Varicella-zoster virus

Varicella-zoster virus (VZV) causes primary, latent, and recurrentinfections.

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

Primary clinical disease can be prevented by immunization with live-attenuated VZV vaccine (varicella vaccine).  

Herpes zoster vaccine (zoster vaccine), higher potency, is recommended for persons ≥60 yr of age to boost their immunity; 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 encodemore than 70 proteins, including proteins that are targets of cellular and humoral immunity.

EPIDEMIOLOGY Most children were infected by 15 yr of age,

withfewer than 5% of adults remaining susceptible. This pattern of infection at younger ages is characteristic in all countries intemperate climates.

In tropical areas, varicella occurs among older persons, with many cases occurring among adults.

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.

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.

predominantly in children in upper elementary school rather than in the preschool years.

Herpes zoster is due to the reactivation of latent VZV.

Herpes zoster is uncommon to children and very rare in healthy children <10 yr of age

Herpes zoster in children tends to be milder than disease in adults

The risk for development of subsequent herpes zoster is lower after vaccine than any natural vzv infection

PATHOGENESIS 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 lesionsoccur during a second viremic phase that lasts 3-7 days.

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.

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 dermatomalin 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.

Suppression of cell-mediated immunity to VZV correlates with an increased risk for VZV reactivation as herpes zoster.

CLINICAL MANIFESTATION 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 perinatalinfection.

Herpes zoster, uncommon in children, causes localized cutaneous symptoms but may disseminate in immunocompromised patients.

Varicella  The illness usually begins 14-16 days

after exposure, although the incubation period can range from 10 to 21 days.

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 beforethe 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 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

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”)

  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

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.

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

varicella-related deaths usually occur within 3 days after the diagnosis of varicella pneumonia

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.

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.

If VariZIG is not available, intravenous immune globulin (IGIV) may provide some protection, althoughvaricella-specific antibody titers may vary from lot to lot. Becauseperinatally acquired varicella may be life threatening, the infantshould be treated with acyclovir (10 mg/kg every 8 hr IV) whenlesions develop

  Infants with neonatal varicella who

receive prompt antiviral therapy have an excellent prognosis.

Congenital Varicella Syndrome 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

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 withatrophy of the affected limb

Many infants with severe manifestations of congenital varicella syndrome (atrophy and scarring of a limb) have significant neurologic deficiencies.

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). VZVspecificIgM 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 but 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.

Acyclovir treatment may be given to the mother with severe varicella 

antiviraltreatment 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

the most frequent complication is postherpetic neuralgia, a painful conditionthat affects the nerves despite resolution of the shingles skin lesions

zoster in children is infrequently associated with localized pain, hyperesthesia, pruritus, and low-grade fever. In children, the rash is mild, complete resolution usually occurs within 1-2 wk.

DIAGNOSIS 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 them from pox virus infections.

Leukopenia is typical during the 1st 72 hours after onset of rash; 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 content of the cerebrospinal fluid; the cerebrospinal fluid glucose concentration is usually normal.

VZV can be identified quickly by direct fluorescence assay (DFA) of cells from cutaneous lesions (vesicular fluid) in 15-20 min, by rapid culture with specific immunofluorescence staining (shell vial technique) in 48-72 hr, and by PCR amplification testing (vesicular fluid, crusts) in 2 hr to days, depending onavailability.

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; foscarnet is the only drug available for the treatment of acyclovir-resistant VZV infections.

Varicella Herpes Zoster The only antiviral drug

available in liquid formulation that is licensed for pediatric use is acyclovir.

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 varicellain 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.

Antiviral drugs are effective for treatment of herpes zoster. In healthy adults, acyclovir and valacyclovir 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.

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

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 

Oral acyclovir, famciclovir, or valacyclovir are options for immunocompromisedpatients 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

COMPLICATIONS

Bacterial Infections 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 manifestationof secondary bacterial infection is erythema of the base of a new vesicle. 

A streptococcus, can have a fatal outcome  Varicella is a well-described risk factor for serious

invasive infections caused by group  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.

Encephalitis and Cerebellar Ataxia Pneumonia Encephalitis and acute cerebellar

are well-described neurologic complicationsof 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 resolutionof the rash.

Clinical recovery is typically rapid, occurring within24-72 hr, and is usually complete. 

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

PROGNOSIS

Primary varicella has a mortality rate of 2-3/100,000 cases, with the lowest case fatality rates among children 1-9 yr of age (~1death per 100,000 cases) 

Compared with these age groups, Infants have a 4 times greater risk of dying and adults have a 25times greater risk of dying.

the most common complications among people who died from varicella were pneumonia, CNS complications, secondary infections, and hemorrhagic conditions.

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 an infected person is contagious for 24-48 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 evidence of varicella immunity. Unvaccinated health care workers without other evidence of immunity who have had a close exposure to VZV should befurloughed for days 8-21 after exposure because they are potentiallyinfectious during this period. 

Vaccine Varicella is a vaccine-preventable disease  .Varicella vaccine contains live, attenuated

VZV (Oka strain) and is indicated for subcutaneous administration.

Recommended for routine administration as a 2-dose regimen to healthy childrenat 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

recommendedfor all persons without evidence of immunity.

Varicella vaccine is contraindicated for pregnant women andpersons with cell-mediated immune deficiencies, including those with leukemia, lymphoma, and other malignant neoplasms affectingthe bone marrow or lymphatic systems

Vaccine-associated Adverse Events 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.

If possible, adults should be tested for VZV IgG antibodies before VariZIG administration, because many adults with no clinical history of varicella are immune.  

Close contact between a susceptible high-risk patient and a patient with herpes zoster is an indication for VariZIG prophylaxis.