Varicella Health Article

Pathogenesis

Varicella-zoster virus is one of eight herpesviruses of the Herpesviridae family that are known to cause disease in people and some other primates. ²⁹ The virus is a DNA α-herpesvirus with a genome of about 125,000 bp that encode 70 genes. ³⁰ During primary lytic infection with varicella virus, these genes are expressed sequentially, in much the same way as they are in herpes simplex virus. ³¹ Sequential expression leads to the production of groups of immediate to early non-structural proteins, early non-structural protein enzymes, and late structural proteins. ³¹ The late structural proteins form a capsid surrounding the DNA core, a tegument, and a lipid-containing envelope (figure 2 ). ³² The envelope of the virion is composed of glycoproteins that also have important functions in pathogenesis. ³³ After infection of a cell, varicella-zoster virus replicates in the nucleus. There, DNA is incorporated into preformed capsids, which leave the nucleus by a first budding event at the inner nuclear membrane. Primary enveloped virions are formed in the perinuclear space. Then the primary envelope fuses with the outer leaflet of the nuclear membrane and the nucleocapsids are released into the cytoplasm. Subsequently virions are re-enveloped at the transGolgi network, and mature virions are released to the environment after fusion of the vesicle membrane with the cell's plasma membrane. ³⁴ Varicella-zoster virus has little molecular variability. ³⁵ So far, three major genotypes of wild-type varicella-zoster virus have been described. ^36,37 The European Dumas strain and both the Japanese Oka vaccine strain and its parental virus have been completely sequenced. ^30,38

The incubation period of varicella is usually 14–15 days (range 10–21 days). Varicella-zoster virus spreads by droplets and aerosols from the nasopharynx 1–2 days before onset of a rash, and from skin lesions during the first 5–7 days after appearance of rash. ^39–42 This contagious period lasts up to several weeks in immunocompromised hosts. ³ The virus is thought to enter a susceptible host via the mucosal surfaces of the respiratory tract, although it is difficult to detect by culture or RT-PCR in this location. ^3,38,40 Several viral glycoproteins act in concert to adhere to mucosal cells, and allow the virus to enter and spread from cell to cell. ⁴³ These glycoproteins also stimulate the host's immune response. ^44–46 Varicella zoster virus is thought to multiply in regional lymph nodes before the first subclinical viraemia after about 4–6 days. During viraemia the virus disseminates to the viscera, as has been shown in animals and in fetal varicella syndrome. ^41,46–48 Virus then multiplies further in reticuloendothelial tissues. A second viraemic phase occurs about 14 days after infection (between 10 and 21 days; figure 3 ). The second viraemic phase promotes viral spread to the nasopharyngeal surfaces and the skin, causing the typical maculopapular–vesicular rash. The vesicles contain large amounts of virus, and might be the most important route of viral transmission. ^40,49,50 The period of contagiousness ends when all lesions have crusted.

The precise roles of humoral and cellular immunity in protection against varicella-zoster virus infection are not entirely understood. However, cell-mediated immunity seems to be more important than humoral immunity, probably because the spread of virus within the body is exclusively via the intracellular route. ^2,3 Antibody responses against glycoproteins and other varicella-zoster virus structures have been detected by serological methods. ^3,51–53 Cell-mediated immunity is measurable by in-vitro stimulation of lymphocytes with specific varicella-zoster virus antigens or, more conveniently, by an ELISA spot-forming cell assay. ⁵⁴ Furthermore, both antibody-dependent cellular cytotoxicity and natural-killer cell cytotoxicity are important in the host's ability to clear infection. ⁵⁵ The importance of cell-mediated immunity for clearance of primary infection, prevention of recurrent infections, and reactivation of infection has been shown indirectly by (1) increased severity of disease in children with cellular immunodeficiencies, ⁵⁶ (2) absence of serious disease in individuals with hypogammaglobulinaemia, ³ (3) increasing risk for herpes zoster associated with cellular immune dysfunction and with waning cellular immunity in elderly people, ²⁴ and (4) enhanced risk of herpes zoster in children infected with varicella-zoster virus in utero or shortly after birth. ^57–59 However, humoral immunity does seem to supplement protection by cell-mediated immunity, as shown by the success of passive immunisation with specific immune globulin. ⁶⁰ Recurrent symptomatic varicella infections have been reported, but are rare in otherwise healthy individuals; subclinical infection can occur more commonly. ^2,61,62