Varicella-Zoster Virus (VZV)

Varicella-Zoster Virus (VZV) Overview

• VZV is a Herpesviridae family member sharing morphologic and genomic features with other herpes viruses
• VZV is spread through the respiratory route
• It causes chickenpox, a primary infection in children
• It causes shingles, a recurrent infection mainly in older adults
• Pathogenesis starts with viral replication in respiratory epithelium
• It spreads to lymph nodes, followed by viremia and dissemination to organs like the reticuloendothelial system and skin
• This leads to pustular vesicles
• Symptoms include fever and lesions on the back of the head and ears, spreading centrifugally to the face, neck, trunk, and proximal extremities
• Both humoral and cell-mediated immunity are important, but cell-mediated immunity primarily controls infection and dissemination
• Immunocompromised hosts may develop viral pneumonia, encephalitis, or hepatitis
• VZV establishes latency in sensory root ganglia, similar to HSV
• Reactivation can occur at any age, but it increases with age, causing shingles
• Acyclovir can help in extreme cases
• A two-dose live attenuated varicella virus vaccine (Varivax or ProQuad) is for children aged 1 and 4 years
• A two-dose recombinant protein subunit shingles vaccine (Shingrix) is for adults ≥50 years, 2 to 6 months apart

Virology of VZV

• VZV shares general structural and morphologic features with herpes simplex and other HHVs
• Features include an enveloped, icosahedral, double-stranded DNA virion
• It contains distinct glycoproteins and is antigenically different
• The VZV genome is approximately 125 kbp, the smallest genome of the HHVs
• VZV encodes a thymidine kinase and responds to acyclovir, similar to HSV
• Cellular features of infected cells, such as multinucleated giant cells and intranuclear eosinophilic inclusion bodies, are similar to HSV
• VZV is more difficult to isolate in cell culture than HSV
• The virus often remains attached to the host cell membrane
• It releases fewer virions into fluids and does not spread well in culture
• VZV is most infectious in vivo

Varicella-Zoster Disease: Epidemiology

• VZV infection is worldwide
• Before vaccination, 4 million people got chickenpox annually in the US, with 10,000-13,000 hospitalizations, and 100-150 deaths
• In temperate climates, over 90% of people contract chickenpox by adulthood, mostly before age 10
• In tropical countries, the mean age of infection is over 20 years, and seroprevalence at age 70 may be only 50%
• Chickenpox incidence declined 97% by 2014 from the prevaccine years after the 1996 vaccination program in the US
• VZV is highly contagious, with attack rates of 75% among susceptible contacts
• Varicella occurs most frequently in winter and spring
• The incubation period is 11 to 21 days
• The major transmission route is respiratory
• Transmission may occur through direct contact with vesicular or pustular lesions
• Communicability is greatest 24-48 hours before rash onset and lasts 3-4 days into the rash phase
• The virus is difficult to isolate from patients once lesions have crusted

Reactivation and Pathogenesis

• Shingles or zoster results from VZV reactivation, occurring in about 20% of the population
• Shingles occurrences depend on the severity of the initial infection
• Shingles are uncommon in children but increase dramatically after age 50
• Shingles provide a constant source of VZV for spread
• Initial VZV infection or spread from shingles/zoster results in varicella or chickenpox
• Respiratory spread leads to infection of the upper respiratory tract
• Replication in regional lymph nodes results in primary viremia
• Infection of the reticuloendothelial system results in a subsequent secondary viremia associated with T lymphocytes
• Secondary viremia leads to skin infection
• Latency is established in the same sensory ganglia as HSV-1 and HSV-2
• The connection between zoster and varicella was first described by Von Bokay in 1892
• Von Bokay proposed that zoster and varicella were different clinical manifestations of the same agent
• Cultivation of VZV in vitro by Weller in 1954 confirmed VZV viruses isolated from chickenpox and shingles are identical
• VZV latency occurs in sensory ganglia, including dorsal root ganglia and trigeminal ganglia
• The VZV latency-associated transcript (VLT) is expressed in the ganglion where VZV DNA resides

