumonia, severe hepatitis, thrombocytopenia, or encephalitis, should receive immediate treatment. IV 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 7–10 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 period.

Acyclovir-resistant VZV has been identified in children infected with HIV. These children may be treated with intravenous foscarnet, 120 mg/kg/day divided every 8 hr for up to 3 wk. The dose should be modified in the presence of renal insufficiency. Resistance to foscarnet has been reported with prolonged use.

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 development of postherpetic neuralgia; concomitant corticosteroid use 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. It is important to start antiviral therapy as soon as possible. Delay beyond 72 hr from onset of rash limits its effectiveness.

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.

Use of corticosteroids in the treatment of herpes zoster in children is not recommended.

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 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 in unvaccinated children) and acute cerebellar ataxia (1/4,000 cases of varicella in unvaccinated children) are well-described 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 24-72 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 those of herpes encephalitis. Reye syndrome (hepatic dysfunction with hypoglycemia and encephalopathy) associated with varicella and other viral illnesses such as influenza has become rare now that salicylates are no longer used as antipyretics in these situations (Chapter 353).

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.

Vaccine

Varicella is a vaccine-preventable disease. Varicella vaccine contains live, attenuated VZV (Oka strain) and is indicated for subcutaneous administration. Varicella vaccine is recommended for routine administration as a 2-dose regimen to healthy children at ages 12-15 mo and 4-6 yr. Catch-up vaccination with the second dose is recommended for children and adolescents who received only 1 dose. Vaccination with 2 doses is recommended for all persons without evidence of immunity. The minimum recommended interval between the two doses is 3 mo for persons ≤12 yr of age and 4 wk for older children, adolescents, and adults. Administration of varicella vaccine within 4 wk of measles-mumps-rubella (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.

Varicella vaccine is contraindicated for pregnant women and persons with cell-mediated immune deficiencies, including those with leukemia, lymphoma, and other malignant neoplasms affecting the bone marrow or lymphatic systems. Compassionate-use protocols are available for immunization of children with leukemia in remission. The vaccine should be considered for HIV-infected children with a CD4+ T-lymphocyte percentage ≥15%. These children should receive 2 doses of vaccine, 3 mo apart. Specific guidelines for immunizing these children should be reviewed before vaccination. Children with isolated humoral immunodeficiencies may receive varicella vaccine.

Zoster vaccine was licensed in 2006 for use as a single immunization of individuals ≥60 yr of age for prevention of herpes zoster and to decrease the frequency of postherpetic neuralgia. It is not indicated for the treatment of zoster or postherpetic neuralgia.

Vaccine-associated Adverse Events

Varicella vaccine is safe and well tolerated. The incidence of injection site complaints observed ≤3 days after vaccination was slightly higher after dose 2 (25%) than after dose 1 (22%). A mild vaccine-associated varicelliform rash was reported in approximately 1-3% of healthy vaccinees, consisting of 6-10 papular-vesicular, erythematous lesions with peak occurrence 8-21 days after vaccination. Transmission of vaccine virus to susceptible contacts is a very rare occurrence.

Postexposure Prophylaxis

Vaccine given to healthy 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 and for outbreak control. Oral acyclovir administered late in the incubation period may modify subsequent varicella in the healthy 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 varicella. Human varicella-zoster immune globulin (VariZIG) is distributed in the USA by FFF Enterprises, California (1-800-843-7477). The recommended dose is 1 vial (125 units) for each 10-kg increment of body weight (maximum 625 units) given intramuscularly as soon as possible but within 96 hr after exposure.

Although licensed pooled immune globulin intravenous (IGIV) preparations contain antivaricella antibodies, the titer varies from lot to lot. The recommended dose of IGIV for postexposure prophylaxis (in situations in which administration of VariZIG does not appear possible within 96 hr of exposure) is 400 mg/kg administered once within 96 hr of exposure. Immunocompromised patients who have received high-dose IGIV (100-400 mg/kg) for other indications within 2-3 wk before VZV exposure can be expected to have serum antibodies to VZV.

Newborns whose mothers demonstrate varicella 5 days before to 2 days after delivery should receive 1 vial of VariZIG. VariZIG is also indicated for: pregnant women without evidence of immunity; premature infants born at <28 wks of gestation (or weight <1,000 g) who were exposed to varicella during the neonatal period, regardless of maternal immunity; and premature infants born at >28 wks of gestation who were exposed to varicella and whose mothers have 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 ensure 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.