Immunity and Clinical Aspects

• Both humoral and cell-mediated immunity are important in the VZV immune response
• Cell-mediated immunity is important for stopping the spread of VZV
• Reinfection with VZV is rare due to circulating antibody
• Reactivation of VZV is controlled by cell-mediated immunity
• Incidence and severity of herpes zoster increase with age in immunocompetent individuals
• VZV-specific cellular immunity decreases with age
• Cellular immunity to VZV declines starting in the fifth decade of life
• Reactivation occurs more often and is more severe in patients with depressed cell-mediated immune responses, such as those with bone marrow transplants, Hodgkin disease, AIDS, lymphoproliferative disorders, immune cancers, and conditions like diabetes
• VZV primary infection in normal children leads to chickenpox or varicella, a generalized vesicular rash
• After clinical infection, the virus can persist for decades with no clinical manifestation
• Chickenpox lesions appear on the back of the head and ears, and then spread to the face, neck, trunk, and proximal extremities
• Involvement of mucous membranes is common with possible fever early in the disease
• Lesions appear in stages of spread during the disease course
• Skin lesions become fluid-filled vesicles that become turbid after 1 to 2 days and then crust over
• Varicella lesions are pruritic (itchy), and vary in number from 10 to several hundred

Herpes Zoster (shingles)

• Reactivation of VZV is associated with herpes zoster
• Shingles frequency increases with age
• Pain in a sensory nerve distribution occurs with eruption onset, usually unilateral, and involving one to three dermatomes
• New lesions may appear over the first 5 to 7 days
• Multiple attacks of VZV reactivation and disease are uncommon
• If recurrent attacks of a vesicular eruption occur in one area, consider HSV infection
• Shingles is 20% as infectious as varicella
• Contact with shingles rash causes varicella

Complications and diagnosis

• Complications vary by age and host immune factors
• Postherpetic neuralgia (PHN) is a common complication of herpes zoster in elderly adults
• PHN is characterized by pain persisting for months to years after zoster lesions resolve
• Immunosuppressed patients may develop localized shingles followed by dissemination of virus with visceral infection, resembling progressive varicella
• Bacterial superinfection is also possible
• Maternal varicella infection during early pregnancy can result in fetal embryopathy
• Severe varicella can occur in seronegative neonates, with a mortality rate as high as 30%
• Varicella or herpes zoster lesions can be diagnosed clinically when the rash is characteristic

Treatment and Prevention

• Antiviral therapy is not recommended for healthy children with chickenpox
• Acyclovir therapy can be considered for patients >12 years of age with increased risk for moderate to severe varicella
• Intravenous acyclovir effectively reduces dissemination in immunocompromised patients
• Controlled trials showed acyclovir is effective in treating herpes zoster in immunocompromised patients
• Acyclovir may be used for herpes zoster in immunocompetent adults, but has moderate impact on PHN development
• Treatment should start within 3 days of shingles onset
• VZV is less susceptible to acyclovir than HSV, requiring a higher dosage
• Famciclovir or valacyclovir is more convenient and effective
• Live, attenuated varicella virus vaccine (Varivax), from Oka strain given in two doses, is 98% effective in preventing varicella and 100% effective against severe varicella disease
• The same vaccine has been in use since 1995 in the United States
• Routine immunization with Varivax or MMRV is recommended at 12 to 15 months for the first dose and 4 to 6 years of age for the second dose
• Vaccination for shingles, Zostavax (a single high dose, live attenuated virus vaccine) stimulated waning cellular immunity, and decreased reactivation
• A new recombinant protein (glycoprotein E antigen) with adjuvant, Shingrix is recommended

Key conclusions

• VZV is a member of Herpesviridae family with an enveloped, icosahedral, double-stranded DNA virus that replicates in the nucleus using host RNA polymerase for transcription and viral DNA polymerase for genome replication
• VZV is transmitted through inhalation and causes chickenpox (primary infection) mainly in children, and symptoms include fever and vesicular rash on head and ears, and then spread to the face, neck, trunk, and proximal extremities, and recovery in 2 weeks.
• Immunocompromised children may develop progressive varicella, including pneumonia, encephalitis, hepatitis, and nephritis.
• Viral latency in dorsal and trigeminal ganglion and reactivation mainly in older adults with increasing age and waning immunity resulting in herpes zoster or shingles, usually vesicular rash unilateral. One of the complications of shingles is PHN.
• Acyclovir can be used in extreme cases of chickenpox and shingles.
• Live attenuated varicella vaccine (Varivax) or MMRV (ProQuad) is recommended in children (first dose at age 12-15 months and second dose at 4-6 years) and recombinant shingles vaccine (Shingrix) in adults aged 50 years and older.